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.     

Hypofractionated radiation therapy for the treatment of malignant melanoma and squamous cell carcinoma in dogs and cats

This study describes the experience with hypofractionated radiation therapy of squamous cell carcinoma and melanoma in dogs and cats. A total dose of 32-48 Gray (Gy) was delivered once a week in 8 Gy fractions. 34 animals in which a complete surgical excision was impossible were treated. There was no tumor detectable macroscopically in 14 patients at the beginning of radiation therapy. In 20 animals the median volume of the tumor was 9.9 cm3. The median survival times and the local tumor control of squamous cell carcinoma of the oral and nasal cavities and of the body are comparable to results which were reached with a Monday-Wednesday-Friday scheme. For the treatment of Melanoma the hypofractionated radiation therapy is first choice. There are no significant side effects. Late side effects did not occur. 88% of the owners are satisfied with this kind of treatment and would choose it again.     

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.     

Treatment of dogs with oral melanoma by hypofractionated radiation therapy and platinum-based chemotherapy (1987-1997)

This retrospective study in 39 dogs with incompletely resected oral melanoma examined the efficacy of hypofractionated radiation therapy and platinum-containing chemotherapy. All dogs were completely staged, with the majority of dogs classified as stage 1. Dogs received 6 weekly fractions of 6-gray (Gy) megavoltage irradiation with a cobalt-60 unit or a 4-MeV (megaelectron volts) linear accelerator. Dogs received cisplatin (10-30 mg/m2 IV) or carboplatin (90 mg/m2 IV) chemotherapy 60 minutes before radiation delivery. Durations of local control, metastasis-free survival time, and overall survival time were recorded. By the Kaplan-Meier method, 15% of the dogs had local recurrence within a median time of 139 days. Fifty-one percent of the dogs developed metastatic disease within a median time of 311 days (range, 24-2, 163 days). Median survival time for all 39 dogs was 363 days. The combined use of chemotherapy and radiation therapy in this protocol provided local control consistent with previous studies. Low-dose chemotherapy was used with the intent of enhancing radiation therapy for the local control of an incompletely excised tumor. Survival times were longer than previously reported for dogs with oral malignant melanoma. Additional studies are required to determine whether these results were due to the effects of chemotherapy on microscopic disease or the enhanced local control provided by chemoradiation therapy.     

Long-term outcome of 56 dogs with nasal tumours treated with four doses of radiation at intervals of seven days

A retrospective study was undertaken on 56 dogs treated for nasal tumours by megavoltage radiotherapy with a hypofractionated schedule consisting of four doses of 9 Gy given at intervals of seven days. The dogs were followed until they died or were euthanased. The clinical signs had improved in 53 of the 56 dogs by the end of the treatment schedule. Mild acute radiation side effects were observed in the majority of the dogs but late radiation side effects were rare. Kaplan-Meier survival analysis revealed a median survival time after the final dose of radiation of 212 days. The one- and two-year survival rates were 45 per cent and 15 per cent. Fifty of the dogs were euthanased because the initial clinical signs recurred.     

RESPONSE OF NINETEEN CATS WITH NASAL LYMPHOMA TO RADIATION THERAPY AND CHEMOTHERAPY

The records of 19 cats treated for stage I nasal lymphoma with radiation therapy and chemotherapy were reviewed to determine response to therapy, treatment outcome and possible prognostic indicators. All cats were treated with megavoltage radiation therapy to a total dose ranging from 22 to 48 Gy (median dose = 42 Gy). All cats were prescribed at least 6 months of multiagent chemotherapy. The median progression-free interval for all cats was 945 days (31 months). Two cats did not achieve clinical remission. Of 17 cats evaluable for relapse, 10 (58.8%) were progression free during the entire follow-up period. Four cats (23.5%) suffered local recurrence, while three (17.6%) experienced distant relapse. The median survival time was 955 days (31.4 months). The only variable found to have a significant negative impact on survival was destruction of the cribriform plate before therapy (P= 0.002). The long progression free and survival times reported here indicate that cats with stage I nasal lymphoma treated with aggressive local and systemic therapy can have a favorable outcome when compared with other anatomic forms of lymphoma. Despite strong clinical responses to the multimodality therapy used, the fact that three (17.6%) cats relapsed distantly supports the recommendation that treatment with radiation therapy alone is insufficient until further prospective studies can be performed.     

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.     

Intraoperative acridine orange photodynamic therapy and cribriform electron-beam irradiation for canine intranasal tumors: A pilot study

Untreated canine intranasal tumors carry a poor prognosis. We retrospectively evaluated the efficacy of marginal tumor resection in combination with intraoperative acridine orange (AO) photodynamic therapy (PDT) and 1 fraction of 5 Gy megavoltage irradiation for canine intranasal malignant tumors. When cribriform plate invasion or turbinate destruction around the cribriform plate was present, an additional fraction of 20 Gy was delivered with an electron beam during surgery. The study included 6 dogs, 2 of which were classified as stage I, 1 as stage II, and 3 as stage IV. The median local disease-free survival time and overall survival after the treatment were 8.5 and 13 months, respectively. Recurrence was noted in 2 of the 6 dogs after 4 and 7 months. Adverse events were mild (subcutaneous emphysema in 1 case, and rhinitis in 3 cases). Combination AO therapy may increase the tumor control time of dogs with marginally resectable intranasal malignant tumors.     

PROTON SPOT SCANNING RADIOTHERAPY OF SPONTANEOUS CANINE TUMORS

Thirty dogs with spontaneous tumors were irradiated with proton therapy using a novel spot scanning technique to evaluate the safety and efficacy of the system, and to study the acute and late radiation reactions. Nasal tumors, soft tissue sarcomas, and miscellaneous tumors of the head were treated with a median total dose of 52.5 Gy given in 3.5 Gy fractions. Acute effects, late effects, tumor response, and outcome were analyzed. No unexpected radiation reactions were seen, however two dogs did develop in-field osteosarcoma, and one dog developed in-field bone necrosis. Complete response to therapy was seen in 40% (12/30), partial response in 47% (14/30), and no response in 13% (4/30). Median survival for all dogs was 385 days (range of 14–4583 days). Dogs with nasal cavity tumors had a median survival of 385 days (range of 131–1851 days) and dogs with soft tissue sarcomas had a median survival time of 612 days (range of 65–4588 days). Treatment outcome was similar to historical controls. This new proton spot scanning technique proved to be safe and reliable.     

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.     

Recurrence analysis of intraoperative acridine orange-photodynamic therapy for dogs with intranasal tumors

Intraoperative acridine orange-photodynamic therapy (AO-PDT) and cribriform plate irradiation are used to treat canine intranasal tumors. The purpose of this study was to evaluate the effects of AO-PDT on intranasal tumors and the recurrence rate of tumors after this treatment. Treatments with AO-PDT were performed on 38 dogs through a narrow window of the dorsal nasal cavity. The median progression-free interval was 12 mo and recurrence was detected in 21 dogs. Based on computed tomography, recurrence in 16 dogs was biased to the following areas: lateral (n = 10), medial (n = 2), ventral (n = 0), rostral (n = 0), and caudal (n = 8). Side effects were mild and included subcutaneous emphysema and rhinitis. The median survival time was 24 mo. Although AO-PDT with cribriform irradiation is an effective treatment for intranasal tumors, AO-PDT techniques should be improved to treat the nasal cavity more uniformly and thoroughly.     

Postoperative radiotherapy for canine soft tissue sarcoma

Thirty-five dogs with 37 soft tissue sarcoma tumors that were incompletely excised and treated with radiotherapy in the postoperative, adjuvant setting were reviewed. Variables evaluated included age, sex, tumor site, tumor histology, total tumor radiation dose, radiotherapy field size. time to recurrence, and survival. The majority of tumors were fibrosarcomas and hemangiopericytomas, but small numbers of other tumor types were also represented. Total tumor radiation dose ranged from 42 to 57 Gy given in 3- to 4.2-Gy daily fractions on a Monday through Friday schedule. Overall median survival was 1,851 days. Median time to local recurrence was greater than 798 days. Soft-tissue sarcoma tumors at oral sites had a statistically significant lower median survival (540 days) as compared to other tumor sites (2,270 days). Radiotherapy may be a useful adjuvant therapy for incompletely excised soft-tissue sarcomas with a reasonable expectation for long-term patient survival.     

Clinical outcome in dogs with nasal tumors treated with intensity-modulated radiation therapy

Intensity-modulated radiation therapy (IMRT) is a valuable tool in human radiation oncology, but information on its use in veterinary medicine is lacking. In this study, 12 dogs with nasal tumors were treated with IMRT at a median radiation dose of 54 Gy. Patient survival times and frequency and severity of side effects on ocular structures, oral mucosa, and skin were recorded. Eight dogs (67%) had resolution of clinical signs during radiation therapy. Median overall survival time was 446 d with a 50% 1-year and a 25% 2-year survival rate. Minimal grade 2 or 3 acute skin toxicity, no grade 2 or 3 late skin toxicity, and no grade 2 or 3 toxicity to oral mucosa or the eye opposite the tumor were identified in the dogs treated with IMRT in this study. The ipsilateral eye could not be routinely spared due to its proximity to the tumor.     

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.     

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.     

Hypofractionated radiation therapy of oral melanoma in five cats

Five cats with melanoma involving the oral cavity were treated with hypofractionated radiation therapy (RT). Cobalt photons were used to administer three fractions of 8.0 Gray (Gy) for a total dose of 24 Gy. Four cats received radiation on days 0, 7, and 21 and one cat received radiation on days 0, 7, and 13. One of the cats received additional irradiation following the initial treatment course. Two cats received chemotherapy. Their age ranged from 11 to 15 years with a median age of 12 years. Three cats had a response to radiation, including one complete response and two partial responses. All five cats were euthanized due to progression of disease, with one cat having evidence of metastatic disease at the time of euthanasia. The median survival time for the five cats was 146 days (range 66-224 days) from the start of RT. The results of this study suggest that oral melanoma in cats may be responsive to hypofractionated RT, but response does not seem to be durable.     

External-beam Co-60 radiotherapy for canine nasal tumors: a comparison of survival by treatment protocol

A retrospective analysis of survival times in dogs with intranasal tumors was performed comparing those treated using hypofractionated or full course Co-60 radiotherapy protocols alone or with surgical adjuvant therapy and those receiving no radiation treatment. One hundred thirty-nine dogs presented to the University of Minnesota Veterinary Medical Center for treatment of histologically-confirmed nasal neoplasia between July 1983 and October 2001 met the criteria for review. Statistically analyzed parameters included age at diagnosis, tumor histologic classification, fractionation schedule (number of treatments, and number of treatment days/week) (classified as hypofractionated if 2 or less treatments/week); calculated minimum tumor dose/fraction; calculated total minimum tumor dose (classified as hypofractionated if less than 37 Gy in six or fewer fractions); number of radiotherapy portals, a treatment gap of more than 7 days in a full course (3-5 treatments/week, 3-3.5 week treatment time) radiotherapy protocol, the influence of eye shields on survival following single portal DV fields, the survey radiographic extent of the disease, and the presence or absence of cytoreductive surgery. There was a significant relationship only between protocols using 3 or more treatments/week and at least 37 Gy cumulative minimum tumor dose and survival. However, there was no significant relationship between either total minimum tumor dose or dose/fraction and survival and there were no significant relationships between survival and any of the other variables analyzed including tumor histologic type.     

SLOW RELEASE CISPLATIN COMBINED WITH RADIATION FOR THE TREATMENT OF CANINE NASAL TUMORS

Thirteen dogs with malignant tumors of the nasal cavity were treated with a combination of slow release cisplatin and megavoltage radiation. Radiation was delivered on a Monday through Friday schedule using a 6 MV linear accelerator. The median total dose was 49.5 Gy (range 49.5-56 Gy). Cisplatin was given using an open-cell polylactic acid polymer, impregnated with the drug and implanted intramus-cularly at a distant site, as a slow release delivery system (OPLAn-Pt [THM Biomedical, Inc]). The median dose used was 60 mg/m2 (range 60–100 mg/m2). When combined with radiation, this delivery system caused no systemic drug toxicity, and a local tissue reaction was seen in only two dogs. Acute side effects to normal tissue from radiation were not enhanced, as measured by subjective assessment. When compared to a group of historical controls that received radiation without OPLA-Pt, the dogs that received combined radiation and cisplatin had longer overall survival times, with a median of 580 days. The control group had a median survival of 325 days. Previously reported median survival times for comparable megavoltage radiation treatment range from 6 to 13 months. Some dogs in both groups also received adjubant chemotherapy but this did not influence survival time. By multivariate analysis, only the use of OPLA-Pt was found to significantly influence survival, with a p value of p = 0.023. Mega-voltage radiation and slow release cisplatin appears to be a well tolerated combination that may favorably affect survival of dogs with nasal tumors.     

High-dose-rate brachytherapy for intranasal tumours in dogs: results of a pilot study

This prospective study describes the feasibility and toxicity of ¹⁹²Iridium high‐dose‐rate (HDR) brachytherapy as an alternative strategy for the treatment of canine intranasal tumours. Fifteen dogs with malignant intranasal tumours were treated twice weekly using a hypofractionated protocol with eight fractions, 5 Gy per fraction, resulting in a total dose of 40 Gy. Acute and chronic adverse side‐effects appeared to be rare. Only 7% of the acute side‐effects and 5% of the chronic were classified as severe (grade 3). Eight dogs showed clinical complete remission, and five dogs had partial remission, with a resolution of tumour‐related symptoms. Magnetic resonance imaging showed a reduced tumour mass in 12 cases. Median survival time was 17 months (range 4–48 months), with four dogs (three without disease) still alive. Median time to recurrence of these dogs was 14 months. In nine dogs, progression or recurrence of the tumour was the cause of death. This study suggests that HDR brachytherapy is feasible and well tolerated.