This is the first randomized, controlled, clinical study to investigate the feasibility and safety of the herbal plant, milk thistle, in combination with the administration of chemotherapy in children undergoing treatment for cancer. We found that a short course of MT can be administered to children in the maintenance phase of treatment for ALL. No unexpected toxicities, reductions in doses of chemotherapy, or delays in therapy were observed during the supplementation period, despite the intervention group receiving slightly higher doses of vincristine and 6-mercaptopurine, and experiencing a lower percentage of chemotherapy dose reductions. Our preclinical data demonstrates that MT does not compromise the anticancer activity of L-asparaginase or vincristine in CCRF-CEM cell lines.
The administration of a 28-day course of MT was associated with a significant reduction in AST and a trend towards a significant reduction in ALT at Day 56, but not immediately after cessation of supplementation. The effect observed on AST and ALT could be due to delayed effects of milk thistle, inadequate dosing, or short duration of supplementation. Evaluation of the clinical literature has reported a wide range of therapeutic doses and duration.(5
) At the time of development of this clinical trials for supportive care, Phase 1 studies were not routinely developed for investigation of herbal or nutrition supplements.(18
) Therefore, we chose a short course of treatment and a conservative dose as this was the first trial conducted among children undergoing treatment for cancer. A recent phase 1 study in men with prostate cancer suggests a dose of 13 grams per day for future trials, thus our dose may have been too conservative.(20
) Phase 1 trials are needed in our patient population to determine appropriate dose and duration for both the prevention and treatment of hepatic toxicity.
Our study was strengthened by the product quality analysis, stability testing, and the goal of quantifying plasma levels of silibinin. Although detectable silibinin plasma concentrations were not observed at the dose prescribed, several hypotheses could account for this. Our limit of detection was 15 ng/mL (0.03 µM) for each compound with a mean recovery of 52%. This corresponds to 0.06 µM for each silybin A or silybin B, or 0.12 µM for the silibinin mixture. Previous studies in adults administered a similar dose found total silibinin plasma concentrations were quite variable and near undetectable (0.3 µM ± 0.3 µM or 144 ± 144 ng/mL).(16
) Since silibinin analysis is comprised of two compounds (silybin A and B) that equates to roughly 72 ng/mL each, the detectable concentrations of each compound was approximately 36 ng/mL or within two-fold of our limits of detection. Moreover, Hoh et al
collected blood samples within 1–4 hours of the final dose.(16
) In the current study, we relied primarily on patient reporting on the timing of the last dose and the time to blood draw was outside of the 4 hour range in several cases. When operating near the limits of detection, the timing of blood draws may be particularly crucial and should be closely controlled in future studies. Finally, no information is available on the metabolism of silibinin in pediatric patients compared to adults. Children may metabolize silibinin isomers at rates different from that of adults. Taken together, this combination of confounding variables contributes to the lack of silybin A or silybin B detection in patient plasma samples.
Our study was weakened by a small sample size. Based upon previously published studies, the study was powered to detect a minimum reduction in liver function tests of 50%. However, analysis of the current data (data not shown), found that the reduction was only 30%, which was achieved by AST at Day 56. Therefore, our current study was under powered to detect a significant treatment effect at Day 28. We also found that the MT group had a significantly lower compliance rate compared to the placebo group. We hypothesize that the treatment effect would be more pronounced had the compliance rate been improved in the MT group. Furthermore, assessment of liver toxicity by ALT and particularly AST are limited by their lack of specificity for chemotherapy-induced hepatocellular injury.
Despite the study limitations, the current study provides preliminary evidence that MT may be a safe, effective supportive care agent. Future investigations are needed to determine the appropriate dose and duration, and identify populations that may gain the largest clinical benefit. Possible populations are those undergoing treatment for acute myelogenous leukemia or stem cell transplantation in which hepatotoxicty frequently results in interruptions of treatment. Hepatoprotectant agents could also advance the management of patients with total parenteral nutrition -induced hepatoxicity.
In conclusion, this was the first study to evaluate milk thistle, a commonly used dietary supplement, in a blinded, controlled, trial among children undergoing treatment for ALL with biochemical evidence of elevated liver function tests. Future clinical trials should explore MT in the setting of patients in which hepatic toxicity prevents the provision of the recommended chemotherapy in individuals with cancer.