Literature
Clinical Pearls & Morning Reports
Published November 24, 2021
Have treatment outcomes improved in recent decades for patients with high-grade osteosarcoma?
Although osteosarcoma is the most common malignant bone tumor, it is rare, with an estimated 800 to 900 cases diagnosed annually in the United States. Approved or investigational agents with real promise for activity in osteosarcoma are needed. Read the NEJM Review Article here.
Clinical Pearls
Q: What are the skeletal sites most often affected by osteosarcoma?
A: Most cases of osteosarcoma occur in children and young adults 10 to 30 years of age, with a peak incidence during the adolescent growth spurt. The most common tumor sites are those with the most extensive longitudinal bone growth: the knee (distal femur and proximal tibia) and the shoulder (proximal humerus).
Q: What is the current prognosis for patients with metastatic osteosarcoma?
A: Currently, the most common treatment for adolescents and young adults with resectable osteosarcoma includes neoadjuvant (presurgical) chemotherapy, with additional cycles after recovery from surgery. Approximately 10 to 15% of patients with newly diagnosed osteosarcoma present with metastatic disease, primarily in the lung. The 5-year survival rate is approximately 60% among patients with localized osteosarcoma but is only 20% among patients presenting with metastases or recurrent disease.
Morning Report Questions
Q: Have treatment outcomes improved in recent decades for patients with high-grade osteosarcoma?
A: The lack of significant improvement in treatment outcomes for patients with high-grade osteosarcoma contrasts with the progress made in the treatment of many other solid tumors. The development of cancer therapies that target known genetic alterations has had a major effect on cancer treatment. This approach has been challenging in osteosarcoma, which lacks common activating kinase mutations. Instead, osteosarcoma is characterized by frequent regions of gene amplification and substantial genetic variability. The complexity of the mutational patterns in osteosarcoma complicates the use of data from other tumors to predict genetic targets of chemotherapy. Harnessing the immune system to treat osteosarcoma would avoid the need to address its genomic complexity, but data on immunotherapy have not been encouraging. The failure of immune checkpoint inhibitors and other immune-based therapies may be related to properties of the osteosarcoma microenvironment that are unfavorable for T-cell infiltration, including vascular abnormalities and alterations in tumor-associated macrophages. Interventions that optimize the tumor microenvironment in order to enhance infiltration of antitumor immune cells might potentiate the activity of the immunotherapeutic approaches currently under investigation.
Q: Describe a new approach to targeted therapy for osteosarcoma based on its genetic features.
A: Given the rarity of osteosarcoma and our limited ability to subgroup this genetically heterogeneous tumor, a strategic approach to targeted therapy based on genetic features is challenging. In a new approach, a fresh tumor sample from a patient is implanted into an immunocompromised mouse, generating a patient-derived xenograft (PDX). The PDX is then analyzed with genetic methods to identify candidate drug targets. Responses to agents directed at these targets in the PDX are used to design a patient-specific regimen. Although this approach is encouraging when applied to the PDX model, studies in patients are still in development. Multiple challenges need to be met to apply the PDX method in real time to patients, including obtaining relevant biopsy specimens, accessing tumor-profiling technologies, and achieving a clinically reasonable timeline for analysis.