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.