BIOLOGIC BEHAVIOR AND CLINICAL STAGE
DEFINITIVE TREATMENTS FOR LOCALIZED DISEASE
Definitive surgery can be performed in most practice settings, requiring neither additional instrumentation nor specialized equipment. Definitive surgery is most appropriate in dogs with localized mast cell tumors of low or intermediate histologic grade (grade I or II, respectively). Surgery is also best suited for tumors involving anatomical sites amenable to wide resection.
Two recent reports describe the effectiveness of surgery alone for treating grade II, localized cutaneous mast cell tumors.12,13 The studies found that surgical resection was an effective treatment option, with recurrence in only 5% to 11% of dogs after complete excision. These studies emphasize that complete excision is often a curative treatment option, when anatomically feasible, for localized cutaneous mast cell tumors in dogs.
Because definitive surgery of localized mast cell tumors may be curative, defining the extent of surgical margins required for complete excision is important. A recent study assessed the surgical margins necessary for completely excising grades I and II cutaneous mast cell tumors greater than 1 cm in diameter. The results suggest that complete excision of cutaneous mast cell tumors should be achievable with lateral surgical margins of 2 cm and deep surgical margins including one fascial plane.14
Although obtaining complete margins should be the goal of any definitive surgical procedure, one recent study did not find any difference between local tumor recurrences in dogs with histologically tumor-free vs. nontumor-free margins. This unexpected finding may be due to the small sample population analyzed, so strong conclusions should not be drawn from this study.15 In addition, when looking at surgical margins for mast cells, normal mast cells often cannot be differentiated from neoplastic ones, complicating the interpretation of clean vs. dirty surgical margins.
ADJUVANT TREATMENTS FOR LOCALIZED OR REGIONAL LYMPH NODE METASTATIC DISEASE
External beam megavoltage radiation therapy
Curative-intent radiation involves delivering multiple sequential fractions, usually every day or every other day, for three to six weeks. As implied, the purpose of curative-intent radiation is to provide durable and definitive local tumor control. Patients receiving radiation therapy are sedated or anesthetized during each treatment session. Adequate patient immobilization ensures the accurate delivery of radiation therapy to the target site, allowing for maximal tumor kill and minimal adverse effects to normal surrounding tissues. However, radiation side effects are common in dogs receiving curative-intent treatment and may include moist desquamation, hair loss, pain, inflammation, and localized erythema.
In several reports, curative-intent radiation therapy has been demonstrated to be effective in treating incompletely resected cutaneous mast cell tumors in dogs.16-19 In these clinical studies, curative-intent radiation therapy for microscopic residual disease prevented local tumor recurrence in most (about 90% to 95%) of the dogs treated.
In addition to its effectiveness in treating localized microscopic disease, curative-intent radiation therapy is useful for treating regionally metastatic cutaneous mast cell tumors. In one report, grade III cutaneous mast cell tumors with or without regional lymph node metastasis, were treated with curative-intent radiation. Both incompletely resected microscopic disease and macroscopic tumor burden within the affected lymph nodes received curative-intent radiation therapy. In this study, dogs receiving radiation therapy achieved a median survival time of 28 months. However, most tumor-related deaths were attributed to regional disease progression, emphasizing the limitation of curative-intent radiation therapy for treating metastatic, high-grade mast cell tumors.20
In a second study, dogs with incompletely excised cutaneous mast cell tumors with regional lymph node metastasis were treated with a combination of oral prednisone and curative-intent radiation therapy. In that study, dogs receiving radiation to both the primary tumor site and metastatic lymph nodes, in conjunction with oral prednisone therapy, achieved an impressive median survival time of 1,240 days.21 These results may suggest that incompletely excised, high-grade mast cell tumors and their associated regional metastasis are best treated with a combination of adjuvant therapies.
Although curative-intent radiation therapy is effective for treating residual microscopic cutaneous mast cell tumors, the need for special facilities and associated high treatment costs have limited its use to pet owners with adequate financial means and a willingness to seek treatment from veterinary specialists. Because of these limitations, other adjuvant treatment options have been evaluated for treating residual cutaneous mast cell tumors, including the use of systemic chemotherapy.
The efficacy of systemic chemotherapy for treating measurable canine mast cell tumors has been recently reported.22-26 Intuitively, if chemotherapeutic agents possess efficacy against measurable cutaneous mast cell tumors, it would be expected that these same antineoplastic drugs would also be effective in managing residual microscopic disease. Unfortunately, prospective clinical trials evaluating the efficacy of systemic chemotherapy or oral prednisone for treating residual microscopic disease are few. In one study, seven dogs with residual microscopic disease were treated with prednisone and vinblastine in lieu of curative-intent radiation therapy.22 The median survival time of these seven dogs was more than 1,013 days, thereby suggesting the therapeutic efficacy of prednisone and vinblastine used in an adjuvant setting for the treatment of residual mast cell tumor disease. To better support the adjuvant use of systemic chemotherapy, a recent report evaluated the therapeutic effectiveness of prednisone and vinblastine in 27 dogs with inadequately excised cutaneous mast cell tumors (24 grade II, three grade III). In that study, 20 dogs available for follow-up were evaluated for local and distant tumor growth after a median of 537 days. Two dogs (10%) experienced local tumor regrowth, but four additional dogs developed new mast cell tumors involving distant cutaneous sites.27
Collectively, it may be concluded from clinical studies evaluating the effectiveness of systemic chemotherapy for treating mast cell tumors that adjuvant systemic chemotherapy for treating residual microscopic disease is an alternative to curative-intent radiation therapy. However, additional studies are required to better define the true effect of different systemic chemotherapy protocols for treating residual neoplastic mast cell disease. Systemic chemotherapy administration is not restricted to referral centers, so it is a more widely available therapeutic option for both pet owners and veterinary practitioners. If you choose to treat an animal with adjuvant systemic chemotherapy, you must know the basic precautions required for the safe handling and administration of chemotherapy.
Intraregional deionized water
Mast cells are sensitive to changes in osmolality and when exposed to hypotonic solutions, will undergo cellular swelling and ultimately membrane lysis. Based on this cellular response, several studies have evaluated the safety and efficacy of intraregional deionized water injections as an adjuvant treatment for incompletely resected cutaneous mast cell tumors. Although all studies suggest that intraregional deionized water injections are well-tolerated, a marked disparity exists among studies regarding the efficacy of the injections in preventing local tumor recurrence.28-30
In one study, the survival times and tumor recurrence rates were compared between two treatment groups: dogs receiving only surgical resection (n = 28) and dogs receiving surgical resection and adjuvant intraregional deionized water injections (n = 27). Disconcertingly, dogs treated with surgery and intraregional deionized water injections experienced greater local tumor recurrences and shorter overall survival times than did dogs treated with surgery alone.29 These results suggested that intraregional deionized water injections may negatively influence the outcome of dogs with mast cell tumors.
In direct contrast, two other reports discuss intraregional deionized water injections as being effective when used in an adjuvant setting. In one study, 74 dogs with 118 mast cell tumors were treated with surgery alone or surgery combined with intraregional deionized water injections.28 The local tumor recurrence rate in dogs receiving only surgery was 52.6% (10/19), while dogs treated with surgery and the injections had a recurrence rate of 26.2% (26/99). Furthermore, in a recent pilot investigation, only one dog out of 17 with incompletely resected cutaneous mast cell tumors treated with adjuvant intraregional deionized water injections developed local tumor regrowth.30 Although intraregional deionized water injections may be reasonable for the adjuvant treatment of small, low- to moderate-grade mast cell tumors, their use is unlikely to be beneficial in treating diffuse, infiltrative tumors or aggressive grade III mast cell tumors.
The cost-effectiveness and ease of administering intraregional deionized water injections makes this investigational adjuvant therapy attractive. However, the direct contradictory results from clinical trials assessing their efficacy for treating resected cutaneous mast cell tumors remain problematic and a reason for concern. Until further studies are conducted to better clarify the role of deionized water injections, it remains difficult to wholeheartedly support this adjuvant treatment option. Additionally, despite being reported as well-tolerated, it is the experience of many clinicians that deionized water injections can cause moderate pain and discomfort.
Brachytherapy is a radiation treatment modality in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near a tumor. Treatment with brachytherapy may be intracavitary, intraluminal, or interstitial. For interstitial brachytherapy, radioactive materials are placed directly through the body tissue encompassing the tumor. Iridium-192 is a radioisotope capable of releasing both gamma and beta particles and can be used as a radioactive source for brachytherapy.
Recently, interstitial brachytherapy with iridium-192 has been evaluated as an adjuvant treatment for cutaneous mast cell tumors in dogs.31 In this study, nine dogs with microscopic residual disease and two dogs with macroscopic disease were treated with interstitial brachytherapy. Five of the 11 treated dogs ultimately had local tumor regrowth at a median of 1,391 days. Although a high percentage of dogs experienced tumor recurrence, the long median latency period before tumor regrowth was impressive. Given the extended period between initial brachytherapy and local regrowth, it remains a possibility that some of the dogs identified as treatment failures may actually have been affected with de novo tumor formation.
Interstitial brachytherapy offers some advantages over conventional external beam megavoltage radiation therapy, including more localized energy deposition, greater normal tissue sparing effect, and decreased total treatment duration. Unfortunately, the number of facilities offering brachytherapy is limited, and in conjunction with the observed high incidence for local tumor regrowth (5/11), it is difficult to recommend interstitial brachytherapy as a realistic or practical adjuvant treatment option for incompletely resected mast cell tumors.
TREATMENTS FOR MACROSCOPIC AND METASTATIC DISEASE
Contrary to the success in treating localized disease with surgery alone or with adjuvant therapies, the effective management of surgically nonresectable macroscopic disease or advanced distant metastatic mast cell disease remains problematic. In these patients with extensive disease, the intent of therapy is no longer curative. Rather, therapy should be focused on reducing tumor burden, improving quality of life, and prolonging survival times. Therapies with these defined goals are categorized as palliative. Several palliative treatment options exist for managing noncurable mast cell tumors in dogs, including systemic chemotherapy, palliative radiation, and intralesional triamcinolone.
Most chemotherapeutic regimens are easy to administer, but specialized equipment is recommended (a biologic safety cabinet) to minimize unnecessary and hazardous exposure to chemotherapeutic agents. In addition, familiarity with the handling, safety, side effects, and administration of each anticancer agent should be considered a necessity before instituting chemotherapy.
Radiation of macroscopic tumors: Curative and palliative fractionation schemes
Although curative-intent radiation may have a role in treating macroscopic disease, a large time and financial commitment is required of pet owners. In some situations, palliative radiation therapy may be considered a more appropriate treatment option. In comparison to curative-intent treatment regimens, palliative radiation involves administering larger doses of radiation at less frequent intervals. A typical palliative protocol would be administering one large dose of radiation every week for four consecutive weeks.
With the intent of increasing therapeutic effectiveness, palliative radiation therapy can be combined with other adjuvant treatments such as oral prednisone or systemic cytotoxic chemotherapy. In one recent study, 35 dogs with nonresectable cutaneous mast cell tumors were treated with oral prednisone and palliative radiation therapy.32 This palliative treatment protocol provided an impressive overall response rate of 88.5%, with 12 complete responses and 19 partial responses. In addition to the high response rate, the median progression-free survival time of treated dogs was 1,031 days.
Radiation therapy, either curative-intent or palliative, to treat nonresectable cutaneous mast cell tumors should be considered a viable treatment option in dogs. Although most dogs will ultimately experience local tumor recurrence or distant metastasis, reasonably long median survival times appear to be achievable. Combining radiation therapy with other systemic adjuvant treatments such as oral prednisone or chemotherapy may provide beneficial additive effects, further improving quality-of-life scores and survival times in dogs with macroscopic tumor burdens.
Corticosteroids are often used to treat cutaneous mast cell tumors, either as single agents or preferably in combination with other adjuvant therapies. The direct injection of the long-acting corticosteroid triamcinolone into cutaneous mast cell tumors has been anecdotally reported to be an effective treatment option (Figure 8). Biologically, the reduction in mast cell tumor size subsequent to intralesional corticosteroid administration may be attributed to reduced peritumoral inflammation and swelling, as well as a direct cytolytic effect on neoplastic mast cells.
Because of the lack of controlled clinical trials evaluating the efficacy of specific intralesional protocols, dosing regimens may vary widely among veterinary practitioners. Anecdotally reported protocols include injecting 1 mg triamcinolone for every centimeter of the tumor's diameter every 14 days and injecting a systemic dose of triamcinolone (0.22 mg/kg) uniformly into the tumor every two or three weeks.
Intralesional corticosteroid administration is an easy and cost-effective means to reduce measurable tumor burden. It is best suited for relatively small mast cell tumors and should be considered a treatment option to reduce the size of localized tumors before definitive surgical resection. In addition to serving as a neoadjuvant before curative surgery, intralesional therapy may be useful as a palliative treatment option in small- to moderate-size tumors that are refractory to radiation therapy or chemotherapy.
Mast cells grow and proliferate in response to specific cellular signals transduced by membrane-bound receptors, such as c-kit. Mutations in c-kit signaling can dysregulate cellular physiology, leading to the formation of a neoplastic population of mast cells. It has been confirmed that some malignant mast cell tumors in dogs carry a mutation in the gene coding for the c-kit receptor, resulting in unregulated intracellular signaling, cell proliferation, and subsequent mast cell tumor formation.33,34
In laboratory experiments, indolinone derivatives capable of inhibiting constitutively activated c-kit mutants have shown promise in killing neoplastic mast cells in vitro.35 As a clinical corollary, one recent study evaluated the use of an indolinone derivative (SU11654) for treating spontaneous canine cutaneous mast cell tumors.36 Study results demonstrate SU11654 to be well-tolerated and therapeutically effective. Of the 22 dogs with mast cell tumors treated with SU11654, 50% experienced tumor shrinkage, with six patients achieving a complete remission. Although the findings from this clinical study are extremely promising and could dramatically change the way we treat cancers such as cutaneous mast cell tumors, additional prospective trials need to delineate the exact role of small molecule inhibitors, such as SU11654, for treating cancer-bearing pets.
In dogs with extensive tumor burden, ancillary therapies to minimize the systemic effects of mast cell degranulation should be implemented. Mast cells are capable of liberating a wide range of preformed and newly synthesized inflammatory mediators, which can cause marked patient morbidity and mortality. Histamine is one predominant inflammatory mediator released by degranulating mast cells, so treatment with histamine-blocking agents may decrease the likelihood of undesirable paraneoplastic complications. Blocking gastric H2 receptors with either cimetidine (5 to 10 mg/kg orally t.i.d. to q.i.d.), ranitidine (1 to 4 mg/kg orally b.i.d. to t.i.d.), or famotidine (0.3 to 0.6 mg/kg orally b.i.d. to t.i.d.) should be implemented to minimize gastroduodenal irritation from excessive parietal cell hydrochloric acid secretion. Occasionally, dogs not responding to H2 blockade may benefit from a proton-pump inhibitor such as omeprazole (0.5 to 1 mg/kg orally once a day). Blocking the H1 receptors with diphenhydramine (1 to 4 mg/kg orally t.i.d.) or hydroxyzine (2.2 mg/kg orally t.i.d.) may be indicated to minimize complications derived from peripheral H1 receptor activation, such as hypotension, bronchospasms, local erythema, swelling, and pain.
Although mast cell tumors in dogs were described more than a century ago, our understanding of the etiopathogenesis for malignant mast cell transformation is constantly expanding. Several treatment options exist for canine cutaneous mast cell tumors. Localized mast cell tumors are often cured with surgery, radiation therapy, or a combination of the two. Successful management of nonresectable mast cell tumors may be achieved with combination adjuvant therapies, with many patients experiencing high quality-of-life scores and long survival times. Most important, the recent discovery of small molecule inhibitors such as SU11654, demonstrating therapeutic efficacy against cutaneous mast cell tumors, may revolutionize cancer management in companion animals.
Timothy M. Fan, DVM, DACVIM (internal medicine, oncology)
Louis-Philippe de Lorimier, DVM
Department of Veterinary Clinical Medicine
College of Veterinary Medicine
University of Illinois
Urbana, Il 61802
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