Prognostic Factors in Patients with Localized Ewing’s Sarcoma: The effect on survival of actual received drug dose intensity and of histologic response to induction therapy

Abstract

To bring to the fore the most important prognostic factors in Ewing's sarcoma (ES) with current protocols, we studied the classical prognostic factors, dose intensity (DI) of actual received drugs, age and histological response to induction therapy and their correlation in 39 patients with localized ES treated from 11/85 to 06/95 to identify eventual predictors of event-free survival (EFS). Inclusion criteria were age 35 yr or less, definitive local treatment by our team and chemotherapy including at least 4 drugs: vincristine (VCR), dactinomycin (DACT), doxorubicin (DOXO) cyclophosphamide (CPX). The endpoint was the absence of relapse. Parameters related to the status of patients were tested using the Chi square test or Fisher's exact test. The non parametric Kruskal-Wallis test was used for quantitative data. When necessary stratified analysis was done using the Mantel Cox test. With a median follow-up of 7 yr, overall survival (OS) and EFS were both 67% at 7 yr. According to univariate analysis, the significant predictors of survival were the DI of VCR and DACT, the histological response to preoperative chemotherapy (CT), the patient's age (< 18 yr DFS: 84%; > 18 yr DFS: 38%). The risk of metastases was almost tenfold higher in patients with low received DI of VCR (DFS 40% versus 95%) and of DACT (DFS 48% versus 94%). The prognostic value of primary tumor characteristics (tumoral volume or location) was erased by the comprehensive treatment. Following multivariate analysis, the actual received DI of VCR (p < 0.02) and DACT (p < 0.03) and the histological response to preoperative CT (p < 0.05) were retained as the only significant independent predictors of EFS. Taking into account the actual received DI of VCR and DACT, the prognostic value of age disappears. In conclusion, this study points out the main role of the drug DI in ES (particularly VCR and DACT) and of histological response to preoperative CT.

Prognostic factors in non-metastatic Ewing's sarcoma tumor of bone: An analysis of 579 patients treated at a single institution with adjuvant or neoadjuvant chemotherapy between 1972 and 1998

“…In the multivariate analyses only the factors significant by the univariate analysis were investigated. The following pretreatment variables were considered (and cut -off set to allow comparisons with other authors): gender, age (/13 years vs 5/13 years) [10], tumor volume (/150 ml vs 5/150 ml) [11], LDH serum level [normal (5/460 U/L) vs elevated ( /460 U/L)], site of the tumor (extremity vs axial tumors). Further variables related to the type of treatment were: type of local therapy (surgery vs radiation therapy or surgery followed by radiation therapy), chemotherapy regimen (REA-1 vs REA-2 vs REN-1 vs REN-2 vs REN-3), number of drugs used in the regimen of chemotherapy (3, 4 or 6) and, in patients locally treated with neoadjuvant chemotherapy and locally by surgery, histologic response to chemotherapy (Grade I, Grade II and Grade III).…”

Cyclophosphamide Dose Intensification during Induction Therapy for Intermediate-Risk Pediatric Rhabdomyosarcoma Is Feasible but Does Not Improve Outcome

“…Similarly, after the start of our clinical trial, Baker et al (12) reported that certain subgroups of patients with embryonal rhabdomyosarcoma benefited from the greater alkylator dose intensity in IRS-IV compared with IRS-III. Studies in other pediatric and adult solid tumors also suggest that dose intensification strategies can improve outcomes (13)(14)(15)(16)(17).…”

Predictive Factors of Histological Response to Primary Chemotherapy in Ewing's Sarcoma

“…In the neoadjuvant treatment of Ewing's sarcoma, the VACA regimen has for years been the standard regimen of chemotherapy (2,6,8,10,13). When at the end of the 1980s ifosfamide alone (18,19) or in combination with etoposide (20) was reported to be very effective in patients with Ewing's sarcoma who relapsed after a VAC or VACA adjuvant regimens, in three multicentric neoadjuvant studies (3, 4, 7) cyclophosphamide was replaced by ifosfamide (VAIA regimen).…”

“…Moreover, in contrast to the widespread use of radiotherapy for the local control of Ewing's sarcoma in the preneoadjuvant era, the treatment of choice for patients receiving primary chemotherapy is currently based on surgery alone or followed by radiotherapy (2,3,6,9,10,13).…”

“…Based on the histologic analysis of residual viable tissue in the final specimen of tumors treated with primary chemotherapy, several authors (6,7,(11)(12)(13), including ourselves with regard to tumors arising in the limbs (14), have provided consistent evidence to show that in Ewing's sarcoma which is locally treated by surgery, prognosis is significantly associated with chemotherapy-induced tumor necrosis.…”