Pharmacokinetic analysis of 5-[18F]fluorouracil tissue concentrations measured with positron emission tomography in patients with liver metastases from colorectal adenocarcinoma.

The purpose of our study was to develop a pharmacokinetic model to quantify the intracellular 5-fluorouracil (5-FU) concentration in liver metastases, which is expected to be closely correlated to therapy response. In addition, the influence of the biomodulator folinic acid on the action of 5-FU in the metastases was investigated. After i.v. application of 5-FU labeled with the positron emitter fluorine-18 (5-[18F]FU), the kinetics of the regional 5-[18F]FU/uptake was measured dynamically with positron emission tomography over 120 min in 14 patients with a total of 27 liver metastases from colorectal adenocarcinoma. Activity-time curves were evaluated in the metastases, the normal liver tissue, as well as in the aorta and analyzed by a six-compartment model. The catabolic breakdown of 5-FU to alpha-fluoro-beta-alanine (FBAL) in the normal liver tissue was modeled to separate the catabolites from the cytostatic agent 5-[18F]FU and the active 5-[18F]fluorodeoxyuridine nucleotides. With our model, all measured activity-time courses could be described adequately with only small interindividual variations in parameters connected with liver and blood. Extrahepatic clearance of 5-FU was estimated as 0.66 +/- 0.33 liters/min, whereas the hepatic clearance was 0.52 +/- 0.25 liters/min. The Michaelis-Menten parameters describing the nonlinear conversion of 5-FU to FBAL were Km = 11.3 +/- 6.4 micromol and Vmax = 147.1 +/- 130.7 micromol/min. The maximum FBAL concentration in the liver was reached between 35 and 65 min after i.v. 5-FU infusion. The most sensitive parameters for therapy monitoring were k(in) and k(out), which characterize the transport in and out of the intracellular volume of the metastases, respectively. Tumor response can only be expected if k(in) is high and k(out) is low ("trapping"). These criteria were met by 6 of the 27 metastases, which were identical to those with high values for the area under the intracellular 5-FU concentration curve (AUC[meta,IC]5-FU). The parameters k(in) and k(out) were also used to investigate the influence of the biomodulating agent folinic acid on drug effect. Five of the six metastases that showed trapping belonged to patients who received folinic acid. With the exception of one patient, however, all patients who received folinic acid had multiple metastases, of which only one was able to trap 5-FU. Because patient response can only be expected when all metastases trap 5-FU, folinic acid showed no effect on the overall clinical response. With the quantitative modeling approach used, trapping of 5-FU can be assessed noninvasively and on an individual basis. This makes it possible to adjust the dose for each individual patient to optimize the treatment schedule.

A system for stereotactic irradiation and magnetic resonance evaluations in the rat brain.

PURPOSE: A stereotactic fixation and localization device developed for small animal stereotactic radiosurgery is described. METHODS AND MATERIALS: Irradiated volumes of spherical shape down to 1.7 mm in diameter at the 80% isodose level are attainable. The fixation device can also be used for magnetic resonance imaging (MRI) and allows target localization during magnetic resonance (MR) image content measurement. The capabilities of the entire system were investigated using a phantom that permitted measurement and localization of the three-dimensional dose distribution. Localization of target isocenter coordinates in MR images was also checked with the phantom. RESULTS: An overall spatial error of about 1 mm for subsequent stereotactic irradiation was obtained. CONCLUSIONS: The accuracy of the fixation and localization techniques is adequate to investigate radiation-induced changes in the rat brain.

Display of organs and isodoses as shaded 3-D objects for 3-D therapy planning.

We have developed a technique that allows the user to assess and modify 3-D dose distributions in planning a treatment. Organs and superimposed isodoses can be displayed as shaded solid objects from any desired point of view. The graphic tools necessary are described in detail. Briefly, after the volumes of interest have been defined as contours taken from CT scans, the beam data can then be defined using the "beam's eye view" technique. Subsequently, the desired isodoses can be extracted from the three-dimensional dose matrices and displayed as a series of "barrel hoops" over the target volume. We have found this technique to be particularly useful for development of treatment plans where the spatial relationship of sensitive organs such as the spinal cord may change considerably within the treatment volume. Such a case is described in detail.

Computerized optimization of 125I implants in brain tumors.

A computer program for treatment planning for the interstitial radiotherapy of brain tumors with 125I stereotactic implants is presented. To minimize brain traumatization only 1-3 catheters loaded with several seeds are implanted. It is possible to position the catheters very accurately due to CT guided stereotactic techniques. Precise treatment planning is necessary because of the high dose gradient of the radiation field. Two planning methods are available: conventional planning with interactive optimization of source configurations and an automatic optimization procedure. The goal of optimization is to identify source parameters (catheter positions and seed activities) for which a prescribed dose at the target surface is approximated as closely as possible.

Precision and accuracy of stereotactic convergent beam irradiations from a linear accelerator.

PURPOSE: The accuracy and the precision for radiosurgery procedures at linear accelerator facilities were investigated. METHODS AND MATERIALS: The technique of convergent beam irradiation, that is a series of successive isocentric arc irradiations, is specifically considered in this paper. Accuracy and precision depend on a sequence of methods and equipment among which localization of the target, patient alignment, and the dose delivery are the most critical steps. The purpose of the investigation was to quantitatively assess their contribution to the overall accuracy. The definitions and methods used to quantify and control accuracy are described. Measurements were carried out at a phantom to analyze the localization and positioning errors. Errors which may occur with the dose delivery technique were studied by a computer simulation. RESULTS: The calculations showed that these errors are not the main contributors to the overall accuracy as long as the linac inaccuracies are in the order or less than 1 mm. The accuracy found in the localization and positioning methods was less than 1 mm. CONCLUSION: It was concluded that an overall accuracy in the order of 1 mm can be obtained also under routine conditions. The great importance of adequate quality control is emphasized.

Cerebral radiation surgery using moving field irradiation at a linear accelerator facility.

A modified irradiation technique at a linear accelerator facility for radiation surgery within the brain is described consisting of several moving field irradiations in non-coplanar planes. Using collimated narrow beams, a localization system and special computer programs for precise patient positioning, a high concentration of dose within small, well circumscribed volumes is obtained. Resulting dose distributions were studied experimentally and by calculations. A simple algorithm for treatment planning was developed and based on CT images. Radiation surgery within the brain is now technically feasible at our linear accelerator. Seventeen patients have now been treated.

Computer systems and mechanical tools for stereotactically guided conformation therapy with linear accelerators.

An integrated system for fractionated, stereotactically guided conformation radiotherapy has been developed. The system components are a stereotactic fixation system that can be used each treatment day, a localization, and positioning unit that can be used during x-ray computer tomography, magnetic resonance imaging, positron emission tomography, and radiographical examinations as well as for treatment. Conformal precision radiotherapy is planned with a new three-dimensional treatment planning system (Voxel-Plan-Heidelberg) which comprises, among others options, a three-dimensional image correlation procedure as well as routines for the calculation of coplanar and non-coplanar irradiations with irregularly shaped fields. Two different multi-leaf collimators have been designed for precision radiotherapy in the head and neck region. A manual multi-leaf collimator is used for irradiations with stationary beams or for moving beam treatments with invariable irregularly shaped fields. This collimator system is now being used for patient treatments. The design of a computer controlled multi-leaf collimator unit for multiple fixed field irradiation techniques is discussed. All system components are aimed at conforming dose distributions for fractionated radiotherapy treatments to the target to improve sparing of adjacent normal tissues, and at achieving a sufficient geometrical accuracy in the dose application.

Dose-response relationship for late functional changes in the rat brain after radiosurgery evaluated by magnetic resonance imaging.

PURPOSE: Only few quantitative data are available on late effects in the healthy brain after radiosurgery. An animal model can contribute to systematically investigate such late effects. Therefore, a model applying radiosurgery at the rat brain was established. A long-term (19 months) follow up study with 66 animals after radiosurgery was carried out. METHODS AND MATERIALS: In 60 animals, an area in the frontal lobe of the brain was irradiated stereotactically with a 15 MV linac. Different doses of 20, 30, 40, 50, and 100 Gy with two field sizes (3.9 and 5.9 mm collimator) were selected, using the integrated logistic formula with input parameters from human brain. The induced alteration of the blood-brain barrier permeability was investigated by means of contrast enhanced magnetic resonance imaging. RESULTS: A first intracranial signal enhancement was observed in one animal 160 days after irradiation with 100 Gy. Beginning at 5 months all animals in the two 100 Gy groups homogeneously showed contrast enhancement, but none of the other groups. This remained until 13 months after irradiation. The volume of contrast enhancement as well as the increase of signal intensity were different between the two 100 Gy groups. After 19 months, the animals irradiated with lower doses also showed contrast enhancements, although not uniformly throughout one group. A maximum likelihood fit of the logistic formula P(D) = 1/[1 + (D50/D)k] to the incidence of late effects for the 5.9 mm collimator at 19 months after irradiation results in the parameters D50 = 37.4(-5.2,+6.1) Gy and k = 4.7 +/- 2.4. CONCLUSIONS: An animal model was established to study late normal brain tissue response. The observed late effects appeared very similar to the estimation of the integrated logistic formula for human brain. Based on these radiosurgery techniques, future experiments will focus on modifications in the irradiation modalities, i.e., irregular volumes, radiation quality or fractionation.

Monte Carlo-based analysis of PET scatter components.

UNLABELLED: This study quantifies the different scatter components in PET and examines how the different components degrade reconstructed PET images. METHODS: We simulated the measurement of various phantoms using Monte Carlo (MC) calculations and compared the MC-generated projections and images with the corresponding experimental data. The coincidences were subdivided in four classes: primaries, object scatter (scattered in the object only), gantry scatter (scattered in the scanner only) and mixed scatter (scattered both in the object and the scanner). RESULTS: In the projections of the line sources, the gantry scatter was closely located around the source position, whereas the object scatter was smeared over the whole field of view and could be parameterized well by a monoexponential function. The mixed scatter had nearly the same distribution as the object scatter, but with a smaller amplitude. The calculations and experimental data were in excellent agreement; i.e., led to the same parameterization of the scatter distribution functions and to a similar localization of the scatter components in the reconstructed images. CONCLUSION: The spatial distribution of the scatter components justifies the widely-used assumption that it is sufficient to restrict experimental scatter correction techniques to the object scatter. Furthermore, it is possible to derive the parameters for the scatter kernels, which are needed for the convolution-subtraction algorithm, by MC simulations.

Performance evaluation of a whole-body PET scanner using the NEMA protocol. National Electrical Manufacturers Association.

UNLABELLED: This study evaluates the performance of the newly developed high-resolution whole-body PET scanner ECAT EXACT HR+. METHODS: The scanner consists of four rings of 72 bismuth germanate block detectors each, covering an axial field of view of 15.5 cm with a patient port of 56.2 cm. A single block detector is divided into an 8 x 8 matrix, giving a total of 32 rings with 576 detectors each. The dimensions of a single detector element are 4.39 x 4.05 x 30 mm3. The scanner is equipped with extendable tungsten septa for two-dimensional two-dimensional measurements, as well as with three 68Ge line sources for transmission scans and daily quality control. The spatial resolution, scatter fraction, count rate, sensitivity, uniformity and accuracy of the implemented correction algorithms were evaluated after the National Electrical Manufacturers Association protocol using the standard acquisition parameters. RESULTS: The transaxial resolution in the two-dimensional mode is 4.3 mm (4.4 mm) in the center and increases to 4.7 mm (4.8 mm) tangential and to 8.3 mm (8.0 mm) radial at a distance of r = 20 cm from the center. The axial slice width measured in the two-dimensional mode varies between 4.2 and 6.6 mm FWHM over the transaxial field of view. In the three-dimensional mode the average axial resolution varies between 4.1 mm FWHM in the center and 7.8 mm at r = 20 cm. The scatter fraction is 17.1% (32.5%) for a lower energy discriminator level of 350 keV. The maximum true event count rate of 263 (345) kcps was measured at an activity concentration of 142 (26.9) kBq/ml. The total system sensitivity for true events is 5.7 (27.7) cps/Bq/ml. From the uniformity measurements, we obtained a volume variance of 3.9% (5.0%) and a system variance of 1.6% (1.7%). The implemented three-dimensional scatter correction algorithm reveals very favorable properties, whereas the three-dimensional attenuation correction yields slightly inaccurate results in low- and high-density regions. CONCLUSION: The ECAT EXACT HR+ has an excellent, nearly isotropic spatial resolution, which is advantageous for brain and small animal studies. While the relatively low slice sensitivity may hamper the capability for performing fast dynamic two-dimensional studies, the scanner offers a sufficient sensitivity and count rate capacity for fully three-dimensional whole-body imaging.

The influence of mineralising radionecrosis on the dose distribution in interstitial radiation therapy of brain tumours.

The influences of radionecroses arising during interstitial radiation of brain tumours with 125I, 192Ir or 198Au on dose distribution was investigated using Monte Carlo methods. The necroses have a higher density than normal tissue due to radiation-induced changes in tissue composition as well as mineral deposits. They can have a diameter of up to 1 cm around the single seeds. The higher density and changed chemical composition compared to homogeneous normal tissue leads to increased absorption of radiation around the necroses which results in a lower dose rate in the surrounding tissue. It is shown that the formation of necroses during treatment with higher energy radiation such as 192Ir (340 keV) or 198Au (400 keV) may be neglected during therapy planning as the dose rate is affected by less than 2%. If low energy radiation, e.g. 125I (28 keV) is used, the dose rate can be reduced by more than 30%. In this case the influence of the necroses on dose distribution, at least for permanent 125I implantation, may not be negligible.

Three-dimensional photon radiotherapy planning for laryngeal and hypopharyngeal cancers. 1. Conventional rotational technique.

Three-dimensional dose distributions have been computed for the photon radiation therapy of laryngeal and hypopharyngeal cancers, using biaxial and eccentric rotatory techniques. Treatment plans obtained under various conditions of irradiation with a 15 MV linear accelarator (MEVATRON 77, Siemens) are analysed and compared. Dose delivery to the tumour and the degree of spinal cord protection are evaluated for both treatment techniques. The eccentric plan is somewhat superior to the biaxial one, suggesting a justifiable preference to use this method in the radiation treatment of these tumours. Simulations show that extreme care is needed in positioning the axis: an accuracy of +/- 3 mm is required in the sagittal plane.

Improved target volume definition for precision radiotherapy planning of meningiomas by correlation of CT and dynamic, Gd-DTPA-enhanced FLASH MR imaging.

In this methodological paper the authors report a fast, T1-weighted gradient-echo sequence (FLASH) for dynamic, Gd-DTPA-enhanced magnetic resonance (MR) imaging of meningiomas and its application in precision radiotherapy planning. Indications for radiotherapy included unresected tumors, tumor remaining after surgery, and recurrences. The patient's head was fixed in a stereotactic localization system which is usable at the CT, MR and the linear accelerator installations. By phantom measurements different materials (steel, aluminum, titanium, plastic, wood, ceramics) used for the stereotactic system were tested for mechanical stability and geometric MR image distortion. All metallic stereotactic rings (closed rings made of massive metal) led to a more or less dramatic geometric distortion and signal cancellation in the MR images. The best properties--nearly no distortion and high mechanic stability--are provided by a ceramic ring. If necessary, the remaining geometric MR image distortion can be 'corrected' (reducing displacements to the size of a pixel) by calculations based on modeling the distortion as a fourth order two-dimensional polynomial. The target volume was defined in dynamic, T1-weighted FLASH MR images, which were measured before, during, and after the controlled intravenous infusion of 0.1 mmol/kg body weight Gd-DTPA. The stereotactic localization technique allows the precise transfer of the target volume information from MR onto CT data to provide a map of the radiation attenuation coefficient for dose calculation. In genera, the superior soft tissue contrast of MR showed an excellent tumor delineation, especially in regions, such as the base of the skull, where the target often was obscured in CT images.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of a three-dimensional treatment planning system for the use of multi-leaf collimators in conformation radiotherapy.

The multi-leaf collimator of the DKFZ is designed as a low cost add-on device for conventional linear accelerators for radiotherapy. The technical specification of the computer controlled collimator is described briefly. A major limitation in the use of the wide capabilities of multi-leaf collimators in the clinic is still an appropriate treatment planning system. This paper describes treatment planning and dose calculation techniques for multi-leaf collimators and shows examples where the capabilities of the collimator are used extensively.

Three-dimensional photon radiotherapy planning for laryngeal and hypopharyngeal cancers. 2. Conformation treatment planning using a multileaf collimator.

Three-dimension dose distributions have been computed for 15 MV X-ray radiation therapy (MEVATRON 77, Siemens) of laryngeal and hypopharyngeal cancers using isocentric rotational technique with multileaf collimator. Using a new concave contour tracing algorithm, satisfactory dose delivery to the target volume and efficient protection of the normal tissues can be achieved.

Radiotherapy treatment planning of basal meningiomas: improved tumor localization by correlation of CT and MR imaging data.

A localization technique, based on three-dimensional CT and MR imaging data for precision radiotherapy of basal meningiomas, is presented. Indications for radiotherapy included unresected tumors, gross disease remaining despite surgery, and recurrences. The patient's head was fixed in a stereotactic localization system which is usable at the CT, MR and the linear accelerator installations. The geometrical distortion of MR imaging data was evaluated in three dimensions by phantom measurements. The geometrical distortion was "corrected" (reducing displacements to the size of a pixel) by calculations based on modelling the distortion as a fourth order two-dimensional polynomial. The target volume was defined in three-dimensional MR imaging data after application of 0.1 mmol/kg b.w. Gd-DTPA solution and transferred precisely from MR onto CT data to provide a map of the radiation attenuation coefficient for dose calculation. The superior soft tissue contrast of MR showed an excellent tumor delineation especially when the bony base of the skull obscured the target in CT images. Target volume, calculated dose distribution, and critical structures could be transferred between CT and MR imaging data and displayed as three-dimensional shaded structures for better assessment for matching of target volume and dose distribution. With the described planning system a more precise target definition of basal meningiomas was possible by integration of the superior tumor delineation in MR compared with CT.

Fractionated stereotactically guided radiotherapy of head and neck tumors: a report on clinical use of a new system in 195 cases.

Between November 1988 and December 1992, 195 patients with tumors of the head and neck (low grade gliomas, meningiomas, neurinomas, chordomas and miscellaneous) were treated with a newly developed stereotactical system for fractionated, conformal, high-precision radiotherapy. The overall preparation time, including head mask production for fixation, CT, MRI, 3-D treatment planning and stereotactical localisation could be reduced to 4-5 h per patient. The use of MR in the target definition was increased to a mean of about 60%. The medial follow-up time is 22 months. Three different patient groups were selected according to pretreatment. Patients with full high-precision radiotherapy survived in 95% of cases, patients with boost treatment in 86% and patients with preirradiated recurrent disease in 64%. Meningiomas as the largest histology group (n = 62) showed partial response in 27% and complete response in 10% of cases. Progression occurred in two patients. All patients are alive. Acute side-effects were minimal and of the order of 10%, no late complications occurred despite tumor doses ranging up to 72 Gy. High-precision radiotherapy as it is performed in Heidelberg can be regarded as an effective, reliable and tolerable system for selected tumors of the head and neck.

Response of the rat Dunning R3327-AT1 prostate tumor to treatment with fractionated fast neutrons.

Reports indicate that cancer of the prostate, soft tissue sarcomas, salivary gland tumors, and melanomas respond well to fast-neutron treatment. To better understand the action of fast neutrons on such tumor tissues, we have begun studies with the versatile Dunning rat prostate tumor system. In our initial studies with the R3327-AT1 subline we observed a relative biological effectiveness (RBE) of approximately 3 for single doses of 14-meV fast neutrons. As a continuation of those studies the present report discusses our findings following fractionated treatments with 10 equal fractions of 14-MeV fast neutrons or 60Co gamma rays at several dose levels per fraction. After either fractionated neutron or photon treatment the volume of the tumors continued to increase for 2 weeks and then reached a plateau, the level of which was dose dependent. Tumor growth resumed and no local control was observed. Analysis of the data using growth delay as biological end point yielded an RBE of approximately 4.2 +/- 1.3.

A chemical dosimeter for the determination of the photodynamic activity of photosensitizers.

Uric acid a known singlet oxygen scavenger, was investigated as a chemical dosimeter in physiological aqueous solution for use in photodynamic therapy. The uric acid test takes the decrease in uric acid (UA) absorbance at 293 nm after laser light irradiation of a solution containing UA and a photosensitizer as a rapid evaluation of relative photodynamic activities of the photosensitizer. A uric acid test standard procedure was defined. To compare photodynamic activity of different photosensitizers or irradiation conditions a proposal for a photodynamic activity scale based on the uric acid test is given. Examples of uric acid test operation are given by comparing the changes in UA absorbance decrease with respect to irradiation wavelength and to photosensitizer concentration of Photofrin II with that of two other photosensitizers (5,10,15,20-tetrakis-[4-hydroxyphenyl]-21H,23H-porphyrin (TOP) and 5,10,15,20-tetrakis-[4-carboxyphenyl)-21H, 23H-porphyrin (TCPP), both derivatized with methoxypolyethyleneglycol (TOP-MPV and TCPP-AMP) as a macromolecular carrier). The photodynamic activity of the three photosensitizers using the proposed photodynamic activity scale is given.

PET imaging of lung tumours and mediastinal lymphoma.

Positron emission tomography (PET) of the lung is evaluated regarding its clinical practicability for staging of bronchogenic carcinomas and lymphomas. Stringent quality control, optimized acquisition and reconstruction techniques are of crucial importance. An analysis of 50 PET studies for tumour (T) and lymphnode (N) staging in comparison to CT shows that PET has the highest diagnostic accuracy to classify lesions and is the most promising technique for non-invasive staging. PET cannot be the first imaging modality, but if unnecessary or invasive procedures can be avoided, the additional expense of a PET study seems justified.