Jill C. Friebele, MD, Jeffrey Peck, MD, Xueliang Pan, PhD, Mahmoud Abdel-Rasoul, MS, MPH, and Joel L. Mayerson, MD
Authors’ Disclosure Statement: The authors report no actual or potential conflict of interest in relation to this article.
Over the past 30 years, treatment advances and the addition of neoadjuvant chemotherapy have led to improved 5-year survival in patients with osteosarcoma. More recent literature suggests the overall prognosis remains highly variable, with little improvement since the introduction of neoadjuvant chemotherapy. Tumor necrosis is an important predictor of patient prognosis. Necrosis of more than 90% correlates with overall survival (OS) approaching 75%.
We reviewed the history of osteosarcoma treatment and survival and performed a meta-analysis of the 2000–2011 literature. Forty articles were included in the study. Five-year OS was 63% (95% confidence interval, 60%-66%) in studies that included patients with metastatic and nonmetastatic disease and 71% (95% confidence interval, 67%-76%) in studies that included only patients with nonmetastatic disease. Fifty percent of the patients in the studies of those with nonmetastatic osteosarcoma achieved 90% necrosis on histology. Five-year OS and number of patients achieving 90% necrosis are consistent with previous reports. Research is needed to improve treatment regimens and patient outcomes.
Osteosarcoma, a primary malignant tumor of the skeleton, is characterized by direct formation of immature bone or osteoid tissue by tumor cells. The World Health Organization histologic classification of bone tumors divides osteosarcoma into central and surface tumors and recognizes a number of subtypes within each group.1 The present review refers only to the classic central high-grade primary osteosarcoma of bone, which represents about 90% of all osteosarcoma cases. Classic osteosarcoma represents about 15% of all biopsy-analyzed primary bone tumors.1 It is the third most common type of neoplasia, preceded by leukemia and lymphoma among older children and adolescents aged 12 to 18 years.2 High-grade primary osteosarcoma is the most common primary skeletal tumor of childhood and adolescence, with an overall annual incidence of 5.6 cases per million children under age 15 years.3-5 Peak incidence is in the second decade of life, and males are affected slightly more often than females.2,6 The period of highest incidence coincides with the growth spurt of the long bones. Osteosarcoma preferentially affects the metaphysis of long bones, the 3 main sites being distal femur, tibia, and proximal humerus.2
Historical Perspective
For most of the 20th century, the 5-year survival rate for classic primary osteosarcoma was under 20%.7 In the 1970s, the first revolution in osteosarcoma treatment arrived with the introduction of adjuvant chemotherapy, which increased survival rates to 50%.8-10 During this expansion of research, several chemotherapeutics (eg, vincristine, bleomycin, dactinomycin) were discarded for poor effectiveness, and others (eg, cisplatin, ifosfamide) were added to doxorubicin and methotrexate, improving 5-year disease-free survival to about 70% in patients with nonmetastatic osteosarcoma. In another significant advance, adjuvant chemotherapy was supplemented with intensive preoperative chemotherapy, resulting in 5-year tumor-free survival that has ranged from 50% to 75% for high-grade osteosarcoma.5,11,12 Adding neoadjuvant chemotherapy and histologic response has allowed for evaluation of surgical margins and early treatment of microscopic disease. Thus, effective limb-sparing procedures can be performed, and the incidence of amputation has decreased from 90% to between 10% and 20%.13,14 However, statistical improvements in survival associated with neoadjuvant treatment may simply delay time of recurrence and metastasis.15 In addition, though chemotherapy has improved survival in osteogenic sarcoma, many have written that this improvement appears to reflect mainly the increase in the intensity of the chemotherapy used, which also leads to a higher propensity for side effects.16
Despite research and advances in chemotherapy regimens, the prognosis of patients with osteosarcoma remains highly variable and often dismal. Mirabello and colleagues17 examined osteosarcoma incidence and survival rates between 1973 and 2004 and found that, with the introduction of neoadjuvant chemotherapy, survival rates improved significantly between 1973 and 1983 and between 1984 and 1993, but there was little improvement between 1993 and 2004.
The long-term outcome for patients with metastatic disease is poor. Investigators have found that 11% to 20% of patients have pulmonary metastasis at initial diagnosis. About half of patients without pulmonary metastases develop them later in the disease course.18 Survival rates for patients with metastasis at initial presentation have ranged from 10% to 40%.19 Recurrent disease still occurs in 30% to 40% of patients, and more than 70% of them die of the tumor.15 The survivors of osteosarcoma are then at increased risk for chronic medical conditions and adverse health status because of the osteosarcoma-related treatments.20
Prognostic Factors
It is important to understand and exploit the influences of different prognostic factors in treating patients with osteosarcoma.7 These factors are important in establishing the best treatment for the individual. Thus, more aggressive treatments can be started in patients with prognostic factors that pose a higher risk of relapse.21 A number of clinical and pathologic features (eg, tumor site, size, subtype; patient sex and age; high alkaline phosphatase or high lactate dehydrogenase [LDH] values; multidrug resistance; genetic variations) have prognostic significance but often with contradictory results because of lack of uniformity in patient analyses and methods.15
Survival for patients with primary osteosarcoma has been analyzed with respect to tumor size and location.7 Studies have found higher survival rates for patients with smaller tumors (<10 cm) and more distal tumor locations.7 These superior survival rates may be the result of earlier detection of tumors and more options for surgical resection of smaller, distal tumors.
Serum LDH levels have helped in risk stratification of patients. High LDH often occurred at time of relapse, and relapse with high LDH correlated with poor prognosis. Meyers and colleagues22 found that 5-year disease-free survival was 72% for patients with normal LDH at presentation and 54% for patients with elevated LDH at presentation.
