Luciano Scopece

Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status.

A recent randomized study conducted on newly diagnosed glioblastoma (GBM) patients demonstrated that concomitant and adjuvant temozolomide added to standard radiotherapy had a survival advantage compared with radiotherapy alone. The overall survival benefit of this aggressive treatment, however, was attenuated in older or poor performance status patients. The aim of the present study was to verify the activity and the toxicity of temozolomide administration concurrent and adjuvant to radiotherapy as first‐line treatment for elderly GBM patients, and to explore correlations between clinical outcome and O6 methylguanine‐DNA methyltransferase (MGMT) promoter methylation status.

Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mgday−1) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1–36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2–104+) weeks and PFS-6 was 14.3% (95% CI 4.0–32.7%). The median overall survival was 24.6 weeks (range 4–104+). No grade 3–4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia

PURPOSE Cisplatin and temozolomide (TMZ) are active in glioblastoma multiforme (GBM), with different profiles of toxicity. A bid regimen of TMZ achieves a strong inhibition of O(6)-alkylguanine DNA-alkyl transferase (AGAT), and cisplatin reduces AGAT activity in vitro, suggesting a possible synergic interaction. The primary end point of the present multicenter phase II study was progression-free survival (PFS) at 6 months (PFS-6); secondary end points included response, toxicity, and overall survival. PATIENTS AND METHODS Chemotherapy-naive patients with GBM who experienced disease recurrence or progression after surgery and standard radiotherapy were eligible. Chemotherapy cycles consisted of cisplatin 75 mg/m(2) on day 1, TMZ 130 mg/m(2) bolus followed by nine doses of 70 mg/m(2) every 12 hours (total of 5 days) from day 2 every 4 weeks. In the absence of hematologic toxicity, TMZ was escalated to 1,000 mg/m(2) in 5 days. RESULTS A total of 50 patients (median age, 53.4 years; range, 27 to 70 years; median Karnofsky performance status, 80; range, 60 to 100) were accrued in the study. PFS-6 was 34% (95% CI, 23% to 50%), and PFS-12 was 4% (95% CI, 0.3% to 16%). Median PFS was 18.4 weeks (95% CI, 13 to 25.9 weeks). Among 49 assessable patients, one complete response and nine partial responses were obtained, with an overall response rate of 20.4% (95% CI, 7.7% to 33%). Among 203 treatment cycles delivered, the most common grade 3 or grade 4 events included granulocytopenia in 7.9% of cycles, thrombocytopenia in 4%, and neurologic toxicity in three patients (6%). CONCLUSION The new cisplatin plus bid TMZ regimen appears active in chemotherapy-naive patients with recurrent GBM and incurs an acceptable toxicity.

The Metastatic Ability of Ewing’s Sarcoma Cells Is Modulated by Stem Cell Factor and by Its Receptor c-kit

Ewings sarcoma is a primitive highly malignant tumor of bone and soft tissues usually metastasizing to bone, bone marrow, and lung. Growth factor receptors and their ligands may be involved in its growth and dissemination. We analyzed the expression of c-kit and its ligand stem cell factor (SCF) in a panel of six Ewings sarcoma cell lines. All cell lines exhibited substantial levels of surface c-kit expression, and five of six displayed transmembrane SCF on the cell surface. Expression of c-kit was down-modulated in all lines by exposure to exogenous SCF. The SCF treatment was able to confer to cells a growth advantage in vitro, due both to an increase in cell proliferation and to a reduction in the apoptotic rate. When used in the lower compartment of a migration chamber, SCF acted as a strong chemoattractant for Ewings sarcoma cells. The pretreatment of cells with SCF reduced their chemotactic response to SCF. In athymic nude mice, Ewings sarcoma cells injected intravenously metastasized to the lung and to a variety of extrapulmonary sites, including bone and bone marrow. Metastatic sites resembled those observed in Ewings sarcoma patients and corresponded to SCF-rich microenvironments. The in vitro pretreatment of cells with SCF strongly reduced the metastatic ability of Ewings sarcoma cells, both to the lung and to extrapulmonary sites. This could be dependent on the down-modulation of c-kit expression observed in SCF-pretreated cells, leading to a reduced sensitivity to the chemotactic and proliferative actions of SCF. Our results indicate that the response to SCF mediated by c-kit may be involved in growth, migration, and metastatic ability of Ewings sarcoma cells.

Identification of new genes related to the myogenic differentiation arrest of human rhabdomyosarcoma cells

Rhabdomyosarcoma is a soft tissue tumor committed to the myogenic lineage but arrested prior to terminal differentiation. To identify new genes implicated in the block in myogenic differentiation of rhabdomyosarcoma cells and those responsible for their proceeding along the myogenic pathway we used cDNA microarrays to compare gene expression profiles of two clones of the human embryonal rhabdomyosarcoma cell line RD with different myogenic potentials: RD/12, which is unable to differentiate, and RD/18, which shows elements able to terminally differentiate, as defined by the expression of myosin heavy chain (up to 50% of the population) and the formation of multinucleated myotube-like structures. We identified 80 genes differentially expressed by the two clones. Differentiating RD/18 cells overexpressed the myogenic transcription factor myogenin along with known myogenic markers; myogenin transfection into undifferentiated RD/12 cells was able to revert the phenotype giving rise to 94% of clones displaying a differentiated morphology. RD/18 cells also expressed several genes not known to be expressed in rhabdomyosarcoma or muscle cells, such as pigment-epithelium derived factor and endothelin-3. Poorly differentiated RD/12 cells, along with genes related to mesenchymal lineage or early myogenic commitment, also expressed genes not previously known to be related to the differentiation block of human rhabdomyosarcoma, such as monocyte chemotactic protein-1, connective tissue growth factor and insulin-like growth factor binding protein-5. Differential expression of these genes in a time course of differentiation suggested their potential roles as either new myogenic markers or repressors of differentiation. These results identify a cluster of new genes related to the aberrant myogenic differentiation program of human rhabdomyosarcoma cells.

Phase II trial of carboplatin and etoposide for patients with recurrent high-grade glioma

We present the results of a phase II trial of carboplatin and etoposide (CE) combination as first-line chemotherapy in patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) after surgery and radiotherapy. We assess the activity and the tolerability of this combination. 30 patients with GBM (25) and AA (5) were treated with VP-16 (etoposide) 120 mg m−2 and CBCDA (carboplatin) 100 mg m−2 for 3 days every 4 weeks. Moreover, we performed a retrospective analysis of topoisomerase IIα gene status using chromogenic in situ hybridisation. The median age was 54 years (21–73 years); Eastern Cooperative Oncology Group performance score was 0-1 in 25 patients and 2 in five patients. All patients had been previously treated with surgical resection (21 radical resections) followed by radiation therapy (40–60 Gy). We observed six (20%) complete responses, three (10%) partial responses and 12 (40%) stable diseases, with a response rate of 30%. The median time to progression was 4 months, while progression-free survival at 6 months was 33.3%. The median survival time was 10 months. Neutropenia occurred in 9 patients: four patients had grade 4, two patients grade 3 and three patients grade 2. In the conclusion of this clinical trial, the CE combination has shown activity in recurrent GBM and AA, with a good toxicity profile. Alterations in the copy number of topoisomerase IIα gene seem to be a rare event and in our series do not influence response to the CE combination.

Carboplatin and etoposide (CE) chemotherapy in patients with recurrent or progressive oligodendroglial tumors

BACKGROUND Oligodendroglial tumors are rare and chemosensitive diseases; but the overall results with current chemotherapy regimens cannot be considered satisfactory and other active treatments are necessary. We decided to determine the efficacy and toxicity profile of the carboplatin and etoposide (CE) regimen in this setting. METHODS In this phase II trial we evaluated the response rate of first or second line CE regimen (Carboplatin AUC 5 on day 1 and Etoposide 120 mg/m2 on days 1-3 every 28 days) in patients with recurrent/progressive oligodendroglial tumors. RESULTS Thirty-two patients were enrolled. Median age was 42 years (range 22-66); median ECOG PS was 0 (range 0-2); 9 patients had oligodendroglioma, 3 patients had oligoastrocytoma, 11 patients had anaplastic oligodendroglioma, 9 patients had anaplastic oligoastrocytoma. CE regimen showed a response rate of 46.9% with 5 complete responses (15.6%) and 10 partial responses (31.3%). Eleven patients (34.4%) had stable disease. Median time to progression was 8 months, progression-free survivals at 6 and 12 months were 80% and 46.9%, respectively. Toxicity was mainly hematological, with grade 3-4 neutropenia in 5 (15.6%) patients. CONCLUSIONS In this trial CE regimen has shown relevant activity with a favourable safety profile.

Evaluation of 1p and 19q chromosomal alterations in oligodendroglial neoplasms using microdissection and microsatellite analysis technique and correlations with response to chemotherapy.

1568 Background: Oligodendroglial tumors are chemosensitive diseases. The evaluation by fluorescence in situ hybridization has been used to assess 1p and 19q alterations that are considered the best chemosensitivity test in these tumors. Here we show another way to evaluate 1p and 19q chromosomal alterations by using microsatellite analysis that could be considered an useful tool in translational research for the accuracy of this method. METHODS Patients DNA was extracted from peripheral blood to define the wild type allelic condition, instead tumoral DNA was obtained from laser microdissected cells. We analized 4 microsatellites on Chr1p and 3 on Chr19q (chosen from sequences described by J.M. Nigro et al., Am J Path 2001); for each locus loss of heterozigosity (LOH), allelic imbalance or chromosomal instability were defined based on allelic peaks pattern. Chemotherapic regimens allowed were: PCV or Temozolomide or Carboplatin-Etoposide (CE). RESULTS At the time of abstract submission we evaluated 21 oligodendroglial tumor adult patients: 4 with oligodendroglioma, 12 with anaplastic oligodendroglioma and 5 with mixed oligoastrocytoma (2 G2 and 3 G3). In 10 patients both primary and recurrent disease samples were available. 16/21 patients were treated with chemotherapy. PCV combination was used as first line in 1 patient, Temozolomide was used as first line in 9 patients and CE combination was used as first line in 6 patients. CONCLUSIONS The evaluation of 1p and 19q status by microsatellite analysis is feasible and provides useful informations about oligodendroglial tumors. Further results and correlations with response to radiotherapy and chemotherapy, and differences in 1p and 19q LOH pattern between primary and recurrence will be presented at the meeting. [Figure: see text] No significant financial relationships to disclose.