Treatment of Ewing sarcoma family of tumors with a modified P6 protocol in children and adolescents

Abstract

INTRODUCTIONEwing sarcoma family of tumors (ESFT) is the second most common bone malignancy in children, accounting for approximately 40% of all bone cancers [1]. ESFT is characterized by a specific balanced chromosomal translocation which fuses the amino-terminal domain of the EWSR1 gene or, in rare cases, the TLS/FUS gene, to the DNA-binding domain of one of five ETS genes [2]. The transcripts resulting from these fusion genes can be detected using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. RT-PCR provides a higher sensitivity than conventional cytological analysis to detect tumor cells in bone marrow (BM) and peripheral blood (PB). Previous studies have reported that among patients with local-regional ESFT, RT-PCR positivity of BM correlates with a high risk of adverse outcome and significantly poorer disease-free survival rates [3]. Thus, RT-PCR analysis of BM might be useful to classify localized and metastatic patients at diagnosis.Treatment of ESFT has improved over the last two decades with reported durable remissions in 50-70% of non-metastatic patients [4]. In 1995, the group at MSKCC published the P6 protocol showing a successful induction of remission in patients with localregional disease and good initial responses with dose-intensive and short-term chemotherapy in patients with distant metastases [5]. A subsequent and extended outcome data on 68 patients (44 localized) with ESFT treated with the P6 protocol showed a 4-year EFS and OS for patients with localized disease of 82% and 89%, respectively. Patients with detectable metastatic disease at diagnosis had a significantly worse prognosis, with a 4-year EFS rate of 12% and OS rate of 17.8% [6].In 1998, the MSKCC group reported a cumulative incidence of therapy related acute myelogenous leukemias (t-AML) and myelodysplastic syndromes (MDS) at 40 months of 8% in survivors of the P6 protocol [7]. The latest report from the MSKCC group [6] details three patients experiencing secondary MDS/t-AML out of 44 non-metastatic patients, which makes a 7% incidence in the population with longest overall survival. This and other experiences suggested that repetitive use of high-dose alkylating agents given with topoisomerase-II inhibitors is strongly leukemogenic, even with modest cumulative doses of each drug. The two well-described kinds of t-AML/MDS occurred, namely, those associated with topoisomerase-II inhibitors and marked by early emergence of t-AML with translocations of the MLL gene at chromosome band 11q23, and those associated with alkylating agents and marked by an MDS, whole or partial deletions of chromosomes 5 or 7, and a latency period of 2-8 years [8,9].In 2001, we modified the original P6 (hereby mP6) protocol by: (1) reducing the number of chemotherapy cycles down to five, three CDV and two IE, in order to decrease the risk of secondary tumors; (2) using higher doses of ifosfamide (2.8 g/m 2 /day instead of 1.8 g) post-surgery in cases with poor histological response; and (3) using dexrazoxane before doxorubicin t...

Polymorphisms in the Calcium-Sensing Receptor Gene Are Associated with Clinical Outcome of Neuroblastoma

“…Bone marrow mononuclear cell isolation, total RNA extraction and cDNA synthesis were carried out as described [33]. Analysis of PHOX2B mRNA expression was performed following previously reported procedures [34] in a 7000 Sequence Detection System (Applied Biosystems).…”

Phase II trial of gemcitabine and nab‐paclitaxel in patients with recurrent Ewing sarcoma: A report from the National Pediatric Cancer Foundation

“…Although 41% of patients had a partial response, 29% experienced progression during this window. All patients then received five‐drug chemotherapy as per the modified P6 protocol 11 followed by local control with surgery and/or radiotherapy. Nonprogressing patients were given up to 12 cycles of GEM/DOC maintenance therapy, and the three‐year event‐free survival for this group was 29%.…”

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

“…Eligible patients were 40 years or younger at enrolment and had diagnosis of ES confirmed by EWSR1 rearrangement by FISH or qRT-PCR analysis. All patients were required to have 2–4 bone marrow (BM) aspirates for centralised study (CdT, Hospital Sant Joan de Déu) of (micro)metastasis according to the methods previously described ( Mora et al , 2011 ). HR-ES was defined as patients presenting with metastasis, primary tumour in the pelvis or axial skeleton, and patients with BM (micro)metastasis.…”

“…Patients with metastatic disease at diagnosis had a significantly worse prognosis, with 4-year EFS rate of 12.0% and OS of 17.8% ( Kolb et al , 2003 ). In 2001, we modified the original P6 (hereby mP6) protocol ( Mora et al , 2011 ) and the results of a single-institution study with 31 patients showed 4-year EFS rate for non-metastatic cases of 83.0% and OS of 92.0%. Patients with metastatic disease showed 3-year EFS rate of 28.0% and OS of 42.0% ( Mora et al , 2011 ).…”