16 Complementary and alternative medicine (CAM) constitutes a diverse and often controversial group of treatments that exist outside of mainstream medicine. Although CAM has yet to produce a single, proven cancer cure,1 this does not stop some veterinarians and lay healers from continuing to claim that these products can “stop cancer in its tracks” or eliminate neoplasia. Other claims for CAM cancer treatments are not as extreme, and scientific evidence shows that some methods or products actually do benefit oncology patients. It is no longer acceptable to patients for physicians to label all of these alleged treatments as ludicrous and unfounded. Medical professionals must be able to converse intelligently about them with patience and learn not to denigrate out of hand those who utilize alternative and complementary techniques, as long as they are safe. Physicians must also warn patients of danger and hoaxes when that is appropriate.2 One way to assist clients is by indicating which CAM treatments have evidence of both efficacy and safety and which ones are deemed ineffective or unsafe.3,4 The popularity of CAM is undeniable. For human patients with cancer, the usage rate is well over 50%.5 A 2006 survey of clients who brought their pet to the Colorado State University Animal Cancer Center found that 76% of surveyed owners used CAM to improve well being. Other reasons they provided included attempting to reduce pain and treatment toxicity, as well as to improve appetite.6 However, a majority of those surveyed had not yet spoken to their veterinarian about CAM. If clients seek input and treatment from nonveterinarian practitioners in lieu of science-based veterinary professionals, patient health and safety could be jeopardized. Lay healers’ lack of formal veterinary medical training hinders their capacity to coordinate medically sound recommendations for animals. Nonveterinarians are, for the most part, unable to rapidly identify health problems and intervene effectively in disease progression. For cancer patients, delays in prompt and appropriate medical attention may make an otherwise treatable condition resistant to therapy.7 … CAVM [Complementary and alternative veterinary medicine] is an important topic that should be addressed in veterinary medical education.… The most common comment reflected strong opinions that inclusion of CAVM … must be evidence-based.… [S]tudents should be aware of CAVM modalities because of strong public interest in CAVM and because practitioners should be able to address client questions from a position of knowledge.8 Acupuncture counteracts pain and other adverse sequelae of cancer treatment through neuromodulation. It may reduce the levels of medication required.9 Nerve fiber stimulation begins at the needle-tissue interface, where local alterations in cytokines and inflammatory mediators lead to modulation (i.e., normalization) of circulation and immune function in the immediate area surrounding the site around the needle. From there, agitation of the connective tissue and subsequent tugging of the collagen fibers, fibroblasts, and myofascia in the region produce activation of sensory somatic and autonomic nerve fibers. When excited, afferent pathways ferry action potentials along large nerve axons that underlie and often define the trajectory of acupuncture channels. A cascade of simultaneous central nervous system (CNS) and autonomic nervous system (ANS) changes follow soon thereafter, producing somatosomatic, somatoautonomic, and somatovisceral reflexes in spinal cord segments related to the excited nerve(s). In addition to propriospinal signaling, acupuncture incites a barrage of brain stimulation in the limbic system, the cerebellum, the cortex, and the brainstem. Functional brain imaging research illustrates, through changes in neuronal metabolism, which centers process pain, regulate autonomic function, and affect moods in response to acupuncture. This aids in the ever deepening understanding of the neurophysiologic premise underlying acupuncture. Human integrative oncology clinics have found acupuncture to be a safe, inexpensive, and valuable intervention for several problems that cancer patients often encounter, including leukopenia, gastrointestinal upset, and systemic reactions.9–12 Acupuncture is often effective in reducing emetic effects of chemotherapy and opioids.13–18 For pain, acupuncture provides benefits along several routes, including normalizing muscle tone, deactivating myofascial trigger points, upregulating analgesic gene expression in the spinal cord, promoting segmental analgesia, reducing neuropathic pain, elevating endogenous opioid release, and promoting a sense of well being through pathways that influence the limbic system.19–28 Acupuncture also activates natural killer (NK) cells that aid in anticancer immune mechanisms at least in part through its effects on neural circuitry connected to somatosympathetic reflexes.29–32 Through neurologic and circulatory modulation, acupuncture affects the diameter of arterial, venous, and lymphatic vessels, working to assist in the alleviation of chronic lymphedema, and accelerates wound healing.33,34 Patients with head and neck cancer also appear to benefit from acupuncture’s effects on glandular function by helping to minimize xerostomia following radiation.35–38 Even for human patients with advanced, incurable cancer, acupuncture has been shown to alleviate a wide range of symptoms with no significant or unexpected adverse effects.39 Any acupuncturist treating animals should have a thorough understanding of animal health and disease, as well as acupuncture anatomy and physiology, in order to minimize risk of injury.40 Although acupuncture provides repeatable and measurable benefits for patients with advanced cancer, the treatment is underutilized.41 Whether due to lack of knowledge about the evidential support for acupuncture in cancer, its scientifically based mechanisms of action, or unsubstantiated bias against the technique, oncologists may forget to recommend it or resist requests for it. Despite accruing facts regarding the mechanisms and clinical benefits of acupuncture, a notable subset of practitioners continue to believe that acupuncture point stimulation moves invisible energy (qi) through invisible pathways on the body (meridians). Although this misconception may not directly harm a patient, metaphysical misimpressions about how needling works may mislead veterinarians and clients in a number of ways. For example, certain energy-based acupuncture courses teach that veterinarians could successfully and easily treat cancer by selecting and stimulating a single acupuncture point chosen according to abstract ideas and psychic powers. The inventor of this technique alludes to “total disappearance or significant regression” of cancer in 80% of patients.42–44 This claim has no rational scientific mechanism nor has it been submitted to experimental scrutiny. It risks delaying proper treatment through conventional means and allowing the cancer to progress to an untreatable stage. Conversely, myths have circulated within the veterinary acupuncture community for decades that acupuncture could raise the risk of metastasis by increasing blood flow to a tumor. This has led to unnecessary underutilization in patients who stood to benefit from this palliative, pain-reducing, and quality-of-life–supporting modality.45 Natural products from both Asian and Western herbs have the capacity to inhibit proliferation, induce apoptosis, reduce angiogenesis, retard metastasis, and even enhance the effects of chemotherapy.46–48 The challenge, however, is to know which herbs to prescribe for each specific cancer type. Another mystery entails how the herbs’ biochemistries interact and possibly interfere with conventional medication or chemotherapy. The pharmacokinetics and pharmacodynamics of herbs are mostly a mystery for nonhuman animals, leading to questions about how the various veterinary species that receive these products metabolize and clear the xenobiotics (herbs). What is more concerning is the multiplicity and undisclosed quantities of herbs, animal residues, and toxic substances such as strychnine and aconite included in traditional Chinese veterinary medicine (TCVM) products.49 Many TCVM practitioners have little to no understanding of the biochemical actions of a plant product, instead relying on metaphoric descriptions of the remedies’ properties. In addition, TCVM practitioners may utilize unvalidated, primitive, folkloric diagnostic methods in order to arrive at a quasi-diagnosis. They assemble subjective impressions derived from various physical observations and pulse palpation into a “pattern,” which is then matched to a TCVM compound that is supposed to address that pattern. This method is fraught with problems and pitfalls but is important to note because a large segment of veterinary herbalists adhere to this approach. Veterinarians treating cancer patients should be conversant with not only the potential value of unconventional cancer approaches50–52 but also their dangers. The likelihood of TCVM herbal toxicity and interactions is in part due to the sheer number of herbal (and animal) ingredients in each mixture. Most have never been tested in typical veterinary species, worsening confusion. Recommending TCVM herbs based on rigorously derived discoveries in botanical research allows practitioners to discard untestable, abstract mechanisms of action such as claiming that they “resolve stagnation, invigorate Qi, and remove phlegm/damp accumulation.”53 Medical professionals should, in contrast, insist on instruction that describes Chinese herb effects in simple, biologic language, especially when scientific investigations have already shown how they work. For example, astragalus upregulates host immune response and reduces chemotherapy toxicity, and Oldenlandia diffusa directly attacks tumor cells through apoptosis. One could then conceive of incorporating these two herbs into a combination with others that work through additive or synergistic means, rather than guessing at their metaphoric effects. An oncologist might choose a third herb that inhibits abnormal gene transcription activity (Coix lachrymal) and a fourth that promotes tumor necrosis (Glycyrrhiza glabra).54 Until more becomes known about how Chinese herbs affect chemotherapy in veterinary cancer patients, Caution should be taken when anticancer drugs are used in combination with herbal medicines, particularly for cytotoxic anticancer drugs with narrow therapeutic indices. Monitoring plasma concentrations of concurrently administered anticancer drugs and observing for possible signs of clinical toxicity are necessary when herbal remedies are used concurrently.55 Computerized databases are further assisting oncologists by enabling determination of relevant, potential interactions between anticancer drugs and Chinese herbs.56 Even oncologists in China are encouraging their colleagues to maintain a watchful eye for surprise sequelae. For example, one paper warned: [P]rofessional complacency about TCM [Traditional Chinese Medicine] use is becoming less acceptable as the knowledge base of TCM-induced toxicities and interactions expands. Being rich sources of bioactive xenobiotics, TCMs are frequent causes of puzzling complications, including hepatotoxicity, nephrotoxicity, and hematologic disorders.57 Some traditional Chinese herbal medicines (TCHMs) are chemosensitizing or radiosensitizing and thus may cause conventional treatment to work more robustly, whereas others directly antagonize medication through one or more mechanisms. Toxicity from Chinese herbs co-administered with chemotherapy may lead to diagnostic dilemmas when clinicians misattribute problems to the drug rather than the TCHM product, thereby delaying discontinuation of the appropriate compound.57 In fact, Chinese herbalists in Taiwan who work directly with herbs in the raw form are finding themselves at increased risk of liver and bladder cancer, possibly due to the heavy metal contamination of TCHMs and/or the intrinsic toxicity of some ingredients.58 This heightened risk for urologic cancers, chronic and unspecified nephritis, renal failure, and renal sclerosis “highlights the urgent need for safety assessments of Chinese herbs.”59 Public perception holds that TCHMs protect cancer patients’ health and well being during chemotherapy.57 A double-blind, randomized, placebo-controlled study questioned this assumption, showing that TCHMs did not significantly reduce any of the hematologic toxicities (leukopenia, neutropenia, and thrombocytopenia) associated with adjuvant chemotherapy for breast and colon cancer.60 Three licensed, experienced TCHM practitioners from China prescribed herbal formulas to patients on an individualized basis, since many believe this approach yields superior benefits. Even the myth that individualizing TCHMs produces better outcomes could be more folklore than fact.61 According to some critics, “[A]lmost all individualized herbal medicine is practiced without the support of any rigorous evidence about effectiveness whatsoever.”62 They continue, Despite these limitations, the potential for Chinese herbs to one day participate legitimately within a methodic, evidence-informed herb and chemotherapy regimen seems imminent. To this end, one group, the nonprofit Consortium for Globalization of Chinese Medicine (http://www.tcmedicine.org) has assembled a broad collective of scientists from academia and industry. Researchers are conducting national and international collaborative clinical trials along with experimental animal and in vitro studies. They aim to fulfill four basic regulatory requirements: batch-to-batch consistency in Chinese herbal preparations; evidence-based clinical effectiveness; safety; and rational understanding of mechanisms of actions, sites of biochemical impact, active ingredients, and drug-herb interactions.63 Many common herbal products modulate intestinal P-glycoprotein and/or cytochrome P450 (CYP450) enzymes, producing clinically important herb-drug interactions.64 Because of this, owners should disclose all dietary supplements and/or herbs they are giving the patient. The veterinarian should then weigh the potential for interactions between the conventional treatment and the supplement against the proven benefits of the product and determine prior to treatment whether or not the patient should stop the product. Whether an herb will interact with chemotherapy and/or radiation therapy is often unknown, although research is gradually illuminating when and how this can happen.65–67 Garlic, often recommended by holistic practitioners for cancer, induces the P-glycoprotein drug efflux transport system to aid the body in ridding itself of perceived toxins, such as chemotherapeutics.68 Clinicians unaware of herbal antiplatelet effects may find themselves surprised by bleeding during biopsies or surgeries. Because of this, the American Society of Anesthesiologists recommends that human patients discontinue dietary supplements at least 2 weeks prior to surgery.69 Botanicals such as angelica root (dong quai), German chamomile, red clover, and ginseng increase the risk of bleeding. Garlic, ginkgo, and saw palmetto also may have significant anticoagulant actions. Cancer patients may already have thrombocytopenia from chemotherapy or myelosuppression from bone marrow invasion that compromises their capacity to clot. Herbs that have anticancer effects but contain phytoestrogens such as Angelica sinensis may adversely affect patients with hormone-sensitive cancer.70 The task of assessing complex herb-drug interactions even in one species, the human, reveals the daunting number of considerations involved when designing research strategies. For example, the herb astragalus is a plant commonly employed for cancer treatment that potentiates host immune function. A 2006 metaanalysis of randomized trials concluded that, when combined with platinum-based chemotherapy, Chinese herbal formulations with astragalus improved survival, increased tumor response, and reduced toxicity from the chemotherapy in human patients with non–small-cell lung cancer.71 Critics of this metaanalysis questioned the findings, citing unevenness in treatment methods.72 Only two of the 30 studies utilized astragalus as a single agent; the rest involved combinations of plants. In addition, the species of astragalus studied in each case was unclear; was it Astragalus membranaceus (huang qi), whose major constituents include triterpene saponins and polysaccharides in the roots, or was another plant in the astragalus genus substituted in some cases? How did the amount of astragalus in each mixture compare, given that single herb preparations putatively contained 100% astragalus, whereas in others it was only one of up to 17 herbs. Finally, which part of the plant was used and how was it prepared? Decoctions, fluid extracts, and dry matter vary considerably in their concentration of active constituents; thus their biochemical make-up and resultant pharmacologic activity may differ dramatically. Mushroom mixtures and mushroom-derived polysaccharide preparations modify tumor response and improve immune function in patients with solid tumors.73 The active agents in Asian mushrooms, polysaccharides, also possess antitumor effects through inhibition of cellular proliferation and tumor growth, invasion, and angiogenesis.74 A proprietary, protein-bound polysaccharide extract of Coriolis versicolor reduced serum levels of immunosuppressive acidic protein in stage II and III colorectal cancer patients, increased 5-year disease-free survival, and decreased relative risk of regional metastases.75 A metaanalysis of three trials involving over a thousand subjects with colorectal cancer confirmed these results.76 A variety of other medicinal mushrooms and extracts have proved beneficial, improving immune parameters such as NK cell activity and cytokines, without significant toxicity. The still-unanswered question regarding medicinal mushrooms pertains to their risk or value in lymphoma, given their immunostimulatory effects. A study of a standardized extract of Maitake mushroom in dogs with lymphoma reported no objective value, although two dogs did develop hyphema and one developed petechiae.77 These agents can inhibit platelet function; whether the bleeding noted in this study related to the Maitake mushroom or the lymphoma remained unknown. Cancer cells employ various pathways to evade host defenses. This means that a drug or herb works best against cancer when it takes more than one route of action to attack the disease. In its interaction with several cellular proteins, curcumin78,79 constituents induce phase II detoxification enzymes, suppress tumor cell proliferation in several cancer cell lines, and downregulate transcription factors (nuclear factor κB [NF-κB], activator protein 1 [AP-1], early growth response 1 [EGR-1]). Curcumin downregulates enzymes such as cyclooxygenase-2 (COX-2), lipoxygenase (LOX), nitric oxide synthase (NOS), matrix metalloproteinase 9 (MMP9), urokinase-type plasminogen activator, and more. Curcumin also downregulates other factors and receptors such as tumor necrosis factor, chemokines, cell surface adhesion molecules, and growth factor receptors (e.g., epidermal growth factor receptor [EGFR], human EGFR 2 [HER2]). Curcumin acts antiangiogenically and enhances the cytotoxicity of certain chemotherapy drugs. Curcumin causes cell death in several human cancer cell lines, including breast, lung, prostate, colon, melanoma, kidney, hepatocellular, ovarian, and leukemia. The effect curcumin has on cell death involves both the usual apoptotic mechanisms such as oligonucleosomal DNA degradation and alternative means. When resistance develops to apoptosis-inducing factors, curcumin can overcome this impediment through alternative cell-signaling pathways, such as mitotic catastrophe.80 Mitotic catastrophe involves a morphologically distinct and aberrant mitotic process that distinguishes it from apoptosis, characterized by the formation of giant, multinucleated cells carrying uncondensed chromosomes. Curcumin may also counteract the induction of prosurvival factors in cells generated by radiation therapy and chemotherapy. Human clinical trials demonstrate no dose-limiting toxicity when given up to 10 g of curcumin in 1 day.81 The amount of curcumin contained in turmeric averages only about 3% by weight82; concentrated curcumin supplements therefore supposedly provide higher levels of the active constituent, provided that the label and actual contents agree. The hurdles of maintaining adequate blood levels of curcumin pertain to its low bioavailability, although absorption varies between species. One way to overcome delivery challenges could include coupling it with compounds that focus curcumin’s activity toward specific target cells. Curcumin could hypothetically negate some of the effects of chemotherapy because it affects so many pathways. Research suggests that curcumin can inhibit chemotherapy-induced apoptosis in breast cancer cells, specifically in combination with camptothecin, mechlorethamine, or doxorubicin. The potential benefits of certain herbs should be considered and compared against the risks. For example, a synthetic analog of curcumin helped reduce doxorubicin-induced cardiotoxicity through an anticancer-antioxidant dual function in vitro.83 Additionally, curcumin and catechin (from green tea) may work synergistically against cancer through cytotoxicity, nuclear fragmentation, and antiproliferative and proapoptotic effects.84 Boswellic acids exhibit potent antiinflammatory properties in vitro and in vivo. Triterpenes in boswellic acid reduce the synthesis of leukotrienes in intact neutrophils by inhibiting 5-LOX, the key enzyme involved in the biosynthesis of leukotrienes, which mediate inflammation.85,86 Boswellia extracts exert immunomodulatory benefits by simultaneously inhibiting T-helper 1 (Th1) and promoting Th2 cytokine production.87 They regulate vascular responses to inflammation86 and stabilize mast cells.89 In cases of intestinal inflammation, boswellic acids may modulate the adhesive interactions between leukocytes and endothelial cells by countering the activation of leukocytes and/or downregulating the expression of endothelial cell-adhesion molecules.90,91 Specific to their anticancer properties, boswellic acids induce antiproliferation, differentiation, and apoptosis in leukemia cell lines.92–95 They exert cytotoxic effects on established human glioblastoma and leukemia cell lines, as well as on primary human meningioma cells.96 Boswellic acids may help reduce cerebral edema in patients with brain tumors.97 Side effects of boswellic acids include abdominal discomfort, nausea, epigastric pain, hyperacidity,98 and diarrhea.99 The presence of food in the stomach, as well as the type of food eaten, dramatically alters the bioavailability of boswellic acids, and bile acids significantly affect their absorption.100 When human subjects ingested boswellic acids along with a high-fat meal, the areas under the plasma concentration-time curves and peak concentrations totaled several times higher than when the herbal preparations are taken in the fasting condition. A human study showed that the elimination half-life for Boswellia was approximately 6 hours, suggesting that oral administration would require dosing every 6 to 8 hours.101 Frankincense extracts, as well as boswellic acids themselves, display moderate-to-potent inhibition of human drug-metabolizing CYP450 enzymes,102 but the clinical significance and comparative effects on nonhuman P450 enzyme systems remain largely unexplored. Most veterinarians are familiar with milk thistle as a liver support supplement, but its value as an adjunct for cancer patients should not be overlooked. The most salient new applications for milk thistle arise in its role as an adjunct for cancer chemoprevention and treatment and to reduce side effects of treatment.103,104 Specifically, silymarin has led to reductions in tumor incidence and a number of chemically induced tumors in rat models for colon, tongue, and bladder cancer. It inhibits the growth of human prostate cancer and lung cancer xenografts in mice.105 Milk thistle derivatives protect the kidneys from radiation injury and cisplatin nephrotoxicity.104,106 They may also protect the heart from doxorubicin-induced lipid peroxidation, as well as the liver from CCNU (lomustine) toxicity (see Chapter 11). When combined with ω-3 fatty acids, milk thistle has reduced the number of radionecrosis sites in cancer patients and prolonged survival.104 Milk thistle potentiated antitumor effects of drugs like cisplatin in both in vivo and in vitro studies.104 The risk of herb-drug interactions from milk thistle appears to be low but not nonexistent. Milk thistle may inhibit certain isoforms of the CYP450 family, namely CYP3A4 and CYP2C9. This becomes significant when combined with agents that depend on CYP3A4 for metabolism, raising concerns about adding milk thistle for “liver protection” during chemotherapy, especially at high doses.107 Silymarin has potentiated chemotherapy toxicity in at least one study.104 However, a recent investigation testing its effects on the disposition of irinotecan as a model drug indicated that milk thistle poses little risk of interfering with agents of similar metabolic profile.108 Still, evaluating clinically significant interactions for each target species will likely prove necessary, given the large interspecies differences in CYP450-mediated metabolic activities between humans, horses, dogs, and cats.109 Milk thistle’s ability to promote liver regeneration could conceivably stimulate tumor growth in cases of hepatocellular carcinoma.104 An in vitro study showed that milk thistle demonstrated strong anticancer (i.e., proapoptotic and growth-inhibiting) activity against human hepatocellular carcinoma cells.110 However, silymarin/silibinin promoted mammary tumor growth in two rodent models. This likely occurred through stimulation of estrogen-receptor signaling by silymarin,105 which raises caution about its safety in cases of breast cancer. Overall, the majority of patients tolerate even high doses of milk thistle. As with most herbs, adverse effects typically involve gastrointestinal upset, diarrhea, or inappetence, although practitioners should monitor blood chemistries and platelet function on a regular basis (at least every 6 months), if animals are taking herbs for months or years.
Complementary and Alternative Medicine for Cancer
The Good, the Bad, and the Dangerous
Acupuncture
How Does Acupuncture Work?
How Might Acupuncture Benefit a Veterinary Patient with Cancer?
The Importance of Approaching Acupuncture Scientifically
Herbs
How Do Herbs Work to Fight Cancer?
Additional Issues with Herbs for Cancer Patients
Examples of Herbs for Patients with Cancer
Asian Mushrooms
Curcumin
Boswellia
Milk Thistle
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Complementary and Alternative Medicine for Cancer: The Good, the Bad, and the Dangerous
