Health-Related Quality of Life Analysis in Metastatic Colorectal Cancer Patients Treated by Second-Line Chemotherapy, Associated With Either Cetuximab or Bevacizumab: The PRODIGE 18 Randomized Phase II Study

Published:October 03, 2021DOI:


      Background and Objectives

      We have previously showed that for patients with wild-type RAS metastatic colorectal cancer (mCRC) progressing after bevacizumab plus chemotherapy, bevacizumab continuation plus a switch of chemotherapy is the most appropriate option (PRODIGE 18 phase II study). Here we aimed to determine treatment impact in patient's Health-Related Quality Of Life (HRQoL) in PRODIGE18 study.


      HRQoL was evaluated in 2 arms bevacizumab or cetuximab—combined with chemotherapy (modified FOLFOX6 [mFOLFOX6] or FOLFIRI) using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 at baseline, first and third tumor evaluation and at the end of the study. The temporal evolution of quality of life scores was investigated using longitudinal linear mixed models of variance. The time until definitive deterioration (TUDD) was estimated using the Kaplan-Meier method and the long-rank test. A univariate Cox model was used to calculate HR with 95% CI. A multivariate Cox model was applied to determine association of TUDD with age and gender. Safety was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events.


      HRQoL QLQ-C30 questionnaire compliance was high at baseline (>90%) and declined over time (∼70% in tumor evaluation 1 and ∼ 60% in tumor evaluation 3), but remained similar in both treatment arms. Patient reported mean diarrhea QLQ-C30 score is significantly higher in bevacizumab treatment arm. Clinician reported mild diarrhea was more frequently declared in bevacizumab treatment arm. Cox multivariate analyses showed no statistically significant differences in TUDD for all QLQ-C30 scales between treatments. TUDD of appetite loss was significantly associated to age.


      Our study shows that no relevant impairment of patients HRQoL between the 2 treatment arms. So, the analysis of the HRQoL with equal effectiveness does not make it possible to favor one treatment over another.


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        • Bray F
        • Ferlay J
        • Soerjomataram I
        • Siegel RL
        • Torre LA
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68 (n.d.;0.): 394-424
        • Ferlay J
        • Colombet M
        • Soerjomataram I
        • et al.
        Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.
        Eur J Cancer. 2018; 103: 356-387
        • Van Cutsem E
        • Cervantes A
        • Nordlinger B
        • Arnold D
        • on behalf of the ESMO Guidelines Working Group
        Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2014; 25: iii1-iii9
        • Saltz LB
        • Clarke S
        • Díaz-Rubio E
        • et al.
        Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.
        J Clin Oncol. 2008; 26: 2013-2019
        • Bokemeyer C
        • Bondarenko I
        • Makhson A
        • et al.
        Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.
        J Clin Oncol. 2009; 27: 663-671
        • Van Cutsem E
        • Köhne CH
        • Hitre E
        • et al.
        Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.
        N Engl J Med. 2009; 360: 1408-1417
        • Van Cutsem E
        • Rivera F
        • Berry S
        • et al.
        Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study.
        Ann Oncol. 2009; 20: 1842-1847
        • Giantonio BJ
        • Catalano PJ
        • Meropol NJ
        • et al.
        Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.
        J Clin Oncol. 2007; 25: 1539-1544
        • Sobrero AF
        • Maurel J
        • Fehrenbacher L
        • et al.
        EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer.
        J Clin Oncol. 2008; 26: 2311-2319
        • Van Cutsem E
        • Cervantes A
        • Adam R
        • et al.
        ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
        Ann Oncol. 2016; 27: 1386-1422
        • Van Cutsem E
        • Lenz H-J
        • Köhne C-H
        • et al.
        Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer.
        J Clin Oncol. 2015; 33: 692-700
        • Bennouna J
        • Hiret S
        • Bertaut A
        • et al.
        Continuation of bevacizumab vs cetuximab plus chemotherapy after first progression in KRAS wild-type metastatic colorectal cancer: the UNICANCER PRODIGE18 randomized clinical trial.
        JAMA Oncol. 2018; 5: 83-90
        • Byrne C
        • Griffin A
        • Blazeby J
        • Conroy T
        • Efficace F.
        Health-related quality of life as a valid outcome in the treatment of advanced colorectal cancer.
        Eur J Surg Oncol. 2007; 33: S95-104
        • Aaronson NK
        • Ahmedzai S
        • Bergman B
        • et al.
        The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
        J Natl Cancer Inst. 1993; 85: 365-376
        • Fayers PM
        • Aaronson N
        • Bjordal K
        • et al.
        EORTC QLQ-C30 Scoring Manual: This Manual Is Intended to Assist Users With Scoring Procedures for the QLQ-C30 Version 3 and Earlier, and the QLQ Supplementary Modules.
        EORTC, Brussels2001
        • National Cancer Institute
        • National Institutes of Health, US Department of Health and Human Services
        Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0.
        • Beckett LA
        • Tancredi DJ
        • Wilson RS.
        Multivariate longitudinal models for complex change processes.
        Stat Med. 2004; 23: 231-239
        • Bonnetain F
        • Dahan L
        • Maillard E
        • et al.
        Time until definitive quality of life score deterioration as a means of longitudinal analysis for treatment trials in patients with metastatic pancreatic adenocarcinoma.
        Eur J Cancer. 2010; 46: 2753-2762
        • Hamidou Z
        • Chibaudel B
        • Hebbar M
        • et al.
        Time to definitive health-related quality of life score deterioration in patients with resectable metastatic colorectal cancer treated with FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI: the MIROX randomized phase III trial.
        PLoS One. 2016; 11: e0157067
        • Hurwitz H
        • Fehrenbacher L
        • Novotny W
        • et al.
        Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
        N Engl J Med. 2004; 350: 2335-2342
        • Bonnetain F
        • Fiteni F
        • Efficace F
        • Anota A.
        Statistical challenges in the analysis of health-related quality of life in cancer clinical trials.
        J Clin Oncol. 2016; 34: 1953-1956
        • Lv Z
        • Ning J
        • Chen H.
        Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials.
        Tumor Biol. 2014; 35: 11741-11750
        • Pinto C
        • Di Fabio F
        • Rosati G
        • et al.
        Observational study on quality of life, safety, and effectiveness of first-line cetuximab plus chemotherapy in KRAS wild-type metastatic colorectal cancer patients: the ObservEr Study.
        Cancer Med. 2016; 5: 3272-3281
        • Bennouna J
        • Sastre J
        • Arnold D
        • et al.
        Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.
        Lancet Oncol. 2013; 14: 29-37
        • Marques RP
        • Heudtlass P
        • Pais HL
        • Quintela A
        • Martins AP.
        Patient-reported outcomes and health-related quality of life for cetuximab versus bevacizumab in metastatic colorectal cancer: a prospective cohort study.
        J Cancer Res Clin Oncol. 2019; 145: 1719-1728