Introduction

Osteosarcoma (OS) is the most common primary bone malignancy, representing 3 to 5% of childhood cancers.1–3 OS has a bimodal distribution, with the majority of cases occurring in adolescents and another peak occurring in late adulthood.4,5 OS is highly aggressive, with 15-30% of patients presenting with metastatic disease at the time of diagnosis, most commonly to the lungs. Monotherapy with surgery is rarely sufficient for cure, as greater than 80% of patients develop distant metastatic disease when treated with surgery alone .6,7 The Multi Institutional Osteosarcoma Study (MIOS) conducted from 1982 to 1984 demonstrated significant increases in 6-year survival rates for patients treated with surgery and chemotherapy compared to surgery alone, highlighting the importance of combined multimodal treatment.8 However, since initial treatment advances in the 1970s and 1980s, survival rates have largely plateaued, with a 5-year event-free survival of approximately 70% in patients with localized disease and 20% in patients with metastatic disease at the time of diagnosis.9–11Current standard of care (SOC) treatment for patients with osteosarcoma includes surgical resection of all sites of disease, when feasible, in addition to systemic chemotherapy. The most established chemotherapeutic regimen incorporates methotrexate, Adriamycin (doxorubicin), and platinum (cisplatin) (MAP), which has demonstrated the best outcomes to date.12–16 Frequently, two cycles of neoadjuvant MAP are administered prior to surgical resection of the primary tumor (Figure 1). Local control (LC), which in most instances consists of surgery, ideally occurs soon after completion of neoadjuvant chemotherapy; however, scheduling challenges and therapy complications can result in delay. After recovery from surgery, patients typically receive an additional four cycles of MAP chemotherapy. In patients with pulmonary metastatic disease, metastasectomy is recommended. Tumor necrosis, calculated by pathologists by analyzing the surgically resected tumor specimen and quantifying the percentage of cells that have become necrotic, is a strong prognostic factor in osteosarcoma.17 Although a continuous variable, several clinical trials defined patients having a good response as having less than 10% of viable tumor remaining (corresponding to 90% tumor necrosis). Patients who do not meet this criterion are referred to as poor responders (less than 90% tumor necrosis) which confers a worse outcome.18Delays greater than 21 days in starting adjuvant chemotherapy have previously been shown to be associated with decreased overall survival in a retrospective analysis, but information is lacking regarding the interval between neoadjuvant chemotherapy completion and surgery.19 The goal of this study was to determine if the time from completion of neoadjuvant chemotherapy to surgical resection has implications on tumor necrosis or outcomes in children and young adults with osteosarcoma.