Herbal Medicines for Irinotecan-Induced Diarrhea

Diarrhea is one of the main drawbacks for cancer patients. Possible etiologies could be radiotherapy, chemotherapeutic agents, decreased physical performance, graft versus host disease and infections. Chemotherapy-induced diarrhea (CID) is a common problem, especially in patients with advanced cancer. The incidence of CID has been reported to be as high as 50-80% of treated patients (≥30% CTC grade 3-5), especially with 5-fluorouracil bolus or some combination therapies of irinotecan and fluoropyrimidines (IFL, XELIRI). Regardless of the molecular targeted approach of tyrosine kinase inhibitors and antibodies, diarrhea is a common side effect in up to 60% of patients with up to 10% having severe diarrhea. Furthermore, the underlying pathophysiology is still under investigation. Despite the number of clinical trials evaluating therapeutic or prophylactic measures in CID, there are just three drugs recommended in current guidelines: loperamide, deodorized tincture of opium and octreotide. Newer strategies and more effective agents are being developed to reduce the morbidity and mortality associated with CID. Recent research focusing on the prophylactic use of antibiotics, budesonide, probiotics or activated charcoal still have to define the role of these drugs in the routine clinical setting. Whereas therapeutic management and clinical work-up of patients presenting with diarrhea after chemotherapy are rather well defined, prediction and prevention of CID is an evolving field. Current research focuses on establishing predictive factors for CID like uridine diphosphate glucuronosyltransferase-1A1 polymorphisms for irinotecan or dihydropyrimidine-dehydrogenase insufficiency for fluoropyrimidines.

PHY906, a four-herb Chinese medicine formula first described 1800 years ago, decreases gastrointestinal toxicity induced by the chemotherapeutic drug CPT-11 (irinotecan), as shown in a phase I/II clinical study. Similarly, in a murine colon 38 allograft model, PHY906 increased the antitumor activity of CPT-11 while decreasing animal weight loss caused by CPT-11. Here, we have further examined the effect of PHY906 on the intestinal toxicity caused by CPT-11 in mice. PHY906 did not protect against the initial DNA damage and apoptosis triggered by CPT-11 in the intestine, but by 4 days after CPT-11 treatment, PHY906 had restored the intestinal epithelium by promoting the regeneration of intestinal progenitor or stem cells and several Wnt signaling components. PHY906 also potentiated Wnt3a activity in human embryonic kidney-293 cells. Furthermore, PHY906 exhibited anti-inflammatory effects in mice by decreasing the infiltration of neutrophils or macrophages, tumor necrosis factor-alpha expression in the intestine, and proinflammatory cytokine concentrations in plasma. Chemical constituents of PHY906 potently inhibited nuclear factor kappaB, cyclooxygenase-2, and inducible nitric oxide synthase. Our results show that the herbal medicine PHY906 can counteract the toxicity of CPT-11 via several mechanisms that act simultaneously.

To update and expand on previously published clinical practice guidelines for the treatment of cancer treatment-induced diarrhea. An expert multidisciplinary panel was convened to review the recent literature and discuss recommendations for updating the practice guidelines previously published by this group in the Journal of Clinical Oncology in 1998. MEDLINE searches were performed and the relevant literature published since 1998 was reviewed by all panel members. The treatment recommendations and algorithm were revised by panel consensus. A recent review of early toxic deaths occurring in two National Cancer Institute-sponsored cooperative group trials of irinotecan plus high-dose fluorouracil and leucovorin for advanced colorectal cancer has led to the recognition of a life-threatening gastrointestinal syndrome and highlighted the need for vigilant monitoring and aggressive therapy for this serious complication. Loperamide remains the standard therapy for uncomplicated cases. However, the revised guidelines reflect the need for recognition of the early warning signs of complicated cases of diarrhea and the need for early and aggressive management, including the addition of antibiotics. Management of radiation-induced diarrhea is similar but may not require hospitalization, and chronic low- to intermediate-grade symptoms can be managed with continued loperamide. With vigilant monitoring and aggressive therapy for cancer treatment-induced diarrhea, particularly in patients with early warning signs of severe complications, morbidity and mortality may be reduced.