TY - JOUR
T1 - Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3)
T2 - patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial
AU - de Boer, Stephanie M.
AU - Powell, Melanie E.
AU - Mileshkin, Linda
AU - Katsaros, Dionyssios
AU - Bessette, Paul
AU - Haie-Meder, Christine
AU - Ottevanger, Petronella B.
AU - Ledermann, Jonathan A.
AU - Khaw, Pearly
AU - D'Amico, Romerai
AU - Fyles, Anthony
AU - Baron, Marie-Helene
AU - Jurgenliemk-Schulz, Ina M.
AU - Kitchener, Henry C.
AU - Nijman, Hans W.
AU - Wilson, Godfrey
AU - Brooks, Susan
AU - Gribaudo, Sergio
AU - Provencher, Diane
AU - Hanzen, Chantal
AU - Kruitwagen, Roy F.
AU - Smit, Vincent T. H. B. M.
AU - Singh, Naveena
AU - Do, Viet
AU - Lissoni, Andrea
AU - Nout, Remi A.
AU - Feeney, Amanda
AU - Verhoeven-Adema, Karen W.
AU - Putter, Hein
AU - Creutzberg, Carien L.
AU - PORTEC Study Grp
N1 - Funding Information:
The PORTEC-3 study was supported by a grant from the Dutch Cancer Society ( UL2006-4168/CKTO 2006-04 ), the Netherlands. PORTEC 3 was supported in the UK by Cancer Research UK ( C7925/A8659 ). Participation in the PORTEC-3 trial by the Australia and New Zealand Gynaecologic Oncology Group (ANZGOG) and the Trans-Tasman Radiation Oncology Group (TROG) were supported by the NHMRC Project Grant 570894 (2008) and by a Cancer Australia Grant (awarded through the 2011 round of the priority-driven Collaborative Cancer Research Scheme and funded by Cancer Australia). Participation by the Italian MaNGO group was partly supported by a grant from the Italian Medicines Agency AIFA ( FARM84BCX2 ). Canadian participation in the PORTEC-3 trial was supported by the Canadian Cancer Society Research Institute ( grants #015469 and #021039 ). We thank all the participating groups: DGOG (the Netherlands), NCRI (UK), ANZGOG (Australia and New Zealand), MaNGO (Italy), Fedegyn (France), and the Canadian Cancer Trials Group (Canada); their coordinating teams, principal investigators, staff, and clinical research teams at the group's participating centres for all their work and efforts, and the women who participated in the trial. The PORTEC-3 trial involved a strong international collaboration within the Gynaecological Oncology InterGroup (GCIG) and the support of the GCIG officers and member groups is gratefully acknowledged. We also thank the members of the data safety monitoring board for their invaluable work and guidance throughout the duration of the trial. This analysis was presented in part at the Annual Meeting of the European Society for Radiotherapy and Oncology, April 20–24, 2018, Barcelona, Spain.
Funding Information:
MEP reports grants from Cancer Research UK during the conduct of the study. LM reports that Hospira provided paclitaxel chemotherapy for ANZGOG patients on the PORTEC-3 trial randomised to the experimental arm. PB reports grants from the Canadian Cancer Trials Group, during the conduct of the study. HWN reports grants from the Dutch Cancer Society, grants from Health Holland, grants from UMCG Cancer fund, outside the submitted work; is the founder of SME Vicinivax; and has collaborated with Aduro, TRON, and Merck. CLC reports grants from the Dutch Cancer Society, during the conduct of the study. All other authors declare no competing interests in relation to this study.
Funding Information:
The PORTEC-3 study was supported by a grant from the Dutch Cancer Society (UL2006-4168/CKTO 2006-04), the Netherlands. PORTEC 3 was supported in the UK by Cancer Research UK (C7925/A8659). Participation in the PORTEC-3 trial by the Australia and New Zealand Gynaecologic Oncology Group (ANZGOG) and the Trans-Tasman Radiation Oncology Group (TROG) were supported by the NHMRC Project Grant 570894 (2008) and by a Cancer Australia Grant (awarded through the 2011 round of the priority-driven Collaborative Cancer Research Scheme and funded by Cancer Australia). Participation by the Italian MaNGO group was partly supported by a grant from the Italian Medicines Agency AIFA (FARM84BCX2). Canadian participation in the PORTEC-3 trial was supported by the Canadian Cancer Society Research Institute (grants #015469 and #021039). We thank all the participating groups: DGOG (the Netherlands), NCRI (UK), ANZGOG (Australia and New Zealand), MaNGO (Italy), Fedegyn (France), and the Canadian Cancer Trials Group (Canada); their coordinating teams, principal investigators, staff, and clinical research teams at the group's participating centres for all their work and efforts, and the women who participated in the trial. The PORTEC-3 trial involved a strong international collaboration within the Gynaecological Oncology InterGroup (GCIG) and the support of the GCIG officers and member groups is gratefully acknowledged. We also thank the members of the data safety monitoring board for their invaluable work and guidance throughout the duration of the trial. This analysis was presented in part at the Annual Meeting of the European Society for Radiotherapy and Oncology, April 20?24, 2018, Barcelona, Spain.
Publisher Copyright:
© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2019/9
Y1 - 2019/9
N2 - 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/m (2) given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m (2) 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. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.
AB - 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/m (2) given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m (2) 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. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.
KW - CARCINOMA PATIENTS
KW - OPEN-LABEL
KW - III TRIAL
KW - CHEMOTHERAPY
KW - RADIATION
KW - MULTICENTER
KW - IRRADIATION
KW - THERAPY
U2 - 10.1016/S1470-2045(19)30395-X
DO - 10.1016/S1470-2045(19)30395-X
M3 - Article
SN - 1470-2045
VL - 20
SP - 1273
EP - 1285
JO - Lancet oncology
JF - Lancet oncology
IS - 9
ER -