Use of alternating administration of carboplatin and doxorubicin in dogs with microscopic metastases after amputation for appendicular osteosarcoma: 50 cases (1999–2006)

Nicholas J. Bacon Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Nicole P. Ehrhart Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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William S. Dernell Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Mary Lafferty Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Stephen J. Withrow Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Abstract

Objective—To evaluate the efficacy and toxicity of an alternating carboplatin and doxorubicin chemotherapy protocol in dogs with putative microscopic metastases after amputation for appendicular osteosarcoma and assess patient-, tumor-, and treatment-related factors for associations with prognosis.

Design—Retrospective case series.

Animals—50 client-owned dogs.

Procedures—Records of dogs that underwent amputation for appendicular osteosarcoma and received an alternating carboplatin and doxorubicin chemotherapy protocol were reviewed. Dogs had full staging and were free of detectable metastases prior to chemotherapy. Data on disease-free interval (DFI), survival time, and toxicoses were retrieved from medical records and owner or referring veterinarian communications.

Results—Median DFI was 202 days. Median survival time was 258 days. Twenty-nine (58%) dogs completed the protocol as planned, and the rest were withdrawn typically because of metastases or toxicoses. Grade 3 or 4 myelosuppression was reported in 9 of 50 (18%) dogs and grade 3 or 4 gastrointestinal toxicosis in 6 of 50 (12%) dogs. There were no chemotherapy-related fatalities. Univariate factors associated with significant improvement in DFI included tumor location (radius), receiving doxorubicin as the first drug, starting chemotherapy more than 14 days after amputation, and no rib lesions on preamputation bone scans. Multivariate factors associated with a significant improvement in survival time were tumor location (radius) and completing chemotherapy.

Conclusions and Clinical Relevance—Alternating administration of carboplatin and doxorubicin resulted in DFI and survival time similar to those reported for single-agent protocols. Clients should be counseled regarding the likelihood of toxicoses. Relevance of sequence and timing of starting chemotherapy should be further evaluated.

Abstract

Objective—To evaluate the efficacy and toxicity of an alternating carboplatin and doxorubicin chemotherapy protocol in dogs with putative microscopic metastases after amputation for appendicular osteosarcoma and assess patient-, tumor-, and treatment-related factors for associations with prognosis.

Design—Retrospective case series.

Animals—50 client-owned dogs.

Procedures—Records of dogs that underwent amputation for appendicular osteosarcoma and received an alternating carboplatin and doxorubicin chemotherapy protocol were reviewed. Dogs had full staging and were free of detectable metastases prior to chemotherapy. Data on disease-free interval (DFI), survival time, and toxicoses were retrieved from medical records and owner or referring veterinarian communications.

Results—Median DFI was 202 days. Median survival time was 258 days. Twenty-nine (58%) dogs completed the protocol as planned, and the rest were withdrawn typically because of metastases or toxicoses. Grade 3 or 4 myelosuppression was reported in 9 of 50 (18%) dogs and grade 3 or 4 gastrointestinal toxicosis in 6 of 50 (12%) dogs. There were no chemotherapy-related fatalities. Univariate factors associated with significant improvement in DFI included tumor location (radius), receiving doxorubicin as the first drug, starting chemotherapy more than 14 days after amputation, and no rib lesions on preamputation bone scans. Multivariate factors associated with a significant improvement in survival time were tumor location (radius) and completing chemotherapy.

Conclusions and Clinical Relevance—Alternating administration of carboplatin and doxorubicin resulted in DFI and survival time similar to those reported for single-agent protocols. Clients should be counseled regarding the likelihood of toxicoses. Relevance of sequence and timing of starting chemotherapy should be further evaluated.

Osteosarcoma is the most common malignant appendicular bone tumor in dogs,1 and survival time following amputation of the affected limb ranges from 134 to 175 days if adjunctive chemotherapy is declined, with dogs typically dying from pulmonary metastases.2–5 The addition of chemotherapy after amputation increases both time to developing gross metastases and overall survival time6; most reported chemotherapy protocols have used the antimicrobial doxorubicin and a platinum-based drug, such as cisplatin or carboplatin. Median DFI and survival times achieved with one of these drugs in a single-agent protocol following amputation were reportedly 73 to 257 days7–9 and 104 to 413 days,3,5,7–12 respectively.

More recently, survival data for combinations of drugs have been reported, as is the standard of care in treatment of humans with pediatric osteosarcoma,13 and it has been theorized that combining 2 chemotherapeutic agents with independent and different modes of action might improve overall efficacy.14 Alternating cisplatin and doxorubicin every 3 weeks or giving both on the same day has failed to improve median survival times substantially.2,15 The greatest improvement was seen when cisplatin and doxorubicin were administered 24 hours apart, every 21 days for 4 cycles, with a reported median survival time of 540 days.16 That study was a pilot study of 16 dogs, and when repeated in 35 dogs, the median survival time decreased to 300 days,17 indicating the importance of larger studies. Use of carboplatin and doxorubicin either 24 hours apart repeated on 3 weekly cycles or alternating 1 drug every 3 weeks has resulted in median survival times of 235 and 320 days, respectively.18,19 Those 2 studies, however, followed small numbers of dogs and were not restricted to patients that had undergone amputation because dogs with a number of limb-sparing surgeries were also included. It has recently been reported that development of infection after a limb-sparing surgery will significantly improve survival time; an interaction between mechanisms or treatments of infection and slowed progression of microscopic metastases was postulated.20 This differential survival time makes it more difficult to compare survival times of limb-spared patients with amputees or to have both in a single study population where the end points are DFI or survival time.

The toxicity of chemotherapy agents often limits their administration rates and frequencies, and patients with severe adverse effects are often withdrawn from treatment prematurely, have delays in treatment, or receive reduced dosages. Platinum compounds and doxorubicin can have adverse gastrointestinal and bone marrow effects, such as vomiting, diarrhea, anorexia, and myelosuppression. Doxorubicin, additionally, is toxic to the myocardium, which may result in dilated cardiomyopathy. When evaluating a combination chemotherapy protocol that uses agents that induce overlapping toxicoses, the frequency of severe adverse gastrointestinal and bone marrow effects should be assessed and compared with those historically reported for single-agent protocols.

The purpose of the single-center retrospective case series study reported here was to evaluate the safety and efficacy of a chemotherapy protocol of alternating administration of carboplatin and doxorubicin for treatment of a large number of dogs with osteosarcoma, all of which had undergone amputation, and to assess patient-, tumor-, and treatment-related factors for prognosis.

Materials and Methods

Criteria for selection of cases—The computerized medical records database at the Colorado State University Veterinary Medical Center was searched for dogs that had a diagnosis of appendicular osteosarcoma, had undergone amputation between 1999 and 2006, and whose owners had subsequently chosen a chemotherapy protocol of carboplatin (300 mg/m2) and doxorubicin (30 mg/m2) given alternately at 3-week intervals for a total of 3 treatments each. All dogs that received at least 1 dose of each drug after surgery were considered to have started the combination protocol.

Exclusion criteria included dogs that did not receive doxorubicin because of clinical cardiac disease or echocardiographic evidence of subclinical dilated cardiomyopathy; dogs that underwent limb-sparing surgery; dogs that received palliative radiation to the affected limb prior to amputation; dogs that had stage III disease (radiographic pulmonary metastases or skeletal sites of increased 99mTc-MDP uptake on bone scan that were clinically, radiographically, or histologically consistent with metastatic bone disease); and dogs with histologic evidence of metastases in a draining lymph node.

Procedures—Mandatory initial staging included performance of a CBC, serum biochemical profile, and 3-view thoracic radiography. A 99mTc-MDP nuclear bone scan was recommended. All dogs underwent amputation, and a diagnosis of osteosarcoma was confirmed histogically, with surgery being carried out at the Colorado State University Veterinary Medical Center or by the referring veterinarian. Histologic examination of the draining lymph node was performed when available.

Chemotherapy was recommended for every patient following amputation after osteosarcoma was confirmed. Single-agent and combination protocols were discussed with the owner, who then made an informed decision on the basis of finances, the presence of cardiac disease, the available survival-time and toxicity data of the published protocols, or the perceived benefits of the combination protocol. Chemotherapy typically started at time of suture removal (10 to 14 days after amputation) with no standardization as to whether the patient received carboplatin or doxorubicin first. Most dogs received all chemotherapy at the Colorado State University Veterinary Medical Center. Occasionally the protocol was started there and completed by the referring veterinarian under university guidance. A CBC was performed prior to administration of either drug and at 7 to 10 days (ie, the nadir) after the first dose of each. The CBC was subsequently only assessed between doses if the patient became unwell. Three-view thoracic radiographs were typically obtained immediately before the third and sixth doses and then subsequently at 3 monthly intervals for the first year, then every 6 months thereafter.

Myelosuppression, specifically neutropenia and thrombocytopenia, was recorded through CBCs performed at the Colorado State University Veterinary Medical Center or by the referring veterinarian and graded according to the VCOG blood-bone marrow toxicosis criteria as described by Vail.21 The grading of myelosuppression assigned to a patient was determined by the highest grade detected during chemotherapy. Gastrointestinal toxicosis was assessed from the medical records of the Colorado State University Veterinary Medical Center or the referring veterinarian. Vomiting, diarrhea, and anorexia were graded according to the VCOG gastrointestinal toxicosis criteria. The grading of gastrointestinal toxicosis assigned to a patient was determined by the highest grade detected during chemotherapy.

Chemotherapy was stopped if gross metastatic disease was diagnosed. In the event of severe toxicosis, owners decided whether to continue the protocol as planned with closer monitoring of CBCs and with prophylactic medication being prescribed (antiemetics and antidiarrheals), reduce the dose of subsequent treatments, omit the drug and convert to a single-agent protocol, or withdraw their dog from further treatment.

Statistical analysis—The DFI was defined as the interval between amputation and clinical evidence of gross metastatic disease. Survival time was defined as the interval between amputation and death. Cause of death was classified as neoplasia- or treatment-related, or non-neoplasia- or non–treatment-related. Dogs with unknown causes of death were presumed to have died from neoplasia- or treatment-related disease. For the purposes of survival calculations, dogs that had neoplasia- or treatment-related death were considered completed events, and dogs lost to follow-up, that died of causes other than osteosarcoma (confirmed by necropsy), or that were still alive without evidence of metastasis were censored at the time of last contact.

Median DFI and survival time were determined by the use of the Kaplan-Meier product-limit method, and log-rank analysis was used to compare DFI and survival times among dogs for the following factors: age, weight, duration of clinical signs, biopsy performed, tumor location, high serum alkaline phosphatase activity, bone scan performed, interval between surgery and chemotherapy, which agent was given first, dose reduction required to complete chemotherapy, myelosuppression observed, gastrointestinal toxicosis observed, and whether chemotherapy was completed. Where appropriate, medians were reported with a 95% CI. Any factors identified as significant (P < 0.05) via univariate analysis for either DFI or overall survival time were tested for significance via multiple logistic regression (proportional hazard analysis [Cox analysis]).

Continuous variables were stratified for the purposes of these analyses. On the basis of the medians, age was classified as < 8 or ≥ 8 years, weight was < 36 or ≥ 36 kg (79.2 lb), duration of clinical signs was < 28 or ≥ 28 days, and interval between amputation and starting chemotherapy was d 14 or > 14 days. Results for all tests were considered significant at P < 0.05. A commercial software package was used for all statistical analysis.a

Results

Fifty dogs in the period from 1999 to 2006 underwent amputation for appendicular osteosarcoma and then started an alternating carboplatin and doxorubicin chemotherapy protocol to treat putative microscopic metastatic disease. Median age was 8.0 years (range, 1.3 to 13.2 years) and median weight was 36 kg (range, 21 to 75 kg [46 to 165 lb]). There were 26 neutered females, 1 sexually intact female, 20 neutered males, and 3 sexually intact males. The most common breeds represented were Labrador Retriever (n = 8), mixed breed (7), Golden Retriever (6), Greyhound (4), Rottweiler (4), Great Pyrenees (3), and Alaskan Malamute (2). Tumors were detected in the proximal portion of the humerus (n = 15), distal portion of the radius (13), distal portion of the femur (9), distal portion of the tibia (4), proximal portion of the tibia (3), distal portion of the humerus (2), proximal portion of the radius (1), proximal portion of the femur (1), proximal portion of the ulna (1), and scapula (1); 66% were in a forelimb and 34% in a hind limb, with 54% being on the right side and 46% on the left side.

Median duration of clinical signs prior to evaluation for this study was 28 days (range, 5 to 365 days). The 99mTc-MDP bone scans were performed in 94% (47/50) of the dogs and were declined by the owners in the remaining 3 dogs. All dogs with clinical or radiographic bone metastases (stage III disease) had been excluded from this study, so 91% (43/47) of bone scans were unremarkable and revealed the primary lesion with or without additional areas of uptake attributable to osteoarthritis or periodontal disease. Unanticipated foci of 99mTc-MDP uptake were seen in 4 of 47 dogs, all of which had rib lesions. None of these locations were associated with clinical signs of pain, and radiographically, they appeared chronic and quiescent (presumed to be rib trauma that had occurred previously), so those 4 dogs were included in the study.

Amputations of the forelimb were full-quarter with scapula resection, and those of the hind limb were predominantly via coxofemoral disarticulation. One dog with a lesion of the proximal femoral region was treated via amputation that included acetabulectomy, and 1 dog with a lesion of the distal portion of the tibia was treated via amputation by the referring veterinarian via midfemoral osteotomy. Results of histologic examination of the draining lymph node were available in 38 of 50 (76%) dogs, and all were negative for metastases. Median interval between amputation and starting chemotherapy was 14 days (range, 1 to 87 days), and 30 of 50 (60%) dogs received carboplatin first, and 20 of 50 (40%) dogs received doxorubicin first. Echocardiography was performed in 25 of 50 (50%) dogs, typically in the breeds at risk for cardiomyopathy. All examinations were performed at the time of administration of the first doxorubicin dose, and 2 of 25 had a second echocardiogram prior to the third doxorubicin dose.

Twenty-nine of 50 (58%) dogs completed the protocol as prescribed, receiving 3 doses of both carboplatin and doxorubicin. Twenty-one of 50 (42%) dogs did not finish the protocol; in 13 of 21 (62%), the protocol was stopped because of metastatic disease (in 11 dogs metastasis occurred to the lungs, in 1 to a vertebra, and in 1 to the amputation site of a midfemoral osteotomy [although conceivably this could have been a synchronous primary, local recurrence or preexisting bony metastasis because the owner declined use of bone scintigraphy]). Eight of 21 (38%) dogs had the protocol stopped or altered because of reasons other than metastasis: in 3 dogs because of toxicosis; in 3 because of an owner's or veterinarian's decision that the dog was not tolerating the chemotherapy well, although no specific toxicosis was recorded; and in 2 (doxorubicin) because cardiac abnormalities were diagnosed.

DFI and survival—Forty-four of the 50 dogs died, and follow-up time for living dogs was 167, 173, 449, 474, 539, and 2,192 days. The DFI for all dogs was 202 days (95% CI, 146 to 258 days; Figure 1). Median overall survival time for all dogs was 258 days (95% CI, 174 to 342 days; Figure 2). Factors that were not significantly associated with either DFI or survival time included age, weight, duration of clinical signs, whether a biopsy was performed, high serum alkaline phosphatase activity, dose reduction to complete chemotherapy, whether myelosuppression was observed, and whether gastrointestinal toxicosis was observed. Factors significantly associated with DFI or survival time via univariate analysis were determined (Table 1).

Figure 1—
Figure 1—

Kaplan-Meier curve of DFI for 50 dogs with appendicular osteosarcoma treated with amputation and alternating carboplatin and doxorubicin chemotherapy. Black circles = Censored dogs.

Citation: Journal of the American Veterinary Medical Association 232, 10; 10.2460/javma.232.10.1504

Figure 2—
Figure 2—

Kaplan-Meier curve of survival time for 50 dogs with appendicular osteosarcoma treated with amputation and alternating carboplatin and doxorubicin chemotherapy. See Figure 1 for key.

Citation: Journal of the American Veterinary Medical Association 232, 10; 10.2460/javma.232.10.1504

Table 1—

Factors associated with DFI or survival time (median values [95% CI]).

FactorDFI in daysSurvival time in days
Interval between surgery and chemotherapyP = 0.034P = 0.097
   ≤ 14 days (n = 27)152 (133–171)
   ≥ 14 days (n = 23)462 (90–834)
Bone scintigraphyP = 0.039P = 0.168
   Rib lesions present (n = 4)103 (0–210)
   No rib lesions present (n = 46)229 (176–282)
Agent given firstP = 0.036P = 0.125
   Carboplatin (n = 30)187 (114–260)
   Doxorubicin (n = 20)239 (0–621)
Tumor location*P = 0.018P = 0.009
   Radius (n = 14)468 (164–771)596 (306–885)
   Not radius (n = 34)187 (136–238)232 (204–259)
Completed chemotherapy courseP< 0.001P< 0.001
   Completed all 6 doses (n = 29)295 (0–643)507 (175–839)
   Did not finish prescribed course (n = 21)106 (65–147)156 (123–189)

Scapula (n = 1) and ulna (1) were excluded from analysis because of low number.

When tumor location was divided into radius or nonradius sites, a significant difference in DFI was seen between sites. A significant difference was also seen in survival time between the radius and nonradius sites (Figure 3). A significant advantage in DFI was observed in patients with negative results of bone scans (including uptake in joints or teeth) versus those with rib lesions. A significant advantage in DFI was observed in patients that received doxorubicin first versus receiving carboplatin first.

Figure 3—
Figure 3—

Kaplan-Meier curve of survival time of 48 dogs with appendicular osteosarcoma in the radius (n = 14) or a nonradius location (34; P = 0.009). Dogs with osteosarcoma in the scapula (n = 1) or ulna (1) were excluded. See Figure 1 for key.

Citation: Journal of the American Veterinary Medical Association 232, 10; 10.2460/javma.232.10.1504

Regarding effect of delay between surgery and starting chemotherapy, a significant advantage in DFI was seen in patients that started more than 14 days after surgery versus those that started 14 days or less from surgery. Regarding the effect of finishing the chemotherapy protocol, a significant increase in DFI was seen in dogs that received all 6 prescribed doses versus those that did not. A significant increase in overall survival time was detected in those dogs that completed the course versus those that did not complete the course. No difference was detected in DFI (P = 0.866) between dogs that finished the chemotherapy course at the recommended doses and those that had dose reductions (typically because of toxicosis) to finish the course.

Multivariate analysis on the significant variables described revealed that only completing the chemotherapy course as prescribed and receiving all 6 doses of drug was significant for improved DFI (P = 0.001). Multivariate analysis revealed that, for improved overall survival time, tumor location in the radius (P = 0.02) and completing chemotherapy (P < 0.001) were significant factors.

Toxicosis—Myelosuppression was identified in 29 of 50 (58%) dogs (Table 2. Neutropenia (VCOG toxicosis grades 1 to 4) was identified from the CBCs in 23 of 50 (46%) dogs; 13 of 23 (57%) had the worst neutropenia during the first alternating cycle of both drugs (carboplatin, n = 7; doxorubicin, 6), 5 of 23 (22%) during the second cycle, and 5 of 23 (22%) during the third and final cycle. Thrombocytopenia (VCOG grades 1 to 3) was identified in 15 of 50 (30%) dogs; 8 of 15 (53%) had the worst thrombocytopenia during the first alternating cycle of both drugs (carboplatin, n = 5; doxorubicin, 3), 3 of 15 (20%) during the second cycle, and 3 of 15 (20%) during the third and final cycle. A CBC was not routinely performed 7 to 10 days after every dose of chemotherapy (other than the first dose of each drug), and only those identified to be abnormal during the course of treatment were recorded.

Table 2—

Distribution (number [%] of affected dogs) of VCOG myelo-suppression toxicosis scores in 50 dogs with osteosarcoma treated with alternating administration of carboplatin and doxorubicin

VCOG toxicosis score
Toxicosis0123 
Neutropenia27 (54)14 (28) 2 (4) 1 (2)   
Thrombocytopenia*35 (70)9 (18) 3 (6) 2 (4)0  
Combined*21 (42)16 (32) 3 (6) 3 (6)6 (12)  

One dog reported as thrombocytopenic in referring veterinarian's records but values not quantified.

Determined via the highest grade of either myelosuppressive toxicosis detected.

Gastrointestinal adverse effects were recorded in 29 of 50 (58%) dogs. The VCOG toxicosis distribution was determined (Table 3). Anorexia was recorded in 13 of 50 (26%) dogs; in 10 (77%), anorexia was reported after the first dose of doxorubicin, with the other 3 (23%) being after the first or second dose of carboplatin. Both grade 3 anorexic toxicoses occurred after the first dose of doxorubicin. Vomiting was recorded in 20 of 50 dogs (40%). Of the 20, 13 (65%) were recorded as vomiting following the first dose of doxorubicin, 4 (20%) following the second and third doses of doxorubicin, and 3 (15%) following the second and third doses of carboplatin. Diarrhea was recorded in 19 of 50 dogs (38%); 11 (58%) cases of diarrhea were reported after the first dose of doxorubicin, with 5 (26%) after the second dose of doxorubicin. Diarrhea occurred after administration of carboplatin in 3 dogs (16%).

Table 3—

Distribution (number [%] of affected dogs) of VCOG gastro-intestinal toxicoses in 50 dogs with osteosarcoma treated with alternating administration of carboplatin and doxorubicin

VCOG toxicosis score
Toxicosis01234
Anorexia37 (74)8 (16)3 (6)2 (4)0
Vomiting30 (60)5 (10)10 (20)4 (8)1 (2)
Diarrhea31 (62)12 (24)3 (6)3 (6)1 (2)
Combined*21 (42)11 (22)12 (24)5 (10)1 (2)

Determined via the highest grade of gastrointestinal toxicosis detected.

Four dogs received dose reductions of carboplatin—3 because of neutropenia following previous administration, and in the fourth, there was no record why the dose had been reduced. Seven dogs received dose reductions of doxorubicin—3 from myelosuppression and 4 following gastrointestinal toxicosis from the previous dose.

Five dogs unexpectedly were evaluated for illness or sepsis and were hospitalized during the protocol—2 dogs with grade 4 gastrointestinal toxicosis after the first doxorubicin treatment and 3 dogs with grade 4 neutropenia. All were hospitalized for approximately 24 hours and received IV administration of fluid, antimicrobial treatment, or both. There were no fatalities associated with this chemotherapy protocol.

Treatment following macrometastasis—Once metastasis was diagnosed, any dogs receiving the alternating chemotherapy protocol were withdrawn from further administrations of carboplatin, doxorubicin, or both. In addition, 25 of 50 dogs (50%) had new treatments added; 19 dogs were administered an NSAID, either alone (n = 6) or in combination (13) with doxycycline, cyclophosphamide, or both (so-called low-dose or metronomic chemotherapy22,23); 3 dogs underwent metastatectomy for lung masses, 2 via thoracotomy and 1 via thoracoscopy; 2 dogs received corticosteroids; and 1 dog received palliative radiation therapy. Treatment of macroscopic metastases did not result in significantly improved survival time; untreated median survival time was 45 days (95% CI, 27 to 63 days), and treated median survival time was 66 days (95% CI, 32 to 104 days; P = 0.317).

Discussion

In the present study, the median DFI and overall survival times of 202 and 258 days, respectively, were not significant improvements over previously reported protocols. The authors have chosen to describe DFI more frequently in this report because it is this, not overall survival time, that theoretically more accurately represents efficacy of chemotherapy agents.

All dogs that received at least 1 dose of each agent were considered to have started the protocol, and the end point of treatment was 3 doses of each agent. Dogs that completed the protocol as planned had significantly longer DFI (median, 295 days) than those that did not (median, 106 days). It is tempting to suggest that a longer course of chemotherapy is therefore more beneficial, but these data are biased because all dogs that completed the protocol were free from metastatic disease at the end of the 6 doses, which skewed DFI in their favor versus dogs that did not finish the protocol.

Every attempt was made to ensure that dogs were free from detectable metastases prior to treatment (stage II disease), and 94% of dogs in this study underwent a 99mTc-MDP bone scan. All dogs judged to have clinical or radiographic suspicion of bone metastases on the basis of findings of the scan (stage III disease) were excluded from this study. Four of 47 dogs had unanticipated uptake of technetium in ribs that were clinically and radiographically silent, and those dogs were included. Those dogs died from metastases at 79 days (metastases in lungs), 173 days (metastases in lungs), 187 days (presumed generalized metastases), and 258 days (metastases in lungs). Those 4 dogs had significantly shorter DFI than those with negative results of bone scans, so it might be prudent to biopsy rib lesions to rule out occult metastases in otherwise benign-appearing lesions.

This extent of staging differs from the approach of many previous investigators. Although some have performed skeletal survey radiography8 and occasionally scintigraphy,11,12 most exclude systemic metastases by 3-view lung radiography alone and do not describe scintigraphy being performed.5,9,15–19,24 It can be postulated that these studies may have missed early bone metastases and so included a number of dogs with stage III disease, which would worsen their results. The results presented here, however, despite more aggressive staging, did not indicate an improved survival time over results published previously.

Primary tumor location was associated with prognosis in this study population because dogs with radial tumors had significantly longer DFIs and survival times than those with tumors in other appendicular sites. This was also a significant variable in multivariate analysis. This is similar to findings in humans in which patients with distally located tumors (distal to the elbow or knee) have a better prognosis than do patients with proximally located tumors.25 The effect of primary tumor location has been evaluated by Bergman et al,9 who identified tumors in the proximal portion of the humerus as a negative prognostic factor and attributed this to more advanced local growth (larger tumor volume) before diagnosis and therefore a higher chance of development of metastases. It is not known whether dogs with tumors of large diameters and volumes are more likely to have pulmonary metastases at necropsy than are dogs with smaller tumors.26 Conversely, the opposite is true of tumors of the radius, with smaller tumor volumes associated with a better prognosis if these cases are diagnosed earlier. Dogs with small distal radial tumors may have been referred to the Colorado State University Veterinary Medical Center for limb-sparing treatments, but the owners subsequently chose amputation. Comparison of the radiographic or scintigraphic volume of radial tumors versus tumors in other appendicular sites would be valuable to help investigate this finding but was beyond the limits of this study.

Dogs that received doxorubicin first had a significantly longer DFI than those that received carboplatin first (median, 468 vs 187 days). This is of great interest but was an unexpected finding and is difficult to explain; it is important to note that this finding was not significant in multivariate analysis. The dogs were not randomized into each group, but the 14 dogs with radial osteosarcoma were split evenly between the 2 groups, which should have eliminated that potential source of bias. The order of the drug sequence used in combination chemotherapy potentially enhances the therapeutic effect of the treatment in humans and is typically explained by either pharmacodynamic interactions between the agents in combination or chemotherapy-induced cell-cycle perturbations.27 Similar data are lacking in the veterinary literature, and this warrants future randomized prospective studies.

Another unanticipated result was that dogs that began receiving chemotherapy more than 14 days after amputation had significantly longer DFIs than those that began 14 days or less after amputation (234 days vs 152 days), but this difference was not significant in multivariate analysis. In human literature, it is suggested that survival times are improved by initiating chemotherapy as soon as possible after surgery,28 and in mice with experimentally induced osteosarcoma, survival times are significantly improved by starting chemotherapy at the time of surgery rather than 2 weeks after surgery.29 A randomized veterinary study,15 however, failed to detect a significant difference in survival time between dogs that began receiving chemotherapy at 2 versus 10 days after amputation for appendicular osteosarcoma; however, dogs that received both cisplatin and doxorubicin 2 days after amputation had greater rates of grade 4 toxicosis than dogs that received the same drugs on day 10.24 A study by Straw8 failed to detect a difference in median DFI between 17 dogs with appendicular osteosarcoma treated with amputation and postoperative administration of cisplatin versus 19 dogs treated with amputation plus preoperative and perioperative administration of cisplatin. Although the optimal time to start chemotherapy for treatment of microscopic metastases is unknown, the finding that dogs in the present study had improved DFI when chemotherapy was delayed is contrary to current theories of tumor biology and behavior. Assignment to the groups in the study reported here was not randomized, and this variable should be investigated prospectively.

In this study, myelosuppression was identified in 29 of 50 (58%) dogs. In 9 of 50 (18%) this was grade 3 myelosuppression or higher. Gastrointestinal toxicosis was recorded in 29 of 50 (58%) dogs. In 6 of 50 (12%) this was grade 3 toxicosis or higher. It appears that these VCOG toxicoses are both more common and more severe when compared to results of previous studies. The VCOG toxicosis grading as described by Vail21 is too recent to have been used by previous investigators, but VCOG grading can be inferred in many previous studies from the clinical signs and toxicoses described. Berg11 describes no appreciable myelosuppression in 22 dogs receiving cisplatin alone, and only 1 dog had transient vomiting. Straw8 describes grade 3 gastrointestinal toxicoses in 11% of dogs receiving cisplatin alone and grade 4 neutropenia in 3%. There were no toxicoses reported by Thompson5 in dogs receiving cisplatin alone. Berg12 describes 35 dogs receiving doxorubicin alone; 2 (6%) developed grade 3 neutropenia, and 2 (6%) had substantial gastrointestinal toxicosis. When cisplatin and doxorubicin were combined, moderate myelosuppression was seen in 13% of dogs and a grade 3 gastrointestinal toxicosis in 6%.16 Bergman,9 reporting use of carboplatin alone, describes grade 4 neutropenia in 2% of dogs and no reported gastrointestinal adverse effects. When carboplatin and doxorubicin were combined on a day-1–day-2 schedule,18 4% of dogs had a grade 3 gastrointestinal toxicosis and 9% a grade 3 thrombocytopenia. When combined as described here in an alternating protocol every 3 weeks,19 grade 3 neutropenia was seen in 3% of dogs, grade 3 thrombocytopenia in 3%, and grade 3 vomiting in 3%. The difference in toxicoses reported between the present study and other combination protocols is possibly a factor of more complete records being available or more aggressive CBC screening, because details on frequency of screening are not always clear from previous studies.

Results of an equivalent treatment protocol used in dogs treated with amputation or limb-sparing procedures indicated a median DFI of 227 days and median overall survival time of 320 days.19 The larger study reported here involved a homogeneous population of dogs treated via amputation and found a median DFI of 202 days and survival time of 258 days, which provides further evidence that this protocol does not seem to offer a substantial survival time advantage over previously described singleor combination-agent protocols.

Limitations of the present study were those inherent to a retrospective case series. In grading toxicoses, the scoring system is only as accurate as the details in the case record, and it is possible that gastrointestinal toxicoses were underreported. The time of occurrence of neutrophil and platelet nadirs after administration of carboplatin is variable (either 7 or 14 days after treatment18,30), so performance of only 1 CBC 7 to 10 days after the first administration of carboplatin increased the probability of missing the true nadir. In addition, after the first dose, postadministration CBCs were only performed if the dog was clinically ill, so it is possible that the true prevalence of myelosuppression during chemotherapy was underestimated. To accurately determine the true prevalence of myelosuppression associated with this alternating drug combination, a prospective study with CBCs obtained weekly would be necessary. An insufficient number of postmortem examinations were performed to definitively diagnose metastatic disease in every case, but in the survival analysis, all deaths were assumed to be tumoror treatment-related unless ruled out by necropsy findings.

The alternating chemotherapy protocol of doxorubicin and carboplatin, as studied retrospectively, did not appear to offer any clear prognostic advantage over single-agent protocols. Whether this would hold true if the combination therapy was compared directly with doxorubicin or carboplatin administered singly in a prospective trial has yet to be determined. The alternating protocol, however, appears to be associated with more toxicosis than in studies of single agents, and owners should be advised of this. Results of multivariate analysis revealed significantly longer survival times in dogs with radial osteosarcoma, compared with other appendicular sites, and this warrants further investigation.

ABBREVIATIONS

DFI

Disease-free interval

99mTc-MDP

Technetium Tc 99m medronate

VCOG

Veterinary Co-operative Oncology Group

CI

Confidence interval

a.

SPSS statistical software, SPSS Inc, Chicago, Ill.

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