Dosimetric Assessment of a High Precision System for Mouse Proton Irradiation to Assess Spinal Cord Toxicity.

The uncertainty associated with the relative biological effectiveness (RBE) in proton therapy, particularly near the Bragg peak (BP), has led to the shift towards biological-based treatment planning. Proton RBE uncertainty has recently been reported as a possible cause for brainstem necrosis in pediatric patients treated with proton therapy. Despite this, in vivo studies have been limited due to the complexity of accurate delivery and absolute dosimetry. The purpose of this investigation was to create a precise and efficient method of treating the mouse spinal cord with various portions of the proton Bragg curve and to quantify associated uncertainties for the characterization of proton RBE. Mice were restrained in 3D printed acrylic boxes, shaped to their external contour, with a silicone insert extending down to mold around the mouse. Brass collimators were designed for parallel opposed beams to treat the spinal cord while shielding the brain and upper extremities of the animal. Up to six animals may be accommodated for simultaneous treatment within the restraint system. Two plans were generated targeting the cervical spinal cord, with either the entrance (ENT) or the BP portion of the beam. Dosimetric uncertainty was measured using EBT3 radiochromic film with a dose-averaged linear energy transfer (LETd) correction. Positional uncertainty was assessed by collecting a library of live mouse scans (n = 6 mice, two independent scans per mouse) and comparing the following dosimetric statistics from the mouse cervical spinal cord: Volume receiving 90% of the prescription dose (V90); mean dose to the spinal cord; and LETd. Film analysis results showed the dosimetric uncertainty to be ±1.2% and ±5.4% for the ENT and BP plans, respectively. Preliminary results from the mouse library showed the V90 to be 96.3 ± 4.8% for the BP plan. Positional uncertainty of the ENT plan was not measured due to the inherent robustness of that treatment plan. The proposed high-throughput mouse proton irradiation setup resulted in accurate dose delivery to mouse spinal cords positioned along the ENT and BP. Future directions include adapting the setup to account for weight fluctuations in mice undergoing fractionated irradiation.

Dose painting by dynamic irradiation delivery on an image-guided small animal radiotherapy platform.

OBJECTIVE:: Using synchronized three-dimensional stage translation and multiangle radiation delivery to improve conformality and homogeneity of radiation delivery to complexly shaped target volumes for precision preclinical radiotherapy. METHODS:: A CT image of a mouse was used to design irradiation plans to target the spinal cord and an orthotopic lung tumour. A dose painting method is proposed that combines heterogeneous two-dimensional area irradiations from multiple beam directions. For each beam direction, a two-dimensional area was defined based on the projection of the target volume. Each area was divided into many single beam Monte Carlo simulations, based on radiochromic film characterization of a 2.4 mm beam of a commercial precision image-guided preclinical irradiation platform. Beam-on time optimization including all simulated beams from multiple beam directions was used to achieve clinically relevant irradiation objects. Dose painting irradiation plans were compared to irradiation plans using a fixed aperture and rotatable variable aperture collimator. RESULTS:: Irradiation plans for the proposed dose painting approach achieved good target coverage, similar dose to avoidance structures in comparison with irradiation using a rotatable variable aperture collimator, and considerably less dose to avoidance volumes in comparison with irradiation using a non-rotatable fixed aperture collimator. Required calculations and beam-on times were considerably longer for the dose painting method. CONCLUSION:: It was shown that the proposed dose painting strategy is a valuable extension to increase the versatility of current generation precision preclinical radiotherapy platforms. More conformal and homogeneous dose delivery may be achieved at the cost of increased radiation planning and delivery duration. ADVANCES IN KNOWLEDGE:: More advanced radiation planning for image-guided preclinical radiotherapy platforms can improve target dose conformality and homogeneity with the use of optimized dynamic irradiations with synchronized couch translation. The versatility of these platforms can be increased without hardware modifications.

Automated Instead of Manual Treatment Planning? A Plan Comparison Based on Dose-Volume Statistics and Clinical Preference.

PURPOSE: Automated planning aims to speed up treatment planning and improve plan quality. We compared manual planning with automated planning for lung stereotactic body radiation therapy based on dose-volume histogram statistics and clinical preference. METHODS AND MATERIALS: Manual and automated intensity modulated radiation therapy plans were generated for 56 patients by use of software developed in-house and Pinnacle 9.10 Auto-Planning, respectively. Optimization times were measured in 10 patients, and the impact of the automated plan (AP) on the total treatment cost was estimated. For the remaining 46 patients, each plan was checked against our clinical objectives, and a pair-wise dose-volume histogram comparison was performed. Three experienced radiation oncologists evaluated each plan and indicated their preference. RESULTS: APs reduced the average optimization time by 77.3% but only affected the total treatment cost by 3.6%. Three APs and 0 manual plans failed our clinical objectives, and 13 APs and 9 manual plans showed a minor deviation. APs significantly reduced D2% (2% of the volume receives a dose of at least D2%) for the spinal cord, esophagus, heart, aorta, and main stem bronchus (P < .05) while preserving target coverage. The radiation oncologists found >75% of the APs clinically acceptable without any further fine-tuning. CONCLUSIONS: APs may help to create satisfactory treatment plans quickly and effectively. Because critical appraisal by qualified professionals remains necessary, there is no such thing as "fully automated" planning yet.

Using percolation networks to incorporate spatial-dose information for assessment of complication probability in radiotherapy.

This study investigates an extension of recent cluster based methods of assessing the probability of complication in normal organs following radiotherapy treatment which delivers a spatially non-uniform radiation dose distribution. Current methods of assessing this complication probability are spatially degenerate and do not adequately assess the contiguity of damage done to tissue. Therefore, new measures of assessing complication after radiation exposure have been proposed for parallel and serial type organs. In parallel organs an interaction between cells within a functional subunit is stipulated and complication is regarded as a weighted sum of all clusters in the organ. This allows the assessment to account for all damage to the tissue whilst emphasising the importance of damage that accumulates into large and connected spatial regions addressing a deficiency in the current method of calculating complication probabilities. Several spatially-varying doses were analysed and simulated in silico. The simulations produce complication risk estimates for homogeneous dose distributions that are comparable to empirical results but which deviate with any dose inhomogeneity. The simulations also show that the standard method of dose transformation to an effective uniform dose is not valid in cluster based models.

Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury.

BACKGROUND: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. METHODS AND MATERIALS: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. RESULTS: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). CONCLUSIONS: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

Concomitant Imaging Dose and Cancer Risk in Image Guided Thoracic Radiation Therapy.

PURPOSE: Kilovoltage cone beam computed tomography (CT) (kVCBCT) imaging guidance improves the accuracy of radiation therapy but imposes an extra radiation dose to cancer patients. This study aimed to investigate concomitant imaging dose and associated cancer risk in image guided thoracic radiation therapy. METHODS AND MATERIALS: The planning CT images and structure sets of 72 patients were converted to CT phantoms whose chest circumferences (Cchest) were calculated retrospectively. A low-dose thorax protocol on a Varian kVCBCT scanner was simulated by a validated Monte Carlo code. Computed doses to organs and cardiac substructures (for 5 selected patients of various dimensions) were regressed as empirical functions of Cchest, and associated cancer risk was calculated using the published models. The exposures to nonthoracic organs in children were also investigated. RESULTS: The structural mean doses decreased monotonically with increasing Cchest. For all 72 patients, the median doses to the heart, spinal cord, breasts, lungs, and involved chest were 1.68, 1.33, 1.64, 1.62, and 1.58 cGy/scan, respectively. Nonthoracic organs in children received 0.6 to 2.8 cGy/scan if they were directly irradiated. The mean doses to the descending aorta (1.43 ± 0.68 cGy), left atrium (1.55 ± 0.75 cGy), left ventricle (1.68 ± 0.81 cGy), and right ventricle (1.85 ± 0.84 cGy) were significantly different (P<.05) from the heart mean dose (1.73 ± 0.82 cGy). The blade shielding alleviated the exposure to nonthoracic organs in children by an order of magnitude. CONCLUSIONS: As functions of patient size, a series of models for personalized estimation of kVCBCT doses to thoracic organs and cardiac substructures have been proposed. Pediatric patients received much higher doses than did the adults, and some nonthoracic organs could be irradiated unexpectedly by the default scanning protocol. Increased cancer risks and disease adverse events in the thorax were strongly related to higher imaging doses and smaller chest dimensions.

HDRMC, an accelerated Monte Carlo dose calculator for high dose rate brachytherapy with CT-compatible applicators.

PURPOSE: To present a new accelerated Monte Carlo code for CT-based dose calculations in high dose rate (HDR) brachytherapy. The new code (HDRMC) accounts for both tissue and nontissue heterogeneities (applicator and contrast medium). METHODS: HDRMC uses a fast ray-tracing technique and detailed physics algorithms to transport photons through a 3D mesh of voxels representing the patient anatomy with applicator and contrast medium included. A precalculated phase space file for the(192)Ir source is used as source term. HDRM is calibrated to calculated absolute dose for real plans. A postprocessing technique is used to include the exact density and composition of nontissue heterogeneities in the 3D phantom. Dwell positions and angular orientations of the source are reconstructed using data from the treatment planning system (TPS). Structure contours are also imported from the TPS to recalculate dose-volume histograms. RESULTS: HDRMC was first benchmarked against the MCNP5 code for a single source in homogenous water and for a loaded gynecologic applicator in water. The accuracy of the voxel-based applicator model used in HDRMC was also verified by comparing 3D dose distributions and dose-volume parameters obtained using 1-mm(3) versus 2-mm(3) phantom resolutions. HDRMC can calculate the 3D dose distribution for a typical HDR cervix case with 2-mm resolution in 5 min on a single CPU. Examples of heterogeneity effects for two clinical cases (cervix and esophagus) were demonstrated using HDRMC. The neglect of tissue heterogeneity for the esophageal case leads to the overestimate of CTV D90, CTV D100, and spinal cord maximum dose by 3.2%, 3.9%, and 3.6%, respectively. CONCLUSIONS: A fast Monte Carlo code for CT-based dose calculations which does not require a prebuilt applicator model is developed for those HDR brachytherapy treatments that use CT-compatible applicators. Tissue and nontissue heterogeneities should be taken into account in modern HDR brachytherapy planning.

Assessing the uncertainty in QUANTEC's dose-response relation of lung and spinal cord with a bootstrap analysis.

PURPOSE: To apply a statistical bootstrap analysis to assess the uncertainty in the dose-response relation for the endpoints pneumonitis and myelopathy reported in the QUANTEC review. METHODS AND MATERIALS: The bootstrap method assesses the uncertainty of the estimated population-based dose-response relation due to sample variability, which reflects the uncertainty due to limited numbers of patients in the studies. A large number of bootstrap replicates of the original incidence data were produced by random sampling with replacement. The analysis requires only the dose, the number of patients, and the number of occurrences of the studied endpoint, for each study. Two dose-response models, a Poisson-based model and the Lyman model, were fitted to each bootstrap replicate using maximum likelihood. RESULTS: The bootstrap analysis generates a family of curves representing the range of plausible dose-response relations, and the 95% bootstrap confidence intervals give an estimated upper and lower toxicity risk. The curve families for the 2 dose-response models overlap for doses included in the studies at hand but diverge beyond that, with the Lyman model suggesting a steeper slope. The resulting distributions of the model parameters indicate correlation and non-Gaussian distribution. For both data sets, the likelihood of the observed data was higher for the Lyman model in >90% of the bootstrap replicates. CONCLUSIONS: The bootstrap method provides a statistical analysis of the uncertainty in the estimated dose-response relation for myelopathy and pneumonitis. It suggests likely values of model parameter values, their confidence intervals, and how they interrelate for each model. Finally, it can be used to evaluate to what extent data supports one model over another. For both data sets considered here, the Lyman model was preferred over the Poisson-based model.

Effect of preconception gamma irradiation on morphometric assessment of adult female mice and embryo / Efecto de la irradiación gamma preconcepción sobre la evaluación morfométrica de ratones hembras adultas y embriones

The aim was to study the effect of preconception gamma irradiation on the gross morphometry of the adult female mice and its embryo. Twenty-seven mice; 18 females and 9 males: subdivided into 3 groups namely (Control, Non-Irradiation and Radiation) containing 6 females and 3 male mice each in 2:1 ratio. A gamma irradiation dose of 1Gy/min was delivered to each batch of mice exposed by a Cobalt 60, Theratron 780c model, by Atomic Energy of Canada Limited (AECL) at the Radiotherapy department of the University College Hospital, Ibadan. All the animals were mated 1 week post irradiation. Vaginal plugs were confirmed, and the pregnant females were sacrificed on day 14 of gestation by chloroform inhalation. The gross morphology of the female mice and their harvested litters were assessed and statistically analysed. A total of 113 embryos were harvested in all groups; 54 for Control, 50 for Non-Irradiated and 9 for the irradiation group. The gross morphologic assessments of the fetuses were statistically significant at P value < 0.05 for all the 3 groups compared. These findings suggest that a preconception irradiation affects the morphology of the female mice and its progeny.

El objetivo fue estudiar el efecto de la irradiación gamma antes de la concepción sobre la morfometría macroscópica de ratones hembra adultos y los embriones de sus crías. Veinte y siete ratones, 18 hembras y 9 machos, divididos en 3 grupos (control, sin irradiación e irradiado) con 6 hembras y 3 machos cada uno en proporción 2:1. Una dosis de radiación gamma de 1 Gy/min fue aplicada a uno de los ratones expuestos por un equipo Cobalt 60, Theratron modelo 780c, Atomic Energy of Canada Limited (AECL) en el departamento de radioterapia del Hospital University College de Ibadan. Todos los animales se aparearon 1 semana después de la irradiación. Se confirmaron los tapones vaginales, y las hembras preñadas fueron sacrificadas en el día 14 de la gestación por inhalación de cloroformo. La morfología general de los ratones hembras y sus camadas fueron evaluadas y analizadas estadísticamente. Un total de 113 embriones se recolectaron en todos los grupos, 54 del grupo control, 50 del grupo no irradiados y 9 del grupo irradiado. Las evaluaciones morfológicas macroscópicas de los fetos fueron estadísticamente significativas (p<0,05) para los 3 grupos de comparación. Estos hallazgos sugieren que una irradiación previa a la concepción afecta a la morfología de los ratones hembra y su progenie.

Statistical assessment of proton treatment plans under setup and range uncertainties.

PURPOSE: To evaluate a method for quantifying the effect of setup errors and range uncertainties on dose distribution and dose-volume histogram using statistical parameters; and to assess existing planning practice in selected treatment sites under setup and range uncertainties. METHODS AND MATERIALS: Twenty passively scattered proton lung cancer plans, 10 prostate, and 1 brain cancer scanning-beam proton plan(s) were analyzed. To account for the dose under uncertainties, we performed a comprehensive simulation in which the dose was recalculated 600 times per given plan under the influence of random and systematic setup errors and proton range errors. On the basis of simulation results, we determined the probability of dose variations and calculated the expected values and standard deviations of dose-volume histograms. The uncertainties in dose were spatially visualized on the planning CT as a probability map of failure to target coverage or overdose of critical structures. RESULTS: The expected value of target coverage under the uncertainties was consistently lower than that of the nominal value determined from the clinical target volume coverage without setup error or range uncertainty, with a mean difference of -1.1% (-0.9% for breath-hold), -0.3%, and -2.2% for lung, prostate, and a brain cases, respectively. The organs with most sensitive dose under uncertainties were esophagus and spinal cord for lung, rectum for prostate, and brain stem for brain cancer. CONCLUSIONS: A clinically feasible robustness plan analysis tool based on direct dose calculation and statistical simulation has been developed. Both the expectation value and standard deviation are useful to evaluate the impact of uncertainties. The existing proton beam planning method used in this institution seems to be adequate in terms of target coverage. However, structures that are small in volume or located near the target area showed greater sensitivity to uncertainties.

Radiotherapy for early mediastinal Hodgkin lymphoma according to the German Hodgkin Study Group (GHSG): the roles of intensity-modulated radiotherapy and involved-node radiotherapy.

PURPOSE: Cure rates of early Hodgkin lymphoma (HL) are high, and avoidance of late complications and second malignancies have become increasingly important. This comparative treatment planning study analyzes to what extent target volume reduction to involved-node (IN) and intensity-modulated (IM) radiotherapy (RT), compared with involved-field (IF) and three-dimensional (3D) RT, can reduce doses to organs at risk (OAR). METHODS AND MATERIALS: Based on 20 computed tomography (CT) datasets of patients with early unfavorable mediastinal HL, we created treatment plans for 3D-RT and IMRT for both the IF and IN according to the guidelines of the German Hodgkin Study Group (GHSG). As OAR, we defined heart, lung, breasts, and spinal cord. Dose-volume histograms (DVHs) were evaluated for planning target volumes (PTVs) and OAR. RESULTS: Average IF-PTV and IN-PTV were 1705 cm(3) and 1015 cm(3), respectively. Mean doses to the PTVs were almost identical for all plans. For IF-PTV/IN-PTV, conformity was better with IMRT and homogeneity was better with 3D-RT. Mean doses to the heart (17.94/9.19 Gy for 3D-RT and 13.76/7.42 Gy for IMRT) and spinal cord (23.93/13.78 Gy for 3D-RT and 19.16/11.55 Gy for IMRT) were reduced by IMRT, whereas mean doses to lung (10.62/8.57 Gy for 3D-RT and 12.77/9.64 Gy for IMRT) and breasts (left 4.37/3.42 Gy for 3D-RT and 6.04/4.59 Gy for IMRT, and right 2.30/1.63 Gy for 3D-RT and 5.37/3.53 Gy for IMRT) were increased. Volume exposed to high doses was smaller for IMRT, whereas volume exposed to low doses was smaller for 3D-RT. Pronounced benefits of IMRT were observed for patients with lymph nodes anterior to the heart. IN-RT achieved substantially better values than IF-RT for almost all OAR parameters, i.e., dose reduction of 20% to 50%, regardless of radiation technique. CONCLUSIONS: Reduction of target volume to IN most effectively improves OAR sparing, but is still considered investigational. For the time being, IMRT should be considered for large PTVs especially when the anterior mediastinum is involved.

Patient-specific three-dimensional concomitant dose from cone beam computed tomography exposure in image-guided radiotherapy.

PURPOSE: The purpose of the present study was to quantify the concomitant dose received by patients undergoing cone beam computed tomography (CBCT) scanning in different clinical scenarios as a part of image-guided radiotherapy (IGRT) procedures. METHODS AND MATERIALS: We calculated the three-dimensional concomitant dose received as a result of CBCT scans in 6 patients representing different clinical scenarios: two pelvis, two head and neck, and two chest. We assessed the effect that a daily on-line IGRT strategy would have on the patient dose distribution, assuming 40 CBCT scans throughout the treatment course. The additional dose to the planning target volume margin region was also estimated. RESULTS: In the pelvis, a single CBCT scan delivered a mean dose to the femoral heads of 2-6 cGy and the rectum of 1-2 cGy. An additional dose to the planning target volume was within 1-3 cGy. In the chest, the mean dose to the planning target volume varied from 2.5 to 5 cGy. The lung and spinal cord planning organ at risk volume received ≤4 cGy and ≤5 cGy, respectively. In the head and neck, a single CBCT scan delivered a mean dose of 0.3 cGy, with bony structures receiving 0.5-0.8 cGy. The femoral heads received an additional dose of 1.5-2.5 Gy. A reduction of 20-30% in the mean dose to the organs at risk was achieved using bowtie filtration. In the head and neck, the dose to the eyes and brainstem was eliminated by decreasing the craniocaudal field size. CONCLUSIONS: The additional dose from on-line IGRT procedures can be clinically relevant. The organ dose can be significantly reduced with the use of appropriate patient-specific settings. The concomitant dose from CBCT should be accounted for and the acquisition settings optimized for optimal IGRT strategies on a patient basis.

Determination of the optimal statistical uncertainty to perform electron-beam Monte Carlo absorbed dose estimation in the target volume.

PURPOSE OF STUDY: Monte Carlo based treatment planning system are known to be more accurate than analytical methods for performing absorbed dose estimation, particularly in and near heterogeneities. However, the required computation time can still be an issue. The present study focused on the determination of the optimum statistical uncertainty in order to minimise computation time while keeping the reliability of the absorbed dose estimation in treatments planned with electron-beams. MATERIALS AND METHODS: Three radiotherapy plans (medulloblastoma, breast and gynaecological) were used to investigate the influence of the statistical uncertainty of the absorbed dose on the target volume dose-volume histograms (spinal cord, intramammary nodes and pelvic lymph nodes, respectively). RESULTS: The study of the dose-volume histograms showed that for statistical uncertainty levels (1 S.D.) above 2 to 3%, the standard deviation of the mean dose in the target volume calculated from the dose-volume histograms increases by at least 6%, reflecting the gradual flattening of the dose-volume histograms. CONCLUSIONS: This work suggests that, in clinical context, Monte Carlo based absorbed dose estimations should be performed with a maximum statistical uncertainty of 2 to 3%.

Computed tomography perfusion assessment of radiation therapy effects on spinal cord hemodynamics.

PURPOSE: We used computed tomography (CT) perfusion to evaluate the acute and late effect of radiation therapy (RT) on spinal cord (SC) hemodynamics in patients without symptoms of myelopathy. We hypothesized that SC perfusion could be acutely altered during RT. METHODS AND MATERIALS: We analyzed neck CT perfusion studies of 36 head-and-neck cancer patients (N1), 16 of whom had previously undergone RT. In a separate group of 6 patients (N2), CT perfusion studies were obtained before RT, after 40 Gy, and after treatment completion. RESULTS: In the N1 group, SC blood flow (BF), blood volume (BV), mean transit time (MTT), and capillary permeability (CP) maps were not significantly different between RT-treated and RT-naive patients. In the N2 group, BF and CP were significantly increased during treatment compared with the baseline and post-RT studies. CONCLUSIONS: Radiation therapy of the head and neck may cause transient perturbations of SC perfusion that seem to reverse after treatment. There are no definite chronic effects of RT on SC perfusion observeable at the typical doses administered during treatment of head and neck malignancies.

Damage assessment in gastric cancer treatment with adjuvant radiochemotherapy: calculation of the NTCP's from the differential HDV of the organs at risk.

OBJECTIVE: To calculate the Normal Tissue Complication Probabilities (NTCP) for the liver, right kidney, left kidney and spinal cord, as well as the global Uncomplicated Tumour Control Probability (UTCP) in gastric cancer patients who underwent a treatment with radiotherapy after radical surgery in our environment. MATERIAL AND METHOD: In April 2000, a postoperative chemotherapy (QT-RT) protocol started in the province of Malaga for Gastric Adenocarcinomas with postsurgical stage II or higher (pT3-4 and/or pN+). This clinical protocol served as a base for our NTCP and UTCP retrospective theorical study. A virtual simulation and a 3D planning were made in all cases. The differential HDV, selected for each patient were obtained for the 4 organs at risk (OR). Hystograms reduction was made by the Kutcher and Burman's Effective Volume method. NTCP calculations by Lyman's models. The following variables were calculated: maximal dose for each organ (Dmax), Effective Volume (Veff), TD50 (Veff/Vref); NTCP for each organ of the patient; global UTCP for each patient. Differences between the 2 treatment techniques were analysed (2-field versus 4-field technique). For the NTCP calculations the computer application Albireo 1.0(R) was used. RESULTS: 29 patients to assess with an average age of 54 +/- 10 years (range: 38-71); 65.5% men/34.5% women. The technique used was the field technique AP-PA in the 51.7% (15) and with 4 fields in 48.3% (14) of the cases. The global damage is estimated in 16% with a range between 0 and 37%. This goes up to 25% with the 2-field technique, with a wide range between 2 and 48% and it remains reduced to 4%, within a range between 0 and 12% when 4 fields are used. There were significant differences concerning the estimated damage probability (NTCP) on liver, spinal cord and left kidney, depending on the use of two or four fields. CONCLUSION: NTCP and the global UTCP values of the organs at risk allow to compare a technique net benefit from another in each particular case, although in our theoretical study the comparison was done among the patients. It is important to stress that the calculations of the TCP and NTCP have a limited quantitative signification but they are useful and beneficial in order to decide between treatment plans when they are supported by the clinical knowledge.

Dose heterogeneity in the target volume and intensity-modulated radiotherapy to escalate the dose in the treatment of non-small-cell lung cancer.

PURPOSE: To quantify the dose escalation achievable in the treatment of non-small-cell lung cancer (NSCLC) by allowing dose heterogeneity in the target volume or using intensity-modulated radiotherapy (IMRT), or both. METHODS AND MATERIALS: Computed tomography data and contours of 10 NSCLC patients with limited movements of the tumor and representing a broad spectrum of clinical cases were selected for this study. Four irradiation techniques were compared: two conformal (CRT) and two IMRT techniques, either prescribing a homogeneous dose in the planning target volume (PTV) (CRT(hom) and IMRT(hom)) or allowing dose heterogeneity (CRT(inhom) and IMRT(inhom)). The dose heterogeneity was allowed only toward high doses, i.e., the minimum dose in the target for CRT(inhom) and IMRT(inhom) could not be lower than for the corresponding homogeneous plan. The dose in the PTV was escalated (fraction size of 2.25 Gy) until either an organ at risk reached the maximum allowed dose or the mean PTV dose reached a maximum level set at 101.25 Gy. RESULTS: When small and convex tumors were irradiated, CRT(hom) could achieve the maximum dose of 101.25 Gy, whereas for bigger and/or concave PTVs the dose level achievable with CRT(hom) was significantly lower, in 1 case even below 60 Gy. The CRT(inhom) allowed on average a 6% dose escalation with respect to CRT(hom). The IMRT(hom) achieved in all except 1 case a mean PTV dose of at least 75 Gy. The gain in mean PTV dose of IMRT(hom) with respect to CRT(hom) ranged from 7.7 to 14.8 Gy and the IMRT(hom) plans were always more conformal than the corresponding CRT(hom) plans. The IMRT(inhom) provided an additional advantage over IMRT(hom) of at least 5 Gy. For all CRT plans the achievable dose was determined by the lung dose threshold, whereas for more than half of the IMRT plans the esophagus was the dose-limiting organ. The IMRT plans were deliverable with 10-12 segments per beam and did not produce an increase of lung volume irradiated at low doses (<20 Gy). CONCLUSIONS: The dose in NSCLC treatments can be escalated by loosening the constraints on maximum dose in the target volume or using IMRT, or both. For large and concave tumors, an average dose escalation of 6% and 17% was possible when dose heterogeneity and IMRT were applied alone. When they were combined, the average dose increase was as high as 35%. Intensity-modulated RT delivered in a static mode can produce homogeneous dose distributions in the target and does not lead to an increase of lung volume receiving (very) low doses, even down to 5 Gy.

Data on dose-volume effects in the rat spinal cord do not support existing NTCP models.

PURPOSE: To evaluate several existing dose-volume effect models for their ability to describe the occurrence of white matter necrosis in rat spinal cord after irradiation with small proton beams. METHODS AND MATERIALS: A large number of dose-volume effect models has been fitted to data on the occurrence of white matter necrosis after irradiation with small proton beams. The fitting was done with the maximum likelihood method. For each model, the goodness of fit was calculated. An empirical tolerance dose-volume (eTDV) model was designed to describe data obtained after uniform irradiation. RESULTS: The eTDV model, the critical element model, and critical volume model with inclusion of the repair-by-migration principle described by Shirato, were able to describe the data obtained after irradiation with uniform dose distributions of varying sizes. However, none of the models under investigation was able to describe all the data. Extension of the developed empirical model with a repair mechanism with a limited range resulted in a good description of the tolerance doses. CONCLUSIONS: In the rat spinal cord, a nonlocal repair mechanism, acting from nonirradiated to irradiated tissue, plays an important role in the (prevention of the) occurrence of white matter necrosis after irradiation. Models that take into account this effect need to be developed.

Monte Carlo evaluation of tissue inhomogeneity effects in the treatment of the head and neck.

PURPOSE: To use Monte Carlo dose calculation to assess the degree to which tissue inhomogeneities in the head and neck affect static field conformal, computed tomography (CT)-based 6-MV photon treatment plans. METHODS AND MATERIALS: We retrospectively studied the three-dimensional treatment plans that had been used for the treatment of 5 patients with tumors in the nasopharyngeal or paranasal sinus regions. Two patients had large surgical cavities. The plans were designed with a clinical treatment planning system that uses a measurement-based pencil-beam dose-calculation algorithm with an equivalent path-length inhomogeneity correction. Each plan employs conformally-shaped 6-MV photon beams. Patient anatomy and electron densities were obtained from the treatment planning CT images. For each plan, the dose distribution was recalculated with the Monte Carlo method, utilizing the same beam geometry and CT images. The Monte Carlo method accurately accounts for the perturbation effects of local tissue heterogeneities. The Monte Carlo calculated dose distributions were compared with those from the clinical treatment planning system. RESULTS: The degree to which tissue inhomogeneity affects the dose distributions of individual fields varies with the specific anatomic geometry, especially the size and location of air cavities in relation to the beam orientation and field size. Most of the beam apertures completely enclose the air cavities within or adjacent to the gross tumor volume (GTV). Equivalent squares (including blocking) ranged from approximately 5 to 9.5 cm. A common feature observed for individual fields is that the Monte Carlo calculated doses to tissue directly behind and within an air cavity are lower. However, after combining the fields employed in each treatment plan, the overall dose distribution shows only small differences between the two methods. For all 5 patients, the Monte Carlo calculated treatment plans showed a slightly lower dose received by the 95% of target volume (D(95)) than the plans calculated with the pencil-beam algorithm. The average difference in the target volume encompassed by the prescription isodose line was less than 2.2%. The difference between the dose-volume histograms (DVHs) of the GTV was generally small. For the brainstem and chiasm, the DVHs of the two plans were similar. For the spinal cord, differences in the details of the DHV and the dose to 1 cc (D(1cc)) of the structure were observed, with Monte Carlo calculation generally predicting increased dose indices to the spinal cord. However, these changes are not expected to be clinically significant. CONCLUSION: For 6-MV photons, the effects of both normal tissue inhomogeneities and surgical air cavities on the target coverage were adequately accounted for by conventional pencil beam methods for all of the cases studied. Although differences in details of the DVHs of the normal structures were observed, depending on whether Monte Carlo or pencil-beam algorithm was used for calculation, these differences are not expected to be clinically significant. In general, the pencil-beam calculation corrected for primary attenuation by the equivalent pathlength is a sufficiently accurate method for head-and-neck treatment planning using 6-MV photons.

Intensity modulated proton therapy: a clinical example.

In this paper, we report on the clinical application of fully automated three-dimensional intensity modulated proton therapy, as applied to a 34-year-old patient presenting with a thoracic chordoma. Due to the anatomically challenging position of the lesion, a three-field technique was adopted in which fields incident through the lungs and heart, as well as beams directed directly at the spinal cord, could be avoided. A homogeneous target dose and sparing of the spinal cord was achieved through field patching and computer optimization of the 3D fluence of each field. Sensitivity of the resultant plan to delivery and calculational errors was determined through both the assessment of the potential effects of range and patient setup errors, and by the application of Monte Carlo dose calculation methods. Ionization chamber profile measurements and 2D dosimetry using a scintillator/CCD camera arrangement were performed to verify the calculated fields in water. Modeling of a 10% overshoot of proton range showed that the maximum dose to the spinal cord remained unchanged, but setup error analysis showed that dose homogeneity in the target volume could be sensitive to offsets in the AP direction. No significant difference between the MC and analytic dose calculations was found and the measured dosimetry for all fields was accurate to 3% for all measured points. Over the course of the treatment, a setup accuracy of +/-4 mm (2 s.d.) could be achieved, with a mean offset in the AP direction of 0.1 mm. Inhalation/exhalation CT scans indicated that organ motion in the region of the target volume was negligible. We conclude that 3D IMPT plans can be applied clinically and safely without modification to our existing delivery system. However, analysis of the calculated intensity matrices should be performed to assess the practicality, or otherwise, of the plan.

Histological assessment of rodent CNS tissues to EPR oximetry probe material.

The effects of the paramagnetic oxygen sensing material, lithium phthalocyanine (LiPc) and fusinite were assessed in the brain of Mongolian gerbils and the spinal columns of rats respectively, to determine if there are histologically discernible changes in the tissue surrounding the probe material. This information is essential for the evaluation of the role of EPR oximetry in the measurements of pO2 in the CNS; the technique has great potential value for such measurements because it reports on the pO2 accurately and sensitively and, after the initial placement, measurements can be made repeatedly without invasive procedures or anesthesia. Histologic assessments demonstrated the inert nature of both the fusinite and LiPc EPR probes in rodent CNS tissue over relatively long (2 month) time periods. The fusinite suspensions and LiPc crystals (size range of approximately 100-200 microns) remained well localized to the point of injection and created mild acute tissue reaction on implantation (which appeared to resolve quickly) and virtually no tissue reaction at later times. The majority of the implanted fusinite and LiPc material was present extracellularly in the brain and spinal cord. MRI provided an accurate, noninvasive assessment of probe placement and was able to investigate pathologic effects (hemorrhage, edema, necrosis) associated with the probe placement and treatment effects.