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M Brada

Publications and source records attributed to M Brada.

At least 19 recordsLinked to original sources
PubMed2006

Optimal dose of stereotactic radiosurgery for acoustic neuromas: A systematic review.

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.

Adolescent↗
PubMed2006

Fractionated stereotactic conformal radiotherapy for secreting and nonsecreting pituitary adenomas.

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.

Adenoma↗
PubMed2005

Neoadjuvant phase II multicentre study of new agents in patients with malignant glioma after minimal surgery. Report of a cohort of 187 patients treated with temozolomide.

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.

Adult↗
PubMed2004

Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years.

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.

Adenoma↗
PubMed2004

Monitoring temozolomide treatment of low-grade glioma with proton magnetic resonance spectroscopy.

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.

Administration, Oral↗
PubMed2003

Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas.

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.

Administration, Oral↗
PubMed2003

Could assessment of glioma methylene lipid resonance by in vivo (1)H-MRS be of clinical value?

The potential clinical role of in vivo (1)H-MRS ((1)H-magnetic resonance spectroscopy) lipid methylene resonance measurements of human glioma has been assessed. 20 patients, 14 with low grade and 6 with high grade gliomas have been investigated using single voxel (1)H-MRS. Three of the low grade group had undergone transformation by clinical and imaging criteria. Short echo time (TE=20 ms, TR=2500 ms) single voxel Stimulated Echo Acquisition (STEAM) spectra with (acquisitions=64) and without (acquisitions=4) water suppression were acquired. Additionally, T(1) weighted (T(1)W) water spectra (TE=20 ms, TR=888 ms) were acquired pre- and post-injection of Gd-DTPA (0.2 mmol x kg(-1)). The T(1)W water spectra were used to determine the water proton enhancement occurring within the spectroscopic voxel. The enhancement expressed as a percentage was compared with the lipid methylene peak. All the high grade tumours had significantly higher levels of lipid than low grade tumours (p=0.002). Low grade tumours had significantly less water proton enhancement than transformers (p=0.04) and high grade tumours (p=0.001). The lipid methylene signal correlated strongly with the voxel water enhancement (r(2)=0.74, p<0.0001). The data support the view that the spectroscopically detected lipid methylene signal may be a useful criterion in grading glioma. The correlation of the lipid methylene signal with blood-brain barrier breakdown suggests that detection of a previously absent (1)H-MRS lipid methylene signal in low grade tumours might be an early indicator of transformation.

Biomarkers, Tumor↗
PubMed2002

Temozolomide as second-line chemotherapy for relapsed gliomas.

BACKGROUND: Temozolomide, an imidazotetrazine prodrug has shown activity in phase II studies in patients with high-grade glioma at first recurrence. We assessed the efficacy of temozolomide as second-line therapy following failure of PCV chemotherapy in patients with recurrent/progressive gliomas. PATIENTS AND METHODS: Between September 1994 and November 2000, 32 patients with high-grade gliomas at second recurrence/progression received temozolomide as salvage therapy and results were reviewed retrospectively. RESULTS: Of 32 assessable patients 7 had clinical improvement; there were no imaging responses. Median survival of the cohort was 4 months, with 28% alive at 6 months. Age, performance status, histology and previous response to PCV chemotherapy did not predict for clinical response to temozolomide. CONCLUSION: In the small cohort of patients with recurrent malignant glioma who failed PCV chemotherapy temozolomide demonstrated limited activity as second-line treatment although this remains within the confidence intervals of response seen in patients with glioblastoma.

Adult↗
PubMed2002

Cerebrovascular mortality in patients with pituitary adenoma.

OBJECTIVE: To assess cerebrovascular mortality in a UK cohort of patients with pituitary adenoma known to have increased incidence of cerebrovascular accidents (CVA). METHODS: A total of 334 patients treated at the Royal Marsden Hospital (RMH) between 1962 and 1986 with surgery and postoperative radiotherapy were followed up via the NHS Central Register (NHSCR) to identify deaths and emigrations. The causes of death were assessed by NHSCR-based death certificates and coded according to the 9th revision of ICD. Follow-up was censored at age 85, on emigration or cancellation of NHSCR. Thirteen patients could not be traced. A total of 4982 person-years was accumulated in the cohort. Expected numbers of deaths were computed from the national age-, sex- and period-specific mortality rates for England and Wales. RESULTS: In the pituitary adenoma cohort, 128 deaths were observed compared to 80.9 expected [relative risk (RR) of death 1.58 (95% CI: 1.32-1.90)]. There were 33 cerebrovascular deaths compared with 8.04 expected (RR 4.11, 95% CI 2.84-5.75). Three deaths were from subarachnoid haemorrhage compared to 0.54 expected (RR 5.51, 95% CI 1.14-16.09). There was an increased cerebrovascular mortality in women (RR 6.93, 95% CI 4.29-10.60) compared to men (RR 2.4, 95% CI 1.24-4.20; P = 0.002) and in patients having debulking surgery (RR 5.19, 95% CI 3.50-7.42) compared to biopsy/no surgery (RR 1.33, 95% CI 0.27-3.88; P = 0.02). The RR in patients with nonsecretory tumours was 3.65 (95% CI 2.26-5.58), compared with 5.23 (95% CI 2.25-10.30) in secretory tumours (P = 0.4). The effect of age at radiotherapy was not significant (P = 0.4). CONCLUSION: Patients with pituitary adenoma treated with surgery and radiotherapy have an increased risk of cerebrovascular mortality compared to the general population, which mirrors the increased incidence of CVA. The possible risk factors include hypopituitarism, radiotherapy and extent of surgery but none are at present proven causes. The evaluation of new treatment strategies should not only assess intermediate end-points of tumour and endocrine control but should concentrate on long-term survival with particular emphasis on CVA incidence and mortality.

Adenoma↗
PubMed2002

High precision focused irradiation in the form of fractionated stereotactic conformal radiotherapy (SCRT) for benign meningiomas predominantly in the skull base location.

OBJECTIVE: To present early clinical results of stereotactic conformal radiotherapy (SCRT) in patients with benign predominantly skull base meningiomas. MATERIAL AND METHODS: Between August 1994 and August 1999, 41 patients with benign residual or recurrent meningiomas were treated with SCRT. Thirty-three were histologically verified. All patients were immobilized in a GTC stereotactic relocatable frame, and underwent a post-contrast CT localization scan with additional MRI for fusion in 15 patients. Treatment was delivered on a 6 MV linear accelerator using three (12 patients), or 4 (29 patients) non-coplanar conformal fixed fields to doses of 50-55 Gy in 30-33 daily fractions. Tumours were relatively large with a median gross tumour volume (GTV) of 17.9 cm3 (range 2.5-183 cm3). RESULTS: At a median follow-up of 21 months (range 6-62 months) none of 41 patients have recurred. The current imaging tumour control rate is 100% at 1 and 3 years. The actuarial survival at 2 years is 100% and 91% at 3 and 5 years. Following SCRT tumour decreased in size in 9 patients. SCRT was well tolerated. Five patients had improvement in vision, and six patients improvement in cranial nerve function. Two patients whose planning target volume (PTV) included the sella developed hypopituitarism during and at 18 months after SCRT. One patient with pre-existing hydrocephalus due to pineal region meningioma developed cognitive impairment 7 months after treatment. One patient with involvement of the optic nerve had visual deterioration at 18 months. CONCLUSIONS: SCRT is a feasible high precision irradiation technique for residual and recurrent skull base meningiomas including both small and larger tumours with excellent early tumour control and low toxicity. Longer follow-up is necessary to demonstrate sustained tumour control and low morbidity of such high precision localized method of fractionated irradiation.

Adult↗
PubMed2001

Design and implementation of a system for treating paediatric patients with stereotactically-guided conformal radiotherapy.

BACKGROUND AND PURPOSE: Stereotactically-guided conformal radiotherapy (SCRT) allows the delivery of highly conformal dose distributions to localised brain tumours. This is of particular importance for children, whose often excellent long-term prognosis should be accompanied by low toxicity. The commercial immobilisation system in use at our hospital for adults was felt to be too heavy for children, and precluded the use of anaesthesia, which is sometimes required for paediatric patients. This paper therefore describes the design and implementation of a system for treating children with SCRT. This system needed to be well tolerated by patients, with good access for treating typical childhood malignancies. MATERIALS AND METHODS: A lightweight frame was developed for immobilisation, with a shell-based alternative for patients requiring general anaesthetic. Procedures were set up to introduce the patients to the frame system in order to maximise patient co-operation and comfort. Film measurements were made to assess the impact of the frame on transmission and surface dose. The reproducibility of the systems was assessed using electronic portal images. RESULTS: Both frame and shell systems are in clinical use. The frame weighs 0.6 kg and is well tolerated. It has a transmission of 92-96%, and fields which pass through it deliver surface doses of 58-82% of the dose at d(max), compared to 18% when no frame is present. However, the frame is constructed to maximise the availability of unobstructed beam directions. Reproducibility measurements for the frame showed a mean random error of 1.0+/-0.2mm in two dimensions (2D) and 1.4+/-0.7 mm in 3D. The mean systematic error in 3D was 2.2mm, and 90% of all overall 3D errors were less than 3.4mm. For the shell system, the mean 2D random error was 1.5+/-0.2mm. CONCLUSIONS: Two well-tolerated immobilisation devices have been developed for fractionated SCRT treatment of paediatric patients. A lightweight frame system gives a wide range of possible unobstructed beam directions, although beams that intersect the frame are not precluded, provided that output corrections are applied. A shell system allows the use of general anaesthesia. Both systems give reproducible immobilisation to complement the high-precision treatment delivery.

Brain Neoplasms↗
PubMed2001

Thalidomide as an anti-angiogenic agent in relapsed gliomas.

BACKGROUND: Thalidomide (alpha-phthalimidoglutarimide), a synthetic sedative drug, has anti-angiogenic properties due to inhibition of growth-factor mediated neovascularisation and has been shown to inhibit tumour growth in experimental solid tumour models. AIM: To assess response of recurrent malignant gliomas to thalidomide. METHODS: Eighteen patients with recurrent gliomas were enrolled to an open, non-randomised phase II trial between October 1997 and December 1999. All patients had failed following treatment with radiotherapy and chemotherapy with PCV and/or temozolomide regimens. Eleven patients had high-grade gliomas de novo and 7 high-grade gliomas following transformation of low-grade gliomas. Thalidomide was prescribed at 100 mg/day p.o. continuously. Response was assessed at 4-weekly intervals. Disease progression was defined as neurological deterioration and/or radiological evidence of increased tumour size. Treatment was discontinued at the time of disease progression, or if toxicity occurred, or at patients' request. RESULTS: Thalidomide was prescribed for a median of 42 days (range 7-244). Treatment was discontinued due to toxicity (peripheral sensory neuropathy) in 1 patient. Six patients died before response could be fully assessed and are classified as non-responders. Of 12 who continued treatment for more than 4 weeks, 1 patient had clinical and radiological response (PR), 2 patients had stable disease for 2 and 4 months respectively and 9 patients had disease progression. The median survival from the start of thalidomide was 2.5 months. CONCLUSION: The efficacy of thalidomide in terms of response in recurrent gliomas is low, with a partial response rate of only 6%. Future studies should investigate thalidomide in combination with other agents and at an earlier stage of disease. Methods to assess anti-angiogenic properties such as changes in tumour vasculature could be employed as initial surrogate end-points in the investigation of efficacy.

Adult↗
PubMed2001

Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse.

BACKGROUND: Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. PATIENTS AND METHODS: We report an open-label, uncontrolled, multicenter phase II trial of temozolomide in 138 patients (intent-to-treat [ITT] population) with glioblastoma multiforme at first relapse and a Karnofsky performance status (KPS) > or = 70. One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma (GS) by independent central review. Chemotherapy-naïve patients were treated with temozolomide 200 mg/m2/day orally for the first five days of a 28-day cycle. Patients previously treated with nitrosourea-containing adjuvant chemotherapy received 150 mg/m2/day for the first five days of a 28-day cycle. In the absence of grade 3 or 4 toxicity, patients on the 150 mg/m2 dose schedule were eligible for a 200 mg/m2 dose on the next cycle. RESULTS: The primary endpoint was six-month progression-free survival assessed with strict radiological and clinical criteria. Secondary endpoints included radiological response and Health-related Quality of Life (HQL). Progression-free survival at six months was 18% (95% confidence interval (CI): 11%-26%) for the eligible-histology population. Median progression-free survival and median overall survival were 2.1 months and 5.4 months, respectively. The six-month survival rate was 46%. The objective response rate (complete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for both the ITT and eligible-histology populations, with an additional 43% and 45% of patients, respectively, having stable disease (SD). Objectively assessed response and maintenance of a progression-free status were both associated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of therapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. CONCLUSIONS: Temozolomide demonstrated modest clinical efficacy, with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agents.

Adult↗
PubMed2001

Stereotactic radiotherapy for solitary brain metastases.

PURPOSE: Surgery is considered to be the treatment of choice for patients with solitary brain metastases. We report a single-centre experience of stereotactic radiotherapy (SRT)/radiosurgery as an alternative to surgery and define prognostic parameters that provide for a more rational selection of patients for appropriate treatment. PATIENTS AND METHODS: Between 1990 and 1997, 96 patients with 106 brain metastases received SRT to a dose of 20 Gy in two fractions (range 20-30 Gy in 24 fractions) either alone or in combination with whole brain radiotherapy. RESULTS: After SRT, 51% of patients had improvement in neurological function. The median survival of the 96 patients was 9 months. The Radiation Therapy Oncology Group prognostic grouping for patients with multiple brain metastases (prognostic factors: age, performance status, systemic metastases, status of primary tumour) was applicable to this cohort, with median survivals of 15, 8 and 2 months for favourable, intermediate and poor prognostic groups respectively. CONCLUSION: SRT is a non-invasive method of treatment of solitary brain metastases and the outcome is comparable with the results obtained after surgical excision. Prognosis is determined by factors defined for patients with multiple brain metastases, with performance status being the most important. SRT/radiosurgery should be reserved for patients with favourable prognostic factors, with a Karnofsky performance status >70, who have a reasonable chance of good quality prolonged survival. In future trials, radiosurgery should be compared in terms of survival, quality of life and health economics to whole brain radiotherapy and surgery.

Adult↗