Clinical Review

Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.

We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.

Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer 

de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285. 

In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.¹ Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.¹ However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).² The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death. 

Adjuvant therapy in high-risk endometrial cancer 

To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.³ As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.⁴ For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.^5,6 

Continue to: Benefit observed with adjuvant chemoradiotherapy...

 

 

Benefit observed with adjuvant chemoradiotherapy 

In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.⁷ Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology. 

Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m² IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m² IV every 3 weeks). 

At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016). 

The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm. 

Results from similar trials 

Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.^8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.⁸ There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.⁸ 

In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.⁹ No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.⁹

Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment 

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415. 

Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.¹⁰ Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.¹¹ Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.¹² As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence. 

Continue to: PARP inhibitors are changing the face of treatment...

 

PARP inhibitors are changing the face of treatment 

Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.¹³ The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.¹⁴ 

Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.^15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.^17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.²⁰ 

Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy. 

Efficacy of veliparib with chemotherapy and as maintenance monotherapy 

In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.²¹ 

Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy. 

Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles. 

Progression-free survival extended 

At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization). 

In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm. 

Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.

Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma? 

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939. 

Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.¹¹ The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.²² 

Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.^23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival^17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified. 

Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...

 

Overall survival after secondary cytoreduction followed by chemotherapy 

Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.²² Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy. 

All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained). 

Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion. 

Shorter survival, decline in quality of life 

Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms. 

At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection. 

Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications. 

While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period. 

 

Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.

We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.

Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer 

de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285. 

In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.¹ Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.¹ However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).² The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death. 

Adjuvant therapy in high-risk endometrial cancer 

To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.³ As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.⁴ For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.^5,6 

Continue to: Benefit observed with adjuvant chemoradiotherapy...

 

 

Benefit observed with adjuvant chemoradiotherapy 

In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.⁷ Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology. 

Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m² IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m² IV every 3 weeks). 

At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016). 

The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm. 

Results from similar trials 

Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.^8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.⁸ There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.⁸ 

In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.⁹ No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.⁹

Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment 

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415. 

Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.¹⁰ Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.¹¹ Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.¹² As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence. 

Continue to: PARP inhibitors are changing the face of treatment...

 

PARP inhibitors are changing the face of treatment 

Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.¹³ The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.¹⁴ 

Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.^15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.^17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.²⁰ 

Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy. 

Efficacy of veliparib with chemotherapy and as maintenance monotherapy 

In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.²¹ 

Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy. 

Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles. 

Progression-free survival extended 

At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization). 

In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm. 

Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.

Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma? 

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939. 

Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.¹¹ The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.²² 

Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.^23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival^17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified. 

Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...

 

Overall survival after secondary cytoreduction followed by chemotherapy 

Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.²² Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy. 

All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained). 

Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion. 

Shorter survival, decline in quality of life 

Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms. 

At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection. 

Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications. 

While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period. 

 

Over the past year, major strides have been made in the treatment of gynecologic malignancies. In this Update, we highlight 3 notable studies. The first is a phase 3, multicenter, international, randomized clinical trial that demonstrated a significant improvement in both overall and failure-free survival with the use of adjuvant chemoradiation versus radiotherapy alone in patients with stage III or high-risk uterine cancer. Additionally, we describe the results of 2 phase 3, multicenter, international, randomized clinical trials in ovarian cancer treatment: use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in combination with platinum and taxane-based chemotherapy followed by the PARP inhibitor as maintenance therapy, and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian cancer.

We provide a brief overview of current treatment strategies, summarize the key findings of these trials, and establish how these findings have changed our management of these gynecologic malignancies.

Adjuvant chemotherapy and radiotherapy improves survival in women with high-risk endometrial cancer 

de Boer SM, Powell ME, Mileshkin L, et al; on behalf of the PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;1273-1285. 

In the United States, it is estimated that more than 61,000 women were diagnosed with endometrial cancer in 2019.¹ Women with endometrial cancer usually have a favorable prognosis; more than 65% are diagnosed with early-stage disease, which is associated with a 95% 5-year survival rate.¹ However, 15% to 20% of patients have disease with high-risk features, including advanced stage (stage II-IV), high tumor grade, lymphovascular space invasion, deep myometrial invasion, or nonendometrioid histologic subtypes (serous or clear cell).² The presence of these high-risk disease features is associated with an increased incidence of distant metastases and cancer-related death. 

Adjuvant therapy in high-risk endometrial cancer 

To date, the optimal adjuvant therapy for patients with high-risk endometrial cancer remains controversial. Prior data from Gynecologic Oncology Group (GOG) protocol 122 demonstrated that chemotherapy significantly improved progression-free survival and overall survival when compared with radiotherapy in patients with advanced-stage endometrial cancer.³ As such, chemotherapy now is frequently used in this population, often in combination with radiation, although data describing the benefit of chemoradiation are limited.⁴ For women with earlier-stage disease with high-risk features, the value of chemotherapy plus radiation is uncertain.^5,6 

Continue to: Benefit observed with adjuvant chemoradiotherapy...

 

 

Benefit observed with adjuvant chemoradiotherapy 

In a multicenter, international, randomized phase 3 trial, known as the PORTEC-3 trial, de Boer and colleagues sought to determine if combined adjuvant chemoradiation improved overall survival (OS) and failure-free survival when compared with external-beam radiation therapy (EBRT) alone in the treatment of women with high-risk endometrial cancer.⁷ Women were eligible for the study if they had histologically confirmed stage I, grade 3 endometrioid endometrial cancer with deep invasion and/or lymphovascular space invasion, stage II or III disease, or stage I-III disease with serous or clear cell histology. 

Participants were randomly assigned in a 1:1 ratio; 330 women received adjuvant EBRT alone (total dose of 48.6 Gy administered in 27 fractions), and 330 received adjuvant chemotherapy during and after radiation therapy (CTRT) (2 cycles of cisplatin 50 mg/m² IV given on days 1 and 22 of EBRT followed by 4 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m² IV every 3 weeks). 

At a median follow-up of 73 months, treatment with adjuvant CTRT, compared with adjuvant EBRT alone, was associated with a significant improvement in both overall survival (5-year OS: 81.4% vs 76.1%, P = .034 [FIGURE]) and failure-free survival (5-year failure-free survival: 76.5% vs 69.1%, P = .016). 

The greatest absolute benefit of adjuvant CTRT, compared with EBRT alone, in survival was among women with stage III endometrial cancer (5-year OS: 78.5% vs 68.5%, P = .043) or serous cancers (19% absolute improvement in 5-year OS), or both. Significant differences in 5-year OS and failure-free survival in women with stage I-II cancer were not observed with adjuvant CTRT when compared with adjuvant EBRT alone. At 5 years, significantly more adverse events of grade 2 or worse were reported in the adjuvant CTRT arm. 

Results from similar trials 

Since the publication of results from the updated analysis of PORTEC-3, results from 2 pertinent trials have been published.^8,9 In the GOG 249 trial, women with stage I-II endometrial cancer with high-risk features were randomly assigned to receive 3 cycles of carboplatin-paclitaxel chemotherapy with vaginal brachytherapy or EBRT.⁸ There was no difference in survival, but a significant increase in both pelvic and para-aortic recurrences were seen after the combination of chemotherapy and vaginal brachytherapy.⁸ 

In GOG 258, women with stage III-IVA endometrial cancer were randomly assigned to receive chemotherapy alone (carboplatin-paclitaxel) or adjuvant chemotherapy after EBRT.⁹ No differences in recurrence-free or overall survival were noted, but there was a significant increase in the number of vaginal and pelvic or para-aortic recurrences in patients in the chemotherapy-only arm.⁹

Role for PARP inhibitor plus first-line chemotherapy, and as maintenance therapy, in ovarian cancer treatment 

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381:2403-2415. 

Ovarian cancer is the leading cause of gynecologic cancer-related deaths among women in the United States.¹⁰ Treatment consists of cytoreductive surgery combined with platinum and taxane-based chemotherapy.¹¹ Despite favorable initial responses, more than 80% of patients experience a recurrence, with an 18-month median time to progression.¹² As a result, recent efforts have focused on finding novel therapeutic approaches to improve treatment outcomes and mitigate the risk of disease recurrence. 

Continue to: PARP inhibitors are changing the face of treatment...

 

PARP inhibitors are changing the face of treatment 

Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes that play a critical role in DNA damage repair. These enzymes promote DNA repair by recruiting proteins involved in repairing single-strand and double-strand DNA breaks and in protecting and restarting stalled DNA replication forks.¹³ The predominant mechanisms of action of PARP inhibitors in cells with homologous-recombination deficiency (HRD) include inhibiting repair of single-strand DNA breaks and trapping PARP-DNA complexes at stalled DNA replication forks.¹⁴ 

Germline or somatic BRCA1/2 mutations and genetic alterations resulting in HRD are present in about 20% and 30% of ovarian carcinomas, respectively, and increase the susceptibility of tumors to platinum-based agents and PARP inhibitors.^15,16 Based on multiple clinical trials that demonstrated the efficacy of single-agent PARP in the treatment of recurrent ovarian carcinoma and as maintenance therapy after an initial response to platinum-based therapy, the US Food and Drug Administration approved olaparib, niraparib, and rucaparib for the treatment of high-grade epithelial ovarian cancer.^17-19 Only olaparib is approved for maintenance therapy after initial adjuvant therapy in patients with BRCA mutations.²⁰ 

Given the robust response to PARP inhibitors, there has been great interest in using these agents earlier in the disease course in combination with chemotherapy. 

Efficacy of veliparib with chemotherapy and as maintenance monotherapy 

In a randomized, double-blind, placebo-controlled phase 3 trial, Coleman and colleagues sought to determine the efficacy of the PARP inhibitor veliparib when administered with first-line carboplatin and paclitaxel induction chemotherapy and subsequently continued as maintenance monotherapy.²¹ 

Women with stage III or IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were eligible for the study. Cytoreductive surgery could be performed prior to the initiation of trial treatment or after 3 cycles of chemotherapy. 

Participants were randomized in a 1:1:1 ratio: 371 women received carboplatin and paclitaxel plus placebo followed by placebo maintenance (control arm); 376 received chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only arm); and 377 received chemotherapy plus veliparib followed by veliparib maintenance therapy (veliparib-throughout arm). Combination chemotherapy consisted of 6 cycles, and maintenance therapy was an additional 30 cycles. 

Progression-free survival extended 

At a median follow-up of 28 months, investigators observed a significant improvement in progression-free survival in the veliparib-throughout (initial and maintenance therapy) arm compared with the control arm in 3 cohorts: the BRCA-mutation cohort, the HRD cohort, and the intention-to-treat population (all participants undergoing randomization). 

In the BRCA-mutation cohort, the median progression-free survival was 12.7 months longer in the veliparib-throughout arm than in the control arm. Similarly, in the HRD cohort, the median progression-free survival was 11.4 months longer in the veliparib-throughout arm than in the control group. In the intention-to-treat population, the median progression-free survival increased from 17.3 to 23.5 months in the veliparib-throughout arm compared with the control arm. 

Women who received veliparib experienced increased rates of nausea, anemia, and fatigue and were more likely to require dose reductions and treatment interruptions. Myelodysplastic syndrome was reported in 1 patient (BRCA1 positive) in the veliparib combination-only arm.

Secondary cytoreductive surgery or chemotherapy alone for platinum-sensitive recurrent ovarian carcinoma? 

Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381:1929-1939. 

Primary surgical cytoreduction combined with platinum and taxane-based chemotherapy remains the mainstay of ovarian cancer treatment.¹¹ The role of surgery for women with recurrent ovarian cancer, so-called secondary cytoreduction, remains controversial.²² 

Data have shown that among women who undergo secondary surgery, those with little or no postoperative residual disease benefit the most from a secondary debulking.^23-26 Prior work largely is based on small retrospective reports and is limited by substantial bias in the selection of patients undergoing surgery. Additionally, with the availability of targeted therapies such as bevacizumab and PARP inhibitors as maintenance—medical interventions with a demonstrated benefit in progression-free survival^17-19,27—the role of secondary cytoreduction in the treatment of ovarian carcinoma needs to be clarified. 

Continue to: Overall survival after secondary cytoreduction followed by chemotherapy...

 

Overall survival after secondary cytoreduction followed by chemotherapy 

Coleman and colleagues conducted a prospective, multicenter, international, randomized phase 3 trial to assess whether secondary cytoreductive surgery followed by chemotherapy would improve overall survival versus chemotherapy alone among women with resectable platinum-sensitive, recurrent ovarian cancer.²² Platinum sensitivity was defined as a disease-free interval of at least 6 months after the last cycle of platinum-based chemotherapy. 

All women had recurrent epithelial ovarian carcinoma considered to be amenable to complete gross surgical resection by the investigator and a history of complete response to at least 3 cycles of platinum-based chemotherapy as determined by a normal CA-125 value or negative imaging studies (if obtained). 

Participants were randomly assigned 1:1, with 240 women assigned to secondary surgical cytoreduction followed by platinum-based chemotherapy, and 245 assigned to chemotherapy alone. The type of adjuvant chemotherapy used (carboplatin-paclitaxel or carboplatin-gemcitabine) and whether or not bevacizumab was administered were at the investigators' discretion. 

Shorter survival, decline in quality of life 

Among the participants assigned to and who underwent surgery, complete gross resection was achieved in 67%. Eighty-four percent of the entire study population received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance therapy, which was equally distributed between the 2 study arms. 

At a median follow-up of 48.1 months, median overall survival was 50.6 months in the surgery arm compared with 64.7 months in the chemotherapy arm, corresponding to a hazard ratio (HR) for death of 1.29 (95% confidence interval [CI], 0.97-1.72; P = .08). This effect was unchanged after adjusting for platinum-free interval, chemotherapy choice, and restricting the analysis to women who had a complete gross resection. 

Similarly, the adjusted HR for disease progression or death was 0.82 (95% CI, 0.66-1.01) and corresponded to a median progression-free survival of 18.9 months for the surgery group and 16.2 months for the chemotherapy group. Surgical morbidity was reported in 9% of patients who underwent surgery, and 1 patient (0.4%) died from postoperative complications. 

While a significant decline in both quality of life and patient-reported outcomes was reported immediately after surgery, significant differences were not noted between the 2 groups after the initial postoperative recovery period. 

 

For more than 45 years, gynecologists have used hysteroscopy to diagnose endometrial carcinoma and to associate morphologic descriptive terms with visual findings.¹ Today, considerably more clinical evidence supports visual pattern recognition to assess the risk for and presence of endometrial carcinoma, improving observer-dependent biopsy of the most suspect lesions (VIDEO 1).

In this article, I discuss the clinical evolution of hysteroscopic pattern recognition of endometrial disease and review the visual findings that correlate with the likelihood of endometrial carcinoma. In addition, I have provided 9 short videos that show hysteroscopic views of various endometrial pathologies in the online version of this article at https://www.mdedge.com/obgyn.

Video 1. Endometrial carcinoma and visually directed biopsy

The negative hysteroscopic view defined

In 1989, Dr. Frank Loffer confirmed the diagnostic superiority of visually directed biopsy. He demonstrated the advantages of using hysteroscopy and directed biopsy in the evaluation of abnormal uterine bleeding (AUB) to obtain a more accurate diagnosis compared with dilation and curettage (D&C) alone (sensitivity, 98% vs 65%, respectively).²

Also derived from this work is the clinical application of the “negative hysteroscopic view” (NHV). Loffer used the following criteria to define the NHV: good visualization of the entire uterine cavity, no structural abnormalities of the cavity, and a uniformly thin, homogeneous-appearing endometrium without variations in thickness (TABLE 1). The last criterion can be expected to occur only in the early proliferative phase or in postmenopausal women.

Use of hysteroscopy therefore can predict accurately the absence of intrauterine and endometrial pathology when visual findings are negative and tissue sampling is not warranted (FIGURE 1, VIDEO 2).

Video 2. Negative hysteroscopic view 

 

Efforts in hysteroscopic classification of endometrial carcinoma

Lesion morphologic characteristics. Sugimoto was among the first to describe the hysteroscopic identification of visual morphologic features that are most likely to be associated with endometrial carcinoma.¹ Patients with AUB were evaluated with hysteroscopy as first-line management to describe lesion morphology and confirm biopsy with histopathology. Sugimoto classified endometrial carcinoma as circumscribed or exophytic with distinct forms, such as polypoid, nodular, papillary, and ulcerated (FIGURE 2). Diffuse or endophytic carcinoma is defined by an ulcerated type of lesion that indicates necrosis; this is most likely to represent an undifferentiated tumor. Sugimoto also described abnormal vascularity that often is associated with carcinoma.¹

Endometrial features. Valli and Zupi created a nomenclature and classification for hysteroscopic endometrial lesions by prospectively grading 4 features: thickness, surface, vascularization, and color.³ Features were scored based on the degree of abnormality and could be considered to be of low or high risk for the presence of carcinoma. High-risk hysteroscopic features included endometrial thickness greater than 10 mm, polymorphous surface, irregular vascularization, and white-grayish color. The sensitivity for accurately diagnosing endometrial lesions was 86.9% for mild lesions and 96% for severe lesions.³ Also, these investigators confirmed the clinical value of the NHV and associated overall risk of precancer or cancer of the endometrium.

Continue to: Amount of endometrial involvement...

 

Amount of endometrial involvement. A few years later, Garuti and colleagues retrospectively related the hysteroscopic tumor features of known endometrial adenocarcinoma to stage, grade, and overall survival.⁴ In this system, they focused on classification of tumor morphology as nodular (bulging), polypoid (thin pedicles), or papillary (numerous dendritic projections), as well as whether the amount of abnormal tissue present was less than or more than half of the endometrium and if the lesion involved the cervix.

Several important findings associated with this system may improve visual diagnosis. First, hysteroscopic evaluation had a 100% negative predictive value for the cervical spread of disease (FIGURE 3, VIDEO 3). Second, the hysteroscopic morphologic tumor type did not relate to surgical stage or pathologic grade. Third, when less than half of the endometrium was involved, stage I disease was found (97%, 33 of 34). Last, when more than half of the endometrium was involved, advanced disease beyond stage I was found (9 of 26, 6 of whom had poorly differentiated disease).⁴

Video 3. Cervical spread of adenocarcinoma and visually directed biopsy

Structured pattern analysis. Recently, Dueholm and co-investigators published a prospective evaluation of women with postmenopausal bleeding and an endometrial thickness of 5 mm or greater.⁵ They used a structured system of visual pattern analysis during hysteroscopy that they termed the hysteroscopic cancer (HYCA) scoring system. The HYCA scoring system is based on surface outline (uneven, polypoid, and papillary projections), necrosis (cotton candy endometrium [FIGURE 4], whitish-grayish areas without vessels on the surface), and vessel pattern (tortuous S-shaped, loops, irregular caliber, irregular branching, and irregular distribution [FIGURE 5]). Structured pattern analysis predicted cancer with higher accuracy than subjective evaluation.⁵

Morphologic variables as indicators. In 2016, Ianieri and colleagues published a retrospective study on a risk scoring system for diagnosing endometrial hyperplasia and adenocarcinoma via hysteroscopy.⁶ They created a statistical risk model for development of the scoring system. A number of morphologic variables were prognostic indicators of atypical endometrial hyperplasia (AEH) and adenocarcinoma. These included widespread and irregular endometrial thickness, presence of multiple polyps with irregular aspects, dilated glandular orifices, irregular endometrial color (grey, white, or hyperemic), atypical vessels, crumbling of the endometrial neoplasms, and growth of cerebroid and arborescent aspects (VIDEO 4).

Video 4. Endometrial adenocarcinoma 

 

 

The scoring system for endometrial adenocarcinoma correctly classified 42 of 44 cancers (sensitivity, 95.4%; specificity, 98.2%), and AEH had a sensitivity of 63.3% and a specificity of 90.4%.⁶ These investigators also showed a high negative predictive value of 99.5% for endometrial adenocarcinoma associated with a negative view at hysteroscopy. Similar to the Dueholm data, Ianieri and colleagues’ morphologic pattern analysis predicted cancer with high accuracy.

Glomerular pattern association. Su and colleagues also showed that pattern recognition could aid in the accurate hysteroscopic diagnosis of endometrial adenocarcinoma.⁷ They used the hysteroscopic presence of a glomerular pattern to predict the association with endometrial adenocarcinoma. A glomerular pattern was described as polypoid endometrium with a papillary-like feature, containing an abnormal neovascularization feature with “intertwined neovascular vessels covered by a thin layer of endometrial tissue” (FIGURE 6). The presence of a glomerular pattern indicated grade 2 or grade 3 disease in 25 of 26 women (96%; sensitivity, 84.6%, specificity, 81.8%)⁷ (see video 4).

TABLE 2 summarizes significant morphologic findings relating to the presences of endometrial carcinoma.

Continue to: Atypical endometrial hyperplasia: A difficult diagnosis...

 

Atypical endometrial hyperplasia: A difficult diagnosis

The most common type of endometrial cancer is endometrioid adenocarcinoma (type 1 endometrial carcinoma), and it accounts for approximately 75% to 80% of endometrial cancer diagnoses.⁸ Risk factors include prolonged unopposed estrogen exposure, obesity, diabetes, and age. Type 1 endometrial carcinoma follows a progressive continuum of histopathologic change: from endometrial hyperplasia without atypia to endometrial hyperplasia with atypia (AEH) to well-differentiated endometrial cancer. Therefore, it is possible for endometrial carcinoma to be present simultaneously with AEH. The reported prevalence of concurrent endometrial carcinoma among patients with AEH on biopsy is between 17% and 52%.⁸ Thus, the clinical consideration is for hysterectomy, especially in the postmenopausal patient with a diagnosis of AEH.

Hysteroscopic diagnosis of AEH, however, is more difficult than identification of endometrial carcinoma because a range of morphologic characteristics exist that resemble normal endometrium as well as more progressive disease (VIDEO 5). De Franciscis and colleagues based a hysteroscopic diagnosis of hyperplasia on one or more of the following findings: focal or diffuse, papillary or polypoid, endometrial thickening; abnormal vascular patterns; evidence of glandular cysts; and abnormal architecture features of the glandular outlets (thickening, irregular gland density, or dilatation)⁹ (VIDEO 6).

Video 5. Endometrial polyp and atypical hyperplasia 

Additional studies, including that from Ianieri and colleagues, also have determined that AEH is difficult to discern visually from normal endometrium and other endometrial pathologies.⁶ In another investigation, Lasmar and coauthors reported a retrospective analysis of 4,054 hysteroscopic procedures with directed biopsies evaluating for concordance between the hysteroscopic view and histopathology.¹⁰ Agreement was 56.3% for AEH versus 94% for endometrial carcinoma. Among those with a histologic diagnosis of AEH, in 35.4% benign disease was suspected; in 2.1%, endometrial carcinoma was suspected; and in 6%, normal findings were presumed.¹⁰

Video 6. Nodular, polypoid atypical hyperplasia 

Because of the similarities in morphologic features between AEH and endometrial carcinoma, tissue biopsy under direct visualization is warranted to assure sampling of the most significantly abnormal tissue and to confirm visual interpretation of findings.

Techniques for hysteroscopic-directed biopsy

Using a visual assessment of endometrial abnormalities allows the surgeon to examine the entire uterine cavity and to biopsy the most suspicious and concerning lesions. The directed biopsy technique can involve a simple grasping maneuver: With the jaws of a small grasper open, push slightly forward to accumulate tissue within the jaw, close the jaw, and remove the tissue carefully through the cervix (VIDEO 7). The size of the sample may be limited, and multiple samples may be needed, depending on the quantity of the tissue retrieved.

Video 7. Visually directed endometrial biopsy

Another technique involves first creating a plane of tissue to be removed with scissors and subsequently grasping and removing the tissue (see video 1 and video 3). This particular technique will yield more tissue with one pass of the hysteroscope into the cavity. Careful removal of tissue through the cervix is facilitated by withdrawing the sample in the grasper and the hysteroscope together at the same time, without pulling the sample through the operative channel of the hysteroscope. Also, by turning off the inflow port, the stream of saline does not wash the sample off the grasper at hysteroscope removal from the cervix.

Blind biopsy. If visual inspection reveals a diffuse process within the uterine cavity such that no normal endometrium is noted and the abnormality is of equal degree throughout the endometrial surface, a decision can be made to replace directed biopsy with a blind biopsy. In this scenario, the blind biopsy is certain to sample the representative disease process and not potentially miss significant lesions (see video 4 and video 6). Otherwise, the hysteroscope-directed biopsy would be preferable.

Continue to: Potential for intraperitoneal dissemination of endometrial cancer...

 

Potential for intraperitoneal dissemination of endometrial cancer

There is some concern about intraperitoneal dissemination of endometrial carcinoma at the time of hysteroscopy and effect on disease prognosis. Chang and colleagues conducted a large meta-analysis and found that hysteroscopy performed in the presence of type 1 endometrial carcinoma statistically significantly increased the likelihood of positive intraperitoneal cytology.¹¹ In the included studies that reported survival rates (6 of 19), positive cytology did not alter the clinical outcome. The investigators recommended that hysteroscopy not be avoided for this reason, as it helps in the diagnosis of endometrial carcinoma, especially in the early stages of disease.¹¹

In a recent retrospective analysis, Namazov and colleagues included only stage I endometrial carcinoma (to exclude the adverse effect of advanced stage on survival) and evaluated the assumed isolated effect of hysteroscopy on survival.¹² They compared women in whom stage I endometrial carcinoma was diagnosed: 355 by hysteroscopy and 969 by a nonhysteroscopy method (D&C or office endometrial biopsy). Tumors were classified and grouped as low grade (endometrioid grade 1-2 and villoglandular) and high grade, consisting of endometrioid grade 3 and type 2 endometrial carcinoma (serous carcinoma, clear cell carcinoma, and carcinosarcoma) (VIDEOS 8 and 9). Positive intraperitoneal cytology at the time of surgery was 2.3% and 2.1% (P = .832), with an average interval from diagnosis to surgery of 34.6 days (range, 7–43 days).

Video 8. Carcinosarcoma 

The authors proposed several explanations for the low rate of intraperitoneal cytology with hysteroscopy. One possibility is having lower mean intrauterine pressure below 100 mm Hg for saline uterine distension, although this was not standardized for all surgeons in the study but rather was a custom of the institution. In addition, the length of time between hysteroscopy and surgery may allow the immune-reactive peritoneum to respond to the cellular insult, thus decreasing the biologic burden at the time of surgery. The median follow-up was 52 months (range, 12–120 months), and there were no differences between the hysteroscopy and the nonhysteroscopy groups in the 5-year recurrence-free survival (90.2% vs 88.2%; P = .53), disease-specific survival (93.4% vs 91.7%; P = .5), and overall survival (86.2% vs 80.6%; P = .22). The authors concluded that hysteroscopy does not compromise the survival of patients with early-stage endometrial cancer.¹²

Video 9. Carcinosarcoma 

Retrospective data from Chen and colleagues regarding type 2 endometrial carcinoma indicated a statistically significant increase in positive intraperitoneal cytology for carcinomas evaluated by hysteroscopy versus D&C (30% vs 12%; P = .008).¹³ Among the patients who died, there was no difference in disease-specific survival (53 months for hysteroscopy and 63.5 months for D&C; P = .34), and there was no difference in overall recurrence rates.¹³ Compared with type 1 endometrial carcinoma, type 2 endometrial carcinoma behaves more aggressively, with a higher incidence of extrauterine disease and an increased propensity for recurrence and poor outcome even in the early stages of the disease. This makes it difficult to determine the role of hysteroscopy in the prognosis of these carcinomas, especially in this study where most patients were diagnosed at a later stage.

Key takeaways

Hysteroscopy and directed biopsy are highly effective for visual and histopathologic diagnosis of atypical endometrial hyperplasia and endometrial carcinoma, and they are recommended in the evaluation of AUB, especially in the postmenopausal woman. When the hysteroscopic view is negative, there is a high correlation with the absence of uterine cavity and endometrial pathology. Hysteroscopic diagnostic accuracy is improved with structured use of visual grading scales, well-defined descriptors of endometrial pathology, and hysteroscopist experience.

Low operating intrauterine pressure may decrease the intraperitoneal spread of carcinoma cells during hysteroscopy, and current evidence suggests that there is no change in type 1 endometrial carcinoma prognosis and overall outcomes. Type 2 endometrial carcinoma is more aggressive and is associated with poor outcomes even in early stages, and the effect on disease progression by intraperitoneal spread of carcinoma cells at hysteroscopy is not yet known. Hysteroscopic evaluation of the uterine cavity and directed biopsy is easily and safely performed in the office and adds significantly to the evaluation and management of endometrial carcinoma.

 

For more than 45 years, gynecologists have used hysteroscopy to diagnose endometrial carcinoma and to associate morphologic descriptive terms with visual findings.¹ Today, considerably more clinical evidence supports visual pattern recognition to assess the risk for and presence of endometrial carcinoma, improving observer-dependent biopsy of the most suspect lesions (VIDEO 1).

In this article, I discuss the clinical evolution of hysteroscopic pattern recognition of endometrial disease and review the visual findings that correlate with the likelihood of endometrial carcinoma. In addition, I have provided 9 short videos that show hysteroscopic views of various endometrial pathologies in the online version of this article at https://www.mdedge.com/obgyn.

Video 1. Endometrial carcinoma and visually directed biopsy

The negative hysteroscopic view defined

In 1989, Dr. Frank Loffer confirmed the diagnostic superiority of visually directed biopsy. He demonstrated the advantages of using hysteroscopy and directed biopsy in the evaluation of abnormal uterine bleeding (AUB) to obtain a more accurate diagnosis compared with dilation and curettage (D&C) alone (sensitivity, 98% vs 65%, respectively).²

Also derived from this work is the clinical application of the “negative hysteroscopic view” (NHV). Loffer used the following criteria to define the NHV: good visualization of the entire uterine cavity, no structural abnormalities of the cavity, and a uniformly thin, homogeneous-appearing endometrium without variations in thickness (TABLE 1). The last criterion can be expected to occur only in the early proliferative phase or in postmenopausal women.

Use of hysteroscopy therefore can predict accurately the absence of intrauterine and endometrial pathology when visual findings are negative and tissue sampling is not warranted (FIGURE 1, VIDEO 2).

Video 2. Negative hysteroscopic view 

 

Efforts in hysteroscopic classification of endometrial carcinoma

Lesion morphologic characteristics. Sugimoto was among the first to describe the hysteroscopic identification of visual morphologic features that are most likely to be associated with endometrial carcinoma.¹ Patients with AUB were evaluated with hysteroscopy as first-line management to describe lesion morphology and confirm biopsy with histopathology. Sugimoto classified endometrial carcinoma as circumscribed or exophytic with distinct forms, such as polypoid, nodular, papillary, and ulcerated (FIGURE 2). Diffuse or endophytic carcinoma is defined by an ulcerated type of lesion that indicates necrosis; this is most likely to represent an undifferentiated tumor. Sugimoto also described abnormal vascularity that often is associated with carcinoma.¹

Endometrial features. Valli and Zupi created a nomenclature and classification for hysteroscopic endometrial lesions by prospectively grading 4 features: thickness, surface, vascularization, and color.³ Features were scored based on the degree of abnormality and could be considered to be of low or high risk for the presence of carcinoma. High-risk hysteroscopic features included endometrial thickness greater than 10 mm, polymorphous surface, irregular vascularization, and white-grayish color. The sensitivity for accurately diagnosing endometrial lesions was 86.9% for mild lesions and 96% for severe lesions.³ Also, these investigators confirmed the clinical value of the NHV and associated overall risk of precancer or cancer of the endometrium.

Continue to: Amount of endometrial involvement...

 

Amount of endometrial involvement. A few years later, Garuti and colleagues retrospectively related the hysteroscopic tumor features of known endometrial adenocarcinoma to stage, grade, and overall survival.⁴ In this system, they focused on classification of tumor morphology as nodular (bulging), polypoid (thin pedicles), or papillary (numerous dendritic projections), as well as whether the amount of abnormal tissue present was less than or more than half of the endometrium and if the lesion involved the cervix.

Several important findings associated with this system may improve visual diagnosis. First, hysteroscopic evaluation had a 100% negative predictive value for the cervical spread of disease (FIGURE 3, VIDEO 3). Second, the hysteroscopic morphologic tumor type did not relate to surgical stage or pathologic grade. Third, when less than half of the endometrium was involved, stage I disease was found (97%, 33 of 34). Last, when more than half of the endometrium was involved, advanced disease beyond stage I was found (9 of 26, 6 of whom had poorly differentiated disease).⁴

Video 3. Cervical spread of adenocarcinoma and visually directed biopsy

Structured pattern analysis. Recently, Dueholm and co-investigators published a prospective evaluation of women with postmenopausal bleeding and an endometrial thickness of 5 mm or greater.⁵ They used a structured system of visual pattern analysis during hysteroscopy that they termed the hysteroscopic cancer (HYCA) scoring system. The HYCA scoring system is based on surface outline (uneven, polypoid, and papillary projections), necrosis (cotton candy endometrium [FIGURE 4], whitish-grayish areas without vessels on the surface), and vessel pattern (tortuous S-shaped, loops, irregular caliber, irregular branching, and irregular distribution [FIGURE 5]). Structured pattern analysis predicted cancer with higher accuracy than subjective evaluation.⁵

Morphologic variables as indicators. In 2016, Ianieri and colleagues published a retrospective study on a risk scoring system for diagnosing endometrial hyperplasia and adenocarcinoma via hysteroscopy.⁶ They created a statistical risk model for development of the scoring system. A number of morphologic variables were prognostic indicators of atypical endometrial hyperplasia (AEH) and adenocarcinoma. These included widespread and irregular endometrial thickness, presence of multiple polyps with irregular aspects, dilated glandular orifices, irregular endometrial color (grey, white, or hyperemic), atypical vessels, crumbling of the endometrial neoplasms, and growth of cerebroid and arborescent aspects (VIDEO 4).

Video 4. Endometrial adenocarcinoma 

 

 

The scoring system for endometrial adenocarcinoma correctly classified 42 of 44 cancers (sensitivity, 95.4%; specificity, 98.2%), and AEH had a sensitivity of 63.3% and a specificity of 90.4%.⁶ These investigators also showed a high negative predictive value of 99.5% for endometrial adenocarcinoma associated with a negative view at hysteroscopy. Similar to the Dueholm data, Ianieri and colleagues’ morphologic pattern analysis predicted cancer with high accuracy.

Glomerular pattern association. Su and colleagues also showed that pattern recognition could aid in the accurate hysteroscopic diagnosis of endometrial adenocarcinoma.⁷ They used the hysteroscopic presence of a glomerular pattern to predict the association with endometrial adenocarcinoma. A glomerular pattern was described as polypoid endometrium with a papillary-like feature, containing an abnormal neovascularization feature with “intertwined neovascular vessels covered by a thin layer of endometrial tissue” (FIGURE 6). The presence of a glomerular pattern indicated grade 2 or grade 3 disease in 25 of 26 women (96%; sensitivity, 84.6%, specificity, 81.8%)⁷ (see video 4).

TABLE 2 summarizes significant morphologic findings relating to the presences of endometrial carcinoma.

Continue to: Atypical endometrial hyperplasia: A difficult diagnosis...

 

Atypical endometrial hyperplasia: A difficult diagnosis

The most common type of endometrial cancer is endometrioid adenocarcinoma (type 1 endometrial carcinoma), and it accounts for approximately 75% to 80% of endometrial cancer diagnoses.⁸ Risk factors include prolonged unopposed estrogen exposure, obesity, diabetes, and age. Type 1 endometrial carcinoma follows a progressive continuum of histopathologic change: from endometrial hyperplasia without atypia to endometrial hyperplasia with atypia (AEH) to well-differentiated endometrial cancer. Therefore, it is possible for endometrial carcinoma to be present simultaneously with AEH. The reported prevalence of concurrent endometrial carcinoma among patients with AEH on biopsy is between 17% and 52%.⁸ Thus, the clinical consideration is for hysterectomy, especially in the postmenopausal patient with a diagnosis of AEH.

Hysteroscopic diagnosis of AEH, however, is more difficult than identification of endometrial carcinoma because a range of morphologic characteristics exist that resemble normal endometrium as well as more progressive disease (VIDEO 5). De Franciscis and colleagues based a hysteroscopic diagnosis of hyperplasia on one or more of the following findings: focal or diffuse, papillary or polypoid, endometrial thickening; abnormal vascular patterns; evidence of glandular cysts; and abnormal architecture features of the glandular outlets (thickening, irregular gland density, or dilatation)⁹ (VIDEO 6).

Video 5. Endometrial polyp and atypical hyperplasia 

Additional studies, including that from Ianieri and colleagues, also have determined that AEH is difficult to discern visually from normal endometrium and other endometrial pathologies.⁶ In another investigation, Lasmar and coauthors reported a retrospective analysis of 4,054 hysteroscopic procedures with directed biopsies evaluating for concordance between the hysteroscopic view and histopathology.¹⁰ Agreement was 56.3% for AEH versus 94% for endometrial carcinoma. Among those with a histologic diagnosis of AEH, in 35.4% benign disease was suspected; in 2.1%, endometrial carcinoma was suspected; and in 6%, normal findings were presumed.¹⁰

Video 6. Nodular, polypoid atypical hyperplasia 

Because of the similarities in morphologic features between AEH and endometrial carcinoma, tissue biopsy under direct visualization is warranted to assure sampling of the most significantly abnormal tissue and to confirm visual interpretation of findings.

Techniques for hysteroscopic-directed biopsy

Using a visual assessment of endometrial abnormalities allows the surgeon to examine the entire uterine cavity and to biopsy the most suspicious and concerning lesions. The directed biopsy technique can involve a simple grasping maneuver: With the jaws of a small grasper open, push slightly forward to accumulate tissue within the jaw, close the jaw, and remove the tissue carefully through the cervix (VIDEO 7). The size of the sample may be limited, and multiple samples may be needed, depending on the quantity of the tissue retrieved.

Video 7. Visually directed endometrial biopsy

Another technique involves first creating a plane of tissue to be removed with scissors and subsequently grasping and removing the tissue (see video 1 and video 3). This particular technique will yield more tissue with one pass of the hysteroscope into the cavity. Careful removal of tissue through the cervix is facilitated by withdrawing the sample in the grasper and the hysteroscope together at the same time, without pulling the sample through the operative channel of the hysteroscope. Also, by turning off the inflow port, the stream of saline does not wash the sample off the grasper at hysteroscope removal from the cervix.

Blind biopsy. If visual inspection reveals a diffuse process within the uterine cavity such that no normal endometrium is noted and the abnormality is of equal degree throughout the endometrial surface, a decision can be made to replace directed biopsy with a blind biopsy. In this scenario, the blind biopsy is certain to sample the representative disease process and not potentially miss significant lesions (see video 4 and video 6). Otherwise, the hysteroscope-directed biopsy would be preferable.

Continue to: Potential for intraperitoneal dissemination of endometrial cancer...

 

Potential for intraperitoneal dissemination of endometrial cancer

There is some concern about intraperitoneal dissemination of endometrial carcinoma at the time of hysteroscopy and effect on disease prognosis. Chang and colleagues conducted a large meta-analysis and found that hysteroscopy performed in the presence of type 1 endometrial carcinoma statistically significantly increased the likelihood of positive intraperitoneal cytology.¹¹ In the included studies that reported survival rates (6 of 19), positive cytology did not alter the clinical outcome. The investigators recommended that hysteroscopy not be avoided for this reason, as it helps in the diagnosis of endometrial carcinoma, especially in the early stages of disease.¹¹

In a recent retrospective analysis, Namazov and colleagues included only stage I endometrial carcinoma (to exclude the adverse effect of advanced stage on survival) and evaluated the assumed isolated effect of hysteroscopy on survival.¹² They compared women in whom stage I endometrial carcinoma was diagnosed: 355 by hysteroscopy and 969 by a nonhysteroscopy method (D&C or office endometrial biopsy). Tumors were classified and grouped as low grade (endometrioid grade 1-2 and villoglandular) and high grade, consisting of endometrioid grade 3 and type 2 endometrial carcinoma (serous carcinoma, clear cell carcinoma, and carcinosarcoma) (VIDEOS 8 and 9). Positive intraperitoneal cytology at the time of surgery was 2.3% and 2.1% (P = .832), with an average interval from diagnosis to surgery of 34.6 days (range, 7–43 days).

Video 8. Carcinosarcoma 

The authors proposed several explanations for the low rate of intraperitoneal cytology with hysteroscopy. One possibility is having lower mean intrauterine pressure below 100 mm Hg for saline uterine distension, although this was not standardized for all surgeons in the study but rather was a custom of the institution. In addition, the length of time between hysteroscopy and surgery may allow the immune-reactive peritoneum to respond to the cellular insult, thus decreasing the biologic burden at the time of surgery. The median follow-up was 52 months (range, 12–120 months), and there were no differences between the hysteroscopy and the nonhysteroscopy groups in the 5-year recurrence-free survival (90.2% vs 88.2%; P = .53), disease-specific survival (93.4% vs 91.7%; P = .5), and overall survival (86.2% vs 80.6%; P = .22). The authors concluded that hysteroscopy does not compromise the survival of patients with early-stage endometrial cancer.¹²

Video 9. Carcinosarcoma 

Retrospective data from Chen and colleagues regarding type 2 endometrial carcinoma indicated a statistically significant increase in positive intraperitoneal cytology for carcinomas evaluated by hysteroscopy versus D&C (30% vs 12%; P = .008).¹³ Among the patients who died, there was no difference in disease-specific survival (53 months for hysteroscopy and 63.5 months for D&C; P = .34), and there was no difference in overall recurrence rates.¹³ Compared with type 1 endometrial carcinoma, type 2 endometrial carcinoma behaves more aggressively, with a higher incidence of extrauterine disease and an increased propensity for recurrence and poor outcome even in the early stages of the disease. This makes it difficult to determine the role of hysteroscopy in the prognosis of these carcinomas, especially in this study where most patients were diagnosed at a later stage.

Key takeaways

Hysteroscopy and directed biopsy are highly effective for visual and histopathologic diagnosis of atypical endometrial hyperplasia and endometrial carcinoma, and they are recommended in the evaluation of AUB, especially in the postmenopausal woman. When the hysteroscopic view is negative, there is a high correlation with the absence of uterine cavity and endometrial pathology. Hysteroscopic diagnostic accuracy is improved with structured use of visual grading scales, well-defined descriptors of endometrial pathology, and hysteroscopist experience.

Low operating intrauterine pressure may decrease the intraperitoneal spread of carcinoma cells during hysteroscopy, and current evidence suggests that there is no change in type 1 endometrial carcinoma prognosis and overall outcomes. Type 2 endometrial carcinoma is more aggressive and is associated with poor outcomes even in early stages, and the effect on disease progression by intraperitoneal spread of carcinoma cells at hysteroscopy is not yet known. Hysteroscopic evaluation of the uterine cavity and directed biopsy is easily and safely performed in the office and adds significantly to the evaluation and management of endometrial carcinoma.

 

For more than 45 years, gynecologists have used hysteroscopy to diagnose endometrial carcinoma and to associate morphologic descriptive terms with visual findings.¹ Today, considerably more clinical evidence supports visual pattern recognition to assess the risk for and presence of endometrial carcinoma, improving observer-dependent biopsy of the most suspect lesions (VIDEO 1).

In this article, I discuss the clinical evolution of hysteroscopic pattern recognition of endometrial disease and review the visual findings that correlate with the likelihood of endometrial carcinoma. In addition, I have provided 9 short videos that show hysteroscopic views of various endometrial pathologies in the online version of this article at https://www.mdedge.com/obgyn.

Video 1. Endometrial carcinoma and visually directed biopsy

The negative hysteroscopic view defined

In 1989, Dr. Frank Loffer confirmed the diagnostic superiority of visually directed biopsy. He demonstrated the advantages of using hysteroscopy and directed biopsy in the evaluation of abnormal uterine bleeding (AUB) to obtain a more accurate diagnosis compared with dilation and curettage (D&C) alone (sensitivity, 98% vs 65%, respectively).²

Also derived from this work is the clinical application of the “negative hysteroscopic view” (NHV). Loffer used the following criteria to define the NHV: good visualization of the entire uterine cavity, no structural abnormalities of the cavity, and a uniformly thin, homogeneous-appearing endometrium without variations in thickness (TABLE 1). The last criterion can be expected to occur only in the early proliferative phase or in postmenopausal women.

Use of hysteroscopy therefore can predict accurately the absence of intrauterine and endometrial pathology when visual findings are negative and tissue sampling is not warranted (FIGURE 1, VIDEO 2).

Video 2. Negative hysteroscopic view 

 

Efforts in hysteroscopic classification of endometrial carcinoma

Lesion morphologic characteristics. Sugimoto was among the first to describe the hysteroscopic identification of visual morphologic features that are most likely to be associated with endometrial carcinoma.¹ Patients with AUB were evaluated with hysteroscopy as first-line management to describe lesion morphology and confirm biopsy with histopathology. Sugimoto classified endometrial carcinoma as circumscribed or exophytic with distinct forms, such as polypoid, nodular, papillary, and ulcerated (FIGURE 2). Diffuse or endophytic carcinoma is defined by an ulcerated type of lesion that indicates necrosis; this is most likely to represent an undifferentiated tumor. Sugimoto also described abnormal vascularity that often is associated with carcinoma.¹

Endometrial features. Valli and Zupi created a nomenclature and classification for hysteroscopic endometrial lesions by prospectively grading 4 features: thickness, surface, vascularization, and color.³ Features were scored based on the degree of abnormality and could be considered to be of low or high risk for the presence of carcinoma. High-risk hysteroscopic features included endometrial thickness greater than 10 mm, polymorphous surface, irregular vascularization, and white-grayish color. The sensitivity for accurately diagnosing endometrial lesions was 86.9% for mild lesions and 96% for severe lesions.³ Also, these investigators confirmed the clinical value of the NHV and associated overall risk of precancer or cancer of the endometrium.

Continue to: Amount of endometrial involvement...

 

Amount of endometrial involvement. A few years later, Garuti and colleagues retrospectively related the hysteroscopic tumor features of known endometrial adenocarcinoma to stage, grade, and overall survival.⁴ In this system, they focused on classification of tumor morphology as nodular (bulging), polypoid (thin pedicles), or papillary (numerous dendritic projections), as well as whether the amount of abnormal tissue present was less than or more than half of the endometrium and if the lesion involved the cervix.

Several important findings associated with this system may improve visual diagnosis. First, hysteroscopic evaluation had a 100% negative predictive value for the cervical spread of disease (FIGURE 3, VIDEO 3). Second, the hysteroscopic morphologic tumor type did not relate to surgical stage or pathologic grade. Third, when less than half of the endometrium was involved, stage I disease was found (97%, 33 of 34). Last, when more than half of the endometrium was involved, advanced disease beyond stage I was found (9 of 26, 6 of whom had poorly differentiated disease).⁴

Video 3. Cervical spread of adenocarcinoma and visually directed biopsy

Structured pattern analysis. Recently, Dueholm and co-investigators published a prospective evaluation of women with postmenopausal bleeding and an endometrial thickness of 5 mm or greater.⁵ They used a structured system of visual pattern analysis during hysteroscopy that they termed the hysteroscopic cancer (HYCA) scoring system. The HYCA scoring system is based on surface outline (uneven, polypoid, and papillary projections), necrosis (cotton candy endometrium [FIGURE 4], whitish-grayish areas without vessels on the surface), and vessel pattern (tortuous S-shaped, loops, irregular caliber, irregular branching, and irregular distribution [FIGURE 5]). Structured pattern analysis predicted cancer with higher accuracy than subjective evaluation.⁵

Morphologic variables as indicators. In 2016, Ianieri and colleagues published a retrospective study on a risk scoring system for diagnosing endometrial hyperplasia and adenocarcinoma via hysteroscopy.⁶ They created a statistical risk model for development of the scoring system. A number of morphologic variables were prognostic indicators of atypical endometrial hyperplasia (AEH) and adenocarcinoma. These included widespread and irregular endometrial thickness, presence of multiple polyps with irregular aspects, dilated glandular orifices, irregular endometrial color (grey, white, or hyperemic), atypical vessels, crumbling of the endometrial neoplasms, and growth of cerebroid and arborescent aspects (VIDEO 4).

Video 4. Endometrial adenocarcinoma 

 

 

The scoring system for endometrial adenocarcinoma correctly classified 42 of 44 cancers (sensitivity, 95.4%; specificity, 98.2%), and AEH had a sensitivity of 63.3% and a specificity of 90.4%.⁶ These investigators also showed a high negative predictive value of 99.5% for endometrial adenocarcinoma associated with a negative view at hysteroscopy. Similar to the Dueholm data, Ianieri and colleagues’ morphologic pattern analysis predicted cancer with high accuracy.

Glomerular pattern association. Su and colleagues also showed that pattern recognition could aid in the accurate hysteroscopic diagnosis of endometrial adenocarcinoma.⁷ They used the hysteroscopic presence of a glomerular pattern to predict the association with endometrial adenocarcinoma. A glomerular pattern was described as polypoid endometrium with a papillary-like feature, containing an abnormal neovascularization feature with “intertwined neovascular vessels covered by a thin layer of endometrial tissue” (FIGURE 6). The presence of a glomerular pattern indicated grade 2 or grade 3 disease in 25 of 26 women (96%; sensitivity, 84.6%, specificity, 81.8%)⁷ (see video 4).

TABLE 2 summarizes significant morphologic findings relating to the presences of endometrial carcinoma.

Continue to: Atypical endometrial hyperplasia: A difficult diagnosis...

 

Atypical endometrial hyperplasia: A difficult diagnosis

The most common type of endometrial cancer is endometrioid adenocarcinoma (type 1 endometrial carcinoma), and it accounts for approximately 75% to 80% of endometrial cancer diagnoses.⁸ Risk factors include prolonged unopposed estrogen exposure, obesity, diabetes, and age. Type 1 endometrial carcinoma follows a progressive continuum of histopathologic change: from endometrial hyperplasia without atypia to endometrial hyperplasia with atypia (AEH) to well-differentiated endometrial cancer. Therefore, it is possible for endometrial carcinoma to be present simultaneously with AEH. The reported prevalence of concurrent endometrial carcinoma among patients with AEH on biopsy is between 17% and 52%.⁸ Thus, the clinical consideration is for hysterectomy, especially in the postmenopausal patient with a diagnosis of AEH.

Hysteroscopic diagnosis of AEH, however, is more difficult than identification of endometrial carcinoma because a range of morphologic characteristics exist that resemble normal endometrium as well as more progressive disease (VIDEO 5). De Franciscis and colleagues based a hysteroscopic diagnosis of hyperplasia on one or more of the following findings: focal or diffuse, papillary or polypoid, endometrial thickening; abnormal vascular patterns; evidence of glandular cysts; and abnormal architecture features of the glandular outlets (thickening, irregular gland density, or dilatation)⁹ (VIDEO 6).

Video 5. Endometrial polyp and atypical hyperplasia 

Additional studies, including that from Ianieri and colleagues, also have determined that AEH is difficult to discern visually from normal endometrium and other endometrial pathologies.⁶ In another investigation, Lasmar and coauthors reported a retrospective analysis of 4,054 hysteroscopic procedures with directed biopsies evaluating for concordance between the hysteroscopic view and histopathology.¹⁰ Agreement was 56.3% for AEH versus 94% for endometrial carcinoma. Among those with a histologic diagnosis of AEH, in 35.4% benign disease was suspected; in 2.1%, endometrial carcinoma was suspected; and in 6%, normal findings were presumed.¹⁰

Video 6. Nodular, polypoid atypical hyperplasia 

Because of the similarities in morphologic features between AEH and endometrial carcinoma, tissue biopsy under direct visualization is warranted to assure sampling of the most significantly abnormal tissue and to confirm visual interpretation of findings.

Techniques for hysteroscopic-directed biopsy

Using a visual assessment of endometrial abnormalities allows the surgeon to examine the entire uterine cavity and to biopsy the most suspicious and concerning lesions. The directed biopsy technique can involve a simple grasping maneuver: With the jaws of a small grasper open, push slightly forward to accumulate tissue within the jaw, close the jaw, and remove the tissue carefully through the cervix (VIDEO 7). The size of the sample may be limited, and multiple samples may be needed, depending on the quantity of the tissue retrieved.

Video 7. Visually directed endometrial biopsy

Another technique involves first creating a plane of tissue to be removed with scissors and subsequently grasping and removing the tissue (see video 1 and video 3). This particular technique will yield more tissue with one pass of the hysteroscope into the cavity. Careful removal of tissue through the cervix is facilitated by withdrawing the sample in the grasper and the hysteroscope together at the same time, without pulling the sample through the operative channel of the hysteroscope. Also, by turning off the inflow port, the stream of saline does not wash the sample off the grasper at hysteroscope removal from the cervix.

Blind biopsy. If visual inspection reveals a diffuse process within the uterine cavity such that no normal endometrium is noted and the abnormality is of equal degree throughout the endometrial surface, a decision can be made to replace directed biopsy with a blind biopsy. In this scenario, the blind biopsy is certain to sample the representative disease process and not potentially miss significant lesions (see video 4 and video 6). Otherwise, the hysteroscope-directed biopsy would be preferable.

Continue to: Potential for intraperitoneal dissemination of endometrial cancer...

 

Potential for intraperitoneal dissemination of endometrial cancer

There is some concern about intraperitoneal dissemination of endometrial carcinoma at the time of hysteroscopy and effect on disease prognosis. Chang and colleagues conducted a large meta-analysis and found that hysteroscopy performed in the presence of type 1 endometrial carcinoma statistically significantly increased the likelihood of positive intraperitoneal cytology.¹¹ In the included studies that reported survival rates (6 of 19), positive cytology did not alter the clinical outcome. The investigators recommended that hysteroscopy not be avoided for this reason, as it helps in the diagnosis of endometrial carcinoma, especially in the early stages of disease.¹¹

In a recent retrospective analysis, Namazov and colleagues included only stage I endometrial carcinoma (to exclude the adverse effect of advanced stage on survival) and evaluated the assumed isolated effect of hysteroscopy on survival.¹² They compared women in whom stage I endometrial carcinoma was diagnosed: 355 by hysteroscopy and 969 by a nonhysteroscopy method (D&C or office endometrial biopsy). Tumors were classified and grouped as low grade (endometrioid grade 1-2 and villoglandular) and high grade, consisting of endometrioid grade 3 and type 2 endometrial carcinoma (serous carcinoma, clear cell carcinoma, and carcinosarcoma) (VIDEOS 8 and 9). Positive intraperitoneal cytology at the time of surgery was 2.3% and 2.1% (P = .832), with an average interval from diagnosis to surgery of 34.6 days (range, 7–43 days).

Video 8. Carcinosarcoma 

The authors proposed several explanations for the low rate of intraperitoneal cytology with hysteroscopy. One possibility is having lower mean intrauterine pressure below 100 mm Hg for saline uterine distension, although this was not standardized for all surgeons in the study but rather was a custom of the institution. In addition, the length of time between hysteroscopy and surgery may allow the immune-reactive peritoneum to respond to the cellular insult, thus decreasing the biologic burden at the time of surgery. The median follow-up was 52 months (range, 12–120 months), and there were no differences between the hysteroscopy and the nonhysteroscopy groups in the 5-year recurrence-free survival (90.2% vs 88.2%; P = .53), disease-specific survival (93.4% vs 91.7%; P = .5), and overall survival (86.2% vs 80.6%; P = .22). The authors concluded that hysteroscopy does not compromise the survival of patients with early-stage endometrial cancer.¹²

Video 9. Carcinosarcoma 

Retrospective data from Chen and colleagues regarding type 2 endometrial carcinoma indicated a statistically significant increase in positive intraperitoneal cytology for carcinomas evaluated by hysteroscopy versus D&C (30% vs 12%; P = .008).¹³ Among the patients who died, there was no difference in disease-specific survival (53 months for hysteroscopy and 63.5 months for D&C; P = .34), and there was no difference in overall recurrence rates.¹³ Compared with type 1 endometrial carcinoma, type 2 endometrial carcinoma behaves more aggressively, with a higher incidence of extrauterine disease and an increased propensity for recurrence and poor outcome even in the early stages of the disease. This makes it difficult to determine the role of hysteroscopy in the prognosis of these carcinomas, especially in this study where most patients were diagnosed at a later stage.

Key takeaways

Hysteroscopy and directed biopsy are highly effective for visual and histopathologic diagnosis of atypical endometrial hyperplasia and endometrial carcinoma, and they are recommended in the evaluation of AUB, especially in the postmenopausal woman. When the hysteroscopic view is negative, there is a high correlation with the absence of uterine cavity and endometrial pathology. Hysteroscopic diagnostic accuracy is improved with structured use of visual grading scales, well-defined descriptors of endometrial pathology, and hysteroscopist experience.

Low operating intrauterine pressure may decrease the intraperitoneal spread of carcinoma cells during hysteroscopy, and current evidence suggests that there is no change in type 1 endometrial carcinoma prognosis and overall outcomes. Type 2 endometrial carcinoma is more aggressive and is associated with poor outcomes even in early stages, and the effect on disease progression by intraperitoneal spread of carcinoma cells at hysteroscopy is not yet known. Hysteroscopic evaluation of the uterine cavity and directed biopsy is easily and safely performed in the office and adds significantly to the evaluation and management of endometrial carcinoma.

 

This is the third and final article in a series focusing on malpractice, liability, and reform. In the first article, we looked at the background on malpractice and reasons malpractice rates have been so high—including large verdicts and lawsuit-prone physicians. In the second article we considered recent experience and developments in malpractice exposure, who is sued and why. Finally, in this third article, we focus on apologies, apology laws, and liability.

“I’m sorry”

In childhood we are all taught the basic courtesies: “please” and “thank you,” and “I’m sorry,” when harm has occurred. Should we as adult health care providers fear the consequences of apologizing? Apologies are a way for clinicians to express empathy; they also serve as a tool to reduce medical malpractice claims.¹

Apologies, ethics, and care

The American Medical Association takes the position that a physician has an ethical duty to disclose a harmful error to a patient.^2,3 Indeed this approach has been an impetus for states to enact apology laws, which we discuss below. As pointed out in this 2013 article title, “Dealing with a medical mistake: Should physicians apologize to patients?”,⁴ the legal benefits of any apology are an issue. It is a controversial area in medicine still today, including in obstetrics and gynecology.

“Ethical codes for both M.D.s and D.O.s suggest providers should display honesty and empathy following adverse events and errors.”^1,3,5 In addition, the American Medical Association states, “a physician should at all times deal honestly and openly with patients.”² Concerns about liability that may result from truthful disclosure should not affect the physician’s honesty (TABLE). Increasingly, the law has sided with that principle through apology laws.

Some patients sue to get answers to the “What happened?” and “Why did it happen?” questions.⁶ They also sometimes are motivated by a desire to help ensure that the same injury does not happen to others. Silence on the part of the clinician may be seen as a lack of sympathy or remorse and patients may fear that other patients will be harmed.¹

The relationship between physician and patient involves vulnerability and requires trust. When an injury occurs, the relationship can be injured as well. Barriers to apology in part reflect “the culture of medicine” as well as the “inherent psychological difficulties in facing one’s mistakes and apologizing for them.” However, apology by the provider may result in “effective resolution of disputes related to medical error.”⁷

The patient’s perspective is critical to this type of outcome, of course. A study from the United Kingdom noted that one-third of patients who experience a medical error have a desire to receive an apology or explanation. Furthermore, patients need assurance that a plan of action to prevent such a future occurrence is in place.⁸ Surveys reflect that patients desire, or even expect, the physician to acknowledge an error.⁹ We will see that there is evidence that some kinds of apologies tend to diminish blame and make the injured patient less likely to pursue litigation.¹⁰ For instance, Dahan and colleagues completed a study that highlights the “act of apology,” which can be seen as a “language art.”¹¹ Medical schools have recognized the importance of the apology and now incorporate training focused on error disclosure and provision of apologies into the curriculum.¹²

Continue to: Legal issues and medical apologies...

 

 

Legal issues and medical apologies

From a legal standpoint, traditionally, an apology from a physician to a patient could be used against a physician in a medical liability (malpractice) case as proof of negligence.

Statements of interest. Such out-of-court statements ordinarily would be “hearsay” and excluded from evidence; there is, however, an exception to this hearsay rule that allows “confessions” or “statements against interest” to be admissible against the party making the statement. The theory is that when a statement is harmful to the person making it, the person likely thought that it was true, and the statement should be admissible at trial. We do not generally go around confessing to things that are not true. Following an auto crash, if one driver jumps out of the car saying, “I am so sorry I hit you. I was using my cell phone and did not see you stop,” the statement is against the interest of the driver and could be used in court.

As a matter of general legal principle, the same issue can arise in medical practice. Suppose a physician says, “I am so sorry for your injury. We made a mistake in interpreting the data from the monitors.” That sounds a lot like not just an apology but a statement against interest. Malpractice cases generally are based on the claim that a “doctor failed to do what a reasonable provider in the same specialty would have done in a similar situation.”¹³ An apology may be little more than general sympathy (“I’m sorry to tell you that we have not cured the infection. Unfortunately, that will mean more time in the hospital.”), but it can include a confession of error (“I’m sorry we got the x-ray backward and removed the wrong kidney.”). In the latter kind of apology, courts traditionally have found a “statement against interest.”

The legal consequence of a statement against interest is that the statement may be admitted in court. Such statements do not automatically establish negligence, but they can be powerful evidence when presented to a jury.

Courts have struggled with medical apologies. General sympathy or feelings of regret or compassion do not generally rise to the level of an admission that the physician did not use reasonable care under the circumstances and ordinarily are not admissible. (For further details, we refer you to the case of Cobbs v. Grant.¹⁴ Even if a physician said to the patient that he “blamed himself for [the patient] being back in the hospital for a second time,…the statement signifies compassion, or at most, a feeling of remorse, for plaintiff’s ordeal.”) On the other hand, in cases in which a physician in an apology referred to a “careless” mistake or even a “negligent” mistake, courts have allowed it admitted at trial as a statement against interest. (A 1946 case, Woronka v. Sewall, is an example.¹⁵ In that case, the physician said to the patient, “My God, what a mess…she had a very hard delivery, and it was a burning shame to get [an injury] on top of it, and it was because of negligence when they were upstairs.”) Some of these cases come down to the provider’s use of a single word: fault, careless, or negligence.

The ambiguity over the legal place of medical apologies in medicine led attorneys to urge medical providers to avoid statements that might even remotely be taken as statements against interest, including real apologies. The confusion over the admissibility of medical apologies led state legislatures to adopt apology laws. These laws essentially limit what statements against interest may be introduced in professional liability cases when a provider has issued a responsibility or apologized.

Continue to: Apology statutes...

 

Apology statutes

Massachusetts was the first state to enact an apology law—in 1986.¹ As of 2019, a clear majority of states have some form of apology statute. “Apology laws are gaining traction,” was the first sentence in a 2012 review on the subject by Saitta and colleagues.³ Only a few (5 states) have “strong” statutes that have broad protection for statements of fault, error, and negligence, as well as sympathy. The other 33 states have statutes that only protect against statements of sympathy.^4,16 FIGURE 1 is a US map showing the apology laws by state.¹

Do apology statutes and apologies reduce liability?

The positive aspects of apology include personal, psychological, and emotional benefits to both the one apologizing and the one receiving the apology. It also may have financial benefits to health care providers.⁴ The assumption has been, and there has been some evidence for the proposition, that apologies reduce the possibility of malpractice claims. That is one of the reasons that institutions may have formal apology policies. Indeed, there is evidence that apologies reduce financial awards to patients, as manifest in the states of Pennsylvania and Kentucky.⁴ Apologies appear to reduce patient anger and can open the door to better communication with the provider. There is evidence that some kinds of apologies tend to diminish blame and make the injured patient less likely to pursue litigation.¹⁰ The conclusion from these studies might be that honest and open communication serves to decrease the incidence of medical malpractice lawsuit initiation and that honesty is the best policy.

It is important to note the difference, however, between apologies (or institutional apology policies) and apology laws. There is some evidence that apology and institutional apology policies may reduce malpractice claims or losses.^17,18 On the other hand, the studies of apology laws have not found that these laws have much impact on malpractice rates. An especially good and thorough study of the effect of apology laws nationwide, using insurance claims data, essentially found little net effect of the apology laws.^19,20 One other study could find no evidence that apology statutes reduce defensive medicine (so no reduction in provider concerns over liability).²¹

It should be noted that most studies on medical apology and its effects on malpractice claims generally have looked at the narrow or limited apology statutes (that do not cover expressions of fault or negligence). Few states have the broader statutes, and it is possible that those broader statutes would be more effective in reducing liability. Removing the disincentives to medical apologies is a good thing, but in and of itself it is probably not a liability game changer.

Continue to: Institutional policy and apology...

 

Institutional policy and apology

Some institutions have established an “inclusion of apology” strategy for medical errors. These policies appear to have a meaningful effect on reducing medical malpractice costs. These programs commonly include a proactive investigation, disclosure of error, and apologies. Such policies have been studied at the University of Michigan and the Veterans Affairs (VA) Hospital in Lexington, Kentucky. The University of Michigan program resulted in a 60% reduction in compensation costs for medical errors.²² It also cut litigation costs by half.²³ The review of the Kentucky VA program also was positive.¹⁷ FIGURE 2 illustrates the key features of the Michigan program.²⁴

Conclusions: Effective apologies

Our conclusions, first, are that apologies are important from all perspectives: ethical, medical, and legal. On the other hand, all of the attention given in recent years to apology statutes may have been misplaced, at least if they were intended to be malpractice reform.¹⁷

Institutional apology and response programs are likely successful because they are thoughtfully put together, generally based on the best understanding of how injured patients respond to apologies and what it takes to be sincere, and communicate that sincerity, in the apology. What is an effective apology?, “The acceptance of responsibility for having caused harm.” It may, for example, mean accepting some financial responsibility for the harm. It is also important that the apology is conveyed in such a way that it includes an element of self-critical expression.²⁵ Although there are many formulations of the elements of an effective apology, one example is, “(1) acknowledging and accepting responsibility for the offense; (2) expressing remorse with forbearance, sincerity, and honesty; (3) explaining the understanding of the offense; and (4) willingness to make reparations.”²⁶

At the other extreme is a medical professional, after a bad event, trying to engage in a half-hearted, awkward, or insincere apology on an ad hoc and poorly planned basis. Worse still, “when victims perceive apologies to be insincere and designed simply to cool them off, they react with more rather than less indignation.”²⁷ Of course, the “forced apology” may be the worst of all. An instance of this was addressed in a New Zealand study in which providers were “forced” to provide a written apology to a couple (Mr. and Mrs. B) and a separate written apology to Baby B when there was failure to discuss vitamin K administration during the antenatal period when it was indicated.²⁸ Rather than emphasizing required apology in such a case, which can seem hollow and disingenuous, emphasis was placed on the apology providing a “positive-physiological” effect for those harmed, and on strategies that “nurture the development of the moral maturity required for authentic apology.”

The great advantage of institutional or practice-wide policies is that they can be developed in the calm of planning, with good foresight and careful consideration. This is much different from having to come up with some approach in the heat of something having gone wrong. Ultimately, however, apologies are not about liability. They are about caring for, respecting, and communicating with those who are harmed. Apologizing is often the right and professional thing to do.

This is the third and final article in a series focusing on malpractice, liability, and reform. In the first article, we looked at the background on malpractice and reasons malpractice rates have been so high—including large verdicts and lawsuit-prone physicians. In the second article we considered recent experience and developments in malpractice exposure, who is sued and why. Finally, in this third article, we focus on apologies, apology laws, and liability.

“I’m sorry”

In childhood we are all taught the basic courtesies: “please” and “thank you,” and “I’m sorry,” when harm has occurred. Should we as adult health care providers fear the consequences of apologizing? Apologies are a way for clinicians to express empathy; they also serve as a tool to reduce medical malpractice claims.¹

Apologies, ethics, and care

The American Medical Association takes the position that a physician has an ethical duty to disclose a harmful error to a patient.^2,3 Indeed this approach has been an impetus for states to enact apology laws, which we discuss below. As pointed out in this 2013 article title, “Dealing with a medical mistake: Should physicians apologize to patients?”,⁴ the legal benefits of any apology are an issue. It is a controversial area in medicine still today, including in obstetrics and gynecology.

“Ethical codes for both M.D.s and D.O.s suggest providers should display honesty and empathy following adverse events and errors.”^1,3,5 In addition, the American Medical Association states, “a physician should at all times deal honestly and openly with patients.”² Concerns about liability that may result from truthful disclosure should not affect the physician’s honesty (TABLE). Increasingly, the law has sided with that principle through apology laws.

Some patients sue to get answers to the “What happened?” and “Why did it happen?” questions.⁶ They also sometimes are motivated by a desire to help ensure that the same injury does not happen to others. Silence on the part of the clinician may be seen as a lack of sympathy or remorse and patients may fear that other patients will be harmed.¹

The relationship between physician and patient involves vulnerability and requires trust. When an injury occurs, the relationship can be injured as well. Barriers to apology in part reflect “the culture of medicine” as well as the “inherent psychological difficulties in facing one’s mistakes and apologizing for them.” However, apology by the provider may result in “effective resolution of disputes related to medical error.”⁷

The patient’s perspective is critical to this type of outcome, of course. A study from the United Kingdom noted that one-third of patients who experience a medical error have a desire to receive an apology or explanation. Furthermore, patients need assurance that a plan of action to prevent such a future occurrence is in place.⁸ Surveys reflect that patients desire, or even expect, the physician to acknowledge an error.⁹ We will see that there is evidence that some kinds of apologies tend to diminish blame and make the injured patient less likely to pursue litigation.¹⁰ For instance, Dahan and colleagues completed a study that highlights the “act of apology,” which can be seen as a “language art.”¹¹ Medical schools have recognized the importance of the apology and now incorporate training focused on error disclosure and provision of apologies into the curriculum.¹²

Continue to: Legal issues and medical apologies...

 

 

Legal issues and medical apologies

From a legal standpoint, traditionally, an apology from a physician to a patient could be used against a physician in a medical liability (malpractice) case as proof of negligence.

Statements of interest. Such out-of-court statements ordinarily would be “hearsay” and excluded from evidence; there is, however, an exception to this hearsay rule that allows “confessions” or “statements against interest” to be admissible against the party making the statement. The theory is that when a statement is harmful to the person making it, the person likely thought that it was true, and the statement should be admissible at trial. We do not generally go around confessing to things that are not true. Following an auto crash, if one driver jumps out of the car saying, “I am so sorry I hit you. I was using my cell phone and did not see you stop,” the statement is against the interest of the driver and could be used in court.

As a matter of general legal principle, the same issue can arise in medical practice. Suppose a physician says, “I am so sorry for your injury. We made a mistake in interpreting the data from the monitors.” That sounds a lot like not just an apology but a statement against interest. Malpractice cases generally are based on the claim that a “doctor failed to do what a reasonable provider in the same specialty would have done in a similar situation.”¹³ An apology may be little more than general sympathy (“I’m sorry to tell you that we have not cured the infection. Unfortunately, that will mean more time in the hospital.”), but it can include a confession of error (“I’m sorry we got the x-ray backward and removed the wrong kidney.”). In the latter kind of apology, courts traditionally have found a “statement against interest.”

The legal consequence of a statement against interest is that the statement may be admitted in court. Such statements do not automatically establish negligence, but they can be powerful evidence when presented to a jury.

Courts have struggled with medical apologies. General sympathy or feelings of regret or compassion do not generally rise to the level of an admission that the physician did not use reasonable care under the circumstances and ordinarily are not admissible. (For further details, we refer you to the case of Cobbs v. Grant.¹⁴ Even if a physician said to the patient that he “blamed himself for [the patient] being back in the hospital for a second time,…the statement signifies compassion, or at most, a feeling of remorse, for plaintiff’s ordeal.”) On the other hand, in cases in which a physician in an apology referred to a “careless” mistake or even a “negligent” mistake, courts have allowed it admitted at trial as a statement against interest. (A 1946 case, Woronka v. Sewall, is an example.¹⁵ In that case, the physician said to the patient, “My God, what a mess…she had a very hard delivery, and it was a burning shame to get [an injury] on top of it, and it was because of negligence when they were upstairs.”) Some of these cases come down to the provider’s use of a single word: fault, careless, or negligence.

The ambiguity over the legal place of medical apologies in medicine led attorneys to urge medical providers to avoid statements that might even remotely be taken as statements against interest, including real apologies. The confusion over the admissibility of medical apologies led state legislatures to adopt apology laws. These laws essentially limit what statements against interest may be introduced in professional liability cases when a provider has issued a responsibility or apologized.

Continue to: Apology statutes...

 

Apology statutes

Massachusetts was the first state to enact an apology law—in 1986.¹ As of 2019, a clear majority of states have some form of apology statute. “Apology laws are gaining traction,” was the first sentence in a 2012 review on the subject by Saitta and colleagues.³ Only a few (5 states) have “strong” statutes that have broad protection for statements of fault, error, and negligence, as well as sympathy. The other 33 states have statutes that only protect against statements of sympathy.^4,16 FIGURE 1 is a US map showing the apology laws by state.¹

Do apology statutes and apologies reduce liability?

The positive aspects of apology include personal, psychological, and emotional benefits to both the one apologizing and the one receiving the apology. It also may have financial benefits to health care providers.⁴ The assumption has been, and there has been some evidence for the proposition, that apologies reduce the possibility of malpractice claims. That is one of the reasons that institutions may have formal apology policies. Indeed, there is evidence that apologies reduce financial awards to patients, as manifest in the states of Pennsylvania and Kentucky.⁴ Apologies appear to reduce patient anger and can open the door to better communication with the provider. There is evidence that some kinds of apologies tend to diminish blame and make the injured patient less likely to pursue litigation.¹⁰ The conclusion from these studies might be that honest and open communication serves to decrease the incidence of medical malpractice lawsuit initiation and that honesty is the best policy.

It is important to note the difference, however, between apologies (or institutional apology policies) and apology laws. There is some evidence that apology and institutional apology policies may reduce malpractice claims or losses.^17,18 On the other hand, the studies of apology laws have not found that these laws have much impact on malpractice rates. An especially good and thorough study of the effect of apology laws nationwide, using insurance claims data, essentially found little net effect of the apology laws.^19,20 One other study could find no evidence that apology statutes reduce defensive medicine (so no reduction in provider concerns over liability).²¹

It should be noted that most studies on medical apology and its effects on malpractice claims generally have looked at the narrow or limited apology statutes (that do not cover expressions of fault or negligence). Few states have the broader statutes, and it is possible that those broader statutes would be more effective in reducing liability. Removing the disincentives to medical apologies is a good thing, but in and of itself it is probably not a liability game changer.

Continue to: Institutional policy and apology...

 

Institutional policy and apology

Some institutions have established an “inclusion of apology” strategy for medical errors. These policies appear to have a meaningful effect on reducing medical malpractice costs. These programs commonly include a proactive investigation, disclosure of error, and apologies. Such policies have been studied at the University of Michigan and the Veterans Affairs (VA) Hospital in Lexington, Kentucky. The University of Michigan program resulted in a 60% reduction in compensation costs for medical errors.²² It also cut litigation costs by half.²³ The review of the Kentucky VA program also was positive.¹⁷ FIGURE 2 illustrates the key features of the Michigan program.²⁴

Conclusions: Effective apologies

Our conclusions, first, are that apologies are important from all perspectives: ethical, medical, and legal. On the other hand, all of the attention given in recent years to apology statutes may have been misplaced, at least if they were intended to be malpractice reform.¹⁷

Institutional apology and response programs are likely successful because they are thoughtfully put together, generally based on the best understanding of how injured patients respond to apologies and what it takes to be sincere, and communicate that sincerity, in the apology. What is an effective apology?, “The acceptance of responsibility for having caused harm.” It may, for example, mean accepting some financial responsibility for the harm. It is also important that the apology is conveyed in such a way that it includes an element of self-critical expression.²⁵ Although there are many formulations of the elements of an effective apology, one example is, “(1) acknowledging and accepting responsibility for the offense; (2) expressing remorse with forbearance, sincerity, and honesty; (3) explaining the understanding of the offense; and (4) willingness to make reparations.”²⁶

At the other extreme is a medical professional, after a bad event, trying to engage in a half-hearted, awkward, or insincere apology on an ad hoc and poorly planned basis. Worse still, “when victims perceive apologies to be insincere and designed simply to cool them off, they react with more rather than less indignation.”²⁷ Of course, the “forced apology” may be the worst of all. An instance of this was addressed in a New Zealand study in which providers were “forced” to provide a written apology to a couple (Mr. and Mrs. B) and a separate written apology to Baby B when there was failure to discuss vitamin K administration during the antenatal period when it was indicated.²⁸ Rather than emphasizing required apology in such a case, which can seem hollow and disingenuous, emphasis was placed on the apology providing a “positive-physiological” effect for those harmed, and on strategies that “nurture the development of the moral maturity required for authentic apology.”

The great advantage of institutional or practice-wide policies is that they can be developed in the calm of planning, with good foresight and careful consideration. This is much different from having to come up with some approach in the heat of something having gone wrong. Ultimately, however, apologies are not about liability. They are about caring for, respecting, and communicating with those who are harmed. Apologizing is often the right and professional thing to do.

This is the third and final article in a series focusing on malpractice, liability, and reform. In the first article, we looked at the background on malpractice and reasons malpractice rates have been so high—including large verdicts and lawsuit-prone physicians. In the second article we considered recent experience and developments in malpractice exposure, who is sued and why. Finally, in this third article, we focus on apologies, apology laws, and liability.

“I’m sorry”

In childhood we are all taught the basic courtesies: “please” and “thank you,” and “I’m sorry,” when harm has occurred. Should we as adult health care providers fear the consequences of apologizing? Apologies are a way for clinicians to express empathy; they also serve as a tool to reduce medical malpractice claims.¹

Apologies, ethics, and care

The American Medical Association takes the position that a physician has an ethical duty to disclose a harmful error to a patient.^2,3 Indeed this approach has been an impetus for states to enact apology laws, which we discuss below. As pointed out in this 2013 article title, “Dealing with a medical mistake: Should physicians apologize to patients?”,⁴ the legal benefits of any apology are an issue. It is a controversial area in medicine still today, including in obstetrics and gynecology.

“Ethical codes for both M.D.s and D.O.s suggest providers should display honesty and empathy following adverse events and errors.”^1,3,5 In addition, the American Medical Association states, “a physician should at all times deal honestly and openly with patients.”² Concerns about liability that may result from truthful disclosure should not affect the physician’s honesty (TABLE). Increasingly, the law has sided with that principle through apology laws.

Some patients sue to get answers to the “What happened?” and “Why did it happen?” questions.⁶ They also sometimes are motivated by a desire to help ensure that the same injury does not happen to others. Silence on the part of the clinician may be seen as a lack of sympathy or remorse and patients may fear that other patients will be harmed.¹

The relationship between physician and patient involves vulnerability and requires trust. When an injury occurs, the relationship can be injured as well. Barriers to apology in part reflect “the culture of medicine” as well as the “inherent psychological difficulties in facing one’s mistakes and apologizing for them.” However, apology by the provider may result in “effective resolution of disputes related to medical error.”⁷

The patient’s perspective is critical to this type of outcome, of course. A study from the United Kingdom noted that one-third of patients who experience a medical error have a desire to receive an apology or explanation. Furthermore, patients need assurance that a plan of action to prevent such a future occurrence is in place.⁸ Surveys reflect that patients desire, or even expect, the physician to acknowledge an error.⁹ We will see that there is evidence that some kinds of apologies tend to diminish blame and make the injured patient less likely to pursue litigation.¹⁰ For instance, Dahan and colleagues completed a study that highlights the “act of apology,” which can be seen as a “language art.”¹¹ Medical schools have recognized the importance of the apology and now incorporate training focused on error disclosure and provision of apologies into the curriculum.¹²

Continue to: Legal issues and medical apologies...

 

 

Legal issues and medical apologies

From a legal standpoint, traditionally, an apology from a physician to a patient could be used against a physician in a medical liability (malpractice) case as proof of negligence.

Statements of interest. Such out-of-court statements ordinarily would be “hearsay” and excluded from evidence; there is, however, an exception to this hearsay rule that allows “confessions” or “statements against interest” to be admissible against the party making the statement. The theory is that when a statement is harmful to the person making it, the person likely thought that it was true, and the statement should be admissible at trial. We do not generally go around confessing to things that are not true. Following an auto crash, if one driver jumps out of the car saying, “I am so sorry I hit you. I was using my cell phone and did not see you stop,” the statement is against the interest of the driver and could be used in court.

As a matter of general legal principle, the same issue can arise in medical practice. Suppose a physician says, “I am so sorry for your injury. We made a mistake in interpreting the data from the monitors.” That sounds a lot like not just an apology but a statement against interest. Malpractice cases generally are based on the claim that a “doctor failed to do what a reasonable provider in the same specialty would have done in a similar situation.”¹³ An apology may be little more than general sympathy (“I’m sorry to tell you that we have not cured the infection. Unfortunately, that will mean more time in the hospital.”), but it can include a confession of error (“I’m sorry we got the x-ray backward and removed the wrong kidney.”). In the latter kind of apology, courts traditionally have found a “statement against interest.”

The legal consequence of a statement against interest is that the statement may be admitted in court. Such statements do not automatically establish negligence, but they can be powerful evidence when presented to a jury.

Courts have struggled with medical apologies. General sympathy or feelings of regret or compassion do not generally rise to the level of an admission that the physician did not use reasonable care under the circumstances and ordinarily are not admissible. (For further details, we refer you to the case of Cobbs v. Grant.¹⁴ Even if a physician said to the patient that he “blamed himself for [the patient] being back in the hospital for a second time,…the statement signifies compassion, or at most, a feeling of remorse, for plaintiff’s ordeal.”) On the other hand, in cases in which a physician in an apology referred to a “careless” mistake or even a “negligent” mistake, courts have allowed it admitted at trial as a statement against interest. (A 1946 case, Woronka v. Sewall, is an example.¹⁵ In that case, the physician said to the patient, “My God, what a mess…she had a very hard delivery, and it was a burning shame to get [an injury] on top of it, and it was because of negligence when they were upstairs.”) Some of these cases come down to the provider’s use of a single word: fault, careless, or negligence.

The ambiguity over the legal place of medical apologies in medicine led attorneys to urge medical providers to avoid statements that might even remotely be taken as statements against interest, including real apologies. The confusion over the admissibility of medical apologies led state legislatures to adopt apology laws. These laws essentially limit what statements against interest may be introduced in professional liability cases when a provider has issued a responsibility or apologized.

Continue to: Apology statutes...

 

Apology statutes

Massachusetts was the first state to enact an apology law—in 1986.¹ As of 2019, a clear majority of states have some form of apology statute. “Apology laws are gaining traction,” was the first sentence in a 2012 review on the subject by Saitta and colleagues.³ Only a few (5 states) have “strong” statutes that have broad protection for statements of fault, error, and negligence, as well as sympathy. The other 33 states have statutes that only protect against statements of sympathy.^4,16 FIGURE 1 is a US map showing the apology laws by state.¹

Do apology statutes and apologies reduce liability?

The positive aspects of apology include personal, psychological, and emotional benefits to both the one apologizing and the one receiving the apology. It also may have financial benefits to health care providers.⁴ The assumption has been, and there has been some evidence for the proposition, that apologies reduce the possibility of malpractice claims. That is one of the reasons that institutions may have formal apology policies. Indeed, there is evidence that apologies reduce financial awards to patients, as manifest in the states of Pennsylvania and Kentucky.⁴ Apologies appear to reduce patient anger and can open the door to better communication with the provider. There is evidence that some kinds of apologies tend to diminish blame and make the injured patient less likely to pursue litigation.¹⁰ The conclusion from these studies might be that honest and open communication serves to decrease the incidence of medical malpractice lawsuit initiation and that honesty is the best policy.

It is important to note the difference, however, between apologies (or institutional apology policies) and apology laws. There is some evidence that apology and institutional apology policies may reduce malpractice claims or losses.^17,18 On the other hand, the studies of apology laws have not found that these laws have much impact on malpractice rates. An especially good and thorough study of the effect of apology laws nationwide, using insurance claims data, essentially found little net effect of the apology laws.^19,20 One other study could find no evidence that apology statutes reduce defensive medicine (so no reduction in provider concerns over liability).²¹

It should be noted that most studies on medical apology and its effects on malpractice claims generally have looked at the narrow or limited apology statutes (that do not cover expressions of fault or negligence). Few states have the broader statutes, and it is possible that those broader statutes would be more effective in reducing liability. Removing the disincentives to medical apologies is a good thing, but in and of itself it is probably not a liability game changer.

Continue to: Institutional policy and apology...

 

Institutional policy and apology

Some institutions have established an “inclusion of apology” strategy for medical errors. These policies appear to have a meaningful effect on reducing medical malpractice costs. These programs commonly include a proactive investigation, disclosure of error, and apologies. Such policies have been studied at the University of Michigan and the Veterans Affairs (VA) Hospital in Lexington, Kentucky. The University of Michigan program resulted in a 60% reduction in compensation costs for medical errors.²² It also cut litigation costs by half.²³ The review of the Kentucky VA program also was positive.¹⁷ FIGURE 2 illustrates the key features of the Michigan program.²⁴

Conclusions: Effective apologies

Our conclusions, first, are that apologies are important from all perspectives: ethical, medical, and legal. On the other hand, all of the attention given in recent years to apology statutes may have been misplaced, at least if they were intended to be malpractice reform.¹⁷

Institutional apology and response programs are likely successful because they are thoughtfully put together, generally based on the best understanding of how injured patients respond to apologies and what it takes to be sincere, and communicate that sincerity, in the apology. What is an effective apology?, “The acceptance of responsibility for having caused harm.” It may, for example, mean accepting some financial responsibility for the harm. It is also important that the apology is conveyed in such a way that it includes an element of self-critical expression.²⁵ Although there are many formulations of the elements of an effective apology, one example is, “(1) acknowledging and accepting responsibility for the offense; (2) expressing remorse with forbearance, sincerity, and honesty; (3) explaining the understanding of the offense; and (4) willingness to make reparations.”²⁶

At the other extreme is a medical professional, after a bad event, trying to engage in a half-hearted, awkward, or insincere apology on an ad hoc and poorly planned basis. Worse still, “when victims perceive apologies to be insincere and designed simply to cool them off, they react with more rather than less indignation.”²⁷ Of course, the “forced apology” may be the worst of all. An instance of this was addressed in a New Zealand study in which providers were “forced” to provide a written apology to a couple (Mr. and Mrs. B) and a separate written apology to Baby B when there was failure to discuss vitamin K administration during the antenatal period when it was indicated.²⁸ Rather than emphasizing required apology in such a case, which can seem hollow and disingenuous, emphasis was placed on the apology providing a “positive-physiological” effect for those harmed, and on strategies that “nurture the development of the moral maturity required for authentic apology.”

The great advantage of institutional or practice-wide policies is that they can be developed in the calm of planning, with good foresight and careful consideration. This is much different from having to come up with some approach in the heat of something having gone wrong. Ultimately, however, apologies are not about liability. They are about caring for, respecting, and communicating with those who are harmed. Apologizing is often the right and professional thing to do.

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and its incidence continues to increase. More than 5 million NMSCs are estimated to occur annually in the United States alone.¹ There are more cases of basal cell carcinoma (BCC) than all other cancers combined, with squamous cell carcinoma (SCC) being the second most common cancer in the United States.^1-3 The rising incidence of NMSCs highlights the importance of investigating additional treatment options with fewer side effects, better cosmetic outcomes, and better efficacy.¹

Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinoma and SCC commonly are treated with cryosurgery; electrodesiccation and curettage; or more definitive surgical options, including excision and Mohs micrographic surgery (MMS). Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors, such as vismodegib, offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects; thus, there is always room for novel therapeutic approaches. We review new and potential treatments from 2018 and beyond. Although only 5% of SCCs become locally advanced, recur, or metastasize, and 0.4% to 0.8% of BCCs progress to advanced disease, many of the newer studies target advanced NMSCs, given their life-threatening and debilitating nature.^4,5 Similarly, the incidence of nevoid basal cell carcinoma (NBCC) syndrome is as low as 1 in 57,000 to 1 in 164,000 but continues to be studied because of its morbidity and the potential to contribute new treatment options for BCC in the general population.⁶

Topical Therapy

Sonidegib
Basal cell carcinoma proliferation is a result of an unregulated Hh pathway that is initiated when the Hh ligand binds to the patched 1 protein (PTCH1).^7-11 Patched 1 protein normally inhibits the smoothened (SMO) transmembrane receptor protein, decreasing the signaling cascade. In BCCs, there is a loss of PTCH1 function, effectively increasing the Hh pathway activity. Sonidegib is an Hh inhibitor that in turn prevents inhibition of PTCH1 in an attempt to reregulate the pathway.^7-11 Although sonidegib is known for its 2015 approval by the US Food and Drug Administration (FDA) as a systemic therapy for locally advanced BCCs,¹² one study investigated a topical formulation on 8 patients with NBCC syndrome.¹³ Patients were treated twice daily with sonidegib cream 0.75% for 4 weeks in a double-blind, randomized, vehicle-controlled study. A total of 27 BCCs were randomized and treated with either vehicle or sonidegib. A biopsy was taken at the end of the study of 1 sonidegib-treated and 1 vehicle-treated BCC lesion per patient. Of the 13 sonidegib-treated BCC lesions, 3 (23.1%) showed complete response, 9 (69.2%) showed partial response, and 1 (7.7%) showed no response vs 13 of 14 (92.8%) lesions that did not respond to the vehicle. Patients tolerated the treatment well without skin irritation or signs of local or systemic side effects.¹³ Topical sonidegib should be further investigated as an adjunct or in different vehicles given the successful regression of BCCs and its minimal side-effect profile.

Systemic Therapy

Cemiplimab
Cemiplimab is a human monoclonal antibody against programmed death receptor 1 (PD-1) that was FDA approved in September 2018 for the treatment of metastatic cutaneous SCC.¹⁴ Programmed death receptor 1 is found on T lymphocytes, B lymphocytes, and macrophages, which normally assist in the immune response to tumor cells. However, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) are found on tumor cells and bind to PD-1. Cemiplimab prevents PD-1 from binding to PD-L1 and PD-L2, allowing an appropriate immune response.^14,15 A phase 1 clinical trial of cemiplimab showed a 50% (13/26) response rate.¹⁶ The phase 2 trial included patients with advanced SCC, but the primary analysis only considered patients with metastatic SCC. Phase 2 results showed a 47.5% (28/59) response rate. Patients received intravenous cemiplimab 3 mg/kg once every 2 weeks for up to 48 weeks in phase 1 and up to 96 weeks in phase 2. Both phases of the trial showed a response to treatment lasting longer than 6 months in more than 50% of patients. The most common adverse events were diarrhea, fatigue, nausea, constipation, and rash.¹⁶

Although immune-mediated adverse reactions are rare, they can occur given cemiplimab’s mechanism of action and may range from severe to fatal. Examples of immune-mediated adverse reactions that occurred during the study included pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus, nephritis with renal dysfunction, and immune-mediated dermatologic reactions.¹⁴ It is important to monitor for immune-mediated adverse reactions and address them immediately once detected.

Other PD-1 Inhibitors
Although PD-1 inhibitors have been studied in advanced SCCs, their clinical data are limited for BCCs.¹⁷ Prior to 2018, there was a small number of case reports of patients with BCC with partial to exceptional response to PD-1 inhibitors. Recently, 2 additional case reports were published with contrasting outcomes using 2 different PD-1 inhibitors. An elderly patient with metastatic non–small cell lung cancer was treated with nivolumab after failing chemotherapy. She subsequently developed a BCC on the nose that was resected but recurred 2 months later despite continuing nivolumab.¹⁷ Another case report detailed a patient with a history of BCC on the shoulder excised 5 years prior who presented with recurrence on the sternum and clavicle.¹⁸ One year later the patient was found to have BCC metastases to the lung. After progression of disease despite vismodegib and recurrence of BCC with taladegib, the patient was then placed on pembrolizumab. At 6 weeks and 12 months, computed tomography showed resolution of multiple lung lesions. Sixteen weeks after initiation of pembrolizumab treatment, spinal metastases were found, but the treatment was continued because of the improvement in the lung metastases.¹⁸

Taladegib
Taladegib is a SMO antagonist that has been through a phase 1 trial in patients with advanced cancer, including treatment-naive and previously treated BCCs.¹⁹ Eighty-four patients were treated to examine the safety profile and determine an appropriate phase 2 dose and administration schedule. The maximum tolerable dose was determined to be 400 mg because of dose-limiting toxicities. All clinical responses were in patients with BCCs (47/84 [55.9%] patients), with a response rate of 46.8%. Eleven of 16 (68.8%) Hh-treatment–naive patients and 11 of 31 (35.5%) patients previously treated with Hh responded to taladegib. Common adverse events were dysgeusia, fatigue, nausea, and muscle spasms.¹⁹ Although vismodegib is an FDA-approved SMO antagonist since 2012, treatment resistance and tolerability issues have been continuing concerns.^20,21 Taladegib is a potential alternative that may be found to have improved pharmacodynamics and pharmacokinetics. Not only did in vitro studies show a preferable protein-binding profile with taladegib, but it also displayed dose proportionality, while vismodegib has been known to have nonlinear pharmacokinetics.¹⁹

 

Posaconazole
Posaconazole is a systemic antifungal agent that is a structural analogue to itraconazole.²² Itraconazole has been found to inhibit the Hh pathway as an SMO antagonist. In a study with mice, posaconazole was found to have strong activity against drug-resistant SMO mutants while inhibiting the growth of Hh-dependent BCCs in vivo. A marked decrease also was seen in the ciliary accumulation of SMO, suggesting a similar mechanism of action to itraconazole. Posaconazole’s use for BCCs currently is limited to basic science studies but may offer a potential alternative to itraconazole, which is known to have many drug-drug interactions and requires dose adjustments in renal and hepatic insufficiency. When used as an antifungal compared to itraconazole, posaconazole has a favorable long-term safety profile due to fewer drug-drug interactions and mild side effects; it also does not require dose adjustments in mild to moderate renal or hepatic insufficiency.²² Thus, posaconazole is a potentially safer alternative to itraconazole for the treatment of BCCs. Although phase 2 studies of itraconazole for BCCs have shown decreased cell proliferation, tumor size, and reduced GLI1 messenger RNA, side effects included fatigue and grade 4 heart failure.^23,24

Radiation Therapy

Radiation therapies (RTs), such as superficial RT, have been long-established treatment options.²⁵ However, there also are emerging methods of delivering RT, including electronic brachytherapy (EB). Although there is a low likelihood of residual tumor after RT given the number of sessions involved and the more aggressive nature of the treatment, these factors also can be a substantial burden on the patient. Furthermore, RT may result in subsequent scar tissue, which can hinder the use of other emerging technologies, such as noninvasive imaging devices, following RT.

Superficial RT
Superficial RT is a secondary option for the treatment of NMSC for use in special circumstances, such as when surgical intervention is contraindicated or refused, and after the benefits and risks of treatment alternatives have been discussed.²⁶ However, depending on the tumor type and anatomical location, 6 to 18 treatments may be required, with treatment frequency ranging from 1 to 5 treatments per week.²⁵ Patients may find this treatment regimen difficult to maintain given the length of time and frequency of treatments required. Side effects include radiation dermatitis and postinflammatory hypopigmentation or hyperpigmentation in patients with dark skin, and there is a risk for recurrence.^25,27

Electronic Brachytherapy
Brachytherapy is a method of delivering RT via radioactive isotopes, whereas EB uses lower-energy photons that require less shielding.²⁸ As a relatively new therapy, studies on the efficacy of EB on NMSC continue to grow but with limited data comparing EB with established treatments. Furthermore, there are limited long-term follow-up data, and future studies should expand the patient demographic to younger patients before treatment guidelines can be established.²⁸

RT With Concurrent and Adjuvant Vismodegib
Vismodegib is an SMO inhibitor that was FDA approved in 2012 for the treatment of locally advanced BCC in patients who are not candidates for surgery or RT.²⁹ Over time, studies have looked into other indications for vismodegib, such as a neoadjuvant to MMS or in patients with NBCC syndrome.¹¹ Prior to 2018, there were only 2 known case reports of concurrent vismodegib and RT used for recurrent advanced BCC.³⁰ Recently, vismodegib has been further examined in combination with RT in a case report,³¹ basic science study,³² and phase 2 trials (ClinicalTrials.gov Identifiers NCT02956889 and NCT01835626).

Prior studies showed low cure rates with vismodegib alone after RT (43%) as well as decreasing cure rates with primary RT alone as tumor size increased.^33,34 In 2018, vismodegib was used concurrently and as an adjuvant to RT in a patient with advanced multifocal BCC.³¹ The patient had multiple large BCCs on the trunk that were painful and bleeding. The patient was started on RT and 150 mg/d vismodegib concurrently, which was then continued adjuvantly for 3 months until it was discontinued because of diarrhea. The patient had complete response in all lesions with resolution of symptoms.³¹ A separate basic science study further supported the potential role of vismodegib in radiation sensitization of both BCCs and head and neck SCCs.³² There presently are 2 phase 2 trials investigating the concurrent use of vismodegib and RT, which could help determine the efficacy of the combined approach for patients with advanced BCCs who are poor surgical candidates (NCT02956889 and NCT01835626).

Photodynamic Therapy

Photodynamic therapy has been in use since the 1970s when Dougherty et al³⁵ performed one of the first studies on its use in skin cancer. Since then, PDT has been used for the treatment of actinic keratoses (AKs) and more recently BCCs. In PDT, a photosensitizer (PS) is applied and activated by a 400-nm blue light or 635-nm red light, depending on the PS used. The PS then produces highly reactive oxygen species, leading to apoptosis of the cancer cells.³⁶ In Europe, red light PDT is licensed for the treatment of AKs as well as superficial and nodular BCCs, though approved indications vary between countries. In the United States, PDT is only FDA approved for the treatment of AKs.³⁷

 

Aminolevulinic Acid Hydrochloride
Aminolevulinic acid hydrochloride is a red light PS used to treat AKs since 2011 and BCCs since 2017 in Europe in addition to AKs in the United States since 2016.^38,39 A phase 3 noninferiority clinical trial in Europe of 281 patients compared the treatment of nonaggressive BCCs with ALA to methyl aminolevulinate (MAL) cream.⁴⁰ The study found a complete response rate of 93.4% vs 91.8%. Superficial BCCs treated with ALA had a clearance rate of 94.7% vs 96.4% with MAL, while nodular BCCs treated with ALA had a clearance rate of 85.7% vs 76.2% with MAL. A 1-year clinical follow-up showed similar recurrence rates (8.4% for ALA vs 8.5% for MAL).⁴⁰ The results of this study led to an expanded indication in Europe to include the treatment of BCCs.³⁸ Aminolevulinic acid hydrochloride currently is undergoing phase 3 clinical trials in the United States for approval for the treatment of superficial BCCs (NCT03573401). If similar outcomes are achieved, US patients may have access to an alternative nonsurgical treatment of BCCs. The ongoing US trial is exclusively investigating the efficacy and safety for superficial BCCs, which may limit FDA approval to only superficial BCCs, accounting for only 8.4% to 24.1% of all BCCs.^35,41,42

Laser Therapy

Ablative and nonablative lasers have been used to treat NMSCs in the literature. Ablative lasers destroy tumors through vaporization of tissue water, whereas nonablative lasers target the vasculature of tumors while preserving the surrounding tissue.^43,44 Nonablative lasers include pulsed dye lasers (PDL) and Nd:YAG lasers. Examples of ablative lasers include CO₂ and erbium:YAG lasers. Given the status of lasers as an emerging treatment method, there currently is no standardized laser setting for any of the laser therapies used to treat NMSCs. Although there is the potential for optimal cosmetic outcomes and a limited side-effect profile for nonablative laser therapies, there are limited data on long-term follow-up to study recurrence rates and establish a more standardized treatment protocol.

Pulsed Dye Lasers
Although there were no studies on PDL therapy alone in 2018, a study published in 2019 evaluated a combination laser treatment using a 595-nm PDL and 1927-nm fractional laser for the treatment of 93 BCCs, yielding a 95.7% (89/93) clearance rate and 4.5% (4/89) recurrence rate over a follow-up period of up to 6 years (range, 2.53 months to 6.03 years).⁴⁵ Studies of PDL prior to 2018 had follow-ups ranging from 2 weeks to 6 months.^46-51 Although the majority were biopsy-proven BCCs, reflectance confocal microscopy also was used for same-day diagnoses. Long-term follow-up included clinical examinations, dermoscopy, and optical coherence tomography.⁴⁵ The clearance rate (95.7%) using noninvasive imaging in conjunction with the combination laser treatment was superior to both histologic and clinical clearance rates of prior PDL-only studies, which ranged from 25% to 95%.^46-51 To have long-term follow-up data, the study used noninvasive imaging with clinical follow-up because histology would not be viable for long-term follow-up. This study was retrospective rather than prospective, which was a limitation.⁴⁵

Nd:YAG Lasers
The majority of studies utilizing Nd:YAG lasers investigated their efficacy in treating BCCs, with the exception of 1 study of facial SCCs. This major study in 2009 of 627 BCCs showed a 2.5% recurrence rate after a follow-up time of 3 months to 5 years.⁵² Nd:YAG lasers continue to be investigated, including a more recent study of 31 extrafacial, biopsy-proven BCCs that were treated with the 1064-nm Nd:YAG laser, which showed a 90% histologic clearance on 1-month follow-up after a single treatment.⁵³ In 2019, a retrospective review of 16 BCC lesions on the head, neck, trunk, and extremities showed 100% clearance after 1 treatment, with an average follow-up period of 9 months (range, 6–15 months).⁵⁴ In a retrospective review, Markowitz and Psomadakis⁵⁵ contributed data supporting the further investigation and use of the 1064-nm Nd:YAG laser for BCC treatment while leveraging noninvasive imaging to demonstrate a same-day management model. Seventeen BCC lesions on the face and body were diagnosed by reflectance confocal microscopy and treated with an Nd:YAG laser, and clearance was monitored clinically, dermoscopically, and by optical coherence tomography. There was 100% clearance of the lesions in the study, with 82.4% (14/17) clearing after 1 treatment; mean follow-up was 103 days (range, 48–371 days).⁵⁵ These studies were limited by their short follow-up time; long-term data are needed to determine true rates of recurrence.

Ablative Lasers
Ablative lasers also have been used in the treatment of NMSCs. In addition to the potentially increased healing time compared to nonablative lasers, other limitations of ablative laser therapy include residual tumor burden or recurrence that may not be easily visualized in scarred tissue after nonablative management.⁴⁴

Conclusion

Although MMS remains the gold standard for invasive management of NMSCs, studies from 2018 and beyond (eTable) expanded not only on MMS topics such as increased patient access and improved techniques but also on the increasing potential of noninvasive treatments. Some of the noninvasive therapies were entirely new compounds, whereas others were already in use for a different disease indication. Furthering our knowledge and expanding our repertoire of management options will prepare us as the number of patients affected by NMSCs increases.

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and its incidence continues to increase. More than 5 million NMSCs are estimated to occur annually in the United States alone.¹ There are more cases of basal cell carcinoma (BCC) than all other cancers combined, with squamous cell carcinoma (SCC) being the second most common cancer in the United States.^1-3 The rising incidence of NMSCs highlights the importance of investigating additional treatment options with fewer side effects, better cosmetic outcomes, and better efficacy.¹

Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinoma and SCC commonly are treated with cryosurgery; electrodesiccation and curettage; or more definitive surgical options, including excision and Mohs micrographic surgery (MMS). Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors, such as vismodegib, offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects; thus, there is always room for novel therapeutic approaches. We review new and potential treatments from 2018 and beyond. Although only 5% of SCCs become locally advanced, recur, or metastasize, and 0.4% to 0.8% of BCCs progress to advanced disease, many of the newer studies target advanced NMSCs, given their life-threatening and debilitating nature.^4,5 Similarly, the incidence of nevoid basal cell carcinoma (NBCC) syndrome is as low as 1 in 57,000 to 1 in 164,000 but continues to be studied because of its morbidity and the potential to contribute new treatment options for BCC in the general population.⁶

Topical Therapy

Sonidegib
Basal cell carcinoma proliferation is a result of an unregulated Hh pathway that is initiated when the Hh ligand binds to the patched 1 protein (PTCH1).^7-11 Patched 1 protein normally inhibits the smoothened (SMO) transmembrane receptor protein, decreasing the signaling cascade. In BCCs, there is a loss of PTCH1 function, effectively increasing the Hh pathway activity. Sonidegib is an Hh inhibitor that in turn prevents inhibition of PTCH1 in an attempt to reregulate the pathway.^7-11 Although sonidegib is known for its 2015 approval by the US Food and Drug Administration (FDA) as a systemic therapy for locally advanced BCCs,¹² one study investigated a topical formulation on 8 patients with NBCC syndrome.¹³ Patients were treated twice daily with sonidegib cream 0.75% for 4 weeks in a double-blind, randomized, vehicle-controlled study. A total of 27 BCCs were randomized and treated with either vehicle or sonidegib. A biopsy was taken at the end of the study of 1 sonidegib-treated and 1 vehicle-treated BCC lesion per patient. Of the 13 sonidegib-treated BCC lesions, 3 (23.1%) showed complete response, 9 (69.2%) showed partial response, and 1 (7.7%) showed no response vs 13 of 14 (92.8%) lesions that did not respond to the vehicle. Patients tolerated the treatment well without skin irritation or signs of local or systemic side effects.¹³ Topical sonidegib should be further investigated as an adjunct or in different vehicles given the successful regression of BCCs and its minimal side-effect profile.

Systemic Therapy

Cemiplimab
Cemiplimab is a human monoclonal antibody against programmed death receptor 1 (PD-1) that was FDA approved in September 2018 for the treatment of metastatic cutaneous SCC.¹⁴ Programmed death receptor 1 is found on T lymphocytes, B lymphocytes, and macrophages, which normally assist in the immune response to tumor cells. However, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) are found on tumor cells and bind to PD-1. Cemiplimab prevents PD-1 from binding to PD-L1 and PD-L2, allowing an appropriate immune response.^14,15 A phase 1 clinical trial of cemiplimab showed a 50% (13/26) response rate.¹⁶ The phase 2 trial included patients with advanced SCC, but the primary analysis only considered patients with metastatic SCC. Phase 2 results showed a 47.5% (28/59) response rate. Patients received intravenous cemiplimab 3 mg/kg once every 2 weeks for up to 48 weeks in phase 1 and up to 96 weeks in phase 2. Both phases of the trial showed a response to treatment lasting longer than 6 months in more than 50% of patients. The most common adverse events were diarrhea, fatigue, nausea, constipation, and rash.¹⁶

Although immune-mediated adverse reactions are rare, they can occur given cemiplimab’s mechanism of action and may range from severe to fatal. Examples of immune-mediated adverse reactions that occurred during the study included pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus, nephritis with renal dysfunction, and immune-mediated dermatologic reactions.¹⁴ It is important to monitor for immune-mediated adverse reactions and address them immediately once detected.

Other PD-1 Inhibitors
Although PD-1 inhibitors have been studied in advanced SCCs, their clinical data are limited for BCCs.¹⁷ Prior to 2018, there was a small number of case reports of patients with BCC with partial to exceptional response to PD-1 inhibitors. Recently, 2 additional case reports were published with contrasting outcomes using 2 different PD-1 inhibitors. An elderly patient with metastatic non–small cell lung cancer was treated with nivolumab after failing chemotherapy. She subsequently developed a BCC on the nose that was resected but recurred 2 months later despite continuing nivolumab.¹⁷ Another case report detailed a patient with a history of BCC on the shoulder excised 5 years prior who presented with recurrence on the sternum and clavicle.¹⁸ One year later the patient was found to have BCC metastases to the lung. After progression of disease despite vismodegib and recurrence of BCC with taladegib, the patient was then placed on pembrolizumab. At 6 weeks and 12 months, computed tomography showed resolution of multiple lung lesions. Sixteen weeks after initiation of pembrolizumab treatment, spinal metastases were found, but the treatment was continued because of the improvement in the lung metastases.¹⁸

Taladegib
Taladegib is a SMO antagonist that has been through a phase 1 trial in patients with advanced cancer, including treatment-naive and previously treated BCCs.¹⁹ Eighty-four patients were treated to examine the safety profile and determine an appropriate phase 2 dose and administration schedule. The maximum tolerable dose was determined to be 400 mg because of dose-limiting toxicities. All clinical responses were in patients with BCCs (47/84 [55.9%] patients), with a response rate of 46.8%. Eleven of 16 (68.8%) Hh-treatment–naive patients and 11 of 31 (35.5%) patients previously treated with Hh responded to taladegib. Common adverse events were dysgeusia, fatigue, nausea, and muscle spasms.¹⁹ Although vismodegib is an FDA-approved SMO antagonist since 2012, treatment resistance and tolerability issues have been continuing concerns.^20,21 Taladegib is a potential alternative that may be found to have improved pharmacodynamics and pharmacokinetics. Not only did in vitro studies show a preferable protein-binding profile with taladegib, but it also displayed dose proportionality, while vismodegib has been known to have nonlinear pharmacokinetics.¹⁹

 

Posaconazole
Posaconazole is a systemic antifungal agent that is a structural analogue to itraconazole.²² Itraconazole has been found to inhibit the Hh pathway as an SMO antagonist. In a study with mice, posaconazole was found to have strong activity against drug-resistant SMO mutants while inhibiting the growth of Hh-dependent BCCs in vivo. A marked decrease also was seen in the ciliary accumulation of SMO, suggesting a similar mechanism of action to itraconazole. Posaconazole’s use for BCCs currently is limited to basic science studies but may offer a potential alternative to itraconazole, which is known to have many drug-drug interactions and requires dose adjustments in renal and hepatic insufficiency. When used as an antifungal compared to itraconazole, posaconazole has a favorable long-term safety profile due to fewer drug-drug interactions and mild side effects; it also does not require dose adjustments in mild to moderate renal or hepatic insufficiency.²² Thus, posaconazole is a potentially safer alternative to itraconazole for the treatment of BCCs. Although phase 2 studies of itraconazole for BCCs have shown decreased cell proliferation, tumor size, and reduced GLI1 messenger RNA, side effects included fatigue and grade 4 heart failure.^23,24

Radiation Therapy

Radiation therapies (RTs), such as superficial RT, have been long-established treatment options.²⁵ However, there also are emerging methods of delivering RT, including electronic brachytherapy (EB). Although there is a low likelihood of residual tumor after RT given the number of sessions involved and the more aggressive nature of the treatment, these factors also can be a substantial burden on the patient. Furthermore, RT may result in subsequent scar tissue, which can hinder the use of other emerging technologies, such as noninvasive imaging devices, following RT.

Superficial RT
Superficial RT is a secondary option for the treatment of NMSC for use in special circumstances, such as when surgical intervention is contraindicated or refused, and after the benefits and risks of treatment alternatives have been discussed.²⁶ However, depending on the tumor type and anatomical location, 6 to 18 treatments may be required, with treatment frequency ranging from 1 to 5 treatments per week.²⁵ Patients may find this treatment regimen difficult to maintain given the length of time and frequency of treatments required. Side effects include radiation dermatitis and postinflammatory hypopigmentation or hyperpigmentation in patients with dark skin, and there is a risk for recurrence.^25,27

Electronic Brachytherapy
Brachytherapy is a method of delivering RT via radioactive isotopes, whereas EB uses lower-energy photons that require less shielding.²⁸ As a relatively new therapy, studies on the efficacy of EB on NMSC continue to grow but with limited data comparing EB with established treatments. Furthermore, there are limited long-term follow-up data, and future studies should expand the patient demographic to younger patients before treatment guidelines can be established.²⁸

RT With Concurrent and Adjuvant Vismodegib
Vismodegib is an SMO inhibitor that was FDA approved in 2012 for the treatment of locally advanced BCC in patients who are not candidates for surgery or RT.²⁹ Over time, studies have looked into other indications for vismodegib, such as a neoadjuvant to MMS or in patients with NBCC syndrome.¹¹ Prior to 2018, there were only 2 known case reports of concurrent vismodegib and RT used for recurrent advanced BCC.³⁰ Recently, vismodegib has been further examined in combination with RT in a case report,³¹ basic science study,³² and phase 2 trials (ClinicalTrials.gov Identifiers NCT02956889 and NCT01835626).

Prior studies showed low cure rates with vismodegib alone after RT (43%) as well as decreasing cure rates with primary RT alone as tumor size increased.^33,34 In 2018, vismodegib was used concurrently and as an adjuvant to RT in a patient with advanced multifocal BCC.³¹ The patient had multiple large BCCs on the trunk that were painful and bleeding. The patient was started on RT and 150 mg/d vismodegib concurrently, which was then continued adjuvantly for 3 months until it was discontinued because of diarrhea. The patient had complete response in all lesions with resolution of symptoms.³¹ A separate basic science study further supported the potential role of vismodegib in radiation sensitization of both BCCs and head and neck SCCs.³² There presently are 2 phase 2 trials investigating the concurrent use of vismodegib and RT, which could help determine the efficacy of the combined approach for patients with advanced BCCs who are poor surgical candidates (NCT02956889 and NCT01835626).

Photodynamic Therapy

Photodynamic therapy has been in use since the 1970s when Dougherty et al³⁵ performed one of the first studies on its use in skin cancer. Since then, PDT has been used for the treatment of actinic keratoses (AKs) and more recently BCCs. In PDT, a photosensitizer (PS) is applied and activated by a 400-nm blue light or 635-nm red light, depending on the PS used. The PS then produces highly reactive oxygen species, leading to apoptosis of the cancer cells.³⁶ In Europe, red light PDT is licensed for the treatment of AKs as well as superficial and nodular BCCs, though approved indications vary between countries. In the United States, PDT is only FDA approved for the treatment of AKs.³⁷

 

Aminolevulinic Acid Hydrochloride
Aminolevulinic acid hydrochloride is a red light PS used to treat AKs since 2011 and BCCs since 2017 in Europe in addition to AKs in the United States since 2016.^38,39 A phase 3 noninferiority clinical trial in Europe of 281 patients compared the treatment of nonaggressive BCCs with ALA to methyl aminolevulinate (MAL) cream.⁴⁰ The study found a complete response rate of 93.4% vs 91.8%. Superficial BCCs treated with ALA had a clearance rate of 94.7% vs 96.4% with MAL, while nodular BCCs treated with ALA had a clearance rate of 85.7% vs 76.2% with MAL. A 1-year clinical follow-up showed similar recurrence rates (8.4% for ALA vs 8.5% for MAL).⁴⁰ The results of this study led to an expanded indication in Europe to include the treatment of BCCs.³⁸ Aminolevulinic acid hydrochloride currently is undergoing phase 3 clinical trials in the United States for approval for the treatment of superficial BCCs (NCT03573401). If similar outcomes are achieved, US patients may have access to an alternative nonsurgical treatment of BCCs. The ongoing US trial is exclusively investigating the efficacy and safety for superficial BCCs, which may limit FDA approval to only superficial BCCs, accounting for only 8.4% to 24.1% of all BCCs.^35,41,42

Laser Therapy

Ablative and nonablative lasers have been used to treat NMSCs in the literature. Ablative lasers destroy tumors through vaporization of tissue water, whereas nonablative lasers target the vasculature of tumors while preserving the surrounding tissue.^43,44 Nonablative lasers include pulsed dye lasers (PDL) and Nd:YAG lasers. Examples of ablative lasers include CO₂ and erbium:YAG lasers. Given the status of lasers as an emerging treatment method, there currently is no standardized laser setting for any of the laser therapies used to treat NMSCs. Although there is the potential for optimal cosmetic outcomes and a limited side-effect profile for nonablative laser therapies, there are limited data on long-term follow-up to study recurrence rates and establish a more standardized treatment protocol.

Pulsed Dye Lasers
Although there were no studies on PDL therapy alone in 2018, a study published in 2019 evaluated a combination laser treatment using a 595-nm PDL and 1927-nm fractional laser for the treatment of 93 BCCs, yielding a 95.7% (89/93) clearance rate and 4.5% (4/89) recurrence rate over a follow-up period of up to 6 years (range, 2.53 months to 6.03 years).⁴⁵ Studies of PDL prior to 2018 had follow-ups ranging from 2 weeks to 6 months.^46-51 Although the majority were biopsy-proven BCCs, reflectance confocal microscopy also was used for same-day diagnoses. Long-term follow-up included clinical examinations, dermoscopy, and optical coherence tomography.⁴⁵ The clearance rate (95.7%) using noninvasive imaging in conjunction with the combination laser treatment was superior to both histologic and clinical clearance rates of prior PDL-only studies, which ranged from 25% to 95%.^46-51 To have long-term follow-up data, the study used noninvasive imaging with clinical follow-up because histology would not be viable for long-term follow-up. This study was retrospective rather than prospective, which was a limitation.⁴⁵

Nd:YAG Lasers
The majority of studies utilizing Nd:YAG lasers investigated their efficacy in treating BCCs, with the exception of 1 study of facial SCCs. This major study in 2009 of 627 BCCs showed a 2.5% recurrence rate after a follow-up time of 3 months to 5 years.⁵² Nd:YAG lasers continue to be investigated, including a more recent study of 31 extrafacial, biopsy-proven BCCs that were treated with the 1064-nm Nd:YAG laser, which showed a 90% histologic clearance on 1-month follow-up after a single treatment.⁵³ In 2019, a retrospective review of 16 BCC lesions on the head, neck, trunk, and extremities showed 100% clearance after 1 treatment, with an average follow-up period of 9 months (range, 6–15 months).⁵⁴ In a retrospective review, Markowitz and Psomadakis⁵⁵ contributed data supporting the further investigation and use of the 1064-nm Nd:YAG laser for BCC treatment while leveraging noninvasive imaging to demonstrate a same-day management model. Seventeen BCC lesions on the face and body were diagnosed by reflectance confocal microscopy and treated with an Nd:YAG laser, and clearance was monitored clinically, dermoscopically, and by optical coherence tomography. There was 100% clearance of the lesions in the study, with 82.4% (14/17) clearing after 1 treatment; mean follow-up was 103 days (range, 48–371 days).⁵⁵ These studies were limited by their short follow-up time; long-term data are needed to determine true rates of recurrence.

Ablative Lasers
Ablative lasers also have been used in the treatment of NMSCs. In addition to the potentially increased healing time compared to nonablative lasers, other limitations of ablative laser therapy include residual tumor burden or recurrence that may not be easily visualized in scarred tissue after nonablative management.⁴⁴

Conclusion

Although MMS remains the gold standard for invasive management of NMSCs, studies from 2018 and beyond (eTable) expanded not only on MMS topics such as increased patient access and improved techniques but also on the increasing potential of noninvasive treatments. Some of the noninvasive therapies were entirely new compounds, whereas others were already in use for a different disease indication. Furthering our knowledge and expanding our repertoire of management options will prepare us as the number of patients affected by NMSCs increases.

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and its incidence continues to increase. More than 5 million NMSCs are estimated to occur annually in the United States alone.¹ There are more cases of basal cell carcinoma (BCC) than all other cancers combined, with squamous cell carcinoma (SCC) being the second most common cancer in the United States.^1-3 The rising incidence of NMSCs highlights the importance of investigating additional treatment options with fewer side effects, better cosmetic outcomes, and better efficacy.¹

Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinoma and SCC commonly are treated with cryosurgery; electrodesiccation and curettage; or more definitive surgical options, including excision and Mohs micrographic surgery (MMS). Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors, such as vismodegib, offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects; thus, there is always room for novel therapeutic approaches. We review new and potential treatments from 2018 and beyond. Although only 5% of SCCs become locally advanced, recur, or metastasize, and 0.4% to 0.8% of BCCs progress to advanced disease, many of the newer studies target advanced NMSCs, given their life-threatening and debilitating nature.^4,5 Similarly, the incidence of nevoid basal cell carcinoma (NBCC) syndrome is as low as 1 in 57,000 to 1 in 164,000 but continues to be studied because of its morbidity and the potential to contribute new treatment options for BCC in the general population.⁶

Topical Therapy

Sonidegib
Basal cell carcinoma proliferation is a result of an unregulated Hh pathway that is initiated when the Hh ligand binds to the patched 1 protein (PTCH1).^7-11 Patched 1 protein normally inhibits the smoothened (SMO) transmembrane receptor protein, decreasing the signaling cascade. In BCCs, there is a loss of PTCH1 function, effectively increasing the Hh pathway activity. Sonidegib is an Hh inhibitor that in turn prevents inhibition of PTCH1 in an attempt to reregulate the pathway.^7-11 Although sonidegib is known for its 2015 approval by the US Food and Drug Administration (FDA) as a systemic therapy for locally advanced BCCs,¹² one study investigated a topical formulation on 8 patients with NBCC syndrome.¹³ Patients were treated twice daily with sonidegib cream 0.75% for 4 weeks in a double-blind, randomized, vehicle-controlled study. A total of 27 BCCs were randomized and treated with either vehicle or sonidegib. A biopsy was taken at the end of the study of 1 sonidegib-treated and 1 vehicle-treated BCC lesion per patient. Of the 13 sonidegib-treated BCC lesions, 3 (23.1%) showed complete response, 9 (69.2%) showed partial response, and 1 (7.7%) showed no response vs 13 of 14 (92.8%) lesions that did not respond to the vehicle. Patients tolerated the treatment well without skin irritation or signs of local or systemic side effects.¹³ Topical sonidegib should be further investigated as an adjunct or in different vehicles given the successful regression of BCCs and its minimal side-effect profile.

Systemic Therapy

Cemiplimab
Cemiplimab is a human monoclonal antibody against programmed death receptor 1 (PD-1) that was FDA approved in September 2018 for the treatment of metastatic cutaneous SCC.¹⁴ Programmed death receptor 1 is found on T lymphocytes, B lymphocytes, and macrophages, which normally assist in the immune response to tumor cells. However, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) are found on tumor cells and bind to PD-1. Cemiplimab prevents PD-1 from binding to PD-L1 and PD-L2, allowing an appropriate immune response.^14,15 A phase 1 clinical trial of cemiplimab showed a 50% (13/26) response rate.¹⁶ The phase 2 trial included patients with advanced SCC, but the primary analysis only considered patients with metastatic SCC. Phase 2 results showed a 47.5% (28/59) response rate. Patients received intravenous cemiplimab 3 mg/kg once every 2 weeks for up to 48 weeks in phase 1 and up to 96 weeks in phase 2. Both phases of the trial showed a response to treatment lasting longer than 6 months in more than 50% of patients. The most common adverse events were diarrhea, fatigue, nausea, constipation, and rash.¹⁶

Although immune-mediated adverse reactions are rare, they can occur given cemiplimab’s mechanism of action and may range from severe to fatal. Examples of immune-mediated adverse reactions that occurred during the study included pneumonitis, colitis, hepatitis, adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus, nephritis with renal dysfunction, and immune-mediated dermatologic reactions.¹⁴ It is important to monitor for immune-mediated adverse reactions and address them immediately once detected.

Other PD-1 Inhibitors
Although PD-1 inhibitors have been studied in advanced SCCs, their clinical data are limited for BCCs.¹⁷ Prior to 2018, there was a small number of case reports of patients with BCC with partial to exceptional response to PD-1 inhibitors. Recently, 2 additional case reports were published with contrasting outcomes using 2 different PD-1 inhibitors. An elderly patient with metastatic non–small cell lung cancer was treated with nivolumab after failing chemotherapy. She subsequently developed a BCC on the nose that was resected but recurred 2 months later despite continuing nivolumab.¹⁷ Another case report detailed a patient with a history of BCC on the shoulder excised 5 years prior who presented with recurrence on the sternum and clavicle.¹⁸ One year later the patient was found to have BCC metastases to the lung. After progression of disease despite vismodegib and recurrence of BCC with taladegib, the patient was then placed on pembrolizumab. At 6 weeks and 12 months, computed tomography showed resolution of multiple lung lesions. Sixteen weeks after initiation of pembrolizumab treatment, spinal metastases were found, but the treatment was continued because of the improvement in the lung metastases.¹⁸

Taladegib
Taladegib is a SMO antagonist that has been through a phase 1 trial in patients with advanced cancer, including treatment-naive and previously treated BCCs.¹⁹ Eighty-four patients were treated to examine the safety profile and determine an appropriate phase 2 dose and administration schedule. The maximum tolerable dose was determined to be 400 mg because of dose-limiting toxicities. All clinical responses were in patients with BCCs (47/84 [55.9%] patients), with a response rate of 46.8%. Eleven of 16 (68.8%) Hh-treatment–naive patients and 11 of 31 (35.5%) patients previously treated with Hh responded to taladegib. Common adverse events were dysgeusia, fatigue, nausea, and muscle spasms.¹⁹ Although vismodegib is an FDA-approved SMO antagonist since 2012, treatment resistance and tolerability issues have been continuing concerns.^20,21 Taladegib is a potential alternative that may be found to have improved pharmacodynamics and pharmacokinetics. Not only did in vitro studies show a preferable protein-binding profile with taladegib, but it also displayed dose proportionality, while vismodegib has been known to have nonlinear pharmacokinetics.¹⁹

 

Posaconazole
Posaconazole is a systemic antifungal agent that is a structural analogue to itraconazole.²² Itraconazole has been found to inhibit the Hh pathway as an SMO antagonist. In a study with mice, posaconazole was found to have strong activity against drug-resistant SMO mutants while inhibiting the growth of Hh-dependent BCCs in vivo. A marked decrease also was seen in the ciliary accumulation of SMO, suggesting a similar mechanism of action to itraconazole. Posaconazole’s use for BCCs currently is limited to basic science studies but may offer a potential alternative to itraconazole, which is known to have many drug-drug interactions and requires dose adjustments in renal and hepatic insufficiency. When used as an antifungal compared to itraconazole, posaconazole has a favorable long-term safety profile due to fewer drug-drug interactions and mild side effects; it also does not require dose adjustments in mild to moderate renal or hepatic insufficiency.²² Thus, posaconazole is a potentially safer alternative to itraconazole for the treatment of BCCs. Although phase 2 studies of itraconazole for BCCs have shown decreased cell proliferation, tumor size, and reduced GLI1 messenger RNA, side effects included fatigue and grade 4 heart failure.^23,24

Radiation Therapy

Radiation therapies (RTs), such as superficial RT, have been long-established treatment options.²⁵ However, there also are emerging methods of delivering RT, including electronic brachytherapy (EB). Although there is a low likelihood of residual tumor after RT given the number of sessions involved and the more aggressive nature of the treatment, these factors also can be a substantial burden on the patient. Furthermore, RT may result in subsequent scar tissue, which can hinder the use of other emerging technologies, such as noninvasive imaging devices, following RT.

Superficial RT
Superficial RT is a secondary option for the treatment of NMSC for use in special circumstances, such as when surgical intervention is contraindicated or refused, and after the benefits and risks of treatment alternatives have been discussed.²⁶ However, depending on the tumor type and anatomical location, 6 to 18 treatments may be required, with treatment frequency ranging from 1 to 5 treatments per week.²⁵ Patients may find this treatment regimen difficult to maintain given the length of time and frequency of treatments required. Side effects include radiation dermatitis and postinflammatory hypopigmentation or hyperpigmentation in patients with dark skin, and there is a risk for recurrence.^25,27

Electronic Brachytherapy
Brachytherapy is a method of delivering RT via radioactive isotopes, whereas EB uses lower-energy photons that require less shielding.²⁸ As a relatively new therapy, studies on the efficacy of EB on NMSC continue to grow but with limited data comparing EB with established treatments. Furthermore, there are limited long-term follow-up data, and future studies should expand the patient demographic to younger patients before treatment guidelines can be established.²⁸

RT With Concurrent and Adjuvant Vismodegib
Vismodegib is an SMO inhibitor that was FDA approved in 2012 for the treatment of locally advanced BCC in patients who are not candidates for surgery or RT.²⁹ Over time, studies have looked into other indications for vismodegib, such as a neoadjuvant to MMS or in patients with NBCC syndrome.¹¹ Prior to 2018, there were only 2 known case reports of concurrent vismodegib and RT used for recurrent advanced BCC.³⁰ Recently, vismodegib has been further examined in combination with RT in a case report,³¹ basic science study,³² and phase 2 trials (ClinicalTrials.gov Identifiers NCT02956889 and NCT01835626).

Prior studies showed low cure rates with vismodegib alone after RT (43%) as well as decreasing cure rates with primary RT alone as tumor size increased.^33,34 In 2018, vismodegib was used concurrently and as an adjuvant to RT in a patient with advanced multifocal BCC.³¹ The patient had multiple large BCCs on the trunk that were painful and bleeding. The patient was started on RT and 150 mg/d vismodegib concurrently, which was then continued adjuvantly for 3 months until it was discontinued because of diarrhea. The patient had complete response in all lesions with resolution of symptoms.³¹ A separate basic science study further supported the potential role of vismodegib in radiation sensitization of both BCCs and head and neck SCCs.³² There presently are 2 phase 2 trials investigating the concurrent use of vismodegib and RT, which could help determine the efficacy of the combined approach for patients with advanced BCCs who are poor surgical candidates (NCT02956889 and NCT01835626).

Photodynamic Therapy

Photodynamic therapy has been in use since the 1970s when Dougherty et al³⁵ performed one of the first studies on its use in skin cancer. Since then, PDT has been used for the treatment of actinic keratoses (AKs) and more recently BCCs. In PDT, a photosensitizer (PS) is applied and activated by a 400-nm blue light or 635-nm red light, depending on the PS used. The PS then produces highly reactive oxygen species, leading to apoptosis of the cancer cells.³⁶ In Europe, red light PDT is licensed for the treatment of AKs as well as superficial and nodular BCCs, though approved indications vary between countries. In the United States, PDT is only FDA approved for the treatment of AKs.³⁷

 

Aminolevulinic Acid Hydrochloride
Aminolevulinic acid hydrochloride is a red light PS used to treat AKs since 2011 and BCCs since 2017 in Europe in addition to AKs in the United States since 2016.^38,39 A phase 3 noninferiority clinical trial in Europe of 281 patients compared the treatment of nonaggressive BCCs with ALA to methyl aminolevulinate (MAL) cream.⁴⁰ The study found a complete response rate of 93.4% vs 91.8%. Superficial BCCs treated with ALA had a clearance rate of 94.7% vs 96.4% with MAL, while nodular BCCs treated with ALA had a clearance rate of 85.7% vs 76.2% with MAL. A 1-year clinical follow-up showed similar recurrence rates (8.4% for ALA vs 8.5% for MAL).⁴⁰ The results of this study led to an expanded indication in Europe to include the treatment of BCCs.³⁸ Aminolevulinic acid hydrochloride currently is undergoing phase 3 clinical trials in the United States for approval for the treatment of superficial BCCs (NCT03573401). If similar outcomes are achieved, US patients may have access to an alternative nonsurgical treatment of BCCs. The ongoing US trial is exclusively investigating the efficacy and safety for superficial BCCs, which may limit FDA approval to only superficial BCCs, accounting for only 8.4% to 24.1% of all BCCs.^35,41,42

Laser Therapy

Ablative and nonablative lasers have been used to treat NMSCs in the literature. Ablative lasers destroy tumors through vaporization of tissue water, whereas nonablative lasers target the vasculature of tumors while preserving the surrounding tissue.^43,44 Nonablative lasers include pulsed dye lasers (PDL) and Nd:YAG lasers. Examples of ablative lasers include CO₂ and erbium:YAG lasers. Given the status of lasers as an emerging treatment method, there currently is no standardized laser setting for any of the laser therapies used to treat NMSCs. Although there is the potential for optimal cosmetic outcomes and a limited side-effect profile for nonablative laser therapies, there are limited data on long-term follow-up to study recurrence rates and establish a more standardized treatment protocol.

Pulsed Dye Lasers
Although there were no studies on PDL therapy alone in 2018, a study published in 2019 evaluated a combination laser treatment using a 595-nm PDL and 1927-nm fractional laser for the treatment of 93 BCCs, yielding a 95.7% (89/93) clearance rate and 4.5% (4/89) recurrence rate over a follow-up period of up to 6 years (range, 2.53 months to 6.03 years).⁴⁵ Studies of PDL prior to 2018 had follow-ups ranging from 2 weeks to 6 months.^46-51 Although the majority were biopsy-proven BCCs, reflectance confocal microscopy also was used for same-day diagnoses. Long-term follow-up included clinical examinations, dermoscopy, and optical coherence tomography.⁴⁵ The clearance rate (95.7%) using noninvasive imaging in conjunction with the combination laser treatment was superior to both histologic and clinical clearance rates of prior PDL-only studies, which ranged from 25% to 95%.^46-51 To have long-term follow-up data, the study used noninvasive imaging with clinical follow-up because histology would not be viable for long-term follow-up. This study was retrospective rather than prospective, which was a limitation.⁴⁵

Nd:YAG Lasers
The majority of studies utilizing Nd:YAG lasers investigated their efficacy in treating BCCs, with the exception of 1 study of facial SCCs. This major study in 2009 of 627 BCCs showed a 2.5% recurrence rate after a follow-up time of 3 months to 5 years.⁵² Nd:YAG lasers continue to be investigated, including a more recent study of 31 extrafacial, biopsy-proven BCCs that were treated with the 1064-nm Nd:YAG laser, which showed a 90% histologic clearance on 1-month follow-up after a single treatment.⁵³ In 2019, a retrospective review of 16 BCC lesions on the head, neck, trunk, and extremities showed 100% clearance after 1 treatment, with an average follow-up period of 9 months (range, 6–15 months).⁵⁴ In a retrospective review, Markowitz and Psomadakis⁵⁵ contributed data supporting the further investigation and use of the 1064-nm Nd:YAG laser for BCC treatment while leveraging noninvasive imaging to demonstrate a same-day management model. Seventeen BCC lesions on the face and body were diagnosed by reflectance confocal microscopy and treated with an Nd:YAG laser, and clearance was monitored clinically, dermoscopically, and by optical coherence tomography. There was 100% clearance of the lesions in the study, with 82.4% (14/17) clearing after 1 treatment; mean follow-up was 103 days (range, 48–371 days).⁵⁵ These studies were limited by their short follow-up time; long-term data are needed to determine true rates of recurrence.

Ablative Lasers
Ablative lasers also have been used in the treatment of NMSCs. In addition to the potentially increased healing time compared to nonablative lasers, other limitations of ablative laser therapy include residual tumor burden or recurrence that may not be easily visualized in scarred tissue after nonablative management.⁴⁴

Conclusion

Although MMS remains the gold standard for invasive management of NMSCs, studies from 2018 and beyond (eTable) expanded not only on MMS topics such as increased patient access and improved techniques but also on the increasing potential of noninvasive treatments. Some of the noninvasive therapies were entirely new compounds, whereas others were already in use for a different disease indication. Furthering our knowledge and expanding our repertoire of management options will prepare us as the number of patients affected by NMSCs increases.

Rotator cuff disease accounts for as many as 65% of shoulder-related visits to physicians’ offices,¹ yet the natural course of rotator cuff tears is still not well understood.² Treatment options are controversial because both conservative and surgical management have been successful. Physical therapy is a durable and reliable treatment option, but there are concerns about long-term progression of the tear.³ Surgical arthroscopic techniques, which result in less morbidity than open surgery, have improved overall surgical care; as such, the rate of rotator cuff procedures has increased significantly.⁴

Our goal in this article is to provide clinical guidance to the primary care provider. We review management options for rotator cuff injury; summarize considerations for proceeding with conservative or surgical management; and discuss surgical risks and complications.

Conservative management: Who is most likely to benefit?

The choice of treatment for rotator cuff injury depends on a host of variables, including shoulder dominance, duration of symptoms, type of tear (partial or full), age, demands (activity level, occupation, sport), and comorbidities (diabetes, tobacco use). Treatment goals include resolution of pain, normalized range of motion and strength, and restored arm and shoulder function.⁵

Initial nonoperative management is indicated in patients who

• have a partial-thickness tear (a notable exception is young patients with traumatic injury),⁶
• have lower functional demands and moderate symptoms, or
• refuse surgery.⁷

Patients who respond to nonoperative management will, typically, do so within 6 to 12 weeks.^5,8

Few randomized, controlled trials have compared conservative and surgical management of rotator cuff tears; furthermore, the findings of these studies have been mixed. Nonoperative management has been shown to be the favored initial treatment for isolated, symptomatic, nontraumatic, supraspinatus tears in older patients.⁹ In a recent study,¹⁰ 5-year outcomes were examined in a prospective cohort enrolled in a rotator cuff treatment program: Approximately 75% of patients remained successfully treated with nonoperative management, and clinical outcomes of the operative and nonoperative groups were not significantly different at 5-year follow-up. Investigators concluded that nonoperative treatment is effective for many patients who have a chronic, full-­thickness rotator cuff tear. 

In a study investigating the treatment of degenerative rotator cuff tear, patients were randomly treated using an operative or nonoperative protocol. No differences in functional outcomes were observed at 1 year after treatment; however, surgical treatment significantly improved subjective parameters of pain and disability.¹¹ A similar study suggested statistically significant improvement in outcomes for patients managed operatively, compared with those treated nonoperatively, but differences in shoulder outcome and the visual analog pain score were small and failed to meet thresholds considered clinically significant. Larger studies, with longer follow-up, are required to determine whether clinical differences between these types of treatment become more evident over time.¹²

Continue to: A look at nonoperative options and outcomes

 

 

A look at nonoperative options and outcomes

Surveillance. Rotator cuff disease of the supraspinatus tendon often results from a degenerative process that progresses to partial and, eventually, full-thickness tearing.⁸ Once a tear develops, progression is difficult to predict. Many rotator cuff tears grow larger over time; this progression is commonly associated with new or increased pain and weakness, or both. Although asymptomatic progression of a tear is uncommon, many patients—and physicians—are apprehensive about proceeding with nonoperative treatment for a full-thickness tear.⁸

Simple analgesics are a low-risk firstline option for pain in rotator cuff injury. Avoid opioids, except during the immediate postoperative period.

To diminish such fears, surveillance can include regular assessment of shoulder motion and strength, with consideration of repeat imaging until surgery is performed or the patient is no longer a surgical candidate or interested in surgical treatment.⁷ Patients and providers need to remain vigilant because tears that are initially graded as repairable can become irreparable if the tendon retracts or there is fatty infiltration of the muscle belly. Results of secondary surgical repair following failed prolonged nonoperative treatment tend to be inferior to results seen in patients who undergo primary tendon repair.⁷

Analgesics. Simple analgesics, such as acetaminophen, are a low-risk first-line option for pain relief; however, there are limited data on the efficacy of acetaminophen in rotator cuff disease. A topical or oral nonsteroidal anti-inflammatory drug (NSAID), or both, can be considered, but potential contraindications, such as gastrointestinal, renal, and cardiovascular risks, should be monitored.¹³ Avoid opioids, given the potential for abuse, except during the immediate postoperative period.⁵

Glucocorticoid injection. Injection of a glucocorticoid drug into the subacromial space should be considered in patients whose pain interferes with sleep, limits activities of daily living, or hinders the ability to participate in physical therapy.⁵ A recent systematic review demonstrated that NSAIDs and glucocorticoids brought similar pain relief and active abduction at 4 to 6 weeks, but that glucocorticoids were significantly better at achieving remission of symptoms.¹⁴ There are no data comparing glucocorticoid preparations (ie, different glucocorticoids or anesthetics, dosages, volumes), and ultrasound guidance does not appear to be necessary for short-term pain relief.¹⁵ Note: Repeated injection has been shown to decrease the durability of surgically repaired tendons¹⁶; if a patient is a candidate for surgery, repeat injections should be carefully considered—and avoided if possible.

Physical therapy. The goals of physical therapy are activity modification, stretching the shoulder capsule, and strengthening the surrounding musculature (periscapular, rotator cuff, and deltoid). Patients advance through 3 phases of recovery: shoulder mobility, strengthening, and function (ie, joint reactivation to improve shoulder proprioception and coordination).

Continue to: A recent meta-analysis...

 

A recent meta-analysis¹⁷ found comparative evidence on treating rotator cuff tears with physical therapy to be inconclusive. At 1-year follow-up, there was no clinically significant difference between surgery and active physical therapy in either improving the Constant Shoulder Score (an assessment of function) or reducing pain caused by a rotator cuff tear. Therefore, the authors proposed, given the low risk of harm, a conservative approach should be the initial treatment modality for a tear.

Consider injection of a glucocorticoid drug into the subacromial space in a patient whose pain interferes with sleep, limits activities of daily living, or hinders physical therapy.

A Cochrane review¹⁸ examined 60 eligible trials, in which the mean age of patients was 51 years and the mean duration of symptoms, 11 months. Overall, the review concluded that the effects of manual therapy and exercise might be similar to those of glucocorticoid injection and arthroscopic subacromial decompression. The authors noted that this conclusion is based on low-quality evidence, with only 1 study in the review that compared the combination of manual therapy and exercise to placebo.

Other conservative options. Ultrasound, topical nitroglycerin, topical ­lidocaine, glucocorticoid iontophoresis, transcutaneous electrical nerve stimulation, massage, acupuncture, extracorporeal shockwave therapy, hyaluronic acid, and platelet-rich plasma have been used to treat rotator cuff disease. These modalities require further study, however, to determine their effectiveness for this indication.^7,19

Who is a candidate for surgical management?

Although nonoperative treatment is preferred for rotator cuff tendinitis or tendinosis and partial-thickness tears, appropriate management of full-thickness tears is debatable.²⁰ Some surgeons advocate early operative intervention of repairable full-thickness tears to prevent further progression and reduce the risk of long-term dysfunction.

The decision to pursue operative repair depends on

• patient characteristics (age, activity level, comorbidities),
• patient function (amount of disability caused by the tear),
• characteristics of the tear (length, depth, retraction), and
• chronicity of the tear (acuity).

Continue to: TABLE 1...

 

TABLE 1^21,22 highlights variables that influence the decision to proceed, or not to proceed, with operative intervention. Because enlargement of a tear usually exacerbates symptoms,²³ patients with a tear who are successfully managed nonoperatively should be counseled on the potential of the tear to progress.

What are the surgical options?

Little clinical evidence favors one exposure technique over another. This equivalency has been demonstrated by a systematic review of randomized controlled trials comparing arthroscopic and mini-open rotator cuff repair, which showed no difference in function, pain, or range of motion.²⁴ That conclusion notwithstanding, arthroscopic repair is increasingly popular because it results in less pain, initially, and faster return to work.²⁰

There is controversy among surgeons regarding the choice of fixation technique: Tendons can be secured using 1 or 2 rows of anchors (FIGURE). Advocates of single-row repair cite shorter surgical time, decreased cost, and equivalent outcomes; surgeons who favor double-row, or so-called transosseous-equivalent, repair claim that it provides better restoration of normal anatomy and biomechanical superiority.^25,26

Regardless of technique, most patients are immobilized for 4 to 6 weeks postoperatively.²⁷ Physical therapy usually commences within the first week or 2 postop, limited to passive motion for 6 to 12 weeks. Active motion and strengthening of rotator-cuff muscles often is initiated by 3 months postop, although this phase is sometimes delayed because of concern over slow tendon ­healing. Typically, patients make a full return to sports and manual work at 6 months postop. Patients experience most symptomatic improvement during the first 6 months following surgery, although functional gains can be realized for as long as 2 years after surgery.²⁸

If a patient is going to respond to nonoperative management at all, they typically do so in 6 to 12 weeks.

Most torn rotator cuffs can be fixed back to the greater tuberosity, but some chronic, massive, retracted tears lack the mobility to be repaired, or re-tear shortly after repair. Over time, the humeral head in a rotator cuff–deficient shoulder can migrate superiorly to abut the undersurface of the acromion, which can lead to significant glenohumeral osteoarthritis. To prevent or remedy elevation of the humeral head, salvage procedures—debridement, partial repair, spanning graft, tendon transfer, superior capsule reconstruction, balloon arthroplasty, reverse total shoulder replacement—can be used to alleviate pain and restore function. These procedures have significant limitations, however, and usually provide less favorable outcomes than standard repair.^29-35

Continue to: Surgical outcomes

 

 

Surgical outcomes

Pain, function, and patient satisfaction outcomes following rotator cuff repair are generally favorable: 90% of patients are “happy” 6 months postop.²⁸ Younger populations often have traumatic rotator cuff tears; they generally are interested in returning to sporting activities following their injury. Nearly 85% of younger patients who undergo rotator cuff repair return to sports, and 65.9% return to an equivalent level of play.³⁶

Variables associated with an unfavorable outcome include increasing age, smoking, increased size of the tear, poor tendon quality, hyperlipidemia, workers’ compensation status, fatty infiltration of muscle, obesity, diabetes, and additional procedures to the biceps tendon and acromioclavicular joint performed at the time of rotator cuff repair.^37-39 Interestingly, a study concluded that, if a patient expects a good surgical outcome, they are more likely to go on to report a favorable outcome—suggesting that a patient’s expectations might influence their actual outcome.⁴⁰

Risks and complications

Although rotator cuff surgery has much lower morbidity than other orthopedic surgeries, it is not without risk of complications. If re-tears are excluded, postop complications have been reported in approximately 10% of patients.⁴¹ Common complications and their anticipated rate of occurrence are listed in TABLE 2.^42-49

Re-tear of the surgically repaired tendon is the most common postop complication. Published re-tear rates range from 20% to 96%^42,43 and generally correlate with initial tear size: A small tear is twice as likely to heal as a massive tear.⁵⁰ That large range—a span of 76%—results from using a variety of methods to measure re-tear and might not have clinical meaning. A meta-analysis that examined more than 8000 shoulder surgeries reported an overall re-tear rate of 26.6%; however, both patients whose tendons healed and those who re-tore demonstrated clinical improvement.⁵¹ In a separate study, patients reported improvement in pain, function, range of motion, and satisfaction regardless of the integrity of the tendon; however, significant improvement in strength was seen only in those whose repair had healed.⁵²

Postop stiffness is more common with arthroscopic repair than with open surgery, and with smaller rather than larger tears.⁵³ Patient variables associated with an increased risk of postop adhesive capsulitis include workers’ compensation insurance, age < 50 years, and preoperative calcific tendonitis or adhesive capsulitis.⁵³ Stiffness generally responds to physical therapy and rarely requires surgical lysis of adhesions or capsular release.

Continue to: Significant injury...

 

Significant injury to the deltoid muscle has become increasingly uncommon with the advancement of arthroscopic surgery. In traditional open surgery, detachment of the deltoid (and subsequent repair) is required to improve visualization; however, doing so can lead to atrophy and muscle rupture and dehiscence. Deltoid damage occurs in ≤ 60% of open surgeries but is negligible in arthroscopic and mini-open repairs, which involve splitting deltoid fibers to gain exposure of the underlying rotator cuff.⁵⁴

CORRESPONDENCE
Cayce Onks, DO, MS, ATC, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Family and Community Medicine H154, 500 University Drive, PO Box 850, Hershey, PA 17033-0850; [email protected].

Rotator cuff disease accounts for as many as 65% of shoulder-related visits to physicians’ offices,¹ yet the natural course of rotator cuff tears is still not well understood.² Treatment options are controversial because both conservative and surgical management have been successful. Physical therapy is a durable and reliable treatment option, but there are concerns about long-term progression of the tear.³ Surgical arthroscopic techniques, which result in less morbidity than open surgery, have improved overall surgical care; as such, the rate of rotator cuff procedures has increased significantly.⁴

Our goal in this article is to provide clinical guidance to the primary care provider. We review management options for rotator cuff injury; summarize considerations for proceeding with conservative or surgical management; and discuss surgical risks and complications.

Conservative management: Who is most likely to benefit?

The choice of treatment for rotator cuff injury depends on a host of variables, including shoulder dominance, duration of symptoms, type of tear (partial or full), age, demands (activity level, occupation, sport), and comorbidities (diabetes, tobacco use). Treatment goals include resolution of pain, normalized range of motion and strength, and restored arm and shoulder function.⁵

Initial nonoperative management is indicated in patients who

• have a partial-thickness tear (a notable exception is young patients with traumatic injury),⁶
• have lower functional demands and moderate symptoms, or
• refuse surgery.⁷

Patients who respond to nonoperative management will, typically, do so within 6 to 12 weeks.^5,8

Few randomized, controlled trials have compared conservative and surgical management of rotator cuff tears; furthermore, the findings of these studies have been mixed. Nonoperative management has been shown to be the favored initial treatment for isolated, symptomatic, nontraumatic, supraspinatus tears in older patients.⁹ In a recent study,¹⁰ 5-year outcomes were examined in a prospective cohort enrolled in a rotator cuff treatment program: Approximately 75% of patients remained successfully treated with nonoperative management, and clinical outcomes of the operative and nonoperative groups were not significantly different at 5-year follow-up. Investigators concluded that nonoperative treatment is effective for many patients who have a chronic, full-­thickness rotator cuff tear. 

In a study investigating the treatment of degenerative rotator cuff tear, patients were randomly treated using an operative or nonoperative protocol. No differences in functional outcomes were observed at 1 year after treatment; however, surgical treatment significantly improved subjective parameters of pain and disability.¹¹ A similar study suggested statistically significant improvement in outcomes for patients managed operatively, compared with those treated nonoperatively, but differences in shoulder outcome and the visual analog pain score were small and failed to meet thresholds considered clinically significant. Larger studies, with longer follow-up, are required to determine whether clinical differences between these types of treatment become more evident over time.¹²

Continue to: A look at nonoperative options and outcomes

 

 

A look at nonoperative options and outcomes

Surveillance. Rotator cuff disease of the supraspinatus tendon often results from a degenerative process that progresses to partial and, eventually, full-thickness tearing.⁸ Once a tear develops, progression is difficult to predict. Many rotator cuff tears grow larger over time; this progression is commonly associated with new or increased pain and weakness, or both. Although asymptomatic progression of a tear is uncommon, many patients—and physicians—are apprehensive about proceeding with nonoperative treatment for a full-thickness tear.⁸

Simple analgesics are a low-risk firstline option for pain in rotator cuff injury. Avoid opioids, except during the immediate postoperative period.

To diminish such fears, surveillance can include regular assessment of shoulder motion and strength, with consideration of repeat imaging until surgery is performed or the patient is no longer a surgical candidate or interested in surgical treatment.⁷ Patients and providers need to remain vigilant because tears that are initially graded as repairable can become irreparable if the tendon retracts or there is fatty infiltration of the muscle belly. Results of secondary surgical repair following failed prolonged nonoperative treatment tend to be inferior to results seen in patients who undergo primary tendon repair.⁷

Analgesics. Simple analgesics, such as acetaminophen, are a low-risk first-line option for pain relief; however, there are limited data on the efficacy of acetaminophen in rotator cuff disease. A topical or oral nonsteroidal anti-inflammatory drug (NSAID), or both, can be considered, but potential contraindications, such as gastrointestinal, renal, and cardiovascular risks, should be monitored.¹³ Avoid opioids, given the potential for abuse, except during the immediate postoperative period.⁵

Glucocorticoid injection. Injection of a glucocorticoid drug into the subacromial space should be considered in patients whose pain interferes with sleep, limits activities of daily living, or hinders the ability to participate in physical therapy.⁵ A recent systematic review demonstrated that NSAIDs and glucocorticoids brought similar pain relief and active abduction at 4 to 6 weeks, but that glucocorticoids were significantly better at achieving remission of symptoms.¹⁴ There are no data comparing glucocorticoid preparations (ie, different glucocorticoids or anesthetics, dosages, volumes), and ultrasound guidance does not appear to be necessary for short-term pain relief.¹⁵ Note: Repeated injection has been shown to decrease the durability of surgically repaired tendons¹⁶; if a patient is a candidate for surgery, repeat injections should be carefully considered—and avoided if possible.

Physical therapy. The goals of physical therapy are activity modification, stretching the shoulder capsule, and strengthening the surrounding musculature (periscapular, rotator cuff, and deltoid). Patients advance through 3 phases of recovery: shoulder mobility, strengthening, and function (ie, joint reactivation to improve shoulder proprioception and coordination).

Continue to: A recent meta-analysis...

 

A recent meta-analysis¹⁷ found comparative evidence on treating rotator cuff tears with physical therapy to be inconclusive. At 1-year follow-up, there was no clinically significant difference between surgery and active physical therapy in either improving the Constant Shoulder Score (an assessment of function) or reducing pain caused by a rotator cuff tear. Therefore, the authors proposed, given the low risk of harm, a conservative approach should be the initial treatment modality for a tear.

Consider injection of a glucocorticoid drug into the subacromial space in a patient whose pain interferes with sleep, limits activities of daily living, or hinders physical therapy.

A Cochrane review¹⁸ examined 60 eligible trials, in which the mean age of patients was 51 years and the mean duration of symptoms, 11 months. Overall, the review concluded that the effects of manual therapy and exercise might be similar to those of glucocorticoid injection and arthroscopic subacromial decompression. The authors noted that this conclusion is based on low-quality evidence, with only 1 study in the review that compared the combination of manual therapy and exercise to placebo.

Other conservative options. Ultrasound, topical nitroglycerin, topical ­lidocaine, glucocorticoid iontophoresis, transcutaneous electrical nerve stimulation, massage, acupuncture, extracorporeal shockwave therapy, hyaluronic acid, and platelet-rich plasma have been used to treat rotator cuff disease. These modalities require further study, however, to determine their effectiveness for this indication.^7,19

Who is a candidate for surgical management?

Although nonoperative treatment is preferred for rotator cuff tendinitis or tendinosis and partial-thickness tears, appropriate management of full-thickness tears is debatable.²⁰ Some surgeons advocate early operative intervention of repairable full-thickness tears to prevent further progression and reduce the risk of long-term dysfunction.

The decision to pursue operative repair depends on

• patient characteristics (age, activity level, comorbidities),
• patient function (amount of disability caused by the tear),
• characteristics of the tear (length, depth, retraction), and
• chronicity of the tear (acuity).

Continue to: TABLE 1...

 

TABLE 1^21,22 highlights variables that influence the decision to proceed, or not to proceed, with operative intervention. Because enlargement of a tear usually exacerbates symptoms,²³ patients with a tear who are successfully managed nonoperatively should be counseled on the potential of the tear to progress.

What are the surgical options?

Little clinical evidence favors one exposure technique over another. This equivalency has been demonstrated by a systematic review of randomized controlled trials comparing arthroscopic and mini-open rotator cuff repair, which showed no difference in function, pain, or range of motion.²⁴ That conclusion notwithstanding, arthroscopic repair is increasingly popular because it results in less pain, initially, and faster return to work.²⁰

There is controversy among surgeons regarding the choice of fixation technique: Tendons can be secured using 1 or 2 rows of anchors (FIGURE). Advocates of single-row repair cite shorter surgical time, decreased cost, and equivalent outcomes; surgeons who favor double-row, or so-called transosseous-equivalent, repair claim that it provides better restoration of normal anatomy and biomechanical superiority.^25,26

Regardless of technique, most patients are immobilized for 4 to 6 weeks postoperatively.²⁷ Physical therapy usually commences within the first week or 2 postop, limited to passive motion for 6 to 12 weeks. Active motion and strengthening of rotator-cuff muscles often is initiated by 3 months postop, although this phase is sometimes delayed because of concern over slow tendon ­healing. Typically, patients make a full return to sports and manual work at 6 months postop. Patients experience most symptomatic improvement during the first 6 months following surgery, although functional gains can be realized for as long as 2 years after surgery.²⁸

If a patient is going to respond to nonoperative management at all, they typically do so in 6 to 12 weeks.

Most torn rotator cuffs can be fixed back to the greater tuberosity, but some chronic, massive, retracted tears lack the mobility to be repaired, or re-tear shortly after repair. Over time, the humeral head in a rotator cuff–deficient shoulder can migrate superiorly to abut the undersurface of the acromion, which can lead to significant glenohumeral osteoarthritis. To prevent or remedy elevation of the humeral head, salvage procedures—debridement, partial repair, spanning graft, tendon transfer, superior capsule reconstruction, balloon arthroplasty, reverse total shoulder replacement—can be used to alleviate pain and restore function. These procedures have significant limitations, however, and usually provide less favorable outcomes than standard repair.^29-35

Continue to: Surgical outcomes

 

 

Surgical outcomes

Pain, function, and patient satisfaction outcomes following rotator cuff repair are generally favorable: 90% of patients are “happy” 6 months postop.²⁸ Younger populations often have traumatic rotator cuff tears; they generally are interested in returning to sporting activities following their injury. Nearly 85% of younger patients who undergo rotator cuff repair return to sports, and 65.9% return to an equivalent level of play.³⁶

Variables associated with an unfavorable outcome include increasing age, smoking, increased size of the tear, poor tendon quality, hyperlipidemia, workers’ compensation status, fatty infiltration of muscle, obesity, diabetes, and additional procedures to the biceps tendon and acromioclavicular joint performed at the time of rotator cuff repair.^37-39 Interestingly, a study concluded that, if a patient expects a good surgical outcome, they are more likely to go on to report a favorable outcome—suggesting that a patient’s expectations might influence their actual outcome.⁴⁰

Risks and complications

Although rotator cuff surgery has much lower morbidity than other orthopedic surgeries, it is not without risk of complications. If re-tears are excluded, postop complications have been reported in approximately 10% of patients.⁴¹ Common complications and their anticipated rate of occurrence are listed in TABLE 2.^42-49

Re-tear of the surgically repaired tendon is the most common postop complication. Published re-tear rates range from 20% to 96%^42,43 and generally correlate with initial tear size: A small tear is twice as likely to heal as a massive tear.⁵⁰ That large range—a span of 76%—results from using a variety of methods to measure re-tear and might not have clinical meaning. A meta-analysis that examined more than 8000 shoulder surgeries reported an overall re-tear rate of 26.6%; however, both patients whose tendons healed and those who re-tore demonstrated clinical improvement.⁵¹ In a separate study, patients reported improvement in pain, function, range of motion, and satisfaction regardless of the integrity of the tendon; however, significant improvement in strength was seen only in those whose repair had healed.⁵²

Postop stiffness is more common with arthroscopic repair than with open surgery, and with smaller rather than larger tears.⁵³ Patient variables associated with an increased risk of postop adhesive capsulitis include workers’ compensation insurance, age < 50 years, and preoperative calcific tendonitis or adhesive capsulitis.⁵³ Stiffness generally responds to physical therapy and rarely requires surgical lysis of adhesions or capsular release.

Continue to: Significant injury...

 

Significant injury to the deltoid muscle has become increasingly uncommon with the advancement of arthroscopic surgery. In traditional open surgery, detachment of the deltoid (and subsequent repair) is required to improve visualization; however, doing so can lead to atrophy and muscle rupture and dehiscence. Deltoid damage occurs in ≤ 60% of open surgeries but is negligible in arthroscopic and mini-open repairs, which involve splitting deltoid fibers to gain exposure of the underlying rotator cuff.⁵⁴

CORRESPONDENCE
Cayce Onks, DO, MS, ATC, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Family and Community Medicine H154, 500 University Drive, PO Box 850, Hershey, PA 17033-0850; [email protected].

Rotator cuff disease accounts for as many as 65% of shoulder-related visits to physicians’ offices,¹ yet the natural course of rotator cuff tears is still not well understood.² Treatment options are controversial because both conservative and surgical management have been successful. Physical therapy is a durable and reliable treatment option, but there are concerns about long-term progression of the tear.³ Surgical arthroscopic techniques, which result in less morbidity than open surgery, have improved overall surgical care; as such, the rate of rotator cuff procedures has increased significantly.⁴

Our goal in this article is to provide clinical guidance to the primary care provider. We review management options for rotator cuff injury; summarize considerations for proceeding with conservative or surgical management; and discuss surgical risks and complications.

Conservative management: Who is most likely to benefit?

The choice of treatment for rotator cuff injury depends on a host of variables, including shoulder dominance, duration of symptoms, type of tear (partial or full), age, demands (activity level, occupation, sport), and comorbidities (diabetes, tobacco use). Treatment goals include resolution of pain, normalized range of motion and strength, and restored arm and shoulder function.⁵

Initial nonoperative management is indicated in patients who

• have a partial-thickness tear (a notable exception is young patients with traumatic injury),⁶
• have lower functional demands and moderate symptoms, or
• refuse surgery.⁷

Patients who respond to nonoperative management will, typically, do so within 6 to 12 weeks.^5,8

Few randomized, controlled trials have compared conservative and surgical management of rotator cuff tears; furthermore, the findings of these studies have been mixed. Nonoperative management has been shown to be the favored initial treatment for isolated, symptomatic, nontraumatic, supraspinatus tears in older patients.⁹ In a recent study,¹⁰ 5-year outcomes were examined in a prospective cohort enrolled in a rotator cuff treatment program: Approximately 75% of patients remained successfully treated with nonoperative management, and clinical outcomes of the operative and nonoperative groups were not significantly different at 5-year follow-up. Investigators concluded that nonoperative treatment is effective for many patients who have a chronic, full-­thickness rotator cuff tear. 

In a study investigating the treatment of degenerative rotator cuff tear, patients were randomly treated using an operative or nonoperative protocol. No differences in functional outcomes were observed at 1 year after treatment; however, surgical treatment significantly improved subjective parameters of pain and disability.¹¹ A similar study suggested statistically significant improvement in outcomes for patients managed operatively, compared with those treated nonoperatively, but differences in shoulder outcome and the visual analog pain score were small and failed to meet thresholds considered clinically significant. Larger studies, with longer follow-up, are required to determine whether clinical differences between these types of treatment become more evident over time.¹²

Continue to: A look at nonoperative options and outcomes

 

 

A look at nonoperative options and outcomes

Surveillance. Rotator cuff disease of the supraspinatus tendon often results from a degenerative process that progresses to partial and, eventually, full-thickness tearing.⁸ Once a tear develops, progression is difficult to predict. Many rotator cuff tears grow larger over time; this progression is commonly associated with new or increased pain and weakness, or both. Although asymptomatic progression of a tear is uncommon, many patients—and physicians—are apprehensive about proceeding with nonoperative treatment for a full-thickness tear.⁸

Simple analgesics are a low-risk firstline option for pain in rotator cuff injury. Avoid opioids, except during the immediate postoperative period.

To diminish such fears, surveillance can include regular assessment of shoulder motion and strength, with consideration of repeat imaging until surgery is performed or the patient is no longer a surgical candidate or interested in surgical treatment.⁷ Patients and providers need to remain vigilant because tears that are initially graded as repairable can become irreparable if the tendon retracts or there is fatty infiltration of the muscle belly. Results of secondary surgical repair following failed prolonged nonoperative treatment tend to be inferior to results seen in patients who undergo primary tendon repair.⁷

Analgesics. Simple analgesics, such as acetaminophen, are a low-risk first-line option for pain relief; however, there are limited data on the efficacy of acetaminophen in rotator cuff disease. A topical or oral nonsteroidal anti-inflammatory drug (NSAID), or both, can be considered, but potential contraindications, such as gastrointestinal, renal, and cardiovascular risks, should be monitored.¹³ Avoid opioids, given the potential for abuse, except during the immediate postoperative period.⁵

Glucocorticoid injection. Injection of a glucocorticoid drug into the subacromial space should be considered in patients whose pain interferes with sleep, limits activities of daily living, or hinders the ability to participate in physical therapy.⁵ A recent systematic review demonstrated that NSAIDs and glucocorticoids brought similar pain relief and active abduction at 4 to 6 weeks, but that glucocorticoids were significantly better at achieving remission of symptoms.¹⁴ There are no data comparing glucocorticoid preparations (ie, different glucocorticoids or anesthetics, dosages, volumes), and ultrasound guidance does not appear to be necessary for short-term pain relief.¹⁵ Note: Repeated injection has been shown to decrease the durability of surgically repaired tendons¹⁶; if a patient is a candidate for surgery, repeat injections should be carefully considered—and avoided if possible.

Physical therapy. The goals of physical therapy are activity modification, stretching the shoulder capsule, and strengthening the surrounding musculature (periscapular, rotator cuff, and deltoid). Patients advance through 3 phases of recovery: shoulder mobility, strengthening, and function (ie, joint reactivation to improve shoulder proprioception and coordination).

Continue to: A recent meta-analysis...

 

A recent meta-analysis¹⁷ found comparative evidence on treating rotator cuff tears with physical therapy to be inconclusive. At 1-year follow-up, there was no clinically significant difference between surgery and active physical therapy in either improving the Constant Shoulder Score (an assessment of function) or reducing pain caused by a rotator cuff tear. Therefore, the authors proposed, given the low risk of harm, a conservative approach should be the initial treatment modality for a tear.

Consider injection of a glucocorticoid drug into the subacromial space in a patient whose pain interferes with sleep, limits activities of daily living, or hinders physical therapy.

A Cochrane review¹⁸ examined 60 eligible trials, in which the mean age of patients was 51 years and the mean duration of symptoms, 11 months. Overall, the review concluded that the effects of manual therapy and exercise might be similar to those of glucocorticoid injection and arthroscopic subacromial decompression. The authors noted that this conclusion is based on low-quality evidence, with only 1 study in the review that compared the combination of manual therapy and exercise to placebo.

Other conservative options. Ultrasound, topical nitroglycerin, topical ­lidocaine, glucocorticoid iontophoresis, transcutaneous electrical nerve stimulation, massage, acupuncture, extracorporeal shockwave therapy, hyaluronic acid, and platelet-rich plasma have been used to treat rotator cuff disease. These modalities require further study, however, to determine their effectiveness for this indication.^7,19

Who is a candidate for surgical management?

Although nonoperative treatment is preferred for rotator cuff tendinitis or tendinosis and partial-thickness tears, appropriate management of full-thickness tears is debatable.²⁰ Some surgeons advocate early operative intervention of repairable full-thickness tears to prevent further progression and reduce the risk of long-term dysfunction.

The decision to pursue operative repair depends on

• patient characteristics (age, activity level, comorbidities),
• patient function (amount of disability caused by the tear),
• characteristics of the tear (length, depth, retraction), and
• chronicity of the tear (acuity).

Continue to: TABLE 1...

 

TABLE 1^21,22 highlights variables that influence the decision to proceed, or not to proceed, with operative intervention. Because enlargement of a tear usually exacerbates symptoms,²³ patients with a tear who are successfully managed nonoperatively should be counseled on the potential of the tear to progress.

What are the surgical options?

Little clinical evidence favors one exposure technique over another. This equivalency has been demonstrated by a systematic review of randomized controlled trials comparing arthroscopic and mini-open rotator cuff repair, which showed no difference in function, pain, or range of motion.²⁴ That conclusion notwithstanding, arthroscopic repair is increasingly popular because it results in less pain, initially, and faster return to work.²⁰

There is controversy among surgeons regarding the choice of fixation technique: Tendons can be secured using 1 or 2 rows of anchors (FIGURE). Advocates of single-row repair cite shorter surgical time, decreased cost, and equivalent outcomes; surgeons who favor double-row, or so-called transosseous-equivalent, repair claim that it provides better restoration of normal anatomy and biomechanical superiority.^25,26

Regardless of technique, most patients are immobilized for 4 to 6 weeks postoperatively.²⁷ Physical therapy usually commences within the first week or 2 postop, limited to passive motion for 6 to 12 weeks. Active motion and strengthening of rotator-cuff muscles often is initiated by 3 months postop, although this phase is sometimes delayed because of concern over slow tendon ­healing. Typically, patients make a full return to sports and manual work at 6 months postop. Patients experience most symptomatic improvement during the first 6 months following surgery, although functional gains can be realized for as long as 2 years after surgery.²⁸

If a patient is going to respond to nonoperative management at all, they typically do so in 6 to 12 weeks.

Most torn rotator cuffs can be fixed back to the greater tuberosity, but some chronic, massive, retracted tears lack the mobility to be repaired, or re-tear shortly after repair. Over time, the humeral head in a rotator cuff–deficient shoulder can migrate superiorly to abut the undersurface of the acromion, which can lead to significant glenohumeral osteoarthritis. To prevent or remedy elevation of the humeral head, salvage procedures—debridement, partial repair, spanning graft, tendon transfer, superior capsule reconstruction, balloon arthroplasty, reverse total shoulder replacement—can be used to alleviate pain and restore function. These procedures have significant limitations, however, and usually provide less favorable outcomes than standard repair.^29-35

Continue to: Surgical outcomes

 

 

Surgical outcomes

Pain, function, and patient satisfaction outcomes following rotator cuff repair are generally favorable: 90% of patients are “happy” 6 months postop.²⁸ Younger populations often have traumatic rotator cuff tears; they generally are interested in returning to sporting activities following their injury. Nearly 85% of younger patients who undergo rotator cuff repair return to sports, and 65.9% return to an equivalent level of play.³⁶

Variables associated with an unfavorable outcome include increasing age, smoking, increased size of the tear, poor tendon quality, hyperlipidemia, workers’ compensation status, fatty infiltration of muscle, obesity, diabetes, and additional procedures to the biceps tendon and acromioclavicular joint performed at the time of rotator cuff repair.^37-39 Interestingly, a study concluded that, if a patient expects a good surgical outcome, they are more likely to go on to report a favorable outcome—suggesting that a patient’s expectations might influence their actual outcome.⁴⁰

Risks and complications

Although rotator cuff surgery has much lower morbidity than other orthopedic surgeries, it is not without risk of complications. If re-tears are excluded, postop complications have been reported in approximately 10% of patients.⁴¹ Common complications and their anticipated rate of occurrence are listed in TABLE 2.^42-49

Re-tear of the surgically repaired tendon is the most common postop complication. Published re-tear rates range from 20% to 96%^42,43 and generally correlate with initial tear size: A small tear is twice as likely to heal as a massive tear.⁵⁰ That large range—a span of 76%—results from using a variety of methods to measure re-tear and might not have clinical meaning. A meta-analysis that examined more than 8000 shoulder surgeries reported an overall re-tear rate of 26.6%; however, both patients whose tendons healed and those who re-tore demonstrated clinical improvement.⁵¹ In a separate study, patients reported improvement in pain, function, range of motion, and satisfaction regardless of the integrity of the tendon; however, significant improvement in strength was seen only in those whose repair had healed.⁵²

Postop stiffness is more common with arthroscopic repair than with open surgery, and with smaller rather than larger tears.⁵³ Patient variables associated with an increased risk of postop adhesive capsulitis include workers’ compensation insurance, age < 50 years, and preoperative calcific tendonitis or adhesive capsulitis.⁵³ Stiffness generally responds to physical therapy and rarely requires surgical lysis of adhesions or capsular release.

Continue to: Significant injury...

 

Significant injury to the deltoid muscle has become increasingly uncommon with the advancement of arthroscopic surgery. In traditional open surgery, detachment of the deltoid (and subsequent repair) is required to improve visualization; however, doing so can lead to atrophy and muscle rupture and dehiscence. Deltoid damage occurs in ≤ 60% of open surgeries but is negligible in arthroscopic and mini-open repairs, which involve splitting deltoid fibers to gain exposure of the underlying rotator cuff.⁵⁴

CORRESPONDENCE
Cayce Onks, DO, MS, ATC, Penn State Health Milton S. Hershey Medical Center, Penn State College of Medicine, Family and Community Medicine H154, 500 University Drive, PO Box 850, Hershey, PA 17033-0850; [email protected].

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.

Condylomata acuminata

Condylomata acuminata (CA), or anogenital warts, are the cutaneous manifestation of infection by human papillomavirus (HPV). The virus is transmitted primarily via sexual contact with infected skin or mucosa, although it also may result from nonsexual contact or vertical transmission during vaginal delivery.¹ More than 200 types of HPV have been identified; however, genotypes 6 and 11 are most commonly implicated in the development of CA and are associated with a low risk for oncogenesis. Nevertheless, CA pose a tremendous economic and psychological burden on the health care system and those affected, respectively, representing the most common sexually transmitted viral disease in the United States.²

Clinical presentation

CA present as discrete or clustered smooth, papillomatous, sessile, exophytic papules or plaques, often lacking the thick, horny scale seen in common warts, and they may be broad based or pedunculated.² The anogenital region is affected, including the external genitalia, perineum, perianal area, and adjacent skin such as the mons pubis and inguinal folds. Extension into the urethra or vaginal, cervical, and anal canals is possible, although rarely beyond the dentate line.^2,3 Lesions typically are asymptomatic but may be extensive or disfiguring, often noticed by patients upon self-inspection and leading to significant distress. Symptoms such as pruritus, pain, bleeding, or discharge may develop in traumatized or secondarily infected lesions.^1,3

Diagnosis

Although CA can be diagnosed clinically, biopsy facilitates definitive diagnosis in less clear-cut cases.^1,3 Histologically, CA are characterized by hyperkeratosis, parakeratosis, acanthosis, and papillomatosis, with the presence of koilocytes in the epidermis.²

Treatment

Treatment of CA is challenging, as there are currently no antiviral therapies available to cure the condition. Treatment options include destructive, immunomodulatory, and antiproliferative therapies, either alone or in combination. There is no first-line therapy indicated for CA, and treatment selection is dependent on multiple patient-specific factors, including the size, number, and anatomic location of the lesions, as well as ease of treatment and adverse effects.²

Topical therapies. For external CA, there are several treatments that may be applied by patients themselves, including topical podophyllotoxin, imiquimod, and sinecatechins (TABLE).¹ Podophyllotoxin (brand name Condylox) is an antiproliferative agent available as a 0.15% cream or 0.5% solution.^1,2 It should be applied twice daily for 3 consecutive days per week for up to 4 weeks. Podophyllotoxin is contraindicated in pregnancy and may cause local irritation.²

Imiquimod (brand names Aldara and Zyclara) is an immunomodulatory, available as a 5% and 3.75% cream. For external genital warts, the cream should be applied 3 times per week for up to 16 weeks; for perianal warts it should be applied daily for up to 8 weeks. Adverse effects of imiquimod include local irritation and systemic flu-like symptoms and are prominent with the 3.75% formulation, reducing adherence.^1,2,4

Sinecatechins (brand name Veregen; 10% or 15% ointment) is an active ingredient in green tea and has reported antioxidant, antiviral, and antitumor properties. It is applied 3 times daily for up to 16 weeks.^2,4 Local reactions may occur and, rarely, severe reactions such as vulvovaginitis and pelvic pain, have been reported in women.^2,4

In-office treatment options include cryotherapy, trichloroacetic acid (TCA), intralesional immunotherapy, laser therapy, phototherapy, and surgical options.² Liquid nitrogen is cost-effective, efficacious, and safe for use in pregnancy; it is used in 2 to 3 freeze/thaw cycles per cryotherapy session to induce cellular damage.^1,2 Its disadvantages include adverse effects, such as blistering, ulceration, dyspigmentation, and scarring. In addition, subclinical lesions in adjacent skin are not addressed during treatment.²

TCA is a caustic agent applied in the office once weekly or every 2 to 3 weeks for a maximum of 3 to 4 months, with similar benefits to cryotherapy in terms of ease of application and safety in pregnancy. There is the risk of blistering and ulceration in treated lesions as well as in inadvertently treated adjacent skin.¹

Intralesional immunotherapy with Candida antigen (brand name Candin) is used in 3 sessions 4 to 6 weeks apart and is safe, with minimal adverse effects.²

Laser therapy treatment options include carbon dioxide laser therapy and ND:YAG laser. Their use is limited, however, by availability and cost.^1,2

CA may be removed surgically via shave excision, scissor excision, curettage, and electrosurgery. These procedures can be painful, however, requiring local anesthesia and having a prolonged healing course.^1,2

CA recurrence

CA unfortunately has a high rate of recurrence despite treatment, and patients require extensive counseling. Patients should be screened for other sexually transmitted infections and advised to notify their sexual partners. If followed properly, safe sexual practices, including condom use and limiting sexual partners, may prevent further transmission.¹ The quadrivalent HPV vaccine (effective for the prevention of infection with HPV genotypes 6, 11, 16, and 18 in unexposed individuals) is ineffective in treating patients with pre-existing CA but can protect against the acquisition of other HPV genotypes included in the vaccine.^1,5

Arriving at the diagnosis

Acrochordons are a common skin finding in the groin, but the onset is more gradual and the individual lesions tend to be more pedunculated. Molluscum is also on the differential and can affect the genitalia. Molluscum lesions have a characteristic central dimple or dell, which is absent in CA.

CASE Treatment course

The patient was treated with successive sessions of cryotherapy in combination with a course of topical imiquimod followed by several injections with Candida antigen, with persistence of some lesions as well as recurrence.

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

 

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

 

Artificial intelligence and embryo selection  

Tran D, Cooke S, Illingworth PJ, et al. Deep learning as a predictive tool for fetal heart pregnancy following time-lapse incubation and blastocyst transfer. Hum Reprod. 2019;34:1011-1018. 

 

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

 

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

 

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

 

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

 

Artificial intelligence and embryo selection  

Tran D, Cooke S, Illingworth PJ, et al. Deep learning as a predictive tool for fetal heart pregnancy following time-lapse incubation and blastocyst transfer. Hum Reprod. 2019;34:1011-1018. 

 

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

 

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

 

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

 

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

 

Artificial intelligence and embryo selection  

Tran D, Cooke S, Illingworth PJ, et al. Deep learning as a predictive tool for fetal heart pregnancy following time-lapse incubation and blastocyst transfer. Hum Reprod. 2019;34:1011-1018. 

 

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

 

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

 

In this second in a series of 3 articles discussing medical malpractice and the ObGyn we look at the reasons for malpractice claims and liability, what happens to malpractice claims, and the direction and future of medical malpractice. The first article dealt with 2 sources of major malpractice damages: the “big verdict” and physicians with multiple malpractice paid claims. Next month we look at the place of apology in medicine, in cases in which error, including negligence, may have caused a patient injury.

CASE 1 Long-term brachial plexus injury

Right upper extremity injury occurs in the neonate at delivery with sequela of long-term brachial plexus injury (which is diagnosed around 6 months of age). Physical therapy and orthopedic assessment are rendered. Despite continued treatment, discrepancy in arm lengths (ie, affected side arm is noticeably shorter than opposite side) remains. The child cannot play basketball with his older brother and is the victim of ridicule, the plaintiff’s attorney emphasizes. He is unable to properly pronate or supinate the affected arm.

The defendant ObGyn maintains that there was “no shoulder dystocia [at delivery] and the shoulder did not get obstructed in the pelvis; shoulder was delivered 15 seconds after delivery of the head.” The nursing staff testifies that if shoulder dystocia had been the problem they would have launched upon a series of procedures to address such, in accord with the delivering obstetrician. The defense expert witness testifies that a brachial plexus injury can happen without shoulder dystocia.

A defense verdict is rendered by the Florida jury.¹
 

CASE 2 Shoulder dystocia

During delivery, the obstetrician notes a shoulder dystocia (“turtle sign”). After initial attempts to release the shoulder were unsuccessful, the physician applies traction several times to the head of the child, and the baby is delivered. There is permanent injury to the right brachial plexus. The defendant ObGyn says that traction was necessary to dislodge the shoulder, and that the injury was the result of the forces of labor (not the traction). The expert witness for the plaintiff testifies that the medical standard of care did not permit traction under these circumstances, and that the traction was the likely cause of the injury.

The Virginia jury awards $2.32 million in damages.²

Note: The above vignettes are drawn from actual cases but are only outlines of those cases and are not complete descriptions of the claims in the cases. Because the information comes from informal sources, not formal court records, the facts may be inaccurate and incomplete. They should be viewed as illustrations only.

The trend in malpractice

It has been clear for many years that medical malpractice claims are not randomly or evenly distributed among physicians. Notably, the variation among specialties has, and continues to be, substantial (FIGURE 1).³ Recent data suggest that, although paid claims per “1,000 physician-years” averages 14 paid claims per 1,000 physician years, it ranges from 4 or 5 in 1,000 (psychiatry and pediatrics) to 53 and 49 claims per 1,000 (neurology and plastic surgery, respectively). Obstetrics and gynecology has the fourth highest rate at 42.5 paid claims per 1,000 physician years.⁴ (These data are for the years 1992–2014.)

Continue to: The number of ObGyn paid malpractice claims has decreased over time...

 

The number of ObGyn paid malpractice claims has decreased over time. Although large verdicts and physicians with multiple paid malpractice claims receive a good deal of attention (as we noted in part 1 of our series), in fact, paid medical malpractice claims have trended downward in recent decades.⁵ When the data above are disaggregated by 5-year periods, for example, in obstetrics and gynecology, there has been a consistent reduction in paid malpractice claims from 1992 to 2014. Paid claims went from 58 per 1,000 physician-years in 1992–1996 to 25 per 1,000 in 2009–2014 (FIGURE 2).^4,6 In short, the rate dropped by half over approximately 20 years.⁴

It is reasonable to expect that such a decline in the cost of malpractice insurance premiums would follow. Robert L. Barbieri, MD, who practices in Boston, Massachusetts, in his excellent recent editorial in OBG Management⁶ reported that his professional liability insurance premiums decreased 18% from 2014 to 2019, and his colleague reported a 22% reduction during the same time period.⁶ An American Medical Association report of 7 states or metropolitan areas for 2008 to 2017 found considerable variance. The study looked at the rates and the trend of rates for malpractice insurance in several areas of the United States (FIGURE 3).⁷ For ObGyns, one of these jurisdictions experienced increased rates; in one other, rates stayed the same, and in 5 jurisdictions, the rates went down. The premiums varied across the country, however. In 2017, Los Angeles/Orange had an average rate of $49,804, and in Nassau and Suffolk counties, New York, the rate was $214,999. The median rate was approximately $170,000.⁷

Why have malpractice payouts declined overall?

Have medical errors declined?

It would be wonderful if the reduction in malpractice claims represented a significant decrease in medical errors. Attention to medical errors was driven by the first widely noticed study of medical error deaths. The Institute of Medicine (IOM) study in 2000, put the number of deaths annually at 44,000 to 98,000.⁸ There have been many efforts to reduce such errors, and it is possible that those efforts have indeed reduced errors somewhat.⁴ Barbieri provided a helpful digest of many of the error-reduction suggestions for ObGyn practice (TABLE 1).⁶ But the number of medical errors remains high. More recent studies have suggested that the IOM’s reported number of injuries may have been low.⁹ In 2013, one study suggested that 210,000 deaths annually were “associated with preventable harm” in hospitals. Because of how the data were gathered the authors estimated that the actual number of preventable deaths was closer to 400,000 annually. Serious harm to patients was estimated at 10 to 20 times the IOM rate.⁹

Therefore, a dramatic reduction in preventable medical errors does not appear to explain the reduction in malpractice claims. Some portion of it may be explained by malpractice reforms—see "The medical reform factor" section below.

The collective accountability factor

The way malpractice claims are paid (FIGURE 4),¹⁰ reported, and handled may explain some of the apparent reduction in overall paid claims. Perhaps the advent of “collective accountability,” in which patient care is rendered by teams and responsibility accepted at a team level, can alleviate a significant amount of individual physician medical malpractice claims.¹¹ This “enterprise liability” may shift the burden of medical error from physicians to health care organizations.¹² Collective accountability may, therefore, focus on institutional responsibility rather than individual physician negligence.^11,13 Institutions frequently hire multiple specialists and cover their medical malpractice costs as well as stand to be named in suits.

Continue to: The institutional involvement in malpractice cases also may affect...

 

The institutional involvement in malpractice cases also may affect apparent malpractice rates in another way. The National Practitioner Data Bank, which is the source of information for many malpractice studies, only requires reporting about individual physicians, not institutions.¹⁴ If, therefore, claims are settled on behalf of an institution, without implicating the physician, the number of physician malpractice cases may appear to decline without any real change in malpractice rates.¹⁴ In addition, institutions have taken the lead in informal resolution of injuries that occur in the institution, and these programs may reduce the direct malpractice claims against physicians. (These “disclosure, apology, and offer,” and similar programs, are discussed in the upcoming third part of this series.)

The medical reform factor

As noted, annual rates paid for medical malpractice in our specialty are trending downward. Many commentators look to malpractice reforms as the reason for the drop in malpractice rates.^15-17 Because medical malpractice is essentially a matter of state law, the medical malpractice reform has occurred primarily at the state level.¹⁸ There have been many different reforms tried—limits on expert witnesses, review panels, and a variety of procedural limitations.¹⁹ Perhaps the most effective reform has been caps being placed on noneconomic damages (generally pain and suffering).²⁰ These caps vary by state (FIGURE 5)^21,22 and, of course, affect the “big verdict” cases. (As we saw in the second case scenario above, Virginia is an example of a state with a cap on malpractice awards.) They also have the secondary effect of reducing the number of malpractice cases. They make malpractice cases less attractive to some attorneys because they reduce the opportunity of large contingency fees from large verdicts. (Virtually all medical malpractice cases in the United States are tried on a contingency-fee basis, meaning that the plaintiff does not pay the attorney handling the case but rather the attorney takes a percentage of any recovery—typically in the neighborhood of 35%.) The reform process continues, although, presently, there is less pressure to act on the malpractice crisis.

Medical malpractice cases are emotional and costly

Another reason for the relatively low rate of paid claims is that medical malpractice cases are difficult, emotionally challenging, time consuming, and expensive to pursue.²³ They typically drag on for years, require extensive and expensive expert consultants as well as witnesses, and face stiff defense (compared with many other torts). The settlement of medical malpractice cases, for example, is less likely than other kinds of personal injury cases.

The contingency-fee basis does mean that injured patients do not have to pay attorney fees up front; however, plaintiffs may have to pay substantial costs along the way. The other side of this coin is that lawyers can be reluctant to take malpractice cases in which the damages are likely to be small, or where the legal uncertainty reduces the odds of achieving any damages. Thus, many potential malpractice cases are never filed.

A word of caution

The news of a reduction in malpractice paid claims may not be permanent. The numbers can conceivably be cyclical, and political reforms achieved can be changed. In addition, new technology will likely bring new kinds of malpractice claims. That appears to be the case, for example, with electronic health records (EHRs). One insurer reports that EHR malpractice claims have increased over the last 8 years.²⁴ The most common injury in these claims was death (25%), as well as a magnitude of less serious injuries. EHR-related claims result from system failures, copy-paste inaccuracies, faulty drop-down menu use, and uncorrected “auto-populated” fields. Obstetrics is tied for fifth on the list of 14 specialties with claims related to EHRs, and gynecology is tied for eighth place.²⁴

Continue to: A federal court ruled that a hospital that changed from...

 

A federal court ruled that a hospital that changed from paper records to EHRs for test results had a duty to “‘implement a reasonable procedure during the transition phase’ to ensure the timely delivery of test results” to health care providers.²⁵ We will address this in a future “What’s the Verdict?”.

Rates of harm, malpractice cases, and the disposition of cases

There are many surprises when looking at medical malpractice claims data generally. The first surprise is how few claims are filed relative to the number of error-related injuries. Given the estimate of 210,000 to 400,000 deaths “associated with preventable harm” in hospitals, plus 10 to 20 times that number of serious injuries, it would be reasonable to expect claims of many hundreds of thousands per year. Compare the probability of a malpractice claim from an error-related injury, for example, with the probability of other personal injuries—eg, of traffic deaths associated with preventable harm.

The second key observation is how many of the claims filed are not successful—even when there was evidence in the record of errors associated with the injury. Studies slice the data in different ways but collectively suggest that only a small proportion of malpractice claims filed (a claim is generally regarded as some written demand for compensation for injuries) result in payments, either through settlement or by trial. A 2006 study by Studdert and colleagues determined that 63% of formal malpractice claims filed did involve injuries resulting from errors.²⁶ The study found that in 16% of the claims (not injuries) there was no payment even though there was error. In 10% of the claims there was payment, even in the absence of error.

Overall, in this study, 56% of the claims received some compensation.²⁶ That is higher than a more recent study by Jena and others, which found only 22% of claims resulted in compensation.³

How malpractice claims are decided is also interesting. Jena and colleagues found that only 55% of claims resulted in litigation.²⁷ Presumably, the other 45% may have resulted in the plaintiff dropping the case, or in some form of settlement. Of the claims that were litigated, 54% were dismissed by the court, and another 35% were settled before a trial verdict. The cases that went to trial (about 10%), overwhelmingly (80%) resulted in verdicts for the defense.^3,27 A different study found that only 9% of cases went to trial, and 87% were a defense verdict.²⁸ The high level of defense verdicts may suggest that malpractice defense lawyers, and their client physicians, do a good job of assessing cases they are likely to lose, and settling them before trial.

ObGyns generally have larger numbers of claims and among the largest payment amounts when there is payment. Fewer of their cases are dismissed by the courts, so more go to trial. At trial, however, ObGyns prevail at a remarkably high rate.²⁷ As for the probability of payment of a malpractice claim for ObGyns, one study suggested that there is approximately a 16% annual probability of a claim being filed, but only a 3% annual probability of a payment being made (suggesting about a 20% probability of payment per claim).³

Continue to: The purposes and effects of the medical malpractice system...

 

The purposes and effects of the medical malpractice system

The essential goals of tort law (including medical malpractice) include compensation for those who are injured and deterrence of future injuries (TABLE 2). What are the overall effects to the medical malpractice system? Unfortunately, the answer is that the law delivers disappointing results at best. It has a fairly high error rate. Many people who deserve some compensation for their injuries never seek compensation, and many deserving injured patients fail in efforts to receive compensation. At the same time, a few of the injured receive huge recoveries (even windfalls), and at least a small fraction receive compensation when there was no medical error. In addition to the high error rate, the system is inefficient and very expensive. Both defendants (through their insurance carriers) and plaintiffs spend a lot of money, years of time, and untold emotional pain dealing with these cases. The system also exacts high emotional and personal costs on plaintiffs and defendants.

Malpractice reform has not really addressed these issues—it has generally been focused on ways to reduce the cost of malpractice insurance. The most effective reform in reducing rates—caps—has had the effect of compensating the most seriously injured as though they were more modestly injured, and dissuading attorneys from taking the cases of those less seriously injured.

The medical and legal professions exist to help patients (the public). It does not seem that we have arrived at a system that does that very fairly or efficiently when a patient is injured because of preventable medical error.

Watch for the third and final article in this series next month, as we are going to look at “apology in medicine and a proactive response” to communication regarding a complication.

 

In this second in a series of 3 articles discussing medical malpractice and the ObGyn we look at the reasons for malpractice claims and liability, what happens to malpractice claims, and the direction and future of medical malpractice. The first article dealt with 2 sources of major malpractice damages: the “big verdict” and physicians with multiple malpractice paid claims. Next month we look at the place of apology in medicine, in cases in which error, including negligence, may have caused a patient injury.

CASE 1 Long-term brachial plexus injury

Right upper extremity injury occurs in the neonate at delivery with sequela of long-term brachial plexus injury (which is diagnosed around 6 months of age). Physical therapy and orthopedic assessment are rendered. Despite continued treatment, discrepancy in arm lengths (ie, affected side arm is noticeably shorter than opposite side) remains. The child cannot play basketball with his older brother and is the victim of ridicule, the plaintiff’s attorney emphasizes. He is unable to properly pronate or supinate the affected arm.

The defendant ObGyn maintains that there was “no shoulder dystocia [at delivery] and the shoulder did not get obstructed in the pelvis; shoulder was delivered 15 seconds after delivery of the head.” The nursing staff testifies that if shoulder dystocia had been the problem they would have launched upon a series of procedures to address such, in accord with the delivering obstetrician. The defense expert witness testifies that a brachial plexus injury can happen without shoulder dystocia.

A defense verdict is rendered by the Florida jury.¹
 

CASE 2 Shoulder dystocia

During delivery, the obstetrician notes a shoulder dystocia (“turtle sign”). After initial attempts to release the shoulder were unsuccessful, the physician applies traction several times to the head of the child, and the baby is delivered. There is permanent injury to the right brachial plexus. The defendant ObGyn says that traction was necessary to dislodge the shoulder, and that the injury was the result of the forces of labor (not the traction). The expert witness for the plaintiff testifies that the medical standard of care did not permit traction under these circumstances, and that the traction was the likely cause of the injury.

The Virginia jury awards $2.32 million in damages.²

Note: The above vignettes are drawn from actual cases but are only outlines of those cases and are not complete descriptions of the claims in the cases. Because the information comes from informal sources, not formal court records, the facts may be inaccurate and incomplete. They should be viewed as illustrations only.

The trend in malpractice

It has been clear for many years that medical malpractice claims are not randomly or evenly distributed among physicians. Notably, the variation among specialties has, and continues to be, substantial (FIGURE 1).³ Recent data suggest that, although paid claims per “1,000 physician-years” averages 14 paid claims per 1,000 physician years, it ranges from 4 or 5 in 1,000 (psychiatry and pediatrics) to 53 and 49 claims per 1,000 (neurology and plastic surgery, respectively). Obstetrics and gynecology has the fourth highest rate at 42.5 paid claims per 1,000 physician years.⁴ (These data are for the years 1992–2014.)

Continue to: The number of ObGyn paid malpractice claims has decreased over time...

 

The number of ObGyn paid malpractice claims has decreased over time. Although large verdicts and physicians with multiple paid malpractice claims receive a good deal of attention (as we noted in part 1 of our series), in fact, paid medical malpractice claims have trended downward in recent decades.⁵ When the data above are disaggregated by 5-year periods, for example, in obstetrics and gynecology, there has been a consistent reduction in paid malpractice claims from 1992 to 2014. Paid claims went from 58 per 1,000 physician-years in 1992–1996 to 25 per 1,000 in 2009–2014 (FIGURE 2).^4,6 In short, the rate dropped by half over approximately 20 years.⁴

It is reasonable to expect that such a decline in the cost of malpractice insurance premiums would follow. Robert L. Barbieri, MD, who practices in Boston, Massachusetts, in his excellent recent editorial in OBG Management⁶ reported that his professional liability insurance premiums decreased 18% from 2014 to 2019, and his colleague reported a 22% reduction during the same time period.⁶ An American Medical Association report of 7 states or metropolitan areas for 2008 to 2017 found considerable variance. The study looked at the rates and the trend of rates for malpractice insurance in several areas of the United States (FIGURE 3).⁷ For ObGyns, one of these jurisdictions experienced increased rates; in one other, rates stayed the same, and in 5 jurisdictions, the rates went down. The premiums varied across the country, however. In 2017, Los Angeles/Orange had an average rate of $49,804, and in Nassau and Suffolk counties, New York, the rate was $214,999. The median rate was approximately $170,000.⁷

Why have malpractice payouts declined overall?

Have medical errors declined?

It would be wonderful if the reduction in malpractice claims represented a significant decrease in medical errors. Attention to medical errors was driven by the first widely noticed study of medical error deaths. The Institute of Medicine (IOM) study in 2000, put the number of deaths annually at 44,000 to 98,000.⁸ There have been many efforts to reduce such errors, and it is possible that those efforts have indeed reduced errors somewhat.⁴ Barbieri provided a helpful digest of many of the error-reduction suggestions for ObGyn practice (TABLE 1).⁶ But the number of medical errors remains high. More recent studies have suggested that the IOM’s reported number of injuries may have been low.⁹ In 2013, one study suggested that 210,000 deaths annually were “associated with preventable harm” in hospitals. Because of how the data were gathered the authors estimated that the actual number of preventable deaths was closer to 400,000 annually. Serious harm to patients was estimated at 10 to 20 times the IOM rate.⁹

Therefore, a dramatic reduction in preventable medical errors does not appear to explain the reduction in malpractice claims. Some portion of it may be explained by malpractice reforms—see "The medical reform factor" section below.

The collective accountability factor

The way malpractice claims are paid (FIGURE 4),¹⁰ reported, and handled may explain some of the apparent reduction in overall paid claims. Perhaps the advent of “collective accountability,” in which patient care is rendered by teams and responsibility accepted at a team level, can alleviate a significant amount of individual physician medical malpractice claims.¹¹ This “enterprise liability” may shift the burden of medical error from physicians to health care organizations.¹² Collective accountability may, therefore, focus on institutional responsibility rather than individual physician negligence.^11,13 Institutions frequently hire multiple specialists and cover their medical malpractice costs as well as stand to be named in suits.

Continue to: The institutional involvement in malpractice cases also may affect...

 

The institutional involvement in malpractice cases also may affect apparent malpractice rates in another way. The National Practitioner Data Bank, which is the source of information for many malpractice studies, only requires reporting about individual physicians, not institutions.¹⁴ If, therefore, claims are settled on behalf of an institution, without implicating the physician, the number of physician malpractice cases may appear to decline without any real change in malpractice rates.¹⁴ In addition, institutions have taken the lead in informal resolution of injuries that occur in the institution, and these programs may reduce the direct malpractice claims against physicians. (These “disclosure, apology, and offer,” and similar programs, are discussed in the upcoming third part of this series.)

The medical reform factor

As noted, annual rates paid for medical malpractice in our specialty are trending downward. Many commentators look to malpractice reforms as the reason for the drop in malpractice rates.^15-17 Because medical malpractice is essentially a matter of state law, the medical malpractice reform has occurred primarily at the state level.¹⁸ There have been many different reforms tried—limits on expert witnesses, review panels, and a variety of procedural limitations.¹⁹ Perhaps the most effective reform has been caps being placed on noneconomic damages (generally pain and suffering).²⁰ These caps vary by state (FIGURE 5)^21,22 and, of course, affect the “big verdict” cases. (As we saw in the second case scenario above, Virginia is an example of a state with a cap on malpractice awards.) They also have the secondary effect of reducing the number of malpractice cases. They make malpractice cases less attractive to some attorneys because they reduce the opportunity of large contingency fees from large verdicts. (Virtually all medical malpractice cases in the United States are tried on a contingency-fee basis, meaning that the plaintiff does not pay the attorney handling the case but rather the attorney takes a percentage of any recovery—typically in the neighborhood of 35%.) The reform process continues, although, presently, there is less pressure to act on the malpractice crisis.

Medical malpractice cases are emotional and costly

Another reason for the relatively low rate of paid claims is that medical malpractice cases are difficult, emotionally challenging, time consuming, and expensive to pursue.²³ They typically drag on for years, require extensive and expensive expert consultants as well as witnesses, and face stiff defense (compared with many other torts). The settlement of medical malpractice cases, for example, is less likely than other kinds of personal injury cases.

The contingency-fee basis does mean that injured patients do not have to pay attorney fees up front; however, plaintiffs may have to pay substantial costs along the way. The other side of this coin is that lawyers can be reluctant to take malpractice cases in which the damages are likely to be small, or where the legal uncertainty reduces the odds of achieving any damages. Thus, many potential malpractice cases are never filed.

A word of caution

The news of a reduction in malpractice paid claims may not be permanent. The numbers can conceivably be cyclical, and political reforms achieved can be changed. In addition, new technology will likely bring new kinds of malpractice claims. That appears to be the case, for example, with electronic health records (EHRs). One insurer reports that EHR malpractice claims have increased over the last 8 years.²⁴ The most common injury in these claims was death (25%), as well as a magnitude of less serious injuries. EHR-related claims result from system failures, copy-paste inaccuracies, faulty drop-down menu use, and uncorrected “auto-populated” fields. Obstetrics is tied for fifth on the list of 14 specialties with claims related to EHRs, and gynecology is tied for eighth place.²⁴

Continue to: A federal court ruled that a hospital that changed from...

 

A federal court ruled that a hospital that changed from paper records to EHRs for test results had a duty to “‘implement a reasonable procedure during the transition phase’ to ensure the timely delivery of test results” to health care providers.²⁵ We will address this in a future “What’s the Verdict?”.

Rates of harm, malpractice cases, and the disposition of cases

There are many surprises when looking at medical malpractice claims data generally. The first surprise is how few claims are filed relative to the number of error-related injuries. Given the estimate of 210,000 to 400,000 deaths “associated with preventable harm” in hospitals, plus 10 to 20 times that number of serious injuries, it would be reasonable to expect claims of many hundreds of thousands per year. Compare the probability of a malpractice claim from an error-related injury, for example, with the probability of other personal injuries—eg, of traffic deaths associated with preventable harm.

The second key observation is how many of the claims filed are not successful—even when there was evidence in the record of errors associated with the injury. Studies slice the data in different ways but collectively suggest that only a small proportion of malpractice claims filed (a claim is generally regarded as some written demand for compensation for injuries) result in payments, either through settlement or by trial. A 2006 study by Studdert and colleagues determined that 63% of formal malpractice claims filed did involve injuries resulting from errors.²⁶ The study found that in 16% of the claims (not injuries) there was no payment even though there was error. In 10% of the claims there was payment, even in the absence of error.

Overall, in this study, 56% of the claims received some compensation.²⁶ That is higher than a more recent study by Jena and others, which found only 22% of claims resulted in compensation.³

How malpractice claims are decided is also interesting. Jena and colleagues found that only 55% of claims resulted in litigation.²⁷ Presumably, the other 45% may have resulted in the plaintiff dropping the case, or in some form of settlement. Of the claims that were litigated, 54% were dismissed by the court, and another 35% were settled before a trial verdict. The cases that went to trial (about 10%), overwhelmingly (80%) resulted in verdicts for the defense.^3,27 A different study found that only 9% of cases went to trial, and 87% were a defense verdict.²⁸ The high level of defense verdicts may suggest that malpractice defense lawyers, and their client physicians, do a good job of assessing cases they are likely to lose, and settling them before trial.

ObGyns generally have larger numbers of claims and among the largest payment amounts when there is payment. Fewer of their cases are dismissed by the courts, so more go to trial. At trial, however, ObGyns prevail at a remarkably high rate.²⁷ As for the probability of payment of a malpractice claim for ObGyns, one study suggested that there is approximately a 16% annual probability of a claim being filed, but only a 3% annual probability of a payment being made (suggesting about a 20% probability of payment per claim).³

Continue to: The purposes and effects of the medical malpractice system...

 

The purposes and effects of the medical malpractice system

The essential goals of tort law (including medical malpractice) include compensation for those who are injured and deterrence of future injuries (TABLE 2). What are the overall effects to the medical malpractice system? Unfortunately, the answer is that the law delivers disappointing results at best. It has a fairly high error rate. Many people who deserve some compensation for their injuries never seek compensation, and many deserving injured patients fail in efforts to receive compensation. At the same time, a few of the injured receive huge recoveries (even windfalls), and at least a small fraction receive compensation when there was no medical error. In addition to the high error rate, the system is inefficient and very expensive. Both defendants (through their insurance carriers) and plaintiffs spend a lot of money, years of time, and untold emotional pain dealing with these cases. The system also exacts high emotional and personal costs on plaintiffs and defendants.

Malpractice reform has not really addressed these issues—it has generally been focused on ways to reduce the cost of malpractice insurance. The most effective reform in reducing rates—caps—has had the effect of compensating the most seriously injured as though they were more modestly injured, and dissuading attorneys from taking the cases of those less seriously injured.

The medical and legal professions exist to help patients (the public). It does not seem that we have arrived at a system that does that very fairly or efficiently when a patient is injured because of preventable medical error.

Watch for the third and final article in this series next month, as we are going to look at “apology in medicine and a proactive response” to communication regarding a complication.

 

In this second in a series of 3 articles discussing medical malpractice and the ObGyn we look at the reasons for malpractice claims and liability, what happens to malpractice claims, and the direction and future of medical malpractice. The first article dealt with 2 sources of major malpractice damages: the “big verdict” and physicians with multiple malpractice paid claims. Next month we look at the place of apology in medicine, in cases in which error, including negligence, may have caused a patient injury.

CASE 1 Long-term brachial plexus injury

Right upper extremity injury occurs in the neonate at delivery with sequela of long-term brachial plexus injury (which is diagnosed around 6 months of age). Physical therapy and orthopedic assessment are rendered. Despite continued treatment, discrepancy in arm lengths (ie, affected side arm is noticeably shorter than opposite side) remains. The child cannot play basketball with his older brother and is the victim of ridicule, the plaintiff’s attorney emphasizes. He is unable to properly pronate or supinate the affected arm.

The defendant ObGyn maintains that there was “no shoulder dystocia [at delivery] and the shoulder did not get obstructed in the pelvis; shoulder was delivered 15 seconds after delivery of the head.” The nursing staff testifies that if shoulder dystocia had been the problem they would have launched upon a series of procedures to address such, in accord with the delivering obstetrician. The defense expert witness testifies that a brachial plexus injury can happen without shoulder dystocia.

A defense verdict is rendered by the Florida jury.¹
 

CASE 2 Shoulder dystocia

During delivery, the obstetrician notes a shoulder dystocia (“turtle sign”). After initial attempts to release the shoulder were unsuccessful, the physician applies traction several times to the head of the child, and the baby is delivered. There is permanent injury to the right brachial plexus. The defendant ObGyn says that traction was necessary to dislodge the shoulder, and that the injury was the result of the forces of labor (not the traction). The expert witness for the plaintiff testifies that the medical standard of care did not permit traction under these circumstances, and that the traction was the likely cause of the injury.

The Virginia jury awards $2.32 million in damages.²

Note: The above vignettes are drawn from actual cases but are only outlines of those cases and are not complete descriptions of the claims in the cases. Because the information comes from informal sources, not formal court records, the facts may be inaccurate and incomplete. They should be viewed as illustrations only.

The trend in malpractice

It has been clear for many years that medical malpractice claims are not randomly or evenly distributed among physicians. Notably, the variation among specialties has, and continues to be, substantial (FIGURE 1).³ Recent data suggest that, although paid claims per “1,000 physician-years” averages 14 paid claims per 1,000 physician years, it ranges from 4 or 5 in 1,000 (psychiatry and pediatrics) to 53 and 49 claims per 1,000 (neurology and plastic surgery, respectively). Obstetrics and gynecology has the fourth highest rate at 42.5 paid claims per 1,000 physician years.⁴ (These data are for the years 1992–2014.)

Continue to: The number of ObGyn paid malpractice claims has decreased over time...

 

The number of ObGyn paid malpractice claims has decreased over time. Although large verdicts and physicians with multiple paid malpractice claims receive a good deal of attention (as we noted in part 1 of our series), in fact, paid medical malpractice claims have trended downward in recent decades.⁵ When the data above are disaggregated by 5-year periods, for example, in obstetrics and gynecology, there has been a consistent reduction in paid malpractice claims from 1992 to 2014. Paid claims went from 58 per 1,000 physician-years in 1992–1996 to 25 per 1,000 in 2009–2014 (FIGURE 2).^4,6 In short, the rate dropped by half over approximately 20 years.⁴

It is reasonable to expect that such a decline in the cost of malpractice insurance premiums would follow. Robert L. Barbieri, MD, who practices in Boston, Massachusetts, in his excellent recent editorial in OBG Management⁶ reported that his professional liability insurance premiums decreased 18% from 2014 to 2019, and his colleague reported a 22% reduction during the same time period.⁶ An American Medical Association report of 7 states or metropolitan areas for 2008 to 2017 found considerable variance. The study looked at the rates and the trend of rates for malpractice insurance in several areas of the United States (FIGURE 3).⁷ For ObGyns, one of these jurisdictions experienced increased rates; in one other, rates stayed the same, and in 5 jurisdictions, the rates went down. The premiums varied across the country, however. In 2017, Los Angeles/Orange had an average rate of $49,804, and in Nassau and Suffolk counties, New York, the rate was $214,999. The median rate was approximately $170,000.⁷

Why have malpractice payouts declined overall?

Have medical errors declined?

It would be wonderful if the reduction in malpractice claims represented a significant decrease in medical errors. Attention to medical errors was driven by the first widely noticed study of medical error deaths. The Institute of Medicine (IOM) study in 2000, put the number of deaths annually at 44,000 to 98,000.⁸ There have been many efforts to reduce such errors, and it is possible that those efforts have indeed reduced errors somewhat.⁴ Barbieri provided a helpful digest of many of the error-reduction suggestions for ObGyn practice (TABLE 1).⁶ But the number of medical errors remains high. More recent studies have suggested that the IOM’s reported number of injuries may have been low.⁹ In 2013, one study suggested that 210,000 deaths annually were “associated with preventable harm” in hospitals. Because of how the data were gathered the authors estimated that the actual number of preventable deaths was closer to 400,000 annually. Serious harm to patients was estimated at 10 to 20 times the IOM rate.⁹

Therefore, a dramatic reduction in preventable medical errors does not appear to explain the reduction in malpractice claims. Some portion of it may be explained by malpractice reforms—see "The medical reform factor" section below.

The collective accountability factor

The way malpractice claims are paid (FIGURE 4),¹⁰ reported, and handled may explain some of the apparent reduction in overall paid claims. Perhaps the advent of “collective accountability,” in which patient care is rendered by teams and responsibility accepted at a team level, can alleviate a significant amount of individual physician medical malpractice claims.¹¹ This “enterprise liability” may shift the burden of medical error from physicians to health care organizations.¹² Collective accountability may, therefore, focus on institutional responsibility rather than individual physician negligence.^11,13 Institutions frequently hire multiple specialists and cover their medical malpractice costs as well as stand to be named in suits.

Continue to: The institutional involvement in malpractice cases also may affect...

 

The institutional involvement in malpractice cases also may affect apparent malpractice rates in another way. The National Practitioner Data Bank, which is the source of information for many malpractice studies, only requires reporting about individual physicians, not institutions.¹⁴ If, therefore, claims are settled on behalf of an institution, without implicating the physician, the number of physician malpractice cases may appear to decline without any real change in malpractice rates.¹⁴ In addition, institutions have taken the lead in informal resolution of injuries that occur in the institution, and these programs may reduce the direct malpractice claims against physicians. (These “disclosure, apology, and offer,” and similar programs, are discussed in the upcoming third part of this series.)

The medical reform factor

As noted, annual rates paid for medical malpractice in our specialty are trending downward. Many commentators look to malpractice reforms as the reason for the drop in malpractice rates.^15-17 Because medical malpractice is essentially a matter of state law, the medical malpractice reform has occurred primarily at the state level.¹⁸ There have been many different reforms tried—limits on expert witnesses, review panels, and a variety of procedural limitations.¹⁹ Perhaps the most effective reform has been caps being placed on noneconomic damages (generally pain and suffering).²⁰ These caps vary by state (FIGURE 5)^21,22 and, of course, affect the “big verdict” cases. (As we saw in the second case scenario above, Virginia is an example of a state with a cap on malpractice awards.) They also have the secondary effect of reducing the number of malpractice cases. They make malpractice cases less attractive to some attorneys because they reduce the opportunity of large contingency fees from large verdicts. (Virtually all medical malpractice cases in the United States are tried on a contingency-fee basis, meaning that the plaintiff does not pay the attorney handling the case but rather the attorney takes a percentage of any recovery—typically in the neighborhood of 35%.) The reform process continues, although, presently, there is less pressure to act on the malpractice crisis.

Medical malpractice cases are emotional and costly

Another reason for the relatively low rate of paid claims is that medical malpractice cases are difficult, emotionally challenging, time consuming, and expensive to pursue.²³ They typically drag on for years, require extensive and expensive expert consultants as well as witnesses, and face stiff defense (compared with many other torts). The settlement of medical malpractice cases, for example, is less likely than other kinds of personal injury cases.

The contingency-fee basis does mean that injured patients do not have to pay attorney fees up front; however, plaintiffs may have to pay substantial costs along the way. The other side of this coin is that lawyers can be reluctant to take malpractice cases in which the damages are likely to be small, or where the legal uncertainty reduces the odds of achieving any damages. Thus, many potential malpractice cases are never filed.

A word of caution

The news of a reduction in malpractice paid claims may not be permanent. The numbers can conceivably be cyclical, and political reforms achieved can be changed. In addition, new technology will likely bring new kinds of malpractice claims. That appears to be the case, for example, with electronic health records (EHRs). One insurer reports that EHR malpractice claims have increased over the last 8 years.²⁴ The most common injury in these claims was death (25%), as well as a magnitude of less serious injuries. EHR-related claims result from system failures, copy-paste inaccuracies, faulty drop-down menu use, and uncorrected “auto-populated” fields. Obstetrics is tied for fifth on the list of 14 specialties with claims related to EHRs, and gynecology is tied for eighth place.²⁴

Continue to: A federal court ruled that a hospital that changed from...

 

A federal court ruled that a hospital that changed from paper records to EHRs for test results had a duty to “‘implement a reasonable procedure during the transition phase’ to ensure the timely delivery of test results” to health care providers.²⁵ We will address this in a future “What’s the Verdict?”.

Rates of harm, malpractice cases, and the disposition of cases

There are many surprises when looking at medical malpractice claims data generally. The first surprise is how few claims are filed relative to the number of error-related injuries. Given the estimate of 210,000 to 400,000 deaths “associated with preventable harm” in hospitals, plus 10 to 20 times that number of serious injuries, it would be reasonable to expect claims of many hundreds of thousands per year. Compare the probability of a malpractice claim from an error-related injury, for example, with the probability of other personal injuries—eg, of traffic deaths associated with preventable harm.

The second key observation is how many of the claims filed are not successful—even when there was evidence in the record of errors associated with the injury. Studies slice the data in different ways but collectively suggest that only a small proportion of malpractice claims filed (a claim is generally regarded as some written demand for compensation for injuries) result in payments, either through settlement or by trial. A 2006 study by Studdert and colleagues determined that 63% of formal malpractice claims filed did involve injuries resulting from errors.²⁶ The study found that in 16% of the claims (not injuries) there was no payment even though there was error. In 10% of the claims there was payment, even in the absence of error.

Overall, in this study, 56% of the claims received some compensation.²⁶ That is higher than a more recent study by Jena and others, which found only 22% of claims resulted in compensation.³

How malpractice claims are decided is also interesting. Jena and colleagues found that only 55% of claims resulted in litigation.²⁷ Presumably, the other 45% may have resulted in the plaintiff dropping the case, or in some form of settlement. Of the claims that were litigated, 54% were dismissed by the court, and another 35% were settled before a trial verdict. The cases that went to trial (about 10%), overwhelmingly (80%) resulted in verdicts for the defense.^3,27 A different study found that only 9% of cases went to trial, and 87% were a defense verdict.²⁸ The high level of defense verdicts may suggest that malpractice defense lawyers, and their client physicians, do a good job of assessing cases they are likely to lose, and settling them before trial.

ObGyns generally have larger numbers of claims and among the largest payment amounts when there is payment. Fewer of their cases are dismissed by the courts, so more go to trial. At trial, however, ObGyns prevail at a remarkably high rate.²⁷ As for the probability of payment of a malpractice claim for ObGyns, one study suggested that there is approximately a 16% annual probability of a claim being filed, but only a 3% annual probability of a payment being made (suggesting about a 20% probability of payment per claim).³

Continue to: The purposes and effects of the medical malpractice system...

 

The purposes and effects of the medical malpractice system

The essential goals of tort law (including medical malpractice) include compensation for those who are injured and deterrence of future injuries (TABLE 2). What are the overall effects to the medical malpractice system? Unfortunately, the answer is that the law delivers disappointing results at best. It has a fairly high error rate. Many people who deserve some compensation for their injuries never seek compensation, and many deserving injured patients fail in efforts to receive compensation. At the same time, a few of the injured receive huge recoveries (even windfalls), and at least a small fraction receive compensation when there was no medical error. In addition to the high error rate, the system is inefficient and very expensive. Both defendants (through their insurance carriers) and plaintiffs spend a lot of money, years of time, and untold emotional pain dealing with these cases. The system also exacts high emotional and personal costs on plaintiffs and defendants.

Malpractice reform has not really addressed these issues—it has generally been focused on ways to reduce the cost of malpractice insurance. The most effective reform in reducing rates—caps—has had the effect of compensating the most seriously injured as though they were more modestly injured, and dissuading attorneys from taking the cases of those less seriously injured.

The medical and legal professions exist to help patients (the public). It does not seem that we have arrived at a system that does that very fairly or efficiently when a patient is injured because of preventable medical error.

Watch for the third and final article in this series next month, as we are going to look at “apology in medicine and a proactive response” to communication regarding a complication.