Highlights
- •The majority of patients on maintenance placebo experienced adverse events (AEs).
- •AEs were associated with dose delays, reductions and discontinuation of placebo.
- •The underlying aetiology is complex and likely involves the nocebo phenomenon.
- •AEs in randomised trials may not reflect true investigational treatment toxicities.
Abstract
Background
Maintenance treatment is standard of care for front-line (FL) and platinum-sensitive
recurrent ovarian cancer (PSROC) following response to chemotherapy. Adverse events
(AEs) on maintenance therapies are common and usually attributable to investigational
treatments but could also be unrelated. Randomised controlled trial (RCT) with blinded
placebo design is the gold standard for determining the relative differences in efficacy
and AEs between treatment arms. We performed a meta-analysis to quantify AE rates
in placebo arms of RCTs to determine AEs not due to investigational agents.
Methods
We performed an electronic search to identify eligible RCTs in FL and PSROC settings.
Data from placebo arms were extracted and pooled using the inverse variance method
to determine the risk of any AE, overall and specific grade 3 or higher (G ≥ 3) AEs,
and AE-related treatment delay, reduction and discontinuation.
Results
We identified 13 eligible RCTs (FL, N = 8; PSROC, N = 5) with 2224 patients who received
placebo (FL, N = 1541; PSROC, N = 683). The majority experienced an AE of any grade
(FL, 93.0%; PSROC, 95.2%). Substantial proportions experienced G ≥ 3 AEs (FL, 14.6%;
PSROC, 18.2%). In the FL setting, AEs led to treatment delay in 14.4%, dose reduction
in 4.1% and discontinuation in 2.6%. Findings were similar for PSROC: 8.4%, 5.5% and
2.1%, respectively.
Conclusions
AEs not due to investigational agents are common in ovarian cancer patients in maintenance
therapy RCTs. Potential explanations include the nocebo effect, residual toxicities
from previous treatment or underlying disease. Further research is required to identify
better approaches to assessing AEs in this population.
Keywords
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References
- Global cancer observatory: cancer today.International Agency for Research on Cancer, Lyon, France2020 (Available from:)
- Ovarian cancer statistics.CA Cancer J Clin. 2018; 68 (2018): 284-296
- Cancer of the ovary, fallopian tube, and peritoneum.Int J Gynaecol Obstet. 2018; 143: 59-78
- Molecular and clinical predictors of improvement in progression-free survival with maintenance PARP inhibitor therapy in women with platinum-sensitive, recurrent ovarian cancer: a meta-analysis.Cancer. 2021; 127: 2432-2441
- Maintenance chemotherapy for ovarian cancer.Cochrane Database Syst Rev. 2013; (2013)Cd007414
- Latest clinical evidence of maintenance therapy in ovarian cancer.Curr Opin Obstet Gynecol. 2020; 32: 15-21
- Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2021; 22: 620-631
- It is not just the drugs that matter: the nocebo effect.Cancer Metastasis Rev. 2019; 38: 315-326
- The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ. 2021; 372: n71
- Higgins J. Thomas J. Chandler J. Cumpston M. Li T. Page M. Cochrane handbook for systematic reviews of interventions. Cochrane, 2021
- Assessing bias in studies of prognostic factors.Ann Intern Med. 2013; 158: 280-286
- A phase III randomized trial of BAY 12-9566 (tanomastat) as maintenance therapy in patients with advanced ovarian cancer responsive to primary surgery and paclitaxel/platinum containing chemotherapy: a National Cancer Institute of Canada Clinical Trials Group Study.Gynecol Oncol. 2006; 102: 300-308
- Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer.J Clin Oncol. 2009; 27: 418-425
- Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO–the MIMOSA study.J Clin Oncol. 2013; 31: 1554-1561
- A randomized phase II trial of maintenance therapy with Sorafenib in front-line ovarian carcinoma.Gynecol Oncol. 2013; 130: 25-30
- Incorporation of pazopanib in maintenance therapy of ovarian cancer.J Clin Oncol. 2014; 32: 3374-3382
- Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2018; 379: 2495-2505
- Niraparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2019; 381: 2391-2402
- Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.Lancet Oncol. 2020; 21: 1661-1672
- Overall survival results of AGO-OVAR16: a phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer.Gynecol Oncol. 2019; 155: 186-191
- Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.N Engl J Med. 2012; 366: 1382-1392
- Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy.Br J Cancer. 2018; 119: 1075-1085
- Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med. 2016; 375: 2154-2164
- Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1274-1284
- Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 390: 1949-1961
- Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2020; 21: 710-722
- Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial.Ann Oncol. 2021; 32: 512-521
- Incidence of placebo adverse events in randomized clinical trials of targeted and immunotherapy cancer drugs in the adjuvant setting: a systematic review and meta-analysis.JAMA Netw Open. 2018; 1: e185617-e
- The placebo effect in thyroid cancer: a meta-analysis.Eur J Endocrinol. 2016; 174: 465-472
- Comparative “nocebo effects” in older patients enrolled in cancer therapeutic trials: observations from a 446-patient cohort.Cancer. 2017; 123: 4193-4198
- Placebo and nocebo effects in randomized double-blind clinical trials of agents for the therapy for fatigue in patients with advanced cancer.Cancer. 2010; 116: 766-774
- Development and validation of the measure of ovarian symptoms and treatment concerns for surveillance (MOST-S26): an instrument to complement the clinical follow-up of women with ovarian cancer after completion of first-line treatment.Gynecol Oncol. 2021; 163: 398-407
- The nocebo effect of drugs.Pharmacol Res Perspect. 2016; 4 (e00208–e)
- Self-evaluation of adjuvant chemotherapy-related adverse effects by patients with breast cancer.JAMA Oncol. 2016; 2: 445-452
Article info
Publication history
Published online: May 30, 2022
Accepted:
April 14,
2022
Received in revised form:
April 8,
2022
Received:
February 2,
2022
Footnotes
☆This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
