title: Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial.
abstract: BACKGROUND
  About 15% of patients with endometrial cancer have high-risk features and are at increased risk of distant metastases and endometrial cancer-related death. We designed the PORTEC-3 trial to investigate the benefit of adjuvant chemoradiotherapy compared with radiotherapy alone for women with high-risk endometrial cancer.
  
  
  METHODS
  PORTEC-3 was a multicentre, open-label, randomised, international trial. Women with high-risk endometrial cancer were randomly allocated (1:1) to radiotherapy alone (48·6 Gy) in 1·8 Gy fractions five times a week or chemoradiotherapy (two cycles concurrent cisplatin 50 mg/m(2) and four adjuvant cycles of carboplatin area under the curve [AUC] 5 and paclitaxel 175 mg/m(2)) using a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The primary endpoints of the PORTEC-3 trial were overall survival and failure-free survival analysed in the intention-to-treat population. This analysis focuses on 2-year toxicity and health-related quality of life as secondary endpoints; analysis was done according to treatment received. Health-related quality of life was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) the cervix cancer module and chemotherapy and neuropathy subscales of the ovarian cancer module at baseline, after radiotherapy and at 6, 12, 24, 36, and 60 months after randomisation. Adverse events were graded with Common Terminology Criteria for Adverse Events version 3.0. The study was closed on Dec 20, 2013, after achieving complete accrual, and follow-up remains ongoing for the primary outcomes analysis. This trial is registered with ISRCTN.com, number ISRCTN14387080, and with ClinicalTrials.gov, number NCT00411138.
  
  
  RESULTS
  Between Sept 15, 2006, and Dec 20, 2013, 686 women were randomly allocated in the PORTEC-3 trial. Of these, 660 met eligibility criteria, and 570 (86%) were evaluable for health-related quality of life. Median follow-up was 42·3 months (IQR 25·8-55·1). At completion of radiotherapy and at 6 months, EORTC QLQ-C30 functioning scales were significantly lower (worse functioning) and health-related quality of life symptom scores higher (worse symptoms) for the chemoradiotherapy group compared with radiotherapy alone, improving with time. At 12 and 24 months, global health or quality of life was similar between groups, whereas physical functioning scores remained slightly lower in patients who received chemoradiotherapy compared with patients who received radiotherapy alone. At 24 months, 48 (25%) of 194 patients in the chemoradiotherapy group reported severe tingling or numbness compared with 11 (6%) of 170 patients in the radiotherapy alone group (p<0·0001). Grade 2 or worse adverse events were found during treatment in 309 (94%) of 327 patients in the chemoradiotherapy group versus 145 (44%) of 326 patients in the radiotherapy alone group, and grade 3 or worse events were found in 198 (61%) of 327 patients in the chemoradiotherapy group versus 42 (13%) of 326 patients in the radiotherapy alone group (p<0·0001), with most of the grade 3 adverse events being haematological (45%). At 12 and 24 months, no significant differences in grade 3 or worse adverse events were found between groups; only grade 2 or higher sensory neuropathy adverse events persisted at 24 months (25 [10%] of 240 patients in the chemoradiotherapy group vs one [<1%] of 247 patients in the radiotherapy alone group; p<0·0001).
  
  
  CONCLUSIONS
  Despite the increased physician and patient-reported toxicities, this schedule of adjuvant chemotherapy given during and after radiotherapy in patients with high-risk endometrial cancer is feasible, with rapid recovery after treatment, but with persistence of patient-reported sensory neurological symptoms in 25% of patients. We await the analysis of primary endpoints before final conclusions are made.
  
  
  BACKGROUND
  Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and Canadian Cancer Society Research Institute.
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands. Electronic address: s.m.de_boer.onco@lumc.nl.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: de Boer
authors.affiliation: Department of Clinical Oncology, Barts Health NHS Trust, London, UK.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Powell
authors.affiliation: Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Mileshkin
authors.affiliation: Department of Surgical Sciences, Gynecologic Oncology, Città della Salute and S Anna Hospital, University of Torino, Torino, Italy.
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.affiliation: NCIC-CTG, Department of Obstetrics and Gynaecology, University of Sherbrooke, QC, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Bessette
authors.affiliation: Department of Radiotherapy, Institut Gustave Roussy, Villejuif, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Haie-Meder
authors.affiliation: Department of Medical Oncology, Radboudumc, Nijmegen, Netherlands.
authors.forename: Petronella B
authors.initials: PB
authors.lastname: Ottevanger
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ledermann
authors.affiliation: Division of Radiation Oncology & Cancer Imaging, Peter MacCallum Cancer Center, East Melbourne, VIC, Australia.
authors.forename: Pearly
authors.initials: P
authors.lastname: Khaw
authors.affiliation: Department of Radiation Oncology, Azienda Ospedaliera della Provincia di Lecco, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colombo
authors.affiliation: NCIC-CTG, Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fyles
authors.affiliation: Department of Radiotherapy, Centre Hospitalier Régional Universitaire de Besançon, Besançon, France.
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Baron
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Kitchener
authors.affiliation: Department of Gynaecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Gynaecology and Obstetrics, and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands.
authors.forename: Roy F
authors.initials: RF
authors.lastname: Kruitwagen
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Comprehensive Cancer Center The Netherlands, Leiden, Netherlands.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Verhoeven-Adema
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Smit
authors.affiliation: Department of Medical Statistics, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000532:radiotherapy / Q000556:secondary / Q000628:therapy*; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D016190:Carboplatin / Q000008:administration & dosage; D016022:Case-Control Studies; D059186:Chemoradiotherapy, Adjuvant / Q000009:adverse effects*; D002945:Cisplatin / Q000008:administration & dosage; D018284:Cystadenocarcinoma, Serous / Q000532:radiotherapy / Q000556:secondary / Q000628:therapy*; D016889:Endometrial Neoplasms / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000175:diagnosis / Q000209:etiology; D006402:Hematologic Diseases / Q000175:diagnosis / Q000209:etiology; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009422:Nervous System Diseases / Q000175:diagnosis / Q000209:etiology; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D011788:Quality of Life; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects*; D015996:Survival Rate
chemical_list: D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin