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1.
Ann Oncol ; 29(9): 1918-1925, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30016392

RESUMO

Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/patologia , Morfolinas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Critérios de Avaliação de Resposta em Tumores Sólidos , Proteínas Quinases S6 Ribossômicas/metabolismo
2.
Ann Oncol ; 26(5): 880-887, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25732040

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. METHODS: We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. RESULTS: We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. CONCLUSION: This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Mutação , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Quimioterapia Adjuvante , Quinase 4 Dependente de Ciclina/genética , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Progressão da Doença , Evolução Fatal , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Glioblastoma/enzimologia , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Mesilato de Imatinib/uso terapêutico , Gradação de Tumores , Recidiva Local de Neoplasia , Procedimentos Neurocirúrgicos , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Temozolomida , Fatores de Tempo , Resultado do Tratamento
3.
Clin Oncol (R Coll Radiol) ; 27(5): 316-23, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25662094

RESUMO

Brain metastases are common and the prognosis for patients with multiple brain metastases treated with whole brain radiotherapy is limited. As systemic disease control continues to improve, the expectations of radiotherapy for brain metastases are growing. Stereotactic radiosurgery (SRS) as a high precision localised irradiation given in a single fraction prolongs survival in patients with a single brain metastasis and functional independence in those with up to three brain metastases. SRS technology has become commonplace and is available in many radiation oncology and neurosurgery departments. With increasing use there is a need for appropriate patient selection, refinement of dose-fractionation and safe integration of SRS with other treatment modalities. We review the evidence for current practice and new developments in the field, with a specific focus on patient-relevant outcomes.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Irradiação Craniana/métodos , Radiocirurgia/métodos , Humanos , Metástase Neoplásica
5.
Vnitr Lek ; 59(12): 1049-56, 2013 Dec.
Artigo em Tcheco | MEDLINE | ID: mdl-24350936

RESUMO

INTRODUCTION: Metformin monotherapy is recommended as initial treatment of type 2 diabetes. The selection of optimal second-line therapy that is often necessary due to the progressive nature of the disease is still a subject of ongoing discussions. AIM OF THE STUDY: The aim of the international EDGE (Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) study was to prospectively compare the efficacy and safety of vildagliptin vs other oral antidiabetic agents in patients with type 2 diabetes not adequately controlled on monotherapy in a real-life clinical setting. In this paper, we present the data of patients participating in the EDGE study in the Czech Republic. MATERIAL AND METHODS: Patients with type 2 diabetes not adequately controlled on monotherapy were enrolled into the study, and randomised into either the vildagliptin arm or control arm with another OAD at the discretion of the treating physician. Patients with the addition of other incretin-based medications were not enrolled into the study. The efficiency was evaluated as a proportion of patients reaching the combined endpoint of decreasing HbA1c> 3 mmol/mol without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects during the 12 months of treatment. RESULTS: 654 patients were enrolled into the study in the Czech Republic. The mean age of the patients when enrolled into the study (vildagliptin group vs control group) was 59.5 ± 10.6 vs 63.7 ± 8.5 years, mean body mass index was 32.4 ± 5.7 vs 31.7 ± 6.5 kg/m2, mean HbA1c was 62 ± 12 vs 64 ± 11 mmol/mol. The probability of reaching the combined primary endpoint (calculated using a binary logistic regression model to calculate the odds ratios with 95% confidence intervals) was higher for vildagliptin regardless of baseline HbA1c or type of medication added in the control group. Primary endpoint was reached by 60.6 % of patients in the vildagliptin group vs 51.3 % of patients in the control group, odds ratio 1.46 (1.06, 1.99); p< 0.019. The proportion of patients reaching secondary endpoint (HbA1c< 54 mmol/mol without hypoglycemic event or weight gain 3 % with baseline glycated hemoglobin > 54 mmol/mol was higher for vildagliptin 45.7 % vs 31.4 % in the control arm, odds ratio 1.84 (1.26, 2.68), p< 0.001. The rate of adverse events was comparable in both groups. CONCLUSION: In a real-life clinical set-ting, the percentage of patients reaching the combined endpoint of decreasing HbA1c> 3 mmol/mol, without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects was higher after the addition of vildagliptin as compared to other antidiabetic agents with comparable rate of side effects.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Adulto , Idoso , Estudos de Coortes , República Tcheca , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Incretinas , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Estudos Prospectivos , Pirrolidinas/efeitos adversos , Vildagliptina , Aumento de Peso
6.
Clin Oncol (R Coll Radiol) ; 25(1): 66-73, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22795232

RESUMO

AIMS: To compare the accuracy of fractionated cranial radiotherapy in a standard three-point thermoplastic shell using daily online correction with accuracy in a Gill-Thomas-Cosman relocatable stereotactic frame. MATERIALS AND METHODS: All patients undergoing fractionated radiotherapy for benign intracranial tumours between March 2009 and August 2010 were included. Patients were immobilised in the frame with those unable to tolerate it immobilised in the shell. The ExacTrac imaging system was used for verification/correction. Daily online imaging before and after correction was carried out for shell patients and systematic and random population set-up errors calculated. These were compared with frame patients who underwent standard departmental imaging/correction with fractions 1-3 and weekly thereafter. Set-up margins were calculated from population errors. RESULTS: Systematic and random errors were 0.3-0.7 mm/° before correction and 0.1-0.2 mm/° after correction in all axes in the frame, and 0.6-1.5 mm/° before correction and 0.1-0.4 mm/° after correction in the shell. Isotropic margins required for patient set-up could be reduced from 2 mm to <1 mm in the frame and from 5 mm to <1 mm in the shell. CONCLUSION: Similar set-up accuracy can be achieved in the standard thermoplastic shell as in a relocatable frame despite less precise immobilisation. The use of daily online correction precludes the need for larger set-up margins.


Assuntos
Neoplasias Encefálicas/cirurgia , Radiocirurgia , Adulto , Idoso , Fracionamento da Dose de Radiação , Feminino , Humanos , Imobilização , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Clin Oncol (R Coll Radiol) ; 24(8): e106-12, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22626521

RESUMO

AIMS: To assess visual outcome, tumour control and treatment-related morbidity in patients with optic nerve sheath meningiomas (ONSMs) treated with fractionated stereotactic radiotherapy (FSRT). PATIENTS AND METHODS: A retrospective analysis of 45 patients (13 men and 32 women, median age 46 years) with ONSMs (51 optic nerves involved) treated in a single institution between 1997 and 2010 was carried out. FSRT was delivered to a dose of 50 Gy in 30 or 33 fractions as primary treatment in 39 patients and after surgery in six patients. RESULTS: At a median follow-up of 30 months (range 1-13 years), the tumour control in 41 evaluable patients (four were lost to follow-up) was 100% at 5 years with no subsequent local or distant recurrence. Of the 46 evaluable optic nerves treated, 41 had residual vision (38 with impaired vision) before radiotherapy and five were blind in one eye. There was no recovery of vision in any of the blind eyes. Of 41 optic nerves with residual vision, 13 had improvement, 24 remained stable and four deteriorated; two patients (4%) developed radiation retinopathy. One patient developed a central retinal artery occlusion in the untreated eye 10 years after treatment. CONCLUSION: FSRT is highly effective at controlling the growth of ONSMs with improvement or stabilisation of visual deficit in 89% of the optic nerves retaining some vision, albeit with a small risk of radiation-induced retinopathy. The results support the use of FSRT as an effective approach in the management of ONSM. The lack of functional benefit in patients with severe visual impairment would argue for earlier institution of treatment before complete visual loss is established.


Assuntos
Meningioma/radioterapia , Neoplasias do Nervo Óptico/radioterapia , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Meningioma/cirurgia , Pessoa de Meia-Idade , Neoplasias do Nervo Óptico/cirurgia , Radioterapia Conformacional/métodos , Estudos Retrospectivos , Técnicas Estereotáxicas , Análise de Sobrevida , Resultado do Tratamento
8.
Br J Radiol ; 85(1010): 168-75, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21828146

RESUMO

OBJECTIVES: The aim of this article was to test a simple approach of using pixel density values from fluoroscopy images to enable gated radiotherapy. METHODS: Anterior and lateral (LAT) from images were acquired from 18 patients referred for radical radiotherapy for non-small cell lung cancer for a period of 30-45 s. The amplitude of movement and the number of breathing cycles were determined in the right-left (RL) and superoinferior (SI) directions on the anterior images and the anteroposterior (AP) and SI directions on the lateral images. The breathing pattern was created by analysing the variation in a summation of pixel values within a defined area. The greatest and lowest 30% of pixel values were set as the duty cycle to represent inhale and exhale amplitude-based gating. RESULTS: A median of eight breathing cycles was captured for each patient with a duration of 2.2-11.8 s per cycle. The mean (range) motion was 4.7 mm (2.4-5.8 mm), 7.2 mm (2.3-17.6 mm), 6.2 mm (1.9-13.8 mm) and 4.8 mm (2.4-11.3 mm) in the RL, SI (AP), SI (LAT) and AP directions, respectively. A total of 10/14 anterior videos and 7/11 LAT videos had correlations between motion and breathing of >0.6. Margins of 5.5 mm, 6.8 mm and 6.6 mm in the RL, SI and AP directions, respectively, were determined to gate in exhale. The benefit of gating was greater when motion was >5 mm. CONCLUSION: The simple approach of using pixel density values from fluoroscopy images to distinguish inhale from exhale and enable gating was successfully applied in all patients. This technique may potentially provide an accurate surrogate for tumour position.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Planejamento da Radioterapia Assistida por Computador/métodos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Expiração/fisiologia , Fluoroscopia , Humanos , Inalação/fisiologia , Neoplasias Pulmonares/radioterapia , Movimento , Fatores de Tempo
9.
Clin Oncol (R Coll Radiol) ; 24(1): 68-75, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21396808

RESUMO

AIMS: The potential advantages of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC) over conventional fractionated radiotherapy include a higher biological effective dose, a reduction in accelerated repopulation, greater patient convenience and reduced demand on radiotherapy resources. Before introducing SBRT in our department, a review of planning and delivery was undertaken, starting with an assessment of optimum beam number and arrangement. MATERIALS AND METHODS: Radiotherapy planning computed tomography scans for five patients previously treated for T1 peripheral NSCLC were selected. In each the contoured tumour had planning target volume (PTV) margins of 1cm in all directions. Forward-planned three-field coplanar and non-coplanar plans and a seven-field coplanar plan were produced and optimised. In-house inverse-planning software (AutoBeam) was used to generate three-, five-, seven- and nine-field coplanar and non-coplanar plans and two volumetric intensity-modulated arc therapy (VMAT) plans. The resulting V(20), V(11), PTV(90), PTV(95) and mean lung dose were compared. RESULTS: Analysis of variance showed non-coplanar plans to have lower V(11) and higher PTV(90) and PTV(95) than coplanar plans. VMAT showed equivalent V(20) and target coverage when compared with the best non-coplanar plans, but with a faster delivery time (2min 8s versus 12min 40s). CONCLUSIONS: Inverse-planned five-field non-coplanar plans and VMAT improve target coverage while minimising the higher dose to normal lung tissue for SBRT of NSCLC compared with coplanar beam arrangements. VMAT is preferable because of significantly shorter treatment delivery times.


Assuntos
Neoplasias Pulmonares/radioterapia , Doses de Radiação , Radiocirurgia , Radioterapia de Intensidade Modulada , Carcinoma Pulmonar de Células não Pequenas , Humanos , Planejamento da Radioterapia Assistida por Computador
11.
Rev Endocr Metab Disord ; 10(2): 135-44, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18787957

RESUMO

Radiotherapy (RT) remains an effective treatment for residual or recurrent pituitary adenomas with excellent rates of tumour control and normalisation of excess hormone secretion. The main late toxicity is hypopituitarism: other side effects are rare. We discuss technical developments in the delivery of radiotherapy (stereotactic conformal radiotherapy (SCRT) and stereotactic radiosurgery (SRS)), all aiming to reduce the amount of normal brain receiving significant doses of radiation. We provide a comprehensive review of published data on outcome of conventional fractionated radiotherapy and modern RT techniques. SCRT is a suitable treatment technique for all sizes of pituitary adenoma and efficacy is comparable to conventional RT; the lack of long term follow up means that currently there is no information on potential reduction in the incidence of late radiation induced toxicity. Single fraction SRS can only be safely delivered to small tumours away from critical structures. There is no evidence that it produces faster decline of elevated hormone levels than fractionated treatment and is not associated with lesser morbidity.


Assuntos
Neoplasias Hipofisárias/radioterapia , Radioterapia/métodos , Humanos , Radiocirurgia/métodos , Radioterapia Conformacional/métodos
12.
Clin Oncol (R Coll Radiol) ; 20(9): 666-76, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18676130

RESUMO

A review of the technical aspects of high-dose hypofractionated radiotherapy for localised non-small cell lung cancer was carried out to allow correlation with outcome measures and with a consensus view of the technique. A Pubmed search carried out between January 2001 and April 2007 identified 15 studies for inclusion. The clinical and technical aspects of treatment were extracted and their effect on survival, progression-free survival and toxicity were assessed using the summary statistic of weighted means. A comparison was made with the RTOG 0236 consensus study protocol. The range of variables in the studies precluded correlation of outcome with tumour parameters, dose fractionation and technical aspects such as immobilisation, techniques dealing with breathing motion, beam number and arrangement and organ at risk dose constraints. Robust data to justify a consensus view were not found, which suggests that further studies are required. They should focus on developing the treatment technique of stereotactic body radiation therapy for early-stage non-small cell lung cancer and correlating it with outcome to provide a rational basis for future randomised trials, comparing the technique with conformal radiotherapy and surgery, and the introduction of the technique into routine clinical practice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Fracionamento da Dose de Radiação , Neoplasias Pulmonares/radioterapia , Radiocirurgia/estatística & dados numéricos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Relação Dose-Resposta à Radiação , Humanos , Neoplasias Pulmonares/mortalidade , Radiocirurgia/métodos , Análise de Sobrevida
13.
Ann Oncol ; 17 Suppl 10: x183-5, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17018720
14.
Br J Neurosurg ; 20(4): 195-202, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16954068

RESUMO

Radiosurgery is increasingly employed in the treatment of acoustic neuroma, but the optimal dose in terms of long-term tumour control and minimal adverse effects has not been established. We performed a systematic review of the published literature of radiosurgery of acoustic neuroma to assess whether the use of low dose radiosurgery is as effective as high dose treatment. Reports of radiosurgery for acoustic neuroma were identified through a Medline search. Studies with at least 15 patients and a median follow-up longer than 12 months were included. The relationship between actuarial 5-year progression-free survival (PFS), and tumour and treatment parameters was examined. Forty-two studies were included. Tumour control following lower radiosurgery doses was similar to that reported following high doses. Only 12 studies reported actuarial outcomes at 5 years. There was no relationship between PFS at 5 years and dose to the tumour margin. Radiosurgery of larger tumours was associated with lower 5 year PFS (p < 0.05). Although on initial inspection radiosurgery of acoustic neuroma with doses of 12 - 13 Gy seems to be as effective as higher dose treatment, the available reports are subject to a number of confounding factors, are not sufficiently statistically powered and there is only limited long-term actuarial outcome data. Currently, available studies do not provide sufficient confidence to support the claim that low dose radiosurgery is equally effective as higher doses in the long-term control of acoustic neuroma.


Assuntos
Neuroma Acústico/cirurgia , Radiocirurgia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Dosagem Radioterapêutica/normas , Resultado do Tratamento
15.
Clin Endocrinol (Oxf) ; 64(5): 542-8, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16649974

RESUMO

OBJECTIVE: To assess the medium-term outcome in a cohort of patients with residual or recurrent pituitary adenoma treated with fractionated stereotactic conformal radiotherapy (SCRT). PATIENTS AND METHODS: Ninety-two patients (median age 50 years) with a residual or recurrent nonfunctioning (67) or a secreting (25) pituitary adenoma were treated between 1995 and 2003. Eighteen patients had a GH-secreting, five PRL-secreting and two an ACTH-secreting pituitary adenoma. Vision was impaired in 39 patients, with visual field deficit (35) and/or reduced visual acuity (25). Sixty-four patients had partial or complete hypopituitarism before SCRT. The treatment was delivered stereotactically by four noncoplanar conformal fixed fields using a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions. RESULTS: At a median follow-up of 32 months (range 4-108) the 1, 3 and 5 years actuarial progression-free survival is 99%, 98% and 98%, and overall survival is 98%. Three patients recurred 5 months, 1 year and 9 years after SCRT requiring surgery. In secreting adenomas, hormone levels declined progressively, becoming normal in more than a third of patients with GH-secreting and PRL-secreting pituitary tumours. 50% of baseline GH level was achieved in just under 2 years. The treatment was well tolerated with minimal acute toxicity. Hypopituitarism was the most common long-term effect; 22% of patients had worsening of pituitary function. One patient developed unilateral quadrantopia without tumour progression. CONCLUSION: SCRT as a high-precision technique of localized irradiation achieves tumour and hormone control of pituitary adenomas comparable with previously published data on the efficacy of conventional radiotherapy. Despite the potential advantage of reducing the volume of normal brain irradiated, the theoretical benefit over conventional radiotherapy in terms of the reduction in long-term morbidity has not yet been demonstrated and requires longer follow-up. Potential effect on long-term cognitive function has not been tested.


Assuntos
Adenoma/radioterapia , Neoplasias Hipofisárias/radioterapia , Radioterapia Conformacional/métodos , Adenoma/metabolismo , Adenoma/patologia , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Idoso , Estudos de Coortes , Feminino , Hormônio do Crescimento/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Neoplasia Residual/patologia , Neoplasia Residual/radioterapia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Prolactinoma/metabolismo , Prolactinoma/radioterapia , Dosagem Radioterapêutica , Estatísticas não Paramétricas , Resultado do Tratamento
16.
Ann Oncol ; 16(6): 942-9, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15870090

RESUMO

BACKGROUND: The aim of this study was to assess the efficacy of new agents in patients with malignant glioma in a neoadjuvant setting not confounded by surgery. The first study of neoadjuvant temozolomide aimed to provide a benchmark for future evaluation of new treatments. PATIENTS AND METHODS: This was a multicentre phase II study of chemotherapy in patients with histologically verified glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) who had undergone biopsy alone. Patients were planned to receive two cycles of temozolomide at 200 mg/m(2) orally daily for 5 days at a 28-day interval prior to radiotherapy. Response was assessed by two central observers on pre- and post-chemotherapy enhanced scans using bi-dimensional criteria and as progression-free survival (PFS) at the time of second assessment prior to radiotherapy. Withdrawal from the study due to worsening clinical condition was, in the absence of second imaging, assessed as progressive disease. Survival and quality of life (QOL) were secondary endpoints. RESULTS: Between August 1999 and June 2002, 188 patients from 15 UK and two Italian centres were entered into the study and 187 were analysed. Overall, 162 patients were assessable for response; seven had partial and 25 had minimal response. The objective response rate was 20% [95% confidence interval (CI) 14-26%] and PFS prior to commencing radiotherapy was 64% (95% CI 57-72%). The median survival was 10 months, and 1-year survival 41%. The median survival of responders was 16 months compared to 3 months in patients with progressive disease (P <0.001 on multivariate analysis). CONCLUSION: The phase II study design of primary chemotherapy in patients with malignant glioma following biopsy alone is feasible and provides as objective a method of assessment of efficacy as is currently available. The baseline data on temozolomide provide a benchmark for assessment of efficacy of other agents and combinations.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Adulto , Idoso , Estudos de Coortes , Dacarbazina/uso terapêutico , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Terapia Neoadjuvante , Temozolomida
17.
J Clin Endocrinol Metab ; 90(2): 800-4, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15562021

RESUMO

We assessed the risk of second brain tumors in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Four hundred and twenty-six patients (United Kingdom residents) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. They were followed up for 5749 person-years. The cumulative incidence of second intracranial tumors and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and the National Health Service Central Register (previously OPCS) to record death and the potential causes. Eleven patients developed a second brain tumor, including five meningiomas, four high grade astrocytomas, one meningeal sarcoma, and one primitive neuroectodermal tumor. The cumulative risk of second brain tumors was 2.0% [95% confidence interval (CI), 0.9-4.4%] at 10 yr and 2.4% (95% CI, 1.2-5.0%) at 20 yr, measured from the date of radiotherapy. The relative risk of second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3-16.7). The relative risk was 7.0 for neuroepithelial and 24.3 for meningeal tumors. The relative risks were 24.2 (95% CI, 4.8-43.5), 2.9 (95% CI, 0-8.5), and 28.6 (95% CI, 0.6-56.6) during the intervals 5-9, 10-19, and more than 20 yr after radiotherapy (four cases occurred >20 yr after treatment). There was no evidence of excess risk of second systemic malignancy. An additional 10-yr update confirmed our previous report of an increased risk of second brain tumors in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 yr remains low and should not preclude the use of radiotherapy as an effective treatment option. However, an increased risk of second brain tumors continues beyond 20 and 30 yr after treatment.


Assuntos
Adenoma/radioterapia , Neoplasias Encefálicas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Neoplasias Hipofisárias/radioterapia , Adulto , Terapia Combinada , Feminino , Seguimentos , Hormônio do Crescimento Humano/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
19.
Br J Cancer ; 90(4): 781-6, 2004 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-14970853

RESUMO

Assessment of low-grade glioma treatment response remains as much of a challenge as the treatment itself. Proton magnetic resonance spectroscopy ((1)H-MRS) and imaging were incorporated into a study of patients receiving temozolomide therapy for low-grade glioma in order to evaluate and monitor tumour metabolite and volume changes during treatment. Patients (n=12) received oral temozolomide (200 mg m(-2) day(-1)) over 5 days on a 28-day cycle for 12 cycles. Response assessment included baseline and three-monthly magnetic resonance imaging studies (pretreatment, 3, 6, 9 and 12 months) assessing the tumour size. Short (TE (echo time)=20 ms) and long (TE=135 ms) echo time single voxel spectroscopy was performed in parallel to determine metabolite profiles. The mean tumour volume change at the end of treatment was -33% (s.d.=20). The dominant metabolite in long echo time spectra was choline. At 12 months, a significant reduction in the mean choline signal was observed compared with the pretreatment (P=0.035) and 3-month scan (P=0.021). The reduction in the tumour choline/water signal paralleled tumour volume change and may reflect the therapeutic effect of temozolomide.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Glioma/tratamento farmacológico , Glioma/metabolismo , Espectroscopia de Ressonância Magnética , Administração Oral , Adulto , Antineoplásicos Alquilantes/administração & dosagem , Colina/metabolismo , Dacarbazina/administração & dosagem , Feminino , Humanos , Masculino , Temozolomida , Resultado do Tratamento , Água/análise
20.
Ann Oncol ; 14(12): 1715-21, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14630674

RESUMO

BACKGROUND: The aim of this study was to assess the efficacy of temozolomide in patients with World Health Organisation (WHO) grade II gliomas treated with surgery alone using imaging and clinical criteria. PATIENTS AND METHODS: Thirty patients with histologically verified WHO grade II gliomas (17 astrocytoma, 11 oligodendroglioma, two mixed oligoastrocytoma) following surgery 2-104 months (median 23 months) after initial diagnosis received temozolomide 200 mg/m(2)/day for 5 days, on a 28-day cycle, for a maximum of 12 cycles or until tumour progression. Median age was 40 years (range 25-68 years). Median follow-up from entry into the study was 3 years [range 23-47 months (for patients alive)]. Objective response was assessed by 3-monthly magnetic resonance imaging and monthly health-related quality of life (HQoL) and clinical assessment. Tumour size was measured as the high signal intensity area on fluid attenuated inversion recovery sequences. Responses were assessed using change in the product of two perpendicular diameters as complete response (CR), partial response (PR), minimal response (MR), stable disease (SD) and progressive disease (PD). RESULTS: Twenty-nine of 30 patients entered into the study were evaluable for response. Three patients had a PR, 14 MR, 11 SD and one PD. Twenty-four patients received 12 cycles of chemotherapy. Of 29 evaluable patients, three discontinued after four, five and six cycles and two after 10 cycles. Nine patients progressed (three during chemotherapy-one PD and two initial SD-and six after completion of chemotherapy); five had evidence of transformation. The 3-year progression-free survival was 66%. Five patients died; the actuarial 3-year survival was 82%. Ninety-six per cent of patients with impaired HQoL had improvement in at least one HQoL domain. There was improvement in 115 of the 207 domains (56%). Fifteen of 28 patients (54%) with epilepsy had reduction in seizure frequency, of whom six became seizure free. Six patients had transient grade III/IV haematological toxicity (11 episodes; 3.5%). CONCLUSIONS: Temozolomide has single-agent activity in patients with WHO grade II cerebral glioma, with modest improvement in quality of life and improvement in epilepsy control. On present evidence, temozolomide cannot be considered as primary therapy without formal comparison with other treatment modalities.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Glioma/tratamento farmacológico , Administração Oral , Adulto , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Dacarbazina/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Feminino , Glioma/patologia , Glioma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/etiologia , Convulsões/prevenção & controle , Temozolomida , Resultado do Tratamento
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