Phase 2 study for nonmetastatic extremity high-grade osteosarcoma in pediatric and adolescent and young adult patients with a risk-adapted strategy based on ABCB1/P-glycoprotein expression: An Italian Sarcoma Group trial (ISG/OS-2).

BACKGROUND: According to retrospective osteosarcoma series, ABCB1/P-glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk-adapted treatment strategy using mifamurtide in Pgp+ patients was performed. METHODS: This was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high-grade osteosarcoma stratified according to Pgp expression. All patients received high-dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis ≥ 90%; good responders [GRs]) or with high-dose ifosfamide (HDIFO) at 3 g/m2 /d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp- patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m2 (from 5 to 10 courses). The primary end point was event-free survival (EFS). A postamendment analysis was performed. RESULTS: In all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp-, and 124 (64%) were Pgp+. The median follow-up was 51 months. For Pgp+ patients, 5-year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%-76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp- patients, the 5-year EFS rate was 66.4% (90% CI, 55.6%-75.1%). CONCLUSIONS: This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.

Unresectable Clival Giant Cell Tumor, Tumor Control With Denosumab After Relapse: A Case Report and Systematic Review of the Literature.

Giant cell tumors (GCTs) of the skull base are rare entities. Although considered histologically benign, GCTs are locally aggressive with a high rate of local recurrence. The present case describes a 14-year-old girl with a clival GCT who underwent long-term therapy with denosumab after local relapse. To our knowledge, it is the second case described with a follow-up term >2 years from the start of denosumab and who did not receive any other adjuvant treatment besides denosumab. The patient achieved a local control of the disease. According to the few available data, radical excision with adjuvant therapy helps in long-term control in uncommon sites, such as the skull. However, the definitive treatment is still controversial because of their rarity and few follow-up data. The present case highlights the benefit of denosumab and its safety as long-term therapy and contributes to the existing literature with analysis and evaluation of the management strategies and prognosis.

Management of Unresectable Metastatic Primitive Myxoid Mesenchymal Tumor of Infancy: A Case Report and Systematic Review of the Literature.

Primitive myxoid mesenchymal tumor of infancy is a rare soft tissue tumor. The present case is one of the most invasive primitive myxoid mesenchymal tumor of infancy reported to date. To our knowledge, it is the first case described with extensive involvement of pelvis and the third described developing metastasis and with an invasion of the spinal canal without evidence of transformation into undifferentiated sarcoma. The patient failed to respond to chemotherapy (CHT). According to the few available data, CHT seems to be more effective in the presence of metastatic disease or increased cellularity. However, CHT, including high-dose ifosfamide, resulted ineffective even after lung metastasis development with pathologic evidence of increased mitotic rate. The management of this case and the data in the literature confirm surgery as the gold standard treatment in this pathology.

Anthracycline-induced cardiotoxicity in patients with paediatric bone sarcoma and soft tissue sarcoma.

OBJECTIVES: Anthracycline cardiotoxicity is an important side-effect in long-term childhood cancer survivors. We evaluated the incidence of and factors associated with anthracycline cardiotoxicity in a population of patients diagnosed with bone or soft tissue sarcoma. Materials and methods We retrospectively enrolled patients diagnosed with bone or soft tissue sarcoma, from 1995 to 2011, treated with anthracycline chemotherapy at our Centre and with a follow-up echocardiography carried out ⩾3 years from cardiotoxic therapy completion. Cardiac toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0. RESULTS: A total of 82 patients were eligible. The median age at treatment was 11.9 years (1.44-18). We evaluated the median cumulative anthracycline dose, age at treatment, sex, thoracic radiotherapy, hematopoietic stem cell transplantation, and high-dose cyclophosphamide treatment as possible risk factors for cardiotoxicity. The median cumulative anthracycline dose was 390.75 mg/m2 (80-580). Of the 82 patients, 12 (14.6%) developed cardiotoxicity with grade ⩾2 ejection fraction decline: four patients were asymptomatic and did not receive any treatment; six patients were treated with pharmacological heart failure therapy; one patient with severe cardiomyopathy underwent heart transplantation and did not need any further treatment; and one patient died while waiting for heart transplantation. The median time at cardiac toxicity, from the end of anthracycline frontline chemotherapy, was 4.2 years (0.05-9.6). Cumulative anthracycline dose ⩾300 mg/m2 (p 0.04) was the only risk factor for cardiotoxicity on statistical analyses. CONCLUSIONS: In our population, the cumulative incidence of cardiotoxicity is comparable to rates in the literature. This underlines the need for primary prevention and lifelong cardiac toxicity surveillance programmes in long-term childhood cancer survivors.

Precision Medicine in Osteosarcoma: MATCH Trial and Beyond.

Osteosarcoma (OS) is a rare bone malignant tumour with a poor prognosis in the case of recurrence. So far, there is no agreement on the best systemic therapy for relapsed OS. The availability of next generation sequencing techniques has recently revolutionized clinical research. The sequencing of the tumour and its matched normal counterpart has the potential to reveal a wide landscape of genetic alterations with significant implications for clinical practice. The knowledge that the genomic profile of a patient's tumour can be precisely mapped and matched to a targeted therapy in real time has improved the development of precision medicine trials (PMTs). PMTs aiming at determining the effectiveness of targeted therapies could be advantageous for patients with a tumour refractory to standard therapies. Development of PMTs for relapsed OS is largely encouraging and is in its initial phase. Assessing OS features, such as its rarity, its age distribution, the technical issues related to the bone tissue origin, and its complex genomic landscape, represents a real challenge for PMTs development. In this light, a multidisciplinary approach is required to fully exploit the potential of precision medicine for OS patients.

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study.

PURPOSE: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI). METHODS: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed. RESULTS: After WLI, grade 1-2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1-79.3), 61.2% (48.4-71.7) and 70.5% (56.3-80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis. CONCLUSIONS: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor.

Survival after second and subsequent recurrences in osteosarcoma: a retrospective multicenter analysis.

PURPOSE: Osteosarcoma (OS) is the most common primary bone tumor. Despite complete surgical removal and intensive chemotherapeutic treatment, 30%-35% of patients with OS have local or systemic recurrence. Some patients survive multiple recurrences, but overall survival after OS recurrence is poor. This analysis aims to describe and identify factors influencing post-relapse survival (PRS) after a second OS relapse. METHODS: This is a retrospective analysis of 60 patients with a second relapse of OS of the extremities in 2 Italian centers between 2003 and 2013. RESULTS: Treatment for first and subsequent relapses was planned according to institutional guidelines. After complete surgical remission (CSR) following the first recurrence, patients experienced a second OS relapse with a median disease-free interval (DFI) of 6 months. Lung disease was prevalent: 44 patients (76%) had pulmonary metastases. Survival after the second relapse was 22% at 5 years. Lung disease only correlated with better survival at 5 years (33.6%) compared with other sites of recurrence (5%; p = 0.008). Patients with a single pulmonary lesion had a better 5-year second PRS (42%; p = 0.02). Patients who achieved a second CSR had a 5-year second PRS of 33.4%. Chemotherapy (p<0.001) benefited patients without a third CSR. CONCLUSIONS: This analysis confirms the importance of an aggressive, repeated surgical approach. Lung metastases only, the number of lesions, DFI and CSR influenced survival. It also confirms the importance of chemotherapy in patients in whom surgical treatment is not feasible.

Survival after Second and Subsequent Recurrences in Osteosarcoma: A Retrospective Multicenter Analysis.

Purpose Osteosarcoma (OS) is the most common primary bone tumor. Despite complete surgical removal and intensive chemotherapeutic treatment, 30%-35% of patients with OS have local or systemic recurrence. Some patients survive multiple recurrences, but overall survival after OS recurrence is poor. This analysis aims to describe and identify factors influencing post-relapse survival (PRS) after a second OS relapse. Methods This is a retrospective analysis of 60 patients with a second relapse of OS of the extremities in 2 Italian centers between 2003 and 2013. Results Treatment for first and subsequent relapses was planned according to institutional guidelines. After complete surgical remission (CSR) following the first recurrence, patients experienced a second OS relapse with a median disease-free interval (DFI) of 6 months. Lung disease was prevalent: 44 patients (76%) had pulmonary metastases. Survival after the second relapse was 22% at 5 years. Lung disease only correlated with better survival at 5 years (33.6%) compared with other sites of recurrence (5%; p = 0.008). Patients with a single pulmonary lesion had a better 5-year second PRS (42%; p = 0.02). Patients who achieved a second CSR had a 5-year second PRS of 33.4%. Chemotherapy (p<0.001) benefited patients without a third CSR. Conclusions This analysis confirms the importance of an aggressive, repeated surgical approach. Lung metastases only, the number of lesions, DFI and CSR influenced survival. It also confirms the importance of chemotherapy in patients in whom surgical treatment is not feasible.