Teaching Old Dogma New Tricks: Changes in Oncology Case Management Recommendations
Carolyn J. Henry, DVM, MS, DACVIM (Oncology)
Advances in the field of veterinary oncology are occurring so rapidly that even specialists find it difficult to stay current on all the new information. With the advent of specialty listserves on the internet, board-certified oncologists have the benefit of rapid access to second opinions and a ready source of individuals who can direct them to new publications and research findings relevant to the question at hand. Meanwhile, practitioners must often rely on textbooks and notes for a quick review of differential diagnoses and case management options. Unfortunately, even those texts and notes published as recently as 5 years ago may provide case management suggestions that are already outdated and, in some cases, inappropriate. Recognizing this challenge, the author has developed a summary of some clinically relevant advances in veterinary oncology over the past decade or two. The selected topics have come from a review of older textbooks, university course notes, and from discussions with practitioners calling about case management and referral options. Those citations shown in italics throughout these notes were taken verbatim from published textbooks or notes, but are not referenced individually, because the purpose of this discussion is not to indict any particular resource or suggest that it provided inaccurate information. Rather, the intent is to highlight some of the more significant changes in case management recommendations that have been adopted in veterinary oncology in recent years. It is understood that information available in the older sources was current at the time of publication and has since been modified as our knowledge of veterinary oncology has progressed. Additional updates will be provided, time permitting.
The primary concern regarding irradiation of epulides has been the potential for malignant transformation at the irradiated site.
Based on an initial report in which Thrall, et al. in 1984 coined the term, "malignant transformation" to describe the development of oral malignancies at the site of previous radiation to treat epulides, treatment recommendations for dogs with epulides are generally delivered along with ample warnings regarding this potential risk.1 Malignant transformation rates of up to 18% have been reported and have prompted many practitioners to recommend other alternatives for treatment of acanthomatous epulides, despite the fact that this tumor type is known to be very responsive to radiation therapy.2 A re-examination of this phenomenon in light of newer radiation sources and techniques was undertaken in order to determine the true risk of malignant transformation.2 Of the 57 dogs in the study that had been irradiated for treatment of epulis, only 2 developed malignancies at the site of previous irradiation and neither developed an epithelial tumor. Thus, the etiology is more likely related to radiation carcinogenesis of normal tissues in the radiation field, versus a transformation of epulides to carcinomas. The malignancies, a sarcoma and an osteosarcoma, developed 5.2 and 8.7 years after the completion of radiation therapy. Overall time to first event and median survival time (MST) were 1210 and 1441 days, respectively. The authors concluded that the term "malignant transformation" in the context of cancer development at the site of previous radiation therapy for epulides should be abandoned. Concerns regarding development of cancer in a radiation field are less relevant in older patients who are unlikely to survive long enough to develop radiation-induced cancer many years down the road. As such, the risk of malignant transformation is no longer considered to be a compelling reason to discourage pursuit of radiation therapy for patients with epulides, especially for those patients that are middle-aged or older at the time of treatment.
The significance of nodal metastasis on outcome is not well established.
For years, the diagnostic evaluation of dogs with appendicular osteosarcoma (OSA) has focused on assessment for pulmonary or bone metastases prior to limb amputation. Given that a poor prognosis and likelihood of morbidity is associated with metastasis to these sites identification of pulmonary or bone metastases may change the treatment plan. Historically, the nodal metastasis rate for canine OSA has been considered low; thus, presurgical evaluation of nodal status has likely been dismissed by many as a low-yield test, especially when nodal excision will occur by default at the time of limb amputation. However, a 2005 report by Hillers, et al. demonstrated the prognostic importance of lymph node assessment in dogs with appendicular OSA.3 Of 228 dogs undergoing limb amputation for OSA, 10 had histological evidence of nodal metastasis at the time of surgery. The median disease free interval for those dogs with nodal metastasis was 48 days, which was significantly shorter than that of dogs without nodal metastasis (238 days). Median survival time also differed significantly between the two groups (59 days versus 318 days). Given the retrospective nature of the study and the variation in treatment amongst dogs, the data must be interpreted with caution. However, the study is the largest evaluation of the prognostic significance of nodal metastasis in canine OSA and the data suggest that lymph node assessment may be critical to informed decision making related to patients with appendicular OSA.
The breeds most at risk for OSA are St. Bernard, Great Dane, Irish Setter, Doberman, German Shepherd Dog and Golden Retriever.
Although breed prevalence does not alter one's clinical approach to case management, it is important to know what breeds are at increased risk of developing a particular cancer in order to make appropriate differential diagnosis lists and to examine features of the disease that may be unique to specific breeds. A recent review of prevalence and risk factors for appendicular OSA in 179 dogs revealed that three of the most commonly affected breeds are Greyhounds, Rottweilers, and Great Danes.4 Unique features in Greyhounds include a higher incidence of pathological fracture at the time of diagnosis and a risk for bleeding complications after amputation. Rottweilers have been shown to have a higher incidence of a specific genetic mutation (MET) that may alter prognosis and could potentially be exploited in a targeted therapy approach.5
Canine Mast Cell Tumors
Chemotherapy has not been efficacious for the treatment of MCT; Chemotherapeutic treatment options for this tumour run a poor third in comparison to successful treatment with surgery and radiation.
Prior to 1999, the prognosis for dogs with nonresectable cutaneous MCT was considered bleak and unlikely to be altered by the addition of chemotherapy. Response rates for gross disease were disappointing for the two medical therapy options evaluated prospectively in veterinary cooperative oncology group (VCOG) trials, namely single-agent prednisone (20%) and vincristine (7%).6,7 Renewed enthusiasm for the use of chemotherapy against MCT developed following a report of responses to vinblastine, prednisone, and cyclophosphamide written by Elmslie and published in the Veterinary Cancer Society Newsletter. Several studies have examined the role of vinblastine in the treatment of canine MCT since that initial report and most have described positive clinical responses and suggest that prolonged survival times may result. Even in the case of grade III MCT, vinblastine and prednisolone or prednisone have resulted in improved outcome, as demonstrated in recent studies.8,9 Use of a vinblastine, cyclophosphamide, and prednisone protocol resulted in a MST >2092 days for 24 dogs with MCT that were incompletely excised or considered to be at high risk for metastasis.10 Like vinblastine-containing protocols, oral lomustine (CCNU) has been shown to provide measurable responses in dogs with cutaneous MCT. In an initial report of lomustine for treatment of canine MCT, the overall response rate was 42%.11 Since the early report, lomustine has been further evaluated and is now being used clinically in combination with vinblastine and prednisone. And in the category of "everything old is new again" comes a 2008 JAVMA report re-examining the role of adjuvant single-agent prednisone for the treatment of canine MCT.12 The authors reported a >80% reduction in tumor volume and suggested that prednisone therapy may be useful for reducing tumor size, thus facilitating excision of otherwise unresectable masses. A more targeted approach to treatment of canine mast cell tumors may become a reality, should licensing of an investigational receptor tyrosine kinase inhibitor be approved. Recent research by Cheryl London and others has provided the pre-clinical support for licensing of this new oral agent for the treatment of MCT. The drug targets the mutated c-kit receptor found in 30 to 50% of advanced canine MCT.13 If this product becomes commercially available, it will likely be used in conjunction with the evolving chemotherapy protocols now being assessed for treatment of canine MCT.
Clinical staging is strongly associated with prognosis.
By strict application of the WHO tumor staging criteria, dogs with multiple MCT are classified as having Stage III disease. Ten dogs had multiple synchronous MCT in a 2005 report by Kiupel, et al, and were shown to have a worse prognosis than those with single lesions14, thus supporting the above statement. However, this has not been uniformly recognized for other dogs with multiple synchronous MCT. In a study evaluating mast cell tumors in pug dogs that had been identified through a search of the Veterinary Medical Data Base (VMDB), McNeil, et al., found that 56% of pugs affected by MCT had multiple cutaneous tumors, yet their median survival time had not been reached after 660 days of follow-up.15 A similar favorable prognosis was noted in 54 dogs with multiple synchronous MCT, with a reported MST > 1917 days.16 And in a report of 128 dogs with cutaneous MCT, 59 of which had multiple lesions, there was no difference in survival times between dogs with single lesions and those with multiple lesions. Eighty-three percent of dogs with multiple lesions were alive at one year and the MST for the group had not been reached at a median follow-up time of 520 days.17 Given the favorable outcome of dogs in the latter studies, one might question the prognostic significance of a staging scheme that classifies dogs with multiple synchronous MCT as having Stage III disease. Indeed, it has recently been asserted that the category of multiple tumors should be removed from the Stage III grouping and, rather, each MCT should be staged individually when multiple synchronous MCT are noted.18 The author agrees with this suggestion and recognizes the limitation of the current staging system for providing prognostic information.
Excision should be wide and deep to a minimum margin of 3 cm around the perceived borders of the tumor...Surgical margins of 3 cm laterally and one fascial plane deep to the tumor are advised.
Consistent in the older literature is the recommendation that 3-cm margins are necessary for complete excision of canine mast cell tumors. Less consistent in the literature is the primary source cited for this recommendation and more often, there is no citation whatsoever. In an effort to support or refute this dogma, Simpson, et al., completed a study evaluating 1-, 2- and 3-cm margins around excised canine mast cell tumors to determine the needed margin of normal tissue to reasonably ensure complete excision.19 Results of this and other studies suggest that 2-cm lateral margins and one fascial plane beneath the tumor tissue are adequate guidelines for complete excision of Grade I and II canine cutaneous MCT.19,20
Feline Mammary Carcinoma
Prospective studies using combined adjuvant chemotherapy and mastectomy in the cat have yet to be performed. No convincing evidence exists that chemotherapy.... is beneficial [for cats with mammary cancer].
Despite the known aggressive biological behavior of feline mammary cancer (FMC), the role of chemotherapy for the primary or adjuvant treatment of this disease has remained undefined. In order to assess the role of chemotherapy in the primary or adjuvant setting, a prospective clinical trial in which one study group is randomized to undergo surgery only and the other receives adjuvant chemotherapy after surgery is necessary. Due, in part, to ethical concerns about withholding chemotherapy from cats afflicted by this cancer type which is known to be highly metastatic, no such study has been published to date. Instead, historical survival times for cats undergoing surgery without adjuvant chemotherapy have been considered the benchmark to which outcomes with adjuvant therapy have been compared. Based on this method, recent evidence suggests a survival advantage for cats receiving chemotherapy. A retrospective study of 67 cats that received adjuvant doxorubicin (1 mg/kg q21d, IV for an intended 5 treatments) beginning at the time of suture removal after mastectomy for mammary adenocarcinoma (ACA) was reported.21 The MST for all cats was 448 days, with 58.9% and 37.2% 1- and 2-year survival rates, respectively. Forty-seven percent of the cats had Stage III (>3 cm tumors) disease and survived an average of 416 days, which compares favorably with the MST of 4- to 6-months reported in the two largest previous reports of outcome with surgery alone for Stage III disease.22,23 The author and others conducted a randomized prospective clinical trial comparing mitoxantrone to doxorubicin as adjuvant therapy for FMC after unilateral or bilateral mastectomy. There was no significant difference in survival times between the two groups (MST=747 days for the mitoxantrone group; MST=484 days for the doxorubicin group). Although there is increasing evidence to support the use of adjuvant chemotherapy for advanced (Stage III) feline mammary cancer, its role in the treatment of lower stage FMC remains unclear.
Canine Thyroid Tumors
There have been no reports of successful I131 treatment of non-functional thyroid tumours. Since the majority of canine thyroid tumors are malignant, contain a mixture of follicular and compact cell types, and are usually not functional or hyperfunctional, radioiodine treatment is not indicated.
The idea of using radioactive iodine to treat functional thyroid carcinomas in dogs is not a new one. What is new is the thought that there is a role for I-131 therapy for canine thyroid carcinomas even when overt hyperthyroidism is not present and T4 levels are not elevated. In a 2006 report, Turrel, et al, described results of I-131 therapy for 39 dogs with thyroid carcinoma.24 Of these, 21 were hyperthyroid, 16 were euthyroid and 2 were hypothyroid. Survival time was not significantly associated with serum T4 concentration prior to I-131 therapy. Dogs with metastatic disease had shorter survival times (366 days) than those without metastasis (839 days). Similar findings were noted in an Australian study reported in 2005 in which 43 dogs underwent I-131 treatment, with or without surgery.25 In the radioiodide alone group, the MST was 30 months and in the surgery/radioiodide treatment group, the MST was 34 months. These MST compare favorably to the 3-month MST reported for untreated dogs.25 Based on these newer reports and similar anecdotal reports elsewhere, many oncologists now recommend thyroid scintigraphy as part of the diagnostic evaluation of dogs with thyroid carcinoma, even with normal or low T4 levels.26 Because the iodine-containing contrast agents used with computed tomography (CT) will interfere with nuclear scintigraphic imaging of thyroid carcinomas, clinicians are advised to plan the order of diagnostic tests accordingly. Thyroid scintigraphy should precede CT imaging when feasible. If a CT scan is performed prior to thyroid scintigraphy, it should be done without use of iodinated contrast agents. The author recommends CT imaging even when scintigraphy shows marked uptake, as the combined imaging modalities are needed to understand the full disease extent and likelihood of success with I-131, surgery, external beam radiation therapy, or a combination thereof and to monitor response to therapy.
Canine Prostate Cancer
Prostatic tumors... most often affect older intact male dogs; Castration of the male dog will help prevent prostatic adenocarcinoma.
Despite years spent asserting that castration has a protective effect against the development of prostate cancer in dogs, we now know that both intact and castrated male dogs can develop prostatic carcinoma. To suggest otherwise is to ignore some compelling evidence that has been gained over the past 20 years. In fact, not only is castration ineffective at reducing prostate cancer risk in dogs, it may actually increase the risk for development of prostatic ACA.27,28 In the late 1980's a report was published suggesting that castration was not protective against canine prostatic ACA.29 However, this was called into question again in a 2000 report that suggested that castration of dogs prior to sexual maturity (~6 months of age) reduced their risk of developing prostatic carcinoma.30 Results of the three most recently reported studies, including a large population study published last year, indicate that castrated dogs are, indeed, at increased risk for prostatic carcinoma.28 However, one can not stress enough the importance of not taking this information out of context and suggesting that castration is ill advised. The overall risk of developing prostatic carcinoma is low and there are certainly other medical and population control benefits associated with castration. Results of the most recent studies imply that androgens are not required for the initiation and progression of canine prostatic ACA and, as such, castration should not be touted as a means to decrease prostate cancer risk in dogs.
The examples presented here emphasize the dynamic character of veterinary oncology and the fact that dogma is constantly challenged. As the field evolves, case management recommendations can, quite literally, vary from one year to the next. As such, it is incumbent upon practitioners to stay current in their knowledge of small animal oncology in order to provide sound medical care to oncology patients. Along with participation in continuing education seminars, case management consultations with specialists and regular review of peer-reviewed journals, it is also helpful to have access to information regarding ongoing clinical trials in veterinary oncology. One such source of information is available at: http://www.vetcancersociety.org/index.php?c=1
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