Showing papers by "Roger Stupp published in 2003"

Mediastinal Lymph Node Clearance After Docetaxel-Cisplatin Neoadjuvant Chemotherapy Is Prognostic of Survival in Patients With Stage IIIA pN2 Non–Small-Cell Lung Cancer: A Multicenter Phase II Trial

Abstract: Purpose: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non–small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. Patients and Methods: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. Results: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19%...

Phase II Study of First-Line Chemotherapy With Temozolomide in Recurrent Oligodendroglial Tumors: The European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971

Abstract: Purpose: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. Patients and Methods: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed....

Classification of Human Astrocytic Gliomas on the Basis of Gene Expression A Correlated Group of Genes with Angiogenic Activity Emerges As a Strong Predictor of Subtypes

Abstract: The development of targeted treatment strategies adapted to individual patients requires identification of the different tumor classes according to their biology and prognosis. We focus here on the molecular aspects underlying these differences, in terms of sets of genes that control pathogenesis of the different subtypes of astrocytic glioma. By performing cDNA-array analysis of 53 patient biopsies, comprising low-grade astrocytoma, secondary glioblastoma (respective recurrent high-grade tumors), and newly diagnosed primary glioblastoma, we demonstrate that human gliomas can be differentiated according to their gene expression. We found that low-grade astrocytoma have the most specific and similar expression profiles, whereas primary glioblastoma exhibit much larger variation between tumors. Secondary glioblastoma display features of both other groups. We identified several sets of genes with relatively highly correlated expression within groups that: (a). can be associated with specific biological functions; and (b). effectively differentiate tumor class. One prominent gene cluster discriminating primary versus nonprimary glioblastoma comprises mostly genes involved in angiogenesis, including VEGF fms-related tyrosine kinase 1 but also IGFBP2, that has not yet been directly linked to angiogenesis. In situ hybridization demonstrating coexpression of IGFBP2 and VEGF in pseudopalisading cells surrounding tumor necrosis provided further evidence for a possible involvement of IGFBP2 in angiogenesis. The separating groups of genes were found by the unsupervised coupled two-way clustering method, and their classification power was validated by a supervised construction of a nearly perfect glioma classifier.

Non steroidal anti‐inflammatory drugs and COX‐2 inhibitors as anti‐cancer therapeutics: hypes, hopes and reality

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) and specific inhibitors of cyclooxygenase (COX)-2, are therapeutic groups widely used for the treatment of pain, inflammation and fever. There is growing experimental and clinical evidence indicating NSAIDs and COX-2 inhibitors also have anti-cancer activity. Epidemiological studies have shown that regular use of Aspirin and other NSAIDs reduces the risk of developing cancer, in particular of the colon. Molecular pathology studies have revealed that COX-2 is expressed by cancer cells and cells of the tumor stroma during tumor progression and in response to chemotherapy or radiotherapy. Experimental studies have demonstrated that COX-2 over expression promotes tumorigenesis, and that NSAIDs and COX-2 inhibitors suppress tumorigenesis and tumor progression. Clinical trials have shown that NSAIDs and COX-2 inhibitors suppress colon polyp formation and malignant progression in patients with familial adenomatous polyposis (FAP) syndrome. Recent advances in the understanding of the cellular and molecular mechanisms of the anti-cancer effects of NSAIDs and COX-2 inhibitors have demonstrated that these drugs target both tumor cells and the tumor vasculature. The therapeutic benefits of COX-2 inhibitors in the treatment of human cancer in combination with chemotherapy or radiotherapy are currently being tested in clinical trials. In this article we will review recent advances in the understanding of the anti-tumor mechanisms of these drugs and discuss their potential application in clinical oncology.

The quest for surrogate markers of angiogenesis: a paradigm for translational research in tumor angiogenesis and anti-angiogenesis trials.

Abstract: Inhibition of tumor angiogenesis suppresses tumor growth and metastatic spreading in many experimental models, suggesting that anti-angiogenic drugs may be used to treat human cancer. During the past decade more than eighty molecules that showed anti-angiogenic activity in preclinical studies were tested in clinical cancer trials, but most of them failed to demonstrate any measurable anti-tumor activity and none have been approved for clinical use. Recent results stemming from trials with anti-VEGF antibodies, used alone or in combination with chemotherapy, suggest that systemic anti-angiogenic therapy may indeed have a measurable impact on cancer progression and patient survival. From the clinical studies it became nevertheless clear that the classical endpoints used in anti-cancer trials do not bring sufficient discriminative power to monitor the effects of anti-angiogenic drugs. It is therefore necessary to identify and validate molecular, cellular and functional surrogate markers of angiogenesis to monitor activity and efficacy of anti-angiogenic drugs in patients. Availability of such markers will be instrumental to re-evaluate the role of tumor angiogenesis in human cancer, to identify new molecular targets and drugs, and to improve planning, monitoring and interpretation of future studies. Future anti-angiogenesis trials integrating biological endpoints and surrogate markers or angiogenesis will require close collaboration between clinical investigators and laboratory-based researchers.

New drugs and combinations for malignant glioma.

Abstract: A new chemotherapy agent and a method for local delivery of carmustine have recently been approved for the treatment of malignant glioma. However, the increase in survival remains modest at best with only a very select patients currently benefiting truly of these treatments. Combination regimen of different alkylating agents or prior O6-alkyltransferase depletion by O6-benzylguanine or continuous temozolomide administration schedules have shown some indication for increased activity. There is preclinical rational for combining temozolomide with radiotherapy and the initial results of a phase II clinical trial were promising. Several new cytotoxic agents are currently in clinical trials in patients with recurrent glioma. More importantly, targeted therapy and antiangiogenic agents have entered the clinical development phase also for patients with glioblastoma and anaplastic astrocytoma. The optimal timing of administration of non-cytotoxic substances and their integration into the currently available treatments remains a challenge. Novel study designs and identification of surrogate markers are necessary in order to make rapid and clinically meaningful progress. This review summarises the currently available evidence of activity of the recently approved drugs against malignant glioma and mentions also agents which have failed to demonstrate a significant antitumour activity. Study endpoints are critically discussed. Combination regimens with other agents and radiation therapy are reviewed. The rational for using antiangiogenic drugs in selected ongoing trials is discussed.

Radiothérapie externe accélérée postopératoire des carcinomes épidermoïdes localement évolués de la sphère ORL : étude prospective de phase II

Abstract: Resume Objectif de l’etude . – Evaluer la faisabilite et la tolerance de la radiotherapie externe acceleree postoperatoire des carcinomes epidermoides localement evolues de la sphere ORL. Patients et methodes . – De decembre 1997 a juillet 2001, nous avons inclus 68 patients (52 hommes, 16 femmes), d’un âge median de 60 ans (variant de 43–81 ans), operes avec intention curative d’un carcinome epidermoide ORL de stades pT1-4 et/ou pN0-3 M0. Il s’agissait d’une population de patients atteints de cancer a haut risque de rechute locoregionale : colonisation ganglionnaire avec depassement capsulaire chez 20 patients, atteinte des tranches de section chez 20 patients ou presence des deux facteurs de risque associes chez 23 patients ; dans deux cas, on retient la presence de lymphangite carcinomateuse sur la piece operatoire et d’autres raisons dans trois cas. La radiotherapie externe acceleree postoperatoire de dose totale de 66 Gy etait etalee sur 37 jours. La duree de surveillance mediane etait de 15 mois. Resultats . – Selon les criteres de CTC 2.0 ( common toxicity criteria ), nous avons observe une mucite de grade 3 chez 15 patients (22 %), une dysphagie de grade 3 chez 19 patients (28 %) et un erytheme cutane de grade 3 chez 21 patients (31 %). La perte ponderale mediane etait de 3,1 kg (0–16 kg). Nous avons observe seulement trois rechutes locales (4 %) et quatre rechutes regionales (6 %), alors que huit patients (12 %) ont souffert de metastases a distance (intervalle median de rechute : 13 mois). Les taux actuariel de controle locoregional, de survie sans maladie et de survie globale a 2 ans etaient respectivement de 83, 73 et 85 %. Conclusion . – La reduction de la duree totale de la radiotherapie externe acceleree postoperatoire par la technique du concomitant boost (six fractions par semaine) est faisable dans les carcinomes de la sphere ORL sans majoration de la toxicite aigue. Le taux de controle locoregional est comparable aux resultats publies.

Accelerated postoperative radiation therapy with weekly concomitant boost in patients with advanced head and neck cancer.

Abstract: Purpose/Objective: To assess the feasibility and efficacy of accelerated weekly 6 fractionated 66-Gy postoperative radiation therapy (RT) using a single fraction regimen from Monday to Thursday and a concomitant boost in the Friday afternoon sessions in patients with advanced head and neck cancer (AHNC). Materials/Methods: Between December 1997 and June 2002, 89 (male to female ratio: 68/21; median age: 60 years [range: 36-81]) consecutive patients (refusing to participate or ineligible for the EORTC 22931 study comparing postoperative RT vs. RT plus chemotherapy) with pT1-pT4 and/or pN0-pN3 AHNC (28 oropharynx, 26 oral cavity, 18 hypopharynx, 6 larynx, 5 unknown primary, 4 salivary gland, and 2 paranasal sinus) were included in this prospective study. Postoperative RT was indicated because surgical margins were not free of tumor (n = 22) or for T4 tumors (n = 4) in 26 (29%) patients; or because of extranodal infiltration with (n = 33) or without (n = 30) positive surgical margins in 63 (71%) patients. Median interval between surgery and RT was 6 weeks (3-15). RT consisted of 66 Gy (2 Gy/fr) in 5 weeks and 3 days. Median RT duration was 39 days (range: 35-67). Prophylactic percutaneous endoscopic gastrostomy was applied in 26 (29%) patients. Median follow-up was 21 months (range: 2-59). Results: All but one patient (not finishing the treatment because of non treatment-related reasons at 56 Gy) received the planned total dose without unplanned interruption. Acute morbidity was acceptable: grade 3 mucositis in 20 (22%) patients, grade 3 dysphagia in 22 (25%) patients, grade 3 skin erythema in 18 (20%) patients. Median weight loss of was 2 kg (range: 0-14.5). No grade 4 toxicity was observed. Considering the late effects, grade 0, 1, 2, or 3 xerostomia was observed in 15 (17%), 57 (64%), 11 (12%), and 6 (7%) patients, respectively; grade 0, 1, 2, and 3 edema in 29 (33%), 46 (52%), 12 (13%), and 2 (2%) patients, respectively. Median time to locoregional relapse was 10 months (range: 2-21); only 4 (4%) local and 9 (10%) regional relapses were observed, and 18 (20%) patients developed distant metastases (all locally controlled but with regional relapses in 4 cases). The 2-year overall, cause-specific, and disease-free survival rates were 70%, 75%, and 63%, respectively; and 2-year actuarial-local and locoregional control rates were 94% and 80%, respectively. Distant metastasis probabilities at 2 and 4 years were 20% and 38%, respectively. Univariate analyses revealed that pT-stage, 3 or more lymph node metastases, and extranodal extension in 2 or more lymph nodes were Related Articles in ScienceDirect significant. Multivariate analysis (Cox model) revealed that pT-stage (pT1, 2 vs. pT3, 4) and extranodal extension (0, 1 vs. 2 or more) were the two factors independently influencing the outcome. Conclusions: We conclude that reducing the overall treatment time using postoperative accelerated RT by weekly concomitant boost (6 fractions per week) is easily feasible with excellent local control. Acute and late RT-related morbidity is highly acceptable. Given the disease progression pattern (distant metastases), adjuvant chemotherapy should be considered.

Radiothérapie externe accélérée postopératoire des carcinomes épidermoïdes localement évolués de la sphère ORL : étude prospective de phase II

Abstract: Resume Objectif de l’etude . – Evaluer la faisabilite et la tolerance de la radiotherapie externe acceleree postoperatoire des carcinomes epidermoides localement evolues de la sphere ORL. Patients et methodes . – De decembre 1997 a juillet 2001, nous avons inclus 68 patients (52 hommes, 16 femmes), d’un âge median de 60 ans (variant de 43–81 ans), operes avec intention curative d’un carcinome epidermoide ORL de stades pT1-4 et/ou pN0-3 M0. Il s’agissait d’une population de patients atteints de cancer a haut risque de rechute locoregionale : colonisation ganglionnaire avec depassement capsulaire chez 20 patients, atteinte des tranches de section chez 20 patients ou presence des deux facteurs de risque associes chez 23 patients ; dans deux cas, on retient la presence de lymphangite carcinomateuse sur la piece operatoire et d’autres raisons dans trois cas. La radiotherapie externe acceleree postoperatoire de dose totale de 66 Gy etait etalee sur 37 jours. La duree de surveillance mediane etait de 15 mois. Resultats . – Selon les criteres de CTC 2.0 ( common toxicity criteria ), nous avons observe une mucite de grade 3 chez 15 patients (22 %), une dysphagie de grade 3 chez 19 patients (28 %) et un erytheme cutane de grade 3 chez 21 patients (31 %). La perte ponderale mediane etait de 3,1 kg (0–16 kg). Nous avons observe seulement trois rechutes locales (4 %) et quatre rechutes regionales (6 %), alors que huit patients (12 %) ont souffert de metastases a distance (intervalle median de rechute : 13 mois). Les taux actuariel de controle locoregional, de survie sans maladie et de survie globale a 2 ans etaient respectivement de 83, 73 et 85 %. Conclusion . – La reduction de la duree totale de la radiotherapie externe acceleree postoperatoire par la technique du concomitant boost (six fractions par semaine) est faisable dans les carcinomes de la sphere ORL sans majoration de la toxicite aigue. Le taux de controle locoregional est comparable aux resultats publies.

Mediastinal L ymph N ode C learance A fter D ocetaxel-Cispla tin Neoadjuvant C hemotherapy I s P rognostic o f S urvival i n Patients W ith S tage I IIA p N2 N on-Small-Cell L ung C ancer: A M ulticenter P hase I I T rial

Abstract: Purpose: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non‐small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. Patients and Methods: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m 2 day 1 plus cisplatin 40 mg/m 2 days 1 and 2, with subsequent surgical resection. Results: Administered dose-intensities were docetaxel 85 mg/m 2 /3 weeks (range, 53 to 96) and cisplatin 95 mg/m 2 /3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0‐1 at surgery was prognostic and significantly prolonged eventfree survival (EFS) and overall survival (OS; P .0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P .0003) and complete resection (hazard ratio, 0.26; P .0006) as strongly prognostic for increased survival. Conclusion: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy. J Clin Oncol 21:1752-1759. © 2003 by American Society of Clinical Oncology.