Treatment

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The two therapeutic modalities currently used in the primary treatment are surgery and chemotherapy. The use of surgery alone results in a 90% rate of recurrence of osteosarcoma. The tumor is radioresistant and radiation therapy does not play a primary role in management.

Surgery

The surgical approach to osteosarcoma includes surgical biopsy, followed by either amputation or limb salvage surgery.

A biopsy is required to confirm the diagnosis. An open biopsy is the preferred method. The biopsy should be performed with surgery in mind, by an orthopedic surgeon experienced in the management of malignant bone tumors. A poorly placed biopsy may jeopardize future limb salvage surgery. Because the biopsy tract and skin are contaminated with tumor cells, the biopsy site needs to be excised en bloc with the tumor during definitive surgery.

Surgery should remove all gross and microscopic tumor with a margin of normal tissue to prevent local recurrence. Appropriate surgical procedures are limb salvage surgery or amputation.

Definitive surgery may be done immediately after diagnosis (by biopsy) or following preoperative chemotherapy. Delaying definitive surgery until after preoper-ative chemotherapy is preferred, because an assessment of the chemotherapeutic responsiveness of the tumor can be determined.

The type of surgery is determined by tumor location, size, extramedullary extent, presence of metastatic disease, age, skeletal development, and patient's lifestyle choices. If complete excision cannot be accomplished with limb-sparing surgery, amputation is indicated.

Limb salvage surgery should be performed by orthopedic surgeons experienced with these techniques. Guidelines for the use of limb-sparing surgery include:

• No major neurovascular involvement by tumor

• Ability to have a wide resection of affected bone with a normal muscle cuff in all directions

• Ability to perform en bloc removal of all previous biopsy sites and all potentially contaminated tissue

• Adequate motor reconstruction

• Adequate soft-tissue coverage.

Contraindications to limb-sparing surgery include:

• Major neurovascular involvement

• Nonhealing pathologic fracture of bone affected by tumor

• Prior inappropriate biopsy with contamination of normal tissue planes and compartments

• Infection of biopsy site

• Young age with immature skeletal development

• Extensive muscle involvement.

Limb salvage has generally been applied to most upper extremity lesions and selected lower extremity lesions where en bloc resection permits adequate tumor margins with an intact joint.

Chemotherapy

The use of chemotherapy in a neoadjuvant (preoperative) or adjuvant (postoperative) fashion results in significant improvement in disease-free survival in patients with osteosarcoma. More than 90% of patients treated with surgery alone will develop metastatic disease. With the addition of multiagent chemotherapy, 60-70% of nonmetastatic extremity osteosarcoma patients will survive without evidence of recurrence. The agents most commonly used in the treatment of osteosarcoma are high-dose methotrexate, cisplatin, and doxorubicin. Addition of ifosfamide, alone or with etoposide, may enhance tumor response; however, its effect on overall and event-free survival (EFS) is less clear.

Although timing of chemotherapy (neoadjuvant versus adjuvant) does not affect EFS, neoadjuvant chemotherapy offers the following advantages:

1. Shrinkage of the tumor at the primary site so as to facilitate less radical surgery such as limb salvage

2. Initial attack on micrometastases present in 80% of patients

3. Assessment of sensitivity of primary tumor to chemotherapy so that poor responders can receive alternative treatment postsurgically.

The degree of tumor necrosis (Table 21-2) following neoadjuvant chemotherapy is an independent predictor of EFS and overall survival, presumably reflecting tumor resistance to chemotherapy. Patients whose tumors exhibit a good response (>90% necrosis) have superior local tumor control as well as EFS and overall survival compared with poor responders (Figure 21-3). In patients whose response is suboptimal, attempts to improve outcome by modifying chemotherapy are continuing.

Figure 21-4 shows the Pediatric Oncology Group POG-8651 protocol for osteosarcoma. This protocol compares immediate surgery to chemotherapy followed by surgery. The presurgical chemotherapy group patients received high-dose methotrexate (12 g/m2) and leucovorin rescue (15 mg every 6 hours for 10 doses) in weeks 0, 1, 5, 6, 13, 14, 18, 19, 23, 24, 37, and 38. For patients treated with immediate surgery this regimen was administered in weeks 3, 4, 8, 9, 13, 14, 18, 19, 23, 24, 37, and 38. Doxorubicin 37.5 mg/m2/day for 2 days and cisplatin 60 mg/m2/day for 2 days were administered in weeks 2, 7, 25, and 28 for the presurgical chemotherapy group and in weeks 5, 10, 25, and 28 for the immediate surgery group. The combination of cyclophosphamide 600 mg/m2/day, bleomycin 15 mg/m2/day, and dactinomycin 0.6 mg/m2/day was administered for 3 days in weeks 15, 31, 34, 39, and 42 for both groups. A single course of doxorubicin 30 mg/m2/day for 3 days was administered in week 20 for both groups. Both of the regimens have the same outcome with 65% EFS at 5 years and a similar incidence of limb salvage.

Table 21-2. Histologic Response of Osteosarcoma to Preoperative Chemotherapy

Grade Description

I Little or no effect of chemotherapy

II Partial response to chemotherapy with more than 50% tumor necrosis but with areas of viable tumor still demonstrable

III Near-complete response to chemotherapy with more than 90% tumor necrosis but with areas of viable tumor still demonstrable

IV Complete response to chemotherapy with no viable tumor cells demonstrable

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