To be a great veterinarian is one thing, but the ability to maintain compassion and caring sets you apart from the rest.
As a member of the Evidence-Based Veterinary Medical Association (EBVMA), I am thrilled with the recent publications focusing on three alternative therapies. People are becoming more and more interested in alternative therapies, for themselves and their pets. Whether this trend is due to a desire for more effective and less toxic therapies, increased research into the mechanism of action of many natural products, dissatisfaction with the effectiveness of traditional medicine or other issues is very much up for debate, but certainly beyond the scope of this column.
The three alternative therapies recently evaluated in the veterinary literature are Yunnan baiyao, Polysaccharopeptide (PSP) from the mushroom Coriolus versicolor, and artesunate.
The Chinese have used artemisinin, a derivative of sweet wormwood, for medicinal purposes for over 2000 years. Its main use, both past and present, is as an anti-malarial medication. Researchers are now starting to evaluate the anti-cancer properties of artemisinin and its derivatives1. It is thought that artemisinin kills cancer cells through the generation of reactive oxygen radicals after binding to iron, which is found in high concentrations in many cancer cells. An additional mechanism of action is through the induction of apoptosis. A recent paper by Rutteman, et al2, documented activity of oral artesunate, a semi-synthetic derivative of artemisinin, in cancer bearing dogs. A potential advantage of artesunate is that its effectiveness is not diminished by the genes that confer multidrug resistance to many of the anti-cancer drugs commonly used in veterinary medicine.
The second alternative therapy is a Coriolus versicolor mushroom derivative, PSP, sold under the trade name I’m-Yunity ®. PSP does inhibit cancer cell growth in vitro, but its effect in vivo were largely unknown prior to the 2012 paper by Brown and Reetz3 in Evidence-Based Complementary and Alternative Medicine (http://www.hindawi.com/journals/ecam/2012/384301/). Their randomized, double-blinded, multidose pilot study evaluated the effect of I’m-Yunity® in dogs with splenic hemangiosarcoma at 3 doses (25, 50 and 100 mg/kg/day). The authors found that dogs treated at the highest dose (100 mg/kg/day) of I’m-Yunity® had significantly delayed progression of metastases compared to dogs treated at the lowest dose. In addition, the dogs in the two highest dose groups had increased median survival times compared to the median survival times of dogs in previously published reports. Although comparing current patients to historical controls is not ideal, the level of evidence generated by randomized, double blind studies is considered very high.
The third is Yunnan baiyao, a Chinese herb used as an anti-coagulant, anti- inflammatory, and pain reliever for over a century, has anecdotally been reported to improve the survival of dogs with hemangiosarcoma. We now have evidence, rather than just anecdotes, about the activity of Yunnan baiyao against canine hemangiosarcoma cells. Wirth, et al4, report on the effects of varying concentrations and exposure of Yunnan baiyao to three canine hemangiosarcoma cell lines in vitro. The authors measure the effects of 5 concentrations (50, 100, 200, 400, 600 and 800 μg mL−1) at 24, 48 and 72 hours and find that Yunnan baiyao causes dose and time dependent cell death. The manner in which this herb kills hemangiosarcoma cells is likely through capsase-mediated apoptosis. These findings warrant further studies, both in vitro and in vivo, about Yunnan baiyao in the treatment of canine hemangiosarcoma.
Dr. Gerald S. Post – 2014
- Lai H, Singh NP, Sasaki T. (2013) Development of artemisinin compounds for cancer treatment. Invest New Drugs 31:230-246.
- Rutteman G, Erich S, Mol J, Spee B, Grinwis G, Fleckenstein L, London C and Efferth T (2013) Safety and Efficacy Field Study of Artesunate for Dogs with Non-resectable Tumours. Anticancer Research 33:1819-1828
- Brown DC and Reetz J. (2012) Single Agent Polysaccharopeptide Delays Metastases and Improves Survival in Naturally Occurring Hemangiosarcoma. Evidence-Based Complementary and Alternative Medicine 2012:1-8
- Wirth KA, Kow K, Salute ME, Bacon NJ and Milner RJ (2014) In vitro effects of Yunnan Baiyao on canine hemangiosarcoma cell lines. Veterinary and Comparative Oncology DOI: 10.1111/vco.12100
Cancer has become a leading health concern in companion animal medicine and contributes significantly to mortality in this population. Significant strides have been made across the fields of chemotherapy, radiation and surgery that allow rapid detection and elimination/reduction of cancer. Along with these advances has come a realization of the burden that cancer and its treatment places on the body. This burden, assessed as quality of life for our patients, is often a significant concern among clients seeking help in treating their companion’s cancer. In many instances, inability to control these side effects may contribute to a decision to euthanize even when the cancer itself is being successfully managed. One of the largest manifestations of this concern relates to pain caused by cancer and its treatment.
Causes of pain in cancer patients is multifactorial. A tumor itself can cause pain by directly invading tissues, compressing nerves, and activating nerve endings in any part of the body. In addition, cancer can worsen preexisting pain and contribute to chronic debilitation through a variety of signaling mechanisms. Surgery and other invasive diagnostic and therapeutic modalities lead to acute pain in cancer patients that may be more likely to become chronic pain because of tumor activity. Pain negatively affects quality of life and has deleterious effects on metabolism and immunity. Painful patients are generally less mobile and less likely to eat, contributing to a cycle of continued debilitation and worsening quality of life.
Luckily, recognition of and treatment for pain has taken great strides. More modalities than ever exist for keeping patients comfortable through the variety of treatments and experiences they are faced with when diagnosed with cancer. As with all types of pain, the approach to cancer pain relies on a step wise approach that includes recognition, categorization, multimodal treatment, and reassessment. Recognition of cancer related pain has improved dramatically through the improved skills of practitioners who are actively looking and the institution of validated pain scoring systems. These scoring systems are now available for acute and chronic pain situations in companion animals and can help greatly in modifying pain treatment.
Categorization of pain guides treatment selection. Pain is most usefully categorized based on intensity (mild, moderate, severe), time (acute, chronic, intermittent), and origin (somatic, visceral, neuropathic). It can also be classified as adaptive (appropriate response to condition) or maladaptive (inappropriate nervous system response duration or intensity). Pain resulting from cancer and its treatment often spans all of these classification systems as time progresses. Presence of multiple conditions may also contribute to pain in cancer patients and should be evaluated. A very common example is the patient with a tumor that also has significant osteoarthritis pain.
Treatment of cancer pain can be complex and should always include multiple modalities. Directed therapies that may remove the source of tumor related pain such as surgery, radiation therapy, and osteoclast inhibitors should be implemented early in the disease course if possible. Early and preventative analgesic strategies should be used for painful procedures such as surgery or biopsy. Loco-regional anesthetic techniques can be key to this effort and are still underutilized. Opioid type drugs and anti-inflammatory medications such as NSAID’s and corticosteroids remain the first line of treatment, especially for pain that is acute or intermittent and of somatic origin. These drugs are helpful but lose much off their utility as cancer pain becomes chronic, neuropathic, and maladaptive. Adjuvant drugs that address pain related excitatory changes in the nervous system have become an exceptionally valuable tool and are often included in cancer care. These include pharmacologic modifiers of both inhibitory and excitatory systems such as GABA, NMDA, serotonin/norepinephrine, and calcium/sodium channels. Non-pharmacologic modalities such as acupuncture and physical rehabilitation have an increasingly realized and important role in treating and preventing pain in cancer patients by maintaining whole body health, muscle tone and metabolism. Importantly, pain should be reassessed often as the cancer patient progresses through treatment. Changes to pain generation and in intensity of preexisting pain are common. Therapy should be adjusted so that it continues to meet the needs of the cancer patient through a variety of experiences and may need adjustment both up or down depending on changing conditions.
In summary, pain is widespread and multifactorial in veterinary cancer patients. Its prevention and treatment can contribute significantly toward maintaining quality of life and improving quality time spent with their human companions. It should be a high priority to seek out and characterize sources of pain in cancer patients. This allows early intervention and aggressive treatment with multimodal analgesic protocols that include directed therapies, pharmacologic management, and multiple supportive modalities.
The practice of Traditional Chinese Veterinary Medicine (TCVM) is gaining in popularity. The past few decades have seen a surge in the popularity and acceptance of Eastern Medicine practices, specifically acupuncture, amongst physicians. As the practice of Traditional Chinese Medicine becomes more widely accepted for people, companion animal clients will look to these modalities to help alleviate aliments of their pets. In 1998, the National Institutes of Health (NIH) published a consensus report summarizing research findings on the usefulness of acupuncture for chemotherapy-induced nausea as well as post-operative pain secondary to tumor removal in people1. The findings confirmed that acupuncture is beneficial for these conditions1. This report sparked major interest in acupuncture as a compliment to physician-based Western Medicine. Since 1998 there has been a surge in funding to support research evaluating the molecular mechanisms and the clinical benefits of acupuncture for various diseases2. As more and more positive research is published, Western medicine practitioners are gaining more confidence in using this modality as a tool in their tool-belt. It is not surprising that the top tier, world-renowned U.S. Cancer Institutes such as, Dana-Farber in Boston, Sloan-Kettering in New York, and MD Anderson in Houston, all have integrative medicine programs closely associated with their cancer centers. As interest in acupuncture rises in physician-based medicine, veterinary medicine is not far behind.
Acupuncture has three key elements: the acupuncture point, the stimulating method, and the therapeutic effect. Research has demonstrated that the acupuncture point has high electrical conductivity, low electrical resistance, and contains large numbers of arterioles, lymphatic vessels, nerve endings, and mast cells. The most common stimulating techniques involve dry needle (placement of needle alone) or electroacupuncture (use of low level electricity connected to a needle in an acupoint). Human and veterinary studies have been reported showing the benefit of acupuncture for conditions including: alleviation of pain3-6, modulation of the immune system and anti-inflammatory response7,8, and alleviation of nausea9,10. Acupuncture modulates the activity of peripheral and central neural pathways. Acupoints overlie major neuronal bundles, for example the pericardial points (Pericardium Meridian) overlie the deep median nerve and the gastrointestinal points (Stomach Meridian) overlie the deep peroneal nerve. As the point is stimulated, there is activation of peripheral and central neural pathways, leading to an effect on hormones, cytokines, neurotransmitters, and other chemical mediators in the body.
How can acupuncture help the oncology patient (human or pet)? Research from physician-based medicine does support the use of this modality for the human oncology patient. Two studies (of many) were chosen to be summarized here. The first study is a three-armed, randomized, prospective clinical trial published in The Journal of the American Medical Association. Women with high grade mammary carcinoma, treated with high dose myeloablative chemotherapy, were randomly assigned to three separate groups: anti-emetic alone, anti-emetic with electroacupuncture, anti-emetic with sham acupuncture (acupuncture at non-therapeutic location). The study found that women in the electroacupuncture and anti-emetic treatment group had significantly less vomiting episodes compared to women in the two other groups10. The second study from The Journal of Clinical Oncology, a randomized, prospective, blinded clinical trial evaluated the benefit of acupuncture in alleviating joint pain secondary to aromatase inhibitor chemotherapy treatment in women with breast cancer5. Aromatase inhibitors are agents known to cause severe joint pain in patients. Women were divided into two groups, one group (‘treatment’) receiving true acupuncture and one group (‘control’) receiving ‘sham’ acupuncture (acupuncture needle placed in a non-therapeutic location)5. The women were blinded as to which group they were enrolled. The study found that women in the treatment group had significantly lower pain scores compared to women in the control group5.
In light of the positive research findings reported for acupuncture use in human oncology patients, we may theorize that this modality may help support the veterinary oncology patient as well. Looking back in veterinary medicine history, if data was lacking, our predecessors looked to research from our physician colleagues to help advance veterinary medicine. Many diagnostic techniques and therapeutic approaches determined to be helpful in people; have also been shown to be beneficial in our pets. Chemotherapy, surgery and radiation are the most common modalities used to treat cancer in veterinary patients. In general, these treatments are better tolerated in veterinary patients compared to human patients. Most chemotherapy protocols for veterinary patients are designed to result in less than 5% hospitalization rate and less than 1% mortality rate11,12. This is accomplished by reducing dose intensity, either by way of less frequent treatment, using single-agent protocols, or lower dose of chemotherapeutic agent11,12. In theory, these adjustments may negatively impact the overall efficacy of the treatment. In addition, despite these adjustments, side effects including gastrointestinal upset, cystitis and bone marrow suppression still occur11,12. Since acupuncture has been shown to help mitigate chemotherapy side effects in people, we may theorize that this modality may be just as useful in the veterinary oncology patient. Acupuncture may be used to help alleviate the severity and decrease the duration of side effects, therefore reducing the recovery and delay time between chemotherapy treatments. Furthermore, it should be evaluated that if the use of acupuncture reduces the risk of side effects, the dose intensity may be increased to potentially improve tumor cell death and benefit efficacy of cancer treatment. In addition, the tumor itself may cause symptoms in the patient which impact the overall quality of life and therefore decrease the survival time. For example: gastroenteritis and poor appetite in GI lymphoma patient, bone pain in osteosarcoma patient, and cystitis pain in patients with transitional cell carcinoma of the bladder. Just as acupuncture helps mitigate pain for human patients; it may help support our veterinary patients, thereby improving their overall quality of life, resulting in potentially longer survival outcomes. To the author’s knowledge, there have been no published studies evaluating acupuncture for issues which may arise for the veterinary oncology patient, specifically, treatment- or tumor-induced side effects. This is an area of study with a great deal of potential.
It is important to note that acupuncture is not a miracle cure-all any more than conventional medical interventions. Both conventional Western medicine and Traditional Chinese Veterinary Medicine have their strengths and weaknesses. The ideal situation is using a combination of both TCVM and Western medicine to complement the strengths of each system.
NIH Consensus Conference. Acupuncture. J Am Medical Assoc. 1998. 280: 1518-24.
Weidong et al. Hematology Oncology Clinics North Am. 2008. 22(4): 631.
Xie, et al. Am J Trad Chinese Vet Med. 2009. 4: 17-29.
Wong, et al. Annals Thoracic Surgery. 2006. 81: 2031-36.
Crew, et al. Journal Clinical Oncology. 2010. 28: 1154-60.
Ju, et al. Neural Regeneration2013. Sep 5;8(25):2350-9.
Pais, et al. Evid Based Complement Alternat Med. 2014. 217397.
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Vail. Veterinary and Comparative Oncology. 2007;5(1):38-46.
Chun, et al. Cancer Chemotherapy. In:Withrow MacEwen Sm An Clin Onco. p 163-192.
Submitted by: Kate Vickery, VMD, MS, DACVIM (Oncology)
Dr Vickery is studying to obtain Certification for Veterinary Acupuncture. In early January she will open the Acupuncture Service at Hope Veterinary Specialists, along with colleague Dr Jeff Wilson (anesthesiologist). Her goal is to use acupuncture on a daily basis to help support the oncology patient, as well as investigate the benefits this modality has for these patients through clinical research studies.
Stallion is a 12 ½ year old male castrated Chihuahua mix who presented for possible seizures and weakness. Approximately 6 months earlier he started to lose his balance and stumble, stare into space and became polyuric and polydypsic (PU/PD). On neurologic exam neck pain, left facial nerve paresis and occasional knuckling on the right thoracic limb were noted. Neuroanatomic localization was multifocal CNS disease. Blood work revealed mildly increased in Alkaline Phosphatase of 352 and ALT of 137. Further bloodwork including a serum cortisol, Accuplex (Lyme/Hearworm/Anaplasma/Ehrlichia ), thyroid panel and Rocky Mountain Spotted Fever titers were submitted. A low TSH was noted on the thyroid panel (TSH 1.46 ng/ml, normal 0-0.6). Serum cortisol, RMSF titer and the Accuplex were all normal. Treatment with thyroxine was initiated. Possible seizure like episodes continued at home and magnetic resonance imaging (MRI) of the brain was elected.
Standard MRI sequences of the brain were performed including sagittal T2-weighted series, transverse T2-weighted, FLAIR, T1-weighted and T2*-GRE series and T1-weight series in transverse, dorsal and sagittal planes following intravenous contrast administration of gadolinium.
The MRI demonstrated a large sellar/suprasellar mass which was hyperintense to adjacent white matter of the brain in T2-W images (Figure 1), isointense in T1-W images and strongly contrast enhancing. The mass was causing marked dorsal and lateral displacement of the overlying hypothalamus and thalamus.
Differential diagnoses for a suprasellar mass include a pituitary tumor, meningioma, craniopharyngioma, germ cell tumor, and hypothalamic glial tumor. Pituitary tumors are by far the most common suprasellar neoplasia and include both adenomas and adenocarcinomas. These originate from the pars intermedius or pars distalis of the pituitary. In general pituitary masses greater than 1 cm in diameter are considered pituitary macroadenomas/adenocarcinomas. Pituitary tumors may be functional or nonfunctional .
The most common clinical signs associated with pituitary macrotumors include those signs indicative of Cushing’s disease. When neurologic signs develop they are consistent with intra-cranial disease with lethargy, anorexia, stupor and tetraparesis most common. Ataxia circling and behavioral changes are also frequently noted (Sarfaty 1988). Blindness is uncommon in contrast to what is seen in people and seizures are actually also uncommon. Disorders of water metabolism and thermoregulation may occur secondary to invasion of the hypothalamus.
Treatment options for pituitary macrotumors include medical treatment for pituitary dependent hyperadrenocorticism (Cushing’s disease) if present with either Mitotane or Trilostane. Neither has been shown to be superior to the other. An anticonvulsant such as phenobarbital to control seizures may be necessary and prednisone can help control peri-tumoral edema and inflammation.
Surgical treatment via a transphenoidal hypophysectomy has been described and is technically difficult but can lead to successful clinical outcome with 2 year survival rates reaching 80% (Meij 1988). Possible complications include tumor recurrence because of incomplete removal, mild post-operative hyponatremia or permanent diabetes insipidus post-operatively. There is also certainly an upper limit as to size of tumor which can be removed and hypophysectomy has most often been performed in dogs with microadenomas rather than macroadenomas.
Radiation therapy is becoming more common in veterinary medicine as availability at Universities and referral practices increases. Median survival time for dogs with pituitary tumors treated with radiation therapy can reach 22-43 month in patients with no neurologic signs at time of presentation. In patients presenting with neurologic signs median survival is lower but can still reach 11.7-22 months (Bley 2005, Dow 1990, Theon 1998), demonstrating the benefit of early intervention in cases of pituitary dependent hyperadrenocorticism. Advanced diagnostic imaging such as CT or MRI in cases of pituitary dependent hyperadrenocorticism can identify those patients with macrotumors who would benefit most from radiation therapy. The diagnostic imaging studies also then are used for radiation therapy treatment planning with fusion of CT and MRI images allowing for precise localization for the delivery of radiation (Figure 2). The recent availability of Cyberknife (stereotatic radiation therapy) also provides exciting and promising new treatment options with many advances over tradition radiation therapy including a much shorter treatment course and improved sparing of normal tissue adjacent to a tumor.
Stallion received a full coarse of traditional radiation therapy (51 Gy) divided over 17 treatments. Repeat MRI 10 months later when neurologic signs recurred showed a marked reduction in tumor size however significant peri-tumoral edema had developed (Figure 3). A second course of radiation therapy was elected utilizing Cyberknife and consisted of a single dose of 15 Gy.