title: Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patients with metastatic colorectal cancer. a meta-analysis.
abstract: BACKGROUND
  The clinical benefit of first-line doublet chemotherapy (including oxaliplatin or irinotecan) compared to single-drug therapy (5FU) in elderly patients (>70 or >75 years old) with metastatic colorectal cancer (MCRC) is controversial. Therefore, we undertook a meta-analysis of all published phase III studies.
  
  
  METHODS
  We performed a PubMed search using keywords metastatic colorectal cancer, phase III studies, oxaliplatin, irinotecan, survival. We also screened Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) proceedings. Few studies have been published corresponding to our inclusion criteria. The efficacy outcomes were overall survival (OS) and progression-free survival (PFS). Toxicity was also examined when available. Hazard ratios (HRs) with their 95 % confidence intervals (CI) were collected from the studies and pooled. By convention, HRs <1 corresponded to a better outcome for doublets. p values <0.05 were considered statistically significant. A fixed-effect model was used. We used Comprehensive Meta-Analysis Software (Biostat, Englewood, NJ, USA).
  
  
  RESULTS
  This meta-analysis (MA) included five original studies (Mitry and Venderbosch for CAIRO both assessing irinotecan, De Gramont and Seymour for FOCUS2 and Ducreux assessing oxaliplatin) and an already published MA (Folprecht) of four trials comparing FOLFIRI with 5FU (Saltz, Douillard, Köhne and Seymour). Our MA included 1225 patients (70 % men). For age, we chose a cut-off of 70 years for oxaliplatin and a cut-off of 75 years for irinotecan. The performance status (PS) score was 0-1 in about 90 % of patients except for the studies by Mitry and Seymour FOCUS2 which both included 30 % of PS2 patients. Overall, doublet chemotherapy, compared to 5FU alone, did not improve OS (HR = 1.00; CI: 0.89-1.13) but significantly improved PFS (HR = 0.82; CI: 0.72-0.93). When assessed separately, FOLFIRI and FOLFOX both significantly improved PFS (HR = 0.83; 0.68-1.00 and HR = 0.81; 0.68-0.97, respectively). The main grade 3-4 toxicities for FOLFIRI were diarrhoea, nausea, vomiting and neutropenia, which occurred significantly more often than with 5FU alone.
  
  
  CONCLUSIONS
  Addition of oxaliplatin or irinotecan to 5FU in metastatic CRC significantly improved PFS in elderly patients more than 70 years old but was associated with an increased risk of toxicity as shown for irinotecan.
authors.affiliation: Unité de Coordination en Onco-Gériatrie UCOG 93, APHP, René Muret Hospital, HUPSSD - Université Paris 13, Sevran, France. thierry.landre@rmb.aphp.fr.|Department of Geriatric Oncology, APHP, René Muret Hospital, HUPSSD, Sevran, France. thierry.landre@rmb.aphp.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Landre
authors.affiliation: Department of Pharmacology, APHP, Avicenne Hospital, HUPSSD, Bobigny, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Uzzan
authors.affiliation: Department of Pharmacology, APHP, Avicenne Hospital, HUPSSD, Bobigny, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nicolas
authors.affiliation: Department of Gastroenterology and Digestive Oncology, APHP, Avicenne Hospital, HUPSSD, Université Paris 13, Sorbonne-Paris Cité, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aparicio
authors.affiliation: Department of Clinical Oncology, APHP, Avicenne Hospital, HUPSSD, Bobigny, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Zelek
authors.affiliation: Department of Gastroenterology and Digestive Oncology, APHP, Avicenne Hospital, HUPSSD, Université Paris 13, Sorbonne-Paris Cité, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Mary
authors.affiliation: Unité de Coordination en Onco-Gériatrie UCOG 93, APHP, René Muret Hospital, HUPSSD - Université Paris 13, Sevran, France.|Department of Geriatric Oncology, APHP, René Muret Hospital, HUPSSD, Sevran, France.
authors.forename: Cherifa
authors.initials: C
authors.lastname: Taleb
authors.affiliation: Unité de Coordination en Onco-Gériatrie UCOG 93, APHP, René Muret Hospital, HUPSSD - Université Paris 13, Sevran, France.|Department of Clinical Oncology, APHP, Avicenne Hospital, HUPSSD, Bobigny, France.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Des Guetz
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D018450:Disease Progression; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D000077150:Oxaliplatin
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin
keywords: Doublet chemotherapy; Elderly; Irinotecan; Meta-analysis; Metastatic colorectal cancer; Oxaliplatin; Survival