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Lancet Oncol. 2019 Sep;20(9):1273-1285. doi: 10.1016/S1470-2045(19)30395-X. Epub 2019 Jul 22.

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.

Author information

1
Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands. Electronic address: s.m.de_boer.onco@lumc.nl.
2
Department of Clinical Oncology, Barts Health NHS Trust, London, UK.
3
Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
4
Department of Surgical Sciences, Gynecologic Oncology, Città della Salute and S Anna Hospital, University of Turin, Turin, Italy.
5
Canadian Cancer Trials Group, Department of Obstetrics and Gynaecology, University of Sherbrooke, Sherbrooke, QC, Canada.
6
Department of Radiotherapy, Institut Gustave Roussy, Villejuif, France.
7
Department of Medical Oncology, Radboudumc, Nijmegen, Netherlands.
8
Cancer Research UK, London, UK; UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
9
Division of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
10
Division of Radiation Oncology, ASST-Lecco, Ospedale AManzoni, Lecco, Italy.
11
Canadian Cancer Trials Group, Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.
12
Department of Radiotherapy, Centre Hospitalier Régional Universitaire de Besançon, Besançon, France.
13
Department of Radiation Oncology, University Medical Center Utrecht, Netherlands.
14
Institute of Cancer Sciences, University of Manchester, Manchester, UK.
15
Department of Gynaecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
16
Department of Pathology, Central Manchester Hospitals NHS Foundation Trust, Manchester Royal Infirmary, Manchester, UK.
17
Department of Radiation Oncology, Auckland City Hospital, Auckland, New Zealand.
18
Department of Oncology - Radiotherapy, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy.
19
Department of Gynaecologic Oncology, Hôpital Notre-Dame de Montreal, Montreal, QC, Canada.
20
Department of Radiation Oncology, Centre Henri Becquerel, Rouen, France.
21
Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht, Netherlands; GROW - School for Oncology and Developmental Biology, Maastricht, Netherlands.
22
Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.
23
Department of Cellular Pathology, Barts Health NHS Trust, London, UK.
24
Department of Radiation Oncology, Liverpool Cancer Therapy Centre, Liverpool, NSW, Australia.
25
Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy.
26
Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.
27
Comprehensive Cancer Center Netherlands, Rotterdam, Netherlands.
28
Department of Medical Statistics, Leiden University Medical Center, Leiden, Netherlands.

Erratum in

Abstract

BACKGROUND:

The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis.

METHODS:

In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.

FINDINGS:

Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.

INTERPRETATION:

This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.

FUNDING:

Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

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