Michael Paulussen

Prognostic Factors in Ewing’s Tumor of Bone: Analysis of 975 Patients From the European Intergroup Cooperative Ewing’s Sarcoma Study Group

PURPOSE To further elaborate on prognostic factors for Ewings sarcoma of bone and to document improvements in relapse-free survival (RFS) and trends in local therapy over the study period (1977 to 1993). PATIENTS AND METHODS A retrospective analysis was performed on a combined Gesellschaft Für Pädiatrische Onkologie und Hämatologie/Cooperative Ewing Sarcoma Study and United Kingdom Childrens Cancer Study Group/Medical Research Council data set of 975 patients registered with the respective trial offices before the current collaborative European Intergroup Cooperative Ewings Sarcoma Study trial. Both groups independently undertook studies with similar chemotherapy during the period. RESULTS The key adverse prognostic factor is metastases at diagnosis (5-year RFS, 22% of patients with metastases at diagnosis v 55% of patients without metastases at diagnosis; P: <.0001). For the group with metastases, there was a trend for better survival for those with lung involvement compared with those with bone metastases or a combination of lung and bone metastases (P: <.0001). In the group of patients with no metastases at diagnosis, multivariate analysis demonstrated that site (axial v other), age-group (< 15 v > or = 15 years), and period of diagnosis had significant influence on RFS (all P: <.005). RFS was superior in the period after 1985 compared with the period before 1985 for nonmetastatic patients (45% v 60%, respectively; P: <.0001) and for metastatic patients (16% v 30%, respectively; P: =.016). Patients who relapsed within 2 years of diagnosis had a less favorable prognosis than patients who relapsed later (5-year survival after relapse, 4% v 23%, respectively; P: <. 0001). There were other changes over the period; in particular, radiotherapy or amputation were more common in the period before 1986, whereas endoprosthetic surgery was widely used in the later period. CONCLUSION Survival and RFS improved over the period. Prognostic factors are metastases at diagnosis, primary site, and age.

Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial

PURPOSE To improve the poor prognosis of patients with primary disseminated multifocal Ewing sarcomas (PDMES) with a dose-intense treatment concept. PATIENTS AND METHODS From 1999 to 2005, 281 patients with PDMES were enrolled onto the Euro-EWING 99 R3 study. Median age was 16.2 years (range, 0.4 to 49 years). Recommended treatment consisted of six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), one cycle of vincristine, dactinomycin, and ifosfamide (VAI), local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by autologous stem-cell transplantation (HDT/SCT). RESULTS After a median follow-up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27% +/- 3% and 34% +/- 4% respectively. Six VIDE cycles were completed by 250 patients (89%); 169 patients (60%) received HDT/SCT. The estimated 3-year EFS from the start of HDT/SCT was 45% for 46 children younger than 14 years. Cox regression analyses demonstrated increased risk at diagnosis for patients older than 14 years (hazard ratio [HR] = 1.6), a primary tumor volume more than 200 mL (HR = 1.8), more than one bone metastatic site (HR = 2.0), bone marrow metastases (HR = 1.6), and additional lung metastases (HR = 1.5). An up-front risk score based on these HR factors identified three groups with EFS rates of 50% for score <or= 3 (82 patients), 25% for score more than 3 to less than 5 (102 patients), and 10% for score >or= 5 (70 patients; P < .0001). CONCLUSION PDMES patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of metastatic spread are relevant risk factors. A score based on these factors may facilitate risk-adapted treatment approaches.

Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO‐E.W.I.N.G. 99 clinical trial

The EUROpean Ewing tumour Working Initiative of National Groups 1999 (EURO‐E.W.I.N.G. 99) protocol prescribes six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy for Ewing tumors (ET). Granulocyte‐colony stimulating factor (G‐CSF) is recommended. Adverse reactions (AR) were evaluated; quality assurance of data collection reviewed.

Ewing's tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing's Sarcoma Studies patients.

PURPOSE To analyze event-free survival (EFS) and prognostic factors in patients who present with Ewings tumors (ET) of bone and synchronous pulmonary and/or pleural metastases (ppm). PATIENTS AND METHODS Of 1,270 patients (pts) registered at the continental office of the German/European Intergroup Cooperative Ewings Sarcoma Studies (CESS81, CESS86, EICESS92), 114 were diagnosed ET with ppm. Patients underwent neoadjuvant therapy and local treatment of the primary tumor. Whole-lung irradiation 15 to 18 Gy was applied to 75 ppm-pts. EFS and 95% confidence intervals (CIs) were estimated according to the Kaplan-Meier method, and prognostic factors were analyzed by log-rank tests and Cox and logistic regression procedures. RESULTS On November 1, 1997, at a median time under study of 5.9 years, the 5-year EFS was 0.36 (95% CI, 0.26 to 0.46) and the 10-year EFS was 0.30 (95% CI, 0.19 to 0.41). Thirty-seven of 59 (63%) first relapses involved lung and/or pleura, and the lungs were the only site of relapse in 26 of 59 (44%) ppm-pts. Risk factors identified in univariate and multivariate tests were poor response of the primary tumor toward chemotherapy, metastatic lesions in both lungs, and treatment without additional lung irradiation. CONCLUSION Chemotherapy response of the primary tumor is a prognostic factor in patients with ET with ppm. Strategies of treatment intensification warrant further evaluation.

Results of the EICESS-92 Study: Two Randomized Trials of Ewing's Sarcoma Treatment—Cyclophosphamide Compared With Ifosfamide in Standard-Risk Patients and Assessment of Benefit of Etoposide Added to Standard Treatment in High-Risk Patients

PURPOSE The European Intergroup Cooperative Ewings Sarcoma Study investigated whether cyclophosphamide has a similar efficacy as ifosfamide in standard-risk (SR) patients and whether the addition of etoposide improves survival in high-risk (HR) patients. PATIENTS AND METHODS SR patients (localized tumors, volume <100 mL) were randomly assigned to receive four courses of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) induction therapy followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide). HR patients (volume >or=100 mL or metastases) were randomly assigned to receive 14 courses of either VAIA or VAIA plus etoposide (EVAIA). Outcome measures were event-free survival (EFS; defined as the time to first recurrence, progression, second malignancy, or death) and overall survival (OS). RESULTS A total of 647 patients were randomly assigned: 79 SR patients were assigned to VAIA, 76 SR patients were assigned to VACA, 240 HR were assigned to VAIA, and 252 HR patients were assigned to EVAIA. The median follow-up was 8.5 years. In the SR group, the hazard ratios (VACA v VAIA) for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. There was a higher incidence of hematologic toxicities in the VACA arm. In the HR group, the EFS and OS hazard ratios (EVAIA v VAIA) indicated a 17% reduction in the risk of an event (95% CI, -35% to 5%; P = .12) and 15% reduction in dying (95% CI, -34% to 10%), respectively. The effect seemed greater among patients without metastases (hazard ratio = 0.79; P = .16) than among those with metastases (hazard ratio = 0.96; P = .84). CONCLUSION Cyclophosphamide seemed to have a similar effect on EFS and OS as ifosfamide in SR patients but was associated with increased toxicity. In HR patients, the addition of etoposide seemed to be beneficial.

EWS-FLI1 and EWS-ERG gene fusions are associated with similar clinical phenotypes in Ewing's sarcoma.

PURPOSE There are a variety of solid tumors in which alternative chromosomal translocations generate related fusion products. In alveolar rhabdomyosarcoma and synovial sarcoma, these variant fusions have been found to have major clinical significance. We investigated whether the two alternative gene fusion products, EWS-FLI1 and EWS-ERG, define different clinical subsets within the Ewings sarcoma family of tumors. PATIENTS AND METHODS We selected 30 cases of Ewings sarcoma with the EWS-ERG gene fusion and 106 cases with the EWS-FLI1 fusion. Clinical data were obtained for each case and compared with the molecular diagnostic findings. RESULTS There were no significant clinical differences observed between the two groups in age of diagnosis, sex, metastasis at diagnosis, primary site, event-free survival, or overall survival. CONCLUSION Differences in the C-terminal partner in the Ewings sarcoma family gene fusions are not associated with significant phenotypic differences.

Bone Tumors in Adolescents and Young Adults

Opinion statementBone tumors, particularly osteosarcomas and members of the Ewing Sarcoma Family of Tumors (ESFT), are typical malignancies of adolescents and young adults. Current diagnostic and therapeutic guidelines for patients of all ages were developed in this specific age group. The aim of bone sarcoma therapy should be to cure the patient from both the primary tumor and all (micro-)metastatic deposits while maintaining as much (extremity) function and causing as few treatment-specific late effects as possible. Bone sarcoma therapy requires close multidisciplinary cooperation. Usually, it consists of induction chemotherapy, followed by local therapy of the primary tumor (and, if present, primary metastases) and further, adjuvant chemotherapy. Local treatment for osteosarcoma should be surgery whenever feasible. Surgery is also gaining importance in ESFT, which was long considered a domain of radiotherapy. Modern reconstructive techniques continue to expand the indications for limb salvage, particularly for patients who have not yet reached skeletal maturity. Treatment within the framework of prospective, multi-institutional trials should be considered standard of care not only for children, but also for affected adolescents and (young) adults. Such trials are essential in guaranteeing that all patients have access to appropriate care and that progress from biological studies can be translated into prognostic improvements without undue delay. The rarity of bone sarcomas increasingly requires trials to be multinational.

Ewing Sarcoma: Current Management and Future Approaches Through Collaboration

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.

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

Adoptive immunotherapy with allogeneic purified natural killer (NK) cell products might exert graft-versus-tumor alloreactivity with little risk of GVHD. In a prospective phase II study in two centers, we administered purified NK cell products to high-risk patients treated with haploidentical T-cell-depleted SCT. Sixteen patients received a total of 29 NK cell infusions on days +3, +40 and +100 after transplantation. Median doses (and ranges) of infused NK- and T-cells per product were 1.21 (0.3–3.8) × 107/kg and 0.03 (0.004–0.72) × 105/kg, respectively. With a median follow-up of 5.8 years 4/16 patients are alive. Cause of death was relapse in five, GVHD in three, graft failure in three, and transplant related neurotoxicity in one patient. Four patients developed acute GVHD⩾grade II, all receiving a total of ⩾0.5 × 105 T cells/kg. Compared with historical controls, NK cell infusions had no apparent effect on the rates of graft failure or relapse. Adoptive transfer of allogeneic NK cells is safe and feasible, but further studies are needed to determine the optimal dose and timing of NK cell therapy. Moreover, NK cell activation/expansion may be required to attain clinical benefit, while careful consideration must be given to the number of T cells infused.

Risk of recurrence and survival after relapse in patients with Ewing sarcoma.

The prognosis in patients with relapsed Ewing sarcoma is unfavorable. Our investigation identifies factors predicting for the outcome following relapse.