wnwbanner.jpg (27305 bytes)

Home

What's New

About Wing-N-Wave

Purchasing a Labrador

Canine Health & Genetics

Just for Fun!

Canine Legislature

Pamela A. Davol, 76 Mildred Avenue, Swansea, MA  02777-1620.
pdavol@labbies.com


Cancer In The Canine

Part 3: Treating Cancer in the Canine

 

Principles of Cancer Treatment

    The goal of cancer treatment is to produce cure by removing the cause of the disease while producing as little harm to the patient as possible. Given that cancer cells originate from cells of the patient, the dilemma of cancer therapy lies in selectively targeting and destroying only the cancer cells and leaving the normal cells unharmed. For this reason, most conventional cancer treatments (radiation and many chemotherapeutic drugs) take advantage of the fact that malignant tumors, unlike normal tissues of the body in which the cells are most often in a resting state, have a higher fraction of cells undergoing growth. Therefore, radiation and conventional anticancer drugs work by interfering with DNA synthesis or function of dividing cancer cells and usually do not kill normal, resting cells unless they divide shortly after exposure to treatment. Because even normal cells (particularly those composing the bone marrow and the gastrointestinal lining) undergo regular division for replacement of old cells, in many cases, cancer therapies provide only a narrow window for safety and efficacy, and mild treatment toxicities often occur. For this reason, new areas of cancer research have explored more specific methods of targeting only cancer cells. Such methods include development of new classes of drugs that are directed to unique sites on cancer cells, as well as techniques that specifically tag only cancer cells for destruction

    One of the major limitations to cancer therapies occurs as a result of the diversity (heterogeneity) of the cancer cells even within a single tumor. As tumors become larger, many cancer cells will become distant from the blood supply, which may cause them to divide less frequently than others in the population. Additionally, as more cancer cells develop there is an increase in genetic mutations with each generation that in some cases allows these cells to escape the toxicity of treatment. These conditions lead to treatment-resistant cancer cells that often survive even when the bulk of the disease may be eradicated and the patient appears to be in remission. Resistant cancer cells are the cause for disease recurrence.

    Treatment-resistant cancer cells are the primary reason for treatment failure. In most cases, because of the diversity of the cancer cells composing a tumor and the possibility of toxic side-effects if treatment dosage is increased, treatment with a single type of therapy or drug is unsuccessful to produce remission or cure. Therefore, clinical oncologists often resort to combination therapeutic regimens that target different mechanisms of cancer cell development to provide the maximal cell killing without increasing toxic side-effects to the patient. These combination regimens have the advantage of targeting a broader range of cancer cells within the tumor population while preventing or slowing the development of new resistant cells.

 

To Treat or Not to Treat?

    In order to make an educated decision on whether or not to treat a dog for cancer, an owner will need to seek a specialist in the field who will be able to address specific questions. Obtaining a second and in some cases a third opinion is also highly recommended. Though some owners may feel ethically and emotionally obligated to treat their dogs for cancer, in some cases, underlying health of the dog may contraindicate treatment. For example, because cancer occurs most frequently in older dogs which are more susceptible to toxicities and other side-effects of treatment, treatment may further compromise health and quality of life while providing little if any benefit in regard to control of the cancer. For this reason and others, it is vital that the owner establishes a comfortable and confident relationship with the veterinarian oncologist who will, ideally, provide them not only with information but also compassionate guidance required to make the necessary decisions.

Some general questions that the owner should consider:

 

Approaches to Cancer Treatment in the Dog

Surgery

    Surgery is the oldest and therefore, at one time was the only form of treatment for cancer. In cases where solid tumors are localized to a particular organ or site, surgery may be curative. The observation, however, that approximately 70% of patients presenting with cancer already have distant micrometastases at the time of diagnosis is the primary reason why surgery alone is rarely effective at providing a cure for cancer. Nonetheless, surgery may provide a preventative approach to some forms of cancer as well as play a vital role for:

1) improving cure rates when combined with other forms of treatment such as radiation and/or chemotherapy,

2) reducing tumor burden for the purpose of relieving pain and removing obstructions that may interfere with normal organ functions,

3) removing secondary tumors arising from metastases, and

4) improving function and cosmetic appearance following treatment.

 

Surgery and Cancer Prevention

    Certain conditions and factors have been found to increase risk of cancer in dogs. Examples of such include unilateral or bilateral cryptorchidism (retention of one or both testicles in the abdominal cavity) which increases risk of testicular cancer in male dogs and benign mammary tumors which increase risk for mammary cancer in female dogs. As such, cancer prevention in the form of castration (neutering) and ovariohysterectomy (spaying), respectively, remove the non-vital organs associated with these forms of cancer thereby preventing subsequent malignancy.

 

Surgery and Cancer Treatment

    The goal of surgery is to completely remove the solid tumor. Though the early consensus regarding surgery for the treatment of cancer recommended aggressive, radical approaches for removing tumors as well as regional lymph nodes and underlying tissues, clinical studies have not demonstrated any therapeutic advantage to this approach. Instead, dependent upon the tumor type, oncologists may combine a regimen of surgery with radiation and/or chemotherapy to target residual disease left by the primary treatment.

Cancers for Which Surgery is Indicated as a Treatment

Mammary Tumors (exception: inflammatory mammary cancer)

Prostate Tumors

Oropharyngeal Tumors

Skin Cancers

Gastrointestinal Tumors

Lung Tumors

Bone Tumors

Complications to Surgery

    Risks associated with surgery increase with the age of the dog and are often associated with the underlying health. Mortalities resulting from surgery are most often associated with pulmonary blood clots (embolism), pneumonia, cardiovascular collapse, and primary disease. Furthermore, in addition to its secondary effects on patient metabolism and immunity, cancer often causes a state of malnutrition in the dog which may further compromise the ability of the dog to recover from the trauma of surgery.

    Other complications associated with surgery include abscess, wound infection, blood loss, and incomplete wound healing.

 

Surgical Applications in the Clinical Treatment of Canine Cancer (use the "Back" command of your internet browser to return to this page after viewing the abstracts of these following journal articles)

Primary gingival malignant melanoma. Report of 3 cases.
Ardekian L, Rosen DJ, Peled M, Rachmiel A, Machtei EE, el Naaj IA, Laufer D.J

Preliminary clinical results of window partial laryngectomy: a combined endoscopic and open technique.
Rebeiz EE, Wang Z, Annino DJ, McGilligan JA, Shapshay SM.

A modified bilateral transfrontal sinus approach to the canine frontal lobe and olfactory bulb: surgical technique and five cases.
Glass EN, Kapatkin A, Vite C, Steinberg SA.

Autogenous onlay grafting for enhancement of extracortical tissue formation over porous-coated segmental replacement prostheses.
Virolainen P, Inoue N, Nagao M, Ohnishi I, Frassica F, Chao EY.

Neurophysiological basis of sympathetic nerve-preserving surgery for lower rectal cancer--a canine model.
Liang JT, Chien CT, Chang KJ, Hsu HC, Chu SH, Lai MK, Wang SM, Chen KM.

Amputation and dexniguldipine as treatment for canine appendicular osteosarcoma.
Hahn KA, Legendre AM, Schuller HM.

Surgical approach for lymph node staging of oral and maxillofacial neoplasms in dogs.
Smith MM.


***For a more complete listing, enter the following format of search terms in the PubMed search window:  canine AND surgery AND cancer

Radiation

    The principles of radiation therapy are the same as surgery: to cure the dog of cancer or to relieve the bulk of cancer in dogs with advanced disease while sparing normal tissues. Radiation produces its biologic effects when it comes in contact with the atoms of the dog's tissues. When radiation travels through these tissues, it causes excitation of these charged atoms that ultimately leads to biologic damage particularly in the form of DNA double-stranded breaks.

    In some situations radiation therapy may provide advantages over surgery, particularly when tumor invasion is widespread or if the dog's general health places him at high risk for surgical complications. Because of the clinical evidence of the efficacy of radiation treatment of dogs with particular tumors, more and more veterinary facilities are beginning to offer this form of treatment for cancer and some benign tumors.

 

Radiation Therapy for Treatment of Cancer

    The higher the dose of radiation that a tumor is exposed to, the greater the chance for destroying all of the tumor cells. Unfortunately, however, high dose radiation also compromises the normal tissue that surrounds the tumor. A way to administer a high, total dose of radiation is to divide it up and administer it in small, equal amounts over a period of time; a procedure termed fractionation, which reduces excessive complications in normal tissues. Administration of treatment may be based on schedules of daily (Monday through Friday), alternate days (Monday, Wednesday, Friday), or twice-weekly treatments (Monday, Friday). During treatments, the dog is usually sedated or anesthetized to reduce movement and insure correct positioning

    Some tumors are exquisitely sensitive to the effects of radiation and therefore, radiation therapy may be used as the only course of therapy with the intent to cure. Such malignancies include tumors of the brain that are often inoperable. Brain tumors respond well to radiation with either complete cures (as in the case of small pituitary tumors), or longer survival times (intracranial tumors and spinal lymphomas). Tumors of the nasal cavity can be difficult to control in terms of growth and invasion by surgical intervention. Additionally, surgical excision of these tumors often produces disfigurement and debilitation. Since these tumors are sensitive to radiation, there is an advantage for utilizing radiation treatment over surgery.

    Limitations to the efficacy of radiation do exist, however. In larger tumors, there is an increased risk for the survival of cancer cells at the center of the mass: a condition that is often responsible for disease recurrence at a later time. Therefore, veterinary oncologists often use radiation in combination with surgery and/or chemotherapeutic drugs to target residual disease that may escape radiation treatment alone.

 

Tumors for which Radiation Therapy is Indicated

(From: A.P. Theon. Indications and Applications of Radiation Therapy. In Kirk's Current Veterinary Therapy XII, Bonagura, J.D. (ed.), W.B. Saunders Co., Philadelphia, 1995. p. 469.)

Highly Indicated and/or of Unique Advantage

Often Indicated and Equivalent to Surgery

Indicated Mainly in Combination Therapy

Rarely Indicated

Oral mycosis fungoides Squamous cell carcinoma (facial skin and oral cavity) Fibrosarcoma (oral and cutaneous) Prostate carcinoma
Extranodal localized lymphoma Mast cell tumors Hemangiopericytoma Mammary carcinoma
Pituitary macroadenoma Epulis (acanthomatous, fibromatous) Liposarcoma Bladder carcinoma
Nasal tumors Adamantinoma Osteosarcoma  
Transmissable venereal tumors Perianal adenoma Adenocarcinoma (perianal, thyroid, salivary)  
Brain tumors      

 

Complications to Radiation Therapy

    Immediate side effects of radiation treatment result from damage to normal tissues that have a relatively rapid renewal rate (old cells being replaced by new cells). These tissues which are at higher risk for damage by radiation exposure include the skin and the tissues lining the oral cavity, small intestine, rectum, and bladder. Tissue death (necrosis), non-healing ulcerations, organ dysfunction, and blindness are some of the common complications that may arise during radiation therapy.

 

Radiation Therapy with Surgery

    Combining radiation and surgery for the treatment of cancer has the advantage of reducing the need for radical surgery, which often produces debilitating functional and cosmetic side effects, while still providing an effective outcome for control of cancer. In veterinary oncology, radiation is most often used following surgery to destroy remaining cancer cells that may have been left behind. However, for the combination of radiation and surgery to provide additive efficacy over surgery or radiation treatment alone, only microscopic evidence of cancer can be left behind following surgery. If too much tumor remains, then advantages of using the combination are significantly reduced. Additionally, there are some drawbacks to administering radiation therapy following surgery. The first is that radiation therapy must be postponed until the surgical incision is completely healed. This provides time for regrowth of residual tumor cells which increases risk for failure to control the cancer. Secondly, cancer cells in the area of scar tissue are often more resistant to destruction by radiation. As an alternative, therefore, radiation therapy may be administered prior to surgery. Exposure to radiation prior to surgery has the advantage of often causing tumor masses to shrink and therefore lessens the extent of surgical invasiveness required to manage the disease. Additionally, radiation prior to surgery may reduce risk for the spread of tumor cells during surgical excision of the tumor. This schedule, however, does have some disadvantages. Radiation therapy prior to surgery may increase the risk for complications during and following surgery. Therefore, the veterinary oncologist must take into consideration what schedule of administration will provide the best outcome with the fewest complications based on each individual patient's disease.

 

Radiation Therapy and Bone Marrow Transplantation

    In widespread cancers such as that which occurs in canine multicentric lymphoma, whole body irradiation to control the disease is often not an option since an effective dose would exceed the limits of toxicity to the bone marrow. However, pre-clinical research exploring the use of bone marrow transplantation with whole-body irradiation in dogs with multicentric lymphoma suggests that this regimen may hold some therapeutic advantage for treating these patients.

 

Radiation Applications in the Clinical Treatment of Canine Cancer (use the "Back" command of your internet browser to return to this page after viewing the abstracts of these following journal articles)

Modification of the University of Washington Neutron Radiotherapy Facility for optimization of neutron capture enhanced fast-neutron
therapy.

Nigg DW, Wemple CA, Risler R, Hartwell JK, Harker YD, Laramore GE.

Factors influencing survival after radiotherapy of nasal tumors in 130 dogs.
LaDue TA, Dodge R, Page RL, Price GS, Hauck ML, Thrall DE.

The short and long term effects of intraoperative electron beam radiotherapy (IORT) on thoracic organs after pneumonectomy an
experimental study in the canine model.

de Boer WJ, Mehta DM, Timens W, Hoekstra HJ.

Transmissible venereal tumor: a retrospective study of 29 cases
Rogers KS, Walker MA, Dillon HB.

An accelerated technique for irradiation of malignant canine nasal and paranasal sinus tumors.
Adams WM, Miller PE, Vail DM, Forrest LJ, MacEwen EG.

Radiation therapy for incompletely resected canine mast cell tumors.
LaDue T, Price GS, Dodge R, Page RL, Thrall DE.

Percutaneous ultrasound-guided radiofrequency electrocautery ablation of prostate tissue in dogs.
McGahan JP, Griffey SM, Budenz RW, Brock JM.

Slow release cisplatin combined with radiation for the treatment of canine nasal tumors.
Lana SE, Dernell WS, LaRue SM, Lafferty MJ, Douple EB, Brekke JH, Withrow SJ.

Transurethral balloon laser enhanced thermotherapy in the canine prostate.
Suzuki T, Kurokawa K, Higashi H, Suzuki K, Daikuzono N, Yamanaka H.

Relationship of natural incidence and radiosensitivity for bone cancer in dogs.
Taylor GN, Lloyd RD, Mays CW, Miller SC, Jee WS, Mori S, Shabestari L, Li XJ.

***For a more complete listing, enter the following format of search terms in the PubMed search window:  canine AND radiation AND cancer

Hyperthermia

    The mechanism for damage to cells through elevation of temperature, a process know as hyperthermia, is not fully understood. Heat exposure, however, does cause conformational changes to proteins within the cells, thereby altering their ability to function. Therefore, it is believed that cell killing induced by hyperthermia may be a result of thermal effects on proteins.

 

Hyperthermia Therapy for the Treatment of Cancer

    The observation that high fevers in some human patients with cancer was associated with subsequent disease remission in these patients led to the idea that elevation of body temperature, a condition called hyperthermia, might provide a new treatment approach to this disease. Research into the use of hyperthermia for the clinical treatment of cancer has indicated that it is lethal to cells, causes tumor regression, increases the efficacy of radiation therapy and enhances the action of many anticancer drugs.

    Local heating of tumors is typically accomplished by microwave radiation, infrared radiation, radiofrequency or ultrasound. The need for specialized equipment for administration of hyperthermia is a limiting factor for its widespread use in veterinary medicine at this time.

    Though cancer cells are destroyed by hyperthermia treatment alone, many factors including the nature and size of the tumor will influence the success of hyperthermia to eradicate the entire disease. Populations of cancer cells that may escape the lethal effects of hyperthermia are often resistant to subsequent heat exposure. Therefore, as with other methods of treatment, hyperthermia is often used in combination with radiation (see Treatment Combinations: Radiation and Hyperthermia) or chemotherapy (see Treatment Combinations: Drugs and Hyperthermia) to increase overall treatment efficacy. In canine cancer, treatment with hyperthermia is more commonly administered in combination with radiation.

 

Complications to Hyperthermia

    Hyperthermia is equally damaging to both cancer cells and normal cells. As such, toxicities associated with hyperthermia may be significant.

 

Radiation with Hyperthermia

    Factors that make some cancer cells resistant to treatment with radiation (ex. decreased blood flow) make these same cells particularly sensitive to hyperthermia. Therefore, it is not surprising that combining radiation therapy with hyperthermia to treat cancer in human patients was found to double the number of complete responses to treatment compared to radiation therapy alone. In dogs, combining hyperthermia with radiation against most types of tumors has improved the rate of complete response in the primary tumor resulting in prolonged survival time. Unfortunately, however, many of these dogs later succumb to metastatic disease indicating the need to further combine this regimen with chemotherapy in an effort to control secondary disease due to metastases.

 

Applications of Hyperthermia in the Clinical Treatment of Canine Cancer (use the "Back" command of your internet browser to return to this page after viewing the abstracts of these following journal articles)

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy
and hyperthermia treatment.

Vujaskovic Z, Poulson JM, Gaskin AA, Thrall DE, Page RL, Charles HC, MacFall JR, Brizel DM, Meyer RE, Prescott DM, Samulski TV,
Dewhirst MW.

Tumour cell kinetics as predictors of response in canine lymphoma treated with chemotherapy alone or combined with whole body
hyperthermia.

Larue SM, Fox MH, Ogilvie GK, Page RL, Getzy DM, Thrall DE, Johnson JL, Dewhirst MW, Gillette EL.

Use of whole body hyperthermia as a method to heat inaccessible tumours uniformly: a phase III trial in canine brain masses.
Thrall DE, Larue SM, Powers BE, Page RL, Johnson J, George SL, Kornegay JN, McEntee MC, Levesque DC, Smith M, Case BC,
Dewhirst MW, Gillette EL.

Thermal ablation of canine prostate using interstitial temperature self-regulating seeds: new treatment for prostate cancer.
Paulus JA, Tucker RD, Loening SA, Flanagan SW.

Development of a canine chemotherapeutic model with ifosfamide.
Ikeda K, Inoue N, Frassica FJ, Donehower RC, Tomita K, Chao EY.

A phase III study on hyperthermia in head and neck canine tumours: not hot enough.
Kapp DS.

Radiation plus local hyperthermia versus radiation plus the combination of local and whole-body hyperthermia in canine sarcomas.
Thrall DE, Prescott DM, Samulski TV, Rosner GL, Denman DL, Legorreta RL, Dodge RK, Page RL, Cline JM, Lee J, Case BC, Evans
SM, Oleson JR, Dewhirst MW.

Histological and immunohistochemical changes after transurethral balloon laser hyperthermia in the canine prostate.
Suzuki T, Kurokawa K, Suzuki K, Matsumoto K, Yamanaka H.

Hyperthermic isolated regional perfusion with cisplatin in the local treatment of spontaneous canine osteosarcoma: assessment of
short-term effects.

Van Ginkel RJ, Hoekstra HJ, Meutstege FJ, Oosterhuis JW, Uges DR, Schraffordt Koops H.

Response of 145 spontaneous canine head and neck tumours to radiation versus radiation plus microwave hyperthermia: results of a
randomized phase III clinical study.

Frew DG, Dobson JM, Stenning SP, Bleehen NM.

***For a more complete listing, enter the following format of search terms in the PubMed search window:  canine AND hyperthermia AND cancer

Photodynamic Therapy (PDT)

    The principle of photodynamic therapy is based on the concept that when certain light-sensitive compounds (photosensitizers) are taken up by cells and then exposed to light, the compounds generate active molecules that are toxic to and thereby kill the cells. Selectivity of photodynamic therapy for certain cell types is accomplished by either using photosensitizers that target only the specific cell type or by exposing only certain cells to light after uptake of the photosensitizer.

 

Photodynamic Therapy (PDT) and Cancer Treatment

    The steps to PDT treatment are two-fold. First the dog is administered a photosensitizer drug. In many cases, the photosensitizer is preferentially uptaken and retained by the cancer cells but excreted from the normal cells of the body. After a period of time, the localized tumor is then exposed to light of a certain wavelength that will activate the photosensitizer. In veterinary oncology, PDT has been used limitedly and usually in dogs with localized, superficial, and minimally invasive tumors.

    A previous limitation to widespread use of PDT was absence of data pertaining to the safe use of photosensitizers in dogs. In the clinical studies that have been conducted, however, there appear to be clear advantages to the use of PDT over radiation therapy in regard to the number of treatment sessions required to achieve therapeutic efficacy. Therapeutic limitations to PDT include the inability of light to penetrate deeply into tumor tissue. Therefore, treatment with PDT has been primarily aimed at superficial mucosal cancers: those effecting the skin, lining of the bladder, and the lining of the oral cavity. Research to develop new classes of photosensitizers that are activated by longer wavelengths of light to allow deeper penetration into tumors is currently underway.

 

Complications to PDT

    One of the major complications to the most common photosensitizer drug is the length of time that the tissues of the body retain it. After administration of this photosensitizer, the dog must remain in subdued light for 4-6 weeks to prevent damage to the skin.

 

Applications of Photodynamic Therapy in the Clinical Treatment of Canine Cancer (use the "Back" command of your internet browser to return to this page after viewing the abstracts of these following journal articles)

Photodynamic therapy as a treatment for esophageal squamous cell carcinoma in a dog.
Jacobs TM, Rosen GM.

Treatment of canine oral squamous cell carcinomas with photodynamic therapy.
McCaw DL, Pope ER, Payne JT, West MK, Tompson RV, Tate D.

Biological responses of dog prostate and adjacent structures after meso-tetra-(m-hydroxyphenyl) chlorin and aluminum disulfonated
phthalocyanine based photodynamic therapy.

Chang SC, Chern IF, Hsu YH.

Preclinical evaluation of benzoporphyrin derivative combined with a light-emitting diode array for photodynamic therapy of brain
tumors.

Schmidt MH, Reichert KW 2nd, Ozker K, Meyer GA, Donohoe DL, Bajic DM, Whelan NT, Whelan HT.

Photodynamic therapy of naturally occurring tumors in animals using a novel benzophenothiazine photosensitizer.
Frimberger AE, Moore AS, Cincotta L, Cotter SM, Foley JW.

Interstitial photodynamic therapy in the canine prostate with disulfonated aluminum phthalocyanine and 5-aminolevulinic acid-induced
protoporphyrin IX.

Chang SC, Buonaccorsi GA, MacRobert AJ, Bown SG.

Interstitial and transurethral photodynamic therapy of the canine prostate using meso-tetra-(m-hydroxyphenyl) chlorin.
Chang SC, Buonaccorsi G, MacRobert A, Bown SG.

Transperineal photodynamic ablation of the canine prostate.
Selman SH, Keck RW, Hampton JA.

Balloon photodynamic therapy of esophageal cancer: effect of increasing balloon size.
Overholt BF, Panjehpour M, DeNovo RC, Peterson MG, Jenkins C.

Novel after-loading interstitial photodynamic therapy of canine transmissible sarcoma with photofrin II and excimer dye laser.
Hashimoto Y, Hirano T, Yamaguchi N.

***For a more complete listing, enter the following format of search terms in the PubMed search window:  canine AND photodynamic-therapy AND cancer

 

Chemotherapeutic Drugs

    The principle of chemotherapy is the treatment of metastasis. Localized treatment of tumors by surgery, radiation, etc. often fails because cancer cells from the tumor have already spread to other parts of the body. These metastatic cells eventually form new tumors even when the primary tumor has been eradicated.

    Chemotherapeutic drugs have not been approved for use in veterinary medicine. This is mainly because of the high costs associated with drug licensing. Nonetheless, a multitude of studies indicating the efficacy of chemotherapy to control and sometimes cure cancer in the dog has led many veterinary oncologists to include chemotherapy, either as the primary treatment or in combination with other forms of therapy, to treat cancer in the dog. Thus, many clinical studies involving the administration of these compounds has been conducted in dogs and extensive data has been collected to provide: 1) information on drugs that provide the best efficacy against specific tumor-types, 2) guidelines for treatment dosage, and 3) information on anticipated toxicities. Major limitations to chemotherapy are toxicities associated with the non-specific action of many of these drugs against normal cells particularly cells of the bone marrow, gastrointestinal lining, and hair follicles. Common side effects resulting from toxicities include immunosuppression, anemia, nausea and vomiting, delayed wound healing, reproductive failure and hair loss. Some individual drugs may target specific organs including the heart, kidneys and central nervous system resulting in symptoms specific to these organ functions.

 

Chemotherapeutic Drugs and Cancer Treatment

Drug Class/Name

Cell Target

Type of Cancer

Toxicity and Side Effects

  • Alkylating Agents

DNA (strand-breaks/cross-links)

Cyclophosphamide

lymphoma, mast cell tumors,mammary tumors, hemangiosarcomas

myelosuppression, gastrointestinal toxicity, hemmorhagic cystitis

Ifosfamide (Ifex)

analogue of cyclophosphamide with fewer toxic side-effects

chemoresistant lymphoma, soft tissue sarcomas

myelosuppression

chlorambucil (Leukeran)

leukemias, mast cell tumors, lymphoma

myelosuppression, gastrointestinal toxicity

melphalan (Alkeran)

multiple myeloma

hematopoietic and gastrointestinal toxicity

busulfan (Myeleran)

leukemias

leukopenia

  • Plant Alkaloids

tubulin (cell cycle arrest)

Vincristine (Oncovin)

lymphoma, venereal tumors, mast cell tumors, sarcomas

gastrointestinal toxicity, hair loss

Vinblastine

lymphoma, mast cell tumors

myelosuppression, gastrointestinal toxicity, hair loss

  • Antimetabolites

DNA synthesis or folic acid metabolism (cell cycle arrest)

Methotrexate

lymphoma, osteosarcoma

myelosuppression, kidney toxicity, liver toxic, pneumonitis

Cytosine Arabinoside (Cytostar, Ara-C)

central nervous system lymphoma, leukemias

myelosuppression, gastrointestinal toxicity

Fluoropyrimidines (Fluorouracil [5-FU])

skin tumors, mammary carcinoma, gastrointestinal tract tumors

myelosuppression, gastrointestinal toxicity,   neurotoxicity

Hydroxyurea

recurrent leukemias

myelosuppression, pulmonary fibrosis

  • Antitumor Antibiotics

DNA synthesis and replication (DNA damage)

Doxorubicin (hydroxydaunomycin)

hemolymphatic malignancies, carcinomas and sarcomas

hair loss, gastrointestinal and bone marrow toxicity,  anaphylactic reactions, cardiac toxicity (esp. in Dobermans, Boxers, Rottweilers, and Great Danes)

Epirubicin (Pharmorubicin); Not available in US; stereoisomer of Doxorubicin that is less cardiotoxic

lymphoma

myelosuppression and gastrointestinal toxicity

Methoxymorpholino-doxorubicon (FCE-23762); derivative of doxorubicin with no cardiotoxicity

chemoresistant lymphoma, sarcomas and carcinomas

myelosuppression and gastrointestinal toxicity

Mitoxanthrone

oral squamous cell carcinoma, lymphoma, sarcomas and carcinomas

loss of appetite, lethargy, and systemic infection

Bleomycin

squamous cell carcinoma

bone marrow and gastrointestinal toxicity, pulmonary fibrosis and allergic reaction

Actinomycin D

lymphoma, sarcoma, carcinoma

myelosuppression, gastrointestinal toxicity, diarrhea, vomiting

  • Platinum Compounds

DNA synthesis and replication (crosslink damage)

 

Cisplatin

osteosarcoma, skin and nasal carcinomas

vomiting, kidney toxicity

Carboplatin (Paraplatin); analogue of Cisplatin, not toxic to kidneys  like Cisplatin but more myelosuppressive

skin and nasal carcinomas

myelouppression, bone marrow toxicity

Lobaplatin

osteosarcoma

myelosuppression, transient depression and vomiting

  • Nitrosoureas

DNA (crosslink damage)

 

Lomustine (CCNU)

brain and central nervous system tumors, lymphomas, mast cell tumors

myelosuppression, gastointestinal, liver, kidney, and eye toxicities

Carmustine (BiCNU)

brain tumors

myelosuppression, pulmonary fibrosis

  • Topoisomerase I   Inhibitors

topoisimerase I (DNA replication)

 

Camptothecins (9-Aminocamptothecin)

lymphoma

myelosuppression

  • Hormones

DNA (cleavage)

 

Prednisone

lymphomas and mast cell tumors

cushingoid syndrome

  • Biologic Response Modifiers

Immune system

 

Piroxicam (Feldene)

squamous cell carcinoma,  mammary adenocarcinoma, transmissable venereal tumors

gastrointestinal irritation

Liposome-encapsulated-murmyl tripeptide phosphatidylethanolamine (L-MTP-PE)

splenic hemangiosarcoma,  osteosarcoma

Retinoids:

Etretinate (Tegison) and Isotretinoin (Accutane)

cutaneous lymphoma, mycosis fungoides (skin lymphoma)

keratoconjunctivitis sicca

  • Miscellaneous Agents
 

Paclitaxel (Taxol)

Targets microtubule dissembly (cell cycle arrest)

mammary carcinomas,  lymphomas

Taxol must be solubilized in and administered  with Cremophor EL which may produce anaphylactic reactions, therefore, dogs must be premedicated with steroids and antihistamines to prevent severe allergic responses; toxicities associated with Taxol: vomiting, diarrhea, hair loss, myelosuppression

Darcarbazine (DTIC)

antimetabolite (protein synthesis)

recurrent lymphoma, melanoma, sarcomas

gastrointestinal toxicity, myelosuppression, soft tissue phlebitis, and venous spasm

L-Asparaginase

antimetabolite (protein synthesis)

lymphoid malignancies, mast cell tumors

anaphylactic reaction (pre-treatment with antihistamines usually required), bloodclotting hemorrhagic pancreatitis

 

Combination Chemotherapies

    The use of a single chemotherapeutic agent is rarely effective for curing cancer. As with other types of therapy, not all tumor cells will be effectively killed by a single agent. Therefore, veterinary oncologists typically combine drugs having different mechanisms of action and non-overlapping toxicities with the goal to target a broader range of cancer cells while preventing the development of new resistant generations of cells.

    In veterinary medicine, lymphoma has been the most extensively studied form of cancer in regard to combination drug treatment.

 

Chemotherapy Combinations for Canine Lymphoma:

COP: Cyclophosphamide+Vincristine+ Prednisone

75%-80% remission rate; median duration of remission for this protocol: 6 months

CHOP: Cyclophosphamide+Vincristine+Prednisone+Doxorubicin 75%-80% remission rate: median survival for dogs treated with this protocol: 216 days
COAP: Cyclophosphamide+Vincristine+Prednisone+Cytosine arabinoside 75%-80% remission rate; median duration of survival: 25 weeks
CDP: Chlorambucil+Dactinomycin+Prednisone 75%-80% remission rate; survival expectation: 6 months
VCAA: L-asparaginase+Vincristine+cyclophosphamide+Doxorubicin followed by monoclonal lymphoma antibody CL/MAb 75% remission rate; median survival:591 days

 

Advanced Drug Combinations for Canine Lymphoma

    The following combinations are associated with a 75%-80% remission rate, median remission durations of 175 to 369 days, and median survival of close to 1 year (with the exception of T-cell lymphomas). The Madison-Wisconsin protocol has reported the highest proportion of patients with 2-year survivals. (Note that where two or more protocols have the same drugs listed, the difference between the protocols is in the dose or frequency of administration of the drugs).

COPLA: Cyclophosphamide, Vincristine, Prednisone, L-Asparaginase, Doxorubicin  
ACOPA I: Vincristine, L-Asparaginase, Cyclophosphamide, Doxorubicin, Prednisone remission rate: 76%; median duration of remission: 330 days (48% of dogs in remission at 1 year);

fatality rate due to toxicity: 12%

ACOPA II: Vincristine, L-Asparaginase; Cyclophosphamide; Doxorubicin remission rate: 65%; median duration of remission: 228 days (34% of dogs in remission at 1 year)
AMC 2: Vincristine, L-Asparaginase, Cyclophosphamide, Doxorubicin, Prednisone  
VELCAP: Vincristine, L-Asparaginase, Cyclophosphamide, Doxorubicin, Prednisone  
Madison-Wisconsin: Vincristine, L-Asparaginase, Cyclophosphamide, Doxorubicin, Methotrexate, Prednisone  

 

Rescue Protocols

    It is expected that the majority of the dogs treated for lymphoma will experience disease recurrence after a period of time. The following protocols have been designed for treatment of relapsing disease.

ADIC: Doxorubicin, Dacarbazine
MOPP: Mechlorethamine, Vincristine, Procarbazine, Prednisone

 

Radiation with Chemotherapy

    Certain drugs act as radiosensitizers, thereby increasing the efficacy of radiation treatment. In veterinary medicine, the chemotherapeutic drugs cisplatin and carboplatin have been studied extensively for their radiosensitizing effects. These drugs are administered concurrently with radiation treatment and often have direct toxic effects on cells in addition to increasing cellular sensitivity to radiation.

    Combinations of cisplatin and radiation followed by surgery have been successfully used in dogs with osteosarcoma and resulted in a one year rate of remission in 92% of treated dogs. Even in dogs not considered candidates for surgery, the combination of cisplatin and radiation was successful for providing palliative treatment of osteosarcoma without increasing complications associated with radiation. This combination is also effective in the treatment of advanced carcinomas of the head, neck and urinary bladder and sarcomas.

 

Hyperthermia with Chemotherapy

    Some drugs work more efficiently at temperatures above normal body temperature. Therefore, these drugs when combined with hyperthermia treatment are expected to increase the efficacy of certain drugs to kill tumor cells. These drugs include cisplatin and the nitrosoureas. Unfortunately, however, clinical studies in dogs exploring the combination of whole-body hyperthermia with cisplatin have not demonstrated any advantage of this combination over treatment with cisplatin alone. Additionally, there was increased toxicity to normal tissues when hyperthermia was combined with either cisplatin or carboplatin necessitating the reduction of drug dosing. Other studies exploring combinations of doxorubicin or mitoxantrone with hyperthermia likewise showed no response and in some cases a decreased response to the combination treatment regimen. Despite these findings, however, some new studies exploring the combination of hyperthermia with novel anti-cancer drugs suggests that hyperthermia may offer a protective effect on normal tissues against non-specific drug toxicity. Studies are on-going to evaluate this protective effect of hyperthermia.

 

"Magic Bullets" to Target Cancer

    The phrase "magic bullet" is used to describe a particular drug or technique that will specifically target and kill only cancer cells while sparing normal, healthy cells. The medical literature is brimming with studies exploring these novel approaches to cancer treatment. The following section provides a brief overview of some of the more promising of these methods to effectively target cancer in the dog.

 

Gene Therapy

The theory behind gene therapy is to introduce foreign DNA into a cancer cell which when incorporated into and expressed by that cell will usually facilitate that cells destruction. There are primarily four approaches to gene therapy: 1) suicide gene therapy in which the protein product of that gene changes an inactive drug into a toxic drug only in the cancer cell carrying the foreign gene; 2) genetic immunotherapy in which the foreign gene causes the cancer cells to express certain molecules on their surfaces that will attract components of the immune system to attack and destroy the cancer cells; 3) tumor suppressor gene therapy in which the foreign gene replaces a mutated gene that has caused unregulated cell growth in the cancer cells; and 4) drug resistance gene therapy in which a foreign gene which makes cells resistant to chemotherapy drugs is introduced into a patient's normal cells so that the patient may be administered higher doses of chemotherapy with reduced toxic side-effects. Gene therapies utilize a number of methods, including viral and non-viral vectors, to deliver genetic material into cells. As such, each of these delivery systems has advantages and disadvantages, and to date is still undergoing clinical evaluation for efficacy and safety issues.

 

Gene Therapy in Canine Cancer

Genetic immunotherapy has been the most explored form of gene therapy for the treatment of dogs with cancer. In one study, dogs with malignant melanoma, a very aggressive form of cancer, who were previously treated with surgery and radiation treatment were treated with green-monkey kidney cells expressing interleukin-2 (IL-2) DNA. Twelve months after treatment, dogs treated with the genetic immunotherapy had a 37% survival rate compared to a survival rate of only 6% in dogs that did not receive the genetic immunotherapy. It is believed that the IL-2 expressing cells induced an inflammatory response at the site of the cancer and facilitated an immune response that caused an anti-tumor effect. In another study, when IL-2 gene therapy was combined with a bacterial gene to enhance the immune effect in dogs with advanced metastatic melanoma (lymph node metastasis), 45% of the dogs showed either complete or partial remissions of tumors with significantly longer survival times compared to untreated dogs. Additionally, no adverse side-effects were observed in any of the dogs treated.

 

Applications of Gene Therapy in the Clinical Treatment of Canine Cancer (use the "Back" command of your internet browser to return to this page after viewing the abstracts of these following journal articles)

In situ gene transfer and suicide gene therapy of gastric cancer induced by N-ethyl-N'-nitro-N-nitrosoguanidine
in dogs

Matsukura N, Hoshino A, Igarashi T, Hasegawa H, Okino T, Onda M, Iijima O, Akiyama K, Goto T, Takubo

In vivo expression of prostate-specific adenoviral vectors in a canine model.
Steiner MS, Zhang Y, Carraher J, Lu Y.

The molecular basis of canine melanoma: pathogenesis and trends in diagnosis and therapy.
Modiano JF, Ritt MG, Wojcieszyn J.

The molecular basis of canine melanoma: pathogenesis and trends in diagnosis and therapy.
Lu Y, Carraher J, Zhang Y, Armstrong J, Lerner J, Rogers WP, Steiner MS.

Preclinical development of human granulocyte-macrophage colony-stimulating factor-transfected melanoma cell
vaccine using established canine cell lines and normal dogs.

Hogge GS, Burkholder JK, Culp J, Albertini MR, Dubielzig RR, Yang NS, MacEwen EG.

Development of human granulocyte-macrophage colony-stimulating factor-transfected tumor cell vaccines for
the treatment of spontaneous canine cancer.

Hogge GS, Burkholder JK, Culp J, Albertini MR, Dubielzig RR, Keller ET, Yang NS, MacEwen EG.

In vivo tumor transfection with superantigen plus cytokine genes induces tumor regression and prolongs survival
in dogs with malignant melanoma.

Dow SW, Elmslie RE, Willson AP, Roche L, Gorman C, Potter TA.

Selective intraarterial gene delivery into a canine meningioma.
Chauvet AE, Kesava PP, Goh CS, Badie B.

Gene therapy of spontaneous canine melanoma and feline fibrosarcoma by intratumoral administration of
histoincompatible cells expressing human interleukin-2.

Quintin-Colonna F, Devauchelle P, Fradelizi D, Mourot B, Faure T, Kourilsky P, Roth C, Mehtali M.

In vivo particle-mediated cytokine gene transfer into canine oral mucosa and epidermis.
Keller ET, Burkholder JK, Shi F, Pugh TD, McCabe D, Malter JS, MacEwen EG, Yang NS, Ershler WB.

Research in canine and human genetic disease.
Sargan DR.

***For a more complete listing, enter the following format of search terms in the PubMed search window:  canine AND gene-therapy AND cancer

Monoclonal Antibodies and Antigen/Receptor-Directed-Toxin Chimeras

    Cancer cells often express certain molecules (antigens, growth factor/cytokine receptors, etc.) on their surfaces that are different or in greater number than expressed on normal cells. These observations gave rise to a strategy whereby these cell surface molecules could be used to specifically target only the cancer cells. This therapeutic approach is achieved by administering antibodies against the specific surface molecules to illicit a passive immune response in the patient against the tumor cells or by linking toxic drugs to molecules (such as antibodies or growth factors/cytokines) that bind to these antigens or receptors in order to deliver them into cancer cells.

 

Monoclonal Antibodies and Antigen/Receptor-Directed-Toxin Chimeras in the Treatment of Canine Cancer

    The monoclonal antibody Mab 231 has specificity against some canine lymphomas and has been undergoing clinical studies since its development reported in 1988. Mab 231 has been primarily assessed for its value as long-term maintenance chemotherapy in dogs that have achieved complete remission through standard lymphoma chemotherapy regimens. Results from these studies indicate that Mab 231 prolongs the remission duration in some dogs while eliminating the necessity for on-going chemotherapy administration to prevent recurrence (through administration of conventional drugs).

Applications of Monoclonal Antibodies and Antigen/Receptor-Directed-Toxin Chimeras in Canine Cancer (use the "Back" command of your internet browser to return to this page after viewing the abstracts of these following journal articles)

Adjuvant therapy for melanoma in dogs: results of randomized clinical trials using surgery,
liposome-encapsulated muramyl tripeptide, and granulocyte macrophage colony-stimulating factor.

MacEwen EG, Kurzman ID, Vail DM, Dubielzig RR, Everlith K, Madewell BR, Rodriguez CO Jr, Phillips B,

The immunotherapeutic potential of activated canine alveolar macrophages and antitumor monoclonal antibodies
in metastatic canine melanoma.

Soergel SA, MacEwen EG, Vail DM, Potter DM, Sondel PM, Helfand SC.

Adoptive therapy of canine metastatic mammary carcinoma with the human MHC non-restricted cytotoxic
T-cell line TALL-104.

Visonneau S, Cesano A, Jeglum KA, Santoli D.

Mixed chimerism: preclinical studies and clinical applications.
McSweeney PA, Storb R.

Adjuvant treatment of canine osteosarcoma with the human cytotoxic T-cell line TALL-104.
Visonneau S, Cesano A, Jeglum KA, Santoli D.

Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine adjuvant immunotherapy for splenic
hemangiosarcoma in the dog: a randomized multi-institutional clinical trial.

Vail DM, MacEwen EG, Kurzman ID, Dubielzig RR, Helfand SC, Kisseberth WC, London CA, Obradovich
JE, Madewell BR, Rodriguez CO Jr, et al.

Successful treatment of canine malignant histiocytosis with the human major histocompatibility complex
nonrestricted cytotoxic T-cell line TALL-104.

Visonneau S, Cesano A, Tran T, Jeglum KA, Santoli D.

Phase I clinical trial with a human major histocompatibility complex nonrestricted cytotoxic T-cell line
(TALL-104) in dogs with advanced tumors
.
Cesano A, Visonneau S, Jeglum KA, Owen J, Wilkinson K, Carner K, Reese L, Santoli D.

Canine osteosarcoma: amputation and chemoimmunotherapy.
MacEwen EG, Kurzman ID.

Chemoimmunotherapy of canine lymphoma with adjuvant canine monoclonal antibody 231.
Jeglum KA.

Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal
papillomas.

Suzich JA, Ghim SJ, Palmer-Hill FJ, White WI, Tamura JK, Bell JA, Newsome JA, Jenson AB, Schlegel R.

In vitro and in vivo cytotoxicity of an anti-osteosarcoma immunotoxin containing pokeweed antiviral protein.
Anderson PM, Meyers DE, Hasz DE, Covalcuic K, Saltzman D, Khanna C, Uckun FM.


***For a more complete listing, enter the following format of search terms in the PubMed search window:  canine AND immunotherapy AND cancer

 

Anti-angiogenic Drugs

    For cancer cells to divide and become solid tumors they are dependent upon the formation of blood vessels, a process known as angiogenesis, that will provide blood flow with oxygen and nutrients to the developing tumor. Many cancer cells excrete molecules into the surrounding tissues that stimulate the formation of new blood vessels. Based on these observations, the novel idea of inhibiting tumor growth by cutting off blood supply to the tumor was developed. Natural and synthetic inhibitors of vascular formation, known as anti-angiogenic drugs, have been purified, formulated and assessed for their abilities as anti-tumor agents. Such drugs include angiostatin, thrombospondin, and endostatin. In preclinical animal studies, anti-angiogenic drugs have been found to significantly inhibit tumor growth and in some instances produce tumor regression.

 

Anti-angiogenic Drugs in the Treatment of Canine Cancer

Many of these anti-angiogenic drugs are in the early stages of clinical development for treatment of human cancers. Although there are several ongoing canine studies utilizing these drugs, currently no clinical information is available on treatment efficacy.

    Dog-related News Article:  "Anti-angiogenesis: Perhaps a new way to address cancer"

 

Applications of Anti-angiogenic Drugs in the Treatment of Cancer (use the "Back" command of your internet browser to return to this page after viewing the abstracts of these following journal articles)

Antiangiogenic strategies and agents in clinical trials.
Rosen L.

Angiogenesis: new targets for the development of anticancer chemotherapies.
Gourley M, Williamson JS.

Angiogenesis and Cancer Control: From Concept to Therapeutic Trial.
Brem S.

Novel cancer therapies: more efficacy, less toxicity and improved organ preservation.
Joensuu H.

***For a more complete listing, enter the following format of search terms in the PubMed search window:  antiangiogenic-therapy AND cancer

 

Other Issues of Cancer Treatment

Nutrition

    Protein-calorie malnutrition, a condition known as "cancer cachexia", is often a debilitating side-effect of cancer in both humans and dogs. Symptoms of cancer cachexia include diminished appetite and food intake, progressive weight-loss, and a number of metabolic abnormalities. Without correction of the nutritional status, many patients succumb to severe debilitation and eventual death. Therefore, attention must be devoted to ensuring that dogs afflicted with cancer receive palatable, highly digestible, and energy-dense diets that may enhance their overall quality of life, their life expectancy, and their ability to undergo aggressive therapy regimens for treatment of their disease.

    Dietary recommendations for dogs with cancer include high-fat (greater than 40-50% of calories) diets that are low in carbohydrates. Premium dog foods offering special "performance" or "stress" formulas are considered appropriate for the critically ill cancer patient. Unfortunately, however, many of these dogs are unwilling or unable to eat for themselves. Therefore, handfeeding and in many cases, feeding tubes or catheters should be used to ensure adequate nutrition. Use of appetite stimulants such as diazepam or cyproheptadine, though causing an immediate increase in food intake following administration of these drugs, does not appear to increase overall food intake over extended periods of time. As such, some veterinarian oncologists prefer to use feeding tubes or catheters that assure increased food intake in lieu of appetite stimulants.

 

Chemoprotective Drugs and Antiemetics

    Some drugs when given in conjunction with chemotherapeutic drugs can help to reduce non-specific toxicities and other side-effects associated with treatment. Such drugs include chemoprotective drugs such as Mesna (which prevents hemorrhagic cystitis associated with ifosfamide or cyclophosphamide chemotherapy) and Dexrazozane (which prevents cardiotoxicity associated with doxorubicin chemotherapy), as well as antiemetic (anti-nausea) drugs such as Butorphanol (which is effective at preventing cisplatin-associated nausea) and Ondansetron (a more effective but more expensive drug which controls nausea associated with chemotherapy).

 

Copyright 1999, 2000. Pamela A. Davol. All rights reserved. Copyright & disclaimer.

Back To Cancer In The Canine--Table of Contents
Back To Main Menu

The Moss Reports - Cancer Decisions - Your lighthouse to guide you through the stormy
      waters of cancer.