J. Java

Long-Term Survival Advantage and Prognostic Factors Associated With Intraperitoneal Chemotherapy Treatment in Advanced Ovarian Cancer: A Gynecologic Oncology Group Study

PURPOSE To determine long-term survival and associated prognostic factors after intraperitoneal (IP) chemotherapy in patients with advanced ovarian cancer. PATIENTS AND METHODS Data from Gynecologic Oncology Group protocols 114 and 172 were retrospectively analyzed. Cox proportional hazards regression models were used for statistical analyses. RESULTS In 876 patients, median follow-up was 10.7 years. Median survival with IP therapy was 61.8 months (95% CI, 55.5 to 69.5), compared with 51.4 months (95% CI, 46.0 to 58.2) for intravenous therapy. IP therapy was associated with a 23% decreased risk of death (adjusted hazard ratio [AHR], 0.77; 95% CI, 0.65 to 0.90; P = .002). IP therapy improved survival of those with gross residual (≤ 1 cm) disease (AHR, 0.75; 95% CI, 0.62 to 0.92; P = .006). Risk of death decreased by 12% for each cycle of IP chemotherapy completed (AHR, 0.88; 95% CI, 0.83 to 0.94; P < .001). Factors associated with poorer survival included: clear/mucinous versus serous histology (AHR, 2.79; 95% CI, 1.83 to 4.24; P < .001), gross residual versus no visible disease (AHR, 1.89; 95% CI, 1.48 to 2.43; P < .001), and fewer versus more cycles of IP chemotherapy (AHR, 0.88; 95% CI, 0.83 to 0.94; P < .001). Younger patients were more likely to complete the IP regimen, with a 5% decrease in probability of completion with each year of age (odds ratio, 0.95; 95% CI, 0.93 to 0.96; P < .001). CONCLUSION The advantage of IP over intravenous chemotherapy extends beyond 10 years. IP therapy enhanced survival of those with gross residual disease. Survival improved with increasing number of IP cycles.

Nodal metastasis risk in endometrioid endometrial cancer

OBJECTIVE: To estimate the risk for nodal metastasis in women with endometrial cancer based on uterine characteristics on pathology. METHODS: From a study of staging for uterine cancer, women were identified as being at low risk for nodal metastasis based on three specific criteria on final pathology reports: 1) less than 50% invasion, 2) tumor size less than 2 cm, and 3) well or moderately differentiated endometrioid histology. If the uterine specimen did not meet all three criteria, it was viewed as high risk for nodal metastasis. RESULTS: Nine hundred seventy-one women were included in this analysis. Approximately 40% (or 389 of 971) of patients in this study were found to be at low risk, with a rate of nodal metastasis of only 0.8% (3 of 389; exact 95% confidence interval [CI] 0.16–2.2). No statistical differences in median age, body mass index, race, performance status, missing clinical data, or open or minimally invasive techniques were found among the patients with and without nodal metastases. Patients with high-risk characteristics of their uterine specimens compared with those with low-risk characteristics have 6.3 times the risk of nodal metastasis (95% CI 1.67–23.8, P=.007). CONCLUSION: Low-risk endometrioid uterine cancer criteria may be used to help guide treatment planning for reoperation in patients with incomplete surgical staging information. LEVEL OF EVIDENCE: II

Prognostic factors for stage III epithelial ovarian cancer treated with intraperitoneal chemotherapy: A Gynecologic Oncology Group study

OBJECTIVES To determine prognostic factors for survival in ovarian cancer patients treated with intraperitoneal (IP) chemotherapy using ancillary data from cooperative group clinical trials. METHODS Data were collected from 428 patients with stage III ovarian cancer who underwent optimal surgical cytoreduction (<1 cm) followed by IP paclitaxel/platinum chemotherapy. Primary endpoints were progression free survival (PFS) and overall survival (OS). Potential prognostic variables were included in Cox proportional hazard regression models. Multivariate analysis was conducted to identify independent prognostic factors. RESULTS Median PFS was 24.9 months (95% CI, 23.0-29.2) and median OS was 61.8 months (95% CI, 55.5-69.8). Predictors for PFS were histology, surgical stage and residual disease. Age, histology, and residual disease were prognostic for OS. There were no differences in the hazard ratio for death or progression between patients with positive, negative, or unknown lymph node status. For patients receiving IP chemotherapy (n=428), 36% of patients had no residual disease with median PFS of 43.2 months (95% CI 32.5-60.4) and median OS of 110 months (95% CI, 60.0-161.3). CONCLUSIONS Age, histology, and extent of residual disease were predictors of OS in stage III patients treated with IP chemotherapy following optimal cytoreduction. Patients with no residual disease following primary surgery that are treated with adjuvant platinum based IP chemotherapy have survival measures that exceed any rates previously seen in this population.

The impact of obesity on surgical staging, complications, and survival with uterine cancer: A Gynecologic Oncology Group LAP2 ancillary data study

OBJECTIVE To determine the association of body mass index (BMI) on complications, recurrence, and survival in GOG LAP2, a randomized comparison of laparoscopic versus open staging in clinically early stage uterine cancer (EC). METHODS An ancillary data analysis of GOG LAP2 was performed. Categorical variables were compared using Pearson chi-square test and continuous variables using the Wilcoxon-Mann-Whitney and Kruskal-Wallis tests by BMI group. Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to evaluate independent prognostic factors on survival. Statistical tests were two-tailed with α=0.05, except where noted. Statistical analyses utilized R programming language. RESULTS 2596 women were included. BMI (kg/m(2)) groups were <25 (29.5%), 25-30 (28.2%), 30-35 (21%), 35-40 (10.9%), and ≥40 (10.4%). Stage (p=0.021), grade (p<0.001), and histology (p=0.005) differed by BMI. Obese women were less likely to have high risk (HR) disease (+lymph nodes/ovaries/cytology) or tumor features that met GOG99 high intermediate risk (HIR) criteria (p<0.001). Adjuvant therapy (p=0.151) and recurrence (p=0.46) did not vary by BMI. Hospitalization >2days, antibiotic use, wound infection, and venous thrombophlebitis were higher with BMI ≥40. BMI (p=0.016), age (p<0.0001), race (p=0.033), and risk group (p<0.0001) predicted all-cause mortality. BMI was not predictive of disease-specific survival (p=0.79), but age (p=0.032) and risk group (p<0.0001) were significant factors. CONCLUSION Obese women have greater surgical risk and lower risk of metastatic disease. BMI is associated with all-cause but not disease-specific mortality, emphasizing the detrimental effect of obesity (independent of EC), which deserves particular attention.

Survival in women with grade 1 serous ovarian carcinoma.

OBJECTIVE: To examine clinicopathologic variables associated with survival among women with low-grade (grade 1) serous ovarian carcinoma enrolled in a phase III study. METHODS: This was an ancillary data analysis of Gynecologic Oncology Group protocol 182, a phase III study of women with stage III-IV epithelial ovarian carcinoma treated with carboplatin and paclitaxel compared with triplet or sequential doublet regimens. Women with grade 1 serous carcinoma (a surrogate for low-grade serous disease) were included in the analysis. RESULTS: Among the 3,686 enrolled participants, 189 had grade 1 disease. The median age was 56.5 years and 87.3% had stage III disease. The median follow-up time was 47.1 months. Stratification according to residual disease after primary surgery was microscopic residual in 24.9%, 0.1–1.0 cm of residual in 51.3%, and more than 1.0 cm of residual in 23.8%. On multivariate analysis, only residual disease status (P=.006) was significantly associated with survival. Patients with microscopic residual had a significantly longer median progression-free (33.2 months) and overall survival (96.9 months) compared with those with residual 0.1–1.0 cm (14.7 months and 44.5 months, respectively) and more than 1.0 cm of residual disease (14.1 months and 42.0 months, respectively; progression-free and overall survival, P<.001). After adjustment for other variables, patients with low-grade serous carcinoma with measurable residual disease had a similar adjusted hazard ratio for death (2.12; P=.002) as their high-grade serous carcinoma counterparts with measurable disease (2.31; P<.001). CONCLUSIONS: Surgical cytoreduction to microscopic residual was associated with improved progression-free and overall survival in women with advanced-stage low-grade serous ovarian carcinoma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00011986. LEVEL OF EVIDENCE: II

Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study

BACKGROUND To determine whether time from surgery to initiation of chemotherapy impacts survival in advanced ovarian carcinoma. PATIENTS AND METHODS This is a post-trial ad hoc analysis of Gynecologic Oncology Group protocol 218, a phase III randomized, double-blind, placebo-controlled trial designed to study the antiangiogenesis agent, bevacizumab, in primary and maintenance therapy for patients with newly diagnosed advanced ovarian carcinoma. Maximum attempt at debulking was an eligibility criterion. Stage III patients, not stage IV, were required to have gross macroscopic or palpable residual disease following surgery. The survival impact of time from surgery to initiation of chemotherapy was studied using Cox regression models and stratified by treatment arm, residual disease and other clinical and pathologic factors. RESULTS One thousand seven hundred eighteen assessable patients were randomized (stage III (n = 1237); stage IV (n = 477), including those with complete resection (stage IV only, n = 81), low-volume residual (≤1 cm, n = 701), and suboptimal (>1 cm, n = 932). On multivariate analysis, time to chemotherapy initiation was predictive of overall survival (P < 0.001), with the complete resection group (i.e. stage IV) encountering an increased risk of death when time to initiation of chemotherapy exceeded 25 days (95% confidence interval 16.6-49.9 days). CONCLUSION Survival for women with advanced ovarian cancer may be adversely affected when initiation of chemotherapy occurs >25 days following surgery. Our analysis applies to stage IV only as women with stage III who underwent complete resection were not eligible for this trial. These results, however, are consistent with Gompertzian first-order kinetics where patients with microscopic residual are most vulnerable. CLINICAL TRIALS IDENTIFIER NCT00262847.

Ascites predicts treatment benefit of bevacizumab in front-line therapy of advanced epithelial ovarian, fallopian tube and peritoneal cancers: An NRG Oncology/GOG study

OBJECTIVES Predictive factors for efficacy of bevacizumab in advanced ovarian cancer have remained elusive. We investigated ascites both as a prognostic factor and as a predictor of efficacy for bevacizumab. METHODS Using data from GOG 0218, patients receiving cytotoxic therapy plus concurrent and maintenance bevacizumab were compared to those receiving cytotoxic therapy plus placebo. The presence of ascites was determined prospectively. Chi-square and Wilcoxon-Mann-Whitney tests compared baseline variables between subgroups. Survival was estimated by Kaplan-Meier method, and Cox proportional hazard models were used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on survival. RESULTS Treatment arms were balanced with respect to ascites and other prognostic factors. Overall, 886 (80%) women had ascites, 221 (20%) did not. Those with ascites were more likely to have: poorer performance status (p<0.001); serous histology (p=0.012); higher baseline CA125 (p<0.001); and suboptimal cytoreduction (p=0.004). In multivariate survival analysis, ascites was prognostic of poor OS (Adjusted HR 1.22, 95% CI 1.00-1.48, p=0.045), but not PFS. In predictive analysis, patients without ascites treated with bevacizumab had no significant improvement in either PFS (AHR 0.81, 95% CI 0.59-1.10, p=0.18) or OS (AHR 0.94, 95% CI 0.65-1.36, p=0.76). Patients with ascites treated with bevacizumab had significantly improved PFS (AHR 0.71, 95% CI 0.62-0.81, p<0.001) and OS (AHR 0.82, 95% CI 0.70-0.96, p=0.014). CONCLUSIONS Ascites in women with advanced ovarian cancer is prognostic of poor overall survival. Ascites may predict the population of women more likely to derive long-term benefit from bevacizumab.

The prognostic significance of pre- and post-treatment CA-125 in grade 1 serous ovarian carcinoma: A Gynecologic Oncology Group study

OBJECTIVES The study objective was to determine the prognostic significance of serum CA-125 levels in patients with grade 1 serous ovarian carcinoma (SOC) enrolled in a Phase III study. METHODS An ancillary analysis of a phase III study of women with advanced epithelial ovarian cancer treated with carboplatin/paclitaxel versus triplet or sequential doublet regimens. Grade 1 SOC was used as a surrogate for low-grade serous carcinoma. RESULTS Among 3686 enrolled patients, 184 (5%) had grade 1 disease and CA-125 levels available. For those with grade 1 SOC, the median patient age was 56.5; 87.3% had Stage III disease. Median follow-up was 102 months and there was no difference in pre-chemotherapy CA-125 by treatment arm (P=0.91). Median pretreatment CA-125 for those with grade 1 SOC was lower (119.1) than for patients with grade 2-3 SOC (246.7; P<0.001). In those with grade 1, pretreatment CA-125 was not prognostic of outcome. However, patients with CA-125 levels that normalized after cycle 1, 2 or 3 were 60-64% less likely to experience disease progression as compared to those who never normalized or normalized after 4 cycles (P ≤ 0.024). Normalization of CA-125 levels before the second cycle was negatively associated with death, with a HR of 0.45 (P=0.025). CONCLUSIONS Pretreatment CA-125 level was significantly lower in women with grade 1 SOC compared to those with high-grade SOC. While pretreatment CA-125 was not associated with survival, serial CA-125 measurements during chemotherapy treatment were prognostic, with normalization before the second chemotherapy cycle associated with a decreased risk of death.

Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in Gynecologic Oncology Group trials of cisplatin-based chemoradiation

OBJECTIVE Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer. METHODS Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. RESULTS Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB2 (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p=0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p=0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies. CONCLUSION Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation.

Chemotherapy-induced neutropenia as a biomarker of survival in advanced ovarian carcinoma: An exploratory study of the Gynecologic Oncology Group

OBJECTIVE To determine whether chemotherapy-induced neutropenia (C-iN) is associated with improved survival in a population of primary advanced ovarian cancer and peritoneal carcinoma patients treated with a carboplatin plus paclitaxel chemotherapy backbone. METHODS A post-hoc exploratory analysis of Gynecologic Oncology Group (GOG) protocol 182 was performed. Landmark analysis was conducted on all patients with progression-free survival >18weeks from the time of study entry. Neutropenia was defined as the absolute neutrophil count <1000mm(3). The occurrence of C-iN was analyzed according to demographic, clinicopathologic, and therapeutic intent, including age, body surface area, and treatment arm. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to evaluate independent prognostic factors and to estimate their effects on PFS and OS. RESULTS Neutropenic data was available for 3447 patients. Neutropenic (n=3196) and non-neutropenic groups (n=251) were similar in demographic and clinicopathologic characteristics. Neutropenic patients experienced significantly improved survival compared to non-neutropenic patients with the adjusted hazard ratio (HR) for death being 0.86 (95% confidence interval 0.74-0.99; p=0.041). There was no survival benefit associated with any of the treatment arms among patients with C-iN. CONCLUSION These data suggest that C-iN may represent a clinical biomarker associated with a survival advantage for patients with untreated advanced ovarian cancer. The absence of C-iN may indicate under-dosing and ultimately attenuated anti-neoplastic effect in vulnerable populations.