General introduction to veterinary oncology: Myths and misconceptions (Proceedings)

Critically important, life-or death decisions regarding euthanasia, treatment, choice to pursue referral, etc. may be made based on information that the owner gets form the primary practicing clinician. There is still a great stigma attached to a diagnosis of cancer, and it is natural for owners of pets with cancer to anthropomorphize and equate cancer treatment in animals with experiences they may have had with treatment of themselves, their friends or family members. Being able to succinctly address these concerns and "dispel" some of the myths that owners may have is a critical component of cancer management in this setting. There are, additionally some myths or misconceptions that veterinarians cling to that may alter their approach to the cancer patient or the information they impart.

Is Cancer Really a Problem in Pets? (Incidence of tumors in Pets)

Unfortunately, yes. Owing to the lack of significant atherosclerosis-associated cardiovascular disease in the species, cancer is the leading "natural" cause of death in dogs, and the 2nd or 3rd most common cause of death in cats. Up to 50% of dogs and 30-35% of cats will be affected by some type of tumor in their lifetime. Nearly half of all households in the United States include at least one companion animal. This places approximately 60 million dogs and 73 million cats at risk for developing cancers in the United States. Estimates of age adjusted overall cancer incidence rates per 100,000 individuals/year at risk range from 381 for dogs to 264 for cats. These are comparable to rates in human beings; approximately 300 from the National Cancer Institute SEER program. Rates for certain tumor types like canine osteosarcoma, canine soft tissue sarcomas, and feline non-Hodgkin's lymphoma (NHL) are significantly higher than that of humans. Similar per capita proportions are thought to exist in Canada and Europe

Client Perception of Cancer Incidence: An online survey by the Morris Animal Foundation in 1998 queried thousands of companion animal owners about their animal's health needs. In response to the question "what conditions most effect the health and well-being of your companions health?", cancer was the number one response for dogs and the number three response for cats. In response to the question "what disease did your companion die of?", cancer was the number one response in both species. Clearly, our clientele perceives cancer as an important aspect of their companion's health and are more informed than in the past, often as a result of Internet browsing. Our clients are demanding high quality medicine and seeking advanced treatments and protocols for their companions.

Why Treat Companion Animals with Cancer?

Because we can! We treat many animals with chronic disease that are never cured (i.e., diabetes, other endocrine diseases, heart disease), and cancer is another chronic disease. Furthermore, cancer is a disease that we can sometimes cure! Even in cases where cure is unlikely, there are many cancers where we can extend an excellent quality of life with treatment leading to a high level of client appreciation for this branch of veterinary medicine. As previously stated, the incidence of the disease and the client demand for honest and aggressive approaches to treatment are factors. Also, the management of cancer carries a high degree of professional challenge and a sense of accomplishment. From a purely economic standpoint, the clinician that carves out a niche for his or herself in the practice of veterinary oncology can greatly increase their practice base. Finally, companion animals with spontaneous tumors can serve as an excellent comparative model for the development of more effective and less toxic therapies for cancer in both humans and veterinary patients. While this final point traditionally has applied only to academic practice, the recruitment of clinical cases from private referral centers is now common in the United States and the practice is growing each year.

In General, What does the Average Practitioner Need to Know about Cancer?

In order to best meet the needs of our clients and the patients under our care, the clinician should have a clear understanding of the biology, behavior and the natural history of the common tumors presenting to them in practice. Additionally, a basic understanding of the techniques applied to diagnose and clinically stage a particular tumor, the modalities of treatment available, the costs involved, the prognosis, and the client's expectations are important. Ultimately, client education is one of the most important functions of the clinical oncologist.

Importance of Knowing the Biology/Natural History of Tumors

The practicing veterinarian should have a working knowledge of the common sites, the malignant potential, and the behavior of the more common tumor types. This will help the clinician choose where to look for metastatic disease, potential distant effects (i.e., paraneoplastic disorders) and precancerous lesions. This knowledge will also suggest the clinical workup necessary for individual cases and will drive the diagnostic approach, the treatments available, the response to treatment, and the overall prognosis.

Clinical Staging of Tumors

Thorough clinical staging of tumors defines the extent of disease present. This information allows for the evaluation of therapeutic 'dose', treatment planning and more accurate prognostication. It also allows for better communication between clinicians who may be working together in the care of patients. The nomenclature applied most commonly is that of the World Health Organization's "TNM" system where 'T' describes the size and invasiveness of the primary tumor; 'N" describes the status of lymphatic (nodal) involvement; and 'M' describes the presence or absence of distant metastasis. The addition of numbers to these components (e.g., T1, T2 .... etc., N0, N1...etc., M0, M1) indicates the extent of the malignant disease. For example, when dealing with mammary gland cancer in dogs, "T3b N2 M0" would indicate the tumor was more than 3 cm in diameter with fixation to underlying fascia or muscle (T3b); that either the axillary or inguinal lymph nodes were palpable and fixed (N2); and that there was no clinical evidence of distant metastasis (M0). More recently, molecular methods of staging have begun to be applied in veterinary medicine. The consequences of earlier diagnosis and the concept of "stage migration" will be discussed.

Biopsy Techniques in Clinical Oncology

A biopsy is no less important to the clinical oncologist than a diagnosis is to the clinical internist. Do we have to biopsy this tumor now? Can't we just wait and see what happens? Remember, the five most dangerous words in the English language are "maybe it will go away" or "let's see if it grows". Putting a name to the tumor type is necessary to most accurately predict the natural biology of the tumor (i.e. malignant vs benign, metastatic potential) and the diagnostic and treatment modalities best suited to the particular tumor. As many of the treatment modalities used in veterinary oncology may be associated with morbidity, haphazard treatment without biopsy procured justification does a disservice to the patient. Doesn't performing a fine needle aspirate/biopsy make the tumor "angry" and increase the risk of spread? NO! Contrary to a major misconception, properly performed biopsies do not increase the likelihood of future metastasis nor do they decrease the likelihood of future tumor control. Getting from the primary tumor into the blood stream is only one of many steps in the "metastatic decathlon". There are probably many circulating tumor cells in the body all the time, but it is only those few tumor cells with the complete genetic program that allow them to survive at a distant site that will be able to successfully metastasize. Exceptions to this rule are: (1) Some mast cell tumors may become inflamed following a fine needle aspirate due to degranulation and histamine release. This is rarely serious and can be treated or prevented with an H1 blocker; (2) Transabdominal needle aspiration/needle core biopsy of splenic and bladder masses is usually contraindicated, due to the risk of local dissemination in the abdomen and/or seeding of the biopsy tract. (3) It is important to plan needle aspirates and biopsies of cutaneous/subcutaneous masses so that the biopsy tract can be incorporated into the definitive surgical excision.

Indications for Biopsy

There are two primary reasons for performing a biopsy. 1) Therapy will be changed or altered based on the result, such as: a) excision will produce a functional defect (e.g. amputation), b) a more effective therapy modality exists, c) the tumor is suspected to have an invasive biology, or d) you suspect the lesion is benign (i.e. inflammatory, lipoma). 2) The clients require a confirmed diagnosis before giving permission for further diagnostics or therapy. It is evident that most lumps or bumps we deal with in practice will justify a biopsy for a least one of these reasons.

Excisional Versus Incisional Biopsies

Excisional biopsies imply the entire tumor is removed with 'clean' margins (i.e. no tumor cells extend beyond the cut surface of the surgical excision; See Enneking's classification of tumor resection table). The greatest theoretical advantage of an excisional biopsy is that the procedure may be curative. An additional advantage is that the entire mass can be presented to the pathologist allowing for better tissue orientation and margin evaluation. Excisional biopsies are used primarily for small, easily accessible tumors (e.g. cutaneous malignancies and most canine mammary tumors) where sufficient normal tissue exists to allow wide surgical margins, or, in cases where presurgical biopsy will not likely alter therapy or surgical approach (i.e. splenic, solitary lung, or intracranial tumors). Incisional biopsies on the other hand are used when lesion are too large or too difficult to excise in the ambulatory setting or if the initial treatment modality may be altered by the result. Care should be exercised in order to ensure the incision is placed where it can be dealt with by the future "definitive" procedure (i.e. biopsy tract in an excisable location). Multiple biopsies should be procured through one incision site, and one tumor/normal tissue margin should be included if possible. The disadvantages of incisional biopsies include its noncurative nature, the possibility of providing the pathologist with non-representative biopsies, the potential for complicating future surgery, and hemorrhage or viscous rupture if within a body cavity. Examples of incisional biopsies include fine needle aspirates (FNA), cutting needle biopsy (e.g. Tru-cut®), keyes punch biopsies and various fibre optically procured samples.

Table 1: Enneking's Classification of Tumor Resection

Proper Tissue Management

Avoid cautery, crush and desiccation injury to procured samples. Shrinkables (e.g. skin, muscle) should be fixed in normal configurations and samples for appropriate ancillary tests (impression smears, culture, immunohistochemical stains) should be separated prior to fixing. Similarly, it is important to avoid submission of parts of excised tissue or a "representative section" of an excised mass rather than the entire mass. This cuts the information gleaned from the pathology report in half, as surgical margins cannot be interpreted. If a mass is too large to be sent in, then the pathologist can be consulted for directions on which sections to send in and how to label them to insure that margins are evaluable. Margins should be submitted in such a way as to identify and orient them for the pathologist (ink, suture, separate containers). Finally, proper labeling and a thorough description of history, location, treatment history and response should be included in the pathology request.

Interpretation of Results

The clinician requires 4 pieces of data from the pathologist: is the lesion malignant or benign; histologic classification into subtypes that are therapeutically and prognostically relevant; the histologic grade if one exists; and most important, are the surgical margins free of tumor. For some biopsies, additional information such as mitotic rate, degree of atypia, necrosis or inflammation may also be helpful. It is extremely important to realize that 5 to 10% of all biopsy reports are incorrect regarding one or more of the above listed data types. This can result from poorly fixed or prepared samples, poor sampling (i.e. assuming the sample is representative), lack of orientation of sample, inexperience with the species in question, an incomplete requisition or failure to remember that invasion and metastasis are the most reliable indices for determining malignancy (e.g. oral tumors). The clinician has the right and the obligation to question the diagnosis if it does not match their clinical judgment and/or impression. It is extremely important that a good working relationship exists between the clinician and the pathologist such that a dialogue can be opened in cases that are not clear cut.

Treatment Modalities Available in Veterinary Oncology

Several modalities of treatment are available to veterinary patients and increasingly, these modalities are applied in combination to enhance efficacy. As stand alone therapies, the 5 general modalities available listed in decreasing order of efficacy (at present) are surgery, radiation therapy, chemotherapy, immunotherapy, and "biology based therapy". The line between immunotherapy and "biology based therapy" is blurred at times, but the latter is generally taken to include treatments using biological systems or molecular targets that are unique to tumors. Time will be devoted to each of these modalities over the course of this conference.

Patient Follow-Up in Veterinary Oncology

The intervals between rechecks for patients with cancer or who have had "curative intent" therapy varies with the biology of the tumor type and the treatment protocol employed. In general, rechecks should occur at 1, 3, 6, 9, 12, and 15 months following curative intent therapy, and then every 6 months thereafter. The data collected at each interval also varies with the known biology of the tumor type. For example, if dealing with an hemangioperycytoma on the distal extremity of a dog following surgical excision, because the metastatic potential is extremely low, a physical exam looking for recurrence and local extension may be all that is required. Conversely, when dealing with a surgically excised digital melanoma in a dog, because of the high metastatic potential, the recheck should include a local lymph node exam and thoracic radiographs.

What Constitutes a Therapeutic Response?

With the advent of immunologic and molecular targeted therapies that often result in stabilization of disease rather than shrinkage of disease, our definitions of what constitutes a therapeutic response have undergone some degree of evolution. Traditionally, for tumors that are being treated in the gross (measurable) disease setting, most oncologists recommend using the RECIST criteria for noting response, which is based on measuring the longest diameter of the tumor(s) rather than volume. Subsequent response should be classified as: complete response (CR) - disappearance of all clinically detectable disease; partial response (PR) - ≥30% decrease in size (i.e. longest diameter) and no new tumors; stable disease (SD) - < 30% decrease or 20% increase in size and no new tumors; progressive disease (PD) - > 20% increase in size or the appearance of new tumors. Historically, only CRs and PRs were considered as responses. Today, however; with the application of so-called "static therapies" like anti-angiogenic drugs, SD may indeed be a response. That is, keeping a tumor from growing may represent "a home run", while not actively killing what disease is already present. Time-to-progression (TTP) then becomes the most important response endpoint. TTP is also an important response endpoint in gross tumors treated by radiotherapy as complete resolution of tumor may not occur, rather the tumor may be "reproductively sterilized" rather than killed outright. For tumors that are treated with a modality that results in apparent eradication of the tumor (surgical excision, CR from chemotherapy) important endpoints are often reported as disease free interval (DFI), time to recurrence (TTR), or disease free survival (DFS); all of which represent the same measure, time from irradiation to recurrence. Overall survival is ultimately the most important endpoint, however; it is muddied by the biased application of euthanasia, which will vary with the client and clinicians perceptions. One important endpoint that has gained significant application in human oncology is the so-called "quality of life" (QOL) indices. These are just gaining application in veterinary oncology; examples include modified Karnofsky measures. The classic scenario where QOL measures became the dominant response endpoint is the use of the chemotherapeutic agent gemcitabine in people with pancreatic carcinoma. While this drug does not effect overall survival times, it significantly and consistently increases QOL scores in treated individuals.