Despina Misailidou

Induction chemotherapy followed by concomitant radiotherapy and weekly cisplatin versus the same concomitant chemoradiotherapy in patients with nasopharyngeal carcinoma: a randomized phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation

BACKGROUND Concomitant administration of radiation therapy (RT) and chemotherapy with cisplatin (CCRT) is considered standard treatment in patients with locally advanced nasopharyngeal cancer (LA-NPC). The role of induction chemotherapy (IC) when followed by CCRT in improving locoregional control remains controversial. PATIENTS AND METHODS Totally, 141 eligible patients with LA-NPC were randomized to either three cycles of IC with cisplatin 75 mg/m(2), epirubicin 75 mg/m(2) and paclitaxel (Taxol) 175 mg/m(2) (CEP) every 3 weeks followed by definitive RT (70 Gy) and concomitant weekly infusion of cisplatin 40 mg/m(2) (investigational arm, 72 patients) or to the same CCRT regimen alone (control arm, 69 patients). RESULTS Sixty-two patients (86%) received three cycles of IC. No difference between the arms was observed in the number of patients who completed RT (61 versus 64, P = 018). Overall and complete response rates were very similar in the two arms and so were 3-year progression-free and overall survival rates. Grade III or IV toxic effects from IC were infrequent, apart of alopecia. Mucositis, weight loss and leukopenia were the most prominent side-effects from CCRT. CONCLUSION IC with three cycles of CEP when followed by CCRT did not significantly improve response rates and/or survival compared with that of CCRT alone.

Volumetric and MGMT parameters in glioblastoma patients: Survival analysis

BackgroundIn this study several tumor-related volumes were assessed by means of a computer-based application and a survival analysis was conducted to evaluate the prognostic significance of pre- and postoperative volumetric data in patients harboring glioblastomas. In addition, MGMT (O6-methylguanine methyltransferase) related parameters were compared with those of volumetry in order to observe possible relevance of this molecule in tumor development.MethodsWe prospectively analyzed 65 patients suffering from glioblastoma (GBM) who underwent radiotherapy with concomitant adjuvant temozolomide. For the purpose of volumetry T1 and T2-weighted magnetic resonance (MR) sequences were used, acquired both pre- and postoperatively (pre-radiochemotherapy). The volumes measured on preoperative MR images were necrosis, enhancing tumor and edema (including the tumor) and on postoperative ones, net-enhancing tumor. Age, sex, performance status (PS) and type of operation were also included in the multivariate analysis. MGMT was assessed for promoter methylation with Multiplex Ligation-dependent Probe Amplification (MLPA), for RNA expression with real time PCR, and for protein expression with immunohistochemistry in a total of 44 cases with available histologic material.ResultsIn the multivariate analysis a negative impact was shown for pre-radiochemotherapy net-enhancing tumor on the overall survival (OS) (p = 0.023) and for preoperative necrosis on progression-free survival (PFS) (p = 0.030). Furthermore, the multivariate analysis confirmed the importance of PS in PFS and OS of patients. MGMT promoter methylation was observed in 13/23 (43.5%) evaluable tumors; complete methylation was observed in 3/13 methylated tumors only. High rate of MGMT protein positivity (> 20% positive neoplastic nuclei) was inversely associated with pre-operative tumor necrosis (p = 0.021).ConclusionsOur findings implicate that volumetric parameters may have a significant role in the prognosis of GBM patients. Furthermore, volumetry could help not only to improve the prediction of outcome but also the outcome itself by identifying patients at high risk of treatment failure and, thus, seek alternative treatment for these patients. In this small series, MGMT protein was associated with less aggressive tumor characteristics.

The Importance of Tumor Volume in the Prognosis of Patients with Glioblastoma

Background and Purpose:The importance of tumor volume as a prognostic factor in high-grade gliomas is highly controversial and there are numerous methods estimating this parameter. In this study, a computer-based application was used in order to assess tumor volume from hard copies and a survival analysis was conducted in order to evaluate the prognostic significance of preoperative volumetric data in patients harboring glioblastomas.Patients and Methods:50 patients suffering from glioblastoma were analyzed retrospectively. Tumor volume was determined by the various geometric models as well as by an own specialized software (Volumio). Age, performance status, type of excision, and tumor location were also included in the multivariate analysis.Results:The spheroid and rectangular models overestimated tumor volume, while the ellipsoid model offered the best approximation. Volume failed to attain any statistical significance in prognosis, while age and performance status confirmed their importance in progression-free and overall survival of patients.Conclusion:Geometric models provide a rough approximation of tumor volume and should not be used, as accurate determination of size is of paramount importance in order to draw safe conclusions in oncology. Although the significance of volumetry was not disclosed, further studies are definitely required.Hintergrund und Ziel:Die Bedeutung des Tumorvolumens als prognostischer Faktor fur maligne Gliome ist nach wie vor umstritten. In dieser Studie wurden eine computerbasierte Methode zur Beurteilung des Tumorvolumens anhand von magnetresonanztomographischen Bildern bei Patienten mit Glioblastoma multiforme (GBM) durchgefuhrt und mittels einer Uberlebensanalyse die prognostische Bedeutung praoperativer volumetrischer Daten untersucht.Patienten und Methodik:50 Patienten mit GBM, welche zwei unterschiedliche Chemotherapieregime erhalten hatten, wurden retrospektiv analysiert und die Tumorvolumina durch verschiedene geometrische Modelle sowie eine spezielle Software (Volumio) gemessen. Alter, Performance-Status, Tumorlokalisation sowie Art der Exzision wurden in der multivariaten Uberlebensanalyse berucksichtigt.Ergebnisse:Die angewandten spharoiden und rektangularen geometrischen Modelle uberschatzten das Tumorvolumen, wohingegen die ellipsoiden Modelle die beste Annaherung im Vergleich zu Volumio ermoglichten. Das Tumorvolumen erwies sich nicht als statistisch signifikanter Prognosefaktor. In der multivariaten Analyse bestatigte sich die Bedeutung des Alters und des Performance-Status fur das progressionsfreie Uberleben und das Gesamtuberleben der Patienten.Schlussfolgerung:Geometrische Modelle bieten eine ungenaue Messung des Tumorvolumens und sollten in der klinischen Praxis nicht zur Anwendung kommen, zumal die prazise Erfassung der Tumorgrose von entscheidender onkologischer Bedeutung ist. Obwohl die vorgelegten Daten den Einfluss des Tumorvolumens als statistisch nicht signifikant zeigten, sind weitere Studien bezuglich der Bedeutung dieses Parameters notwendig.

The importance of tumor volume in the prognosis of patients with glioblastoma: comparison of computerized volumetry and geometric models.

Background and Purpose:The importance of tumor volume as a prognostic factor in high-grade gliomas is highly controversial and there are numerous methods estimating this parameter. In this study, a computer-based application was used in order to assess tumor volume from hard copies and a survival analysis was conducted in order to evaluate the prognostic significance of preoperative volumetric data in patients harboring glioblastomas.Patients and Methods:50 patients suffering from glioblastoma were analyzed retrospectively. Tumor volume was determined by the various geometric models as well as by an own specialized software (Volumio). Age, performance status, type of excision, and tumor location were also included in the multivariate analysis.Results:The spheroid and rectangular models overestimated tumor volume, while the ellipsoid model offered the best approximation. Volume failed to attain any statistical significance in prognosis, while age and performance status confirmed their importance in progression-free and overall survival of patients.Conclusion:Geometric models provide a rough approximation of tumor volume and should not be used, as accurate determination of size is of paramount importance in order to draw safe conclusions in oncology. Although the significance of volumetry was not disclosed, further studies are definitely required.Hintergrund und Ziel:Die Bedeutung des Tumorvolumens als prognostischer Faktor fur maligne Gliome ist nach wie vor umstritten. In dieser Studie wurden eine computerbasierte Methode zur Beurteilung des Tumorvolumens anhand von magnetresonanztomographischen Bildern bei Patienten mit Glioblastoma multiforme (GBM) durchgefuhrt und mittels einer Uberlebensanalyse die prognostische Bedeutung praoperativer volumetrischer Daten untersucht.Patienten und Methodik:50 Patienten mit GBM, welche zwei unterschiedliche Chemotherapieregime erhalten hatten, wurden retrospektiv analysiert und die Tumorvolumina durch verschiedene geometrische Modelle sowie eine spezielle Software (Volumio) gemessen. Alter, Performance-Status, Tumorlokalisation sowie Art der Exzision wurden in der multivariaten Uberlebensanalyse berucksichtigt.Ergebnisse:Die angewandten spharoiden und rektangularen geometrischen Modelle uberschatzten das Tumorvolumen, wohingegen die ellipsoiden Modelle die beste Annaherung im Vergleich zu Volumio ermoglichten. Das Tumorvolumen erwies sich nicht als statistisch signifikanter Prognosefaktor. In der multivariaten Analyse bestatigte sich die Bedeutung des Alters und des Performance-Status fur das progressionsfreie Uberleben und das Gesamtuberleben der Patienten.Schlussfolgerung:Geometrische Modelle bieten eine ungenaue Messung des Tumorvolumens und sollten in der klinischen Praxis nicht zur Anwendung kommen, zumal die prazise Erfassung der Tumorgrose von entscheidender onkologischer Bedeutung ist. Obwohl die vorgelegten Daten den Einfluss des Tumorvolumens als statistisch nicht signifikant zeigten, sind weitere Studien bezuglich der Bedeutung dieses Parameters notwendig.

MMP9 but Not EGFR, MET, ERCC1, P16, and P-53 Is Associated with Response to Concomitant Radiotherapy, Cetuximab, and Weekly Cisplatin in Patients with Locally Advanced Head and Neck Cancer

Concomitant administration of radiotherapy with cisplatin or radiotherapy with cetuximab appear to be the treatment of choice for patients with locally advanced head and neck cancer. In the present retrospective analysis, we investigated the predictive role of several biomarkers in an unselected cohort of patients treated with concomitant radiotherapy, weekly cisplatin, and cetuximab (CCRT). We identified 37 patients treated with this approach, of which 13 (35%) achieved a complete response and 10 (27%) achieved a partial response. Severe side effects were mainly leucopenia, dysphagia, rash, and anemia. Tumor EGFR, MET, ERCC1, and p-53 protein and/or gene expression were not associated with treatment response. In contrast, high MMP9 mRNA expression was found to be significantly associated with objective response. In conclusion, CCRT is feasible and active. MMP9 was the only biomarker tested that appears to be of predictive value in cetuximab treated patients. However, this is a hypothesis generating study and the results should not be viewed as definitive evidence until they are validated in a larger cohort.

Induction chemotherapy with cisplatin, epirubicin, and paclitaxel (CEP), followed by concomitant radiotherapy and weekly paclitaxel for the management of locally advanced nasopharyngeal carcinoma. A Hellenic Cooperative Oncology Group phase II study.

Background:Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control.Patients and Methods:Untreated patients with stage IIB–IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m2 followed by paclitaxel 175 mg/m2 as 3-h infusion on day 1 and cisplatin 75 mg/m2 on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m2.Results:From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet.Conclusion:IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.Hintergrund:Die klinische Forschung in der Behandlung des Nasopharynxkarzinoms (NPC) fokussiert vorrangig auf die Reduktion von Fernmetastasen und die Verbesserung der lokoregionären Kontrolle.Patienten und Methodik:Unbehandelte Patienten mit nicht metastasiertem NPC wurden mit drei Zyklen Induktionschemotherapie (IC), bestehend aus Epirubicin 75 mg/m2 und Paclitaxel 175 mg/m2 als 3-stündige Infusion an Tag 1 sowie Cisplatin 75 mg/m2 an Tag 2 alle 3 Wochen, gefolgt von simultaner Radiochemotherapie (RCT) mit 70 Gy und 60 mg/m2 Paclitaxel wöchentlich, behandelt.Ergebnisse:Von November 1999 bis April 2003 wurden 47 Patienten in die Studie aufgenommen. Die Rate an kompletten Remissionen nach IC betrug 15% und konnte nach Abschluss der konsekutiven RCT auf 66% angehoben werden. Die häufigste Nebenwirkung der IC war Myelotoxizität (55%), der RCT dagegen Stomatitis und Xerostomie (Grad 3, 4). Eine Epstein-Barr-Virus-(EBV-)Positivität wurde durch In-situ-Hybridisierung in Tumorgewebe oder Polymerase-Kettenreaktion im peripheren Blut in 37 von 46 Fällen (80%) nachgewiesen. Alle drei histologischen Typen gingen mit EBV-Positivität einher. Bei einer medianen Nachbeobachtungszeit von 23,5 Monaten betrug die mediane Zeit bis zum Therapieversagen 17,9 Monate; das mediane Überleben hingegen ist noch nicht determiniert.Schlussfolgerung:IC, gefolgt von RCT, geht bei der Mehrzahl der Patienten mit NPC mit lang anhaltenden Komplettremissionen einher. Die Kontaminationsrate mit EBV in dieser Studie ähnelt der endemisch betroffener Regionen.

Induction Chemotherapy with Cisplatin, Epirubicin, and Paclitaxel (CEP), Followed by Concomitant Radiotherapy and Weekly Paclitaxel for the Management of Locally Advanced Nasopharyngeal Carcinoma

Background:Clinical research on the treatment of nasopharyngeal cancer (NPC) has been focused primarily on the reduction of incidence of the development of distant metastases as well as the improvement of locoregional control.Patients and Methods:Untreated patients with stage IIB–IVB nonmetastatic NPC were treated with three cycles of induction chemotherapy (IC) consisting of epirubicin 75 mg/m2 followed by paclitaxel 175 mg/m2 as 3-h infusion on day 1 and cisplatin 75 mg/m2 on day 2 every 3 weeks, followed by concomitant radiation therapy (70 Gy), and chemotherapy (CCRT) with weekly paclitaxel 60 mg/m2.Results:From November 1999 until April 2003, 47 patients entered the study. Complete response rate post IC therapy was 15%, which was raised to 66% after the completion of CCRT. The most frequent side effect from IC was myelotoxicity (55%), whereas stomatitis and xerostomia were the most pronounced (grade 3, 4) toxicities during CCRT. The presence of Epstein-Barr virus (EBV) was detected either by in situ hybridization in tumor tissue sections or by polymerase chain reaction in the peripheral blood in 37 out of 46 patients tested (80%). All three histological types were associated with the presence of EBV. After a median follow-up of 23.5 months, median time to treatment failure was 17.9 months, whilst median survival has not been reached yet.Conclusion:IC followed by CCRT is feasible and produces durable complete responses in the majority of patients with NPC. The case detection rate of EBV in this study appears to be similar to that reported from endemically infected regions.Hintergrund:Die klinische Forschung in der Behandlung des Nasopharynxkarzinoms (NPC) fokussiert vorrangig auf die Reduktion von Fernmetastasen und die Verbesserung der lokoregionären Kontrolle.Patienten und Methodik:Unbehandelte Patienten mit nicht metastasiertem NPC wurden mit drei Zyklen Induktionschemotherapie (IC), bestehend aus Epirubicin 75 mg/m2 und Paclitaxel 175 mg/m2 als 3-stündige Infusion an Tag 1 sowie Cisplatin 75 mg/m2 an Tag 2 alle 3 Wochen, gefolgt von simultaner Radiochemotherapie (RCT) mit 70 Gy und 60 mg/m2 Paclitaxel wöchentlich, behandelt.Ergebnisse:Von November 1999 bis April 2003 wurden 47 Patienten in die Studie aufgenommen. Die Rate an kompletten Remissionen nach IC betrug 15% und konnte nach Abschluss der konsekutiven RCT auf 66% angehoben werden. Die häufigste Nebenwirkung der IC war Myelotoxizität (55%), der RCT dagegen Stomatitis und Xerostomie (Grad 3, 4). Eine Epstein-Barr-Virus-(EBV-)Positivität wurde durch In-situ-Hybridisierung in Tumorgewebe oder Polymerase-Kettenreaktion im peripheren Blut in 37 von 46 Fällen (80%) nachgewiesen. Alle drei histologischen Typen gingen mit EBV-Positivität einher. Bei einer medianen Nachbeobachtungszeit von 23,5 Monaten betrug die mediane Zeit bis zum Therapieversagen 17,9 Monate; das mediane Überleben hingegen ist noch nicht determiniert.Schlussfolgerung:IC, gefolgt von RCT, geht bei der Mehrzahl der Patienten mit NPC mit lang anhaltenden Komplettremissionen einher. Die Kontaminationsrate mit EBV in dieser Studie ähnelt der endemisch betroffener Regionen.

A randomised phase III trial of adjuvant radio-chemotherapy comparing Irinotecan, 5FU and Leucovorin to 5FU and Leucovorin in patients with rectal cancer: a Hellenic Cooperative Oncology Group Study.

The primary objective was to compare the 3-year survival of rectal cancer patients randomised postoperatively to irinotecan (IRI), Leucovorin (LV) and bolus 5-fluorouracil (5FU) or LV-bolus 5FU with radiotherapy. Secondary objectives included disease-free survival, local relapse and toxicity. The study included 321 eligible patients. The treatment consisted of weekly administration of IRI 80 mg/m(2) intravenously (IV), LV 200 mg/m(2) and 5FU 450 mg/m(2) bolus (arm A) versus LV 200 mg/m(2) and 5FU 450 mg/m(2) IV bolus (arm B). One cycle included four infusions and treatment was continued for a total of six cycles. The first cycle was followed by pelvic irradiation plus 5FU. There were no differences between the arms in 3-year overall, disease-free and local relapse-free survival. Grades 3 and 4 toxicity was similar in both the arms with the exception of leucopaenia, neutropaenia and alopecia, which were higher in the IRI arm. IRI added to adjuvant radiochemotherapy with LV and bolus 5FU was not shown to improve survival, whereas the incidence of severe leucopaenia was significantly higher in the IRI arm.

Paclitaxel, cisplatin, leucovorin, and continuous infusion fluorouracil followed by concomitant chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck: a Hellenic Cooperative Oncology Group Phase II Study.

The primary objective of this phase II study was to access the complete response (CR) rate to a new innovative induction regimen in patients with locally advanced head and neck cancer (LA-HNC). From October 2000 until October 2003 a total of 38 eligible patients (33 men and 5 women) entered the study. The large majority of them presented with a performance status of 0–1 and with clinical stage IV disease. Treatment consisted of three cycles of induction chemotherapy (IC) with paclitaxel 175 mg/m2 in a 3-h infusion on d 1, leucovorin (LV) 200 mg/m2 over 20 min immediately followed by FU 400 mg/m2 bolus and then 600 mg/m2 as a 24-h continuous infusion on d 1 and 2 and a cisplatin 75 mg/m2 over 1-h infusion on d 2 every 3 wk. This was then followed by radiation (70 Gy) and weekly cisplatin 40 mg/m2. After the completion of IC, 6/38 (16%) patients had CR. The CR rate was increased to 66% post-concomitant chemoradiotherapy (CCRT). Neutropenia (37.5%), pain (62%), nausea/vomiting (21%), and alopecia (79%) were the most frequent side effects during IC. The most pronounced toxicities during chemoradiotherapy were stomatitis (62.5%) and xerostomia (53%). Median time to progression was 11.0 mo and median survival 16.7 mo. One- and 2-yr survival rates were 73% and 38%, respectively. In conclusion, this novel induction regimen is active, is well tolerated, and can be successfully followed by CCRT with weekly cisplatin. CCRT should remain standard treatment for patients with LA-HNC. Novel induction combinations, such as that reported in the present study, should be evaluated in combination with CCRT only in the context of clinical trials.

The Importance of Tumor Volume in the Prognosis of Patients with Glioblastoma@@@Tumorvolumen als prognostischer Faktor für Patienten mit Glioblastoma. Vergleich der computerbasierten Volumetrie mit geometrischen Modellen: Comparison of Computerized Volumetry and Geometric Models

Background and Purpose:The importance of tumor volume as a prognostic factor in high-grade gliomas is highly controversial and there are numerous methods estimating this parameter. In this study, a computer-based application was used in order to assess tumor volume from hard copies and a survival analysis was conducted in order to evaluate the prognostic significance of preoperative volumetric data in patients harboring glioblastomas.Patients and Methods:50 patients suffering from glioblastoma were analyzed retrospectively. Tumor volume was determined by the various geometric models as well as by an own specialized software (Volumio). Age, performance status, type of excision, and tumor location were also included in the multivariate analysis.Results:The spheroid and rectangular models overestimated tumor volume, while the ellipsoid model offered the best approximation. Volume failed to attain any statistical significance in prognosis, while age and performance status confirmed their importance in progression-free and overall survival of patients.Conclusion:Geometric models provide a rough approximation of tumor volume and should not be used, as accurate determination of size is of paramount importance in order to draw safe conclusions in oncology. Although the significance of volumetry was not disclosed, further studies are definitely required.Hintergrund und Ziel:Die Bedeutung des Tumorvolumens als prognostischer Faktor fur maligne Gliome ist nach wie vor umstritten. In dieser Studie wurden eine computerbasierte Methode zur Beurteilung des Tumorvolumens anhand von magnetresonanztomographischen Bildern bei Patienten mit Glioblastoma multiforme (GBM) durchgefuhrt und mittels einer Uberlebensanalyse die prognostische Bedeutung praoperativer volumetrischer Daten untersucht.Patienten und Methodik:50 Patienten mit GBM, welche zwei unterschiedliche Chemotherapieregime erhalten hatten, wurden retrospektiv analysiert und die Tumorvolumina durch verschiedene geometrische Modelle sowie eine spezielle Software (Volumio) gemessen. Alter, Performance-Status, Tumorlokalisation sowie Art der Exzision wurden in der multivariaten Uberlebensanalyse berucksichtigt.Ergebnisse:Die angewandten spharoiden und rektangularen geometrischen Modelle uberschatzten das Tumorvolumen, wohingegen die ellipsoiden Modelle die beste Annaherung im Vergleich zu Volumio ermoglichten. Das Tumorvolumen erwies sich nicht als statistisch signifikanter Prognosefaktor. In der multivariaten Analyse bestatigte sich die Bedeutung des Alters und des Performance-Status fur das progressionsfreie Uberleben und das Gesamtuberleben der Patienten.Schlussfolgerung:Geometrische Modelle bieten eine ungenaue Messung des Tumorvolumens und sollten in der klinischen Praxis nicht zur Anwendung kommen, zumal die prazise Erfassung der Tumorgrose von entscheidender onkologischer Bedeutung ist. Obwohl die vorgelegten Daten den Einfluss des Tumorvolumens als statistisch nicht signifikant zeigten, sind weitere Studien bezuglich der Bedeutung dieses Parameters notwendig.