Herb-Drug Interactions in Cancer Care.

Herbs have served as medicine throughout human history. Since the passage of the Dietary Supplement Health and Education Act (DSHEA), inconsistent regulatory practices have resulted in widespread, indiscriminate use of herbal supplements. Available data indicate that cancer patients use these products (along with standard treatments) more often than the general population. The reasons cited for such use include improving health, reducing the risk of recurrence, and reducing the side effects of cancer treatments. Herbs, however, contain biologically active compounds and can potentially interact with prescription medications, including chemotherapy drugs. We describe the mechanisms via which these interactions may occur, as divided into pharmacokinetics and pharmacodynamics. We highlight four popular herbs and a medicinal mushroom commonly used by cancer patients-turmeric, green tea, ginger, ashwagandha, and reishi mushroom-along with reports of their interactions with standard drugs. We conclude by emphasizing the need to inform patients and physicians about herb-drug interactions and how to advise patients on appropriate use of herbal supplements to minimize the risk for interactions.

Herbal medicine for depression and anxiety: A systematic review with assessment of potential psycho-oncologic relevance.

Anxiety and depression are prevalent among cancer patients, with significant negative impact. Many patients prefer herbs for symptom relief to conventional medications which have limited efficacy/side effects. We identified single-herb medicines that may warrant further study in cancer patients. Our search included PubMed, Allied and Complementary Medicine, Embase, and Cochrane databases, selecting only single-herb randomized controlled trials between 1996 and 2016 in any population for data extraction, excluding herbs with known potential for interactions with cancer treatments. One hundred articles involving 38 botanicals met our criteria. Among herbs most studied (≥6 randomized controlled trials each), lavender, passionflower, and saffron produced benefits comparable to standard anxiolytics and antidepressants. Black cohosh, chamomile, and chasteberry are also promising. Anxiety or depressive symptoms were measured in all studies, but not always as primary endpoints. Overall, 45% of studies reported positive findings with fewer adverse effects compared with conventional medications. Based on available data, black cohosh, chamomile, chasteberry, lavender, passionflower, and saffron appear useful in mitigating anxiety or depression with favorable risk-benefit profiles compared to standard treatments. These may benefit cancer patients by minimizing medication load and accompanying side effects. However, well-designed larger clinical trials are needed before these herbs can be recommended and to further assess their psycho-oncologic relevance.

Maitake mushroom extract in myelodysplastic syndromes (MDS): a phase II study.

BACKGROUND: Myelodysplastic syndromes (MDS) are characterized by ineffective erythropoiesis with dysplastic bone marrow leading to peripheral cytopenia, risk of infection, and progression to acute myelogenous leukemia. Maitake mushroom beta-glucan, a dietary supplement, stimulates hematopoietic progenitor cell differentiation, granulocyte colony-stimulating factor production, and recovery of peripheral blood leukocytes after bone marrow injury. This phase II trial examined the effects of Maitake on innate immune function in MDS. METHODS: Myelodysplastic syndromes patients with International Prognostic Scoring System Low- and Intermediate-1-risk disease received oral Maitake extract at 3 mg/kg twice daily for 12 weeks. Primary endpoints included neutrophil count and function tested as endogenous or stimulated neutrophil production of reactive oxygen species (ROS) by flow cytometry compared with age-matched healthy controls (HC). ROS activators were Escherichia coli, phorbol ester, and the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Complete blood counts, chemistry panels, iron studies, and monocyte function were evaluated. RESULTS: Of 21 patients enrolled, 18 completed the study and were evaluable. Maitake increased endogenous (basal) neutrophil (p = 0.005) and monocyte function (p = 0.021). Pre-treatment monocyte response to E. coli was reduced in MDS patients compared with HC (p = 0.002) and increased (p = 0.0004) after treatment. fMLP-stimulated ROS production response also increased (p = 0.03). Asymptomatic eosinophilia occurred in 4 patients (p = 0.014). Other changes in albumin, hemoglobin, and total protein were not clinically relevant. CONCLUSIONS: Maitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment demonstrate that Maitake has beneficial immunomodulatory potential in MDS. Further study is warranted.

Acupuncture in the treatment of upper-limb lymphedema: results of a pilot study.

BACKGROUND: Current treatments for lymphedema after breast cancer treatment are expensive and require ongoing intervention. Clinical experience and our preliminary published results suggest that acupuncture is safe and potentially useful. This study evaluates the safety and potential efficacy of acupuncture on upper-limb circumference in women with lymphedema. METHODS: Women with a clinical diagnosis of breast cancer-related lymphedema (BCRL) for 0.5-5 years and with affected arm circumference ≥2 cm larger than unaffected arm received acupuncture treatment twice weekly for 4 weeks. Affected and unaffected arm circumferences were measured before and after each acupuncture treatment. Response, defined as ≥30% reduction in circumference difference between affected/unaffected arms, was assessed. Monthly follow-up calls for 6 months thereafter were made to document any complications and self-reported lymphedema status. RESULTS: Among 37 enrolled patients, 33 were evaluated; 4 discontinued due to time constraints. Mean reduction in arm circumference difference was 0.90 cm (95% CI, 0.72-1.07; P < .0005). Eleven patients (33%) exhibited a reduction of ≥30% after acupuncture treatment. Seventy-six percent of patients received all treatments; 21% missed 1 treatment, and another patient missed 2 treatments. During the treatment period, 14 of the 33 patients reported minor complaints, including mild local bruising or pain/tingling. There were no serious adverse events and no infections or severe exacerbations after 255 treatment sessions and 6 months of follow-up interviews. CONCLUSIONS: Acupuncture for BCRL appears safe and may reduce arm circumference. Although these results await confirmation in a randomized trial, acupuncture can be considered for women with no other options for sustained arm circumference reduction.

A phase II, randomized, controlled trial of acupuncture for reduction of Postcolectomy Ileus.

PURPOSE: Postoperative ileus (POI) prolongs hospital stay and increases risk of postoperative complications. We conducted a randomized, sham-controlled trial to evaluate whether acupuncture reduces POI more effectively than sham acupuncture. METHODS: Colon cancer patients undergoing elective colectomy were randomized to receive 30 min of true or sham acupuncture twice daily during their first 3 postoperative days. GI-3 (the later of the following two events: time that the patient first tolerated solid food, AND time that the patient first passed flatus OR a bowel movement) and GI-2 (the later of the following two events: time patient first tolerated solid food AND time patient first passed a bowel movement) were determined. Pain, nausea, vomiting, and use of pain medications were evaluated daily for the first 3 postoperative days. RESULTS: Ninety patients were randomized. Eighty-one received the allocated intervention: 39 in the true acupuncture group and 42 in the sham acupuncture group, all evaluated for the primary endpoint. The mean time to GI-3 was 149 h [standard deviation (SD) 71 h] and 146 (SD 62 h) after surgery for the acupuncture group and the sham acupuncture group (difference between means -2 h; 95 % confidence interval -31, 26; p = 0.9). No significant differences were found between groups for secondary endpoints. CONCLUSIONS: True acupuncture as provided in this study did not reduce POI more significantly than sham acupuncture. The study was limited by a standard deviation much larger than expected, suggesting that a study with a larger sample size might be required.

Acupuncture for the treatment of post-chemotherapy chronic fatigue: a randomized, blinded, sham-controlled trial.

PURPOSE: Many cancer patients experience persistent fatigue after the completion of chemotherapy. A previous single-arm study provided evidence for an effect of acupuncture in this population. We conducted a randomized controlled trial to determine whether acupuncture reduces post-chemotherapy chronic fatigue more effectively than sham acupuncture. METHODS: Cancer patients reporting significant fatigue persisting for at least 2 months following the completion of chemotherapy were randomized to receive once weekly true or sham acupuncture for 6 weeks. Fatigue was evaluated before and after treatment using the Brief Fatigue Inventory (BFI, the primary endpoint). Secondary endpoints included the Hospital Anxiety and Depression Scale (HADS) and Functional Assessment of Cancer Treatment-General (FACT-G) scores. RESULTS: One hundred one patients were randomized with 74 (34 true acupuncture; 40 sham control) evaluated for the primary endpoint. BFI scores fell by about one point between baseline and follow-up in both groups with no statistically significant difference between groups. HADS and FACT-G scores also improved in both groups, but there was no significant difference between groups. Patients in the sham acupuncture group crossed over to receive true acupuncture in week 7. No long-term reduction of fatigue scores was observed at the 6-month evaluation. CONCLUSIONS: True acupuncture as provided in this study did not reduce post-chemotherapy chronic fatigue more than did sham acupuncture. The study is limited by the number of patients lost to follow-up. We also cannot exclude the possibility that a more intensive treatment regimen may be more effective.

The known immunologically active components of Astragalus account for only a small proportion of the immunological adjuvant activity when combined with conjugate vaccines.

The 95 % ethanol extract of Astragalus has been demonstrated to have potent activity as an immunological adjuvant when administered with vaccines of various types. We endeavor here to identify the components of this extract that are responsible for this adjuvant activity. Mice were immunized with KLH conjugated to cancer carbohydrate antigens globo H and GD3 and cancer peptide antigen MUC1 combined with different Astragalus fractions or with commercially available Astragalus saponins and flavonoids. The antibody responses against cancer antigens and KLH were quantitated in ELISA assays, and toxicity was calculated by weight loss. Astragalosides II and IV were the most active components, but the toxicity of these two differed dramatically. Astragaloside II was the most toxic Astragalus component with 5-10 % weight loss at a dose of 500 µg while astragaloside IV showed no weight loss at all at this dose, suggesting that astragaloside IV might be utilized as an immunological adjuvant in future studies. Several flavonoids also had significant adjuvant activity. However, when the activities of these known immunologically active components of Astragalus (and of endotoxin) are calculated based on the extent of their presence in the 95 % ethanol extract, they provide only a small proportion of the immunological activity. This raises the possibility that additional uniquely active components of Astragalus may contribute to adjuvant activity, or that the adjuvant activity of Astragalus is greater than the activity of the sum of its parts.

Evidence-based botanical research: applications and challenges.

Use of herbal supplements is on the rise around the world, but limited data exist on the safety and efficacy of botanical products. Efforts to subject botanicals to rigorous scientific research began recently. There are many problems associated with botanicals research, however. These include procuring the study agents, selecting appropriate study method and clinical trial design, navigating through regulatory obstacles, and obtaining funding. Evidence-based botanical research can help to validate traditional uses and to facilitate new drug development. Concerted efforts of governmental agencies and industry are essential to ensure continuance of high-quality botanicals research.

Herbs and other botanicals in cancer patient care.

OPINION STATEMENT: Non-prescription herbal remedies are commonly used by cancer patients in efforts to control their disease or to manage symptoms associated with cancer and cancer treatments. We address the issues surrounding the use of herbs, herbal compounds, and other botanical agents in the oncology context. Botanicals are biologically active agents that can be useful under appropriate circumstances, but they may be counterproductive when used by patients on chemotherapy or on other prescription medications. Herbs and other botanical agents, despite common public belief, are not benign. They should be understood as unrefined pharmaceuticals, with the capacity to produce physiologic change for better or worse. Indeed, many prescription drugs, chemotherapeutic agents among them, were derived from plants and other natural agents, and the search for additional constituents of plants, animals, and minerals for use as pharmaceutical agents remains an active effort on many fronts. Cautions, appropriate application, and potential utility of botanical agents are discussed below, and sources of reliable information are provided.

Complementary therapies for cancer-related symptoms.

Relief of cancer-related symptoms is essential in the supportive and palliative care of cancer patients. Complementary therapies such as acupuncture, mind-body techniques, and massage therapy can help when conventional treatment does not bring satisfactory relief or causes undesirable side effects. Controlled clinical trials show that acupuncture and hypnotherapy can reduce pain and nausea. Meditation, relaxation therapy, music therapy, and massage mitigate anxiety and distress. Pilot studies suggest that complementary therapies may treat xerostomia, hot flashes, and fatigue. Botanicals or dietary supplements are popular but often problematic. Concurrent use of herbal products with mainstream medical treatment should be discouraged.

Integrating dietary supplements into cancer care.

Many studies confirm that a majority of patients undergoing cancer therapy use self-selected forms of complementary therapies, mainly dietary supplements. Unfortunately, patients often do not report their use of supplements to their providers. The failure of physicians to communicate effectively with patients on this use may result in a loss of trust within the therapeutic relationship and in the selection by patients of harmful, useless, or ineffective and costly nonconventional therapies when effective integrative interventions may exist. Poor communication may also lead to diminishment of patient autonomy and self-efficacy and thereby interfere with the healing response. To be open to the patient's perspective, and sensitive to his or her need for autonomy and empowerment, physicians may need a shift in their own perspectives. Perhaps the optimal approach is to discuss both the facts and the uncertainty with the patient, in order to reach a mutually informed decision. Today's informed patients truly value physicians who appreciate them as equal participants in making their own health care choices. To reach a mutually informed decision about the use of these supplements, the Clinical Practice Committee of The Society of Integrative Oncology undertook the challenge of providing basic information to physicians who wish to discuss these issues with their patients. A list of leading supplements that have the best suggestions of benefit was constructed by leading researchers and clinicians who have experience in using these supplements. This list includes curcumin, glutamine, vitamin D, Maitake mushrooms, fish oil, green tea, milk thistle, Astragalus, melatonin, and probiotics. The list includes basic information on each supplement, such as evidence on effectiveness and clinical trials, adverse effects, and interactions with medications. The information was constructed to provide an up-to-date base of knowledge, so that physicians and other health care providers would be aware of the supplements and be able to discuss realistic expectations and potential benefits and risks.

A single arm phase II study of a Far-Eastern traditional herbal formulation (sho-sai-ko-to or xiao-chai-hu-tang) in chronic hepatitis C patients.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatitis C is a major public health problem internationally. Many patients cannot benefit from the current treatment regimen (interferon/ribavirin combinations) due to its side effects or ineffectiveness. Xiao-Chai-Hu-Tang or Sho-sai-ko-to (SST), a compound of seven botanical extracts used for liver diseases traditionally in East Asia, was shown to reduce transaminases and the incidence of hepatocellular carcinoma in hepatitis B patients. We conducted a phase II trial of SST in hepatitis C patients who were not candidates for interferon-based therapy to determine whether this agent is worthy of further study. MATERIALS AND METHODS: Twenty four chronic hepatitis C patients received SST at 2.5 g per os (p.o.) three times daily (t.i.d.) for 12 months. Liver function, hepatitis C virus (HCV) viral load and liver biopsy histology were assessed before and after the intervention. RESULTS: Improvement of aspartate aminotransferase (AST) was observed in 16 (67%) of study participants. Improvement of alanine aminotransferase (ALT) was seen in 18 (75%) patients. Viral load response was mixed, with 7 patients showing reductions, 10 increases and 7 indeterminate due to assay limitations. Among the 9 (38%) subjects who showed improvement per Knodell's histology activity index (HAI) scores in paired comparison of pre- and post-treatment liver biopsy (the primary endpoints of the study), 5 (21%) showed an improvement of 2 points or greater, meeting the pre-defined criteria for "response. CONCLUSIONS: Sho-sai-ko-to (SST or Xiao Chai Hu Tang) may improve liver pathology in selected hepatitis C patients who are not candidates for interferon based treatment. Larger, controlled studies of this botanical formulation may be warranted.

Acupuncture for pain and dysfunction after neck dissection: results of a randomized controlled trial.

PURPOSE: To determine whether acupuncture reduces pain and dysfunction in patients with cancer with a history of neck dissection. The secondary objective is to determine whether acupuncture relieves dry mouth in this population. PATIENTS AND METHODS: Patients at a tertiary cancer center with chronic pain or dysfunction attributed to neck dissection were randomly assigned to weekly acupuncture versus usual care (eg, physical therapy, analgesia, and/or anti-inflammatory drugs, per patient preference or physician recommendation) for 4 weeks. The Constant-Murley score, a composite measure of pain, function, and activities of daily living, was the primary outcome measure. Xerostomia, a secondary end point, was assessed using the Xerostomia Inventory. RESULTS: Fifty-eight evaluable patients were accrued and randomly assigned from 2004 to 2007 (28 and 30 patients on acupuncture and control arms, respectively). Constant-Murley scores improved more in the acupuncture group (adjusted difference between groups = 11.2; 95% CI, 3.0 to 19.3; P = .008). Acupuncture produced greater improvement in reported xerostomia (adjusted difference in Xerostomia Inventory = -5.8; 95% CI, -0.9 to -10.7; P = .02). CONCLUSION: Significant reductions in pain, dysfunction, and xerostomia were observed in patients receiving acupuncture versus usual care. Although further study is needed, these data support the potential role of acupuncture in addressing post-neck dissection pain and dysfunction, as well as xerostomia.

Safety and pharmacokinetic trial of docetaxel plus an Astragalus-based herbal formula for non-small cell lung cancer patients.

PURPOSE: To study a commonly used Astragalus-based herbal formula previously found effective in non-small cell lung cancer (NSCLC) on the pharmacokinetics of docetaxel in patients with NSCLC. METHODS: Patients with advanced NSCLC who progressed after prior platinum-containing chemotherapy were accrued and received docetaxel at 35 mg/m(2) for 3 weeks followed by 1 week of rest. At 4 days prior to the second dosing, Jinfukang was given orally. Pharmacokinetic studies of initial-dose docetaxel (in the absence of Jinfukang) and the third dose (in the presence of Jinfukang) were compared. RESULTS: Of the 24 patients enrolled, 21 started Jinfukang and docetaxel. Jinfukang had no significant impact on the pharmacokinetics of docetaxel. Median time to progression or withdrawal from treatment was 7 weeks. Twelve patients were removed from study for progression of disease; nine patients withdrew. CONCLUSIONS: Jinfukang did not alter the pharmacokinetics of docetaxel nor appear to affect survival in this study.

Evaluation of widely consumed botanicals as immunological adjuvants.

BACKGROUND: Many widely used botanical medicines are claimed to be immune enhancers. Clear evidence of augmentation of immune responses in vivo is lacking in most cases. To select botanicals for further study based on immune enhancing activity, we study them here mixed with antigen and injected subcutaneously (s.c.). Globo H and GD3 are cell surface carbohydrates expressed on glycolipids or glycoproteins on the cell surface of many cancers. When conjugated to keyhole limpet hemocyanin (KLH), mixed with an immunological adjuvant and administered s.c. the magnitude of the antibody responses against globo H, GD3 and KLH depend largely on the potency of the adjuvant. We describe here the results obtained using this s.c. immunization model with seven botanicals purported to have immune stimulant effects. METHODS: Groups of 5-10 mice were immunized with globo H-KLH or GD3-KLH mixed with botanical, saline or positive control immunological adjuvant, s.c. three times at 1 week intervals. Antibody responses were measured 1 and 2 weeks after the 3rd immunization. The following seven botanicals and fractions were tested: (1) H-48 (Honso USA Co.), (2) Coriolus versicolor raw water extract, purified polysaccharide-K (PSK) or purified polysaccharide-peptide (PSP) (Institute of Chinese Medicine (ICM)), (3) Maitake extract (Yukiguni Maitake Co. Ltd. and Tradeworks Group), (4) Echinacea lipophilic, neutral and acidic extracts (Gaia Herbs), (5) Astragalus water, 50% or 95% ethanol extracts (ICM), (6) Turmeric supercritical (SC) or hydro-ethanolic (HE) extracts (New Chapter) or 60% ethanol extract (ICM) and (7) yeast beta-glucan (Biotec Pharmacon). Purified saponin extract QS-21 (Antigenics) and semisynthetic saponin GPI-0100 (Advanced BioTherapies) were used as positive control adjuvants. Sera were analyzed by ELISA against synthetic globo H ceramide or GD3 and KLH. RESULTS: Consistent significant adjuvant activity was observed after s.c. vaccination with the Coriolus extracts (especially PSK), a 95% ethanol extract of Astragalus and yeast beta-glucan, and (to a lesser extent) Maitake. Antibodies against KLH in all cases and against globo H in most cases were induced by these botanicals. Little or no adjuvant activity was demonstrated with H-48 or Echinacea extracts or the Astragalus water extract. Experiments with GD3-KLH as immunogen confirmed the adjuvant activity of the Coriolus, yeast beta-glucan and Astragalus extracts. While extraction with ethanol concentrated the active ingredients in Astragalus, it had no impact on Coriolus where the 90% ethanol precipitate and solute were equally active. CONCLUSIONS: Some, but not all, botanicals purported to be immune stimulants had adjuvant activity in our model. PSK and Astragalus were surprisingly active and are being further fractionated to identify the most active adjuvant components.

Clinical guide to herb-drug interactions in oncology.

Cancer patients are increasingly using herbal supplements for relief of symptoms. However, there is a great potential for interactions with concurrent use of herbs and chemotherapy agents. Physicians should be aware of such interactions and encourage patients to discuss supplement use.