80

Osteosarcoma

Epidemiology and Risk Factors

Osteosarcoma is the most common malignant bone tumor in childhood, representing approximately 50% of newly diagnosed malignant pediatric bone tumors or 700 new U.S. cases annually (27). The annual incidence is 4.5 per million in girls and 5.5 per million in boys (27). This incidence peaks in those ages 10 to 19 years (40). There does not appear to be a difference in incidence among African Americans and whites.

The etiology of osteosarcoma is unknown in most cases. The incidence does correlate with the growth spurt in teenagers. However, specific pathways associated with this finding are elusive. For a minority of patients, a specific risk factor is identified. These risk factors include, prior radiotherapy (58), and specific genetic syndrome. Survivors of hereditary retinoblastoma carry a risk of osteosarcoma of 6% at 18 years (20), Li-Fraumeni syndrome (6), and in older adults, there is an association between Paget's.

Clinical Presentation

Most patients present with pain in the affected limb or region and soft tissue swelling. In some patients, trauma and a subsequent pathologic fracture brings the individual to medical attention.

Approximately 90% present in the diaphysis of the extremities, with the distal femur and proximal tibia being the most common sites. Other sites such as the pelvis and head and neck represent significant minority of the locations (27).

Diagnostic Evaluation

Radiologic investigation begins with a plain radiograph (Fig. 80.1A). Classic findings include an ill-defined zone of transition, Codman's triangle (defined as osteoid formation under the periosteum), and bone formation in the adjacent soft tissue. The lesion itself may be sclerotic (Fig. 80.2), lytic (Fig. 80.1A), or mixed. Most lesions are subsequently evaluated by magnetic resonance imaging (Fig. 80.1B). This will show the proximal and distal extent of involvement, evaluate any soft tissue component, and establish the proximity of nerves, vessels, and the joint space. Skip metastases are a well-defined but uncommon entity in osteosarcoma. Modern series place the incidence of isolated skip metastases at diagnosis at <5% (33,51).

At diagnosis, approximately 15% of patients have detectable distant metastases. More than 80% of metastases are pulmonary, followed by metastases at bony sites (5). Therefore, chest computed tomography and radionuclide bone scan are needed to complete staging.

Positron emission tomography is being investigated as a part of the initial staging work-up and as a modality to evaluate response to chemotherapy (8). However, to date, it is not a part of the recommended work-up.

Staging Systems

There are two major staging systems for this disease: the Enneking system (22) and the American Joint Committee on Cancer system (1) (Table 80.1). However, most practitioners usually classify the disease state as nonmetastatic or metastatic, based on the presence or absence of distant metastases.

Pathology

The commonly accepted histologic description of osteosarcoma is based on the World Health Organization classification (53). This divides osteosarcomas into intramedullary and surface subtypes. The most commonly encountered subtype is the conventional category of medullary tumors. These are further subclassified into osteoblastic, chondroblastic, fibroblastic, and mixed types based on the pathologist's visualization of the specific elements. Other categories of medullary (or conventional) osteosarcoma are small cell, telangiectatic, and well-differentiated (or low-grade) types.

Surface osteosarcomas are divided into parosteal (juxtacortical), periosteal, and high grade.

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Overall Management

Chemotherapy is essential for cure. In the nonmetastatic setting, the overall schema consists of chemotherapy followed by resection of the primary tumor, and adjuvant chemotherapy.

In patients with pulmonary metastatic disease, the treatment program is the same as for nonmetastatic disease, with the addition of possible resection of any pulmonary nodules remaining after the completion of chemotherapy.

Low-grade osteosarcomas are usually managed with surgery alone.

Surgical Management

Resection of the primary tumor is part of the standard management. Subsequent to an en bloc resection of the tumor, reconstruction is usually required. The goal of the surgical intervention is to remove the tumor en bloc and achieve adequate negative margins.

Presurgical planning includes careful evaluation of the pre- and postneoadjuvant chemotherapy imaging and determination of the anticipated reconstruction. For extremity tumors, imaging will often show a decrease in the soft tissue component of the tumor and allows visualization of the neurovascular structure, muscle groups, and fascial planes; the relationship of the tumor to the epiphysis and articular surface; and provides an estimate of the length of bone to be removed.

There are several options for surgery. Amputation should be recommended if the patient will be left with a nonfunctioning limb (39). Most individuals will undergo some type of limb-sparing procedure. Reconstruction options include autologous bone grafts, allografts, and endoprosthetics. Less commonly, rotationplasty or arthrodesis is employed. In the current era, 80% to 90% of patients will undergo a limb salvage (39).

Reconstructions can suffer infections, nonunion, and fracture, depending on the technique. Endoprosthetics are prone to infection. Allografts can fracture up to 20% of the time (37). However, the functional outcome of various reconstructive techniques can be good in 60% to 90% of cases (24,37).

Traditionally, pelvic osteosarcomas present a challenge to the orthopaedic oncologist. Small tumors may be adequately resected with or without reconstruction. Resection of large tumors may mean not only the loss of the ipsilateral lower extremity, but compromising of bowel and bladder function.

Chemotherapy

Systemic chemotherapy is standard of care for all patients who are able to tolerate the intensive regimens.

Two randomized studies demonstrated the efficacy of adjuvant chemotherapy (21,29). Table 80.2 shows various randomized trials of adjuvant chemotherapy. Notably, an early randomized trial had negative findings (36). The standard agents used are methotrexate, cisplatin, and doxorubicin, all of these with or without ifosfamide.

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Subsequent studies investigated neoadjuvant chemotherapy as a way to evaluate tumor response. A randomized Pediatric Oncology Group study showed no difference in outcome whether preoperative or postoperative chemotherapy was administered (26) Advantages of neoadjuvant chemotherapy include the determination of the pathologic response, early treatment of micrometastatic disease, and allowing adequate time for surgical planning and ordering of a custom prosthesis.

The percent necrosis after neoadjuvant chemotherapy is a prognostic factor (5,32). The classification scheme is according to the Huvos grade. The overall survival of patients with nonmetastatic disease with >90% necrosis is near 70%, compared with 50% in those with <90% necrosis (31). Therefore, the next therapeutic question was whether the survival of poor responders could be improved by altering and/or intensifying chemotherapy administered after surgery. Several studies have investigated this, but no improvement in survival has been demonstrated (3,61). Likewise, attempts to intensify the chemotherapy regimen delivered preoperatively have failed to show an increase in survival despite a small increase in the percentage of good responders (41,48).

Radiotherapy

Historically, radiotherapy has been used in the treatment of osteosarcoma. Prior to effective chemotherapy, Cade (13) pioneered a technique of radiotherapy with delayed amputation in those who did not develop distant metastases. Subsequently, others questioned the need for amputation. The radiotherapy doses employed were 5,000 to 8,000 R. Of note, in these series many patients did have resolution of their symptoms (pain and swelling) soon after starting radiation. Beck et al. (4) report only 1 of 21 survivors in a group treated with definitive radiotherapy. However, prior to death, three patients had local recurrences. deMoor (18) describes a cohort treated with “radical radiotherapy.” Of the 27 initial patients, 9 had survived at least 5 years and 3 had local recurrences.

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With the advent of chemotherapy, Caceres et al. (12) reported on a group of 16 patients who were treated with chemotherapy and definitive radiotherapy. Tumors and surrounding tissue received 6,000 rad after one cycle of chemotherapy. Chemotherapy was then continued for 1 year. Biopsies were performed at the primary site in 15 of 16 patients every 3 months after the initiation of treatment. Results of this study showed that 80% of patients had a complete pathologic response. Complications included soft tissue fibrosis in nine patients, fracture in four, infection in two, and necrosis in two.

The role of radiotherapy in osteosarcoma therapy in the 21st century is now limited to select situations. Specifically, irradiation is considered in patients who refuse surgery, those with positive margins after resection, those with sites that are not amenable to resection and reconstruction, and palliation.

Modern External-beam Radiotherapy

Table 80.3 gives an overview of modern radiotherapy treatment. In recent years, contemporary chemotherapy and definitive radiotherapy in those refusing amputation has been reported by Machak et al. (38). A median of 60 Gy was given using conventional fractionation. The 5-year local progression-free survival was 56%, with an overall survival of 61%. Those with a good response to neoadjuvant chemotherapy had an overall survival of 90%, compared with 35% in those who were poor responders. This phenomenon was also paralleled in local control. There were no local failures in good responders, but nearly one third of poor responders failed locally.

Conversely, Delaney et al. (17) reported only a 22% local control rate in patients who were treated with chemotherapy and local radiotherapy. For the group of patients receiving radiotherapy adjuvantly after surgery, the local control rate was 74%, with a gross total resection or a subtotal resection.

Dincbas et al. (19) recently reported preoperative radiotherapy integrated in the usual osteosarcoma treatment protocol. Local control was excellent at 97% with good limb salvage. However, this is similar to what would be expected in the cooperative group trials. Therefore, it is not clear that radiotherapy added to the overall outcome.

Extracorporeal and Definitive Intraoperative Radiotherapy

The techniques of extracorporeal and definitive intraoperative radiotherapy (IORT) have been investigated in bone tumors (Table 80.4) (9,15,28,44,58,59). The extracorporeal technique includes en bloc resection of the tumor and surrounding soft tissues, irradiation of the specimen, and reimplantation, often with the aid of prostheses. With definitive IORT, the operative field is exposed and radiotherapy is administered. No resection of the tumor is performed.

Extracorporeal irradiation is associated with a low rate of local recurrence (<5%). Chen et al. (15) noted a higher rate of complications (62%) in their initial series. The events included fractures, nonunions, wound infections, and loss of cartilage. Subsequently, they incorporated the use of prostheses placed at the time of reimplantation. Their local recurrence rate

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continued to be low and there was only one complication (a nerve palsy) in their series of 14 patients (15).

The reported local control rate for definitive IORT is 20% to 25% (44,57). The complication rate is >50% as reported by Tsuboyama et al. (57), but minimal in the hands of Oya et al. (44).

Particle Therapy

Because of the difficulty of achieving adequate local control with photons, neutrons and protons have been employed in the treatment of osteosarcoma (Table 80.5). Neutrons are thought to have a higher relative biologic effectiveness and oxygen-enhancement ratio, making them radiobiologically more effective against osteosarcomas. The advantage of protons is in the physical properties of the Bragg peak, which falls off rapidly and spares adjacent tissue.

The earliest studies of particle therapy are with neutrons in the 1970s and 1980s, prior to optimal chemotherapy and surgical reconstruction. The review of the early data by Laramore et al. (35) shows an overall local control rate of 55% in 73 patients pooled from seven institutions worldwide.

In a more recent review of head and neck sarcomas, Oda et al. (43) report local control in a patient treated with chemotherapy, surgery, and neutron irradiation. One other patient who received only surgery and neutron therapy had local failure. Carrie et al. (14) describe local control in 4/4 pelvic osteosarcomas treated with modern chemotherapy and a combination of photons and neutrons.

The major complications surrounding neutron therapy are severe fibrosis and scarring of the soft tissues and adjacent organs (35).

The largest proton experience is at the Massachusetts General Hospital (30). Fifteen patients with osteosarcoma of the base of skull or vertebra were treated by this form of therapy. The 5-year local control is reported at 59%.

Whole-lung Irradiation

Prophylactic lung irradiation has been investigated in osteosarcoma. Three randomized trials were conducted in the 1970s and 1980s (Table 80.6) (9,11,49). The Mayo Clinic and first European Organisation for Research and Treatment of Cancer studies were conducted prior to the routine use of chemotherapy (9,49). They both showed trends toward improved survival with whole-lung irradiation. However, a three-arm EORTC/SIOP study that compared chemotherapy, whole-lung irradiation, or a combination of both, showed the same disease-free survival and overall survival in both arms (43% and 24%) (11). Therefore, with the recognition of the other advantages of systemic therapy, prophylactic lung irradiation has fallen out of favor (60).

Radionuclide Therapy

Several investigators have used radionuclides in the treatment of bony metastatic osteosarcoma (Table 80.7). There are case reports of the use of rhenium (52), strontium (25), and samarium (10). The major toxicity is decreased in the platelet and white blood cell counts.

Anderson et al. (2) conducted a phase I dose-escalation study of samarium-153 in metastatic osteosarcoma. The goal was to evaluate the toxicity of increasing doses of radionuclide using hematopoietic stem cells to decrease the bone marrow toxicity. Bone marrow toxicity and transient hypocalcemia were seen at the highest dose level. The authors report good pain relief.

Results of Radiotherapy in Specific Disease Sites

Pelvis

The management of large pelvic osteosarcomas continues to present a challenge. Definitive surgery often includes a hemipelvectomy. Despite being the most common nonextremity site of osteosarcomas, the percentage is <10%. The overall local failure rate in the 22 patients with spinal primaries was 70% in the Cooperative Osteosarcoma Study Group (45). Eleven of 67 patients received radiotherapy. Seven patients were treated definitively and four were treated in a postoperative fashion. The definitive dose was 56 to 68 Gy and the postoperative dose was 45 to 51 Gy. The majority of those patients receiving radiotherapy failed locally (6/7 treated definitively, and three of four treated after an intralesional surgery).

In the St. Jude Children's Research Hospital experience, local control was achieved in three-fourths of the patients using 50 to

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98 Gy and modern chemotherapy (50). Promising local control was achieved in the University of South Florida series of five patients treated with intra-arterial cisplatin and radiotherapy (23).

Spine

Fewer than 2% of patients present with spinal primaries. Within the Cooperative Osteosarcoma Study (COSS) studies, overall survival for patients with spinal primaries is <2 years and the local failure rate was near 70% in the 22 patients studied (46). Seven of the 17 patients who underwent an intralesional procedure or biopsy received radiotherapy only as part of their care. Radiotherapy doses ranged from 20 to 60 Gy. Five of seven patients had local recur-rences.

When the group from Memorial Sloan-Kettering Cancer Center analyzed their series, 5 of 11 patients in the cohort treated with resection, external-beam radiotherapy, and chemotherapy were long-term survivors (56).

Head and Neck

Most head and neck osteosarcomas present in the mandible or maxilla. The age of presentation tends to be somewhat older than that of patients with extremity lesions (55). The review by Kassir et al. (34) finds an overall local control rate of 50% at these sites. Almost 40% of the patients received radiotherapy (external-beam or brachytherapy), but no comment is made on the effect of irradiation on local control. Those receiving radiotherapy did have a lower survival rate than those treated with surgery and chemotherapy.

St. Jude Children's Research Hospital researchers reported on four children who received 31 to 74 Gy postoperatively (21). The two who received 31 Gy and 40 Gy both had local failure. In the University of Washington experience, five patients received postoperative radiotherapy (49). The three who received chemotherapy have maintained local control. However, the two who did not receive chemotherapy died, but no comment was made regarding the status of the primary site.

Late Effects

Late complications are largely related to chemotherapy and surgical interventions. Doxorubicin can cause cardiomyopathy (47) and cisplatin results in high-frequency hearing loss in about half of patients (54). Some patients will exhibit transient changes in renal function, but late complications are unusual. Second malignancies, with a minimum 5-year follow-up, were reported in 7% (42).

Nicholson et al. (42) report long-term survivors having more difficulty climbing stairs; the patients had similar employment and marital status as sibling controls.

With respect to radiotherapy, the data are limited. This is largely because this modality is used in patients with unfavorable prognoses, with a low chance of long-term survival. Laramore et al. (35) report a 25% to 40% complication rate of study results gleaned from reviewing the literature for neutron therapy, which is often related to dense fibrotic reactions. Delaney et al. (17) report a 24% complication rate in a proton/photon cohort. In a definitive external-beam radiotherapy series, Machak et al. (38) describe three-quarters of the patients as having good limb function. Three of the 31 patients had pathologic fractures and 1 had skin necrosis.