Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.

PURPOSE: Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results. The present study was designed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents. PATIENTS AND METHODS: Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas (primary diameter ≥ 5 cm or any size recurrent tumor) in extremities or girdles were eligible. Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm. One hundred four patients were randomized, 51 to the control group and 53 to the treatment group (five cycles of 4′-epidoxorubicin 60 mg/m² days 1 and 2 and ifosfamide 1.8 g/m² days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor). RESULTS: After a median follow-up of 59 months, 60 patients had relapsed and 48 died (28 and 20 in the treatment arm and 32 and 28 in the control arm, respectively). The median disease-free survival (DFS) was 48 months in the treatment group and 16 months in the control group (P = .04); and the median overall survival (OS) was 75 months for treated and 46 months for untreated patients (P = .03). For OS, the absolute benefit deriving from chemotherapy was 13% at 2 years and increased to 19% at 4 years (P = .04). CONCLUSION: Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months. Therefore, our data favor an intensified treatment in similar cases. Although cure is still difficult to achieve, a significant delay in death is worthwhile, also considering the short duration of treatment and the absence of toxic deaths.

BACKGROUND: The evaluation variables influencing systemic and local recurrence and final outcome are extremely important in defining risk‐adapted treatments for patients with nonmetastatic osteosarcoma of the extremity.METHODS: A homogeneous group of 789 patients treated at a single institution between March 1983 and March 1999 with different protocols of neoadjuvant chemotherapy, with a minimum followup of 5 years, were retrospectively evaluated in relation to gender, age, serum levels of alkaline phosphatase, tumor site and size of the pathologic fracture, type of surgery, protocol of chemotherapy, surgical margins, and histologic response to preoperative treatment.RESULTS: The 5‐year event‐free survival (EFS) and overall survival rates were 60.1% and 67.5%, respectively. Upon univariate analysis, EFS was significantly related to the age of patients, serum value of alkaline phosphatase, tumor volume, histologic subtype, type of surgery, surgical margins, histologic response to preoperative treatment, and chemotherapy protocol. Local recurrences (4.8%) were significantly correlated with surgical margins. The 5‐year postrecurrence EFS survival was 17% and was significantly lower for patients who had a local recurrence and metastases than for those with metastases only. Patients who had a recurrence only in the lung had a postrecurrence survival rate significantly better than others, correlated with the number of metastatic nodules and the length of the disease‐free interval.CONCLUSIONS: Upon multivariate analysis, age ≤ 14 years, high serum levels of alkaline phosphatase, tumor volume > 200 mL, a two‐drug regimen chemotherapy, inadequate surgical margins, and poor histologic response to treatment maintained independent prognostic values on the outcome of nonmetastatic osteosarcoma of the extremities. These factors must be considered when deciding risk‐adapted treatments for osteosarcoma patients. Cancer 2006. © 2006 American Cancer Society.

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing. The Ewing sarcoma family of tumors is a group of aggressive cancers that primarily affects the pediatric and young adult population. Increasingly, genomics are being used to better define the disease biology and to identify targets for therapy in many cancer types. Here, we report one of the first and largest genomic studies to date in the Ewing sarcoma family of tumors. Using a combination of modern sequencing techniques in >100 samples, we discover that Ewing sarcomas have a genome that is less complex compared to most cancer types previously surveyed. We find that this cancer is frequently affected by mutations in STAG2, a gene that has recently gained attention due to its importance in the biology of several cancer types. We show that Ewing sarcoma patients whose tumors are affected by STAG2 loss may have a worse prognosis. Additionally, we identify a subset of tumors that were diagnosed as Ewing sarcoma that appear to be distinct from the majority based on genetic and molecular characteristics. Our findings help to define the genetic landscape of Ewing sarcoma and provide a starting point for improving individualization of diagnosis, prognosis and treatment in this cancer.

Osteosarcoma is a primary malignant tumour of the skeleton characterised by the direct formation of immature bone or osteoid tissue by the tumour cells. The classic osteosarcoma is a rare (0.2% of all malignant tumours) highly malignant tumour, with an estimated incidence of 3 cases/million population/year. Osteosarcoma arises predominantly in the long bones and rarely in the soft tissues. The age at presentation ranges from 10 to 25 years of age. Plain radiographs, computed tomography, magnetic resonance imaging, angiography and dynamic bone scintigraphy are used for diagnosis, evaluation the extent of tumour involvement and decision of the type of operation and, if necessary, the type of reconstruction. Years ago, all patients with osteosarcoma were treated by amputation but the cure rate was under 10% and almost all patients died within a year from diagnosis. Today, for localised osteosarcoma at onset (80% of cases) treated in specialized bone tumour centres with pre- and postoperative chemotherapy associated with surgery, the percentage of patients cured varies between 60% and 70%. Surgery is conservative (limb salvage) in more than 90% of patients. Prognosis is more severe (cure rate about 30%) for tumours located in the axial skeleton and in patients with metastasis at onset.

Purpose: To explore the effect of high-dose ifosfamide in first-line treatment for patients ≤ 40 years of age with nonmetastatic osteosarcoma of the extremity. Patients and Methods: From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m²), methotrexate (12 g/m²), cisplatin (120 mg/m²), and doxorubicin (75 mg/m²). Postoperatively, patients received two cycles of doxorubicin (90 mg/m²), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m²). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. Results: No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence. Conclusion: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.