4463 - Effects of dietary restriction in cancer patients receiving irinotecan

Background

Irinotecan is widely used, but also known for its severe toxicities neutropenia and diarrhea. Based on preclinical data, combined caloric and protein restriction (CCPR) might improve treatment tolerability without impairing antitumor effect. Therefore, we studied the influence of CCPR on irinotecan pharmacokinetics and toxicity.

Methods

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 CCPR (∼30% caloric and ∼70% protein restriction) during the 1^st cycle and a 2^nd cycle preceded by a normal diet (ND) or vice versa. During both cycles, 24-hours blood sampling was performed and 24-26 hours after infusion biopsies of both healthy liver (HL) and liver metastasis (LM) were taken. Primary endpoint was the relative difference in geometric means for the active metabolite SN-38 concentration in HL, as analyzed by a linear mixed model. Secondary endpoints included irinotecan and SN-38 concentrations in LM, plasma area under the curve (AUC_0-24h), and toxicity.

Results

Interpatient variability (n = 19) in tissue irinotecan and SN-38 concentrations was high, showing no significant differences in irinotecan (+16.8%, 95% CI: -9.7-51.1%, P = 0.227) and SN-38 (+9.8%, 95% CI: -16.4-44.2%, P = 0.48) concentrations between CCPR and ND in HL, as well as in LM (irinotecan: -38.8%, 90% CI: -59.3:-7.9%, P = 0.05 and SN-38: -13.8%, 90% CI:-40.7-25.4%, P = 0.50). CCPR increased irinotecan plasma AUC_0-24h with 7.1% (95% CI: 0.3-14.5%, P = 0.04) compared to ND, while the SN-38 plasma AUC_0-24h increased with 50.3% (95% CI: 34.6-67.9%, P < 0.001). CCPR was well tolerated with low incidence of grade ≥3 therapy related toxicity. Grade ≥3 toxicity was not increased during CCPR 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), febrile neutropenia (5% vs 16% P = 0.50) and hospitalization (11% vs 21% P = 0.634) during CCPR vs ND.

Conclusions

CCPR resulted in a dramatically increased plasma SN-38 exposure, while toxicity did not change. CCPR did not result in altered irinotecan and SN-38 exposure in HL and LM. CCPR might therefore potentially improve the therapeutic window in patients treated with irinotecan.

Clinical trial identification

Netherlands Trial Register NL5624 (NTR5731) release date: 2016-03-04.

Editorial acknowledgement

Legal entity responsible for the study

A.H.J. Mathijssen.

Funding

Has not received any funding.

Disclosure

S.L. Koolen: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Pfizer; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. R.H.J. Mathijssen: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier; Honoraria (institution): Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Astellas. All other authors have declared no conflicts of interest.