Addition of Bevacizumab to Chemotherapy Improves Patient-Reported Outcomes in Platinum-Resistant Ovarian Cancer
The recently reported open-label phase III AURELIA trial showed 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 women with recurrent platinum-resistant ovarian cancer. As reported in the Journal of Clinical Oncology by Stockler et al, analysis of patient-reported outcomes in the trial showed significant improvement in abdominal/gastrointestinal (GI) symptoms with bevacizumab/chemotherapy, as well as significant improvement in other symptoms and global health/quality-of-life measures.
Study Details
In AURELIA, 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 at topotecan 4 mg/m2 on days 1, 8, and 15 every 4 weeks or at 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. Crossover to single-agent bevacizumab was permitted after disease progression in patients in the chemotherapy-alone group.
Patient-reported outcomes, a prespecified secondary endpoint in the trial, 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 outcomes scale were similar in the two treatment groups.
Improvement in Abdominal/GI Symptoms
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% vs1.3%, 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.
The investigators 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.
Martin R. Stockler, MD, of The University of Sydney, is the corresponding author for the Journal of Clinical Oncology article on patient-reported outcomes in AURELIA.
The study was sponsored by F. Hoffmann-La Roche (Basel, Switzerland). For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
