Abstract
The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian‐based administration (chronoIFLO5) as either first‐ or second‐line treatment, within the time‐finding EORTC 05011 trial. Five‐day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil‐leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first‐ and second‐line settings. Primary endpoints included Grade 3‐4 toxicity rates, best objective response rate (ORR), progression‐free survival (PFS) and overall survival (OS). One‐hundred forty‐nine and 44 patients were treated in first‐line and second‐line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty‐six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2‐70.4] and resulted in median PFS and OS of 8.7 months [7.5‐9.9] and 19.9 months [15.4‐24.5]. Corresponding figures in second line were 37.5% [22.5‐52.5], 6.7 months [4.8‐8.9] and 16.3 months [11.8‐20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.
Highlights
Colorectal cancer is the second most common neoplastic disease across Europe in terms of both incidence and mortality.[1]
Relative dose intensity was calculated as the ratio between the actual dose of the three cytotoxic drugs delivered over the whole treatment duration and the theoretical full dose (60 mg/sqm/week for irinotecan, 26.7 mg/sqm/week for oxaliplatin and 933.3 mg/sqm/ week for fluorouracil).[14]
Frontline chronoIFLO5 was associated with a median overall survival of 19.9 months [95% CI: 15.4-24.5 months] (Figure 4A) and a median progression-free survival of 8.7 months [7.5-9.9] (Figure 4C)
Summary
Colorectal cancer is the second most common neoplastic disease across Europe in terms of both incidence and mortality.[1]. The administration of each chemotherapy drug at a defined time based on its circadian tolerability constitutes the rationale of chronotherapy.[7,8,9] the chronomodulated triplet has demonstrated satisfactory safety and efficacy in monocentric studies in patients with metastatic colorectal cancer.[10,11,12,13] Based on this evidence, we conducted an international time-finding study (EORTC 05011) to identify the least toxic administration time of Irinotecan, combined with chronomodulated oxaliplatin and 5-fluorouracil + leucovorin.[14] This trial failed to meet its primary endpoint of determining the time of irinotecan delivery causing the lowest toxicity in the whole population.[14] in accordance with recent evidence of the impact of gender in outcomes of chemotherapy against colorectal cancer, we found a lag in the least toxic time of irinotecan administration according to gender. 149 patients received the treatment as a first-line regimen, while 44 received it as salvage therapy In both settings, the safety and efficacy of chronomodulated triple therapy were validated, the optimal timing of irinotecan for minimizing toxicity remains to be determined. We performed a final update of the EORTC 05011 trial data, which complements overall safety and efficacy of chronomodulated triplet both in the first-line setting, comparatively to existing data with conventional administration, and as a second-line regimen, for which scant prospective multicentric data exist
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