Helen Q. Huang

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.).

Quality of life of patients with endometrial cancer undergoing laparoscopic International Federation of gynecology and obstetrics staging compared with laparotomy: A Gynecologic Oncology Group study

PURPOSE The studys objective was to compare the quality of life (QoL) of patients with endometrial cancer undergoing surgical staging via laparoscopy versus laparotomy. PATIENTS AND METHODS The first 802 eligible patients (laparoscopy, n = 535; laparotomy, n = 267) participated in the QoL study in a Gynecologic Oncology Group (GOG) randomized trial of laparoscopy versus laparotomy (GOG 2222). Patients completed QoL assessments at baseline; at 1, 3, and 6 weeks; and at 6 months postsurgery. RESULTS In an intent-to-treat analysis, laparoscopy patients reported significantly higher Functional Assessment of Cancer Therapy-General (FACT-G) scores (P = .001), better physical functioning (P = .006), better body image (BI; P < .001), less pain (P < .001) and its interference with QoL (P < .001), and an earlier resumption of normal activities (P = .003) and return to work (P = .04) over the 6-week postsurgery period, as compared with laparotomy patients. However, the differences in BI and return to work between groups were modest, and the adjusted FACT-G scores did not meet the minimally important difference (MID) between the two surgical arms over 6 weeks. By 6 months, except for better BI in laparoscopy patients (P < .001), the difference in QoL between the two surgical techniques was not statistically significant. CONCLUSION Although the FACT-G did not show a MID between the two surgical groups, and only modest differences in return to work and BI were found between the two groups, statistically significantly better QoL across many parameters in the laparoscopy arm at 6 weeks provides modest support for the QoL advantage of using laparoscopy to stage patients with early endometrial cancer.

Health-Related Quality of Life During and After Intraperitoneal Versus Intravenous Chemotherapy for Optimally Debulked Ovarian Cancer: A Gynecologic Oncology Group Study

PURPOSE A Gynecologic Oncology Group (GOG) randomized phase III trial (GOG 172) in optimal stage III epithelial ovarian cancer showed that intravenous (IV) paclitaxel plus intraperitoneal (IP) cisplatin and paclitaxel significantly lengthened progression-free survival and overall survival compared with IV paclitaxel and cisplatin. The purpose of this report is to comprehensively evaluate the patient-reported outcomes associated with IP versus IV therapy. PATIENTS AND METHODS Four hundred fifteen eligible women were enrolled onto GOG 172 at member institutions. The Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI; which includes physical, functional, and ovarian subscales) and neurotoxicity (Ntx) and abdominal discomfort (AD) subscales were used to assess patient-reported outcomes. Assessments were completed before random assignment, before cycle 4, and 3 to 6 weeks and 12 months after treatment. RESULTS Physical and functional well-being and ovarian cancer symptoms were significantly worse in the IP arm before cycle 4 (P < .001) and 3 to 6 weeks after treatment (P = .001 for FACT-TOI). Patients in the IP arm also reported significantly worse AD before cycle 4 (P < .001) and significantly worse Ntx 3 to 6 weeks (P = .001) and 12 months (P = .003) after completing IP treatment. In general, however, the quality of life of both groups improved over time. CONCLUSION During active treatment, patients on the IP arm experienced more health-related quality-of-life disruption, AD, and Ntx compared with patients receiving conventional IV therapy. However, only Ntx remained significantly greater for IP patients 12 months after treatment. This trade-off should be included when discussing treatment options with patients. Future studies to mitigate the added burden associated with IP therapy are planned.

Quality of Life Outcomes From a Randomized Phase III Trial of Cisplatin With or Without Topotecan in Advanced Carcinoma of the Cervix: A Gynecologic Oncology Group Study

PURPOSE To prospectively assess the impact of treatment with cisplatin alone or in combination with topotecan (CT) on quality of life (QOL) in patients with advanced or recurrent cervical cancer, and to explore the prognostic value of baseline QOL scores. PATIENTS AND METHODS Patients entered on Gynecologic Oncology Group (GOG) Protocol 179 were expected to complete QOL assessments at four time points using Functional Assessment of Cancer Therapy-General (FACT-G), Cervix subscale (Cx subscale), FACT/GOG-Neurotoxicity subscale (NTX subscale), Brief Pain Inventory (BPI), and UNISCALE (UNI). Adjusting for patient age, baseline scores, and effects of time, we longitudinally examined treatment effect on QOL during and after chemotherapy. RESULTS Among patients randomly allocated to receive cisplatin (n = 146) or CT (n = 147), there were no statistically significant differences in QOL up to 9 months after randomization despite more hematologic toxicity in the combination arm. QOL assessments were completed at rates of 98%, 85%, 68%, and 59%, respectively, for the four time points, with similar rates and reasons for nonparticipation between regimens. Baseline FACT-G (P = .0016) and BPI (P = .0001) scores were significantly associated with patient age; older patients had better QOL and less pain. Baseline UNI was positively correlated with FACT-G (r = 0.66; P < .001) and Cx subscale (r = 0.29; P < .001), and negatively related to BPI (r = -0.41; P < .0001). Baseline FACT-Cx (FACT-G + Cx subscale) was associated with survival. CONCLUSION Despite increased toxicity, CT did not significantly reduce patient QOL when compared with cisplatin alone. Patient-reported QOL measures may be an important prognostic tool in advanced cervix cancer.

Validation and reduction of FACT/GOG-Ntx subscale for platinum/paclitaxel-induced neurologic symptoms: a gynecologic oncology group study

The FACT/GOG (Gynecologic Oncology Group) Neurotoxicity (Ntx) subscale for assessing platinum/paclitaxel-induced neurologic symptoms was evaluated. The 11-item questionnaire was administered to patients with advanced endometrial cancer treated with doxorubicin/cisplatin (AP) or doxorubicin/cisplatin/paclitaxel (TAP) prior to 1–7 cycles of treatment in GOG 177. The subscale was evaluated in 134 patients in the TAP group for internal reliability, construct validity, criteria validity, sensitivity to treatment differences, and change over time. Cronbach coefficients for internal consistency prior to cycles 1–7 were 0.85, 0.80, 0.84, 0.82, 0.82, 0.85, and 0.84, respectively. The area under the receiver operating characteristic curve was 0.81 for the Ntx score prior to cycle 3. The TAP arm Ntx scores increased significantly from 3.67 at baseline to 8.13 prior to cycle 7; these were higher than the AP arm Ntx scores, which increased from 3.54 at baseline to 4.72 prior to cycle 7. The four sensory items accounted for 80% of treatment differences and 63% of longitudinal changes in the observed subscale score. The 11-item Ntx subscale reliably and validly assesses platinum/paclitaxel-induced peripheral neuropathy. A reduced four-item version is an efficient alternative in measuring this toxicity in clinical trials without compromising its performance

Quality-of-Life Comparisons in a Randomized Trial of Interval Secondary Cytoreduction in Advanced Ovarian Carcinoma: A Gynecologic Oncology Group Study

PURPOSE To compare self-reported quality of life (QOL) in patients who did versus did not undergo interval secondary cytoreduction after initial surgery and combination chemotherapy for advanced ovarian cancer and to assess the association between baseline QOL scores and survival. PATIENTS AND METHODS Consenting patients participating in a Gynecologic Oncology Group (GOG) phase III treatment trial (GOG 152) completed the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire and treatment-specific supplemental questions at the third and sixth chemotherapy cycles and at 6 and 12 months after starting treatment. RESULTS For all patients, QOL decreased approximately 1 unit from the first to second assessment. Significant improvement observed at 6 months (P < .001) was sustained at 12 months, with no appreciable between-group difference. The baseline FACT-O score was associated with overall survival (P = .048) but not progression-free survival. Less neurotoxicity was reported among patients who did (38.4%) versus did not (54.0%) undergo interval secondary cytoreduction at the third assessment (P = .005), and older patients experienced more long-term effects. CONCLUSION This is the first multicenter randomized trial in ovarian cancer to longitudinally examine self-reported QOL and establish a predictive value of baseline QOL on survival, attributed primarily to the lowest-scoring quartile. Although interval secondary cytoreduction resulted in no notable long-term difference, a clinically significant improvement was seen in both arms at 6 and 12 months after starting therapy. Interestingly, there were fewer complaints of neurotoxicity at 6 months among patients who did versus did not undergo interval secondary cytoreduction.

Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer

BACKGROUND A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.).

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.

Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial

BACKGROUND Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. METHODS The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel [175 mg/m2 of body surface area] and carboplatin [area under the curve 5]) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00565851. FINDINGS Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5-62·2 for chemotherapy plus bevacizumab; IQR 40·8-59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7-46·2) versus 37·3 months (32·6-39·7) in the chemotherapy group (hazard ratio [HR] 0·829; 95% CI 0·683-1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680-0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 [12%] vs two [1%]), fatigue (27 [8%] vs eight [2%]), and proteinuria (27 [8%] vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection [n=1] and myelodysplastic syndrome [n=1]) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection [n=1], febrile neutropenia [n=1], myelodysplastic syndrome [n=1], secondary malignancy [n=1]; deaths not classified with CTCAE terms: disease progression [n=3], sudden death [n=1], and not specified [n=1]). INTERPRETATION The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. FUNDING National Cancer Institute and Genentech.

Assessment of factors that contribute to decreased quality of life in gynecologic oncology group ovarian cancer trials

The objective of this study was to assess which quality‐of‐life (QOL) line items on the Functional Assessment of Cancer Therapy‐Ovarian (FACT‐O) were associated with low QOL in women who were receiving chemotherapy for ovarian cancer.