Effects of protein and calorie restriction on the metabolism and toxicity profile of irinotecan in cancer patients.
de Man, Femke M; van Eerden, Ruben A G; van Doorn, Gerdien M; Oomen-de Hoop, Esther; Koolen, Stijn L W; Olieman, Joanne F; de Bruijn, Peter; Veraart, Joris N; van Halteren, Henk K; Sandberg, Yorick; Moelker, Adriaan; IJzermans, Jan N M; Lolkema, Martijn P; van Gelder, Teun; Dollé, Martijn E T; de Bruin, Ron W F; Mathijssen, Ron H J
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Open Access
Type
Article
Language
en
Date
2020-10-29
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Title
Effects of protein and calorie restriction on the metabolism and toxicity profile of irinotecan in cancer patients.
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Clin Pharnacol Ther 2021: 109(5):1304-13
Abstract
Preclinical data suggests that protein and calorie restriction (PCR) might improve treatment tolerability without impairing antitumor effect. Therefore, we have studied the influence of PCR on irinotecan pharmacokinetics and toxicity. In this cross-over trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of PCR (~30% caloric and ~70% protein restriction) during the 1st cycle and a 2nd cycle preceded by a normal diet (ND) or vice versa. Pharmacokinetic blood sampling and biopsies of both healthy liver (HL) and liver metastasis (LM) were performed. Primary endpoint was the relative difference in geometric means for the active metabolite SN-38 concentration in HL analyzed by a linear mixed model. No significant differences were seen in irinotecan (+16.8%, P=0.22) and SN-38 (+9.8%, P=0.48) concentrations between PCR and ND in HL, as well as in LM (irinotecan: -38.8%, P=0.05 and SN-38: -13.8%, P=0.50). PCR increased irinotecan plasma AUC0-24h with 7.1% (P=0.04) compared to ND, while the SN-38 plasma AUC0-24h increased with 50.3% (P<0.001). Grade ≥3 toxicity was not increased during PCR vs ND (P=0.69). No difference was seen in neutropenia grade ≥3 (47% vs 32% P=0.38), diarrhea grade ≥3 (5% vs 21% P=0.25) and febrile neutropenia (5% vs 16% P=0.50) during PCR vs ND. In conclusion, plasma SN-38 exposure increased dramatically after PCR, while toxicity did not change. PCR did not alter the irinotecan and SN-38 exposure in HL and LM. PCR might therefore potentially improve the therapeutic window in patients treated with irinotecan.