Effects of Protein and Calorie Restriction on the Metabolism and Toxicity Profile of Irinotecan in Cancer Patients

Femke M. de Man*, Ruben A.G. van Eerden, Gerdien M. van Doorn, Esther Oomen-de Hoop, Stijn L.W. Koolen, Joanne F. Olieman, Peter de Bruijn, Joris N. Veraart, Henk K. van Halteren, Yorick Sandberg, Adriaan Moelker, Jan N.M. IJzermans, Martijn P. Lolkema, Teun van Gelder, Martijn E.T. Dollé, Ron W.F. de Bruin, Ron H.J. Mathijssen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)


Preclinical data suggests that protein and calorie restriction (PCR) might improve treatment tolerability without impairing antitumor efficacy. Therefore, we have studied the influence of PCR on irinotecan pharmacokinetics and toxicity. In this crossover 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 first cycle and a second cycle preceded by a normal diet or vice versa. Pharmacokinetic blood sampling and biopsies of both healthy liver and liver metastases were performed. The primary end point was the relative difference in geometric means for the active metabolite SN-38 concentration in healthy liver 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 normal diet in healthy liver, as well as in liver metastases (irinotecan: −38.8%, P = 0.05 and SN-38: −13.8%, P = 0.50). PCR increased irinotecan plasma area under the curve from zero to 24 hours (AUC0–24h) with 7.1% (P = 0.04) compared with normal diet, whereas the SN-38 plasma AUC0–24h increased with 50.3% (P < 0.001). Grade ≥ 3 toxicity was not increased during PCR vs. normal diet (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. normal diet. In conclusion, plasma SN-38 exposure increased dramatically after PCR, whereas toxicity did not change. PCR did not alter the irinotecan and SN-38 exposure in healthy liver and liver metastases. PCR might therefore potentially improve the therapeutic window in patients treated with irinotecan.

Original languageEnglish
Pages (from-to)1304-1313
Number of pages10
JournalClinical Pharmacology and Therapeutics
Issue number5
Early online date29 Oct 2020
Publication statusPublished - May 2021

Bibliographical note

Funding Information:
No funding was received for this work. The authors thank Lucie Venrooij (Erasmus University Medical Center Rotterdam, The Netherlands) for performing indirect calorimetry and calculating food diaries and dietary restriction.

Publisher Copyright:
© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics


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