The dosimetric impact of leaf interdigitation and leaf width on VMAT treatment planning in Pinnacle: comparing Pareto fronts.

To evaluate in an objective way the effect of leaf interdigitation and leaf width on volumetric modulated arc therapy plans in Pinnacle. Three multileaf collimators (MLCs) were modeled: two 10 mm leaf width MLCs, with and without interdigitating leafs, and a 5 mm leaf width MLC with interdigitating leafs. Three rectum patients and three prostate patients were used for the planning study. In order to compare treatment techniques in an objective way, a Pareto front comparison was carried out. 200 plans were generated in an automated way, per patient per MLC model, resulting in a total of 3600 plans. From these plans, Pareto-optimal plans were selected which were evaluated for various dosimetric variables. The capability of leaf interdigitation showed little dosimetric impact on the treatment plans, when comparing the 10 mm leaf width MLC with and without leaf interdigitation. When comparing the 10 mm leaf width MLC with the 5 mm leaf width MLC, both with interdigitating leafs, improvement in plan quality was observed. For both patient groups, the integral dose was reduced by 0.6 J for the thin MLC. For the prostate patients, the mean dose to the anal sphincter was reduced by 1.8 Gy and the conformity of the V(95%) was reduced by 0.02 using the thin MLC. The V(65%) of the rectum was reduced by 0.1% and the dose homogeneity with 1.5%. For rectum patients, the mean dose to the bowel was reduced by 1.4 Gy and the mean dose to the bladder with 0.8 Gy for the thin MLC. The conformity of the V(95%) was equivalent for the 10 and 5 mm leaf width MLCs for the rectum patients. We have objectively compared three types of MLCs in a planning study for prostate and rectum patients by analyzing Pareto-optimal plans which were generated in an automated way. Interdigitation of MLC leafs does not generate better plans using the SmartArc algorithm in Pinnacle. Changing the MLC leaf width from 10 to 5 mm generates better treatment plans although the clinical relevance remains to be proven.

Reconstruction of a time-averaged midposition CT scan for radiotherapy planning of lung cancer patients using deformable registration.

PURPOSE: lower lobe lung tumors move with amplitudes of up to 2 cm due to respiration. To reduce respiration imaging artifacts in planning CT scans, 4D imaging techniques are used. Currently, we use a single (midventilation) frame of the 4D data set for clinical delineation of structures and radiotherapy planning. A single frame, however, often contains artifacts due to breathing irregularities, and is noisier than a conventional CT scan since the exposure per frame is lower. Moreover, the tumor may be displaced from the mean tumor position due to hysteresis. The aim of this work is to develop a framework for the acquisition of a good quality scan representing all scanned anatomy in the mean position by averaging transformed (deformed) CT frames, i.e., canceling out motion. A nonrigid registration method is necessary since motion varies over the lung. METHODS AND MATERIALS: 4D and inspiration breath-hold (BH) CT scans were acquired for 13 patients. An iterative multiscale motion estimation technique was applied to the 4D CT scan, similar to optical flow but using image phase (gray-value transitions from bright to dark and vice versa) instead. From the (4D) deformation vector field (DVF) derived, the local mean position in the respiratory cycle was computed and the 4D DVF was modified to deform all structures of the original 4D CT scan to this mean position. A 3D midposition (MidP) CT scan was then obtained by (arithmetic or median) averaging of the deformed 4D CT scan. Image registration accuracy, tumor shape deviation with respect to the BH CT scan, and noise were determined to evaluate the image fidelity of the MidP CT scan and the performance of the technique. RESULTS: Accuracy of the used deformable image registration method was comparable to established automated locally rigid registration and to manual landmark registration (average difference to both methods < 0.5 mm for all directions) for the tumor region. From visual assessment, the registration was good for the clearly visible features (e.g., tumor and diaphragm). The shape of the tumor, with respect to that of the BH CT scan, was better represented by the MidP reconstructions than any of the 4D CT frames (including MidV; reduction of "shape differences" was 66%). The MidP scans contained about one-third the noise of individual 4D CT scan frames. CONCLUSIONS: We implemented an accurate method to estimate the motion of structures in a 4D CT scan. Subsequently, a novel method to create a midposition CT scan (time-weighted average of the anatomy) for treatment planning with reduced noise and artifacts was introduced. Tumor shape and position in the MidP CT scan represents that of the BH CT scan better than MidV CT scan and, therefore, was found to be appropriate for treatment planning.

Laboratory and field validation of a combined NO2-SO2 Radiello passive sampler.

A combined NO2-SO2 Radiello radial-type diffusive sampler was validated under controlled laboratory conditions and compared with NO2-SO2 results of 3 other type of samplers in a field comparison at two locations Ghent-Mariakerke and Borgerhout in Flanders. Laboratory exposures at different temperatures (-5, 10 and 30 degrees C) and relative humidities (0, 50 and 80% RH) in combination with varying concentration levels and exposure times were carried out, with a focus on extreme conditions. Concentration level and exposure time were changed together following suppliers linear working range of samplers and assuring absolute amounts of compounds on the sampler corresponding to those of environmental levels. The average uptake rate for NO2 for 24 hour exposures at 10 degrees C and 50% RH and tested concentration levels (+/-73, 146 and 293 ppb NO2) was 0.076 +/- 0.011 ng ppb(-1) min(-1). Uptake rates during all experiments were lower than the uptake rate given in the instruction manual of the sampler. A significant effect of temperature and relative humidity on NO2 uptake rate was observed. The temperature effect from 10 to 30 degrees C corresponds to the temperature effect given by the supplier of the samplers. High relative humidity (70 to 80%) caused a strong non-reproducible decrease of uptake rate for NO2 at 24 hour experiments but this effect was not observed at longer exposures except for the tests at -5 degrees C. At the tested temperature below zero in combination with high relative humidity the sampler showed anomalous behaviour for NO2. The possible effect of concentration level and exposure time for NO2 needs further research. The average uptake rate for SO2 calculated from all exposures is 0.478 +/- 0.075 ng of sulfate ion each ppb min of SO2 and accords to suppliers uptake rate. No clear effects of temperature, relative humidity or concentration level/exposure time on the uptake rate for SO2 were found, partly due to the large scatter of results. Although NO2 accuracy of Radiello samplers was better during field campaigns than during laboratory validation, IVL and OGAWA samplers gave better results for NO2. In the field, IVL samplers showed best agreement with the continuous analyzers for both NO2 and SO2.

Fusion of respiration-correlated PET and CT scans: correlated lung tumour motion in anatomical and functional scans.

Lower lobe lung tumours in particular can move up to 2 cm in the cranio-caudal direction during the respiration cycle. This breathing motion causes image artefacts in conventional free-breathing computed tomography (CT) and positron emission tomography (PET) scanning, rendering delineation of structures for radiotherapy inaccurate. The purpose of this study was to develop a method for four-dimensional (4D) respiration-correlated (RC) acquisition of both CT and PET scans and to develop a framework to fuse these modalities. The breathing signal was acquired using a thermometer in the breathing airflow of the patient. Using this breathing signal, the acquired CT and PET data were grouped to the corresponding respiratory phases, thereby obtaining 4D CT and PET scans. Tumour motion curves were assessed in both image modalities. From these tumour motion curves, the deviation with respect to the mean tumour position was calculated for each phase. The absolute position of the centre of the tumour, relative to the bony anatomy, in the RCCT and gated PET scans was determined. This 4D acquisition and 4D fusion methodology was performed for five patients with lower lobe tumours. The peak-to-peak amplitude range in this sample group was 1-2 cm. The 3D tumour motion curve differed less than 1 mm between PET and CT for all phases. The mean difference in amplitude was less than 1 mm. The position of the centre of the tumour (relative to the bony anatomy) in the RCCT and gated PET scan was similar (difference <1 mm) when no atelectasis was present. Based on these results, we conclude that the method described in this study allows for accurate quantification of tumour motion in CT and PET scans and yields accurate respiration-correlated 4D anatomical and functional information on the tumour region.

Three-dimensional dose reconstruction of breast cancer treatment using portal imaging.

In this study, we present an algorithm for three-dimensional (3-D) dose reconstruction using portal images obtained with an electronic portal imaging device (EPID). For this purpose an algorithm for 2-D dose reconstruction, which was previously developed in our institution, was adapted. The external contour of the patient was used to correct for absorption of primary photons, but the presence of inhomogeneities was not taken into account. The accuracy of the algorithm was determined by irradiating two anthropomorphic breast phantoms with 6 MV photons. The dose values derived from portal images were compared with results from 3-D dose calculations, which, in turn, were verified with data obtained with an ionization chamber and film dosimetry. It was found that the application of contour information significantly improves the accuracy of 2-D dose reconstruction. If the total dose at the isocenter plane resulting from all treatment beams is reconstructed, the average deviation from the planned dose is 0.1%+/-1.7% (1 SD). If contour information is not available, the differences increase up to +/-20% for the individual beams. In that case, the dose can only be reconstructed with reasonable accuracy when (nearly) opposing beams are used. The average deviation of the 3-D reconstructed dose from the planned dose in the irradiated volume is 1.4%+/-5.4% (1 SD). If the irradiated volume is enclosed by planes less than 5 cm distant from the isocenter plane, then the average deviation is only 0.5%+/-3.4% (1 SD). It can be concluded that the proposed algorithm for a 3-D dose reconstruction allows a determination of the dose at the isocenter plane and the dose-volume histogram with an accuracy acceptable for an independent verification of the treatment.

Field size reduction enables iso-NTCP escalation of tumor control probability for irradiation of lung tumors.

PURPOSE: With the mean lung dose (MLD) as an estimator for the normal tissue complication probability (NTCP) of the lung, we assessed whether the probability of tumor control of lung tumors might be increased by dose escalation in combination with a reduction of field sizes, thus increasing target dose inhomogeneity while maintaining a constant MLD. METHODS AND MATERIALS: An 8-MV AP-PA irradiation of a lung tumor, located in a cylindrically symmetric lung-equivalent phantom, was modeled using numerical simulation. Movement of the clinical target volume (CTV) due to patient breathing and setup errors was simulated. The probability of tumor control, expressed as the equivalent uniform dose (EUD) of the CTV, was assessed as a function of field size, under the constraint of a constant MLD. The approach was tested for a treatment of a non-small cell lung cancer (NSCLC) patient using the beam directions of the clinically applied treatment plan. RESULTS: In the phantom simulation it was shown that by choosing field sizes that ensured a minimum dose of 95% in the CTV ("conventional" plan) taking into account setup errors and tumor motion, an EUD of the CTV of 43.8 Gy can be obtained for a prescribed dose of 44.2 Gy. By reducing the field size and thus shifting the 95% isodose surface inwards, the EUD increases to a maximum of 68.3 Gy with a minimum dose in the CTV of 55.2 Gy. This increase in EUD is caused by the fact that field size reduction enables escalation of the prescribed dose while maintaining a constant MLD. Further reduction of the field size results in decrease of the EUD because the minimum dose in the CTV becomes so low that it has a predominant effect on the EUD, despite further escalation of the prescribed dose. For the NSCLC patient, the EUD could be increased from an initial 62.2 Gy for the conventional plan, to 83.2 Gy at maximum. In this maximum, the prescribed dose is 88.1 Gy, and the minimum dose in the CTV is 67.4 Gy. In this case, the 95% isodose surface is conformed closely to the "static" CTV during treatment planning. CONCLUSIONS: Iso-NTCP escalation of the probability of tumor control is possible for lung tumors by reducing field sizes and allowing a larger dose inhomogeneity in the CTV. Optimum field sizes can be derived, having the highest EUD and highest minimum dose in the CTV under condition of a constant NTCP of the lungs. We conclude that the concept of homogeneous dose in the target volume is not the best approach to reach the highest probability of tumor control for lung tumors.

Impact of simple tissue inhomogeneity correction algorithms on conformal radiotherapy of lung tumours.

BACKGROUND AND PURPOSE: Conformal radiotherapy requires accurate dose calculation at the dose specification point, at other points in the planning target volume (PTV) and in organs at risk. To assess the limitations of treatment planning of lung tumours, errors in dose values, calculated by some simple tissue inhomogeneity correction algorithms available in a number of currently applied treatment planning systems, have been quantified. MATERIALS AND METHODS: Single multileaf collimator-shaped photon beams of 6, 8, 15 and 18 MV nominal energy were used to irradiate a 50 mm diameter spherical solid tumour, simulated by polystyrene, which was located centrally inside lung tissue, simulated by cork. The planned dose distribution was made conformal to the PTV, which was a 15 mm three-dimensional expansion of the tumour. Values of both the absolute dose at the International Commission on Radiation Units and Measurement (ICRU) reference point and relative dose distributions inside the PTV and in the lung were calculated using three inhomogeneity correction algorithms. The algorithms investigated in this study are the pencil beam algorithm with one-dimensional corrections, the modified Batho algorithm and the equivalent path length algorithm. The calculated data were compared with measurements for a simple beam set-up using radiographic film and ionization chambers. RESULTS: For this specific configuration, deviations of up to 3.5% between calculated and measured values of the dose at the ICRU reference point were found. Discrepancies between measured and calculated beam fringe values (distance between the 50 and 90% isodose lines) of up to 14 mm have been observed. The differences in beam fringe and penumbra width (20-80%) increase with increasing beam energy. Our results demonstrate that an underdosage of the PTV up to 20% may occur if calculated dose values are used for treatment planning. The three algorithms predict a considerably higher dose in the lung, both along the central beam axis and in the lateral direction, compared with the actual delivered dose values. CONCLUSIONS: The dose at the ICRU reference point of such a tumour in lung geometry is calculated with acceptable accuracy. Differences between calculated and measured dose distributions are primarily due to changes in electron transport in the lung, which are not adequately taken into account by the simple tissue inhomogeneity correction algorithms investigated in this study. Particularly for high photon beam energies, clinically unacceptable errors will be introduced in the choice of field sizes employed for conformal treatments, leading to underdosage of the PTV. In addition, the dose to the lung will be wrongly predicted which may influence the choice of the prescribed dose level in dose-escalation studies.

Anticancer prodrugs for application in monotherapy: targeting hypoxia, tumor-associated enzymes, and receptors.

In order to improve current chemotherapeutic treatment and diminish severe side effects, several prodrug strategies have evolved to achieve site-specific delivery of cytotoxic anticancer agents. This review concentrates on recent developments of antitumor prodrug monotherapy with prodrugs that are designed for direct recognition of tumor-associated factors, such as hypoxia, tumor-associated enzymes and receptors. Firstly, oxygen deficiency in the core of solid tumors leads to enhanced activity of reducing enzymes, like for example nitroreductases, which can be used for site- specific conversion of prodrug to drug. Secondly, some enzymes are present in elevated levels in tumor tissue: beta-glucuronidase leaks from necrotic areas within tumors, while tumor cells for invasive and metastatic activities need several tumor-associated proteases, like plasmin. These enzymes form an attractive target for designing selective prodrugs. Finally, tumor-selective expression of receptors can be exploited for the delivery of antitumor agents. Low molecular weight binding motifs for these receptors can be coupled to cytotoxic drugs in order to obtain tumor-homing conjugates. At present, receptor-binding motifs for a number of receptors that are required for angiogenesis are used for prodrug monotherapy. There exists an increasing body of literature, which describes the complex interplay not only between tumor-associated enzymes, but also between these enzymes and tumor-associated receptors in the process of tumor invasion and metastasis, indicating the feasibility of targeting cytotoxic drugs to these key players in tumor growth. This paper reviews the development and evaluation of anticancer prodrugs, and their application in the various prodrug monotherapy approaches.

The effect of breathing and set-up errors on the cumulative dose to a lung tumor.

BACKGROUND AND PURPOSE: To assess the impact of both set-up errors and respiration-induced tumor motion on the cumulative dose delivered to a clinical target volume (CTV) in lung, for an irradiation based on current clinically applied field sizes. MATERIALS AND METHODS: A cork phantom, having a 50 mm spherically shaped polystyrene insertion to simulate a gross tumor volume (GTV) located centrally in a lung was irradiated with two parallel opposed beams. The planned 95% isodose surface was conformed to the planning target volume (PTV) using a multi leaf collimator. The resulting margin between the CTV and the field edge was 16 mm in beam's eye view. A dose of 70 Gy was prescribed. Dose area histograms (DAHs) of the central plane of the CTV (GTV+5 mm) were determined using radiographic film for different combinations of set-up errors and respiration-induced tumor motion. The DAHs were evaluated using the population averaged tumor control probability (TCP(pop)) and the equivalent uniform dose (EUD) model. RESULTS: Compared with dose volume histograms of the entire CTV, DAHs overestimate the impact of tumor motion on tumor control. Due to the choice of field sizes a large part of the PTV will receive a too low dose resulting in an EUD of the central plane of the CTV of 68.9 Gy for the static case. The EUD drops to 68.2, 66.1 and 51.1 Gy for systematic set-up errors of 5, 10 and 15 mm, respectively. For random set-up errors of 5, 10 and 15 mm (1 SD), the EUD decreases to 68.7, 67.4 and 64.9 Gy, respectively. For similar amplitudes of respiration-induced motion, the EUD decreases to 68.8, 68.5 and 67.7 Gy, respectively. For a clinically relevant scenario of 7.5 mm systematic set-up error, 3 mm random set-up error and 5 mm amplitude of breathing motion, the EUD is 66.7 Gy. This corresponds with a tumor control probability TCP(pop) of 41.7%, compared with 50.0% for homogeneous irradiation of the CTV to 70 Gy. CONCLUSION: Systematic set-up errors have a dominant effect on the cumulative dose to the CTV. The effect of breathing motion and random set-up errors is smaller. Therefore the gain of controlling breathing motion during irradiation is expected to be small and efforts should rather focus on minimizing systematic errors. For the current clinically applied field sizes and a clinically relevant combination of set-up errors and breathing motion, the EUD of the central plane of the CTV is reduced by 3.3 Gy, at maximum, relative to homogeneous irradiation of the CTV to 70 Gy, for our worst case scenario.

Neurological disease associated with EHV-1-infection in a riding school: clinical and virological characteristics.

An outbreak of neurological disease caused by EHV-1 infection is described with emphasis on diagnosis and prognosis for recumbent horses. In April 1995, an outbreak of the neurological form of Equine herpesvirus type 1 (EHV-1) occurred in a well-managed riding school with 41 horses: 34 horses showed a temperature spike and 20 some degree of neurological signs, of which 10 were nursed intensively in the indoor arena of the riding school for 3 to 20 days, 8 having to be maintained in slings for 2-18 days, while 9 needed bladder catheterisation b.i.d. for 2-16 days. Within the first 3 days, one horse was subjected to euthanasia and another horse died. Postmortem examination revealed a mild vasculitis with perivascular mononuclear cuffing and axonal degeneration in the central nervous system. Clinical diagnosis was confirmed by serology and virology: 28 horses seroconverted in one or more tests during the outbreak, whereas 12 had already high CF and SN titres in the first sample, suggestive of recent infection. Virus was isolated from nasal swabs of 4 horses, and identified as EHV-1 with type-specific monoclonal antibodies. Restriction enzyme analysis revealed that the EHV-1 strains from this outbreak belonged to genome type EHV-1.IP. The electropherotypes were identical to those from another, epidemiologically unrelated, outbreak of neurological disease 2 months earlier. The timing of the temperature spikes and seroconversions indicated that the infection was probably introduced by a horse purchased 3 weeks before neurological signs occurred. At follow-up one year later, the 10 horses that showed mild neurological signs had recovered completely. Of the 8 horses that survived intensive care, 3 had returned to around their former performance level (2 of which had been in slings), while the other 5 had become pasture-sound. At follow-up 4 years later, all pasture-sound horses had been subjected to euthanasia because of persistent mild ataxia and incontinence. In conclusion, the prognosis for recumbent horses due to EHV-1 infection is grave. For virological diagnosis, extensive and strategic sampling of febrile in-contact horses is required, and the EHV-1-specific glycoprotein G (gG) ELISA is a valuable tool for specific serological diagnosis of EHV-1 infection causing neurological disease.

Planning, computer optimization, and dosimetric verification of a segmented irradiation technique for prostate cancer.

PURPOSE: To develop and verify a multisegment technique for prostate irradiation that results in better sparing of the rectal wall compared to a conventional three-field technique, for patients with a concave-shaped planning target volume (PTV) overlapping the rectal wall. METHODS AND MATERIALS: Five patients have been selected with various degrees of overlap between PTV and rectal wall. The planned dose to the ICRU reference point is 78 Gy. The new technique consists of five beams, each having an open segment covering the entire PTV and several smaller segments in which the rectum is shielded. Segment weights are computer-optimized using an algorithm based on simulated annealing. The score function to be minimized consists of dose-volume constraints for PTV, rectal wall, and femoral heads. The resulting dose distribution is verified for each patient by using point measurements and line scans made with an ionization chamber in a water tank and by using film in a cylindrical polystyrene phantom. RESULTS: The final number of segments in the five-field technique ranges from 7 to 9 after optimization. Compared to the standard three-field technique, the maximum dose to the rectal wall decreases by approximately 3 Gy for patients with a large overlap and 1 Gy for patients with no overlap, resulting in a reduction of the normal tissue complication probability (NTCP) by a factor of 1.3 and 1.2, respectively. The mean dose to the PTV is the same for the two techniques, but the dose distribution is slightly less homogeneous with the five-field technique (Average standard deviation of five patients is 1.1 Gy and 1.7 Gy for the three-field and five-field technique, respectively). Ionization chamber measurements show that in the PTV, the calculated dose is in general within 1% of the measured dose. Outside the PTV, systematic dose deviations of up to 3% exist. Film measurements show that for the complete treatment, the position of the isodose lines in sagittal and coronal planes is calculated fairly accurately, the maximum distance between measured and calculated isodoses being 4 mm. CONCLUSIONS: We developed a relatively simple multisegment "step-and-shoot" technique that can be delivered within an acceptable time frame at the treatment machine (Extra time needed is approximately 3 minutes). The technique results in better sparing of the rectal wall compared to the conventional three-field technique. The technique can be planned and optimized relatively easily using automated procedures and a predefined score function. Dose calculation is accurate and can be verified for each patient individually.

Changes in local pulmonary injury up to 48 months after irradiation for lymphoma and breast cancer.

PURPOSE: To assess the recovery from early local pulmonary injury after irradiation and to determine whether regional differences exist. METHODS: For 110 patients treated for breast cancer or malignant lymphoma, single photon emission computed tomography (SPECT) perfusion and ventilation scans and CT scans were made before, 3, 18, and 48 months after radiotherapy. Dose-effect relations for changes in local perfusion, ventilation, and density were determined for each individual patient using spatially correlated SPECT and CT data sets, for each follow-up period. Average dose-effect relations for both subgroups were determined, as well as dose-effect relations for different regions. RESULTS: In general, partial improvement of local pulmonary injury was observed between 3 and 18 months for each of the three endpoints. After 18 months, no further improvement was seen. Patients with breast cancer and malignant lymphoma showed a similar improvement (except for the perfusion parameter), which was attributed to a recovery from the early radiation response and could not be explained by contraction effects of fibrosis of lung parenchyma. No regional differences in radiosensitivity 18 months after treatment were observed, except for the dorsal versus ventral region. This difference was attributed to a gravity-related effect in the measuring procedure. CONCLUSION: For all patients, a partial recovery from early local perfusion, ventilation, and density changes, was seen between 3 and 18 months after radiotherapy. After 18 months, local lung function did not further improve (lymphoma patients).

Paclitaxel esters of malic acid as prodrugs with improved water solubility.

The synthesis of paclitaxel esters of malic acid is described. These compounds were found to have improved water solubility and are stable in solution at neutral pH. The C2' modified compounds behave as prodrugs, that is, paclitaxel is generated upon exposure to human plasma, whereas the C7 modified derivatives do not. 2'-Malyl paclitaxel sodium salt demonstrated enhanced antitumour activity and less toxicity in a P388 murine leukaemia in vivo model when compared to paclitaxel.

Novel anthracycline-spacer-beta-glucuronide,-beta-glucoside, and -beta-galactoside prodrugs for application in selective chemotherapy.

A series of anthracycline prodrugs containing an immolative spacer was synthesized for application in selective chemotherapy. The prodrugs having the general structure anthracycline-spacer-beta-glycoside were designed to be activated by beta-glucuronidase or beta-galactosidase. Prodrugs with -chloro, -bromo or -n-hexyl substituents on the spacer were synthesized as well as prodrugs containing a -beta-glucuronyl, -beta-glucosyl or -beta-galactosyl carbamate specifier. The key step in the synthesis of all prodrugs is the highly beta-diastereoselective addition reaction of the anomeric hydroxyl of a glycosyl donor to a spacer isocyanate resulting in the respective beta-glycosyl carbamate pro-moieties. The resulting protected pro-moieties were coupled to an anthracycline. Prodrugs were evaluated with respect to activation rate by the appropriate enzyme and additionally, their IC50 values were determined. Optimal prodrugs in this study were at least 100- to 200-fold less toxic than their corresponding drug in vitro and were activated to the parent drug in a half-life time of approximately 2 h.

Dose-effect relations for early local pulmonary injury after irradiation for malignant lymphoma and breast cancer.

PURPOSE: To quantify the influence of treatment- and patient-related factors on the severity of early local pulmonary injury and to establish whether regional differences are present for local dose-effect relations for early radiation-induced pulmonary injury. METHODS: Forty-two patients with malignant lymphoma and 40 breast cancer patients were examined prior to and 3 months after radiotherapy. The lymphoma patients were irradiated with mantle fields to an average dose of 38 Gy and the breast cancer patients were irradiated with internal mammary node fields with or without tangential breast fields to an average dose of 50 Gy. Dose-effect relations for local perfusion, ventilation and density changes were determined using correlated single photon emission computed tomography (SPECT) and CT data. A multivariate analysis was performed to study the influence of irradiated volume, chemotherapy (CMF and MOPP/ABV), smoking, age and gender. In addition, dose-effect relations for different regions in the lung were determined. RESULTS: A similar and almost linear increase of early functional changes as a function of radiation dose was observed for perfusion and ventilation, whereas the shape of the dose-effect relation and the magnitude of early structural changes were different for density. For the three end-points studied, regional differences in radiosensitivity could not be demonstrated. For the posterior lung region compared to the anterior lung region, however, a difference was observed, which could be attributed to a gravity-related effect in the measuring procedure. Local structural changes (density) were significantly smaller for smokers (P = 0.002) and young patients (P = 0.007), whereas the CMF chemotherapy regimen given after radiotherapy (P = 0.017) significantly increased the amount of functional changes (perfusion). The magnitude of local pulmonary changes was independent of the irradiated volume, the MOPP/ABV chemotherapy regimen and gender. CONCLUSION: The dose-effect relations for early radiation-induced local pulmonary changes were independent of the irradiated volume, MOPP/ABV, gender and lung region. CMF, smoking and age influenced the magnitude of early pulmonary changes and should be taken into account in dose-escalation protocols.

Evaluation of two dose-volume histogram reduction models for the prediction of radiation pneumonitis.

PURPOSE: To evaluate the similarities between the mean lung dose and two dose-volume histogram (DVH) reduction techniques of 3D dose distributions of the lung. PATIENTS AND METHODS: DVHs of the lungs were calculated from 3D dose distributions of patients treated for malignant lymphoma (44), breast cancer (42) and lung cancer (20). With a DVH reduction technique, a DVH is summarized by the equivalent uniform dose (EUD), a quantity which is directly related to the normal tissue complication probability (NTCP). Two DVH reduction techniques were used. The first was based on an empirical model proposed by Kutcher et al. (Kutcher, G.J., Burman, C., Brewster, M.S., Goitein, M. and Mohan, R. Histogram reduction method for calculating complication probabilities for three-dimensional treatment planning evaluations. Int. J. Radiat. Oncol. Biol. Phys. 21: 137-146, 1991), which needs a volume exponent n. Several values for n were tested. The second technique was based on a radiobiological model, the parallel functional subunit model developed by Niemierko et al. (Niemierko, A. and Goitein, M. Modeling of normal tissue response to radiation: the critical volume model. Int. J. Radiat. Oncol. Biol. Phys. 25: 135-145, 1993) and Jackson et al. (Jackson, A., Kutcher, G.J. and Yorke, E.D. Probability of radiation-induced complications for normal tissues with parallel architecture subject to non-uniform irradiation. Med. Phys. 20: 613-625, 1993), for which a local dose-effect relation needed to be specified. This relation was obtained from an analysis of perfusion and ventilation SPECT data. RESULTS: It can be shown analytically that the two DVH reduction techniques are identical, if the local dose-effect relation obeys a power-law relationship in the clinical dose range. Local dose-effect relations based on perfusion and ventilation SPECT data can indeed be fitted with a power-law relationship in the range 0-80 Gy, from which values of n = 0.8-0.9 were deduced. These correspond to the commonly used value of n = 0.87 for lung tissue and yielded EUDn=0.87 values which were almost identical to the mean lung doses. For other n values, for which no experimental data are present, differences exist between EUD and mean dose values. Six patients with malignant lymphoma (6/44) and none of the breast cancer patients (0/42) developed radiation pneumonitis. These cases occurred only at high values for the mean lung dose. CONCLUSION: The two DVH reduction techniques are identical for lung and are very similar to mean dose calculations. The two techniques are also relatively similar for other model parameter values.

Automatic three-dimensional matching of CT-SPECT and CT-CT to localize lung damage after radiotherapy.

UNLABELLED: The aim of this study was to develop a fast and clinically robust automatic method to register SPECT and CT scans of the lungs. METHODS: CT and SPECT scans were acquired in the supine position from 20 patients with healthy lungs. After partial irradiation of the lungs by radiotherapy, the scans were repeated. Two matching methods were compared: a conventional method with external skin markers and a new method using chamfer matching of the lung contours. In the latter method, a unique value for the SPECT threshold, needed for segmentation of the SPECT lungs, was determined by iteratively applying the chamfer matching algorithm. RESULTS: The new technique for CT-SPECT matching could be implemented in a fully automatic manner and required less than 2 min. No large systematic shifts or rotations were present between the matches obtained with the marker method and the lung contour method for healthy or partially irradiated lungs. For healthy lungs, the number of ventilation SPECT counts outside the CT-defined lung was taken as a measure for a good match. This number of outside counts was slightly lower for the new method than for the conventional method, which indicates that the accuracy of the new method is at least comparable to the conventional method. For ventilation, a systematic difference between the results of the matching methods, a small translation in the anterior --> posterior direction, could be attributed to an inconsistency of the marker positions (2 mm). For perfusion, a somewhat larger anterior --> posterior shift was found, which was attributed to the gravity force. CT-CT correlation on the lung contours using chamfer matching was tested with the same dataset. For accurate matching, the CT slices encompassing the diaphragm had to be deleted. CONCLUSION: The new method based on lung contour matching is a fast, automatic procedure and allows accurate clinical follow-up.

Prediction of overall pulmonary function loss in relation to the 3-D dose distribution for patients with breast cancer and malignant lymphoma.

PURPOSE: To predict the changes in pulmonary function tests (PFTs) 3-4 months after radiotherapy based on the three-dimensional (3-D) dose distribution and taking into account patient- and treatment-related factors. METHODS: For 81 patients with malignant lymphoma and breast cancer, PFTs (VA, VC, FEV1 and TL,COc) were performed prior to and 3-4 months after irradiation and dose-effect relations for early changes in local perfusion, ventilation and air-filled fraction were determined using correlated CT and SPECT data. The 3-D dose distribution of each patient was converted into four different dose-volume parameters, i.e. the mean dose in the lung and three overall response parameters (ORPs, which represent the average local injury over the complete lung). ORPs were determined using the dose-effect relations for early changes in local perfusion, ventilation and air-filled fraction. Correlation coefficients were calculated between these dose-volume parameters and the changes in PFTs. In addition, the impact of the variables chemotherapy (MOPP/ABV and CMF), tamoxifen, smoking, age and gender on the relation between the mean lung dose and the relative changes in PFTs following radiotherapy was studied using multiple regression analysis. RESULTS: The mean lung dose proved to be the easiest parameter to predict the reduction in PFTs 3-4 months following radiotherapy. For all patients the relation between the mean lung dose and the changes in PFTs could be described with one regression line through the origin and a slope of 1% reduction in PFT for each increase of 1 Gy in mean lung dose. Smoking and CMF chemotherapy influenced the reduction in PFTs significantly for VA and TL,COc, respectively. Patients treated with MOPP/ABV prior to radiotherapy had lower pre-radiotherapy PFTs than other patient groups, but did not show further deterioration after radiotherapy (at 3-4 months). CONCLUSIONS: The relative reduction in VA, VC, FEV1 and TL,COc 3-4 months after radiotherapy for breast cancer and malignant lymphoma can be estimated before radiotherapy based on the mean lung dose of each individual patient and taking into account the use of chemotherapy and smoking habits of the patient.

An analysis of the effect of ovoid shields in a selectron-LDR cervical applicator on dose distributions in rectum and bladder.

PURPOSE: A disadvantage of ovoid shields in a Fletcher-type applicator is that these shields cause artifacts on postimplant CT images. CT images, however, make it possible to calculate the dose distribution in the rectum and the bladder. To be able to estimate the possible advantage of having CT information over the use of ovoid shields without having CT information, we investigated the influence of shielding segments in a Fletcher-type Selectron-LDR applicator on the dose distribution in rectum and bladder. METHODS AND MATERIALS: Contours of rectum and bladder were delineated on transaxial CT slices of 15 unshielded applications. Of the volumes contained within these structures dose-volume histograms (DVHs) were calculated. In a similar way, DVHs of simulated shielded applications were calculated. The reduction, due to shielding, of the dose to the 2 cm3 (D2) and 5 cm3 (D5) volume of the cumulative DVHs of rectum and bladder, were determined. An isodose pattern in the sagittal plane through the center of each applicator was plotted to compare the location of the shielded area with the location of maximum dose in rectum and bladder in the unshielded situation. In two cases local dose reductions to the rectal wall were determined by calculating the dose in points at 10-mm intervals on the rectal contours. RESULTS: For the rectum, the reduction of D2 ranged from 0 to 11.1%, with an average of 5.0%; the reduction of D5 ranged from 2.3 to 12.1%, with an average of 6.4%. The reduction of D2 and D5 for the bladder ranged from 0 to 11.9% and from 0 to 11.6%, with average values of 2.2 and 2.6%, respectively. In 8 out of 15 cases the rectal maximum dose was located inferior to the shielded area. In all cases except one the bladder maximum dose was located superior to the shielded area. Local dose reductions on the rectal wall can be as high as 30% or more in an optimally shielded area. CONCLUSIONS: Reductions of D2 and D5 to rectum and bladder due to shielding are rather small, because the shielded area does usually not coincide with the high dose region and even if it does, the shielded area is too small to result in large reductions of these values. Because local dose reductions vary largely, one should proceed with caution when calculating the dose in just one rectal or bladder reference point. Because large overall dose reductions cannot be achieved with shielding, it is safe to use an unshielded applicator when post implant CT images are used to realize optimized dose distributions.

The differential effects of extremity and movement side on the scalp distribution of the readiness potential (RP) and the stimulus-preceding negativity (SPN).

In a time estimation task subjects had to press a button 3 s after the presentation of a warning stimulus. Two seconds after the movement they were informed about their performance by a knowledge of results (KR) stimulus. Preceding the movement a readiness potential (RP) and prior to the presentation of the KR stimulus a stimulus-preceding negativity (SPN) was recorded. Movement side (left/right) and extremity (hand/foot) were varied within subjects to demonstrate that the RP but not the SPN is affected by such manipulations. The scalp distribution of the late part of the RP was affected by movement side and extremity. Yet it exhibited the expected lateral asymmetry only preceding a movement of the left hand or of the right foot. The scalp distribution of the SPN was not affected by extremity. The size of the right hemisphere preponderance of the SPN depended on movement side following a finger flexion, but not following a plantar flexion of the foot. The experimental design was intended to avoid the temporal overlap between movement-related and stimulus-related activity. Yet it is argued that both results of this experiment can best be explained by such an overlap.