Adverse events during first-line treatments for mCRC: The Toxicity over Time (ToxT) analysis of three randomised trials.

BACKGROUND

In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic low-grade AEs, single patient's perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC).

PATIENTS AND METHODS

We applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4-6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone.

RESULTS

Out of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance.

CONCLUSIONS

Most of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AR: Honoraria for speaker bureau for Servier and Elma Academy. FM: Honoraria from Servier, Pierre-Fabre and Lilly; Research grant from Incyte.GT: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eli Lilly, Novartis, Amgen, Roche, Merck; Participation on a Data Safety Monitoring Board or Advisory Board: Eli Lilly, Amgen, Roche. MN: Travel expenses from Celgene and AstraZeneca; Speaker honorarium from Accademia della Medicina and Incyte; Honoraria from Sandoz, Medpoint SRL and Servier for editorial collaboration; Consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte, MSD Italia, Servier, Astrazeneca and Taiho. AZ: Speaker Bureau for Amgen, Merck-Serono, Servier, Pierre-Fabre. FP: Honoraria from Amgen, Bayer, Servier, Merck-Serono, Lilly, MSD, Organon, BMS, Astrazeneca, Pierre-Fabre; Research grants from Bristol-Myers Squibb, AstraZeneca, Agenus and Incyte. CC: Honoraria from Amgen, Bayer, Merck, Roche and Servier; Consulting or advisory role: Amgen, Bayer, MSD, Roche; Speakers’ Bureau: Servier; Research funding: Bayer, Merck, Servier; Travel accommodations and expenses: Roche and Servier. All the other authors have declared no conflicts of interest.