RESUMEN
PURPOSE: We retrospectively evaluated the association between postoperative pre-radiotherapy tumour burden and overall survival (OS) adjusted for the prognostic value of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with newly diagnosed glioblastoma treated with radio-/chemotherapy with temozolomide. MATERIALS AND METHODS: Patients were included from the CENTRIC (EORTC 26071-22072) and CORE trials if postoperative magnetic resonance imaging scans were available within a timeframe of up to 4weeks before radiotherapy, including both pre- and post-contrast T1w images and at least one T2w sequence (T2w or T2w-FLAIR). Postoperative (residual) pre-radiotherapy contrast-enhanced tumour (CET) volumes and non-enhanced T2w abnormalities (NT2A) tissue volumes were obtained by three-dimensional segmentation. Cox proportional hazard models and Kaplan Meier estimates were used to assess the association of pre-radiotherapy CET/NT2A volume with OS adjusted for known prognostic factors (age, performance status, MGMT status). RESULTS: 408 tumour (of which 270 MGMT methylated) segmentations were included. Median OS in patients with MGMT methylated tumours was 117 weeks versus 61weeks in MGMT unmethylated tumours (p < 0.001). When stratified for MGMT methylation status, higher CET volume (HR 1.020; 95% confidence interval CI [1.013-1.027]; p < 0.001) and older age (HR 1.664; 95% CI [1.214-2.281]; p = 0.002) were significantly associated with shorter OS while NT2A volume and performance status were not. CONCLUSION: Pre-radiotherapy CET volume was strongly associated with OS in patients receiving radio-/chemotherapy for newly diagnosed glioblastoma stratified by MGMT promoter methylation status.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/terapia , Glioblastoma/tratamiento farmacológico , Antineoplásicos Alquilantes/uso terapéutico , Estudios Retrospectivos , Metilación , Carga Tumoral , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamiento farmacológico , Pronóstico , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Metilación de ADN , Proteínas Supresoras de Tumor/genéticaRESUMEN
Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients' molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.
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Neoplasias Torácicas , Neoplasias del Timo , Europa (Continente) , Humanos , Estudios Prospectivos , Neoplasias Torácicas/diagnósticoRESUMEN
We report on a phase II clinical trial to determine the effect of a concurrent ultra-fractionated radiotherapy and temozolomide treatment in inoperable glioblastoma patients. A phase II study opened; patients over 18 years of age who were able to give informed consent and had histologically proven, newly diagnosed inoperable diagnosed and supratentorial glioblastoma were eligible. Three doses of 0.75 Gy spaced apart by at least 4 hr were delivered daily, 5 days a week for six consecutive weeks for a total of 67.5 Gy. Chemotherapy was administered during the same period, which consisted of temozolomide given at a dose of 75 mg/m(2) for 7 days a week. After a 4-week break, chemotherapy was resumed for up to six cycles of adjuvant temozolomide treatment, given every 28 days, according to the standard 5-day regimen. Tolerance and toxicity were the primary endpoints; survival and progression-free survival were the secondary endpoints. In total, 40 patients were enrolled in this study, 29 men and 11 women. The median age was 58 years, and the median Karnofsky performance status was 80. The concomitant ultra-fractionated radiotherapy and temozolomide treatment was well tolerated. Complete responses were seen in four patients, and partial responses were reported in seven patients. The median survival from the initial diagnosis was 16 months. Several long-term survivors were noted. Concurrent ultra-fractionated radiation therapy and temozolomide treatment are well accepted by the patients. The results showed encouraging survival rates for these unfavorable patients.
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Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Glioblastoma/patología , Glioblastoma/terapia , Radioterapia de Intensidad Modulada/métodos , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Neoplasias Encefálicas/mortalidad , Quimioradioterapia , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Femenino , Francia , Glioblastoma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Radioterapia de Intensidad Modulada/efectos adversos , Temozolomida , Resultado del Tratamiento , Carga Tumoral , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome. METHODS: Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated. RESULTS: At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS(12wks)), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P<0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS(12wks), and OS (both P<0.05). CONCLUSION: Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment.
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Inhibidores de la Angiogénesis/sangre , Antineoplásicos/uso terapéutico , Citocinas/sangre , Proteínas de la Membrana/sangre , Proteínas Gestacionales/sangre , Pirimidinas/uso terapéutico , Sarcoma/sangre , Sarcoma/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Indazoles , Subunidad p40 de la Interleucina-12/sangre , Masculino , Persona de Mediana Edad , Factor de Crecimiento Placentario , Proteínas del Grupo Polycomb , Pirimidinas/efectos adversos , Proteínas Represoras/sangre , Sulfonamidas/efectos adversos , Adulto JovenRESUMEN
The progression-free survival rate at 6 months (PFS-6) has long been considered the best end-point for assessing the efficacy of new agents in phase II trials in patients with recurrent glioblastoma. However, due to the introduction of antiangiogenic agents in this setting, and their intrinsic propensity to alter neuroradiological disease assessment by producing pseudoregression, any end-point based on neuroradiological modifications should be reconsidered. Further, statistically significant effects on progression-free survival (PFS) only should not automatically be considered reliable evidence of meaningful clinical benefit. In this context, because of its direct and unquestionable clinical relevance, overall survival (OS) represents the gold standard end-point for measuring clinical efficacy, despite the disadvantage that it is influenced by subsequent therapies and usually takes longer time to be evaluated. Therefore, while awaiting novel imaging criteria for response evaluation and/or new imaging tools to distinguish between 'true' and 'pseudo'-responses to antiangiogenic agents, the measurement of OS or OS rates should be considered primary end-points, also in phase II trials with these agents.
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Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Ensayos Clínicos Fase II como Asunto/métodos , Determinación de Punto Final/métodos , Glioblastoma/tratamiento farmacológico , Glioblastoma/mortalidad , Neoplasias Encefálicas/patología , Supervivencia sin Enfermedad , Glioblastoma/patología , Humanos , Recurrencia Local de Neoplasia , Tasa de SupervivenciaRESUMEN
BACKGROUND: Adding docetaxel (Taxotere, T) to induction chemotherapy with platinum/infusional 5-FU (PF) has been shown to improve overall survival of patients with head and neck cancer. The aim of the study was to analyze the cost-utility of TPF in patients with unresectable disease. DESIGN: We developed a Markov model to represent patient's weekly transitions among different health states, related to treatment or disease status. Transition probabilities were obtained from the TAX 324 clinical trial report and from the European Organization for Research and Treatment of Cancer (EORTC) 24971/TAX 323 raw data. Costs were estimated in Italy from a Regional Healthcare System perspective. A 5-year temporal horizon was adopted and a 3.5% yearly discount rate was applied. RESULTS: When compared with PF, TPF treatment increases life expectancy by 0.33 quality-adjusted life-years (QALYs) in TAX 323 and 0.41 QALYs in TAX 324. The benefit was achieved at a cost of 11,822/QALY for TAX 323 and 6757/QALY for TAX 324. Monte Carlo sensitivity analysis showed that 69% (TAX 323) and 99% (TAX 324) of the results lie below the threshold of 50,000/QALY saved. CONCLUSIONS: In our analysis, TPF induction chemotherapy proved to be cost-effective when compared with PF, having a cost-utility ratio comparable to other widely accepted healthcare interventions.
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Protocolos de Quimioterapia Combinada Antineoplásica/economía , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/mortalidad , Cisplatino/administración & dosificación , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Docetaxel , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/mortalidad , Quimioterapia de Inducción/economía , Cadenas de Markov , Método de Montecarlo , Ensayos Clínicos Controlados Aleatorios como Asunto , Sensibilidad y Especificidad , Análisis de Supervivencia , Taxoides/administración & dosificaciónRESUMEN
OBJECTIVE: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. METHODS: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. RESULTS: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). CONCLUSIONS: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.
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Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Glioblastoma/mortalidad , Ácido Valproico/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Canadá/epidemiología , Dacarbazina/uso terapéutico , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Temozolomida , Adulto JovenRESUMEN
The purpose of this analysis was to assess the potential of BNCT, with L-boronophenylalanine (L-BPA), as first line radiotherapy for glioblastoma multiforme (GBM). The survival of patients with newly diagnosed GBM from a phase II BNCT study was compared with those from the two arms of a phase III study with conventional radiotherapy (RT) vs. RT plus concomitant and adjuvant medication with temozolomide (TMZ). A small subgroup, for which the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene was known, was also considered. The results indicated that the use of BNCT with BPA should be explored in a stratified randomized phase II trial in which patients with the unmethylated MGMT DNA-repair gene are offered BNCT vs. RT plus TMZ.
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Terapia por Captura de Neutrón de Boro , Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Metilación de ADN , Reparación del ADN , HumanosRESUMEN
Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.
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Neoplasias Encefálicas/terapia , Glioma/terapia , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Glioma/mortalidad , Glioma/patología , Humanos , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Resultado del TratamientoRESUMEN
BACKGROUND: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. PATIENTS AND METHODS: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. RESULTS: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. CONCLUSIONS: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.
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Antineoplásicos/uso terapéutico , Benzotiazoles/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Epotilonas/uso terapéutico , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Astrocitoma/sangre , Astrocitoma/tratamiento farmacológico , Benzotiazoles/efectos adversos , Benzotiazoles/sangre , Benzotiazoles/farmacocinética , Neoplasias Encefálicas/sangre , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Epotilonas/efectos adversos , Epotilonas/sangre , Epotilonas/farmacocinética , Femenino , Glioblastoma/sangre , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Adulto JovenRESUMEN
The purpose of this study was to assess the potential of boron neutron capture therapy (BNCT), with a 6-h infusion of the boron carrier l-boronophenylalanine as a fructose preparation (BPA-f), as first-line radiotherapy for newly diagnosed glioblastoma multiforme (GBM). Patient survival data from a Phase II study using BNCT were compared with retrospective data from the two arms of a Phase III study using conventional radiotherapy (RT) in the reference arm and using RT plus concomitant and adjuvant medication with temozolomide (TMZ) in the experimental arm, and were also compared with small subgroups of these patients for whom the methylation status of the MGMT (O(6)-methylguanine-DNA methyltransferase) DNA repair gene was known. Differences in the baseline characteristics, salvage therapy after recurrence and levels of severe adverse events were also considered. The results indicate that BNCT offers a treatment that is at least as effective as conventional RT alone. For patients with an unmethylated MGMT DNA repair gene, a possible clinical advantage of BNCT over RT/TMZ was suggested. BNCT is a single-day treatment, which is of convenience to patients, with mild side effects, which would offer an initial 6 weeks of good-quality life during the time when patients would otherwise be undergoing daily treatments with RT and TMZ. It is suggested that the use of BNCT with a 6-h infusion of BPA-f should be explored in a stratified randomised Phase II trial in which patients with the unmethylated MGMT DNA repair gene are offered BNCT in the experimental arm and RT plus TMZ in the reference arm.
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Compuestos de Boro/uso terapéutico , Terapia por Captura de Neutrón de Boro , Fructosa/análogos & derivados , Glioblastoma/radioterapia , Adulto , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Fructosa/uso terapéutico , Glioblastoma/tratamiento farmacológico , Humanos , Persona de Mediana Edad , O(6)-Metilguanina-ADN Metiltransferasa/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Temozolomida , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance. PATIENTS AND METHODS: Postmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS). RESULTS: Of 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1-15.2), 8.0 (6.2-12.4) and 10.8 (7.1-16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1-21.1), 13.2 (8.8-19.8) and 24.0 (16.9-60.9) months, respectively (p<0.001), without translation in differences in survival times. CONCLUSION: Intermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer. Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Acetato de Medroxiprogesterona/administración & dosificación , Acetato de Medroxiprogesterona/efectos adversos , Persona de Mediana Edad , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversosRESUMEN
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. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.
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Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Oligodendroglioma/tratamiento farmacológico , Adulto , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Neoplasias Encefálicas/patología , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Oligodendroglioma/patología , Temozolomida , Resultado del TratamientoRESUMEN
BACKGROUND: To determine whether the cost of prophylactic antibiotics during chemotherapy is offset by cost savings due to a decreased incidence of febrile leukopenia (FL). PATIENTS AND METHODS: Small-cell lung cancer (SCLC) patients were randomised to standard or intensified chemotherapy with granulocyte colony-stimulating factor to assess the impact on survival (n = 244). In addition, patients were randomised to prophylactic ciprofloxacin and roxithromycin or placebo to assess the impact on FL (n = 161). The economic evaluation examined the costs and effects of patients taking antibiotics versus placebo. Medical resource utilisation was documented prospectively, including 33 patients from one centre in The Netherlands (NL) and 49 patients from one centre in Germany (GE). The evaluation takes the perspective of the health insurance systems and of the hospitals. Sensitivity analyses were performed. RESULTS: In the main trial, prophylactic antibiotics reduced the incidence of FL, hospitalisation due to FL and use of therapeutic antibiotics by 50%. In GE, the incidence of FL was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros [95% confidence interval (CI) (-)1.713-2.263] in favour of prophylaxis (not significant). In NL, prophylaxis reduced the incidence of FL by nearly 50%, comparable with the results of the main trial, resulting in a cost difference of 2706 Euros [95% CI 810-5948], demonstrating savings in favour of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50%, and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will incur over a broad range of baseline risks for FL; that is, a risk >10-20% for FL per cycle. CONCLUSIONS: Giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost-savings and superior efficacy. The sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL. We recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.
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Profilaxis Antibiótica , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Leucopenia/inducido químicamente , Leucopenia/prevención & control , Neoplasias Pulmonares/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Ahorro de Costo , Análisis Costo-Beneficio , Ciclofosfamida/administración & dosificación , Método Doble Ciego , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Fiebre , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Costos de la Atención en Salud/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Humanos , Incidencia , Leucopenia/economía , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Factores de Riesgo , SobrevidaRESUMEN
BACKGROUND: Vinorelbine and cisplatin are active against squamous cell oesophageal carcinoma. The purpose of this phase II study was to evaluate the efficacy and safety of vinorelbine plus cisplatin in previously untreated patients with metastatic squamous cell oesophageal carcinoma and to estimate the progression-free survival, overall survival and quality of life (QoL) of the patient population. PATIENTS AND METHODS: Seventy-one eligible patients were entered into a study of vinorelbine 25 mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1, every 3 weeks. Degree of dysphagia relief was monitored and QoL was measured using the EORTC QLQ-C30. RESULTS: All eligible patients were assessed for response and 24 achieved a confirmed partial response (33.8%; 95% confidence interval 23-46); the median duration of response was 6.8 months, progression-free survival was 3.6 months and median survival of the whole group was 6.8 months. Toxicity was mainly related to neutropenia (grade 3/4 in 41% of patients). At cycle 2, 43% of the patients reported at least a moderate improvement in global health status/QoL and 25% experienced a large improvement. CONCLUSIONS: Vinorelbine plus cisplatin represents a well-tolerated active palliative regimen for patients with advanced squamous cell carcinoma of the oesophagus. This combination may offer a better therapeutic index than cisplatin-5-fluorouracil.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/secundario , Cisplatino/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/mortalidad , Cuidados Paliativos , Calidad de Vida , Vinblastina/análogos & derivados , Vinblastina/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidad , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Neoplasias Esofágicas/diagnóstico , Esofagectomía/métodos , Femenino , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Medición de Riesgo , Estadísticas no Paramétricas , Análisis de Supervivencia , Resultado del Tratamiento , Vinblastina/efectos adversos , VinorelbinaRESUMEN
The problem of estimating expected outcomes for the economic evaluation of treatments for which the outcome of principal interest is (quality adjusted) survival time has so far not received sufficient attention in the literature. The best estimate of expected survival is mean survival time, but with censored survival data, the true survival time for all the subjects is not known, so the mean is not defined.A possible solution to this estimation problem is illustrated by a retrospective cost-effectiveness analysis of the addition of hormonal therapy to standard radiotherapy for patients with locally advanced prostate cancer. A recently proposed method is used to approach the problem caused by censored cost data, and the impact of uncertainty is assessed by bootstrap resampling techniques. Mean survival time is estimated by a restricted means analysis with the time point of restriction determined by statistical criteria. When average total costs and mean survival time is evaluated at this time point of restriction, the result is that the combined therapy (radiotherapy plus hormonal therapy) increases mean survival time by about 1 year, while reducing the costs per patient for the French health insurance system by 12 700 FF. The time point of restriction may also be determined by other criteria and mean survival time may be estimated by extrapolating the survival curves by means of various parametric survival distributions. We show that the exact results of the economic evaluation are decisively determined by the restriction time point chosen and the approach taken to estimate mean survival time.
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Antineoplásicos Hormonales/uso terapéutico , Quimioterapia Adyuvante/economía , Goserelina/uso terapéutico , Costos de la Atención en Salud/estadística & datos numéricos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Años de Vida Ajustados por Calidad de Vida , Antineoplásicos Hormonales/economía , Análisis Costo-Beneficio , Costos de los Medicamentos/estadística & datos numéricos , Francia , Goserelina/economía , Humanos , Masculino , Modelos Estadísticos , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata/economía , Neoplasias de la Próstata/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The methodology for conducting cancer clinical trials has undergone enormous changes over the past 25-30 years since the EORTC Data Center was created. The purpose of this paper is to highlight and to provide a historical perspective for the main methodological concepts, both practical and theoretical, which form the basis for the design and analysis of phase III cancer clinical trials within the EORTC Data Center. Some statistical aspects of other associated topics such as quality of life, health economics, meta-analysis and treatment outcome will also be briefly discussed. Finally, some future perspectives and topics for further statistical methodological research will be presented in order to spur statisticians to meet the challenge of efficiently designing and analysing the clinical trials of tomorrow.
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Ensayos Clínicos Fase III como Asunto/métodos , Estadística como Asunto/métodos , Ensayos Clínicos Fase III como Asunto/tendencias , Predicción , Humanos , Metaanálisis como Asunto , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Proyectos de Investigación , Estadística como Asunto/tendenciasRESUMEN
We present a retrospective cost-effectiveness analysis using data from a randomised controlled trial (EORTC 22863) of the addition of early hormonal therapy with a luteinising hormone-releasing hormone (LHRH) analogue to radiotherapy in the treatment of patients with locally advanced prostate cancer. Data on the use of medical resources were extracted from the hospital charts of 90 patients recruited into the trial by one French hospital. Costs are assessed from the viewpoint of the French healthcare financing system and adjusted for censoring. Expected costs per patient of each treatment is related to the expected outcome, mean survival time, estimated by a restricted means analysis. The time point of restriction is determined by statistical criteria. In the base case analysis with a cut-off time point at 8.58 years, the combined therapy group (COMB) had a gain in mean survival time of 1.06 years (7.05 versus 5.99 years) and a reduction of average total costs of 12700 French francs (FF) (58300 FF versus 71000 FF). The analysis of uncertainty uses bootstrap techniques with 5000 replicates to examine the joint distribution of cost and survival outcomes. In 76% of the cases, COMB results in longer mean survival time and lower costs than the radiotherapy group (RT). In cases where COMB therapy raises costs (13% of the cases), it is rarely by more than 20000 FF per patient, no matter the size of the associated survival gain. It is thus highly likely that COMB should be considered a cost-effective option compared with RT for these patients. The exact result of the economic evaluation is decisively determined by the restriction time point selected for the determination of mean survival time, partly also because the average total costs of the two treatments develop entirely differently as a function of the survival time.