A Clinical Approach to Integrating Chinese Herbal Therapies and Chemotherapy

This exclusive article is part of the MettaPets Veterinary Professional Blog Series

This article is the intellectual property of Dr. Erin Bannink, February 2022.

Distribution of this article in part or entirety without written permission from Dr. Bannink is prohibited.

Chinese Herbal Formulas and Chemotherapy

Clinical research on concomitant use of Chinese herbal formulas and chemotherapy is evolving. Many published research articles are epidemiological studies or retrospective evaluations and meta-analyses. Limitations typical of these types of studies apply to these articles. With increasing efforts to improve the biomedical understanding and clinical utility of herbal medicine in cancer therapies, some prospective clinical trials have been published, with more currently underway in human medicine. For your information, below is a summary of some recent meta-analyses and research articles on the use of Chinese herbal medicine in cancer care for humans as well as some information on pharmacodynamics and pharmacokinetics.

Risk of metabolic P450 (CYP3A4) interaction with chemotherapy for the formulas Xiao Chai Hu Tang, Xue Fu Zhu Yu Tang and Bu Yang Huang Wu Tang should be low based on evidence that these formulas did not inhibit CYP34A in human and rat studies in vivo. The main component of Liu Jun Zi Tang, the base formula Si Jun Zi Tang, does not affect P450 enzymes. Liu Jun Zi Tang does contain 14% of its formulation as Citrus Peel (Chen Pi) which may inhibit CYP3A4. At this low concentration at proper doses within the whole formula this is highly unlikely to be clinically relevant and I have seen no clinically relevant adverse drug-herb interactions in my patients for whom I have prescribed Liu Jun Zi Tang based on TCM prescribing principles at appropriate doses using companies with whom I am familiar.

Herbal medications, like any other prescribed treatment, should always be used with informed consent from clients regarding what is and is not known about efficacy, toxicity and combination therapies. Based on the published retrospective evaluation of human cases, integration seems to be well-tolerated with no overt evidence that Chinese herbal therapies decrease survival or increase toxicity when administered with chemotherapy in most of these retrospective populations. This also fits with my personal clinical experience. In fact, many of these studies suggest the potential for improving disease control and/or decreasing toxicities, motivating development of prospective clinical trials. (Hormone responsive cancers may require special consideration as some herbs display estrogenic activity.)

Patients receiving other P450 substrate medications, medications with a narrow therapeutic index, or medications in which small changes in blood levels may significantly impact patient wellness (such as cardiac medications), should be managed carefully with thoughtful consideration given to risk versus benefit of administration of herbal formulas with chemotherapy. One practical consideration may be to separate administration of medications and herbs.

Concomitant medications which may affect P450 drug metabolism for drugs commonly used in veterinary oncology: on-line resource

CYP3A4 substrates: Adriamycin, Vinca Alkyloids, Tyrosine Kinase Inhibitors, dexamethasone/prednisone, tramadol, fentanyl, etoposide, zonisamide

CYP3A4 inhibitors: erythromycin, ketoconazole, ciprofloxacin, diltiazem, enrofloxacin

CYP3A4 inducers: phenobarbital

CPY2C19 substrates: Cytoxan, Plavix, diazepam

CPY2C19 inhibitors: cimetidine, omeprazole, fluoxetine, fluconazole, ketoconazole

Note that many of these pharmaceutical drugs are routinely used together with no clinically relevant drug interactions commonly reported.

Review Articles

A number of review article have recently been published on the potential role of herbal therapies for mitigation of chemotherapy side effects and possible mechanisms for these effects.

A Note on Interpreting the Research

A majority of published research on potential anti-neoplastic action of herbs and their compounds exists as in vitro and in vivo studies, many of which evaluate individual compounds found in single herbs with the goal of identifying compounds which can be developed into pharmaceutical drugs. This information provides some scientific proof of principle and aides in our understanding of the mechanisms by which these herbs may be exerting their clinical effects. However conclusions derived from these types of studies must be interpreted with the understanding that effects in vitro, or in in vivo studies using injectable forms of the herbs, do not necessarily predict biological or clinically relevant activity in a patient.

Chinese herbal medicine is prescribed as complex multi-herb formulas which contain numerous compounds and herbs. Studies have shown herb combining results in synergistic activity and also modulates absorption, metabolism and potential side effects of sister herbs within the formula. Additionally, herbal formulas are ingested orally so are also impacted by the gut microbiome, which may alter the compounds which are ultimately absorbed into the living system.

Complicating determination of clinically relevant herb-drug interactions based on published literature of this type is the fact that in vitro evidence of interaction does not necessarily correlate with clinically relevant toxicities or in vivo interactions in a living biological system orally ingesting whole herbs (rather than specific isolated compounds) or complex formulas. For example, milk thistle and Panax ginseng show CYP3A4 inhibition in vitro, raising theoretical concern for risk of increasing toxicity of drugs metabolized through this pathway. However, in clinical studies these herbal supplements did not cause significant pharmacokinetic interactions with midazolam, irinotecan, docetaxel and imatinib. Additionally, the brand and dosing of herbal products as well as timing of oral administration with chemotherapy may affect these potential interactions.

Similarly, there is in vitro evidence of CYP3A4 inhibition by single herbs which contradicts the in vivo information. This suggests that in vitro data may not correlate with metabolism in a living organism or with clinically relevant herb-drug interactions. There is also evidence that certain herbs, like Angelica Root/Dang Gui, inhibit CYP3A4 in vivo although the formulas they are contained in do not. Based on this information, then, individual herbs may have different effects on the P450 system than the multi-herb formulas in which they are contained. It may be that the amount of single herb within a larger formula is not sufficient to cause inhibition seen with the individual herb or that the complex interaction of the herbs within the whole formula alters the pharmacodynamics seen with individual herbs.

Additionally, pharmacodynamics related to P450 effects from herbal therapies are complex. Some plants and compounds which inhibit P450 enzymes in vitro have shown tissue specific effects. The importance of this is that inhibition of P450 enzymes by these compounds may, for example, positively impact drug absorption from the intestines via these routes and/or positively impact tumor response in tumor tissue without impacting pharmacokinetics of drug clearance effects on liver P450. Quercitin and Tetradine (derived from Stephania/Hang Fang Ji) are two examples of this.

References

A Clinical Approach to Herbal Therapies and Chemotherapy

With intentional patient selection and client education, I have used a number of herbal formulas from Natural Path, Golden Flower Herbs and Evergreen Herbs simultaneously with Adriamycin, Cytoxan, Leukeran, Vincristine, Vinblastine, Mitoxantrone, Actinomycin D, Carboplatin and Palladia with no anecdotally observed increase in clinically relevant chemotherapy toxicity in my practice over the past 15 years. Before starting herbal formulas, I first document tumor response when gross disease is present. This allows for more objective assessment about how herbal treatments are affecting tumor response. Herbal prescriptions are always made on a patient specific basis using Traditional Chinese Herbal Medicine prescribing principles.

In patients receiving combination treatment with chemotherapy and herbs, I recommend introducing herbal therapies after the first cycle of chemotherapy is administered in order to determine baseline responses and toxicities in individual patients. This allows for ease in clinical management and better determination of cause of any observed side effects. Because individual patient metabolism and sensitivities can vary, this tapered introduction is also prudent and clinically responsible.

Another, more conservative, approach would be to stop herbal therapies 48 hours before chemotherapy and start again 48 hours after. Alternatively, some clinicians or clients may choose to wait until completion of chemotherapy and implement herbal therapies as a type of maintenance therapy or supportive care. Unless herbs are being used specifically with the goal of mitigating side effect of chemotherapy, such as myelosuppression, these are good options for those who are uncomfortable combining herbal therapies concurrent with chemotherapy administration.

I have not, personally, had a patient hospitalized for adverse drug reactions related to herb administration, even when given along with chemotherapy. However, some patients might develop diarrhea from herbs, or food aversion if the herbs are mixed in their meal food. If gastrointestinal upset is due to herbs, this will resolve within 24-48 hours of discontinuation of the formula.

Patients with inflammatory bowel disease or history of chronic diarrhea can be treated successfully with herbs, often with improvement of symptoms. However these patients may be more likely to develop diarrhea when herbal therapies are started and may require frequent adjustment of herbal prescriptions before the best combination is achieved. I always warn owners of this, as it can be frustrating for both client and clinician. Although it does not happen often, I have had a handful of these types of patients who could not tolerate any herbal medications, at least within my skill set. So, as with any new therapy, the pros and cons should be discussed and the client educated about these prior to starting treatment.