On the basis of the statistically significantly improved [progression-free survival], together with response rate and safety results, bevacizumab combined with chemotherapy should be considered a standard option in platinum-resistant ovarian cancer.
—Eric Pujade-Lauraine, MD, PhD, and colleagues
The results of these prespecified [quality-of-life] analyses indicate that the benefits of bevacizumab in AURELIA extended beyond the prolongation of [progression-free survival] to include greater improvements in abdominal/GI symptoms and other aspects of [quality of life]…
—Martin R. Stockler, MD, and colleagues
Single-agent chemotherapy is standard in platinum-resistant ovarian cancer. In the open-label phase III AURELIA trial reported in the Journal of Clinical Oncology, Eric Pujade-Lauraine, MD, PhD, of Université Paris Descartes, and colleagues found that the addition of bevacizumab (Avastin) to chemotherapy resulted in significant improvement in progression-free survival, the primary study endpoint, and objective response rate in patients with platinum-resistant ovarian cancer.1 However, no significant difference in overall survival was observed.
In the trial, investigators selected chemotherapy consisting of pegylated liposomal doxorubicin at 40 mg/m2 on day 1 every 4 weeks (n = 126), paclitaxel at 80 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (n = 115), or topotecan at 4 mg/m2 on days 1, 8, and 15 every 4 weeks or 1.25 mg/m2 on days 1 to 5 every 3 weeks (n = 120) for women with measurable/assessable ovarian cancer that had progressed within 6 months of completing platinum-based therapy. Recruitment was capped for each chemotherapy cohort, with the doxorubicin cohort being the first to be fully recruited, in October 2010, and recruitment to the paclitaxel and topotecan cohorts being completed in April 2011.
Once chemotherapy was selected, patients were randomly assigned to receive chemotherapy alone (n = 182) or with bevacizumab (n = 179) at 10 mg/kg every 2 weeks or at 15 mg/kg every 3 weeks in patients receiving topotecan on the every-3-week schedule. Patients with refractory disease or a history of bowel obstruction as well as those who had received more than two prior anticancer regimens were ineligible.
Patients were stratified according to selected chemotherapy, prior antiangiogenic therapy, and platinum-free interval. Crossover to single-agent bevacizumab was permitted after disease progression in patients in the chemotherapy-alone group.
The bevacizumab/chemotherapy and chemotherapy-alone groups were generally balanced for age (median, 62 and 61 years), ovary as origin of cancer (93% and 86%), histology (serous/adenocarcinoma in 87% and 84%, endometrioid in 5% in both, clear cell in 2% and 7%), histologic grade (1 in 6% and 5%, 2 in 30% and 26%, 3 in 53% and 58%), prior antiangiogenic therapy (7% and 8%), receipt of two prior chemotherapy regimens (40% and 43%), platinum-free interval less than 3 months (28% and 25%), Eastern Cooperative Oncology Group performance status (0 in 60% and 54%, 1 in 32% and 38%, 2 in 7% and 6%), measurable disease (80% and 79%), and presence of ascites (33% and 30%).
Improved Progression-Free Survival
Median follow-up was 13.0 months in the bevacizumab/chemotherapy group and 13.9 months in the chemotherapy-alone group. Median progression-free survival by RECIST criteria was 6.7 vs 3.4 months (hazard ratio [HR] = 0.48, P < .001, on unstratified log-rank test; HR = 0.42, P < .001, on stratified log-rank test). The progression-free survival benefit was consistent across all subgroups evaluated.
Response Rate and Overall Survival
Response was evaluable by RECIST or Gynecologic Cancer Intergroup cancer antigen (GCIC CA)-125 criteria in 350 patients. Objective response rates were 30.9% in the combination group and 12.6% in the chemotherapy-alone group (P < .001), including 27.3% vs 11.8% on RECIST (n = 287; P = .001) and 31.8% vs 11.6% on GCIG CA-125 criteria (n = 297; P < .001).
At the time of data cutoff for the final overall survival analysis, 40% of patients in the chemotherapy-alone group had received single-agent bevacizumab after progression. Median overall survival was 16.6 months in the bevacizumab/chemotherapy group and 13.3 months in the chemotherapy-alone group (HR = 0.85, P = .174).
Among patients with ascites at baseline, paracentesis was performed in 17% of those in the chemotherapy-alone group and in 2% of those in the bevacizumab/chemotherapy group (one patient, who received paracentesis on the first day of bevacizumab treatment).
Adverse events of special interest with regard to bevacizumab occurred in 57.0% of the bevacizumab/chemotherapy group vs 40.3% of the chemotherapy-alone group, including grade ≥ 2 hypertension (20% vs 7%), gastrointestinal (GI) perforation (2% vs 0%), and fistula/abscess (2% vs 0%). Grade ≥ 3 adverse events included hypertension (7% vs 1%), proteinuria (2% vs 0%), GI perforation (2% vs 0%), thromboembolic events (5% vs 4%), fistula/abscess (1% vs 0%), and reversible posterior leukoencephalopathy syndrome (1% vs 0%).
Rates of grade ≥ 3 bleeding (1% in both) and congestive heart failure (1% in both) were identical in the two groups, and no cases of wound healing complications or other cardiac disorders were observed in either group. Among other grade ≥ 3 adverse events, the frequency of neutropenia was similar in both groups, and leukopenia and events potentially related to tumor burden, such as fatigue, abdominal pain, vomiting and dyspnea, were more common in the chemotherapy-alone group. Hand-foot syndrome and peripheral sensory neuropathy were more common in the bevacizumab/chemotherapy group, likely reflecting the longer exposure to chemotherapy in this group associated with prolonged time to progression.
Five deaths (2.8% of patients) in each group were considered to be not primarily due to progressive disease, including death due to infection with neutropenia, GI hemorrhage, GI perforation, cardiac arrest, and shock in the bevacizumab/chemotherapy group and to infection with neutropenia, cardiac failure, septic shock, peritonitis, and GI hemorrhage in the chemotherapy-alone group.
Dr. Pujade-Lauraine and colleagues concluded:
Adding bevacizumab to chemotherapy statistically significantly improved [progression-free survival] and [objective response rate]; the [overall survival] trend was not significant. No new safety signals were observed…. AURELIA is the first trial to our knowledge demonstrating a significant [progression-free survival] benefit of either a combination regimen or a biologic agent in platinum-resistant ovarian cancer. On the basis of the statistically significantly improved [progression-free survival], together with response rate and safety results, bevacizumab combined with chemotherapy should be considered a standard option in platinum-resistant ovarian cancer.
A patient-reported outcomes analysis in the trial, reported separately in the Journal of Clinical Oncology by Martin R. Stockler, MD, of The University of Sydney, and colleagues, showed significant improvement in abdominal/GI symptoms with the bevacizumab/chemotherapy regimen, as well as significant improvement in other symptoms and global health/quality-of-life measures.2
A prespecified secondary endpoint in AURELIA, patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30), EORTC QLQ-Ovarian Cancer Module 28 (EORTC QLQ-OV28), and the Functional Assessment of Cancer Therapy-Ovarian Cancer symptom index (FOSI) at baseline and every two to three cycles (8/9 weeks) until disease progression. The primary hypothesis was that a greater proportion of patients in the bevacizumab/chemotherapy group would achieve absolute improvement of ≥ 15% (≥ 15 points) on the QLQ-OV28 abdominal/GI symptom subscale (items 31–36) at week 8/9.
Patients with missing week 8/9 questionnaires were included as unimproved. Questionnaires from all assessments through disease progression were analyzed using a linear mixed-model repeated-measures analysis of patient-reported outcomes as continuous variables.
Baseline questionnaires were completed by 155 patients in the bevacizumab/chemotherapy group and 162 in the chemotherapy-alone group (87.8% of all patients). Questionnaires were completed at week 8/9 by 122 patients (78.8%) and 84 patients (51.9%), respectively. There were no marked differences in baseline characteristics between patients evaluable for patient-reported outcomes and the intent-to-treat population, and mean scores for each patient-reported outcome scale were similar in the two treatment groups.
At week 8/9, a ≥ 15% improvement in abdominal/GI symptoms on the EORTC QLQ-OV28 was reported by 21.9% of patients in the bevacizumab/chemotherapy group vs 9.3% patients in the chemotherapy-alone group (difference = 12.7%, P = .002). Sensitivity analyses, including analysis with improvement defined as a ≥ 10% increase, yielded similar results.
Analysis excluding all patients with questionnaires missing at week 8/9, to a large degree reflecting patients with early progressive disease, showed a smaller, nonsignificant effect size for bevacizumab/chemotherapy vs chemotherapy alone (27.9% vs 17.9%, difference = 10.0%, P = .13). Subgroup analyses among 233 patients with sufficient symptoms at baseline (score ≥ 15) to allow detectable improvement (29.6% vs 12.7%, P = .002) and among 99 patients with ascites at baseline (44.0% vs 4.1%, P < .001) also showed improved outcome with bevacizumab/chemotherapy, as did analysis at week 16/18 among all patients (15.5% vs 5.6%, P = .005).
The mixed-model repeated-measures analysis of score as a continuous variable showed a difference of 6.4 points favoring the bevacizumab/chemotherapy group (P = .015).
Overall Symptoms and Quality of Life
With regard to secondary endpoints, significantly greater proportions of bevacizumab/chemotherapy patients had ≥ 15% improvement in FOSI score (≥ 5 point increase) at week 8/9 among all patients (12.2% vs 3.1%, P = .003), among a subgroup of 267 with sufficient symptoms at baseline (score < 27) to allow detectable improvement (14.6% vs 3.6%, P = .002), among the subgroup of 99 with ascites at baseline (21.6% vs 2.1%, P = .004), as well as at week 16/18 among all patients (9.0% vs 1.3%, P = .002). Mixed-model repeated-measures analysis did not show important treatment effects either overall or at week 8/9 (between-group difference = 0.7, P = .21).
For the QLQ-C30 findings at week 8/9, significantly greater proportions of bevacizumab/chemotherapy patients had ≥ 15% improvement on the physical function (12.0% vs 1.8%, P < .001), role function (22.2% vs 10.0%, P = .003), social function (22.7% vs 12.6%, P = .020), and global health status/quality-of-life subscales (24.4% vs 13.0%, P = .011), with a nonsignificantly greater proportion having improvement on the emotional function subscale (23.8% vs 15.5%, P = .072).
When patients with missing questionnaires at week 8/9 were excluded from analysis, only the difference on the physical function subscale remained significant (P = .006). The mixed-model repeated-measures analysis of the global health/quality-of-life subscale showed no significant difference between treatment groups.
Dr. Stockler and colleagues concluded:
Bevacizumab increased the proportion of patients achieving a 15% improvement in patient-reported abdominal/gastrointestinal symptoms during chemotherapy for platinum-resistant ovarian cancer…. The results of these prespecified [quality-of-life] analyses indicate that the benefits of bevacizumab in AURELIA extended beyond the prolongation of [progression-free survival] to include greater improvements in abdominal/GI symptoms and other aspects of [quality of life], supporting a role for bevacizumab with chemotherapy in the treatment of women with platinum-resistant ovarian cancer. ■
Disclosure: The AURELIA study was sponsored by F. Hoffmann-La Roche. For full disclosures of the study authors, visit jco.ascopubs.org.
1. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. March 17, 2014 (early release online).
2. Stockler MR, Hilpert F, Friedlander M, et al: Patient-reported outcome results from the open-label phase III AURELIA trial evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer. J Clin Oncol. March 31, 2014 (early release online).