Andreas Zoubek

Primary Metastatic Osteosarcoma: Presentation and Outcome of Patients Treated on Neoadjuvant Cooperative Osteosarcoma Study Group Protocols

PURPOSE To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. PATIENTS AND METHODS Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. RESULTS With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes. CONCLUSION The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.

Osteosarcoma Relapse After Combined Modality Therapy: An Analysis of Unselected Patients in the Cooperative Osteosarcoma Study Group (COSS)

PURPOSE To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. PATIENTS AND METHODS Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). RESULTS After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. CONCLUSION Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.

Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients

PURPOSE Because of the high heterogeneity of EWS gene fusions with FLI1 and ERG genes due to variable chromosomal breakpoint locations in Ewing tumors (ET) (14 different chimeric transcripts identified so far), we evaluated the clinical impact of the expression of diverse fusion transcripts in ET patients. PATIENTS AND METHODS In a European multicenter study, 147 ET were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR) and the molecular data statistically compared with all clinical data available. RESULTS Most tumors expressed chimeric transcripts with fusion of EWS exon 7 to FLI1 exon 6 (75 of 147) (type I) or five (39 of 147) and EWS exon 10 to FLI1 exon 5 (eight of 147) or 6 (five of 147). In five cases, chimerism between EWS exon 9 and FLI1 exons 4 and EWS exon 7 and FLI1 exon 7 or 8 was observed. Fifteen cases of EWS-ERG rearrangement were identified. In 85 of these patients treated in the European Cooperative Ewing Sarcoma Studies, molecular results were analyzed in comparison to age, sex, tumor localization, tumor volume, and disease extension. No significant correlation between the various fusion types and these features were observed. Relapse-free survival (RFS) for the 31 patients with localized disease and fusion type I tended to be longer compared with the 24 patients with localized tumors bearing other chimeric transcripts (P = .04). CONCLUSION Results suggest a possible advantage in PFS for patients with localized disease and fusion type I transcripts, although this will require prospective validation with a larger number of patients and longer follow-up periods.

Primary metastatic (stage IV) Ewing tumor: Survival analysis of 171 patients from the EICESS studies

BACKGROUND In the multicenter European Intergroup Cooperative Ewings Sarcoma Studies, localized Ewing tumors of bone were treated by combination chemotherapy with surgery and/or radiotherapy. Patients with primary metastases (pm-pts) were treated in high risk protocols. PATIENTS AND METHODS One hundred seventy-seven pm-pts were registered from January 1990 to December 1995, 171 were evaluable for survival analyses. Thirty-six pm-pts received myeloablative megatherapy with stem cell rescue following conventional treatment. Bilateral whole lung irradiation (WLI) was administered in 57 pm-pts with pulmonary involvement. Event-free survival (EFS) rates were estimated by Kaplan-Meier analysis. Prognostic factors were identified by log-rank statistics, Cox procedures and logistic regression. RESULTS Eighty-nine deaths were recorded by 1 February 1997, EFS four years after diagnosis for all 171 pm-pts was 0.27. EFS for isolated lung metastases was 0.34, for bone/bone marrow (BM) metastases, 0.28, and for combined lung plus bone/BM metastases, 0.14 (P < 0.005). WLI improved outcome in case of isolated pulmonary involvement (0.40 vs. 0.19, P < 0.05). In pm-pts with combined pulmonary/skeletal metastases, intensification by megatherapy and/or WLI improved EFS from 0.00 to 0.27 (P = 0.0001). CONCLUSIONS EFS four years after diagnosis in patients with disseminated Ewing tumors is 0.27. Whole lung irradiation and megatherapy improve outcome in subgroups of patients with disseminated Ewing tumors is 0.27. Whole lung irradiation and megatherapy improve outcome in subgroups of patients with disseminated Ewing disease.

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.

Second and Subsequent Recurrences of Osteosarcoma: Presentation, Treatment, and Outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group Patients

PURPOSE To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma. PATIENTS AND METHODS Two hundred forty-nine consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes. RESULTS Five-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions. CONCLUSION To our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.

Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors

The pRB cell cycle regulatory cascade is frequently perturbed in neoplasia by overexpression of a component of the pRB-phosphorylating cyclin D1/CDK4 complex or by inactivation of pRB or the CDK4 inhibitors p16 and p15. We investigated the status and expression of p16, p15, CCND1, CDK4 and RB genes in the Ewing family of tumors. P16 loss was observed in 8 of 27 tumors (30%) and in 12 of 23 (52%) tumor cell lines from unrelated patients. There were no discrepancies in the p16 status between primary tumors and the corresponding cell lines and between cell lines established from consecutive tumor samples. p15 was codeleted in most cases but p15 mRNA was absent also in cell lines retaining the gene. In addition, posttranscriptional p16 inactivation was observed in two cases. Although no evidence for CDK4 or CCND1 amplification was obtained, expression of these genes varied considerably in the cell lines in a case specific manner. In wild-type p16 cell lines, pRB expression was lost in one case. Our data indicate that, despite the absence of cytogenetically detectable 9p21 chromosomal aberrations, p16 deletions constitute the most frequent secondary molecular aberration in Ewing tumors so far. These results are discussed in the context of the stage of disease and the clinical outcome of the patients. The potential prognostic impact of these findings remains to be further evaluated.