RESUMEN
Overall survival of patients with anaplastic oligodendroglial tumors has been improved due to the addition of procarbazine, lomustine and vincristine (PCV) chemotherapy to radiotherapy (RT), especially in 1p/19q-codeleted tumors. With improved survival, quality of survival becomes pivotal. We evaluated cognitive functioning and health-related quality of life (HRQOL) in a cohort of long-term anaplastic oligodendroglioma survivors. Thirty-two out of 37 long-term survivors included in European Organisation for Research and Treatment of Cancer (EORTC) study 26951 in the Netherlands and France participated. Cognition was assessed using neuropsychological tests for 6 domains, and HRQOL with the EORTC Quality of Life Questionnaire (EORTC QLQ-C30) and Brain Cancer Module (EORTC QLQ-BN20). Fatigue and mood were evaluated. Results were compared to healthy controls and to patients' own HRQOL 2.5 years following initial treatment. At the time of assessment, median survival for the patients was 147 months, 27 were still progression-free since initial treatment. Of progression-free patients, 26% were not, and 30% were severely cognitively impaired; 41% were employed and 81% could live independently. Patients' HRQOL was worse compared to controls, but similar to 2.5 years after initial treatment. Initial treatment (RT versus RT + PCV) was not correlated with cognition or HRQOL. In conclusion, cognitive functioning in long-term anaplastic oligodendroglioma survivors is variable. However, most patients function independently. In progression-free patients, HRQOL is relatively stable during the disease course. In this small sample, no effect of the addition of PCV on cognition or HRQOL was identified.
Asunto(s)
Astrocitoma/complicaciones , Astrocitoma/psicología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/psicología , Trastornos del Conocimiento/etiología , Calidad de Vida , Anciano , Astrocitoma/terapia , Neoplasias Encefálicas/terapia , Estudios de Cohortes , Metilasas de Modificación del ADN , Enzimas Reparadoras del ADN , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Radioterapia , Estadísticas no Paramétricas , Sobrevivientes/psicología , Temozolomida , Proteínas Supresoras de TumorRESUMEN
PURPOSE: Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT). PATIENTS AND METHODS: Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. RESULTS: A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. CONCLUSION: The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Oligodendroglioma/tratamiento farmacológico , Oligodendroglioma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/radioterapia , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Estudios de Seguimiento , Eliminación de Gen , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Lomustina/administración & dosificación , Lomustina/efectos adversos , Oligodendroglioma/radioterapia , Procarbazina/administración & dosificación , Procarbazina/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7-9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90-110 mg/m(2)) and dasatinib (100-200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Dasatinib , Supervivencia sin Enfermedad , Femenino , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Lomustina/administración & dosificación , Lomustina/efectos adversos , Lomustina/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Tiazoles/farmacocinéticaRESUMEN
PURPOSE: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls. PATIENTS AND METHODS: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood. RESULTS: In all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P = .08). Among 756 survivors with children before treatment, 12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous post-treatment parenthood. CONCLUSION: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful post-treatment parenthood was 76%.
Asunto(s)
Preservación de la Fertilidad/estadística & datos numéricos , Enfermedad de Hodgkin/epidemiología , Enfermedad de Hodgkin/psicología , Sobrevivientes/estadística & datos numéricos , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Europa (Continente)/epidemiología , Femenino , Fertilidad , Enfermedad de Hodgkin/terapia , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Encuestas y Cuestionarios , Adulto JovenRESUMEN
PURPOSE: In this large cohort of Hodgkin's lymphoma survivors with long follow-up, we estimated the impact of treatment regimens on premature ovarian failure (POF) occurrence and motherhood, including safety of nonalkylating chemotherapy and dose-response relationships for alkylating chemotherapy and age at treatment. PATIENTS AND METHODS: The Life Situation Questionnaire was sent to 1,700 women treated in European Organisation for Research and Treatment of Cancer and Groupe d'Étude des Lymphomes de l'Adulte trials between 1964 and 2004. Women treated between ages 15 and 40 years and currently not using hormonal contraceptives (n = 460) were selected to assess occurrence of POF. Cumulative POF risk was estimated using the life-table method. Predictive factors were assessed by Cox regression analysis. RESULTS: Median follow-up was 16 years (range, 5 to 45 years). Cumulative risk of POF after alkylating chemotherapy was 60% (95% CI, 41% to 79%) and only 3% (95% CI, 1% to 7%) after nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine; epirubicin, bleomycin, vinblastine, and prednisone). Dose relationship between alkylating chemotherapy and POF occurrence was linear. POF risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy at age younger than 32 years and age 32 years or older, cumulative POF risks were 3% (95% CI, 1% to 16%) and 9% (95% CI, 4% to 18%), respectively. If menstruation returned after treatment, cumulative POF risk was independent of age at treatment. Among women who ultimately developed POF, 22% had one or more children after treatment, compared with 41% of women without POF. CONCLUSION: Nonalkylating chemotherapy carries little to no excess risk of POF. Dose-response relationships for alkylating chemotherapy and age at treatment are both linear. Timely family planning is important for women at risk of POF.
Asunto(s)
Fertilidad , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/terapia , Insuficiencia Ovárica Primaria/etiología , Sobrevivientes , Adolescente , Adulto , Estudios de Cohortes , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Europa (Continente) , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/patología , Humanos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Encuestas y Cuestionarios , Adulto JovenRESUMEN
AIMS: BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1. We performed a multi-centre, multi-tumour phase II trial to investigate the efficacy, safety and pharmacokinetics of BI 2536 in five solid tumour types. PATIENTS AND METHODS: Patients with advanced head and neck, breast and ovarian cancer, soft tissue sarcoma and melanoma were selected according to protocol-defined general and tumour-specific criteria. They were 18years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4weeks ago. BI 2536 200-250mg was given intravenously on day 1 every 3 weeks until intolerance, progression or refusal. The study was based on a Simon two-stage design, with 12 patients entering in stage 1 and additional 25 patients to be entered in case of at least one response in the first stage. The rate of objective responses (RECIST criteria) was chosen as primary end-point. RESULTS: Seventy six patients were included, 71 started treatment and received a median number of two cycles (four in ovarian cancer). Frequent grade 3-4 adverse events were neutropaenia (81.6%), thrombocytopaenia (19.7%), febrile neutropaenia (19.7%), anaemia (15.5%) and pain (9.9%). We did not observe confirmed objective responses. All cohorts were closed after the entry of 14-15 eligible non-responding patients. Pharmacokinetic analyses revealed multi-compartmental behaviour and a rapid distribution of BI 2536. CONCLUSIONS: BI 2536 showed limited antitumour activity according to the design of this trial in five different tumour types. Derivatives of BI 2536 with a more favourable pharmacological profile are currently explored further in prospective studies.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Pteridinas/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Estudios de Factibilidad , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Infusiones Intravenosas , Masculino , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Cooperación del Paciente , Pteridinas/efectos adversos , Pteridinas/farmacocinética , Sarcoma/tratamiento farmacológico , Sarcoma/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Terapia Combinada , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Dacarbazina/uso terapéutico , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas , Análisis de Supervivencia , Tasa de Supervivencia , Temozolomida , Proteínas Supresoras de Tumor/genéticaRESUMEN
Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFR(amp)), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p(loss)19q(loss)) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFR(amp) were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients with AOA with only endothelial proliferation had better overall survival. In univariate analyses, all molecular factors except loss of 10q were of prognostic significance, but on multivariate analysis a histopathological diagnosis of AOA, necrosis, and 1p(loss)19q(loss) remained independent prognostic factors. AOA tumors with necrosis are to be considered WHO grade IV tumors (GBM). Of all molecular markers analyzed in this study, especially loss of 1p/19q carried prognostic significance, while the others contributed little prognostic value to classical histology.
Asunto(s)
Astrocitoma/genética , Neoplasias Encefálicas/genética , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 19/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 7/genética , Oligodendroglioma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Astrocitoma/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Proliferación Celular , Quimioterapia Adyuvante , Deleción Cromosómica , Ensayos Clínicos Fase III como Asunto , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Humanos , Hibridación Fluorescente in Situ , Lomustina/administración & dosificación , Necrosis , Estadificación de Neoplasias , Oligodendroglioma/tratamiento farmacológico , Oligodendroglioma/patología , Procarbazina/administración & dosificación , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: In a previous randomised EORTC study on adjuvant dibromodulcitol (DBD) and bichloroethylnitrosourea (BCNU) in adults with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), a clinically significant trend towards a longer overall survival (OS) and a progression-free survival (PFS) was observed in the subgroup of AA. The aim of the present study was to test this adjuvant regimen in a larger number of AA patients. METHODS: Continuation of the previous phase III trial for newly diagnosed AA according to the local pathologist. Patients were randomised to either radiotherapy only or to radiotherapy in combination with BCNU on day 2 and weekly DBD, followed by adjuvant DBD and BCNU in cycles of six weeks for a maximum total treatment duration of one year. OS was the primary end-point. RESULTS: Patients (193 ) with newly diagnosed AA according to local pathological assessment were randomised to radiotherapy (RT) alone (n=99), or to RT plus DBD/BCNU (n=94); 12 patients were considered not eligible. At central pathology review, over half (53%) of the locally diagnosed AA cases could not be confirmed. On intent-to-treat analysis, no statistically significant differences in OS (p=0.111) and PFS (p=0.087) were observed, median OS after RT was only 23.9 months 95% confidence interval (CI), [18.4-34.0] after RT plus DBD/BCNU 27.3 months 95% CI [21.4-46.8]. CONCLUSION: No statistically significant improvement in survival was observed after BCNU/DBD adjuvant chemotherapy in AA patients. The trend towards improved survival is consistent with previous reports. Central pathology review of grade 3 tumours remains crucial.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Adulto , Anciano , Astrocitoma/radioterapia , Carmustina/administración & dosificación , Carmustina/efectos adversos , Quimioterapia Adyuvante , Femenino , Enfermedades Hematológicas/inducido químicamente , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mitolactol/administración & dosificación , Mitolactol/efectos adversos , Insuficiencia del TratamientoRESUMEN
BACKGROUND: A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival. We aimed to undertake an exploratory subanalysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma, derive nomograms that predict an individual patient's prognosis, and suggest stratification factors for future trials. METHODS: Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Nomograms were developed to predict an individual patient's median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care. FINDINGS: Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT, better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator. INTERPRETATION: MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient's prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Nomogramas , Adulto , Antineoplásicos Alquilantes/efectos adversos , Terapia Combinada , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Femenino , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Supervivencia , TemozolomidaRESUMEN
PURPOSE: Little is known about the health-related quality of life (HRQOL) of patients treated for anaplastic oligodendrogliomas. The impact of combined procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy after radiotherapy (RT) compared with RT alone on HRQOL in the randomized European Organisation for Research and Treatment of Cancer (EORTC) 26951 trial was studied. PATIENTS AND METHODS: Adult patients with anaplastic oligodendrogliomas received RT alone or RT plus PCV chemotherapy. HRQOL was assessed with the EORTC Quality of Life Questionnaire C30 and Brain Cancer Module. Seven prespecified HRQOL end points were selected. We hypothesized that chemotherapy would impair HRQOL during treatment but that there would be a similar HRQOL between treatment arms once off treatment. Assessments were performed at randomization, at the end of RT, and then every 3 to 6 months until progression. RESULTS: A total of 368 patients were randomly assigned to one of the two arms; overall, 58% were male, and the median age was 49 years. Compliance with HRQOL was 78% at baseline and dropped to 55% to 72% up to 2.5 years post-RT. Baseline scores demonstrated considerable impairments in HRQOL for both treatment groups. The longitudinal analysis showed a significant increase in nausea/vomiting in the RT plus PCV chemotherapy arm during and shortly after chemotherapy. Because of a difference in baseline scores for fatigue and physical functioning, the differences between treatment arms during PCV did not reach significance. The nonselected scales of appetite loss and drowsiness demonstrated significant differences between treatment arms during chemotherapy in favor of the RT arm. The long-term results showed no difference between arms. CONCLUSION: The major impact of PCV on HRQOL is on nausea/vomiting, loss of appetite, and drowsiness during and shortly after treatment. There are no long-term effects of PCV chemotherapy.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Oligodendroglioma/tratamiento farmacológico , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/patología , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Humanos , Lomustina/administración & dosificación , Masculino , Persona de Mediana Edad , Procarbazina/administración & dosificación , Radioterapia , Vincristina/administración & dosificaciónRESUMEN
PURPOSE: The European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada trial on temozolomide (TMZ) and radiotherapy (RT) in glioblastoma (GBM) has demonstrated that the combination of TMZ and RT conferred a significant and meaningful survival advantage compared with RT alone. We evaluated in this trial whether the recursive partitioning analysis (RPA) retains its overall prognostic value and what the benefit of the combined modality is in each RPA class. PATIENTS AND METHODS: Five hundred seventy-three patients with newly diagnosed GBM were randomly assigned to standard postoperative RT or to the same RT with concomitant TMZ followed by adjuvant TMZ. The primary end point was overall survival. The European Organisation for Research and Treatment of Cancer RPA used accounts for age, WHO performance status, extent of surgery, and the Mini-Mental Status Examination. RESULTS: Overall survival was statistically different among RPA classes III, IV, and V, with median survival times of 17, 15, and 10 months, respectively, and 2-year survival rates of 32%, 19%, and 11%, respectively (P < .0001). Survival with combined TMZ/RT was higher in RPA class III, with 21 months median survival time and a 43% 2-year survival rate, versus 15 months and 20% for RT alone (P = .006). In RPA class IV, the survival advantage remained significant, with median survival times of 16 v 13 months, respectively, and 2-year survival rates of 28% v 11%, respectively (P = .0001). In RPA class V, however, the survival advantage of RT/TMZ was of borderline significance (P = .054). CONCLUSION: RPA retains its prognostic significance overall as well as in patients receiving RT with or without TMZ for newly diagnosed GBM, particularly in classes III and IV.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Adulto , Anciano , Neoplasias Encefálicas/cirugía , Canadá , Quimioterapia Adyuvante , Dacarbazina/uso terapéutico , Europa (Continente) , Femenino , Glioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Radioterapia Adyuvante , Análisis de Supervivencia , Temozolomida , Resultado del TratamientoRESUMEN
PURPOSE: Anaplastic oligodendrogliomas are more responsive to chemotherapy than high-grade astrocytomas. We investigated, in a multicenter randomized controlled trial, whether adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy improves overall survival (OS) in newly diagnosed patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas. PATIENTS AND METHODS: The primary end point of the study was OS; secondary end points were progression-free survival (PFS) and toxicity. Patients were randomly assigned to either 59.4 Gy of radiotherapy (RT) in 33 fractions only or to the same RT followed by six cycles of standard PCV chemotherapy (RT/PCV). 1p and 19q deletions were assessed with fluorescent in situ hybridization. RESULTS: A total of 368 patients were included. The median follow-up time was 60 months, and 59% of patients have died. In the RT arm, 82% of patients with tumor progression received chemotherapy. In 38% of patients in the RT/PCV arm, adjuvant PCV was discontinued for toxicity. OS time after RT/PCV was 40.3 months compared with 30.6 months after RT only (P = .23). RT/PCV increased PFS time compared with RT only (23 v 13.2 months, respectively; P = .0018). Twenty-five percent of patients were diagnosed with combined 1p/19q loss; 74% of this subgroup was still alive after 60 months. RT/PCV did not improve survival in the subgroup of patients with 1p/19q loss. CONCLUSION: Adjuvant PCV chemotherapy does not prolong OS but does increase PFS in anaplastic oligodendroglioma. Combined loss of 1p/19q identifies a favorable subgroup of oligodendroglial tumors. No genetic subgroup could be identified that benefited with respect to OS from adjuvant PCV.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Oligodendroglioma/tratamiento farmacológico , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Quimioterapia Adyuvante , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Lomustina/uso terapéutico , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Oligodendroglioma/genética , Oligodendroglioma/radioterapia , Procarbazina/uso terapéutico , Análisis de Supervivencia , Vincristina/uso terapéuticoRESUMEN
BACKGROUND: Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. METHODS: Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. RESULTS: A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. CONCLUSIONS: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.