The objective of systemic therapy in the treatment of localized bone sarcoma is to treat both the primary tumor and any micrometastatic deposits. Since the introduction of systemic multiagent chemotherapy in the 1970s, 5-year survival rates for patients with localized osteosarcoma have dramatically improved, from 20% to 65%-70%.¹ Several studies in the early 1980s demonstrated the efficacy of chemotherapy and surgery versus surgery alone.^2,3 The use of neoadjuvant chemotherapy became standard as limb-sparing surgery became the focus. In addition, the significance of a good histologic response to neoadjuvant chemotherapy, defined as more than 90% necrosis on the surgical specimen, has been shown to be predictive of survival regardless of which chemotherapy regimen is chosen postoperatively.^4,5 The 5-year disease-free survival and overall survival were shown to be significantly superior in patients who were good versus poor responders; disease-free survival of 67.9% versus 51.3% (P < 0.0001),
respectively, and overall survival of 78.4% versus 63.7% (P < 0.0001), respectively.^6,7

There is no consensus worldwide on the standard chemotherapy regimen for the treatment of osteosarcoma. In the United States, high-dose methotrexate plus doxorubicin and cisplatin (MAP) is considered standard in children and in adults younger than 40 years and is a category 1 recommendation according to national consensus guidelines in this patient population. The data for MAP are taken from the control arm of the EURAMOS (the European and American Osteosarcoma Study)-1, which remains the largest collaborative group trial on osteosarcoma to date, including more than 2,000 patients.⁸ The published results of this trial focused on patients with localized, newly diagnosed osteosarcoma who had poor responses to two cycles of MAP induction and were then randomly assigned to receive adjuvant MAP or MAP plus ifosfamide and etoposide. The trial affirmed the efficacy of MAP as a standard chemotherapy approach, with outcomes similar to those of historical control groups of multiagent regimens and more efficacious than cisplatin and doxorubicin alone. In addition, there was no difference in event-free survival (EFS) (hazard ratio 0.98 [95% confidence interval 0.78-1.23]) or overall survival with the addition of ifosfamide and etoposide, and toxicity was shown to be significantly higher with addition of these agents.⁸ Other trials have similarly not shown any meaningful difference in outcomes when changing the adjuvant regimen in poor responders.^9,10 Thus, MAP remains the standard therapy in both the neoadjuvant and adjuvant setting in patients younger than 40 years with an excellent performance status.

Because of the relative rarity of osteosarcoma in older adults, data are limited for the treatment of this patient population. Most clinical trials have historically excluded patients older than 40 years. One retrospective analysis demonstrated that osteosarcoma in adults is potentially curable and warrants intense treatment in patients who are able tolerate it.¹¹ As in children, a poor histologic response predicts a poor outcome in adults. Treatment with doxorubicin and cisplatin remains the standard therapy in localized disease as inferred from pediatric data. The addition of methotrexate in adult populations is not well studied but can cause significant toxicity; therefore, it has limited use in older adults.

Systemic therapy is associated with improved outcomes in patients who present with metastatic disease, but as expected, outcomes are significantly worse compared with those of patients with localized disease. The 5-year disease-free survival rate is only 20% compared with 70% in patients with metastatic versus localized disease, respectively.^12,13,14 Approximately 10% to 20% of patients are shown to have metastatic disease at the time of diagnosis.^15,16 Approximately 15% to 30% of patients with an initial diagnosis of localized osteosarcoma and who undergo treatment will relapse.^17,18

A study that evaluated more than 1,700 patients with newly diagnosed osteosarcoma found that in 11.4% of patients with metastatic disease at diagnosis, both the number of metastases and the completeness of surgical resection of all detected tumor sites were the most independent prognostic factors for survival.¹⁹ Improved outcomes have been shown in patients undergoing a combination of aggressive chemotherapy followed by resection of the primary and all metastatic sites if feasible, and is thus the recommended treatment approach. Single-beam radiation therapy is an alternative to surgery if metastatic sites are not able to be resected.^20,21 As with localized disease, MAP is often used first for the treatment of metastatic osteosarcoma. Other recommended regimens by the European Society of Medical Oncology and national consensus guidelines include ifosfamide with or without etoposide, cyclophosphamide, and gemcitabine in combination with docetaxel. These recommendations are mainly from retrospective and phase II clinical trials with limited patient numbers with response rates in the 20% to 50% range.^22,23,24

In recent years, targeted therapy has shown promise in the treatment of metastatic osteosarcoma^{25,26,27,28,29,30,31,32,33,34,35,36,37,38,39} (Table 1). This treatment strategy inhibits tumor growth at the molecular and cellular level and has the advantage of conferring specific antineoplastic activity with lower toxicity than traditional chemotherapy. These therapies, which are broadly divided by the pathways they inhibit, target cell cycle regulation, DNA damage repair, and antiangiogenic pathways, among others. Drugs that target vascular endothelial growth factor such as sorafenib, regorafenib, and cabozantinib have shown the most promise in recent clinical trials. In a phase II trial conducted in 35 patients with advanced osteosarcoma, sorafenib demonstrated a progression-free survival (PFS) rate of 46% at 4 months, with 3 partial responses (8%) and 12 stable diseases (34%).²⁵ In the 2020 phase II CABONE trial, cabozantinib demonstrated stable disease in 14 of 42 patients (33%) with overall good tolerability.²⁸ Data from the osteosarcoma cohort of the REGOBONE, a double-blind, placebo-controlled trial run by the French Sarcoma Group using regorafenib, were recently reported. These results demonstrated that 17 of 26 patients (65%) in the regorafenib group did not progress at 8 weeks compared with zero patients in the placebo group.²⁶ In the United States, a similarly designed randomized double-blind, placebo-controlled trial was conducted in 42 patients and demonstrated a significantly better PFS rate of 3.6 versus 1.7 months in the regorafenib arm (hazard ratio, 0.42; 95% confidence interval, 0.21-0.85; P = 0.017) compared with placebo.²⁷ Despite the promise held for targeted therapy for this disease, many challenges such as drug resistance and minimizing adverse reactions require further study.

The use of checkpoint inhibition in the treatment of osteosarcoma has been an area of ongoing interest, but its efficacy in clinical trials has been limited. In the bone sarcoma cohort of SARC028 investigating the use of pembrolizumab, only 1 of 22 patients with osteosarcoma and 1 of 5 patients with chondrosarcoma demonstrated an objective response.²⁹ Adoptive cell therapy approaches involving intravenous transfer of extracted and genetically modified blood or tumor-derived immune cells are under investigation. In particular, the use of tumor-infiltrating lymphocytes extracted from the patient, expanded in the laboratory, and ultimately transfused back to the patient has been shown to prolong survival when combined with adjuvant chemotherapy in patients with poor histologic response following neoadjuvant treatment, as discussed in a 2020 study.⁴⁰ Ongoing preclinical work in osteosarcoma aims to increase understanding of the complex immune microenvironment of these tumors and how to best modulate the immune system to enhance therapeutic response.

Ewing sarcoma is a small round blue cell malignancy arising in soft tissue or bone, which predominantly affects adolescents and young adults. Ewing sarcoma is a translocation-driven tumor most often associated with EWSR1 (Chr22) and the ETS family transcription factor FLI1 (Chr11). When treated solely with local therapy (surgery with or without radiation), historically, mortality was extremely high, with 5-year EFS of only 20%.⁴¹ However, the use of adjuvant chemotherapy, which began in the 1970s, resulted in significant improvement in EFS. The pivotal first Intergroup Ewing’s Sarcoma Study (IESS-I) enrolled patients between May 1973 and November 1978 and demonstrated an improvement in 5-year EFS to 60% with doxorubicin-based therapy.⁴² IESS-II and subsequent meta-analyses demonstrated the importance of doxorubicin dose intensity.⁴³ Systemic therapy further evolved based on the National Cancer
Institute protocol INT-0091 (CCG7881 and POG-8850) was opened to all member institutions of the Children’s Cancer Group and the Pediatric Oncology Group from December 1988 through November 1992. In this study, the addition of ifosfamide and etoposide to standard doxorubicin-based therapy led to improvement in 5-year EFS to 70% for patients with nonmetastatic Ewing sarcoma. No advantage was seen for patients who were already metastatic at presentation.⁴⁴ The Children’s Oncology Group went on to show a further improvement in 5-year EFS to 73% in a 2022 randomized trial comparing dose intensification with every 2-week chemotherapy cycles with growth factor support compared with standard every 3-week chemotherapy cycles. No increase in toxicity was observed in this study. This regimen of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with etoposide and ifosfamide was compared with the other commonly used regimen in the United States that used vincristine, ifosfamide, doxorubicin, and etoposide induction and was found to be more effective and less toxic.⁴⁵ Ultimately these data have led to the current standard of care for nonmetastatic Ewing sarcoma, which comprised local therapy (surgery with or without radiation) and 17 cycles of chemotherapy with alternating cycles of VDC and ifosfamide and etoposide at 2-week intervals with growth factor support, as discussed in a 2021 study.⁴¹