Non–small-cell lung cancer (NSCLC) remains the leading cause of cancer death in the United States, where 29% of patients will present with stage III disease.^1,2 Ongoing research efforts seek to improve these outcomes using novel systemic therapy options or modern radiation techniques. However, there have also been recent studies showing the importance of marital and/or partner status on clinical outcomes.^3-7 For example, in a large Surveillance, Epidemiology, and End Results (SEER) analysis of 734,889 patients diagnosed with several types of cancer (including lung cancer), patients identified as married were less likely to present with metastatic disease, more likely to receive definitive therapy, and had superior cancer-related mortality even after adjusting for other variables such as cancer stage and treatment when compared with single patients.³ Population-based assessments are important in relaying information about trends and general outcomes based on marital status, but because they are large, they often lack patient-specific information such as nutrition, immunologic status, and variability in treatment paradigms, all of which can independently have an impact on overall survival (OS) in stage III NSCLC.^8-10 In addition, population analyses have typically included patients of all cancer stages and hence involved a multitude of treatment approaches ranging from curative to palliative. There are limited well-annotated institutional data on the association of marital status on nonmetastatic, locally advanced (LA-NSCLC) in the setting of National Comprehensive Cancer Network-guided, standard-of-care definitive treatment.

The objective of this analysis is to evaluate the effect of marital status on OS and freedom from recurrence (FFR) in patients with stage III NSCLC who were treated at a National Cancer Institute–designated cancer center with curative intent from 2000 through 2013. We performed a detailed multivariate analysis (MVA) of patient-, disease-, and treatment-specific factors, including the interaction with racial, nutritional, and immunologic status, which to our knowledge has not been previously reported, to comprehensively evaluate the benefit of marital status in patients with LA-NSCLC.
 

Methods

Patient population and treatment

From January 2000 through December 2013, 355 patients diagnosed with clinical stage III NSCLC (American Joint Committee on Cancer 7th edition) were definitively treated at the University of Maryland in Baltimore, Maryland. Their clinical data were retrospectively analyzed under internal review board approval (GCC 1175, Thoracic Oncology Database). All of the patients were evaluated before treatment by a multidisciplinary team consisting of thoracic surgeons and medical and radiation oncologists. Before treatment, the patients underwent standard work-up, which included systemic imaging with positron-emission (PET), computed-tomographic (CT), PET–CT, and/or bone scan, brain imaging consisting of magnetic-resonance imaging or CT with contrast, and routine blood. Patients had documentation of mediastinal disease by either imaging, mediastinoscopy, or endobronchial ultrasound biopsy.

Definitive therapy was administered using the backbone of chemoradiation therapy (CRT) with (trimodality) or without (bimodality) surgical resection. Concurrent CRT was typically administered with weekly carboplatin–paclitaxel (areas under the curve [AUCs], 2 and 50 mg/m², respectively) and was generally followed with 2 cycles of consolidative treatment with definitive doses of carboplatin–paclitaxel (AUCs, 5-6 and 200-225 mg/m², respectively) as tolerated. The entire cohort was also assessed for possible trimodality therapy at the time of initial diagnosis, and patients who were potential surgical candidates were reassessed for mediastinal nodal clearance following repeat radiographic staging after full-dose CRT. Patients who experienced pathologic mediastinal clearance of disease underwent resection followed by consolidative chemotherapy. Unless there was evidence of disease progression, patients who did not have mediastinal lymph node clearance or who were found not to be a surgical candidate proceeded directly to consolidative chemotherapy. The details of patient selection for trimodality therapy and the oncological outcomes have been previously reported.¹⁰ For follow-up, patients were normally followed with serial CT or PET–CT scans as clinically indicated every 3 months for the first year, 4 to 6 months for the next 2 to 5 years, and then yearly thereafter.

For the analysis, patients were categorized as being either married or single based on self-reporting. As a surrogate for nutrition status, patients were stratified into 4 pretreatment body mass index (BMI) cohorts based on the following World Health Organization criteria: underweight, <18.5 kg/m²; normal weight, 18.5 to <25 kg/m²; overweight, 25 to <30 kg/m²; and obesity, ≥30 kg/m². Pretreatment albumin was also evaluated as a continuous variable. For assessment of immunological status, neutrophil-to-lymphocyte ratio (NLR) was calculated at the time of diagnosis by dividing the absolute neutrophil count by the absolute lymphocyte count.
 

Statistics

We used the Pearson chi-square test to compare categorical variables. OS was calculated from the date of diagnosis (by biopsy of either primary tumor or mediastinal nodes) to the time of death or date of last follow-up. Patients were only censored if they were lost to follow-up. FFR was determined by the date of diagnosis to the time of first failure, with either distant or locoregional disease progression. For this analysis, patients were censored at the time of their last follow-up or death. The Kaplan-Meier product limit method was used to estimate OS and FFR, and we applied the log-rank test to compare outcomes between the 2 cohorts.

We conducted the multivariate analyses using Cox regression with forward model selection. Variables analyzed included age (<60 vs ≥60 years), sex, race (black vs nonblack), median household income, insurance status (Yes vs No), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (range: 0-3; 0 = fully active and 3 = capable of limited self-care, confined to bed/chair >50% of day) at time of diagnosis (0 vs ≥1), pre-CRT BMI, smoking (pack-years), chronic obstructive pulmonary disorder (Yes vs No), Charlson Comorbidity Index score (≤6 vs >7; range, 3-15; this score takes into consideration age, cardiovascular disease, malignancy, and other chronic conditions to calculate 1-year mortality), histology, calculated pretreatment NLR (as a continuous variable), pretreatment albumin (as a continuous variable), T stage, N stage, overall stage (IIIA vs IIIB), radiation technique (3D-CRT vs intensity-modulated radiation therapy [IMRT]), date of diagnosis (divided into quartiles based on proportion diagnosed by years: 2000-2002, 2003-2005, 2006-2009, 2010-2013), use of trimodality therapy, and consolidation chemotherapy. SPSS software (version 23.0) was used for statistical analysis (IBM Corp, Armonk, NY).

Results

Treatment cohorts

Table 1 compares and summarizes patient demographics, disease, and treatment characteristics for married (n = 185; 52.1%) and nonmarried (n = 170; 47.9%) patients. Married patients were more likely to self-identify as being white (P < .0001), reside in zip codes with a higher household median income (P < .0001), have an ECOG PS of 0 (P = .001), have a higher distribution of pretreatment albumin levels (P = .009), and undergo trimodality therapy (P = .001), and they were twice as likely to have insurance (P = .029). Both cohorts were evenly distributed in terms of T stage, N stage, and overall staging. There was no difference in pretreatment NLR or pretreatment BMI between married and single patients. Concurrent CRT was used in more than 85% of patients in both groups, with approximately two-thirds also receiving consolidation chemotherapy (Table 1). Median delivered radiation dose was 64.8 Gy (range, 10.8-81.6 Gy). There was no statistically significant difference in radiation dose delivered to either group, with nearly 90% of the cohort receiving ≥60 Gy.

OS and FFR

With a median follow-up of 15 months for all patients and 89 months for surviving patients (range, 1-184 months), married patients had improved OS when compared with the single cohort, with a median survival of 29.6 and 18.4 months, respectively (unadjusted hazard ratio [HR] of married vs nonmarried, .640; 95% confidence interval [CI], 0.502-0.816; P < .0001; Figure 1A). The estimated 2- and 5-year OS for married and single patients were 56% and 31% and 38.6% and 15%, respectively. When stratified by stage, married patients with stage IIIB disease (median survival, 25 months; Figure 1B) had a similar survival to unmarried patients with stage IIIA disease (median survival, 24 months; Figure 1B).

Survival as it pertains to marital status was further stratified by sex (Figure 2A) and race (Figure 2B). Married men had an improved estimated median survival of 30 months when compared with single men, whose median survival was 16 months (unadjusted HR, .541; 95% CI, 0.392-0.746; P < .0001). On the other hand, marital status had no statistically significant effect on OS when comparing married women with their single counterparts (unadjusted HR, .717; 95% CI, 0.491-1.048; P = .085; Figure 2A), with an overall median survival of approximately 28 months for the entire female cohort. Stratification by race also showed similar results, with married nonblack patients demonstrating better OS when compared with single nonblack patients (HR, .586; 95% CI, 0.420-0.820; P = .002; Figure 2B), with a median survival of 29 and 17 months, respectively. Black patients also had a similar improvement in survival when comparing the married (median survival, 30 months) and nonmarried groups (median survival, 19.6 months; unadjusted HR, .676; 95% CI, 0.457-1.000; P = .050; Figure 2B).

Clinical predictors of survival

On MVA, factors that were independent predictors for OS are summarized in Table 2. Risk of death was reduced by approximately 65% and 45% in patients who underwent trimodality treatment (P < .0001) or were able to undergo consolidative chemotherapy (P = .004) when compared with those who were treated definitively with bimodality treatment or did not undergo systemic doses of adjuvant chemotherapy, respectively. Having insurance (P = .048) and use of IMRT over 3D-CRT (P = .008) was associated with a reduction of mortality by about half in this cohort. Both gender (improved OS with female sex; P = .004) and marital status (improved OS with marriage; P = .006) were associated with a decreased the risk of death by 40% (Table 2). By contrast, a higher NLR resulted

Discussion

Our study continues to support the notion that marital status is an independent indicator of survival in stage III NSCLC (adjusted HR, .59; 95% CI, 0.404-0.859; P = .006). The benefit of marriage in this population seems to be better than that reported in the SEER analysis for all stages, wherein the HR for death of married patients compared with their single counterparts was .85 (95% CI, 0.83-0.87). In their analysis, the investigators hypothesized that this survival advantage could partially be explained by better access to health care and adherence to therapy, as was supported by the higher likelihood of married patients presenting with localized disease and receiving definitive treatment.³ Another population-based study using the Florida Cancer Data System identified 161,228 lung cancer patients (NSCLC and small-cell lung histology included), and on MVA, marital status remained an important prognostic indicator for OS when compared with never-married patients (HR, .86; P = .001).⁶ In addition to typically including patients with all stages of diseases, population-based studies often include patients who receive a heterogeneous combination of treatment modalities, possibly confounding the analysis. Furthermore, large population analyses typically do not report on patient-specific variables such as nutrition (ie, BMI and albumin) or immunologic status (ie, NLR), both of which have been shown to be independent predictors of survival in LA-NSCLC.^8,9

In contrast, some other studies have failed to demonstrate an OS advantage with marital status in patients with NSCLC. For example, in a meta-analysis that evaluated the influence of race, gender, and marital status on 1,365 nonoperative NSCLC patients who were enrolled in 9 Radiation Therapy Oncology Group (RTOG) trials, the investigators did not find marital status to be independently predictive of survival.¹¹ In addition, for the 5,898 patients who were prospectively enrolled in a Mayo Clinic Lung Cancer Cohort (MCLCC), marital status was also found not to be prognostic for NSCLC outcomes when all stages of the disease were analyzed together.⁴ There are some possible confounding factors in these studies. Patients recruited for clinical trials tend to be healthier with a better performance status and have a support system (including close monitoring by the study team) when compared with the general population diagnosed with lung cancer. About 70% to 76% of the patients in both the RTOG and MCLCC studies were married, which is significantly higher than both the national average (51%) and our group (52.1%). Like other population-based studies, the MCLCC included patients with all stages getting a variety of treatments. Although no overall impact on survival was noted, the investigators noted that single, divorced, and widowed patients were more likely to not receive cancer therapy(P < .0001). The marital status also influenced the choice of therapy, with subgroup analysis revealing inferior outcomes in widowed and divorced patients with stage IA, IIB, or IIIB disease. The authors also recognized an inherent referral bias from patients, with support system being typically seen at the Mayo clinics, which may have played an additional role. All of the patients in our analysis were appropriately staged and received curative-intent treatment by a team of physicians using essentially identical therapeutic strategies, thus minimizing some of these confounding factors. This allowed us to explore the impact of marital status while a patient was undergoing stage-appropriate treatment. We demonstrated a strong association with marital status and survival that even overcame the effects of stage (IIIA vs IIIB) on clinical outcomes (Figure 1B).

Conclusions

In patients with locally advanced NSCLC treated with curative-intent following uniform treatment algorithms, marital status was linked with improvement in survival even when adjusted for other key variables, with the second highest HR (after insurance status) among pretreatment demographic variables. Although marriage is an unmodifiable factor in itself, it is most likely a surrogate for better psychosocial support. The scale of these positive survival improvements emphasizes the need to institute targeted supportive care strategies to help advance overall outcomes in a tumor for which modern therapeutic approaches (novel systemic therapy and radiation) have yielded only modest improvement in outcomes yet come at the cost of considerable treatment-related toxicity.

Non–small-cell lung cancer (NSCLC) remains the leading cause of cancer death in the United States, where 29% of patients will present with stage III disease.^1,2 Ongoing research efforts seek to improve these outcomes using novel systemic therapy options or modern radiation techniques. However, there have also been recent studies showing the importance of marital and/or partner status on clinical outcomes.^3-7 For example, in a large Surveillance, Epidemiology, and End Results (SEER) analysis of 734,889 patients diagnosed with several types of cancer (including lung cancer), patients identified as married were less likely to present with metastatic disease, more likely to receive definitive therapy, and had superior cancer-related mortality even after adjusting for other variables such as cancer stage and treatment when compared with single patients.³ Population-based assessments are important in relaying information about trends and general outcomes based on marital status, but because they are large, they often lack patient-specific information such as nutrition, immunologic status, and variability in treatment paradigms, all of which can independently have an impact on overall survival (OS) in stage III NSCLC.^8-10 In addition, population analyses have typically included patients of all cancer stages and hence involved a multitude of treatment approaches ranging from curative to palliative. There are limited well-annotated institutional data on the association of marital status on nonmetastatic, locally advanced (LA-NSCLC) in the setting of National Comprehensive Cancer Network-guided, standard-of-care definitive treatment.

The objective of this analysis is to evaluate the effect of marital status on OS and freedom from recurrence (FFR) in patients with stage III NSCLC who were treated at a National Cancer Institute–designated cancer center with curative intent from 2000 through 2013. We performed a detailed multivariate analysis (MVA) of patient-, disease-, and treatment-specific factors, including the interaction with racial, nutritional, and immunologic status, which to our knowledge has not been previously reported, to comprehensively evaluate the benefit of marital status in patients with LA-NSCLC.
 

Methods

Patient population and treatment

From January 2000 through December 2013, 355 patients diagnosed with clinical stage III NSCLC (American Joint Committee on Cancer 7th edition) were definitively treated at the University of Maryland in Baltimore, Maryland. Their clinical data were retrospectively analyzed under internal review board approval (GCC 1175, Thoracic Oncology Database). All of the patients were evaluated before treatment by a multidisciplinary team consisting of thoracic surgeons and medical and radiation oncologists. Before treatment, the patients underwent standard work-up, which included systemic imaging with positron-emission (PET), computed-tomographic (CT), PET–CT, and/or bone scan, brain imaging consisting of magnetic-resonance imaging or CT with contrast, and routine blood. Patients had documentation of mediastinal disease by either imaging, mediastinoscopy, or endobronchial ultrasound biopsy.

Definitive therapy was administered using the backbone of chemoradiation therapy (CRT) with (trimodality) or without (bimodality) surgical resection. Concurrent CRT was typically administered with weekly carboplatin–paclitaxel (areas under the curve [AUCs], 2 and 50 mg/m², respectively) and was generally followed with 2 cycles of consolidative treatment with definitive doses of carboplatin–paclitaxel (AUCs, 5-6 and 200-225 mg/m², respectively) as tolerated. The entire cohort was also assessed for possible trimodality therapy at the time of initial diagnosis, and patients who were potential surgical candidates were reassessed for mediastinal nodal clearance following repeat radiographic staging after full-dose CRT. Patients who experienced pathologic mediastinal clearance of disease underwent resection followed by consolidative chemotherapy. Unless there was evidence of disease progression, patients who did not have mediastinal lymph node clearance or who were found not to be a surgical candidate proceeded directly to consolidative chemotherapy. The details of patient selection for trimodality therapy and the oncological outcomes have been previously reported.¹⁰ For follow-up, patients were normally followed with serial CT or PET–CT scans as clinically indicated every 3 months for the first year, 4 to 6 months for the next 2 to 5 years, and then yearly thereafter.

For the analysis, patients were categorized as being either married or single based on self-reporting. As a surrogate for nutrition status, patients were stratified into 4 pretreatment body mass index (BMI) cohorts based on the following World Health Organization criteria: underweight, <18.5 kg/m²; normal weight, 18.5 to <25 kg/m²; overweight, 25 to <30 kg/m²; and obesity, ≥30 kg/m². Pretreatment albumin was also evaluated as a continuous variable. For assessment of immunological status, neutrophil-to-lymphocyte ratio (NLR) was calculated at the time of diagnosis by dividing the absolute neutrophil count by the absolute lymphocyte count.
 

Statistics

We used the Pearson chi-square test to compare categorical variables. OS was calculated from the date of diagnosis (by biopsy of either primary tumor or mediastinal nodes) to the time of death or date of last follow-up. Patients were only censored if they were lost to follow-up. FFR was determined by the date of diagnosis to the time of first failure, with either distant or locoregional disease progression. For this analysis, patients were censored at the time of their last follow-up or death. The Kaplan-Meier product limit method was used to estimate OS and FFR, and we applied the log-rank test to compare outcomes between the 2 cohorts.

We conducted the multivariate analyses using Cox regression with forward model selection. Variables analyzed included age (<60 vs ≥60 years), sex, race (black vs nonblack), median household income, insurance status (Yes vs No), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (range: 0-3; 0 = fully active and 3 = capable of limited self-care, confined to bed/chair >50% of day) at time of diagnosis (0 vs ≥1), pre-CRT BMI, smoking (pack-years), chronic obstructive pulmonary disorder (Yes vs No), Charlson Comorbidity Index score (≤6 vs >7; range, 3-15; this score takes into consideration age, cardiovascular disease, malignancy, and other chronic conditions to calculate 1-year mortality), histology, calculated pretreatment NLR (as a continuous variable), pretreatment albumin (as a continuous variable), T stage, N stage, overall stage (IIIA vs IIIB), radiation technique (3D-CRT vs intensity-modulated radiation therapy [IMRT]), date of diagnosis (divided into quartiles based on proportion diagnosed by years: 2000-2002, 2003-2005, 2006-2009, 2010-2013), use of trimodality therapy, and consolidation chemotherapy. SPSS software (version 23.0) was used for statistical analysis (IBM Corp, Armonk, NY).

Results

Treatment cohorts

Table 1 compares and summarizes patient demographics, disease, and treatment characteristics for married (n = 185; 52.1%) and nonmarried (n = 170; 47.9%) patients. Married patients were more likely to self-identify as being white (P < .0001), reside in zip codes with a higher household median income (P < .0001), have an ECOG PS of 0 (P = .001), have a higher distribution of pretreatment albumin levels (P = .009), and undergo trimodality therapy (P = .001), and they were twice as likely to have insurance (P = .029). Both cohorts were evenly distributed in terms of T stage, N stage, and overall staging. There was no difference in pretreatment NLR or pretreatment BMI between married and single patients. Concurrent CRT was used in more than 85% of patients in both groups, with approximately two-thirds also receiving consolidation chemotherapy (Table 1). Median delivered radiation dose was 64.8 Gy (range, 10.8-81.6 Gy). There was no statistically significant difference in radiation dose delivered to either group, with nearly 90% of the cohort receiving ≥60 Gy.

OS and FFR

With a median follow-up of 15 months for all patients and 89 months for surviving patients (range, 1-184 months), married patients had improved OS when compared with the single cohort, with a median survival of 29.6 and 18.4 months, respectively (unadjusted hazard ratio [HR] of married vs nonmarried, .640; 95% confidence interval [CI], 0.502-0.816; P < .0001; Figure 1A). The estimated 2- and 5-year OS for married and single patients were 56% and 31% and 38.6% and 15%, respectively. When stratified by stage, married patients with stage IIIB disease (median survival, 25 months; Figure 1B) had a similar survival to unmarried patients with stage IIIA disease (median survival, 24 months; Figure 1B).

Survival as it pertains to marital status was further stratified by sex (Figure 2A) and race (Figure 2B). Married men had an improved estimated median survival of 30 months when compared with single men, whose median survival was 16 months (unadjusted HR, .541; 95% CI, 0.392-0.746; P < .0001). On the other hand, marital status had no statistically significant effect on OS when comparing married women with their single counterparts (unadjusted HR, .717; 95% CI, 0.491-1.048; P = .085; Figure 2A), with an overall median survival of approximately 28 months for the entire female cohort. Stratification by race also showed similar results, with married nonblack patients demonstrating better OS when compared with single nonblack patients (HR, .586; 95% CI, 0.420-0.820; P = .002; Figure 2B), with a median survival of 29 and 17 months, respectively. Black patients also had a similar improvement in survival when comparing the married (median survival, 30 months) and nonmarried groups (median survival, 19.6 months; unadjusted HR, .676; 95% CI, 0.457-1.000; P = .050; Figure 2B).

Clinical predictors of survival

On MVA, factors that were independent predictors for OS are summarized in Table 2. Risk of death was reduced by approximately 65% and 45% in patients who underwent trimodality treatment (P < .0001) or were able to undergo consolidative chemotherapy (P = .004) when compared with those who were treated definitively with bimodality treatment or did not undergo systemic doses of adjuvant chemotherapy, respectively. Having insurance (P = .048) and use of IMRT over 3D-CRT (P = .008) was associated with a reduction of mortality by about half in this cohort. Both gender (improved OS with female sex; P = .004) and marital status (improved OS with marriage; P = .006) were associated with a decreased the risk of death by 40% (Table 2). By contrast, a higher NLR resulted

Discussion

Our study continues to support the notion that marital status is an independent indicator of survival in stage III NSCLC (adjusted HR, .59; 95% CI, 0.404-0.859; P = .006). The benefit of marriage in this population seems to be better than that reported in the SEER analysis for all stages, wherein the HR for death of married patients compared with their single counterparts was .85 (95% CI, 0.83-0.87). In their analysis, the investigators hypothesized that this survival advantage could partially be explained by better access to health care and adherence to therapy, as was supported by the higher likelihood of married patients presenting with localized disease and receiving definitive treatment.³ Another population-based study using the Florida Cancer Data System identified 161,228 lung cancer patients (NSCLC and small-cell lung histology included), and on MVA, marital status remained an important prognostic indicator for OS when compared with never-married patients (HR, .86; P = .001).⁶ In addition to typically including patients with all stages of diseases, population-based studies often include patients who receive a heterogeneous combination of treatment modalities, possibly confounding the analysis. Furthermore, large population analyses typically do not report on patient-specific variables such as nutrition (ie, BMI and albumin) or immunologic status (ie, NLR), both of which have been shown to be independent predictors of survival in LA-NSCLC.^8,9

In contrast, some other studies have failed to demonstrate an OS advantage with marital status in patients with NSCLC. For example, in a meta-analysis that evaluated the influence of race, gender, and marital status on 1,365 nonoperative NSCLC patients who were enrolled in 9 Radiation Therapy Oncology Group (RTOG) trials, the investigators did not find marital status to be independently predictive of survival.¹¹ In addition, for the 5,898 patients who were prospectively enrolled in a Mayo Clinic Lung Cancer Cohort (MCLCC), marital status was also found not to be prognostic for NSCLC outcomes when all stages of the disease were analyzed together.⁴ There are some possible confounding factors in these studies. Patients recruited for clinical trials tend to be healthier with a better performance status and have a support system (including close monitoring by the study team) when compared with the general population diagnosed with lung cancer. About 70% to 76% of the patients in both the RTOG and MCLCC studies were married, which is significantly higher than both the national average (51%) and our group (52.1%). Like other population-based studies, the MCLCC included patients with all stages getting a variety of treatments. Although no overall impact on survival was noted, the investigators noted that single, divorced, and widowed patients were more likely to not receive cancer therapy(P < .0001). The marital status also influenced the choice of therapy, with subgroup analysis revealing inferior outcomes in widowed and divorced patients with stage IA, IIB, or IIIB disease. The authors also recognized an inherent referral bias from patients, with support system being typically seen at the Mayo clinics, which may have played an additional role. All of the patients in our analysis were appropriately staged and received curative-intent treatment by a team of physicians using essentially identical therapeutic strategies, thus minimizing some of these confounding factors. This allowed us to explore the impact of marital status while a patient was undergoing stage-appropriate treatment. We demonstrated a strong association with marital status and survival that even overcame the effects of stage (IIIA vs IIIB) on clinical outcomes (Figure 1B).

Conclusions

In patients with locally advanced NSCLC treated with curative-intent following uniform treatment algorithms, marital status was linked with improvement in survival even when adjusted for other key variables, with the second highest HR (after insurance status) among pretreatment demographic variables. Although marriage is an unmodifiable factor in itself, it is most likely a surrogate for better psychosocial support. The scale of these positive survival improvements emphasizes the need to institute targeted supportive care strategies to help advance overall outcomes in a tumor for which modern therapeutic approaches (novel systemic therapy and radiation) have yielded only modest improvement in outcomes yet come at the cost of considerable treatment-related toxicity.

Non–small-cell lung cancer (NSCLC) remains the leading cause of cancer death in the United States, where 29% of patients will present with stage III disease.^1,2 Ongoing research efforts seek to improve these outcomes using novel systemic therapy options or modern radiation techniques. However, there have also been recent studies showing the importance of marital and/or partner status on clinical outcomes.^3-7 For example, in a large Surveillance, Epidemiology, and End Results (SEER) analysis of 734,889 patients diagnosed with several types of cancer (including lung cancer), patients identified as married were less likely to present with metastatic disease, more likely to receive definitive therapy, and had superior cancer-related mortality even after adjusting for other variables such as cancer stage and treatment when compared with single patients.³ Population-based assessments are important in relaying information about trends and general outcomes based on marital status, but because they are large, they often lack patient-specific information such as nutrition, immunologic status, and variability in treatment paradigms, all of which can independently have an impact on overall survival (OS) in stage III NSCLC.^8-10 In addition, population analyses have typically included patients of all cancer stages and hence involved a multitude of treatment approaches ranging from curative to palliative. There are limited well-annotated institutional data on the association of marital status on nonmetastatic, locally advanced (LA-NSCLC) in the setting of National Comprehensive Cancer Network-guided, standard-of-care definitive treatment.

The objective of this analysis is to evaluate the effect of marital status on OS and freedom from recurrence (FFR) in patients with stage III NSCLC who were treated at a National Cancer Institute–designated cancer center with curative intent from 2000 through 2013. We performed a detailed multivariate analysis (MVA) of patient-, disease-, and treatment-specific factors, including the interaction with racial, nutritional, and immunologic status, which to our knowledge has not been previously reported, to comprehensively evaluate the benefit of marital status in patients with LA-NSCLC.
 

Methods

Patient population and treatment

From January 2000 through December 2013, 355 patients diagnosed with clinical stage III NSCLC (American Joint Committee on Cancer 7th edition) were definitively treated at the University of Maryland in Baltimore, Maryland. Their clinical data were retrospectively analyzed under internal review board approval (GCC 1175, Thoracic Oncology Database). All of the patients were evaluated before treatment by a multidisciplinary team consisting of thoracic surgeons and medical and radiation oncologists. Before treatment, the patients underwent standard work-up, which included systemic imaging with positron-emission (PET), computed-tomographic (CT), PET–CT, and/or bone scan, brain imaging consisting of magnetic-resonance imaging or CT with contrast, and routine blood. Patients had documentation of mediastinal disease by either imaging, mediastinoscopy, or endobronchial ultrasound biopsy.

Definitive therapy was administered using the backbone of chemoradiation therapy (CRT) with (trimodality) or without (bimodality) surgical resection. Concurrent CRT was typically administered with weekly carboplatin–paclitaxel (areas under the curve [AUCs], 2 and 50 mg/m², respectively) and was generally followed with 2 cycles of consolidative treatment with definitive doses of carboplatin–paclitaxel (AUCs, 5-6 and 200-225 mg/m², respectively) as tolerated. The entire cohort was also assessed for possible trimodality therapy at the time of initial diagnosis, and patients who were potential surgical candidates were reassessed for mediastinal nodal clearance following repeat radiographic staging after full-dose CRT. Patients who experienced pathologic mediastinal clearance of disease underwent resection followed by consolidative chemotherapy. Unless there was evidence of disease progression, patients who did not have mediastinal lymph node clearance or who were found not to be a surgical candidate proceeded directly to consolidative chemotherapy. The details of patient selection for trimodality therapy and the oncological outcomes have been previously reported.¹⁰ For follow-up, patients were normally followed with serial CT or PET–CT scans as clinically indicated every 3 months for the first year, 4 to 6 months for the next 2 to 5 years, and then yearly thereafter.

For the analysis, patients were categorized as being either married or single based on self-reporting. As a surrogate for nutrition status, patients were stratified into 4 pretreatment body mass index (BMI) cohorts based on the following World Health Organization criteria: underweight, <18.5 kg/m²; normal weight, 18.5 to <25 kg/m²; overweight, 25 to <30 kg/m²; and obesity, ≥30 kg/m². Pretreatment albumin was also evaluated as a continuous variable. For assessment of immunological status, neutrophil-to-lymphocyte ratio (NLR) was calculated at the time of diagnosis by dividing the absolute neutrophil count by the absolute lymphocyte count.
 

Statistics

We used the Pearson chi-square test to compare categorical variables. OS was calculated from the date of diagnosis (by biopsy of either primary tumor or mediastinal nodes) to the time of death or date of last follow-up. Patients were only censored if they were lost to follow-up. FFR was determined by the date of diagnosis to the time of first failure, with either distant or locoregional disease progression. For this analysis, patients were censored at the time of their last follow-up or death. The Kaplan-Meier product limit method was used to estimate OS and FFR, and we applied the log-rank test to compare outcomes between the 2 cohorts.

We conducted the multivariate analyses using Cox regression with forward model selection. Variables analyzed included age (<60 vs ≥60 years), sex, race (black vs nonblack), median household income, insurance status (Yes vs No), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (range: 0-3; 0 = fully active and 3 = capable of limited self-care, confined to bed/chair >50% of day) at time of diagnosis (0 vs ≥1), pre-CRT BMI, smoking (pack-years), chronic obstructive pulmonary disorder (Yes vs No), Charlson Comorbidity Index score (≤6 vs >7; range, 3-15; this score takes into consideration age, cardiovascular disease, malignancy, and other chronic conditions to calculate 1-year mortality), histology, calculated pretreatment NLR (as a continuous variable), pretreatment albumin (as a continuous variable), T stage, N stage, overall stage (IIIA vs IIIB), radiation technique (3D-CRT vs intensity-modulated radiation therapy [IMRT]), date of diagnosis (divided into quartiles based on proportion diagnosed by years: 2000-2002, 2003-2005, 2006-2009, 2010-2013), use of trimodality therapy, and consolidation chemotherapy. SPSS software (version 23.0) was used for statistical analysis (IBM Corp, Armonk, NY).

Results

Treatment cohorts

Table 1 compares and summarizes patient demographics, disease, and treatment characteristics for married (n = 185; 52.1%) and nonmarried (n = 170; 47.9%) patients. Married patients were more likely to self-identify as being white (P < .0001), reside in zip codes with a higher household median income (P < .0001), have an ECOG PS of 0 (P = .001), have a higher distribution of pretreatment albumin levels (P = .009), and undergo trimodality therapy (P = .001), and they were twice as likely to have insurance (P = .029). Both cohorts were evenly distributed in terms of T stage, N stage, and overall staging. There was no difference in pretreatment NLR or pretreatment BMI between married and single patients. Concurrent CRT was used in more than 85% of patients in both groups, with approximately two-thirds also receiving consolidation chemotherapy (Table 1). Median delivered radiation dose was 64.8 Gy (range, 10.8-81.6 Gy). There was no statistically significant difference in radiation dose delivered to either group, with nearly 90% of the cohort receiving ≥60 Gy.

OS and FFR

With a median follow-up of 15 months for all patients and 89 months for surviving patients (range, 1-184 months), married patients had improved OS when compared with the single cohort, with a median survival of 29.6 and 18.4 months, respectively (unadjusted hazard ratio [HR] of married vs nonmarried, .640; 95% confidence interval [CI], 0.502-0.816; P < .0001; Figure 1A). The estimated 2- and 5-year OS for married and single patients were 56% and 31% and 38.6% and 15%, respectively. When stratified by stage, married patients with stage IIIB disease (median survival, 25 months; Figure 1B) had a similar survival to unmarried patients with stage IIIA disease (median survival, 24 months; Figure 1B).

Survival as it pertains to marital status was further stratified by sex (Figure 2A) and race (Figure 2B). Married men had an improved estimated median survival of 30 months when compared with single men, whose median survival was 16 months (unadjusted HR, .541; 95% CI, 0.392-0.746; P < .0001). On the other hand, marital status had no statistically significant effect on OS when comparing married women with their single counterparts (unadjusted HR, .717; 95% CI, 0.491-1.048; P = .085; Figure 2A), with an overall median survival of approximately 28 months for the entire female cohort. Stratification by race also showed similar results, with married nonblack patients demonstrating better OS when compared with single nonblack patients (HR, .586; 95% CI, 0.420-0.820; P = .002; Figure 2B), with a median survival of 29 and 17 months, respectively. Black patients also had a similar improvement in survival when comparing the married (median survival, 30 months) and nonmarried groups (median survival, 19.6 months; unadjusted HR, .676; 95% CI, 0.457-1.000; P = .050; Figure 2B).

Clinical predictors of survival

On MVA, factors that were independent predictors for OS are summarized in Table 2. Risk of death was reduced by approximately 65% and 45% in patients who underwent trimodality treatment (P < .0001) or were able to undergo consolidative chemotherapy (P = .004) when compared with those who were treated definitively with bimodality treatment or did not undergo systemic doses of adjuvant chemotherapy, respectively. Having insurance (P = .048) and use of IMRT over 3D-CRT (P = .008) was associated with a reduction of mortality by about half in this cohort. Both gender (improved OS with female sex; P = .004) and marital status (improved OS with marriage; P = .006) were associated with a decreased the risk of death by 40% (Table 2). By contrast, a higher NLR resulted

Discussion

Our study continues to support the notion that marital status is an independent indicator of survival in stage III NSCLC (adjusted HR, .59; 95% CI, 0.404-0.859; P = .006). The benefit of marriage in this population seems to be better than that reported in the SEER analysis for all stages, wherein the HR for death of married patients compared with their single counterparts was .85 (95% CI, 0.83-0.87). In their analysis, the investigators hypothesized that this survival advantage could partially be explained by better access to health care and adherence to therapy, as was supported by the higher likelihood of married patients presenting with localized disease and receiving definitive treatment.³ Another population-based study using the Florida Cancer Data System identified 161,228 lung cancer patients (NSCLC and small-cell lung histology included), and on MVA, marital status remained an important prognostic indicator for OS when compared with never-married patients (HR, .86; P = .001).⁶ In addition to typically including patients with all stages of diseases, population-based studies often include patients who receive a heterogeneous combination of treatment modalities, possibly confounding the analysis. Furthermore, large population analyses typically do not report on patient-specific variables such as nutrition (ie, BMI and albumin) or immunologic status (ie, NLR), both of which have been shown to be independent predictors of survival in LA-NSCLC.^8,9

In contrast, some other studies have failed to demonstrate an OS advantage with marital status in patients with NSCLC. For example, in a meta-analysis that evaluated the influence of race, gender, and marital status on 1,365 nonoperative NSCLC patients who were enrolled in 9 Radiation Therapy Oncology Group (RTOG) trials, the investigators did not find marital status to be independently predictive of survival.¹¹ In addition, for the 5,898 patients who were prospectively enrolled in a Mayo Clinic Lung Cancer Cohort (MCLCC), marital status was also found not to be prognostic for NSCLC outcomes when all stages of the disease were analyzed together.⁴ There are some possible confounding factors in these studies. Patients recruited for clinical trials tend to be healthier with a better performance status and have a support system (including close monitoring by the study team) when compared with the general population diagnosed with lung cancer. About 70% to 76% of the patients in both the RTOG and MCLCC studies were married, which is significantly higher than both the national average (51%) and our group (52.1%). Like other population-based studies, the MCLCC included patients with all stages getting a variety of treatments. Although no overall impact on survival was noted, the investigators noted that single, divorced, and widowed patients were more likely to not receive cancer therapy(P < .0001). The marital status also influenced the choice of therapy, with subgroup analysis revealing inferior outcomes in widowed and divorced patients with stage IA, IIB, or IIIB disease. The authors also recognized an inherent referral bias from patients, with support system being typically seen at the Mayo clinics, which may have played an additional role. All of the patients in our analysis were appropriately staged and received curative-intent treatment by a team of physicians using essentially identical therapeutic strategies, thus minimizing some of these confounding factors. This allowed us to explore the impact of marital status while a patient was undergoing stage-appropriate treatment. We demonstrated a strong association with marital status and survival that even overcame the effects of stage (IIIA vs IIIB) on clinical outcomes (Figure 1B).

Conclusions

In patients with locally advanced NSCLC treated with curative-intent following uniform treatment algorithms, marital status was linked with improvement in survival even when adjusted for other key variables, with the second highest HR (after insurance status) among pretreatment demographic variables. Although marriage is an unmodifiable factor in itself, it is most likely a surrogate for better psychosocial support. The scale of these positive survival improvements emphasizes the need to institute targeted supportive care strategies to help advance overall outcomes in a tumor for which modern therapeutic approaches (novel systemic therapy and radiation) have yielded only modest improvement in outcomes yet come at the cost of considerable treatment-related toxicity.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults in the United States.¹ In 2018, the estimated annual incidence of AML is 19,520 (32.4% of all new leukemia cases), with 10,670 projected deaths (43.8% of all leukemia deaths).¹ New molecularly targeted treatments are increasingly being used in treating AML, and some of them have shown improved health outcomes. In general, age, white blood cell (WBC) count at presentation, cytogenetics, and molecular characteristics are the major determinants of prognosis and treatment outcome. Studies analyzing the Surveillance Epidemiology and End Results database have also shown racial differences in outcomes.² It is well known to the oncology community that patients with similar characteristics may respond differently to treatment and that outcome is not uniformly related to the well-defined clinical and laboratory characteristics. Issues related to health care disparities and access to health care are also known to affect the outcome in patients with cancer.^3-9

AML is generally considered by the medical community as a time-sensitive condition. Treatment of patients with AML usually consists of induction chemotherapy followed by consolidation treatment with consideration for stem cell transplant. The duration of time from admission to treatment (TAT) of AML with induction chemotherapy is dependent on multiple factors. These may include the assessment of comorbid conditions and the availability of molecular studies at the time of treatment, which can be time consuming. The effect of treatment delays after AML diagnosis has been investigated, but with conflicting results. One study showed that time from diagnosis to treatment initiation affects survival in younger patients, and another showed it has no effect on survival regardless of patient age.^10,11 We describe here the results of a retrospective analysis evaluating the impact of TAT and day of admission on outcomes of patients with AML who received treatment at a tertiary care referral center.

Methods and materials

We did a retrospective medical record review of all newly diagnosed AML patients at the Oklahoma University Health Sciences Center (OUHSC). Our sample was composed of 154 adult patients. Our inclusion criteria were an age of 18 years or older with complete insurance data, a diagnosis of AML, and having received treatment at our institution from January 2000 through June 2015. Data were obtained on laboratory values at diagnosis, pathology data including cytogenetics, molecular data, and bone marrow biopsies. Data on patient characteristics such as age, race and/or ethnicity, and comorbidities were obtained from the electronic medical records. Treatment data on type and dose of chemotherapy during induction, subsequent treatment phases, and number of treatments to achieve complete response (CR) as well as response data of CR achievement, relapse, date of CR, date of relapse, stem cell transplantation data, date of death, and date of last follow-up visit were recorded retrospectively from the electronic medical record. The study was approved by the OUHSC Institutional Review Board.
 

Statistical analysis

TAT was analyzed categorically (0-4 days vs >4 days), and day of admission was analyzed categorically (Monday to Thursday vs Friday to Sunday). Descriptive statistics were calculated overall and by TAT group. The chi-square test was used to compare the association between our covariates and TAT. Kaplan-Meier estimates (with a log-rank test) were used to assess the unadjusted effect of TAT with overall survival (OS) and event-free survival (EFS). Median OS and EFS and 95% confidence intervals (CIs) were also calculated. We used the Cox proportional hazards regression modeling to evaluate the relationship between OS and TAT. The initial model was built by including covariates, with P < .25 for the association between the covariates with OS. TAT was maintained in the final model because it was the primary variable of interest, whereas age and risk group were also included in the final model because those covariates are known prognostic risk factors in AML. Among the set of variables screened in, all 2-way interactions were assessed using P < .05. No significant interactions were found. Backward elimination was then performed. During the backward elimination, confounding was deemed to have been present if the measure of association of significant variables in the model changed by more than 20% and the P-value of the confounding variable was less than .30. Variables with P-values of less than .05 or deemed a confounder would then be retained. A similar modeling approach was used to examine EFS and CR. To evaluate the association between CR with potential predictors, binary logistic regression was used, whereby day of admission and time to treatment were explored unadjusted and then adjusted for age, WBC count, risk group, and undergoing allogeneic stem cell transplant (AlloSCT). SAS version 9.4 (SAS Institute Inc, Cary, North Carolina) was used for all analyses. A final alpha of 0.05 was used unless otherwise noted.

Results

Baseline characteristics are presented in Table 1. Treatment was initiated within 4 days for 71% (109/154) of patients. Most patients in our study were younger than 60 years (70%), male (64%), and white (77%). Most patients were admitted to the hospital for treatment between Monday and Thursday (75%). A higher proportion of patients in the 0-4 days TAT group were <60 years of age compared with patients in the >4 days TAT group (P = .0427). A higher proportion of patients in the 0-4 days TAT group had a WBC count of ≥50 x 10³ μ/L compared with patients in the >4 days TAT group (27% vs 9%, respectively; P = .0148). A higher proportion of patients were admitted Friday to Sunday in the TAT >4 days group. Insured and uninsured patients were equally distributed between the 2 groups (P = .0014). Cytogenetic and/or molecular risk was not statistically different between the 0-4 days and >4 days TAT groups (unfavorable risk, 25% vs 23%, respectively; P = .6214). A higher proportion of patients received 7 + 3 induction chemotherapy (7 days cytarabine and 3 days anthracycline) in the TAT 0-4 days group compared with the >4 days TAT group (84% vs 69%, respectively; P = .0448). The most common intensive chemotherapy regimen used was 7 + 3 (80%). The rest of the patients (20%) received high-dose cytarabine clofarabine-based chemotherapy, hypomethylating agents, or other treatments. The proportion of patients who received an AlloSCT did not differ between the 0-4 days and >4 days TAT groups (24% vs 20%, respectively; P = .5655).

The median OS for all patients was 10.9 months (95% CI, 8.3-15.1), and the median EFS was 9.1 months (95% CI, 7.4-13.8). Median follow-up time was 8.6 months (95% CI, 6.7-11). We found a significant association between TAT and both OS and EFS without any adjustment (Table 2).

Discussion

Treatment outcomes for patients with AML are known to be affected by several patient- and disease-related factors. Patient-related factors can include age, performance status, comorbidities, and availability of a stem cell donor. Examples of disease-related factors include molecular alterations and site of disease involvement. Little is known about whether the timing of treatment initiation affects patient outcomes. Short-term treatment delays after the diagnosis of leukemia are not uncommon. Generally, patients are treated with anthracycline-based induction chemotherapy, but the response rate and survival are particularly poor in the older age group.¹² Moreover, increasing comorbidities with aging are expected to lead to lower treatment tolerability.¹³ Therefore, elderly patients are particularly prone to treatment delays while providers await the results of the molecular studies to guide the use of less intensive targeted therapies.¹⁰ Other reasons for treatment delays may also include transfers between hospitals, suspected or documented infections, and evaluation of chronic illnesses. Our analysis also indicates that admission to the hospital on the weekend contributes to a delay in therapy compared with admission on a weekday.

We found a decreased OS and EFS in patients who received treatment >4 days after admission to the hospital compared with patients who received treatment within 0 to 4 days of admission. This association was statistically significant in a bivariate analysis as well as in a multivariable analysis with adjustment for age, WBC count on presentation, molecular risk group, and undergoing AlloSCT. A previous large retrospective study showed that the time from diagnosis to treatment initiation predicts survival in younger, but not older, patients with AML.¹⁰ This remained true after adjusting for age, performance status, WBC count, and the type of AML in a multivariable analysis. In our study, the declines in overall survival and event-free survival were evident after a delay of more than 4 days.

Another retrospective study that included 599 newly diagnosed AML patients, with a median time from diagnosis to treatment of 8 days, did not show any impact of treatment delay on overall survival, early death, or response rate.¹¹ These differences in the effect of treatment delay on outcomes could be related to the differences in baseline characteristics of patients in these studies. Our study had a higher proportion of patients younger than 60 years, for example. We hypothesize that treatment delays, especially in patients with a high WBC count on presentation, might lead to further organ compromise and poorer outcomes with chemotherapy.

In our study, a higher proportion of patients were admitted over the weekend in the >4 days TAT group, but when we analyzed the day of admission to hospital separately, it was not associated with OS or EFS. Admission over the weekend was also not associated with clinical outcomes including 30-day mortality in a larger study that included 422 patients treated at a large teaching referral hospital.¹⁴

Limitations of our study include a small sample size and a short median follow-up time. Most of our patients were young and white, which may not be representative of the general population.

In conclusion, we found that treatment delays are associated with inferior outcomes in AML patients. It remains to be elucidated whether the benefit gained from using targeted and less-intensive chemotherapy, especially in elderly patients, outweighs the potential harm from delaying treatment. Additional studies are needed to confirm our findings in different settings and patient populations.

Acknowledgment

Statistical support was provided by the Stephenson Cancer Center Biostatistics and Research Design Shared Resource.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults in the United States.¹ In 2018, the estimated annual incidence of AML is 19,520 (32.4% of all new leukemia cases), with 10,670 projected deaths (43.8% of all leukemia deaths).¹ New molecularly targeted treatments are increasingly being used in treating AML, and some of them have shown improved health outcomes. In general, age, white blood cell (WBC) count at presentation, cytogenetics, and molecular characteristics are the major determinants of prognosis and treatment outcome. Studies analyzing the Surveillance Epidemiology and End Results database have also shown racial differences in outcomes.² It is well known to the oncology community that patients with similar characteristics may respond differently to treatment and that outcome is not uniformly related to the well-defined clinical and laboratory characteristics. Issues related to health care disparities and access to health care are also known to affect the outcome in patients with cancer.^3-9

AML is generally considered by the medical community as a time-sensitive condition. Treatment of patients with AML usually consists of induction chemotherapy followed by consolidation treatment with consideration for stem cell transplant. The duration of time from admission to treatment (TAT) of AML with induction chemotherapy is dependent on multiple factors. These may include the assessment of comorbid conditions and the availability of molecular studies at the time of treatment, which can be time consuming. The effect of treatment delays after AML diagnosis has been investigated, but with conflicting results. One study showed that time from diagnosis to treatment initiation affects survival in younger patients, and another showed it has no effect on survival regardless of patient age.^10,11 We describe here the results of a retrospective analysis evaluating the impact of TAT and day of admission on outcomes of patients with AML who received treatment at a tertiary care referral center.

Methods and materials

We did a retrospective medical record review of all newly diagnosed AML patients at the Oklahoma University Health Sciences Center (OUHSC). Our sample was composed of 154 adult patients. Our inclusion criteria were an age of 18 years or older with complete insurance data, a diagnosis of AML, and having received treatment at our institution from January 2000 through June 2015. Data were obtained on laboratory values at diagnosis, pathology data including cytogenetics, molecular data, and bone marrow biopsies. Data on patient characteristics such as age, race and/or ethnicity, and comorbidities were obtained from the electronic medical records. Treatment data on type and dose of chemotherapy during induction, subsequent treatment phases, and number of treatments to achieve complete response (CR) as well as response data of CR achievement, relapse, date of CR, date of relapse, stem cell transplantation data, date of death, and date of last follow-up visit were recorded retrospectively from the electronic medical record. The study was approved by the OUHSC Institutional Review Board.
 

Statistical analysis

TAT was analyzed categorically (0-4 days vs >4 days), and day of admission was analyzed categorically (Monday to Thursday vs Friday to Sunday). Descriptive statistics were calculated overall and by TAT group. The chi-square test was used to compare the association between our covariates and TAT. Kaplan-Meier estimates (with a log-rank test) were used to assess the unadjusted effect of TAT with overall survival (OS) and event-free survival (EFS). Median OS and EFS and 95% confidence intervals (CIs) were also calculated. We used the Cox proportional hazards regression modeling to evaluate the relationship between OS and TAT. The initial model was built by including covariates, with P < .25 for the association between the covariates with OS. TAT was maintained in the final model because it was the primary variable of interest, whereas age and risk group were also included in the final model because those covariates are known prognostic risk factors in AML. Among the set of variables screened in, all 2-way interactions were assessed using P < .05. No significant interactions were found. Backward elimination was then performed. During the backward elimination, confounding was deemed to have been present if the measure of association of significant variables in the model changed by more than 20% and the P-value of the confounding variable was less than .30. Variables with P-values of less than .05 or deemed a confounder would then be retained. A similar modeling approach was used to examine EFS and CR. To evaluate the association between CR with potential predictors, binary logistic regression was used, whereby day of admission and time to treatment were explored unadjusted and then adjusted for age, WBC count, risk group, and undergoing allogeneic stem cell transplant (AlloSCT). SAS version 9.4 (SAS Institute Inc, Cary, North Carolina) was used for all analyses. A final alpha of 0.05 was used unless otherwise noted.

Results

Baseline characteristics are presented in Table 1. Treatment was initiated within 4 days for 71% (109/154) of patients. Most patients in our study were younger than 60 years (70%), male (64%), and white (77%). Most patients were admitted to the hospital for treatment between Monday and Thursday (75%). A higher proportion of patients in the 0-4 days TAT group were <60 years of age compared with patients in the >4 days TAT group (P = .0427). A higher proportion of patients in the 0-4 days TAT group had a WBC count of ≥50 x 10³ μ/L compared with patients in the >4 days TAT group (27% vs 9%, respectively; P = .0148). A higher proportion of patients were admitted Friday to Sunday in the TAT >4 days group. Insured and uninsured patients were equally distributed between the 2 groups (P = .0014). Cytogenetic and/or molecular risk was not statistically different between the 0-4 days and >4 days TAT groups (unfavorable risk, 25% vs 23%, respectively; P = .6214). A higher proportion of patients received 7 + 3 induction chemotherapy (7 days cytarabine and 3 days anthracycline) in the TAT 0-4 days group compared with the >4 days TAT group (84% vs 69%, respectively; P = .0448). The most common intensive chemotherapy regimen used was 7 + 3 (80%). The rest of the patients (20%) received high-dose cytarabine clofarabine-based chemotherapy, hypomethylating agents, or other treatments. The proportion of patients who received an AlloSCT did not differ between the 0-4 days and >4 days TAT groups (24% vs 20%, respectively; P = .5655).

The median OS for all patients was 10.9 months (95% CI, 8.3-15.1), and the median EFS was 9.1 months (95% CI, 7.4-13.8). Median follow-up time was 8.6 months (95% CI, 6.7-11). We found a significant association between TAT and both OS and EFS without any adjustment (Table 2).

Discussion

Treatment outcomes for patients with AML are known to be affected by several patient- and disease-related factors. Patient-related factors can include age, performance status, comorbidities, and availability of a stem cell donor. Examples of disease-related factors include molecular alterations and site of disease involvement. Little is known about whether the timing of treatment initiation affects patient outcomes. Short-term treatment delays after the diagnosis of leukemia are not uncommon. Generally, patients are treated with anthracycline-based induction chemotherapy, but the response rate and survival are particularly poor in the older age group.¹² Moreover, increasing comorbidities with aging are expected to lead to lower treatment tolerability.¹³ Therefore, elderly patients are particularly prone to treatment delays while providers await the results of the molecular studies to guide the use of less intensive targeted therapies.¹⁰ Other reasons for treatment delays may also include transfers between hospitals, suspected or documented infections, and evaluation of chronic illnesses. Our analysis also indicates that admission to the hospital on the weekend contributes to a delay in therapy compared with admission on a weekday.

We found a decreased OS and EFS in patients who received treatment >4 days after admission to the hospital compared with patients who received treatment within 0 to 4 days of admission. This association was statistically significant in a bivariate analysis as well as in a multivariable analysis with adjustment for age, WBC count on presentation, molecular risk group, and undergoing AlloSCT. A previous large retrospective study showed that the time from diagnosis to treatment initiation predicts survival in younger, but not older, patients with AML.¹⁰ This remained true after adjusting for age, performance status, WBC count, and the type of AML in a multivariable analysis. In our study, the declines in overall survival and event-free survival were evident after a delay of more than 4 days.

Another retrospective study that included 599 newly diagnosed AML patients, with a median time from diagnosis to treatment of 8 days, did not show any impact of treatment delay on overall survival, early death, or response rate.¹¹ These differences in the effect of treatment delay on outcomes could be related to the differences in baseline characteristics of patients in these studies. Our study had a higher proportion of patients younger than 60 years, for example. We hypothesize that treatment delays, especially in patients with a high WBC count on presentation, might lead to further organ compromise and poorer outcomes with chemotherapy.

In our study, a higher proportion of patients were admitted over the weekend in the >4 days TAT group, but when we analyzed the day of admission to hospital separately, it was not associated with OS or EFS. Admission over the weekend was also not associated with clinical outcomes including 30-day mortality in a larger study that included 422 patients treated at a large teaching referral hospital.¹⁴

Limitations of our study include a small sample size and a short median follow-up time. Most of our patients were young and white, which may not be representative of the general population.

In conclusion, we found that treatment delays are associated with inferior outcomes in AML patients. It remains to be elucidated whether the benefit gained from using targeted and less-intensive chemotherapy, especially in elderly patients, outweighs the potential harm from delaying treatment. Additional studies are needed to confirm our findings in different settings and patient populations.

Acknowledgment

Statistical support was provided by the Stephenson Cancer Center Biostatistics and Research Design Shared Resource.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults in the United States.¹ In 2018, the estimated annual incidence of AML is 19,520 (32.4% of all new leukemia cases), with 10,670 projected deaths (43.8% of all leukemia deaths).¹ New molecularly targeted treatments are increasingly being used in treating AML, and some of them have shown improved health outcomes. In general, age, white blood cell (WBC) count at presentation, cytogenetics, and molecular characteristics are the major determinants of prognosis and treatment outcome. Studies analyzing the Surveillance Epidemiology and End Results database have also shown racial differences in outcomes.² It is well known to the oncology community that patients with similar characteristics may respond differently to treatment and that outcome is not uniformly related to the well-defined clinical and laboratory characteristics. Issues related to health care disparities and access to health care are also known to affect the outcome in patients with cancer.^3-9

AML is generally considered by the medical community as a time-sensitive condition. Treatment of patients with AML usually consists of induction chemotherapy followed by consolidation treatment with consideration for stem cell transplant. The duration of time from admission to treatment (TAT) of AML with induction chemotherapy is dependent on multiple factors. These may include the assessment of comorbid conditions and the availability of molecular studies at the time of treatment, which can be time consuming. The effect of treatment delays after AML diagnosis has been investigated, but with conflicting results. One study showed that time from diagnosis to treatment initiation affects survival in younger patients, and another showed it has no effect on survival regardless of patient age.^10,11 We describe here the results of a retrospective analysis evaluating the impact of TAT and day of admission on outcomes of patients with AML who received treatment at a tertiary care referral center.

Methods and materials

We did a retrospective medical record review of all newly diagnosed AML patients at the Oklahoma University Health Sciences Center (OUHSC). Our sample was composed of 154 adult patients. Our inclusion criteria were an age of 18 years or older with complete insurance data, a diagnosis of AML, and having received treatment at our institution from January 2000 through June 2015. Data were obtained on laboratory values at diagnosis, pathology data including cytogenetics, molecular data, and bone marrow biopsies. Data on patient characteristics such as age, race and/or ethnicity, and comorbidities were obtained from the electronic medical records. Treatment data on type and dose of chemotherapy during induction, subsequent treatment phases, and number of treatments to achieve complete response (CR) as well as response data of CR achievement, relapse, date of CR, date of relapse, stem cell transplantation data, date of death, and date of last follow-up visit were recorded retrospectively from the electronic medical record. The study was approved by the OUHSC Institutional Review Board.
 

Statistical analysis

TAT was analyzed categorically (0-4 days vs >4 days), and day of admission was analyzed categorically (Monday to Thursday vs Friday to Sunday). Descriptive statistics were calculated overall and by TAT group. The chi-square test was used to compare the association between our covariates and TAT. Kaplan-Meier estimates (with a log-rank test) were used to assess the unadjusted effect of TAT with overall survival (OS) and event-free survival (EFS). Median OS and EFS and 95% confidence intervals (CIs) were also calculated. We used the Cox proportional hazards regression modeling to evaluate the relationship between OS and TAT. The initial model was built by including covariates, with P < .25 for the association between the covariates with OS. TAT was maintained in the final model because it was the primary variable of interest, whereas age and risk group were also included in the final model because those covariates are known prognostic risk factors in AML. Among the set of variables screened in, all 2-way interactions were assessed using P < .05. No significant interactions were found. Backward elimination was then performed. During the backward elimination, confounding was deemed to have been present if the measure of association of significant variables in the model changed by more than 20% and the P-value of the confounding variable was less than .30. Variables with P-values of less than .05 or deemed a confounder would then be retained. A similar modeling approach was used to examine EFS and CR. To evaluate the association between CR with potential predictors, binary logistic regression was used, whereby day of admission and time to treatment were explored unadjusted and then adjusted for age, WBC count, risk group, and undergoing allogeneic stem cell transplant (AlloSCT). SAS version 9.4 (SAS Institute Inc, Cary, North Carolina) was used for all analyses. A final alpha of 0.05 was used unless otherwise noted.

Results

Baseline characteristics are presented in Table 1. Treatment was initiated within 4 days for 71% (109/154) of patients. Most patients in our study were younger than 60 years (70%), male (64%), and white (77%). Most patients were admitted to the hospital for treatment between Monday and Thursday (75%). A higher proportion of patients in the 0-4 days TAT group were <60 years of age compared with patients in the >4 days TAT group (P = .0427). A higher proportion of patients in the 0-4 days TAT group had a WBC count of ≥50 x 10³ μ/L compared with patients in the >4 days TAT group (27% vs 9%, respectively; P = .0148). A higher proportion of patients were admitted Friday to Sunday in the TAT >4 days group. Insured and uninsured patients were equally distributed between the 2 groups (P = .0014). Cytogenetic and/or molecular risk was not statistically different between the 0-4 days and >4 days TAT groups (unfavorable risk, 25% vs 23%, respectively; P = .6214). A higher proportion of patients received 7 + 3 induction chemotherapy (7 days cytarabine and 3 days anthracycline) in the TAT 0-4 days group compared with the >4 days TAT group (84% vs 69%, respectively; P = .0448). The most common intensive chemotherapy regimen used was 7 + 3 (80%). The rest of the patients (20%) received high-dose cytarabine clofarabine-based chemotherapy, hypomethylating agents, or other treatments. The proportion of patients who received an AlloSCT did not differ between the 0-4 days and >4 days TAT groups (24% vs 20%, respectively; P = .5655).

The median OS for all patients was 10.9 months (95% CI, 8.3-15.1), and the median EFS was 9.1 months (95% CI, 7.4-13.8). Median follow-up time was 8.6 months (95% CI, 6.7-11). We found a significant association between TAT and both OS and EFS without any adjustment (Table 2).

Discussion

Treatment outcomes for patients with AML are known to be affected by several patient- and disease-related factors. Patient-related factors can include age, performance status, comorbidities, and availability of a stem cell donor. Examples of disease-related factors include molecular alterations and site of disease involvement. Little is known about whether the timing of treatment initiation affects patient outcomes. Short-term treatment delays after the diagnosis of leukemia are not uncommon. Generally, patients are treated with anthracycline-based induction chemotherapy, but the response rate and survival are particularly poor in the older age group.¹² Moreover, increasing comorbidities with aging are expected to lead to lower treatment tolerability.¹³ Therefore, elderly patients are particularly prone to treatment delays while providers await the results of the molecular studies to guide the use of less intensive targeted therapies.¹⁰ Other reasons for treatment delays may also include transfers between hospitals, suspected or documented infections, and evaluation of chronic illnesses. Our analysis also indicates that admission to the hospital on the weekend contributes to a delay in therapy compared with admission on a weekday.

We found a decreased OS and EFS in patients who received treatment >4 days after admission to the hospital compared with patients who received treatment within 0 to 4 days of admission. This association was statistically significant in a bivariate analysis as well as in a multivariable analysis with adjustment for age, WBC count on presentation, molecular risk group, and undergoing AlloSCT. A previous large retrospective study showed that the time from diagnosis to treatment initiation predicts survival in younger, but not older, patients with AML.¹⁰ This remained true after adjusting for age, performance status, WBC count, and the type of AML in a multivariable analysis. In our study, the declines in overall survival and event-free survival were evident after a delay of more than 4 days.

Another retrospective study that included 599 newly diagnosed AML patients, with a median time from diagnosis to treatment of 8 days, did not show any impact of treatment delay on overall survival, early death, or response rate.¹¹ These differences in the effect of treatment delay on outcomes could be related to the differences in baseline characteristics of patients in these studies. Our study had a higher proportion of patients younger than 60 years, for example. We hypothesize that treatment delays, especially in patients with a high WBC count on presentation, might lead to further organ compromise and poorer outcomes with chemotherapy.

In our study, a higher proportion of patients were admitted over the weekend in the >4 days TAT group, but when we analyzed the day of admission to hospital separately, it was not associated with OS or EFS. Admission over the weekend was also not associated with clinical outcomes including 30-day mortality in a larger study that included 422 patients treated at a large teaching referral hospital.¹⁴

Limitations of our study include a small sample size and a short median follow-up time. Most of our patients were young and white, which may not be representative of the general population.

In conclusion, we found that treatment delays are associated with inferior outcomes in AML patients. It remains to be elucidated whether the benefit gained from using targeted and less-intensive chemotherapy, especially in elderly patients, outweighs the potential harm from delaying treatment. Additional studies are needed to confirm our findings in different settings and patient populations.

Acknowledgment

Statistical support was provided by the Stephenson Cancer Center Biostatistics and Research Design Shared Resource.

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³

The approval of Bcl-2 inhibitor venetoclax was expanded by the US Food and Drug Administration in June 2018 to include the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), regardless of their genotype, who have received at least 1 prior therapy.¹ It was previously approved in 2016 for the treatment of patients who had a chromosome 17p deletion, which leads to loss of the tumor-suppressor gene TP53.

Approval was based on the positive results of the phase 3, randomized, multicenter, open-label MURANO trial in which 389 patients were randomized 1:1 to receive a combination of venetoclax and the CD20-targeting monoclonal antibody rituximab (venetoclax–rituximab) or bendamustine in combination with rituximab (bendamustine–rituximab).

Eligible patients were 18 years of age or older, had been diagnosed with relapsed/refractory CLL that required treatment, had received 1-3 prior therapies (including at least 1 chemotherapy regimen), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (on a 5-point scale, with 5 indicating the greatest level of disability), and had adequate bone marrow, renal, and hepatic function.

Patients who had received prior bendamustine treatment were eligible for the trial provided they had experienced a duration of response of 24 months or longer. However, patients with transformed CLL, central nervous system involvement, prior treatment with allogeneic or autologous stem cell transplant, major organ dysfunction, other active malignancy, or who were pregnant or breastfeeding, were excluded from the study.

Patients in the venetoclax arm received a 5-week ramp-up schedule, followed by a dose of 400 mg once daily for 24 months. Rituximab treatment started at the end of the venetoclax ramp-up period and was administered at a dose of 375 mg/m² intravenously on cycle 1 day 1 and 500 mg/m² on day 1 of cycles 2-6. In the control arm, patients received 6 cycles with the same rituximab dosing and schedule as the study group and bendamustine at a dose of 70 mg/m² on days 1 and 2 of each 28-day cycle.

The primary endpoint was progression-free survival (PFS), as assessed by an independent review committee over a median follow-up of 23 months. Median PFS was significantly improved in the venetoclax arm (not yet reached versus 18.1 months in the bendamustine arm [HR, 0.19; P < .001]). In addition, objective response rate (ORR) and event-free survival (EFS) also favored the venetoclax arm; ORR was 92% compared with 72%, respectively, and 2-year EFS was 84.9% compared with 34.8%. There was also a trend toward improved 24-month overall survival (OS) rate (91.9% vs 86.6%), however this did not achieve statistical significance, nor did median OS.

The most common adverse events (AEs) in patients treated with venetoclax were neutropenia, diarrhea, upper-respiratory tract infection, fatigue, cough, and nausea. Grade 3/4 neutropenia occurred in 64% of patients, and serious AEs in 46% of patients. Serious infections occurred in 21% of patients, most commonly pneumonia. Ten deaths in the venetoclax arm were attributed to treatment, compared with 11 deaths in the bendamustine arm.²

The prescribing information details warnings and precautions relating to the risk of tumor lysis syndrome, which is increased in patients with higher tumor burden, reduced renal function, or in receipt of strong or moderate CYP3A inhibitors or P-gp inhibitors during the ramp-up stage. Patients should receive appropriate preventive strategies, including hydration and antihyperuricemics, blood chemistry should be monitored and abnormalities managed promptly, and dosing should be interrupted or adjusted as necessary.

Other warnings relate to neutropenia (complete blood counts should be monitored throughout treatment and venetoclax treatment interrupted or dose reduced for severe neutropenia, alongside possible use of supportive measures), immunization (live vaccines should not be administered before or during treatment or after treatment until B-cell recovery, and patients should be advised of the potentially reduced efficacy of vaccines), and embryofetal toxicity (patients should be advised of the risks and the need for effective contraception during and after treatment). Venetoclax is marketed as Venclexta by Genentech.³

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).¹

Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.

A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.

Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.

Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.

Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).

The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.

The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.²

The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.

Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.

New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.^3,4

BOSTON – Hemithyroidectomy rates increased following the 2015 release of clinical practice guidelines that position the procedure as equivalent to total thyroidectomy, an analysis of U.S. hospital data shows.

Andrew Bowser/MDedge News

Patients undergoing hemithyroidectomy had fewer complications and shorter length of stay versus patients who received a bilateral procedure, with no corresponding increase in completion thyroidectomy, according to results of the retrospective analysis reported here at the annual clinical congress of the American College of Surgeons.

“We think this suggests that surgeons might be changing their practice at these hospitals, at least in part in response to the guidelines,” investigator Timothy M. Ullmann, MD, endocrine oncology research fellow in the department of surgery at New York Presbyterian Hospital–Weill Cornell Medical Center, New York.

Dr. Ullmann and colleagues queried the American College of Surgeons National Surgical Quality Improvement Program database for the 2014-2016 period to illustrate operative trends before and after release of the 2015 guidelines from the American Thyroid Association guidelines. They looked at a total of 26,562 procedures done before the guidelines were release, and 7,422 done after.

The rate of hemithyroidectomy increased from 15.6% before guidelines to 18.3% afterward (P less than .001), according to Dr. Ullmann. By contrast, the rates of completion thyroidectomy were 7.8% for the pre-guidelines period and 7.4% post-guidelines (P = .19).

Andrew Bowser/MDedge News

The increase was gradual throughout the 2014-2016 period, though it was especially steep after the guideline introduction, according to co-investigator Toni Beninato, MD, of Weill Cornell Medicine.

“While we can’t say that the guidelines directly caused an increase, it’s a pretty good association,” Dr. Beninato said in a press conference. “I think going forward, we would expect this to continue to increase, because the vast majority of patients with thyroid cancer probably fit criteria to have a hemithyroidectomy rather than a total thyroidectomy.”

Patients treated by otolaryngologists were more likely to undergo hemithyroidectomies versus those treated by general surgeons, multivariate analysis of this data set suggested (odds ratio, 1.13, P less than .001). On the other hand, Hispanic patients and those with a higher operative risk classification were less likely to undergo a unilateral procedure.

Complications were less likely in the hemithyroidectomy patients, according to investigators. There were significantly fewer superficial surgical site infections, at 0.2% versus 0.4% for total thyroidectomy, and operative time was 91.6 minutes versus 141.1 minutes.

Hemithyroidectomy patients were less likely to be reintubated after surgery, had a shorter length of stay, and were more likely to be managed on an outpatient basis, they added at the press conference.

Prior ATA guidelines, in place since 2009, called for near-total or total thyroidectomy for cancers that were at least 1 cm in size in patients with no contraindications to the procedure. The 2015 update says the initial surgical procedure could also be a unilateral procedure, or lobectomy, in cancers greater than 1 cm, or smaller than 4 cm with no extrathyroidal extension.

Dr. Ullmann and Dr. Beninato had no relevant financial relationships with commercial interests pertaining to the content of their presentation.

SOURCE: Ullmann TM et al. Abstract SF121 presented at the American College of Surgeons Clinical Congress.

BOSTON – Hemithyroidectomy rates increased following the 2015 release of clinical practice guidelines that position the procedure as equivalent to total thyroidectomy, an analysis of U.S. hospital data shows.

Andrew Bowser/MDedge News

Patients undergoing hemithyroidectomy had fewer complications and shorter length of stay versus patients who received a bilateral procedure, with no corresponding increase in completion thyroidectomy, according to results of the retrospective analysis reported here at the annual clinical congress of the American College of Surgeons.

“We think this suggests that surgeons might be changing their practice at these hospitals, at least in part in response to the guidelines,” investigator Timothy M. Ullmann, MD, endocrine oncology research fellow in the department of surgery at New York Presbyterian Hospital–Weill Cornell Medical Center, New York.

Dr. Ullmann and colleagues queried the American College of Surgeons National Surgical Quality Improvement Program database for the 2014-2016 period to illustrate operative trends before and after release of the 2015 guidelines from the American Thyroid Association guidelines. They looked at a total of 26,562 procedures done before the guidelines were release, and 7,422 done after.

The rate of hemithyroidectomy increased from 15.6% before guidelines to 18.3% afterward (P less than .001), according to Dr. Ullmann. By contrast, the rates of completion thyroidectomy were 7.8% for the pre-guidelines period and 7.4% post-guidelines (P = .19).

Andrew Bowser/MDedge News

The increase was gradual throughout the 2014-2016 period, though it was especially steep after the guideline introduction, according to co-investigator Toni Beninato, MD, of Weill Cornell Medicine.

“While we can’t say that the guidelines directly caused an increase, it’s a pretty good association,” Dr. Beninato said in a press conference. “I think going forward, we would expect this to continue to increase, because the vast majority of patients with thyroid cancer probably fit criteria to have a hemithyroidectomy rather than a total thyroidectomy.”

Patients treated by otolaryngologists were more likely to undergo hemithyroidectomies versus those treated by general surgeons, multivariate analysis of this data set suggested (odds ratio, 1.13, P less than .001). On the other hand, Hispanic patients and those with a higher operative risk classification were less likely to undergo a unilateral procedure.

Complications were less likely in the hemithyroidectomy patients, according to investigators. There were significantly fewer superficial surgical site infections, at 0.2% versus 0.4% for total thyroidectomy, and operative time was 91.6 minutes versus 141.1 minutes.

Hemithyroidectomy patients were less likely to be reintubated after surgery, had a shorter length of stay, and were more likely to be managed on an outpatient basis, they added at the press conference.

Prior ATA guidelines, in place since 2009, called for near-total or total thyroidectomy for cancers that were at least 1 cm in size in patients with no contraindications to the procedure. The 2015 update says the initial surgical procedure could also be a unilateral procedure, or lobectomy, in cancers greater than 1 cm, or smaller than 4 cm with no extrathyroidal extension.

Dr. Ullmann and Dr. Beninato had no relevant financial relationships with commercial interests pertaining to the content of their presentation.

SOURCE: Ullmann TM et al. Abstract SF121 presented at the American College of Surgeons Clinical Congress.

BOSTON – Hemithyroidectomy rates increased following the 2015 release of clinical practice guidelines that position the procedure as equivalent to total thyroidectomy, an analysis of U.S. hospital data shows.

Andrew Bowser/MDedge News

Patients undergoing hemithyroidectomy had fewer complications and shorter length of stay versus patients who received a bilateral procedure, with no corresponding increase in completion thyroidectomy, according to results of the retrospective analysis reported here at the annual clinical congress of the American College of Surgeons.

“We think this suggests that surgeons might be changing their practice at these hospitals, at least in part in response to the guidelines,” investigator Timothy M. Ullmann, MD, endocrine oncology research fellow in the department of surgery at New York Presbyterian Hospital–Weill Cornell Medical Center, New York.

Dr. Ullmann and colleagues queried the American College of Surgeons National Surgical Quality Improvement Program database for the 2014-2016 period to illustrate operative trends before and after release of the 2015 guidelines from the American Thyroid Association guidelines. They looked at a total of 26,562 procedures done before the guidelines were release, and 7,422 done after.

The rate of hemithyroidectomy increased from 15.6% before guidelines to 18.3% afterward (P less than .001), according to Dr. Ullmann. By contrast, the rates of completion thyroidectomy were 7.8% for the pre-guidelines period and 7.4% post-guidelines (P = .19).

Andrew Bowser/MDedge News

The increase was gradual throughout the 2014-2016 period, though it was especially steep after the guideline introduction, according to co-investigator Toni Beninato, MD, of Weill Cornell Medicine.

“While we can’t say that the guidelines directly caused an increase, it’s a pretty good association,” Dr. Beninato said in a press conference. “I think going forward, we would expect this to continue to increase, because the vast majority of patients with thyroid cancer probably fit criteria to have a hemithyroidectomy rather than a total thyroidectomy.”

Patients treated by otolaryngologists were more likely to undergo hemithyroidectomies versus those treated by general surgeons, multivariate analysis of this data set suggested (odds ratio, 1.13, P less than .001). On the other hand, Hispanic patients and those with a higher operative risk classification were less likely to undergo a unilateral procedure.

Complications were less likely in the hemithyroidectomy patients, according to investigators. There were significantly fewer superficial surgical site infections, at 0.2% versus 0.4% for total thyroidectomy, and operative time was 91.6 minutes versus 141.1 minutes.

Hemithyroidectomy patients were less likely to be reintubated after surgery, had a shorter length of stay, and were more likely to be managed on an outpatient basis, they added at the press conference.

Prior ATA guidelines, in place since 2009, called for near-total or total thyroidectomy for cancers that were at least 1 cm in size in patients with no contraindications to the procedure. The 2015 update says the initial surgical procedure could also be a unilateral procedure, or lobectomy, in cancers greater than 1 cm, or smaller than 4 cm with no extrathyroidal extension.

Dr. Ullmann and Dr. Beninato had no relevant financial relationships with commercial interests pertaining to the content of their presentation.

SOURCE: Ullmann TM et al. Abstract SF121 presented at the American College of Surgeons Clinical Congress.

BOSTON – A survey of U.S. humanitarian surgical non-governmental organizations (NGOs) revealed a range of practices and suggests that a best-practices guide would be beneficial in helping them adhere more closely to standard protocols.

While most NGOs follow guideline-based practices, some deviations from standard of care do occur. Deviations occurred most often in the areas of preoperative workup, operative technique, and pain management, according to survey results presented at the annual clinical congress of the American College of Surgeons.

Consensus guidelines specific to the NGO sector would be used by the great majority of NGOs surveyed, reported Peter F. Johnston, MD, a general surgery resident and the Ben Rush Global Surgery Fellow at Rutgers New Jersey Medical School.

“There is a lot of heterogeneity in the sector, based on the different organizations doing general surgery and organizations doing plastics,” Dr. Johnston said in an interview. “What we think we can do in terms of low-hanging fruit is come up with guidelines for things like perioperative antibiotics that are pretty much common to all types of surgeries.”

The survey conducted by Dr. Johnston and colleagues is one of the first to characterize the clinical practices of U.S. humanitarian organizations that provide general or subspecialty care through short-term surgical missions. It was completed by representatives of 30 of 83 organizations (36%) that were contacted.

Of respondents, 20% said their organizations deviated from standard U.S. practice often or very often, Dr. Johnston said in his presentation. The respondents mentioned deviation from standard practice in pain management (18%), preoperative workup (16%), and operative technique (16%).

Only about one-third of respondents said they believed those deviations impacted patient outcomes, the results show.

In all, 67% of respondents adhered to at least four protocol-driven practices. Those NGOs that adhered most closely to standard protocol tended to be older, more established organizations, compared with those less protocolized organizations, according to Dr. Johnston (age of organization 22 vs. 14 years, P < .05).

“It makes sense... from my own experience of going back to the same countries,” said Dr. Johnston, who has participated in missions in countries including Ghana, Sierra Leone, and Peru. “As an organization, and even within different countries, the process gets smoother as you keep working at it.”

A total of 85% of respondents expressed interest in best-practice guidelines to guide short-term surgical missions, according to the survey data.

Dr. Johnston reported no conflicts of interest related to his presentation.
 

SOURCE: Johnston P, et al. Abstract SF121 presented at the American College of Surgeons Clinical Congress.

BOSTON – A survey of U.S. humanitarian surgical non-governmental organizations (NGOs) revealed a range of practices and suggests that a best-practices guide would be beneficial in helping them adhere more closely to standard protocols.

While most NGOs follow guideline-based practices, some deviations from standard of care do occur. Deviations occurred most often in the areas of preoperative workup, operative technique, and pain management, according to survey results presented at the annual clinical congress of the American College of Surgeons.

Consensus guidelines specific to the NGO sector would be used by the great majority of NGOs surveyed, reported Peter F. Johnston, MD, a general surgery resident and the Ben Rush Global Surgery Fellow at Rutgers New Jersey Medical School.

“There is a lot of heterogeneity in the sector, based on the different organizations doing general surgery and organizations doing plastics,” Dr. Johnston said in an interview. “What we think we can do in terms of low-hanging fruit is come up with guidelines for things like perioperative antibiotics that are pretty much common to all types of surgeries.”

The survey conducted by Dr. Johnston and colleagues is one of the first to characterize the clinical practices of U.S. humanitarian organizations that provide general or subspecialty care through short-term surgical missions. It was completed by representatives of 30 of 83 organizations (36%) that were contacted.

Of respondents, 20% said their organizations deviated from standard U.S. practice often or very often, Dr. Johnston said in his presentation. The respondents mentioned deviation from standard practice in pain management (18%), preoperative workup (16%), and operative technique (16%).

Only about one-third of respondents said they believed those deviations impacted patient outcomes, the results show.

In all, 67% of respondents adhered to at least four protocol-driven practices. Those NGOs that adhered most closely to standard protocol tended to be older, more established organizations, compared with those less protocolized organizations, according to Dr. Johnston (age of organization 22 vs. 14 years, P < .05).

“It makes sense... from my own experience of going back to the same countries,” said Dr. Johnston, who has participated in missions in countries including Ghana, Sierra Leone, and Peru. “As an organization, and even within different countries, the process gets smoother as you keep working at it.”

A total of 85% of respondents expressed interest in best-practice guidelines to guide short-term surgical missions, according to the survey data.

Dr. Johnston reported no conflicts of interest related to his presentation.
 

SOURCE: Johnston P, et al. Abstract SF121 presented at the American College of Surgeons Clinical Congress.

BOSTON – A survey of U.S. humanitarian surgical non-governmental organizations (NGOs) revealed a range of practices and suggests that a best-practices guide would be beneficial in helping them adhere more closely to standard protocols.

While most NGOs follow guideline-based practices, some deviations from standard of care do occur. Deviations occurred most often in the areas of preoperative workup, operative technique, and pain management, according to survey results presented at the annual clinical congress of the American College of Surgeons.

Consensus guidelines specific to the NGO sector would be used by the great majority of NGOs surveyed, reported Peter F. Johnston, MD, a general surgery resident and the Ben Rush Global Surgery Fellow at Rutgers New Jersey Medical School.

“There is a lot of heterogeneity in the sector, based on the different organizations doing general surgery and organizations doing plastics,” Dr. Johnston said in an interview. “What we think we can do in terms of low-hanging fruit is come up with guidelines for things like perioperative antibiotics that are pretty much common to all types of surgeries.”

The survey conducted by Dr. Johnston and colleagues is one of the first to characterize the clinical practices of U.S. humanitarian organizations that provide general or subspecialty care through short-term surgical missions. It was completed by representatives of 30 of 83 organizations (36%) that were contacted.

Of respondents, 20% said their organizations deviated from standard U.S. practice often or very often, Dr. Johnston said in his presentation. The respondents mentioned deviation from standard practice in pain management (18%), preoperative workup (16%), and operative technique (16%).

Only about one-third of respondents said they believed those deviations impacted patient outcomes, the results show.

In all, 67% of respondents adhered to at least four protocol-driven practices. Those NGOs that adhered most closely to standard protocol tended to be older, more established organizations, compared with those less protocolized organizations, according to Dr. Johnston (age of organization 22 vs. 14 years, P < .05).

“It makes sense... from my own experience of going back to the same countries,” said Dr. Johnston, who has participated in missions in countries including Ghana, Sierra Leone, and Peru. “As an organization, and even within different countries, the process gets smoother as you keep working at it.”

A total of 85% of respondents expressed interest in best-practice guidelines to guide short-term surgical missions, according to the survey data.

Dr. Johnston reported no conflicts of interest related to his presentation.
 

SOURCE: Johnston P, et al. Abstract SF121 presented at the American College of Surgeons Clinical Congress.

ATLANTA – Statin use among a cohort of veterans with traumatic spinal cord injury reduced all-cause mortality, results from a novel observational study showed.

“This is the first clinical study to show that administration of statins irrespective of the lipid levels reduces all-cause mortality, not just cardiovascular mortality,” lead study author Meheroz H. Rabadi, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “This clinical study confirms the impression of several prior studies in animal models with spinal cord injury, which have shown the anti-inflammatory and neuro-protective effects of statins.”

To determine whether statin use in a cohort of patients with traumatic spinal cord injuries (SCI) reduced overall and cause-specific mortality, Dr. Rabadi and his colleagues retrospectively reviewed the medical charts and death records of 163 individuals with SCI who were treated at the Oklahoma City Veterans Administration Medical Center Spinal Cord Injury & Disease, Multiple Sclerosis, and ALS Program, an outpatient clinic, from 2000 to 2014. They collected data on statin use, duration of statin use, and intensity of statin therapy, as well as cause-specific mortality.

Of the 163 subjects studied, 75 (46%) had taken statins for an average of 5.7 years, and had greater cardiovascular risk burdens than those who had not taken statins. The mortality rate for patients on statins, however, was 33.8-49.9 per 1,000 person-years, compared with 47.4-66.8 deaths per 1,000 person-years among those who had not taken statins. Kaplan-Meier survival curves showed a significant difference between the two groups (P less than .0052). Within the statin group, neither duration nor average intensity of statin therapy affected mortality.

“We were surprised to note statins reduced pneumonia-related mortality in patients with SCI,” Dr. Rabadi said. “Since our publication there have been several publications, including a meta-analysis of statins reducing community-acquired pneumonia-related mortality and reducing the need for mechanical ventilation or ICU admission (see CHEST 2015;148:523-32, Clin Med (Lond) 2017;17(5):403-7, and Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2018;40(1):30-40). Another surprise was neither the intensity, duration, or types of statin affected the result.”

He acknowledged certain limitations of the analysis, including its retrospective design, its relatively small sample size, and the fact that most of the subjects were non-Hispanic white men. “Routine prescription of statins in any dose in patients with SCI – even if the lipid profile is normal – is more beneficial than detrimental over the long haul,” concluded Dr. Rabadi, who also directs the Oklahoma VAMC Stroke Program. “Nearly all our patients with SCI continue to be on varying doses of statins.”

Dr. Rabadi reported having no financial disclosures.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S127. Abstract S302.


 

ATLANTA – Statin use among a cohort of veterans with traumatic spinal cord injury reduced all-cause mortality, results from a novel observational study showed.

“This is the first clinical study to show that administration of statins irrespective of the lipid levels reduces all-cause mortality, not just cardiovascular mortality,” lead study author Meheroz H. Rabadi, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “This clinical study confirms the impression of several prior studies in animal models with spinal cord injury, which have shown the anti-inflammatory and neuro-protective effects of statins.”

To determine whether statin use in a cohort of patients with traumatic spinal cord injuries (SCI) reduced overall and cause-specific mortality, Dr. Rabadi and his colleagues retrospectively reviewed the medical charts and death records of 163 individuals with SCI who were treated at the Oklahoma City Veterans Administration Medical Center Spinal Cord Injury & Disease, Multiple Sclerosis, and ALS Program, an outpatient clinic, from 2000 to 2014. They collected data on statin use, duration of statin use, and intensity of statin therapy, as well as cause-specific mortality.

Of the 163 subjects studied, 75 (46%) had taken statins for an average of 5.7 years, and had greater cardiovascular risk burdens than those who had not taken statins. The mortality rate for patients on statins, however, was 33.8-49.9 per 1,000 person-years, compared with 47.4-66.8 deaths per 1,000 person-years among those who had not taken statins. Kaplan-Meier survival curves showed a significant difference between the two groups (P less than .0052). Within the statin group, neither duration nor average intensity of statin therapy affected mortality.

“We were surprised to note statins reduced pneumonia-related mortality in patients with SCI,” Dr. Rabadi said. “Since our publication there have been several publications, including a meta-analysis of statins reducing community-acquired pneumonia-related mortality and reducing the need for mechanical ventilation or ICU admission (see CHEST 2015;148:523-32, Clin Med (Lond) 2017;17(5):403-7, and Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2018;40(1):30-40). Another surprise was neither the intensity, duration, or types of statin affected the result.”

He acknowledged certain limitations of the analysis, including its retrospective design, its relatively small sample size, and the fact that most of the subjects were non-Hispanic white men. “Routine prescription of statins in any dose in patients with SCI – even if the lipid profile is normal – is more beneficial than detrimental over the long haul,” concluded Dr. Rabadi, who also directs the Oklahoma VAMC Stroke Program. “Nearly all our patients with SCI continue to be on varying doses of statins.”

Dr. Rabadi reported having no financial disclosures.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S127. Abstract S302.


 

ATLANTA – Statin use among a cohort of veterans with traumatic spinal cord injury reduced all-cause mortality, results from a novel observational study showed.

“This is the first clinical study to show that administration of statins irrespective of the lipid levels reduces all-cause mortality, not just cardiovascular mortality,” lead study author Meheroz H. Rabadi, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “This clinical study confirms the impression of several prior studies in animal models with spinal cord injury, which have shown the anti-inflammatory and neuro-protective effects of statins.”

To determine whether statin use in a cohort of patients with traumatic spinal cord injuries (SCI) reduced overall and cause-specific mortality, Dr. Rabadi and his colleagues retrospectively reviewed the medical charts and death records of 163 individuals with SCI who were treated at the Oklahoma City Veterans Administration Medical Center Spinal Cord Injury & Disease, Multiple Sclerosis, and ALS Program, an outpatient clinic, from 2000 to 2014. They collected data on statin use, duration of statin use, and intensity of statin therapy, as well as cause-specific mortality.

Of the 163 subjects studied, 75 (46%) had taken statins for an average of 5.7 years, and had greater cardiovascular risk burdens than those who had not taken statins. The mortality rate for patients on statins, however, was 33.8-49.9 per 1,000 person-years, compared with 47.4-66.8 deaths per 1,000 person-years among those who had not taken statins. Kaplan-Meier survival curves showed a significant difference between the two groups (P less than .0052). Within the statin group, neither duration nor average intensity of statin therapy affected mortality.

“We were surprised to note statins reduced pneumonia-related mortality in patients with SCI,” Dr. Rabadi said. “Since our publication there have been several publications, including a meta-analysis of statins reducing community-acquired pneumonia-related mortality and reducing the need for mechanical ventilation or ICU admission (see CHEST 2015;148:523-32, Clin Med (Lond) 2017;17(5):403-7, and Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2018;40(1):30-40). Another surprise was neither the intensity, duration, or types of statin affected the result.”

He acknowledged certain limitations of the analysis, including its retrospective design, its relatively small sample size, and the fact that most of the subjects were non-Hispanic white men. “Routine prescription of statins in any dose in patients with SCI – even if the lipid profile is normal – is more beneficial than detrimental over the long haul,” concluded Dr. Rabadi, who also directs the Oklahoma VAMC Stroke Program. “Nearly all our patients with SCI continue to be on varying doses of statins.”

Dr. Rabadi reported having no financial disclosures.

[email protected]

SOURCE: Ann Neurol. 2018;84[S22]:S127. Abstract S302.


 

BOSTON–Vitamin C, angiotensin-II, and methylene blue are emerging options on the cutting edge of refractory septic shock treatment that require more investigation, but nevertheless appear promising, Rishi Rattan, MD, said at the annual clinical congress of the American College of Surgeons.

Andrew Bowser/MDedge News

Trials evaluating vitamin C in this setting have demonstrated a large mortality impact with an absence of side effects, according to Dr. Rattan, a trauma and critical care surgeon with the Ryder Trauma Center at the University of Miami.

“It’s something that I have decided to start early adopting, and many of my colleagues at University of Miami do as well,” Dr. Rattan said in a panel session on updates in septic shock. “We’re anecdotally so far at least seeing good results and are going to be excited to see what these ongoing trials show.”

As an antioxidant, vitamin C has anti-inflammatory properties that may possibly attenuate the overly exuberant inflammatory response seen in septic shock, Dr. Rattan said in his presentation.

The limited clinical data for vitamin C in refractory shock include three studies, of which two are randomized controlled trials, comprising a total of 146 patients, he added.

“I will admit an N of 146 is hardly practice-changing for most people,” Dr. Rattan said. “There’s still a significant and sustained large mortality effect for the use of vitamin C, with nearly no adverse effects.”

Pooled analysis of all three studies revealed a marked reduction in mortality with the use of vitamin C (odds ratio, 0.17, 95% confidence interval 0.07–0.40; P less than .001), according to a meta-analysis recently just published in Critical Care that Dr. Rattan referenced in his presentation (Critical Care 2018;22:258, DOI:10.1186/s13054-018-2191-x).

When taken in recommended dosages, vitamin C given with corticosteroids and thiamine is without known side effects, researcher Paul E. Marik wrote earlier this year in an editorial in Pharmacology & Therapeutics (2018;189[9]:63-70, DOI:10.1016/j.pharmthera.2018.04.007) noted Dr. Rattan, who said he uses the intravenous vitamin C, thiamine, and hydrocortisone protocol previously reported by Dr. Marik and colleagues.

There are 13 ongoing trials, including some prospective blinded, randomized trials, looking at the role of vitamin C in refractory shock, he added.

Angiotensin-II is another intervention that may be promising in refractory septic shock, Dr. Rattan told attendees, pointing to the 2017 publication of the ATHOS-3 trial in the New England Journal of Medicine (2017; 377:419-430,DOI: 10.1056/NEJMoa1704154) showing that treatment increased blood pressure in patients with vasodilatory shock not responding to conventional vasopressors at high doses.

Likewise, methylene blue has shown promise in septic shock, at least in some limited clinical investigations and anecdotally in patients not improving despite standard interventions. “I’ve been able to have a couple patients walk out of the hospital with the use of methylene blue,” Dr. Rattan said. “Again, the plural of ‘anecdote’ is not ‘data,’ but it’s something to consider for the early adopters.”

Dr. Rattan had no disclosures related to his presentation.

BOSTON–Vitamin C, angiotensin-II, and methylene blue are emerging options on the cutting edge of refractory septic shock treatment that require more investigation, but nevertheless appear promising, Rishi Rattan, MD, said at the annual clinical congress of the American College of Surgeons.

Andrew Bowser/MDedge News

Trials evaluating vitamin C in this setting have demonstrated a large mortality impact with an absence of side effects, according to Dr. Rattan, a trauma and critical care surgeon with the Ryder Trauma Center at the University of Miami.

“It’s something that I have decided to start early adopting, and many of my colleagues at University of Miami do as well,” Dr. Rattan said in a panel session on updates in septic shock. “We’re anecdotally so far at least seeing good results and are going to be excited to see what these ongoing trials show.”

As an antioxidant, vitamin C has anti-inflammatory properties that may possibly attenuate the overly exuberant inflammatory response seen in septic shock, Dr. Rattan said in his presentation.

The limited clinical data for vitamin C in refractory shock include three studies, of which two are randomized controlled trials, comprising a total of 146 patients, he added.

“I will admit an N of 146 is hardly practice-changing for most people,” Dr. Rattan said. “There’s still a significant and sustained large mortality effect for the use of vitamin C, with nearly no adverse effects.”

Pooled analysis of all three studies revealed a marked reduction in mortality with the use of vitamin C (odds ratio, 0.17, 95% confidence interval 0.07–0.40; P less than .001), according to a meta-analysis recently just published in Critical Care that Dr. Rattan referenced in his presentation (Critical Care 2018;22:258, DOI:10.1186/s13054-018-2191-x).

When taken in recommended dosages, vitamin C given with corticosteroids and thiamine is without known side effects, researcher Paul E. Marik wrote earlier this year in an editorial in Pharmacology & Therapeutics (2018;189[9]:63-70, DOI:10.1016/j.pharmthera.2018.04.007) noted Dr. Rattan, who said he uses the intravenous vitamin C, thiamine, and hydrocortisone protocol previously reported by Dr. Marik and colleagues.

There are 13 ongoing trials, including some prospective blinded, randomized trials, looking at the role of vitamin C in refractory shock, he added.

Angiotensin-II is another intervention that may be promising in refractory septic shock, Dr. Rattan told attendees, pointing to the 2017 publication of the ATHOS-3 trial in the New England Journal of Medicine (2017; 377:419-430,DOI: 10.1056/NEJMoa1704154) showing that treatment increased blood pressure in patients with vasodilatory shock not responding to conventional vasopressors at high doses.

Likewise, methylene blue has shown promise in septic shock, at least in some limited clinical investigations and anecdotally in patients not improving despite standard interventions. “I’ve been able to have a couple patients walk out of the hospital with the use of methylene blue,” Dr. Rattan said. “Again, the plural of ‘anecdote’ is not ‘data,’ but it’s something to consider for the early adopters.”

Dr. Rattan had no disclosures related to his presentation.

BOSTON–Vitamin C, angiotensin-II, and methylene blue are emerging options on the cutting edge of refractory septic shock treatment that require more investigation, but nevertheless appear promising, Rishi Rattan, MD, said at the annual clinical congress of the American College of Surgeons.

Andrew Bowser/MDedge News

Trials evaluating vitamin C in this setting have demonstrated a large mortality impact with an absence of side effects, according to Dr. Rattan, a trauma and critical care surgeon with the Ryder Trauma Center at the University of Miami.

“It’s something that I have decided to start early adopting, and many of my colleagues at University of Miami do as well,” Dr. Rattan said in a panel session on updates in septic shock. “We’re anecdotally so far at least seeing good results and are going to be excited to see what these ongoing trials show.”

As an antioxidant, vitamin C has anti-inflammatory properties that may possibly attenuate the overly exuberant inflammatory response seen in septic shock, Dr. Rattan said in his presentation.

The limited clinical data for vitamin C in refractory shock include three studies, of which two are randomized controlled trials, comprising a total of 146 patients, he added.

“I will admit an N of 146 is hardly practice-changing for most people,” Dr. Rattan said. “There’s still a significant and sustained large mortality effect for the use of vitamin C, with nearly no adverse effects.”

Pooled analysis of all three studies revealed a marked reduction in mortality with the use of vitamin C (odds ratio, 0.17, 95% confidence interval 0.07–0.40; P less than .001), according to a meta-analysis recently just published in Critical Care that Dr. Rattan referenced in his presentation (Critical Care 2018;22:258, DOI:10.1186/s13054-018-2191-x).

When taken in recommended dosages, vitamin C given with corticosteroids and thiamine is without known side effects, researcher Paul E. Marik wrote earlier this year in an editorial in Pharmacology & Therapeutics (2018;189[9]:63-70, DOI:10.1016/j.pharmthera.2018.04.007) noted Dr. Rattan, who said he uses the intravenous vitamin C, thiamine, and hydrocortisone protocol previously reported by Dr. Marik and colleagues.

There are 13 ongoing trials, including some prospective blinded, randomized trials, looking at the role of vitamin C in refractory shock, he added.

Angiotensin-II is another intervention that may be promising in refractory septic shock, Dr. Rattan told attendees, pointing to the 2017 publication of the ATHOS-3 trial in the New England Journal of Medicine (2017; 377:419-430,DOI: 10.1056/NEJMoa1704154) showing that treatment increased blood pressure in patients with vasodilatory shock not responding to conventional vasopressors at high doses.

Likewise, methylene blue has shown promise in septic shock, at least in some limited clinical investigations and anecdotally in patients not improving despite standard interventions. “I’ve been able to have a couple patients walk out of the hospital with the use of methylene blue,” Dr. Rattan said. “Again, the plural of ‘anecdote’ is not ‘data,’ but it’s something to consider for the early adopters.”

Dr. Rattan had no disclosures related to his presentation.

SEATTLE – Recent events have highlighted the issue of sexual assault in adolescents. But the onus still is on psychiatrists and other clinicians to ask patients whether they’ve ever been a victim of sexual assault or other kinds of trauma, according to an expert.

“It turns out that these experiences are common for kids, and they’re very correlated with the development of all kinds of psychiatric disorders. And if we ask, they will tell us. If we don’t ask they probably won’t,” said Lucy Berliner, director of the Harborview Center for Sexual Assault and Traumatic Stress, who discussed the epidemiology of sexual trauma in adolescents at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

A common misconception is that victims of sexual assault have endured multiple, chronic traumas. A more common scenario, however, is a single incident, much like the one described by Christine Blasey Ford, PhD, in her testimony before Congress, and clinicians should be more on the lookout for such cases. “I think those young people get a little bit lost,” Ms. Berliner said at the meeting.

A 2001 study of adolescents (aged 12-17) who reported and sought treatment for sexual assault in the Seattle area found that 54% of cases resulted from a single incident.

Unlike the incident described by Dr. Ford, coercion often was not physical. Fifty-two percent of the time, the adolescents experienced abuse by authority figures, such as an assault by a teacher or coach, or even someone who used social advantage such as being older or more popular. In 17% of the cases, the victim was drugged or unconscious. Physical restraint was reported in 20% of cases. Weapons were involved only 7% of the time.

Twenty-eight percent of the adolescents were victims of a teenager, compared with 54% who attributed the assault to an adult. Overall, 72% of the subjects presented at an emergency department rather than a counseling clinic, which suggests that screening in medical environments also is a key factor in identifying and responding to people who have been assaulted.

All study subjects were offered counseling, but the uptake was low: The median was 2 sessions.

“My guess is that in the beginning, a lot of people say, ‘I just want to put it behind me, or I want to try to figure it out myself,’ and it only comes around later, in mental health settings, where these kids are in there for some type of psychiatric disorder. And unless we ask, we’re not going to find out (about a previous assault), and we won’t be able to give them the help that would help them with this psychiatric disorder,” said Ms. Berliner, also a clinical associate professor at the University of Washington School of Social Work in Seattle.

Clinicians might not ask about these experiences, she said, because of fears of triggering raw emotions. But such fears are unfounded, she stated. “We need to get over ourselves,” Ms. Berliner said. “If we don’t create the opportunity, why would they tell us? And if they don’t want to tell us, they won’t. But you can’t traumatize a kid by talking about something that’s already actually happened to them.”

That point can even extend to the legal system. Also during the session, Emily Petersen, senior deputy prosecuting attorney in the Special Assault Unit in King County, Washington, emphasized that, in her experience, young people who are victims of sexual and other forms of assault are resilient – and they will not be traumatized by speaking with a prosecutor or to police about their experiences.

But the legal system cannot provide healing, she and Ms. Berliner noted. That must come from the victim’s support system. “These experiences don’t have to define victims of sexual assault as long as the adults in their lives are responding appropriately to them,” Ms. Petersen said.

Ms. Berliner and Ms. Petersen disclosed no conflicts of interest.

SEATTLE – Recent events have highlighted the issue of sexual assault in adolescents. But the onus still is on psychiatrists and other clinicians to ask patients whether they’ve ever been a victim of sexual assault or other kinds of trauma, according to an expert.

“It turns out that these experiences are common for kids, and they’re very correlated with the development of all kinds of psychiatric disorders. And if we ask, they will tell us. If we don’t ask they probably won’t,” said Lucy Berliner, director of the Harborview Center for Sexual Assault and Traumatic Stress, who discussed the epidemiology of sexual trauma in adolescents at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

A common misconception is that victims of sexual assault have endured multiple, chronic traumas. A more common scenario, however, is a single incident, much like the one described by Christine Blasey Ford, PhD, in her testimony before Congress, and clinicians should be more on the lookout for such cases. “I think those young people get a little bit lost,” Ms. Berliner said at the meeting.

A 2001 study of adolescents (aged 12-17) who reported and sought treatment for sexual assault in the Seattle area found that 54% of cases resulted from a single incident.

Unlike the incident described by Dr. Ford, coercion often was not physical. Fifty-two percent of the time, the adolescents experienced abuse by authority figures, such as an assault by a teacher or coach, or even someone who used social advantage such as being older or more popular. In 17% of the cases, the victim was drugged or unconscious. Physical restraint was reported in 20% of cases. Weapons were involved only 7% of the time.

Twenty-eight percent of the adolescents were victims of a teenager, compared with 54% who attributed the assault to an adult. Overall, 72% of the subjects presented at an emergency department rather than a counseling clinic, which suggests that screening in medical environments also is a key factor in identifying and responding to people who have been assaulted.

All study subjects were offered counseling, but the uptake was low: The median was 2 sessions.

“My guess is that in the beginning, a lot of people say, ‘I just want to put it behind me, or I want to try to figure it out myself,’ and it only comes around later, in mental health settings, where these kids are in there for some type of psychiatric disorder. And unless we ask, we’re not going to find out (about a previous assault), and we won’t be able to give them the help that would help them with this psychiatric disorder,” said Ms. Berliner, also a clinical associate professor at the University of Washington School of Social Work in Seattle.

Clinicians might not ask about these experiences, she said, because of fears of triggering raw emotions. But such fears are unfounded, she stated. “We need to get over ourselves,” Ms. Berliner said. “If we don’t create the opportunity, why would they tell us? And if they don’t want to tell us, they won’t. But you can’t traumatize a kid by talking about something that’s already actually happened to them.”

That point can even extend to the legal system. Also during the session, Emily Petersen, senior deputy prosecuting attorney in the Special Assault Unit in King County, Washington, emphasized that, in her experience, young people who are victims of sexual and other forms of assault are resilient – and they will not be traumatized by speaking with a prosecutor or to police about their experiences.

But the legal system cannot provide healing, she and Ms. Berliner noted. That must come from the victim’s support system. “These experiences don’t have to define victims of sexual assault as long as the adults in their lives are responding appropriately to them,” Ms. Petersen said.

Ms. Berliner and Ms. Petersen disclosed no conflicts of interest.

SEATTLE – Recent events have highlighted the issue of sexual assault in adolescents. But the onus still is on psychiatrists and other clinicians to ask patients whether they’ve ever been a victim of sexual assault or other kinds of trauma, according to an expert.

“It turns out that these experiences are common for kids, and they’re very correlated with the development of all kinds of psychiatric disorders. And if we ask, they will tell us. If we don’t ask they probably won’t,” said Lucy Berliner, director of the Harborview Center for Sexual Assault and Traumatic Stress, who discussed the epidemiology of sexual trauma in adolescents at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

A common misconception is that victims of sexual assault have endured multiple, chronic traumas. A more common scenario, however, is a single incident, much like the one described by Christine Blasey Ford, PhD, in her testimony before Congress, and clinicians should be more on the lookout for such cases. “I think those young people get a little bit lost,” Ms. Berliner said at the meeting.

A 2001 study of adolescents (aged 12-17) who reported and sought treatment for sexual assault in the Seattle area found that 54% of cases resulted from a single incident.

Unlike the incident described by Dr. Ford, coercion often was not physical. Fifty-two percent of the time, the adolescents experienced abuse by authority figures, such as an assault by a teacher or coach, or even someone who used social advantage such as being older or more popular. In 17% of the cases, the victim was drugged or unconscious. Physical restraint was reported in 20% of cases. Weapons were involved only 7% of the time.

Twenty-eight percent of the adolescents were victims of a teenager, compared with 54% who attributed the assault to an adult. Overall, 72% of the subjects presented at an emergency department rather than a counseling clinic, which suggests that screening in medical environments also is a key factor in identifying and responding to people who have been assaulted.

All study subjects were offered counseling, but the uptake was low: The median was 2 sessions.

“My guess is that in the beginning, a lot of people say, ‘I just want to put it behind me, or I want to try to figure it out myself,’ and it only comes around later, in mental health settings, where these kids are in there for some type of psychiatric disorder. And unless we ask, we’re not going to find out (about a previous assault), and we won’t be able to give them the help that would help them with this psychiatric disorder,” said Ms. Berliner, also a clinical associate professor at the University of Washington School of Social Work in Seattle.

Clinicians might not ask about these experiences, she said, because of fears of triggering raw emotions. But such fears are unfounded, she stated. “We need to get over ourselves,” Ms. Berliner said. “If we don’t create the opportunity, why would they tell us? And if they don’t want to tell us, they won’t. But you can’t traumatize a kid by talking about something that’s already actually happened to them.”

That point can even extend to the legal system. Also during the session, Emily Petersen, senior deputy prosecuting attorney in the Special Assault Unit in King County, Washington, emphasized that, in her experience, young people who are victims of sexual and other forms of assault are resilient – and they will not be traumatized by speaking with a prosecutor or to police about their experiences.

But the legal system cannot provide healing, she and Ms. Berliner noted. That must come from the victim’s support system. “These experiences don’t have to define victims of sexual assault as long as the adults in their lives are responding appropriately to them,” Ms. Petersen said.

Ms. Berliner and Ms. Petersen disclosed no conflicts of interest.

For patients with hemophilia and high-titer inhibitors, a new era of treatment has begun with the development of improved variants of traditional bypassing agents and novel, nonfactor-based, prophylactic agents, say authors of a recent review article.

©designer491/Thinkstock

“These new agents may transform the treatment of inhibitor patients and inhibitor-related bleeds, potentially decreasing morbidity and mortality and improving patients’ quality of life,” Amy D. Shapiro, MD, and coauthors wrote in the Journal of Thrombosis and Haemostasis.

Until recently, the only two bypassing agents available were activated prothrombin complex concentrates and recombinant factor VIIa, noted Dr. Shapiro, who is CEO and co-medical director of the Indiana Hemophilia and Thrombosis Center, Indianapolis, and her coauthors.

The first of the novel targeted agents, emicizumab, is a humanized, bispecific monoclonal antibody that was approved for prophylactic use in hemophilia A in the United States in November 2017.

Emicizumab could transform the treatment of patients with inhibitors, but it also requires reconsideration of how to treat breakthrough bleeds and eliminate the underlying inhibitor, the authors said.

In a phase 3 study, this biologic significantly decreased the annualized bleeding rate by 87% versus on-demand bypassing agent therapy, and by 79% versus a prophylactic bypassing agent regimen, they said, noting that 63% of patients had no bleeding events during the study.

Serious adverse events were seen in patients receiving emicizumab prophylaxis, including thrombosis in 2 out of 103 subjects and thrombotic microangiopathy in 3. In all cases, the patients were treating breakthrough bleeds with activated prothrombin complex concentrate, Dr. Shapiro and coauthors wrote.

Other novel agents in clinical development include fitusiran and tissue factor pathway inhibitors, which each target a different natural anticoagulant and could result in new prophylactic options, according to the study coauthors.

“The possibility of multiple therapeutic targets may allow for a highly personalized approach to prophylaxis therapy, with traditional bypassing agents providing options when breakthrough bleeds occur,” they wrote.

In the meantime, eptacog alfa is the “de facto standard” for recombinant factor VIIa, though a new variant under development, eptacog beta, has been accepted for regulatory review in the United States. In a phase 3 clinical trial, eptacog beta appeared to provide improved efficacy and decreased dosing requirements, possibly due to increased binding affinity to endothelial protein C receptor (EPCR), the authors said.

“The addition of improved rFVIIa variants with unique pharmacological and pharmacokinetic profiles will provide new tools to treat bleeding events in inhibitor patients,” Dr. Shapiro and her colleagues wrote.

The use of traditional bypassing agents is expected to decrease over time as new and improved therapeutics are developed. Traditional agents, however, will “remain a necessity” for breakthrough bleeds in hemophilia A patients with inhibitors, and until novel agents become available for hemophilia B, the authors said.

The review article was supported by an unrestricted educational grant from HEMA Biologics, LLC, which had no involvement or editorial control in research, writing or submission. Dr. Shapiro reported disclosures related to HEMA Biologics, Shire, Novo Nordisk, Kedrion Biopharma, Bioverativ, and Genentech.
 

SOURCE: Shapiro AD, et al. J Thromb Haemost. 2018 Sep 28.

For patients with hemophilia and high-titer inhibitors, a new era of treatment has begun with the development of improved variants of traditional bypassing agents and novel, nonfactor-based, prophylactic agents, say authors of a recent review article.

©designer491/Thinkstock

“These new agents may transform the treatment of inhibitor patients and inhibitor-related bleeds, potentially decreasing morbidity and mortality and improving patients’ quality of life,” Amy D. Shapiro, MD, and coauthors wrote in the Journal of Thrombosis and Haemostasis.

Until recently, the only two bypassing agents available were activated prothrombin complex concentrates and recombinant factor VIIa, noted Dr. Shapiro, who is CEO and co-medical director of the Indiana Hemophilia and Thrombosis Center, Indianapolis, and her coauthors.

The first of the novel targeted agents, emicizumab, is a humanized, bispecific monoclonal antibody that was approved for prophylactic use in hemophilia A in the United States in November 2017.

Emicizumab could transform the treatment of patients with inhibitors, but it also requires reconsideration of how to treat breakthrough bleeds and eliminate the underlying inhibitor, the authors said.

In a phase 3 study, this biologic significantly decreased the annualized bleeding rate by 87% versus on-demand bypassing agent therapy, and by 79% versus a prophylactic bypassing agent regimen, they said, noting that 63% of patients had no bleeding events during the study.

Serious adverse events were seen in patients receiving emicizumab prophylaxis, including thrombosis in 2 out of 103 subjects and thrombotic microangiopathy in 3. In all cases, the patients were treating breakthrough bleeds with activated prothrombin complex concentrate, Dr. Shapiro and coauthors wrote.

Other novel agents in clinical development include fitusiran and tissue factor pathway inhibitors, which each target a different natural anticoagulant and could result in new prophylactic options, according to the study coauthors.

“The possibility of multiple therapeutic targets may allow for a highly personalized approach to prophylaxis therapy, with traditional bypassing agents providing options when breakthrough bleeds occur,” they wrote.

In the meantime, eptacog alfa is the “de facto standard” for recombinant factor VIIa, though a new variant under development, eptacog beta, has been accepted for regulatory review in the United States. In a phase 3 clinical trial, eptacog beta appeared to provide improved efficacy and decreased dosing requirements, possibly due to increased binding affinity to endothelial protein C receptor (EPCR), the authors said.

“The addition of improved rFVIIa variants with unique pharmacological and pharmacokinetic profiles will provide new tools to treat bleeding events in inhibitor patients,” Dr. Shapiro and her colleagues wrote.

The use of traditional bypassing agents is expected to decrease over time as new and improved therapeutics are developed. Traditional agents, however, will “remain a necessity” for breakthrough bleeds in hemophilia A patients with inhibitors, and until novel agents become available for hemophilia B, the authors said.

The review article was supported by an unrestricted educational grant from HEMA Biologics, LLC, which had no involvement or editorial control in research, writing or submission. Dr. Shapiro reported disclosures related to HEMA Biologics, Shire, Novo Nordisk, Kedrion Biopharma, Bioverativ, and Genentech.
 

SOURCE: Shapiro AD, et al. J Thromb Haemost. 2018 Sep 28.

For patients with hemophilia and high-titer inhibitors, a new era of treatment has begun with the development of improved variants of traditional bypassing agents and novel, nonfactor-based, prophylactic agents, say authors of a recent review article.

©designer491/Thinkstock

“These new agents may transform the treatment of inhibitor patients and inhibitor-related bleeds, potentially decreasing morbidity and mortality and improving patients’ quality of life,” Amy D. Shapiro, MD, and coauthors wrote in the Journal of Thrombosis and Haemostasis.

Until recently, the only two bypassing agents available were activated prothrombin complex concentrates and recombinant factor VIIa, noted Dr. Shapiro, who is CEO and co-medical director of the Indiana Hemophilia and Thrombosis Center, Indianapolis, and her coauthors.

The first of the novel targeted agents, emicizumab, is a humanized, bispecific monoclonal antibody that was approved for prophylactic use in hemophilia A in the United States in November 2017.

Emicizumab could transform the treatment of patients with inhibitors, but it also requires reconsideration of how to treat breakthrough bleeds and eliminate the underlying inhibitor, the authors said.

In a phase 3 study, this biologic significantly decreased the annualized bleeding rate by 87% versus on-demand bypassing agent therapy, and by 79% versus a prophylactic bypassing agent regimen, they said, noting that 63% of patients had no bleeding events during the study.

Serious adverse events were seen in patients receiving emicizumab prophylaxis, including thrombosis in 2 out of 103 subjects and thrombotic microangiopathy in 3. In all cases, the patients were treating breakthrough bleeds with activated prothrombin complex concentrate, Dr. Shapiro and coauthors wrote.

Other novel agents in clinical development include fitusiran and tissue factor pathway inhibitors, which each target a different natural anticoagulant and could result in new prophylactic options, according to the study coauthors.

“The possibility of multiple therapeutic targets may allow for a highly personalized approach to prophylaxis therapy, with traditional bypassing agents providing options when breakthrough bleeds occur,” they wrote.

In the meantime, eptacog alfa is the “de facto standard” for recombinant factor VIIa, though a new variant under development, eptacog beta, has been accepted for regulatory review in the United States. In a phase 3 clinical trial, eptacog beta appeared to provide improved efficacy and decreased dosing requirements, possibly due to increased binding affinity to endothelial protein C receptor (EPCR), the authors said.

“The addition of improved rFVIIa variants with unique pharmacological and pharmacokinetic profiles will provide new tools to treat bleeding events in inhibitor patients,” Dr. Shapiro and her colleagues wrote.

The use of traditional bypassing agents is expected to decrease over time as new and improved therapeutics are developed. Traditional agents, however, will “remain a necessity” for breakthrough bleeds in hemophilia A patients with inhibitors, and until novel agents become available for hemophilia B, the authors said.

The review article was supported by an unrestricted educational grant from HEMA Biologics, LLC, which had no involvement or editorial control in research, writing or submission. Dr. Shapiro reported disclosures related to HEMA Biologics, Shire, Novo Nordisk, Kedrion Biopharma, Bioverativ, and Genentech.
 

SOURCE: Shapiro AD, et al. J Thromb Haemost. 2018 Sep 28.