Description and efficacy of a response-based “QUAD” cyclical hypofractionated palliative-intent radiation protocol in dogs with macroscopic solid tumours: 108 cases

Palliative-intent radiation therapy can alleviate pain and clinical signs in dogs with cancer, but optimal fractionation scheme is unknown. The objective of this retrospective case series is to evaluate clinical benefit, objective response, adverse effects, and outcomes in 108 dogs with macroscopic solid tumours treated with a cyclical “QUAD” hypofractionated palliative-intent radiation therapy protocol. Median QUAD dose was 14 Gy (14–16 Gy). Median total dose was 28 Gy (14–48 Gy). Clinical benefit rate was 93%, with median onset of subjective palliation 21 days after the first QUAD, lasting a median of 134 days. Tumour volumetric objective response was assessed with CT prior to the third QUAD in 36 dogs, with stable disease in 24 dogs (67%) and partial response in 9 dogs (25%). Sinonasal and oral were the most common tumour locations in 32 and 30 dogs, respectively. Median progression-free survival was 153 days (95% CI 114–200). Median overall survival was 212 days (95% CI 152–259). Number of QUAD cycles completed, clinical benefit achieved, anti-inflammatory received, total radiation dose, time to maximum clinical benefit, and response duration were positively associated with progression-free and overall survival. Acute toxicities were observed in 15 dogs (14%) with 3 high-grade (grade 3) toxicities (3%). Low-grade (grade 1 and 2) late skin and ocular toxicities were observed in 31 dogs (29%), predominantly leukotrichia, alopecia, keratoconjunctivitis sicca, and cataracts. This report demonstrates that QUAD radiation is an alternative protocol to be considered for palliation of dogs with inoperable or advanced stage solid tumours.     

Four-fraction radiation therapy for macroscopic soft tissue sarcomas in 16 dogs

A retrospective study of 16 dogs with macroscopic soft tissue sarcomas was performed to evaluate response to a four-fraction radiotherapy protocol (prescribed dose of 32 Gy). Radiation was well tolerated with minimal side effects. The overall response rate was 50%, with seven partial responses and one complete response. The median time to progression was 155 days, and the median survival time was 309 days. Coarsely fractionated radiation therapy may be a reasonable palliative option for dogs with unresectable soft tissue sarcomas, although the response is relatively short-lived.     

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.     

Hypofractionated radiation therapy for the treatment of microscopic canine soft tissue sarcoma

Soft tissue sarcomas (STSs) are locally invasive and surgery with or without radiation therapy is the current standard of care in dogs. Typical protocols for treating incompletely excised STSs involve curative intent radiation with total dose in excess of 50 Gy. Forty‐eight dogs with histologically confirmed incomplete or closely excised STSs were treated with a hypofractionated protocol that is typically reserved for palliative radiation therapy (RT) (6–8 Gy/weekly fractions to a total dose of 24–32 Gy). Ten dogs (21%) developed local recurrence, 11 dogs (23%) developed metastasis, and 3 dogs developed both (included in each group). The median progression free survival was 698 days. The local failure‐free probability at 1 and 3 years was 81 and 73%. The 1 and 3 years tumour‐specific overall survival was 81 and 61%. Long‐term local tumour control was achieved in the majority of dogs. This protocol is reasonable to prescribe in older patients or when financial limitations exist.     

PALLIATIVE RADIATION THERAPY OUTCOMES FOR CATS WITH ORAL SQUAMOUS CELL CARCINOMA (1999–2005)

Squamous cell carcinoma (SCC) accounts for approximately 10% of all feline tumors. The purpose of this retrospective study was to describe outcomes for a group of cats with oral SCC that were treated with palliative radiation therapy. Fifty‐four cats met the inclusion criteria of nonresectable, oral SCC treated with coarse fractionated megavoltage (MeV) radiation therapy. Radiation therapy for all cats was delivered with a 6 MeV linear accelerator. Total radiation doses of 24 Gray to 40 Gray were administered in three to four fractions, once‐per‐week over 4 to 5 weeks. Concurrent chemotherapy protocols varied and were administered at the discretion of the clinician and client. Forty‐nine patients completed the planned treatment protocols. Overall mean and median survival times for cats completing the planned treatment protocols were 127 and 92 days (n = 49). Mean and median survival times of cats receiving palliative radiation therapy alone were 157 and 113 days (n = 12). Mean and median survival times of patients receiving both radiation therapy and chemotherapy were 116 and 80 days (n = 37). Patients with sublingual tumors had a median survival time of 135 days (n = 15), compared to mandibular tumors that had a median survival time of 80 days (n = 26). For the majority of patients that completed the planned treatment protocol (65%), owners reported a subjectively improved quality of life. Findings from this uncontrolled study supported the use of palliative radiation therapy for cats with nonresectable oral squamous cell carcinoma.     

Retrospective study of canine nasal tumor treated with hypofractionated radiotherapy

The object of this study was to evaluate hypofractionated multiportal field and two-portion (rostral and caudal portions divided by the eyelid) radiation therapy for canine nasal tumors. Sixty-three dogs underwent multiportal hypofractionated radiation therapy. The radiation field was divided into rostral and caudal portions by the eyelid. Treatments were performed four times for 57 dogs. The median irradiation dose/fraction was 8 Gy (range, 5-10 Gy); the median total dose was 32 Gy (10-40 Gy). Improvement of clinical symptoms was achieved in 53 (84.1%) of 63 cases. Median survival time was 197 days (range, 2-1,080 days). Median survival times with and without destruction of the cribriform plate before radiotherapy were 163 and 219 days, respectively. There was no significant difference between them. No other factors were related to survival according to a univariate analysis. All radiation side effects, except one, were grade I according to the VRTOG classification. It was not necessary to treat any dogs for skin side effects. One dog (1.6%) developed an oronasal fistula 1 year after completion of radiation therapy. This radiation protocol may be useful in reducing radiation side effects in dogs with cribriform plate destruction.     

CONCOMITANT LIPOSOMAL DOXORUBICIN AND DAILY PALLIATIVE RADIOTHERAPY IN ADVANCED FELINE SOFT TISSUE SARCOMAS

Local recurrence of feline soft tissue sarcomas is common despite aggressive treatment. Liposomal doxorubicin might serve as a depot radiosensitizer if administered concomitantly with daily radiotherapy and thus improve tumor control. In this pilot study, the feasibility of concomitant liposomal radiochemotherapy was evaluated in a palliative setting in 10 cats with advanced soft tissue sarcomas. Cats were treated with median number of 5 (range 5–7) daily fractions of radiotherapy and a median total dose of 20 Gy (range 20–31.5 Gy). One dose of liposomal doxorubicin was administered at the beginning of radiotherapy. Seven cats received further free or liposomal doxorubicin after completion of the liposomal doxorubicin/radiation protocol. Seven of the treated 10 cats (70%) achieved a partial (n=5) or complete (n=2) response with a median response duration of 237 days. The median progression free interval in all 10 cats was 117 days and the median overall survival time was 324 days. Concomitant liposomal radiochemotherapy was tolerated well in nine cats, one cat experienced temporary anorexia. Although the number of patients is too small to make definitive conclusions, results appear promising enough to investigate the role of liposomal doxorubicin as a radiosensitizer further.     

Hypofractionated radiation therapy in the treatment of canine thymoma: Retrospective study of eight cases

Thymomas are one of the most common tumors of the cranial mediastinum in dogs; however there is limited information available on the use of radiation therapy for treating this neoplasm. Objectives of the current retrospective observational study were to describe outcomes and side effects of a hypofractionated radiation therapy protocol in a group of dogs with confirmed thymoma. A total of eight dogs were included. To generate individualized treatment plans, we designed the planning target volume according to the limits on mean lung dose and the percentage of the total lung volume exceeding 20 Gy (V20). The total administered dose was 48–49 Gy, with one fraction per week for a total of six to seven fractions. After therapy, two dogs achieved complete responses, two achieved partial responses, and the disease remained stable in two. Two dogs died during the radiation therapy protocol and were not classified. The median mean lung dose and V20 were 6.0 Gy (range: 3.1–15.0 Gy) and 12.4% (range: 2.3–27.5%), respectively. The overall response rate was 50.0%, and the median time to response following treatment initiation was 22 days (range: 14–115 days). Acute and late side effects were common in the skin and/or lung and were self‐limiting or asymptomatic. The median survival time was not reached (range: 8–1128 days) and the 1 year survival rate was 75.0%. Hypofractionated radiation therapy was well tolerated in this sample of dogs with thymoma and may be considered when owners decline surgical treatment or the tumor is deemed unresectable.     

Piroxicam, mitoxantrone, and coarse fraction radiotherapy for the treatment of transitional cell carcinoma of the bladder in 10 dogs: a pilot study

Ten dogs with transitional cell carcinoma (TCC) of the bladder were treated with a combination of once-weekly coarse fraction radiation therapy (six weekly fractions of 5.75 Gray [Gy]), mitoxantrone chemotherapy, and piroxicam. All dogs completed the radiation therapy protocol, and only minimal side effects were observed. Only two (22%) dogs achieved a measurable partial response; however, 90% of the dogs had amelioration of their urinary clinical signs. The median survival time for all dogs was 326 days. While this treatment protocol was well tolerated, the response rate and overall survival duration was not superior to reports using mitoxantrone and piroxicam without radiation therapy in dogs with TCC.     

Orthovoltage radiation and weekly low dose of doxorubicin for the treatment of incompletely excised soft-tissue sarcomas in 39 dogs

The efficacy and toxicity of orthovoltage radiation therapy and concurrent low doses of doxorubicin for the treatment of incompletely excised soft-tissue sarcomas in 39 dogs was investigated retrospectively. The 39 dogs had 40 soft-tissue sarcomas and received 51 Gy orthovoltage radiation in 17 daily 3 Gy fractions; they also received 10 mg/m(2) doxorubicin once a week administered intravenously one hour before the dose of radiation. The median follow-up time was 910 days. The tumours recurred locally in seven of the dogs, in five of them within the radiation field; the median time to their recurrence was 213 days (range 63 to 555 days). Six of the dogs developed a distant metastasis after a median time of 276 days (range eight to 826 days). The one-year and two- to four-year tumour control rates were 84 per cent and 81 per cent, respectively, and the one-, two- and three- to four-year survival rates were 85 per cent, 79 per cent and 72 per cent, respectively. Tumours with a mitotic rate of more than 9 per 10 high-power fields were significantly more likely to recur, and the dogs with such tumours survived for significantly shorter periods.     

Retrospective analysis of axial skeleton osteosarcoma in 22 large-breed dogs

Medical-records of 22 large-breed dogs (>15 kg) with osteosarcoma (OSA) of the axial skeleton were reviewed to determine prevalence of metastasis and survival associated with this neoplasm. All dogs were treated with more than 1 mode of therapy including palliative radiation (n = 12), definitive radiation (n = 8), surgery (n = 7), chemotherapy (n = 12), or some combination of these therapies. Metastasis was documented in 10 of 22 dogs (46%), and the median survival for all dogs was 137 days. Primary cause of death was local tumor recurrence (54%). Breed (retriever versus purebred versus mixed-breed survival was 100, 182, and 264 days, respectively) and radiation therapy protocol (survival in dogs treated with palliative radiation therapy versus those treated with definitive radiation therapy was 79 and 265 days, respectively) were significantly related to survival (P < .05). Prevalence of metastasis and median survival for large-breed dogs with axial skeleton OSA seems to be similar to that reported for large-breed dogs with appendicular skeleton OSA. Definitive radiation therapy may have a role in the treatment of axial skeleton osteosarcoma.     

Long‐term survival with stereotactic radiotherapy for imaging‐diagnosed pituitary tumors in dogs

Published studies on the use of stereotactic radiotherapy for dogs with pituitary tumors are limited. This retrospective observational study describes results of stereotactic radiotherapy for 45 dogs with imaging‐diagnosed pituitary tumors. All dogs were treated at a single hospital during the period of December 2009–2015. The stereotactic radiotherapy was delivered in one 15 Gray (Gy) fraction or in three 8 Gy fractions. At the time of analysis, 41 dogs were deceased. Four were alive and censored from all survival analyses; one dog received 8 Gy every other day and was removed from protocol analyses. The median overall survival from first treatment was 311 days (95% confidence interval 226–410 days [range 1–2134 days]). Thirty‐two dogs received 15 Gy (median overall survival 311 days; 95% confidence interval [range 221–427 days]), and 12 received 24 Gy on three consecutive days (median overall survival 245 days, 95% confidence interval [range 2–626 days]). Twenty‐nine dogs had hyperadrenocorticism (median overall survival 245 days), while 16 had nonfunctional masses (median overall survival 626 days). Clinical improvement was reported in 37/45 cases. Presumptive signs of acute adverse effects within 4 months of stereotactic radiotherapy were noted in 10/45, and most had improvement spontaneously or with steroids. Late effects versus tumor progression were not discernable, but posttreatment blindness (2), hypernatremia (2), and progressive neurological signs (31) were reported. There was no statistical difference in median overall survival for different protocols. Patients with nonfunctional masses had longer median overall survival than those with hyperadrenocorticism (P = 0.0003). Survival outcomes with stereotactic radiotherapy were shorter than those previously reported with definitive radiation, especially for dogs with hyperadrenocorticism.     

Linac‐based stereotactic radiation therapy for canine non‐lymphomatous nasal tumours: 29 cases (2013‐2016)

Twenty‐nine dogs were treated with linac‐based stereotactic radiation therapy (SRT) for non‐lymphomatous nasal tumours. Only dogs with a follow‐up time >365 days were included in this retrospective analysis. No dogs had evidence of distant metastasis at diagnosis. Treatment was planned and a total of 30 Gy in 3 daily 10 Gy fractions was delivered using intensity‐modulation, cone‐beam CT‐based image guidance and a robotic treatment couch. Clinical signs improved in all cases. Nineteen dogs had CT scans 3‐4 months post‐SRT and all had partial or complete tumour response. Minimal acute toxicities were detected. Clinically significant late toxicities included oronasal or nasocutaneous fistulas (N = 3) and biopsy‐confirmed fungal rhinitis with no evidence of tumour progression (N = 2). The median progression‐free survival (PFS) was 354 days, with 49% and 39% progression‐free at 1 and 2 years post‐SRT, respectively. The median survival time (ST) was 586 days, with 69% and 22% alive 1 and 2 years post‐SRT, respectively. Neither the clinical parameters evaluated (modified Adams’ stage, histopathology, presence of intracranial extension of the tumour) nor dosimetric data were predictive for PFS or ST. This SRT protocol appears to be well tolerated, and PFI and ST are comparable or superior to those reported in other definitive‐intent radiotherapy protocols.     

RESPONSE OF FELINE ORAL SQUAMOUS CELL CARCINOMA TO PALLIATIVE RADIATION THERAPY

Seven cats with advanced oral squamous cell carcinoma were treated with palliative radiotherapy. Megavoltage radiation in 8 Gray (Gy) fractions was delivered on days 0, 7, and 21 for a total dose of 24 Gy. Treatment field included the mandible, oropharynx, retropharyngeal lymph nodes, and tonsils. Adjuvant treatment with chemotherapy was variable. Age ranged from 13 to 18 years old with a median age of 15 years. Three of the seven cats (43%) did not complete treatment. Six cats were euthanized due to tumor growth and/or radiation side effects with a median survival time of 60 days (range = 42 to 97 days, mean = 63 +/- 8.4 days). Radiotherapy complications or progression of disease occurred in 6 of 7 (85.7 %) cats and included adverse clinical signs, such as mucositis, serosanguinous oral discharge, pain, and dysphagia. These data suggest that coarse fractionation radiotherapy did not result in palliation in cats with inoperable oral squamous cell carcinoma.     

Response rate and duration associated with a 4Gy 5 fraction palliative radiation protocol

The purpose of this retrospective study was to determine if 4Gy fractions over 5 consecutive days is an effective and safe palliative radiation protocol for dogs and cats. Eighty patients (22 cats, 58 dogs) with complete follow-up information were evaluated. Overall response rate (ORR) for all patients was 67%. Median progression free survival (MPFS) was 3.3 months and median survival (MST) was 4.2 months. Primary bone tumors were the most common tumors treated. The ORR for primary bone tumors was 66.6%, the MPFS was 3.5 months, and MST was 3 months. The most common tumor treated in cats was oral squamous cell carcinoma and ORR was 54.5 %, the MPFS was 1.8 months, and MST was 3 months. Soft tissue sarcomas were the second most common tumor treated in dogs (10). ORR was 80% and the two other patients had stable disease. MPFS was 5.7 months and MST was 7.9 months. Overall rate of toxicity was 18.4% in 65 sites that were evaluated for toxicity. Acute toxicities were all grade I or II and occurred in 16.9 % of patients evaluated. All late toxicity was grade I alopecia and leukotrichia. There appears to be a comparable response rate for this palliative protocol as compared to others historically. This response was seen over a wide range of tumors. We also documented a low toxicity profile in a shorter overall treatment time, making this protocol more attractive for some clients.     

Four fraction palliative radiotherapy for osteosarcoma in 24 dogs

Twenty-four dogs underwent palliative radiotherapy consisting of four 8 gray (Gy) fractions of 60Co radiation on days 0, 7, 14, and 21 at 26 sites for axial (n=11) or appendicular (n=15) osteosarcoma. Response was noted in 92% of sites treated. Seventeen dogs were euthanized due to local or metastatic disease, one dog died of metastatic disease, five dogs died of unrelated causes, and one dog is alive. The four fraction protocol is effective for palliation of clinical signs associated with axial or appendicular osteosarcoma and may result in a higher response rate and longer survival time than three fraction palliative protocols.     

TOLERABILITY AND TUMOR RESPONSE OF A NOVEL LOW‐DOSE PALLIATIVE RADIATION THERAPY PROTOCOL IN DOGS WITH TRANSITIONAL CELL CARCINOMA OF THE BLADDER AND URETHRA

Previously reported radiation protocols for transitional cell carcinoma of the canine lower urinary tract have been ineffective or associated with increased side effects. Objectives of this retrospective, cross‐sectional study were to describe safety of and tumor responses for a novel palliative radiation protocol for transitional cell carcinoma in dogs. Included dogs had cytologically or histologically confirmed transitional cell carcinoma of the bladder or urethra, and were treated with 10 once‐daily fractions (Monday–Friday) of 2.7 Gy. Thirteen dogs were sampled, with six treated using radiation as first‐line (induction) therapy and seven treated using radiation as rescue therapy after failing previous chemotherapy. Within 6 weeks of radiation, 7.6% (1/13) dogs had a complete response, 53.8% (7/13) partial response, 38.5% (5/13) stable disease, and none had progressive disease. Three patients presenting with urethral obstruction had spontaneous micturition restored during the treatment protocol. A single patient with unilateral ureteral obstruction was patent at recheck examination. Median survival time from time of initial diagnosis was 179 days. Median survival time from start of radiation was 150 days. Acute radiation side effects occurred in 31% (4/13) patients and were classified as grade 1 or 2. No significant late side radiation side effects were reported. No variables examined were identified as prognostic factors. Findings indicated that the reported radiation protocol was safe in this sample of dogs with bladder and urethral transitional cell carcinoma. Future prospective studies are needed to determine utility of this treatment as a rescue therapy in patients with complete urinary tract obstruction.     

REIRRADIATION OF RECURRENT CANINE NASAL TUMORS

Canine nasal tumors are typically treated with radiation therapy but most patients develop local recurrence. Our purpose was to evaluate tumor and normal tissue response to reirradiation in nine dogs. The median dose delivered with the first protocol was 50 Gy (range 44–55 Gy) and the median fraction number was 18 (range 15–20). For the second protocol, the median dose was lower intentionally, median of 36 Gy (range 23–44 Gy), without changing the median fraction number of 18 (range 14–20) to avoid late effects. The median time between protocols was 539 days (range 258–1652 days). Median survival was 927 days (95% confidence interval [CI] 423–1767 days). Median time to progression following the first and second courses was 513 days (95% CI 234–1180 days) and 282 days (95% CI 130–453 days), respectively. These were not significantly different (P=0.086). The qualitative response assessment was better for the first course compared with the second (P=0.018). Severity and timing of skin, mucous membrane, and ocular effects were similar for early side effects between the two courses (P>0.05 for all comparisons). All dogs experienced some late side effects, with two out of nine being classified as severe. These severe effects were blindness in each dog, possibly related to tumor recurrence. Reirradiation of canine nasal tumors resulted in a second clinical remission in eight of nine dogs, although the second response was less complete. Acute and late effects for seven of nine patients were not life threatening, indicating that reirradiation of canine nasal tumors may be a viable treatment option after recurrence.