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.

    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.

    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.

    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.

    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.

Mammary Tumors (exception: inflammatory mammary cancer)

Prostate Tumors

Oropharyngeal Tumors

Skin Cancers

Gastrointestinal Tumors

Lung Tumors

Bone Tumors

    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.

    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.

    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

    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.

    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.

    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.

    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.

    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.

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

    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.

    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.

    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.

    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.

    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.

    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.

    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).

    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.

    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.

    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.

    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.

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.

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.

    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.

    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).

    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.

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.

    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.

    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).