Adverse events and outcomes in dogs with appendicular osteosarcoma treated with limb amputation and a single subcutaneous infusion of carboplatin

Alessandra C. Santamaria 1Southpaws Specialty Surgery for Animals, 3 Roper St, Moorabbin, VIC 3189, Australia.

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James O. Simcock 1Southpaws Specialty Surgery for Animals, 3 Roper St, Moorabbin, VIC 3189, Australia.

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Charles A. Kuntz 1Southpaws Specialty Surgery for Animals, 3 Roper St, Moorabbin, VIC 3189, Australia.

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Abstract

OBJECTIVE

To evaluate adverse events and outcomes in dogs with appendicular osteosarcoma treated with limb amputation followed by a single SC infusion of carboplatin.

ANIMALS

45 client-owned dogs with appendicular osteosarcoma treated with limb amputation and SC infusion of carboplatin between January 1, 2006, and January 15, 2017.

PROCEDURES

Medical records were reviewed, and data collected included signalment, tumor location, treatment, results of clinicopathologic analyses and diagnostic imaging, adverse effects of chemotherapy, metastasis-free interval, survival time, and communications with owners and referring veterinarians. Findings were evaluated with the Kaplan-Meier survival analysis and Mantel-Haenszel log-rank test.

RESULTS

45 dogs were identified that met the inclusion criteria (12 of the 45 dogs had been reported in a previous case series). No dogs had pulmonary metastases detectable by CT or radiography before treatment. All dogs completed the protocol as planned. Median survival time (MST) was 196 days; metastasis-free interval was 197 days. Three of the 45 (7%) dogs required hospitalization for gastrointestinal signs related to chemotherapy. There were no chemotherapy-related deaths.

CONCLUSIONS AND CLINICAL RELEVANCE

Results indicated that although treatment with SC infusion of carboplatin was well tolerated, the MST for dogs in the present study was similar to reported MSTs in dogs with appendicular osteosarcoma treated with limb amputation alone and was in the lower range of historically reported survival times for dogs receiving IV adjunctive chemotherapy. Therefore, we could not recommend this protocol of SC infusion of carboplatin but recommended that protocols with IV administration of carboplatin be used instead.

Abstract

OBJECTIVE

To evaluate adverse events and outcomes in dogs with appendicular osteosarcoma treated with limb amputation followed by a single SC infusion of carboplatin.

ANIMALS

45 client-owned dogs with appendicular osteosarcoma treated with limb amputation and SC infusion of carboplatin between January 1, 2006, and January 15, 2017.

PROCEDURES

Medical records were reviewed, and data collected included signalment, tumor location, treatment, results of clinicopathologic analyses and diagnostic imaging, adverse effects of chemotherapy, metastasis-free interval, survival time, and communications with owners and referring veterinarians. Findings were evaluated with the Kaplan-Meier survival analysis and Mantel-Haenszel log-rank test.

RESULTS

45 dogs were identified that met the inclusion criteria (12 of the 45 dogs had been reported in a previous case series). No dogs had pulmonary metastases detectable by CT or radiography before treatment. All dogs completed the protocol as planned. Median survival time (MST) was 196 days; metastasis-free interval was 197 days. Three of the 45 (7%) dogs required hospitalization for gastrointestinal signs related to chemotherapy. There were no chemotherapy-related deaths.

CONCLUSIONS AND CLINICAL RELEVANCE

Results indicated that although treatment with SC infusion of carboplatin was well tolerated, the MST for dogs in the present study was similar to reported MSTs in dogs with appendicular osteosarcoma treated with limb amputation alone and was in the lower range of historically reported survival times for dogs receiving IV adjunctive chemotherapy. Therefore, we could not recommend this protocol of SC infusion of carboplatin but recommended that protocols with IV administration of carboplatin be used instead.

Osteosarcoma comprises 85% of all primary bone tumors in dogs, with approximately 75% of occurrences in the appendicular skeleton.1 For dogs with primary osteosarcoma, treatment may be nonsurgical (palliative medical treatment [MST, < 3 months] or radiation treatment [MST, 4 to 10 months]2–4) or surgical (amputation or limb salvage surgery alone [MST, 4 to 6 months5–7] or with adjuvant chemotherapy with platinum-based drugs or other chemotherapeutic agents such as doxorubicin alone or in combination [MST, 8 to 18 months8,9]). Although chemotherapeutic agents are usually administered by IV injection, slow-release chemotherapy delivery systems, such as biodegradable polymers soaked with cisplatin, have also been described.10–13 The advantage of slow-release chemotherapy is its minimization of potential systemic toxic effects while maintaining efficacy. However, SC infusion of carboplatin was postulated to provide similar slow-release benefits when administered as an adjunct to amputation in 17 dogs with osteosarcoma. The authors reported comparable chemotherapy-related adverse events and an MST of 365 days.14

The purpose of the present study was to evaluate adverse events and outcomes in dogs with appendicular osteosarcoma treated with amputation and a single SC infusion of carboplatin. Our hypothesis was that the MST following limb amputation and SC administration of carboplatin would be equivalent to historically reported MSTs following limb amputation and IV chemotherapeutic protocols for osteosarcoma in dogs but with fewer adverse events related to chemotherapy.

Materials and Methods

Animals

A computerized search of the Southpaws Specialty Surgery for Animals medical records was performed to retrospectively identify dogs in which appendicular osteosarcoma had been diagnosed between January 1, 2006, and January 15, 2017. Dogs were eligible for inclusion if they had appendicular osteosarcoma without detectable metastases on thoracic radiography or CT, underwent limb amputation followed by a single SC infusion of carboplatin, and had a histologically confirmed diagnosis of osteosarcoma.

Treatments and monitoring

Preoperative imaging (thoracic radiography or CT) and routine hematologic and serum biochemical analyses were performed in all dogs. Amputation of the affected limb was performed by veterinary surgeons certified by the American College of Veterinary Surgeons or by surgery residents. All thoracic limb amputations were performed by forequarter amputation, and all pelvic limb amputations were performed by coxofemoral disarticulation as previously described.15 Premedication, anesthesia, and postoperative analgesia were the same as previously described.14 Histologic evaluation was performed on all resected bone specimens.

In conjunction with the amputation procedure, a sterile 8F urinary cathetera was surgically placed in each dog for the delivery of the SC infusion of carboplatin.b For dogs that underwent thoracic limb amputation, the catheter was placed subcutaneously in the surgical site prior to closure, whereas for dogs that underwent pelvic limb amputation, the catheter was placed subcutaneously between the scapulae through a surgical incision immediately following the limb amputation. The catheter was then covered with an adhesive dressing.

Following surgery, each dog received a single SC infusion of carboplatin (300 mg/m2 total) diluted in 5% glucose solution per the manufacturer's recommendations and delivered through the surgically placed catheter. The infusion was started within 24 hours after recovery from anesthesia and was administered with a constant rate infusion pump.c

Owners and hospital personnel were educated in chemotherapy safety, with a focus on minimizing personal exposure and environmental contamination. Protocols implemented were based on human hospital guidelines.16,17 After the infusion was completed, the infusion pump and catheter were removed by the attending veterinarian, and skin staples were placed to close the surgical wound. Routine hematologic evaluation was performed at 14 and 21 days after the initiation of carboplatin infusion and, if indicated, at other time points during the immediate 5 weeks following treatment. Dogs were monitored during and after carboplatin administration for signs of any adverse events.

Data collection

Medical records of dogs that met the inclusion criteria were reviewed. Information collected included signalment (eg, age, sex, and breed), tumor location, preoperative serum ALP activity, duration of carboplatin infusion, results of hematologic and biochemical analyses before and after treatment, postoperative wound infection, development adverse events (eg, anorexia, vomiting, diarrhea, neutropenia, and thrombocytopenia) related to chemotherapy, MFI, survival time, and communications with owners and referring veterinarians. Adverse events that affected either or both the bone marrow (determined on the basis of hematologic findings) and gastrointestinal system were graded.18 Suspected postoperative wound infection was defined as the development of discharge or a draining sinus from the surgical incision at any time following surgery. Metastasis-free interval was defined as the number of days from the date when the SC infusion of carboplatin was initiated to the date when metastasis was suspected on the basis of results from diagnostic imaging or other assessments. Survival time was defined as the number of days from the date that the SC infusion of carboplatin was initiated to the date of death or last follow-up. All deaths, regardless of cause, were considered to have been related to osteosarcoma.

Statistical analysis

Data for continuous variables were expressed as mean ± SD or median (IQR), depending on the distribution, and data for categorical variables were expressed as percentages. Variables reported to be prognostic for survival time or MFI in a previous study,1 including age (≤ 5 years vs > 5 years), serum ALP activity (within vs above the reference interval), tumor location (proximal aspect of the humerus vs other appendicular sites), breed (Rottweiler vs all other breeds), and suspected infection (present vs absent), were evaluated with Kaplan-Meier survival analysis and the Mantel-Haenszel log-rank test. Dogs were censored for survival analysis if they were still alive at the study census date or at the date they were lost to follow-up. Multivariate Cox regression analysis19 was also performed. All analyses were performed with available software,d and values of P < 0.05 were considered significant.

Results

Animals

Through a search of the medical records, 45 dogs were identified that met the inclusion criteria. Data, including outcomes, for 12 of the 45 dogs had been reported in a case series14 of 17 dogs treated with the same protocol of SC infusion of carboplatin; however, the remaining 5 of those 17 dogs did not meet the inclusion criteria for the present study because they underwent limb-salvage surgery (n = 3), had incomplete histologic data (1), or underwent contrast-enhanced radiation treatment before limb amputation and chemotherapy (1).

Of the 45 included dogs, there were 22 castrated males, 19 spayed females, and 4 sexually intact males. There were 13 Rottweilers, 9 mixed-breed dogs, 5 Labrador Retrievers, 4 Greyhounds, 2 Staffordshire Bull Terriers, 2 Boxers, and 1 each of Cavalier King Charles Spaniel, American Bulldog, Pyrenean Mastiff, Alaskan Malamute, Hungarian Wire-Haired Vizsla, Bull Terrier, Australian Cattle Dog, Giant Schnauzer, Borzoi, and Rhodesian Ridgeback. The mixed-breed dogs included 3 Labrador Retriever crosses, 2 Rottweiler crosses, and 1 each of Staffordshire Bull Terrier cross, Great Dane cross, Mastiff cross, and Golden Retriever-Poodle cross. The median age was 8.0 years (range, 1.0 to 13.0 years), and the median body weight was 37.3 kg (82.1 lb; range, 9.2 to 59.0 kg [20.2 to 129.8 lb]).

Treatment

Presurgical thoracic imaging techniques used to evaluate for metastases were CT (n = 39) or thoracic radiography (6). Bones affected with osteosarcoma included the humerus (n = 21; 19 proximally and 2 distally), radius (9 distally), femur (8; 6 distally and 2 proximally), tibia (6; 3 proximally and 3 distally), and ulna (3 distally). Thoracic limb amputation was performed in 31 dogs, and pelvic limb amputation was performed in 14 dogs.

Following recovery, but within 24 hours after surgery, a single SC infusion of carboplatin (300 mg/m2 total) diluted in 5% glucose solution, the volume of which ranged from 9.14 to 51.0 mL on the basis of body size and infusion duration, was initiated through the surgically placed catheter. The rate of infusion was 13 mL/d for all dogs. Median duration of the SC infusion of carboplatin was 4 days (range, 3 to 7 days), and individual infusion durations were 3 days (n = 16), 4 days (23), 5 days (1), or 7 days (5). Initially, dogs were discharged from the hospital with the carboplatin delivery system attached (5 dogs with 7-day infusions). However, because of a change in hospital policy to further mitigate owner exposure to chemotherapeutic agents, this protocol was changed, and dogs were subsequently hospitalized for the duration of the carboplatin infusion (40 dogs with 3-, 4-, and 5-day infusions). The total dose of carboplatin (300 mg/m2) administered by SC infusion was equivalent to established IV doses of carboplatin in dogs20; therefore, even if an entire SC infusion dose was inadvertently administered as a bolus to a dog because of an infusion pump failure, the maximum amount of carboplatin that the affected dog could have received was the same as the recommended IV dose.

Adverse events of chemotherapy

Adverse events that affected bone marrow were assessed on the basis of hematologic findings before and after administration of carboplatin. Forty of 45 (88%) dogs had hematologic changes, including 3 dogs that developed grade 4 neutropenia (ie, < 500 neutrophils/μX; reference range, 2.95 × 109 neutrophils/L to 11.64 × 109 neutrophils/L) and 4 dogs that developed grade 4 thrombocytopenia (ie, < 25,000 platelets/μL; reference range, 148 × 109 platelets/L to 484 × 109 platelets/L; Table 1). None of these dogs required hospitalization. Furthermore, of the dogs with thrombocytopenia, none had signs of bleeding and all had platelet counts within reference limits in subsequent evaluations.

Table 1—

Signs stratified by grade of bone marrow- and gastrointestinal-related adverse events of carboplatin (300 mg/m2 total, SC infusion on day 0) chemotherapy in 45 dogs following limb amputation for appendicular osteosarcoma.

  No. of dogs affected per grade* of adverse event
SignsNo. of dogs evaluatedGrade 1Grade 2Grade 3Grade 4
Neutropenia     
  Day 04039010
  Day 143634002
  Day 213230101
Thrombocytopenia     
  Day 03535000
  Day 143023313
  Day 213129200
Vomiting450300
Diarrhea451000

Graded according to the Veterinary Co-operative Oncology Group Common Terminology Criteria for Adverse Events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats.18

Results of serum biochemical analyses performed after carboplatin infusion were available for 22 dogs. Two of the 22 (9%) dogs had slightly high BUN concentrations (10.1 and 12.1 mmol/L; reference range, 2.5 to 9.6 mmol/L). However, serum creatinine concentration for all dogs remained within reference limits (44.0 to 159 μmol/L). Therefore, none of the dogs were considered to have had renal toxicosis.

Adverse events that affected the gastrointestinal system were reported in 4 of 45 (9%) dogs (Table 1). One dog developed grade 1 gastrointestinal toxicosis on the basis of mild diarrhea (ie, an increase above baseline of > 2 stools/24 h) that resolved with a bland diet. The remaining 3 (7%) dogs developed grade 2 toxicosis on the basis of vomiting (ie, 3 to 5 vomiting episodes/24 h or < 3 vomiting episodes/24 h for > 2 days but < 5 days and parental fluids administered for < 24 hours). Because of their vomiting, pyrexia, and signs of inappetence, these 3 dogs were hospitalized for 24 hours and treated with antimicrobials, fluid therapy, and supportive care. All 3 of these dogs recovered within 24 hours and were discharged with prescriptions of a proton pump inhibitor (omeprazole; 1.0 mg/kg [0.45 mg/lb], PO, q 24 h) and an H2 receptor antagonist (ranitidine; 2.0 mg/kg [0.9 mg/lb], PO, q 12 h). None of these 3 dogs developed grade 3 or 4 neutropenia.

Suspected postoperative infection

Twenty-two of 45 (49%) dogs developed a suspected postoperative infection after the carboplatin infusion was completed and the infusion delivery system was removed. Six of these 22 dogs had swab samples collected from the surgery sites (all 6 were forelimb amputation sites) for bacterial culture. Results yielded single bacterial isolates (Staphylococcus intermedius, S aureus, or Escherichia coli) in 3 dogs and mixed bacterial populations (Actinobacter spp, Enterobacter spp, and Enterococcus spp) in 3 dogs. Bacterial growth was recorded as moderate or heavy for all cultures. All dogs with suspected postoperative infections were treated with antimicrobials, although no standardized antimicrobial protocol was used. All suspected infections resolved without the need for surgical debridement. The mean ± SD neutrophil count did not meaningfully differ between dogs with (4.83 ± 3.22 × 109/L) versus without (4.37 ± 2.64 × 109/L) a suspected postoperative infection.

Outcomes

Six dogs were censored for survival analysis because they were alive at the study census date (n = 2) or were lost to follow-up (4). Thirty-nine dogs were euthanized at the owner's request or died during the study period. Of these 39 nonsurvivors, 29 had suspected tumor progression (lung metastases [n = 19], additional bone lesions [9], or multiple cutaneous metastases [1]) on the basis of results from diagnostic imaging (CT or radiography) or cytologic evaluation (confirmed multiple cutaneous metastatic lesions in the affected dog).

Overall, the MST was 196 days (IQR, 109 to 393 days; Figure 1) and the median MFI was 197 days (IQR, 104 to 566 days). When evaluated further, the MST was significantly (P = 0.08) longer for the 12 dogs that had also been included in a previous case series14 (249 days; IQR, 212 to 660 days), compared with results for the 33 dogs newly identified in the present study (181 days; IQR, 104 to 348 days). The median MFI, however, did not differ significantly (P = 0.12) between the 12 previously identified dogs (660 days; IQR, 185 to 1,622 days) and the 33 newly identified dogs (184 days; IQR, 104 to 489 days). However, the previous study14 had a longer median follow-up duration for long-term outcomes (157 days) than the present study (156 days; range, 103 to 1,622 days).

Figure 1—
Figure 1—

Kaplan-Meier curve of survival times for 45 dogs with appendicular osteosarcoma treated with limb amputation followed by SC infusion of carboplatin (300 mg/m2 total). Median survival time was 196 days (range, 103 to 1,622 days; IQR, 109 to 271 days). Dogs were censored (tick marks) for survival analysis if they were still alive at the study census date or at the date they were lost to follow-up.

Citation: Journal of the American Veterinary Medical Association 255, 3; 10.2460/javma.255.3.345

The MST did not differ significantly (P = 0.22) between Rottweilers (136 days; IQR,103 to 226 days; n = 13) and all other breeds (204 days; IQR, 134 to 526 days; 32). Similarly, the median MFI did not differ significantly (P = 0.27) between Rottweilers (104 days; IQR, 63 to 185 days) and all other breeds (171 days; IQR, 54 to 351 days).

When age was considered, the MST did not differ significantly (P = 0.09) between dogs ≤ 5 years of age (136 days; IQR, 104 to 171 days; n = 5) and dogs > 5 years of age (212 days; IQR, 109 to 489 days; 40). However, the median MFI for dogs ≤ 5 years of age (104 days; IQR, 45 to 134 days) was significantly (P = 0.01) shorter than that for dogs > 5 years of age (271 days; IQR, 109 to 660 days).

On the basis of tumor location, the MST did not differ significantly (P = 0.26) between dogs with osteosarcoma in the proximal aspect of the humerus (196 days; IQR, 135 to 245 days; n = 19) versus in all other appendicular locations (184 days; IQR, 90 to 526 days; 26). Similarly, the median MFI did not differ significantly (P = 0.18) between dogs with osteosarcoma in the proximal aspect of the humerus (185 days; IQR, 109 to 489 days) versus in all other appendicular locations (348 days; IQR, 103 to 829 days).

The preoperative serum ALP activity was available for 36 dogs, and 5 dogs had serum ALP activity > 212 U/L (reference range, 23 to 212 U/L), with a median serum ALP activity of 446 U/L. The MST of these 5 dogs (171 days; IQR, 54 to 181 days) did not differ significantly (P = 0.47) from that for the 31 dogs with serum ALP activity within reference limits (196 days; IQR, 109 to 271 days). Similarly, the median MFI did not differ significantly (P = 0.42) between dogs with high ALP (54 days; IQR, 45 to 134 days) and dogs with serum ALP activity within reference limits (197 days; IQR, 119 to 351 days).

Duration of carboplatin infusion did not significantly (P = 0.294) affect survival time, and no variable achieved statistical significance (P < 0.05) on univariate analysis. Therefore, multivariable (Cox regression) analysis was not reported.

The MST did not differ significantly (P = 0.84) between dogs with (212 days; IQR,119 to 271 days; n = 22) and dogs without (184 days; IQR, 109 to 489 days; 23) suspected postoperative infections. Similarly, the median MFI did not differ significantly (P = 0.98) between dogs with (197 days; IQR, 95 to 829 days) and dogs without (198 days; IQR, 128 to 526 days) suspected postoperative infections.

Discussion

Findings indicated that the dogs in the present study were typical in respect to age, sex, breed, body weight, and location of the primary tumor for dogs with appendicular osteosarcoma.1 In addition, results indicated that the MST was 196 days for dogs with appendicular osteosarcoma undergoing amputation and a single SC infusion of carboplatin (300 mg/m2 total, diluted in 5% glucose) and that the SC infusion of carboplatin was well tolerated by most dogs. The MST of 196 days for all dogs in the present study was between reported MSTs of 134 to 175 days for dogs with appendicular osteosarcoma treated with limb amputation alone5,21,22 and reported MSTs of 224 to 479 days for similarly affected dogs treated with limb amputation and IV administration of carboplatin.8,9 However, the MST of the present study was inconsistent with a previous study14 that shows an MST of 365 days for dogs with appendicular osteosarcoma treated with amputation or limb salvage surgery and a single adjunctive SC infusion of carboplatin. Potential reasons for this discrepancy were that the previous study14 had a smaller sample size (greater risk for type I error) and more censored data points and that the present study excluded dogs that underwent limb salvage surgery.

Rottweilers have an increased risk of developing osteosarcoma23; thus, it was not unexpected that there were more Rottweilers than other breeds in the present study. In addition, our findings of no significant differences in MST and median MFI between Rottweilers and other breeds represented were consistent with similar findings in another study.24

In the present study, 22 of 45 (49%) dogs developed suspected postoperative infections. This finding was higher than expected on the basis of surgical site infection rates previously reported25–27 as 2.5% to 5% for surgical procedures with no complications. A possible reason for the greater number of animals being classified as having had an infection in the present study may have been that our definition of surgical site infection included any wound discharge. Bacterial cultures were performed in only 6 dogs; therefore, it was possible that the discharge identified in some dogs may have been from a sterile immunogenic reaction or direct tissue irritation by the carboplatin, rather than from true colonization by bacteria.26 A previous study13 investigating the response of normal tissue to locally delivered cisplatin shows a transient mild delay in bone healing and a mild local tissue toxicosis manifested by increased swelling at the site and increased numbers of macrophages. These changes are transient and not associated with an increased rate of infection.13 Although tissue swelling and drainage of surgical sites have been noted with concurrent use of open-cell polyacetic acid polymer impregnated with cisplatin, this is possibly related to the implanted polymer rather than the cisplatin.11 Alternatively, infections may be potentiated by translocation of bacteria into the surgical site by the presence of foreign material,28 such as the infusion catheter used in the present study. In addition, postoperative surgical site infection in dogs undergoing limb salvage surgery and amputation for osteosarcoma is associated with a survival advantage, with investigators postulating that infection leads to stimulation of the immune system and that this stimulation has an antitumor effect.29–32 However, no meaningful difference in MST was detected between dogs with versus without suspected postoperative infection in the present study.

Several negative prognostic indicators and biomarkers, including young age at diagnosis33 and tumor affecting the proximal aspect of the humerus,34–36 have been reported for osteosarcoma in dogs. In contrast, neither age (ie, ≤ 5 years of age vs > 5 years of age) nor tumor location (ie, proximal aspect of the humerus vs all other appendicular locations) was associated with a shorter survival time in the present study; however, sample size could have attributed to this lack of association.

Although studies show that high serum ALP activity is associated with a negative prognosis in dogs with osteosarcoma36–39 and may be attributed to greater tumor burden and consequently more advanced disease,40 results of the present study suggested that high serum ALP activity, compared with serum ALP activity within reference limits, did not have prognostic significance. We recognized that the small number of dogs (n = 5) with high serum ALP activity in the present study may have hindered detection of significance. Nonetheless, our finding was consistent with other studies28,41 that indicate no prognostic significance of high serum ALP activity in dogs with osteosarcoma.

The presence of lymph node metastases is a negative prognostic indicator for dogs with osteosarcoma.42 Although local lymph nodes were routinely submitted for histologic examination in conjunction with limb amputations performed, the presence or absence of metastatic spread to the lymph nodes was not stated in pathology reports for dogs in the present study; therefore, we were unable to evaluate the prognostic association of lymph node metastases in dogs of the present study.

The proportion of dogs that had tumor progression with suspected pulmonary metastases was lower in the present study (19/39 [49%]), compared with a previous study34 that shows 6 of the 7 dogs with osteosarcoma treated with limb amputation and carboplatin chemotherapy had pulmonary metastases on necropsy. However, it was likely that our findings underrepresented the extent of metastatic disease because necropsies were not performed on any of the dogs in the present study. Nonetheless, our findings were consistent with a study43 in which 28 of 41 (56%) dogs developed pulmonary metastases.

Adverse events that affected bone marrow (determined on the basis of hematologic findings), gastrointestinal function, and renal function in dogs receiving a SC infusion of carboplatin in the present study compared favorably with results from previous studies44,45 that evaluated IV administration of carboplatin. Similarly, previous studies46,47 indicate that the maximally tolerated dose of cisplatin is greater when administered by open-cell polyacetic acid polymer impregnated with cisplatin (120 mg/m2) than when administered by IV injection (70 mg/m2). Future studies of carboplatin infusion protocols for adjuvant treatment of appendicular osteosarcoma in dogs could include evaluations of the efficacy of multiple administrations versus a single administration of carboplatin, efficacy of higher doses of carboplatin administered SC, and efficacy of SC infusion of carboplatin in treating other malignancies traditionally responsive to carboplatin. We speculated that although it may be possible to escalate the dose of carboplatin administered SC to improve efficacy as has been shown with the use of cisplatin,13 such escalations may result in greater incidences of adverse events. Pharmacokinetic studies are needed to investigate serum carboplatin concentration-versus-time relationships and to determine whether the concentration can be optimized to minimize adverse effects and maximize efficacy.

A potential benefit of a single SC administration of carboplatin after limb amputation for appendicular osteosarcoma is a shortened duration of treatment with fewer recheck appointments (eg, limited to hematologic and serum biochemical analyses performed at 14 and 21 days after surgery), enabling dogs to recover and readjust more quickly. However, because the MST in the present study was lower than MSTs reported1,8 for dogs treated with IV administration of carboplatin at the same dose, we could not recommend the protocol of SC infusion of carboplatin.

Further, we could not recommend the protocol of a single SC infusion of carboplatin as an effective adjuvant chemotherapy protocol for dogs with appendicular osteosarcoma treated with limb amputation because the MST of 181 days for the 33 dogs newly identified for the present study was similar to the MSTs (134 to 175 days5,20,21) for dogs treated with limb amputation alone and was substantially shorter than the MST of 249 days for the 12 dogs in the present study that had also been included in a previous study14 with the same protocol of SC infusion of carboplatin. This finding was critical because it conflicted with results from a previous study14 that investigated SC administration of carboplatin for the prevention of metastasis following surgery for osteosarcoma in dogs. However, additional studies to evaluate multiple or higher dosages could be considered.

The present study had limitations. The lack of a control group, a group that underwent amputation alone, or a group that underwent amputation and received carboplatin IV precluded direct comparisons of outcomes for a contemporary cohort of dogs at the same institution. In addition, the surgeries were performed by multiple surgeons, durations of carboplatin infusions varied, and our sample size may have been too small to allow detection of significant factors.

Acknowledgments

The authors declare that there were no conflicts of interest.

The authors thank Associate Professor John Santamaria, MBBS, MD, FRACP, FCICM, FCCP, for assistance with statistical analysis and intellectual contribution and Dr. Antony S. Moore, BVSc, MVSc, for his intellectual contribution.

ABBREVIATIONS

ALP

Alkaline phosphatase

IQR

Interquartile (25th to 75th percentile) range

MFI

Metastasis-free interval

MST

Median survival time

Footnotes

a.

8F urinary catheter, Unomedical Ltd, Sydney, Australia.

b.

Carboplatin, Pfizer Ltd, Perth, Australia.

c.

Infusion pump, Baxter Healthcare Corp, Deerfield, Ill.

d.

Stata Statistical Software, version 14.2, StataCorp LP, College Station, Tex.

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  • 18. Veterinary Co-operative Oncology Group. Veterinary Co-operative Oncology Group - Common Terminology Criteria for Adverse Events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Vet Comp Oncol 2004;2:195213.

    • Search Google Scholar
    • Export Citation
  • 19. Cox DR. Regression models and life-tables. J Royal Stat Soc Series B (Methodol) 1972;34:187220.

  • 20. Fox LE. Carboplatin. J Am Anim Hosp Assoc 2000;36:1314.

  • 21. Mauldin GN, Matus RE, Withrow SJ, et al. Canine osteosarcoma. Treatment by amputation versus amputation and adjunctive chemotherapy using doxorubicin and cisplatin. J Vet Intern Med 1988;2:177180.

    • Search Google Scholar
    • Export Citation
  • 22. Thompson JP, Fugent MJ. Evaluation of survival times after limb amputation, with and without subsequent administration of cisplatin, for treatment of appendicular osteosarcoma in dogs: 30 cases (1979–1990). J Am Vet Med Assoc 1992;200:531533.

    • Search Google Scholar
    • Export Citation
  • 23. Rosenberger JA, Pablo NV, Crawford PC. Prevalence of and intrinsic risk factors of appendicular osteosarcoma in dogs: 179 cases (1996–2005). J Am Vet Med Assoc 2007;231:10761080.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. McNeill CJ, Overley B, Shofer SF, et al. Characterization of the biological behavior of appendicular osteosarcoma in Rottweilers and a comparison with other breeds: a review of 258 dogs. Vet Comp Oncol 2007;5:9098.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Brown DC, Conzemius MG, Shofer F, et al. Epidemiologic evaluation of postoperative wound infections in dogs and cats. J Am Vet Med Assoc 1997;210:13021306.

    • Search Google Scholar
    • Export Citation
  • 26. Turk R, Singh A, Weese JS. Prospective surgical site infection surveillance in dogs. Vet Surg 2015;44:28.

  • 27. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg 2017;152:784791.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Magee C, Rodeheaver GT, Golden GT, et al. Potentiation of wound infection by surgical drains. Am J Surg 1976;131:547549.

  • 29. Lascelles BD, Dernell WS, Correa MT, et al. Improved survival associated with postoperative wound infections in dogs treated with limb salvage surgery for osteosarcoma. Ann Surg Oncol 2005;12:10731083.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30. Liptak JM, Dernell WS, Ehrhart N, et al. Cortical allograft and endoprosthesis for limb-sparing surgery in dogs with distal radial osteosarcoma: a prospective clinical comparison of two different limb-spearing techniques. Vet Surg 2006;35:518533.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Culp WT, Olea-Popelka F, Sefton J, et al. Evaluation of outcome and prognostic factors for dogs living greater than one year after diagnosis of osteosarcoma: 90 cases (1997–2008). J Am Vet Med Assoc 2014;245:11411146.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Mehl ML, Withrow SJ, Séguin B, et al. Spontaneous regression of osteosarcoma in four dogs. J Am Vet Med Assoc 2001;219:614617.

  • 33. Phillips B, Powers BE, Dernell WS, et al. Use of single-agent carboplatin as adjuvant or neoadjuvant therapy in conjunction with amputation for appendicular osteosarcoma in dogs. J Am Anim Hosp Assoc 2009;45:3338.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Bergman PJ, MacEwen EG, Kurzman ID. Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1191–1993). J Vet Intern Med 1996;10:7681.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35. Schmidt AF, Nielen M, Klungel OH, et al. Prognostic factors of early metastasis and mortality in dogs with appendicular osteosarcoma after receiving surgery: an individual patient data meta-analysis. Prev Vet Med 2013;112:414422.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Boerman I, Selvarajah GT, Nielen M, et al. Prognostic factors in canine appendicular osteosarcoma - a meta-analysis. BMC Vet Res 2012;8:56.

  • 37. Selvarajah GT, Kirpensteijn J. Prognostic and predictive biomarkers of canine osteosarcoma. Vet J 2010;185:2835.

  • 38. Ehrhart N, Dernell WS, Hoffmann WE, et al. Prognostic importance of alkaline phosphatase activity in serum from dogs with appendicular osteosarcoma: 75 cases (1990–1996). J Am Vet Med Assoc 1998;213:10021006.

    • Search Google Scholar
    • Export Citation
  • 39. Garzotto CK, Berg J, Hoffmann WE, et al. Prognostic significance of serum alkaline phosphatase activity in canine appendicular osteosarcoma. J Vet Intern Med 2000;14:587592.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40. Sternberg RA, Pondenis HC, Yang X, et al. Association between absolute tumor burden and serum bone-specific alkaline phosphatase in canine appendicular osteosarcoma. J Vet Intern Med 2013;27:955963.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41. Saam DE, Liptak JM, Stalker MJ, et al. Predictors of outcome in dogs treated with adjuvant carboplatin for appendicular osteosarcoma: 65 cases (1996–2006). J Am Vet Med Assoc 2011;238:195206.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42. Hillers KR, Dernell WS, Lafferty MH, et al. Incidence and prognostic importance of lymph node metastases in dogs with appendicular osteosarcoma: 228 cases (1986–2003). J Am Vet Med Assoc 2005;226:13641367.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43. McMahon M, Mathie T, Stingle N, et al. Adjuvant carboplatin and gemcitabine combination chemotherapy postamputation in canine appendicular osteosarcoma. J Vet Intern Med 2011;25:511517.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44. Rassnick KM, Ruslander DM, Cotter SM, et al. Use of carboplatin for treatment of dogs with malignant melanoma: 27 cases (1989–2000). J Am Vet Med Assoc 2001;218:14441448.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45. Chun R, Knapp DW, Widmer WR, et al. Phase II clinical trial of carboplatin in canine transitional cell carcinoma of the urinary bladder. J Vet Intern Med 1997;11:279283.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46. Ogilvie GK, Krawiec DR, Gelberg HB, et al. Evaluation of a short-term saline diuresis protocol for the administration of cisplatin. Am J Vet Res 1988;49:10761078.

    • Search Google Scholar
    • Export Citation
  • 47. Ogilvie GK, Straw RC, Powers BE, et al. Prevalence of nephrotoxicosis associated with a short-term saline solution diuresis protocol for the administration of cisplatin to dogs with malignant tumors: 61 cases (1987–1989). J Am Vet Med Assoc 1991;199:613616.

    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Kaplan-Meier curve of survival times for 45 dogs with appendicular osteosarcoma treated with limb amputation followed by SC infusion of carboplatin (300 mg/m2 total). Median survival time was 196 days (range, 103 to 1,622 days; IQR, 109 to 271 days). Dogs were censored (tick marks) for survival analysis if they were still alive at the study census date or at the date they were lost to follow-up.

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  • 9. Selmic LE, Burton JH, Thamm DH, et al. Comparison of carboplatin and doxorubicin-based chemotherapy protocols in 470 dogs after amputation for treatment of appendicular osteosarcoma. J Vet Intern Med 2014;28:554563.

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  • 10. Withrow SJ, Straw RC, Brekke JH, et al. Slow release adjuvant cisplatin for treatment of metastatic canine osteosarcoma. Eur J Exp Musculoskelet Res 1995;4:105110.

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  • 13. Straw RC, Withrow SJ, Douple EB, et al. Effects of cis-diamminedichloroplatinum II released from D,L-polylactic acid implanted adjacent to cortical allografts in dogs. J Orthop Res 1994;12:871877.

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  • 18. Veterinary Co-operative Oncology Group. Veterinary Co-operative Oncology Group - Common Terminology Criteria for Adverse Events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.0. Vet Comp Oncol 2004;2:195213.

    • Search Google Scholar
    • Export Citation
  • 19. Cox DR. Regression models and life-tables. J Royal Stat Soc Series B (Methodol) 1972;34:187220.

  • 20. Fox LE. Carboplatin. J Am Anim Hosp Assoc 2000;36:1314.

  • 21. Mauldin GN, Matus RE, Withrow SJ, et al. Canine osteosarcoma. Treatment by amputation versus amputation and adjunctive chemotherapy using doxorubicin and cisplatin. J Vet Intern Med 1988;2:177180.

    • Search Google Scholar
    • Export Citation
  • 22. Thompson JP, Fugent MJ. Evaluation of survival times after limb amputation, with and without subsequent administration of cisplatin, for treatment of appendicular osteosarcoma in dogs: 30 cases (1979–1990). J Am Vet Med Assoc 1992;200:531533.

    • Search Google Scholar
    • Export Citation
  • 23. Rosenberger JA, Pablo NV, Crawford PC. Prevalence of and intrinsic risk factors of appendicular osteosarcoma in dogs: 179 cases (1996–2005). J Am Vet Med Assoc 2007;231:10761080.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. McNeill CJ, Overley B, Shofer SF, et al. Characterization of the biological behavior of appendicular osteosarcoma in Rottweilers and a comparison with other breeds: a review of 258 dogs. Vet Comp Oncol 2007;5:9098.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Brown DC, Conzemius MG, Shofer F, et al. Epidemiologic evaluation of postoperative wound infections in dogs and cats. J Am Vet Med Assoc 1997;210:13021306.

    • Search Google Scholar
    • Export Citation
  • 26. Turk R, Singh A, Weese JS. Prospective surgical site infection surveillance in dogs. Vet Surg 2015;44:28.

  • 27. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg 2017;152:784791.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Magee C, Rodeheaver GT, Golden GT, et al. Potentiation of wound infection by surgical drains. Am J Surg 1976;131:547549.

  • 29. Lascelles BD, Dernell WS, Correa MT, et al. Improved survival associated with postoperative wound infections in dogs treated with limb salvage surgery for osteosarcoma. Ann Surg Oncol 2005;12:10731083.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30. Liptak JM, Dernell WS, Ehrhart N, et al. Cortical allograft and endoprosthesis for limb-sparing surgery in dogs with distal radial osteosarcoma: a prospective clinical comparison of two different limb-spearing techniques. Vet Surg 2006;35:518533.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Culp WT, Olea-Popelka F, Sefton J, et al. Evaluation of outcome and prognostic factors for dogs living greater than one year after diagnosis of osteosarcoma: 90 cases (1997–2008). J Am Vet Med Assoc 2014;245:11411146.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Mehl ML, Withrow SJ, Séguin B, et al. Spontaneous regression of osteosarcoma in four dogs. J Am Vet Med Assoc 2001;219:614617.

  • 33. Phillips B, Powers BE, Dernell WS, et al. Use of single-agent carboplatin as adjuvant or neoadjuvant therapy in conjunction with amputation for appendicular osteosarcoma in dogs. J Am Anim Hosp Assoc 2009;45:3338.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Bergman PJ, MacEwen EG, Kurzman ID. Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1191–1993). J Vet Intern Med 1996;10:7681.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35. Schmidt AF, Nielen M, Klungel OH, et al. Prognostic factors of early metastasis and mortality in dogs with appendicular osteosarcoma after receiving surgery: an individual patient data meta-analysis. Prev Vet Med 2013;112:414422.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Boerman I, Selvarajah GT, Nielen M, et al. Prognostic factors in canine appendicular osteosarcoma - a meta-analysis. BMC Vet Res 2012;8:56.

  • 37. Selvarajah GT, Kirpensteijn J. Prognostic and predictive biomarkers of canine osteosarcoma. Vet J 2010;185:2835.

  • 38. Ehrhart N, Dernell WS, Hoffmann WE, et al. Prognostic importance of alkaline phosphatase activity in serum from dogs with appendicular osteosarcoma: 75 cases (1990–1996). J Am Vet Med Assoc 1998;213:10021006.

    • Search Google Scholar
    • Export Citation
  • 39. Garzotto CK, Berg J, Hoffmann WE, et al. Prognostic significance of serum alkaline phosphatase activity in canine appendicular osteosarcoma. J Vet Intern Med 2000;14:587592.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40. Sternberg RA, Pondenis HC, Yang X, et al. Association between absolute tumor burden and serum bone-specific alkaline phosphatase in canine appendicular osteosarcoma. J Vet Intern Med 2013;27:955963.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41. Saam DE, Liptak JM, Stalker MJ, et al. Predictors of outcome in dogs treated with adjuvant carboplatin for appendicular osteosarcoma: 65 cases (1996–2006). J Am Vet Med Assoc 2011;238:195206.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42. Hillers KR, Dernell WS, Lafferty MH, et al. Incidence and prognostic importance of lymph node metastases in dogs with appendicular osteosarcoma: 228 cases (1986–2003). J Am Vet Med Assoc 2005;226:13641367.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43. McMahon M, Mathie T, Stingle N, et al. Adjuvant carboplatin and gemcitabine combination chemotherapy postamputation in canine appendicular osteosarcoma. J Vet Intern Med 2011;25:511517.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44. Rassnick KM, Ruslander DM, Cotter SM, et al. Use of carboplatin for treatment of dogs with malignant melanoma: 27 cases (1989–2000). J Am Vet Med Assoc 2001;218:14441448.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45. Chun R, Knapp DW, Widmer WR, et al. Phase II clinical trial of carboplatin in canine transitional cell carcinoma of the urinary bladder. J Vet Intern Med 1997;11:279283.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46. Ogilvie GK, Krawiec DR, Gelberg HB, et al. Evaluation of a short-term saline diuresis protocol for the administration of cisplatin. Am J Vet Res 1988;49:10761078.

    • Search Google Scholar
    • Export Citation
  • 47. Ogilvie GK, Straw RC, Powers BE, et al. Prevalence of nephrotoxicosis associated with a short-term saline solution diuresis protocol for the administration of cisplatin to dogs with malignant tumors: 61 cases (1987–1989). J Am Vet Med Assoc 1991;199:613616.

    • Search Google Scholar
    • Export Citation

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