Chemotherapy and targeted therapy

The EFS rate for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6%–19%).

There was no significant difference in EFS between the trials according to the number of previous treatment regimens or patient age, sex, and ethnicity.

The 12-month EFS rate for the 42 evaluable patients enrolled in this study was 20% (95% CI, 10%–34%).

Ifosfamide alone with mesna uroprotection, or in combination with etoposide. Ifosfamide alone with mesna uroprotection, or in combination with etoposide, has been active in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[16-21]

Gemcitabine and docetaxel. A nonrandomized comparison of two doses of gemcitabine, both given with docetaxel, suggested that a higher dose of gemcitabine (900 mg/m2) was associated with a better response rate and longer survival than was a lower dose of gemcitabine (675 mg/m2) for patients with recurrent or refractory osteosarcoma.[22][Level of evidence C1] The combination of gemcitabine (at a dose of 900 mg/m2) and docetaxel has also been reported to have activity in some studies that included patients with unresectable disease.[23-25]; [26][Level of evidence C3]

Cyclophosphamide and etoposide. Cyclophosphamide and etoposide have been shown to have activity in recurrent osteosarcoma.[23]

Sorafenib. The Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma.[27]

Sorafenib and everolimus. The Italian Sarcoma Group also reported the outcome of patients with metastatic recurrent osteosarcoma treated with the combination of sorafenib and everolimus. They observed two partial responses and two minor responses in 38 patients; 17 of 38 patients were progression free at 6 months from study entry but toxicity was greater than with sorafenib monotherapy.[28][Level of evidence B4]

Regorafenib. Two prospective, randomized, double-blind trials have evaluated the role of regorafenib in the treatment of metastatic recurrent osteosarcoma. Both studies used the approved treatment regimen of 160 mg by mouth daily for 21 days followed by 7 days without treatment. The trial conducted in France included patients who were randomly assigned 2:1 between regorafenib and placebo and allowed crossover for patients assigned to placebo.[29] Seventeen of 26 patients (65%; one-sided 95% CI, 47%) in the regorafenib group did not have disease progression at 8 weeks, compared with 0 of 12 patients in the placebo group. The Sarcoma Alliance for Research Collaboration (SARC) group randomly assigned adult patients 1:1 between regorafenib and placebo.[30] Median progression-free survival (PFS) was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0–7.6 months) versus 1.7 months (95% CI, 1.2–1.8 months), respectively (HR, 0.42; 95% CI, 0.21–0.85; P = .017).

Dinutuximab in combination with GM-CSF. The COG performed a phase II study of dinutuximab, an antidisialoganglioside antibody, in combination with GM-CSF for patients with recurrent osteosarcoma. Of 39 patients, 28 experienced an event, and only 28.2% (95% CI, 15%–44.9%) of patients were event-free at the 12-month benchmark. Dinutuximab did not demonstrate sufficient evidence of efficacy.[31]

Denosumab. The COG performed a phase II study of denosumab, a fully human monoclonal antibody to the receptor activator of nuclear factor-kappa beta ligand (RANKL). Patients aged 11 to 49 years with recurrent osteosarcoma were eligible for the study. Patients with measurable disease were eligible for cohort 1, and patients who underwent complete surgical resection of all sites of recurrent disease were eligible for cohort 2. The event-free rate did not exceed the historical rate experienced in previous COG trials to meet the study defined efficacy criteria in either cohort.[32]

Lenvatinib with ifosfamide and etoposide. A multi-institutional group performed a phase I/II study using a combination of lenvatinib, ifosfamide, and etoposide to treat patients with relapsed or refractory osteosarcoma.[33][Level of evidence B4] The study suggested phase II doses for each drug: 1) 14 mg/m2 per day of lenvatinib (with a daily dose cap of 24 mg), 2) 100 mg/m2 per day of etoposide, and 3) 3,000 mg/m2 per day of ifosfamide. These drugs were given to patients intravenously on days 1 to 3 of each 3-week cycle for five cycles at most. Thirty-five patients from the phase I (cohort 3A; n = 15) and phase II (cohort 3B; n = 20) trials were treated at the recommended phase II doses, and their results were pooled. Eighteen of 35 patients had PFS rates of 51% (95% CI, 34%–69%) after 4 months, per the binomial estimate.

Cabozantinib. A phase II clinical trial of this VEGFR2 and MET inhibitor evaluated 43 patients aged 12 years and older with relapsed osteosarcoma, 39 of whom had pulmonary metastases. The 6-month PFS rate was 33%, and five patients (12%) had a partial response.[34]

Apatinib. A phase II clinical trial of this VEGFR2 inhibitor enrolled 37 patients aged 16 years and older. Sixteen patients (43%) had a partial response, and the 4-month PFS rate was 57%.[35] In a retrospective review of 19 patients with osteosarcoma who were treated with apatinib, 3 patients had a partial response (16%).[36]

Anlotinib. A retrospective analysis reported the efficacy of the multitargeted tyrosine kinase inhibitor anlotinib in patients with recurrent metastatic osteosarcoma.[37] The study included 15 patients who were treated in China between June 2018 and April 2020. The median PFS was 9.8 months (± 0.9 months). The 6-month PFS rate was 73%, and the 10-month PFS rate was 33%. The median OS was 11.4 months (± 0.6 months). No patients achieved complete responses.

Immunotherapy. Osteosarcoma frequently expresses PD-1, but trials of PD-1 inhibitors have been disappointing.[38-40] In these three studies, objective responses were observed in 1 of 14, 0 of 10, and 1 of 19 patients. HER2-expressing chimeric antigen receptor (CAR) T-cell therapy is also being studied.[41]

High-dose chemotherapy with autologous hematopoietic stem cell transplant (HSCT). A study analyzed the addition of high-dose chemotherapy with autologous HSCT to treat Korean patients with relapsed osteosarcoma who achieved a complete response to salvage therapy.[42] Among 25 patients who achieved a complete response with salvage therapy, 15 were assigned to receive high-dose chemotherapy with autologous HSCT by investigator choice. In a subgroup analysis of outcomes in patients who achieved a complete response, there were no significant differences in the 5-year OS rates between patients who did and did not receive high-dose chemotherapy with autologous HSCT (83.9% ± 0.1% for 13 of 15 patients vs. 80.0% ± 0.1% for 8 of 10 patients, respectively; P = .923).