Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full-dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9):a randomised, open-label phase 2 trial

Autor: Halfdan Sorbye, Jesper Ryg, Bengt Glimelius, Åke Berglund, Laurids Østergaard Poulsen, Carl Henrik Shah, Gabor Liposits, Eva Hofsli, Stine Braendegaard Winther, Camilla Qvortrup, Per Pfeiffer, Pia Österlund, Halla Skuladottir
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Diarrhea
Male
medicine.medical_specialty
Lung Neoplasms
Bevacizumab
Population
Adenocarcinoma
Irinotecan
03 medical and health sciences
0302 clinical medicine
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Progression-free survival
education
Geriatric Assessment
Fatigue
Peritoneal Neoplasms
Aged
Tegafur
Aged
80 and over
education.field_of_study
Intention-to-treat analysis
Dehydration
Dose-Response Relationship
Drug
Hand Strength
Hepatology
business.industry
Liver Neoplasms
Hazard ratio
Gastroenterology
Combination chemotherapy
Physical Functional Performance
Progression-Free Survival
3. Good health
Oxaliplatin
Drug Combinations
Oxonic Acid
030220 oncology & carcinogenesis
Female
030211 gastroenterology & hepatology
Topoisomerase I Inhibitors
Colorectal Neoplasms
business
medicine.drug
Zdroj: Winther, S B, Liposits, G, Skuladottir, H, Hofsli, E, Shah, C H, Poulsen, L Ø, Ryg, J, Osterlund, P, Berglund, Å, Qvortrup, C, Glimelius, B, Sorbye, H & Pfeiffer, P 2019, ' Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full-dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9) : a randomised, open-label phase 2 trial ', The Lancet Gastroenterology and Hepatology, vol. 4, no. 5, pp. 376-388 . https://doi.org/10.1016/S2468-1253(19)30041-X
Winther, S B, Liposits, G, Skuladottir, H, Hofsli, E, Shah, C-H, Poulsen, L Ø, Ryg, J, Osterlund, P, Berglund, Å, Qvortrup, C, Glimelius, B, Sorbye, H & Pfeiffer, P 2019, ' Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full-dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9) : a randomised, open-label phase 2 trial ', The Lancet Gastroenterology & Hepatology, vol. 4, no. 5, pp. 376-388 . https://doi.org/10.1016/S2468-1253(19)30041-X
DOI: 10.1016/S2468-1253(19)30041-X
Popis: Background: Older or vulnerable patients with metastatic colorectal cancer are seldom included in randomised trials. The multicentre NORDIC9 trial evaluated reduced-dose combination chemotherapy compared with full-dose monotherapy in older, vulnerable patients. Methods: This randomised, open-label phase 2 trial was done in 23 Nordic oncology clinics and included patients aged 70 years or older with previously untreated metastatic colorectal cancer who were not candidates for full-dose combination chemotherapy. Patients were block randomised (1:1) using a web-based tool to full-dose S-1 (30 mg/m 2 orally twice daily on days 1–14 every 3 weeks) followed by second-line treatment at progression with irinotecan (250 mg/m 2 intravenously on day 1 every 3 weeks or 180 mg/m 2 intravenously on day 1 every 2 weeks) or reduced-dose combination chemotherapy with S-1 (20 mg/m 2 orally twice daily on days 1–14) and oxaliplatin (100 mg/m 2 intravenously on day 1 every 3 weeks) followed by second-line treatment at progression with S-1 (20 mg/m 2 orally twice daily on days 1–14) and irinotecan (180 mg/m 2 intravenously on day 1 every 3 weeks). Use of bevacizumab (7·5 mg/kg intravenously on day 1 of each cycle) was optional. Treatment allocation was not masked and randomisation was stratified for institution and bevacizumab. The primary outcome was progression-free survival. Survival analyses were by intention to treat and safety analyses were done on the treated population. This trial is registered with EudraCT, number 2014-000394-39, and is closed to new participants. Findings: From March 9, 2015, to Oct 11, 2017, 160 patients with a median age of 78 years (IQR 76–81) were randomly assigned to full-dose monotherapy (n=83) or reduced-dose combination chemotherapy (n=77). At data cutoff (Sept 1, 2018; median follow-up 23·8 months [IQR 18·8–30·9]), 81 (98%) patients in the full-dose monotherapy group and 71 (92%) patients in the reduced-dose combination group had progressed or died. Median progression-free survival was significantly longer with reduced-dose combination chemotherapy (6·2 months [95% CI 5·3–8·3]) than with full-dose monotherapy (5·3 months [4·1–6·8]; hazard ratio [HR] 0·72 [95% CI 0·52–0·99]; p=0·047). Toxicity was evaluated in 157 patients who received treatment. Significantly more patients in the full-dose monotherapy group (51 [62%] of 82 patients) experienced at least one grade 3–4 adverse event than in the reduced-dose combination group (32 [43%] of 75 patients; p=0·014). Grade 3–4 diarrhoea (12 [15%] vs two [3%]; p=0·018), fatigue (ten [12%] vs three [4%]; p=0·083), and dehydration (five [6%] vs none; p=0·060) were more frequent in the full-dose monotherapy group than in the reduced-dose combination group. Treatment-related deaths occurred in three patients during first-line treatment and three patients during second-line treatment (two in the full-dose monotherapy group vs one in the reduced-dose combination group in both cases). Interpretation: Reduced-dose combination chemotherapy with S-1 and oxaliplatin for older, vulnerable patients with metastatic colorectal cancer was more effective and resulted in less toxicity than full-dose monotherapy with S-1. Reduced-dose combination chemotherapy could be a preferred treatment for this population. Funding: Taiho Pharmaceuticals, Nordic Group, the Danish Cancer Society, the Swedish Cancer Society, Academy of Geriatric Research (AgeCare), and Region of Southern Denmark.
Databáze: OpenAIRE
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