A Preliminary Exploratory Clinical Study of Xiao-Chai-Hu-Tang Co-Administered with Irinotecan-Based Chemotherapy in Advanced Colorectal Cancer

ETHNOPHARMACOLOGICAL RELEVANCE:Xiao-Chai-Hu-Tang (XCHT) is a classical multi-herb formula widely used for gastrointestinal symptoms and peptic ulcers. Our previous preclinical studies have shown that XCHT attenuated irinotecan-induced severe delayed-onset diarrhea (SDOD). However, the clinical safety of XCHT combined with irinotecan remains unclear. AIM OF THE STUDY:To evaluate the clinical safety of concomitant XCHT administration with an irinotecan-based regimen (FOLFIRI) in patients with advanced colorectal cancer. MATERIALS AND METHODS:Six postmenopausal women with advanced colorectal cancer who had not previously been treated with irinotecan were enrolled. Patients received XCHT once daily for 5 consecutive days (9 g, p.o.). On day 4, irinotecan (180 mg/m2, i.v.) and XCHT were administered simultaneously. The diarrhea severity was evaluated following standard criteria in National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTC AE V5.0). Routine safety parameters (e.g. blood, hepatic and renal function tests) were performed before the next cycle of chemotherapy. The blood samples were collected on day 4. Then XCHT ingredients and its metabolites in plasma were identified by ultra-high performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF/MS) and the plasma contents of XCHT ingredients, irinotecan and its major metabolites, were determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). RESULTS:During Cycle 1 safety monitoring, grade 1 diarrhea was observed in 5/6 patients and grade 2 diarrhea in 1/6 patient; no grade 3-4 diarrhea was observed. Pharmacokinetic (PK) results revealed that the systemic exposure of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) were similar to those in historical controls. Forty compounds were identified, mainly including flavonoids, saponins, phenols, alkaloids, gingerols and fatty acid related compounds. Twelve ingredients of XCHT, including baicalin, wogonoside, baicalein, wogonin, glycyrrhizic acid, glycyrrhetinic acid, formononetin, liquiritin, zingerone, ginsenoside Rb1, ginsenoside Rd and ginsenoside Rg3 have been detected in plasma. CONCLUSION:In this preliminary pilot study, co-administration of XCHT with FOLFIRI was well tolerated under the assessed conditions. The findings provide preliminary short-term safety and systemic pharmacokinetic information to inform the design of larger randomized controlled trials (RCTs).