Abstract
OBJECTIVE
To report local progression and survival in dogs following surgery and postoperative definitive radiotherapy (dRT) for management of soft tissue sarcoma (STS) and to evaluate risk factors for local progression and survival.
METHODS
Records were retrospectively reviewed at 9 referral hospitals for dogs managed with postoperative dRT between January 1, 2010, and January 1, 2020, following surgery for STS. Data related to presentation, surgery, dRT, systemic therapy, and outcome were abstracted. Selected variables were assessed for association with local progression and overall survival.
RESULTS
272 dogs were included. Histologic grade was reported in 249 dogs: 102 were grade 1 (40.9%), 120 were grade 2 (48.2%), and 27 were grade 3 (10.8%). Local progression was suspected or confirmed in 56 dogs. Local progression rates were similar for grade 1 (24 of 89 [26.7%]), grade 2 (23 of 111 [20.7%]), and grade 3 tumors (6 of 22 [27.3%]). Previous recurrence (P = .010) and subsequent distant metastasis (P = .014) were associated with more frequent local progression; intensity-modulated radiotherapy was associated with decreased local progression (P = .025) compared to other forms of delivery. Age (P = .049), grade (P = .009), previous recurrence (P = .009), and institution type for surgery (P = .043) were associated with overall survival.
CONCLUSIONS
Outcomes for most dogs were good; however, the frequency of local progression indicates an ongoing need to critically appraise local management strategies, particularly for low-grade STS. Intensity-modulated radiotherapy was associated with lower rates of local progression and may be preferred to less precise forms of delivery.
CLINICAL RELEVANCE
These data may guide clinicians when making decisions regarding dRT for management of STS.
Introduction
Soft tissue sarcoma (STS) consists of a group of malignant tumors that arise from mesenchymal tissues and share similar biological behaviors. Cutaneous and subcutaneous STSs typically have a low to moderate metastatic rate but may infiltrate into surrounding tissues.1–8 Histologic margin status has been repeatedly associated with risk of local recurrence following resection, although many dogs with incomplete margins may still not develop recurrence.2,3,9–12 Given the potential for local invasion, aggressive surgical excision, often involving wide lateral margins and an uninvolved fascial plane at the deep margin, has been advocated to achieve complete histologic resection in both dogs and people undergoing curative-intent surgery.1,4,13 Canine STS can, however, vary in growth rate or infiltration and can arise from any part of the body. Due to tumor, anatomic, or owner factors, some sarcomas may not be amenable to curative-intent resection or may require more morbid resection to achieve complete margins.4,14,15
A multimodal approach of surgical excision and adjuvant radiotherapy (RT) may allow acceptable local control with reduction in surgical dose or the potential for salvage following resection with unanticipated positive margins.13,16–24 Surgery and postoperative RT has been associated with long survival times and recurrence rates of 17% to 31.4% in dogs with STS; however, the available studies have low case numbers, focus on a specific population, or are over 2 decades old.20–24 Radiotherapy is a technology-driven modality, and it is possible that previously published data regarding definitive RT (dRT) may no longer be representative. Although hypofractionated protocols have been reported in both dogs and people, dRT involving a high total dose of 50 to 66 Gy, delivered with fine fractionation, remains the standard of care in humans.17–19 Definitive RT may be delivered preoperatively or postoperatively, without clear evidence of a difference in local control.25,26 Preoperative dRT is associated with higher rates of major wound complications in people but can allow more focused targeting of a tumor, with decreased long-term effects, such as fibrosis, lymphedema, and bone fracture.19,25,26 The increased risk of wound complications has likely led postoperative dRT to become predominant in veterinary medicine, given potential management challenges and the cost of ongoing wound care.
Our understanding of the role of dRT in management of canine STS is currently limited by the scope of the available literature. Detail regarding outcomes of postoperative dRT in a modern population of dogs with STS and variables associated with disease progression could be useful to guide clinicians and owners. The objectives of this study were to (1) report local progression and overall survival in dogs following surgery and postoperative dRT for management of STS in a large-scale, recent population and (2) evaluate risk factors for local progression and survival within this population.
Methods
Inclusion criteria
A multi-institutional retrospective analysis of data from dogs with surgically removed STS followed by dRT, initiated between January 1, 2010, and January 1, 2020, was performed. Data were collected by means of searching 9 referral hospital databases for dogs with surgically excised soft tissue sarcomas followed by initiation of dRT on an intent-to-treat basis (dRT defined as a total RT dose of > 48 Gy in at least 12 fractions). Dogs were included if they underwent surgical resection with histopathological confirmation of an STS and postoperative treatment with dRT. Dogs with a diagnosis of osteosarcoma, chondrosarcoma, histiocytic sarcoma, hemangiosarcoma, synovial cell sarcoma, or peripheral nerve sheath tumor associated with a major nerve plexus as well as a sarcoma located in the nose, the mouth, or a body cavity were excluded. Dogs were also excluded if they received neoadjuvant chemotherapy or had presence of metastatic disease at the time of RT.
Presentation and diagnostics
Data collected from the medical records included signalment, time since diagnosis of the STS, size and location of the STS, any previous therapy administered, results of preoperative fine-needle aspirates and biopsies, and results of staging diagnostic tests performed. Location of STS was categorized into head, neck, distal limb, proximal limb, thorax, abdomen, pelvic region, and perineum. Distal and proximal limb were distinguished by the tumor location relative to the stifle and elbow joint. If at the level of the stifle or elbow joint, the location was labeled as distal.
Clinical staging for distant metastasis was primarily based on thoracic radiographs or CT. Additional staging data collected included cytological examination of draining lymph nodes, local imaging (radiographs, CT, PET-CT, or MRI), and any additional imaging taken perioperatively.
Surgery
The institution type for the last surgery prior to dRT was defined as general practice (GP) or referral, when available. Surgery reports were reviewed to determine surgical dose intended based on the Enneking classification system (intralesional, marginal, wide, or radical).27 Intraoperative residual gross disease and hemoclip placement were recorded, if available. When recorded, intraoperative complications were classified according to the Classification of Intraoperative Complications (CLASSIC) scheme and postoperative complications were graded by use of the abbreviated Accordion classification system.28
Histopathology
Data regarding histopathology were retrieved from the original report. Histopathologic grade was based on the grading scheme proposed by Kuntz et al.1 Dogs with grades using other schemes (eg, Bostock) or without grades were excluded from analysis of grade. Histologic factors collected included mitotic count (mitotic figures per 2.37 mm2 hpf or per ten 400X fields viewed with a 10xX ocular with a field number of 22 mm) and margins (incomplete/complete). Tumor margins were considered histologically incomplete if microscopic evidence of tumor was found at the margins.
Radiation therapy
Pre-RT data included the rationale for treatment (planned prior to surgery, postoperative salvage, or treatment of recurrent disease), time from surgery to RT, and the burden of disease at RT (microscopic or macroscopic). Data regarding planning and treatment were collected, where available, and included pretreatment imaging, the radiation source used, mode of planning, delivery, radiation quality, criteria used to delineate gross tumor target volume, clinical target volume (both lateral and deep) and planning target volume (PTV), prescribed total dose to 95% of the PTV, prescribed central axis dose, number of fractions, dose per fraction, and the duration of RT, with any treatment interruptions noted. Radiation toxicity was graded by use of the Veterinary Radiation Therapy Oncology Group criteria (version 1), with a 90-day cutoff from initiation of therapy for acute effects.29
Adjuvant chemotherapy
Administration of chemotherapy was recorded, including drug, dose(s), the intended number of doses, and the doses administered to each patient.
Statistical analysis
Study outcome measures included local progression and overall survival time, measured from the date of completion of dRT. Local progression was defined as recurrence following no evidence of disease or progression of residual gross primary tumor. Continuous data were assessed for normality with the Shapiro-Wilk test. Mean and SD were used to describe normally distributed continuous data. Median and range were used to describe nonparametric continuous data. Age was compared between GP and referral populations using the Mann-Whitney test. The proportion of dogs with insufficient records to determine Enneking classification of resection was compared between GP and referral populations with the Fisher exact test. P < .05 was considered statistically significant. Rates of local progression and metastasis were reported for dogs with at least 6 months’ follow-up or if the event was identified at any time point.
Multivariate analysis: local progression
In our initial analysis, we employed a binomial logistic regression model incorporating age, body weight, grade, burden of disease (microscopic/macroscopic) based on records, previous recurrence, institution type for pre-RT surgery, resection (intralesional/other), RT to surgery interval, RT delivery (intensity-modulated RT [IMRT]/other), and distant metastasis to evaluate the strength of their associations with the probability of local progression in dogs. We checked for linearity of the continuous variables against the logit of the outcome variable with the Box-Tidwell test. To adjust for multiple comparisons, we applied a Bonferroni correction across the 16 variables in the model, setting the threshold for statistical significance at P < .003125. A second binomial logistic regression was then conducted to evaluate the effects of variables considered type on the probability of tumor recurrence in dogs. Overall model fit was assessed with the Nagelkerke R2, diagnostic accuracy measures, and the Hosmer-Lemeshow test. To assess the discriminative power of the binomial logistic regression model in distinguishing between dogs with and without recurrence, we performed receiver operating characteristic curve analysis.
Multivariate analysis: survival
The Kaplan-Meier method was used to assess differences in survival for categorical candidate variables, and the log rank test was used to assess candidacy for inclusion in a final model. Continuous candidate variables were assessed with the Wald test. Variables included age, body weight, grade, burden of disease (microscopic/macroscopic), previously recurrent disease, intralesional resection versus other, histologic margins, institution type for last surgery (GP/referral), and delivery (IMRT/other). Local progression and distant metastasis were assessed for impact on survival alone, following introduction of the previously listed variables. Selected variables were then included in a multivariable Cox proportional hazards model, created in stepwise fashion, with subsequent reordering of variables to determine optimal model fit. All statistical analyses were performed with dedicated software (Prism 10, GraphPad Software; and SPSS 29, IBM Corp).
Results
Population
Two hundred seventy-two dogs were included in the study from 9 different institutions (101 at the University of Missouri, 63 at Colorado State University, 24 at the University of Guelph, 24 at Purdue University, 21 at the University of Wisconsin-Madison, 16 at the University of Pennsylvania, 10 at The Ohio State University, 10 at the University of Georgia, and 3 at VCA West Coast) between January 1, 2010, and January 1, 2020. One hundred thirty-three dogs were male (9 intact), and 136 were female (1 intact). The mean age was 8.9 years (± 2.5 years). Median body weight was 28.2 kg (range, 3.1 to 86.8 kg). Sixty-one breeds were represented, with the most common being Labrador Retriever (n = 41) and Golden Retriever (30), in addition to 68 mixed-breed dogs.
Staging
Tumor site was reported in 271 dogs, and distribution was as follows: head (n = 13), neck (9), distal limb (142), proximal limb (51), thorax (25), abdomen (9), pelvic region (12), and perineum (10). The identified duration of the mass prior to resection was known in 215 dogs, with a median time of 50 days (range, 1 to 1,461 days). Tumor size prior to surgery was not consistently recorded, precluding use of this variable. Disease was recurrent at the time of the most recent surgery in 60 of 267 dogs (22.4%), with 22 of 60 (36.7%) being first recurrence, 27 of 60 (45%) second recurrence, 10 of 60 (16.7%) third recurrence, and 1 of 60 (1.6%) fifth recurrence. Preoperative tumor sampling was reported in 154 dogs (58.1%), not performed in 111 dogs (41.9%), and unable to be determined for 7 dogs. Fine-needle aspirates were performed before surgery in 126 of 265 dogs (47.5%) and incisional biopsy in 53 of 267 (20.2%), with 25 dogs (9.4%) being assessed with both modalities. Pretreatment thoracic staging was documented in 243 dogs; radiographs were performed in 195 dogs, thoracic CT in 28 dogs, and both modalities in 20 dogs. No record of thoracic staging was available for 29 dogs. No dog was considered to have definitive evidence of pulmonary metastasis prior to treatment, although 2 of 243 dogs (0.8%) had equivocal nodules on imaging. Regional lymph node fine-needle aspirates were performed in 35 dogs (13.5%). Of these, 28 (80%) were considered nonneoplastic and 7 (20%) were nondiagnostic.
Surgery
The most recent surgical excision was performed by primary veterinarians in 158 dogs, while 72 dogs underwent tumor resection at a specialty referral hospital. Forty-two dogs did not have institutional data available. Dogs managed surgically in GP prior to RT were significantly younger (8 years, 9 months) than dogs with tumors excised in referral practice (10 years, 0 months; P = .005).
The intended Enneking classification category was available in 220 dogs, with the majority (170 [77.3%]) considered marginal; 23 (10.5%) were considered intralesional, 26 (11.8%) were wide intent, and 1 (0.5%) involved an intended radical resection. The intended Enneking classification was available more frequently for dogs that underwent surgery in a referral setting (85 of 90) than dogs that underwent surgery in GP (147 of 191; P = .0002). Residual gross disease was reported in 12 of 216 dogs (5.5%) with available information. Surgical metallic clips were placed to aid radiation planning in 14 of 219 dogs (6.4%) with available information.
Intraoperative complications were reported in 5 dogs, including 2 grade 1 and 3 grade 2 complications (Supplementary Table S1). Postoperative complications were reported in 33 dogs, including 18 grade 1, 11 grade 2, and 7 grade 3 events (Supplementary Table S2).
Histopathology
Grade was reported in 249 dogs: 102 (40.9%) were grade 1, 120 (48.2%) were grade 2, and 27 (10.8%) were grade 3. Area for mitotic count and/or microscope field number were not consistently reported, and so mitotic count was excluded as a variable for both reporting and statistical analysis. Complete histologic margins were reported in 42 of 253 dogs (16.6%).
Radiation therapy
Postoperative dRT was planned prior to surgery in 49 dogs (19.2%), considered postoperative salvage in 200 dogs (78.4%), and used to treat recurrence in 6 dogs (2.4%), with circumstances unknown in 17 dogs. Data regarding the timing of RT were available for 257 dogs, with a median interval of 33 days (range, 11 to 174 days) from surgery. The burden of disease at initiation of RT was considered microscopic in 238 (89.5%) dogs and macroscopic in 28 (10.5%), with no information available for 6 dogs. Additional data regarding dRT planning and delivery variables are included in Supplementary Table S3. The prescribed total dose to 95% of the PTV was available in 167 dogs with computer planning, with a median of 5,400 cGy (range, 4,194 to 6,000 cGy). The prescribed central axis dose was available for 54 dogs, with a median of 5,700 cGy (range, 4,800 to 5,700 cGy). Dogs were treated with a median of 18 fractions (range, 3 to 24 fractions) at a median of 300 cGy/fraction (range, 50.3 to 330 cGy) over a median total treatment period of 24 days (range, 17 to 65 days). At least 1 treatment interruption was encountered in 24 dogs (due to public holidays in 13 dogs, technical delays in 6 dogs, other medical issues in 7 dogs, owner factors in 3 dogs, and direct effects of radiation in 1 dog). A further 240 dogs had no treatment interruptions, while no record was available for 4 dogs. Treatment was discontinued early in 4 dogs due to adverse skin effects and in 2 dogs due to evidence of unrelated cancer. Information regarding RT-related complications was provided for 247 dogs, of which 232 (93.9%) experienced at least 1 adverse event (Table 1). Two hundred thirty-one dogs experienced at least 1 acute adverse event, with skin/hair most commonly involved (228 dogs). Data regarding late effects were not reported consistently, precluding determination of rate; however, 100 dogs were reported to have at least 1 late effect. Again, skin/hair was most commonly affected (99 dogs).
Frequency of radiotherapy (RT)-associated adverse events, classified according to the Veterinary Radiology Therapy Oncology Group criteria. Information regarding acute effects was available for 247 dogs. Late effects were recorded in 100 dogs, with the number truly unaffected unclear from many records.
| Grade | Skin/hair | Mucous membranes | Eye | Ear | Lower GI | GU | CNS | Lung | |
|---|---|---|---|---|---|---|---|---|---|
| Acute | 1 | 78 | 3 | 3 | — | 5 | 2 | 1 | 1 |
| 2 | 110 | 1 | 1 | 1 | 8 | — | 1 | 1 | |
| 3 | 40 | 3 | — | 1 | 1 | — | — | — | |
| Total | 228 | 7 | 4 | 2 | 14 | 2 | 2 | 2 |
| Grade | Skin/hair | Bone | Eye | Heart | Joint | Bladder | CNS | Lung | |
|---|---|---|---|---|---|---|---|---|---|
| Late | 1 | 96 | — | — | — | 2 | — | — | 1 |
| 2 | 2 | 2 | 1 | — | — | — | 2 | — | |
| 3 | 1 | — | — | — | — | — | — | — | |
| Total | 99 | 2 | 1 | 0 | 2 | 0 | 2 | 1 |
GI = Gastrointestinal. GU = Genitourinary.
Chemotherapy
Twenty-six dogs (9.6%) received adjuvant chemotherapy for STS (Supplementary Table S4). Cytotoxic chemotherapy was used in 18 dogs (6.6%; predominantly doxorubicin alone in 14 dogs), metronomic chemotherapy in 6 dogs (2.2%), toceranib was used as a small molecule inhibitor in 1 dog shortly prior to euthanasia, and the drug used was unavailable in 1 dog. Chemotherapy was administered to an additional 5 dogs as part of treatment of concurrent neoplasia, including lymphoma (n = 3), mast cell tumor (1), and osteosarcoma (1).
Outcome
Median follow-up time following dRT was 765 days (range, 10 to 2,843 days). Of the 28 dogs listed with macroscopic disease, 5 were recorded to have a complete response to RT. Insufficient information was recorded to determine response for the remaining 23 dogs. Local progression was suspected (25 dogs) or confirmed (31 dogs) in 56 dogs at a median of 348.5 days (range, 76 to 1,841 days). A further 184 dogs had at least 6 months of local progression-free follow-up, resulting in 240 dogs that contributed to assessment of rate of recurrence and an overall recurrence rate of 23.3%. Local progression rates were similar for grade 1 (24 of 89 [26.7%]), grade 2 (23 of 111 [20.7%]), and grade 3 tumors (6 of 22 [27.3%]). Local recurrence rates in the context of microscopic disease were also similar for grade 1 (20 of 80 [25.0%]), grade 2 (19 of 100 [19.0%]), and grade 3 tumors (5 of 25 [25.0%]). Local progression was comparable for dogs with complete (11 of 42 [26.2%]) and incomplete histologic margins (42 of 211 [19.9%]). Median time to local progression for the entire population, assessed with the Kaplan-Meier method, was not reached (Figure 1). Of progressive lesions, 39 were considered in-field, 1 edge-of-field, and 4 out-of-field, with no data for the remaining 12 dogs.
Kaplan-Meier survival curves detailing local progression (A) and overall survival (B); 95% CIs are shown in yellow. A—Dogs were censored at the last follow-up date if they had no evidence of local progression, indicated by a vertical tick. Median time to local progression was not reached in this population. One-, 2-, and 3-year local progression-free rates were 88.1%, 79.8%, and 74.9%, respectively. B—Dogs were censored at the last follow-up time if alive, indicated by a vertical tick. The median overall survival time was 1,239 days (95% CI, 1,057 to 1,420 days). One-, 2-, and 3-year survival rates were 90.9%, 76.7%, and 57.9%, respectively.
Citation: Journal of the American Veterinary Medical Association 263, 3; 10.2460/javma.24.06.0363
Pulmonary metastasis was suspected on the basis of imaging in 25 dogs (9.2%) at a median of 799 days (range, 103 to 1,947 days) after completion of dRT. A further 161 dogs were reported not to have metastasis at least 6 months after treatment. Distant metastatic rates were 5 of 75 (6.7%) for grade 1, 10 of 77 (13.0%) for grade 2, and 5 of 18 (27.8%) for grade 3. One dog had cytologically confirmed lymph node metastasis at 191 days after completion of dRT. Median overall survival time was 1,239 days (95% CI, 1,111 to 1,427 days; Figure 1). The Kaplan-Meier method was used to assess differences in survival and local progression for categorical variables depicted in Figures 2 and 3.
Kaplan-Meier survival curves detailing categorical variables evaluated for association with local progression. Dogs were censored at the last follow-up date if they had no evidence of local progression, indicated by a vertical tick. A—Median (95% CI) time to local progression could not be calculated for grade 1 and grade 2 sarcomas but was 1,265 days (95% CI undefined) for grade 3. One-, 2-, and 3-year local progression-free rates were 85.5%, 80.2%, and 72.5% for grade 1; 88.0%, 78.0%, and 78.0% for grade 2; and 86.4%, 80.2%, and 72.2% for grade 3, respectively. B—Median (95% CI) time to local progression could not be calculated for dogs without previous recurrence but was 1,516 days (343 to 2,589 days) for dogs with previous recurrence. One-, 2-, and 3-year local progression-free rates were 92.4%, 85.8%, and 79.9% for dogs without previous recurrence and 73.4%, 59.8%, and 59.8% for dogs with previous recurrence, respectively. C—Median time to local progression could not be calculated for either institution type. One-, 2-, and 3-year local progression-free rates were 87.7%, 83.0%, and 77.7% for dogs that underwent surgery in general practice (GP) and 89.3%, 72.8%, and 69.4% for dogs that underwent surgery at a referral hospital, respectively. D—Median (95% CI) time to local progression could not be calculated for dogs with either intralesional resection or other Enneking classifications. One-, 2-, and 3-year local progression-free rates were 70.4%, 61.6%, and 51.3% for dogs with intralesional resection and 88.3%, 83.3%, and 77.7% for dogs with other resection classifications, respectively. E—Median (95% CI) time to local progression could not be calculated for dogs with microscopic disease at treatment but was 1,841 days (947 to 2,735 days) for dogs with macroscopic disease. One-, 2-, and 3-year local progression-free rates were 88.7%, 81.2%, and 76.7% for dogs with microscopic disease and 84.4%, 69.9%, and 62.1% for dogs with previous recurrence, respectively. F—Median (95% CI) time to local progression could not be calculated for dogs with either intensity-modulated radiotherapy (IMRT) or other forms of RT delivery. One-, 2-, and 3-year local progression-free rates were 91.2%, 83.4%, and 80.2% for dogs treated with IMRT and 84.5%, 75.5%, and 71.9% for dogs treated with other forms of RT delivery, respectively. G—Median (95% CI) time to local progression was 1,265 days (148 to 1,382 days) for dogs with metastasis but could not be calculated for dogs without metastasis. One-, 2-, and 3-year local progression-free rates were 66.8%, 56.5%, and 56.5% for dogs with metastasis and 88.3%, 79.8%, and 73.3% for dogs without metastasis, respectively.
Citation: Journal of the American Veterinary Medical Association 263, 3; 10.2460/javma.24.06.0363
Kaplan-Meier survival curves detailing categorical variables evaluated for association with overall survival time (OST). Dogs were censored at the last follow-up time if alive, indicated by a vertical tick. A—Median (95% CI) OST was 1,445 days (1,297 to 1,593 days) for grade 1, 1,201 days (1,051 to 1,351 days) for grade 2, and 767 days (670 to 864 days) for grade 3. One-, 2-, and 3-year survival rates were 90.5%, 82.8%, and 70.0% for grade 1; 90.6%, 76.8%, and 55.6% for grade 2; and 79.2%, 60.5%, and 25.1% for grade 3, respectively. B—Median (95% CI) OST was 1,402 days (1,227 to 1,576 days) for dogs without previous recurrence and 872 days (714 to 1,029 days) for dogs with previous recurrence. One-, 2-, and 3-year survival rates were 92.0%, 82.8%, and 63.9% for dogs without and 83.0%, 59.6%, and 41.5% for dogs with previous recurrence, respectively. C—Median (95% CI) OST was 1,405 days (1,192 to 1,618 days) for dogs that underwent surgery in GP and 993 days (810 to 1,176 days) for dogs that underwent surgery at a referral practice. One-, 2-, and 3-year survival rates were 93.9%, 81.4%, and 67.5% for dogs that underwent surgery in GP and 81.2%, 67.8%, and 40.7% for dogs that underwent surgery at a referral practice, respectively. D—Median (95% CI) OST was 1,072 days (818 to 1,326 days) for dogs that developed local progression and 1,324 days (1,137 to 1,511 days) for dogs that did not develop local progression. One-, 2-, and 3-year survival rates were 83.0%, 68.4%, and 46.1% for dogs that developed local progression and 91.6%, 79.4%, and 62.5% for dogs that did not develop local progression, respectively. E—Median (95% CI) OST was 1,289 days (937 to 1,641 days) for dogs with complete histologic margins and 1,240 days (1,041 to 1,439 days) for dogs with incomplete margins. One-, 2-, and 3-year survival rates were 95.2%, 75.7%, and 50.5% for dogs with complete margins and 87.7%, 76.7%, and 60.2% for dogs with incomplete margins, respectively. F—Median (95% CI) OST was 1,240 days (1,036 to 1,444 days) for dogs with microscopic disease at treatment and 1,239 days (341 to 2,137 days) for dogs with macroscopic disease. One-, 2-, and 3-year survival rates were 89.8%, 77.9%, and 58.6% for dogs with microscopic disease and 88.7%, 66.3%, and 51.3% for dogs with macroscopic disease, respectively. G—Median (95% CI) OST was 1,089 days (990 to 1,188 days) for dogs treated with IMRT and 1,402 days (1,209 to 1,595 days) for dogs treated with other forms of RT delivery. One-, 2-, and 3-year survival rates were 88.2%, 72.3%, and 47.7% for dogs treated with IMRT and 90.9%, 79.9%, and 65.3% for dogs treated with other forms of RT delivery, respectively. H—Median (95% CI) OST was 1,324 days (1,137 to 1,511 days) for dogs without local progression and 1,072 days (818 to 1,326 days) for dogs with local progression. One-, 2-, and 3-year survival rates were 91.6%, 79.4%, and 62.5% for dogs without local progression and 83.0%, 68.4%, and 46.0% for dogs with local progression. I—Median (95% CI) OST was 993 days (548 to 1,438 days) for dogs that developed metastasis and 1,301 days (1,066 to 1,536 days) for dogs that did not develop metastasis. One-, 2-, and 3-year survival rates were 72.0%, 60.0%, and 44.3% for dogs that developed metastasis and 92.0%, 79.5%, and 60.8% for dogs that did not develop metastasis, respectively.
Citation: Journal of the American Veterinary Medical Association 263, 3; 10.2460/javma.24.06.0363
Multivariate analysis: local progression
Continuous variables were linearly related to the logit of the dependent variable. Notably, age, previous recurrence, distant metastasis, and the form of RT delivery were significantly associated with the risk of local progression (Table 2). A second binomial logistic regression was then conducted to evaluate the effects of age, previous recurrence, distant metastasis, and delivery type on the probability of local progression in dogs. This logistic regression model was statistically significant (χ2[4] = 19.41; P = .001). Out of the 4 predictors, previous recurrence, distant metastasis, and delivery type retained statistical significance; however, age fell short of traditional significance (P = .054). The findings indicate that dogs with a history of recurrence were 2.8 times more likely to experience local progression compared to those without such a history. Dogs with distant metastasis had 3.4 higher odds of developing local progression. Dogs treated with IMRT had 0.4 times lower odds of developing local progression compared to those receiving other forms of RT delivery. The area under the receiver operating characteristic curve was 0.700, with a 95% CI of 0.615 to 0.785, denoting an acceptable level of discrimination.
Preliminary (A) and final (B) multivariate logistic regression models evaluating variables associated with local progression.
| A. Preliminary analysis | ||||||
|---|---|---|---|---|---|---|
| Variable | N | No. (%) recurred | Wald | OR (95% CI) | P value | |
| Age | — | — | 4.913 | 0.824 (0.694–0.978) | .027 | |
| Weight | — | — | 0.172 | 1.006 (0.977–1.037) | .679 | |
| Grade | 1 | 102 | 24 (23.5) | 0.462 | — | .794 |
| 2 | 120 | 23 (19.2) | 0.444 | 0.744 (0.311–1.777) | .505 | |
| 3 | 27 | 6 (22.2) | 0.126 | 0.793 (0.219–2.870) | .723 | |
| Previous recurrence | No | 207 | 34 (16.4) | 4.930 | 2.950 (1.135–7.664) | .026 |
| Yes | 60 | 21 (35.0) | ||||
| Institution type | GP | 181 | 36 (19.9) | 1.497 | 0.570 (0.232–1.402) | .221 |
| Referral | 90 | 19 (21.1) | ||||
| Resection | Intralesional | 23 | 7 (30.4) | 0.517 | 0.576 (0.128–2.595) | .472 |
| Other | 249 | 49 (19.7) | ||||
| Burden of disease | Microscopic | 234 | 44 (18.8) | 1.902 | 2.324 (0.701–7.704) | .168 |
| Macroscopic | 28 | 10 (35.7) | ||||
| RT to surgery interval | — | — | 0.000 | 1.000 (0.983–1.017) | .993 | |
| RT delivery | IMRT | 119 | 15 (12.6) | 4.065 | 0.382 (0.150–0.973) | .044 |
| Other | 153 | 41 (26.8) | ||||
| Distant metastasis | No | 185 | 40 (21.6) | 8.122 | 5.449 (1.698–17.488) | .004 |
| Yes | 25 | 12 (48.0) | ||||
| B. Final multivariate model | ||||||
|---|---|---|---|---|---|---|
| Variable | B | SE | df | Wald | OR (95% CI) | P value |
| Age | –0.131 | 0.068 | 1 | 3.714 | 0.878 (0.768–1.002) | .054 |
| Previous recurrence | 1.018 | 0.394 | 1 | 6.667 | 2.768 (1.278–5.995) | .010 |
| RT delivery | –0.912 | 0.406 | 1 | 5.035 | 0.402 (0.181–0.891) | .025 |
| Distant metastasis | 1.217 | 0.494 | 1 | 6.076 | 3.376 (1.283–8.885) | .014 |
Odds ratios and P values of significant variables are bolded. The final model accounted for 13.4% of the variance in local progression, as indicated by the Nagelkerke R2, and accurately classified 76.7% of the cases. The sensitivity of the model was 14%, while specificity reached 96.8%. The positive predictive value was 58.3%, and the negative predictive value stood at 77.8%. Additionally, the Hosmer-Lemeshow test showed a χ2(8) = 3.16 and P = .924, suggesting that the model’s predictions fit well with the observed data.
GP = General practice. IMRT = Intensity-modulated radiotherapy.
Multivariate analysis: overall survival
Age, grade, previous recurrence, and institution type for surgery were retained for inclusion in the final overall survival multivariable model (Table 3). Radiation delivery was not significantly associated with survival in multivariate analysis and its retention in the model resulted in age becoming insignificant, suggesting a relationship between these variables. Metastasis was not significantly associated with survival if the selected variables were included, indicating that the selected variables sufficiently explained survival. As the variables selected for the final model were available at the time of treatment, metastasis was not retained in the final analysis. To further explore the reasons behind the effect of institution type on survival, the proportions of dogs that developed metastasis were compared between those that underwent resection in GP and those that underwent surgery at a referral practice; no difference was identified between groups (GP, 14 of 153 [9.2%]; referral, 10 of 80 [12.5%]; P = .498).
Univariate (A) survival data for categorical variables and final multivariate Cox proportional hazards model (B) evaluating variables associated with overall survival.
| A. Univariate | ||||||
|---|---|---|---|---|---|---|
| Variable | N | No. (%) that died | Median survival (d) | 95% CI | P value | |
| Grade | 1 | 102 | 42 (41.2) | 1,445 | 1,297–1,593 | .008 |
| 2 | 120 | 59 (49.2) | 1,201 | 1,051–1,351 | ||
| 3 | 27 | 17 (63.0) | 767 | 670–864 | ||
| Previous recurrence | No | 207 | 93 (44.9) | 1,402 | 1,228–1,576 | .001 |
| Yes | 60 | 37 (61.7) | 872 | 714–1,030 | ||
| Institution type | GP | 181 | 79 (43.6) | 1,405 | 1,192–1,618 | .003 |
| Referral | 90 | 53 (58.9) | 993 | 810–1,176 | ||
| Resection | Intralesional | 23 | 11 (47.8) | 1,137 | 536–1,737 | .634 |
| Other | 249 | 122 (49.0) | 1,301 | 1,094–1,508 | ||
| Histologic margins | Complete | 42 | 21 (50.0) | 1,289 | 937–1,641 | .941 |
| Incomplete | 211 | 105 (50.2) | 1,240 | 1,041–1,439 | ||
| Burden of disease | Microscopic | 234 | 114 (48.7) | 1,240 | 1,036–1,444 | .982 |
| Macroscopic | 28 | 16 (57.1) | 1,239 | 341–2,137 | ||
| RT delivery | IMRT | 119 | 57 (47.9) | 1,089 | 990–1,188 | .007 |
| Other | 153 | 76 (50.3) | 1,402 | 1,209–1,595 | ||
| Local progression | No | 216 | 96 (44.4) | 1,324 | 1,137–1,511 | .053 |
| Yes | 56 | 37 (66.1) | 1,072 | 818–1,326 | ||
| Metastasis | No | 185 | 89 (48) | 1,301 | 1,066–1,536 | .026 |
| Yes | 25 | 20 (80) | 993 | 548–1,438 | ||
| B. Final multivariate model | ||||||
|---|---|---|---|---|---|---|
| Variable | β | SE | Wald | df | OR (95% CI) | P value |
| Age | 0.081 | 0.041 | 3.873 | 1 | 1.084 | .049 |
| Grade 1 | — | — | 9.516 | 2 | — | .009 |
| Grade 2 | 0.301 | 0.220 | 1.879 | 1 | 1.251 | .170 |
| Grade 3 | 0.912 | 0.297 | 9.442 | 1 | 2.490 | .002 |
| Previous recurrence | 0.580 | 0.221 | 6.863 | 1 | 1.786 | .009 |
| Institution type | –0.422 | 0.208 | 4.091 | 1 | 0.656 | .043 |
Odds ratios and P values of significant variables are bolded.
Discussion
In this large, retrospective population, the median overall survival was long and a median time to local progression was not reached; however, local progression was still suspected or confirmed in an important minority of patients (23.3%). Previous local recurrence and subsequent distant metastasis were associated with higher rates of local progression, while IMRT was associated with a lower rate of local progression than grouped other forms of RT delivery. Interestingly, grade was not associated with local progression in this population but was associated with overall survival time. Age, previous recurrence, and institution type for the pre-RT surgery were also associated with survival time.
Grade has been associated with risk of local recurrence of STS in dogs.2,3,11 Higher-grade tumors are typically thought to present a higher risk for infiltrative behavior or development of satellite lesions that could predispose to local recurrence. Most dogs in this population had incomplete histologic margins, and those that did not likely had other clinical concerns leading to a recommendation for RT. This selection bias likely contributes to the similarity in local progression rates between complete and incomplete margin status tumors in our study but would seem to raise the risk of recurrence in dogs with high-grade tumors compared to a population including more dogs with adequate primary resection. A small population of dogs with macroscopic disease at the start of radiation therapy could also affect the local progression across grades, but additional studies will need to be performed to investigate this variable. It is possible, however, that more biologically active high-grade sarcomas were more susceptible to the effects of radiation. Differential radiosensitivity has been reported in people with soft tissue sarcoma, and more radioresistant sarcomas include a high proportion of low-grade tumors.30,31 Could low-grade canine soft tissue sarcomas be less radiosensitive than their high-grade counterparts, perhaps due to decreased proliferation, with or without differential intrinsic radiosensitivity? A simple determination of radioresistant or radiosensitive may be reductive, however, and it is possible that some sarcomas may respond better to higher dose per fraction protocols, while others may benefit from traditional dRT.32 Regardless, while we cannot compare effectively to historic literature, the local progression rates for low-grade tumors in particular were higher than expected and call into question the relative benefit of dRT in this population. Further work will be needed to examine variables, such as the burden of disease at treatment, that could influence management and/or therapeutic strategies that can decrease recurrence in this group.
Even within dRT, variations in delivery and timing may influence local control. In our study, dogs treated with IMRT were significantly less likely to develop local progression than dogs treated with other protocols. Interestingly, this is consistent with findings in people managed with postoperative IMRT when compared to both 3-D conformal radiation therapy (3D-CRT) and 2-D conformal radiation therapy (2D-CRT).33,34 While the mechanisms underpinning this difference are uncertain, it is possible that the increased dose conformality afforded by IMRT could reduce heterogeneity and focal underdosing within the radiation field. In a study35 assessing use of RT in children, IMRT plans had significantly improved coverage of the clinical target volume to 100% of the prescription dose when compared to 3D-CRT plans. This improved coverage could thereby minimize focal survival of cancer cells to contribute to repopulation. The majority of recurrences were considered in-field in our population, concurrent with similar findings in people.36 A predominance of in-field recurrence could fit with both heterogeneity in dosing and relative radioresistance as potential mechanisms for local failure.36 It is, however, important to recognize that all the available clinical literature indicating reduced recurrence with IMRT is retrospective, raising the possibility of selection bias or concurrent changes, such as improved imaging, that may have contributed to local control.33 Failures of local control within a population are, of course, likely multifactorial, and ongoing work will be needed to delineate relative responsibility. That being said, the improved toxicity profile of IMRT in people and the building evidence for improved local control compared to other forms of dRT make it an appealing option, should owner finances allow. The decreased rate of adverse effects has even led to IMRT being identified as more cost-effective in people than 3D-CRT, despite the higher up-front cost.37
Importantly, adjuvant RT is one part of multimodal therapy for STS. Our study did not identify a clear impact of the classification of resection, institution type for surgery, or residual burden of disease, although the latter was associated with local progression on univariate analysis. The reasons for this are unclear, although selection bias and variation in documentation may both play a role. Operative reports were not available for many dogs, and when they were available, the quality was widely variable. While intralesional resection was not significantly associated with local progression in our study, it has been associated with increased risk of local failure in humans.38
Dogs that underwent surgery in GP had significantly longer survival, although the reasons for this are unclear. Without a difference in either local progression or metastatic rate, we suspect this represents selection bias or influence of undefined variables, such as tumor size at resection. Any contributing effects on survival may be exacerbated by the significantly older population seen in the referral-based population, which may be more at risk of unrelated diseases. Previous recurrence was associated with both shorter survival and a higher risk of local progression. The high proportion of dogs in our study without either preoperative diagnosis or planned wide margins suggest that the majority of dogs detailed here underwent unplanned excision, which has been defined as a resection without adequate preoperative evaluation and/or surgical margins.39,40 Unplanned excision followed by re-excision (± RT) has been infrequently associated with improved survival in people, although after weighting for variables, this effect may disappear.41 We suspect that an analogous effect underlies the improved survival between dogs that underwent the last surgery in GP. More commonly, unplanned resections in people with STS are identified as a negative prognostic indicator for both local recurrence and survival, particularly among patients with residual disease at histopathology.39,42–44 Primary re-excision of the surgical site is widely accepted as the next step following unplanned excision due to the high rate of residual disease identified at histopathology, although both neoadjuvant RT prior to re-excision and RT alone have been reported.18,40,43,45 Re-excision will typically require wider margins to allow resection of not just the cutaneous scar but the subcutaneous wound bed, and the feasibility of re-excision depends on tissue availability, including collagen-rich tissue to provide an adequate deep margin.46–48 Such tissue may not always be available, especially after previous resection(s), placing a greater onus on RT to support local control. As such, identification of tumor type preoperatively and identification of dogs at risk of recurrence should be priorities in management of soft tissue tumors. Furthermore, repeated resection in the face of recurrence should be strictly avoided without either a shift to more aggressive resection or planned adjuvant therapy.
Limitations of this study were largely a product of its multicenter, retrospective design. We encountered marked variation in records available, and this heterogeneity led to frequent data gaps that precluded analysis of multiple variables we had planned to assess. Foremost among these were the R-classification and size of the primary tumor prior to resection, which was frequently unavailable or only available as a scar length, which may or may not correlate well with the maximum diameter of the primary tumor, depending on the form of resection executed.49 Histopathology samples were not assessed by a single pathologist to ensure consistency in grading or with a defined protocol for trimming to standardize margin assessment. Metric lateral and deep margins were frequently not provided, preventing assessment of the extent of a complete margin on local progression. Mitotic count was not consistently reported. While it is likely that the 10 hpf reported by many pathologists was equivalent to 2.37 mm2, the field number of some microscopes may have varied, which could have resulted in a differing area assessed for some sarcomas. Variables associated with RT were particularly challenging due to frequent data gaps and variation in protocols between institutions. Follow-up times varied, and most dogs did not undergo consistent staging, which is unfortunately consistent with low rates of adherence to follow-up recommendations in veterinary oncology.50 The cause of death in this population was also difficult to determine due to incomplete records, and when death was reported, necropsies were not performed. As a result, it is likely that local progression and metastasis rates were higher than stated, especially given the potentially prolonged time to these events seen in our population.
In conclusion, outcomes for most dogs in this population were good; however, the relative frequency of local failures indicates an ongoing need to critically appraise local management strategies. No difference in local progression was identified between grades, and further work is needed to examine the role of RT in management of low-grade STS. Our data indicate a high rate of unplanned excision in dogs managed with surgery and postoperative dRT, as well as a negative impact of previous recurrence on both local progression and overall survival. As such, clinicians need to identify dogs at high risk of recurrence earlier to allow timely intervention to attempt to mitigate this risk. Intensity-modulated RT was associated with lower rates of local progression and may be preferred to less precise forms of delivery, although ongoing investigation is necessary to corroborate or refute this finding.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
The authors would like to thank all clinicians and staff at contributing hospitals for their work in the included cases.
Disclosures
Dr. Wustefeld-Janssens is a member of the JAVMA Scientific Review Board, but was not involved in the editorial evaluation of or decision to accept this article for publication.
No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to disclose.
ORCID
I. Hildebrandt https://orcid.org/0000-0003-0462-7567
O. Skinner https://orcid.org/0000-0002-3765-429X
T. Martin https://orcid.org/0000-0002-9258-4861
M. Griffin https://orcid.org/0000-0001-9714-1579
I. Vanhaezebrouck https://orcid.org/0000-0001-9662-3584
L. Selmic https://orcid.org/0000-0001-6695-6273
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