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Clinical Trial
. 2023 May;24(5):468-482.
doi: 10.1016/S1470-2045(23)00147-X. Epub 2023 Apr 17.

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial

Linda R Mileshkin  1 , Kathleen N Moore  2 , Elizabeth H Barnes  3 , Val Gebski  3 , Kailash Narayan  4 , Madeleine T King  5 , Nathan Bradshaw  3 , Yeh Chen Lee  3 , Katrina Diamante  3 , Anthony W Fyles  6 , William Small Jr  7 , David K Gaffney  8 , Pearly Khaw  4 , Susan Brooks  9 , J Spencer Thompson  2 , Warner K Huh  10 , Cara A Mathews  11 , Martin Buck  12 , Aneta Suder  13 , Thomas E Lad  14 , Igor J Barani  15 , Christine H Holschneider  16 , Sylvia Van Dyk  4 , Michael Quinn  17 , Danny Rischin  18 , Bradley J Monk  19 , Martin R Stockler  3
Affiliations
Clinical Trial

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial

Linda R Mileshkin et al. Lancet Oncol. 2023 May.

Abstract

Background: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy.

Methods: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088.

Findings: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths.

Interpretation: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting.

Funding: National Health and Medical Research Council and National Cancer Institute.

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Conflict of interest statement

Declaration of interests LRM reports grant from National Health and Medical Research Council (NHMRC) Australia for support for the present manuscript. KNM reports research funding to institution outside of submitted work from PTC Therapeutics, Lilly, Merck, and GSK/Tesaro; participation on an Advisory Board for AstraZeneca, Aravive, Alkemeres, Addi, Blueprint Medicines, Eisai, EMD Serono, Elevar Therapeutics, GSK/Tesaro, Genentench/Roche, Hengrui, Immunogen, INXmed, IMab, Lilly, Mereo, Mersana Therapeutics, Merck, Myriad, Novartis, Novocure, OncXerna, Onconova Therapeutics, Tarveda Therapeutics, VBL Therapeutics, and Verastem Oncology; and leadership role as Associate Director of Gynecological Oncology Group Partners and on the Board of Directors for GOG Foundation. WSJ reports honoraria for invited talks from Carl Zeiss; payments made for participation on a data and safety monitoring board from Novocure; and Co-Chair of Gynaecological Committee until June 2020 with NRG Oncology. DKG reports grants and contracts from Elekta; payment or honoraria from ANZGOG, payment for expert testimony from in a Montana court case, participating on a DSMB or Advisory Board for Merck; and leadership role in NRG Oncology as Co-Chair of the Gyn Committee. PK reports funding outside of this submitted work from ANZGOG Fund for New Research and Medical Research Future Fund Reproductive Cancers Grant; is the Deputy Chair of Treatment Pillar for the National Cervical Cancer Elimination Strategy; is on the Board Director for ANZGOG and AMA Victoria. WKH reports consulting fee payments from AstraZeneca and SeaGen and payment for participation on a DSMB from Syneos and Inovio. CAM reports support for the present manuscript from National Cancer Institute, and funding to their institution from Syros, Deciphera, Astellas Pharma GlaxoSmithKline/Tesaro, Seagen, Genmab, EMD Serono, Merck, Regeneron, Moderna, Astra Zeneca, and Genentech, outside of the submitted work. TEL reports support for the present manuscript from the National Cancer Institute Community Research Program and support for attending meetings and travel from SHCC MU NCORP Grant. CHH reports support for the present manuscript from GOG and NRG, and leadership role in the Executive Board, Western Association of Gynecologic Oncology, and the 2023 Program Committee Chair, Western Association of Gynecologic Oncology. MQ reports personal payment as Chair of an independent data and safety monitoring committee for the Garnet Study and Tesaro Study from GSK, and Chair of DSMB for the COMPASS Study. DR reports trial funding all to institution outside of submitted work from MSD, GSK, Regeneron, Roche, Bristol Myers Squibb, Kura, ALX Oncology and participation on a DSMB for MSD, Regeneron, Sanofi. BJM reports consulting fees from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, and VBL Therapeutics, Verastem, Zentalis and payment or honoraria from AstraZeneca, Merck, Myriad, TESARO/GSK, Roche/Genentech, Clovis, and Easai. MRS reports grant to institution from NHMRC Australia for support for the present manuscript, and grants to their institution from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Tilray. All other authors declare no competing interests.

Figures

Figure 1:
Figure 1:
Trial profile
Figure 2:
Figure 2:
Kaplan-Meier estimates for overall survival
Figure 3:
Figure 3:
Kaplan-Meier estimates for progression-free survival
Figure 4:
Figure 4:
Forest plots estimates for overall survival and progression-free survival
Figure 4:
Figure 4:
Forest plots estimates for overall survival and progression-free survival
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