New targets and approaches in osteosarcoma

Abstract

Osteosarcoma is the most common primary tumor of bone. Approximately 2/3 of patients who present with localized osteosarcoma can be expected to be cured of their disease with surgery and routine chemotherapy. Only 1/3 of patients with metastases detectable at presentation will be cured. These survival trends have stagnated over the past 20 years using conventional chemotherapy. New agents need to be rationally investigated to strive for improvement in the survival of patients diagnosed with osteosarcoma. This manuscript will review the rationale for conventional chemotherapy used in the treatment of osteosarcoma, as well as agents in varying stages of development that may have promise for treatment in the future.

Introduction

Osteosarcoma (OS) is the most common primary malignant tumor arising from bone in children and young adults. It arises from mesenchymal cells and is pathologically characterized by spindle cells and aberrant osteoid formation. The incidence of OS has a bimodal distribution with a peak in adolescence and a second peak occurring in the seventh and eighth decade of life. The latter peak, in the era prior to the advent of bisphosphonates, likely represents a consequence of long-standing Paget's disease of bone (Mirabello et al., 2009). In children and young adults, approximately 400 new cases of OS are diagnosed in the United States each year, making it the eighth most common malignancy of childhood (Ottaviani & Jaffe, 2009).

High-grade OS can occur in any bone. Most commonly, OS originates juxtaposed to the knee joint involving the distal femur (43%) or proximal tibia (23%). The proximal humerus, the next most common site of disease, represents approximately 10% of cases (Bielack et al., 2002). These bones experience rapid cell division to facilitate the increased growth velocity during adolescence. Within the bone, OS typically occurs in the metaphysis in proximity to the growth plate. The stimulatory signals associated with pubertal growth may represent an inciting event in the oncogenesis of OS.

Most patients with newly diagnosed OS present with localized disease. Approximately 15–20% of patients have metastases detectable at presentation. The lung is the most common site of metastasis, comprising more than 85% of metastatic disease, with bone being the second most common site of distant disease (Bielack et al., 2002). However, these data are limited by the technology available to detect metastatic disease. Prior to the era of modern chemotherapy, greater than 80% of patients with localized disease treated by amputation alone developed metastases, most occurring within one year of diagnosis (Marcove et al., 1970). Given this experience, it is considered that most patients with localized OS have micrometastases at presentation.

The curative approach to OS entails both surgery and chemotherapy. The benefit of chemotherapy has been validated by Multi-Institutional Osteosarcoma Study (MIOS) conducted in the 1980's, in which patients were randomized to surgery alone versus adjuvant chemotherapy following amputation for localized OS. The patients randomized to receive chemotherapy had a significant improvement in their 2-year relapse-free survival: 66 versus 17% (Link et al., 1986). This significant difference persisted at follow-up greater than 5-years, validating that the addition of chemotherapy improves overall survival and does not just delay time to progression.

Chemotherapy for osteosarcoma is administered in both the neoadjuvant and adjuvant setting. The rationale for preoperative chemotherapy originated in the late 1970's in centers, accustomed to using chemotherapy for osteosarcoma, looking to avoid amputation. Preoperative chemotherapy provided a necessary bridge until a custom-fitted prosthesis could be constructed, which in the initial protocols required several months (Rosen et al., 1979). Despite improvements in manufacturing, this legacy has persisted, and most protocols today mandate 10–12 weeks of preoperative chemotherapy before proceeding to definitive resection. A randomized trial comparing neoadjuvant chemotherapy to surgery followed by adjuvant chemotherapy found that immediate surgery provided no benefit over delayed surgery (Goorin et al., 2003).

Another legacy of neoadjuvant chemotherapy is the ability to measure the chemoresponsiveness of a patient's tumor by evaluating the degree of tumor necrosis. This was initially codified into the Huvos grading system, ranging from grade I (little or no effect identified) to grade IV (no histologic evidence of viable tumor identified within the entire specimen) (Rosen et al., 1983). This has been further modified into the tumor necrosis grading which reports the percent necrosis within the resected tumor. The degree of tumor necrosis following neoadjuvant chemotherapy has been shown to be predictive of overall survival. Patients with Huvos grade III or IV, corresponding to greater than 90% necrosis, are generally considered good responders. Patients with a good response to chemotherapy have a disease-free survival greater than 65%. Some studies have demonstrated that patients with a grade IV response to chemotherapy have markedly better outcomes than patients with a grade III response. In comparison, the poor-responders' disease-free survival approaches 50% (Bacci et al., 2005). The tumor necrosis grade can thus be used as a surrogate marker for the chemoresponsiveness of the individual's tumor to neoadjuvant chemotherapy.

Investigators attempting to identify new agents or combination regimens have used this tool to extrapolate differences in tumor necrosis to effects on survival. To that effect, it has been demonstrated that increasing the number of agents in the neoadjuavant period increases the percentage of patients with higher grades of necrosis (Bacci et al., 2003). Likewise, it has been shown that increasing the duration of preoperative chemotherapy increases the percentage of patients with higher grades of necrosis. However, the predictive value of tumor necrosis grade on overall survival is blunted by the intensification of preoperative chemotherapy (Meyers et al., 1998). Hence, the use of the preoperative window period to test the anti-tumor activity of new agents has to be done with caution as those results may not reflect an anti-cancer effect leading to improvement in survival, but may be more reflective of the innate biology of the individual's tumor. Likewise, some biomarkers have been shown to correlate with survival but not with histologic response. A case in point is the biomarker, p-glycoprotein, the protein product of the multidrug resistance gene MDR1¸which functions as an ATP dependent efflux pump. In a meta-analysis, p-glycoprotein expression nearly doubles the risk of progression at 2 years, but had a sensitivity and specificity approaching 50% for histologic response (Pakos & Ioannidis, 2003). This discordance highlights the difficulty of using the grade of tumor necrosis as a surrogate marker for overall survival. To date, no molecular markers have been prospectively validated to predict response to chemotherapy and overall survival. For patients with poor response to neoadjuvant chemotherapy, no markers have been validated to help delineate patients who are likely to be cured with the current chemotherapeutic regimens or those who may benefit from investigational or escalation of therapy.