Management of Canine Appendicular Osteosarcoma

Clinical Management of the Cancer Patient

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Management of Canine Appendicular Osteosarcoma

Rodney C. Straw, BVSc,* Stephen]. Withrow, DVM,t and Barbara E. Powers, DVM, PhD+

Osteosarcomas or osteogenic sarcomas are malignant tumors primarily arising in bone. Histologically they are composed of anaplastic mesenchymal cells which produce osteoid. Histologic subgroups include osteoblastic, chondroblastic, fibroblastic, osteoclastic, poorly differentiated, and telangiectatic osteosarcoma. 29 • 47 To date, these subgroups have not been shown to influence biologic behavior or response to treatment in dogs. The key to the histologic diagnosis, however, is the presence of tumor osteoid. Seventy-five percent of osteosarcomas develop in long bones, whereas 25% arise in the skull and axial skeleton. 9 Most osteosarcomas arise in the medullary canal of long bones, usually in the metaphysis, but some arise on the cortical surfaces, periosteum (periosteal, parosteal, or juxtacortical osteosarcoma), and in extraskeletal sites such as mammary gland, liver, spleen, or intestine. 29 • 52 At presentation, canine appendicular osteosarcoma is commonly staged liB; that is, the tumor is usually clinically confined to the primary site but extends outside the medullary canal ("II") and is of high histologic grade ("B"). 17 • 18 Osteosarcoma causes local destruction of surrounding tissue at the primary site and readily metastasizes (usually to the lungs). From the Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, Colorado *Diplomate, American College of Veterinary Surgeons; Assistant Professor, Comparative Oncology Unit, Department of Clinical Sciences tDiplomate, American College of Veterinary Internal Medicine (Oncology) and American College of Veterinary Surgeons; Professor and Chief, Comparative Oncology Unit, Department of Clinical Sciences :j:Diplomate, American College of Veterinary Pathologists; Assistant Professor, Comparative Oncology Unit, Department of Radiology and Radiation Biology Supported in part by PHS grant l POl CA 29582, awarded by the National Cancer Institute, Department of Health and Human Services Veterinary Clinics of North America: Small Animal Practice-Val. 20, No.4, July 1990

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INCIDENCE AND SITE PREDILECTION Osteosarcoma accounts for 2 to 7% of all canine malignancies and affects between 8000 and 10,000 dogs per year in the United States. 16· 49 Large to giant breed dogs are at risk and the median age is 7 years; however, dogs as young as 6 months may be affected. 9 • 45 Males are reported to be more frequently affected except in St. Bernards, where females outnumber males in incidence. 9 Primary tumors most commonly arise in metaphyseal sites. The most common long bone site affiicted is the distal radius, followed by the proximal humerus and proximal or distal femur, or proximal or distal tibia. Other sites include·the ulna and, rarely, metatarsal, metacarpal, and digital bones. It is extremely rare for osteosarcoma to arise in sites adjacent to the elbow. RADIOGRAPHIC APPEARANCE AND DIFFERENTIAL DIAGNOSIS Radiographically, osteosarcomas of long bones may be primarily lytic, blastic, or mixed in appearance. There is usually discontinuity of cortical bone owing to lysis, and there are varying degrees of periosteal reaction and tumor extension into the soft tissue. There is usually a poorly defined transitional zone in the medulla, and Cadman's triangle or a "sunburst" appearance may be seen (Fig. 1). The radiographic appearance is not pathognomonic for osteosarcoma, however, and differential diagnoses to consider include the following: other primary bone tumors (chondrosarcoma, fibrosarcoma, hemangiosarcoma), which account for 5 to 10% of primary bone tumors of long bones; tumors arising from bone marrow elements (multiple myeloma and, rarely, lymphoma); metastatic bone tumor (virtually any malignancy, but commonly urogenital tumors); bacterial osteomyelitis; and systemic mycosis (usually blastomycosis or coccidioidomycosis). Other, less likely diagnostic possibilities include benign bone tumors, fractures, and degenerative/reparative lesions. Metastatic tumor may be suspected if a site of primary cancer is known in an older dog. Bacterial osteomyelitis may be suspected if there has been surgery or a penetrating wound at the site or if there is a discharging sinus. Systemic mycosis may be suspected if the dog lives in or has traveled to an endemic area and if there have been or there are respiratory signs. Strong circumstantial evidence of osteosarcoma can be found in large-breed, middle/ older-age dogs with a lytic/blastic lesion of the metaphysis of a long bone. Definitive diagnosis of osteosarcoma can only be made by histologic examination of tissue. WORK-UP Careful history-taking should include information regarding travel, previous surgery (particularly internal fixation for fracture repair), previous cancer within 2 years, and trauma (particularly a history of fractures or

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Figure l. Lateral radiograph showing features of an osteosarcoma primary located in the proximal fe moral metaphysis: (l ) discontinuity of cortical bone due to lysis; (2) poorly defin ed transitional zone; (3) Cadman's triangle; (4) sunburst; (5) pathologic fracture.

penetrating injury). Travel history to an endemic area is relevant to systemic mycosis as a potential differential diagnosis. Cancer history may implicate bone metastasis. Recent surgery may implicate bacterial osteomyelitis, and previous fractures with or without surgery have been associated with osteosarcoma. Many dogs with osteosarcoma will present with a history of minor trauma causing acute and progressive lameness. The overall health status needs careful assessment. Advancing years do not preclude treatment; however, prolonged anesthesia and chemotherapy may not be tolerated in dogs with organ compromise. Particular attention to the cardiovascular system is important. Coexisting cardiomyopathy or any degree of heart failure may lead to serious complications, particularly during fluid diuresis at surgery or during administration of chemotherapy. An electrocardiogram and echocardiogram should be performed on dogs where the history or physical findings implicate a cardiac disorder. Renal function must be evaluated prior to administration of cisplatin (Platinol, Bristol-Myers Co., Syracuse, NY). A minimum data base should include a complete blood count, platelet count, serum biochemical analysis, and urinalysis. For safe administration of cisplatin, dogs should have more than 3000 polymorphonuclear leukocytes per uL, more than 150,000 platelets per uL, normal blood urea nitrogen and creatinine, and urine specific gravity of at least l. 030, with no proteinuria or casts in the urine sediment.

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Tumor staging includes radiographs of the affected limb, regional lymph node palpation, fine-needle aspiration cytology if lymphadenopathy is detected, thoracic radiography, and biopsy of the primary site. Other staging tools include abdominal ultrasound, skeletal scintigraphy, bone survey radiography, lung tomography, and computer tomography of the lungs and primary site. Of these staging techniques, bone survey radiography has been most useful in detecting dogs with second skeletal sites of tumor. 34 Bone surveys include lateral radiographs of all bones in the body using standard radiographic technique appropriate for the region radiographed. One hundred and seventy-one dogs with primary bone tumors at Colorado State University (CSU) underwent radiographic bone surveys and thoracic radiography between January 1981 and August 1989. At presentation, a higher yield in finding other nonclinically detectable neoplastic sites was determined with radiographic bone survey (6.4%, 11 of 171 dogs) than with thoracic radiographs (4%, 7 of 171 dogs). There are conflicting reports on the usefulness of nuclear scintigraphy for clinical staging of dogs with osteosarcoma. Bone scintigraphy was used in one study to identifY suspected second bone sites of osteosarcoma in 14 of 25 dogs with appendicular primaries. 26 Seven of these lesions were biopsied and confirmed to be osteosarcoma. Another study of 70 dogs with appendicular primary bone tumors resulted in only one scintigraphy-detectable occult bone lesion. 5 In a third report, of 23 dogs with suspected skeletal neoplasia that were evaluated with scintigraphy and radiography, 15 had appendicular osteosarcoma. 44 Of these, 4 dogs had second skeletal sites suspected as neoplastic. The suspicious site in 1 of these dogs was found, on histologic evaluation, to be normal bone. IdentifYing dogs with second skeletal lesions obviously has an impact on the treatment plan.

BIOPSY TECHNIQUES

A diagnosis of primary malignant bone tumor is often suggested by signalment and radiographic findings. However, biopsy is necessary to confirm the diagnosis. With new treatments such as limb-sparing, knowledge of the specific tumor type may help avoid overextensive or inappropriate treatment of bone tumors thought to be osteosarcoma (for example, chondrosarcoma or lymphosarcoma). Bone biopsy may be performed as an open incisional or trephine biopsy, or a closed needle or trephine biopsy. The advantage of the open techniques is that a large sample of tissue is procured, which presumably improves the likelihood of establishing an accurate histologic diagnosis. Unfortunately, this advantage is outweighed by the disadvantages of (1) an involved operative procedure, and (2) risk of postsurgical complications such as hematoma formation, wound breakdown, infection, local seeding of tumor, and pathologic fracture. 15• 54 Although closed biopsy with a Michelle trephine yields a diagnostic accuracy rate of 93.8%, there is increased risk of creating pathologic fracture over that found with a needle. 65 For these reasons, the authors prefer a closed biopsy using a Jamshidi bone marrow

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biopsy needle (American Pharmaseal Co., Valencia, CA) or similar type of needle (Bone marrow biopsy needle, Sherwood Medical Co., St. Louis, MO). Jamshidi needle biopsy has an accuracy rate of 91.9% for detecting tumor versus nontumor and an 82.3% accuracy rate for diagnosis of specific turiwr subtype. 46 The biopsy site is selected carefully. Radiographs (two views) are taken of the limb and the center of the lesion chosen for biopsy. The skin incision is made with consideration of possible subsequent treatment so the biopsy tract and any potentially seeded tumor cells can be completely removed at the time of definitive surgery. Care is used to avoid major nerves, vessels, and joint spaces. A 4-inch 8- or 11-gauge needle is used (Fig. 2). With the dog anesthetized, prepared, and draped for surgery, a small stab incision (2 to 3 mm) is made in the skin with a No. 11 scalpel blade. The bone needle cannula, with the stylet locked in place, is pushed through the soft tissue to the bone cortex. The stylet is removed and the cannula is advanced through the bone cortex into the medullary cavity using a gentle twisting motion and firm pressure. The opposite cortex is not penetrated. The needle is removed and the specimen is gently pushed out of the base of the cannula by inserting the probe into the cannula tip. One or two more samples can be obtained by redirecting the needle through the same skin incision. Specimens should be 1 or 2 em in length and not fragmented. Biopsy is repeated until solid tissue cores are obtained. Material for culture and cytology (if indicated) are then taken from the samples prior to fixation in 10% neutral buffered formalin. Diagnostic accuracy is clearly improved when samples are evaluated by a pathologist thoroughly familiar with bone cancer. After tumor removal (amputation or limb-sparing), histology should be performed on a larger specimen to confirm the preoperative diagnosis. BIOLOGIC BEHAVIOR

Osteosarcoma has very aggressive local effects, causing lysis of bone and inducing varying degrees of lameness. The local disease is usually attended by soft-tissue swelling, and pathologic fracture is not uncommon. Metastasis is common and arises early (albeit subclinically) in the course of the disease. Although fewer than 5% of dogs have radiographically detectable pulmonary metastasis at presentation, 90% die with metastatic disease to the lungs within 1 year when amputation is the only treatment. 9 Metastasis via the hematogenous route is most common; however, extension to regional nodes will occur in up to 5% of cases. Although the lung is the most commonly reported site for metastasis, tumor spread to bones or other soft-tissue sites occurs with some frequency. A recent multi-institutional study of 162 dogs with appendicular osteosarcoma treated with amputation alone confirmed the earlier findings of Brodey;9 that is, the median survival was 5 months, with a 10% 1-year survival. In this study, dogs under 5 years of age had worse survival than older dogs (Berg RJ: Personal communication). There has not been any large study in dogs to date that has consistently documented other variables (site, size, sex, breed, and so on) with prognostic significance.

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D Figure 2. A , The Jamshidi type biopsy needle: cannula and screw-on cap (a), tapered point (inset b), pointed stylet to advance cannula through soft tissue (c), and probe to expel specimen from cannula (d). B, With the stylet locked in place, the cannula is advanced through soft tissue until bone is reached . Inset: close-up of portion of bone with stylet up to cortex. C, The stylet removed and the bone cortex penetrated with the cannula. The cannula is withdrawn and the procedure is repeated with redirection of the needle. D , The probe is then inserted into the tip of the cannula and the specimen expelled through the cannula base (inset ). (From Powers BE, LaRue SM, Withrow SJ, e t a!: Jamshidi needle biopsy for diagnosis of bone lesions in small animals. J Am Vet Med Assoc 193:205- 210, 1988, with permission.)

SURGERY Amputation of the affected limb is the standard treatment for canine appendicular osteosarcoma. Even large- and giant-breed dogs can function

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well after limb amputation, and most owners are pleased with their pets' mobility after surgery. 12• 63 Pre-existing orthopedic or neurologic conditions may cause poor results in some cases, and careful preoperative examination is important. Surgery alone must be considered palliative for osteosarcoma. Euthanasia is usually requested by owners when their dogs become symptomatic for metastatic disease. Dogs rarely have respiratory signs as the first clinical evidence of pulmonary metastasis; rather, their first signs are usually vague. With radiographically detectable pulmonary metastasis, dogs may remain asymptomatic for many months, but most dogs become listless and anorexic within 1 month.

MULTIMODAL THERAPY Because occult metastatic disease is present in 90% of dogs at presentation, it is obvious that some form of systemic therapy is necessary if survival is to be improved. Previous attempts to treat micrometastatic disease with various adjuvant therapies have generally been unsuccessful. 14• 24 · 38 • 41 In a recent study, median survival was 222 days for dogs treated with amputation and intravenously administered liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (liposome/MTP-PE). 37 The agent MTP-PE is a lipophilic derivative of muramyl dipeptide, which is a synthetic analogue of a fragment of Mycobacterium cell wall. There is evidence that liposome/MTP-PE can activate macrophages to destroy malignant cells. Although this study showed that liposome/MTP-PE significantly delayed the time to metastasis and prolonged survival when compared to dogs that received empty liposomes, more than 50% of the dogs were dead by 8 months after surgery. There are reports that suggest cisplatin either alone or in combination with doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) improved survival in dogs with osteosarcoma after amputation. 40 • 53 The authors have evaluated 36 dogs with appendicular osteosarcoma treated with cisplatin and amputation. Seventeen dogs (group 1) were treated with two doses of IV cisplatin 21 days apart, beginning on average 18 days after amputation. Nineteen dogs (group 2) were treated at diagnosis with IV cisplatin and received a second dose immediately after amputation 21 days later. The median survival for group 1 was 262 days, with 1- and 2-year survivals of 38% and 18%. The median survival for group 2 was 282 days, with 1- and 2-year survivals of 43% and 16%. The survival of dogs receiving two doses of cisplatin was significantly longer than for 35 amputation-alone historical control dogs (median survival, 119 days; 1- and 2-year survival of 11% and 4% ). There was no significant difference between the survival of group 1 and group 2. There is a large body of evidence, however, reported in clinical studies of human osteosarcoma30· 50• 51 • 62 and laboratory studies with rodents 4 · 19 which supports perioperative use of chemotherapy. Therefore, the authors recommend either neoadjuvant use of cisplatin-that is, prior to definitive surgery (especially if limb-sparing is planned)-or perioperative use of cisplatin with continued administration postoperatively.

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The authors have safely administered six doses of IV cisplatin 21 days apart at 70 mg/m 2 body surface area to 9 dogs with osteosarcoma (unpublished data). Chemotherapy was begun immediately after amputation. It is too early to report survival data; however, none of these dogs developed renal failure, and toxicity was considered very mild. Cisplatin chemotherapy does improve survival, but the most effective route of administration, timing of administration relative to surgery, cumulative dose, and other drug combinations need to be elucidated. In all dogs, cisplatin was used at 70 mg/m 2 body surface area. Saline diuresis helps prevent nephrotoxicity, which is the dose-limiting toxicity. The protocol recommended is that described by Ogilvie et al. 42 Figure 3 is a form letter used by the authors to advise veterinarians on the technique of administration of cisplatin. As with any chemotherapeutic agent, owners need to be carefully informed of the potential toxic effects, and educational material which explains toxicity should be given to the client. COMPARATIVE ASPECTS

Animal models for the study of human diseases have been and are important in our understanding of mechanisms, etiologies, and treatments of disease. Spontaneously developing diseases in animal populations are particularly useful for study. Canine osteosarcoma has many similarities to human osteosarcoma, so the dog can serve as a valuable comparative model for study. 6 · 64 Osteosarcoma is more common in dogs than in humans; therefore, case accrual can be rapid in dogs. 22 • 32 • 49 Because disease progression is more rapid in dogs than in humans, results of treatment protocols can be reported earlier than would those of similar trials in humans. Table 1 summarizes the comparisons between human and canine osteosarcoma. METASTATIC DISEASE

The usual cause of death in humans and dogs following amputation as the sole treatment for osteosarcoma is diffuse pulmonary metastasis. A change over recent years in the pattern of metastatic disease in human osteosarcoma has been described. 2 • u, 23 • 27 This change is primarily an increase in bone metastases. Possible explanations for this change include the following: a change in the behavior of this cancer independent of treatment; selective killing of metastatic cancer by chemotherapy in certain sites, such as lung, which allows metastasis in other sites to become clinically relevant; lung resection and chemotherapy having improved survival and non-lung sites becoming clinically relevant; more sensitive detection methods which allow previously undetectable metastases to be seen; more complete and detailed necropsies compared to those performed previously, which identify asymptomatic metastatic sites. If metastatic sites reported in dogs treated by amputation or, rarely, limb-sparing with no aggressive or successful adjuvant are compiled, 178 dogs are represented (Morrison WB, MacEwen EG: Personal communication). 7• 24 • 40 • 43 • 53 • 58 Sixty-two percent had lung metastases, 12% had bone metastases, and 27% had metastases to other sites. 25• 38• 40• 53 Data from 55

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Cisplatin Administration Techniques at Colorado State University Veterinary Teaching Hospital

Dosage and Frequency: The dosage for cisplatin in dogs is 70 mg/M 2 given intravenously every 3 weeks for up to 6 treatments. Note: This. dosage is not safe for use in cats. A safe dosage has not been determined in cats. Potential Side Effects of Cisplatin: l. Kianey damage. This is the reason for the diuresis protocol outlined below. 2. Nausea, vomiting, and/or loss of appetite. Nausea and vomiting often occur during drug administration; however, it is rarely persistent. 3. Bone marrow suppression. White blood cell counts drop to the lowest points on days 6 and 15 post treatment (bimodal nadir). We do not routinely test for these changes unless symptoms occur. 4. Deafness. This is a problem in human patients but is difficult to evaluate in dogs. We have not recognized this problem in animals. 5. Hair loss. This is not common; however, shaved areas will be slow to regrow. 6. Peripheral neuropathy. This is rare in animals but has been observed in people. Due to these potential side effects, the following diagnostic tests should be performed prior to each drug administration: l. Complete blood count (CBC) and platelet count. A neutrophil count of less than 3000 or a platelet count of less than 75,000 generally necessitates drug delay or withdrawal. In these patients, CBCs should be performed weekly until the neutrophil and platelet counts exceed 3000 and 75,000 respectively, at which time the drug can be readministered. 2. Blood urea nitrogen (BUN), serum creatinine, and urine specific gravity. The presence of underlying renal disease greatly increases the likelihood of cisplatin-induced kidney damage and would necessitate alternate treatment plans. The BUN and creatinine should be normal, and urine specific gravity should ideally exceed l. 035, without an abnormal sediment (casts/protein). Short-term (6 hour and 20 minute) saline diuresis protocol for the administration of cisplatin: l. Following placement of an indwelling intravenous catheter, normal saline (0. 9% NaCl) solution is administered intravenously for 4 hours at 18.3 mUkg/hour. This may require an infusion pump to deliver fluids at a high enough rate. 2. At the end of the 4th hour, the cisplatin (70 mg/M 2) is diluted in 6 mL/kg of normal saline (0.9% NaCl) and administered intravenously over 20 minutes. 3. Mter cisplatin injection, saline diuresis is continued at 18.3 mL!kgihr for 2 more hours. Note: Dogs should be placed on racks during cisplatin administration and subsequent diuresis. Urine should be treated as if contaminated with cisplatin: i.e., hospital staff should wear latex gloves when handling or cleaning up urine. Dogs should be washed (bathed or hosed off) and allowed to void their bladder prior to discharge. Figure 3. Administration technique for intravenous cisplatin.

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Table l. Summary of Comparisons Between Human and Canine Osteosarcoma DOG

Incidence in US Mean age Race/breed Sex Body weight Site

Stage Metastatic rate without chemotherapy Metastatic sites Improved survival with chemotherapy

HUMAN

> 8000/year 7 Large purebreds 1.5:1 male 90% > 20 kg 77% long bones Metaphyseal Distal radius > prox humerus Distal femur > tibia 80 to 90% stage liB 90% before 1 year

1000/year 14 None 1.5:1 male Heavy 90% long bones Metaphyseal Distal femur > prox tibia Proximal humerus 80 to 90% stage liB 80% before 2 years

Lung > bone > soft tissue Yes

Lung Yes

> bone > soft tissue

dogs in various published studies where treatment was amputation and adjuvant chemotherapy (mostly including cisplatin) indicate the metastatic sites were 65% with lung metastasis, 27% with bone metastasis, and 15% with metastasis to other sites. Data from current protocols at CSU and North Carolina State University (NCSU) utilizing adjuvant cisplatin chemotherapy show 66% dogs dead with metastasis. Eighty-three percent had lung metastasis, 52% had bone metastasis, and 48% had metastasis to other sites. It appears from these data that there is an increase in the incidence of bone metastasis in dogs with osteosarcoma that may be related to the use of cisplatin. Further work is necessary to elucidate the mechanism of this apparent change in the pattern of metastatic disease in humans and dogs with osteosarcoma. Resection of pulmonary metastasis from osteosarcoma or other solid tumors has been reported in humans. 31 At CSU, 22 dogs have undergone pulmonary metastasectomy for osteosarcoma. The surgical approach was intercostal thoracotomy in 21 dogs and sternotomy in 1 dog. Lesions which were located subpleurally were gently lifted from the lung parenchyma by thumb forceps and a single purse-string of 2-0 or 3-0 polygalactan 910 (Vicryl, Ethicon, Somerville, NJ) was tied around the base of normal tissue. Larger lesions which were located deeper in the lung parenchyma were treated by complete or partial lobectomy using surgical staples (TA30 or TA55, United States Surgical Corp., New York, NY). No chemotherapy was given after these surgeries. All but 4 dogs received cisplatin as part of their treatment before the development of detectable metastasis. Although the treatments varied among dogs, the median survival time of the entire group was 13 months, with 64% alive at 1 year. The median survival from pulmonary metastasectomy was 3 months, with 4 dogs still alive at 1, 11, 16, and 36 months, respectively. The criteria for case selection for pulmonary metastasectomy is still unclear; however, our guidelines are the following: (1) the primary tumor is under control, preferably for a long relapse-free interval (longer than 6 months); (2) fewer than three nodules

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are visible, (3) doubling time is long (more than 30 days) with no new visible lesions within this time. Further studies are necessary before the optimal indications for surgery and additional chemotherapy after pulmonary metastasectomy can be recommended.

LIMB-SPARING TECHNIQUES

Because survival with osteosarcoma was so dismal (20% 5-year survival) with amputation alone in humans, and because amputation had adverse functional and psychological effects, techniques to spare limbs were investigated. Th~ philosophy underscoring limb-sparing is that the local tumor is removed; the patient ultimately has a functional, pain-free limb; and the patient's survival is not jeopardized by saving the tumor-bearing limb. Because either an endoprosthesis of metal had to be custom-made or the surgeons needed time to prepare rods and allografts, patients were often treated with chemotherapy while they awaited surgery. 3 This was coined "neoadjuvant" therapy, although many other terms have been used, such as "induction chemotherapy," "preoperative chemotherapy," and "protochemotherapy. " 20 • 21 At surgery, tumors were removed with either marginal or wide margins, and the tumor bone replaced with a custom endoprosthesis, allograft, or a combination of the two. Overall, most patients had satisfactory function 39 and, interestingly, with the use of chemotherapy survival improved dramatically. Reported 5-year survivals are now 50% or better at many centers. 55· 56 Although most dogs function well with amputation, there are some dogs in which limb-sparing would be preferred over amputation, such as dogs with pre-existing orthopedic or neurologic disease, very large dogs, or dogs with owners who absolutely will not permit amputation. Dogs with spontaneously occurring appendicular osteosarcoma are also excellent models for studying the treatment of local disease, metastatic disease, and the healing of allografts in the face of limb-sparing treatment. Until recently, only a few reports of limb-sparing in dogs, with limited follow-up, have appeared in the literature. 57• 60 A recent study described limb-sparing in 20 dogs performed at CS U. 33 Since this report, an additional 60 dogs have had limb-sparing procedures performed at CSU. Limb function has been good to excellent in most dogs, and survival has not been adversely affected by removing the primary tumor with marginal margins, as compared to.radical margins as with amputation. Case Selection Suitable candidates for limb-sparing are dogs with osteosarcoma clinically confined to the leg, where the primary tumor affects less than 50% of the bone determined radiographically and dogs that are in otherwise good general health. Most dogs treated at CSU with limb-sparing received some form of preoperative treatment, either IA cisplatin, IV cisplatin, radiotherapy to the tumor bone, or a combination of radiotherapy with IV or IA cisplatin. Some dogs had cisplatin given intravenously after surgery. Many of the dogs treated with IA cisplatin on two occasions 21 days

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Figure 4. A , Cranial-caudal projection of distal femur of a springer spaniel with chondrosarcoma of the medial condyle (arrows). B, Radiographs following medial hemicondylectomy. Arrows indicate osteochondral allograft.

Illustration continued on opposite page

apart, with the last treatment 21 days prior to surgery, showed marked decrease in the degree of vascularization of the tumor. Usually, this correlated with a high percentage of tumor necrosis in the resected specimen. Therefore, angiographic changes may be useful in selecting cases for limb-sparing. The most suitable cases fo r limb-sparing are dogs with tumors in the distal radius. Dogs with tumors in proximal humeral sites may also be potential limb-sparing candidates. Dogs with tumors located in the distal tibia are not as suitable, because the infection rate is high in these dogs owing to minimal soft-tissue coverage. Tumors located in the proximal tibia or distal femur present special problems, because it is usually impossible to save the knee joint. Dogs with limb-sparing and stifle arthrodeses have poor function . Preservation of knee function using osteochondral allografts has been attempted in only two dogs by the authors. In one dog with a small chondrosarcoma of the medial femoral condyle, a hemicondylectomy was performed, with reconstruction with an osteochondral allograft. This dog had excellent function for 8.5 months, at which time euthanasia was performed because of symptomatic pulmonary metastases (Fig. 4). In one

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Figure 4 (Continued). C, Radiograph 6 months after surgery.

dog, a distal femoral osteosarcoma was removed, and the distal femur was replaced with an osteochondral allograft. This dog had only fair function and died due to metastatic disease 5 months after diagnosis. Surgical Technique Second-generation cephalosporin antibiotic is administered IV immediately preoperatively, intraoperatively, and for 24 hours postoperatively. Meticulous aseptic technique is used. For a distal radius site, the dog is placed in lateral recumbency, with the affected limb uppermost. A skin incision is made on the dorsolateral aspect of the antebrachium from a point just distal to the elbow, to just proximal to the metacarpophalangeal joint. Soft tissue is dissected to the level of the tumor pseudocapsule. Care is taken not to enter the tumor. The bone is cut with an oscillating bone saw 2 to 3 em proximal to the proximal radiographic margin of the tumor. The extensor carpi radialis muscle is transected, and the distal part of this muscle and its tendon are removed with the tumor. The common digital extensor tendon usually is closely involved with the tumor pseudocapsule, and it is usually transected proximal and distal to the tumor and also removed with the mass. The distal margin is usually at the level of the radiocarpal joint. The joint

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capsule is incised, keeping close to the proximal row of carpal bones. For tumors that have extension to the ulna, the ulna is also cut with a bone saw and the distal third removed with the tumor. Care is taken to preserve as much vasculature as possible, especially on the palmar surface. Large vessels associated with the tumor are ligated and divided. Surgical hemostatic staples (Surgiclip, United States Surgical Corp, New York, New York) are very useful. The specimen is radiographed, then submitted for histologic evaluation, including assessment of completeness of surgical margins and percent tumor necrosis. A fresh-frozen cortical allograft59 is thawed in 1 L of an antibiotic/saline solution (Neomycin 1 g, polymyxin B 500,000 U, potassium penicillin 5,000,000 U), the articular cartilage is removed, the graft is cut to fit, and the medullary cavity is reamed to remove fat and cellular debris. The articular cartilage of tlie proximal carpal bones is removed (Fig. 5), and the allograft is stabilized using Association for the Study of Internal Fixation principles. A dynamic compression plate with a minimum of three screws proximal and four screws distal to the graft is used; 4. 5-mm narrow or broad plates are usually selected. The plate extends distally to a level just proximal to the metacarpophalangeal joint (Fig. 6). While new surgical garments and gloves are worn and different instruments are used to prevent potential contamination with tumor cells,

Figure 5. Resected tumor and distal radius (solid arrow), allograft (open arrow), and site from which tumor was removed during limbsparing surgery.

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Figure 6. A, Radiograph following limb-sparing procedure to remove an osteosarcoma of the distal radius in a 10-year-old fe male Golden Retriever. Arrows depict the proximal and distal limits of the allograft. The distal ulna was re moved with the tumor and not replaced. Dog also received two intra-arterial doses of cisplatin. B, Radiographic appearance of the same limb 9 months after surgery. Note healing of both the proximal and distal graft-host interfaces. The dog was still alive, with excellent limb function and free of disease, 31 months after surgery. (Modified from LaRue SM, Withrow SJ: Tumors of the skeletal system . In Withrow SJ, MacEwen EG (eds): Clinical Veterinary Oncology. Philadelphia, JB Lippincott, 1989, p 241. )

autogenous cancellous bone graft is procured from the proximal humeral metaphysis or iliac crest. Cancellous graft is packed around the host-bone interfaces. A closed suction drain (Redi-Vascette System, Biomet, Warsaw, IN) is inserted adjacent to the allograft and the wound is closed. The leg is supported in a padded bandage. The drain is re moved the day after surgery in most cases. It is most important to prevent self-mutilation (licking) after surgery, and Elizabethan collars should be used as necessary. No external coaptation is used , and most dogs use the limb fairly well by 10 days after surgery. Postoperative swelling can be considerable but usually resolves by 2 weeks. Although decreased exercise is recommended for the first 3 to 4 weeks to allow soft tissues to heal, no exercise restriction need apply after

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this time. In fact, it is important that limb use be encouraged even in early postoperative times, so that flexure contracture of the digits does not occur. The principles of resection are the same for other sites; however, because of abundant soft tissue in the area, wider margins are often attained with proximal humerus resections. Proximal humerus resections are, however, more difficult, and limb use immediately following surgery is usually poor but improves over about 1 month. Vigorous physiotherapy is important after surgery in these dogs. Results

Limb function was good to excellent in 69% of dogs evaluated from the first 20 limb-sparing surgeries performed at CSU. Local tumor control was attained in 79% of dogs evaluated, and median survival was 8 months. All dogs received IA or IV cisplatin, and the limbs of some dogs were also irradiated preoperatively. Subsequently, dogs with appendicular osteosarcoma have been randomized to receive either radiation alone, IA cisplatin alone, or both in combination prior to limb-sparing surgery at either CSU or NCSU. Because of the short survival time and high incidence of metastasis in dogs treated with radiation alone, that arm of the study was discontinued after 21 dogs were randomized to it. Results from these 21 dogs have been reported, 58 and it was concluded that radiation therapy alone given in large doses per fraction was unsatisfactory for preservation of life or limb. Evaluation of the response of the primary tumor by determining percent necrosis is considered a valuable determinant of the effectiveness of preoperative treatment in humans. 1• 3 • 13• 28 • 51 • 61 If the percent tumor necrosis is low, the response is considered inadequate and the postoperative chemotherapeutic regimen is often modified. 51 Percent tumor necrosis has been evaluated in resected specimens from dogs with osteosarcoma with various preoperative treatments from CSU and NCSU. 48 Mean percent tumor necrosis was as follows: untreated tumors (n = 94), 27%; radiation therapy alone (n = 23), 82%; two doses of IA cisplatin at 70 mg/m 2/dose (n = 14), 45%; two doses of IV cisplatin at 70 mg/m 2/dose (n = 6), 24%; two doses of IA cisplatin at 70 mg/m 2/dose and radiation therapy (n = 45), 82%, and 10 doses of IV cisplatin at 10 mg/m 2/dose and radiation therapy (n = 8), 78%. There was no significant difference between percent tumor necrosis in dogs with untreated osteosarcoma compared to those receiving IV cisplatin alone, but a significant increase in percent tumor necrosis was present in all other groups. Percent tumor necrosis was strongly correlated with local tumor control, as 91% of dogs with more than 90% tumor necrosis had local control, whereas 78% of dogs with 80 to 89% tumor necrosis had local tumor control, and only 30% of dogs with less than 79% tumor necrosis had local control. Because those dogs with irradiation as part of their preoperative treatments had higher mean percent tumor necrosis, irradiation in combination with chemotherapy may still play a role in the management of osteosarcoma. Fifty-seven dogs with osteosarcoma have been treated preoperatively with cisplatin (with or without radiation) prior to limb-sparing at CSU. In comparing survival of these dogs to survival of dogs in which cisplatin was

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1.00 ---amputation (n=35) .......... amputation+ cisplotin (n=36) ----- limb sporing +cisplotin (n=57) >. 0.75 .....

:0 c

.J:l

0

c..

0.50

c

> > .....

::::>

(/) 0.25

0+-----.-----.----,.----,-----.-----.----. 700 500 600 100 200 300 400 0 Time (days) Figure 7. Comparison of survival of dogs with osteosarcoma undergoing different treatment methods.

used with amputation (n = 36), no significant difference is seen. Dogs receiving cisplatin and either limb-sparing or amputation had longer survival times than did dogs treated with amputation alone (n = 35) (Fig. 7). Limbsparing does not appear to adversely affect survival in selected dogs with appendicular osteosarcoma. Overall, limb function has been satisfactory, with approximately 80% of dogs experiencing good to excellent limb function. Complications Limb-sparing requires a dedicated owner and clinician. It is a multidisciplinary treatment demanding close liaison among chemotherapist, interventional radiologist, radiation therapist, pathologist, and surgeon. Complications can arise in any phase of treatment (chemotherapy, radiation, and/or surgery). However, the risk of complications can be minimized by a team approach, experience, and attention to detail. Complications as a direct result of chemotherapy (for example, sepsis and renal failure) are extremely rare. Radiation therapy may complicate wound and allograft healing and potentiate allograft infection. 58 This modality in combination with chemotherapy may, however, be useful for control of local disease, as indicated by percent tumor necrosis data. 48 The major complications related mainly to surgery are recurrent local disease and allograft infection. In the 70 evaluable dogs that have had limbsparing surgeries performed at CSU so far, there have been 24% with local disease recurrence and 31% with allograft infection. Some dogs had their locally recurrent disease resected en bloc and remained disease-free for an extended period (with one dog still alive 22 months after a second surgery for an ulna recurrence from a primary osteosarcoma of the radius). Of the

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22 dogs with allograft infection, 7 required amputation and the remainder had their infections adequately controlled with systemic antibiotics with or without local antibiotics (gentamycin-impregnated polymethyl methacrylate beads). 10 These dogs continued to have evidence of infection; however, their function was not severely affected by it. Included in these 70 dogs are cases that, in retrospect, should not have undergone limb-sparing owing to very extensive local disease or lack of preoperative consolidation therapy. These are preliminary findings, as the study is ongoing.

SUMMARY Canine appendicular osteosarcoma is a highly malignant primary bone cancer that closely resembles the same disease in humans. Although amputation alone usually controls local disease, metastatic cancer is common and is the cause of death or euthanasia in 90% of dogs by 1 year. Cisplatin ( ± doxorubicin) chemotherapy appears to improve survival time in dogs; however, metastatic cancer remains a problem. Pulmonary metastasectomy may prolong survival in carefully selected dogs. Limb-sparing, although involved and potentially fraught with complications, can result in local disease control and a functional, pain-free limb in selected dogs without adversely affecting their survival. Studies are ongoing to improve local disease control with limb-sparing and improve disease-free survival in dogs with appendicular osteosarcoma. In conclusion, dogs with osteosarcoma were previously thought to have a hopeless prognosis, but the outlook is beginning to appear more optimistic. Limb-sparing in dogs is still evolving; however, it is possible in selected cases to optimize survival and preserve limb function.

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Address reprint requests to Rodney C. Straw, BVSc Comparative Oncology Unit Department of Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, CO 80523