Phase I trial of temozolomide using an extended continuous oral schedule.

Temozolomide, a methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanoma, and mycosis fungoides and is presently administered as a 5-day oral schedule every 4 weeks. This Phase I study aimed to determine the maximum tolerated dose of temozolomide administered as a single oral daily dose for a continuous 6- or 7-week period, evaluate the plasma pharmacokinetics on this schedule, and compare total plasma exposure over 7 weeks with the conventional 5-day regimen. Twenty-four patients with varying tumor types (17 of 24 gliomas) received temozolomide. All had clinically evaluable, refractory disease; normal renal, hepatic, and bone marrow function; and WHO performance status < or = 2. Temozolomide was administered at 50 mg/m2/day, increasing by 25 mg/m2/day/cohort until at 100 mg/m2/day grade 4 myelotoxicity forced dose reductions to 85 mg/m2/day, then 75 mg/m2/day. At 75 mg/m2/day the regimen was extended to 7 weeks, allowing the future potential combination with irradiation for primary gliomas. Patient responses (standard Union International Contre Cancer criteria; for gliomas objective response) and toxicity were assessed. Temozolomide plasma pharmacokinetics were determined on day 1 and at the beginning of the final week of administration (n = 5). The most frequent toxicities were myelosuppression and grades 1 and 2 nausea and vomiting. Grade 4 leucopenia and thrombocytopenia occurred in one of four patients receiving 100 mg/m2/day temozolomide and in one of seven patients receiving 85 mg/m2/day. These hematological toxicities did not exceed grade 2 in 10 patients receiving 75 mg/m2/day temozolomide. One of 4 malignant melanoma patients and 7 of 17 glioma patients (41%) demonstrated tumor responses. The overall response rate for this prolonged schedule was 33% (objective response, 7 of 24 patients; partial response, 1 of 24 patients); also, 6 of 17 glioma patients maintained SD. Peak plasma temozolomide concentrations were obtained 30-90 min after oral administration. Elimination in plasma was best described by a monoexponential equation with an elimination half-life of 96 +/- 16 min. No plasma accumulation of temozolomide occurred. Toxicity was greatest in higher dose cohorts, with a resultant maximum tolerated dose of 85 mg/m2/day, whereas lower dose cohorts tolerated the schedule well. The area under the temozolomide plasma versus time curve was noncumulative between the first and last week of the schedule. Temozolomide administration of 75 mg/m2/day over a 7-week period permits a 2.1-fold greater drug exposure/4 weeks in comparison with the 5-day schedule of 200 mg/m2/day repeated every 28 days. The overall response rate was 33% (glioma patients, 41% and a further 25% SD). Temozolomide (75 mg/m2/day) for 7 weeks is the recommended starting dose for further assessment of this schedule.

Glucose metabolism in brain tumours can be estimated using [18F]2-fluorodeoxyglucose positron emission tomography and a population-derived input function scaled using a single arterialised venous blood sample.

The aim of this study was to assess simplified methods for deriving input functions for estimating glucose metabolism using 18F-FDG-PET. Nine glioma patients underwent paired 18F-FDG-PET scans as part of a phase II study and the data used to estimate the metabolic rate of glucose (MRGlu) using a population-derived input function (arterial data from 14 scans) scaled using a single arterial blood sample taken at 20 min. Paired studies were performed in four further glioma patients with stable disease at least four months following radiotherapy to determine whether scaling the population-derived input function using a 20-min arterialised venous or venous sample further simplified the method. The heated hand method was used to obtain arterialised venous blood that approximated arterial blood. In the 9 phase II glioma patients, there was a good, statistically significant correlation between the MRGlu values estimated using the individual arterial input functions and the single arterial sample scaled population-derived input functions (r(2)=0.88, p<0.001, n=36). Blood samples collected during three scans on two of the stable disease patients showed no significant difference between the arterialised venous and arterial plasma concentrations of 18F (p>0.1, n=15) when the degree of arterialisation of the blood was monitored and maintained using a thermocouple. A significant difference was found between the plasma arterial and venous levels of 18F. There was an excellent correlation between MRGlu estimated using an arterial input function and a population-derived input function scaled using a single arterialised venous blood sample (r(2)=0.98, n=12). The method was reproducible with less than 4.4% variation between repeat tumour scans. Therefore, a population-derived input function scaled using a single arterialised venous blood sample at 20 min can be used for estimating MRGlu using 18F-FDG PET in glioma patients.

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: a feasibility study.

PURPOSE: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). METHODS: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. RESULTS: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n = 22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. CONCLUSIONS: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

Current perspectives in gliomas.

The annual incidence of primary central nervous system tumors, including gliomas, is increasing, however, the prognosis of these tumors remains poor with a median survival of only 5 years. The imaging of tumors by computerised tomography, magnetic resonance imaging and newer methods such as positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) is increasing our knowledge of tumor biology and extent of the disease. Advances within the field of neurosurgery have improved operative procedures reducing mortality and morbidity. Furthermore, radiotherapy planning, tumor targeting and repositioning for treatment have all improved initial tumor management. The role of adjuvant chemotherapy remains controversial. Chemotherapy for advanced and recurrent disease has been extensively investigated, and although improvements in quality of life have been recorded, no prolongation of survival has been documented. With new discoveries and increasing knowledge of the physiology and molecular biology of these tumors the potential for targeting therapy at a genetic level is becoming increasingly promising. This review provides an overview of these current perspectives in glioma management.

Anti-angiogenic strategies and vascular targeting in the treatment of lung cancer.

The generation of new blood vessels, angiogenesis, is important for tumour proliferation and metastasis. This involves a number of interacting processes and factors, such as growth factors and the receptor tyrosine kinases, matrix metalloproteinases and integrins. Studies have shown that tumour vascularity and the overexpression of growth factors and their receptors are of independent prognostic importance in different cancers, including lung cancer. The present article provides a background to angiogenesis and describes the potential targets for anti-angiogenic and vascular targeting strategies in cancer, focusing specifically on carcinoma of the lung. It also describes the anti-angiogenic drugs presently under phase I, II and III investigation and highlights some of the problems associated with the standard methodologies for assessing tumour response and drug efficacy using these agents.

Does fluorine-18 fluorodeoxyglucose metabolic imaging of tumours benefit oncology?

Fluoro-deoxyglucose (FDG) is a metabolic marker, which follows the same route into cells as that of glucose, and it can be radiolabelled with fluorine-18, 18F-FDG making it suitable for imaging with positron emission tomography (PET). The fact that rapidly proliferating cells such as tumour cells accumulate 18F-FDG more avidly than those with a normal turnover rate has given rise to its potential in oncology. The rationale and previous published uses of 18F-FDG in oncology are reviewed, together with the various analysis techniques and associated methodological difficulties.

Trends in testicular carcinoma in England and Wales, 1971-99.

OBJECTIVES: To examine incidence, mortality and survival trends in England and Wales for testicular cancer, using the recently developed national cancer and national mortality databases. METHODS: The directly age-standardized incidence rates for testicular cancer in England and Wales were calculated for the period 1971-97 and age-standardized mortality for years 1971-99. Trends in the data were then assessed, including the influence of social deprivation on testicular cancer incidence and survival. RESULTS: The number of newly diagnosed cases of testicular carcinoma in 1971-97 in England and Wales increased from almost 650 to 1400. The age-standardized rates were 2.9 per 100000 cases in 1971 and 5.4 per 100000 in 1997, an increase of 88% over 26 years. There was a large decrease in mortality since the mid-1970s, with an age-standardized mortality of < 0.5 per 100000 since 1985. For men with testicular carcinoma diagnosed in 1991-93, the 1-year relative survival was almost 98% and 5-year relative survival almost 95%, compared with 82% and 69%, respectively, for men diagnosed during 1971-75. There is a 'deprivation gap' for the 5-year survival of > 6% in favour of the most affluent socio-economic group, with no significant change over recent years. CONCLUSIONS: The incidence of testicular cancer is increasing in England and Wales, consistent with the trend documented in other developed countries. The reduction in mortality has been marked since the mid-1970s, reflecting improved cancer management, in particular the introduction of platinum-based chemotherapy regimens for advanced disease. Survival rates in England and Wales are as good as in other European countries. Further developments in chemotherapy are unlikely to produce such a marked improvement in survival rates again, and minimizing the effect of social status on survival rates should be an important target of future care.

MRI of the brain with ultra-short echo-time pulse sequences.

As well as the long-T2 relaxation components normally detected with conventional imaging techniques, the brain has short-T2 components. We wished to use ultra-short (0.08 ms) echo time (UTE) pulse sequences to assess the feasibility of imaging these in normal subjects and patients. UTE sequences were employed, with or without fat suppression, 90 degree long-T2 suppression pulses, and selective nulling of long-T2 components using an inversion pulse. Subtraction of later echoes from the first was also used to reduce the signal from long-T2 components. We studied dive normal subjects and 15 patients with various diseases. Short-T2 components were demonstrated in grey and white matter. Increased signal from these components was seen in meningeal disease, probable calcification, presumed cavernomas, melanoma metastases and probable gliosis. Reduced signal was seen in some tumours, infarcts, mild multifocal vascular disease and vasogenic oedema. Further development and evaluation of these pulse sequences is warranted.

Early evaluation of tumour metabolic response using [18F]fluorodeoxyglucose and positron emission tomography: a pilot study following the phase II chemotherapy schedule for temozolomide in recurrent high-grade gliomas.

Quantitation of metabolic changes in tumours may provide an objective measure of clinical and subclinical response to anticancer therapy. This pilot study assesses the value of quantitation of metabolic rate of glucose (MRGlu) measured in mmol min(-1) ml(-1) to assess early subclinical response to therapy in a relatively non-responsive tumour. Nine patients receiving the CRC Phase II study schedule of temozolomide were assessed with [18F]fluorodeoxyglucose ([18F]FDG) dynamic positron emission tomography (PET) scans prior to and 14 days after treatment with temozolomide given as 750-1000 mg m(-2) over 5 days every 28 days. Tumour MRGlu was calculated and compared with objective response at 8 weeks. Pretreatment MRGlu was higher in responders than non-responders. The responding patient group had a greater than 25% reduction in MRGlu in regions of high focal tumour uptake (HFU). Whole tumour changes in MRGlu did not correlate with response. Percentage change in HFU standardized uptake value (SUV) did discriminate the responding from the non-responding patients, but not as well as with MRGlu. Large differences also occurred in the normal brain SUV following treatment. Thus, MRGlu appeared to be a more sensitive discriminator of response than the simplified static SUV analysis. Changes in MRGlu may reflect the degree of cell kill following chemotherapy and so may provide an objective, quantitative subclinical measure of response to therapy.