Treatment of retroperitoneal sarcoma results in improved outcomes

Kyla M. Walter Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA

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William T. N. Culp Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Michelle A. Giuffrida Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Pierre Amsellem College of Veterinary Medicine, University of Minnesota, Saint Paul, MN

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Mandy L. Wallace College of Veterinary Medicine, University of Georgia, Athens, GA

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Janet A. Grimes College of Veterinary Medicine, University of Georgia, Athens, GA

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Brandan Wustefeld-Janssens College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO

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Meaghan O’Neill College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO

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Sita S. Withers School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA

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Dylan Shannon School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA

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Janis Lapsley College of Veterinary Medicine, Cornell University, Ithaca, NY

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Joanne Tuohy Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA

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Haleigh Hixson Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA

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Cassie N. Lux College of Veterinary Medicine, University of Tennessee, Knoxville, TN

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Brad Matz College of Veterinary Medicine, Auburn University, Auburn, AL

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Laura E. Selmic College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Alysha McGrath College of Veterinary Medicine, The Ohio State University, Columbus, OH

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Maureen A. Griffin School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA

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Philipp D. Mayhew Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Michele A. Steffey Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Ingrid M. Balsa Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Robert B. Rebhun Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Michael S. Kent Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Abstract

OBJECTIVE

To report the clinical characteristics, treatments, and outcomes in a cohort of dogs with histologically confirmed retroperitoneal sarcoma (RPS) and to identify potential variables of prognostic significance.

ANIMALS

46 client-owned dogs from 10 clinics with histopathologic diagnosis of a sarcoma originating from the retroperitoneal space.

METHODS

Medical records were retrospectively reviewed to obtain information regarding clinical characteristics, treatments, and outcomes. Recorded variables were analyzed to report descriptive data for all cases and overall survival time. Multivariate analysis was utilized to evaluate prognostic factors for overall survival.

RESULTS

Hemangiosarcoma was the most common histologic subtype diagnosed (76.1%). Cytoreductive and curative intent surgical excision of the RPS was attempted in 12 and 22 dogs, respectively; 12 dogs underwent no surgery or had an exploratory laparotomy with incisional biopsy only. Nineteen dogs received adjuvant chemotherapy, either injectable or metronomic, and 1 dog received adjuvant radiation therapy. Fourteen of the 34 (41.2%) surgically treated dogs developed evidence of local recurrence, but there was no difference in local recurrence when comparing dogs categorized as curative intent versus cytoreductive surgery. The median overall survival time was 238 days. On multivariable analysis, treatment approach was associated with survival with surgical excision (vs palliative treatment) and adjuvant chemotherapy following surgery being protective against death. A diagnosis of hemangiosarcoma was associated with a greater hazard of death.

CLINICAL RELEVANCE

This study demonstrates a substantially greater survival time than previously published and suggests a survival benefit from surgical excision and adjuvant chemotherapy.

Abstract

OBJECTIVE

To report the clinical characteristics, treatments, and outcomes in a cohort of dogs with histologically confirmed retroperitoneal sarcoma (RPS) and to identify potential variables of prognostic significance.

ANIMALS

46 client-owned dogs from 10 clinics with histopathologic diagnosis of a sarcoma originating from the retroperitoneal space.

METHODS

Medical records were retrospectively reviewed to obtain information regarding clinical characteristics, treatments, and outcomes. Recorded variables were analyzed to report descriptive data for all cases and overall survival time. Multivariate analysis was utilized to evaluate prognostic factors for overall survival.

RESULTS

Hemangiosarcoma was the most common histologic subtype diagnosed (76.1%). Cytoreductive and curative intent surgical excision of the RPS was attempted in 12 and 22 dogs, respectively; 12 dogs underwent no surgery or had an exploratory laparotomy with incisional biopsy only. Nineteen dogs received adjuvant chemotherapy, either injectable or metronomic, and 1 dog received adjuvant radiation therapy. Fourteen of the 34 (41.2%) surgically treated dogs developed evidence of local recurrence, but there was no difference in local recurrence when comparing dogs categorized as curative intent versus cytoreductive surgery. The median overall survival time was 238 days. On multivariable analysis, treatment approach was associated with survival with surgical excision (vs palliative treatment) and adjuvant chemotherapy following surgery being protective against death. A diagnosis of hemangiosarcoma was associated with a greater hazard of death.

CLINICAL RELEVANCE

This study demonstrates a substantially greater survival time than previously published and suggests a survival benefit from surgical excision and adjuvant chemotherapy.

Introduction

Retroperitoneal sarcomas (RPSs) comprise a heterogenous group of rare mesenchymal tumors arising from the structures within the retroperitoneal space. Within this retroperitoneal space the major organs include the kidneys, ureters, and adrenal glands as well as fat, connective tissue, nerves, and blood vessels.1 In both human and veterinary medicine, RPS has historically been defined as a mesenchymal tumor that originates from within the retroperitoneal potential space but does not include tumors arising from retroperitoneal organs such as the kidneys, ureters, or adrenal glands.2,3

Retroperitoneal sarcomas are not commonly diagnosed in dogs, with the published literature consisting of two retrospective studies4,13 of 14 and 12 dogs, respectively, and several individual case reports.59 Previously reported morphologic subtypes of RPS in dogs include hemangiosarcoma (HSA), osteosarcoma, leiomyosarcoma, peripheral nerve sheath tumor (PNST), chondrosarcoma, fibrosarcoma, and hemangiopericytoma.46,8,9 In a study4 of 14 dogs diagnosed with RPS over the course of 10 years, HSA was the most common histologic diagnosis in 9 of 14 (64%) dogs. In humans, the most frequently diagnosed RPS include liposarcoma (approx 63%), leiomyosarcoma (approx 19%), solitary fibrous tumor, fibrosarcoma, malignant PNST, and malignant fibrous histiocytoma, but 80 different histologic subtypes have been reported.2,10

The cornerstone of treatment for RPS in both humans and dogs is surgical resection. Curative intent surgical resection is typically recommended; however, RPS tend to be large and locally invasive, often making complete resection challenging. There is a lack of evidence to support the use of chemotherapy and radiation therapy; however, in humans, these therapies may be key components of treatment in sensitive subtypes and when complete resection is not achieved.10,11 In humans, RPSs are considered to have a poor prognosis with a 5-year survival rate of 39% to 70%; predictive factors associated with survival include age, tumor size, completeness of resection, grade, and multifocality.10,12 In the case series of 14 dogs previously reported, 6 were treated with surgical excision; overall, 13 died or were euthanized as a result of the RPS with a median survival time (MST) of 37.5 days.4 A recent retrospective study13 evaluated 12 dogs with retroperitoneal HSA treated surgically with or without adjuvant doxorubicin chemotherapy. This study demonstrated a MST of 168 days (MST, 129.5 days with surgery alone and 241.5 days with surgery and adjuvant doxorubicin); however, neither adjuvant chemotherapy nor any other factors analyzed were significantly associated with survival.

The severity of this disease and limited available information underscore the importance of evaluating this disease further in a larger cohort of dogs. Additionally, in the veterinary literature, there are no reported data on prognostic factors in dogs with RPS. Therefore, the objectives of this study were to evaluate the clinical features and outcome with treatment of a larger group of dogs with RPS and to subsequently evaluate these dogs for associated prognostic factors.

Methods

Case selection

The medical record databases of 10 referral veterinary clinics were retrospectively searched to identify dogs that were diagnosed with sarcomas originating from the retroperitoneal space between the time frame of January 1, 2000, to December 31, 2020. This included all dogs with tumors originating from the retroperitoneal space with a histopathologic diagnosis of sarcoma via incisional biopsy, excisional biopsy, or necropsy. Tumors originating from retroperitoneal organs (kidney, adrenal glands, or ureters) were excluded.

Medical records review

Information obtained from the medical records included signalment, history, presenting complaints, type and duration of clinical signs, physical examination findings, results of preoperative diagnostic imaging and laboratory diagnostic testing, method of histopathologic diagnosis, treatments pursued (surgery, chemotherapy, and/or radiation therapy), complications arising from treatments pursued, recurrence of the primary tumor, documentation of new or progressive metastatic disease, and timing and cause of death (if known). Intraoperative and postoperative complications were graded according to the Veterinary Cooperative Oncology Group–Common Terminology Criteria for Adverse Events.14 Individual data for each patient included are presented in Supplementary Table S1.

Statistical analysis

Summary statistics were calculated and reported as numbers, percentages, and means with SD. Tests of skewness and kurtosis were used to assess normal distribution. A Fisher exact test was used to compare local recurrence rate between dogs that underwent curative intent surgical excision versus cytoreductive excisions. Overall survival time (from date of diagnosis) was estimated using the Kaplan-Meier method, and dogs that were alive or lost to follow-up were censored at the date they were last known to be alive. Dogs that died from causes unrelated to RPS were censored at that time. Unadjusted survival estimates by therapeutic approach (palliative only [NSAIDS, prednisone, and/or supportive medication], excision only, excision plus chemotherapy) were compared with the log-rank test. Multivariable Cox proportional hazards regression was used to evaluate prognostic factors for overall survival. Independent variables tested in the model were age, body weight, sex, tumor size, diagnosis of HSA, presence of metastasis at diagnosis, surgical excision (curative intent and cytoreductive combined), and treatment with chemotherapy following surgery. Clinical stage was not classified for patients included in this study as RPS staging criteria for humans and those previously used for dogs utilize tumor grade in the criteria, and this was only reported in 8 out of 46 patients. Variables with P < .20 on univariable regression were tested in the multivariable model and retained if P < .05 or identified as a confounder on the main effects. All tests were 2-sided, and P < .05 was considered statistically significant. Analyses were performed using statistical software (Stata, version 16; StataCorp LLC.)

Results

Dogs

Between 2000 and 2020, 46 dogs from 10 institutions met the inclusion criteria (Supplementary Table S1). The mean age of included dogs was 9.1 ± 3.2 years. Dog breeds included Boxer (n = 10), mixed-breed dogs (9), Golden Retriever (7), Labrador Retriever (4), German Shepherd Dog (2), and 1 each of Pit Bull Terrier, Goldendoodle, Havanese, Rhodesian Ridgeback, Saluki, Dogo Argentino, Springer Spaniel, Boston Terrier, Spinone Italiano, Cocker Spaniel, Bichon Frise, Weimaraner, Labradoodle, and Greyhound. Patient sex included 16 (34.8%) spayed females, 24 (52.2%) castrated males, 2 (4.3%) intact females, and 4 (8.7%) intact males. All patient demographics are summarized in Table 1.

Table 1

Summary of patient demographics, clinical signs at the time of presentation, and physical examination findings.

Patient demographics
Age (mean ± SD) 9.1 ± 3.2 y
Sex
  Spayed female 16 (34.8%)
  Castrated male 24 (52.2%)
  Intact female 2 (4.3%)
  Intact male 4 (8.7%)
Body weight (mean ± SD) 28 ± 10.7 kg
Clinical signs
Clinical signs at diagnosis 41/46 (89.1%)
Duration of clinical signs (mean ± SD) 23 ± 39 (d)
Inappetence 25 (54.3%)
Lethargy 23 (50.0%)
PU/PD 9 (19.6%)
Abdominal pain 7 (15.2%)
Pelvic limb lameness 5 (10.9%)
Diarrhea 4 (8.7%)
Tenesmus 4 (8.7%)
Weight loss 3 (6.5%)
Vomiting 3 (6.5%)
Collapse 3 (6.5%)
Stranguria 2 (4.4%)
Hematuria 1 (2.2%)
Physical examination
Abdominal enlargement 19 (41.3%)
Palpable abdominal mass 12 (26.1%)
Abdominal discomfort 8 (17.4%)
Lower motor deficits 4 (8.7%)

PU/PD = Polyuria/polydipsia.

Clinical signs

Forty-one of 46 (89.1%) dogs had clinical signs associated with the RPS at the time of diagnosis (Table 1). Clinical signs included inappetence (25/46 [54.3%]), lethargy (23/46 [50.0%]), polyuria/polydipsia (9/46 [19.6%]), abdominal pain (7/46 [15.2%]), pelvic limb lameness (5/46 [10.9%]), diarrhea (4/46 [8.7%]), tenesmus (4/46 [8.7%]), weight loss (3/46 [6.5%]), vomiting (3/46 [6.5%]), collapse (3/46 [6.5%]), stranguria (2/46 [4.4%]), and hematuria (1/46 [2.2%]). The RPS was an incidental finding in the other 5 (10.9%) dogs. The mean duration of clinical signs was 23 ± 39 days. This was calculated on the basis of the history provided by the owners regarding the duration of their pets’ clinical signs. Of the 5 dogs that did not have clinical signs at the time of diagnosis, 3 had RPSs that measured < 5 cm and the other 2 had RPSs measuring 5 to 10 cm.

Physical examination

Physical examination findings documented by the clinician at the time of initial presentation are summarized in Table 1. The mean weight was 28 ± 10.7 kg. Abdominal enlargement was appreciated in 19 (41.3%) dogs, and a palpable mass was noted on abdominal palpation or rectal examination in 12 (26.1%) dogs. Abdominal discomfort during palpation was noted in 8 (17.4%) dogs. Four of 5 dogs that presented with pelvic limb lameness were found to have lower motor neuron signs on examination.

Clinical laboratory findings

Among the 46 dogs included in the study, complete staging including a CBC, chemistry panel, abdominal imaging (ultrasound or CT), and thoracic imaging (radiographs or CT) was performed in 33 (71.7%) dogs (Table 2). Blood work (performed in 37 dogs) demonstrated anemia (Hct < 40%) in 22 of 37 (59.4%) dogs. Sixteen of these dogs had Hct between 30% and 40%, and 6 had Hct between 20% and 30%. No dogs had Hct < 20%. Thirteen of 37 (35.1%) dogs had a leukocytosis, 17 (45.9%) were neutrophilic, 10 (27%) were lymphopenic, 6 (16.2%) were thrombocytopenic, and 4 (10.8%) demonstrated thrombocytosis. An elevated creatinine (0.8 to 1.5 IU/L) was noted on initial staging in 6 of 36 (17%) dogs.

Table 2

Summary of diagnostics and treatments.

Clinical laboratory data (37 dogs)
Anemia (Hct < 40%) 22/37 (59.4%)
  Hct 30%–40% 16
  Hct 20%–30% 6
  Hct < 20% 0
Leukocytosis 13/37 (35.1%)
Neutrophilia 17/37 (45.9%)
Lymphopenia 10/37 (27%)
Thrombocytopenia 6/37 (16.2%)
Thrombocytosis 4/37 (10.8%)
Elevated creatinine (> 1.5 IU/L) 6/36 (17%)
Diagnostic imaging (45 dogs)
RPS size* n (%)
  < 5 cm 4/33 (12.2%)
  5–9.9 cm 10/33 (30.3%)
  10–14.9 cm 13/33 (39.4%)
  > 15 cm 6/33 (18.2%)
Laterality
  Right 25 (55.6%)
  Left 15 (33.3%)
  Central/bilateral 5 (11.1%)
Fluid cavitation or free retroperitoneal fluid described 20/35 (57%)
Treatments
No surgery 8/46 (17.4%)
Surgery 38/46 (82.6%)
  Ex-lap + biopsy 4/46 (8.7%)
  Cytoreductive 12/46 (26.1%)
  Curative intent 22/46 (47.8%)
Chemotherapy 19/46 (41.3%)
  IV chemo 17/46 (37.0%)
  Oral metronomic 2/46 (4.3%)
Radiation 1/46 (2.2%)

Ex-lap = Exploratory laparotomy. RPS = Retroperitoneal sarcoma.

*Tumor size is based on the maximum dimension measured during surgical exploration or on abdominal imaging if surgery was not performed.

†Only 35 dogs had full descriptions of abdominal imaging findings, which were evaluated for descriptions of fluid cavitation or retroperitoneal fluid.

Diagnostic imaging

Forty-five dogs had abdominal imaging (either an abdominal ultrasound or CT scan) performed as part of their diagnostic evaluation (Table 2). The single dog that did not have abdominal ultrasound or CT scan had an abdominal radiograph and a definitive diagnosis of RPS during necropsy. Utilizing imaging, RPSs were found to be right-sided in 25 (55.6%) and left-sided in 15 (33.3%) dogs; 5 dogs with abdominal imaging had RPS that were bilateral or central (11.1%). The size of the RPS was measured utilizing abdominal imaging in 33 dogs; RPS measured < 5 cm (n = 4 dogs), 5 to 9.9 cm (10 dogs), 10 to 14.9 cm (13 dogs), and > 15 cm (6 dogs). There were 35 dogs for which full description of their abdominal ultrasounds was available; 20 dogs had their masses described as having fluid cavitations or free retroperitoneal fluid. Of these 20 dogs, 18 were ultimately diagnosed with HSA; the others were diagnosed with sarcoma or myxosarcoma.

Of 46 dogs, 34 had thoracic radiographs performed, and 10 had thoracic CT performed. Ten of 44 (22.7%) dogs were diagnosed with metastatic disease at the time of initial staging on the basis of imaging, cytology, and/or histopathology. One (1/44 [2.3%]) dog had local lymph node metastasis alone, 7 (7/44 [15.9%]) dogs had distant metastasis to the lungs or another abdominal organ, and 2 (2/44 [4.5%]) dogs had both local lymph node and distant metastasis diagnosed. Two of the dogs diagnosed with local lymph node metastasis were ultimately diagnosed with HSA, and 1 was diagnosed with a malignant PNST.

Treatment and histopathology

The median time from diagnosis to treatment was 1 day (range, 0 to 22 days). Eight (17.4%) dogs did not undergo surgery and had RPS diagnosed on necropsy or nonsurgical biopsy. Four (8.7%) dogs had an exploratory laparotomy with only an incisional biopsy performed, 12 (26.1%) had cytoreductive surgical excision, and 22 (47.8%) had curative intent excision of the mass. The histopathologic margins were not consistently reported, so treatment groups were based on surgical intent and whether there was evidence of gross disease left behind at the time of surgery (cytoreductive group). Of the 38 dogs that underwent an exploratory laparotomy, procedures in addition to mass excision or biopsy included nephrectomy in 9 (23.7%) dogs, adrenalectomy in 5 (13.2%) dogs, and splenectomy in 8 (21.1%) dogs. Nephrectomy and/or adrenalectomy were performed due to association with the mass. The reason for splenectomy was not specified in all cases, but no additional splenic neoplasia was reported. Table 2 provides a summary of treatments received among the 46 dogs included, and Table 3 summarizes how many were included in each combined category of surgical treatment and chemotherapy.

Table 3

Summary of patients receiving surgical and chemotherapy treatment.

Chemotherapy Surgery
None (n = 8) Ex-lap + biopsy (n = 4) Cytoreductive (n = 12) Curative intent (n = 22)
None (n = 27) 7 2 7 11
IV (n = 17) 1 1 4 11
Metronomic (n = 2) 1 1 0

Ex-lap = Exploratory laparotomy.

Twelve of 38 (31.6%) dogs had intraoperative complications. Intraoperative hemorrhage occurred in 11 of 38 (28.9%) surgically treated dogs, including 5 grade 1, 3 grade 2, 1 grade 3, and 2 grade 4 hemorrhages. No dogs died during surgery. One dog with hemorrhage also had a grade 2 iatrogenic injury. One dog had a retained surgical sponge, considered a grade 3 postoperative complication on the basis of the need for repeat surgical intervention to retrieve the sponge.

Eight of 38 (21.1%) dogs had postoperative complications. These included the following: grade 1 anorexia (n = 1), grade 1 hyporexia (1), grade 2 surgical site infection (1), grade 2 anemia (1), grade 3 hypertension (1), grade 1 cough and grade 1 vomiting (1), grade 2 dehiscence and grade 2 surgical site infection (2), and grade 2 acute kidney injury (1). The dog with the grade 2 acute kidney injury had concurrent adrenalectomy and nephrectomy for excision of the RPS. No dogs died in the perioperative period, and all were discharged from the hospital.

Histopathologic diagnosis was made from evaluation of the excised mass in dogs that had surgery and from incisional biopsy and/or necropsy in dogs that did not have surgery. The most diagnosed sarcoma among the dogs included in the study was HSA, which was diagnosed in 35 of 46 (76.1%) dogs. Other diagnoses included soft tissue sarcomas in 5 (10.9%; including 3 malignant PNST, 1 perivascular wall tumor, and 1 undefined) dogs, anaplastic sarcoma in 2 (4.4%) dogs, and 1 each (2.2%) of extraskeletal osteosarcoma, leiomyosarcoma, myxosarcoma, and undifferentiated sarcoma. The histologic grade was only reported in 8 of 46 dogs; therefore, this information was not able to be evaluated for prognostic significance. In addition, published staging criteria for RPSs by the American Joint Committee on Cancer15 and the staging criteria used previously4 utilize the tumor grade for determining patient stage; therefore, clinical stage was not used for classification in this study.

Of the 46 dogs, 19 (41.3%) received chemotherapy; 17 (37.0%) received intravenous chemotherapy and 2 (4.3%) received metronomic oral chemotherapy (Tables 2 and 3). One of the 8 dogs that had no surgery or local therapy received a single dose of intravenous chemotherapy with doxorubicin following diagnosis of HSA from an incisional biopsy. None of the other dogs that had no surgery received any chemotherapy. Two dogs that had an exploratory laparotomy with incisional biopsy only received chemotherapy: one injectable doxorubicin and the other metronomic cyclophosphamide. Sixteen of the 34 dogs that had local therapy consisting of surgical excision (cytoreduction or curative intent) also received adjuvant chemotherapy. Table 3 summarizes the number of dogs receiving each combination of surgical and chemotherapy intervention. These dogs include 13 diagnosed with HSA, 1 dog diagnosed with extraskeletal osteosarcoma, and 1 dog diagnosed with PNST. The single dog diagnosed with extraskeletal osteosarcoma had cytoreductive surgery followed by adjuvant radiation therapy and chemotherapy with carboplatin. The radiation protocol consisted of 5 fractions of 8 Gy prescribed to > 99% of gross tumor volume over 5 consecutive business days. Two of the 4 dogs that underwent exploratory surgery without surgical excision received adjuvant chemotherapy (doxorubicin or cyclophosphamide metronomic for HSA); the other 2 dogs received no further treatment. Of the 17 dogs receiving intravenous chemotherapy, 16 were treated primarily with doxorubicin and one was treated with carboplatin. Dogs receiving metronomic chemotherapy-only protocols were given cyclophosphamide. Six dogs that received 5 doses of doxorubicin chemotherapy were later started on metronomic chemotherapy with cyclophosphamide (n = 4) or chlorambucil (2).

Outcome

Median follow-up time was 123 days (range, 0 to 948 days) for 32 dogs that died and 48 days (range, 2 to 713 days) for dogs that were lost to follow-up (Table 4). The intervals for restaging were not consistently reported and were highly variable for different patients; therefore, this is a possible confounding factor regarding disease progression. Fourteen (14/34 [41.2%]) of the 34 dogs with surgically excised tumors had evidence of local tumor recurrence. The median time to local recurrence was 150 days (range, 25 to 776 days). There was no difference in the incidence of local recurrence when comparing dogs that were categorized as curative intent excision versus cytoreductive excision (8/22 [36.4%] vs 6/12 [50.0%]; P > .99). Four surgically treated dogs with metastatic disease at the time of diagnosis developed evidence of progressive metastatic disease with a median time to progression of 203 days (range, 38 to 776 days). Seven surgically treated dogs without metastatic disease at the time of diagnosis developed new metastases, often to multiple sites. Sites of new metastases included the spleen (n = 3), liver (3), abdominal lymph nodes (2), peritoneum (2), subcutaneous tissue of a previous surgical site (2), lungs (2), and mesentery (1). The median time to developing new metastases was 73 days (range, 17 to 314 days). In the 14 dogs with local recurrence, 5 were euthanized at the time recurrence was diagnosed, 2 had additional surgical excision performed and additional metronomic chemotherapy with cyclophosphamide, 1 had a course of palliative radiotherapy, and the others received no treatment and were either lost to follow-up or euthanized at a later date. These additional treatments may have influenced the overall survival times for these dogs; however, analysis of these factors on survival was beyond the scope and statistical capability of this study. Median overall survival time of all 46 dogs was 238 days (95% CI, 119 to 429 days; Table 4). On unadjusted analysis, treatment approach was associated with survival (Figure 1; P < .001). The MST for 3 treatment groups, palliative treatment only, surgical excision only, and surgical excision with adjuvant chemotherapy, were calculated; however, the data were insufficient to determine 95% CI. The MST for palliative treatment only was 39 days. The MST for dogs undergoing surgical excision only was 119 days, and the MST for dogs undergoing surgical excision with adjuvant chemotherapy was 261 days. Multivariable Cox proportional hazards regression was used to evaluate prognostic factors for overall survival (Table 5). Sex and body weight were not associated with outcomes. Tumor size on imaging was not associated with overall survival. Diagnosis of HSA, treatment with surgical excision, and treatment with chemotherapy (combined injectable and metronomic) in addition to surgery were all prognostic for survival, whereas age and presence of metastasis at diagnosis were both confounders but not independent risk factors for survival. When adjusting for age and metastasis at diagnosis, a diagnosis of HSA was associated with greater hazard of death (HR, 4.08; 95% CI, 1.20 to 13.87; P = .024), whereas surgical excision (HR, 0.25; 95% CI, 0.07 to 0.83; P = .024) and adjuvant chemotherapy treatment following surgery (HR, 0.29; 95% CI, 0.10 to 0.81; P = .019) were protective against death (Figure 1). In summary, survival increased significantly (P = .001) when comparing dogs across the ordered treatment groups: palliative treatment only (NSAIDS, prednisone, and/or supportive medication), surgical excision only, and surgical excision with chemotherapy

Table 4

Summary of outcomes following treatment for retroperitoneal sarcomas.

Duration of follow-up
  Died 123 d (range, 0–948 d)
  Lost to follow-up 48 d (range, 2–713 d)
Progression
  Incidence of recurrence P > .99
   All surgically treated 14/34 (41.2%)
   Cytoreductive surgery 6/12 (50%)
   Curative intent surgery 8/22 (36.4%)
  Median time to recurrence 150 d (range, 25–776 d)
Incidence of progressive metastasis 4/9
Median time to progressive metastasis 203 d (range, 38–776 d)
Incidence of new metastasis 7/27
Median time to new metastasis 73 d (range, 17–314 d)
Median survival times*
  All 46 dogs 238 d (95% CI, 119–429 d)
  By tumor type P = .8
   HSA 238 d (95% CI, 138–501 d)
   Non-HSA tumors 255 d (95% CI, 13–697 d)
  By treatment group P < .001
   Palliative 39 d
   Surgical excision 119 d
   Surgical excision + chemotherapy 261 d

HSA = Hemangiosarcoma.

*Median survival times based on unadjusted univariable analysis.

Figure 1
Figure 1

Kaplan-Meier survival estimates according to treatment of retroperitoneal sarcomas. Survival increased significantly (P = .001) when comparing dogs across the ordered treatment groups: palliative treatment only, surgical excision only, and surgical excision with chemotherapy. The overall median survival time for all 46 dogs was 238 days (95% CI, 119 to 429 days). The median survival times for dogs undergoing palliative treatment, surgical excision only, and surgical excision with adjuvant chemotherapy were 39, 119, and 261 days, respectively.

Citation: Journal of the American Veterinary Medical Association 2024; 10.2460/javma.23.09.0507

Table 5

Multivariable Cox proportional hazards regression to evaluate prognostic factors for overall survival.

Variable Univariable analysis Multivariable analysis
Hazard ratio 95% CI P value Hazard ratio 95% CI P value
Age (y) 0.77 0.68–0.91 .001 0.59 0.68–1.01 .06
Body weight (kg) 0.99 0.96–1.04 .77
Male 0.99 0.45–2.18 .99
Metastasis at diagnosis 2.10 0.93–4.77 .08 1.98 0.81–4.88 .14
Diagnosis of HSA 1.12 0.47–2.66 .80 4.08 1.12–12.36 .024
Surgical excision 0.22 0.08–0.57 .002 0.25 0.07–0.83 .011
Adjuvant chemotherapy 0.44 0.20–0.96 .040 0.29 0.10–0.81 .019

HSA = Hemangiosarcoma.

Discussion

Historically, canine RPSs have been considered to have a poor prognosis, with treatment offering little benefit. Due to the large potential space of the retroperitoneum, RPSs often grow asymptomatically until their size begins to impact adjacent structures and multiorgan invasion occurs. Additionally, surgical resection is often technically challenging due to location and the potential for multiple organ involvement. In human medicine, different histologic subtypes have heterogenous behavior and response to treatment, making evidence-based guidelines for these rare tumors uncertain.

Most dogs diagnosed with RPS in this study had clinical signs at the time of diagnosis; however, clinical signs were typically nonspecific such as inappetence, lethargy, polyuria/polydipsia, abdominal pain, weight loss, vomiting, and diarrhea. It is likely that since the retroperitoneum is a large potential space, tumors often grow to a large size and are locally invasive before clinical signs are apparent. Of the 5 dogs without clinical signs, 3 had tumors that measured < 5 cm and the other 2 had tumors that measured 5 to 10 cm. Other clinical signs noted may be attributed to RPS size and mass effect on adjacent organs, including pelvic limb lameness, tenesmus, and stranguria. Four of the 5 dogs that were presented for lameness had pelvic limb lower motor neuron signs on physical examination, suggestive of sciatic neuropathy. In humans with RPS, a malignant PNST is typically suspected when neurologic signs are presented. In this series, 2 out of 4 dogs with pelvic limb lameness and neurologic deficits were diagnosed with a malignant PNST. The other 2 had HSA in the caudal abdomen; one was described on abdominal ultrasound as being confluent with the ventral margins of the caudal lumbar and sacral vertebral bodies, and the other had evidence of sacral lysis on abdominal radiographs (no additional imaging was performed).

Anemia was diagnosed in nearly 60% of dogs. In the 6 dogs with Hct between 20% and 30%, all were diagnosed with HSA; in the 16 dogs with Hct between 30% and 40%, 14 were diagnosed with HSA. Similar to HSA that is diagnosed in visceral locations, the potential for anemia is high, likely due to blood loss into or outside of the tumor.16,17 Eighteen out of 35 (51.4%) dogs diagnosed with HSA had evidence of cavitation within the mass or free fluid in the retroperitoneal space on abdominal ultrasound.

In this study, HSA was the most commonly diagnosed histologic type of RPS, representing 76.1% of cases. This is similar to the finding of the largest previous study, in which 64.3% of dogs were diagnosed with HSA.4 Anaplastic sarcoma and perivascular wall tumor have not been previously reported in the retroperitoneal space of dogs, to our knowledge.

In humans, curative intent en bloc surgical resection is generally recommended, despite complete excision being challenging. In humans, the appropriateness of resecting adjacent organs in RPS surgeries is controversial.18,19 In 1 study,20 84% of people who underwent resection of a primary RPS had at least 1 organ resected, most commonly kidney, colon, or adrenal gland. Reasoning for organ resection typically includes tumor adherence, organ encasement, suspected invasion, or involvement of end-organ vasculature. In humans, it has been documented that even incomplete resection offers a survival benefit in patients with RPS considered to be nonresectable.18 In the present study, 9 of 38 (23.7%) dogs had concurrent nephrectomy and 5 of 38 (13.2%) dogs had concurrent adrenalectomy to facilitate tumor excision. Stahl et al21 demonstrated a higher risk of postoperative acute kidney injury or acute renal failure in humans who had a nephrectomy with RPS resection; 1 patient in the present study that had a concurrent nephrectomy and adrenalectomy at the time of surgical excision had a grade 2 acute kidney injury postoperatively.

In humans, local recurrence of RPS is common, with about 50% of patients developing recurrence within 5 years22; however, recurrence is known to vary with histologic type.12 Local recurrence is the primary cause of mortality in RPS with up to 75% of mortalities occurring without evidence of distant metastasis.23 In this study, 14 of 38 (36.8%) dogs with surgically excised tumors had local recurrence, but there was no difference in local recurrence when comparing dogs categorized as having curative intent surgical excision versus cytoreductive surgery. The histopathologic margins were not reported for many of these cases, and there was insufficient data to compare recurrence on the basis of histopathologic margins. Therefore, it is possible that this may influence recurrence rate but was not reflected in the dataset. In addition, the intervals for restaging were not consistently reported and were highly variable for different patients; therefore, this is a possible confounding factor regarding disease progression. In the human literature, there is inconsistency in the data regarding the impact of complete versus incomplete margins on the incidence of local recurrence.12,24

In contrast to what has been demonstrated in humans, for which adjuvant chemotherapy has not demonstrated a benefit to local recurrence rates or improved overall survival time,19,25 adjuvant chemotherapy was protective against death in the dogs of this study. Soft tissue sarcomas are typically considered to have poor response to systemic chemotherapy; however, other histologic types of RPS, including high-grade dedifferentiated liposarcomas, leiomyosarcoma, and undifferentiated pleomorphic sarcoma, may be more chemosensitive.26 Doxorubicin is the most commonly used agent for treatment of RPS in both humans and dogs. The demonstrated benefit of adjuvant chemotherapy shown in this study may be due to the significantly higher proportion of HSA diagnosed in dogs, as doxorubicin chemotherapy is typically recommended due to demonstrated survival benefit2729 for HSA in other locations. These findings suggest that adjuvant chemotherapy may play a role in dogs diagnosed with RPS after surgical resection. Further studies will be required to fully evaluate this.

The role of radiation therapy in the treatment of RPS in humans and dogs is still under investigation. Concerns regarding preoperative radiation therapy include adverse damage to nearby structures, increased postoperative complications, and failure to undergo curative surgery due to disease progression or treatment complications.25 Alternatively, benefits of preoperative radiation may include improved margin-negative resection rates, a more clearly defined tumor in situ, improved oxygenation of the tumor while receiving radiation therapy, and lower total doses to smaller treatment volume, which can reduce late side effects. Preoperative radiotherapy with selective augmentation on the margins at highest risk for recurrence has been shown to be safe and advantageous for nonresectable tumors in humans.30 However, in a randomized prospective phase 3 study of 266 people, Bonvalot et al31 showed no improvement in recurrence-free survival when preoperative radiotherapy was performed prior to surgery compared to surgery alone; the authors concluded that preoperative radiotherapy should not be considered as standard-of-care treatment for RPS. The role of radiotherapy in the treatment of RPSs in dogs is virtually unknown due to the small number of dogs that have received radiotherapy.

In this study, the MST was substantially longer (238 days), as compared to the previous largest study of RPS (37.5 days).4 Factors found to positively influence prognosis included treatment with surgery and treatment with chemotherapy in addition to surgery. The only factor found to negatively influence prognosis was diagnosis of HSA. In the current study, a similar percentage of dogs underwent surgical excision (82.6%) compared to the previous report on RPS (85.7%)4; however, a slightly higher percentage of dogs that underwent surgical excision had curative intent excision (vs cytoreductive surgery) in the current study (57.8%) compared to the previous report (50%). The previously reported MST was calculated on the basis of time from surgical intervention to death; however, we calculated survival from the time of diagnosis. While this may have influenced the reported MST, the median time from diagnosis to treatment was 1 day (range, 0 to 22 days), so it is unlikely this had a significant influence. Other theories for improved survival found in the current study include diagnosis earlier in the course of disease, a larger proportion of dogs receiving adjuvant chemotherapy, and greater availability of highly trained veterinary surgeons. It is relevant to note that the patients reported in the previous study were treated 8 to 28 years earlier than the patients included in the present study. The reported greater survival is likely, in part, a reflection of changing attitudes of owners to treat advanced cancers with surgery and chemotherapy and greater access to specialty veterinary care for diagnostics and oncologic treatment.

Limitations of the current study were mostly related to the retrospective nature, including potential lack of available clinical data, loss to follow-up, and disparity in how data were recorded. In addition, the small number of cases included for histologic subtypes of RPS other than HSA introduced limitations in statistical evaluations and may have increased potential for error. For example, with the small number of dogs diagnosed with RPS other than HSA, there was not sufficient statistical power to evaluate whether the response to chemotherapy varies between tumor type, which is an important question to guide adjuvant therapy. The requirement for a histologic diagnosis of RPS for inclusion may have also created selection bias, as those with more invasive-appearing tumors or extensive metastatic disease may have been less likely to have biopsy, excision, or necropsy. Thus, some of the dogs with worse outcomes may not have been appropriately represented in this dataset. Lastly, while a multi-institutional approach has many benefits, there may also be disparity in how dogs were treated.

This study was the largest to date evaluating dogs with RPS, and important information related to treatment and outcomes was obtained. Given the greater survival time demonstrated in this study, treatment of dogs with RPS should be considered. Further investigation into alternative treatment options is warranted. Additional questions to consider include time to recurrence, survival times for various histologic types of RPS in comparison to HSA, the role of adjuvant radiation therapy in dogs with incomplete surgical resection, and the role of varying chemotherapeutic regimens.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org.

Acknowledgments

None reported.

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.

References

  • 1.

    Johnston DE. The retroperitoneum in dogs: anatomy and clinical significance. Compend Contin Educ Pract Vet. 1990;12:1027-1033.

  • 2.

    Choi JH, Ro JY. Retroperitoneal sarcomas: an update on the diagnostic pathology approach. Diagnostics (Basel). 2020;10(9):642. doi:10.3390/diagnostics10090642

    • Search Google Scholar
    • Export Citation
  • 3.

    Herman K, Kusy T. Retroperitoneal sarcoma-the continued challenge for surgery and oncology. Surg Oncol. 1998;7(1-2):77-81. doi:10.1016/s0960-7404(99)00002-x

    • Search Google Scholar
    • Export Citation
  • 4.

    Liptak JM, Dernell WS, Ehrhart EJ, Rizzo SA, Rooney MB, Withrow SJ. Retroperitoneal sarcomas in dogs: 14 cases (1992-2002). J Am Vet Med Assoc. 2004;224(9):1471-1477. doi:10.2460/javma.2004.224.1471

    • Search Google Scholar
    • Export Citation
  • 5.

    Jones JC, Rossmeisl JH, Waldron DR, Tromblee TC. Retroperitoneal hemangiosarcoma causing chronic hindlimb lameness in a dog. Vet Comp Orthop Traumatol. 2007;20(4):335-339. doi:10.1160/vcot-06-12-0097

    • Search Google Scholar
    • Export Citation
  • 6.

    Munday JS, Prahl A. Retroperitoneal extraskeletal mesenchymal chondrosarcoma in a dog. J Vet Diagn Invest. 2002;14(6):498-500. doi:10.1177/104063870201400609

    • Search Google Scholar
    • Export Citation
  • 7.

    Salm R, Mayes SE. Retroperitoneal osteosarcoma in a dog. Vet Rec. 1969;85(23):651-653.

  • 8.

    Vanhaesebrouck AE, Maes S, Van Soens I, Baeumlin Y, Saey V, Van Ham LM. Bilateral obturator neuropathy caused by an intrapelvic fibrosarcoma with myofibroblastic features in a dog. J Small Anim Pract. 2012;53(7):423-427. doi:10.1111/j.1748-5827.2012.01225.x

    • Search Google Scholar
    • Export Citation
  • 9.

    Yap FW, Huizing XB, Rasotto R, Bowlt-Blacklock KL. Primary ureteral leiomyosarcoma in a dog. Aust Vet J. 2017;95(3):68-71. doi:10.1111/avj.12538

    • Search Google Scholar
    • Export Citation
  • 10.

    Gladdy RA, Gupta A, Catton CN. Retroperitoneal sarcoma: fact, opinion, and controversy. Surg Oncol Clin N Am. 2016;25(4):697-711. doi:10.1016/j.soc.2016.05.003

    • Search Google Scholar
    • Export Citation
  • 11.

    von Mehren M, Kane JM, Agulnik M, et al. Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(7):815-833. doi:10.6004/jnccn.2022.0035

    • Search Google Scholar
    • Export Citation
  • 12.

    Gronchi A, Strauss DC, Miceli R, et al. Variability in patterns of recurrence after resection of primary retroperitoneal sarcoma (RPS): a report on 1007 patients from the multi-institutional collaborative RPS working group. Ann Surg. 2016;263(5):1002-1009. doi:10.1097/SLA.0000000000001447

    • Search Google Scholar
    • Export Citation
  • 13.

    Ichimata M, Toshima A, Matsuyama F, et al. Clinical features and prognosis of retroperitoneal hemangiosarcoma in dogs with surgical resection with or without adjuvant doxorubicin. J Vet Med Sci. 2023;85(11):1231-1236. doi:10.1292/jvms.22-0533

    • Search Google Scholar
    • Export Citation
  • 14.

    LeBlanc AK, Atherton M, Bentley RT, et al. Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats. Vet Comp Oncol. 2021;19(2):311-352. doi:10.1111/vco.12677

    • Search Google Scholar
    • Export Citation
  • 15.

    Fisher SB, Chiang YJ, Feig BW, et al. An evaluation of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for retroperitoneal sarcomas using the National Cancer Data Base (NCDB): does size matter? Am J Clin Oncol 2019;42:160-165.

    • Search Google Scholar
    • Export Citation
  • 16.

    Masyr AR, Rendahl AK, Winter AL, Borgatti A, Modiano JF. Retrospective evaluation of thrombocytopenia and tumor stage as prognostic indicators in dogs with splenic hemangiosarcoma. J Am Vet Med Assoc. 2021;258(6):630-637. doi:10.2460/javma.258.6.630

    • Search Google Scholar
    • Export Citation
  • 17.

    Moore AS, Rassnick KM, Frimberger AE. Evaluation of clinical and histologic factors associated with survival time in dogs with stage II splenic hemangiosarcoma treated by splenectomy and adjuvant chemotherapy: 30 cases (2011-2014). J Am Vet Med Assoc. 2017;251(5):559-565. doi:10.2460/javma.251.5.559

    • Search Google Scholar
    • Export Citation
  • 18.

    Guo Q, Zhao J, Du X, Huang B. Survival outcomes of surgery for retroperitoneal sarcomas: a systematic review and meta-analysis. PLoS One. 2022;17(7):e0272044. doi:10.1371/journal.pone.0272044

    • Search Google Scholar
    • Export Citation
  • 19.

    Spillane AJ. Retroperitoneal sarcoma: time for a change in attitude? ANZ J Surg. 2001;71(5):303-308. doi:10.1046/j.1440-1622.2001.02109.x

    • Search Google Scholar
    • Export Citation
  • 20.

    Fairweather M, Wang J, Jo VY, Baldini EH, Bertagnolli MM, Raut CP. Surgical management of primary retroperitoneal sarcomas: rationale for selective organ resection. Ann Surg Oncol. 2018;25(1):98-106. doi:10.1245/s10434-017-6136-4

    • Search Google Scholar
    • Export Citation
  • 21.

    Stahl CC, Schwartz PB, Ethun CG, et al. Renal function after retroperitoneal sarcoma resection with nephrectomy: a matched analysis of the United States Sarcoma Collaborative Database. Ann Surg Oncol. 2021;28(3):1690-1696. doi:10.1245/s10434-020-09290-z

    • Search Google Scholar
    • Export Citation
  • 22.

    Trans-Atlantic RPS Working Group. Management of recurrent retroperitoneal sarcoma (RPS) in the adult: a consensus approach from the Trans-Atlantic RPS Working Group. Ann Surg Oncol. 2016;23(11):3531-3540. doi:10.1245/s10434-016-5336-7

    • Search Google Scholar
    • Export Citation
  • 23.

    Raut CP, Callegaro D, Miceli R, et al. Predicting survival in patients undergoing resection for locally recurrent retroperitoneal sarcoma: a study and novel nomogram from TARPSWG. Clin Cancer Res. 2019;25(8):2664-2671. doi:10.1158/1078-0432.CCR-18-2700

    • Search Google Scholar
    • Export Citation
  • 24.

    Alvarenga J-C, Ball ABS, Fisher C, Fryatt I, Jones L, Thomas JM. Limitations of surgery in the treatment of retroperitoneal sarcoma. Br J Surg. 1991;78(8):912-916. doi:10.1002/bjs.1800780806

    • Search Google Scholar
    • Export Citation
  • 25.

    Carbone F, Pizzolorusso A, Di Lorenzo G, et al. Multidisciplinary management of retroperitoneal sarcoma: diagnosis, prognostic factors and treatment. Cancers (Basel). 2021;13(16):4016. doi:10.3390/cancers13164016

    • Search Google Scholar
    • Export Citation
  • 26.

    Casali PG, Abecassis N, Aro HT, et al.; ESMO Guidelines Committee and EURACAN. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(suppl 4):iv51-iv67. doi:10.1093/annonc/mdy096

    • Search Google Scholar
    • Export Citation
  • 27.

    Clifford CA, Mackin AJ, Henry CJ. Treatment of canine hemangiosarcoma: 2000 and beyond. J Vet Intern Med. 2000;14(5):479-485. doi:10.1892/0891-6640(2000)014<0479:tochab>2.3.co;2

    • Search Google Scholar
    • Export Citation
  • 28.

    Ogilvie GK, Powers BE, Mallinckrodt CH, Withrow SJ. Surgery and doxorubicin in dogs with hemangiosarcoma. J Vet Intern Med. 1996;10(6):379-384. doi:10.1111/j.1939-1676.1996.tb02085.x

    • Search Google Scholar
    • Export Citation
  • 29.

    Story AL, Wavreille V, Abrams B, Egan A, Cray M, Selmic LE. Outcomes of 43 small breed dogs treated for splenic hemangiosarcoma. Vet Surg. 2020;49(6):1154-1163. doi:10.1111/vsu.13470

    • Search Google Scholar
    • Export Citation
  • 30.

    Tzeng CW, Fiveash JB, Popple RA, et al. Preoperative radiation therapy with selective dose escalation to the margin at risk for retroperitoneal sarcoma. Cancer. 2006;107(2):371-379. doi:10.1002/cncr.22005

    • Search Google Scholar
    • Export Citation
  • 31.

    Bonvalot S, Gronchi A, Le Péchoux C, et al. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(10):1366-1377. doi:10.1016/S1470-2045(20)30446-0

    • Search Google Scholar
    • Export Citation

Supplementary Materials

  • Figure 1

    Kaplan-Meier survival estimates according to treatment of retroperitoneal sarcomas. Survival increased significantly (P = .001) when comparing dogs across the ordered treatment groups: palliative treatment only, surgical excision only, and surgical excision with chemotherapy. The overall median survival time for all 46 dogs was 238 days (95% CI, 119 to 429 days). The median survival times for dogs undergoing palliative treatment, surgical excision only, and surgical excision with adjuvant chemotherapy were 39, 119, and 261 days, respectively.

  • 1.

    Johnston DE. The retroperitoneum in dogs: anatomy and clinical significance. Compend Contin Educ Pract Vet. 1990;12:1027-1033.

  • 2.

    Choi JH, Ro JY. Retroperitoneal sarcomas: an update on the diagnostic pathology approach. Diagnostics (Basel). 2020;10(9):642. doi:10.3390/diagnostics10090642

    • Search Google Scholar
    • Export Citation
  • 3.

    Herman K, Kusy T. Retroperitoneal sarcoma-the continued challenge for surgery and oncology. Surg Oncol. 1998;7(1-2):77-81. doi:10.1016/s0960-7404(99)00002-x

    • Search Google Scholar
    • Export Citation
  • 4.

    Liptak JM, Dernell WS, Ehrhart EJ, Rizzo SA, Rooney MB, Withrow SJ. Retroperitoneal sarcomas in dogs: 14 cases (1992-2002). J Am Vet Med Assoc. 2004;224(9):1471-1477. doi:10.2460/javma.2004.224.1471

    • Search Google Scholar
    • Export Citation
  • 5.

    Jones JC, Rossmeisl JH, Waldron DR, Tromblee TC. Retroperitoneal hemangiosarcoma causing chronic hindlimb lameness in a dog. Vet Comp Orthop Traumatol. 2007;20(4):335-339. doi:10.1160/vcot-06-12-0097

    • Search Google Scholar
    • Export Citation
  • 6.

    Munday JS, Prahl A. Retroperitoneal extraskeletal mesenchymal chondrosarcoma in a dog. J Vet Diagn Invest. 2002;14(6):498-500. doi:10.1177/104063870201400609

    • Search Google Scholar
    • Export Citation
  • 7.

    Salm R, Mayes SE. Retroperitoneal osteosarcoma in a dog. Vet Rec. 1969;85(23):651-653.

  • 8.

    Vanhaesebrouck AE, Maes S, Van Soens I, Baeumlin Y, Saey V, Van Ham LM. Bilateral obturator neuropathy caused by an intrapelvic fibrosarcoma with myofibroblastic features in a dog. J Small Anim Pract. 2012;53(7):423-427. doi:10.1111/j.1748-5827.2012.01225.x

    • Search Google Scholar
    • Export Citation
  • 9.

    Yap FW, Huizing XB, Rasotto R, Bowlt-Blacklock KL. Primary ureteral leiomyosarcoma in a dog. Aust Vet J. 2017;95(3):68-71. doi:10.1111/avj.12538

    • Search Google Scholar
    • Export Citation
  • 10.

    Gladdy RA, Gupta A, Catton CN. Retroperitoneal sarcoma: fact, opinion, and controversy. Surg Oncol Clin N Am. 2016;25(4):697-711. doi:10.1016/j.soc.2016.05.003

    • Search Google Scholar
    • Export Citation
  • 11.

    von Mehren M, Kane JM, Agulnik M, et al. Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(7):815-833. doi:10.6004/jnccn.2022.0035

    • Search Google Scholar
    • Export Citation
  • 12.

    Gronchi A, Strauss DC, Miceli R, et al. Variability in patterns of recurrence after resection of primary retroperitoneal sarcoma (RPS): a report on 1007 patients from the multi-institutional collaborative RPS working group. Ann Surg. 2016;263(5):1002-1009. doi:10.1097/SLA.0000000000001447

    • Search Google Scholar
    • Export Citation
  • 13.

    Ichimata M, Toshima A, Matsuyama F, et al. Clinical features and prognosis of retroperitoneal hemangiosarcoma in dogs with surgical resection with or without adjuvant doxorubicin. J Vet Med Sci. 2023;85(11):1231-1236. doi:10.1292/jvms.22-0533

    • Search Google Scholar
    • Export Citation
  • 14.

    LeBlanc AK, Atherton M, Bentley RT, et al. Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats. Vet Comp Oncol. 2021;19(2):311-352. doi:10.1111/vco.12677

    • Search Google Scholar
    • Export Citation
  • 15.

    Fisher SB, Chiang YJ, Feig BW, et al. An evaluation of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for retroperitoneal sarcomas using the National Cancer Data Base (NCDB): does size matter? Am J Clin Oncol 2019;42:160-165.

    • Search Google Scholar
    • Export Citation
  • 16.

    Masyr AR, Rendahl AK, Winter AL, Borgatti A, Modiano JF. Retrospective evaluation of thrombocytopenia and tumor stage as prognostic indicators in dogs with splenic hemangiosarcoma. J Am Vet Med Assoc. 2021;258(6):630-637. doi:10.2460/javma.258.6.630

    • Search Google Scholar
    • Export Citation
  • 17.

    Moore AS, Rassnick KM, Frimberger AE. Evaluation of clinical and histologic factors associated with survival time in dogs with stage II splenic hemangiosarcoma treated by splenectomy and adjuvant chemotherapy: 30 cases (2011-2014). J Am Vet Med Assoc. 2017;251(5):559-565. doi:10.2460/javma.251.5.559

    • Search Google Scholar
    • Export Citation
  • 18.

    Guo Q, Zhao J, Du X, Huang B. Survival outcomes of surgery for retroperitoneal sarcomas: a systematic review and meta-analysis. PLoS One. 2022;17(7):e0272044. doi:10.1371/journal.pone.0272044

    • Search Google Scholar
    • Export Citation
  • 19.

    Spillane AJ. Retroperitoneal sarcoma: time for a change in attitude? ANZ J Surg. 2001;71(5):303-308. doi:10.1046/j.1440-1622.2001.02109.x

    • Search Google Scholar
    • Export Citation
  • 20.

    Fairweather M, Wang J, Jo VY, Baldini EH, Bertagnolli MM, Raut CP. Surgical management of primary retroperitoneal sarcomas: rationale for selective organ resection. Ann Surg Oncol. 2018;25(1):98-106. doi:10.1245/s10434-017-6136-4

    • Search Google Scholar
    • Export Citation
  • 21.

    Stahl CC, Schwartz PB, Ethun CG, et al. Renal function after retroperitoneal sarcoma resection with nephrectomy: a matched analysis of the United States Sarcoma Collaborative Database. Ann Surg Oncol. 2021;28(3):1690-1696. doi:10.1245/s10434-020-09290-z

    • Search Google Scholar
    • Export Citation
  • 22.

    Trans-Atlantic RPS Working Group. Management of recurrent retroperitoneal sarcoma (RPS) in the adult: a consensus approach from the Trans-Atlantic RPS Working Group. Ann Surg Oncol. 2016;23(11):3531-3540. doi:10.1245/s10434-016-5336-7

    • Search Google Scholar
    • Export Citation
  • 23.

    Raut CP, Callegaro D, Miceli R, et al. Predicting survival in patients undergoing resection for locally recurrent retroperitoneal sarcoma: a study and novel nomogram from TARPSWG. Clin Cancer Res. 2019;25(8):2664-2671. doi:10.1158/1078-0432.CCR-18-2700

    • Search Google Scholar
    • Export Citation
  • 24.

    Alvarenga J-C, Ball ABS, Fisher C, Fryatt I, Jones L, Thomas JM. Limitations of surgery in the treatment of retroperitoneal sarcoma. Br J Surg. 1991;78(8):912-916. doi:10.1002/bjs.1800780806

    • Search Google Scholar
    • Export Citation
  • 25.

    Carbone F, Pizzolorusso A, Di Lorenzo G, et al. Multidisciplinary management of retroperitoneal sarcoma: diagnosis, prognostic factors and treatment. Cancers (Basel). 2021;13(16):4016. doi:10.3390/cancers13164016

    • Search Google Scholar
    • Export Citation
  • 26.

    Casali PG, Abecassis N, Aro HT, et al.; ESMO Guidelines Committee and EURACAN. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(suppl 4):iv51-iv67. doi:10.1093/annonc/mdy096

    • Search Google Scholar
    • Export Citation
  • 27.

    Clifford CA, Mackin AJ, Henry CJ. Treatment of canine hemangiosarcoma: 2000 and beyond. J Vet Intern Med. 2000;14(5):479-485. doi:10.1892/0891-6640(2000)014<0479:tochab>2.3.co;2

    • Search Google Scholar
    • Export Citation
  • 28.

    Ogilvie GK, Powers BE, Mallinckrodt CH, Withrow SJ. Surgery and doxorubicin in dogs with hemangiosarcoma. J Vet Intern Med. 1996;10(6):379-384. doi:10.1111/j.1939-1676.1996.tb02085.x

    • Search Google Scholar
    • Export Citation
  • 29.

    Story AL, Wavreille V, Abrams B, Egan A, Cray M, Selmic LE. Outcomes of 43 small breed dogs treated for splenic hemangiosarcoma. Vet Surg. 2020;49(6):1154-1163. doi:10.1111/vsu.13470

    • Search Google Scholar
    • Export Citation
  • 30.

    Tzeng CW, Fiveash JB, Popple RA, et al. Preoperative radiation therapy with selective dose escalation to the margin at risk for retroperitoneal sarcoma. Cancer. 2006;107(2):371-379. doi:10.1002/cncr.22005

    • Search Google Scholar
    • Export Citation
  • 31.

    Bonvalot S, Gronchi A, Le Péchoux C, et al. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(10):1366-1377. doi:10.1016/S1470-2045(20)30446-0

    • Search Google Scholar
    • Export Citation

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