A phase II study to evaluate the toxicity and efficacy of alternating CCNU and high‐dose vinblastine and prednisone (CVP) for treatment of dogs with high‐grade,metastatic or nonresectable mast cell tumours

Safety and efficacy of a protocol of alternating 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU; 70 mg m^?2) and vinblastine (3.5 mg m^?2), and prednisone (1–2 mg kg^?1; CVP) in dogs with mast cell tumours (MCT) were evaluated. A total of 17 dogs had nonresectable MCTs and 35 received CVP as adjunctive treatment to locoregional control of metastatic MCTs or grade III MCTs. Neutropenia with fever occurred in 8% of dogs after treatment with vinblastine and in 2% after treatment with CCNU. Persistent elevation of serum alanine transaminase, suggestive of hepatotoxicity, occurred in 9% of the dogs. Response rate in dogs with nonresectable MCTs was 65%; five achieved a complete response (median, 141 days) and six achieved a partial response (median, 66 days). Overall median progression‐free survival (PFS) time in dogs treated in the adjuvant setting was 489 days. Dogs with grade III MCTs had shorter PFS compared with dogs with metastatic grade II MCTs (190 days versus 954 days; P < 0.001). Phase III studies are needed to provide reliable information about the comparative efficacy of this protocol.     

Treatment of canine mast cell tumours with vinblastine, cyclophosphamide and prednisone: 35 cases (1997–2004)

The purpose of this retrospective study was to determine the efficacy and toxicity of a combined protocol of vinblastine, cyclophosphamide and prednisone (VCP) in 35 dogs with mast cell tumours (MCTs). Eleven dogs had measurable disease (group 1) and 24 dogs had incompletely excised MCT or were at high risk for metastasis (group 2). Five patients in group 1 achieved complete response, two partial responses, two stable diseases and two progressive diseases. The median progression‐free survival time (PFST) for group 1 and 2 dogs was 74 and 865 days, respectively. The median overall survival time (OST) for group 1 and 2 dogs was 145 and >2092 days, respectively. Significant negative multivariate prognostic factors included macroscopic disease and reduced vinblastine (VBL) treatments for PFST, and presence of MCT in bone marrow analysis, Patnaik grade III MCT and reduced VBL treatments for OST. Toxicity was infrequent and self‐limiting. This study suggests that the VCP protocol should be considered as an option in the treatment of MCT in dogs.     

Evaluation of prognostic indicators in dogs with multiple,simultaneously occurring cutaneous mast cell tumours: 63 cases

Sixty‐three dogs with multiple contemporaneous cutaneous mast cell tumours (MCTs) were identified. The aim of this study was to determine the significance of breed, concurrent dermatological condition; number of cutaneous MCTs, size, location, histological grade and mitotic index; completeness of excision (complete, close or incomplete); local recurrence, metastasis and adjuvant therapy for the prognostic evaluation of dogs with a unique disease presentation of multiple, simultaneously occurring cutaneous MCTs. On the basis of multivariable survival analysis, dogs with one recorded grade 3 MCT had shorter progression‐free survival (PFS) times (18.7 versus 2.2 months) and median survival times (MSTs) (24 versus 3 months). Dogs treated with adjuvant vinblastine/lomustine had a 16 times increased risk of dying. MSTs were found to be significantly longer in dogs with one recorded MCT on an extremity. For all dogs, the PFS (range 14–1835 days) and MSTs (range 28–1835 days) were not reached.     

Retrospective outcome evaluation for dogs with surgically excised,solitary Kiupel high‐grade,cutaneous mast cell tumours

Published outcomes for dogs with specifically high‐grade mast cell tumours (MCTs), controlled for clinical stage, are few. Clinical outcomes for 49 dogs with Kiupel high‐grade, clinical stage I, cutaneous MCTs were evaluated. Median survival time (MST) was 1046 days; 1 and 2‐year survival rates were 79.3% and 72.9%, respectively. At study end 24 dogs had died, 23 dogs were alive (median follow‐up 980 days) and 2 dogs were lost to follow‐up. Death was considered MCT‐related in 14 of 20 dogs with a known cause of death. Local tumour recurrence developed in nine dogs (18.4%); regional lymph node metastasis occurred in six dogs (12.2%); and a new MCT developed in 15 dogs (30.1%). Tumour location, histologic margin size and use of chemotherapy did not affect MST; increasing mitotic count (P = .001) and increasing tumour diameter (P = .024) were independently negatively prognostic. Six dogs that developed lymph node metastasis after surgery had worse MST (451 days) than 42 dogs that did not develop metastasis (1645 days); (P < .001). Our study suggests that dogs with local surgical control of clinical stage I histologically high Kiupel grade cutaneous MCT may have a long survival time; especially those with smaller tumours and a lower mitotic count. Our results suggest that evaluation of staging information and mitotic count may be equally helpful as histologic grading when making a prognosis; and highlight the importance of not relying on histologic grade alone when predicting survival for dogs with MCT.     

Long‐term survival in dogs with localized histiocytic sarcoma treated with CCNU as an adjuvant to local therapy*

Histiocytic sarcoma (HS) is associated with a poor prognosis owing to the presence of metastasis at the time of diagnosis in most dogs. Improved outcome has been reported in several dogs with localized HS following local therapy, however, distant metastasis occurs in 70–91% of dogs suggesting that adjuvant systemic therapy is necessary. The purpose of this retrospective study was to describe clinical characteristics and outcome in dogs with localized HS treated with aggressive local therapy plus adjuvant CCNU chemotherapy. Data from 16 dogs were evaluated. The median disease‐free interval was 243 days. Two dogs had local recurrence and eight dogs developed metastatic disease with a median time to relapse of 201 days in these 10 dogs. The median survival time for all 16 dogs was 568 days. These results support the recommendation for aggressive local therapy combined with adjuvant CCNU chemotherapy in dogs with localized HS.     

Histiocytic sarcomas in flat-coated retrievers: a summary of 37 cases (November 1998–March 2005)

Thirty‐seven cases of histiocytic‐like sarcomas (HLSs) in flat‐coated retriever dogs were evaluated retrospectively. This tumour accounted for 36% of the malignant tumours seen in this breed during the study period. The median age at presentation was 8.2 years. Thirty‐four dogs presented with a swelling or mass in a muscle group or surrounding a joint. The remaining three presented for rib (1), cutaneous (1) or primary splenic origin (1). A high rate of metastasis to local lymph nodes (45%), thorax (20%) and abdominal organs (20% confirmed) was seen. Overall metastastic rate by the time of death was 70%. The median survival for all dogs was 123 days. The most significant prognostic indicator was presence of distant metastasis at the time of diagnosis with median survival of 68 or 200 days, with or without metastasis, respectively. Chemotherapy and radiation therapy significantly improved survival. Dogs given chemotherapy survived a median of 185 versus 34 days for dogs that were not (P = 0.0008). Dogs treated with radiation survived a median of 182 versus 60 days for those that were not (P = 0.0282). Dogs receiving only palliative therapy survived a median of 17 versus 167 days in dogs receiving any kind of radiation, chemotherapy, surgery or combinations. A set protocol of radiation and CCNU (RTCCNU) induced minimal toxicity and provided a median survival of 208 versus 68 days for all other dogs. While this tumour carries a poor long‐term prognosis in flat‐coated retrievers, it is reasonable to treat these dogs for palliation of signs and extension of life.     

Outcome and prognostic factors following adjuvant prednisone/vinblastine chemotherapy for high-risk canine mast cell tumour: 61 cases

The medical records of 61 dogs with MCT at high risk for metastasis that were treated with prednisone and VBL following excision+/-radiation therapy were reviewed, and median disease-free interval (DFI), median overall survival time (OS) and prognostic factors assessed. Adverse effects, mostly mild, were noted in 26% of patients, usually after the first VBL dose. 6.5% experienced severe neutropenia. The DFI was 1305 days, and the OS was not reached, with 65% alive at 3 years. 100% of dogs with "high-risk" grade II MCT were alive at 3 years. The OS for dogs with grade III MCT was 1374 days. Histologic grade, location (mucous membrane vs. skin) and use of prophylactic nodal irradiation predicted outcome. Prednisone and VBL chemotherapy is well tolerated, and results in good outcomes following surgery in dogs with MCT at high risk for metastasis. High-grade and mucocutaneous tumors had a worse outcome, and the use of prophylactic nodal irradiation appeared to improve outcome in this group of dogs.     

Prednisone and Vinblastine Chemotherapy for Canine Mast Cell Tumor—41 Cases (1992–1997)

Forty-one dogs with mast cell tumors (MCTs) were treated with oral prednisone and injectable vinblastine (VBL), both in the adjuvant setting (23 dogs) and in dogs with gross disease (18 dogs). Adverse effects were noted in 20% (8/41) of the patients, usually after the 1st dose of VBL. Adverse effects were considered mild in 6, and severe, necessitating treatment discontinuation, in 2 (5%). Overall response rate in the evaluable dogs with gross disease was 47% (7/15), consisting of 5 complete responses and 2 partial responses. Median response duration was 154 days (24 to >645 days). As adjuvant therapy to incomplete surgical resection, prednisone and VBL conferred a 57% 1- and 2-year disease-free rate. Median survival time (MST) for the entire patient population was not reached with a median follow-up of 573 days; however, the MST for dogs with grade III MCT was 331 days, with 45% of dogs alive at 1 and 2 years. This is an apparent improvement over historical survival data employing surgery alone. Upon univariate analysis, significant prognostic factors (P < .05) for survival included presence of a locally recurrent tumor, presence of gross disease, argyrophilic nucleolar organizer region frequency, lymph node status, histologic grade, previous chemotherapy, and ulceration of the tumor. Similar criteria were significant when analyzed for time to treatment failure. Response to therapy was also predictive of survival in the gross disease group. Upon multivariate analysis, histologic grade (P = .012) and presence of a locally recurrent tumor (P < .001) were significant factors for survival.     

Treatment of canine mast cell tumors with CCNU (lomustine)

The efficacy and toxicity of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosourea) were evaluated in 23 dogs with measurable mast cell tumors (MCT). Twenty-two dogs had cutaneous MCT and 1 dog had an intranasal MCT Nineteen (83%) dogs had biopsy of their original mass performed and 4 (17%) had aspiration cytology of masses. Of the 19 tumors histologically graded, 1 (5%) neoplasm was classified as grade I, 10 (53%) were grade II, and the remaining 8 (42%) were grade III. Dogs were treated with CCNU at a dosage of 90 mg/m2 body surface area every 3 weeks. Response could be evaluated in 19 dogs. Eight of the 19 dogs (42%) had a measurable response to CCNU. One dog had a durable complete response for 440 days. Seven dogs (37%) had a partial response for a median and mean duration of 77 days and 109 days, respectively (range, 21-254 days). Treatment with CCNU resulted in stable disease in 6 dogs (32%) for a median and mean duration of 78 days and 122 days, respectively (range, 42-347 days). The acute dose-limiting toxicity was neutropenia 7 days after administration of CCNU. The median and mean neutrophil counts 7 days after CCNU were 1,452 cells/microL and 1,683 cells/microL, respectively (n = 17). Other toxicoses were uncommon. CCNU should be considered an active agent in the treatment of MCT in dogs.     

Survival in Dogs with Nasal Adenocarcinoma: 64 Cases (1981–1995)

Case records of 64 dogs with nasal adenocarcinoma were reviewed. The effects of age, gender, tumor stage, presence of metastatic lesions, and treatment method on survival time were examined. Surgery groups included rhinotomy (n = 9), transnasal curettage (n = 29), and no surgery (n = 26). Chemotherapy groups included fluorouracil-cyclophosphamide combination therapy (n = 15), mitoxantrone (n = 7), and no chemotherapy (n = 42). Fifty-three dogs received fractionated cobalt 60 radiation therapy. Surgical procedure, chemotherapy group, and stage of primary tumor were not significantly associated with survival time ( P > .05). Dogs that received radiation therapy had a significantly longer median survival time (424 days) than dogs that did not (126 days) ( P = .0001). The presence of either regional lymph node or pulmonary metastasis was associated with significantly shorter median survival time (109 days) when compared to dogs without metastases (393 days) ( P = .0125). When only dogs that had received radiation therapy were considered, neither surgical treatment nor chemotherapy group was associated with significant changes in median survival time. An alternate staging system emphasizing the presence or absence of metastases is proposed. Key words: Chemotherapy; Metastasis; Radiotherapy.     

Curative-intent radiation therapy as a treatment modality for appendicular and axial osteosarcoma: a preliminary retrospective evaluation of 14 dogs with the disease

Canine osteosarcoma is a common bone malignancy associated with aggressive local disease and rapid metastasis. Current local therapeutic modalities do not provide curative‐intent options for dogs with significant orthopaedic or neurologic disease, dogs which are denied amputation or dogs with non‐resectable lesions. The goals of this retrospective study included the evaluation of local control, survival, and time to the development of metastases in 14 dogs treated with curative‐intent radiation therapy and chemotherapy. Median local disease control was 202 days (79–777). Median survival was 209 days (79–781). Median time to metastasis was 314 days (7–645). No significant correlation was found between the outcome and pre‐treatment alkaline phosphatase levels, radiographic appearance, tumour site, radiation dose or chemotherapeutics administered. In these dogs, full‐course radiation therapy in conjunction with chemotherapy was not found to yield equivalent results to the standard of care options.     

A retrospective review of treatment and response of high‐risk mast cell tumours in dogs

This retrospective case series evaluates survival outcome of 94 dogs with high metastatic risk mast cell tumours (MCT). Patients were treated with a cytotoxic chemotherapy protocol or the tyrosine kinase inhibitor masitinib, in the presence of gross disease or as an adjunct to surgical resection of the primary tumour. In patients presenting with metastatic disease, surgical resection of the primary tumour with adjunctive therapy with any chemotherapy incurred a significant survival advantage [median survival time (MST): 278 days] compared to patients receiving chemotherapy without surgical excision of the primary tumour (MST: 91 days, P < 0.0001). Patients with a surgically excised Patnaik grade II tumour and high Ki‐67 in the absence of metastatic disease treated with vinblastine and prednisolone showed a significantly longer survival (MST: 1946 days) than those treated with masitinib (MST: 369 days, P = 0.0037). Further prospective case‐controlled clinical trials of high‐risk MCTs are required to make precise evidence‐based treatment decisions for individual patients.     

Adjuvant medical therapy provides no therapeutic benefit in the treatment of dogs with low‐grade mast cell tumours and early nodal metastasis undergoing surgery

Lymph node (LN) metastasis is a negative prognostic factor in dogs with cutaneous mast cell tumours (cMCTs). While elective lymphadenectomy of metastatic LNs improves outcome, the benefit of adjuvant medical therapy in dogs with early metastatic (HN2) LNs is debated. The aim of this retrospective multicentre study was to evaluate the therapeutic benefit of adjuvant medical therapy following surgical removal of the primary low‐grade cMCT (Patnaik grade 1‐2 and Kiupel low‐grade) and lymphadenectomy of HN2 LNs by analysing survival rates and patterns of recurrence. Seventy‐three dogs were included: 42 received adjuvant medical treatment (chemotherapy and/or kinase inhibitors), and 31 did not. The median follow‐up time for medically treated dogs was 619 days: two experienced local recurrence, three nodal relapse and four distant relapse. For dogs undergoing surgery only, the median follow‐up time was 545 days. None of them experienced local recurrence, nodal, or distant relapse. Time to progression was significantly shorter in dogs receiving adjuvant medical treatment (P = .021). A similar tendency was observed for overall survival (P = .056). The current study shows that dogs with low‐grade cMCTs, that undergo surgical excision of the primary tumour and elective lymphadenectomy of the HN2 regional LN harbour a good prognosis. The use of adjuvant medical treatment in these dogs does not seem to provide any benefit in terms of progression and survival.     

Definitive‐intent intensity‐modulated radiation therapy for treatment of canine prostatic carcinoma: A multi‐institutional retrospective study

No standard of care is currently recognized for treatment of canine prostatic carcinoma (PC). This retrospective study assesses outcome following definitive‐intent, intensity‐modulated radiation therapy (RT) in dogs with PC. Medical records review was performed, including 18 patients from four institutions undergoing definitive‐intent intensity‐modulated radiotherapy to treat PC. Diagnosis was incidental in 7/18 (39%) patients. Five dogs (28%) had evidence of metastasis to loco‐regional lymph nodes at diagnosis. Seventeen patients received concurrent non‐steroidal anti‐inflammatory drugs; 15/18 (83%) patients received maximally‐tolerated dose (MTD) chemotherapy, with variable drugs and protocols employed. Total prescribed radiation dose ranged from 48 to 54 Gy (median 50 Gy) delivered as daily doses of 2.5‐2.8 Gy. One patient was euthanized prior to completing radiotherapy. Acute toxicity was observed in nine patients; Grade 1‐2 diarrhoea was the most common toxicity observed. Suspected late toxicity (urethral stricture, ureteral stricture and hindlimb oedema) was observed in three patients. Median event‐free survival (EFS) following RT was 220 days, and median overall survival was 563 days. Local progression occurred in seven patients at a median of 241 days. Median overall survival was significantly longer in incidentally diagnosed dogs (581 vs 220 days in symptomatic dogs, P = .042). EFS was significantly longer in patients treated with MTD chemotherapy (241 vs 25 days, P < .001), and significantly shorter in patients presenting with evidence of metastatic disease (109 days) vs those without (388 days, P = .008). These findings suggest that definitive‐intent radiotherapy is a valuable treatment option for local control of canine PC with moderate risk of toxicity.     

RESULTS OF RADIATION THERAPY IN 19 DOGS WITH CUTANEOUS MAST CELL TUMOR AND REGIONAL LYMPH NODE METASTASIS

The records of 19 dogs with cutaneous mast cell tumor and regional lymph node metastasis (WHO Stage 2) were reviewed to determine the efficacy of radiation therapy in this population. Dogs with grade I (n = 1), grade II (n = 16), and grade III (n = 2) cutaneous mast cell tumor were included in this study. All dogs were treated with a combination of pre-irradiation surgical cytoreduction of the primary tumor, irradiation of the primary tumor and regional lymph node, and oral prednisone. Total radiation dose to the primary tumor and regional lymph node ranged from 48 to 57 Gray (Gy). The medial iliac and hypogastric lymph nodes were irradiated prophylactically in 11 dogs with primary tumor of the pelvic limb and positive ipsilateral popliteal lymph node. Total radiation dose to these lymph nodes ranged from 48 to 57 Gy. For all radiation fields, dose per fraction was 3 Gy, and therapy was administered on a Monday through Friday schedule. Acute and late radiation side effects observed in this study were considered acceptable. The median disease-free survival was 1,240 days (95% confidence interval 256 to 2,391 days). The disease-free survival in dogs with stage 2 mast cell tumor suggests that the combination of surgery, irradiation, and prednisone for the primary tumor along with irradiation of the positive lymph node is effective.     

Vinblastine and prednisolone chemotherapy for surgically excised grade III canine cutaneous mast cell tumours

The effect of treatment with vinblastine and prednisolone chemotherapy in dogs undergoing only surgical excision of Patnaik grade III cutaneous mast cell tumours is reported. Potential explanatory variables were explored using Kaplan–Meier survival analysis with log‐rank tests. During a median follow‐up period of 429 days, the overall median survival time (MST) was not reached (lower 95% CI = 322 days). The 1‐year survival probability was 0.71 (standard error 0.1), remaining unchanged at 2 years. Secondary disease at presentation was an independent risk factor for survival (P= 0.045). The MST of dogs presenting with secondary disease was 322 days, with a lower 95% confidence interval of 142 days and a 1‐year survival of probability of 0.47 (standard error 0.19). Adverse effects were recorded in 6 of the 108 (5.6%) vinblastine doses given. This chemotherapy regimen is a well‐tolerated adjunct to surgery for grade III mast cell tumours and appears to prolong survival compared with that expected with surgery alone.     

Biologic behavior and prognostic factors for mast cell tumors of the canine muzzle: 24 cases (1990-2001)

The medical records of 24 dogs with histologically confirmed mast cell tumors (MCT) of the muzzle were retrospectively evaluated to determine their biologic behavior and prognostic factors. Information on signalment, tumor grade and stage, treatment methods, and pattern of and time to failure and death was obtained from the medical record. Twenty-three dogs were treated with combinations of radiotherapy, surgery, and chemotherapy; 1 dog received no treatment. There were 2 Grade 1, 15 Grade 11, and 7 Grade III tumors. Tumors were stage 0 (n = 8), stage 1 (5), stage 2 (6), stage 3 (4), and stage 4 (1). Mean and median survival times of treated dogs were 36 and 30 months, respectively. Prognostic factors affecting survival time included tumor grade and presence of metastasis at diagnosis. Dogs with Grade I and II tumors survived longer than dogs with Grade III tumors. Variables, including sex, age, gross versus microscopic disease, and treatment type were not found to affect survival. Local control rate was 75% at 1 year and 50% at 3 years. Tumor grade was the only variable found to affect local control. Dogs with Grade I tumors had longer disease-free intervals than those with Grade II tumors, and dogs with Grade II tumors had longer disease-free intervals than dogs with Grade III tumors. Eight of 9 dogs dying of MCT had local or regional disease progression. Muzzle MCT a rebiologically aggressive tumors with higher regional metastatic rates than previously reported for MCT in other sites.     

Ultrasound is a poor predictor of early or overt liver or spleen metastasis in dogs with high‐risk mast cell tumours

Conflicting evidence exists regarding the importance of routine abdominal ultrasound (US) with hepatic and splenic fine needle aspiration (FNA) cytology during staging of canine mast cell tumours (MCT). The objective of this study was to correlate ultrasonographic and cytologic findings in dogs with strictly defined high‐risk MCTs and to determine the influence on outcome. Our hypothesis was that US poorly predicts visceral metastasis in high‐risk MCTs and that early metastasis is associated with improved outcome when compared to overt metastasis. US of liver and spleen correlated to cytologic results, categorized as no metastasis, early metastasis or overt metastasis. Of 82 dogs prospectively enrolled, 18% had early visceral metastasis and 7% had overt metastasis on cytology; 67% with visceral metastasis had regional LN metastasis. US was a poor predictor of metastasis with sensitivity, specificity, positive predictive value and negative predictive value for the spleen of 67%, 68%, 21% and 94%, respectively and for the liver of 29%, 93%, 56% and 82%, respectively. Median time to progression (TTP) for dogs with no metastasis, early metastasis and overt metastasis was not reached, 305 and 69 days, respectively (P < .001). Median survival time (MST) for the 3 groups were not reached, 322 and 81 days, respectively (P < .001). High Patnaik or Kiupel grade, early metastasis, overt metastasis and adequate local control were significantly associated with outcome. Early visceral metastasis was associated with poorer outcome compared to dogs without metastasis, however, a subset of dogs experienced long‐term control.