Response to 'Probable hepatotoxicity related to Nerium oleander extract in a patient with metastatic synovial sarcoma of the knee'.

Dear Editor: A recent letter by Altan et al. suggested that a 43-year-old female patient with synovial sarcoma of the knee developed progressive liver toxicity due to administration of a hot water extract of Nerium oleander. Because of our direct preclinical and clinical research experience with Anvirzel (a defined hot water extract of N. oleander; Nerium Biotechnology, San Antonio, TX) as well as a concentrated supercritical CO2 extract derived from this plant (i.e., PBI05204; Phoenix Biotechnology, San Antonio, TX) currently in Phase 1 trial in patients with cancer at the University of Texas M.D. Anderson Cancer Center (Houston, TX), we would like to respond to the suggestion that oleander-based products might be associated with hepatotoxicity. Despite implying that Anvirzel might have led to development of liver injury, the authors acknowledged that they could find no evidence of published reports of human hepatotoxicity that was caused either directly or indirectly from administration of Anvirzel. Our experience with Anvirzel and, indeed, the more concentrated oleander extract product PBI-05204 currently in clinical Phase 1 trial, has indicated absolutely no propensity toward producing liver injury. In thorough rodent and canine toxicology studies submitted to and reviewed by the U.S. Food and Drug Administration, hepatotoxicity was never encountered in either species. Additionally, no prior human report for oleander-related hepatotoxicity has been found. The authors fail to comment on the fact that the hepatotoxicity observed in their patient could well have been caused by the intensive chemotherapy treatment she received. Due to progression of pulmonary metastases, the patient had undergone six courses of ifosfamide and etoposide, apparently concluding in March 2008. Etoposide in particular has been associated with hepatotoxicity, in both high-dose and standard-dose regimens. Hepatotoxicity, including a case with fatal outcome, has been reported in ifosfamide–etoposide combination chemotherapy. These reports have included both immediate toxicity during chemotherapy and delayed manifestation of toxicity, as was the case in the patient described by Altan et al. Several other chemotherapy regimens have been associated with delayed hepatotoxicity. The relative clinical merits of the use of oleander-derived products such as PBI-05204 (or indeed other natural products proposed for use in patients with cancer) should of course be fully evaluated in a comprehensive cancer center with full attention to efficacy and toxicities. The conclusion that a product such as Anvirzel is associated with hepatotoxicity when no published evidence exists for such a claim and when no such toxicity has been associated with Anvirzel or an even more concentrated oleander-based product in Phase 1 testing, without discussion of possible alternative causes for such injury, is premature. Additionally, past analyses of case reports attributing hepatotoxicity to natural products have often shown that toxicity was more likely due to comedications or other predisposing factors.