- •Severe drug toxicity has a negative impact on prognosis in metastatic colorectal cancer.
- •Early toxicity within 3 months after first-line regimen initiation may be a key factor.
- •Early grade III or more toxicity is a new prognostic marker.
- •Some baseline characteristics are associated with ET3 occurrence.
- •Early grade III or more toxicity correlates with poorer overall survival.
Few studies have explored the association between baseline characteristics and the occurrence of early toxicities in patients treated with first-line chemotherapy for metastatic colorectal cancer (mCRC).
Patients and methods
Individual patient data of 2190 patients enrolled in 10 prospective FFCD (Fédération Francophone de Cancérologie Digestive) trials were analysed. Severe early toxicity was defined as the occurrence of grade ≥III toxicity within 3 months after initiation of chemotherapy (ET3).
Patients received monotherapy based on 5-FU (n = 1068), a cytotoxic doublet (n = 395) or tritherapy with a cytotoxic doublet plus anti-VEGF agent or a cytotoxic triplet (n = 727). The patients received 5-FU (100%), Irinotecan (39.6%), Oxaliplatin (13.4%), Bevacizumab (29.6%) or Aflibercept (1.8%). ET3 occurred in 244 patients (22.8%) with monotherapy, 248 patients (62.8%) with doublet and 392 patients (53.9%) with tritherapy. The most frequent ET3s were related to biological abnormalities and/or gastrointestinal, general and vascular disorders. The prognostic factors for the occurrence of an ET3 in multivariate analysis were a performance status of 2 rather than 0–1 (OR 2.57; 95% CI [1.16, 5.73]; p = 0.02), tritherapy versus monotherapy (OR 2.31; 95% CI [0.84, 6.33]; p = 0.02), alkaline phosphatase > 300 UI/l (OR 3.07; 95% CI [1.79, 5.27]; p < 0.001) and non-resected primary tumour versus resection (OR 1.59; 95% CI [1.06, 2.39]; p = 0.02). Median overall survival in patients without ET3 was significantly longer than that in patients with ET3 (HR 0.87; 95% CI [0.80–0.96]; p = 0.004).
ET3 is frequent whatever the treatment regimen and is associated with certain baseline characteristics. The clinical impact of ET3 on prognosis in mCRC warrants further investigation.
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- Clinical determinants of survival in patients with 5-fluorouracil- based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients.Ann Oncol. 2002; 13: 308-317https://doi.org/10.1093/annonc/mdf034
- Simplified prognostic model in patients with oxaliplatin-based or irinotecan-based first-line chemotherapy for metastatic colorectal cancer: a GERCOR study.Oncologist. 2011; 16: 1228-1238https://doi.org/10.1634/theoncologist.2011-0039
- Quality of life of patients with gastrointestinal cancers undergoing chemotherapy.Qual Life Res Int J Qual Life Asp Treat Care Rehabil. 2018; 27: 1865-1876https://doi.org/10.1007/s11136-018-1860-1
- Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.J Clin Oncol Off J Am Soc Clin Oncol. 1997; 15: 808-815https://doi.org/10.1200/JCO.19184.108.40.2068
- Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer. Final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial.Oncology. 2006; 70: 222-230https://doi.org/10.1159/000094357
- Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial.Lancet Oncol. 2011; 12: 1032-1044https://doi.org/10.1016/S1470-2045(11)70199-1
- Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02).Ann Oncol Off J Eur Soc Med Oncol. 2016; 27: 121-127https://doi.org/10.1093/annonc/mdv491
- High-dose FOLFIRI plus bevacizumab in the treatment of metastatic colorectal cancer patients with two different UGT1A1 genotypes: FFCD 0504 study.Mol Canc Ther. 2015; 14: 2782-2788https://doi.org/10.1158/1535-7163.MCT-15-0293
- Primary prophylactic granulocyte colony-stimulating factor (GCSF) in Gilbert's disease patients treated with FOLFIRI first line for metastatic colorectal cancer (mCRC): final results of the FFCD 0604 study.J Clin Oncol. 2013; 31 (3614–3614)https://doi.org/10.1200/jco.2013.31.15_suppl.3614
- Bevacizumab+chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial-PRODIGE 20 study results.Ann Oncol Off J Eur Soc Med Oncol. 2018; 29: 133-138https://doi.org/10.1093/annonc/mdx529
- FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases: results of the FFCD 1102 phase II trial.Eur J Canc. 2018; 104: 108-116https://doi.org/10.1016/j.ejca.2018.09.006
- Aflibercept in combination with FOLFIRI as first-line chemotherapy in patients with metastatic colorectal cancer (mCRC): a phase II study (FFCD 1302).Clin Colorectal Canc. 2020; https://doi.org/10.1016/j.clcc.2020.06.003
- Bevacizumab maintenance versus No maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9).J Clin Oncol Off J Am Soc Clin Oncol. 2018; 36: 674-681https://doi.org/10.1200/JCO.2017.75.2931
- Tumor-size responses to first-line is a predictor of overall survival in metastatic colorectal cancer.Eur Radiol. 2019; 29: 3871-3880https://doi.org/10.1007/s00330-018-5967-0
- Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma.J Clin Oncol Off J Am Soc Clin Oncol. 2004; 22: 454-463https://doi.org/10.1200/JCO.2004.06.132
- Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer.J Clin Oncol. 2009; https://doi.org/10.1200/JCO.2008.20.2879
- Sex and adverse events of adjuvant chemotherapy in colon cancer: an analysis of 34 640 patients in the ACCENT database.JNCI J Natl Canc Inst. 2020; https://doi.org/10.1093/jnci/djaa124
- Geriatric factors predict chemotherapy feasibility: ancillary results of FFCD 2001-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients.J Clin Oncol Off J Am Soc Clin Oncol. 2013; 31: 1464-1470https://doi.org/10.1200/JCO.2012.42.9894
- Primary tumor resection in patients with incurable localized or metastatic colorectal cancer: a systematic review and meta-analysis.World J Surg. 2019; 43: 1829-1840https://doi.org/10.1007/s00268-019-04984-2
Published online: June 12, 2021
Accepted: April 25, 2021
Received: March 15, 2021
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