Vitalvar.huInternational Journal of Medicinal Mushrooms, 11(2):167–184 (2009) Preclinical Evaluation of Concurrent Medicinal
Supplementation in Dogs Undergoing
Chemotherapy for Various Cancers
John C. Holliday,1,* Britt M. Gianotti,1 Matt P. Cleaver,1 Marie N. Mullins,2,3 & Sharon Y. West31Aloha Medicinals Inc., Carson City, NV 89706, USA; 2Animal Hospital Specialty Center, Highlands Ranch, CO 80126, USA; 3Veterinary Cancer Care of Santa Fe, NM, USA * Address all correspondence to John C. Holliday, Aloha Medicinals Inc., 2300 Arrowhead Dr., Carson City, NV 89706, USA; ABSTRACT: Chemotherapy is one of the most common treatments for canine cancer, although it is
frequently quite toxic and can result in disruptions of the dog's normal biochemical and physiological
cycles. Chemotherapy is known to often drive the dog's white blood cell count down (neutropenia),
causing the immune system to weaken and raising susceptibility to opportunistic infections. This often
causes chemotherapy schedules to be interrupted, resulting in less-effi cacious treatment. Neutropenic
patients are commonly symptomatic, exhibiting such side effects as anorexia, diarrhea, vomiting, fever,
and death. Historically, neutropenia is one of the main factors considered in directing chemotherapy
cycles. This study was conducted to determine the effectiveness of a popular mushroom-based vet-
erinary immune-enhancement supplement, K-9 Immunity™, and its adjunct K-9 Transfer Factor™,
when used concurrently with chemotherapy. The objectives of this study were several: to determine if
immune supplementation could reduce neutropenia when partnered with chemotherapy, to determine if
the incidence of side effects would be reduced, and to determine the overall effect on quality of life in
the face of the chemotherapy. In addition to their regularly prescribed cancer treatments and medicines,
dogs in this study received a daily dose of nonspecifi c immune-enhancement supplements: one 500 mg
capsule per 4.5 kg body weight per day of K-9 Immunity™ and one 3000 mg wafer per day (for dogs
greater than 11 kg) or 1/2 wafer per day (for dogs under 11 kg) of K-9 Transfer Factor™. Four different
cancer types were tracked and evaluated in this study: lymphosarcoma (LSA) (N = 21), osteosarcoma
(OSA) (N = 20), mast cell tumor (MCT) (N = 19), and hemangiosarcoma (HSA) (N = 4). Various
chemotherapy or palliative therapy protocols were used according to tumor type and patient suitability.
Standard chemotherapy protocols were followed throughout the study, so long as biological parameters
were found to be within the normal ranges. Blood parameters monitored included CBC, chemistry panel,
and urinalysis, as well as radiographs and other tests per individual protocol. All patients remained in
their homes with clients who were asked to make daily assessments of appetite, attitude, vomiting, diar-
rhea, diet, medications, and other supplements, by way of a questionnaire. Patients were brought to the
clinic routinely for assessment by the veterinary staff and received treatment as prescribed. The results
of this study indicate that as an adjunct to chemotherapy, these supplements do reduce the common side
effects for dogs who become neutropenic. The study also showed that this type of immune-modulation
therapy relieves many of the symptoms usually associated with chemotherapy and allowed the dogs to
maintain a quality of life more closely related to their norm. These results indicate that further research
into nonspecifi c immune-modulation therapy as an adjunct to chemotherapy is warranted, with the goal
of improving the quality of care and quality of life that we can deliver to our canine cancer patients.
KEY WORDS: immune supplements, K-9 Immunity, K-9 Transfer Factor, dog chemotherapy, canine
lympho sarcoma, mast cell tumor, canine osteosarcoma, canine hemangiosarcoma, medicinal mushrooms
1521-9437/09/$35.00 2009 by Begell House, Inc.
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CBC: complete blood cell count; CCNU (Lomustine): 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; CHEM: full
blood chemistry panel; CHOP: chemo protocol using a specifi c regime of drugs; DFI: disease-free interval; DIC:
disseminated intravascular coagulation; GI: gastrointestinal; HSA: hemangiosarcoma; IgA: Immunoglobulin A;
IgG: Immunoglobulin G; IgY: Immunoglobulin Y; i.l.: intralesional; i.m.: intramuscular; i.v.: intravenous; LSA:
lymphosarcoma; LTFU: lost to follow-up; MCT: mast cell tumor (mastocytoma); N = 21: number of cases is 21;
NED: no evidence of disease; NSAID: nonsteroidal anti-infl ammatory drug; NT: new tumor type appeared; OSA:
osteosarcoma; PD: progressive disease; SD: stable disease; s.q.: subcutaneous; TLR: Toll-like receptors; u: units;
UA: urine analysis; VCCC: Veterinary Cancer Care Center; VCOG: Veterinary Co-Operative Oncology Group;
VSS: Veterinary Surgical Specialists; WBC: white blood cell; WHO: World Health Organization; 5FU: 5 fl urourosil;
>/=50%: greater than or equal to 50%; </=50%: less than or equal to 50%.
cells shifts the balance more toward the destruction of these cells than their replication. Modern cancer Cancer is the body's failure to recognize and de- treatment protocols are focused only on destruc- stroy cells that do not replicate normally. A healthy tion of the aberrant cells. Although this is vital in immune system searches out and destroys these any successful cancer treatment, it can only be irregular cells before overgrowth can occur. When viewed as one arm of a two-pronged approach, if the immune system is not functioning properly, we hope to increase long-term survival rates. The this cell overgrowth is free to continue to tumor real issue to be addressed in long-term survival is formation. The key to successful cancer treatment that when the chemotherapy, radiation, and surgery is in triggering the immune system's recognition are all fi nished, and all the cancer cells have been and response to these cells before uncontrolled destroyed, the underlying immune dysfunction that overgrowth occurs. The body's own immune system allowed the proliferation of the tumor in the fi rst thereby is able to fi ght off the cancer.1–5 place still exists. This is why it is so important to The currently accepted theory of solid-tumor try to enhance immune response during cancer formation is that three criteria must take place for treatments, and why immune supplementation is thought to positively affect the outcome of con-ventional cancer-treatment methods.6,7 1. Cells must have errors in the replication Cancer is the leading cause of death in senior process. These replication errors can be in- dogs (>5 years old) in the United States, account- fl uenced by toxins (environmental or other- ing for approximately 50% of deaths in this group wise), viral infection, radiation, age, and other of animals.8,9 Because the mechanisms of action in unknown factors.
most cancers are similar or even identical between 2. Once these errors in replication occur, the im- humans and canines,10,11 it has become common mune system fails to recognize them as aberrant, practice in the veterinary fi eld to apply the same allowing further replication of these errors.
palliative protocols to dogs as would be used in 3. The immune system remains in an unrespon- treatments for similar human diseases. As the use of sive state for a long enough period of time, mushroom-derived polysaccharides has been shown allowing the aberrant growth to become self- to positively affect the outcome of chemotherapy sustaining, resulting in tumor formation.
and reduce the chemotherapy-associated side ef-fects in a number of human studies, their use as When considered in this context, cancer is an adjunct with cancer treatment over the last 20 viewed primarily as an immune-dysfunction disease. years has become quite common. There is a large Anything that can be done to enhance or correct quantity of research indicating the effectiveness of the immune recognition and destruction of aberrant this type of adjunct treatment.3,4,12–18 International Journal of Medicinal Mushrooms Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 188.8.131.52 by Dr. john holliday (alohamed) EVALUATION OF IMMUNE SUPPLEMENTATION IN DOGS UNDERGOING CHEMOTHERAPY This report is on a 1-year-long study of dogs II. MATERIALS AND METHODS
receiving immune supplementation concurrently with chemotherapy. It was initiated in June of 2007 A. Study Entry Criteria and Explanation
at the Veterinary Cancer Care Center (VCCC) in of Cancer Types
Santa Fe, New Mexico (USA). The main purpose of this study was to assess whether the same posi- Subjects were chosen based on four of the most tive effects would be seen in canines undergoing common canine tumor types: lymphosarcoma (LSA) similar chemotherapy regimens as has been seen (n = 21); osteosarcoma (OSA) (n = 20); mast cell in human trials.
tumor (MCT) (n = 19); and hemagiosarcoma (HSA), Dogs undergoing chemotherapy may experience both splenic (n = 2) and cutaneous (n = 2). There several side effects due to the toxic drugs adminis- were no control patients for this study; rather, all tered, which include (but are not limited to) pain, comparisons were taken from historical data. The diarrhea, constipation, hair loss, nausea, vomiting, standard measurements used for assessing the se- fever, and death. In addition, blood-related side ef- verity and disease progression for these and other fects, such as a decrease in the number of infection- cancer types are referred to as stages and grades. fi ghting white blood cells (neutropenia), low red According to the National Cancer Institute, tumor blood cell count (anemia), and low platelet count grade is a system used to classify cancer cells in (thrombocytopenia) have also been noted.18, 19,20 terms of how abnormal they look under a microscope Of these various side effects, one of the most and how quickly the tumor is likely to grow and critical is neutropenia. This is a blood disorder spread. Staging describes the extent or severity of an characterized by an abnormally low number of individual's cancer based on the original (primary) neutrophils, a type of white blood cell that usually tumor and the spread of that cancer in the body.22 comprises 50%–70% of the circulating white blood Dogs involved in this study received either cells. Neutrophils provide the initial major defense chemotherapy per prescribed protocols based on against infections by destroying bacteria and viruses Veterinary Co-Operative Oncology Group (VCOG) in the blood. Neutropenia is often seen with chemo- accepted practices and dosages, or other approved therapy and can impair the patient's ability to fi ght therapies such as surgery with no chemotherapy, as off opportunistic infections, leaving the patient determined on an individual basis by the attending more susceptible to illness. Without prompt medical veterinarian. Chemotherapy dosages were adjusted atten tion, the condition may become life-threatening on a case-by-case basis according to the dog's (febrile neutropenia or neutropenic sepsis).20,21 response, to ensure humane and safe administra- One purpose of this study was to explore the tion and outcome. Subjects were evaluated at the possibility of dietary immune supplementation Veterinary Cancer Care Center (VCCC) for protocol helping to boost white blood cell (WBC) levels procedures associated with the individual tumor type in dogs undergoing chemotherapy treatments for diagnosed. Clinical parameters noted were weight, various types of cancer. Other considerations ad- tumor size (where applicable), biological data, side dressed in this study were disease-free intervals effects, tumor status, immune-supplement disburse- and various biologic parameters, such as blood ment, and retrieval count, as well as treatment type chemistry, urinalysis (UA), radiographs, and overall and/or rest weeks. Miscellaneous medications, patient quality of life, as measured by symptomatic supplements, or procedures were also noted.
episodes. The basic questions posed at the onset of All patients in this study were housed in their this study were as follows: Can K-9 Immunity™ own home environment, and the immune supple- prevents neutropenia, thereby avoiding missed ments were administered by the individual dog chemotherapy treatments? Will K-9 Immunity™ owners on a daily basis. Assessments of appetite, supplementation present a more favorable treatment attitude, and activity levels were also made by the outcome? Is it possible that K-9 Immunity™ can owners on a daily basis using a "monthly calendar" improve quality of life for those patients undergoing that was supplied to them, with parameters for the chemotherapy or palliative treatments? assessment of the pet's daily routine, including not Volume 11, Issue 2, 2009 Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 184.108.40.206 by Dr. john holliday (alohamed) J. C. HOLLIDAY ET AL.
only appetite and attitude, but diet, vomiting, and 2. Partial remission (>/=50% reduction of gross diarrhea, ease of administration of supplements, and usage of other medications or supplements. Calen- 3. Progressive disease (</=25% reduction of dars and supplement containers were returned to the gross disease or new lesions) clinic at each visit for evaluation and monitoring 4. Stable disease (<50% decrease or <25% in- to assure compliance. This information was then crease in gross disease) transferred to a master spread sheet for each patient. The master sheet for each subject also contained biologic information such as complete blood cell D. Monitoring of Chemotherapy Patients
count (CBC), chemistry, urinalysis, radiographs, weight, and patient status.
Patients undergoing chemotherapy had a CBC performed at each chemotherapy visit and nadir; OSA patients had additional serum chemistry at B. Entry Criteria for All Tumor Types
the halfway point and at the end of therapy. Each of the monthly calendars was also reviewed and The entry criteria for each tumor type are very similar recorded. All tumor types underwent restaging as among the four cancers monitored. All patients were required; HSA and LSA patients were restaged required to have a CBC and a full blood chemistry after 4 cycles of chemotherapy and then every 3 panel (CHEM) (with or without UA), as appropriate, months thereafter until 1 year. MCT patients were a surgical report or baseline abdominal ultrasound restaged at the last chemotherapy session, then every for MCT and HSA, a 2-view abdominal radiograph 3 months for 1 year. OSA patients were restaged for LSA, and bone-lesion radiographs for OSA. For every 3 months for 1 year. Any dog undergoing MCT and LSA, a 2-view chest radiograph may or multiple chemotherapy protocols had full chemistry may not have been required according to patient workup prior to each doxorubicin treatment.
presentation, and 3-view chest radiographs were required for all OSA and HSA patients. A fi ne needle E. Monitoring for Surgery Only or
aspirate of the lymph nodes, with or without liver or spleen aspirate (if abnormal), was required for MCT, and an aspirate of the bone marrow was needed for The monitoring for patients who received surgery LSA if the CBC was abnormal. MCT dogs had their only or palliative treatments included a monthly masses and lymph nodes measured, and all cancer physical exam and repeat blood work every 3 types had a cytological (LSA), histopathologic (HSA, months (CBC, CHEM, with or without UA, as MCT, OSA), or radiographic (OSA) diagnosis.
appropriate). Also reviewed and recorded were the monthly calendar, measurement of the masses, and lymph nodes. The patients were also restaged every C. Parameters Recorded
3 months for the full year according to the tumor type. In addition, OSA patients had remission status The parameters recorded for the tumor types in- recorded; a lameness score; graded I–IV; 3-view cluded the side effects of chemotherapy; VCOG chest radiographs; bone-lesion radiographs; and a grades of neutropenia, if present; the number of full blood workup every 3 months.
unscheduled rest weeks; GI toxicity; disease-free intervals (DFI); review of monthly calendars; tumor or lymph node size for OSA and LSA; and survival F. Explanation of Individual Tumor Types
time and/or remission status. The remission status recorded was as follows: 1. Lymphosarcoma (LSA)
1. Complete remission (100% resolution of gross LSA is one of the most common cancer types seen in dogs and begins in cells of the immune system. International Journal of Medicinal Mushrooms Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 220.127.116.11 by Dr. john holliday (alohamed) EVALUATION OF IMMUNE SUPPLEMENTATION IN DOGS UNDERGOING CHEMOTHERAPY It is characterized by an uncontrolled growth of aged to older large and giant breed dogs are most lymphocytes (cells that normally function as part often affected. Dogs with this type of cancer often of the immune system). It affects dogs of any breed undergo surgery to remove the limb where the tumor and age, although most dogs are middle-aged or is located, or occasionally limb-sparing surgery is older at the time of diagnosis.21 There are several performed. Following surgery, it is common practice stages used in assessing LSA according to standards to follow with chemotherapy treatment. Approxi- of the WHO clinical staging system22: mately one half of the dogs with OSA treated in this manner will be living 1 year after diagnosis. Stage I: Single lymph node enlarged Approximately 25% of the dogs treated in this Stage II: Multiple nodes enlarged on either side fashion are still living 2 years after diagnosis. Dogs of the diaphragm (the body cavity separating the treated with either amputation or palliative radiation chest and abdominal regions) therapy (without chemotherapy) live, on average, approximately 6 months before complications of Stage III: Multiple nodes enlarged on both side of the local tumor or metastasis cause death or prompt owners to consider euthanasia.19,21 Stage IV: Involvement of the liver and/or spleen Staging for OSA is based on human values and Stage V: Bone marrow involvement or involve- consists of grade, anatomic location of the primary ment of other organs (e.g., gastrointestinal, skin, tumor, and the presence of regional or distant or nervous system) metastasis. Substages are A (intracompartmental tumor) and B (extracompartmental tumor).
Each numbered stage is further divided into Stage I: Low-grade tumor without metastasis substages (A and B). Patients substaged A feel well, whereas patients with substage B are ill. Survival Stage II: High-grade tumor without metastasis times for most LSA dogs treated with combina- Stage III: Presence of regional or distant metastasis tion chemotherapy protocols are in the range of approximately 1 year.21,22 In this study, all LSA On the basis of this grading system, most dogs patients were quite far along in disease progres- with OSA present in stage IIB. In fact, nineteen sion. Of the twenty-one LSA dogs on this study, of the twenty OSA dogs involved in this study three were staged as IIIA and one was staged as were staged as IIB, and four of the nineteen had IIIB and was also found to have hypercalcemia. distant metastasis. One of the twenty dogs was Seven of the twenty-one were staged as IVA, one staged as IIIB.
of those having T-cell lymphoma, one having hy-percalcemia, and two having both hypercalcemia and T-cell lymphoma concurrently. Three of the 3. Mast Cell Tumor (MCT)
twenty-one dogs were staged as IVB, and three of the twenty-one were staged as VB, one having MCT is an overgrowth or mass composed of mast cells. MCTs can involve the skin, subcutaneous tissue, and muscle tissue. MCTs in dogs are very common, accounting for approximately 20% of all 2. Osteosarcoma (OSA)
skin tumors.19,21 These tumors can arise from any skin site on the body and can have a variety of ap- OSA is the most common primary bone cancer in pearances. It is recommended that before any skin dogs and is estimated to account for roughly 85% mass is removed, the cells from it be collected for of tumors in the canine skeleton. This type of cancer examination to rule out mast cell or other malignant most often occurs in the front limbs, with tumors or benign tumor.21 Mast cells are easily identifi ed near the "wrist" (in the radius or ulna), but it can on aspiration (withdrawing of cells from the mass actually occur in any bone in the body. Middle- via needle).
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MCTs are staged and graded according to the excised mass after surgery it was found that not WHO clinical staging system23: all the cancer cells were removed. Three of these fourteen dogs also showed a high mitotic index, Stage I: One tumor confi ned to the skin, with no whereas six of them had a low mitotic index. Two regional lymph node involvement of the nineteen MCT dogs were classifi ed as Grade Stage II: One tumor confi ned to the skin but with III, one with dirty margins and high mitotic index regional lymph node involvement and the other with dirty margins and low mitotic Stage III: Many tumors that are often large, deeply index. One subject had gross disease, and stage and infi ltrating tumors, with or without lymph node grade were unknown, whereas six of the nineteen dogs had an unknown mitotic index.
Stage IV: Any tumor with distant spread evident. This stage is further divided into substage A, the 4. Hemangiosarcoma (HSA)
dog is apparently well with no clinical signs of illness, and B, with clinical signs of illness. To HSA most often appears on the spleen, right heart determine the tumor stage, evaluation of other base, or liver, although varieties can also appear on lymphoid organs must be performed.
the skin or in other locations. HSA of the spleen or liver is the most common tumor to cause hemor- In determining the prognosis of MCT of the rhage in the abdomen. HSA of the skin usually skin, grade must also be considered. Grade is de- appears as a small red or bluish-black mass. This termined by the biopsy results (histopathology).
type of cancer can also occur under the skin, it and is suspected that in the skin, it is caused by sun Grade I: Well-differentiated, mature cells with a exposure. Occasionally, HSA of the skin can be a low potential for metastasis metastasis from visceral HSA. Other sites of the Grade II: Intermediately differentiated cells with tumor may include bone, kidney, bladder, muscle, potential for local invasion and moderate metastatic mouth, and the central nervous system. HSA can cause anemia, thrombocytopenia (low platelet Grade III: Undifferentiated, immature cells with a count), and disseminated intravascular coagulation high potential for metastasis (DIC). Clinical signs of visceral HSA include loss of appetite, arrhythmia, weight loss, weakness, The prognosis for completely excised Grades lethargy, collapse, pale mucous membranes, and/or I and II tumors is excellent. The prognosis for in- sudden death. An enlarged abdomen is often seen, completely removed Grades I and II tumors treated due to hemorrhage. Metastasis is most common with radiation therapy after surgery is also excellent, to the liver, omentum, lungs, or brain. The usual with approximately 90%–95% of dogs having no estimate of the average time from discovery of the recurrence of the tumor within 3 years of receiving tumor until death occurs in affected dogs is 6 to 8 radiation therapy. The prognosis for dogs with Grade weeks, but death occurs more rapidly than this in III tumors is considered guarded because local recur- a number of cases, usually due to hemorrhage.
rence and/or spread is likely in most dogs.
Staging for HSA is based on WHO criteria23: Of the nineteen dogs involved with this study, two were classifi ed as Grade I, both having clean Stage I: Primary tumor confi ned to spleen, without margins, meaning that all the aberrant cells were evidence of rupture, and measuring less than 5 cm, removed during surgical excision, and they both with no evidence of metastasis had a low mitotic index, meaning that the remain- Stage II: Primary tumor less than 5 cm or evidence ing cells were likely slow replicating. Fourteen of of rupture, with or without regional metastasis the nineteen MCT dogs in this study were classi-fi ed as Grade II, and six of the fourteen had dirty Stage III: Invasive tumor greater than 5 cm with margins, meaning that upon examination of the evidence of regional metastasis International Journal of Medicinal Mushrooms Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 22.214.171.124 by Dr. john holliday (alohamed) EVALUATION OF IMMUNE SUPPLEMENTATION IN DOGS UNDERGOING CHEMOTHERAPY Of the four HSA dogs involved in this study, addition to this, LSA treatment comprises a mul- two had subcutaneous tumors, one of which had titude of different protocols because it is a highly distant metastasis. The other two HSA dogs had variable cancer that may enter into and exit out of splenic HSA, one of which had a "burst" or hemor- remission several times during the lifetime of the rhagic spleen.
patient. Once a patient comes out of remission, a different protocol is used because the aberrant cells become resistant to previously administered G. Chemotherapy Drugs Used in Study
Carboplatine (dosage of 300 mg/m2 i.v. every 3 weeks.) for use with LSA and OSA. Lomustine 1. LSA Chemotherapy Protocols
(CCNU) (dosage of 60–90 mg/m2 by mouth every 3 weeks) for use with LSA and MCT. 5 Flurourosil Chemotherapy was administered for 16–24 weeks, ac- (5FU) (dosage of 150 mg/m2 i.l. weekly) use in cording to one or more of the following protocols: MCT. Doxorubicin (adriamycin) (dose of 25–30 mg/m2 every 3 weeks) for use with LSA and OSA. 1. CHOP protocol. Vincristine is administered in Oncovin (Vincristine) (dosage of 0.5–0.7 mg/m2 the 1st week, cytoxan in the 2nd week, vincris- i.v. weekly) for use with LSA and HSA. Cyclo- tine again for the 3rd week, and adriamyacin phosphamide (Cytoxan) (dosage of 200– 300 mg/ for the 4th week, repeated for 4–6 cycles.
m2 by mouth over 2–3 days; may also be dosed at 2. Doxorubicin/dacarbazine protocol. Doxoru- 250 mg/m2 i.v.) for use with LSA, MCT, and HSA. bicin is administered for 1 week, dacarbazine Chlorambucil (Leukeran) (dosage of 2–6 mg/m2 by for the 2nd week, and then the weekly cycles mouth daily, every other day) for use with LSA and are repeated.
MCT. Vinblastine (dosage of 2.0 mg/m2 i.v. every 3. Lomustine protocol. This single agent is ad- week) for use with LSA and MCT. Bleomycin (dose ministered repeatedly once or twice a week, of 10–20 mg/m2 s.q.) for use with MCT and LSA. repeated every 3–6 weeks, depending on the Cisplatin (dose of 10 mg/m2 i.l.) for use with OSA. tolerance of the animal.
Prednisone (dosage of 1–2 mg/kg by mouth for 3 4. Vincristine and cyclophosphamide proto- weeks, then taper) for use with LSA, OSA, and col. Vincristine and cyclophosphamide are MCT. Dacarbazine (dosage of 800–1000 mg/m2 i.v. administered during week 1, vincristine is every 3 weeks) for use in LSA rescue therapy after administered during weeks 2 and 3, and both coming out of remission. Asparaginase (dosage of vincristine and cyclophosphamide are admin- 10,000 µ/m2 i.m. or s.q.) for use with LSA.
istered again during week 4 and routinely, Metronomic Therapy (low-dose continuous
every 2–3 weeks, for maintenance over a chemotherapy) is a combination of chemotherapy, 6-month period.
pain relief, antibiotic, and antiangiogenesis thera- 5. L-asparaginase/lomustine protocol. L-aspara- pies. Drugs used are Cytoxin 10–25 mg/m2 by ginase is administered for the 1st week, then mouth every other day; Piroxicam (feldene) or other lomustine is administered the 2nd week. A NSAID therapy based on clinician preference, typi- CBC is taken for baseline chemistry in weeks cally 0.3 mg/kg by mouth daily; and Doxycycline 3 and 4 and before any dosage of lomustine, 10 mg/kg orally, daily.
or after every 3 doses have been administered. This treatment cycle is repeated for a period of 4–6 months.
H. Treatment Protocols
6. Vincristine/lomustine protocol is administered weekly for 16–24 weeks. The 1st week vin- There are several protocols used for each cancer cristine is given, with lomustine administered type, and they are used according to both the tumor in the 2nd week and only a CBC taken for type and the tolerance of the individual animal. In weeks 3 and 4. Weeks 1–4 are repeated, and Volume 11, Issue 2, 2009 Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 126.96.36.199 by Dr. john holliday (alohamed) J. C. HOLLIDAY ET AL.
prednisone is given initially at 5 mg every 2. Lomustine was used as a single agent every 12–24 hours then tapered.
3–4 weeks for a total of 6–8 treatments. Both 7. Vincristine/chlorambucil protocol was ad- CBC and blood chemistry were monitored. ministered weekly for 16–24 weeks. The 1st Prednisone was administered daily for 2 week both vincristine (vinblastine may be weeks, then tapered.
substituted) and chlorambucil were adminis- 3. Vinblastine was used as a single agent weekly tered. Chlorambucil alone was administered for a total of 6–8 treatments. CBC was taken for weeks 2 and 3 and then the drug cycle and monitored. Prednisone was administered was repeated.
daily for 2 weeks, then tapered.
8. Chlorambucil was used as a single agent; 4. Vinblastine/lomustine protocol administered administration was repeated once or twice a vinblastine during week 1, required CBC only week, and this once or twice weekly admin- for week 2, lomustine was administered for istration was repeated every 3–6 weeks.
week 3, and the CBC was taken only for week 9. Lomustine was used as a single agent; admin- 4. This protocol was continued for 4 cycles with istration was repeated every 3–6 weeks.
the CBC being monitored weekly as well as 10. Doxorubicin was used as a single agent; ad- chemistry for lomustine treatments. Prednisone ministration was repeated every 3–6 weeks was given daily for 2 weeks, then tapered.
for a maximum of 5 doses or 180–240 mg/m2 5. Intralesional chemotherapy with the single agent 5-FU or bleomycin was administered weekly.
2. OSA Chemotherapy Protocols
4. HSA Chemotherapy Protocol
1. Carboplatine was used as a single agent protocol every 3 weeks for 4–6 treatments.
1. Doxorubicin/metronomic protocol required 2. Doxorubicin was used as a single agent every doxorubicin every 2 weeks × 5 treatments 2–3 weeks for 4–6 treatments.
along with metronomic chemotherapy (piroxi- 3. Doxorubicin/carboplatine or cisplatin pro- cam, cytoxan, doxycycline) daily to every tocols were administered for 3 cycles, with the CBC taken and doxorubicin administered 2. Maintenance chemotherapy protocol required in week 1, only CBC taken in week 2, CBC vincristine every 2–3 weeks along with metro- taken and carboplatine administered during nomic chemotherapy daily to every other day.
week 3, only CBC is taken during weeks 4 and 5, and both CBC taken and doxorubicin administered during week 6. This cycle was 5. Immune-Enhancement Supplements
repeated for a total of 3 doxorubicin treatments Used in Conjunction.with Chemotherapy
and 3 carboplatine treatments.
4. Intralesional chemotherapy was administered K9 ImmunityTM is an orally administered medicine every other week, with cisplatin, until a pain (class "Dietary Supplement" in the United States) response was noted.
intended for daily use in adult dogs undergoing conventional therapy. It assists in optimizing immune-system function and consists of a hetero- 3. MCT Chemotherapy Protocols
geneous mixture of multiple heteropolysaccharide moieties derived from six species of medicinal 1. Chlorambucil was used as a single agent daily mushrooms (Agaricus brasiliensis (= A. blazei or weekly for 4–6 months. CBC must be done ss. Heinem.), hybrid Cordyceps sinensis, Lentinus very 2–3 weeks. Prednisone was administered edodes, Grifola frondosa, Ganoderma lucidum, daily for 2 weeks, then tapered.
and Trametes versicolor). It is supplied in red- and International Journal of Medicinal Mushrooms Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 188.8.131.52 by Dr. john holliday (alohamed) EVALUATION OF IMMUNE SUPPLEMENTATION IN DOGS UNDERGOING CHEMOTHERAPY white-colored capsules containing 500 mg active Samples were taken aseptically from the jugular vein ingredients each.
when possible via sterile procedure with needle and K9 Transfer Factor™ is a specially formulated syringe. Urine for UA was normally obtained via canine supplement containing several types of free catch, unless there was an indication for cysto- antibodies, proline-rich polypeptides (aka Transfer centesis (i.e., possibility of urinary tract infection), Factors), and other immunoproteins for use adjunc- which then was performed by sterile procedure with tively with K-9 Immunity™. These immune protein needle and syringe. Cytol ogies, chemistries, and UA molecules enhance the absorption and bioavailabil- were performed both in house for speed of diagnosis, ity of the polysaccharide immune modulators in with confi rmation at Antech Labs. Cytology samples K-9 Immunity™ by bonding to the polysaccharides were obtained by fi ne needle aspirate using a ster- and acting as a bridge between the immune-cell ile procedure. Biopsy samples were interpreted at surface receptors and the polysaccharides. Both Antech Labs, as well as at the Colorado State Uni- K-9 Immunity™ and K-9 Transfer Factor™ are versity School of Veterinary Medicine laboratories, manufactured by Aloha Medicinals Inc. of Carson Colorado State University (USA). Most samples City, NV (USA), and were obtained directly from were obtained by the referring veterinarian prior to the manufacturer for this trial.
the subject's initial visit to VCCC. Those requir-ing biopsy or surgery were referred to Veterinary Surgical Specialists of New Mexico. Ultrasound, 6. Supplement Dosage Adjuncts
when required, was performed at VCCC and also at Veterinary Surgical Specialists of New Mexico, 4000 Montgomery Blvd., NE Albuquerque, NM Standard canine chemotherapy protocols were 87109 (VSS). All radiographs were obtained either used according to cancer type, along with daily at the referring veterinarian or at VSS. Where ap- supplementation with the veterinary supplements. plicable, measurements of tumors were taken with Each dog received a dose of one 500 mg capsule standard metric caliper. Other testing and laboratory of K9 Immunity™ per 4.5 kg body weight per procedures performed were at the discretion of the day. Each capsule contains 500 mg of a formula attending veterinarian and in keeping with the best comprising over 200 different structural types of and most humane treatment for the patient. All test- immune-modulators of the complex polysaccharide ing was performed per standard protocol.
class, enzymatically derived from six species of medicinal mushroom. To ensure proper uptake and bioavailability of the K-9 Immunity™ supplement, III. RESULTS
all dogs also received K9 Transfer Factor™ daily, at a dose of one 3000 mg wafer per day for dogs A. Incidence of Neutropenia for All
greater than 11 kg and 1/ 2 wafer per day for dogs Tumor Types
11 kg and under. Each K9 Transfer Factor™ wafer contains 3000 mg of the immune proteins IgA, IgG, The severity of neutropenia is divided into four and IgY, along with proline-rich polypeptides, also grades according to neutrophil count as determined known as Transfer Factors. These immunoproteins by the Veterinary Co-Operative Oncology Group are derived from bovine colostrums, bovine serum, and avian sources (chicken egg yolk).
Grade I - Neutrophil count of 1500–2500/µL. This is fairly common in patients undergoing 7. Laboratory and Chemistry Panels
chemotherapy. These patients should be closely monitored, with delayed treatment until cells reach All lab work was preformed either in house at normal levels (above 3000/µL).
VCCC, at the referring veterinarians' offi ces, or at Grade II - Neutrophil count of 1000–1500/µL. Antech Diagnostic Laboratories, Phoenix, AZ (USA). Broad-spectrum antibiotics should be adminis- Volume 11, Issue 2, 2009 Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 184.108.40.206 by Dr. john holliday (alohamed) J. C. HOLLIDAY ET AL.
tered and regular blood counts taken to monitor one (5.26%) showed any symptoms. Another one the bone marrow.
(5.26%) of the nineteen dogs developed Grade Grade III - Neutrophil count of 500–1000/µL.
II neutropenia but didn't show symptoms, none of the dogs developed Grade III neutropenia and Grade IV - Neutrophil count of 1–500/µL.
one (5.26%) dog developed Grade IV neutropenia Grades III and IV require immediate action because and showed symptoms. Both subjects who became there is a very high risk for infection.
symptomatic each had to postpone one chemo-therapy treatment.
B. Neutropenia in LSA Patients
E. Neutropenia in HSA Patients
Of the twenty-one dogs diagnosed with LSA, eleven (52.38%) developed Grade I neutropenia, but only Of the four dogs diagnosed with HSA, none were one (4.76%) was symptomatic. Four (19.04%) of neutropenic; however, two (50%) became ill with these 21 subjects developed Grade II neutropenia, either vomiting or diarrhea but missed no chemo- but only two (9.52%) were symptomatic. One therapy treatments. Both of these symptomatic dogs (4.76%) dog developed Grade III neutropenia and was symptomatic, whereas two (9.52%) dogs developed Grade IV neutropenia, but only one (4.76%) of them became symptomatic. According F. Summary of Appetite and
to the VCOG neutropenia scores, four (19.04%) of Attitude for All Tumor
the twenty-one dogs attained both Grade I and II neutropenia over the course of the study, whereas one (4.76%) of the twenty-one dogs attained both Appetite and attitude were based on a median aver- Grades I and IV neutropenia. Five subjects had to age of Grades 1–5, with 1 being anorexic with no postpone 1 treatment, two subjects had to postpone 2 appetite and having little or no interest in activity treatments, one subject had to postpone 3 treatments, and 5 having normal or better appetite and or ac- and one subject had to postpone 4 treatments.
tivity, as indicated by the pet owner on a monthly calendar provided by VCCC. These numbers were C. Neutropenia in OSA Patients
then assigned based on the subject having a consistent score for 3 consecutive days.
Of the twenty dogs diagnosed with OSA, four (20%) developed Grade I neutropenia, none of which showed any symptoms. Three (15%) dogs developed Grade II neutropenia, and no dogs de-veloped Grades III or IV neutropenia. None of the Of the twenty-one dogs diagnosed with LSA, none neutropenic dogs with OSA showed any symptoms were recorded as having the anorexic Grade 1 of their condition. However, one non-neutropenic appetite or attitude. Three (14.28%) dogs were subject became symptomatic and had to postpone recorded as having Grade 2 appetite, but none one chemotherapy treatment. In addition, one sub- of the dogs were recorded as having Grade 2 ject was categorized as having both Grades I and attitude. Four (19.04%) dogs were recorded as II neutropenia over the course of the study.
having Grade 3 appetite, and 5 (23.80%) dogs were recorded as having a Grade 3 attitude. One (4.76%) dog was logged as having a Grade 4 D. Neutropenia in MCT Patients
appetite, and fi ve (23.8%) dogs were logged as having a Grade 4 attitude. Eleven (52.38%) dogs Of the nineteen dogs diagnosed with MCT, two maintained a Grade 5 appetite, and nine dogs (10.53%) developed Grade I neutropenia, but only (42%) maintained a Grade 5 attitude. There were International Journal of Medicinal Mushrooms Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 220.127.116.11 by Dr. john holliday (alohamed) EVALUATION OF IMMUNE SUPPLEMENTATION IN DOGS UNDERGOING CHEMOTHERAPY 2 subjects whose data was unknown because their attitude, and two (50%) of these dogs maintained calendars were not received.
a Grade 5 attitude.
G. Symptomatic Gastrointestinal
Of the twenty dogs diagnosed with OSA, none of them were recorded as having a Grade 1 or 2 ap- Each value was assigned based on client observation petite, whereas two (10%) of them were recorded of the subject in their home environment and in as having a median Grade 3 appetite, 6 (30%) correspondence to the VCOG scoring for GI values. were recorded as having an almost normal Grade 4 A grade of I was given to any subject who vomited appetite, and ten (50%) dogs were recorded as or had diarrhea, or both, for 3 consecutive days. A having normal or better Grade 5 appetite. One grade of II was given to any subject who exhibited (5%) of the twenty dogs was recorded as having these side effects for 3 days or more but less than a Grade 1 attitude, 4 (20%) were recorded as hav- 5 days. There were no grades higher than II.
ing a Grade 2 attitude, four (20%) were recorded as having a Grade 3 attitude, six (30%) were recorded as having a Grade 4 attitude, and three (15%) were recorded as having a Grade 5 attitude. There were two subjects whose appetite and at- Of the twenty-one dogs diagnosed with LSA, sixteen titude data was unknown because their calendars (76.2%) dogs did not show any symptoms of GI were not received.
toxicity, fi ve (23.8%) attained Grade 1 GI toxicity, and none attained Grade 2. One of the dogs that attained Grade 1 toxicity ate a large amount of green chili peppers and was sick for 3 days. This toxicity may or may not have been related to the Of the nineteen dogs diagnosed with MCTs, none were recorded as having a Grade 1 or 2 appetite or attitude. There was one (5.26%) dog that was recorded as having a Grade 3 appetite and two (10.52%) dogs were recorded as having a Grade 3 Of the twenty dogs diagnosed with OSA, seventeen attitude. There was one dog (5.26%) that was logged (85%) did not show any GI toxicity at all, whereas as having a Grade 4 appetite, and fi ve (26%) dogs three (15%) of them attained Grade 1 GI toxicity. that were logged as having a Grade 4 attitude. None of the dogs attained Grade 2.
There were fourteen (73%) dogs that maintained a Grade 5 appetite, and nine dogs (47.36%) that maintained a Grade 5 attitude. There were three subjects whose data was unknown because their calendars were not returned.
Of the nineteen dogs diagnosed with MCT, fourteen (73.7%) did not show any GI toxicity at all, four (21.05%) of them attained Grade 1 GI toxicity, and only one dog (5.26%) attained Grade 2 toxicity.
Of the four dogs diagnosed with HSA, one (25%) of the dogs was recorded as having a median Grade 3 appetite, and three (75%) maintained nor-mal or better Grade 5 appetite habits. Two (50%) Of the four dogs diagnosed with HSA, two (50%) of these dogs were recorded as having a Grade 4 did not show any GI toxicity at all, whereas two Volume 11, Issue 2, 2009 Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 18.104.22.168 by Dr. john holliday (alohamed) J. C. HOLLIDAY ET AL.
(50%) attained Grade 1 GI toxicity. None of them type stayed in the study anywhere from 2 to 12 attained Grade 2 GI toxicity.
months before the dog either died or the study was completed. It is noteworthy to mention that most subjects in this study, when fi rst presented, H. Summary of Survival Status for Each
already had advanced disease; one subject had Tumor Type as of June 1, 2008
pulmonary carcinoma, one subject had T-cell LSA, two subjects had hypercalcemia, and two subjects Status of the disease was evaluated and recorded had T-cell LSA + hypercalcemia.
by the attending veterinarian at each visit based on physical exam and/or lab fi ndings. Some of these subjects did not undergo chemotherapy treatments. Surgery, amputation, and IL treatment modalities were also used. These factors may have had an infl u- Four (20%) of the twenty dogs diagnosed with OSA ence on disease status. For survival and remission had NED at end of trial, four (20%) had PD, two status, it is important to note that any individual (10%) had SD, nine (45%) dogs with this cancer dogs may have been classifi ed as belonging to one type died over the course of the trial, and one (5%) or more of these status categories throughout the was lost to follow-up. The dogs with this cancer study. NED means No Evidence of Disease, which type stayed in the study from 1 to 11 months before includes complete remission (100% resolution of the dog either died or the study was completed.
gross disease) and partial remissions (greater than or equal to 50% reduction of gross disease). SD means Stable Disease (tumor stable or growth less than 20% after the start of therapy). PD means Progressive Disease (tumor increase of greater than Thirteen (68.42%) of the nineteen dogs diagnosed 20% after start of therapy). Deceased means death with MCT had NED at end of trial, three (15.80%) via euthanasia (by euthasol dose 1 mL per 10 kg of the nineteen had PD, all of which died before the body weight) or home death. NT means that a New completion of the trial. One (5.26%) of the nineteen Tumor type appeared. LTFU means that the dog was had an NT develop, one (5.26%) of the nineteen Lost To Follow Up visits. In more than one case, had SD, and one (5.26%) of the nineteen was lost the client chose early euthanasia over prolonged to follow-up. Of the four dogs (21.05%) diagnosed treatment if a subject came out of remission.
with MCT that died by the end of this study, three were classifi ed as having PD, and because of the aggressive cancer type, would normally have a low life expectancy. All dogs with this cancer type stayed in the study from 1 to 9 months before the At the end of the year-long study, eight (38.09%) dog either died or the study was completed.
of the twenty-one dogs diagnosed with LSA showed no evidence of disease and were classifi ed as experiencing complete remission, fi ve (23.8%) of the twenty-one dogs experienced partial remis-sions for different periods of time on an individual One (25%) of the four dogs diagnosed with HSA basis, one (4.76%) of these dogs developed a new showed NED at the end of the study, one of the tumor type, fourteen (66.66%) were classifi ed as four (25%) had PD, and two (50%) of the dogs were having stable disease, twelve (57.14%) of the dogs deceased. The dogs with this cancer type stayed in were classifi ed as having progressive disease, ten the study from 2 to 9 months before the dog either (47.62%) dogs in total with this cancer type died died or the study was completed. One of the HSA during the course of the study, and two (9.52%) patients died acutely at home with no evidence of were lost to follow-up. The dogs with this cancer International Journal of Medicinal Mushrooms Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 22.214.171.124 by Dr. john holliday (alohamed) EVALUATION OF IMMUNE SUPPLEMENTATION IN DOGS UNDERGOING CHEMOTHERAPY and proteoglycan components of K-9 ImmunityTM and K-9 Transfer FactorTM appear to be activation Studies to determine the effi cacy of dietary supple- and enhancement of various aspects of innate and ments such as K-9 Immunity™ in the treatment specifi c immune response (host-mediated immune of canine cancer are few. Many of these trials are response). The number and activity of T lympho- simple studies with many variables. Because the cytes (T cells), B lymphocytes (B cells), macro- average owners of cancer pets may already be phages, and antigen-presenting cells (APC) were instituting multiple supplement therapies on their stimulated and/or modulated. The exact mechanism own, it is diffi cult to get precise information and of action for these products is only partially under- dosing procedures. The nature of the cancer process stood, but it is thought to be mainly accomplished itself does not lend itself to ease of study because by binding beta-glucans, proteoglycans, and other protocols are constantly changing, depending on the heteropolysaccharides to specifi c cellular receptors patient's disease and remission status, among other on the surface of the various classes of immune variables. Economics must also be considered be- cells, probably the CR3, Dectin-1, LacCer, TLR, cause some cancer treatments are quite costly. This and scavenger receptors.25 study was directed toward issues with neutropenia As seen in Table 1 and Figure 1, it appears and the resulting side effects, but it became appar- that the study subjects suffered fewer symptomatic ent during this trial that cancer treatment and its episodes in conjunction with their neutropenia than side effects are multifactoral, and other indicators could be expected based upon previous experience need to be looked at as well. The statistical analysis with similar patients. The number of patients who needs to be evaluated, as well as a follow-up of became neutropenic yet who were free of symptoms patients and a confi rmation of data comparisons to seemed (in the experience of these authors) to be historical or other controls.
better than historical averages, although defi nitive An easy and relatively inexpensive method historical data on neutropenia and its associated of tracking the immune response to cancer treat- side effects could not be found in a search of the ment involves evaluation of the neutrophils in the scientifi c literature. Of the sixty-four dogs involved bloodstream. Immunomodulators are used to boost with this study, 56% showed no neutropenia, while the nonspecifi c immune components of the white only 44% acquired some grade of neutropenia. Of blood cell line.25 The neutrophil component of the those that became neutropenic, only about 10% complete blood count is associated with the short- showed symptoms. This is less than 5% of the total term response of the immune system to an insult, subject becoming symptomatic. Only one of the such as chemotherapy. In tracking the response of study patients who was non-neutropenic became the neutrophil line, this study noted that the K-9 symptomatic. In addition, it is noteworthy that of Immunity™ supplement did defend the patient the LSA patients, one subject had pulmonary car- from the onslaught of opportunistic infections cinoma, one subject had T-cell LSA, two subjects when affected by neutropenia, and that the qual- had hypercalcemia, and two subjects had T-cell LSA ity of life the patient had previously experienced + hypercalcemia. Having these additional factors was maintained, in most cases. The main actions added to the diagnosis indicates that the disease has exhibited by the mushroom-derived polysaccharide progressed to a higher stage of illness. Hypercalce- TABLE 1
Neutropenia and Symptomatic Episodes for All
Grade I Grade II Grade III Grade IV
Neutropenia 26.56% 12.55% 1.56% 4.68%Symptomatic 3.12% 3.12% 1.56% 3.12% Volume 11, Issue 2, 2009 Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 126.96.36.199 by Dr. john holliday (alohamed) J. C. HOLLIDAY ET AL.
Grade I Grade II Grade III Grade IV
FIGURE 1. Number of dogs involved with this study that attained any grade of neutropenia and associated symptoms.
mia is not only a cause of morbidity on its own, but addition, totaling the successive results in Table 4 is usually associated with T-cell lymphoma, which shows that 76.56% of all dogs in the study had no historically has a shorter survival time than B-cell gastrointestinal toxicity whatsoever. This supports lymphoma. T-cell lymphoma affects the immune the fi nding that most dogs were able to continue system directly and so may initiate both a higher normal routines with little or no problem.
incidence of neutropenia and other symptoms. In ad- The overall median survival for all subjects on dition, there were a few subjects who were classifi ed trial appeared to be improved from historic aver- as having more then one grade of neutropenia over ages, although this information is hard to tabulate the course of the study. Symptomatic response was on such a short open-label trial. The indications of based on episodes of vomiting and/or diarrhea, as Table 5 show that at least 50% of the total number well as overall activity level as reported by owners of dogs taking K-9 ImmunityTM and K-9 Transfer on the monthly calendar. An overall average was FactorTM adjunctively with chemotherapy in all taken, based on the subject being symptomatic for cancer types reviewed were still living at the close 3 consecutive days or more. One subject became of our year-long study. It is important to note that symptomatic, even though neutrophil counts re- for Figure 5, any individual dog may have been mained in the normal range.
classifi ed as belonging to one or more of these status Appetite and attitude were both based on a categories throughout the study. It can be clearly median average of Grades 1–5, with 1 being poor seen from these fi ndings that K-9 Immunity™ does (little or no appetite/activity on the subject's part), indeed improve the patient's quality of life when and 5 being normal or great, with the subject acting used adjunctively with chemotherapy, at least in the happy and exhibiting a normal routine. These values types of cancers evaluated in this study. For canine were assessed by pet owners daily and reported cancer families, this quality-of-life consideration is to the clinic at each visit. An overall average was an important part of the decision-making process taken, and a grade of 1–5 was given to each dog when considering treatment for their pets.
based on an appetite and attitude score recorded consistently for 3 consecutive days. Study fi ndings seen in Tables 2–4 and Figures 2–4 reveal the V. FUTURE STUDIES
general trend that appetite and attitude remained above average with low percentages of GI toxicity The results of this study indicate that further re- for all cancer types. Of the sixty-four total dogs search into nonspecifi c immune-modulation therapy in the study, 60.94% of them maintained a nor- as an adjunct to chemotherapy is warranted, with mal or better Grade 5 appetite, whereas 35.94% the goal of improving the quality of care and qual- maintained a normal or better Grade 5 attitude. In ity of life that we can deliver to our canine cancer International Journal of Medicinal Mushrooms Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 188.8.131.52 by Dr. john holliday (alohamed) EVALUATION OF IMMUNE SUPPLEMENTATION IN DOGS UNDERGOING CHEMOTHERAPY Grade 1 (worst) Grade 2 Grade 3 Grade 4 Grade 5 (best)
Note: LSA = lymphosarcoma; OSA = osteosarcoma; MCT = mast cell tumor; HSA = hemangiosarcoma.
Grade 1 (worst) Grade 2 Grade 3 Grade 4 Grade 5 (best)
Note: LSA = lymphosarcoma; OSA = osteosarcoma; MCT = mast cell tumor; HSA = hemangiosarcoma.
Percentage of Dogs Showing No GI Toxicity
1 76.20% 85% 78.95% 50% 2 100% 100% 94.74% 100% Note: LSA = lymphosarcoma; OSA = osteosarcoma; MCT = mast cell tumor; HSA = hemangiosarcoma.
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
FIGURE 2. Appetites of all the dogs in the study by tumor type and grade. Grade 1 = no appetite; Grade 5 = normal
or better appetite.
Volume 11, Issue 2, 2009 Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 184.108.40.206 by Dr. john holliday (alohamed) J. C. HOLLIDAY ET AL.
FIGURE 3. Grades of attitude for all tumor types for dogs in this study.
patients. There are many avenues to be explored in the study of immune modulators in cancer therapy in dogs. This particular study, in revealing This project was funded in part by Aloha Medicinals the fact that neutropenia is not entirely controlled Inc., in cooperation with the staff of Veterinary by immune supplementation, begs the question of Cancer Care Center in Santa Fe, NM. Special thanks how long those neutropenic periods were, or if to Aloha Medicinals Inc,, who provided K-9 Immu- the neutropenic episodes were any shorter due to nity™ and K-9 Transfer Factor™ to subjects at no the concurrent supplementation. Diets must also cost to their owners. They have been kind enough to be explored in conjunction with supplements. continue the supply of these supplements for these Chemistry values can be further explored as well cancer dogs at no cost through out the lifespan of as other blood parameters such as effect on neu- the dogs, not just for the duration of the trial.
trophil functions. This preclinical trial evaluation shows the great promise held by combining some alternative medicine techniques with conventional FULL DISCLOSURE OF FINANCIAL
medicine protocols. Further double-blind, placebo- TIES OF AUTHORS
controlled trials are planned in conjunction with a major veterinary university to further explore the J. Holliday and B. Gianotti are employed by Aloha potential of this method of treatment.
Medicinals Inc., which manufactures the products FIGURE 4. Percentage of dogs per tumor type without gastrointestinal side effects.
International Journal of Medicinal Mushrooms Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 220.127.116.11 by Dr. john holliday (alohamed) EVALUATION OF IMMUNE SUPPLEMENTATION IN DOGS UNDERGOING CHEMOTHERAPY TABLE 5
Status of Disease per Tumor Type as of June 1, 2008
MCT 68.42% 5.26% 15.80% 21.05% 5.26% 5.26%HSA 0% 0% 25% 20% 10% 20% 45% 0% 5% LSA 38.90% 66.66% 57.14% 47.62% 4.76% 9.52% Note: NED = no evidence of disease; SD = stable disease; PD = pro- gressive disease; NT = new tumor type; LTFU = lost to follow-up; MCT = mast cell tumor; HSA = hemangiosarcoma; OSA = osteosarcoma; LSA = lymphosarcoma.
FIGURE 5. Disease status per tumor type at one year. NED = no evidence of disease; SD = stable disease; PD =
progressive disease; DEAD = euthanasia or home death; NT = new tumor; LTFU = lost to follow-up.
used in this preclinical evaluation. M. Cleaver has Medicinals, Inc., 2300 Arrowhead, Dr. Carson City, NV worked as a consultant for Aloha Medicinals Inc. 89706. [Updated daily; cited 2008 Sep 15]. Available at various times. M. Mullins and S. West have no fi nancial ties with Aloha Medicinals Inc. or any 3. Chang S-T, Miles Ph G. Mushrooms: cultivation, nutri- tional value, medicinal effect, and environmental impact. other companies making similar or competing 2nd ed. Canada: Publishers Group West; 2004.
products. None of the authors was remunerated for 4. Wasser SP. Medicinal mushrooms as a source of anti- conducting this study, other than the normal fees tumor and immunomodulating polysaccharides. Appl charged by the Veterinary Cancer Care Clinic in Microbiol Biotechnol. 2002;60(3):258–74.
the administration of the treatments.
5. Hellstrom K, Hellstrom I. Therapeutic vaccination with tumor cells that engage CD137. J Mol Med. 2003;81(2):71–86.
6. Hsiao YW, Liao KW, Chung TF, Liu CH, Hsu CD, Chu RM. Interactions of host IL-6 and IFN-gamma and cancer-derived TGF-beta1 on MHC molecule expression 1. Smith JE, Rowan NJ, Sullivan R. Medicinal mushrooms: during tumor spontaneous regression. Cancer Immunol their therapeutic properties and current medical usage with special emphasis on cancer treatments. University 7. Nepom GT, Hellström I, Hellström KE. Suppressor of Strathclyde (UK): Cancer Research; 2002.
mechanisms in tumor immunity. Cell Mol Life Sci 2. Aloha Medicinals Inc. Information for consumers on K-9 Immunity™ [Internet]. Corporate Head- 8. Rusk A. (compiler). Cancer: cases likely will rise in quarters/Research and Manufacturing Facility Aloha aging animals. DVM Newsmagazine. 2005. Available Volume 11, Issue 2, 2009 Begell House Inc., http://begellhouse.com Downloaded 2009-6-18 from IP 18.104.22.168 by Dr. john holliday (alohamed) J. C. HOLLIDAY ET AL.
CDDP/Lentinan combination therapy. Gan To Kagaku Ryoho. 2008;35(6):995–7 (in Japanese).
9. American Veterinary Medical Association. What you 17. Chen T, Li D, Fu YL, Hu W. Screening of QHF formula should know about cancer in animals. [Internet]. for effective ingredients from Chinese herbs and its anti-hepatic cell cancer effect in combination with che- brochures /cancer /cancer_brochure.asp.
motherapy. Chin Med J (Engl). 2008;121(4):363–8.
10. Argyle DJ. Prostate cancer in dogs and men: a 18. Ruwei W, Yiyuan X, Peijun J, Xingli W, Holliday J. unique opportunity to study the disease. Vet J. Immune-Assist™ brand dietary supplement as an adjunct 2008. Available from: http://www.sciencedirect.com/ for chemo- and radiation therapy in cancer treatment. [Clinical trial report available on the Internet.] [Updated 2001 May; cited 2008 Nov 12]. Available from: http:// 19. Messonnier S, Blaylock R. The natural vet's guide to preventing and treating cancer in dogs. Canada: Publish- 11. Maggie M (compiler). Purdue research fi nds similarities ers Group West, 2006.
in dog. Human breast cancer pre-malignant lesions 20. Richards M. Encyclopedia of canine veterinary medical [internet]. Purdue University School of Veterinary information. [Internet.] Available from: Vetinfo.com Medicine. [Updated 2007 Nov 15; cited 2008 Nov Tiercom1996–2008. [Updated 2008 Jan 1; cited 2008 17]. Available from http://www.purdue.edu/UNS/ Sep 15, 2008]. Available from: http://www.vetinfo.com/ 12. Kuo YC, Tsai WJ, Shiao MS, Chen CF, Lin CY. 21. Veterinary Cancer Care Quarterly Newsletter. Neutro- Cordyceps sinensis as an immunomodulatory agent. penia. Veterinary Cancer Care Clinic of Santa Fe, NM. J Natl Res Inst Chin Med. 1996;24(2):111–25.
Spring 2007 issue. p. 4–5.
13. Holliday JC, Cleaver M, Wasser SP. Cordyceps. In: 22. Washington State University College of Veterinary Coates PM, Blackman MR, Cragg GM, Levine M, Moss Medicine. An overview of cancer. [Internet.] Washington J, White JB, editors. Encyclopedia of dietary supple- State University, Pullman, WA, USA. [Updated 2008 ments. New York: Marcel Dekker; 2005. p. 1–13.
Jun 20; cited 2008 Sept 15]. Available from: http://www.
14. Chen GZ, Chen GL, Sun T, Hsieh GC, Henshall JM. Effects of Cordyceps sinensis on murine T lymphocyte 23. World Health Organization. Cancer [Internet]. WHO subsets. Chin Med J (Engl). 1991;104(1):4–8.
website 2008. [Cited 2008 Nov 12]. Available from: 15. Wynn S, Fougere B. Veterinary herbal medicine. Amsterdam, The Netherlands: Elsevier; 2007. 298 p.
24. Vail D. Veterinary Cooperative Oncology Group 16. Matsusaki K, Hirose N, Yamada T, Morita M, Okamoto (VCOG) Consensus Document. Wiley InterScience F, Kawano T, Miura O, Okazaki Y, Toda T, Minamisono Publishing [Internet]. [Updated 2004 Dec 2; cited 2008 Y, Nagasaki S. Case of gastric cancer with recurrence Sep 15]; 2(4):194.
of carcinomatous lymphangiosis of the lung 7.6 years 25. Chen J, Seviour R. Medicinal importance of fungal after surgery and successfully treated with S-1/low-dose β-(1→3), (1→6)-glucans. Mycol Res. 2007;111(6):635–52.
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Achieving effective outcomes in patients with overgranulation Jackie Stephen-Haynes RGN DN DipH BSc (Hons) ANP. PG DipR PGDip Ed, Masters in Clinical Nursing Consultant Nurse and Senior Lecturer in Tissue Viability for Worcestershire Primary Care Trusts and University of Worcester. Stourport Health centre, Worcester St, Stouport on Severn, Worcestershire.DY13 8EH
Analysis and comment An iatrogenic pandemic of panicLuc Bonneux, Wim Van Damme Nine decades after the disappearance of the infamous sive food poisoning such as the dioxin crisis. Airborne Spanish flu, its ghost is threatening again. In many transmission of the extremely lethal Ebola Zaire virus countries, panicking citizens are buying drugs from might cause a devastating epidemic and is popular in