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.
Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach ...to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.
This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734).
Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar.
For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.
To compare three-drug chemotherapy with cisplatin, doxorubicin, and methotrexate with four-drug chemotherapy with cisplatin, doxorubicin, methotrexate, and ifosfamide for the treatment of ...osteosarcoma. To determine whether the addition of muramyl tripeptide (MTP) to chemotherapy enhances event-free survival (EFS) and overall survival in newly diagnosed patients with osteosarcoma.
Six hundred sixty-two patients with osteosarcoma without clinically detectable metastatic disease and whose disease was considered resectable received one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 x 2 factorial design. The primary end points for analysis were EFS and overall survival.
In the current analysis, there was no evidence of interaction, and we were able to examine each intervention separately. The chemotherapy regimens resulted in similar EFS and overall survival. There was a trend toward better EFS with the addition of MTP (P = .08). The addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P = .03). The hazard ratio for overall survival with the addition of MTP was 0.71 (95% CI, 0.52 to 0.96).
The addition of ifosfamide to cisplatin, doxorubicin, and methotrexate did not enhance EFS or overall survival for patients with osteosarcoma. The addition of MTP to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better EFS.
The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival ...outcomes for patients with previously untreated nonmetastatic Ewing sarcoma.
Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests.
Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A
regimen B, 78%
79%;
= .192; 5-year OS 86%
88%;
= .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96;
= .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS.
While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.
To simplify the recommended staging evaluation by correlating tumor and clinical features with patterns of distant metastasis in newly diagnosed patients with embryonal rhabdomyosarcoma (ERMS) or ...alveolar rhabdomyosarcoma (ARMS).
Patient data from the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group over two periods were analyzed: 1991 to 1997 and 1999 to 2004. We used recursive partitioning analyses to identify factors (including histology, age, regional nodal and distant metastatic status, tumor size, local invasiveness, and primary site) that divided patients into subsets with the most different rates of metastatic disease.
Of the 1,687 patients analyzed, 5.7% had lung metastases, 4.8% had bone involvement, and 6% had bone marrow (BM) involvement. Rhabdomyosarcoma (RMS) without local invasion (T1) had a low rate of metastasis for all distant sites, especially ERMS (0% bone, 0% BM). ARMS with local invasion (T2) had a higher rate of metastasis for all distant sites (13% lung, 18% bone, 23% BM). ERMS, T2 also had a higher rate of metastatic lung involvement (9%). The likelihood of bone or BM involvement increased in the presence of lung metastases (41% with, 6% without). Regional nodal metastases (N1) predicted a high rate of metastasis in all distant sites (14% lung, 14% bone, 18% BM). A staging algorithm was developed.
Staging studies in childhood RMS can be tailored to patients' presenting characteristics. Bone marrow aspirate and biopsy and bone scan are unnecessary in at least one third of patients with RMS.
Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients ...with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes.
AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m2/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m2/day over 20 h (2 days) and 17.5 mg/m2/day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10–34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics.
Thirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15–44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules.
The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.
•GD2 is expressed in most osteosarcoma tumours and cell lines.•Dinutuximab with granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with recurrent osteosarcoma was evaluated.•Dinutuximab failed to improve 12-month disease control rate in these patients.•Study provides safety and PK of dinutuximab in adolescent and young adult patients.•Novel therapeutics to target GD2 are being evaluated.
Background
The prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to ...compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES.
Methods
Patients had localized ES and were treated on two consecutive protocols using five‐drug chemotherapy (INT‐0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event‐free survival (EFS) was estimated using the Kaplan–Meier method, compared using the log‐rank test, and modeled using Cox multivariate regression.
Results
Patients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors >8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50–0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS.
Conclusion
Clinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site.
To identify potential clinical prognostic factors associated with a higher risk of local recurrence in patients with localized pelvic Ewing sarcoma treated with radiation therapy.
Data for 101 ...patients treated with definitive radiation therapy (RT) or both surgery and radiation (S + RT) to primary pelvic tumors on INT-0091, INT-0154, and AEWS0031 were analyzed. Imaging data for patients who did not receive radiation were not available for central review; therefore, patients with surgery alone were not included. Cumulative incidence rates for local failure at 5 years from time of local control were calculated accounting for competing risks.
The most common pelvic subsite was sacrum (44.6%). RT was used in 68% of patients and S + RT in 32%. The local failure rate was 25.0% for RT and 6.3% for S + RT (P = .046). There was no statistically significant difference in local control modality by tumor characteristics. Tumors originating in the ischiopubic-acetabulum region were associated with the highest local failure incidence, 37.5% (P = .02, vs sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, P = .06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (P = .04). Multivariable analysis demonstrated RT alone (hazard ratio HR, 5.1; P = .04), tumor subsite (particularly ischiopubic-acetabulum tumors; HR 4.6; P = .02), and increasing volume per 100 mL (HR, 1.2; P = .01) were associated with a higher incidence of local recurrence.
Combination surgery and RT is associated with improved local control in patients with pelvic Ewing sarcoma compared with definitive RT. Tumors involving the ischiopubic-acetabulum region and increasing tumor volume at diagnosis are associated with inferior local control. Tumor characteristics did not correlate with choice of local therapy modality suggesting an opportunity to develop best local therapy practices guidelines for future studies based on tumor features.
PURPOSE Ewing sarcoma family tumors (ESFTs) exhibit chromosomal translocations that lead to the creation of chimeric fusion oncogenes. Combinatorial diversity among chromosomal breakpoints produces ...varying fusions. The type 1 EWS-FLI1 transcript is created as a result of fusion between exons 7 of EWS and 6 of FLI1, and retrospective studies have reported that type 1 tumors are associated with an improved outcome. We have re-examined this association in a prospective cohort of patients with ESFT treated according to current Children's Oncology Group (COG) treatment protocols. METHODS Frozen tumor tissue was prospectively obtained from patients diagnosed with ESFT, and reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine translocation status. Analysis was confined to patients with localized tumors who were diagnosed after 1994 and treated according to COG protocols. Translocation status was correlated with disease characteristics, event-free survival (EFS), and overall survival (OS). Results RT-PCR identified chimeric fusion oncogenes in 119 of 132 ESFTs. Eighty-nine percent of identified transcripts were EWS-FLI1, and of these, 58.8% were type 1. Five-year EFS and OS rates for patients with type 1 and non-type 1 fusions diagnosed between 2001 and 2005 were equivalent (type 1: EFS, 63% +/- 7%; OS, 83% +/- 6%; non-type 1: EFS, 71% +/- 9%; OS, 79% +/- 8%). CONCLUSION Current intensive treatment protocols for localized ESFT have erased the clinical disadvantage that was formerly observed in patients with non-type 1 EWS-FLI1 fusions.
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