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Principles of Cancer Chemotherapy
Symposium on Clinical Veterinary Oncology
Principles of Cancer Chemotherapy Paul W. Hess, D.V.M.*
In the early 1950's, the first reports appeared concerning the clinical response of naturally occurring canine tumors to modern cancer chemotherapy. 4 The use of cancer chemotherapy in veterinary medicine has made slow progress since that time. This was due to the expense of antitumor drugs, the poor prognosis in most cases, the unpleasant side effects which occur when most of these drugs are used in therapeutic doses, and the lack of accurate biological behavior data of animal tumors. For years scientists have used normal, healthy dogs to elicit the toxic side effects and safe dosage levels of new anticancer drugs prior to their use in preliminary studies in humans. This information can be used by veterinary oncologists to formulate drug protocols used in treating cancer in dogs. The effectiveness of these protocols can then be reported to the practitioner and subsequently offered to the client whose dog is suffering from cancer. The recent advances in chemotherapy of human cancer patients, whether used alone or in combination with other modalities, have made pet owners aware of the potential benefits t\) be obtained from cancer chemotherapy. As a result the practicing veterinarian should now be able to offer chemotherapy to pets who have developed tumors. The purpose of this paper is to describe the principles of cancer chemotherapy and some of the most commonly used drugs together with their beneficial applications and detrimental side effects. Tumor, Host, and Drug Interrelationships
The veterinarian, when using cancer chemotherapy drugs, should always remember the close relationship between the tumor, host, and drugs. These interactions are: (a) disease, i.e., the effect of the tumor on the host; (b) therapy, the effects of the drug on the tumor; and (c) toxicity, the effects of the drug on the host. The predominant factor or factors in this relationship determine the final outcome for the animal *Private Practitioner, St. Thomas. Virgin Islands; Formerly, Head of Cancer Therapy Unit, Henry Bergh Memorial Hospital, New York, and Research Associate, ~fc morial Sloan-Kettering Cancer Center, New York, New York
l'eterinary Clinics o/North America- Vol. 7, No. l, February 1977
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receiving cancer chemotherapy. For example, an excellent response to therapy encompasses remission of signs or symptoms of disease without impairment of normal function of the host due to toxicity. The quality of survival is determined by these interactions and is very important to the client and veterinarian since there exists the alternative of euthanasia as opposed to treatment in pet animals. Selection of Patients
Chemotherapy is the most suitable form of therapy for patients with tumors which are not amenable to surgery or radiotherapy. Patients that should be considered for chemotherapy include those with disseminated tumors such as leukemia, lymphosarcoma, multiple myeloma, and other hemopoietic tumors, or those with highly malignant solid tumors which metastasize rapidly. 19 • 20 • 23 • 2 5 , 26, 3° Those animals which have tumors in which the results of surgery or radiotherapy are poor may have prolonged survival if treated with chemotherapy. For instance, the average survival for cats with intraoral carcinomas treated with radiotherapy is only 12 weeks; the median survival time for dogs with osteosarcoma treated with amputation is 18 weeks. 7 • 9 In man, adjunctive chemotherapy has significantly prolonged survival in osteosarcoma and mammary cancer patients. 5 • 22 • 27 Also, chemotherapy may be used in animals with tumors of prostate, pharynx, and nasal cavities since they are located in difficult sites for surgical procedures. Until recently, there has been considerable reluctance to administer toxic drugs to patients apparently clinically free of tumor after surgery or radiotherapy. However, there is strong evidence that such patients are not free of malignant cells and that aggressive chemotherapy before metastases are clinically detectable increases the chances of survival. The problem is to identify those patients with clinically undiscernible metastases who would benefit from adjunctive therapy. In general, chemotherapy should not be administered to animals with undetectable tumors unless the biological behavior of the tumor is known. For example, canine osteosarcoma and undifferentiated mast cell tumors rapidly metastasize and dogs with these tumors are candidates for adjunctive chemotherapy following surgery. 6 • 9 Healthy feline leukemia virus infected cats should not be treated with chemotherapy since the drugs cannot eliminate the virus. In fact, chemotherapy may be detrimental since most antitumor drugs are immunosuppressive and thus increase the chances of disease development. Patients with non-neoplastic diseases such as canine pemphigus and polycythemia respond to the immunosuppressive action of chemotherapeutic drugs. 19 In man, disease conditions such as refractory psoriasis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune
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hemolytic anemia, idiopathic thrombocytopenic purpura, and various renal diseases such as nephrotic syndrome, glomerulonephritis, and lupus nephritis are managed with cancer chemotherapy.11· 29 Their use in veterinary medicine needs to be evaluated. Before any animal is selected to receive chemotherapy, the clinician must be able to meet the following standards in order to utilize chemotherapeutic agents safely: Establish a histological diagnosis of malignancy and a known sensitivity to antineoplastic drugs. Be familiar with the drugs and their potential toxicity. Use safe dosage schedules established for dogs and cats. Be able to monitor toxicity at regular intervals. Be able to evaluate an adequate response. Establish a willingness on the part of the client to cooperate fully with the veterinarian during a carefully planned therapy program.
The decision to initiate therapy or select which drugs may be best administered may be influenced by the pre-treatment evaluation of the patient. A complete history should be taken to establish if any previous therapy has been given or if there has been any other recent illness which may influence the effectiveness of the drugs. A complete physical examination along with base line hematological data such as complete blood counts and liver and kidney function tests are mandatory. Other special tests such as bone marrow examination or special radiological procedures may be needed to completely evaluate the extent of disease or underlying complications. Other factors which may influence the effectiveness of drugs will be discussed later.
Cell Kinetics A knowledge of the cell cycle or the proliferative state of the cell population is important for understanding the cytotoxic effects of cancer chemotherapy. 2L 31 The cell cycle can be defined as an orderly sequence of events occurring during the time interval from one cell division to the next. The cell cycle is divided into the following phases: mitosis (M), postmitotic growth in which RNA and protein synthesis occur prior to DNA synthesis (G 1 ), resting or nonproliferating phase for differentiated cells (G 0 ), new DNA synthesis (S), RNA and protein synthesis prior to mitosis (G2 ) (Fig. 1). Cell populations differ in relationship to DNA synthesis and mitosis in that some cells continuously move through the cell cycle; other cells leave the cycle but can be induced to synthesize DNA and divide by certain stimuli; and finally, some cells will leave the cycle permanently and will die without further division. Normal cells have four basic properties: (1) ability to proliferate; (2) capacity for self-renewal; (3) ability to differentiate; (4) sensitivity to regulatory mechanisms. Malignant cells have the first two properties and differentiation may be present but abnormal. The main
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M
Figure 1. A schematic diagram of the cell cycle. Mitosis (M) is followed by a growth phase (G 1), or in differentiated cells a resting phase (G 0). DNA synthesis (S) then takes place followed by another growth phase (G 2) before the cell divides.
s difference between normal and malignant cells is response to regulation; in malignant cells this property is either greatly reduced or completely absent. The ideal treatment would bring about maximum normal cell survival and minimal tumor cell recovery. 21 The response of cells to drugs depends on the mechanism of action of the drug and the position of the cell in the cell cycle. 2 • 10 • lL 15 Cells in the S phase are especially susceptible to drugs which prevent the formation of nucleotides or inhibit DNA repair. Anticancer drugs can be divided into six classes according to their mechanism of action: 12 Alkylating agents act by crosslinking cellular DNA, thus impeding its ability to act as a template for RNA synthesis. Antimetabolites interfere with the biosynthesis of nucleic acids by substituting for normal metabolites and inhibiting normal enzymatic reactions. Antibiotics are thought to bind nonspecifically to cellular DNA and inhibit transcription. Mitotic inhibitors destroy the mitotic spindle of the cell and prevent further cell division. Hormones are thought to act by interfering with cell membrane receptors that stimulate growth. Miscellaneous drugs are those which do not act in any of the ways described above or whose mechanism of action is at present unknown.
The mechanisms by which antitumor drugs exert their effect govern the basic principles of cancer chemotherapy. The sensitivity of a tumor cell to a particular drug is determined by its position in the cell cycle at the time the drug exerts its maximum effect. Also, rapidly growing tumors are the most susceptible to chemotherapy, whereas slow growing tumors, in which there is a greater proportion of resting cells, are less susceptible. However, certain drugs are effective against resting cells as well as growing cells. 21 Also, drugs which are primarily effective against growing cells can be toxic to nonproliferating cells by
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increasing the dosage. These, in addition to other factors, increase the chances of killing all the malignant cells in the body. In both experimental and clinical trials, the effectiveness of chemotherapy is inversely related to the number of malignant cells present. The fewer the malignant cells, the more effective is chemotherapy. Thus chemotherapy should be started as soon as possible and used as an adjunct to surgery, radiotherapy, or immunotherapy when indicated.13. 14. 16 Anticancer Drugs Currently, there are over 20 anticancer drugs commercially available to the veterinarian (Table 1). Detailed pharmacological information is not included in this paper, but is readily available from other sources. 1· 10· 11 • 23 The drugs are listed according to class of action with the following information: generic and brand name, manufacturer, preparations, sensitive neoplasms, suggested dosages, and frequency of administration. More detailed information concerning the use of these agents in specific neoplastic conditions is dealt with in other reports or elsewhere in this symposium. 20· 25 The most common method of expressing drug dosages is by body weight (i.e., mg per kg). However, it has been found that body surface area is related to several physiological parameters such as the blood volume and urea clearance, and that the maximum toxic dose of several drugs is the same in a wide variety of species when the doses are expressed in terms of body surface area. Since toxicity data is often only available in other species, and because the activity of most drugs depends on some physiological process, drug doses for veterinary cancer patients should be expressed in terms of body surface area. An objection to this method is that body surface area is difficult to measure. A conversion table of weights to body surface area is available, and a method of converting dosages given by body weight (i.e., mg per kg) to dosages based on body surface area is explained in other reports. 20· 30 Toxicity and Complications Most chemotherapeutic drugs are toxic to all dividing cells and there can be a fine line between therapeutic and toxic doses. The toxic side effects, if manifested, may limit the use of a single drug or combination of drugs. These side effects may be slight; mild alopecia, anorexia, vomiting, and diarrhea may necessitate only a temporary withdrawal of chemotherapy. Side effects such. as thrombocytopenia, leukopenia, severe anemia, and gastrointestinal bleeding can be so severe that chemotherapy may have to be discontinued permanently11 It is essential that all animals being given anticancer drugs be monitored frequently for toxic side effects. Monitoring should include a thorough physical examination, complete blood cell counts, serum
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Table 1. DRUG
Alkylating Agents Cyclophosphamide (Cytoxan) Mead Johnson; 25 and 50 mg tablets; 100, 200 and 500 mg vials
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Antineoplastic Agents SENSITIVE NEOPLASMS
SUGGESTED DOSAGES
Lymphosarcoma, lymphoreticular leukemias, reticulum cell sarcoma, mast cell tutnors, transmissible venereal tumor, miscellaneous solid tumors
6.6 mg/kg for 3 days, then 2.2 mg/kg daily orally. Pulse: 10 mg/kg intravenously every 7-10 days
Nitrogen mustard (Mustargen) Merck Sharp and Dome; 10 mg vials
Lymphosarcoma, mast cell tumors
0.1-0.5 mg/kg daily, intravenously
Chlorambucil (Leukeran) Burroughs Wellcome; 2 mg tablets
Chronic lymphocytic leukemia, macroglobulinemia
0.2 mg/kg daily, orally
n, n', n",-triethylenethio-
Mast cell tumors, miscellaneous sarcomas and carinomas
0.5 mg/kg daily for I 0 days, intralesionally or intravenously
Busulfan (Myleran) Burroughs Wellcome; 2 mg tablets
Granulocvtic leukemias, myleop~oliferative disorders
1 mg;kg daily, orally
Melphalan (Alkeran) Burroughs Wellcome; 2 mg tablets
Multiple myeloma, monoclonal gammopathies
0.05-0.1 mg/kg daily, orally
Lymphosarcoma, acute lymphocytic
0.06 mg/kg daily, orally; 0.3-0.8 mg/ kg intravenously, weekly
phosphoramide (Thiotepa) Led erie; 15 mg vials
Antimetabolites Methotrexate- Led erie; 2.5 mg tablets, 5 and 50 mg vials
leukemia, transmissible venereal tumor, various solid tumors
6 Mercaptopurine (Purinethol, 6-MP) Burroughs Wellcome; 50 mg tablets
Lymphosarcoma, acute lymphocytic leukemia, myelogenous leukemia
2.2 mg/kg daily
6-Thioguanine (Tabloid) Burroughs Wellcome; 40 mg tablets
Lymphosarcoma, mast cell tumor
2.5 rng/kg daily
5-Fluorouracil (5-Fluorouracil, Fluorouracil) Roche Laboratories; 500 mg vials
Miscellaneous carcinomas and
Do not use in cats
Efudex (5-Fluorouracil Cream and Solution 2% and 5%) Roche Laboratories Cytosine arabinoside (Ara-C, Cytosar) UpJohn; I 00 and 500 mg vials
sarcomas
Dogs: 5 mg/kg every 5-7 days, intravenously
Cutaneous tumors
Apply twice daily for 2-4 weeks
Lymphosarcomas, granulocytic leukemia, mast cell tumors
5-10 mg/kg daily for 2 weeks or 30-50 mg/kg weekly (intramuscularly, subcutaneously, intravenously)
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Table I. DRUG
Antibiotics Actinomycin D (Cosmegen) Merck, Sharp and Dome; 500 !Lg/vial
Antineoplastic Agents (Continued) SENSITIVE NEOPLASMS
SUGGESTED DOSAGES
Lymphosarcoma, miscellaneous sarcomas and carcinomas
0.015 mg/kg for 3-5 days, then wait 3 weeks for marrow recovery
Doxorubicin hydrochloride (Adriamycin) Adria Laboratory; 10 mg vials
Osteosarcoma, miscellaneous sarcomas and carcinomas
Not available for dogs or cats; in humans, 2 mg/kg intravenously every 3 weeks
Bleomycin (Blenoxane) Bristol Labs; 15 units/ vial
Squamous cell carcinomas, miscellaneous carcinomas
Not available for dogs or cats; in humans, 0.3-0.5 units/kg once or twice weekly, intravenously or iiltramuscularly
Lymphosarcoma, acute lymphoblastic leukemia, reticulum cell sarcoma, mast cell tumor, transmissible venereal tumor
0.025-0.05 mg/kg every 7-10 days, intravenously
Lymphosarcoma, rnast cell tun1or
0.1-0.4 mg/kg every 7-10 days intravenously
Lvmphosarcoma, acute lymphoblastic leukemia, mast cell tumors, multiple rnyeloma, and mis<.:ellaneous tumors
0.5-1 mg/lb divided twice daily
Estrogens DES, ECP
Perianal adenomas, advanced carcinotnas of prostate
DES-1 mg every other day; ECP-12 mg every 2-4 weeks
Testosterone
Mammary tumors, bone marrow depression
2 mg/kg intramuscularly 3 times weekly
Myelogenous leukemia, mast cell tumor
80 mg/kg every 3 days or 40-50 mg/kg divided twice daily, orally
O,p'-DDD (Mitotane Lysodren) Calbio; 500 mg tablets
Adrenal cortical adenomas, and carcinomas
50 mg/kg daily to effect
Dacarbazine (DTIC-Dome) Dome Laboratories; 100 and 200 mg vials
Malignant melanoma
Not available for dogs or cats; in humans, 2.0-4.5 mg/kg intravenously daily for 10 days. Repeat at 4-6 week intervals
Procarbazine (Matulane) Roche Laboratories; 50 mg capsules
Lymphosarcoma
Not available for dogs or cats; in humans, 50-100 mg daily until bone marrow depression
Plant Alkaloids Vincristine (Oncovin) Eli Lilly; I and 5 mg vials Vinblastine (V elban) Eli Lilly; 10 mg/vial
Hormones Adrenal corticosteroids (Prednisone)
Miscellaneous Hydroxyurea (Hydrea) Squibb; 500 mg capsules
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enzyme levels, and renal function tests every 7 to 10 days. Drugs should be discontinued if bone marrow depression is manifested by a total white blood count below 3,000 per cubic mm and/or a platelet count less that 50,000 per cubic mm. It is very important for the veterinarian to remember that once a drug (except for methotrexate) has been administered, there is nothing that can neutralize its action or prevent serious delayed side effects. A thorough explanation to the client about toxic side effects before the use of anticancer drugs will help the client observe the patient at home and detect the earliest signs of complications, thus allowing early treatment. Certain agents, usually given by the intravenous route, are very irritating and cause local reactions when they are inadvertently leaked into the extravascular tissue. Severe pain, erythema, and erosion of tissue will occur. Great care should be taken, therefore, when administering vincristine, vinblastine, actinomycin D, and Adriamycin (doxorubicin hydrochloride). If these drugs are accidentally given outside the vein, infiltration of the area with saline, xylocaine, and corticosteroids, or the topical application of a mixture of dimethylsulfoxide and corticosteroids will lessen the extent of tissue damage. In general, most of the anticancer drugs cause myleosuppression, but a few of the drugs have unique toxic side effects. Cyclophosphamide can induce hemorrhagic cystitis. This complication can be prevented by administering the agent in the morning, forcing fluid intake by salting food, and encouraging urination. With 5-fluorouracil, bizarre central nervous system reactions have been seen. The reactions are characterized by apparent hallucinations, hyperexcitability, fright, and severe personality change. This drug should not be given to cats at current recommended dosages. Vincristine causes neuromuscular weakness and constipation (gastrointestinal atony), which is easily treated by withdrawal of the drug and the use of laxatives. Side effects indirectly related to the drugs are those due to rapid tumor cell breakdown and can lead to abnormal hepatic or renal function. Local reactions such as pain, edema, inflammation, and abscess formation or tissue necrosis can occur as the tumor cells die and are eliminated from the body. Immunosuppression
The effect of anticancer drugs on the immune system may be beneficial or detrimentaU· 18 • 24 ' 28 ' 29 These drugs affect both the humoral and cellular immunity. With appropriate drug dose and timing, primary and secondary antibody production can be completely blocked or delayed. Also, tolerance to antigens can be established. New and established delayed hypersensitivity reactions may be suppressed by the
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same mechanism of action these drugs exert on any cells which need to proliferate. The transplantation of allogeneic grafts has been successful in humans due to the administration of drugs before and after antigenic stimulation, i.e., transplantation. Cyclophosphamide and corticosteroids are effective before transplantation, whereas 6-mercaptopurine, azathioprine, and methotrexate are given post transplantation. The first group appears to interact with antigen-sensitive cells and to interfere with cell proliferation, whereas the second group interferes with cell transformation, cell differentiation, and initiation of antibody formation. Agents used to treat autoimmune diseases include cyclophosphamide, methotrexate, 6-mercaptopurine, 6-thioguanine, azathioprine, chlorambucil, and corticosteroids. Their actions suppress inflammatory response and inhibit the synthesis of autoantibodies. The immunosuppressed patient is much more susceptible to infection by opportunistic organisms. Generally these organisms are nonpathogenic and, when encountered by hosts with a normal immune system, are disposed of and cause no difficulties. The organisms include a wide variety of bacteria, viruses, fungi, and protozoa. Massive antibiotic therapy along with blood transfusions and other intensive care procedures are used to support the patient during these infections. However, many patients die despite heroic efforts. Resistance
The development in tumor cells of varying degrees of resistance to drugs is one of the limiting factors in tumor chemotherapy. Unfortunately, normal cells which are sensitive to antitumor drugs do not develop resistance. It is not known whether drug-resistant cells preexist in drug-sensitive tumors .or whether resistant cells appear as the result of drug-induced mutations. Some of the most important ways in which tumor cells may acquire resistance are: 2 • 8 ' 15 (l) the development of alternative metabolic pathways; (2) the devlopment of repair mechanisms to correct the damage done by the drug; (3) destruction of the drug by the cell; (4) changes in the permeability of the cell membrane; (5) tumor cells entering the resting (G0 ) phase of the cell cycle; and (6) deletion of cellular drug activation mechanisms. Some tumors are naturally resistant to chemotherapy, but in most cases the reasons for this resistance are unknown. Sometimes, drug resistance is the result of the anatomical location of the tumor. For example, most chemotherapeutic agents cannot cross the blood brain barrier, thus primary or secondary metastatic neoplasms in the central nervous system survive the intended actions of these drugs. Combination chemotherapy can limit the development of drug resistance because of the additive antitumor effects of combined drug therapy, and
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because a few tumors become more susceptible to one drug as they become more resistant to another. Miscellaneous Factors Affecting Drug Usefulness
Several factors determine the clinical usefulness of chemotherapeutic drugs.U As previously mentioned, cancer cells may be resistant to the effect of these drugs due to anatomical location. Pharmacological factors influence the concentration of a drug at its primary site of action or the period of time that drug is available for activity. The route of administration may improve the antitumor effect of a given drug by allowing it to reach high concentrations in the area of greatest need. The isolation perfusion technique using methotrexate has improved the therapy of head and neck tumors in humans. The distribution of drugs is important because drugs may accumulate in certain areas as a result of binding or active transport, and thus may not be available at the tumor site. Certain drugs are inactive prior to administration and must be metabolized to achieve their active form. An example of this is cyclophosphamide which requires metabolism by the liver. The excretion of some drugs is critical in that they accumulate and produce severe toxicity if organ function is not adequate. Major hematologic toxicity may result from impaired renal excretion of methotrexate or neurotoxicity from vincristine if bile excretion is impaired by liver dysfunction. The simultaneous administration of clinically useful antibiotics and anticancer drugs can be synergistic or antagonistic. For example, hydrocortisone and cephalothin inhibit cellular uptake of methotrexate by 20 and 28 per cent respectively, whereas vincristine enhances methotrexate uptake approximately 60 per cent by inhibiting methotrexate cellular effiux. 3 All these factors must be considered when attempting to treat cancer with various combinations of drugs. Combination Chemotherapy It has been found that when used alone many chemotherapeutic agents can only produce limited remission. Combinations of agents have proved to be more effective than when these agents are used alone. 14 For example, combination chemotherapy can suppress or delay the eventual development of drug resistant cells and prolong the time necessary for these cells to produce clinically apparent disease. Also, if combination chemotherapy is given in intensive intermittent courses rather than in continuous low dose form, there tends to be gr:eater tumor cell death and much less immunosuppression. Intermittent, intensive chemotherapy may augment the endogenous cellular immune response to tumor cells during the recovery period. When designing a protocol for combination chemotherapy, a better response may be expected if the following guidelines or principles
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are followed: (1) Use only drugs with known activity against a specific neoplasm. (2) Drugs with different mechanisms of action should be chosen so that the antitumor effects will be additive. (3) Choose drugs with different ranges of toxicity so that the toxic effects are not additive and each drug can be used at its maximum dose. (4) The fraction of tumor cells killed by one drug is independent of the fraction killed by another drug. Currently, several combinations of drugs are used to control various neoplastic diseases in animals. Canine lymphosarcoma can be treated with vincristine (a mitotic inhibitor) which has neural toxicity, cyclophosphamide (an alkylating agent) which causes bone marrow depression, and prednisone (a hormone) which stimulates gluconeogenesis. Canine transmissible venereal tumor can be very effectively treated with a combination of vincristine, cyclophosphamide, and methotrexate (a folic acid inhibitor). Future Considerations
The future use of chemotherapeutic drugs in veterinary medicine depends on many factors. First, the biological behavior of different tumors must be established. Currently, veterinary oncologists are able to predict accurately the survival time of animals that develop only a few types of malignant tumors, such as osteosarcoma, lymphosarcoma, undifferentiated mast cell tumors, and oral melanoma. Second, new information concerning cellular kinetics and the pharmacology of current and new drugs will help the clinician establish more effective dose ranges, frequency of administration, better drug combination, and reduced toxic side effects. The use of chemotherapeutic drugs in combination with other therapy modalities, such as surgery, radiotherapy, and immunotherapy, should increase survival rates and possibly "cure" many other types of malignant disease in animals. This has already been demonstrated in humans with certain tumor types. Information needs to be gained concerning the proper timing of the use of drugs with surgery and the least immunosuppressive regimen of drugs used in combination with various types of immunopotentiating agents. In veterinary medicine, oncologists must cooperate in developing standards for clinical staging of various tumors. Accepted definitions for remission and for response to therapy and the reporting of results with statistical analysis will help practicing veterinarians decide whether or not to offer these treatment protocols to their clients' animals. Probably no single miracle drug to cure cancer will be discovered in the future. It seems that we now have the drugs and therapeutic techniques necessary, but we need to learn how to employ them in better combination or sequence in order to provide a more permanent control of malignant cells.
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REFERENCES l. Aisenberg, A. C.: Introduction to immunosuppressants. Adv. Pharmacol. Chemother., 8:32, 1970. 2. Ball, C. R.: Intracellular factors affecting the response of tumors to chermotherapeutic agents. Sci. Basis Cancer Chemother., 21:26, 1969. 3. Bender, R. A., et a!.: Alteration of methotrexate uptake in human leukemia cells by other agents. Cancer Res., 35:1305, 1975. 4. Bloom, F.: Effect of cortisone on mast cell tumors (mastocytoma) of the dog. Proc. Soc. Exp. Bioi. Med., 79:651, 1952. 5. Bonadonna, G., eta!.: Combination chemotherapy as an adjuvant treatment in operable breast cancer. New Engl. J. Med., 294:405, 1976. 6. Bostock, D. E.: The prognosis following surgical removal of mastocytoma in dogs. J. Small Anim. Pract., 14:27, 1973. 7. Bostock, D. E., and Owen, L. N.: Chemotherapy of canine and feline neoplasia. J. Small Anim. Pract., 13:359, 1972. 8. Brockman, R. W.: Mechanisms of resistance to anticancer drugs. Adv. Cancer Res., 7:129, 1963. 9. Brodey, R. S., and Abt, D. A.: Results of surgical treatment in 65 dogs with osteosarcoma. J.A.V.M.A., 168:1032, 1976. 10. Chabner, B. A., Meyer, C. E., et a!.: The clinical pharmacology of antineoplastic agents. New Engl. J. Med., 292:1159, 1975. 11. Cline, M. J ., and Haskell, C. M.: Cancer Chemotherapy. Philadelphia, W. B. Saunders Co., 1975. 12. Dowling, M. D., Jr., Krakoff, I. H., and Karnofsky, D. A.: Mechanism of action of anticancer drugs. In Cole, W. E. (ed.): Chemotherapy of Cancer. Philadelphia, Lea and Febiger, 1970. 13. Fisher, B., Wolmark, N., Rubin, H., et al.: Further observations on the inhibition of tumor growth by C. parvum with cyclophosphamide. I. Variation in administration of both agents. J. Nat. Cancer Inst., 55:ll47, 1975. 14. Frei, E., III: Combination cancer therapy. Cancer Res., 32:2593, 1972. 15. Goldin, A.: Factors pertaining to complete drug-induced remission of tumors in animals and man. Cancer Res., 29:2285, 1969. 16. Gutterman, .J. U., Mavlight, G., Gottlieb, J. A., eta!.: Chemoimmunotherapy of disseminated malignant melanoma with DTIC and BCG. New Engl. J. Med., 291:592, 1974. 17. Hall, T. C.: Use of cancer chemotherapeutic agents in non-neoplastic diseases. Cancer, 31:1256, 1973. 18. Harris, J., Sengar, D., eta!.: The effect of immunosuppressive chemotherapy on immune function in patients with malignant disease. Cancer, 37:1058, 1976. 19. Hess, P. W.: Principles of cancer chemotherapy. In Kirk, R., (ed.): Current Veterinary Therapy VI. Philadelphia, W. B. Saunders Co., 1977. 20. Hess, P. W., MacEwen, E. G., and McClelland, A . .J.: Chemotherapy of canine and feline tumors. J.A.A.H.A., 12:350, 1976. 21. Hill, B. T., and Baserga, R.: The cell cycle and its significance for cancer treatment. Cancer Treat. Rev., 2:159, 1975. 22. Jaffe, N ., eta!.: Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. New Engl. .J. Med., 291:994, 1974. 23. Krakoff, I. H.: Cancer chemotherapeutic agents. Cancer Chemotherapy Course. New York, Memorial Sloan-Kettering Cancer Center, 1974. 24. Kruegar, G., Morphology of chemical immunosuppression. Adv. Pharmacal. Chemother., 10:1, 1972. 25. MacEwen, E. G., and Hess, P. W.: Management of canine hematopoietic neoplasms. Current Veterinary Therapy VI. Philadelphia. W. B. Saunders Co., 1977. 26. Owen, L. N., Bostock, D. E., et a!.: The role of spontaneous canine tumors in the evaluation of the etiology and therapy of human cancer. J. Small Anim. Pract., 16: 155, 1975. 27. Rosen, G., eta!.: High dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma. Cancer, 33:1151, 1974.
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28. Schein, P. S., and Winokur, S. H.: Immunosuppressive and cytotoxic chemotherapy: Long term complications. Ann. Intern. Med., 82:84, 1975. 29. Skinner, M.D., and Schwartz, R. S.: Immunosuppressive therapy. New Engl. J. Med., 287:221, 281, 1972. 30. Theilen, G. H.: Veterinary medical oncology. In Ettinger, S. J. (ed.): Textbook of Veterinary Internal Medicine. Philadelphia, W. B. Saunders Co., 1975, p. 127. 31. Valeriote, F., and van Putten, L.: Proliferation-dependent cytotoxicity of anticancer agents: A review. Cancer Res., 35:2619, 1975. Box 384 St. Thomas United States Virgin Islands 00801
Principles of Cancer Chemotherapy Paul W. Hess, D.V.M.*
In the early 1950's, the first reports appeared concerning the clinical response of naturally occurring canine tumors to modern cancer chemotherapy. 4 The use of cancer chemotherapy in veterinary medicine has made slow progress since that time. This was due to the expense of antitumor drugs, the poor prognosis in most cases, the unpleasant side effects which occur when most of these drugs are used in therapeutic doses, and the lack of accurate biological behavior data of animal tumors. For years scientists have used normal, healthy dogs to elicit the toxic side effects and safe dosage levels of new anticancer drugs prior to their use in preliminary studies in humans. This information can be used by veterinary oncologists to formulate drug protocols used in treating cancer in dogs. The effectiveness of these protocols can then be reported to the practitioner and subsequently offered to the client whose dog is suffering from cancer. The recent advances in chemotherapy of human cancer patients, whether used alone or in combination with other modalities, have made pet owners aware of the potential benefits t\) be obtained from cancer chemotherapy. As a result the practicing veterinarian should now be able to offer chemotherapy to pets who have developed tumors. The purpose of this paper is to describe the principles of cancer chemotherapy and some of the most commonly used drugs together with their beneficial applications and detrimental side effects. Tumor, Host, and Drug Interrelationships
The veterinarian, when using cancer chemotherapy drugs, should always remember the close relationship between the tumor, host, and drugs. These interactions are: (a) disease, i.e., the effect of the tumor on the host; (b) therapy, the effects of the drug on the tumor; and (c) toxicity, the effects of the drug on the host. The predominant factor or factors in this relationship determine the final outcome for the animal *Private Practitioner, St. Thomas. Virgin Islands; Formerly, Head of Cancer Therapy Unit, Henry Bergh Memorial Hospital, New York, and Research Associate, ~fc morial Sloan-Kettering Cancer Center, New York, New York
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receiving cancer chemotherapy. For example, an excellent response to therapy encompasses remission of signs or symptoms of disease without impairment of normal function of the host due to toxicity. The quality of survival is determined by these interactions and is very important to the client and veterinarian since there exists the alternative of euthanasia as opposed to treatment in pet animals. Selection of Patients
Chemotherapy is the most suitable form of therapy for patients with tumors which are not amenable to surgery or radiotherapy. Patients that should be considered for chemotherapy include those with disseminated tumors such as leukemia, lymphosarcoma, multiple myeloma, and other hemopoietic tumors, or those with highly malignant solid tumors which metastasize rapidly. 19 • 20 • 23 • 2 5 , 26, 3° Those animals which have tumors in which the results of surgery or radiotherapy are poor may have prolonged survival if treated with chemotherapy. For instance, the average survival for cats with intraoral carcinomas treated with radiotherapy is only 12 weeks; the median survival time for dogs with osteosarcoma treated with amputation is 18 weeks. 7 • 9 In man, adjunctive chemotherapy has significantly prolonged survival in osteosarcoma and mammary cancer patients. 5 • 22 • 27 Also, chemotherapy may be used in animals with tumors of prostate, pharynx, and nasal cavities since they are located in difficult sites for surgical procedures. Until recently, there has been considerable reluctance to administer toxic drugs to patients apparently clinically free of tumor after surgery or radiotherapy. However, there is strong evidence that such patients are not free of malignant cells and that aggressive chemotherapy before metastases are clinically detectable increases the chances of survival. The problem is to identify those patients with clinically undiscernible metastases who would benefit from adjunctive therapy. In general, chemotherapy should not be administered to animals with undetectable tumors unless the biological behavior of the tumor is known. For example, canine osteosarcoma and undifferentiated mast cell tumors rapidly metastasize and dogs with these tumors are candidates for adjunctive chemotherapy following surgery. 6 • 9 Healthy feline leukemia virus infected cats should not be treated with chemotherapy since the drugs cannot eliminate the virus. In fact, chemotherapy may be detrimental since most antitumor drugs are immunosuppressive and thus increase the chances of disease development. Patients with non-neoplastic diseases such as canine pemphigus and polycythemia respond to the immunosuppressive action of chemotherapeutic drugs. 19 In man, disease conditions such as refractory psoriasis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune
PRINCIPLES OF CANCER CHEMOTHERAPY
23
hemolytic anemia, idiopathic thrombocytopenic purpura, and various renal diseases such as nephrotic syndrome, glomerulonephritis, and lupus nephritis are managed with cancer chemotherapy.11· 29 Their use in veterinary medicine needs to be evaluated. Before any animal is selected to receive chemotherapy, the clinician must be able to meet the following standards in order to utilize chemotherapeutic agents safely: Establish a histological diagnosis of malignancy and a known sensitivity to antineoplastic drugs. Be familiar with the drugs and their potential toxicity. Use safe dosage schedules established for dogs and cats. Be able to monitor toxicity at regular intervals. Be able to evaluate an adequate response. Establish a willingness on the part of the client to cooperate fully with the veterinarian during a carefully planned therapy program.
The decision to initiate therapy or select which drugs may be best administered may be influenced by the pre-treatment evaluation of the patient. A complete history should be taken to establish if any previous therapy has been given or if there has been any other recent illness which may influence the effectiveness of the drugs. A complete physical examination along with base line hematological data such as complete blood counts and liver and kidney function tests are mandatory. Other special tests such as bone marrow examination or special radiological procedures may be needed to completely evaluate the extent of disease or underlying complications. Other factors which may influence the effectiveness of drugs will be discussed later.
Cell Kinetics A knowledge of the cell cycle or the proliferative state of the cell population is important for understanding the cytotoxic effects of cancer chemotherapy. 2L 31 The cell cycle can be defined as an orderly sequence of events occurring during the time interval from one cell division to the next. The cell cycle is divided into the following phases: mitosis (M), postmitotic growth in which RNA and protein synthesis occur prior to DNA synthesis (G 1 ), resting or nonproliferating phase for differentiated cells (G 0 ), new DNA synthesis (S), RNA and protein synthesis prior to mitosis (G2 ) (Fig. 1). Cell populations differ in relationship to DNA synthesis and mitosis in that some cells continuously move through the cell cycle; other cells leave the cycle but can be induced to synthesize DNA and divide by certain stimuli; and finally, some cells will leave the cycle permanently and will die without further division. Normal cells have four basic properties: (1) ability to proliferate; (2) capacity for self-renewal; (3) ability to differentiate; (4) sensitivity to regulatory mechanisms. Malignant cells have the first two properties and differentiation may be present but abnormal. The main
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M
Figure 1. A schematic diagram of the cell cycle. Mitosis (M) is followed by a growth phase (G 1), or in differentiated cells a resting phase (G 0). DNA synthesis (S) then takes place followed by another growth phase (G 2) before the cell divides.
s difference between normal and malignant cells is response to regulation; in malignant cells this property is either greatly reduced or completely absent. The ideal treatment would bring about maximum normal cell survival and minimal tumor cell recovery. 21 The response of cells to drugs depends on the mechanism of action of the drug and the position of the cell in the cell cycle. 2 • 10 • lL 15 Cells in the S phase are especially susceptible to drugs which prevent the formation of nucleotides or inhibit DNA repair. Anticancer drugs can be divided into six classes according to their mechanism of action: 12 Alkylating agents act by crosslinking cellular DNA, thus impeding its ability to act as a template for RNA synthesis. Antimetabolites interfere with the biosynthesis of nucleic acids by substituting for normal metabolites and inhibiting normal enzymatic reactions. Antibiotics are thought to bind nonspecifically to cellular DNA and inhibit transcription. Mitotic inhibitors destroy the mitotic spindle of the cell and prevent further cell division. Hormones are thought to act by interfering with cell membrane receptors that stimulate growth. Miscellaneous drugs are those which do not act in any of the ways described above or whose mechanism of action is at present unknown.
The mechanisms by which antitumor drugs exert their effect govern the basic principles of cancer chemotherapy. The sensitivity of a tumor cell to a particular drug is determined by its position in the cell cycle at the time the drug exerts its maximum effect. Also, rapidly growing tumors are the most susceptible to chemotherapy, whereas slow growing tumors, in which there is a greater proportion of resting cells, are less susceptible. However, certain drugs are effective against resting cells as well as growing cells. 21 Also, drugs which are primarily effective against growing cells can be toxic to nonproliferating cells by
PRINCIPLES OF CANCER CHEMOTHERAPY
25
increasing the dosage. These, in addition to other factors, increase the chances of killing all the malignant cells in the body. In both experimental and clinical trials, the effectiveness of chemotherapy is inversely related to the number of malignant cells present. The fewer the malignant cells, the more effective is chemotherapy. Thus chemotherapy should be started as soon as possible and used as an adjunct to surgery, radiotherapy, or immunotherapy when indicated.13. 14. 16 Anticancer Drugs Currently, there are over 20 anticancer drugs commercially available to the veterinarian (Table 1). Detailed pharmacological information is not included in this paper, but is readily available from other sources. 1· 10· 11 • 23 The drugs are listed according to class of action with the following information: generic and brand name, manufacturer, preparations, sensitive neoplasms, suggested dosages, and frequency of administration. More detailed information concerning the use of these agents in specific neoplastic conditions is dealt with in other reports or elsewhere in this symposium. 20· 25 The most common method of expressing drug dosages is by body weight (i.e., mg per kg). However, it has been found that body surface area is related to several physiological parameters such as the blood volume and urea clearance, and that the maximum toxic dose of several drugs is the same in a wide variety of species when the doses are expressed in terms of body surface area. Since toxicity data is often only available in other species, and because the activity of most drugs depends on some physiological process, drug doses for veterinary cancer patients should be expressed in terms of body surface area. An objection to this method is that body surface area is difficult to measure. A conversion table of weights to body surface area is available, and a method of converting dosages given by body weight (i.e., mg per kg) to dosages based on body surface area is explained in other reports. 20· 30 Toxicity and Complications Most chemotherapeutic drugs are toxic to all dividing cells and there can be a fine line between therapeutic and toxic doses. The toxic side effects, if manifested, may limit the use of a single drug or combination of drugs. These side effects may be slight; mild alopecia, anorexia, vomiting, and diarrhea may necessitate only a temporary withdrawal of chemotherapy. Side effects such. as thrombocytopenia, leukopenia, severe anemia, and gastrointestinal bleeding can be so severe that chemotherapy may have to be discontinued permanently11 It is essential that all animals being given anticancer drugs be monitored frequently for toxic side effects. Monitoring should include a thorough physical examination, complete blood cell counts, serum
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Table 1. DRUG
Alkylating Agents Cyclophosphamide (Cytoxan) Mead Johnson; 25 and 50 mg tablets; 100, 200 and 500 mg vials
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Antineoplastic Agents SENSITIVE NEOPLASMS
SUGGESTED DOSAGES
Lymphosarcoma, lymphoreticular leukemias, reticulum cell sarcoma, mast cell tutnors, transmissible venereal tumor, miscellaneous solid tumors
6.6 mg/kg for 3 days, then 2.2 mg/kg daily orally. Pulse: 10 mg/kg intravenously every 7-10 days
Nitrogen mustard (Mustargen) Merck Sharp and Dome; 10 mg vials
Lymphosarcoma, mast cell tumors
0.1-0.5 mg/kg daily, intravenously
Chlorambucil (Leukeran) Burroughs Wellcome; 2 mg tablets
Chronic lymphocytic leukemia, macroglobulinemia
0.2 mg/kg daily, orally
n, n', n",-triethylenethio-
Mast cell tumors, miscellaneous sarcomas and carinomas
0.5 mg/kg daily for I 0 days, intralesionally or intravenously
Busulfan (Myleran) Burroughs Wellcome; 2 mg tablets
Granulocvtic leukemias, myleop~oliferative disorders
1 mg;kg daily, orally
Melphalan (Alkeran) Burroughs Wellcome; 2 mg tablets
Multiple myeloma, monoclonal gammopathies
0.05-0.1 mg/kg daily, orally
Lymphosarcoma, acute lymphocytic
0.06 mg/kg daily, orally; 0.3-0.8 mg/ kg intravenously, weekly
phosphoramide (Thiotepa) Led erie; 15 mg vials
Antimetabolites Methotrexate- Led erie; 2.5 mg tablets, 5 and 50 mg vials
leukemia, transmissible venereal tumor, various solid tumors
6 Mercaptopurine (Purinethol, 6-MP) Burroughs Wellcome; 50 mg tablets
Lymphosarcoma, acute lymphocytic leukemia, myelogenous leukemia
2.2 mg/kg daily
6-Thioguanine (Tabloid) Burroughs Wellcome; 40 mg tablets
Lymphosarcoma, mast cell tumor
2.5 rng/kg daily
5-Fluorouracil (5-Fluorouracil, Fluorouracil) Roche Laboratories; 500 mg vials
Miscellaneous carcinomas and
Do not use in cats
Efudex (5-Fluorouracil Cream and Solution 2% and 5%) Roche Laboratories Cytosine arabinoside (Ara-C, Cytosar) UpJohn; I 00 and 500 mg vials
sarcomas
Dogs: 5 mg/kg every 5-7 days, intravenously
Cutaneous tumors
Apply twice daily for 2-4 weeks
Lymphosarcomas, granulocytic leukemia, mast cell tumors
5-10 mg/kg daily for 2 weeks or 30-50 mg/kg weekly (intramuscularly, subcutaneously, intravenously)
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PRINCIPLES OF CANCER CHEMOTHERAPY
Table I. DRUG
Antibiotics Actinomycin D (Cosmegen) Merck, Sharp and Dome; 500 !Lg/vial
Antineoplastic Agents (Continued) SENSITIVE NEOPLASMS
SUGGESTED DOSAGES
Lymphosarcoma, miscellaneous sarcomas and carcinomas
0.015 mg/kg for 3-5 days, then wait 3 weeks for marrow recovery
Doxorubicin hydrochloride (Adriamycin) Adria Laboratory; 10 mg vials
Osteosarcoma, miscellaneous sarcomas and carcinomas
Not available for dogs or cats; in humans, 2 mg/kg intravenously every 3 weeks
Bleomycin (Blenoxane) Bristol Labs; 15 units/ vial
Squamous cell carcinomas, miscellaneous carcinomas
Not available for dogs or cats; in humans, 0.3-0.5 units/kg once or twice weekly, intravenously or iiltramuscularly
Lymphosarcoma, acute lymphoblastic leukemia, reticulum cell sarcoma, mast cell tumor, transmissible venereal tumor
0.025-0.05 mg/kg every 7-10 days, intravenously
Lymphosarcoma, rnast cell tun1or
0.1-0.4 mg/kg every 7-10 days intravenously
Lvmphosarcoma, acute lymphoblastic leukemia, mast cell tumors, multiple rnyeloma, and mis<.:ellaneous tumors
0.5-1 mg/lb divided twice daily
Estrogens DES, ECP
Perianal adenomas, advanced carcinotnas of prostate
DES-1 mg every other day; ECP-12 mg every 2-4 weeks
Testosterone
Mammary tumors, bone marrow depression
2 mg/kg intramuscularly 3 times weekly
Myelogenous leukemia, mast cell tumor
80 mg/kg every 3 days or 40-50 mg/kg divided twice daily, orally
O,p'-DDD (Mitotane Lysodren) Calbio; 500 mg tablets
Adrenal cortical adenomas, and carcinomas
50 mg/kg daily to effect
Dacarbazine (DTIC-Dome) Dome Laboratories; 100 and 200 mg vials
Malignant melanoma
Not available for dogs or cats; in humans, 2.0-4.5 mg/kg intravenously daily for 10 days. Repeat at 4-6 week intervals
Procarbazine (Matulane) Roche Laboratories; 50 mg capsules
Lymphosarcoma
Not available for dogs or cats; in humans, 50-100 mg daily until bone marrow depression
Plant Alkaloids Vincristine (Oncovin) Eli Lilly; I and 5 mg vials Vinblastine (V elban) Eli Lilly; 10 mg/vial
Hormones Adrenal corticosteroids (Prednisone)
Miscellaneous Hydroxyurea (Hydrea) Squibb; 500 mg capsules
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enzyme levels, and renal function tests every 7 to 10 days. Drugs should be discontinued if bone marrow depression is manifested by a total white blood count below 3,000 per cubic mm and/or a platelet count less that 50,000 per cubic mm. It is very important for the veterinarian to remember that once a drug (except for methotrexate) has been administered, there is nothing that can neutralize its action or prevent serious delayed side effects. A thorough explanation to the client about toxic side effects before the use of anticancer drugs will help the client observe the patient at home and detect the earliest signs of complications, thus allowing early treatment. Certain agents, usually given by the intravenous route, are very irritating and cause local reactions when they are inadvertently leaked into the extravascular tissue. Severe pain, erythema, and erosion of tissue will occur. Great care should be taken, therefore, when administering vincristine, vinblastine, actinomycin D, and Adriamycin (doxorubicin hydrochloride). If these drugs are accidentally given outside the vein, infiltration of the area with saline, xylocaine, and corticosteroids, or the topical application of a mixture of dimethylsulfoxide and corticosteroids will lessen the extent of tissue damage. In general, most of the anticancer drugs cause myleosuppression, but a few of the drugs have unique toxic side effects. Cyclophosphamide can induce hemorrhagic cystitis. This complication can be prevented by administering the agent in the morning, forcing fluid intake by salting food, and encouraging urination. With 5-fluorouracil, bizarre central nervous system reactions have been seen. The reactions are characterized by apparent hallucinations, hyperexcitability, fright, and severe personality change. This drug should not be given to cats at current recommended dosages. Vincristine causes neuromuscular weakness and constipation (gastrointestinal atony), which is easily treated by withdrawal of the drug and the use of laxatives. Side effects indirectly related to the drugs are those due to rapid tumor cell breakdown and can lead to abnormal hepatic or renal function. Local reactions such as pain, edema, inflammation, and abscess formation or tissue necrosis can occur as the tumor cells die and are eliminated from the body. Immunosuppression
The effect of anticancer drugs on the immune system may be beneficial or detrimentaU· 18 • 24 ' 28 ' 29 These drugs affect both the humoral and cellular immunity. With appropriate drug dose and timing, primary and secondary antibody production can be completely blocked or delayed. Also, tolerance to antigens can be established. New and established delayed hypersensitivity reactions may be suppressed by the
PRINCIPLES OF CANCER CHEMOTHERAPY
29
same mechanism of action these drugs exert on any cells which need to proliferate. The transplantation of allogeneic grafts has been successful in humans due to the administration of drugs before and after antigenic stimulation, i.e., transplantation. Cyclophosphamide and corticosteroids are effective before transplantation, whereas 6-mercaptopurine, azathioprine, and methotrexate are given post transplantation. The first group appears to interact with antigen-sensitive cells and to interfere with cell proliferation, whereas the second group interferes with cell transformation, cell differentiation, and initiation of antibody formation. Agents used to treat autoimmune diseases include cyclophosphamide, methotrexate, 6-mercaptopurine, 6-thioguanine, azathioprine, chlorambucil, and corticosteroids. Their actions suppress inflammatory response and inhibit the synthesis of autoantibodies. The immunosuppressed patient is much more susceptible to infection by opportunistic organisms. Generally these organisms are nonpathogenic and, when encountered by hosts with a normal immune system, are disposed of and cause no difficulties. The organisms include a wide variety of bacteria, viruses, fungi, and protozoa. Massive antibiotic therapy along with blood transfusions and other intensive care procedures are used to support the patient during these infections. However, many patients die despite heroic efforts. Resistance
The development in tumor cells of varying degrees of resistance to drugs is one of the limiting factors in tumor chemotherapy. Unfortunately, normal cells which are sensitive to antitumor drugs do not develop resistance. It is not known whether drug-resistant cells preexist in drug-sensitive tumors .or whether resistant cells appear as the result of drug-induced mutations. Some of the most important ways in which tumor cells may acquire resistance are: 2 • 8 ' 15 (l) the development of alternative metabolic pathways; (2) the devlopment of repair mechanisms to correct the damage done by the drug; (3) destruction of the drug by the cell; (4) changes in the permeability of the cell membrane; (5) tumor cells entering the resting (G0 ) phase of the cell cycle; and (6) deletion of cellular drug activation mechanisms. Some tumors are naturally resistant to chemotherapy, but in most cases the reasons for this resistance are unknown. Sometimes, drug resistance is the result of the anatomical location of the tumor. For example, most chemotherapeutic agents cannot cross the blood brain barrier, thus primary or secondary metastatic neoplasms in the central nervous system survive the intended actions of these drugs. Combination chemotherapy can limit the development of drug resistance because of the additive antitumor effects of combined drug therapy, and
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because a few tumors become more susceptible to one drug as they become more resistant to another. Miscellaneous Factors Affecting Drug Usefulness
Several factors determine the clinical usefulness of chemotherapeutic drugs.U As previously mentioned, cancer cells may be resistant to the effect of these drugs due to anatomical location. Pharmacological factors influence the concentration of a drug at its primary site of action or the period of time that drug is available for activity. The route of administration may improve the antitumor effect of a given drug by allowing it to reach high concentrations in the area of greatest need. The isolation perfusion technique using methotrexate has improved the therapy of head and neck tumors in humans. The distribution of drugs is important because drugs may accumulate in certain areas as a result of binding or active transport, and thus may not be available at the tumor site. Certain drugs are inactive prior to administration and must be metabolized to achieve their active form. An example of this is cyclophosphamide which requires metabolism by the liver. The excretion of some drugs is critical in that they accumulate and produce severe toxicity if organ function is not adequate. Major hematologic toxicity may result from impaired renal excretion of methotrexate or neurotoxicity from vincristine if bile excretion is impaired by liver dysfunction. The simultaneous administration of clinically useful antibiotics and anticancer drugs can be synergistic or antagonistic. For example, hydrocortisone and cephalothin inhibit cellular uptake of methotrexate by 20 and 28 per cent respectively, whereas vincristine enhances methotrexate uptake approximately 60 per cent by inhibiting methotrexate cellular effiux. 3 All these factors must be considered when attempting to treat cancer with various combinations of drugs. Combination Chemotherapy It has been found that when used alone many chemotherapeutic agents can only produce limited remission. Combinations of agents have proved to be more effective than when these agents are used alone. 14 For example, combination chemotherapy can suppress or delay the eventual development of drug resistant cells and prolong the time necessary for these cells to produce clinically apparent disease. Also, if combination chemotherapy is given in intensive intermittent courses rather than in continuous low dose form, there tends to be gr:eater tumor cell death and much less immunosuppression. Intermittent, intensive chemotherapy may augment the endogenous cellular immune response to tumor cells during the recovery period. When designing a protocol for combination chemotherapy, a better response may be expected if the following guidelines or principles
PRINCIPLES OF CANCER CHEMOTHERAPY
31
are followed: (1) Use only drugs with known activity against a specific neoplasm. (2) Drugs with different mechanisms of action should be chosen so that the antitumor effects will be additive. (3) Choose drugs with different ranges of toxicity so that the toxic effects are not additive and each drug can be used at its maximum dose. (4) The fraction of tumor cells killed by one drug is independent of the fraction killed by another drug. Currently, several combinations of drugs are used to control various neoplastic diseases in animals. Canine lymphosarcoma can be treated with vincristine (a mitotic inhibitor) which has neural toxicity, cyclophosphamide (an alkylating agent) which causes bone marrow depression, and prednisone (a hormone) which stimulates gluconeogenesis. Canine transmissible venereal tumor can be very effectively treated with a combination of vincristine, cyclophosphamide, and methotrexate (a folic acid inhibitor). Future Considerations
The future use of chemotherapeutic drugs in veterinary medicine depends on many factors. First, the biological behavior of different tumors must be established. Currently, veterinary oncologists are able to predict accurately the survival time of animals that develop only a few types of malignant tumors, such as osteosarcoma, lymphosarcoma, undifferentiated mast cell tumors, and oral melanoma. Second, new information concerning cellular kinetics and the pharmacology of current and new drugs will help the clinician establish more effective dose ranges, frequency of administration, better drug combination, and reduced toxic side effects. The use of chemotherapeutic drugs in combination with other therapy modalities, such as surgery, radiotherapy, and immunotherapy, should increase survival rates and possibly "cure" many other types of malignant disease in animals. This has already been demonstrated in humans with certain tumor types. Information needs to be gained concerning the proper timing of the use of drugs with surgery and the least immunosuppressive regimen of drugs used in combination with various types of immunopotentiating agents. In veterinary medicine, oncologists must cooperate in developing standards for clinical staging of various tumors. Accepted definitions for remission and for response to therapy and the reporting of results with statistical analysis will help practicing veterinarians decide whether or not to offer these treatment protocols to their clients' animals. Probably no single miracle drug to cure cancer will be discovered in the future. It seems that we now have the drugs and therapeutic techniques necessary, but we need to learn how to employ them in better combination or sequence in order to provide a more permanent control of malignant cells.
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REFERENCES l. Aisenberg, A. C.: Introduction to immunosuppressants. Adv. Pharmacol. Chemother., 8:32, 1970. 2. Ball, C. R.: Intracellular factors affecting the response of tumors to chermotherapeutic agents. Sci. Basis Cancer Chemother., 21:26, 1969. 3. Bender, R. A., et a!.: Alteration of methotrexate uptake in human leukemia cells by other agents. Cancer Res., 35:1305, 1975. 4. Bloom, F.: Effect of cortisone on mast cell tumors (mastocytoma) of the dog. Proc. Soc. Exp. Bioi. Med., 79:651, 1952. 5. Bonadonna, G., eta!.: Combination chemotherapy as an adjuvant treatment in operable breast cancer. New Engl. J. Med., 294:405, 1976. 6. Bostock, D. E.: The prognosis following surgical removal of mastocytoma in dogs. J. Small Anim. Pract., 14:27, 1973. 7. Bostock, D. E., and Owen, L. N.: Chemotherapy of canine and feline neoplasia. J. Small Anim. Pract., 13:359, 1972. 8. Brockman, R. W.: Mechanisms of resistance to anticancer drugs. Adv. Cancer Res., 7:129, 1963. 9. Brodey, R. S., and Abt, D. A.: Results of surgical treatment in 65 dogs with osteosarcoma. J.A.V.M.A., 168:1032, 1976. 10. Chabner, B. A., Meyer, C. E., et a!.: The clinical pharmacology of antineoplastic agents. New Engl. J. Med., 292:1159, 1975. 11. Cline, M. J ., and Haskell, C. M.: Cancer Chemotherapy. Philadelphia, W. B. Saunders Co., 1975. 12. Dowling, M. D., Jr., Krakoff, I. H., and Karnofsky, D. A.: Mechanism of action of anticancer drugs. In Cole, W. E. (ed.): Chemotherapy of Cancer. Philadelphia, Lea and Febiger, 1970. 13. Fisher, B., Wolmark, N., Rubin, H., et al.: Further observations on the inhibition of tumor growth by C. parvum with cyclophosphamide. I. Variation in administration of both agents. J. Nat. Cancer Inst., 55:ll47, 1975. 14. Frei, E., III: Combination cancer therapy. Cancer Res., 32:2593, 1972. 15. Goldin, A.: Factors pertaining to complete drug-induced remission of tumors in animals and man. Cancer Res., 29:2285, 1969. 16. Gutterman, .J. U., Mavlight, G., Gottlieb, J. A., eta!.: Chemoimmunotherapy of disseminated malignant melanoma with DTIC and BCG. New Engl. J. Med., 291:592, 1974. 17. Hall, T. C.: Use of cancer chemotherapeutic agents in non-neoplastic diseases. Cancer, 31:1256, 1973. 18. Harris, J., Sengar, D., eta!.: The effect of immunosuppressive chemotherapy on immune function in patients with malignant disease. Cancer, 37:1058, 1976. 19. Hess, P. W.: Principles of cancer chemotherapy. In Kirk, R., (ed.): Current Veterinary Therapy VI. Philadelphia, W. B. Saunders Co., 1977. 20. Hess, P. W., MacEwen, E. G., and McClelland, A . .J.: Chemotherapy of canine and feline tumors. J.A.A.H.A., 12:350, 1976. 21. Hill, B. T., and Baserga, R.: The cell cycle and its significance for cancer treatment. Cancer Treat. Rev., 2:159, 1975. 22. Jaffe, N ., eta!.: Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. New Engl. .J. Med., 291:994, 1974. 23. Krakoff, I. H.: Cancer chemotherapeutic agents. Cancer Chemotherapy Course. New York, Memorial Sloan-Kettering Cancer Center, 1974. 24. Kruegar, G., Morphology of chemical immunosuppression. Adv. Pharmacal. Chemother., 10:1, 1972. 25. MacEwen, E. G., and Hess, P. W.: Management of canine hematopoietic neoplasms. Current Veterinary Therapy VI. Philadelphia. W. B. Saunders Co., 1977. 26. Owen, L. N., Bostock, D. E., et a!.: The role of spontaneous canine tumors in the evaluation of the etiology and therapy of human cancer. J. Small Anim. Pract., 16: 155, 1975. 27. Rosen, G., eta!.: High dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma. Cancer, 33:1151, 1974.
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28. Schein, P. S., and Winokur, S. H.: Immunosuppressive and cytotoxic chemotherapy: Long term complications. Ann. Intern. Med., 82:84, 1975. 29. Skinner, M.D., and Schwartz, R. S.: Immunosuppressive therapy. New Engl. J. Med., 287:221, 281, 1972. 30. Theilen, G. H.: Veterinary medical oncology. In Ettinger, S. J. (ed.): Textbook of Veterinary Internal Medicine. Philadelphia, W. B. Saunders Co., 1975, p. 127. 31. Valeriote, F., and van Putten, L.: Proliferation-dependent cytotoxicity of anticancer agents: A review. Cancer Res., 35:2619, 1975. Box 384 St. Thomas United States Virgin Islands 00801