How to improve effects of radiation and control its toxicity.
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Humans↗
Biomedical subjects
A Gregor
Publications and source records attributed to A Gregor.
Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer.
PURPOSE: The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non-small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients were randomized to receive either cisplatin (100 mg/m(2) intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m(2) intravenously on day 1) plus gemcitabine (1,000 mg/m(2) administered intravenously on days 1, 8, and 15 of a 28-day cycle). RESULTS: From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25. 4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P <.0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P =.0013), and overall survival (9.1 months compared with 7.6 months, respectively; P =.004). CONCLUSIONS: For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.
Adult↗
Randomized trial of surgery versus radiotherapy in patients with stage IIIA (N2) non small-cell lung cancer after a response to induction chemotherapy. EORTC 08941.
Combined modality treatment of patients with stage III non small-cell lung cancer (NSCLC) has recently become widely accepted. Standard combinations are neoadjuvant chemotherapy followed by radiotherapy or concurrent chemotherapy and radiotherapy. The effect of combined modality treatment on survival is dependent on both the efficacy of chemotherapy to eradicate micrometastases and optimal local control. The European Organization for Research and Treatment of Cancer (EORTC) Lung Cancer Cooperative Group has chosen to investigate in a comparative way the side effects and the effect on survival of radiotherapy versus surgery in stage IIIA (N2) NSCLC.
Journal Article↗
Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group.
BACKGROUND: Prophylactic cranial irradiation reduces the incidence of brain metastasis in patients with small-cell lung cancer. Whether this treatment, when given to patients in complete remission, improves survival is not known. We performed a meta-analysis to determine whether prophylactic cranial irradiation prolongs survival. METHODS: We analyzed individual data on 987 patients with small-cell lung cancer in complete remission who took part in seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation. The main end point was survival. RESULTS: The relative risk of death in the treatment group as compared with the control group was 0.84 (95 percent confidence interval, 0.73 to 0.97; P= 0.01), which corresponds to a 5.4 percent increase in the rate of survival at three years (15.3 percent in the control group vs. 20.7 percent in the treatment group). Prophylactic cranial irradiation also increased the rate of disease-free survival (relative risk of recurrence or death, 0.75; 95 percent confidence interval, 0.65 to 0.86; P<0.001) and decreased the cumulative incidence of brain metastasis (relative risk, 0.46; 95 percent confidence interval, 0.38 to 0.57; P<0.001). Larger doses of radiation led to greater decreases in the risk of brain metastasis, according to an analysis of four total doses (8 Gy, 24 to 25 Gy, 30 Gy, and 36 to 40 Gy) (P for trend=0.02), but the effect on survival did not differ significantly according to the dose. We also identified a trend (P=0.01) toward a decrease in the risk of brain metastasis with earlier administration of cranial irradiation after the initiation of induction chemotherapy. CONCLUSIONS: Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission.
Adult↗
Imaging features of leptomeningeal metastases.
AIMS: To assess the range of appearances, and accuracy of various methods of diagnosing leptomeningeal metastases. MATERIALS AND METHODS: In a retrospective study, the notes and imaging of all patients with a radiological and/or CSF cytological diagnosis of leptomeningeal metastasis (LM) were identified, and assessed for the following: age and sex, primary tumour type, presenting symptoms, initial radiological and cytological diagnosis, radiological appearances and length of survival following diagnosis. Discordance between the CSF cytology and radiological diagnosis of LM was also noted. RESULTS: 41 positive cases (36 female) of LM were identified over a 2.7 year period (diagnosis based on: imaging only--19 cases, cytology only--6, both--16 cases). The average age was 48 years, and the most frequent primary tumour was breast carcinoma (27/41). Two thirds of patients presented with at least one cranial or spinal nerve palsy. Where performed, contrast-enhanced CT was normal in 40% (10/25), with LM mistaken for parenchymal disease in a further 24% (6/25). CSF cytology was positive in 85% (22/26). Gadolinium-enhanced MRI was positive in all cases where it was performed (25/25). Pial enhancement and nodularity was the commonest finding (67%), but other manifestations included nodular disease, neural enhancement and white matter changes. Prognosis was uniformly poor. CONCLUSION: Leptomeningeal metastatic disease has a poor prognosis, and treatment regimen may differ from those of parenchymal CNS metastases. CT is normal or misleading in two thirds of patients, and CSF cytology may also be negative. Gadolinium-enhanced T1-weighted MRI complements CSF cytology, and is the investigation of choice in patients with a non-haematological primary tumour and suspected LM.
Adolescent↗
Phase II studies of RMP-7 and carboplatin in the treatment of recurrent high grade glioma. RMP-7 European Study Group.
The selective bradykinin analogue, RMP-7, transiently increases the permeability of the blood brain barrier and the delivery of hydrophilic agents into brain tumours. In 87 recurrent glioma patients (WHO Grade III/IV, median age 46, Karnofsky 70%) clinical and Magnetic Resonance Imaging (MRI) responses to i.v. cycles (q 28 days) of RMP-7 (300 ng/kg given as a 10 min infusion) and carboplatin (AUC 4-9) were assessed. 45 of these patients were chemotherapy naive (CN-RMP) and 42 had received one prior course of chemotherapy (CP-RMP). Neurological impairment, performance status and steroid use were measured prior to dosing at each cycle and tumour volume by 3-D MRI at the end of cycles 2, 4, 6, 9 and 12. Clinical evaluation of response demonstrated that 61% of CN-RMP patients were either stable or improved whilst this was 39% for CP-RMP patients, of which 37% and 8% improved respectively. Radiological evaluation showed 79% of CN-RMP patients were either stable, partial or complete responses and 24% for CP-RMP patients, of which 32% and 5% were CR or PR respectively. The median duration of response was 30.3 weeks in CN-RMP patients and 19.6 weeks in the CP-RMP group. Lack of response was associated with substantial baseline tumour volume. Drug toxicity was as previously reported for carboplatin. 11 patients had treatment-associated transient focal seizures. These results indicate that RMP-7 and carboplatin have significant activity in recurrent malignant glioma following radiotherapy.
Adult↗
The management of non-small-cell lung cancer: a case history.
Accurate assessment and treatment of the patient with lung cancer requires a team approach involving respiratory physicians, cardiothoracic surgeons, oncologists and the palliative care team. Adequate staging and assessment of prognostic factors are essential before deciding what treatment is appropriate for an individual patient. Surgery is the mainstay of treatment for early disease. Patients with medically inoperable stage 1 (T1, T2, N0) tumours should be considered for radical radiotherapy; additional chemotherapy in early stage disease may offer an additional survival advantage, but its overall role can only be assessed by further clinical trials. In more locally advanced tumours radical radiotherapy has never been formally tested. It is however, often used in patients where the tumour can be encompassed safely within a radiation field. This will depend on total dose and fractionation schedule as well as the volume of tissue irradiated. Neo-adjuvant chemotherapy prolongs survival in these patients. As only a few patients are cured, symptom control and quality of life are usually the most important goals of management and can be achieved by a variety of interventions. It is disappointing that in such a common disease less than 5% of patients are entered into clinical trials. Without such evidence the therapeutic outcomes in NSCLC cannot be improved.
Carcinoma, Non-Small-Cell Lung↗
Dynamics of reactive oxygen intermediate production in human glioma: n-6 essential fatty acid effects.
BACKGROUND: Reactive oxygen intermediates (ROIs) are important signals controlling cell growth and cell death. Local essential fatty acid (EFA) deficiencies in tumour cells may limit tumour ROI generation. This deficiency may be rectified by the addition of exogenous EFA. MATERIALS AND METHODS: The n-6 EFA effects on tumour ROIs were analysed in terms of kinetics, dose-response and individual cell type responses using flow cytometry of intracellular 2',7'-dichlorofluorescin oxidation. ROI formation in 30 gliomas and five paired samples of normal brain tissue, > 500 000 cells per specimen, was analysed every 10 s for 0-25 min. RESULTS: Tumour cell basal ROI was lower than normal brain tissue ROI from the same subjects (P < 0.00002). Normal and tumour cell ROIs were stimulated by 4-40 micromol L-1 n-6 EFAs, arachidonic acid (AA) and gamma-linolenic acid (GLA). The stimulated ROI rate was exponential, with the maximum dependent on EFA concentration and tumour grade. CONCLUSIONS: EFAs stimulated tumour cells more than normal cells (P < 0.0000017, n = 71) and increased ROIs in glial fibrillary acidic protein-positive cells in tumours. This indicated high sensitivity of glioma cell ROIs to n-6 EFAs.
Adolescent↗
[[35 Years of effort to improve the diagnosis of porphyria].
World history of porphyria is given in brief. The activities of Porphyria Center during period of 25 years have shown how difficult it was to introduce diagnostic measures for this rare and very little known group of diseases. The obstacles encountered during the popularization of the knowledge of porphyria were: minimal information on porphyria, very seldom seen in Poland, therefore rather negative approach of the doctors to these patients,--almost never porphyria was seen in differential diagnostics of abdominal pains or polyneuropathies, herefore diagnosis, if made, was very late, often just before death. From the other side insufficient support for doctors was given by laboratories because of the lack of simple diagnostic tests. Along the 35 years of the work in the Institute of Haematology and Transfusiology the situation was steadily improving but slowly due to technical and economical difficulties. The Center was organized, now well equipped and able to diagnose and differentiate all types of porphyrias. A computerised basis of the collected material consist of 383 families (6000 persons registered). Among them there are nearly 600 acute (who have passed one or more attacks of porphyria) and about 1000 latent cases of porphyria. The mortality which was 52% in the first collected group of patients (1960-1970) has fallen to less than 10% concerning very severe and late diagnosed attacks. In 1996-1998 there were only two deaths during attacks of porphyria in Poland.
Hematology↗
Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study.
BACKGROUND AND PURPOSE: To evaluate the efficacy of WBRT as a single treatment modality in patients with brain metastases of small cell lung cancer. PATIENTS AND METHODS: The patients had brain metastases of small cell lung cancer without any sign of tumour outside the brain and were treated with 10 x 3.0 Gy WBRT. Response and neurological functions were evaluated after 6, 18 and 36 weeks. RESULTS: Twenty of 22 eligible patients were evaluable for response. In six patients a complete response was seen and in five patients a partial response was seen giving a response rate of 50% (95% CI 28-72%). Response duration was 5.4 months (range 63-260 days) and median survival was 4.7 months (range 14-743 days). In the majority of patients the first site of progression after WBRT was in the central nervous system. Twelve of the patients had stabilization or improvement of the neurological function. CONCLUSION: WBRT for brain metastases of small cell lung cancer gives a 50% response rate with stabilization or improvement of neurological function. Response duration and survival are short.
Adult↗
Age has no impact on acute and late toxicity of curative thoracic radiotherapy.
BACKGROUND AND PURPOSE: Radiotherapy is a treatment method frequently employed in the management of thoracic tumours. Although the highest incidence of these tumours is found in elderly people, tolerance to radiotherapy is not well documented in older age groups. Many physicians are tempted to alter the radiotherapy planning in a population with a supposed lower life expectancy in order to prevent acute reactions whereas late reactions are often ignored. The current study aimed to determine the influence of age on the frequency and severity of acute and late side-effects and also whether the prognosis of tumours sufficiently differed between ages to justify different attitudes towards their management. MATERIALS AND METHODS: Data from 1208 patients receiving chest irradiation and included in arms designed with RT of six EORTC randomized trials were evaluated. Data were extracted by a computer program elaborated for each study and were merged in a single database for analysis. Patients were split into six age ranges from 50 to 70 years and over. Survival and late toxicity were calculated with the Kaplan-Meier method and comparison between age groups was performed with the logrank test. The gamma-statistic test was used to test the impact of age on acute toxicity occurrence. RESULTS: Survival adjusted for the primary location of the tumour was comparable in each age group (P = 0.82). Data regarding age and acute toxicity were available for 1208 patients who experienced 640 grade > or =1 toxicities. The difference in distribution over age was not significant for acute nausea, dyspnea, oesophagitis, weakness and WHO performance status alteration. Weight loss was significantly different with regards to age with a trend toward increased weight loss in older age groups (P = 0.002). To minimize actuarial bias, only patients surviving more than 90 days were analyzed for late effect risks. Late toxicities were examined only if they occurred before an eventual tumour failure in order to avoid confusion between effects of first and second line treatments. In such conditions, 1082 grade > or =1 late toxicities were recorded in 935 patients of 1106 available for analysis. The mean time to complication was 13 months and was similar in all age groups. Forty percent of patients were free of complication at 4 years, the logrank test showing no significant difference between age groups (P = 0.57). For grade >2 side-effects, the calculation did not show any difference between each age group (P = 0.1). A detailed analysis of late dyspnea and late weakness studied with the same method did not demonstrate any difference between age groups. Only grade >2 late oesophagitis demonstrated a significant trend to be more frequent in older patients (P = 0.01), but this difference disappeared after adjustment on study (P = 0.32). CONCLUSION: The absence of toxicity observed in the current study regardless of age reinforces the conviction that age per se is not a sufficient reason to exclude patients in good general condition with thoracic tumour from curative radiotherapy when medically indicated.
Actuarial Analysis↗
The treatment of brain metastases from lung cancer.
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Antineoplastic Agents↗
An audit of 3D treatment planning facilities and practice in the UK.
The availability and use of 3D treatment planning facilities in the UK was investigated by questionnaire. Fifty-eight of the 62 UK radiotherapy centres responded (94%). There was considerable variation in the facilities available and in the manner in which they were used. Although 36 centres (62%) have the facilities to undertake complex, non-coplanar treatment planning, only 12 did so on a regular basis. More surprising was the inconsistent implementation of coplanar CT planning. It is suggested that we need to work towards reaching a consensus on best practice in radiotherapy planning. This will require the creation of systems for guidance and further training of the various staff involved.
Ambulatory Care Facilities↗
Apoptosis in human primary brain tumours: actions of arachidonic acid.
It has been postulated that loss of proliferative control in tumour cells is a consequence of depletion of cellular arachidonic acid (AA) and that exogenous AA and n-6 fatty acids may restore control of proliferation. To test this hypothesis and to investigate the activity of AA, apoptosis in human primary brain tumour cells was analysed using flow terminal deoxynucleotide transferase uridine nick end-labelling (TUNEL). The effect of exogenous AA (30 microM) was analysed in collagenase-dispersed tissue from seven human primary brain tumours and in the normal brain tissue surrounding one of the tumours. Exogenous AA stimulated apoptosis in tumour tissue. A rapid three-fold increase in endonuclease activity was detected in tumour cells incubated with AA. The increase in apoptosis was significantly greater than the contemporary (< 15%) increase in necrosis detected using propidium iodide permeability and was greater than AA effects on normal brain tissue. These results are consistent with activation of the pathways of apoptosis by AA.
Apoptosis↗
Significant change in tests of neurological impairment in patients with brain tumours.
There is a need for valid objective tests of neurological improvement or deterioration to more accurately define response or progression in phase II studies of malignant glioma. The Edinburgh Functional Impairment Tests (EFIT) incorporate objective measures of upper and lower limb function, memory and a rating scale for dysphasia. We examined the intra-observer repeatability of the (EFIT) 24 hours apart in 55 patients with brain tumors and stable neurological disease and the inter-rater repeatability in 33 patients in the perioperative period (54 dual assessments). Intra-observer studies of the four subtests, failed to demonstrate any learning effect and showed close agreement. Inter-rater studies were affected by a treatment effect (steroids) and identified slight inter-rater bias for the ten meter walk. Altman-Bland plots showed that the level of agreement was less good in patients with more severe impairment. Correction for the severity of handicap was possible using a simple formulae: (timed tests: [rater 1 - rater 2]/[rater 1 + rater 2], Williams Delayed Recall Test [WDRT] (rater 1 - 2/81). Using this correction, all intra- and inter-rater variance of patients tested within 12 hours were < 0.2. A change of > or = 0.2 for the timed tests and WDRT, and a change in dysphasia score of > or = 2, represent a significant change in impairment using the EFIT. The EFIT should be a useful addition in phase II studies where objectively recording response or time to progression is important.
Adolescent↗
Kinetics of reactive oxygen intermediate formation and apoptosis in human glioma and glioma C6 cell line: effects of radiation and n-6 essential fatty acids.
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Animals↗
The costs of managing patients with malignant glioma at a neuro-oncology clinic.
Malignant glioma (glioblastoma and anaplastic astrocytoma) remain incurable despite extensive resection, radiotherapy, chemotherapy and experimental therapies. Few studies have addressed either the costs of various treatments for malignant glioma or their cost effectiveness. The aims of this study were to identify direct hospital costs of treating patients with biopsy proven malignant glioma. The study was carried out within the setting of a dedicated neuro-oncology clinic at a university teaching hospital and included 236 patients treated between 1989 and 1995. The study used the unit costing of each item of treatment according to NHS National Costing Project. The cost of treatment was broken down into its various components: bed days, investigations, surgery, radiotherapy, chemotherapy and neuro-oncology out-patient follow-ups. The mean costs for each of the items based on 1995 figures for the 157 patients having surgery followed by radiotherapy were neuroradiological investigations (442 Pounds), neurosurgical bed days (2407 Pounds), neurosurgery (2068 Pounds), neuropathology (434 Pounds), radiotherapy (8832 Pounds), out-patients (1078 Pounds) and chemotherapy (440 Pounds). Total treatment costs per patient ranged from 1978 Pounds to 26,980 Pounds. Median costs of care decreased sequentially with worsening MRC Brain Tumour prognostic group. Management of patients with the best prognosis (MRC index score of 1-10) cost a median of 16,550 Pounds (range 4572-26,090 Pounds) whilst the median management cost of those in the worst prognostic group (MRC score 34-38) was 6514 Pounds (range 1978-18,360 Pounds). The median cost of each week of survival in the patients with the best outcome (MRC score 1-10) was < 150 Pounds compared to 232 Pounds for each week of survival for patients in the worst prognostic group (MRC score 34-38). This study made no attempt to collect costs of supportive or community-based care. Prospective studies are required to collect such data, as well as assessing the costs effectiveness of alternative treatment strategies.
Brain Neoplasms↗
Application of the MRC brain tumour prognostic index to patients with malignant glioma not managed in randomised control trial.
OBJECTIVES: The MRC brain tumour prognostic index, which uses clinical variables to place patients in different outcome categories, has not been evaluated on a cohort outside a randomised controlled trial. The aims of this study were to (a) determine in a large cohort of patients, derived solely from one centre and not in a clinical trial, whether the MRC prognostic index stratified patients for outcome; (b) compare actual outcomes with those obtained in the original studies; and (c) examine whether neuropathological diagnosis was an independent prognostic variable. METHODS: The MRC prognostic index was calculated for 236 patients with either glioblastoma or anaplastic astrocytoma managed at a dedicated neuro-oncology clinic in Edinburgh between 1989 and 1995. RESULTS: For this mixed population of malignant glioma the median survival was 8.6 months. Two year survival was 72.2% for patients with an MRC index score of 1-10; 36.3% for those with an index score of 11-15; 25.1% for those scoring 16-20; 20.4% with those scoring 21-25; 4.8% with those scoring 26-33; and 0% for those scoring 34-38. Exclusion of 79 patients who would not have been eligible for the MRC studies from which the index was derived, because they were either too old or did not receive radiotherapy, still resulted in a similar pattern of stratification but with significantly improved median survival times for the lowest two categories. Multivariate analysis of prognostic variables in the Edinburgh cohort showed that patients with anaplastic astrocytoma did significantly better than those with glioblastoma (p<0.001). CONCLUSIONS: Although there were some differences in median survival times between the patients in the original MRC studies and the Edinburgh cohort in similar prognostic categories and a tendency to improved two year survivorship in the Edinburgh cohort these differences have arisen because (a) the Edinburgh cohort was accrued about 10 years later than the study has shown that even outside the setting of a prospective controlled trial and with relaxed inclusion criteria the Medical Research Council (MRC) prognostic index is a robust predictor of outcome in patients with malignant glioma. Survival clearly declines as the prognostic index increases. Moreover, the prognostic model can be substantially improved by the addition of histology data, although there is some evidence that this will require complex modelling procedures.
Adult↗