You Shall Not Pass: Pharmacist Review of Drug-Herb Interactions in Cancer Treatment

PRÉCIS

Use of herbal supplements poses many risks for patients with cancer on oral therapies; pharmacists play a key role in managing safety and treatment efficacy.

Image Credit: amazing studio | stock.adobe.com

Abstract

Herbal supplement use among patients with cancer, particularly those undergoing oral oncology treatment, is common, but it poses potential risks. This narrative review focuses on the 5 most commonly encountered herbal supplements at the University of California Davis, identified through pharmacist survey data collected during routine patient care: curcumin, reishi mushroom (Ganoderma lucidum), quercetin, elderberry (Sambucus spp), and maitake mushroom (Grifola frondosa). This review highlights key concerns regarding the safety and efficacy of these supplements, including drug-herb interactions, metabolic effects, and possible influence on cancer treatment outcomes. The findings stress the importance of thorough evaluation and evidence-based recommendations when managing herbal supplement use in patients with cancer. Clinical oncology pharmacists play a pivotal role in ensuring patient safety by identifying possible interactions and conveying appropriate recommendations to patients and providers.

Introduction

Among patients with cancer, self-medication with herbal supplements is prevalent, with estimates suggesting that 20% to 78% of patients with cancer use some form of herbal supplements.^1-3 Patients use herbal supplements for various reasons, ranging from managing chemotherapy adverse effects (AEs) to serving as an alternative or complementary modality to traditional anticancer therapy. Common herbal supplements taken by patients with cancer include garlic, curcumin, primrose, and echinacea, although specific patterns of use may vary over time.¹ It is also noted that up to 70% of patients do not disclose their use of herbal supplements to oncology providers due to their perception that these therapies are natural and thus safe.⁴

The landscape of cancer treatment has witnessed a dramatic shift, with a rapid
regulatory expansion encompassing a range of therapies, including targeted drugs, immunotherapies, and combination treatments tailored to specific cancer types and molecular profiles. From May 2021 to May 2022, the FDA granted regulatory approval or indication expansion for over 40 oncology drugs, including 15 oral agents.⁵ Study results suggest that patients with cancer prefer oral treatment rather than intravenous, citing convenience, avoiding travel for care, and flexible treatment schedule.⁶ However, oral treatments also present challenges, particularly the risk of severe drug-drug interactions (DDIs) or drug-herb interactions with other medications or supplements. Results from a recent study found that polypharmacy is
common among older patients with cancer, with an average of 9.8 medications per patient, including an average of 0.5 herbal supplements.⁷ Additionally, the prevalence of DDIs among patients with cancer taking an oral therapy is estimated at 46% to 55%.^8,9

Although believed to be benign by many patients, herbal supplements are well-known DDI offenders. For example, St John’s wort (Hypericum perforatum), commonly used for depression, induces cytochrome P450 (CYP450) enzyme and is a P-glycoprotein (PGP) efflux pump inducer, leading to significant interactions with many oral and intravenous cancer medications.^3,10 Similarly, turmeric (Curcuma longa) is used as complementary therapy for its purported anticancer activity, but it has been shown to inhibit CYP450 enzymes, reducing the effectiveness of drugs such as tamoxifen.¹⁰ The impact of herbal supplements on patients with cancer is further complicated by the lack of comprehensive data on their clinical effect, with most pharmacokinetic or pharmacodynamic studies limited to in vitro studies or animal models, and only sporadic case reports and clinical trials.³ Additional challenges include variations in herbal supplement content and quality, uncertainty around dose optimization, and unclear dose adjustments for organ function or body size, among others.¹⁰

At our institution, University of California (UC) Davis, oncology specialty pharmacists play a vital role in managing interactions between herbal supplements and oral oncolytic therapies. In this review, we share our experience with managing common herbal supplements used by patients with cancer and summarize evidence and recommendations for addressing these drug-herb interactions.

Methods

This narrative review was informed by an observational, survey-based assessment of herbal supplement use among patients with cancer undergoing oral oncology treatment at UC Davis Health, a National Cancer Institute–designated Comprehensive Cancer Center. Oncology specialty pharmacists were asked to complete standardized surveys each time they encountered a patient concurrently using herbal supplements with their oral cancer therapy. A formal definition of herbal supplement was not provided to pharmacists, and inclusion was based on individual clinical judgment. The pharmacist intervention consisted of a binary recommendation: continue the herbal supplement or discontinue it based on potential safety concerns. This recommendation was communicated either directly to the patient or the prescribing provider, depending on the clinical context. The survey prompted pharmacists to record the type of herbal supplement used, the method by which the herbal supplement use was disclosed to them (eg, medication reconciliation, physician inquiry, patient disclosure), and whether the patient and provider accepted the pharmacist’s intervention. Although no specific prompting questions were used during medication reconciliation, asking about herbal supplement use is standard practice for pharmacists and clinicians at our institution. To ensure confidentiality, no patient-identifying data were collected. Initiated in January 2020, the survey aimed to collect data from the first 100 patients identified who used herbal supplements. This research was deemed exempt from institutional review board approval.

After survey completion, the top 5 herbal supplements were subject to an in-depth analysis aimed at compiling a comprehensive literature review and developing evidence-based recommendations. The databases PubMed, Medline, and Cochrane Library were searched for publications available up to March 2023 using the following terms: drug interactions, adverse drug reaction, toxicity, safety, side effects, pharmacokinetic, pharmacodynamic, and the names of active ingredients. The selection of search terms and databases was based on previous literature assessing drug-herb interactions.¹¹ Data from human studies, clinical trials, and, where relevant, in vitro studies and animal models were included.

Results

We identified 100 instances of herbal supplement use among patients taking an oral cancer therapy, with data collection spanning from January 2020 to March 2023. Five of the most frequently used herbal supplements were curcumin (17%), reishi mushroom (7%), quercetin (6%), elderberry (4%), and maitake mushroom (4%). A comprehensive listing of all identified oral supplements and their incidence rates is provided in the Table.

Table

Pharmacist-led medication reconciliation was the most common method through which herbal supplement use was identified, accounting for 57% of instances, whereas 37% were reported by providers and 6% by nurses (Figure 1). Providers universally accepted the pharmacists’ recommendations for managing the herbal supplements and oral oncology therapy, with a 100% acceptance rate. Patient acceptance of these recommendations was also high (94%).

Figure 1

Review and Recommendations: Curcumin

Turmeric is a common cooking spice and coloring agent. Its active compounds—known as curcuminoids—include curcumin, which is the most biologically active. First isolated in 1815, curcumin has been extensively studied for its antioxidant, anti-inflammatory, and antimicrobial properties.¹² In oncology, interest in curcumin has grown due to its potential anticancer effects, both for treatment and prevention. These effects are believed to be mediated through various signaling pathways and molecular targets. Curcumin has been investigated for use in several types of cancer, including pancreatic, breast, colorectal, and head and neck cancers.^13,14

The regular use of curcumin in oncology is limited by a lack of clinical studies, low bioavailability, and numerous drug interactions.¹⁵ Although curcuminoids have been designated Generally Recognized as Safe (GRAS) by the FDA, the wide range of dosages and formulations makes it challenging to evaluate AEs directly associated with these compounds. The FDA’s GRAS designation is based on studies showing good tolerability and safety profiles at doses of 4000 to 12,000 mg/day of 95% concentrated curcuminoids, specifically curcumin, bisdemethoxycurcumin, and demethoxycurcumin.^16,17 The most common AE of curcumin is local, reversible allergic dermatitis. Case reports have also indicated potential hepatotoxicity, neutropenia, iron deficiency anemia, and nephropathy.¹⁸ Of particular concern is curcumin’s antiplatelet activity, especially when used in combination with chemotherapy or other drugs with similar effects.¹⁹

Curcumin is available in several formulations, including capsules, tablets, powder nanoparticles, liposomal encapsulation, and emulsions. Despite these options, curcumin itself has poor aqueous solubility and chemical instability, leading to overall poor bioavailability.¹² Its hydrophobic nature after oral administration results in low absorption rates through the gastrointestinal (GI) tract. Additionally, the small percentage of curcumin that is absorbed is subject to extensive reductive and conjugative metabolism in the liver.^12,15 Studies suggest that combining curcumin with black pepper (Piper nigrum) or long pepper (Piper longum) can enhance its bioavailability by up to 2000%. These pepper varieties are known as bioavailability enhancers because they are believed to reduce drug glucuronidation in the liver and small intestine.²⁰ However, the exact ratio of pepper to curcumin needed for optimal effectiveness in clinical settings remains unclear.

Curcumin has been suggested to inhibit various CYP450 enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2D6, and CYP3A4. However most supporting data come from in vitro studies. One small study of adults (n = 8) found that turmeric extract is unlikely to result in clinically significant interaction involving CYP3A4 and CYP2C9. Another study further highlighted this discrepancy, noting that although curcumin exhibits strong in vitro inhibitory effects on CYP3A4 and CYP2C8, its interactions with imatinib (Gleevec; Novartis Pharmaceuticals) or bosutinib (Bosulif; Pfizer)—both major CYP3A4 substrates—were unlikely to be clinically relevant due to its poor bioavailability. The likely explanation is that despite its demonstrated in vitro inhibitory activity on major CYP enzymes, curcumin has poor bioavailability. As a result, systemic exposure to curcumin is low, making it unlikely to produce significant drug-drug interactions in the liver. Various formulations of black pepper are marketed as bioavailability enhancers for curcumin, but the extent of this effect is unclear and may vary widely between products, making their clinical impact uncertain. Additionally, the presumed antioxidant effect of curcumin may be problematic. For certain chemotherapeutic agents, oxidative stress is the mechanism through which cancer cell death occurs, and curcumin’s antioxidant properties may reduce the therapeutic efficacy of such treatments. Studies have shown a higher risk of cancer recurrence and mortality in patients taking supplemental antioxidants during chemotherapy.^19,21,22

Despite claims of curcumin’s potential as an anticancer agent, its unpredictable bioavailability, significant metabolic interactions, and antioxidant properties limit its clinical use in oncology. For patients with cancer, especially those taking oral oncolytics, the regular use of curcumin as a supplement is not recommended until further studies demonstrate that the benefits outweigh the risks.

Review and Recommendations: Reishi Mushroom

Reishi mushroom (Ganoderma lucidum) has been utilized as a medicinal mushroom in China, Japan, and other Asian countries for more than 2000 years to promote health and longevity. It is a popular supplement with healthy individuals for its antioxidant effects and among patients with cancer because of its proposed antitumor effects. Its antioxidant and antitumor activity is often attributed to its high molecular weight polysaccharide structures and triterpene compounds that are extracted and incorporated into over-the-counter supplements.²³ In vitro studies assessing the antitumors effects of reishi mushrooms have demonstrated activity leading to cell cycle arrest and apoptosis in human and rodent tumor cells and have also shown antiangiogenic activity when studied on prostate cell lines. These anticancer effects require further elucidation in vivo through human randomized, controlled clinical trials.23-25 In addition to the antioxidant and anticancer effects, reishi mushrooms are thought to lower glucose levels in patients with type 2 diabetes. They have also been used in the treatment of patients with hepatitis, nephritis, hypertension, asthma, and gastric ulcers.^23,26

Reishi mushrooms are thought to generally lack toxicity, but reported AEs include nausea and insomnia.²⁷ Although one of the purported benefits of reishi mushrooms is their hepatoprotective effects, there have been 2 reports of hepatotoxicity and 1 report of hypereosinophilia with hepatic nodules attributed to their use.^28,29

Notable drugs that interact with reishi mushrooms include anticoagulants, antiplatelets, antihypertensives, and glucose-lowering agents. Patients taking anticoagulants and antiplatelets should be monitored for increased risk of bleeding if they also are taking reishi mushrooms; concomitant use may cause decreased platelet aggregation.³⁰ Given their theoretical use in lowering blood glucose and blood pressure, concurrent use of reishi mushrooms may increase risk of hypotension and hypoglycemia.²³ Similar theoretical caution should be considered for patients on chemotherapeutic agents, as the potential antioxidant effects of reishi mushrooms may interfere with the anticancer effects of chemotherapies that act on free radicals.³¹ It has been reported that the triterpenoid component of reishi mushrooms has been shown to inhibit activity of CYP3A4 in vitro; however, human pharmacokinetic data have not shown relevant interactions even at high doses of reishi mushroom (oral dose of 3000 mg); therefore, it does not seem to be clinically significant.³² Overall, reishi mushroom may be used by patients with cancer with caution and careful considerations of concomitant medications.

Review and Recommendations: Quercetin

Bioflavonoids are a family of plant polyphenols that have garnered significant interest as health supplements. These substances play important roles in plant pigmentation, growth, and reproduction and have been studied for their potential antioxidative, anti-inflammatory, and anticarcinogenic effects. Bioflavonoids are categorized into 6 main types based on their pharmacological substituent groups: flavones, flavanols, flavanones, flavonols, isoflavones, and anthocyanidins.33 Quercetin, a type of flavonol, is found in high concentrations in onions, kale, lettuce, tomatoes, apples, grapes, berries, dark cherries, cranberries, red wine, tea, broccoli, nuts, many flowers, and olive oil. It is also present in traditional medicinal herbs such as Ginkgo biloba and St John’s wort.^33,34

Quercetin has been specifically studied and marketed for its cardiovascular, anticancer, anti-inflammatory, antihyperglycemic, antihypertensive, and anti-infective properties. Its anticancer mechanisms include inhibition of angiogenesis, antiproliferative effects, antimetastatic activity, and induction of apoptosis.34,35 For example, there are reports of concomitant quercetin use with tamoxifen potentially enhancing the anticancer effect on breast cancer cells; however, these studies are limited to in vitro cell lines and have yet to demonstrate clinical significance in human trials.³⁶

Consuming quercetin through dietary intake of fruits and vegetables has not been linked to significant AEs. Isolated quercetin in dietary supplements is generally well tolerated, with occasional reports of mild headaches or tingling sensations in the extremities.³⁷ However, the benefits and safety of long-term quercetin supplementation at high doses (greater than 1000 mg for more than 12 weeks) remain unclear and lack substantial evidence.³⁸ In contrast, intravenous administration of quercetin has been associated with significant AEs, including severe nausea and vomiting, diaphoresis, dyspnea, and nephrotoxicity.^38,39

There are significant herb-drug interactions to consider in patients with cancer taking quercetin supplements.⁴⁰ Quercetin has been shown to increase exposure to certain antihypertensives and anticoagulants. Additionally, there are concerns regarding the concomitant use of quercetin and anticancer medications.⁴¹ Quercetin inhibits several CYP450 (enzymes, including CYP2C8, CYP2C9, CYP2D6, and CYP3A4. Furthermore, evidence suggests that quercetin may inhibit mechanisms that promote drug elimination via organic anion transporter (ie, OAT1, OAT3, and OATP) and the PGP efflux pump.^40,42

As an example of the risks associated with such metabolic changes, the metabolism of EGFR inhibitors is pertinent. This class of oral drugs is essential for treating numerous cancers, including lung cancer, soft tissue sarcomas, renal cell carcinoma, and endometrial cancer.⁴³ Many oral EGFR inhibitors, such as osimertinib (Tagrisso; AstraZeneca) and erlotinib (Tarceva; Genentech), require metabolism via the CYP450 and/or OAT/PGP systems.⁴⁴ Concomitant use of quercetin may lead to higher-than-expected drug plasma levels and increased toxicity. This could be detrimental to patients with cancer, as severe toxicity may warrant a drug interruption, dose reduction, or even complete discontinuation of therapy.

Overall, quercetin may be used in patients with cancer with caution and only after careful evaluation of possible alterations to the pharmacokinetics and pharmacodynamics of the oral oncolytic in question.

Review and Recommendations: Elderberry

Elderberry (Sambucus spp) is a small, flowering shrub native to Europe found in North America, West Asia, and North Africa. Its dark purple berries are proposed to have antioxidant, anti-inflammatory, analgesic, diuretic, and laxative effects.^45-47 Elderberry contains high levels of flavonoids, with anthocyanins cyanidin 3-glucoside and cyanidin 3-sambubioside being the most prominent, both believed to possess antiviral and immunostimulatory activity.⁴⁶ This has led to the common use of elderberry in treating cold and influenza symptoms.^47,48 A randomized, double-blind, placebocontrolled study found that elderberry supplementation may shorten the duration of cold symptoms by 3 to 4 days and reduce symptom intensity. However, this study is limited due to small sample size and exclusion of patients who had received the influenza vaccine.⁴⁹ During the height of the COVID-19 pandemic, elderberry was claimed to treat the virus, although no data support this claim.⁵⁰ Traditionally, elderberry extract has been used for its proposed anti-inflammatory properties to treat joint and muscle pain.⁴⁷ Nonetheless, no data exist to confirm the efficacy of elderberry as an analgesic.

Elderberry supplementation typically ranges from 175 to 1200 mg daily. When appropriately used, elderberry supplements are generally safe and well tolerated, without significant AEs.⁵¹ However, consuming raw elderberry or other parts of the plant can be hazardous due to the risk of cyanide toxicity. Eating raw berries, seeds, leaves, or other plant parts can cause severe GI issues, such as nausea, vomiting, and diarrhea, and can also lead to symptoms such as weakness, dizziness, and numbness.⁵¹

Elderberry is generally not recognized as a significant or predictable cause of drug-herb interactions. In vitro studies of elderberry have shown weak inhibition of CYP3A4.⁵² However, a case study involving a woman aged 65 years with localized sarcoma who was undergoing therapy with pazopanib and radiation therapy while taking elderberry supplements to boost her immune system presents a potential concern. Upon starting pazopanib (Votrient; Novartis), she experienced severe nausea, diarrhea, and elevated liver enzymes. After discontinuing all medications, her GI symptoms resolved within days, and her liver enzymes normalized within 2 weeks. When pazopanib was reintroduced at a lower dose, the AEs did not recur, suggesting a possible drug-herb interaction with elderberry.⁵³ Despite this, there are limited published data to further elucidate or predict clinically significant interactions with elderberry. Given elderberry’s potential as an immunostimulant, clinicians should exercise caution when recommending it to patients undergoing immunotherapy, due to the theoretical risk of increased immunotherapy-related AEs.⁵⁴ Overall, elderberry, when consumed as supplement at the normal dose range of 175 to 1200 mg, appears to be a safe option for patients with cancer. However, uncertainties regarding its pharmacokinetic and pharmacodynamic interactions, as well as its overall benefit, warrant cautious consideration.

Review and Recommendations: Maitake Mushroom

Maitake mushroom (Grifola frondosa), also known as hen-of-the-woods, is an edible fungus in the Basidiomycetes family. The mushroom contains a host of bioactive molecules, including polysaccharides, proteins/peptides, fatty acids, ergosterols, flavonoids, alkaloids, ascorbic acid, and tocopherol.^55,56 The bioactive ingredient in maitake is referred to as the D-fraction, which is a protein-bound polysaccharide compound (eg, a proteoglycans), and has been shown to have both antioxidant and immunomodulatory effects in vitro.^57-59 In addition to these biological effects, maitake has been shown in vivo to have various anticancer properties, including immunostimulatory and antitumor activities.^60,61 The exact mechanisms underlying maitake’s anticancer potential are not fully elucidated and vary in the literature. However, it is believed to result from a combination of direct cytotoxic effects, stimulation of cytokines IFN-γ and IL-2, activation of natural killer cells, and, in some experiments, the enhancement of the cytotoxic effects of monoclonal antibodies such as trastuzumab (Herceptin; Genentech).^60-64

Multiple studies on various animal models have shown that maitake has a low potential for causing AEs.⁶⁵ Additionally, 3 different clinical trials involving both healthy individuals and patients with cancer have reported no serious AEs, with mild GI symptoms being the most commonly noted issue, suggesting that maitake is generally well tolerated in humans.^66-68 However, the clinical significance of these effects remains to be fully determined.

A literature review identified only 3 references addressing the potential of maitake to interact with other medications.^69-71 The first was a case report of a patient who experienced an increased international normalized ratio (INR) when maitake was prescribed concomitantly with warfarin.⁶⁹ The authors suggested that maitake displaced warfarin from protein binding, thereby increasing warfarin’s activity and, consequently, the patient’s INR. Thus, any anticancer drug with protein-binding effects similar to warfarin, such as tyrosine kinase inhibitors (eg, imatinib) or hormonal agents (eg, tamoxifen), should be used with caution when combined with maitake because of the potential for displacement and altered drug exposure.^72,73 The latter 2 references were review articles citing theoretical concerns based on in vitro data.^70,71 In summary, considering both the theoretical and known risks, maitake appears to be reasonably safe when used with antineoplastic chemotherapy as well as oral anticancer targeting agents. However, because of the known effects of maitake on the immune system, combining it with immunotherapy is not recommended.

Discussion/Conclusions

Herbal supplement use among patients with cancer is relatively common, but the effect on the patients’ anticancer therapies can be complex and influenced by factors such as patient age, comorbidities, organ function, and concomitant medications. It is crucial to consistently and accurately evaluate a patient’s usage and interest in herbal supplements and provide evidence-based recommendations. In our investigation of 100 patients, more than 40 different herbal supplements were documented, reflecting the diverse range of agents that patients explore and use. Although provider acceptance of pharmacist interventions related to herbal supplements was universal in our study, approximately 6% of patients declined the recommended change. This highlights the need for further research to understand the reasons behind patients’ reluctance to adhere to pharmacist recommendations regarding initiating or discontinuing herbal supplements.

Before suggesting that a patient initiate an herbal supplement alongside anticancer therapy, pharmacists should employ a thorough, evidencebased evaluation. They should also be familiar with established clinical resources to guide patient counseling. Organizations such as the National Comprehensive Cancer Network, the Society for Integrative Oncology, the National Institute of Health’s Office of Dietary Supplements, and the National Center for Complementary and Integrative Health provide evidence-based frameworks that support clinical decision-making.^74-78 These tools assist pharmacists in identifying potential interactions, evaluating efficacy, and clearly communicating risks to patients considering complementary therapies. Memorial Sloan Kettering Cancer Center’s Herbal Oncology Program is a leading model for integrating herbal supplement guidance into cancer care.⁷⁹ The program promotes a shared decision-making approach involving the patient, provider, and pharmacist to ensure safe and effective use. This collaborative framework underscores the importance of open dialogue and evidence-based counseling in managing complementary therapies within oncology.

Building on these resources, pharmacists should also apply practical strategies when assessing individual supplements and counseling patients. We suggest researching the herb’s active ingredients, potential benefits, and any clinical studies or trials that support its efficacy. It is advisable to avoid herbal supplements containing proprietary blends, as they often lack transparency regarding the specific amounts of active and inactive ingredients, making it difficult to assess their potency, safety, and effectiveness.

To aid in evaluation of herbal supplements, a comprehensive schematic is provided to guide clinicians and pharmacists in evaluating the safety of herbal supplements among patients with cancer receiving active cancer-directed therapy (Figure 2). Moreover, when engaging with patients regarding herbs and supplements, we recommend using the following verbiage: “Generally speaking, we do not recommend herbal supplements/products as these are not reviewed by the FDA in the same way prescription medications are. For this reason, we cannot be certain that the statements they make about effectiveness and/or potential adverse effects are accurate. This includes patient testimonials that have not been subject to peer review and may be misleading for various reasons. However, we recognize that patients may still be interested in these products, and in some cases, the benefits of using them may outweigh the potential harms.” Finally, in addition to carefully evaluating the quality and safety of an herbal supplement, it is important to perform a medication reconciliation prior to starting any oral oncolytic therapy, ensuring that any potential interactions with current prescriptions, over-thecounter drugs, or other supplements are identified and addressed. In our practice, we utilize the Natural Medicines Database and the Memorial Sloan Kettering Cancer Center’s herbs database to assess possible interactions and other safety risks.^80,81

Figure 2

The generalizability of our study is limited by the types of herbal supplements that our center’s patients were using. The FDA estimates that there are more than 29,000 herbal supplements, all of which have the potential to interact with anticancer medications and other pharmacotherapies for different disease states.⁸² Additionally, we failed to identify a comprehensive list of articles showing safety and/or efficacy of herbal supplements when combined with anticancer medications. Given this limitation, further research is needed to evaluate the safety and efficacy of the most commonly used herbal supplements in combination with oral oncolytic therapies. Because many of our recommendations are based on theoretical assumptions, clinicians should exercise caution and aim to balance potential risks and benefits when
advising patients on herbal supplement use.

An important consideration not discussed in depth in this review is the potential for myelosuppression when herbal supplements are used concurrently with myelosuppressive anticancer therapies, which may increase risk of hematologic toxicities. A further limitation of our research is that we only included 5 herbal supplements frequently identified at our center. This may not reflect the broader oncology population, and other institutions may encounter certain agents more frequently. Additionally, a formal definition of herbal supplement was not provided to pharmacists, and inclusion was based on individual judgment. As a result, agents such as folic acid or fenbendazole may have been variably classified, depending on the pharmacist’s interpretation and the context of use. Similarly, no standardized prompting questions were used to elicit herbal supplement use during medication reconciliation, which may have affected the consistency of supplement reporting.

Additionally, we did not collect data on the specific follow-up or clinical outcomes after pharmacist recommendations were made, limiting our ability to assess their impact on patient care.

Future studies should also explore additional patient-level factors that may influence herbal supplement use, including demographics, cancer types, and number of supplements per patient. Metrics such as median number of supplements per patient and differences in use across cancer types could provide deeper insights into usage patterns and guide tailored counseling strategies.

Our findings further reinforce the critical role of medication reconciliation in patient safety and treatment efficacy among patients with cancer treated with oral anticancer medication. Reconciliation should be conducted prior to starting anticancer therapies and periodically throughout therapy to identify interactions and address safety or efficacy concerns. In this study, more than one-third of herbal supplements were identified through pharmacistled medication reconciliation, emphasizing the critical role of clinical pharmacists in managing oncology treatments. Qualitative research has consistently shown that pharmacists are among the most trusted health care professionals.⁸³ This trust allows pharmacists to foster open, supportive relationships with patients, making them more likely to disclose the use of herbal supplements and thus helping to bridge the gap between conventional and complementary therapies.

REFERENCES

1. Asiimwe JB, Nagendrappa PB, Atukunda EC, et al. Prevalence of the use of herbal medicines among patients with cancer: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2021;2021:9963038. doi:10.1155/2021/9963038
2. Damery S, Gratus C, Grieve R, et al. The use of herbal medicines by people with cancer: a cross-sectional survey. Br J Cancer. 2011;104(6):927-933. doi:10.1038/bjc.2011.47
3. Fasinu PS, Rapp GK. Herbal interaction with chemotherapeutic drugs-a focus on clinically significant findings. Front Oncol. 2019;9:1356. doi:10.3389/fonc.2019.01356
4. Vasques AC Sr, Cavaco P, Duarte T, et al. The use of herbal medicines among cancer patients. Cureus. 16(2):e53455. doi:10.7759/cureus.53455
5. Bell D. New FDA-approved oncology drugs (2021–2022). June 3, 2022. Accessed April 29, 2024. ASCO Post. https://ascopost.com/issues/june-3-2022-narratives-special-issue/new-fda-approvedoncology-drugs-2021-2022/
6. Eek D, Krohe M, Mazar I, et al. Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: a review of the literature. Patient Prefer Adherence. 2016;10:1609-1621. doi:10.2147/PPA.S106629
7. Nightingale G, Pizzi LT, Barlow A, et al. The prevalence of major drug-drug interactions in older adults with cancer and the role of clinical decision support software. J Geriatr Oncol. 2018;9(5):526-533. doi:10.1016/j.jgo.2018.02.001
8. Solomon JM, Ajewole VB, Schneider AM, Sharma M, Bernicker EH. Evaluation of the prescribing patterns, adverse effects, and drug interactions of oral chemotherapy agents in an outpatient cancer center. J Oncol Pharm Pract. 2018;25(7):1564-1569. doi:10.1177/1078155218798150
9. van Leeuwen RWF, Brundel DHS, Neef C, et al. Prevalence of oral anticancer drugs. Br J Cancer. 2013;108(5):1071-1078. doi:10.1038/bjc.2013.48
10. Chan WJJ, Adiwidjaja J, McLachlan AJ, Boddy AV, Harnett JE. Interactions between natural products and cancer treatments: underlying mechanisms and clinical importance. Cancer Chemother Pharmacol. 2023;91(2):103-119. doi:10.1007/s00280-023-04504-z
11. Shi S, Klotz U. Drug interactions with herbal medicines. Clin Pharmacokinet. 2012;51(2):77-104. doi:10.2165/11597910-000000000-00000
12. Sharifi-Rad J, Rayess YE, Rizk AA, et al. Turmeric and its major compound curcumin on health: bioactive effects and safety profiles for food, pharmaceutical, biotechnological and medicinal applications. Front Pharmacol. 2020;11:01021. doi:10.3389/fphar.2020.01021
13. Giordano A, Tommonaro G. Curcumin and cancer. Nutrients. 2019;11(10):2376. doi:10.3390/nu11102376
14. Tomeh MA, Hadianamrei R, Zhao X. A review of curcumin and its derivatives as anticancer agents. Int J Mol Sci. 2019;20(5):1033. doi:10.3390/ijms20051033
15. Dei Cas M, Ghidoni R. Dietary curcumin: correlation between bioavailability and health potential. Nutrients. 2019;11(9):2147. doi:10.3390/nu11092147
16. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15(1):195-218. doi:10.1208/s12248-012-9432-8
17. Hewlings SJ, Kalman DS. Curcumin: a review of its effects on human health. Foods. 2017;6(10):92. doi:10.3390/foods6100092
18. Turmeric. Memorial Sloan Kettering Cancer Center. March 11, 2024. Accessed January 9, 2025. https://www.mskcc.org/cancer-care/integrative-medicine/herbs/turmeric
19. Unlu A, Nayir E, Dogukan Kalenderoglu M, Kirca O, Ozdogan M. Curcumin (turmeric) and cancer. J BUON. 2016;21(5):1050-1060.
20. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64(4):353-356. doi:10.1055/s-2006-957450
21. Ambrosone CB, Zirpoli GR, Hutson AD, et al. Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a cooperative group clinical trial (SWOG S0221). J Clin Oncol. 2020;38(8):804-814. doi:10.1200/JCO.19.01203
22. D’Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J Clin. 2005;55(5):319-321. doi:10.3322/canjclin.55.5.319
23. Wachtel-Galor S, Yuen J, Buswell JA, Benzie IFF. Ganoderma lucidum (lingzhi or reishi): a medicinal mushroom. In: Benzie IFF, Wachtel-Galor S, eds. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. CRC Press/Taylor & Francis; 2011.
24. Shang D, Zhang J, Wen L, Li Y, Cui Q. Preparation, characterization, and antiproliferative activities of the Se-containing polysaccharide SeGLP-2B-1 from Se-enriched Ganoderma lucidum. J Agric Food Chem. 2009;57(17):7737-7742. doi:10.1021/jf9019344
25. Stanley G, Harvey K, Slivova V, Jiang J, Sliva D. Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-β1 from prostate cancer cells. Biochem Biophys Res Commun. 2005;330(1):46-52. doi:10.1016/j.bbrc.2005.02.116
26. Wasser SP. Reishi or ling zhi (Ganoderma lucidum). International Mycotherapy Institute. Accessed January 9, 2025. https://www.imispain.com/blog/wp-content/uploads/2010/11/7_49_IMI.pdf
27. Jin X, Beguerie JR, Sze DMY, Chan GCF. Ganoderma lucidum (reishi mushroom) for cancer treatment. Cochrane Database Syst Rev. 2016;4(4):CD007731. doi:10.1002/14651858.CD007731.pub3
28. Kogure T, Koiwai A, Fukushi D, et al. Hypereosinophilia with hepatic nodule formation caused by Ganoderma lucidum. Intern Med Tokyo Jpn. 2021;60(24):3897-3903. doi:10.2169/internalmedicine.7431-21
29. Yuen MF, Ip P, Ng WK, Lai CL. Hepatotoxicity due to a formulation of Ganoderma lucidum (lingzhi). J Hepatol. 2004;41(4):686-687. doi:10.1016/j.jhep.2004.06.016
30. Tao J, Feng KY. Experimental and clinical studies on inhibitory effect of Ganoderma lucidum on platelet aggregation. J Tongji Med Univ. 1990;10(4):240-243. doi:10.1007/BF02887938
31. Wachtel-Galor S, Szeto YT, Tomlinson B, Benzie IFF. Ganoderma lucidum (‘Lingzhi’); acute and short-term biomarker response to supplementation. Int J Food Sci Nutr. 2004;55(1):75-83. doi:10.1080/09637480310001642510
32. Rodseeda C, Yamanont P, Pinthong D, Korprasertthaworn P. Inhibitory effects of Thai herbal extracts on the cytochrome P450 3A-mediated metabolism of gefitinib, lapatinib and sorafenib. Toxicol Rep. 2022;9:1846-1852. doi:10.1016/j.toxrep.2022.10.004
33. Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:e47. doi:10.1017/jns.2016.41
34. Anand David AV, Arulmoli R, Parasuraman S. Overviews of biological importance of quercetin: a bioactive flavonoid. Pharmacogn Rev. 2016;10(20):84-89. doi:10.4103/0973-7847.194044
35. Lotfi N, Yousefi Z, Golabi M, et al. The potential anti-cancer effects of quercetin on blood, prostate and lung cancers: an update. Front Immunol. 2023;14:1077531. doi:10.3389/fimmu.2023.1077531
36. Paulpandi M, Kavithaa K, Sumathi S, Padma PR. Increased anticancer efficacy by the combined administration of quercetin in multidrug resistant breast cancer cells. Ann Oncol. 2013;24(suppl 3):III19. doi:10.1093/annonc/mdt081.4
37. Andres S, Pevny S, Ziegenhagen R, et al. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res. 2018;62(1):10.1002/mnfr.201700447. doi:10.1002/mnfr.201700447
38. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 2007;45(11):2179-2205. doi:10.1016/j.fct.2007.05.015
39. Ferry DR, Smith A, Malkhandi J, et al. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996;2(4):659-668.
40. Huang M, Wu F, Zuo X, et al. Quercetin simultaneously inhibited cytochrome P450 and P-glycoprotein to improve the pharmacokinetics of osthole in rat plasma. Rev Bras Farmacogn. 2024;34(2):328-337. doi:10.1007/s43450-023-00487-3
41. Quercetin. Memorial Sloan Kettering Cancer Center. October 10, 2023. Accessed January 9, 2025. https://www.mskcc.org/cancer-care/integrative-medicine/herbs/quercetin
42. Rastogi H, Jana S. Evaluation of inhibitory effects of caffeic acid and quercetin on human liver cytochrome P450 activities. Phytother Res. 2014;28(12):1873-1878. doi:10.1002/ptr.5220
43. Zubair T, Bandyopadhyay D. Small molecule EGFR inhibitors as anti-cancer agents: discovery, mechanisms of action, and opportunities. Int J Mol Sci. 2023;24(3):2651. doi:10.3390/ijms24032651
44. Tagrisso. Prescribing information. AstraZeneca Pharmaceuticals; 2024. Accessed January 9, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/208065s030lbl.pdf
45. Elderberry. Memorial Sloan Kettering Cancer Center. March 27, 2023. Accessed January 9, 2025. https://www.mskcc.org/cancer-care/integrative-medicine/herbs/elderberry-01
46. Charlebois D, Byers PL, Finn CE, Thomas AL. Elderberry: botany, horticulture, potential. In: Horticultural Reviews. Vol 37. John Wiley & Sons; 2010:213-280. doi:10.1002/9780470543672.ch4
47. Jabbari M, Daneshfard B, Emtiazy M, Khiveh A, Hashempur MH. Biological effects and clinical applications of dwarf elder (Sambucus ebulus L): a review. J Evid Based Complement Altern Med. 2017;22(4):996-1001. doi:10.1177/2156587217701322
48. Mocanu ML, Amariei S. Elderberries-a source of bioactive compounds with antiviral action. Plants (Basel). 2022;11(6):740. doi:10.3390/plants11060740
49. Zakay-Rones Z, Thom E, Wollan T, Wadstein J. Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections. J Int Med Res. 2004;32(2):132-140. doi:10.1177/147323000403200205
50. Asgary S, Pouramini A. The pros and cons of using elderberry (Sambucus nigra) for prevention and treatment of COVID-19. Adv Biomed Res. 2022;11:96. doi:10.4103/abr.abr_146_21
51. NatMed Pro - professional monograph. Accessed January 9, 2025. https://naturalmedicines.therapeuticresearch.com/Data/ProMonographs/Elderberry#adverse-effects
52. Schrøder-Aasen T, Molden G, Nilsen OG. In vitro inhibition of CYP3A4 by the multiherbal commercial product Sambucus Force and its main constituents Echinacea purpurea and Sambucus nigra. Phytother Res. 2012;26(11):1606-1613. doi:10.1002/ptr.4619
53. Agarwal N, Mangla A. Elderberry interaction with pazopanib in a patient with soft-tissue sarcoma: a case report and literature review. Mol Clin Oncol. 2024;20(5):36. doi:10.3892/mco.2024.2734
54. Barak V, Halperin T, Kalickman I. The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. inflammatory cytokines. Eur Cytokine Netw. 2001;12(2):290-296
55. Wu JY, Siu KC, Geng P. Bioactive ingredients and medicinal values of Grifola frondosa (maitake). Foods Basel Switz. 2021;10(1):95. doi:10.3390/foods10010095
56. Klaus A, Kozarski M, Vunduk J, et al. Biological potential of extracts of the wild edible Basidiomycete mushroom Grifola frondosa. Food Res Int. 2015;67:272-283. doi:10.1016/j.foodres.2014.11.035
57. Kjellén L, Lindahl U. Proteoglycans: structures and interactions. Annu Rev Biochem. 1991;60:443-475. doi:10.1146/annurev.bi.60.070191.002303
58. Hong L, Xun M, Wutong W. Anti-diabetic effect of an alpha-glucan from fruit body of maitake (Grifola frondosa) on KK-Ay mice. J Pharm Pharmacol. 2007;59(4):575-582. doi:10.1211/jpp.59.4.0013
59. Hetland G, Tangen JM, Mahmood F, et al. Antitumor, anti-inflammatory and antiallergic effects of Agaricus blazei mushroom extract and the related medicinal basidiomycetes mushrooms, Hericium erinaceus and Grifola frondosa: a review of preclinical and clinical studies. Nutrients. 2020;12(5):1339. doi:10.3390/nu12051339
60. Alonso EN, Ferronato MJ, Gandini NA, et al. Antitumoral effects of D-fraction from Grifola frondosa (maitake) mushroom in breast cancer. Nutr Cancer. 2017;69(1):29-43. doi:10.1080/01635581.2017.1247891
61. He Y, Wang H, Zhang L. The biological activities of the antitumor drug Grifola frondosa polysaccharide. Prog Mol Biol Transl Sci. 2019;163:221-261. doi:10.1016/bs.pmbts.2019.02.01
62. Zhao F, Guo Z, Ma ZR, Ma LL, Zhao J. Antitumor activities of Grifola frondosa (maitake) polysaccharide: a meta-analysis based on preclinical evidence and quality assessment. J Ethnopharmacol. 2021;280:114395. doi:10.1016/j.jep.2021.114395
63. Masuda Y, Murata Y, Hayashi M, Nanba H. Inhibitory effect of MD-fraction on tumor metastasis: involvement of NK cell activation and suppression of intercellular adhesion molecule (ICAM)-1 expression in lung vascular endothelial cells. Biol Pharm Bull. 2008;31(6):1104-1108. doi:10.1248/bpb.31.1104
64. Masuda Y, Yamashita S, Nakayama Y, Shimizu R, Konishi M. Maitake beta-glucan enhances the therapeutic effect of trastuzumab via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Biol Pharm Bull. 2024;47(4):840-847. doi:10.1248/bpb.b23-00802
65. He Y, Li X, Hao C, et al. Grifola frondosa polysaccharide: a review of antitumor and other biological activity studies in China. Discov Med. 2018;25(138):159-176
66. Deng G, Lin H, Seidman A, et al. A phase I/II trial of a polysaccharide extract from Grifola frondosa (Maitake mushroom) in breast cancer patients: immunological effects. J Cancer Res Clin Oncol. 2009;135(9):1215-1221. doi:10.1007/s00432-009-0562-z
67. Glauco S, Jano F, Paolo G, Konno S. Safety of maitake D-fraction in healthy patients: assessment of common hematologic parameters. Altern Complement Ther. 2004;10(4):228-230. doi:10.1089/1076280041580341
68. Hu Q, Xie B. Effect of maitake D-fraction in advanced laryngeal and pharyngeal cancers during concurrent chemoradiotherapy: a randomized clinical trial. Acta Biochim Pol. 2022;69(3):625-632. doi:10.18388/abp.2020_5996
69. Hanselin MR, Vande Griend JP, Linnebur SA. INR elevation with maitake extract in combination with warfarin. Ann Pharmacother. 2010;44(1):223-224. doi:10.1345/aph.1M510
70. Posadzki P, Watson L, Ernst E. Herb-drug interactions: an overview of systematic reviews. Br J Clin Pharmacol. 2013;75(3):603-618. doi:10.1111/j.1365-2125.2012.04350.x
71. Ulbricht C, Weissner W, Basch E, et al. Maitake mushroom (Grifola frondosa): systematic review by the natural standard research collaboration. J Soc Integr Oncol. 2009;7(2):66-72
72. Di Muzio E, Polticelli F, Trezza V, Fanali G, Fasano M, Ascenzi P. Imatinib binding to human serum albumin modulates heme association and reactivity. Arch Biochem Biophys. 2014;560:100-112. doi:10.1016/j.abb.2014.07.001
73. Jordan VC. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids. 2007;72(13):829-842. doi:10.1016/j.steroids.2007.07.009
74. Treatment by cancer type. National Comprehensive Cancer Network. Accessed May 19, 2025. https://www.nccn.org/guidelines/category_1
75. Carlson LE, Ismaila N, Addington EL, et al. Integrative oncology care of symptoms of anxiety and depression in adults with cancer: Society for Integrative Oncology–ASCO guideline. J Clin Oncol. 2023;41(28):4562-4591. doi:10.1200/JCO.23.00857
76. Mao JJ, Ismaila N, Bao T, et al. Integrative medicine for pain management in oncology: Society for Integrative Oncology–ASCO guideline. J Clin Oncol. 2022;40(34):3998-4024. doi:10.1200/JCO.22.01357
77. Office of Dietary Supplements. National Institutes of Health. Accessed May 19, 2025. https://ods.od.nih.gov/index.aspx
78. Herbs at a glance. National Center for Complementary and Integrative Health. Accessed May 19, 2025. https://www.nccih.nih.gov/health/herbsataglance
79. Hou YN, Chimonas S, Gubili J, Deng G, Mao JJ. Integrating herbal medicine into oncology care delivery: development, implementation, and evaluation of a novel program. Support Care Cancer. 2023;31(2):128. doi:10.1007/s00520-023-07577-x
80. Clinical tools. NatMed. Accessed January 9, 2025. https://naturalmedicines.therapeuticresearch.com/
81. Search about herbs. Memorial Sloan Kettering Cancer Center. Accessed January 9, 2025. https://www.mskcc.org/cancer-care/diagnosis-treatment/symptom-management/integrative-medicine/herbs/search
82. Dietary supplements. FDA. Updated October 1, 2024. Accessed January 9, 2025. https://www.fda.gov/food/dietary-supplements
83. Lynas K. Professionals you can trust: pharmacists top the list again in Ipsos Reid survey. Can Pharm J (Ott). 2012;145(2):55. doi:10.3821/145.2.cpj55c