Lisa Landrum

Improved Survival with Bevacizumab in Advanced Cervical Cancer

BACKGROUND Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).

Evaluation of the Diagnostic Accuracy of the Risk of Ovarian Malignancy Algorithm in Women With a Pelvic Mass

OBJECTIVE: It is often difficult to distinguish a benign pelvic mass from a malignancy and tools to help referring physician are needed. The purpose of this study was to validate the Risk of Ovarian Malignancy Algorithm in women presenting with a pelvic mass. METHODS: This was a prospective, multicenter, blinded clinical trial that included women who presented to a gynecologist, a family practitioner, an internist, or a general surgeon with an adnexal mass. Serum HE4 and CA 125 were determined preoperatively. A Risk of Ovarian Malignancy Algorithm score was calculated and classified patients into high-risk and low-risk groups for having a malignancy. The sensitivity, specificity, negative predictive value, and positive predictive value of the Risk of Ovarian Malignancy Algorithm were estimated. RESULTS: A total of 472 patients were evaluated with 383 women diagnosed with benign disease and 89 women with a malignancy. The incidence of all cancers was 15% and 10% for ovarian cancer. In the postmenopausal group, a sensitivity of 92.3% and a specificity of 76.0% and for the premenopausal group the Risk of Ovarian Malignancy Algorithm had a sensitivity of 100% and specificity of 74.2% for detecting ovarian cancer. When considering all women together, the Risk of Ovarian Malignancy Algorithm had a sensitivity of 93.8%, a specificity of 74.9%, and a negative predictive value of 99.0%. CONCLUSION: The use of the serum biomarkers HE4 and CA 125 with the Risk of Ovarian Malignancy Algorithm has a high sensitivity for the prediction of ovarian cancer in women with a pelvic mass. These findings support the use of the Risk of Ovarian Malignancy Algorithm as a tool for the triage of women with an adnexal mass to gynecologic oncologists. 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.

Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: An NRG Oncology and Gynecologic Oncology Group study

Purpose The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Conclusion Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

Bevacizumab for advanced cervical cancer

BACKGROUND GOG 240 was a practice-changing randomised phase 3 trial that concluded that chemotherapy plus bevacizumab for advanced cervical cancer significantly improves overall and progression-free survival, and the proportion of patients achieving an overall objective response, compared with chemotherapy alone. In this study, we aimed to analyse patient-reported outcomes in GOG 240. METHODS Eligible adult participants (aged ≥18 years) had primary stage IVB or recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0-1. Participants were randomly assigned by web-based permuted block randomisation (block size 4) in a 1:1:1:1 ratio to the four treatment groups: cisplatin (50 mg/m(2) intravenously on day 1 or 2 of the treatment cycle) and paclitaxel (135 mg/m(2) intravenously over 24 h or 175 mg/m(2) intravenously over 3 h on day 1), with or without bevacizumab (15 mg/kg intravenously on day 1 or 2), or paclitaxel (175 mg/m(2) over 3 h on day 1) and topotecan (0·75 mg/m(2) for 30 min on days 1-3) with or without bevacizumab (15 mg/kg intravenously on day 1). Treatment assignment was concealed at randomisation (everyone was masked to treatment assignment, achieved by the use of a computer encrypted numbering system at the National Cancer Institute) and became open-label when each patient was registered to the trial. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred first. The coprimary endpoints of the trial were overall survival and safety; the primary quality-of-life endpoint was the score on the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI). For our analysis of patient-reported outcomes, participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1, with the FACT-Cx TOI, items from the FACT-GOG-Neurotoxicity subscale, and a worst pain item from the Brief Pain Inventory. All patients who completed baseline quality-of-life assessments and at least one further follow-up assessment were evaluable for quality-of-life outcomes. This study is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS Between April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial, of whom 390 completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes. In these patients, patient-reported outcome completion declined from 426 (94%) of 452 (at baseline) to 193 (63%) of 307 (9 months post-cycle 1), but completion rates did not differ significantly between treatment regimens (p=0·78). The baseline FACT-Cx TOI scores did not differ significantly between patients who received bevacizumab versus those who did not (p=0·27). Compared with patients who received chemotherapy alone, patients who received chemotherapy plus bevacizumab reported FACT-Cx TOI scores that were an average of 1·2 points lower (98·75% CI -4·1 to 1·7; p=0·30). INTERPRETATION Improvements in overall survival and progression-free survival attributed to the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life. Patients responding to anti-angiogenesis therapy who maintain an acceptable quality of life could be suitable at progression for treatment with other novel therapies that might confer additional benefit. FUNDING National Institutes of Health.

Ovarian cancer in the octogenarian: Does the paradigm of aggressive cytoreductive surgery and chemotherapy still apply?

OBJECTIVE The cornerstone of therapy for advanced ovarian cancer is cytoreductive surgery (CRS) followed by platinum based chemotherapy. Optimal management for very elderly women (>80) is unclear. This study sought to review the experience with treating ovarian cancer in this population. MATERIALS AND METHODS This is a retrospective analysis of patients treated between 1991 and 2006. Outcomes included post-operative complications, chemotherapy received and overall survival. Statistical analysis was performed with SAS v.9.1. RESULTS 85 patients were identified with a mean age of 84 years. 86% of patients presented with advanced disease. Primary CRS was performed on 80%. Among patients with advanced disease who underwent either primary (68) or interval debulking (2), 74% were left with <1 cm residual disease. Post-operative complications were common with 15% of patients suffering cardiac or pulmonary complications, over 10% with prolonged ileus, wound complications or mental status changes and over 30% requiring transfusion or antibiotics. Death prior to hospital discharge and within 60 days of surgery occurred in 13% and 20%. Among patients who underwent CRS, 13% were unable to receive indicated adjuvant therapy. Among those who were treated, 25% were treated with single agent platinum and 43% completed <3 cycles. Two-year overall survival for those who underwent CRS followed by adjuvant therapy is 51%. CONCLUSIONS Our data suggests that patients >80 may not tolerate combination surgery and chemotherapy. The extremely high proportion of post-operative complications and relatively high proportion of post-operative deaths argues for a more prudent approach to this group of patients.

Do uterine risk factors or lymph node metastasis more significantly affect recurrence in patients with endometrioid adenocarcinoma

OBJECTIVES Controversy continues over the importance of lymph node (LN) status in treating and predicting recurrence in endometrial cancer. Several predictive models are available which use uterine factors to stratify risk groups. Our objective was to determine how LN status affects recurrence and survival compared to uterine factors alone. METHODS A retrospective review was performed of patients undergoing complete surgical staging for clinical stage 1 endometrioid adenocarcinoma of the uterus. Patients were assessed based on PORTEC 1 high intermediate risk (H-IR) criteria (2 factors : age>60, grade 3, >50% DOI), GOG-99 H-IR criteria (age >70+1 factor, age 50-70+2 factors, any age +3 factors: grade 2 or 3, LVSI, >50% DOI), and PORTEC 2 criteria. Rates of nodal involvement, recurrence rates, PFS, and OS were compared. RESULTS We identified 352 clinical stage I patients with positive LN in 24% (87). 175 patients met PORTEC 1 eligibility and 66 met H-IR criteria. Rates of LN positivity were similar among groups (18.4% vs 19.7%, p=0.83) but recurrence rates were dissimilar (7.4% vs 27.3%, p=0.0004). Only 93 met PORTEC 2 criteria for treatment with no association between LN status, recurrence, and eligibility. 188 patients met H-IR eligibility criteria for GOG-99 with LN positive and recurrence rates higher in the H-IR group compared to GOG-99 eligible (34.6% vs 16.3%, p=0.0004, 28.3% vs. 10.6%, p=0.0002). CONCLUSIONS Patients with H-IR disease based on uterine characteristics alone have substantial risk of nodal involvement. Knowledge of LN status may better define risk, prognosis, and postoperative treatment.

Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group.

3 Background: Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab (B), a humanized anti-VEGF monoclonal antibody, has shown single-agent activity in pretreated recurrent disease. We aimed to evaluate B in chemotherapy (CTX)-naive recurrent/persistent/metastatic cervical cancer. METHODS Using a 2x2 factorial design, patients were randomly assigned to CTX with or without B 15 mg/kg. The CTX regimens included cisplatin 50 mg/m2 plus paclitaxel 135-175 mg/m2 and topotecan 0.75 mg/m2 d1-3 plus paclitaxel 175 mg/m2d1. Cycles were repeated every 21 days until disease progression, unacceptable toxicity, or complete response. Overall survival (OS) was the primary endpoint with a reduction in the hazard of death by 30% using anti-VEGF therapy considered important (90% power, 1-sided alpha=2.5%). Final analysis was planned when 346 deaths were observed. RESULTS 452 patients were accrued from 4/6/09 to 1/3/12. The scheduled interim analysis occurred after 174 patients had died and showed that the topotecan-paclitaxel backbone was not superior to the cisplatin-paclitaxel backbone. A second interim analysis was conducted after 271 deaths. A total of 225 patients received CTX alone and 227 patients received CTX plus B. The randomized treatment groups were similar with regard to age, histology, performance status, previous platinum as a radiosensitizer, and recurrence, persistence, or advanced disease. The B-to-no-B hazard ratio (HR) of death was 0.71 (97.6% CI 0.54-0.95; 1-sided p=0.0035). Median survival was 17 m (CTX plus B) and 13.3 m (CTX alone). The RR were 48% (CTX plus B) and 36% (CTX alone) (p=0.0078). Treatment with B was associated with more grade 3-4 bleeding (5 vs 1%) thrombosis/embolism (9 vs 2%), and GI fistula (3 vs 0%). CONCLUSIONS For the first time a targeted agent significantly improved OS in gynecologic cancer. The second interim analysis crossed the boundary for efficacy, warranting early release of this information. The nearly 4-month increase in median OS with the addition of B to CTX in women with recurrent cervical cancer is considered to be clinically significant. CLINICAL TRIAL INFORMATION NCT00803062.

Stage IVB endometrial cancer: Does applying an ovarian cancer treatment paradigm result in similar outcomes? A case-control analysis

OBJECTIVE The pattern of metastasis for Stage IV endometrial carcinoma (EC) is similar to that for ovarian carcinoma (OC), hence the goal of surgical management for both diseases is optimal cytoreduction (CRS) followed by adjuvant chemotherapy. The objective of this study is to evaluate overall survival (OS) and progression-free survival (PFS) in patients with advanced EC compared to a cohort of patients with OC matched for age and residual disease. METHODS Patients with Stage IVB EC treated with curative intent between the years of 1990-2006 were identified and data abstracted regarding demographics, surgical procedures, pathologic factors, and follow-up. Two patients with Stage IIIC OC were matched for each Stage IVB EC based on age and residual disease. Stage IVB EC patients with distant metastasis were excluded. All OC patients underwent primary CRS and received combination platinum based chemotherapy. PFS and OS were evaluated using Kaplan-Meier curves and log-rank analysis. RESULTS 55 patients with Stage IVB EC underwent primary CRS and adjuvant therapy with curative intent. Optimal CRS (<1 cm residual disease) was achieved in 87% (n=48). The most common histologic subtypes were serous (53%, n=29), endometrioid (44%, n=24) and clear cell (3%, n=2). Adjuvant therapy with curative intent included platinum based combination chemotherapy (60%, n=33), platinum based chemotherapy with radiation (25%, n=14), and radiation alone (15%, n=8) depending on the time period of treatment. Seven patients had residual disease >1 cm following CRS, 6 of whom received chemotherapy alone. Two-year OS for the entire cohort was 52 vs. 76% for patients with EC compared to OC (p=0.008). For suboptimal EC vs. OC patients was 33% vs. 66% for OC patients (p=NS). EC patients with optimal CRS had OS of 57% at 2 years compared to 82% for OC patients (p=0.02). Median PFS was 13 months vs. 20 months for all EC and OC patients, respectively (p=0.01). Using a Cox proportional hazards model, optimal CRS was associated with a survival advantage over suboptimal for EC patients with a hazard ratio of 2.4. CONCLUSIONS The treatment paradigm for advanced EC has undergone a drastic evolution from palliation to CRS and combination chemotherapy. Despite similarities in disease distribution and histology, OS for EC patients with intraperitoneal metastasis does not approach that of patients with advanced OC. Further research to identify the molecular characteristics of EC may identify important differences from OC and provide insight for the development of novel primary and salvage treatment strategies for patients with advanced EC.

Patterns of recurrence in stage i endometrioid endometrial adenocarcinoma with lymphovascular space invasion

Objective The objective of this study was to determine the patterns of recurrence of stage IB–IIA endometrioid endometrial adenocarcinoma (EMCA) with lymphovascular invasion (LVSI). Methods A multicenter retrospective study of 1988 International Federation of Gynecology and Obstetrics stage IB–IIA EMCA patients with LVSI treated with surgery with or without radiation was conducted. Those with papillary serous or clear cell histologies and women treated with chemotherapy were excluded. Data regarding surgical-pathologic factors, treatment, and outcome were collected. Data were analyzed using χ2 test, Kaplan-Meier estimates, and Cox multivariate proportional hazards models. Results From 1997 to 2008, we identified 131 patients with LVSI who met entry criteria among 5 institutions. Median age was 67 years (25%–75%: 60–75 years), and median follow-up was 4.25 years (25%–75%: 3–10 years). Following surgery, 45 patients were observed (Obs), and 86 patients received adjuvant radiation. We observed 30 total relapses 30/131 (23%): 11/45 (24%) in the Obs group and 19/86 (22%) in the adjuvant radiation group. Recurrence rates were similar between staged and unstaged patients: 24% (20/84) and 21% (10/47), respectively. Among Obs patients, 82% of relapses were local, whereas in patients treated with adjuvant radiation, 84% were distant. Relapses were significantly associated with invasion of the lower uterine segment (LUS) (P = 0.035). Both cancer-related survival and overall survival (OS) were not significantly impacted by adjuvant radiation, because of distant failure rates. Adjuvant radiation significantly improved pelvic control (P = 0.007). In a multivariate analysis, OS correlated with LUS invasion (P = 0.008) and was borderline-associated with stage (P = 0.06), whereas age (P = 0.12), grade (P = 0.31), myometrial invasion (P = 0.99), and radiation treatment (P = 0.23) were not. Conclusions Overall recurrence rates for stage IB–IIA EMCA patients with LVSI are high (23%). Although adjuvant radiation therapy improved pelvic control, it did not impact recurrence rates, cancer-related survival, and OS, likely secondary to distant failures. The role of systemic therapy with or without radiotherapy for early-stage EMCA with LVSI should be evaluated, particularly in patients with high-grade tumors or involvement of the LUS.