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A trip through the history of gynecologic oncology
The subspecialty of gynecologic oncology was formalized less than 50 years ago with the creation of the Society of Gynecologic Oncology and subspecialty training and board certification. The formation of the Gynecologic Oncology Group (GOG) – and the many clinical trials spearheaded by that group – has further advanced evidence-based treatments, resulting in improved survival outcomes, quality of life, and preventive strategies.
While it is not possible to provide a comprehensive and exhaustive review of all of the advances, we hope to highlight many of the notable advances in this article.Cervical cancer
Cervical cancer is the fourth most common cancer in women worldwide with 528,000 new cases in 2012. The majority of cervical cancer cases are caused by infection with human papillomavirus (HPV). While the standard therapies for cervical cancer have been long established (radical hysterectomy for stage I and radiation therapy for locally advanced disease), one of the most significant advances in the past 50 years was the addition of radiation-sensitizing chemotherapy (cisplatin) administered concurrently with radiation therapy.
In randomized trials in both early and advanced cervical cancer, the risk of death was reduced by 30%-50%. These studies changed the paradigm for the treatment of cervical cancer (N Engl J Med. 1999 Apr 15;340[15]:1137-43; N Engl J Med. 1999 Apr 15;340[15]:1144-53; J Clin Oncol. 2000 Apr;18[8]:1606-13).
Future studies evaluating biologic adjuncts or additional chemotherapy are currently underway or awaiting data maturation.
The American Society of Clinical Oncology (ASCO) highlighted the “Top 5 advances in 50 years of Modern Oncology” in 2014, and second on the list was the approval of the HPV vaccine to prevent cervical cancer. Vaccines have been developed that can protect against types 2, 4 or 9 of HPV. In a 2014 study, depending on vaccination coverage, the relative number of cervical cancer cases avoided was 34% in Africa, 27% for America, 26% for Asia, 21% for Europe, and worldwide was estimated at 27% (Vaccine. 2014 Feb 3;32[6]:733-9).
While the benefit from HPV vaccination has been proven, in the United States, only about a third of eligible girls and women have been vaccinated. Efforts should focus on expanding vaccination penetration to eligible girls, boys, women, and men.
Endometrial cancer
Endometrial cancer is the most common gynecologic malignancy in the United States with an estimated 54,870 cases and 10,170 deaths annually. Notable advances in the management of women with endometrial cancer have arisen because of a better understanding that there are two types of endometrial cancer – type I and type II.
The type I endometrial cancers tend to be associated with lower stage of disease at the time of diagnosis and fewer recurrences, while type II endometrial cancer is associated with worse outcomes.
Tailoring the surgical approaches and adjuvant therapy for women with endometrial cancer has led to improved outcomes. The GOG conducted a large prospective randomized trial of laparotomy versus laparoscopic surgical staging for women with clinical early-stage endometrial cancer (LAP2). Laparoscopy was associated with improved perioperative outcomes and was found to be noninferior to laparotomy with regards to survival outcomes (J Clin Oncol. 2012 Mar 1;30[7]:695-700). Therefore, minimally invasive surgery has become widely accepted for the surgical staging of women with endometrial cancer.
Appropriate surgical staging allows for tailoring of postoperative adjuvant therapy. The current evidence suggests that vaginal brachytherapy should be the adjuvant treatment of choice over whole pelvic radiation in women with early-stage endometrial cancer (Lancet. 2010 Mar 6;375[9717]:816-23). Studies are underway to evaluate the role of both adjuvant radiation and chemotherapy in women with early-stage type II endometrial cancer who are felt to be at high risk for recurrent disease, as well as how to improve on the therapeutic options for women with advanced or recurrent disease.
Ovarian cancer
Epithelial ovarian cancer is the most deadly gynecologic malignancy in the United States with 21,290 cases and 14,180 deaths in 2015. The concept of ovarian tumor debulking was first described by Dr. Joe Meigs in 1934, but did not gain traction until the mid-1970s when Dr. C. Thomas Griffiths published his work (Natl Cancer Inst Monogr. 1975 Oct;42:101-4).
While there are no randomized trials proving that surgical cytoreduction improves overall survival, most retrospective studies support this concept. In 2009, Chi et al. showed improved median survival in women with ovarian cancer based on the increased percentage of women who underwent optimal cytoreduction (Gynecol Oncol. 2009 Jul;114[1]:26-31). This has led to modifications of surgical techniques and surgical goals with an effort to maximally cytoreduce all of the visible disease.
While initial surgical debulking is the goal, there are circumstances when a different approach may be indicated. Vergote et al. conducted a prospective randomized trial of 670 women with advanced ovarian cancer. In this study, neoadjuvant chemotherapy followed by interval debulking was not inferior to primary debulking followed by chemotherapy with regards to progression-free survival and overall survival. However, initial surgery was associated with increased surgical complications and perioperative mortality as compared with interval surgery. Therefore, in women who are not felt to be candidates for optimal cytoreduction, neoadjuvant chemotherapy followed by interval surgery may be an appropriate treatment strategy (N Engl J Med. 2010 Sep 2;363[10]:943-53.).
There have been several notable advances and a series of randomized trials – predominately conducted by the GOG – that have resulted in improved overall survival and progression-free interval in women with ovarian cancer. However, none are as significant as the discovery of paclitaxel and platinum-based chemotherapy (cisplatin and carboplatin).
In 1962, samples of the Pacific Yew’s bark were collected and, 2 years later, the extracts from this bark were found to have cytotoxic activity. There were initial difficulties suspending the drug in solution; however, ultimately a formulation in ethanol, cremophor, and saline was found to be effective. In 1984, the National Cancer Institute began clinical trials of paclitaxel and it was found to be highly effective in ovarian cancer. In 1992, it was approved for the treatment of ovarian cancer.
Cisplatin was approved in 1978. Carboplatin entered clinical trials in 1982 and was approved for women with recurrent ovarian cancer in 1989.
There were a series of trials beginning in the late 1980s that established the role of platinum agents and led us to GOG 111. This trial evaluated cisplatin with either cyclophosphamide or paclitaxel. The paclitaxel combination was superior and in 2003 two trials were published that solidified carboplatin and paclitaxel as the cornerstone in the treatment of women with ovarian cancer (J Clin Oncol. 2003 Sep 1;21[17]:3194-200; J Natl Cancer Inst. 2003 Sep 3;95[17]:1320-9).
What has most recently been debated is the route and schedule for both paclitaxel and the platinum agents. In January 2006, the National Cancer Institute released a Clinical Announcement regarding the role of intraperitoneal (IP) chemotherapy for the treatment of women with optimally debulked ovarian cancer. Of the six trials included in the announcement, four trials showed a benefit for progression-free survival and five studies showed an improvement in overall survival. Armstrong et al (GOG 172) showed a 16-month improvement in overall survival with intravenous (IV) paclitaxel, IP cisplatin, and IP paclitaxel. IP chemotherapy has not been universally embraced by physicians and patients in part because of its toxicity, treatment schedule, and the fact that no IP regimen has been compared with the current standard of IV carboplatin and paclitaxel (N Engl J Med. 2006 Jan 5;354[1]:34-43).
While there have been improvements in 5-year survival over time, most women with advanced ovarian cancer will undergo additional chemotherapy in order to achieve subsequent remissions or maintain stability of disease. Other drugs that have Food and Drug Administration approval in the setting of recurrent ovarian cancer include topotecan, liposomal doxorubicin, gemcitabine, bevacizumab, altretamine, carboplatin, cisplatin, cyclophosphamide, and melphalan. Olaparib was recently approved as monotherapy in women with a germline BRCA-mutation who had received three or more prior lines of chemotherapy.
Minimally invasive surgery
Over the last 30 years, minimally invasive surgery (MIS) in gynecologic oncology, particularly for endometrial cancer, has gone from a niche procedure to the standard of care. The introduction of laparoscopy into gynecologic oncology started in the early 1990s. In a series of 59 women undergoing laparoscopy for endometrial cancer, Childers et al. demonstrated feasibility of the technique and low laparotomy conversion rates (Gynecol Oncol. 1993 Oct;51[1]:33-8.). The GOG trial, LAP2, supported the equivalent oncologic outcomes of MIS versus laparotomy for the treatment of endometrial cancer. While many surgeons and centers offered laparoscopic surgery, there were issues with the learning curve that limited its widespread use.
In 2005, the FDA approval of the robotic platform for gynecologic surgery resulted in at least a doubling of the proportion of endometrial cancer patients treated with MIS (Int J Med Robot. 2009 Dec;5[4]:392-7.). In 2012, the Society of Gynecologic Oncology published a consensus statement regarding robotic-assisted surgery in gynecologic oncology (Gynecol Oncol. 2012 Feb;124[2]:180-4.). This review highlights the advantages of the robotics platform with regards to expanding MIS to women with cervical and ovarian cancer; the improvements in outcomes in the obese woman with endometrial cancer; and that the learning curve for robotic surgery is shorter than for traditional laparoscopy. Issues requiring further research include cost analysis as the cost of the new technology decreases, and opportunities for improvement in patient and physician quality of life.
Sentinel node mapping
The rationale for sentinel node mapping is that if one or more sentinel lymph nodes is/are negative for malignancy, then the other regional lymph nodes will also be negative. This would thereby avoid the need for a complete lymph node dissection and its resultant complications, including chronic lymphedema. Much of the work pioneering this strategy has been in breast cancer and melanoma, but data are rapidly emerging for these techniques in gynecologic malignancies.
Candidates for sentinel lymph node biopsy for vulvar cancer include those with a lesion more than 1mm in depth, a tumor less than 4 cm in size, and no obvious metastatic disease on exam or preoperative imaging. Additionally, recommendations have been made regarding case volume in order to achieve limited numbers of false-negative results and to maintain competency. In the study by Van der Zee et al. of 403 patients (623 groins) who underwent sentinel node procedures, the false-negative rate was 0-2%. The overall survival rate was 97% at 3 years (J Clin Oncol. 2008 Feb 20;26[6]:884-9). However, a more recent data from the Gynecologic Oncology Group (GOG 173) showed a slightly higher false-negative rate of 8% (J Clin Oncol. 2012 Nov 1;30[31]:3786-91). Overall survival data are pending from this study.
While sentinel lymph node mapping for endometrial cancer has been feasible for many years and has been well described, the questioned role of completed lymphadenectomy for early-stage endometrial cancer has led to a resurgence of interest in these techniques. While blue dye and radiolabeled tracer methods have historically been the most popular mapping solutions, the advent of endoscopic near-infrared imaging, with its higher sensitivity and good depth penetration, has added options. Indocyanine green fluorescence can be easily detected during robotic surgery and as experience with these techniques increase, successful mapping and sensitivity will increase.
Genetics
While hereditary cancer syndromes have been recognized for many years, detecting the genetic mutations that may increase an individual’s risk of developing a malignancy were not elucidated until the early 1990s. In gynecologic oncology, the most commonly encountered syndromes involve mutations in BRCA1 and BRCA2 and hereditary non–polyposis colorectal cancer, which causes mutations in DNA mismatch-repair genes and increase the risk of endometrial and ovarian cancer.
The SGO recently published a statement on risk assessment for inherited gynecologic cancer predispositions. In this statement “the evaluation for the presence of a hereditary cancer syndrome enables physicians to provide individualized and quantified assessment of cancer risk, as well as options for tailored screening and preventions strategies that may reduce morbidity associated with the development of malignancy” (Gynecol Oncol. 2015 Jan;136[1]:3-7). Beyond risk-reducing salpingo-oophorectomy, therapeutic strategies targeting patients with germline mutations have been developed (PARP inhibitors in BRCA-mutated women with ovarian cancer).
In August 2015, ASCO released an updated policy statement on genetic and genomic testing for cancer susceptibility and highlighted five key areas: germ-line implications of somatic mutation profiling; multigene panel testing for cancer susceptibility; quality assurance in genetic testing; education for oncology professionals; and access to cancer genetic services.
Antiemetics
Rounding out ASCO’s “Top 5 advances in 50 years of Modern Oncology” was the improvement in patients’ quality of life from supportive therapies, in particular antinausea medications.
Several of the agents commonly used in gynecologic oncology rate high (cisplatin) to moderate (carboplatin, cyclophosphamide, doxorubicin, ifosfamide) with regards to emetogenicity. The advent of 5-HT3 receptor antagonists (for example, ondansetron) has significantly improved the quality of life of patients undergoing cytotoxic chemotherapy. In addition to improving quality of life, the decrease in nausea and vomiting can also decrease life-threatening complications such as dehydration and electrolyte imbalance. Both ASCO and the National Comprehensive Cancer Network both have guidelines for the management of nausea and vomiting in patients undergoing chemotherapy.
Throughout 2016, Ob.Gyn. News will celebrate its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit. Look for these articles and more special features in the pages of Ob.Gyn. News and online at obgynnews.com.
Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.
The subspecialty of gynecologic oncology was formalized less than 50 years ago with the creation of the Society of Gynecologic Oncology and subspecialty training and board certification. The formation of the Gynecologic Oncology Group (GOG) – and the many clinical trials spearheaded by that group – has further advanced evidence-based treatments, resulting in improved survival outcomes, quality of life, and preventive strategies.
While it is not possible to provide a comprehensive and exhaustive review of all of the advances, we hope to highlight many of the notable advances in this article.Cervical cancer
Cervical cancer is the fourth most common cancer in women worldwide with 528,000 new cases in 2012. The majority of cervical cancer cases are caused by infection with human papillomavirus (HPV). While the standard therapies for cervical cancer have been long established (radical hysterectomy for stage I and radiation therapy for locally advanced disease), one of the most significant advances in the past 50 years was the addition of radiation-sensitizing chemotherapy (cisplatin) administered concurrently with radiation therapy.
In randomized trials in both early and advanced cervical cancer, the risk of death was reduced by 30%-50%. These studies changed the paradigm for the treatment of cervical cancer (N Engl J Med. 1999 Apr 15;340[15]:1137-43; N Engl J Med. 1999 Apr 15;340[15]:1144-53; J Clin Oncol. 2000 Apr;18[8]:1606-13).
Future studies evaluating biologic adjuncts or additional chemotherapy are currently underway or awaiting data maturation.
The American Society of Clinical Oncology (ASCO) highlighted the “Top 5 advances in 50 years of Modern Oncology” in 2014, and second on the list was the approval of the HPV vaccine to prevent cervical cancer. Vaccines have been developed that can protect against types 2, 4 or 9 of HPV. In a 2014 study, depending on vaccination coverage, the relative number of cervical cancer cases avoided was 34% in Africa, 27% for America, 26% for Asia, 21% for Europe, and worldwide was estimated at 27% (Vaccine. 2014 Feb 3;32[6]:733-9).
While the benefit from HPV vaccination has been proven, in the United States, only about a third of eligible girls and women have been vaccinated. Efforts should focus on expanding vaccination penetration to eligible girls, boys, women, and men.
Endometrial cancer
Endometrial cancer is the most common gynecologic malignancy in the United States with an estimated 54,870 cases and 10,170 deaths annually. Notable advances in the management of women with endometrial cancer have arisen because of a better understanding that there are two types of endometrial cancer – type I and type II.
The type I endometrial cancers tend to be associated with lower stage of disease at the time of diagnosis and fewer recurrences, while type II endometrial cancer is associated with worse outcomes.
Tailoring the surgical approaches and adjuvant therapy for women with endometrial cancer has led to improved outcomes. The GOG conducted a large prospective randomized trial of laparotomy versus laparoscopic surgical staging for women with clinical early-stage endometrial cancer (LAP2). Laparoscopy was associated with improved perioperative outcomes and was found to be noninferior to laparotomy with regards to survival outcomes (J Clin Oncol. 2012 Mar 1;30[7]:695-700). Therefore, minimally invasive surgery has become widely accepted for the surgical staging of women with endometrial cancer.
Appropriate surgical staging allows for tailoring of postoperative adjuvant therapy. The current evidence suggests that vaginal brachytherapy should be the adjuvant treatment of choice over whole pelvic radiation in women with early-stage endometrial cancer (Lancet. 2010 Mar 6;375[9717]:816-23). Studies are underway to evaluate the role of both adjuvant radiation and chemotherapy in women with early-stage type II endometrial cancer who are felt to be at high risk for recurrent disease, as well as how to improve on the therapeutic options for women with advanced or recurrent disease.
Ovarian cancer
Epithelial ovarian cancer is the most deadly gynecologic malignancy in the United States with 21,290 cases and 14,180 deaths in 2015. The concept of ovarian tumor debulking was first described by Dr. Joe Meigs in 1934, but did not gain traction until the mid-1970s when Dr. C. Thomas Griffiths published his work (Natl Cancer Inst Monogr. 1975 Oct;42:101-4).
While there are no randomized trials proving that surgical cytoreduction improves overall survival, most retrospective studies support this concept. In 2009, Chi et al. showed improved median survival in women with ovarian cancer based on the increased percentage of women who underwent optimal cytoreduction (Gynecol Oncol. 2009 Jul;114[1]:26-31). This has led to modifications of surgical techniques and surgical goals with an effort to maximally cytoreduce all of the visible disease.
While initial surgical debulking is the goal, there are circumstances when a different approach may be indicated. Vergote et al. conducted a prospective randomized trial of 670 women with advanced ovarian cancer. In this study, neoadjuvant chemotherapy followed by interval debulking was not inferior to primary debulking followed by chemotherapy with regards to progression-free survival and overall survival. However, initial surgery was associated with increased surgical complications and perioperative mortality as compared with interval surgery. Therefore, in women who are not felt to be candidates for optimal cytoreduction, neoadjuvant chemotherapy followed by interval surgery may be an appropriate treatment strategy (N Engl J Med. 2010 Sep 2;363[10]:943-53.).
There have been several notable advances and a series of randomized trials – predominately conducted by the GOG – that have resulted in improved overall survival and progression-free interval in women with ovarian cancer. However, none are as significant as the discovery of paclitaxel and platinum-based chemotherapy (cisplatin and carboplatin).
In 1962, samples of the Pacific Yew’s bark were collected and, 2 years later, the extracts from this bark were found to have cytotoxic activity. There were initial difficulties suspending the drug in solution; however, ultimately a formulation in ethanol, cremophor, and saline was found to be effective. In 1984, the National Cancer Institute began clinical trials of paclitaxel and it was found to be highly effective in ovarian cancer. In 1992, it was approved for the treatment of ovarian cancer.
Cisplatin was approved in 1978. Carboplatin entered clinical trials in 1982 and was approved for women with recurrent ovarian cancer in 1989.
There were a series of trials beginning in the late 1980s that established the role of platinum agents and led us to GOG 111. This trial evaluated cisplatin with either cyclophosphamide or paclitaxel. The paclitaxel combination was superior and in 2003 two trials were published that solidified carboplatin and paclitaxel as the cornerstone in the treatment of women with ovarian cancer (J Clin Oncol. 2003 Sep 1;21[17]:3194-200; J Natl Cancer Inst. 2003 Sep 3;95[17]:1320-9).
What has most recently been debated is the route and schedule for both paclitaxel and the platinum agents. In January 2006, the National Cancer Institute released a Clinical Announcement regarding the role of intraperitoneal (IP) chemotherapy for the treatment of women with optimally debulked ovarian cancer. Of the six trials included in the announcement, four trials showed a benefit for progression-free survival and five studies showed an improvement in overall survival. Armstrong et al (GOG 172) showed a 16-month improvement in overall survival with intravenous (IV) paclitaxel, IP cisplatin, and IP paclitaxel. IP chemotherapy has not been universally embraced by physicians and patients in part because of its toxicity, treatment schedule, and the fact that no IP regimen has been compared with the current standard of IV carboplatin and paclitaxel (N Engl J Med. 2006 Jan 5;354[1]:34-43).
While there have been improvements in 5-year survival over time, most women with advanced ovarian cancer will undergo additional chemotherapy in order to achieve subsequent remissions or maintain stability of disease. Other drugs that have Food and Drug Administration approval in the setting of recurrent ovarian cancer include topotecan, liposomal doxorubicin, gemcitabine, bevacizumab, altretamine, carboplatin, cisplatin, cyclophosphamide, and melphalan. Olaparib was recently approved as monotherapy in women with a germline BRCA-mutation who had received three or more prior lines of chemotherapy.
Minimally invasive surgery
Over the last 30 years, minimally invasive surgery (MIS) in gynecologic oncology, particularly for endometrial cancer, has gone from a niche procedure to the standard of care. The introduction of laparoscopy into gynecologic oncology started in the early 1990s. In a series of 59 women undergoing laparoscopy for endometrial cancer, Childers et al. demonstrated feasibility of the technique and low laparotomy conversion rates (Gynecol Oncol. 1993 Oct;51[1]:33-8.). The GOG trial, LAP2, supported the equivalent oncologic outcomes of MIS versus laparotomy for the treatment of endometrial cancer. While many surgeons and centers offered laparoscopic surgery, there were issues with the learning curve that limited its widespread use.
In 2005, the FDA approval of the robotic platform for gynecologic surgery resulted in at least a doubling of the proportion of endometrial cancer patients treated with MIS (Int J Med Robot. 2009 Dec;5[4]:392-7.). In 2012, the Society of Gynecologic Oncology published a consensus statement regarding robotic-assisted surgery in gynecologic oncology (Gynecol Oncol. 2012 Feb;124[2]:180-4.). This review highlights the advantages of the robotics platform with regards to expanding MIS to women with cervical and ovarian cancer; the improvements in outcomes in the obese woman with endometrial cancer; and that the learning curve for robotic surgery is shorter than for traditional laparoscopy. Issues requiring further research include cost analysis as the cost of the new technology decreases, and opportunities for improvement in patient and physician quality of life.
Sentinel node mapping
The rationale for sentinel node mapping is that if one or more sentinel lymph nodes is/are negative for malignancy, then the other regional lymph nodes will also be negative. This would thereby avoid the need for a complete lymph node dissection and its resultant complications, including chronic lymphedema. Much of the work pioneering this strategy has been in breast cancer and melanoma, but data are rapidly emerging for these techniques in gynecologic malignancies.
Candidates for sentinel lymph node biopsy for vulvar cancer include those with a lesion more than 1mm in depth, a tumor less than 4 cm in size, and no obvious metastatic disease on exam or preoperative imaging. Additionally, recommendations have been made regarding case volume in order to achieve limited numbers of false-negative results and to maintain competency. In the study by Van der Zee et al. of 403 patients (623 groins) who underwent sentinel node procedures, the false-negative rate was 0-2%. The overall survival rate was 97% at 3 years (J Clin Oncol. 2008 Feb 20;26[6]:884-9). However, a more recent data from the Gynecologic Oncology Group (GOG 173) showed a slightly higher false-negative rate of 8% (J Clin Oncol. 2012 Nov 1;30[31]:3786-91). Overall survival data are pending from this study.
While sentinel lymph node mapping for endometrial cancer has been feasible for many years and has been well described, the questioned role of completed lymphadenectomy for early-stage endometrial cancer has led to a resurgence of interest in these techniques. While blue dye and radiolabeled tracer methods have historically been the most popular mapping solutions, the advent of endoscopic near-infrared imaging, with its higher sensitivity and good depth penetration, has added options. Indocyanine green fluorescence can be easily detected during robotic surgery and as experience with these techniques increase, successful mapping and sensitivity will increase.
Genetics
While hereditary cancer syndromes have been recognized for many years, detecting the genetic mutations that may increase an individual’s risk of developing a malignancy were not elucidated until the early 1990s. In gynecologic oncology, the most commonly encountered syndromes involve mutations in BRCA1 and BRCA2 and hereditary non–polyposis colorectal cancer, which causes mutations in DNA mismatch-repair genes and increase the risk of endometrial and ovarian cancer.
The SGO recently published a statement on risk assessment for inherited gynecologic cancer predispositions. In this statement “the evaluation for the presence of a hereditary cancer syndrome enables physicians to provide individualized and quantified assessment of cancer risk, as well as options for tailored screening and preventions strategies that may reduce morbidity associated with the development of malignancy” (Gynecol Oncol. 2015 Jan;136[1]:3-7). Beyond risk-reducing salpingo-oophorectomy, therapeutic strategies targeting patients with germline mutations have been developed (PARP inhibitors in BRCA-mutated women with ovarian cancer).
In August 2015, ASCO released an updated policy statement on genetic and genomic testing for cancer susceptibility and highlighted five key areas: germ-line implications of somatic mutation profiling; multigene panel testing for cancer susceptibility; quality assurance in genetic testing; education for oncology professionals; and access to cancer genetic services.
Antiemetics
Rounding out ASCO’s “Top 5 advances in 50 years of Modern Oncology” was the improvement in patients’ quality of life from supportive therapies, in particular antinausea medications.
Several of the agents commonly used in gynecologic oncology rate high (cisplatin) to moderate (carboplatin, cyclophosphamide, doxorubicin, ifosfamide) with regards to emetogenicity. The advent of 5-HT3 receptor antagonists (for example, ondansetron) has significantly improved the quality of life of patients undergoing cytotoxic chemotherapy. In addition to improving quality of life, the decrease in nausea and vomiting can also decrease life-threatening complications such as dehydration and electrolyte imbalance. Both ASCO and the National Comprehensive Cancer Network both have guidelines for the management of nausea and vomiting in patients undergoing chemotherapy.
Throughout 2016, Ob.Gyn. News will celebrate its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit. Look for these articles and more special features in the pages of Ob.Gyn. News and online at obgynnews.com.
Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.
The subspecialty of gynecologic oncology was formalized less than 50 years ago with the creation of the Society of Gynecologic Oncology and subspecialty training and board certification. The formation of the Gynecologic Oncology Group (GOG) – and the many clinical trials spearheaded by that group – has further advanced evidence-based treatments, resulting in improved survival outcomes, quality of life, and preventive strategies.
While it is not possible to provide a comprehensive and exhaustive review of all of the advances, we hope to highlight many of the notable advances in this article.Cervical cancer
Cervical cancer is the fourth most common cancer in women worldwide with 528,000 new cases in 2012. The majority of cervical cancer cases are caused by infection with human papillomavirus (HPV). While the standard therapies for cervical cancer have been long established (radical hysterectomy for stage I and radiation therapy for locally advanced disease), one of the most significant advances in the past 50 years was the addition of radiation-sensitizing chemotherapy (cisplatin) administered concurrently with radiation therapy.
In randomized trials in both early and advanced cervical cancer, the risk of death was reduced by 30%-50%. These studies changed the paradigm for the treatment of cervical cancer (N Engl J Med. 1999 Apr 15;340[15]:1137-43; N Engl J Med. 1999 Apr 15;340[15]:1144-53; J Clin Oncol. 2000 Apr;18[8]:1606-13).
Future studies evaluating biologic adjuncts or additional chemotherapy are currently underway or awaiting data maturation.
The American Society of Clinical Oncology (ASCO) highlighted the “Top 5 advances in 50 years of Modern Oncology” in 2014, and second on the list was the approval of the HPV vaccine to prevent cervical cancer. Vaccines have been developed that can protect against types 2, 4 or 9 of HPV. In a 2014 study, depending on vaccination coverage, the relative number of cervical cancer cases avoided was 34% in Africa, 27% for America, 26% for Asia, 21% for Europe, and worldwide was estimated at 27% (Vaccine. 2014 Feb 3;32[6]:733-9).
While the benefit from HPV vaccination has been proven, in the United States, only about a third of eligible girls and women have been vaccinated. Efforts should focus on expanding vaccination penetration to eligible girls, boys, women, and men.
Endometrial cancer
Endometrial cancer is the most common gynecologic malignancy in the United States with an estimated 54,870 cases and 10,170 deaths annually. Notable advances in the management of women with endometrial cancer have arisen because of a better understanding that there are two types of endometrial cancer – type I and type II.
The type I endometrial cancers tend to be associated with lower stage of disease at the time of diagnosis and fewer recurrences, while type II endometrial cancer is associated with worse outcomes.
Tailoring the surgical approaches and adjuvant therapy for women with endometrial cancer has led to improved outcomes. The GOG conducted a large prospective randomized trial of laparotomy versus laparoscopic surgical staging for women with clinical early-stage endometrial cancer (LAP2). Laparoscopy was associated with improved perioperative outcomes and was found to be noninferior to laparotomy with regards to survival outcomes (J Clin Oncol. 2012 Mar 1;30[7]:695-700). Therefore, minimally invasive surgery has become widely accepted for the surgical staging of women with endometrial cancer.
Appropriate surgical staging allows for tailoring of postoperative adjuvant therapy. The current evidence suggests that vaginal brachytherapy should be the adjuvant treatment of choice over whole pelvic radiation in women with early-stage endometrial cancer (Lancet. 2010 Mar 6;375[9717]:816-23). Studies are underway to evaluate the role of both adjuvant radiation and chemotherapy in women with early-stage type II endometrial cancer who are felt to be at high risk for recurrent disease, as well as how to improve on the therapeutic options for women with advanced or recurrent disease.
Ovarian cancer
Epithelial ovarian cancer is the most deadly gynecologic malignancy in the United States with 21,290 cases and 14,180 deaths in 2015. The concept of ovarian tumor debulking was first described by Dr. Joe Meigs in 1934, but did not gain traction until the mid-1970s when Dr. C. Thomas Griffiths published his work (Natl Cancer Inst Monogr. 1975 Oct;42:101-4).
While there are no randomized trials proving that surgical cytoreduction improves overall survival, most retrospective studies support this concept. In 2009, Chi et al. showed improved median survival in women with ovarian cancer based on the increased percentage of women who underwent optimal cytoreduction (Gynecol Oncol. 2009 Jul;114[1]:26-31). This has led to modifications of surgical techniques and surgical goals with an effort to maximally cytoreduce all of the visible disease.
While initial surgical debulking is the goal, there are circumstances when a different approach may be indicated. Vergote et al. conducted a prospective randomized trial of 670 women with advanced ovarian cancer. In this study, neoadjuvant chemotherapy followed by interval debulking was not inferior to primary debulking followed by chemotherapy with regards to progression-free survival and overall survival. However, initial surgery was associated with increased surgical complications and perioperative mortality as compared with interval surgery. Therefore, in women who are not felt to be candidates for optimal cytoreduction, neoadjuvant chemotherapy followed by interval surgery may be an appropriate treatment strategy (N Engl J Med. 2010 Sep 2;363[10]:943-53.).
There have been several notable advances and a series of randomized trials – predominately conducted by the GOG – that have resulted in improved overall survival and progression-free interval in women with ovarian cancer. However, none are as significant as the discovery of paclitaxel and platinum-based chemotherapy (cisplatin and carboplatin).
In 1962, samples of the Pacific Yew’s bark were collected and, 2 years later, the extracts from this bark were found to have cytotoxic activity. There were initial difficulties suspending the drug in solution; however, ultimately a formulation in ethanol, cremophor, and saline was found to be effective. In 1984, the National Cancer Institute began clinical trials of paclitaxel and it was found to be highly effective in ovarian cancer. In 1992, it was approved for the treatment of ovarian cancer.
Cisplatin was approved in 1978. Carboplatin entered clinical trials in 1982 and was approved for women with recurrent ovarian cancer in 1989.
There were a series of trials beginning in the late 1980s that established the role of platinum agents and led us to GOG 111. This trial evaluated cisplatin with either cyclophosphamide or paclitaxel. The paclitaxel combination was superior and in 2003 two trials were published that solidified carboplatin and paclitaxel as the cornerstone in the treatment of women with ovarian cancer (J Clin Oncol. 2003 Sep 1;21[17]:3194-200; J Natl Cancer Inst. 2003 Sep 3;95[17]:1320-9).
What has most recently been debated is the route and schedule for both paclitaxel and the platinum agents. In January 2006, the National Cancer Institute released a Clinical Announcement regarding the role of intraperitoneal (IP) chemotherapy for the treatment of women with optimally debulked ovarian cancer. Of the six trials included in the announcement, four trials showed a benefit for progression-free survival and five studies showed an improvement in overall survival. Armstrong et al (GOG 172) showed a 16-month improvement in overall survival with intravenous (IV) paclitaxel, IP cisplatin, and IP paclitaxel. IP chemotherapy has not been universally embraced by physicians and patients in part because of its toxicity, treatment schedule, and the fact that no IP regimen has been compared with the current standard of IV carboplatin and paclitaxel (N Engl J Med. 2006 Jan 5;354[1]:34-43).
While there have been improvements in 5-year survival over time, most women with advanced ovarian cancer will undergo additional chemotherapy in order to achieve subsequent remissions or maintain stability of disease. Other drugs that have Food and Drug Administration approval in the setting of recurrent ovarian cancer include topotecan, liposomal doxorubicin, gemcitabine, bevacizumab, altretamine, carboplatin, cisplatin, cyclophosphamide, and melphalan. Olaparib was recently approved as monotherapy in women with a germline BRCA-mutation who had received three or more prior lines of chemotherapy.
Minimally invasive surgery
Over the last 30 years, minimally invasive surgery (MIS) in gynecologic oncology, particularly for endometrial cancer, has gone from a niche procedure to the standard of care. The introduction of laparoscopy into gynecologic oncology started in the early 1990s. In a series of 59 women undergoing laparoscopy for endometrial cancer, Childers et al. demonstrated feasibility of the technique and low laparotomy conversion rates (Gynecol Oncol. 1993 Oct;51[1]:33-8.). The GOG trial, LAP2, supported the equivalent oncologic outcomes of MIS versus laparotomy for the treatment of endometrial cancer. While many surgeons and centers offered laparoscopic surgery, there were issues with the learning curve that limited its widespread use.
In 2005, the FDA approval of the robotic platform for gynecologic surgery resulted in at least a doubling of the proportion of endometrial cancer patients treated with MIS (Int J Med Robot. 2009 Dec;5[4]:392-7.). In 2012, the Society of Gynecologic Oncology published a consensus statement regarding robotic-assisted surgery in gynecologic oncology (Gynecol Oncol. 2012 Feb;124[2]:180-4.). This review highlights the advantages of the robotics platform with regards to expanding MIS to women with cervical and ovarian cancer; the improvements in outcomes in the obese woman with endometrial cancer; and that the learning curve for robotic surgery is shorter than for traditional laparoscopy. Issues requiring further research include cost analysis as the cost of the new technology decreases, and opportunities for improvement in patient and physician quality of life.
Sentinel node mapping
The rationale for sentinel node mapping is that if one or more sentinel lymph nodes is/are negative for malignancy, then the other regional lymph nodes will also be negative. This would thereby avoid the need for a complete lymph node dissection and its resultant complications, including chronic lymphedema. Much of the work pioneering this strategy has been in breast cancer and melanoma, but data are rapidly emerging for these techniques in gynecologic malignancies.
Candidates for sentinel lymph node biopsy for vulvar cancer include those with a lesion more than 1mm in depth, a tumor less than 4 cm in size, and no obvious metastatic disease on exam or preoperative imaging. Additionally, recommendations have been made regarding case volume in order to achieve limited numbers of false-negative results and to maintain competency. In the study by Van der Zee et al. of 403 patients (623 groins) who underwent sentinel node procedures, the false-negative rate was 0-2%. The overall survival rate was 97% at 3 years (J Clin Oncol. 2008 Feb 20;26[6]:884-9). However, a more recent data from the Gynecologic Oncology Group (GOG 173) showed a slightly higher false-negative rate of 8% (J Clin Oncol. 2012 Nov 1;30[31]:3786-91). Overall survival data are pending from this study.
While sentinel lymph node mapping for endometrial cancer has been feasible for many years and has been well described, the questioned role of completed lymphadenectomy for early-stage endometrial cancer has led to a resurgence of interest in these techniques. While blue dye and radiolabeled tracer methods have historically been the most popular mapping solutions, the advent of endoscopic near-infrared imaging, with its higher sensitivity and good depth penetration, has added options. Indocyanine green fluorescence can be easily detected during robotic surgery and as experience with these techniques increase, successful mapping and sensitivity will increase.
Genetics
While hereditary cancer syndromes have been recognized for many years, detecting the genetic mutations that may increase an individual’s risk of developing a malignancy were not elucidated until the early 1990s. In gynecologic oncology, the most commonly encountered syndromes involve mutations in BRCA1 and BRCA2 and hereditary non–polyposis colorectal cancer, which causes mutations in DNA mismatch-repair genes and increase the risk of endometrial and ovarian cancer.
The SGO recently published a statement on risk assessment for inherited gynecologic cancer predispositions. In this statement “the evaluation for the presence of a hereditary cancer syndrome enables physicians to provide individualized and quantified assessment of cancer risk, as well as options for tailored screening and preventions strategies that may reduce morbidity associated with the development of malignancy” (Gynecol Oncol. 2015 Jan;136[1]:3-7). Beyond risk-reducing salpingo-oophorectomy, therapeutic strategies targeting patients with germline mutations have been developed (PARP inhibitors in BRCA-mutated women with ovarian cancer).
In August 2015, ASCO released an updated policy statement on genetic and genomic testing for cancer susceptibility and highlighted five key areas: germ-line implications of somatic mutation profiling; multigene panel testing for cancer susceptibility; quality assurance in genetic testing; education for oncology professionals; and access to cancer genetic services.
Antiemetics
Rounding out ASCO’s “Top 5 advances in 50 years of Modern Oncology” was the improvement in patients’ quality of life from supportive therapies, in particular antinausea medications.
Several of the agents commonly used in gynecologic oncology rate high (cisplatin) to moderate (carboplatin, cyclophosphamide, doxorubicin, ifosfamide) with regards to emetogenicity. The advent of 5-HT3 receptor antagonists (for example, ondansetron) has significantly improved the quality of life of patients undergoing cytotoxic chemotherapy. In addition to improving quality of life, the decrease in nausea and vomiting can also decrease life-threatening complications such as dehydration and electrolyte imbalance. Both ASCO and the National Comprehensive Cancer Network both have guidelines for the management of nausea and vomiting in patients undergoing chemotherapy.
Throughout 2016, Ob.Gyn. News will celebrate its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit. Look for these articles and more special features in the pages of Ob.Gyn. News and online at obgynnews.com.
Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at UNC. They reported having no relevant financial disclosures.
Preop risk assessment, prophylaxis for VTE
The majority of women with gynecologic cancer will undergo surgery for their disease. Deep vein thrombosis and pulmonary embolism, or venous thromboembolic events are common, serious complications. The rate of pulmonary embolism in women with gynecologic malignancy may be as high as 6.8%, with the case fatality rate being 11%-12%. Hence, one key strategy to lower the rate of fatal pulmonary embolism depends on proper prophylaxis for deep vein thrombosis prevention.
Factors associated with the development of venous thromboembolic events (VTE) include prior VTE, malignancy, older age, African American race, prolonged operative time, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of pulmonary embolism (PE) in women undergoing gynecologic surgery is quadrupled in the presence of malignancy (Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE, compared with matched controls (Gynecol. Oncol. 2007;106:439-45). In addition, cancer patients are typically older and have longer and more complex surgeries. Furthermore, the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).
Other risk factors associated with the development of VTE include hormone replacement therapy, oral contraceptives, use of tamoxifen, and inherited thrombophilias. The most common is factor V Leiden deficiency, affecting up to 20% of patients with VTE. Affected heterozygotes have a 3- to 8-fold increased risk of VTE, whereas homozygotes have a 50- to 80-fold increased risk (Blood 1995;85:1504-8).
Depending on additional risk factors, both the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin and guidelines published by the American College of Chest Physicians (ACCP) place women with gynecologic cancers into "high" or "highest" risk categories (Obstet. Gynecol. 2007;110:429-40; Chest 2012;141:e227S-77S).
Currently, thromboprophylaxis regimens include mechanical and pharmacologic methods. Mechanical devices include graduated compression stockings and intermittent pneumatic compression, which reduce venous stasis and may promote endogenous fibrinolysis. Pharmacologic prophylaxis includes unfractionated heparin (UFH) and low-molecular weight heparin (LMWH). Prospective controlled trials have shown that UFH reduces VTE in patients with gynecologic cancer. Trials comparing LMWH with UFH have demonstrated equivalent efficacy and similar bleeding complications. The recommended prophylactic dose for LMWH is 40 mg subcutaneous injection daily. However, this dose may need to be adjusted in morbidly obese patients (body mass index greater than 40 kg/m2) as well as in women with abnormal renal clearance. UFH should be administered as a dose of 5,000 units subcutaneously three times daily. Intermittent pneumatic compression also has been shown to reduce the incidence of VTE in this patient population.
A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients, such as women with gynecologic cancer. Although limited data exist to support this approach in gynecology patients, studies from other surgical disciplines suggest benefit from a combined regimen. With regards to addressing the timing of initiation, a large retrospective trial of patients undergoing hysterectomy for benign indications concluded that postoperative rather than preoperative administration of UFH or LMWH may reduce the risk of bleeding complications without apparent risk of increased VTE (Acta. Obstet. Gynecol. Scand. 2008;87:1039-47).
In summary, the majority of gynecologic oncology patients are considered to be at the highest risk for developing VTE. For this group of women, double prophylaxis with either UFH or LMWH, and a mechanical method (intermittent pneumatic compression) are recommended in the perioperative setting. In addition, ACCP further recommends that these patients receive extended postoperative prophylaxis with LMWH for 4 weeks. Further evidence is needed to determine acceptable timing for initiation of therapy in order to find a balance between adequate thromboprophylaxis and bleeding complications.
Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant disclosures. Scan this QR code or go to obgynnews.com to view similar columns.
The majority of women with gynecologic cancer will undergo surgery for their disease. Deep vein thrombosis and pulmonary embolism, or venous thromboembolic events are common, serious complications. The rate of pulmonary embolism in women with gynecologic malignancy may be as high as 6.8%, with the case fatality rate being 11%-12%. Hence, one key strategy to lower the rate of fatal pulmonary embolism depends on proper prophylaxis for deep vein thrombosis prevention.
Factors associated with the development of venous thromboembolic events (VTE) include prior VTE, malignancy, older age, African American race, prolonged operative time, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of pulmonary embolism (PE) in women undergoing gynecologic surgery is quadrupled in the presence of malignancy (Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE, compared with matched controls (Gynecol. Oncol. 2007;106:439-45). In addition, cancer patients are typically older and have longer and more complex surgeries. Furthermore, the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).
Other risk factors associated with the development of VTE include hormone replacement therapy, oral contraceptives, use of tamoxifen, and inherited thrombophilias. The most common is factor V Leiden deficiency, affecting up to 20% of patients with VTE. Affected heterozygotes have a 3- to 8-fold increased risk of VTE, whereas homozygotes have a 50- to 80-fold increased risk (Blood 1995;85:1504-8).
Depending on additional risk factors, both the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin and guidelines published by the American College of Chest Physicians (ACCP) place women with gynecologic cancers into "high" or "highest" risk categories (Obstet. Gynecol. 2007;110:429-40; Chest 2012;141:e227S-77S).
Currently, thromboprophylaxis regimens include mechanical and pharmacologic methods. Mechanical devices include graduated compression stockings and intermittent pneumatic compression, which reduce venous stasis and may promote endogenous fibrinolysis. Pharmacologic prophylaxis includes unfractionated heparin (UFH) and low-molecular weight heparin (LMWH). Prospective controlled trials have shown that UFH reduces VTE in patients with gynecologic cancer. Trials comparing LMWH with UFH have demonstrated equivalent efficacy and similar bleeding complications. The recommended prophylactic dose for LMWH is 40 mg subcutaneous injection daily. However, this dose may need to be adjusted in morbidly obese patients (body mass index greater than 40 kg/m2) as well as in women with abnormal renal clearance. UFH should be administered as a dose of 5,000 units subcutaneously three times daily. Intermittent pneumatic compression also has been shown to reduce the incidence of VTE in this patient population.
A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients, such as women with gynecologic cancer. Although limited data exist to support this approach in gynecology patients, studies from other surgical disciplines suggest benefit from a combined regimen. With regards to addressing the timing of initiation, a large retrospective trial of patients undergoing hysterectomy for benign indications concluded that postoperative rather than preoperative administration of UFH or LMWH may reduce the risk of bleeding complications without apparent risk of increased VTE (Acta. Obstet. Gynecol. Scand. 2008;87:1039-47).
In summary, the majority of gynecologic oncology patients are considered to be at the highest risk for developing VTE. For this group of women, double prophylaxis with either UFH or LMWH, and a mechanical method (intermittent pneumatic compression) are recommended in the perioperative setting. In addition, ACCP further recommends that these patients receive extended postoperative prophylaxis with LMWH for 4 weeks. Further evidence is needed to determine acceptable timing for initiation of therapy in order to find a balance between adequate thromboprophylaxis and bleeding complications.
Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant disclosures. Scan this QR code or go to obgynnews.com to view similar columns.
The majority of women with gynecologic cancer will undergo surgery for their disease. Deep vein thrombosis and pulmonary embolism, or venous thromboembolic events are common, serious complications. The rate of pulmonary embolism in women with gynecologic malignancy may be as high as 6.8%, with the case fatality rate being 11%-12%. Hence, one key strategy to lower the rate of fatal pulmonary embolism depends on proper prophylaxis for deep vein thrombosis prevention.
Factors associated with the development of venous thromboembolic events (VTE) include prior VTE, malignancy, older age, African American race, prolonged operative time, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of pulmonary embolism (PE) in women undergoing gynecologic surgery is quadrupled in the presence of malignancy (Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE, compared with matched controls (Gynecol. Oncol. 2007;106:439-45). In addition, cancer patients are typically older and have longer and more complex surgeries. Furthermore, the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).
Other risk factors associated with the development of VTE include hormone replacement therapy, oral contraceptives, use of tamoxifen, and inherited thrombophilias. The most common is factor V Leiden deficiency, affecting up to 20% of patients with VTE. Affected heterozygotes have a 3- to 8-fold increased risk of VTE, whereas homozygotes have a 50- to 80-fold increased risk (Blood 1995;85:1504-8).
Depending on additional risk factors, both the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin and guidelines published by the American College of Chest Physicians (ACCP) place women with gynecologic cancers into "high" or "highest" risk categories (Obstet. Gynecol. 2007;110:429-40; Chest 2012;141:e227S-77S).
Currently, thromboprophylaxis regimens include mechanical and pharmacologic methods. Mechanical devices include graduated compression stockings and intermittent pneumatic compression, which reduce venous stasis and may promote endogenous fibrinolysis. Pharmacologic prophylaxis includes unfractionated heparin (UFH) and low-molecular weight heparin (LMWH). Prospective controlled trials have shown that UFH reduces VTE in patients with gynecologic cancer. Trials comparing LMWH with UFH have demonstrated equivalent efficacy and similar bleeding complications. The recommended prophylactic dose for LMWH is 40 mg subcutaneous injection daily. However, this dose may need to be adjusted in morbidly obese patients (body mass index greater than 40 kg/m2) as well as in women with abnormal renal clearance. UFH should be administered as a dose of 5,000 units subcutaneously three times daily. Intermittent pneumatic compression also has been shown to reduce the incidence of VTE in this patient population.
A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients, such as women with gynecologic cancer. Although limited data exist to support this approach in gynecology patients, studies from other surgical disciplines suggest benefit from a combined regimen. With regards to addressing the timing of initiation, a large retrospective trial of patients undergoing hysterectomy for benign indications concluded that postoperative rather than preoperative administration of UFH or LMWH may reduce the risk of bleeding complications without apparent risk of increased VTE (Acta. Obstet. Gynecol. Scand. 2008;87:1039-47).
In summary, the majority of gynecologic oncology patients are considered to be at the highest risk for developing VTE. For this group of women, double prophylaxis with either UFH or LMWH, and a mechanical method (intermittent pneumatic compression) are recommended in the perioperative setting. In addition, ACCP further recommends that these patients receive extended postoperative prophylaxis with LMWH for 4 weeks. Further evidence is needed to determine acceptable timing for initiation of therapy in order to find a balance between adequate thromboprophylaxis and bleeding complications.
Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant disclosures. Scan this QR code or go to obgynnews.com to view similar columns.
Gynecologic Oncology Consult: Obesity and gynecologic surgery
Obesity poses challenges to all modes of gynecologic surgery from open to minimally invasive to vaginal procedures. Operating on obese women results in more intraoperative and postoperative complications, particularly with regard to blood loss, wound infections, and venous thromboembolic disease, and contributes to increased length of hospital stay (J. Minim. Invasive Gynecol. 2014;21:259-65). Obesity has also been associated with longer operative and nonoperative times in laparoscopy, compared with those for normal-weight patients (J. Minim. Invasive Gynecol. 2012;19:701-7;Gynecol. Oncol. 2006;103:938-41; J. Minim. Invasive Gynecol. 2014;21:259-65).
While it was initially felt that obese patients were poor candidates for laparoscopic surgery, it is now widely supported that minimally invasive surgery is both feasible and may be the optimal approach in this population (Gynecol. Oncol. 2008;111:41-5; J. Minim. Invasive Gynecol. 2010;17:576-82). When obese patients are able to undergo minimally invasive procedures, the result is shorter hospitalizations, less postoperative pain, a faster return to activity, and fewer postoperative wound infections (10.5% vs. 1.3%) (Ann. Surg. 2006;243:181-8). These improved surgical outcomes are seen with both laparoscopic and robotic surgeries, compared with laparotomy in obese patients (Int. J. Gynecol. Cancer 2012;22:76-81; Ann. Surg. Oncol. 2007;14:2384-91; J. Clin. Oncol. 2009;27:5331-6).
Obesity affects most organ systems, resulting in several challenges for our anesthesiology colleagues. In addition to difficult airway management, hemodynamic concerns and metabolic changes must be considered (J. Anesth. 2012;26:758-65). Physiologically, obesity results in an increased oxygen requirement, which leads to increased cardiac output, increased stroke volume, decreased vascular resistance, and increased cardiac work. These physiologic changes result in a higher incidence of hypertension and cardiomegaly in obese patients. Both oxygen consumption and carbon dioxide production are more marked in obese patients. This requires increased ventilation. Because of the excess chest wall weight with subsequent reduced chest wall compliance, ventilation is even more difficult in obese patients.
In addition to the baseline physiology of obesity, minimally invasive surgery adds the additional obstacle of abdominal insufflation. Insufflation increases the intra-abdominal pressure, leading to venous stasis as well as a further lowering in chest wall compliance and increased airway pressure (Ann. Surg. 2005;241:219-26; Anesth. Analg. 2002;94:1345-50). Finally, the need for Trendelenburg positioning for pelvic surgery further complicates an already difficult to ventilate patient.
In addition to the anesthetic challenges, obesity poses multiple challenges for the surgeon. With regard to laparoscopic surgery, key challenges for surgeons include safe and effective patient positioning on the operating room table, access to the abdominal cavity, and difficulty with surgical field visualization. Optimal positioning of the patient remains crucial to avoid nerve injuries.
The depth of the abdominal wall makes safely accessing the abdominal cavity more challenging. The thickness of the abdominal wall can place more torque on laparoscopic ports and instruments, which can require contorted positioning on the part of the surgeon. The surgeon risks significant personal ergonomic strain operating on patients, particularly obese patients (Gynecol. Oncol. 2012;126:437-42). Lastly, visualization in obese patients is impaired regardless of mode of surgery. All of these challenges often can be overcome or at least optimized, particularly in the hands of skilled surgical teams.
In addition to making the surgery more challenging for the surgical team, obesity increases the cost of providing surgical care. In fact, hospital-associated surgical costs totaled an additional $160 million spent annually on the care of obese patients, compared with their nonobese counterparts receiving the same services (Ann. Surg. 2013;258:541-53). Given the continued rise in the number of obese patients, particularly those with a BMI greater than 40 kg/m2, the surgical concerns addressed in this column will continue to pose challenges to surgeons.
Dr. Clark is a chief resident in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology, at the university. Dr. Clark and Dr. Clarke-Pearson said they had no relevant financial disclosures.
Obesity poses challenges to all modes of gynecologic surgery from open to minimally invasive to vaginal procedures. Operating on obese women results in more intraoperative and postoperative complications, particularly with regard to blood loss, wound infections, and venous thromboembolic disease, and contributes to increased length of hospital stay (J. Minim. Invasive Gynecol. 2014;21:259-65). Obesity has also been associated with longer operative and nonoperative times in laparoscopy, compared with those for normal-weight patients (J. Minim. Invasive Gynecol. 2012;19:701-7;Gynecol. Oncol. 2006;103:938-41; J. Minim. Invasive Gynecol. 2014;21:259-65).
While it was initially felt that obese patients were poor candidates for laparoscopic surgery, it is now widely supported that minimally invasive surgery is both feasible and may be the optimal approach in this population (Gynecol. Oncol. 2008;111:41-5; J. Minim. Invasive Gynecol. 2010;17:576-82). When obese patients are able to undergo minimally invasive procedures, the result is shorter hospitalizations, less postoperative pain, a faster return to activity, and fewer postoperative wound infections (10.5% vs. 1.3%) (Ann. Surg. 2006;243:181-8). These improved surgical outcomes are seen with both laparoscopic and robotic surgeries, compared with laparotomy in obese patients (Int. J. Gynecol. Cancer 2012;22:76-81; Ann. Surg. Oncol. 2007;14:2384-91; J. Clin. Oncol. 2009;27:5331-6).
Obesity affects most organ systems, resulting in several challenges for our anesthesiology colleagues. In addition to difficult airway management, hemodynamic concerns and metabolic changes must be considered (J. Anesth. 2012;26:758-65). Physiologically, obesity results in an increased oxygen requirement, which leads to increased cardiac output, increased stroke volume, decreased vascular resistance, and increased cardiac work. These physiologic changes result in a higher incidence of hypertension and cardiomegaly in obese patients. Both oxygen consumption and carbon dioxide production are more marked in obese patients. This requires increased ventilation. Because of the excess chest wall weight with subsequent reduced chest wall compliance, ventilation is even more difficult in obese patients.
In addition to the baseline physiology of obesity, minimally invasive surgery adds the additional obstacle of abdominal insufflation. Insufflation increases the intra-abdominal pressure, leading to venous stasis as well as a further lowering in chest wall compliance and increased airway pressure (Ann. Surg. 2005;241:219-26; Anesth. Analg. 2002;94:1345-50). Finally, the need for Trendelenburg positioning for pelvic surgery further complicates an already difficult to ventilate patient.
In addition to the anesthetic challenges, obesity poses multiple challenges for the surgeon. With regard to laparoscopic surgery, key challenges for surgeons include safe and effective patient positioning on the operating room table, access to the abdominal cavity, and difficulty with surgical field visualization. Optimal positioning of the patient remains crucial to avoid nerve injuries.
The depth of the abdominal wall makes safely accessing the abdominal cavity more challenging. The thickness of the abdominal wall can place more torque on laparoscopic ports and instruments, which can require contorted positioning on the part of the surgeon. The surgeon risks significant personal ergonomic strain operating on patients, particularly obese patients (Gynecol. Oncol. 2012;126:437-42). Lastly, visualization in obese patients is impaired regardless of mode of surgery. All of these challenges often can be overcome or at least optimized, particularly in the hands of skilled surgical teams.
In addition to making the surgery more challenging for the surgical team, obesity increases the cost of providing surgical care. In fact, hospital-associated surgical costs totaled an additional $160 million spent annually on the care of obese patients, compared with their nonobese counterparts receiving the same services (Ann. Surg. 2013;258:541-53). Given the continued rise in the number of obese patients, particularly those with a BMI greater than 40 kg/m2, the surgical concerns addressed in this column will continue to pose challenges to surgeons.
Dr. Clark is a chief resident in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology, at the university. Dr. Clark and Dr. Clarke-Pearson said they had no relevant financial disclosures.
Obesity poses challenges to all modes of gynecologic surgery from open to minimally invasive to vaginal procedures. Operating on obese women results in more intraoperative and postoperative complications, particularly with regard to blood loss, wound infections, and venous thromboembolic disease, and contributes to increased length of hospital stay (J. Minim. Invasive Gynecol. 2014;21:259-65). Obesity has also been associated with longer operative and nonoperative times in laparoscopy, compared with those for normal-weight patients (J. Minim. Invasive Gynecol. 2012;19:701-7;Gynecol. Oncol. 2006;103:938-41; J. Minim. Invasive Gynecol. 2014;21:259-65).
While it was initially felt that obese patients were poor candidates for laparoscopic surgery, it is now widely supported that minimally invasive surgery is both feasible and may be the optimal approach in this population (Gynecol. Oncol. 2008;111:41-5; J. Minim. Invasive Gynecol. 2010;17:576-82). When obese patients are able to undergo minimally invasive procedures, the result is shorter hospitalizations, less postoperative pain, a faster return to activity, and fewer postoperative wound infections (10.5% vs. 1.3%) (Ann. Surg. 2006;243:181-8). These improved surgical outcomes are seen with both laparoscopic and robotic surgeries, compared with laparotomy in obese patients (Int. J. Gynecol. Cancer 2012;22:76-81; Ann. Surg. Oncol. 2007;14:2384-91; J. Clin. Oncol. 2009;27:5331-6).
Obesity affects most organ systems, resulting in several challenges for our anesthesiology colleagues. In addition to difficult airway management, hemodynamic concerns and metabolic changes must be considered (J. Anesth. 2012;26:758-65). Physiologically, obesity results in an increased oxygen requirement, which leads to increased cardiac output, increased stroke volume, decreased vascular resistance, and increased cardiac work. These physiologic changes result in a higher incidence of hypertension and cardiomegaly in obese patients. Both oxygen consumption and carbon dioxide production are more marked in obese patients. This requires increased ventilation. Because of the excess chest wall weight with subsequent reduced chest wall compliance, ventilation is even more difficult in obese patients.
In addition to the baseline physiology of obesity, minimally invasive surgery adds the additional obstacle of abdominal insufflation. Insufflation increases the intra-abdominal pressure, leading to venous stasis as well as a further lowering in chest wall compliance and increased airway pressure (Ann. Surg. 2005;241:219-26; Anesth. Analg. 2002;94:1345-50). Finally, the need for Trendelenburg positioning for pelvic surgery further complicates an already difficult to ventilate patient.
In addition to the anesthetic challenges, obesity poses multiple challenges for the surgeon. With regard to laparoscopic surgery, key challenges for surgeons include safe and effective patient positioning on the operating room table, access to the abdominal cavity, and difficulty with surgical field visualization. Optimal positioning of the patient remains crucial to avoid nerve injuries.
The depth of the abdominal wall makes safely accessing the abdominal cavity more challenging. The thickness of the abdominal wall can place more torque on laparoscopic ports and instruments, which can require contorted positioning on the part of the surgeon. The surgeon risks significant personal ergonomic strain operating on patients, particularly obese patients (Gynecol. Oncol. 2012;126:437-42). Lastly, visualization in obese patients is impaired regardless of mode of surgery. All of these challenges often can be overcome or at least optimized, particularly in the hands of skilled surgical teams.
In addition to making the surgery more challenging for the surgical team, obesity increases the cost of providing surgical care. In fact, hospital-associated surgical costs totaled an additional $160 million spent annually on the care of obese patients, compared with their nonobese counterparts receiving the same services (Ann. Surg. 2013;258:541-53). Given the continued rise in the number of obese patients, particularly those with a BMI greater than 40 kg/m2, the surgical concerns addressed in this column will continue to pose challenges to surgeons.
Dr. Clark is a chief resident in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology, at the university. Dr. Clark and Dr. Clarke-Pearson said they had no relevant financial disclosures.
Ruling out malignancy in setting of an adnexal mass
An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.
The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).
We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.
The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.
The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.
Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.
A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.
Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.
Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).
Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).
CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.
Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.
In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.
If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.
Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].
An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.
The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).
We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.
The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.
The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.
Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.
A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.
Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.
Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).
Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).
CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.
Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.
In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.
If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.
Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].
An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.
The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).
We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.
The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.
The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.
Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.
A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.
Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.
Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).
Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).
CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.
Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.
In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.
If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.
Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].
Ovarian cancer screening has more ‘harms’ than ‘benefit’
Ovarian cancer remains the leading cause of death from gynecologic malignancy in the United States. The poor survival rate associated with ovarian cancer is largely because of the advanced stage of the cancer at the time of diagnosis in the majority of patients. As with other cancers, survival is significantly increased when ovarian cancer is detected at an early stage. For example, for women with stage I cancer, the 5-year survival rate is 89%; 66% for stage II; 34% for stage III, and 18% for stage IV. Consequently, there has been a significant amount of research aimed at early detection and the development of screening strategies. Screening methods evaluated include serum tumor markers and ultrasonography. An ovarian cancer symptom index has been developed which has been used in combination with tumor markers. Nevertheless, the current evidence strongly argues against routine screening in average-risk women with CA-125 and/or ultrasonography (JAMA 2011;305:2295-303). We will briefly discuss the current evidence as well as the current guidelines for screening inpatients with and without a strong family history.
Tumor markers, most specifically CA-125, have received significant attention as they are noninvasive, easy to repeat, and relatively inexpensive. While serum CA-125 is elevated in 50% of women with early stage ovarian cancer, it is nonspecific and can be elevated in up to 1% of healthy women as well as in women with other benign and malignant conditions. Therefore, trials looking at annual screening CA-125 levels have failed to show sufficient specificity for the test to be used in an average risk population. In addition, the lifetime risk of developing ovarian cancer in the United States is 1.4%. As a consequence of this low prevalence, CA-125 has shown unacceptably low positive predictive values as a stand-alone test, ranging from 2.6%-3.7% (Am. J. Obstet. Gynecol. 2005; 193:163-9; Obstet. Gynecol. 2009;113:775-82).
A second tumor marker, with similar sensitivity to CA-125, is HE4, human epididymis protein 4. In a validated algorithm, using both tests appears to be more sensitive than either test alone, correctly classifying 93.8% of masses as high risk of being an epithelial ovarian cancer (Gynecol. Oncol. 2009;112:40-6).
Nevertheless, the HE4 assay has not been studied for the purpose of screening. The improved sensitivity seen with this combination suggests that such a strategy may provide improved detection rates as the first step in screening protocols. However, in order for any of these tumor markers to serve as screening tests, they should be able to predict disease before the clinical diagnosis has been established, and this has not been the case.
Both of these tumor markers have been evaluated in combination with the ovarian cancer symptom index. The index screens women for symptoms related to ovarian cancer such as bloating, increased abdominal girth or early food satiety occurring more than 12 times per month for less than a year. The symptom index, when used in combination with CA-125, improves the sensitivity over CA-125 alone. Furthermore, if HE4 is included, the sensitivity is 84% when two of the three tests are positive. However, because of the lack of specificity of the symptoms included in the index, the test should only be used in a stepwise fashion, and women who test positive need follow-up with transvaginal ultrasound.
Unfortunately, the sensitivity of transvaginal ultrasonography (TVUS) is user dependent, and the test has not been shown to be much better than CA-125 when used alone or in combination with the tumor marker. In the UKCTOCS (U.K. Collaborative Trial of Ovarian Cancer Screening) trial, TVUS detected 25 invasive carcinomas but only 12 of those were early-stage disease. The UKCTOCS trial also enrolled patients into a multimodal screening arm. In that arm, the Risk of Ovarian Cancer Algorithm (ROCA) was utilized as the first screening step and patients that were deemed high risk based on the algorithm had a TVUS. The ROCA is a computer algorithm that essentially compares changes that happen in a woman’s baseline CA-125 levels over time with the baseline changes seen in women who developed ovarian cancer. Patients are then deemed low risk, intermediate or high risk based on their ROCA score. For those who are low risk, a CA-125 is repeated in a year; patients at intermediate risk have a CA-125 repeated within 3 months. Each time the CA-125 is checked, the patient undergoes a new risk stratification using ROCA and her risk may be upgraded or downgraded, based on the new score. Lastly, if a patient is deemed to be at high risk, she undergoes a TVUS for further evaluation. Using this algorithm, the UKCTOCS demonstrated that multimodal screening with TVUS and CA-125 had better sensitivity, specificity, and positive predictive for detection of invasive primary cancer than TVUS alone (Lancet Oncol. 2009;10:327-40).
Similarly, a single-arm prospective study in the United States looking at a two-stage screening strategy using ROCA and TVUS showed comparable specificity and positive predictive values to those reported on UKCTOCS (Cancer 2013;119:3454-61). Consequently, multimodal screening resulted in significantly fewer surgeries performed to detect a case of cancer in both studies. However, survival studies are needed to supplement the U.S.-based trial, and the UKCTOCS study has not yet shown an improved survival in the "screened" population. The final results for the latter trial will not be available until 2015.
Ideally, a good screening test would decrease unnecessary operations because of the risks for serious complications that they carry. This was demonstrated by the randomized PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening) trial, in which multimodal screening (CA-125 and TVUS) was evaluated. Complications ("harms") from screening were one of the secondary outcomes. Screening led to surgery for almost a third of the women who had positive findings. Because the positive predictive value in this study was only 3.7%, many surgeries were performed for benign conditions. A total of 15% of the women who had surgery for a false-positive result experienced at least one serious complication. Furthermore, the increased harm did not come with improved detection or survival rates. The women in the screening arm had similar disease-specific and all-cause mortality as did the women in the nonintervention arm, and there was no difference in ovarian cancer stage at the time of diagnosis.
In summary, based on the significant potential harms without significant benefits, there is no role for the use of either CA-125 or ultrasound in screening for ovarian cancer in women without a suspected family history of hereditary ovarian cancer syndromes. This position has been endorsed by the U.S. Preventive Services Task Force, the Society of Gynecologic Oncology (SGO), and the American College of Obstetricians and Gynecologists (ACOG).
The benefit, or lack thereof, of ovarian cancer screening in women with BRCA1, BRCA2 mutations, or Lynch syndrome is less well defined, mainly because of the paucity of data. Randomized trials addressing screening are unlikely to be performed in this population because the low likelihood that any patient would agree to be in the no-screening arm. The small amount of evidence that exists does not show improved early detection and is consequently not very reassuring. However, given the high lifetime risk of these patients developing ovarian cancer, SGO, AGOG, and the National Comprehensive Cancer Network recommend routine screening with CA-125 and TVUS every 6 months starting at age 30-35 years old or 5-10 years before the age of first diagnosis in the family.
In conclusion, the current evidence suggests that the harm of screening for ovarian cancer with CA-125 and ultrasound outweighs the benefits in women at average risks for the development of the disease. Thus, screening in this group is neither effective nor indicated (N. Engl. J. Med. 2009;361:170-7). In women with hereditary ovarian cancer syndromes, screening is encouraged, although we currently lack evidence that early detection or survival will be improved. Further research is needed in order to develop safer, more reliable, and cost-effective screening strategies.
Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor of in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].
Ovarian cancer remains the leading cause of death from gynecologic malignancy in the United States. The poor survival rate associated with ovarian cancer is largely because of the advanced stage of the cancer at the time of diagnosis in the majority of patients. As with other cancers, survival is significantly increased when ovarian cancer is detected at an early stage. For example, for women with stage I cancer, the 5-year survival rate is 89%; 66% for stage II; 34% for stage III, and 18% for stage IV. Consequently, there has been a significant amount of research aimed at early detection and the development of screening strategies. Screening methods evaluated include serum tumor markers and ultrasonography. An ovarian cancer symptom index has been developed which has been used in combination with tumor markers. Nevertheless, the current evidence strongly argues against routine screening in average-risk women with CA-125 and/or ultrasonography (JAMA 2011;305:2295-303). We will briefly discuss the current evidence as well as the current guidelines for screening inpatients with and without a strong family history.
Tumor markers, most specifically CA-125, have received significant attention as they are noninvasive, easy to repeat, and relatively inexpensive. While serum CA-125 is elevated in 50% of women with early stage ovarian cancer, it is nonspecific and can be elevated in up to 1% of healthy women as well as in women with other benign and malignant conditions. Therefore, trials looking at annual screening CA-125 levels have failed to show sufficient specificity for the test to be used in an average risk population. In addition, the lifetime risk of developing ovarian cancer in the United States is 1.4%. As a consequence of this low prevalence, CA-125 has shown unacceptably low positive predictive values as a stand-alone test, ranging from 2.6%-3.7% (Am. J. Obstet. Gynecol. 2005; 193:163-9; Obstet. Gynecol. 2009;113:775-82).
A second tumor marker, with similar sensitivity to CA-125, is HE4, human epididymis protein 4. In a validated algorithm, using both tests appears to be more sensitive than either test alone, correctly classifying 93.8% of masses as high risk of being an epithelial ovarian cancer (Gynecol. Oncol. 2009;112:40-6).
Nevertheless, the HE4 assay has not been studied for the purpose of screening. The improved sensitivity seen with this combination suggests that such a strategy may provide improved detection rates as the first step in screening protocols. However, in order for any of these tumor markers to serve as screening tests, they should be able to predict disease before the clinical diagnosis has been established, and this has not been the case.
Both of these tumor markers have been evaluated in combination with the ovarian cancer symptom index. The index screens women for symptoms related to ovarian cancer such as bloating, increased abdominal girth or early food satiety occurring more than 12 times per month for less than a year. The symptom index, when used in combination with CA-125, improves the sensitivity over CA-125 alone. Furthermore, if HE4 is included, the sensitivity is 84% when two of the three tests are positive. However, because of the lack of specificity of the symptoms included in the index, the test should only be used in a stepwise fashion, and women who test positive need follow-up with transvaginal ultrasound.
Unfortunately, the sensitivity of transvaginal ultrasonography (TVUS) is user dependent, and the test has not been shown to be much better than CA-125 when used alone or in combination with the tumor marker. In the UKCTOCS (U.K. Collaborative Trial of Ovarian Cancer Screening) trial, TVUS detected 25 invasive carcinomas but only 12 of those were early-stage disease. The UKCTOCS trial also enrolled patients into a multimodal screening arm. In that arm, the Risk of Ovarian Cancer Algorithm (ROCA) was utilized as the first screening step and patients that were deemed high risk based on the algorithm had a TVUS. The ROCA is a computer algorithm that essentially compares changes that happen in a woman’s baseline CA-125 levels over time with the baseline changes seen in women who developed ovarian cancer. Patients are then deemed low risk, intermediate or high risk based on their ROCA score. For those who are low risk, a CA-125 is repeated in a year; patients at intermediate risk have a CA-125 repeated within 3 months. Each time the CA-125 is checked, the patient undergoes a new risk stratification using ROCA and her risk may be upgraded or downgraded, based on the new score. Lastly, if a patient is deemed to be at high risk, she undergoes a TVUS for further evaluation. Using this algorithm, the UKCTOCS demonstrated that multimodal screening with TVUS and CA-125 had better sensitivity, specificity, and positive predictive for detection of invasive primary cancer than TVUS alone (Lancet Oncol. 2009;10:327-40).
Similarly, a single-arm prospective study in the United States looking at a two-stage screening strategy using ROCA and TVUS showed comparable specificity and positive predictive values to those reported on UKCTOCS (Cancer 2013;119:3454-61). Consequently, multimodal screening resulted in significantly fewer surgeries performed to detect a case of cancer in both studies. However, survival studies are needed to supplement the U.S.-based trial, and the UKCTOCS study has not yet shown an improved survival in the "screened" population. The final results for the latter trial will not be available until 2015.
Ideally, a good screening test would decrease unnecessary operations because of the risks for serious complications that they carry. This was demonstrated by the randomized PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening) trial, in which multimodal screening (CA-125 and TVUS) was evaluated. Complications ("harms") from screening were one of the secondary outcomes. Screening led to surgery for almost a third of the women who had positive findings. Because the positive predictive value in this study was only 3.7%, many surgeries were performed for benign conditions. A total of 15% of the women who had surgery for a false-positive result experienced at least one serious complication. Furthermore, the increased harm did not come with improved detection or survival rates. The women in the screening arm had similar disease-specific and all-cause mortality as did the women in the nonintervention arm, and there was no difference in ovarian cancer stage at the time of diagnosis.
In summary, based on the significant potential harms without significant benefits, there is no role for the use of either CA-125 or ultrasound in screening for ovarian cancer in women without a suspected family history of hereditary ovarian cancer syndromes. This position has been endorsed by the U.S. Preventive Services Task Force, the Society of Gynecologic Oncology (SGO), and the American College of Obstetricians and Gynecologists (ACOG).
The benefit, or lack thereof, of ovarian cancer screening in women with BRCA1, BRCA2 mutations, or Lynch syndrome is less well defined, mainly because of the paucity of data. Randomized trials addressing screening are unlikely to be performed in this population because the low likelihood that any patient would agree to be in the no-screening arm. The small amount of evidence that exists does not show improved early detection and is consequently not very reassuring. However, given the high lifetime risk of these patients developing ovarian cancer, SGO, AGOG, and the National Comprehensive Cancer Network recommend routine screening with CA-125 and TVUS every 6 months starting at age 30-35 years old or 5-10 years before the age of first diagnosis in the family.
In conclusion, the current evidence suggests that the harm of screening for ovarian cancer with CA-125 and ultrasound outweighs the benefits in women at average risks for the development of the disease. Thus, screening in this group is neither effective nor indicated (N. Engl. J. Med. 2009;361:170-7). In women with hereditary ovarian cancer syndromes, screening is encouraged, although we currently lack evidence that early detection or survival will be improved. Further research is needed in order to develop safer, more reliable, and cost-effective screening strategies.
Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor of in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].
Ovarian cancer remains the leading cause of death from gynecologic malignancy in the United States. The poor survival rate associated with ovarian cancer is largely because of the advanced stage of the cancer at the time of diagnosis in the majority of patients. As with other cancers, survival is significantly increased when ovarian cancer is detected at an early stage. For example, for women with stage I cancer, the 5-year survival rate is 89%; 66% for stage II; 34% for stage III, and 18% for stage IV. Consequently, there has been a significant amount of research aimed at early detection and the development of screening strategies. Screening methods evaluated include serum tumor markers and ultrasonography. An ovarian cancer symptom index has been developed which has been used in combination with tumor markers. Nevertheless, the current evidence strongly argues against routine screening in average-risk women with CA-125 and/or ultrasonography (JAMA 2011;305:2295-303). We will briefly discuss the current evidence as well as the current guidelines for screening inpatients with and without a strong family history.
Tumor markers, most specifically CA-125, have received significant attention as they are noninvasive, easy to repeat, and relatively inexpensive. While serum CA-125 is elevated in 50% of women with early stage ovarian cancer, it is nonspecific and can be elevated in up to 1% of healthy women as well as in women with other benign and malignant conditions. Therefore, trials looking at annual screening CA-125 levels have failed to show sufficient specificity for the test to be used in an average risk population. In addition, the lifetime risk of developing ovarian cancer in the United States is 1.4%. As a consequence of this low prevalence, CA-125 has shown unacceptably low positive predictive values as a stand-alone test, ranging from 2.6%-3.7% (Am. J. Obstet. Gynecol. 2005; 193:163-9; Obstet. Gynecol. 2009;113:775-82).
A second tumor marker, with similar sensitivity to CA-125, is HE4, human epididymis protein 4. In a validated algorithm, using both tests appears to be more sensitive than either test alone, correctly classifying 93.8% of masses as high risk of being an epithelial ovarian cancer (Gynecol. Oncol. 2009;112:40-6).
Nevertheless, the HE4 assay has not been studied for the purpose of screening. The improved sensitivity seen with this combination suggests that such a strategy may provide improved detection rates as the first step in screening protocols. However, in order for any of these tumor markers to serve as screening tests, they should be able to predict disease before the clinical diagnosis has been established, and this has not been the case.
Both of these tumor markers have been evaluated in combination with the ovarian cancer symptom index. The index screens women for symptoms related to ovarian cancer such as bloating, increased abdominal girth or early food satiety occurring more than 12 times per month for less than a year. The symptom index, when used in combination with CA-125, improves the sensitivity over CA-125 alone. Furthermore, if HE4 is included, the sensitivity is 84% when two of the three tests are positive. However, because of the lack of specificity of the symptoms included in the index, the test should only be used in a stepwise fashion, and women who test positive need follow-up with transvaginal ultrasound.
Unfortunately, the sensitivity of transvaginal ultrasonography (TVUS) is user dependent, and the test has not been shown to be much better than CA-125 when used alone or in combination with the tumor marker. In the UKCTOCS (U.K. Collaborative Trial of Ovarian Cancer Screening) trial, TVUS detected 25 invasive carcinomas but only 12 of those were early-stage disease. The UKCTOCS trial also enrolled patients into a multimodal screening arm. In that arm, the Risk of Ovarian Cancer Algorithm (ROCA) was utilized as the first screening step and patients that were deemed high risk based on the algorithm had a TVUS. The ROCA is a computer algorithm that essentially compares changes that happen in a woman’s baseline CA-125 levels over time with the baseline changes seen in women who developed ovarian cancer. Patients are then deemed low risk, intermediate or high risk based on their ROCA score. For those who are low risk, a CA-125 is repeated in a year; patients at intermediate risk have a CA-125 repeated within 3 months. Each time the CA-125 is checked, the patient undergoes a new risk stratification using ROCA and her risk may be upgraded or downgraded, based on the new score. Lastly, if a patient is deemed to be at high risk, she undergoes a TVUS for further evaluation. Using this algorithm, the UKCTOCS demonstrated that multimodal screening with TVUS and CA-125 had better sensitivity, specificity, and positive predictive for detection of invasive primary cancer than TVUS alone (Lancet Oncol. 2009;10:327-40).
Similarly, a single-arm prospective study in the United States looking at a two-stage screening strategy using ROCA and TVUS showed comparable specificity and positive predictive values to those reported on UKCTOCS (Cancer 2013;119:3454-61). Consequently, multimodal screening resulted in significantly fewer surgeries performed to detect a case of cancer in both studies. However, survival studies are needed to supplement the U.S.-based trial, and the UKCTOCS study has not yet shown an improved survival in the "screened" population. The final results for the latter trial will not be available until 2015.
Ideally, a good screening test would decrease unnecessary operations because of the risks for serious complications that they carry. This was demonstrated by the randomized PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening) trial, in which multimodal screening (CA-125 and TVUS) was evaluated. Complications ("harms") from screening were one of the secondary outcomes. Screening led to surgery for almost a third of the women who had positive findings. Because the positive predictive value in this study was only 3.7%, many surgeries were performed for benign conditions. A total of 15% of the women who had surgery for a false-positive result experienced at least one serious complication. Furthermore, the increased harm did not come with improved detection or survival rates. The women in the screening arm had similar disease-specific and all-cause mortality as did the women in the nonintervention arm, and there was no difference in ovarian cancer stage at the time of diagnosis.
In summary, based on the significant potential harms without significant benefits, there is no role for the use of either CA-125 or ultrasound in screening for ovarian cancer in women without a suspected family history of hereditary ovarian cancer syndromes. This position has been endorsed by the U.S. Preventive Services Task Force, the Society of Gynecologic Oncology (SGO), and the American College of Obstetricians and Gynecologists (ACOG).
The benefit, or lack thereof, of ovarian cancer screening in women with BRCA1, BRCA2 mutations, or Lynch syndrome is less well defined, mainly because of the paucity of data. Randomized trials addressing screening are unlikely to be performed in this population because the low likelihood that any patient would agree to be in the no-screening arm. The small amount of evidence that exists does not show improved early detection and is consequently not very reassuring. However, given the high lifetime risk of these patients developing ovarian cancer, SGO, AGOG, and the National Comprehensive Cancer Network recommend routine screening with CA-125 and TVUS every 6 months starting at age 30-35 years old or 5-10 years before the age of first diagnosis in the family.
In conclusion, the current evidence suggests that the harm of screening for ovarian cancer with CA-125 and ultrasound outweighs the benefits in women at average risks for the development of the disease. Thus, screening in this group is neither effective nor indicated (N. Engl. J. Med. 2009;361:170-7). In women with hereditary ovarian cancer syndromes, screening is encouraged, although we currently lack evidence that early detection or survival will be improved. Further research is needed in order to develop safer, more reliable, and cost-effective screening strategies.
Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor of in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at [email protected].
