Richard Gorlick and Paul A. Meyers
Osteosarcoma is the most common malignant primary bone tumor in children and adolescents.
The diagnosis of osteosarcoma can be made based on histologic examination of pathologic material, staging can be performed with imaging procedures, and multimodality therapy including chemotherapy and surgery successfully treat the majority of patients. Despite all of these advances, osteosarcoma remains enigmatic. The biology of the tumor is incompletely understood, and recent trials modifying therapy have failed to produce further advances. Patients with localized disease have a 5-year survival of at least 70%; patients with metastatic or recurrent disease have a < 20% chance of long-term survival despite aggressive therapies. These figures have changed little in the past 2 decades.3-6
EPIDEMIOLOGY/ETIOLOGY
Osteosarcoma has a bimodal age distribution with the first peak in the second decade of life and the second among older adults. The approximate incidence of osteosarcoma is 4.8 per million children younger than 20 years of age.7There are approximately 400 new cases per year in those under 20 years of age in the United States.8 Primary bone tumors account for approximately 5% to 10% of all new pediatric cancer diagnoses in the United States, of which osteosarcoma is the most common.7 The male-to-female ratio is approximately 1.3:1 in this age range.
The peak age of incidence coincides with a period of rapid bone growth in young people, which suggests a correlation between bone growth and the evolution of osteosarcoma.8,9
CLINICAL PRESENTATION
The most common features in the clinical presentation of osteosarcoma are pain and swelling in the involved region, with or without an associated soft tissue mass. Symptoms are usually present for several months before the diagnosis is made. The median time from onset of symptoms to diagnosis is 4 months.242-246 Occasionally, patients present more dramatically with a pathologic fracture. The most common primary site is the metaphysis of a long bone, but osteosarcoma can occur in any bone of the body. Approximately half of all osteosarcomas originate in the region around the knee.40,41 The most common sites of disease are the distal femur, the proximal tibia, and the proximal humerus. The anatomic distribution of osteosarcoma is shown in Figure 453-1.7 Approximately 20% of patients present with radiographically detectable metastatic disease. Eighty percent of patients present with localized disease, but the vast majority of this group are known to have subclinical, microscopic metastases.8 The most frequent site of metastases is the lung. The vast majority of patients at presentation do not have systemic symptoms such as fever or weight loss even with overt meta-static disease. Death from osteosarcoma is almost always the result of progressive pulmonary metastasis.8 Bone lesions, although extremely painful, are usually not life threatening.3-6,8,240
FIGURE 453-1. Anatomic site distribution of osteosarcoma in individuals less than 20 years of age.7
EVALUATION
The evaluation of suspected osteosarcoma begins with history, physical examination, laboratory evaluations, and plain radiographs. History may be significant only for pain. Physical examination is typically remarkable only for a soft tissue mass, not always present, at the primary site.3-6,8,240,241 Laboratory evaluation is seldom revealing. Elevation of the serum alkaline phosphatase and lactate dehydrogenase is observed in a large proportion of patients but is not sensitive or specific.8 In a patient with a suspected bone tumor, obtaining a plain radiograph of the site is critical for making an appropriate diagnosis.3-6,8,240,241
The diagnosis of osteosarcoma is typically suspected from its radiographic appearance. Osteosarcoma can present as a lytic, a sclerotic, or a mixed lytic-sclerotic lesion. Ossification in the soft tissue suggestive of bone spicule formation in a “sunburst”’ pattern is classic for osteosarcoma but is not a sensitive or specific feature.40,41 Cortical destruction with periosteal new bone formation can lead to the appearance of a Codman’s triangle. In addition to the lesion’s appearance, features such as location in the metaphysis and the bone involved as well as the patient’s age help to distinguish osteosarcoma from other clinical entities.40,41 Appearance of the tumor on plain radiographs can be highly suggestive of the diagnosis. A typical radiograph of a patient with an osteosarcoma in the femur is shown in Figure 453-2. Despite the utility of plain radiographs, computerized tomography (CT) and magnetic resonance imaging (MRI) both offer improved resolution and better delineation of tumor extension and are routinely performed with suspected osteosarcoma.247-249
It is mandatory to obtain a biopsy for pathological confirmation of the diagnosis.
STAGING
Prior to initiation of therapy, accurate staging is necessary to determine the extent of disease which has prognostic significance.257 Routine posteroanterior and lateral radiographs of the chest allow detection of metastases in the majority of cases. CT of the chest is more sensitive in detecting pulmonary metastases and has become the imaging procedure of choice.258
FIGURE 453-2. Typical plain radiograph appearance of an osteosarcoma in the femur. A postero-anterior projection is shown in panel A and a lateral projection in panel B.
A radionuclide bone scan, with methylene diphosphonate labeled with technetium-99m is also routinely performed at diagnosis.258,263 It defines the extent of the primary tumor and is useful in the detection of “skip lesions” within the same bone, as well as distant bone metastases.264-267
Successful treatment of high-grade osteosarcoma requires the use of systemic chemotherapy. Many of the agents have both acute and long-term toxicity; therefore, it is essential to obtain baseline studies prior to the initiation of chemotherapy so that these toxicities can be monitored. Baseline evaluations of renal function, cardiac function, and hearing are usually performed. All young men past the age of puberty typically are offered the opportunity to carry out sperm banking.
PROGNOSTIC FACTORS
The most consistent prognostic factor at diagnosis is the presence of clinically detectable meta-static disease, which confers an unfavorable prognosis.241,245,261,262,278,279 The site of the primary tumor has some prognostic significance, with axial lesions prognostically inferior to tumors of the appendicular skeleton.245 Both serum lactate dehydrogenase and alkaline phosphatase have been suggested to correlate with outcome; higher levels of either enzyme predict an inferior prognosis.281-284 These factors most likely influence outcome by reflecting the size of the tumor or its resectability. One predictor of outcome which has been used to stratify therapy is the percentage of tumor necrosis (ie, “Huvos” grade) assessed at the time of definitive resection after a period of preoperative chemotherapy.285,286 Although tumor necrosis based on Huvos grading has been shown to correlate with disease-free survival, this variable cannot be assessed at diagnosis and thus cannot serve as a true prognostic factor because stratification of therapy based on Huvos grade occurs after 10 weeks of chemotherapy/surgery.
PATHOLOGY
The diagnosis of osteosarcoma depends on the identification of malignant spindle cells associated with the production of tumor osteoid. Great variability exists in the histologic patterns seen in this tumor and in the degree of osteoid production, so that extensive review of the pathologic material may be required to demonstrate tumor osteoid.40-42
TREATMENT
In the 1970s, several investigators reported that chemotherapy had activity against relapsed or metastatic osteosarcoma. The cytotoxic agents with the highest single-agent activity in osteosarcoma include methotrexate (at high doses only, 30% to 40%), cisplatin (∼30%), doxorubicin (30% to 40%), and ifosfamide (∼30%).3 When these agents were administered to patients with relapsed or metastatic osteosarcoma, tumor responses were observed.310-318 Every reported trial of adjuvant chemotherapy for osteosarcoma demonstrated a disease-free survival superior to the historical rate of 25%.241,310,312,325-331
To clarify the issues surrounding the value of adjuvant chemotherapy, the Multi-Institution Osteosarcoma Study (MIOS) was initiated. Patients who did not receive chemotherapy after surgery had a probability of disease-free survival of 11% as compared to 66% for those who received chemotherapy. This study unequivocally demonstrated that adjuvant chemotherapy was of clear benefit.336 Since this study, systemic chemotherapy has been the standard of care for all patients with high-grade osteosarcoma.241
In the same era, Rosen and colleagues introduced the concept of giving chemotherapy before carrying out definitive surgery on the primary tumor.285,338 It became possible to examine the histologic response of the tumor to induction chemotherapy to assess the effectiveness of therapy.41,241,285,286,338 A strong correlation between the degree of necrosis (Huvos grade) and the probability of subsequent disease-free survival was observed, and this prognostic value has been confirmed in multiple clinical trials.278,338-344 Given the advantages in facilitating limb salvage procedures and in assessing chemotherapeutic efficacy, the use of induction chemotherapy became the standard treatment approach for osteosarcoma. Numerous studies have demonstrated that resection of all sites of bulk tumor is similarly necessary for a favorable outcome; additional surgery is discussed subsequently.
Soon after the identification of the prognostic value of the degree of necrosis following induction chemotherapy, it was suggested that chemotherapy be modified for the patients with less necrosis (currently referred to as either standard or poor responders, and variably defined as < 90% or < 98% tumor necrosis) in order to increase their probability of disease-free survival. Modifying therapy to achieve a better outcome in patients with a poor histologic response was initially reported as showing benefit in the results of the T10 protocol at Memorial Sloan-Kettering Cancer Center.338 Longer follow-up of this patient population, however, showed no benefit to the therapy intensification.261,262,278 The vast majority of studies have demonstrated that intensified therapy cannot change the outcome of a patient who has had a standard response.288,293,340,343,344,346-349 Intensification of therapy in the induction period to increase the proportion of patients with greater amounts of necrosis (currently referred to as favorable responders) likewise did not change the outcome.241,287
FIGURE 453-3. Overall survival of the osteosarcoma patients who presented with localized disease by assignment to receive muramyl tripeptide–phosphatidyl ethanolamine (MTP-PE).
Several trials have been conducted to clarify the role of the various chemotherapeutic agents in the treatment of osteosarcoma as well as their method of delivery.
The last North American–based randomized Phase III pediatric cooperative group study (INT-0133), jointly administered by the Children’s Cancer Group and the Pediatric Oncology Group, addressed two study questions.359 The study tested whether the addition of ifosfamide or muramyl tripeptide–phosphatidyl ethanolamine (MTP-PE) to the three other agents used in the standard treatment of osteosarcoma (doxorubicin, cisplatin, high-dose methotrexate) would improve the probability of disease-free survival.359 Muramyl tripeptide is a component of the bacillus Calmette-Guerin (BCG) cell wall. It is conjugated to phosphatidyl ethanolamine and liposome encapsulated to improve delivery to the reticuloendothelial system.360-362 The primary rationale supporting the use of this relatively nonspecific immune adjuvant were the encouraging results obtained in a prospective randomized trial of this compound in canines.363 The results of this trial did not demonstrate a benefit in either event-free survival or survival for the addition of ifosfamide.359,364 The addition of muramyl tripeptide–phosphatidyl ethanolamine demonstrated an overall survival advantage.364 The overall survival at 6 years for the patients who did not receive the muramyl tripeptide–phosphatidyl ethanolamine was 70% and for those who did was 78% as shown in Figure 453-3.364 These overall survival numbers represent among the best reported in a cooperative group study for the treatment of this disease, and the 3-drug chemotherapy backbone remains the standard of care for the treatment of osteosarcoma. The importance of MTP-PE in the treatment of osteosarcoma remains under intensive discussion.364-366
The EURAMOS 1 clinical trial, launched in 2005, is a large ongoing phase III trial. The aim of the study is to evaluate whether it is possible to improve the outcome of both poor and good responders to preoperative chemotherapy by modification of postoperative chemotherapy. All patients receive preoperative methotrexate, doxorubicin, and cisplatin (MAP) as given in the control arm of the INT-0133 study. Poor responders are randomized to receive MAP with or without the addition of high-dose ifosfamide and etoposide. Good responders will continue on MAP chemotherapy and are randomized to the addition of pegylated interferon-α.241,368
Surgery
Preparation for surgical management should begin even before the initial biopsy is performed.6,241 Poorly planned biopsies may compromise a patient’s oncologic and functional outcome, because the complete biopsy tract and overlying skin need to be resected when the definitive resection is performed.251-256 In general, a biopsy should be obtained by the same surgeon who will ultimately perform the subsequent resection.241
Tumors at the primary site as well as at all sites of radiographically visible metastatic disease require local control.241 Osteosarcoma is considered resistant to radiation therapy; therefore, local control is usually surgery. Advances made in surgery have significantly improved the clinical practice and options available. Surgical management of osteosarcoma involves both the complete extirpation of the tumor and its ensuing bone and soft-tissue reconstruction.6,241
SUMMARY
Standard treatment for patients with nonmeta-static osteosarcoma, although variable, would include a biopsy to establish the diagnosis. This would be followed by induction therapy including cisplatin, doxorubicin, and high-dose methotrexate; after about 10 weeks of initial therapy, patients proceed to surgical ablation. This approach would be expected to yield a survival rate of approximately 70%. Patients who present with metastatic disease at diagnosis or have recurrent disease have a markedly worse outcome, and long-term cure is only obtained with aggressive approaches to achieve complete resection of all disease sites. The survival of these patients is generally less than 20%.