Radiation Therapy for Incompletely Excised Grade II Canine Mast Cell Tumors
Forty-five dogs with incompletely excised grade II mast cell tumors were treated with radiation using a cobalt 60 teletherapy unit (15 fractions of 3.2 Gy for a total of 48 Gy). Twenty-four of the dogs underwent prophylactic regional lymph node irradiation. Three (6.7%) dogs had tumor recurrence, two (4.4%) dogs developed metastasis, and 14 (31%) dogs developed a second cutaneous mast cell tumor. No difference in overall survival rate was observed between the dogs receiving and not receiving prophylactic irradiation of the regional lymph node.
Introduction
Canine mast cell tumors (MCTs) are common in dogs and account for 16% to 21% of all cutaneous tumors.1 The biological behavior of MCTs varies from benign to highly malignant and metastatic.1,2 Significant prognostic factors include histological grade, clinical stage, silver-stained nucleolar organizer region (AgNOR) frequency, proliferating cell nuclear antigen labeling, and the Ki-67 proliferation index of the tumor.3–9 Histological grade and clinical staging are the most widely applied prognostic factors for therapeutic considerations.1 A grading system was developed by Patnaik based on histomorphological features such as invasion, cellularity, cellular morphology, mitotic index, and stromal reaction.4 Grade I is the most benign, and grade III is the most malignant. Grade II is the most common grade of MCTs encountered in small animals.4
Wide surgical excision remains the treatment of choice for a localized MCT. A recent report of 55 dogs with completely excised grade II MCT showed a 5% local recurrence rate, a 5% metastasis rate, and, in 11% of the dogs, the development of de novo (new) MCT when no adjunctive therapy was applied.10 Another recent study suggested that 2-cm lateral margins and deep margins of one fascial plane appear to be adequate for complete excision of grade I and II MCTs.11
Adjunctive radiation therapy has been used for local control of incompletely excised grade II MCTs. A study of 32 dogs reported an 88% disease-free survival at 2 to 5 years after treatment when microscopic (stage 0) grade II MCTs were treated with a total dose of 54 Gy (18 fractions of 3 Gy) over 39 days.12,13 In another report of 37 incompletely excised grade II MCTs, a disease-free survival of 93% at 3 years was found for dogs treated with megavoltage or orthovoltage at doses of 46.2 to 48 Gy using several different fraction sizes and schedules.14 Another report of 19 dogs with various grade tumors (16 were grade II) and regional lymph node metastasis that were treated with a radiation dose of 48 to 57 Gy to the primary tumor and the regional lymph node resulted in a median disease-free survival time of 1240 days.15
The purpose of this retrospective study was to compare the efficacy and toxicity of two radiation therapy protocols for the treatment of incompletely excised grade II MCTs (stage 0). One protocol consisted of a total dose of 48 Gy given in 15 fractions of 3.2 Gy over a 19-day period to the primary tumor site. The other protocol consisted of an identical treatment of the primary tumor site, with concomitant regional lymph node irradiation. The hypothesis was that irradiating the lymph node draining the primary site would decrease the incidence of lymph node metastasis and lead to extended disease-free and overall survival rates.
Materials and Methods
Case Selection
Medical records of dogs diagnosed histologically with incompletely excised grade II MCTs at the University of Wisconsin-Madison Veterinary Medical Teaching Hospital (UW-VMTH) from January 1992 to May 2002 were retrospectively reviewed. Histology was confirmed by a single pathologist (Dubielzig). Dogs were included in the study if they were treated with a single course of cobalt teletherapy (15 fractions of 3.2 Gy), received no prednisone and/or chemotherapy, were stage 0 (i.e., local microscopic disease defined as the presence of tumor cells at the margins of the surgical specimen without lymph node metastasis), and had follow-up information available. Clinical staging included a complete blood count, serum biochemical profile, urinalysis, cytological examination of regional lymph nodes (n=34), thoracic radiography (n=45), abdominal ultrasonography (n=45), and bone marrow aspiration (n=45). Information obtained from medical records included signalment, clinical stage, location of tumor, previous surgery, radiation therapy details and side effects, response to therapy, date of progression, and date of death. Cause of death or reason for euthanasia was obtained from the medical record when available or through conversations with the client or referring veterinarian.
Radiation Therapy
All dogs were treated with an isocentric cobalt 60 teletherapy unit.a The total prescribed dose of radiation was 48 Gray (Gy) given in 15 daily (Monday through Friday) fractions of 3.2 Gy, over a 19-day period. Nongraphic (manual) planning or computer-based planningb was used, depending on the complexity of the tumor location. Treatment field margins were set at 3 cm from the scar when possible, and the target depth dose was set at a minimum of 1 cm. Cytologically negative regional lymph nodes were not irradiated prior to 1998. Beginning in 1998, all negative regional lymph nodes were irradiated prophylactically when possible, unless they were surgically removed. The reason for this change in the protocol was a recommendation made in a retrospective study that regional metastasis is a clinically significant event, even for intermediate MCTs.16 Regional lymph nodes received the same radiation protocol as the primary site and were included in the same field as the primary site if they were within 6 cm of the surgical scar. When the regional node was more distant, it was treated as a separate field. Physical examinations were recommended at 2 weeks, 1 month, and then at 3-month intervals until 1.5 year after radiotherapy, and then every 6 months thereafter. Follow-up information was obtained from medical records or by telephone communication with the referring veterinarian or client.
Toxicity Assessment
Radiation toxicity was assessed through review of the weekly medical record maintained during radiation therapy and the history reported at recheck examinations. Acute and late radiation effects were assessed and scored according to the toxicity criteria of the Veterinary Radiation Therapy Oncology Group (VRTOG).17
Statistical Analysis
Time to local recurrence was defined as the time (days) from the first radiation therapy treatment to the time when local recurrent disease (i.e., within or directly adjacent to the radiation field) was noted. Disease-free survival rate was defined as the time (days) from the first radiation therapy treatment until the development of local disease, metastatic disease, or a de novo second MCT outside of the radiation therapy field. Overall survival rate was defined as the time (days) from the first radiation therapy treatment until death. Graphic curves for time to local recurrence rate, disease-free survival rate, and overall survival time were generated using the Kaplan-Meier product-limit method. Data were censored if dogs were alive at end of study, were lost to follow-up, or died of disease other than MCT. In addition, the effects of tumor location, lymph node irradiation, and development of a second MCT were compared using the logrank test. All tests of statistical significance were two-sided at a P value of <0.05.c
Results
Forty-five dogs met the entry criteria. Nineteen were male (17 castrated), and 26 were female (24 spayed). Median age was 6 years (range 3 to 13 years). Nineteen different breeds were represented, including the Labrador retriever (n=14), mixed-breed dog (n=6), Rhodesian ridgeback (n=4), golden retriever (n=2), boxer (n=2), German shepherd dog (n=2), and American cocker spaniel (n=2).
The baseline clinical staging data (i.e., complete blood count, serum biochemical profile, urinalysis, thoracic radiography, abdominal ultrasonography) were considered normal in all dogs. Thirty-four of 45 (76%) dogs had lymph node aspirates, all of which were negative for metastasis (i.e., no mast cells or clusters of mast cells identified on cytological examination). The cytological slides were not available for review, and the results were based on the cytological report in the medical record. The sensitivity and specificity of cytology for regional lymph node metastasis of MCTs have been reported to be high, so these results were considered relevant.18 In the remaining 11 cases, the immediate draining lymph nodes were intra-abdominal or intrathoracic, and all of the nodes appeared normal on abdominal ultrasonography or thoracic radiography. All bone marrow samples were negative for mast cells.
Tumors were located on the head (n=5), the extremities (n=32), and on the trunk (n=8). Only two dogs (two and four surgeries, respectively) had more than one surgery prior to radiation therapy. Both had surgery performed after primary tumor recurrence. The median time from the last surgery to the start of radiation therapy was 30 days (range 14 to 99 days) for the 42 dogs for which it was recorded. This time parameter was evaluated statistically.
Radiation Therapy
From 1992 to 2002, the radiotherapy protocols used to treat incompletely excised, grade II MCTs at UW-VTH were consistent. Twenty-two dogs had the surgical site treated by a single radiation field (target depth dose of 1 to 2.5 cm; median 1.5 cm); 20 dogs were treated with two parallel-opposed, equally weighted fields; and three dogs were treated with three fields. All dogs in the study completed the prescribed radiation therapy protocol. Twenty-four dogs had prophylactic irradiation of the regional lymph node that involved the prescapular lymph nodes (n=7), popliteal lymph nodes (n=10), medial iliac lymph nodes (n=4), retropharyngeal lymph node (n=1), or both the popliteal and medial iliac lymph nodes (n=2). The two dogs that had both popliteal and medial iliac lymph nodes irradiated had primary tumors located at the distal stifle, and because the exact route of lymphatic drainage could not be determined, both lymph nodes were irradiated.
Four dogs with tumors located on the thorax (n=2) or the lumbar region (n=2) had computer-based radiation therapy plans generated from pretreatment computed tomography scans. For the remaining dogs, the radiation therapy dose was calculated using nongraphic (manual) planning. Portal radiography was performed to document appropriate field positioning in all cases. The size of the radiation therapy field varied (median size 90 cm2; range 30 to 288 cm2). All dogs had a 0.5-cm tissue equivalent applied overlying the surgical scar in order to focus the radiation dose at the skin surface.
Toxicity Assessment
Using the VRTOG chart for acute toxicity, 18 (40%) dogs experienced self-limiting, grade 1 to 2 toxicities. Grade 1 cutaneous toxicity consisted of erythema, dry desquamation with alopecia, and epilation. Grade 2 cutaneous toxicity consisted of patchy, moist desquamation without edema. Twenty-six (58%) dogs developed a grade 3 toxicity that included sloughing of footpads (n=2) and confluent desquamation with edema (n=3). Acute toxicity was not recorded in one dog. Late toxicity effects included some degree of alopecia (n=31) or leukotrichia (n=8) within the radiation field, which generally developed 2 to 3 months postirradiation. One dog developed a colonic stricture at the site of sublumbar lymph node irradiation, 1 year after completion of radiation therapy. This stricture probably resulted from the lymph node radiation field partially overlapping with the colon. Associated clinical signs were controlled with a low-residue, high-fiber diet.
Responses and Outcomes
Three (6.7%) dogs developed tumor recurrence in the radiation field at 39, 130, and 203 days after completion of radiation therapy. All three received additional treatment that consisted of limb amputation (n=1) or additional marginal excision followed by vinblastine and prednisone chemotherapy (n=2). Two of these dogs are alive at the time of reporting and were censored from the overall survival rate at days 975 and 1294. One dog died 147 days after radiation therapy from systemic mastocytosis. The median disease-free survival rate was not reached, with a 1-year disease-free survival rate of 80.6%, and 2- and 3-year disease-free survival rates of 67.1% [Figure 1]. The 1-year local recurrence-free survival rate was 94%, and the 2- and 3-year local recurrence-free survival rates were each 94% [Figure 2]. The 1-, 2-, and 3-year overall survival rates were each 97.6%, with a median follow-up time of 933 days [Figure 3]. Two (4%) dogs had metastatic mast cell disease diagnosed during follow-up—one with systemic mastocytosis and one with metastasis to a distant lymph node not included in the radiation field. Twenty-seven dogs were still alive at the conclusion of the study, and four were lost to follow-up. Seven (15%) dogs died of unrelated diseases, such as other cancers outside of the radiation field (n=6) and immune-mediated hemolytic anemia (n=1).
Overall, 18 (40%) dogs developed a second neoplasm during the follow-up period. Fourteen (31%) dogs developed a second MCT in another cutaneous site (away from the radiation therapy site) 14 to 1141 days after completion of radiation therapy (median 301 days). Two of these dogs developed both a second MCT and another malignancy. Of these tumors, 13 were grade II MCTs, and one was a grade III MCT. All 14 dogs that developed second MCTs were treated with surgery.
When comparisons were made between dogs that received prophylactic irradiation of the regional lymph node and dogs that did not, no statistically significant differences were observed in disease-free survival rate (P=0.534), time to local recurrence (P=0.521), or overall survival rate (P=0.438). The 1-year disease-free survival rate for dogs that did not receive prophylactic lymph node irradiation was 87.3%, and the 2- and 3-year disease-free survival rates were each 72.8%. The Kaplan-Meier curves for disease-free survival rate for the two treatment groups were not significantly different (P=0.534). No significant differences were noticed in overall survival rates for dogs that developed a second MCT compared to those that did not. Tumor site was not prognostic for overall survival rate, disease-free survival rate, or local recurrence rate.
Discussion
Three (6.7%) dogs in the study reported here had local recurrence of tumor in the radiation therapy field, and the tumors recurred early in the follow-up period (<7 months). These results suggest that the schedule for recheck examinations may be less stringent after an event-free survival of 1 year has been reached. The observed recurrence rate in this study was similar to that reported for completely excised grade II MCTs and for incompletely excised grade II MCTs followed by radiation therapy.12,14,19 These results indicate that local tumor control can be achieved in most cases with either complete surgical excision or incomplete surgical excision followed by appropriate radiation therapy. A dose response effect has been reported for canine MCT, with a high rate of failure at <40 Gy total dose.16 Although the ideal radiation dose and schedule have yet to be determined, based on the 6% incidence of local recurrence reported here, a total dose of <48 Gy appears inadequate.
Controversy exists over the actual local recurrence rate of incompletely excised grade II MCTs. Local recurrence rates have ranged from 6% to 50%, and the status of the surgical margins has not always been reported.3,4,20–22 Ideally, a randomized prospective trial may determine the importance of postoperative radiation therapy for incompletely excised grade II MCTs; however, results of the study reported here (and other recent studies) suggest that the chance of local recurrence can be greatly reduced using postoperative radiotherapy.12,14 The metastatic rate observed in this study was also similar to that reported in other studies for grade II MCTs.5,10,14
The biological rationale for the shorter treatment schedule used (19 days for this protocol) in this study was based on a previous report that showed smaller intervals between fractions were beneficial for dogs with MCT.16 It was interesting to note that the lower total dose (48 Gy) used in this study, as well as the shorter overall treatment period, were as efficacious as another protocol using 54 Gy.12
A major finding of the current study was a lack of benefit for the prophylactic irradiation of regional lymph nodes, which suggests that such irradiation may not be necessary for lymph nodes with no documented metastasis. Despite the absence of chemotherapy or prednisone use in the cases reported here, the incidence of metastasis was low (4%), which suggests that routine use of systemic therapy may not be justifiable for incompletely excised grade II MCTs followed by radiation therapy.
The proportion of dogs with grade II MCTs that die from their disease varies greatly (5% to 56%) between reports.3–6,10,12 Only one (2%) dog in the present report died of mast cell disease. Fourteen (31%) dogs developed a second MCT during the follow-up period and were treated successfully with a second surgery. It was possible that these second MCTs represented cutaneous metastatic lesions resulting from the original cutaneous mass; however, the timing of their development, the lack of correlation with the primary tumor site, and overall survival rate made this less likely. None of these second MCTs resulted in the animal’s death.
The limitations of this study included its retrospective nature (i.e., some information such as necropsy information was not available). It was also not possible to statistically determine prognostic factors, because too few dogs died or developed local recurrence or metastasis. Additionally, in 11 cases, lymph node cytology was not done because of their intracavitary location. However, lack of lymphadenopathy following imaging in all cases and failure to discover regional lymph node metastasis during the follow-up period supported the conclusion that these cases had stage 0 disease. An additional limitation was the time-period bias that developed; those cases treated with nodal irradiation all were presented after 1998, and those without nodal irradiation were presented prior to this date.
Conclusion
In this study, 45 dogs with incompletely excised, stage 0, grade II MCTs were treated at the surgical site with radiation therapy, and 24 dogs had prophylactic irradiation of the regional lymph node. The adjunctive radiation therapy protocol of 15 fractions (3.2 Gy each) was well tolerated and efficacious. Prophylactic irradiation of the regional lymph node did provide additional benefit for these dogs. A randomized, prospective trial would be necessary to confirm this finding.
Theratron 780; Atomic Energy of Canada Ltd, Kanata, Ontario, Canada
Prowess 3000 Radiotherapy Treatment Planning System; Prowess, Inc., Chico, CA 95973
Prism Graph Pad Software; Graph Pad Software, Inc., San Diego, CA 92121
Citation: Journal of the American Animal Hospital Association 42, 6; 10.5326/0420430
Citation: Journal of the American Animal Hospital Association 42, 6; 10.5326/0420430
Citation: Journal of the American Animal Hospital Association 42, 6; 10.5326/0420430
Kaplan-Meier curve for disease-free survival rate in dogs with incompletely excised, grade II mast cell tumors that were treated with adjunctive radiation therapy. Vertical lines represent cases censored if alive or dead of another cause and disease-free at that time point.
Kaplan-Meier curve for local recurrence-free survival rate in dogs with incompletely excised, grade II mast cell tumors that were treated with adjunctive radiation therapy. Vertical lines represent cases censored if alive or dead of another cause and without local recurrence at that time point.
Kaplan-Meier curve for overall survival time in dogs with incompletely excised, grade II mast cell tumors that were treated with adjunctive radiation therapy. Vertical lines represent cases censored if alive or dead of another cause at that time point.
