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