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Adverse events in the placebo arm of maintenance therapy trials in advanced ovarian cancer: A systematic review and meta-analysis

  • Sandy Simon
    Correspondence
    Corresponding author: Department of Medical Oncology, St George Hospital, Gray St, Kogarah, Sydney, 2217 NSW, Australia.
    Affiliations
    Department of Medical Oncology, St George Hospital, Gray St, Kogarah, Sydney, NSW, 2217, Australia
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  • Katherine E. Francis
    Affiliations
    Department of Medical Oncology, St George Hospital, Gray St, Kogarah, Sydney, NSW, 2217, Australia

    National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Locked Bag 77, Camperdown, NSW, 1450, Australia
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  • Janene E. Dalrymple
    Affiliations
    Department of Medical Oncology, St George Hospital, Gray St, Kogarah, Sydney, NSW, 2217, Australia
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  • Val Gebski
    Affiliations
    National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Locked Bag 77, Camperdown, NSW, 1450, Australia
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  • Sarah J. Lord
    Affiliations
    National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Locked Bag 77, Camperdown, NSW, 1450, Australia
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  • Michael Friedlander
    Affiliations
    University of New South Wales Clinical School, Prince of Wales Hospital, Barker St, Randwick, NSW, 2031, Australia

    Department of Medical Oncology, Prince of Wales Hospital, Barker St, Randwick, NSW, 2031, Australia
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  • Chee Khoon Lee
    Affiliations
    Department of Medical Oncology, St George Hospital, Gray St, Kogarah, Sydney, NSW, 2217, Australia

    National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Locked Bag 77, Camperdown, NSW, 1450, Australia
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      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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