Palliative radiation therapy has been a mainstay for the treatment of human patients with advanced malignancies for many years and is being used for the treatment of veterinary patients with malignancies with increasing frequency.1 The goal of PRT is to improve the patient's QOL by the alleviation of clinical signs such as those associated with pain, bleeding, or obstruction and differs from curative-intent (ie, definitive) therapy, in which the goal is to destroy the malignancy and restore the patient to a disease-free state.1,2 Although improvement in the QOL for some patients treated with PRT is positively associated with survival time, extending the survival time is a secondary effect and not the primary goal of PRT. In some instances, palliative protocols result in long-term tumor control, but this is not expected. Palliative treatment is indicated when a curative outcome (eg, tumor eradication) is not a reasonable expectation such as for patients with evidence of metastasis or advanced local disease. Also, patients with comorbidities that preclude daily anesthesia or that limit life expectancy may influence the decision to pursue a PRT protocol.
Palliative radiation therapy typically consists of the weekly administration of a few large doses of radiation. There are several variations to this schedule such as a quad shot (2 fractions administered daily for 2 consecutive days) or a 5-daily-dose protocol.3–5 In contrast to definitive radiation therapy protocols, PRT protocols are designed to minimize the acute adverse effects of radiation treatment. Although PRT increases the risk for the development of chronic adverse effects, the patients treated with PRT are not expected to live long enough for those chronic effects to become clinically relevant.6
Peer-reviewed scientific literature is limited regarding the clinical response, effect of treatment on survival time, and adverse effects of hypofractionated radiotherapy in veterinary patients with solid tumors of various histologic subtypes at various locations. A clinical response to PRT has been described for dogs with various types of tumors such as osteosarcomas, nasal tumors, soft tissue sarcomas, melanomas, and mast cell tumors. For dogs with osteosarcoma that received PRT in which 16 to 32 Gy was divided into 2,7–9 3,7,10–12 and 410,13 fractions, the median onset of a clinical response ranged from 11 to 21 days, the median duration of the clinical response ranged from 53 to 130 days, and the overall response rate ranged from 50% to 93%.2,7,10–14 For dogs with various types (ie, carcinoma, sarcoma, SCC, lymphoma, mast cell tumor, melanoma, and neuroblastoma) of nasal tumors that were treated with PRT in which 16 to 40 Gy was divided into 2,15 3,15,16 4,15–18 and 55,15,16,19 fractions, the overall response rate ranged from 57% to 100% and the MST ranged from 146 to 441 days.5,15–19 For dogs with soft tissue sarcomas, the MST was 332 days following administration of three 8-Gy fractions20 and 309 days following administration of four 8-Gy fractions.21 Although PRT has been used to effectively control local tumor growth in dogs with malignant oral melanoma,22–24 an optimal fractionation scheme has not been established. In a study25 that involved 35 dogs with nonresectable grade I to III mast cell tumors that were treated with prednisolone and PRT (four 8-Gy fractions administered at 7-day intervals), the overall response rate was 88.6% (31/35) and the MPFST was 1,031 days. Studies that describe the use of PRT for dogs with various histologic subtypes of carcinoma such as transitional cell carcinoma, anal sac adenocarcinoma, and tonsillar and nontonsillar SCC are lacking.
Various outcomes can be expected following PRT. Although the literature contains limited data regarding tumor response and MST for dogs following PRT, much remains to be learned about the use of PRT for the treatment of solid tumors in dogs. The purpose of the study reported here was to evaluate the clinical response, adverse effects, and outcomes associated with PRT in dogs with various solid tumor types at various body locations that were treated at a veterinary referral hospital.
Materials and Methods
Case selection
The medical records database at the University of Pennsylvania Matthew J. Ryan Veterinary Hospital was searched to identify records of dogs with malignant neoplasia that were treated with radiation treatment between July 2007 and January 2011. To be enrolled in the study, a dog had to have a histologically confirmed malignant solid tumor that was measureable and was treated with radiation therapy with palliative intent. A PRT protocol was recommended for dogs that were not considered candidates for curative-intent radiation therapy (eg, dogs with advanced local disease, evidence of metastasis, or comorbidities that precluded daily anesthesia or otherwise limited life expectancy). Dogs were excluded from the study if histologic results to confirm the diagnosis of a malignant solid tumor were unavailable, lymphoma was diagnosed, or the tumor was surgically excised and only microscopic disease was present prior to radiation therapy.
Medical records review
For each dog enrolled in the study, information extracted from the medical record included signalment, age at the time the tumor was diagnosed, tumor type and anatomic location, and results of initial staging tests. The initial staging tests performed varied among patients but generally consisted of a physical examination, CBC, serum biochemical analysis, urinalysis, regional lymph node palpation and aspiration for cytologic evaluation, thoracic radiography, abdominal ultrasonography, and CT or MRI for determination of the extent of the tumor. In a few patients, fine-needle aspirate samples were obtained from the liver or spleen for cytologic evaluation. Information regarding tumor-specific therapy (eg, surgical excision or debulking of the tumor, chemotherapy, and administration of analgesics or anti-inflammatory medications) before, after, or concurrent with PRT was recorded as was the clinical response of both the patient and tumor, duration of that clinical response, date of tumor progression, any adverse effects observed during or after PRT, and the date of death or last known follow-up. Data recorded regarding the PRT protocol included the number of planned versus delivered doses, whether the protocol was determined by manual or computerized treatment planning, dates of treatment, fraction number, doses per fraction, total dose, and whether regional lymph nodes were irradiated. After PRT was completed, information for each dog was obtained during recheck examinations at the hospital, by telephone communications with the owner or referring veterinarian, or by follow-up questionnaires that were sent to owners approximately every 6 months.
PRT protocols
Radiation therapy was administered to all dogs with a 6-MeV linear accelerator.a For some dogs, CTb was used for computerized treatment planning.c Each study dog received 1 of 3 PRT protocols (8-Gy fractions administered once weekly for 4 weeks [four 8-Gy fraction protocol], 6-Gy fractions administered once or twice weekly for 6 weeks [six 6-Gy fraction protocol], or 3.5-Gy fractions administered twice daily for 2 consecutive days [quad shot protocol]).
Data analysis
Because of the retrospective nature of the study, adverse effects associated with PRT could not be classified in accordance with the toxicity criteria established by the Veterinary Radiation Therapy Oncology Group.26 Instead, acute and chronic adverse effects were defined as complications that were observed within 1 month or > 3 months, respectively, after completion of PRT. Tumor response was measured in 2 or 3 dimensions when possible and classified as complete response, partial response, stable disease, or progressive disease. If the tumor was not measured, the measurements were not documented in the medical record, or if serial diagnostic imaging was not performed, tumor response was determined on the basis of clinical signs recorded in the medical record or reported by the owner in response to a follow-up questionnaire. A clinical response was defined as improvements in clinical signs such as appetite, energy, lameness, nasal discharge, hemorrhage, signs of pain, inflammation, and obstruction. A complete response was defined as disappearance of all measurable tumors and clinical signs associated with those tumors. A partial response was defined as a decrease in tumor size > 50% but < 100% and improvement but not resolution of clinical signs. Stable disease was defined as a < 50% decrease in tumor size or < 25% increase in tumor volume with no apparent improvement or worsening of tumor-associated clinical signs. Progressive disease was defined as a > 25% increase in tumor size and worsening of tumor-associated clinical signs or failure to maintain a complete or partial response or stable disease for a minimum of 30 days. The overall response rate was calculated as the number of dogs that responded to PRT (ie, number of dogs that were classified as having a complete response, partial response, and stable disease) divided by the number of dogs enrolled in the study.
For each dog, overall survival time was defined as the interval between the date when PRT was initiated and the date of death regardless of cause. Survival time was considered a surrogate measure for QOL because it was assumed most dog owners chose to euthanize their pets when QOL began to deteriorate. Progression-free survival time was defined as the interval between initiation of PRT and local tumor progression, metastasis, or death. The duration of the clinical response was defined as the interval between initiation of PRT and tumor progression and was only calculated for dogs that had a response to PRT (ie, did not have progressive disease). Dogs that were lost to follow-up or still alive at the time of analysis were censored at the last date of contact.
Tumors were categorized on the basis of tissue type (carcinoma, sarcoma, primary bone tumor, melanoma, mast cell tumor, or other tumor type) and location (head and neck, trunk, visceral, appendicular, mixed [tumors located in multiple locations], or other). Fisher exact tests were used to compare the clinical response among tumor types and locations. Fisher exact tests were also used to compare the tumor response (complete and partial response, stable disease, or progressive disease) and incidence of acute adverse effects between the 2 most commonly used PRT protocols (four 8-Gy fractions and six 6-Gy fractions). The Kaplan-Meier product limit method was used to calculate the MST and MPFST. Log rank tests were used to evaluate the association of tumor type, tumor location, PRT protocol, and metastatic status with both MST and MPFST; the association between MST and tumor response; and the association between duration of clinical response and tumor type. Cox proportional hazards regression was used to determine the effect of PRT on MST while controlling for other variables that included age, sex, breed (mixed breed or purebred), tumor type (sarcoma, carcinoma, melanoma, primary bone tumor, mast cell tumor, or other tumor type), tumor location, presence of metastatic disease prior to PRT, chemotherapy administration, surgical excision of tumor, and PRT protocol (four 8-Gy fractions or six 6-Gy fractions). Continuous variables were centered prior to analysis. Univariate models were initially evaluated, and any variables with P < 0.20 on univariate analysis were included in a multivariable model. All possible interaction terms were evaluated in the multivariable model, as was confounding. A confounder was defined as a variable that changed the hazard associated with PRT by ≥ 15% when it was added to or removed from the model. All identified confounders were retained in the model regardless of their P values; otherwise, only variables with P < 0.05 were retained in the final multivariable model. The proportional hazards assumption was evaluated with Schoenfeld residuals, and 95% CIs were calculated for all binomial proportions. All analyses were performed with a statistical software program.d
Results
Dogs
The medical records of 138 dogs that received hypofractionated radiation at the veterinary teaching hospital between July 2007 and January 2011 were reviewed. Thirty-two dogs were excluded from the study because histologic results were unavailable. Two dogs were excluded from the study because they had lymphoma, and 1 dog was excluded from the study because only microscopic disease was present before initiation of radiation therapy. Thus, 103 dogs were included in the study.
The study population consisted of 10 sexually intact males, 58 castrated males, 1 sexually intact female, and 34 spayed females and had a median age of 10 years (range, 1 to 15 years). The breeds most commonly represented were mixed breed (n = 23), Labrador Retriever (16), and Golden Retriever (9); 13 other breeds were also represented.
Tumor types and location
Dogs were primarily classified on the basis of tumor type and tumor location (Table 1). Types of carcinomas represented in the study population included nasal adenocarcinoma (n = 9), transitional cell carcinoma (6), tonsillar SCC (5), anal sac adenocarcinoma (3), oral nontonsillar carcinoma (2), thyroid carcinoma (2), salivary carcinoma (2), sebaceous carcinoma (2), and perianal adnexal carcinoma, anorectal carcinoma, mammary carcinoma, neuroendocrine carcinoma, aural SCC, and nasal planum SCC (1 each). Types of sarcomas represented in the study population included soft tissue sarcoma (n = 13), fibrosarcoma (7), hemangiosarcoma (5), hemangiopericytoma (2), anaplastic sarcoma (2), and soft tissue osteosarcoma (1). Of the 13 primary bone tumors, 12 were osteosarcomas and 1 was a chondrosarcoma. Eleven dogs had oral malignant melanoma, and 8 dogs had mast cell tumors that were generally appendicular (n = 4) or located in the head and neck (3). The other types of solid tumors represented in the study population included acanthomatous ameloblastoma (n = 2), tonsillar SCC and sarcoma of the trunk (1), and thyroid carcinoma and oral melanoma (1).
Descriptive data for 103 dogs with histologically confirmed malignant solid tumors that were treated with PRT at a veterinary teaching hospital between July 2007 and January 2011.
| Tumor type | ||||||
|---|---|---|---|---|---|---|
| Variable | Carcinoma | Sarcoma | Primary bone tumor | Melanoma | Mast cell tumor | Other |
| No. of dogs | 37 | 30 | 13 | 11 | 8 | 4 |
| Tumor location | ||||||
| Head and neck | 25 | 14 | 6 | 10 | 3 | 3 |
| Trunk | 1 | 7 | 0 | 0 | 0 | 0 |
| Visceral | 8 | 0 | 0 | 0 | 0 | 0 |
| Appendicular | 0 | 8 | 6 | 0 | 4 | 0 |
| Mixed* | 1 | 1 | 0 | 1 | 1 | 1 |
| Other | 2 | 0 | 1 | 0 | 0 | 0 |
| Metastasis | ||||||
| To lymph nodes | 17 | 1 | 0 | 5 | 6 | 1 |
| To lungs | 2 | 1 | 1 | 0 | 0 | 2 |
| To spleen | 0 | 0 | 0 | 0 | 1 | 0 |
| None | 18 | 28 | 12 | 6 | 1 | 1 |
| PRT protocol | ||||||
| Four 8-Gy fractions | 13 | 24 | 12 | 9 | 6 | 4 |
| Six 6-Gy fractions | 22 | 6 | 1 | 2 | 2 | 0 |
| Quad shot† | 2 | 0 | 0 | 0 | 0 | 0 |
| Chemotherapy‡ | ||||||
| Before PRT | 12 | 8 | 1 | 5 | 8 | 0 |
| Concurrent with PRT | 2 | 3 | 4 | 6 | 2 | 0 |
| After PRT | 7 | 6 | 0 | 3 | 3 | 0 |
| None | 20 | 17 | 8 | 3 | 0 | 4 |
| Tumor excision | ||||||
| Before PRT | 10 | 10 | 3 | 7 | 6 | 1 |
| After PRT | 0 | 2 | 0 | 0 | 1 | 0 |
| None | 27 | 18 | 10 | 4 | 1 | 3 |
| Overall response rate to PRT (%)§ | 65 (47–80) | 87 (69–96) | 85 (55–98) | 73 (39–94) | 50 (16–84) | 100 (40–100) |
| Clinical response to PRT (%)‖ | 68 (50–82) | 83 (65–94) | 69 (39–91) | 91 (59–100) | 63 (24–91) | 100 (40–100) |
Values represent the No. of dogs or percentage (95% CI).
Tumors located in multiple locations.
3.5-Gy fractions administered twice daily for 2 consecutive days.
Some dogs were included in multiple categories for chemotherapy; therefore, the sum for the chemotherapy categories may exceed the number of dogs within a particular tumor type.
An overall response was defined as a decrease in tumor size or stable tumor size. If the tumor was not measured, then tumor response was determined on the basis of clinical signs.
A clinical response was defined as improvements in clinical signs such as appetite, energy, lameness, nasal discharge, hemorrhage, signs of pain, inflammation, and obstruction; it did not include assessment of tumor size.
Initial staging
Of the 103 dogs evaluated, 98 (95%) had thoracic radiographs obtained, 54 (52%) had regional lymph node aspiration performed, 34 (33%) had abdominal ultrasonography performed, 4 (4%) had aspiration of the spleen performed, and 2 (2%) had aspiration of the liver performed. Metastatic disease was definitively diagnosed in 37 of the 103 (36%) dogs prior to initiation of PRT and was suspected on the basis of abdominal ultrasonography results in an additional 8 dogs. Prior to initiation of PRT, the majority of dogs were administered oral analgesics (66/103 [64%]) or anti-inflammatories (98/103 [95%]) such as NSAIDs or glucocorticoids. Thirty-four (33%) dogs received chemotherapy prior to PRT. Thirty-seven (36%) dogs had undergone surgical resection of the tumor prior to PRT, and all of those dogs had gross recurrence of the tumor. Forty-two (41%) dogs had recurrent or progressive disease following surgery or chemotherapy, and 43 (42%) dogs had advanced disease that was manifested as metastatic or aggressive infiltrative disease that was not amenable to surgery prior to PRT.
PRT
The PRT protocol administered to each dog was determined on the basis of the attending clinician's preference. Generally, a protocol that consisted of four 8-Gy fractions was selected unless sensitive structures such as the brain, spinal cord, or colon were in the planned radiation field, in which case a protocol that consisted of six 6-Gy fractions was typically selected because the smaller fraction size was less likely to induce chronic adverse effects. Computerized treatment planning was used for 47 of 103 (46%) dogs. Of the 103 dogs, 62 (60%) were initially scheduled to receive four 8-Gy fractions once a week, 6 were initially scheduled to receive two 8-Gy fractions weekly that were to be repeated as necessary for alleviation of signs of pain and other clinical signs, 33 (32%) were initially scheduled to receive five or six 6-Gy fractions once or twice weekly, and 2 (2%) were scheduled to receive the quad shot protocol (3.5 Gy fractions twice daily for 2 consecutive days). Seventy-one (69%) dogs completed the planned PRT protocol, including 50 the 68 (74%) dogs that were treated with a four 8-Gy fraction protocol, 19 of the 33 (58%) dogs treated with a six 6-Gy fraction protocol, and both dogs that were treated with the quad shot protocol. The proportion of dogs that completed the planned protocol did not differ significantly (P = 0.20) between the four 8-Gy fraction protocol and the six 6-Gy fraction protocol. Reasons that the PRT protocol was not completed as planned included anesthesia intolerance (n = 1), other comorbidities that interfered with the PRT (6), tumor progression despite treatment (15), adverse effects that negatively affected QOL (5), and achievement of a palliative response with fewer doses of PRT than planned (5). The regional lymph nodes were irradiated in addition to the primary tumor in 12 of the 103 (12%) dogs.
Following PRT initiation, 57 (55%) dogs developed acute adverse effects, the most common of which were dermatitis (n = 34 dogs), alopecia (23), mucositis (19), and periocular inflammation (4); less common acute adverse effects included colitis, mast cell degranulation, and incisional dehiscence from a previous biopsy site. Forty-one of the 68 (60%) dogs treated with a four 8-Gy fraction protocol and 16 of the 33 (48%) dogs treated with a six 6-Gy fraction protocol developed acute adverse effects; however, the proportion of dogs that developed acute adverse effects did not differ significantly (P = 0.14) between those 2 protocols.
Chronic adverse effects were observed in 8 of the 68 (12%) dogs that lived at least 3 months following PRT and included neuropathy, blindness, laryngeal paralysis, xerostomia (diagnosed on the basis of clinical signs that included a subjectively dry mouth [ie, no drooling observed and saliva appeared thick and scant] and the palpation of small atrophied or fibrotic salivary glands), leukotrichia, lymphedema, keratoconjunctivitis sicca, alopecia, hyperpigmentation, and scar tissue formation. All 8 of those dogs survived at least 9 months following PRT, and most survived > 2 years.
One dog with appendicular osteosarcoma developed a pathological fracture 57 days after initiation of PRT, and 1 dog with axial osteosarcoma died while anesthetized for PRT. Other complications associated with PRT included aspiration pneumonia (n = 1) and secondary infection at the treatment site (1).
Clinical outcome
Of the 103 dogs, 3 (3%; 95% CI, 1% to 8%) developed a complete response, 15 (15%; 95% CI, 8% to 23%) developed a partial response, 59 (57%; 95% CI, 47% to 67%) developed stable disease, and 26 (25%; 95% CI, 17% to 35%) developed progressive disease following PRT. The overall response rate for PRT was 75% (77/103; 95% CI, 65% to 83%), and the overall clinical response rate for PRT was 77% (79/103; 95% CI, 67% to 84%); neither varied significantly among tumor types or tumor locations.
Following PRT, metastatic disease was detected in the lymph nodes of 7 (7%) dogs, in the lungs of 15 (15%) dogs, and at other sites for 6 (6%) dogs. Of the 103 dogs, 80 (78%) died because of tumor-related disease, 13 (13%) died because of non–tumor-related disease, 9 (9%) were lost to follow-up, and 1 dog was still alive at the time the data were analyzed.
Tumor staging after PRT was not standardized and varied depending on the attending clinician and tumor type. Thoracic radiographs were obtained for 42 dogs, lymph node aspiration was performed in 13 dogs, and other diagnostic testing (ie, ultrasonography, appendicular radiography, and fine-needle aspiration) was performed in 25 dogs.
For all 103 study dogs, the MST was 134 days (range 1 to 1,183 days) and the MPFST was 106 days (range, 1 to 855 days). The MST and MPFST did not vary significantly among tumor types (P = 0.51) or locations (P = 0.45). However, the MST (89 days; range, 1 to 754 days; P = 0.023) and MPFST (34 days; range, 1 to 286 days; P < 0.001) for dogs with metastatic disease prior to PRT were significantly shorter than the MST (184 days; range, 3 to 1,183 days) and MPFST (147 days; range, 3 to 855 days) for dogs without metastatic disease before PRT.
The MPFSTs and MSTs for each tumor type and tumor response were summarized (Table 2). The MSTs for dogs that developed a complete or partial response (265 days; range, 101 to 1,023 days) and stable disease (184 days; range, 33 to 1,183 days) following PRT were significantly (P < 0.001) longer than the MST for dogs that had progressive disease (25 days; range, 1 to 238 days). The difference between the MST for dogs that developed a complete or partial response and the MST for dogs with stable disease did not quite reach significance (P = 0.06). The MPFST was 216 days (range, 15 to 855 days) for dogs that developed a complete or partial response and 121 days (range, 21 to 690 days) for dogs with stable disease following PRT. The MPFST did not differ significantly (P = 0.12) among tumor types. A significant (P < 0.001) positive association was noted between tumor response and improvement in patient clinical signs.
The MPFST and MST for the dogs of Table 1.
| Tumor type | Tumor response* | No. of dogs | MPFST (d) | MST (d) |
|---|---|---|---|---|
| Carcinoma | Complete and partial response | 10 | 216 (15–572) | 265 (110–576)† |
| Stable disease | 14 | 98 (21–286) | 213 (34–603)† | |
| Progressive disease | 13 | — | 28 (7–238) | |
| Sarcoma | Complete and partial response | 3 | 163 (106–173) | 206 (106–460)† |
| Stable disease | 23 | 251 (31–443) | 279 (35–754)† | |
| Progressive disease | 4 | — | 5 (3–29) | |
| Primary bone tumor | Complete and partial response | 4 | 177 (85–855) | 128 (101–1,023)† |
| Stable disease | 7 | 104 (49–300) | 104 (54–303)† | |
| Progressive disease | 2 | — | 7 (7–15) | |
| Melanoma | Complete and partial response | 0 | — | — |
| Stable disease | 8 | 69 (34–451) | 150 (112–451)† | |
| Progressive disease | 3 | — | 30 (21–32) | |
| Mast cell tumor | Complete and partial response | 0 | — | — |
| Stable disease | 4 | 106 (31–210) | 161 (33–1183)† | |
| Progressive disease | 4 | — | 15 (1–85) | |
| Other tumor type | Complete and partial response | 1 | 358 | 923 |
| Stable disease | 3 | 195 (99–690) | 195 (99–690) | |
| Progressive disease | 0 | — | — |
Values represent the median (range) or the actual value if there was only 1 dog within a particular response.
A complete response was defined as disappearance of all measurable tumors and clinical signs associated with those tumors. A partial response was defined as a decrease in tumor size > 50% but < 100% and improvement but not resolution of clinical signs. Stable disease was defined as a < 50% decrease in tumor size or < 25% increase in tumor volume with no apparent improvement or worsening of tumor-associated clinical signs. Progressive disease was defined as a > 25% increase in tumor size and worsening of tumor-associated clinical signs or failure to maintain a complete or partial response or stable disease for a minimum of 30 days.
Within a tumor type, value differs significantly (P < 0.05) from that for the dogs with progressive disease.
— = Not calculated.
See Table 1 for remainder of key.
On the basis of the results of the univariate Cox proportional hazards regression analyses, response to PRT, chemotherapy, presence of metastatic disease prior to PRT, and other tumor types were eligible for consideration in the multivariable Cox proportional hazards regression analysis. No significant interactions were identified among those 4 variables. The presence of metastatic disease prior to PRT was identified as a confounder and was retained in the final model. The only other variable besides the presence of metastatic disease prior to PRT retained in the final model was response to PRT. Compared with dogs with progressive disease, the hazard for death was significantly (P < 0.001) lower for dogs that developed a complete or partial response (hazard ratio, 0.08; 95% CI, 0.04 to 0.15) or stable disease (hazard ratio, 0.10; 95% CI, 0.06 to 0.18) following PRT.
The MST (P = 0.17) and tumor response (P = 0.186) did not differ significantly between the four 8-Gy fraction protocol and the six 6-Gy fraction protocol. Similarly, the MPFST did not differ significantly between the four 8-Gy fraction protocol (104 days) and the six 6-Gy fraction protocol (110 days).
Tumor-specific outcomes
The Kaplan-Meier survival curves for the 6 major tumor types were summarized (Figure 1). Of the 9 dogs with nasal adenocarcinoma, 2 dogs developed a compete response and 4 dogs developed a partial response, whereas the remaining 3 dogs had progressive disease following PRT. Thus, the overall response rate was 67% (95% CI, 30% to 93%) for dogs with nasal adenocarcinoma that were treated with PRT. Serial tumor measurement was not possible without serial diagnostic imaging, so response was primarily determined on the basis of improvement in clinical signs. The response to PRT was characterized by an improvement in clinical signs such as epistaxis, nasal congestion, and facial deformation. The MST for dogs with nasal adenocarcinoma that received PRT was 265 days (range, 22 to 530 days).
Kaplan-Meier survival curves for 37 dogs with carcinoma (orange line), 30 dogs with soft tissue sarcoma (green line), 13 dogs with primary bone tumors (pink line), 11 dogs with oral malignant melanoma (blue line), 8 dogs with mast cell tumors (gray line), and 4 dogs with other types of malignant solid tumors (brown line) that were treated with PRT at a veterinary teaching hospital between July 2007 and January 2011.
Citation: Journal of the American Veterinary Medical Association 248, 1; 10.2460/javma.248.1.72
Kaplan-Meier survival curves for 37 dogs with carcinoma (orange line), 30 dogs with soft tissue sarcoma (green line), 13 dogs with primary bone tumors (pink line), 11 dogs with oral malignant melanoma (blue line), 8 dogs with mast cell tumors (gray line), and 4 dogs with other types of malignant solid tumors (brown line) that were treated with PRT at a veterinary teaching hospital between July 2007 and January 2011.
Citation: Journal of the American Veterinary Medical Association 248, 1; 10.2460/javma.248.1.72
Kaplan-Meier survival curves for 37 dogs with carcinoma (orange line), 30 dogs with soft tissue sarcoma (green line), 13 dogs with primary bone tumors (pink line), 11 dogs with oral malignant melanoma (blue line), 8 dogs with mast cell tumors (gray line), and 4 dogs with other types of malignant solid tumors (brown line) that were treated with PRT at a veterinary teaching hospital between July 2007 and January 2011.
Citation: Journal of the American Veterinary Medical Association 248, 1; 10.2460/javma.248.1.72
Of the 5 dogs with tonsillar SCC, 1 dog developed a partial response, 3 dogs had stable disease, and 1 dog had progressive disease following PRT. One of those dogs was treated with carboplatin concurrently with PRT, and another was treated with carboplatin following PRT. The overall response rate was 80% (95% CI, 28% to 99%) for dogs with tonsillar SCC that were treated with PRT. Response to PRT was characterized by an improvement in appetite, comfort, and energy. The MST for dogs with tonsillar SCC that received PRT was 127 days (range, 73 to 286 days).
Both of the dogs with oral nontonsillar SCC that received PRT developed a clinical response that was characterized by a stable tumor size and improvement in clinical signs. Following PRT, 1 dog survived 324 days and the other survived 458 days.
Prior to PRT, all 3 dogs with anal sac adenocarcinoma had undergone tumor resection and developed local recurrence with metastatic disease in the pelvic lymph nodes. Two of the dogs also had hypercalcemia. All 3 dogs developed stable disease following PRT. Two dogs had an improvement in tenesmus and gained weight, whereas the remaining dog had no apparent improvement or exacerbation of clinical signs. None of the dogs received adjunct chemotherapy. The MST was 217 days (range, 34 to 603 days) for dogs with anal sac adenocarcinoma that received PRT.
Of the 6 dogs with histologic results most consistent with urothelial transitional cell carcinoma, 3 dogs had transitional cell carcinoma of the bladder (1 of those dogs also had metastasis to the maxilla) and the remaining 3 dogs had transitional cell carcinoma of the prostate (in 1 of those dogs, the tumor also involved the bladder). Prior to PRT, 3 dogs had regional metastasis to the urethra, ureters, or lumbar portion of the vertebral column and 2 dogs had both urethral and ureteral stents placed. Following PRT, 1 dog developed stable disease, whereas the remaining 5 dogs had progressive disease that was manifested as exacerbation of clinical signs or an increase in tumor size as determined by serial ultrasonography (n = 3). The dog that had transitional cell carcinoma of the bladder that metastasized to the maxilla received PRT at the metastatic tumor site only. None of the dogs received chemotherapy concurrently with PRT; however, all dogs received either piroxicam or another cyclooxygenase-2 preferential NSAID. The MST was 31 days (range, 7 to 238 days) for dogs with urothelial transitional cell carcinoma that were treated with PRT.
Of the 11 dogs with oral malignant melanoma, 3 had a sublingual tumor, 4 had a mandibular tumor, 1 had a maxillary tumor, 1 had a tumor in the soft palate, 1 had a tumor in the buccal mucosa, 1 had a tumor localized to the neck and larynx, and 1 had tumors in the mandible and appendicular tissues. Ten of the tumors were pigmented, and 1 was amelanotic. Nine of the dogs received the melanoma vaccine as an adjuvant treatment. The MST was 134 days (range, 21 to 451 days) for dogs with oral malignant melanoma that received PRT.
Of the 8 dogs with mast cell tumors, 5 had grade II tumors and 3 had grade III tumors. Prior to PRT, all 8 dogs had been treated with various chemotherapy protocols and 6 had undergone resection of the tumor with local recurrence. One dog had resection of the tumor after PRT. Concurrent with PRT, all 8 dogs received prednisone, famotidine, and diphenhydramine, and 2 dogs received adjunct chemotherapy. The MST was 71 days (range, 1 to 1,183 days) for dogs with mast cell tumors that were treated with PRT.
Of the 4 dogs with other types of solid tumors, 2 had acanthomatous ameloblastoma, 1 had tonsillar SCC and sarcoma in the trunk, and 1 had thyroid cancer and oral melanoma. The 2 dogs with ameloblastoma had progression-free survival times of 690 and 358 days and survival times of 690 and 923 days. The MST was 195 days (range, 99 to 923 days) for all dogs in the other tumor category that received PRT.
Discussion
Results of the present study suggested that hypofractionated radiation therapy is a viable treatment option for most types of solid tumors in dogs. Although the mean overall response rate to PRT was 75% for all tumor types evaluated, it varied among tumor types and ranged from 50% to 100%. Most owners of the dogs of the present study appreciated an improvement in the clinical signs and QOL for their dogs following PRT. Information regarding the tumor response and MST for the dogs of the present study can be used as preliminary guidelines for clinicians when discussing the prognosis for dogs with solid tumors following PRT with owners.
By design, dogs treated with PRT are at low risk for the development of acute adverse effects and at high risk for the development of chronic adverse effects.6 In the present study, 57 of 103 (55%) dogs developed acute adverse effects following PRT, the most common of which were dermatitis, alopecia, and mucositis. Similar to findings in other studies,15,27 most of the acute adverse effects in the dogs of the present study were self-limiting and resolved with supportive care. In the present study, chronic adverse effects were defined as adverse effects that developed ≥ 3 months following PRT and were recorded for 8 of the 68 (12%) dogs that survived ≥ 3 months. All 8 of those dogs survived > 9 months, and most survived > 2 years. Dogs that receive PRT generally have a short life expectancy; therefore, the likelihood that those dogs will survive to develop chronic adverse effects from the PRT is low.2 Nevertheless, dogs treated with PRT are at risk of developing severe complications, and those risks should be discussed with clients before initiation of treatment.
Data regarding the use of PRT for the treatment of dogs with sarcoma is limited. The MPFST and MST for dogs with soft tissue sarcomas that received PRT at a total dose of 24 Gy (ie, three 8-Gy fractions)20 or 32 Gy (ie, four 8-Gy fractions)21 were longer than the MPFST and MST for similar dogs in the present study (Table 3). The reason that the MPFST and MST were shorter for the dogs of the present study, compared with those of those other studies,20,21 was likely attributable to the fact that a fairly large percentage of dogs with soft tissue sarcomas in the present study had high-grade tumors including hemangiosarcomas and soft-tissue osteosarcomas, which tend to progress more rapidly than other types of soft tissue sarcomas. Also, the number of dogs with soft tissue sarcomas evaluated in the present study was substantially higher than that in those other studies20,21; therefore, the results of the present study might represent a more accurate estimate of patient response following PRT than the results of those other studies.20,21 In a study5 in which dogs with soft tissue sarcoma received PRT that consisted of the administration of a 4-Gy fraction daily for 5 consecutive days, the MPFST and MST were 5.7 and 7.9 months, respectively, values that were similar to those for dogs with soft tissue sarcomas in the present study. Although the MST for dogs with soft tissue sarcomas following PRT in the present study was not as long as that reported in some other studies,20,21 the overall response rate to PRT was high (87%) and the majority of owners (25/30 [83%]) reported improvement in their pet's appetite, energy, activity, and signs of pain following PRT.
Overall response rates and MSTs for dogs with various types of malignant solid tumors that were treated with PRT in the present and other studies.
| Overall response rate (%) | MST (d) | |||||
|---|---|---|---|---|---|---|
| Tumor type | Present study | Other studies | Reference No. | Present study | Other studies | Reference No. |
| Soft tissue sarcoma | 87 (69–96) | 50–93 | 20,21 | 184 (3–754) | 309–322 | 20,21 |
| Anal sac adenocarcinoma | 100 (29–100*) | 75 | 5 | 217 (34–603) | 231 | 5 |
| Tonsillar SCC | 80 (28–99) | 80 | 29 | 127 (73–286) | 179–211 | 28,29 |
| Transitional cell carcinoma | 16 (0–64) | 90 | 32 | 31 (7–238) | 326 | 32 |
| Nasal tumors | 67 (30–93) | 57–100 | 5,15,16,19 | 265 (22–530) | 146–441 | 5,15–19 |
| Oral malignant melanoma | 73 (39–94) | 83–94 | 22,24 | 134 (21–451) | 210–237 | 23,24 |
| Osteosarcoma | 85 (55–98) | 50–93 | 2,7,10–14 | 104 (7–1,023) | 122–313 | 7,12–14 |
| Mast cell tumor | 50 (16–84) | 39–84 | 25,34,e | 71 (1–1,183) | 98–1,827 | 25,e |
Even though several studies have been performed to evaluate the use of PRT to treat dogs with various types of carcinoma, information regarding the outcome for dogs with anal sac adenocarcinoma, tonsillar SCC, nontonsillar SCC, and transitional cell carcinoma following PRT is limited. In the present study, the MST was 217 days for the 3 dogs with anal sac adenocarcinoma that received a six 6-Gy fraction PRT protocol, which was similar to the MST (231 days) for dogs with anal sac adenocarcinoma that received a 4-Gy fraction daily for 5 consecutive days.5 The dogs with anal sac adenocarcinoma in the present study tolerated PRT well and did not develop any severe adverse effects. One dog developed acute colitis, and another developed dermatitis following initiation of PRT; however, both conditions were self-limiting and did not affect the planned PRT protocol or survival, which suggested that PRT was a palliative treatment option for dogs with anal sac adenocarcinoma.
In 2 studies28,29 in which dogs with tonsillar SCC received various combinations of multimodal treatments including surgery, chemotherapy, and hypofractionated radiation therapy, the MST ranged from 179 to 211 days. In the present study, the MST was only 127 days for dogs with tonsillar SCC; however, all dogs were treated with palliative intent, and only 2 of 5 dogs received adjunct chemotherapy. To our knowledge, the present study was the first to evaluate the use of PRT for treatment of oral nontonsillar SCC. The 2 dogs with oral nontonsillar SCC that received PRT and were evaluated in the present study survived 324 and 458 days, respectively, which was similar to the MST (15 to 16 months) reported for dogs with oral nontonsillar SCC that underwent curative-intent radiation therapy (total dose, 48 to 57 Gy).30,31
In a study32 of 10 dogs with transitional cell carcinoma that were treated with a PRT protocol that consisted of a 5.75-Gy fraction once weekly for 6 weeks in conjunction with mitoxantrone and piroxicam, the MST was 326 days, which did not differ significantly from that for dogs with transitional cell carcinoma that were treated with mitoxantrone and piroxicam without PRT. The 6 dogs with transitional cell carcinoma in the present study had an MST of only 31 days following PRT; however, prior to initiation of PRT, 3 of those dogs had regional metastasis and 2 dogs had to have ureteral and urethral stents placed because the tumor was impairing urine flow. None of the dogs with transitional cell carcinoma evaluated in the present study received chemotherapy concurrently with PRT, although all of them were treated with either piroxicam or another cyclooxygenase-2 preferential NSAID. Palliative radiation therapy did not result in a substantial tumor response or prolong the survival time for dogs with transitional cell carcinoma in the present study. Carcinomas have diverse biologic behaviors, and the ideal treatment may vary on the basis of tumor type. Results of the present study suggested that PRT might be a reasonable treatment option for dogs with anal sac adenocarcinoma, tonsillar SCC, and nontonsillar SCC when definitive treatment options are impractical.
Use of PRT for the treatment of dogs with osteosarcoma has been extensively studied, and the associated MSTs range from 122 to 313 days.7,12–14 In the present study, the MPFST and MST for dogs with osteosarcoma or chondrosarcoma that received PRT were both 104 days. Following PRT, 9 of the 13 dogs with primary bone tumors in the present study had an improvement in their clinical signs, which is the primary end point of PRT. Tumor location was not significantly associated with either the progression-free interval or survival time for the dogs of the present study. That finding was consistent with results of other studies13,33 in which the MST for dogs with osteosarcoma of the axial skeleton was similar to that for dogs with osteosarcoma of the appendicular skeleton following PRT.
In the present study, dogs with mast cell tumors had a short MPFST (31 days) and MST (71 days) following PRT. Those results were similar to those of another studye in which dogs with mast cell tumors that were treated with hypofractionated radiotherapy and either prednisone or chemotherapy had an MPFST of 61 days and MST of 98 days. Results of other studies25,34 suggest a more favorable response to radiotherapy. Dogs with mast cell tumors that were treated with hypofractionated radiotherapy and prednisolone had an MPFST of 1,031 days.25 However, only 1 of 35 dogs in that study25 had a grade III tumor, whereas 3 of 8 dogs with mast cell tumors in the present study had grade III tumors, and tumor grade is negatively associated with survival.35,36 In another study,34 dogs with mast cell tumors that were treated with hypofractionated radiotherapy, toceranib, and prednisone had an MPFST of 316 days; however, histologic evaluation to determine tumor grade was performed in only 5 of the 17 dogs in that study,34 and all of those dogs received concurrent chemotherapy with toceranib. Prior to initiation of PRT, 6 of the 8 dogs with mast cell tumors evaluated in the present study underwent surgical tumor resection and subsequent recurrence of the tumor. Local recurrence of a mast cell tumor is associated with a poor prognosis.37,38 Results of the present study indicated that administration of PRT and prednisone to dogs with mast cell tumors that had undergone previous surgical tumor resection and chemotherapy was associated with a short MPFST and MST, although these results should be interpreted with caution because the number of dogs with mast cell tumors evaluated in this study was small.
In dogs, acanthomatous ameloblastoma (formerly known as acanthomatous epulis) is a locally invasive benign odontogenic tumor. The primary goal for treatment of those tumors is local control because they do not metastasize.39 The MST was 48 months for 57 dogs with acanthomatous ameloblastoma that were treated with curative-intent radiotherapy, and the investigators of that study40 concluded that radiotherapy was an effective treatment for acanthomatous ameloblastoma. To our knowledge, the present study was the first to evaluate the use of PRT for the treatment of acanthomatous ameloblastoma in dogs. The 2 dogs with acanthomatous ameloblastoma that were evaluated in the present study survived 690 and 923 days, respectively, after PRT, which suggested that PRT is a viable treatment option for dogs with that type of tumor when curative-intent treatment is not feasible.
The present study had several limitations. Although the total number of dogs evaluated in the study was fairly large, the number of dogs evaluated with specific types of tumors or tumors at specific locations was often small and might have biased our findings. Because of the study's retrospective nature, tumor measurements were not always obtained by the same individual, follow-up of patients was not standardized, adverse effects associated with radiotherapy were not classified in accordance with the Veterinary Radiation Therapy Oncology Group scoring criteria, and we were unable to account for all possible adverse effects. Although tumor measurements were used whenever possible to allow for objective evaluation of the response to PRT, some dogs could only be evaluated on the basis of recorded clinical signs. Administration of analgesics and anti-inflammatories could have alleviated clinical signs and may have interfered with our assessment of the patients’ clinical responses to PRT. Also, QOL is a subjective response,11 and instruments to measure QOL have not been validated for use in veterinary patients. Although we used survival time as a surrogate measure for QOL, a positive association between survival time and QOL has not been definitively established for dogs with cancer. Another limitation of the present study was the lack of standardized treatment protocols. Dogs treated with PRT may have undergone tumor resection or chemotherapy concurrently, which might have affected the observed response. Additionally, the PRT protocols used varied, and there appeared to be some bias for certain protocols on the basis of tumor type. For example, most dogs with sarcoma were treated with a four 8-Gy fraction protocol, whereas most dogs with carcinoma were treated with a six 6-Gy fraction protocol. Those factors in addition to metastatic status prior to PRT may have confounded our results, and a study with a larger sample size is warranted to investigate the interrelationship of these variables. Finally, this study lacked a control group of dogs with malignant solid tumors that did not receive PRT; therefore, it is unknown whether PRT had a definitive effect on survival time. However, a study in which dogs with malignant solid tumors were randomly allocated to either receive or not receive treatment is not feasible or ethical.
Evaluation of the effects of palliative-intent treatments has inherent difficulties. For example, tumor response is evaluated by objective measures such as a decrease in tumor size and duration of survival, whereas the overall clinical response of the patient is assessed by subjective measures such as an improvement in clinical signs and QOL as determined by owners. Following radiotherapy, tumor size might remain unchanged but the patient may have marked clinical improvement in regard to signs of pain. The survival time for pets that undergo PRT is variable because it is largely dependent on the expectations and beliefs of each individual owner. Some owners may choose to euthanize their pets early in the disease process because of past negative experiences or the anticipation of distress, whereas other owners may pursue continued treatment because they do not believe in euthanasia or do not appreciate a decline in the QOL for their pets. The timing of palliative treatment in relation to stage of disease can also affect response. Administration of PRT to dogs with advanced disease is likely to result in a more modest response than administration of PRT to dogs in the early stages of disease. Most dogs that receive PRT have been previously or will be concurrently or subsequently treated with various combinations of treatment modalities such as surgery, chemotherapy, analgesics, and anti-inflammatories. Administration of multimodal treatment makes it difficult to evaluate the efficacy of each individual treatment. This variability is intrinsic to the palliative treatment of terminal cancer patients and likely affected many of the survival times and tumor responses reported in the veterinary literature.
In the present study, dogs with various types of histologically confirmed malignant solid tumors that received PRT had objective beneficial responses and an improvement in QOL that was positively associated with survival time. Tumor response to PRT varied among tumor types, and tumor location was not significantly associated with survival time. The dogs of the present study tolerated PRT well, and most adverse effects observed were self-limiting. However, PRT can result in severe adverse effects, and owners should be informed of those risks prior to its initiation. Results of this study will provide clinicians with preliminary guidelines for possible adverse effects and expected survival times that they can use when discussing PRT as a treatment option with the owners of dogs with solid tumors. Prospective studies that evaluate the use of PRT in a large number of dogs with specific types of malignant solid tumors at specific sites are warranted to further elucidate the efficacy of that treatment modality.
ABBREVIATIONS
| CI | Confidence interval |
| MPFST | Median progression-free survival time |
| MST | Median survival time |
| PRT | Palliative radiation therapy |
| QOL | Quality of life |
| SCC | Squamous cell carcinoma |
Footnotes
MD-2 linear accelerator, Siemens, Erlangen, Del.
BrightSpeed Elite Select 16 slice helical CT scanner, GE Healthcare, Wauwatosa, Wis.
Panther treatment planning system, Prowess Inc, Concord, Calif.
STATA, version 11, Stata Corp, College Station, Tex.
Rau SE, Clifford C, Lang V. Treatment of bulky MCT with palliative radiation treatment ± chemotherapy: a multi-institutional retrospective study (abstr), in Proceedings. 27th Vet Cancer Soc Conf 2007;3.
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