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The convolution method can be used to model the effect of random geometric uncertainties into planned dose distributions used in radiation treatment planning. This is effectively done by linearly adding infinitesimally small doses, each with a particular geometric offset, over an assumed infinite number of fractions. However, this process inherently ignores the radiobiological dose-per-fraction effect since only the summed physical dose distribution is generated. The resultant potential error on predicted radiobiological outcome [quantified in this work with tumor control probability (TCP), equivalent uniform dose (EUD), normal tissue complication probability (NTCP), and generalized equivalent uniform dose (gEUD)] has yet to be thoroughly quantified. In this work, the results of a Monte Carlo simulation of geometric displacements are compared to those of the convolution method for random geometric uncertainties of 0, 1, 2, 3, 4, and 5 mm (standard deviation). The alpha/betaCTV ratios of 0.8, 1.5, 3, 5, and 10 Gy are used to represent the range of radiation responses for different tumors, whereas a single alpha/betaOAR ratio of 3 Gy is used to represent all the organs at risk (OAR). The analysis is performed on a four-field prostate treatment plan of 18 MV x rays. The fraction numbers are varied from 1-50, with isoeffective adjustments of the corresponding dose-per-fractions to maintain a constant tumor control, using the linear-quadratic cell survival model. The average differences in TCP and EUD of the target, and in NTCP and gEUD of the OAR calculated from the convolution and Monte Carlo methods reduced asymptotically as the total fraction number increased, with the differences reaching negligible levels beyond the treatment fraction number of > or =20. The convolution method generally overestimates the radiobiological indices, as compared to the Monte Carlo method, for the target volume, and underestimates those for the OAR. These effects are interconnected and attributed to assuming an infinite number of fractions inherent in the implementation of the convolution technique, irrespective of the uniqueness of each treatment schedule. Based on the fraction numbers analyzed (1-50), and the range of fraction numbers normally used clinically (> or =20), the convolution method can be used safely to estimate the effects of random geometric uncertainties on prostate treatment radiobiological outcomes, for both the target and the OAR. Although the results of this study is likely to apply to other clinical sites and treatment techniques other than the four-field, further validation similar to those done in this study may be necessary prior to clinical implementation.

Purpose: The evolution of three-dimensional conformal radiation treatment has led to the use of multileaf collimators (MLCs) in intensity-modulated radiation therapy (IMRT) and other treatment techniques to increase the conformity of the dose distribution. A new quality assurance (QA) phantom has been designed to check the handling of MLC settings in treatment planning and delivery., Methods and Materials: The phantom consists of a Perspex block with stepped edges that can be rotated in all planes. The design allows for the assessment of several MLC and micro-MLC types from various manufacturers, and is therefore applicable to most radiation therapy institutions employing MLCs. The phantom is computed tomography (CT) scanned as is a patient, and QA assessments can be made of field edge display for a variety of shapes and orientations on both radiation treatment planning systems (RTPS) and computed tomography simulators., Results: The dimensions of the phantom were verified to be physically correct within an uncertainty range of 0-0.7 mm. Errors in leaf position larger than 1 mm were easily identified by multiple observers., Conclusions: The MLC geometry phantom is a useful tool in the QA of radiation therapy with application to RTPS, CT simulators, and virtual simulation packages with MLC display capabilities.

Helical tomotherapy (HT) is a novel radiotherapy technique that utilizes intensity modulated fan beams that deliver highly conformal dose distributions in a helical beam trajectory. The most significant limitation in dose delivery with a constant fan beam thickness (FBT) is the penumbra width of the dose distribution in the craniocaudal direction, which is equivalent to the FBT. We propose to employ a half-blocked fan beam at start and stop location to reduce the penumbra width by half. By opening the jaw slowly during the helical delivery until the desired FBT is achieved it is possible to create a sharper edge in the superior and inferior direction from the target. The technique was studied using a tomotherapy beam model implemented on a commercial treatment planning system (Theraplan Plus V3.0). It was demonstrated that the dose distribution delivered using a 25 mm fan beam can be improved significantly, to reduce the dose to normal structures located superiorly and inferiorly of the target. Dosimetry for this technique is straightforward down to a FBT of 15 mm and implementation should be simple as no changes in couch movement are required compared to a standard HT delivery. We conclude that the use of asymmetric collimated fan beams for the start and stop of the helical tomotherapeutic dose delivery has the potential of significantly improving the dose distribution in helical tomotherapy.

Lung cancer treatment is one of the most challenging fields in radiotherapy. The aim of the present study was to investigate what role helical tomotherapy (HT), a novel approach to the delivery of highly conformal dose distributions using intensity-modulated radiation fan beams, can play in difficult cases with large target volumes typical for many of these patients. Tomotherapy plans were developed for 15 patients with stage III inoperable non-small-cell lung cancer. While not necessarily clinically indicated, elective nodal irradiation was included for all cases to create the most challenging scenarios with large target volumes. A 2 cm margin was used around the gross tumour volume (GTV) to generate primary planning target volume (PTV2) and 1 cm margin around elective nodes for secondary planning target volume (PTV1) resulting in PTV1 volumes larger than 1000 cm3 in 13 of the 15 patients. Tomotherapy plans were created using an inverse treatment planning system (TomoTherapy Inc.) based on superposition/convolution dose calculation for a fan beam thickness of 25 mm and a pitch factor between 0.3 and 0.8. For comparison, plans were created using an intensity-modulated radiation therapy (IMRT) approach planned on a commercial treatment planning system (TheraplanPlus, Nucletron). Tomotherapy delivery times for the large target volumes were estimated to be between 4 and 19 min. Using a prescribed dose of 60 Gy to PTV2 and 46 Gy to PTV1, the mean lung dose was 23.8+/-4.6 Gy. A 'dose quality factor' was introduced to correlate the plan outcome with patient specific parameters. A good correlation was found between the quality of the HT plans and the IMRT plans with HT being slightly better in most cases. The overlap between lung and PTV was found to be a good indicator of plan quality for HT. The mean lung dose was found to increase by approximately 0.9 Gy per percent overlap volume. Helical tomotherapy planning resulted in highly conformal dose distributions. It allowed easy achievement of two different dose levels in the target simultaneously. As the overlap between PTV and lung volume is a major predictor of mean lung dose, future work will be directed to control of margins. Work is underway to investigate the possibility of breath-hold techniques for tomotherapy delivery to facilitate this aim.

Background and Purpose: To perform a systematic review of the predictive ability of various dose-volume histogram (DVH) parameters (V(dose), mean lung dose (MLD), and normal tissue complication probability (NTCP)) in the incidence of radiation pneumonitis (RP) caused by external-beam radiation therapy., Methods and Materials: Studies assessing the relationship between CT-based DVH reduction parameters and RP rate in radically treated lung cancer were eligible for the review. Synonyms for RP, lung cancer, DVH and its associated parameters (NTCP, V(20), V(30), MLD) were combined in a search strategy involving electronic databases, secondary reference searching, and consultation with experts. Individual or group data were abstracted from the various reports to calculate operating characteristics and odds ratios for the different DVH metrics., Results: A total of 12 published studies and two abstracts were identified. Eleven studies assessed V(dose), seven assessed MLD, and eight assessed NTCP. Nine studies exclusively analyzed the association between various DVH metrics and RP risk. Five studies also analyzed other patient, tumor, and treatment variables in conjunction with standard DVH metrics. A direct comparison between studies and the generation of summary statistics (i.e. meta-analysis) could not be achieved due to significant predictive and outcome variable heterogeneity. Most studies did show an association between DVH parameters and RP risk. However, overall accuracy, sensitivity, specificity, and positive predictive value were generally poor to fair for all three classes of DVH metrics., Conclusions: An association between DVH parameters and RP risk has been demonstrated in the literature. However, the ideal DVH metric with excellent operating characteristics, either alone or in a model with other predictive variables, for RP risk prediction has not yet been identified. Several recommendations for reporting and conduct of future research into the association between DVH metrics and RP risk are provided.

Background and Purpose: To assess the patterns of practice among Canadian radiation oncologists who treat lung cancers., Patients and Methods: A questionnaire detailing different aspects of radiation treatment of lung cancer was mailed to all radiation oncologists treating lung cancer in Canada. Seventy-two percent (74/103) of radiation oncologists who treat lung cancer from all 34 Canadian cancer centres replied to the questionnaire., Results: (a) Radiotherapy regimens in Canadian cancer centres are in accordance with several major randomised studies. There is still some variation in treatment practice that may be due to unresolved controversies or limited resources. The most frequently used prescription dose was 40Gy/15f/3w (where f stands for fractions and w stands for weeks) for small cell lung cancer (SCLC) and 60Gy/30f/6w for non-small cell lung cancer (NSCLC). If there were no resource constraints, 30% (22/74) and 20% (15/74) would prefer to use a different dose-fractionation scheme for SCLC and NSCLC, respectively; 95% (70/74) would prefer to use 3D-conformal or intensity-modulated radiotherapy. (b) Among the various modern technologies assessed by respondents, CT (computed tomography) simulator, multi-leaf collimator, on-line electronic portal imaging and PET (positron-emission tomography) scanning were rated the highest in terms of potential patient benefit. Discrepancy between demand and availability of technology was greatest for PET scanning., Conclusions: Canadian practice in the treatment of lung cancers shows some variations although it is consistent with the trends in the literature. The lack of some modern technologies and human resources is an ongoing concern, especially the lack of PET imaging equipment.

The goal of this research is to calculate the daily and cumulative dose distribution received by the radiotherapy patient while accounting for variable anatomy, by tracking the dose distribution delivered to tissue elements (voxels) that move within the patient. Non-linear image registration techniques (i.e., thin-plate splines) are used along with a conventional treatment planning system to combine the dose distributions computed for each 3D computed tomography (CT) study taken during treatment. For a clinical prostate case, we demonstrate that there are significant localized dose differences due to systematic voxel motion in a single fraction as well as in 15 cumulative fractions. The largest positive dose differences in rectum, bladder and seminal vesicles were 29%, 2% and 24%, respectively, after the first fraction of radiation treatment compared to the planned dose. After 15 cumulative fractions, the largest positive dose differences in rectum, bladder and seminal vesicles were 23%, 32% and 18%, respectively, compared to the planned dose. A sensitivity analysis of control point placement is also presented. This method provides an important understanding of actual delivered doses and has the potential to provide quantitative information to use as a guide for adaptive radiation treatments.

Purpose: Recent publications indicate alpha/beta for prostate carcinoma could be lower than assumed. Therefore, hypofractionation might increase the therapeutic ratio. However, patient repositioning and organ motion may affect hypofractionated treatments more than conventional treatments. Our purpose is to evaluate the potential impact of geometric uncertainties on hypofractionated treatments., Methods and Materials: Tumor control probability (TCP) and normal tissue complication probability (NTCP) are calculated for simulated conventional and hypofractionated treatments, assuming alpha/beta of 1.5 Gy for prostate and 3.0 Gy for rectum. A Monte Carlo simulation randomly samples systematic and random displacements and produces the cumulative dose distribution for the prostate and rectum. The limiting number of fractions and the impact of different alpha/beta values are also explored., Results: A consistent but small reduction in TCP is seen with hypofractionation (generally <1%) as a result of geometric uncertainties. Escalated hypofractionation seems to allow large TCP gains ( approximately 20%) without increasing NTCP. Treatments of five fractions seem to affect outcome minimally. The alpha/beta value has a much greater impact on TCP than geometric uncertainties., Conclusion: The potential increased influence of geometric uncertainties on hypofractionation seems small. Limited knowledge of radiobiologic response is likely a greater obstacle to prostate hypofractionation than geometric uncertainties.

The objective of this study is to seek an accurate and efficient method to calculate the dose distribution of a photon arc. The algorithms tested include Monte Carlo, pencil beam kernel (PK), and collapsed cone convolution (CCC). For the Monte Carlo dose calculation, EGS4/DOSXYZ was used. The SRCXYZ source code associated with the DOSXYZ was modified so that the gantry angle of a photon beam would be sampled uniformly within the arc range about an isocenter to simulate a photon arc. Specifically, photon beams (6/18 MV, 4 x 4 and 10 x 10 cm2) described by a phase space file generated by BEAM (MCPHS), or by two point sources with different photon energy spectra (MCDIV) were used. These methods were used to calculate three-dimensional (3-D) distributions in a PMMA phantom, a cylindrical water phantom, and a phantom with lung inhomogeneity. A commercial treatment planning system was also used to calculate dose distributions in these phantoms using equivalent tissue air ratio (ETAR), PK and CCC algorithms for inhomogeneity corrections. Dose distributions for a photon arc in these phantoms were measured using a RK ion chamber and radiographic films. For homogeneous phantoms, the measured results agreed well (approximately 2% error) with predictions by the Monte Carlo simulations (MCPHS and MCDIV) and the treatment planning system for the 180 degrees and 360 degrees photon arcs. For the dose distribution in the phantom with lung inhomogeneity with a 90 degrees photon arc, the Monte Carlo calculations agreed with the measurements within 2%, while the treatment planning system using ETAR, PK and CCC underestimated or overestimated the dose inside the lung inhomogeneity from 6% to 12%.

This document presents recommendations of the American Association of Physicists in Medicine (AAPM) for quality assurance of computed-tomography- (CT) simulators and CT-simulation process. This report was prepared by Task Group No. 66 of the AAPM Radiation Therapy Committee. It was approved by the Radiation Therapy Committee and by the AAPM Science Council.

Convolution methods can be used to model the effect of geometric uncertainties on the planned dose distribution in radiation therapy. This requires several assumptions, including that the patient is treated with an infinite number of fractions, each delivering an infinitesimally small dose. The error resulting from this assumption has not been thoroughly quantified. This is investigated by comparing dose distributions calculated using the Convolution method with the result of Stochastic simulations of the treatment. Additionally, the dose calculated using the conventional Static method, a Corrected Convolution method, and a Direct Simulation are compared to the Stochastic result. This analysis is performed for single beam, parallel opposed pair, and four-field box techniques in a cubic water phantom. Treatment plans for a simple and a complex idealized anatomy were similarly analyzed. The average maximum error using the Static method for a 30 fraction simulation for the three techniques in phantoms was 23%, 11% for Convolution, 10% for Corrected Convolution, and 10% for Direct Simulation. In the two anatomical examples, the mean error in tumor control probability for Static and Convolution methods was 7% and 2%, respectively, of the result with no uncertainty, and 35% and 9%, respectively, for normal tissue complication probabilities. Convolution provides superior estimates of the delivered dose when compared to the Static method. In the range of fractions used clinically, considerable dosimetric variations will exist solely because of the random nature of the geometric uncertainties. However, the effect of finite fractionation appears to have a greater impact on the dose distribution than plan evaluation parameters.

Convolution methods have been used to model the effect of geometric uncertainties on dose delivery in radiation therapy. Convolution assumes shift invariance of the dose distribution. Internal inhomogeneities and surface curvature lead to violations of this assumption. The magnitude of the error resulting from violation of shift invariance is not well documented. This issue is addressed by comparing dose distributions calculated using the Convolution method with dose distributions obtained by Direct Simulation. A comparison of conventional Static dose distributions was also made with Direct Simulation. This analysis was performed for phantom geometries and several clinical tumor sites. A modification to the Convolution method to correct for some of the inherent errors is proposed and tested using example phantoms and patients. We refer to this modified method as the Corrected Convolution. The average maximum dose error in the calculated volume (averaged over different beam arrangements in the various phantom examples) was 21% with the Static dose calculation, 9% with Convolution, and reduced to 5% with the Corrected Convolution. The average maximum dose error in the calculated volume (averaged over four clinical examples) was 9% for the Static method, 13% for Convolution, and 3% for Corrected Convolution. While Convolution can provide a superior estimate of the dose delivered when geometric uncertainties are present, the violation of shift invariance can result in substantial errors near the surface of the patient. The proposed Corrected Convolution modification reduces errors near the surface to 3% or less.

In order to calculate the dose distribution delivered by a prostate brachytherapy implant, the seed positions and prostate volume are normally identified on post-implant CT images. We have systematically considered the impact of uncertainties in contouring the prostate, seed localization, and visualization of all the seeds on the calculated dose distributions, dose-volume histograms, and predicted radiobiological outcome. This study was done for a collection of 27 clinical 125I prostate brachytherapy implants, performed at the London Regional Cancer Centre during our early adoption of this technique. For these clinical dose distributions, the median D90 was 76% of the prescription dose, or 110 Gy, and the median V90 was 80%. We calculated the changes in these dosimetric indices (D90 and V90) and radiobiological outcome (SF2 TCP) as a function of contouring uncertainty, seed localization uncertainty, inability to localize all of the seeds, and binary combinations of these three. The results are presented for a range of uncertainties, which allows the possible application of these results to a variety of imaging modalities that have differing spatial resolutions. We found that both contouring uncertainties and seed localization uncertainties had a large impact on the predicted radiobiological outcome, but that seed localization uncertainties of 6 mm had the largest impact on the dosimetric indices. We also found that the variability in both the predicted radiobiological and dosimetric outcome was largest for contouring uncertainties of 4-8 mm. We conclude that accounting for contouring uncertainties is crucial in accurately deducing the DVHs for post-implant prostate brachytherapy, and hence enabling valid correlation with ultimate clinical outcome.

This document is the report of a task group of the Radiation Therapy Committee of the AAPM and has been prepared primarily to advise hospital physicists involved in external beam treatment of patients with pelvic malignancies who have high atomic number (Z) hip prostheses. The purpose of the report is to make the radiation oncology community aware of the problems arising from the presence of these devices in the radiation beam, to quantify the dose perturbations they cause, and, finally, to provide recommendations for treatment planning and delivery. Some of the data and recommendations are also applicable to patients having implanted high-Z prosthetic devices such as pins, humeral head replacements. The scientific understanding and methodology of clinical dosimetry for these situations is still incomplete. This report is intended to reflect the current state of scientific understanding and technical methodology in clinical dosimetry for radiation oncology patients with high-Z hip prostheses.

Background and Purpose: Radiation pneumonitis and fibrosis are limiting factors in radiation treatment (RT) of thoracic tumors. The objectives of this study were to quantify the influence of irradiated lung volume and dose on lung response, and to evaluate the influence of other prognostic factors., Material and Methods: Treatment histories of 55 thymoma patients were evaluated retrospectively for radiation pneumonitis and fibrosis. Complications were scored as pneumonitis if observed within 6 months of completion of RT, and as fibrosis if observed after 6 months. Complications were classified as 'all pneumonitis' and 'all fibrosis' if a patient either showed symptoms (such as chronic cough and dyspnea) or radiographic changes in lung. The second group scored as 'symptomatic pneumonitis' and 'symptomatic fibrosis' consisted of patients that exhibited clinical symptoms. Dose-volume data were estimated using representative anatomies combined with available individual dose data. The Lyman NTCP model was used to assess the dependence of lung complication incidence on dose and volume., Results: The derived values of the parameters governing dose-volume dependence for symptomatic complications agreed with currently accepted and recently published values within the margins of error. Dose-response curves for complications that included radiographic changes were less steep than for symptomatic complications. The volume dependence for symptomatic fibrosis was more pronounced compared to all fibrosis. A strong correlation was observed between developing pneumonitis and developing fibrosis., Conclusions: The long survival allowed the assessment of lung complication data in thymoma patients for both acute and late response. Mean dose in lung strongly correlated with lung complications that manifest clinically. The determination of the dose-volume dependence is affected by the choice of endpoints (i.e. whether complications are scored based on clinical symptoms or radiographic changes not accompanied by clinical symptoms).

Purpose: These studies were designed to examine radiation-induced in-field and out-of-field DNA damage in rat lung as a function of dose and various volumes of irradiation. They also determined whether superoxide dismutase (SOD) and nitro-L-arginine methyl ester (L-NAME) protected against this damage., Methods and Materials: The whole lung, or various volumes of the lower or upper lungs of Sprague-Dawley rats were exposed to doses up to 20 Gy of 60Co gamma rays. Radiation-induced DNA damage was quantified in fibroblasts obtained at 18 h after irradiation from both irradiated and shielded lung regions using a micronucleus assay. The radioprotective role of SOD (CuZnSOD: 10 mg/kg body weight; MnSOD: 50-100mg/kg body weight) and L-NAME (0.2 mg/kg body weight.) in vivo was determined by injecting them into rats 30 min before or immediately after a dose of 10 Gy., Results: Micronucleus formation was approximately linear with dose up to 15 Gy. When 70% of the lung volume was irradiated with 10 Gy, irradiated lower lung gave similar numbers of micronuclei (MN)/binucleate cell (BN) to that observed following whole lung irradiation (0.91 MN/BN), whereas the irradiated upper lung gave only 0.66 MN/BN. Following lower lung irradiation, the shielded upper lung (30% of lung volume) showed substantial (out-of-field) damage (0.43 MN/BN). When 30% of the lung was given 10 Gy, irradiated upper or lower lung showed similar amounts of in-field damage (0.43 MN/BN) but this was smaller than that seen following irradiation of 70% of the lung volume. For 30% lower lung irradiation, the shielded upper lung showed only a small out-of-field effect (0.1 MN/BN). For both volumes of irradiation there was a similar or smaller effect in the shielded lower lung after upper lung irradiation. Injection of SOD before or L-NAME after 10 Gy to the lower 70% lung volume resulted in a reduction in DNA damage both in-field and out-of-field but the percentage was much greater for out-of-field damage (50-60%) than for in-field damage (10-30%). Following whole lung irradiation (10 Gy) significantly greater DNA damage was observed in fibroblasts from the left lung than from the right lung (0.93 MN/BN vs. 0.82 MN/BN). Following whole lung irradiation there was no significant difference in DNA damage observed in fibroblasts from the lower lung and the upper lung., Conclusions: With partial lung irradiation the lower lung sustains more in-field DNA damage following irradiation than the upper lung, whereas out-of-field effects are observed primarily in the upper lung (i.e. following lower lung irradiation). Following whole lung irradiation the left lung sustains more damage than the right lung but there is no difference between the upper and lower lung. The protective effects of SOD and L-NAME suggest that inflammatory cytokines induced by the irradiation may be involved in the initiation of a reaction resulting in the production of reactive oxyradicals and nitric oxide that cause indirect DNA damage both in and out of the radiation field.

Purpose: Three-dimensional conformal radiation therapy requires the precise definition of the target volume. Its potential benefits could be offset by the inconsistency in target definition by radiation oncologists. In a previous survey of radiation oncologists, a large degree of variation in target volume definition of cervical esophageal cancer was noted for the boost phase of radiotherapy. The present study evaluated whether special training could improve the consistency in target volume definitions., Methods and Materials: A pre-training survey was performed to establish baseline values. This was followed by a special one-on-one training session on treatment planning based on the RTOG 94-05 protocol to 12 radiation oncologists. Target volumes were redrawn immediately and at 1-2 months later. Post-training vs. pre-training target volumes were compared., Results: There was less variability in the longitudinal positions of the target volumes post-training compared to pre-training (p < 0.05 in 5 of 6 comparisons). One case had more variability due to the lack of a visible gross tumor on CT scans. Transverse contours of target volumes did not show any significant difference pre- or post-training., Conclusion: For cervical esophageal cancer, this study suggests that special training on protocol guidelines may improve consistency in target volume definition. Explicit protocol directions are required for situations where the gross tumor is not easily visible on CT scans. This may be particularly important for multicenter clinical trials, to reduce the occurrences of protocol violations.

We have evaluated the effect of the anisotropy of individual seeds on dose distributions for permanent prostate implants using 125I and 103Pd. The dose distributions were calculated for various implants using both the line source and point source calculational formalisms, for two different models of 125I and 103Pd seeds. The dose distributions were compared using cumulative dose volume histograms (DVH) and cumulative difference dose volume histograms (deltaDVH) for the prostate target volume and for the rectum surface. The DVHs could not distinguish between the dose distributions from isotropic and non-isotropic seeds. However, the deltaDVHs were useful in determining the fraction of the target volume for which the difference between the dose distribution for line sources and for point sources exceeded a threshold value. The dose distributions were calculated (1) for all the seeds oriented co-linearly, along either the x-, y-, or z-axis, and (2) for the seeds at randomized orientations, more closely resembling the clinical situation. For all cases, there was a significant difference in the effect of seed anisotropy from the different seed types. For the geometrically simpler test cases with a small number of seeds, the effect of anisotropy on the dose distribution was too large to ignore for any of the seed types investigated. For the idealized pre-plan case, the effect was much smaller. For clinical prostate implants, the calculations done with seeds oriented co-linearly along the z-axis (needle implant axis) were a reasonable approximation for those from simulations of seeds with randomized orientations. Again, the effect of anisotropy varied drastically between different seed models, and also between different clinical cases. However, the effect of anisotropy must be considered in the context of all the other uncertainties in clinical brachytherapy treatments.

Purpose: Uncertainties in patient repositioning and organ motion are accounted for by defining a planning target volume (PTV). We make recommendations on issues not explicitly discussed in existing protocols for PTV design., Methods: A quantity called "coverage" is defined to quantify how effectively a PTV encompasses the clinical target volume, and is applied to examine the impact of several factors. A stochastic simulation is used to determine the coverage required for a desirable balance between tumor control probability (TCP) and the irradiated volume. Using a sample anatomy, we assess the importance of the method used to add uncertainties, the shape of the uncertainty distribution, the effect of systematic uncertainties, and the use of nonuniform margins. Additionally, we examine the benefit of patient immobilization techniques., Results: Our example indicates that 95% coverage is a reasonable goal for treatment planning. Using this as a comparison value, our example indicates quadrature addition of uncertainties predicts smaller margins (7 mm) than linear addition (11 mm), Gaussian distribution of uncertainties (7 mm) require the same margin as a uniform distribution (7 mm), systematic uncertainties have a small effect on TCP below a threshold value (4 mm), and nonuniform margins allow only a slight reduction of irradiated volume., Conclusion: We recommend that uncertainties should generally be added in quadrature, the exact shape of the uncertainty distribution is not critical, systematic uncertainties should be maintained below some threshold value, and nonuniform margins may be effective when uncertainties are anisotropic.

Purpose: Recent observations have shown that there are regional variations in radiation response in mouse lung as measured by functional assays. Furthermore, there are both in-field and out-of-field effects in radiation-induced lung damage as observed by DNA assay in rats. The purpose of this work is: (a) to examine mice lethality data following partial volume lung irradiation to assess the possibility of directional or regional effects, (b) to evaluate the correlation between mice lethality data and DNA damage assayed by micronuclei production in rat lung, and (c) to re-interpret mice lethality considering the existence of directional effects in lung cellular response to partial volume irradiation., Methods and Materials: The lethality data for mice, generated at the M. D. Anderson Cancer Center, Houston, and micronuclei yield data for rats obtained at Princess Margaret Hospital, Toronto, were used. A radiobiological model that allows for out-of-field and in-field effects for lung cell damage and lung response was developed. This model is based on the observation of DNA damage in shielded parts of rat lung that was assumed relevant to cell lethality and consequently overall lung response., Results: While the experimental data indicated directional or regional volume effects, the applicability of dose and volume as sole predictors of lung response to radiation was found to be unreliable for lower lung (base) irradiation in mice. This conforms well to rat lung response where micronuclei were observed in shielded apical parts of lung following base irradiation. The radiobiological model, which was specifically developed to account for the lung response outside of primary irradiated volume, provides a good fit to mice lethality data, using parameters inferred from rat micronuclei data., Conclusion: Response to lung irradiation in rodents, in particular, elevated sensitivity to base irradiation, can be interpreted with a hypothesis of in-field and out-of-field effects for cellular response. If the existence of these effects for lung is subsequently proven in humans, it will require the incorporation of geometrical and directional information in normal tissue complication probability calculations for lung. These considerations are ignored in present approaches based only on conventional dose-volume histograms.

Purpose: To assess the patterns of practice among Canadian radiation oncologists who treat esophageal cancers, using a trans-Canada survey, completed at the end of 1996., Methods and Materials: One of 3 case presentations of different stages of cervical esophageal cancer was randomly assigned and sent to participating radiation oncologists by mail. Respondents were asked to fill in questionnaires regarding treatment techniques and to outline target volumes for the boost phase of radiotherapy. Radiation oncologists from 26 of 27 (96%) of all Canadian centers participated., Results: High-energy X-rays (>/= 10 MV) were employed by 68% of the respondents in part of the treatment course. The majority (83%) of the radiation oncologists used at least two phases of treatment. Very few, 10 of 59 (17%), responses started with multifield treatment. The most frequently used prescription dose was 60 Gy/30 fractions/6 weeks, given with concurrent chemotherapy. Dose prescriptions were to the isocenter in 39 of 48 (81%) or to a particular isodose line in 9 of 48 (19%) of respondents., Conclusion: There was a variety of radiation treatment techniques in this trans-Canada survey. The majority of the patients had combined cisplatin-based chemoradiation. The isocenter was not used consistently as a dose prescription point.

Two new Fricke dosimeter gel systems with low diffusion rates have been developed for 3D radiation dosimetry purposes. Both systems consist of a solution of 20% (by weight) polyvinyl alcohol (PVA) in a 50 mM H2SO4 solution with 0.4 mM ferrous ammonium sulphate and xylenol orange (FX). The difference in the two gels is the way that the gelation process was initiated: either by bringing the temperature to (a) +5 degrees C or (b) -20 degrees C before returning them to room temperature. These gels are termed 'hydrogel' and 'cryogel', respectively. The hydrogel is optically transparent, and can be used with either optical or MRI detection methods for dosimetric imaging. The cryogel is rubbery in texture but opaque, so its internal Fe3+ concentration can only be measured with MRI. The hydrogel's optical attenuation coefficient is linear (r2 = 0.99) with dose from 0 to 20 Gy with a sensitivity of 0.106 cm(-1) Gy(-1) (at 543 nm). In terms of MR relaxation rate, the dose response for both the hydrogel and cryogel was linear (r2 = 0.99) with a sensitivity of 0.020 s(-1) Gy(-1) (at 1.5 T). The Fe3+ diffusion coefficient (at 20 degrees C) was measured to be 0.14 mm2 h(-1), which is significantly lower than similar preparations reported for porcine gelatin or agarose. The PVA-FX gels can be stored for long periods of time before exposure to radiation, since the auto-oxidation rate was 10 times less than that of gelatin-Fricke recipes. The new gels developed in this work are a significant improvement on previous Fricke gel systems.

Purpose: To evaluate the impact of dose-volume histogram (DVH) reduction schemes and models of normal tissue complication probability (NTCP) on ranking of radiation treatment plans., Methods and Materials: Data for liver complications in humans and for spinal cord in rats were used to derive input parameters of four different NTCP models. DVH reduction was performed using two schemes: "effective volume" and "preferred Lyman". DVHs for competing treatment plans were derived from a sample DVH by varying dose uniformity in a high dose region so that the obtained cumulative DVHs intersected. Treatment plans were ranked according to the calculated NTCP values., Results: Whenever the preferred Lyman scheme was used to reduce the DVH, competing plans were indistinguishable as long as the mean dose was constant. The effective volume DVH reduction scheme did allow us to distinguish between these competing treatment plans. However, plan ranking depended on the radiobiological model used and its input parameters., Conclusions: Dose escalation will be a significant part of radiation treatment planning using new technologies, such as 3-D conformal radiotherapy and tomotherapy. Such dose escalation will depend on how the dose distributions in organs at risk are interpreted in terms of expected complication probabilities. The present study indicates considerable variability in predicted NTCP values because of the methods used for DVH reduction and radiobiological models and their input parameters. Animal studies and collection of standardized clinical data are needed to ascertain the effects of non-uniform dose distributions and to test the validity of the models currently in use.

Setting: Isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) are first-line antituberculosis drugs. Due to difficulties in producing effective combined formulations of these three drugs, the bioavailability of new combination formulations needs to be assessed prior to registration., Objective: To develop a rapid, simple and sensitive high performance liquid chromatography (HPLC) assay method suitable for assaying RIF, INH and PZA in large numbers of plasma samples generated in bioavailability studies., Method: RIF, desacetyl-rifampicin (DRIF), INH and PZA were extracted simultaneously from plasma using a solid phase extraction column. RIF and DRIF were quantitated by HPLC using an 80% acetonitrile/0.1% trifluoroacetic acid (TFA) mobile phase and a C8 reversed phase column. INH and PZA were also quantitated on a C8 reversed phase column, but a 3% acetonitrile/0.6% TFA mobile phase was used., Results: Mean recovery of RIF, DRIF and PZA from plasma was well over 90%, and over 70% for INH. Calibration graphs were linear for all the drugs in their therapeutic range. Correlation coefficients were all above 0.9995, and between- and within-run coefficients of variation below 10%., Conclusion: A simple, accurate, sensitive and cost effective assay for first-line antituberculosis drugs has been developed.

Purpose: Three-dimensional (3D) radiation treatment planning is facilitated through the use of computerized radiation treatment planning systems (RTPSs) and CT simulators (CT-sims). Quality assurance (QA) of these systems is necessary for ensuring that they fulfill their potential. However, comprehensive tools for the systematic QA of these systems have not been developed. We present a phantom that facilitates the evaluation of a large number of nondosimetric functions. These include CT image acquisition and transfer, graphical displays of 3D radiation beams, multiplanar CT image reconstructions, digitally reconstructed radiographs, the representation and manipulation of contoured patient anatomy, dose volume histograms, and the conversion of CT numbers to relative electron densities., Methods and Materials: A phantom was constructed which contains materials and geometries that are appropriate for the routine QA of the features described above. The anatomy of the phantom is used as a standard against which the performance of the 3D-RTPS or CT-sim is evaluated. The phantom was used to evaluate three different 3D-RTPSs and a CT-sim at four institutions., Results: Using this phantom, clinically significant errors and limitations in commercially available 3D treatment planning software were discovered. No errors were discovered in the beam display or image reconstructions in the systems examined. Problems were found in the anatomy display, automatic tools, and the CT number to relative electron density conversion data used in some of the systems., Conclusion: This phantom is a unique tool designed explicitly for the QA of 3D treatment planning software. Errors and limitations discovered through its use indicate that the QA of commercial treatment planning software is necessary, and that this phantom is an effective device for this task.

Purpose: Three-dimensional (3D) conformal radiation therapy (CRT) assumes and requires the precise delineation of the target volume. To assess the consistency of target volume delineation by radiation oncologists, who treat esophageal cancers, we have performed a transCanada survey., Materials and Methods: One of three case presentations, including CT scan images, of different stages of cervical esophageal cancer was randomly chosen and sent by mail. Respondents were asked to fill in questionnaires regarding treatment techniques and to outline boost target volumes for the primary tumor on CT scans, using ICRU-50 definitions., Results: Of 58 radiation oncologists who agreed to participate, 48 (83%) responded. The external beam techniques used were mostly anterior-posterior fields, followed by a multifield boost technique. Brachytherapy was employed by 21% of the oncologists, and concurrent chemotherapy by 88%. For a given case, and the three volumes defined by ICRU-50 (i.e., gross tumor volume [GTV], clinical target volume [CTV], and planning target volume [PTV]) we determined: 1. The total length in the cranio-caudal dimension; 2. the mean diameter in the transverse slice that was located in a CT slice that was common to all participants; 3. the total volume for each ICRU volume; and 4. the (5, 95) percentiles for each parameter. The PTV showed a mean length of 14.4 (9.6, 18.0) cm for Case A, 9.4 (5.0, 15.0) cm for Case B, 11.8 (6.0, 16.0) cm for Case C, a mean diameter of 6.4 (5.0, 9.4) cm for Case A, 4.4 (0.0, 7.3) cm for Case B, 5.2 (3.9, 7.3) cm for Case C, and a mean volume of 320 (167, 840) cm3 for Case A and 176 (60, 362) cm3 for Case C. The results indicate variability factors (95 percentile divided by 5 percentile values) in target diameters of 1.5 to 2.6, and in target lengths of 1.9 to 5.0., Conclusion: There was a substantial inconsistency in defining the planning target volume, both transversely and longitudinally, among radiation oncologists. The potential benefits of 3D treatment planning with high-precision dose delivery could be offset by this inconsistency in target-volume delineation by radiation oncologists. This may be particularly important for multicenter clinical trials, for which quality assurance of this step will be essential to the interpretation of results.

Purpose: 1. To investigate early DNA damage induced in rat lung cells following single-dose, partial-volume irradiation (lung base and lung apex). 2. To determine the variation in DNA damage in different lung regions. 3. To investigate the possible mechanisms associated with early DNA damage after lung irradiation., Methods and Materials: The whole lung or the upper or lower half of the entire lung of Sprague-Dawley rats was exposed to 10 Gy 60Co gamma rays. The animals were sacrificed at various times up to 42 h after irradiation. A trypsin-digested lung cell suspension was prepared and cells that attached to slides in the initial 24-h period were then grown in the presence of culture medium with cytochalasin-B for a further 72 h. Radiation-induced DNA damage was quantified in the cells (primarily fibroblasts) from both irradiated and unirradiated lung regions by using a well-characterized micronucleus assay., Results: When the lungs were removed at 16-18 h after whole-lung irradiation, about 0.85 micronuclei (MN) per binucleate cell (BNC) were observed in the lung cells of the irradiated animals, compared to 0.02 MN/BNC in the lung cells of the controls. When only the lung base was irradiated, the frequency of micronuclei was 0.85 MN/BNC compared to 0.43 MN/BNC observed in cells from the irradiated lung apex. Of particular interest was the finding that the unirradiated lung apex also showed a large frequency of micronuclei (0.43 MN/BNC) after the irradiation of the lung base, whereas the unirradiated lung base showed only a marginal (approximately 2-fold) increase relative to the spontaneous frequency following irradiation of the lung apex. The changes in the frequency of micronuclei varied with the time at which the lungs were removed from the rats for early times, but had stabilized by 18 h after irradiation. Normal (unirradiated) cells grown in filtered or unfiltered conditioned media obtained from irradiated cell cultures showed an insignificant marginal increase in the number of micronuclei relative to the spontaneous frequency. Lung cells obtained from the lung base or the lung apex of healthy controls and irradiated separately in vitro showed no regional differences in the induction of micronuclei. Cells from the lungs of rats injected with superoxide dismutase, within 1 h prior to irradiation of the lung base, and processed 16-18 h after irradiation showed a reduction in the number of MN in the shielded lung apex, indicating the possible involvement of oxygen radicals., Conclusions: These data indicate that cells in the lung base sustain more DNA damage than those in the lung apex when either region is irradiated; however, when the whole lung, is irradiated, the lung damage observed is similar in the two regions. Also, out-of-field effects are observed for the lung apex but not the lung base. Possible mechanisms include a clastogenic (chromosome damaging) factor produced in the plasma following irradiation and/or the production of oxygen radicals by activated lymphocytes/monocytes. The partial blocking of the DNA damage, observed in the unirradiated lung apex following irradiation of the lung base, by superoxide dismutase, suggests that oxygen radicals are involved in this out-of-field effect. These radicals are likely produced as a result of the induction of inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) by the irradiation. The reason for the lack of an out-of-field effect in the lung base when the lung apex is irradiated is unknown, but may be due to the greater volume of lung irradiated in the lower lung field, because this is likely to affect the level of cytokines produced. Alternatively, it may reflect cytokines produced as a result of the partial liver irradiation that occurs with the lower lung field.

Previously published FFT dose calculations and their verifications have been performed for field sizes greater than 10 cm x 10 cm with photon energies up to 18 MV [Zhu and Boyer, Phys. Med. Biol. 35, 351-368 (1990)]. With a smaller field size at megavoltage energies, lateral electronic disequilibrium exists in low density inhomogeneities which is not handled properly by the FFT calculations. In this paper, we extend FFT dose calculations to address this problem without significantly increasing the computational time. We employ lateral scaling of the field size at each depth along with an inverse scaling of the resultant dose distribution. The concept of effective density in introduced for the lateral and inverse scaling. We demonstrate that electron transport can be adequately captured in the presence of inhomogeneities, thus improving 3D FFT dose calculations in inhomogeneous media.

A theory is presented on dose calculations in inhomogeneous media that takes advantage of fast Fourier transform (FFT) convolution for practical three-dimensional treatment planning using photon beams. While the initial work of Boyer and Mok [Med. Phys. 13, 503-509 (1986)] provided a theory which is based on first principles, it failed to give satisfactory predictions inside inhomogeneities. Subsequently, Zhu and Boyer [Phys. Med. Biol. 35, 351-368 (1990)] showed that their formulas agreed well with measured data, but these formulas were empirically altered from Boyer and Mok's. In this work, Boyer and Mok's first-order theory is extended to include second-order inhomogeneity effects. A new correction dose formula is derived which corrects the first scattered dose due to the presence of inhomogeneities. This correction dose formula works better than Zhu and Boyer's empirical correction dose formula. Furthermore, the primary dose formula used by Zhu and Boyer, which was empirically modified from Boyer and Mok's, is justified theoretically. Clear statements are made about the assumptions and the approximations that enter into the derivation which in turn uncover the limitations of this FFT convolution dose calculation.

Transmission through a beam-modifying absorber consists of attenuated primary beam and scattered radiation generated by the absorber. The primary component of the transmitted beam is characterized by the narrow beam attenuation coefficient which depends upon the energy of the beam and type of the absorber. In addition to beam energy and absorber material, the scatter component also depends on field size, thickness and shape of the absorber, location of the absorber with respect to the source, and the point of calculation. Based upon Compton first-scatter, a method has been developed to calculate effective broad beam transmission through any arbitrarily shaped absorber with variable thickness for any points on and off the central axis. The method requires predetermined narrow beam attenuation coefficients as a function of thickness. Transmission calculations for various absorbers such as wedges and attenuators were performed for cobalt-60 and 6-MV beams and were compared with measured data. For a cobalt-60 beam, the measured transmission fraction through a 1.33-cm-thick absorber (alloy, consisting of 55% bismuth and 45% lead) for a field size of 24 x 24 cm2 is 17% higher than the calculated value using a narrow beam attenuation coefficient. Also, for the same absorber, measured central axis transmission is as much as 3.6% higher compared to off-axis locations. The measured transmission fraction through a 1.33-cm absorber was found to differ by as much as 13% and 14% for Cobalt-60 and 6 MV, respectively, as the chamber-to-source distance was varied from 70 to 110 cm. The agreement between calculated and measured values is within 0.5% for both energies whereas conventional narrow beam calculations would have yielded errors of 18% and 19%, respectively. Similar agreement was obtained when comparing calculated and measured wedge factors as a function of field size, with the maximum deviation being 0.7%. Measured scattered doses, due to an attenuator covering part of a beam, show a maximum for a thickness of approximately one mean-free path. This is also predicted by calculations with an agreement of 0.3%.

Purpose: To evaluate the influence of dose fractionation and other factors on the development of late complications in mandibular bone, muscle, and mucosa of the oral cavity after external beam radiation therapy for carcinoma of the tonsil., Methods and Materials: A retrospective analysis was made of the results in 676 patients treated with a spectrum of fractionation regimens in nine centers during the years 1976-1985. Only severe (Grades 3-4) late complications were analyzed., Results: With more than 5 years follow-up, it was found that total dose was a factor for all three types of complications, but that in other respects, the radiobiology of late-(> 3 months) developing mucosal ulcerations was different from that for mandibular necrosis and muscle injury. Dose per fraction was a significant factor for bone and muscle (estimated alpha/beta values of 0.85 Gy and 3.1 Gy, respectively). By contrast, mucosa showed no influence on response from change in fraction size over the range of approximately 1.0-3.5 Gy. Complications in bone and muscle were not related to overall treatment duration, whereas there was a significant inverse relationship for mucosa breakdown. The rate of development of complications was fastest in mucosa and slowest in bone. The appearance of complications by 4 years after treatment was about 80% of those developing by 8 years in the mucosa, 66% in muscle, and about 50% in bone. The high alpha/beta ratio, inverse relationship with overall treatment duration, and faster development of mucosal complications suggests that they may develop as a consequence of earlier mucosal injury. As anticipated, adequate retrospective analysis of acute complications could not be made even when objective criteria such as weight loss, unplanned delays in completing treatment, or hospitalization during treatment were the measures. Field size was a significant factor for mandible complications, but not for muscle or mucosa., Conclusion: The radiobiological characteristics of bone and muscle were those characteristic of other late-responding tissues, whereas late sequelae in mucosa had radiobiological parameters similar to those for acute responses. Field size was a significant factor for bone complications but not for others.

Purpose: To investigate the importance to outcome of treatment for squamous cell carcinomas of the tonsillar fossa, of dose per fraction, overall treatment duration, and total dose., Methods and Materials: A collaborative retrospective study was undertaken in nine centers that used widely different dose-fractionation patterns for external beam radiation therapy., Results: There were 676 eligible cases treated only with photon beams during the years 1976-1985. The probability of local control (of the tonsillar fossa primary) was influenced by both T-stage and N-stage. Significant treatment parameters were total dose and overall treatment duration, but not dose per fraction. Over the range of about 40 to 90% and for a constant overall treatment duration, local tumor control probability increased by nearly 2% for each 1 Gy increase in total dose. For a constant total dose there was a decrease in the probability of local control associated with prolongation of overall treatment duration, presumed to result from accelerated regrowth of surviving tumor clonogens during the course of treatment. If it is assumed that accelerated regrowth occurred at a constant rate and began within 9 days of the start of treatment, an average of 0.53 Gy extra dose per day's extension of treatment would be required to maintain a constant probability of local control. Correspondingly, the probability of local control from a constant dose would be lowered by an average of at least 1% for each day's extension of treatment duration. However, the data are slightly more consistent with an average delay of as long as 30 days before onset of accelerated repopulation, with a consequent increase to an average of 0.73 Gy per day for the value of the compensatory dose. The alpha/beta ratio for this tumor is high enough that the effect of fraction size on the probability of local control can be ignored; a precise estimate is not possible because the best value for beta was close to zero. After accounting for the significant variables studied (treatment time, T-stage, N-stage), the dose-response curves for tumor control were still shallow, suggesting that there are additional causes for heterogeneity of responses among these tumors., Conclusions: Total dose is important to treatment outcome: After accounting for other treatment variables, there is about a 2% per Gy increase in probability of tumor control over the ranges of control commonly achieved. Overall treatment duration is important. There is at least a 1% per day decrease in tumor control probability if delivery of a constant total dose is prolonged, requiring a compensatory increase in dose by 0.5-0.7 Gy per day to achieve a constant rate of tumor control. Fraction size is not, of itself, an important factor in the response of primary carcinoma of the tonsil. If a tumor has demonstrated a capacity for metastatic spread to lymph nodes, a higher total dose should be considered to achieve control rates at the primary site equivalent to those in node negative patients. Even after accounting for variables such as tumor stage, total dose, and overall treatment duration, there is sufficient heterogeneity in other undocumented determinants of tumor control to cause the tumor control probability curve to be a shallow function of dose.

Current intensive investigations of electronic portal imaging devices (EPIDs) have prompted their potential application to portal dosimetry. In this paper, the progress made in using a commercial liquid ion chamber matrix EPID for portal dosimetry is discussed. The pixel value of the liquid ion chamber element was calibrated against dose by exposing the imager to 6-MV x-ray beams of various intensities obtained with various thicknesses of lead attenuators and a range of source to detector distances. Absolute dose values were determined using an ion chamber on the central axis at the depth of maximum dose in a solid water phantom. The pixel values of the matrix were determined for various field sizes in order to evaluate the dependence of pixel value on dose at those field sizes. It was confirmed that the pixel value was proportional to the square root of the dose rate and was nearly independent of the field size. The 2D pixel values were converted to 2D dose maps in the water phantom after applying a correction for the effect of horns in the flood calibration field. The flood calibration field was used to obtain the relative sensitivity of each pixel. Good agreement was observed (normally better than 1% in relative standard deviation) between the converted dose distribution obtained from the pixel matrix and the direct dose measurement using an ion chamber scanned in a water phantom in regions of shallow dose gradient. For application to on-line portal dosimetry, both the short- and long-term stability of this EPID system were found to be within 1% relative standard deviation.(ABSTRACT TRUNCATED AT 250 WORDS)

The photon beam dose calculation methods using fast Fourier transform (FFT) convolution require that the primary beam energy spectrum is accurately known; however, a quantitative assessment of the required accuracy is not yet provided. In this study, the sensitivity of various parameters such as central axis depth dose and dose under attenuators to the incident photon spectrum was simulated and evaluated for 6- and 18-MV photon beams. The central axis depth-dose data using the modified spectrum were compared with those calculated using the original spectrum. Maximum errors on the central axis between these two sets of depth-dose data were found by changing the weighting of each energy bin of the primary spectrum. The maximum change in percent depth dose is proportional to the change in average incident energy relating to the quality of the x ray. To keep the maximum depth-dose error to less than 1%, the relative change in average energy brought about by changes in single spectral bins should be less than 2%. The accuracy required for each energy bin varies dramatically, dependent on its deviation from the original average energy and its relative weighting. For example, for the 6-MV x-ray spectrum, the energy bins centered around 0.76 MeV (first bin) and 6.8 MeV (fifth bin) need to have accuracies of 5% and 40%, respectively, to obtain a 1% accuracy in percent depth dose.

Purpose: To assess the latent time, survival and dose-fractionation factors associated with permanent radiation myelopathy following single and multiple courses of radiotherapy to the spinal cord., Methods and Materials: A retrospective analysis was undertaken of all patients who were registered at the Princess Margaret Hospital between 1955 and 1985, and who developed permanent radiation myelopathy. There were 22 males and 13 females with ages ranging from 30 to 72 years. Twenty-four patients developed permanent myelopathy after one course of radiation therapy and 11 patients following retreatment. Seven patients had histological confirmation of radiation myelopathy at autopsy., Results: The actuarial survival was 14% at 5 years (median: 8.3 months) from the date of diagnosis of radiation myelopathy. Latent times for myelopathy following a single course of treatment (mean: 18.5 months, 7-57 months), were significantly longer than those after reirradiation (mean: 11.4 months, 4-25 months), p = 0.03. There was not a single incident of myelopathy in patients who received fractionated radiotherapy given once daily to an extrapolated response dose (ERD) of < or = 100 Gy2 (equivalent to 50 Gy in 25 daily fractions). Four patients who developed myelopathy after an ERD of < 100 Gy2 were all treated on accelerated fractionation protocols with multiple fractions given per day. Patients who were reirradiated received significantly higher doses (mean ERD of 148 Gy2) than those who had a single course of treatment (mean ERD of 121 Gy2), p = 0.001., Conclusion: We conclude that the risk of radiation myelopathy following conventionally fractionated radiotherapy to the spinal cord is extremely small; giving multiple fractions per day reduces the spinal cord tolerance; latent time to myelopathy decreases following retreatment; and there is possible long-term recovery of radiation damage in the human spinal cord.

Purpose: To investigate the potential role of Magnetic Resonance for assessing radiation-Induced lung damage., Methods and Materials: T1 and T2 relaxation times were measured for lungs excised from Sprague-Dawley rats at various times following thoracic irradiation., Results: Although on average a 10% increase was observed in the T2 relaxation times between 30 and 80 days after irradiation, this is too small to affect image contrast., Conclusions: The results indicate that relaxation measurements are unlikely to yield new information to characterize changes in lung tissue caused by radiation.

Purpose: Evaluation of radiation dose rate and fractionation effects on clonogenic myeloma cells., Methods and Materials: The radiosensitivity of clonogenic myeloma cells was evaluated for seven human myeloma cell lines. The lines were maintained in liquid suspension culture. Following radiation, cells were plated in semisolid medium using methylcellulose as viscous support. Radiation doses up to 12 Gy were delivered at dose rates of 0.05 and 0.5 Gy/min by a 60Co source. Each total dose was administered either as a single dose or in multiple fractions of 2 Gy. The data were analyzed according to the linear quadratic and multi target model of irradiation., Results: Clonogenic progenitors of the seven myeloma cell lines differed in their radiosensitivity as measured by multiple parameters. The differences were mainly observed at low dose. The most effective cytoreduction was seen when radiation was administered in a single fraction at high dose rate. The cytoreductive effect on clonogenic myeloma cells was compared for clinically practiced total body irradiation (TBI) schedules delivered either in a single or in multiple fractions without causing significant pulmonary toxicity. The administration of 12 Gy delivered in six fractions of 2 Gy resulted in a superior reduction of clonogenic cells compared to a single fraction of 5 Gy., Conclusion: The preparation of bone marrow transplant recipients with multiple myeloma using fractionated radiation with a total dose of 12 Gy appears to afford better ablation than a single dose of 5 Gy while maintaining a low incidence of pulmonary toxicity.

Purpose: The objective of this work was to assess the incidence of radiological changes compatible with radiation-induced lung damage as determined by computed tomography (CT), and subsequently calculate the dose effect factors (DEF) for specified chemotherapeutic regimens., Methods and Materials: A prospective, clinical study was conducted to determine the response of normal lung tissue to combined chemotherapy and radiotherapy. Radiation treatments were administered once daily, 5 days-per-week. Six clinical protocols were evaluated: ABVD (adriamycin, bleomycin, vincristine, and DTIC) followed by 35 Gy in 20 fractions; MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) followed by 35 Gy in 20; MOPP/ABVD followed by 35 Gy in 20; CAV (cyclophosphamide, adriamycin, and vincristine) followed by 25 Gy in 10; and 5-FU (5-fluorouracil) concurrent with either 50-52 Gy in 20-21 or 30-36 Gy in 10-15 fractions. CT examinations were taken before and at predetermined intervals following radiotherapy. CT evidence for the development of radiation-induced damage was defined as an increase in lung density within the irradiated volume. The radiation dose to lung was calculated using a CT-based algorithm to account for tissue inhomogeneities. Different fractionation schedules were converted using two isoeffect models, the estimated single dose (ED) and the normalized total dose (NTD)., Results: A total of 102 patients were entered and 70 completed the study. Forty-two patients developed CT changes compatible with lung damage. The actuarial incidence of radiological pneumonitis was 71% for the ABVD, 49% for MOPP, 52% for MOPP/ABVD, 67% for CAV, 73% for 5-FU radical, and 58% for 5-FU palliative protocols. Depending on the isoeffect model selected and the method of analysis, the DEF was 1.11-1.14 for the ABVD, 0.96-0.97 for the MOPP, 0.96-1.02 for the MOPP/ABVD, 1.03-1.10 for the CAV, 0.74-0.79 for the 5-FU radical, and 0.94 for the 5-FU palliative protocols., Conclusion: Quantitative dose effect factors (DEF) were measured by comparing the incidences of CT-observed lung damage in patients receiving chemotherapy and radiotherapy to those receiving radiotherapy alone. The addition of ABVD or CAV appeared to reduce the tolerance of lung to radiation.

Purpose: When the linear-quadratic model is used to predict fractionated treatments which are isoeffective, it is usually assumed that each (equal size) treatment fraction has an equal effect, independent of the time at which it was delivered during a course of treatment. Previous work by our group has indicated that this assumption may not be valid in the context of radiation-induced lung damage in rats. Consequently we tested directly the validity of the assumption that each fraction has an equal effect, independent of the time it is delivered., Methods and Materials: An experiment was completed in which fractionated irradiation was given to whole thoraces of Sprague-Dawley rats. All treatment schedules consisted of eleven equal dose fractions in 36 days given as a split course, with some groups receiving the bulk of the doses early in the treatment schedule, before a 27-day gap, and others receiving most of the dose toward the end of the treatment schedule, after the time gap. To monitor the incidence of radiation-induced damage, breathing rate and lethality assays were used., Results: The maximum differences in the LD50s and breathing rate ED50s for the different fractionation schedules were 4.0% and 7.7% respectively. The lethality data and breathing rate data were consistent with results expected from modelling using the linear-quadratic model with the inclusion of an overall time factor, but not the generalized linear-quadratic model which accounted for fraction spacing., Conclusion: For conventional daily fractionation, and within the range of experimental uncertainties, the results indicate that the effect of a treatment fraction does not depend on the time at which it is given (its position) in the treatment. The results indicate no need to extend isoeffect formulae to consider the effect of each fraction separately for radiation-induced lung damage.

Contemporary cardiac pacemakers can fail from radiation damage at doses as low as 10 gray and can exhibit functional changes at doses as low as 2 gray. A review and discussion of this potential problem is presented and a protocol is offered that suggests that radiation therapy patients with implanted pacemakers be planned so as to limit accumulated dose to the pacemaker to 2 gray. Although certain levels and types of electromagnetic interference can cause pacemaker malfunction, there is evidence that this is not a serious problem around most contemporary radiation therapy equipment.

A commercial megavoltage constancy meter was tested for routine checks of the x-ray output of an orthovoltage therapy unit. A practical method of using the meter for both output and energy checks was developed and is presented as part of an orthovoltage quality assurance program.

Purpose: An ultrasound breathing rate measurement technique and a computer analysis algorithm have been developed to reduce the amount of time needed to collect and analyze animal breathing rate data, as well as to improve the testing environment. The system is not airtight, therefore, acclimatization and collection time is not limited, and the technique makes use of a top loading apparatus to facilitate animal entry., Methods and Materials: Breathing rate is measured using two ultrasound transducers housed directly above the rat thorax in the plexiglass jig. The breathing rate signal is stored and evaluated by computer. The ultrasound technique was tested using a loud speaker driven by a signal generator, over a range of 30 to 450 cycles/min. In addition, the ultrasonic breathing rate method was used to record the breathing rate response of Sprague Dawley rats, treated with graded single doses of radiation, over a period of 170 days., Results: For the loud speaker tests, the measured frequency agreed with that of the input signal with a maximum deviation of 1%. For the animal irradiations, all breathing rate data were analyzed by both user and computer selection of regular breathing. The techniques gave the same results at the 95% confidence limit. Using the computer program to assess the traces, 240 breathing rates can be determined per hour, from previously measured data., Conclusion: A new technique for measuring breathing rate has been developed and enhances both the collection and analysis of data.

The metabolism of lidocaine to monoethylglycinexylidide has been found useful as an indicator of liver function in association with liver transplantation. It has been postulated that this is due to the common effect of hypoxic damage on liver function and lidocaine metabolism. The effects of hypoxia on the elimination of lidocaine and the formation of monoethylglycinexylidide and on indexes of liver function were investigated with the isolated perfused pig liver preparation. This study was performed at similar hepatic effluent lidocaine concentrations of approximately 5 micrograms.ml-1 in normoxic (n = 7) and hypoxic (n = 8) livers of similar mass harvested from male Landrace x Large White pigs and perfused at standard unit hepatic flow rates. Whole blood lidocaine extraction ratio was 0.63 +/- 0.02 in normoxic livers (30% O2 at oxygenator inflow). It was significantly less (0.23 +/- 0.03) in livers subjected to hypoxia (2% O2 at oxygenator inflow), as were hepatic clearance (57.1 +/- 2.1 vs. 20.3 +/- 3.1 ml.min-1.100 gm-1), intrinsic clearance (1,706 +/- 182 vs. 284 +/- 53 ml.min-1.100 gm-1) and monoethylglycinexylidide formation as indicated by monoethylglycinexylidide/lidocaine ratios in the hepatic venous effluent (0.379 +/- 0.061 vs. 0.073 +/- 0.014) (p < 0.01). Hepatic oxygen consumption, adenine nucleotide status and bile flow were significantly impaired by hypoxia. Whereas perfusate potassium concentration increased early, AST levels showed delayed increases and ALT levels showed no changes. These changes correlated strongly with hepatic lidocaine elimination (p < 0.01). We conclude that lidocaine metabolism may be an early indicator of severe hepatic hypoxia.

One hundred and sixty-six patients between the ages of 12 and 48 years with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation following single fraction total body irradiation (TBI) of 500 cGy from a cobalt source. Patients also received one of three chemotherapeutic regimens according to their diagnosis or disease status at time of transplant. The median follow-up was 67 months with a range of 33-120 months. The actuarial 5-year event-free survival (EFS) for the subgroup of patients with good risk disease (first complete remission AML and ALL or first chronic phase CML) was 43% with an actuarial relapse rate at 5 years of 26%. Patients with poor risk disease (other than first remission AML and ALL or other than first chronic phase CML) had an EFS at 5 years of 15% with a relapse rate of 62%. Disease status at the time of transplantation was the most important factor predicting outcome in this patient population. We conclude that preparation of good risk patients with chemotherapy and single fraction TBI of 500 cGy at a dose rate of 42-91 cGy/min resulted in EFS and relapse rates similar to those observed by centers using fractionated radiotherapy schedules, without a concomitant increase in toxicity, in particular interstitial pneumonitis and cataracts.

To investigate the possibility of using computerized tomography (CT) as a prognostic indicator of radiation induced lung toxicity, a series of CT scans were performed on one patient. These scans suggested an increase in lung density at day 73 after an upper half body irradiation. Because of the difficulty in lung density follow-up in patients irradiated for palliation, further studies were performed with LAF1 mice. Serial scans were taken on three groups of mice: (1) control group, (2) irradiated to 11.0 Gy and (3) irradiated to 14.0 Gy. Lung density increases between 10 and 15% were observed in the two irradiated groups. The time course was dependent on dose with an earlier onset for the high dose group (14 weeks) than for the low dose group (24 weeks). These density changes were observed only a few weeks prior to the death of the animals, indicating that small animals such as mice will not likely be useful for assessing CT scanning as an early predictor of radiation damage to lungs.