Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240)

Abstract

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.

Conflict of interest statement

Declaration of interest statement

Dr. Richard T. Penson served on Advisory Boards and received research funding from Genentech Inc. Dr. Bradley Monk discloses his institution has received grants/contracts from Genentech. Dr. Monk has received honorarium from speakers bureaus from Roche/Genentech and has been a consultant for Roche/Genentech.

Dr. Krishnansu Tewari served as a consultant for Genentech/Roche (travel/accommodations) to advisory board.

All other co-authors have no conflicts of interest to report.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Patient-reported outcomes (PROs) using the Functional Assessment of Cancer Therapy – Cervix (FACT-Cx) Trial Outcome Index (TOI) by treatment group

During the period of assessment, the mean FACT-Cx TOI scores did not significantly differ between the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 1A); cisplatin and paclitaxel with and without bevacizumab (Panel 1B); topotecan and paclitaxel with and without bevacizumab (Panel 1C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 1. Patient-reported outcomes (PROs) using the Functional Assessment of Cancer Therapy – Cervix (FACT-Cx) Trial Outcome Index (TOI) by treatment group

During the period of assessment, the mean FACT-Cx TOI scores did not significantly differ between the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 1A); cisplatin and paclitaxel with and without bevacizumab (Panel 1B); topotecan and paclitaxel with and without bevacizumab (Panel 1C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 1. Patient-reported outcomes (PROs) using the Functional Assessment of Cancer Therapy – Cervix (FACT-Cx) Trial Outcome Index (TOI) by treatment group

During the period of assessment, the mean FACT-Cx TOI scores did not significantly differ between the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 1A); cisplatin and paclitaxel with and without bevacizumab (Panel 1B); topotecan and paclitaxel with and without bevacizumab (Panel 1C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 2. Patient-reported outcomes (PROs) using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group (FACT/GOG) Neurotoxicity subscale (Ntx)

During the period of assessment, patients treated with chemotherapy plus bevacizumab as well as those on the topotecan-paclitaxel backbone who received bevacizumab had less odds of reporting neurotoxicity. Among those patients reporting neurotoxcity there were no significant differences in severity of neurotoxic symptoms for the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 2A); cisplatin and paclitaxel with and without bevacizumab (Panel 2B); topotecan and paclitaxel with and without bevacizumab (Panel 2C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 2. Patient-reported outcomes (PROs) using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group (FACT/GOG) Neurotoxicity subscale (Ntx)

During the period of assessment, patients treated with chemotherapy plus bevacizumab as well as those on the topotecan-paclitaxel backbone who received bevacizumab had less odds of reporting neurotoxicity. Among those patients reporting neurotoxcity there were no significant differences in severity of neurotoxic symptoms for the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 2A); cisplatin and paclitaxel with and without bevacizumab (Panel 2B); topotecan and paclitaxel with and without bevacizumab (Panel 2C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 2. Patient-reported outcomes (PROs) using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group (FACT/GOG) Neurotoxicity subscale (Ntx)

During the period of assessment, patients treated with chemotherapy plus bevacizumab as well as those on the topotecan-paclitaxel backbone who received bevacizumab had less odds of reporting neurotoxicity. Among those patients reporting neurotoxcity there were no significant differences in severity of neurotoxic symptoms for the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 2A); cisplatin and paclitaxel with and without bevacizumab (Panel 2B); topotecan and paclitaxel with and without bevacizumab (Panel 2C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 3. Patient-reported outcomes (PROs) using the Brief Pain Inventory (BPI) single item

During the period of assessment, there were no significant differences in the reporting of pain or in the severity of pain for the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 3A); cisplatin and paclitaxel with and without bevacizumab (Panel 3B); topotecan and paclitaxel with and without bevacizumab (Panel 3C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 3. Patient-reported outcomes (PROs) using the Brief Pain Inventory (BPI) single item

During the period of assessment, there were no significant differences in the reporting of pain or in the severity of pain for the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 3A); cisplatin and paclitaxel with and without bevacizumab (Panel 3B); topotecan and paclitaxel with and without bevacizumab (Panel 3C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 3. Patient-reported outcomes (PROs) using the Brief Pain Inventory (BPI) single item

During the period of assessment, there were no significant differences in the reporting of pain or in the severity of pain for the following treatment groups: chemotherapy alone (both backbones) vs chemotherapy (both backbones) with bevacizumab (Panel 3A); cisplatin and paclitaxel with and without bevacizumab (Panel 3B); topotecan and paclitaxel with and without bevacizumab (Panel 3C). Ctx: chemotherapy; Bev: bevacizumab; CP: cisplatin and paclitaxel; TP: topotecan and paclitaxel.

Figure 4. Effect of substitution of topotecan for cisplatin on the FACT-Cx TOI, FACT/GOG-Ntx, and BPI

During the period of assessment, the mean FACT-Cx TOI (Panel 4A) and FACT/GOG-Ntx (Panel 4B) scores did not significantly differ between the cisplatin-paclitaxel and topotecan-paclitaxel chemotherapy backbones. Among patients reporting pain the treatment difference in the reported BPI pain score was not constant over the assessment time (p=0.02) (Panel 4C).

Figure 4. Effect of substitution of topotecan for cisplatin on the FACT-Cx TOI, FACT/GOG-Ntx, and BPI

During the period of assessment, the mean FACT-Cx TOI (Panel 4A) and FACT/GOG-Ntx (Panel 4B) scores did not significantly differ between the cisplatin-paclitaxel and topotecan-paclitaxel chemotherapy backbones. Among patients reporting pain the treatment difference in the reported BPI pain score was not constant over the assessment time (p=0.02) (Panel 4C).

Figure 4. Effect of substitution of topotecan for cisplatin on the FACT-Cx TOI, FACT/GOG-Ntx, and BPI

During the period of assessment, the mean FACT-Cx TOI (Panel 4A) and FACT/GOG-Ntx (Panel 4B) scores did not significantly differ between the cisplatin-paclitaxel and topotecan-paclitaxel chemotherapy backbones. Among patients reporting pain the treatment difference in the reported BPI pain score was not constant over the assessment time (p=0.02) (Panel 4C).

Figure 5. Quartile Analysis of patient-reported outcomes (PROs) using the Functional Assessment of Cancer Therapy – Cervix (FACT-Cx) Trial Outcome Index (TOI)

For the entire study population, the baseline FACT-Cx TOI was significantly associated with overall survival (OS) (Panel 5A) and progression-free survival (PFS) (Panel 5B).

Figure 5. Quartile Analysis of patient-reported outcomes (PROs) using the Functional Assessment of Cancer Therapy – Cervix (FACT-Cx) Trial Outcome Index (TOI)

For the entire study population, the baseline FACT-Cx TOI was significantly associated with overall survival (OS) (Panel 5A) and progression-free survival (PFS) (Panel 5B).