Evaluation of a single subcutaneous infusion of carboplatin as adjuvant chemotherapy for dogs with osteosarcoma: 17 cases (2006–2010)

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

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Sita S. Withers Southpaws Specialty Surgery for Animals, 3 Roper St, Moorabbin, VIC 3189, Australia.

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Cassandra Y. Prpich Southpaws Specialty Surgery for Animals, 3 Roper St, Moorabbin, VIC 3189, Australia.

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

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Bronwyn E. Rutland Southpaws Specialty Surgery for Animals, 3 Roper St, Moorabbin, VIC 3189, Australia.

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Abstract

Objective—To evaluate adverse effects and survival times in dogs with osteosarcoma that received a single SC infusion of carboplatin as adjunctive chemotherapeutic treatment following limb amputation or limb-sparing surgery.

Design—Retrospective case series.

Animals—17 client-owned dogs with spontaneously occurring osteosarcoma.

Procedures—Medical records of dogs that underwent limb amputation or limb-sparing surgery followed by a single continuous SC infusion of carboplatin (total dose, 300 mg/m2 infused over 3, 5, or 7 days) were evaluated. Signalment, tumor location, type of surgery (amputation or limb-sparing), duration of carboplatin infusion, results of hematologic and serum biochemical analyses, and adverse effects were recorded. Kaplan-Meier survival analysis was performed.

Results—Median survival time for all dogs was 365 days. Nine dogs had adverse bone marrow–related (hematologic) effects, 1 had adverse gastrointestinal effects, and 7 had infections at the surgical site. No significant differences were detected in survival times of dogs grouped according to tumor location, type of surgery, duration of carboplatin infusion, or development of postoperative infection.

Conclusions and Clinical Relevance—Median survival time and adverse effects in dogs with osteosarcoma that received a single SC infusion of carboplatin over a 3-, 5-, or 7-day period as adjunctive treatment following limb amputation or limb-sparing surgery were comparable to those of previously reported chemotherapy protocols requiring IV drug administration over several weeks. Further investigation is needed to evaluate the efficacy of this protocol as adjunctive treatment for osteosarcoma and other tumors in dogs.

Abstract

Objective—To evaluate adverse effects and survival times in dogs with osteosarcoma that received a single SC infusion of carboplatin as adjunctive chemotherapeutic treatment following limb amputation or limb-sparing surgery.

Design—Retrospective case series.

Animals—17 client-owned dogs with spontaneously occurring osteosarcoma.

Procedures—Medical records of dogs that underwent limb amputation or limb-sparing surgery followed by a single continuous SC infusion of carboplatin (total dose, 300 mg/m2 infused over 3, 5, or 7 days) were evaluated. Signalment, tumor location, type of surgery (amputation or limb-sparing), duration of carboplatin infusion, results of hematologic and serum biochemical analyses, and adverse effects were recorded. Kaplan-Meier survival analysis was performed.

Results—Median survival time for all dogs was 365 days. Nine dogs had adverse bone marrow–related (hematologic) effects, 1 had adverse gastrointestinal effects, and 7 had infections at the surgical site. No significant differences were detected in survival times of dogs grouped according to tumor location, type of surgery, duration of carboplatin infusion, or development of postoperative infection.

Conclusions and Clinical Relevance—Median survival time and adverse effects in dogs with osteosarcoma that received a single SC infusion of carboplatin over a 3-, 5-, or 7-day period as adjunctive treatment following limb amputation or limb-sparing surgery were comparable to those of previously reported chemotherapy protocols requiring IV drug administration over several weeks. Further investigation is needed to evaluate the efficacy of this protocol as adjunctive treatment for osteosarcoma and other tumors in dogs.

Osteosarcoma is the most common bone tumor in dogs, comprising up to 80% of all malignant bone tumors and up to 98% of primary appendicular bone tumors in this species.1 It is highly malignant, with 90% of animals having micrometastasis at the time of diagnosis.2 Definitive treatment involves amputation or limb-sparing surgery and is often combined with adjunctive chemotherapy to improve survival time. The median survival time for dogs treated with amputation alone ranges from 134 to 175 days, with death commonly resulting from pulmonary metastasis.3–5 Various factors have been identified that can influence survival time, including tumor location at the proximal aspect of the humerus,6,7 high serum ALP activity,8–11 postoperative wound infection,12,13 tumor size,14 patient age,4 presence or absence of lymph node metastasis,9 and tumor grade.11

Traditionally, adjunctive chemotherapy protocols used for dogs with osteosarcoma involve IV administration of carboplatin, cisplatin, or doxorubicin alone or a combination of doxorubicin with either carboplatin or cisplatin. These protocols typically require multiple treatments to be administered every 2 to 3 weeks. Reported median survival times range from 207 to 321 days when treated with carboplatin alone, from 262 to 413 days when treated with cisplatin alone, and from 240 to 366 days when treated with doxorubicin alone; median survival times from 235 to 320 days have been described for dogs that received carboplatin with doxorubicin, and a median survival time of 300 days has been reported for dogs treated with a combination of doxorubicin and cisplatin.2–5,8,15–22 Drug-dependent adverse events have been reported following IV administration of each of these medications and may involve the bone marrow as well as gastrointestinal, renal, and cardiovascular systems.6,7,15–20,23–26

A slow-release delivery system has been described for the administration of cisplatin that has been shown to improve survival time for dogs with osteosarcoma, compared with amputation alone. Median survival times in dogs with OPLA-Pt implanted at the surgical site following amputation or limb-sparing surgery are reportedly 240 and 233 days, respectively.27,28 Pharmacokinetic studies27,29 have shown that the use of OPLA-Pt results in a low serum concentration of cisplatin that is sustained over a number of days. The peak dose is lower, but the area under the curve for whole-body exposure is up to 27 times as great as that achieved with an equivalent IV dose of cisplatin. This is thought to increase efficacy because it allows tumor cells to be exposed to cisplatin for a longer period, whereas the lower peak dose decreases potential systemic toxicity.27,29

A single SC infusion of carboplatin was investigated in the study reported here because OPLA-Pt is not commercially available. Carboplatin was chosen because protocols involving IV administration of this drug have been shown to have similar efficacy to those that involve IV administration of cisplatin, with potentially fewer adverse effects.6,7,30 Additionally, intralesional and intracavitary administration of carboplatin have been reported without extravasation-related injury.31–34 The purpose of the study reported here was to retrospectively evaluate survival times and adverse effects in dogs with osteosarcoma that received a single SC infusion of carboplatin as adjunctive chemotherapeutic treatment following limb amputation or limb-sparing surgery. Our hypothesis was that the median survival time of these dogs would be greater than that reported for dogs treated by means of amputation alone and that adverse effects would be comparable to those reported for protocols involving IV administration of carboplatin.

Materials and Methods

Criteria for selection of cases—A computerized search of the hospital medical records was performed to retrospectively identify dogs that had a diagnosis of osteosarcoma between January 1, 2006, and July 31, 2010. Dogs with spontaneously occurring appendicular osteosarcoma that were treated by means of limb amputation or limb-sparing surgery followed by a single SC infusion of carboplatin were eligible for study inclusion. Diagnosis was confirmed with histopathologic findings in all cases. Dogs were excluded from the study if metastasis was detected at the time of initial evaluation, or if they received any other form of treatment for the primary tumor (including IV administration of the chemotherapeutic agent).

Owners of dogs in the present study were encouraged to approve treatment with traditional chemotherapy protocols, but had declined these on the basis of concerns regarding expense or duration of treatment. All owners signed consent forms prior to treatment.

Treatments and monitoring—Preoperative staging included CT or 3-view radiography of the thorax, routine serum biochemical analysis, and hematologic evaluation. Patients were treated with limb-sparing surgery or amputation of the affected limb. All limb-sparing procedures were performed by the same surgeon (CAK), and amputations were performed by an American board-certified surgeon or surgery resident. All thoracic limb amputations were performed by means of scapulectomy, and pelvic limb amputations were performed by means of coxofemoral disarticulation as previously described.35 Limb-sparing surgery was performed in dogs that had distal radial tumors only; an endoprosthesis was applied in these patients as described elsewhere.12 Antimicrobial prophylaxis consisted of cephalexin (22 mg/kg [10.0 mg/lb], IV) administered 30 minutes prior to surgery; this was repeated every 90 minutes for the duration of anesthesia. All dogs were premedicated with methadone (0.3 mg/kg [0.14 mg/lb], IV) and acepromazine (0.01 mg/kg [0.005 mg/lb], IV). Dogs undergoing pelvic limb amputation received epidural administration of morphine (0.1 mg/kg [0.05 mg/lb]) and bupivacaine (1.0 mg/kg [0.45 mg/lb]). Dogs undergoing thoracic limb amputation received a bupivacaine splash block at the time of surgery (maximum dose, 2.0 mg/kg [0.91 mg/lb]). Postoperative analgesia included bolus injections of methadone (0.3 mg/kg, IV), transdermal fentanyl patch (2 μg/kg/h), and NSAIDs.

Patients that underwent thoracic limb amputation had an 8F urinary cathetera placed SC in the surgical site prior to closure. Patients that underwent pelvic limb amputation had the catheter placed SC between the scapulae through a surgical incision immediately following the amputation. For patients that had limb-sparing surgery performed, the catheter was placed in the surgical site prior to closure. Approximately 10 cm of the urinary catheter was placed under the skin, and the catheter was secured at the skin with a purse-string and Chinese fingertrap suture. The drain was then covered with an adhesive dressing.

The aqueous carboplatin solutionb was prepared by a commercial compounding pharmacy.c Following the surgery, a single 300-mg/m2 treatment of carboplatin diluted in 5% glucose solution was delivered through the surgically placed catheter. The volume of glucose used for dilution varied according to size of the animal and duration of administration. The infusion was started on the day following surgery and was administered by use of a commercially available constant rate infusion pumpd over 3, 5, or 7 days.

Initially, patients were discharged from the hospital with the chemotherapy delivery system attached (7-day administrations). Subsequently, patients were hospitalized for the duration of carboplatin administration (3- and 5-day administrations). Owners and hospital personnel were educated in chemotherapy safety with a focus on minimizing exposure and personal or environmental contamination. Protocols implemented were based on human hospital guidelines.36 After the infusion was completed, the pump and catheter were removed by the attending veterinarian. Following removal, skin staples were used to close the wound. Routine serum biochemical analysis and hematologic evaluation were performed at various times in the 5 weeks following treatment. Patients were monitored during and after drug administration for signs of any adverse events.

Procedures—Medical records of dogs that met the inclusion criteria were reviewed. Information was collected, including age, sex, breed, tumor location, preoperative serum ALP activity, surgical treatment (limb amputation or limb-sparing surgery), duration of carboplatin administration, serum BUN and creatinine concentrations and results of hematologic analysis after treatment, and development of anorexia, vomiting, or diarrhea. Adverse effects related to bone marrow (determined on the basis of hematologic findings) and the gastrointestinal system were graded according to the Veterinary Co-operative Oncology Group grading scheme (Appendix).37 Any other adverse effects were also recorded. Postoperative wound infection was defined as the development of discharge or a draining sinus from the surgical incision at any time following surgery.

Statistical analysis—Statistical analysis was performed with commercially available statistical software.e Median survival time was calculated via Kaplan-Meier analysis. Survival time was defined as the interval between surgery (the day of surgery was considered day 0) and death resulting from tumor-related causes. Patients were censored if they died of non–tumor-related causes or were still alive at the time of survival analysis.

Log-rank analysis was used to compare survival times among dogs grouped according to the following criteria: tumor location (proximal humeral or other), duration of carboplatin infusion (3 days or > 3 days), postoperative infection (yes or no), and surgical treatment (limb amputation or limb-sparing surgery). Any factors identified as significant (P < 0.05) in univariate analysis were evaluated via multivariate analysis with multiple logistic regression (Cox analysis). Associations between duration of administration and adverse events were investigated by use of a Fisher exact test. For all calculations, a value of P < 0.05 was considered significant.

Results

The records search identified 97 dogs with a diagnosis of osteosarcoma; 17 of these met inclusion criteria for the study. These included 8 females (7 spayed and 1 sexually intact) and 9 males (6 castrated and 3 sexually intact). Breeds included Rottweiler (n = 6), large mixed (3), Greyhound (2), and 1 each of Labrador Retriever, Boxer, Dalmatian, Viszla, Malamute, and Doberman Pinscher. The median age was 9 years (range, 2 to 13 years), and median body weight was 36 kg (79.2 lb; range, 17 to 69 kg; [37.4 to 151.8 lb]). Fourteen dogs underwent limb amputation, and 3 had limb-sparing surgery. The duration of carboplatin administration was 3 days in 10 dogs, 5 days in 1 dog, and 7 days in 6 dogs. At the time of initial evaluation, 16 dogs had a thoracic CT scan performed, and 1 was evaluated via 3-view thoracic radiography. Tumor locations included the distal aspect of the radius (n = 6), the proximal aspect of the humerus (5), the proximal aspect of the tibia (3), the distal aspect of the femur (2), and the distal aspect of the ulna (1).

Seven dogs were alive at the time of survival analysis, and 10 dogs had died or were euthanized; none were lost to follow-up. Of the 10 nonsurviving dogs, 7 were euthanized because of tumor progression; 6 of these had thoracic imaging results consistent with pulmonary metastasis, and 1 developed multiple cutaneous masses for which cytologic evaluation was consistent with metastatic osteosarcoma. The remaining 3 nonsurviving dogs were censored from the analysis. One dog died of gastric dilation–volvulus 19 days after surgery. One dog was euthanized at the request of the owner because of suspected renal failure 314 days after surgery; no further information was available from the medical record. One dog was euthanized 294 days after surgery because its clinical condition had deteriorated; results of thoracic imaging revealed no evidence of metastasis, and the cause of deterioration was not identified in the medical record. Necropsies were not performed in any of the dogs.

Overall, 9 of 17 dogs had bone marrow–related adverse effects. Duration of carboplatin infusion was 3 days in 7 of these dogs and 7 days in the remaining 2. Among dogs that underwent a 3-day infusion of carboplatin, 3 developed neutropenia (1 each of grades 1, 2, and 4), 3 developed thrombocytopenia (2 were grade 1 and 1 was grade 2), and 1 developed grade 4 neutropenia and grade 2 thrombocytopenia. Among dogs that underwent a 7-day infusion of carboplatin, 1 developed grade 4 neutropenia and 1 developed grade 1 thrombocytopenia. One of the dogs with grade 4 neutropenia developed sepsis and required hospitalization; this dog recovered uneventfully with supportive care. Only 1 dog had adverse gastrointestinal effects (grade 2); this dog developed diarrhea and its clinical signs were treated without complications. No association was found between duration of carboplatin administration and the number of dogs that had bone marrow–related adverse effects (P = 0.153) or between duration of administration and the number of dogs that had adverse bone marrow–related or gastrointestinal effects (P = 0.058).

Preoperative serum ALP activity was measured in 13 dogs and was high (492 U/L; reference range, 23 to 212 U/L) in 1 of these. This dog died 619 days after surgery and had evidence of metastatic disease at the time of death. Serum creatinine and BUN concentrations were measured at various time points after surgery in 14 dogs. One of these dogs developed a mild increase in creatinine concentration 8 days after the carboplatin infusion ended (184 μmol/L; reference range, 44 to 159 μmol/L) and died of gastric dilation–volvulus 12 days later.

Postoperative infections (defined as development of discharge or a draining sinus from the surgical incision at any time following surgery) developed in 7 dogs (2 after limb-sparing surgery, 4 after thoracic limb amputation, and 1 after pelvic limb amputation). Microbial cultures were performed for samples from 6 dogs. Three of these yielded single bacterial isolates, and 3 yielded mixed bacterial isolates. Isolates included Staphylococcus intermedius, Staphylococcus aureus, Actinobacter spp, Enterobacter spp, Enterococcus spp, and Escherichia coli. Bacterial growth was recorded as moderate or heavy for all species isolated. Infections developed in 2 patients that had been discharged to their home environments for duration of the infusion; the remainder of these were in patients that had been hospitalized during infusion. All of the infections developed after the infusion was completed and the delivery system was removed. All patients with postoperative infections were treated with antimicrobials, although no consistent antimicrobial protocol was used for all patients. All of the infections resolved except those in patients that underwent limb-sparing surgery; these dogs were receiving antibiotics at the time of euthanasia. The time to resolution of the infection in other dogs was not apparent from the medical record.

Median survival time for all dogs was 365 days (Figure 1). Median time of follow-up was 157 days. No significant differences were detected in survival times of dogs grouped according to tumor location, type of surgery, duration of carboplatin infusion, or development of postoperative infection. Dogs with tumors of the proximal aspect of the humerus (n = 5) had a median survival time of 135 days, compared with 619 days for dogs with tumors in other locations (12; P = 0.11). Patients that underwent limb amputation (n = 14) had a median survival time of 365 days; those that had limb-sparing surgery (3) did not reach the median survival time (P = 0.73). The median time of follow-up for dogs that had limb-sparing surgery was 294 days. Dogs for which the duration of carboplatin infusion was 3 days (n = 10) and > 3 days (7) had median survival times of 271 and 365 days, respectively (P = 0.79). Patients that did not develop a postoperative infection (n = 10) had a median survival time of 365 days, and those that did develop an infection (7) did not reach the median survival time (P = 0.64). The median time of follow-up for dogs with postoperative infections was 226 days.

Figure 1—
Figure 1—

Kaplan-Meier survival curve for dogs (n = 17) that received 300 mg of carboplatin/m2, SC, over a 3-, 5-, or 7-day period as adjunctive chemotherapy following limb amputation or limb-sparing surgery for spontaneously occurring osteosarcoma.

Citation: Journal of the American Veterinary Medical Association 241, 5; 10.2460/javma.241.5.608

Discussion

The overall median survival time of 365 days in the present study was greater than that reported for dogs treated by means of amputation alone (134 to 175 days)3–5 and was comparable to that previously reported for dogs with osteosarcoma managed by means of amputation or limb-sparing surgery and adjuvant treatment with OPLA-Pt implanted at the surgical site or various other chemotherapeutic drugs administered IV.2,5–8,15–19,27,28 The population demographic of the present study was similar to that in the previous studies.

In the present study, adverse bone marrow–related effects (determined on the basis of hematologic findings) were detected in 9 of 17 dogs and 3 of these were grade 4 on the Veterinary Co-operative Oncology Group scale37 of 1 to 4. The investigators of previous studies23,24,38 evaluating IV administration of carboplatin reported adverse bone marrow–related effects in 10 of 28 and 7 of 14 of dogs, with 6 of 28 and 2 of 14 dogs respectively developing Veterinary Co-operative Oncology Group grade 3 to 4 or equivalent adverse effects. The proportion of dogs with adverse bone marrow–related effects and the degree of severity of those effects in the present study appears similar to those in the previous studies. In contrast, one of the reported advantages of the use of OPLA-Pt, compared with IV administration of cisplatin, is its ability to provide similar efficacy against tumor cells while minimizing the potential for toxic systemic effects. This is reportedly related to the pharmacokinetics of OPLA-Pt, in particular the serum concentration-time relationship. Results of 1 study29 revealed mild and transient systemic effects associated with OPLA-Pt; in that study, the peak serum concentration of cisplatin was 20% of that detected following a similar dose of cisplatin administered IV, whereas the area under the serum platinum concentration-versus-time curve was 27 times as great as that following IV administration. Currently, the relationship between serum carboplatin concentration and time for the dose and schedule used in the present study is unknown.

A difference in normal tissue tolerance between carboplatin administered via bolus injection IV and via continuous low-dose infusion SC may explain why adverse gastrointestinal effects were reported for only 1 in 17 dogs in the present study, compared with the 19% to 75% reported in other studies6,24,38,39 involving dogs treated with carboplatin IV. Although the incidence of adverse bone marrow–related effects appeared similar and that of adverse gastrointestinal effects appeared lower in the present study than in previous reports, a randomized, controlled study would be required for direct comparison.

Clean surgery is defined as being a nontraumatic, elective procedure in which no acute inflammation, break in aseptic technique, or entry into the gastrointestinal, urogenital, or respiratory tract occurs.40 In the present study, infection of the surgical site was recorded in 7 of 17 dogs. This rate of infection is much greater than the 2.5% to 6% reported for clean surgery.41,42 Six of these 7 dogs had carboplatin infused SC at the surgical site. Two had limb-sparing surgery, and 4 had thoracic limb amputation. In the present study, infection was defined as the development of discharge or a draining sinus from the surgical incision at any time following surgery. Microbial cultures were performed in 6 cases; however, the cultured samples were collected superficially and only from the discharge fluid. Bacterial contamination may have contributed to the results, causing the number of true infections to be overestimated. For dogs that did have positive culture results, the bacterial species isolated were consistent with common wound contaminants.35 It is possible that the discharge may have been related to sterile immunogenic reaction to the drain or to carboplatin. Chemotherapy-induced myelosuppression along with direct tissue irritation by the carboplatin and the presence of foreign material (the urinary catheter) in the wound may also have contributed to infection by delaying wound healing, interfering with host defenses, and allowing translocation of bacteria into the surgical site. It is not surprising that 2 of the 3 dogs that underwent limb-sparing surgery developed infections, given that postoperative infections have been reported in 44% to 68% of dogs with bone tumors undergoing limb-sparing surgery.12,13,43,44 In addition, a tumor-bearing surgical site with diminished local defenses, surgical attenuation of blood supply in an already poorly perfused site, lack of substantial soft tissue coverage of the surgical implants, implantation of an endoprosthesis or sterilized autograft, and implantation of a metal orthopedic device have all been reported as potential causes for postoperative infections in dogs undergoing limb-sparing surgery.44

The rate of administration of cisplatin from OPLA-Pt has been shown to influence disease-free interval and survival time.27 In the present study, a 7-day administration of carboplatin was chosen initially because it was thought that this would most closely emulate the pharmacokinetics of OPLA-Pt, wherein the greatest serum cisplatin concentrations are achieved in the first 4 days following implantation and decrease to low concentrations by day 21.27 A decision was made to reduce the administration period to 5 and 3 days and hospitalize patients for the duration of chemotherapy administration to minimize the risk of the chemotherapy exposure to people outside the hospital. The optimum dose and rate of administration of carboplatin was not established in the present study. No significant (P = 0.79) difference in survival time was detected between dogs that received carboplatin over 3 days and dogs that received the drug over a period of > 3 days.

Although low-dose administration of cisplatin has been previously investigated, the authors elected to use carboplatin in the present study because it has been shown to have an efficacy similar to cisplatin against osteosarcoma in dogs, with less potential for adverse effects.6,7,30 Additionally, cisplatin administered SC via bolus injection was found in 1 study45 to have an unacceptable degree of toxic effects. The dose of carboplatin (300 mg/m2) was extrapolated from the established IV dose.30 Studies25,26 have identified that the maximally tolerated dose of cisplatin is greater for OPLA-Pt, compared with an IV injection of the drug (120 vs 70 mg/m2, respectively). To our knowledge, there are no published data comparing the maximally tolerated dose of carboplatin administered IV with other routes of administration. We chose not to use a dose > 300 mg/m2, in case the delivery system malfunctioned and delivered the entire dose of carboplatin in a shorter than anticipated time. Even at this dose, it is possible that the adverse effects may have been more profound than expected because of differences in pharmacokinetics and pharmacodynamics between IV and SC administration.

Although the difference was not significant (P = 0.11), the 5 dogs with tumors of the proximal aspect of the humerus appeared to have a shorter survival time (135 days) than did the 12 dogs that had tumors in other locations (619 days). It is possible that this difference might have reached significance if larger numbers of dogs were available for the study. There was also no significant (P = 0.68) difference in survival time between the 7 patients that developed an infection and the 10 that did not. As discussed, it is possible that drainage from the wound sites may have been related to sterile processes in some dogs and infection may have been overestimated. It is also possible that infections may not have influenced survival time or that the numbers were too small to detect a difference.

Only 1 dog in the present study had high serum ALP activity before surgery, and this did not allow for comparison of survival times with dogs that had normal serum ALP activity. Similarly, only 1 patient was < 5 years old, and comparison of survival times between dogs < 5 years old and > 5 years old was not possible. Because of the retrospective nature of the study, information regarding tumor size and grade was not available for analysis. Patients that underwent limb amputation or limb-sparing surgery were included in the same group for overall survival analysis because the survival times for both procedures when combined with chemotherapy have been shown to be similar.44

In the present study, we evaluated survival times rather than disease-free interval. Disease-free interval is often defined as the time from treatment until recurrence of the tumor or appearance of metastasis. With respect to metastasis to the thorax, we believe that this outcome measure is somewhat subjective in that it depends on the frequency with which thoracic imaging is performed, the type and sensitivity of imaging methods, and the interpretation of imaging results. In 1 study,46 10 of 36 human patients with osteosarcoma who had pulmonary metastasis diagnosed on the basis of thoracic radiographic evaluation were found to have benign disease following metastasectomy. Computed tomography is considered the gold standard for thoracic imaging in humans as part of clinical staging for osteosarcoma.47 Although the sensitivity of CT is greater than that of conventional radiographs for detecting pulmonary lesions, care must be taken with interpretation.48,49 In 1 study,47 pulmonary metastasis was diagnosed on the basis of CT findings in 51 human patients; of these, 57% had histologic confirmation of metastatic osteosarcoma and 43% had benign disease. Dogs that had been euthanized were included in survival time calculations in the present study, and this was also influenced by subjective decisions and may have influenced the results of survival analysis; however, this would be expected to underestimate rather than overestimate the survival time, whereas periodic screening for metastasis may overestimate the disease-free interval.

The use of CT for detection of thoracic metastasis in most dogs of the present study was different from methods used in previous studies6,12,13,43,50 evaluating osteosarcoma in which 3-view thoracic radiographs were used for staging. The increased sensitivity of CT, compared with conventional 3-view thoracic radiography, may have excluded some patients that would otherwise have been included49 in the study. This may have caused stage drift and inadvertently selected for tumors that were potentially less biologically aggressive. This in turn may have positively affected the reported survival time. The present study had a number of limitations related to its retrospective nature, including lack of a control population, small sample size, and inconsistency in data reporting. It is possible that if hematologic evaluation was performed consistently at 14 days following the start of carboplatin administration, the number of dogs with adverse bone marrow–related adverse effects may have been higher than the 9 of 17 reported. Any future studies investigating this treatment modality should include standardized follow-up and clinicopathologic monitoring.

In the present study, carboplatin administered SC to dogs over a variable number of days had adverse effects comparable to those reported following IV administration. Results of the present study suggest that this form of treatment has biologic activity, as evidenced by the survival time and the incidence of bone marrow suppression. This protocol may potentially offer an alternative adjunctive chemotherapy protocol for dogs with osteosarcoma undergoing limb amputation or limb-sparing surgery. The protocol described in this report may be more attractive to some owners because of the convenience of a single treatment. Pharmacokinetic studies are needed to investigate the serum carboplatin concentration-versus-time relationship and to determine whether this can be optimized to minimize adverse effects and maximize efficacy. Other areas for future investigation of this protocol include comparative studies of efficacy and toxic effects of sustained-release carboplatin administration and traditional adjunctive chemotherapy protocols; efficacy of multiple administrations, compared with a single administration; and efficacy of this protocol against other tumor types traditionally treated with carboplatin.

ABBREVIATIONS

ALP

Alkaline phosphatase

OPLA-Pt

Open-cell polyacetic acid impregnated with cisplatin

a.

Unomedical, Sydney, NSW, Australia.

b.

Pfizer, Perth, WA, Australia.

c.

Baxter Pharmacy Services, Melbourne, VIC, Australia.

d.

Baxter International, Deerfield, Ill.

e.

Prism, GraphPad Software Inc, La Jolla, Calif.

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Appendix

Veterinary Co-operative Oncology Group adverse events grading scheme.37

 GastrointestinalBone-marrow related
GradeVomitingDiarrheaNeutrophilsPlatelets
1< 3 episodes in 24 hoursIncrease of > 2 stools/d over baseline to < LLN1,500 neutrophils/μL100,000 platelets/μL to < LLN
23–5 episodes in 24 hours; < 3 episodes/d for > 2 days but < 5 days; parenteral (IV or SC) fluids indicated for < 24 hoursIncrease of 2–6 stools/d over baseline; parenteral (IV or SC fluids indicated for < 24 hours1,000–1,499 neutrophils/μL50,000–99,000 platelets/μL
3> 5 episodes in 24 hours; vomiting > 4 days; IV fluids, PPN, or TPN indicated for > 24 hoursIncrease of > 6 stools/d over baseline; incontinence; IV fluids indicated for > 24 hours; hospitalization500–999 neutrophils/μL25,000–49,000 platelets/μL
4Life-threatening (eg, hemodynamic collapse)Life-threatening (eg, hemodynamic collapse)< 500 neutrophils/μL< 25,000 platelets/μL
5DeathDeath

Bone marrow–related adverse effects were determined on the basis of hematologic findings.

LLN = Low limit of normal reference range. PPN = Partial parenteral nutrition. TPN = Total parenteral nutrition. — = Not applicable.

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