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Aim/objectives/background The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO) have jointly developed the following practice parameter for image-guided radiation therapy (IGRT). IGRT is radiation therapy that employs imaging to maximize accuracy and precision throughout the entire process of treatment delivery with the goal of optimizing accuracy and reliability of radiation therapy to the target, while minimizing dose to normal tissues. Methods The ACR-ASTRO Practice Parameter for IGRT was revised according to the process described on the ACR website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parametersand-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the ASTRO. Both societies then reviewed and approved the document. Results This practice parameter is developed to serve as a tool in the appropriate application of IGRT in the care of patients with conditions where radiation therapy is indicated. It addresses clinical implementation of IGRT including personnel qualifications, quality assurance standards, indications, and suggested documentation. Conclusions This practice parameter is a tool to guide clinical use of IGRT and does not make recommendations on site-specific IGRT directives. It focuses on the best practices and principles to consider when using IGRT effectively, especially with the significant increase in imaging data that is now available with IGRT. The clinical benefit and medical necessity of the imaging modality and frequency of IGRT should be assessed for each patient.

PURPOSE/OBJECTIVE(S) Dual energy (DE) fluoroscopy is being considered for markerless tumor tracking (MTT) of lung tumors. The principal advantage of this technique is that it can be used to remove overlaying bony anatomy, and hence improve the tracking accuracy vs. single energy (SE) fluoroscopy. Previous studies using phantoms have demonstrated the superiority of DE vs. SE imaging for MTT. The goal of this study is to clinically evaluate MTT with fast-kV switching DE imaging on a cohort of SBRT lung cancer patients using the on-board imager (OBI) of a commercial linear accelerator. MATERIALS/METHODS In this Institutional Review Board (IRB)-approved prospective study, DE images were acquired for 10 SBRT lung cancer patients. For each patient, DE images were obtained over 180o arc using fast-kV switching implemented on the OBI of a commercial linear accelerator. This fast-kV switching technique produced x-ray pulses that alternate between programmed tube voltages (i.e., 120 and 60 kVp) at a rate of 15 Hz. Weighted logarithmic subtraction was performed offline on consecutive high-low energy projections to produce soft tissue images. For comparison, SE image sequences were obtained by using the 120 kVp images. Separately, a template was derived from the contoured gross tumor volume (GTV) on the CT simulation scan. A template-based matching algorithm was then used to track target motion on both DE and SE image sequences. Successful matching was defined as any instance in which the algorithm matched the template on the respective fluoroscopic image. Ground truth positions were estimated from both the DE and SE images using Bayesian inference. RESULTS A total of 2278 SE and DE image frames were analyzed. DE imaging resulted in significantly improved tracking vs. SE on 884/2278 (38.8%) of image frames. In those frames, the average tracking error was 1.78 +/- 2.02 mm vs. 2.21 +/- 2.38 mm, for DE vs. SE imaging, respectively (P 0.7 mm. No correlation was observed between tumor volume/location and improved tracking accuracy with DE imaging. Additionally, the fraction of images that could not be tracked with SE was 91/2278 (4.0%). The addition of DE imaging decreased this number to 33/2278 (1.4%) (P < 0.001). CONCLUSION This is the first prospective study to evaluate fast-kV switching DE imaging for MTT in a cohort of SBRT lung cancer patients. This study has demonstrated that by removal of overlapping bony anatomy, DE imaging increases tracking accuracy and decreases the number of images where tracking fails. Future work includes optimization of template parameters to further improve DE tracking accuracy.

Purpose/Objective(s) Symptomatic radiation pneumonitis (RP) is a common cause of treatment related toxicity in patients receiving radiation therapy for lung cancer. Machine learning techniques have been utilized to determine predictors of RP, but most of these models have used dosimetric features to generate results. The identification of pretreatment factors related to the development of symptomatic RP and implementation of these factors into a machine learning model would be clinically useful to guide treatment decisions, risk estimation, and risk reduction of development of symptomatic RP. Materials/Methods We retrospectively reviewed data from 278 lung cancer patients that underwent stereotactic body radiation therapy (SBRT). Pretreatment factors including patient demographics, pulmonary function data, and tumor characteristics were previously analyzed for the development of symptomatic RP, defined as CTCAE v4.0 ≥ Grade 2. A programming environment was used to generate classification machine learning models based on this dataset. Models were tested for accuracy in classification, area-under-the-curve (AUC), and special attention was paid to the false negative rate. The performance of several different algorithms using various combinations of predictors was evaluated including Decision Trees, Discriminant Analysis, Logistic Regression, Naive Bayes Classifiers, Support Vector Machines, Nearest Neighbor Classifiers and Ensemble Classifiers. Each model utilized 5-fold cross-validation to prevent overfitting. Results Of the 278 patients receiving SBRT, 42 patients (15.1%) developed symptomatic RP. A RUSBoosted Trees Ensemble Classifier was found to be the most accurate model tested. Features identified as significant risk factors for symptomatic RP in prior univariate and multivariate analyses were found to be the most important predictors in the machine learning models tested. These features included prior radiation treatment to the thorax or lung resection, location of tumor in the right lower lobe, a higher T Stage and age. When this model was used to classify cases of symptomatic RP, it had an AUC of 0.86 and an accuracy of 87%, correctly predicting 36 out of 42 pneumonitis cases. The model had a false negative rate of 14% and false positive rate of 13%. Conclusion A machine learning model was developed to identify pretreatment factors predictive of symptomatic RP. The advantage of this model when compared to others with a similar goal is that it depends solely on pretreatment factors, and therefore could be applied in a clinical setting prior to radiation therapy. Next steps include testing with an independent dataset to confirm the model's accuracy and prospective studies to verify the model's clinical utility.

Objective: To investigate the effects of adaptive radiotherapy on dosimetric, clinical, and toxicity outcomes for patients with head and neck cancer undergoing chemoradiotherapy with intensity-modulated radiotherapy. Methods: Fifty-one patients with advanced head and neck cancer underwent definitive chemoradiotherapy with the original plan optimized to deliver 70.2 Gy. All patients were resimulated at a median dose of 37.8 Gy (range, 27.0-48.6 Gy) due to changes in tumor volume and/or patient weight loss (>15% from baseline). Thirty-four patients underwent adaptive replanning for their boost planning (21.6 Gy). The dosimetric effects of the adaptive plan were compared to the original plan and the original plan copied on rescan computed tomography. Acute and late toxicities and tumor local control were assessed. Gross tumor volume reduction rate was calculated. Results: With adaptive replanning, the maximum dose to the spinal cord, brain stem, mean ipsilateral, and contralateral parotid had a median reduction of −4.5%, −3.0%, −6.2%, and −2.5%, respectively (median of 34 patients). Median gross tumor volume and boost planning target volume coverage improved by 0.8% and 0.5%, respectively. With a median follow-up time of 17.6 months, median disease-free survival and overall survival was 14.8 and 21.1 months, respectively. Median tumor volume reduction rate was 35.2%. For patients with tumor volume reduction rate ≤35.2%, median disease-free survival was 8.7 months, whereas it was 16.9 months for tumor volume reduction rate >35.2%. Four patients had residual disease after chemoradiotherapy, whereas 64.7% (20 of 34) of patients achieved locoregional control. Conclusion: Implementation of adaptive radiotherapy in head and neck cancer offers benefits including improvement in tumor coverage and decrease in dose to organs at risk. The tumor volume reduction rate during treatment was significantly correlated with disease-free survival and overall survival.

Purpose: To evaluate a method for reducing metal artifacts, arising from dental fillings, on cone-beam computed tomography images. Materials and Methods: A projection interpolation algorithm is applied to cone-beam computed tomography images containing metal artifacts from dental fillings. This technique involves identifying metal regions in individual cone-beam computed tomography projections and interpolating the surrounding values to remove the metal from the projection data. Axial cone-beam computed tomography images are then reconstructed, resulting in a reduction in the streak artifacts produced by the metal. Both phantom and patient imaging data are used to evaluate this technique. Results: The interpolation substitution technique successfully reduced metal artifacts in all cases. Corrected images had fewer or no streak artifacts compared to their noncorrected counterparts. Quantitatively, regions of interest containing the artifacts showed reduced variance in the corrected images versus the uncorrected images. Average pixel values in regions of interest around the metal object were also closer in value to nonmetal regions after artifact reduction. Artifact correction tended to perform better on patient images with less complex metal objects versus those with multiple large dental fillings. Conclusion: The interpolation substitution is potentially an efficient and effective technique for reducing metal artifacts caused by dental fillings on cone-beam computed tomography image. This technique may be effective in reducing such artifacts in patients with head and neck cancer receiving daily image-guided radiotherapy.

Template-based matching algorithms are currently being considered for markerless motion tracking of lung tumors. These algorithms use tumor templates derived from the planning CT scan, and track the motion of the tumor on single energy fluoroscopic images obtained at the time of treatment. In cases where bone may obstruct the view of the tumor, dual energy fluoroscopy may be used to enhance soft tissue contrast. The goal of this study is to predict which tumors will have a high degree of accuracy for markerless motion tracking based on radiomic features obtained from the planning CT scan, using peak-to-sidelobe ratio (PSR) as a surrogate of tracking accuracy. In this study, CT imaging data of 8 lung cancer patients were obtained and analyzed through the open source IBEX program to generate 2,287 radiomic features. Agglomerative hierarchical clustering was used to narrow down these features into 145 clusters comprised of the highest correlation to PSR. The features among the clusters with the least inter-correlation were then chosen to limit redundancy in the data. The results of this study demonstrated a number of radiomic features that are positively correlated to PSR. The features with the highest degree of correlation included complexity, orientation and range. This approach may be used to determine patients for whom markerless motion tracking would be beneficial.

Objective: To develop decision trees predicting for tumor volume reduction in patients with head and neck (H&N) cancer using pretreatment clinical and pathological parameters. Methods: Forty-eight patients treated with definitive concurrent chemoradiotherapy for squamous cell carcinoma of the nasopharynx, oropharynx, oral cavity, or hypopharynx were retrospectively analyzed. These patients were rescanned at a median dose of 37.8 Gy and replanned to account for anatomical changes. The percentages of gross tumor volume (GTV) change from initial to rescan computed tomography (CT; %GTVΔ) were calculated. Two decision trees were generated to correlate %GTVΔ in primary and nodal volumes with 14 characteristics including age, gender, Karnofsky performance status (KPS), site, human papilloma virus (HPV) status, tumor grade, primary tumor growth pattern (endophytic/exophytic), tumor/nodal/group stages, chemotherapy regimen, and primary, nodal, and total GTV volumes in the initial CT scan. The C4.5 Decision Tree induction algorithm was implemented. Results: The median %GTVΔ for primary, nodal, and total GTVs was 26.8%, 43.0%, and 31.2%, respectively. Type of chemotherapy, age, primary tumor growth pattern, site, KPS, and HPV status were the most predictive parameters for primary %GTVΔ decision tree, whereas for nodal %GTVΔ, KPS, site, age, primary tumor growth pattern, initial primary GTV, and total GTV volumes were predictive. Both decision trees had an accuracy of 88%. Conclusions: There can be significant changes in primary and nodal tumor volumes during the course of H&N chemoradiotherapy. Considering the proposed decision trees, radiation oncologists can select patients predicted to have high %GTVΔ, who would theoretically gain the most benefit from adaptive radiotherapy, in order to better use limited clinical resources.

Purpose: We evaluated the performance of organ contour propagation from a planning computed tomography to cone-beam computed tomography with deformable image registration by comparing contours to manual contouring. Materials and Methods: Sixteen patients were retrospectively identified based on showing considerable physical change throughout the course of treatment. Multiple organs in the 3 regions (head and neck, prostate, and pancreas) were evaluated. A cone-beam computed tomography from the end of treatment was registered to the planning computed tomography using rigid registration, followed by deformable image registration. The contours were copied on cone-beam computed tomography image sets using rigid registration and modified by 2 radiation oncologists. Contours were compared using Dice similarity coefficient, mean surface distance, and Hausdorff distance. Results: The mean physician-to-physician Dice similarity coefficient for all organs was 0.90. When compared to each physician’s contours, the overall mean for rigid was 0.76 (P < .001), and it was improved to 0.79 (P < .001) for deformable image registration. Comparing deformable image registration to physicians resulted in a mean Dice similarity coefficient of 0.77, 0.74, and 0.84 for head and neck, prostate, and pancreas groups, respectively; whereas, the physician-to-physician mean agreement for these sites was 0.87, 0.90, and 0.93 (P < .001, for all sites). The mean surface distance for physician-to-physician contours was 1.01 mm, compared to 2.58 mm for rigid-to-physician contours and 2.24 mm for deformable image registration-to-physician contours. The mean physician-to-physician Hausdorff distance was 11.32 mm, and when compared to any physician’s contours, the mean for rigid and deformable image registration was 12.1 mm and 12.0 mm (P < .001), respectively. Conclusion: The physicians had a high level of agreement via the 3 metrics; however, deformable image registration fell short of this level of agreement. The automatic workflows using deformable image registration to deform contours to cone-beam computed tomography to evaluate the changes during treatment should be used with caution.

To quantify, through an observer study, the reduction in metal artifacts on cone beam computed tomographic (CBCT) images using a projection-interpolation algorithm, on images containing metal artifacts from dental fillings and implants in patients treated for head and neck (HN) cancer.An interpolation-substitution algorithm was applied to HN CBCT images containing metal artifacts from dental fillings and implants. Image quality with respect to metal artifacts was evaluated subjectively and objectively. First, 6 independent radiation oncologists were asked to rank randomly sorted blinded images (before and after metal artifact reduction) using a 5-point rating scale (1 = severe artifacts; 5 = no artifacts). Second, the standard deviation of different regions of interest (ROI) within each image was calculated and compared with the mean rating scores.The interpolation-substitution technique successfully reduced metal artifacts in 70% of the cases. From a total of 60 images from 15 HN cancer patients undergoing image guided radiation therapy, the mean rating score on the uncorrected images was 2.3 ± 1.1, versus 3.3 ± 1.0 for the corrected images. The mean difference in ranking score between uncorrected and corrected images was 1.0 (95% confidence interval: 0.9-1.2, P.05). The standard deviation of each ROI significantly decreased after artifact reduction (P.01). Moreover, a negative correlation between the mean rating score for each image and the standard deviation of the oral cavity and bilateral cheeks was observed.The interpolation-substitution algorithm is efficient and effective for reducing metal artifacts caused by dental fillings and implants on CBCT images, as demonstrated by the statistically significant increase in observer image quality ranking and by the decrease in ROI standard deviation between uncorrected and corrected images.

There is a lack of understanding of the casual mechanisms behind the observation that some breast adenocarcinomas have identical morphology and comparatively different cellular growth behavior. This is exemplified by a differential response to radiation, chemotherapy, and other biological intervention therapies. Elevated concentrations of the free radical nitric oxide (NO), coupled with the up-regulated enzyme nitric oxide synthase (NOS) which produces NO, are activities which impact tumor growth. Previously, we adapted four human breast cancer cell lines: BT-20, Hs578T, T-47D, and MCF-7 to elevated concentrations of nitric oxide (or high NO [HNO]). This was accomplished by exposing the cell lines to increasing levels of an NO donor over time. Significantly, the HNO cell lines grew faster than did each respective ("PARENT") cell line even in the absence of NO donor-supplemented media. This was evident despite each "parent" being morphologically equivalent to the HNO adapted cell line. Herein, we characterize the HNO cells and their biological attributes against those of the parent cells. Pairs of HNO/parent cell lines were then analyzed using a number of key cellular activity criteria including: cell cycle distribution, DNA ploidy, response to DNA damage, UV radiation response, X-ray radiation response, and the expression of significant cellular enzymes. Other key enzyme activities studied were NOS, p53, and glutathione S-transferase-pi (GST-pi) expression. HNO cells were typified by a far more aggressive pattern of growth and resistance to various treatments than the corresponding parent cells. This was evidenced by a higher S-phase percentage, variable radioresistance, and up-regulated GST-pi and p53. Taken collectively, this data provides evidence that cancer cells subjected to HNO concentrations become resistant to free radicals such as NO via up-regulated cellular defense mechanisms, including p53 and GST-pi. The adaptation to NO may explain how tumor cells acquire a more aggressive tumor phenotype. © 2012 International Society of Oncology and BioMarkers (ISOBM)

For radiation delivery tracking systems that monitor intrafraction prostate motion, generalized departmental threshold protocols may be used. The purpose of this study is to determine whether predefined action thresholds can be generally applied or if patient-specific action thresholds may be required. Software algorithms were developed in the MatLab (The Mathworks Inc., Natick, MA) software environment to simulate shifts of the patient structure set consisting of prostate, bladder, and rectum. These structures were shifted by +/- 10 mm in each direction in 1 mm increments to simulate displacements during treatment, without taking into consideration organ deformity. Dose-volume data at each shift were plotted and analyzed. A linear relationship was observed between planning dose-volume parameters and shifted dose-volume parameters. For a 5 mm anterior shift, it was observed that individual rectal V70 values increased by absolute magnitudes of 6–15%, dependent on the planning rectal V70 of each patient. Likewise, for a 5 mm inferior shift, individual bladder V70 values increased by 1–14%, dependent on planning bladder V70. This linear relationship was observed for all levels of shifts up to 10 mm. Since rectum and bladder dose-volume changes due to patient shifts are dependent on dose-volume parameters, this study suggests that patient-specific action thresholds may be necessary.

To determine factors predictive for hematologic toxicity (HT) associated with concurrent chemoradiation for Stage II through IV cervical cancer.The medical records of 40 women receiving concurrent chemoradiation for cervical cancer were reviewed. Hematologic toxicity was defined by use of Common Terminology Criteria for Adverse Events (version 3.0). Variables predicting for HT including age, body mass index, transfusions, and bone marrow volumes irradiated were included in the data analysis.Of the patients, 13 (32.5%) had Grade 0 or 1 HT and 27 (67.5%) had Grade 2 through 4 HT (HT2+). Multiple logistic regression analysis of potential predictors showed that only the volume of bone receiving 20 Gy (V20) for whole pelvic bone tended toward significance for predicting HT2+. A strong correlation was noted between HT2+ and V20 (r = 0.8, p0.0001). A partitioning analysis to predict HT2+ showed a cutoff value of 79.42% (approximately 80%) for V20 of whole pelvic bone. That is, if the V20 of the whole pelvis exceeds 80%, the risk of HT2+ developing increases by a factor (odds ratio) of 4.5 (95%, confidence interval, 1.08-18.69) (p0.05).We have shown a correlation between bone marrow volume radiated and development of HT. This has implications for use of pelvic intensity-modulated radiation therapy, which can potentially decrease the volume of bone marrow radiated.

Purpose To investigate the dosimetric feasibility of linear accelerator-based intensity-modulated total marrow irradiation (IM-TMI) in patients with hematologic malignancies. Methods and Materials Linear accelerator-based IM-TMI treatment planning was performed for 9 patients using the Eclipse treatment planning system. The planning target volume (PTV) consisted of all the bones in the body from the head to the mid-femur, except for the forearms and hands. Organs at risk (OAR) to be spared included the lungs, heart, liver, kidneys, brain, eyes, oral cavity, and bowel and were contoured by a physician on the axial computed tomography images. The three-isocenter technique previously developed by our group was used for treatment planning. We developed and used a common dose–volume objective method to reduce the planning time and planner subjectivity in the treatment planning process. Results A 95% PTV coverage with the 99% of the prescribed dose of 12 Gy was achieved for all nine patients. The average dose reduction in OAR ranged from 19% for the lungs to 68% for the lenses. The common dose–volume objective method decreased the planning time by an average of 35% and reduced the inter- and intra- planner subjectivity. Conclusion The results from the present study suggest that the linear accelerator-based IM-TMI technique is clinically feasible. We have demonstrated that linear accelerator-based IM-TMI plans with good PTV coverage and improved OAR sparing can be obtained within a clinically reasonable time using the common dose–volume objective method proposed in the present study.

Purpose: To test the hypothesis that the volume of pelvic bone marrow (PBM) receiving 10 and 20 Gy or more (PBM-V{sub 10} and PBM-V{sub 20}) is associated with acute hematologic toxicity (HT) in anal cancer patients treated with concurrent chemoradiotherapy. Methods and Materials: We analyzed 48 consecutive anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiation therapy. The median radiation dose to gross tumor and regional lymph nodes was 50.4 and 45 Gy, respectively. Pelvic bone marrow was defined as the region extending from the iliac crests to the ischial tuberosities, including the os coxae, lumbosacral spine, and proximal femora. Endpoints included the white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin, and platelet count nadirs. Regression models with multiple independent predictors were used to test associations between dosimetric parameters and HT. Results: Twenty patients (42%) had Stage T3-4 disease; 15 patients (31%) were node positive. Overall, 27 (56%), 24 (50%), 4 (8%), and 13 (27%) experienced acute Grade 3-4 leukopenia, neutropenia, anemia, and thrombocytopenia, respectively. On multiple regression analysis, increased PBM-V{sub 5}, V{sub 10}, V{sub 15}, and V{sub 20} were significantly associated with decreased WBC and ANC nadirs, as were female gender, decreased body mass index, andmore » increased lumbosacral bone marrow V{sub 10}, V{sub 15}, and V{sub 20} (p < 0.05 for each association). Lymph node positivity was significantly associated with a decreased WBC nadir on multiple regression analysis (p < 0.05). Conclusion: This analysis supports the hypothesis that increased low-dose radiation to PBM is associated with acute HT during chemoradiotherapy for anal cancer. Techniques to limit bone marrow irradiation may reduce HT in anal cancer patients.« less

Purpose To report a multicenter experience treating anal canal cancer patients with concurrent chemotherapy and intensity-modulated radiation therapy (IMRT). Patients and Methods From October 2000 to June 2006, 53 patients were treated with concurrent chemotherapy and IMRT for anal squamous cell carcinoma at three tertiary-care academic medical centers. Sixty-two percent were T1-2, and 67% were N0; eight patients were HIV positive. Forty-eight patients received fluorouracil (FU)/mitomycin, one received FU/cisplatin, and four received FU alone. All patients underwent computed tomography–based treatment planning with pelvic regions and inguinal nodes receiving a median of 45 Gy. Primary sites and involved nodes were boosted to a median dose of 51.5 Gy. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All late toxicity was scored using Radiation Therapy Oncology Group criteria. Results Median follow-up was 14.5 months (range, 5.2 to 102.8 months). Acute grade 3+ toxicity included 15.1% GI and 37.7% dermatologic toxicity; all acute grade 4 toxicities were hematologic; and acute grade 4 leukopenia and neutropenia occurred in 30.2% and 34.0% of patients, respectively. Treatment breaks occurred in 41.5% of patients, lasting a median of 4 days. Forty-nine patients (92.5%) had a complete response, one patient had a partial response, and three had stable disease. All HIV-positive patients achieved a complete response. Eighteen-month colostomy-free survival, overall survival, freedom from local failure, and freedom from distant failure were 83.7%, 93.4%, 83.9%, and 92.9%, respectively. Conclusion Preliminary outcomes suggest that concurrent chemotherapy and IMRT for anal canal cancers is effective and tolerated favorably compared with historical standards.

Recently, nanoparticles have been considered as a method of providing radiation dose enhancement in tumors. In order to quantify this affect, a dose enhancement factor (DEF) is defined that represents the ratio of the dose deposited in tumor with nanoparticles, divided by the dose deposited in the tumor without nanoparticles. Materials with atomic numbers (Z) ranging from 25 to 90 are considered in this analysis. In addition, the energy spectrum for a number of external beam x-ray sources and common radionuclides are evaluated. For a nanoparticle concentration of 5 mg/ml, the DEF is < 1.05 for Co-60, Ir-192, Au-198, Cs-137, 6, 18, and 25 MV x-rays for all materials considered. However, relatively large increases in the DEF are observed for 50, 80, 100, and 140 KVp x-rays as well as Pd-103 and I-125. The DEF increases for all sources as Z varies from 25–35. From Z = 40–60, the DEF plateaus or slightly decreases. For higher Z materials (Z>70), the DEF increases and is a maximum for the highest Z materials. High atomic number nanoparticles coupled with low energy external beam x-rays or brachytherapy sources offer the potential of significantly enhancing the delivered dose.

Purpose: To investigate how the temporal pattern of dose applied during a single-intensity modulated radiation therapy (IMRT) fraction can be arranged to maximize or minimize cell kill. Methods and Materials: Using the linear-quadratic repair-time model and a simplified IMRT delivery pattern model, the surviving fraction of cells for a single fraction was calculated for all permutations of the dose delivery pattern for an array of clinically based IMRT cases. Maximization of cell kill was achieved by concentrating the highest doses in the middle of a fraction, while minimization was achieved by spreading the highest doses between the beginning and end. The percent difference between maximum and minimum cell kill (%Diff min/max ) and the difference between maximum and minimum total doses normalized to 2 Gy/fx (ΔNTD 2 Gy ) was calculated for varying fraction durations (T), α/β ratios, and doses/fx. Results: %Diff min/max and ΔNTD 2 Gy both increased with increasing T and with decreasing α/β. The largest increases occurred with dose/fx. With α/β = 3 Gy and 30 min/fx, %Diff min/max ranged from 2.7–5.3% for 2 Gy/fx to 48.6–74.1% for 10 Gy/fx, whereas ΔNTD 2 Gy ranged from 1.2 Gy–2.4 Gy for 30 fractions of 2 Gy/fx to 2.3–4.8 Gy for 2 fractions of 10.84 Gy/fx. Using α/β = 1.5 Gy, an analysis of prostate hypofractionation schemes yielded differences in clinical outcome based on the pattern of applied dose ranging from 3.2%–6.1% of the treated population. Conclusions: Rearrangement of the temporal pattern of dose for a single IMRT fraction could be used to optimize cell kill and to directly, though modestly, affect treatment outcome.

Purpose To assess the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) in pancreatic and bile duct (cholangiocarcinoma) malignancies. Methods and materials Twenty-five patients with pancreatic and bile duct cancer were treated with IMRT. Twenty-three received concurrent 5-fluoruracil. One patient with a pancreatic primitive neuroectodermal tumor received concurrent etoposide and ifosfamide. Eight patients had resected tumors, and 17 had unresectable primary ( n = 14) or recurrent ( n = 3) tumors. Six patients underwent treatment planning with conventional three-dimensional four-field techniques for dosimetric comparison with IMRT. Results Compared with conventional RT, IMRT reduced the mean dose to the liver, kidneys, stomach, and small bowel. IMRT was well tolerated, with 80% experiencing Grade 2 or less acute upper GI toxicity. At a median follow-up of 10.2 months, no resected patients had local failure, and only 1 of 10 assessable patients with unresectable cancer had local progression. The median survival and distant metastasis-free survival of the 24 patients with adenocarcinoma was 13.4 and 7.3 months, respectively. Grade 4 late liver toxicity occurred in 1 patient surviving >5 years. The remainder of the assessable patients experienced no ( n = 9) or Grade 1 ( n = 4) late toxicity. Conclusion In this hypothesis-generating analysis, the acute and chronic toxicity profile with IMRT in the treatment of pancreatic and bile duct cancer was encouraging. Local control was not compromised, despite efforts to increase conformality and avoid doses to normal structures. Distant failure remains a major obstacle in pancreatic cancer.

BACKGROUND The objective of the current study was to evaluate the content and quality of patient-oriented information regarding intensity-modulated radiotherapy (IMRT) on the Internet. METHODS IMRT websites were identified by reviewing the first 50 uniform resource locators on 5 search engines using the search terms IMRT and intensity modulated radiation therapy. Each site was evaluated by three observers for informational content, presentation, accuracy, and balance. A score of low, moderate, or high was assigned to each category based on a predefined scoring system. An overall score was assigned to each site, ranging from −35 to 100 points. RESULTS Seventy-seven patient-oriented IMRT websites were identified (45% private, 21% academic, and 18% commercial). Most sites (58%) had a low level of informational content, with information on fundamental aspects of IMRT planning (target delineation and inverse planning) appearing on < 50% of sites. The most commonly discussed tumors were genitourinary (65%) and head and neck (53%) lesions. Few sites, however, described the potential benefits of IMRT (toxicity and tumor control). Most sites (82%) used patient-appropriate language. False and/or misleading information was seen on 42% of sites and was equally common on academic, private, and commercial sites. Balance statements were present on 24% of sites (most of which were commercial). The median overall score was 20 points (range, −25 to 70 points). The median overall scores for academic, private, commercial, and other sites were 10, 20, 25, and 20 points, respectively (P = 0.26). CONCLUSIONS In general, the content and quality of patient-oriented information regarding IMRT on the Internet were poor. Patients and their physicians need to be aware of these problems when selecting treatment courses. Cancer 2004. © 2004 American Cancer Society.

A new type of alpha-particle irradiator allows survival of each cell to be observed individually along with the size and shape of its nucleus and the positions of the hits it receives. This paper discusses methods of data analysis that can utilize these additional data. Using idealizations of the cell nucleus geometry (i.e., spheres, ellipsoids), the path length (l), energy deposited (e), and specific energy (z) has been determined on a cell-by-cell basis for 772 cells all subjected to the same fluence. Each cell is regarded as a Bernoulli trial with a different probability for success (colony formation). For the survival expectation, A exp(-z/z(o)), the values of A and z(o) are chosen to maximize the likelihood for the observed outcome. Similar results are presented using the alternate functional forms A exp(-e/e(o)) and A exp(-l/l(o)). With these parameter values, the goodness of fit is also evaluated using a chi-square method with variances given by the binary (Bernoulli) methods. A further purpose of the paper is to assess the validity of the microdosimetric computations that would have had to be made if these individual cell-by-cell experimental measurements were not available or were incomplete.

In cases where both the source and cell geometry are well known, track-etch dosimetry allows the potential for individual cell dosimetry. However, analysis of track-etch images is both tedious and time-consuming. We describe here several image processing tools that we are using in conjunction with a track-etch based irradiator. Briefly, cells grown on LR 115 (a track-etch material) are irradiated from below by a collimated, planar alpha-particle source. Prior to irradiation, images of the cells are obtained. A computer program reads each image and automatically determines the location of individual cells. Next, the algorithm automatically identifies the cellular and nuclear boundaries. Following irradiation, and after the cells have reached their biological endpoint (e.g., cell survival), the cell dish is etched and images are obtained of alpha-particle tracks. Using the characteristic background pattern in the LR 115, the etched images are spatially registered to the original images. These two sets of images are then superimposed to create a composite image of the cells and associated alpha-particle tracks. Incorporating this tool into our irradiation scheme will enable more efficient analysis of the large amounts of data that are essential in assessing biological endpoints.

Purpose: This study attempted to correlate patient, treatment, and dosimetric factors with the risk of late rectal sequelae in patients treated with radiation therapy (RT) for cervical carcinoma. Methods and Materials: A total of 183 patients with cervical carcinoma (67 Stage I, 93 Stage II, and 23 Stage III) treated with definitive RT with a minimum of 2 years follow-up were evaluated. Treatment consisted of external beam pelvic RT (EBRT) followed by intracavitary RT (ICRT) consisting of one or two insertions. Complications were scored and analyzed as a function of 25 patient and treatment factors. Conventional total rectal doses were obtained by adding together the EBRT and ICRT rectal doses. To account for differences in dose rate between the ICRT and EBRT, and variations in EBRT fractionation schemes, biologically equivalent rectal doses (BED) were calculated using a linear quadratic model. In addition, the influence of the varying proportions of EBRT and ICRT rectal doses were evaluated. Results: Twenty-eight patients (15.3%) developed late rectal sequelae (13 Grade 1,3 Grade 2, and 12 Grade 3). Diabetes (p = 0.03), Point A dose (p = 0.04), and conventional EBRT dose (p = 0.03) were the most significant factors on multivariate analysis. Logistic regression analysis demonstrated a low risk (~10%) of late rectal sequelae below conventional and biological rectal doses of 75 Gy and 135 BED, respectively. The percentage of rectal dose delivered by the EBRT significantly influenced the dose-response relationship. A defined threshold percentage above which rectal sequelae were more common was identified over the range of doses evaluated. This threshold was 87% at a total rectal dose of 60 Gy and decreased to 60% at 80 Gy. Conclusion: Diabetes, Point A, and EBRT doses are the most significant factors associated with the risk of late rectal sequelae in patients treated with RT for cervical carcinoma. The percentage of rectal dose delivered by the EBRT significantly affects the conventional and biological dose-response relationship. This suggests that the volume of rectum irradiated is an important and independent parameter in the development of late rectal sequelae. 0 1997 Elsevier Science Inc.

A prospective feasibility study was conducted to investigate the utility of dual-energy (DE) imaging compared to conventional x-ray imaging for patients undergoing kV-based image guided radiation therapy (IGRT) for lung cancer.An institutional review board-approved feasibility study enrolled patients with lung cancer undergoing IGRT and was initiated in September 2011. During daily setup, 2 sequential respiration-gated x-ray images were obtained using an on-board imager. Imaging was composed of 1 standard x-ray image at 120 kVp (1 mAs) and a second image obtained at 60 kVp (4 mAs). Weighted logarithmic subtraction of the 2 images was performed offline to create a soft tissue-selective DE image. Conventional and DE images were evaluated by measuring relative contrast and contrast-to-noise ratios (CNR) and also by comparing spatial localization, using both approaches. Imaging dose was assessed using a calibrated ion chamber.To date, 10 patients with stage IA to IIIA lung cancer were enrolled and 57 DE images were analyzed. DE subtraction resulted in complete suppression of overlying bone in all 57 DE images, with an average improvement in relative contrast of 4.7 ± 3.3 over that of 120 kVp x-ray images (P.0002). The improvement in relative contrast with DE imaging was seen for both smaller (gross tumor volume [GTV] ≤5 cc) and larger tumors (GTV5 cc), with average relative contrast improvement ratios of 3.4 ± 4.1 and 5.4 ± 3.6, respectively. Moreover, the GTV was reliably localized in 95% of the DE images versus 74% of the single energy (SE images, (P=.004). Mean skin dose per DE image set was 0.44 ± 0.03 mGy versus 0.43 ± 0.03 mGy, using conventional kV imaging parameters.Initial results of this feasibility study suggest that DE thoracic imaging may enhance tumor localization in lung cancer patients receiving kV-based IGRT without increasing imaging dose.

Purpose : To document the size and location of the prostate, seminal vesicles, bladder, and rectum throughout the course of external beam radiotherapy. The frequency and range of motion of these organs are quantified. Methods and Materials : Ten patients with localized carcinoma of the prostate had conventional simulation followed immediately by a treatment planning computed tomography scan (TPCT 0 ). Once treatment was initiated, each patient had a weekly CT (TPCT 1-N ) before or after his daily treatment. Anatomical structures from CT were delineated on a computer workstation for analysis. The serial CT sets were spatially registered to the initial scan using image correlation software that brings into congruence the bony pelvis of the different scans. The location of the prostate, seminal vesicles, bladder, and rectum on subsequent scans were compared to TPCT 0 , as well as to each other. Results : Prostate volumes were observed to vary by an average of ±10% during the course of radiation therapy, while the seminal vesicle volumes varied by as much as 100%. Bladder and rectal volumes varied by ±30%. Compared to TPCT 0 , movement of the prostate was demonstrated in all patients. Quantitation of the center-of-mass (CM) showed motion of less than 1 mm in the left-right direction, while motion ranging from 0 to ± 1 cm was observed in the anterior-posterior and superior-inferior directions. The individual standard deviations of these motions varied from approximately 1-5 mm. These variations were correlated to changes in the dimensions of the bladder and rectum. Conclusions : Changes in the location of the prostate, seminal vesicles, and normal tissue volumes during the course of radiation therapy occur and have dosimetric consequences that may impact tumor control and normal tissue complication probabilities. Conformal therapy for prostate cancer will require the incorporation of knowledge of the anatomic relationships of these structures as a function of time. Therefore, these uncertainties must be taken into account when designing treatment plans and in considering dose escalation trials.

152 Background: We are working to electronically integrate our radiation oncology EMR and our hospital EMR to improve communication and facilitate patient care. To guide integration, we surveyed providers and support staff at our academic cancer center to identify the important encounters/documents and how well these are currently communicated. Methods: We sent an email survey to 182 MDs, nurses, and administrative staff at our cancer center. Respondents identified their role in the patient care team, and rated how important several radiation oncology-specific encounters/documents from “not important at all” to “extremely important” and rated the accessibility of these encounters/documents from “not at all accessible” to “exceptionally accessible.” Encounters/documents are listed in the table. Descriptive statistics were then performed to identify opportunities to improve communication. Results: There were 32 responses to our survey from staff outside of our department, including 18 physicians, 2 APN/PAs, 8 nurses, 2 nutritionists, 1 receptionist, and 1 social worker. Of the physicians, there were 8 medical oncologists, 2 neurosurgeons, 5 urologists, 1 breast surgeon, 1 gynecologic oncologist, and 1 reconstructive surgeon. The table describes the number of respondents who felt the encounter/document was “moderately,” “very,” or “extremely important”, and within this group of respondents, what percent thought each item was “very” or “exceptionally accessible.” Conclusions: We prioritized the importance of encounters/documents for integration between EMRs and identified deficiencies in communication. We will use the results of this study to guide our electronic integration of our two EMR systems. We will repeat the survey after integration is complete to identify improvement. [Table: see text]

To implement the "plan-do-check-act" (PDCA) cycle for the continual quality improvement of normal tissue contours used for radiation therapy treatment planning.The CT scans of patients treated for tumors of the brain, head and neck, thorax, pancreas and prostate were selected for this study. For each scan, a radiation oncologist and a diagnostic radiologist, outlined the normal tissues ("gold" contours) using Radiation Therapy Oncology Group (RTOG) guidelines. A total of 30 organs were delineated. Independently, 5 board-certified dosimetrists and 1 trainee then outlined the same organs. Metrics used to compare the agreement between the dosimetrists' contours and the gold contours included the Dice Similarity Coefficient (DSC), and a penalty function using distance to agreement. Based on these scores, dosimetrists were re-trained on those organs in which they did not receive a passing score, and they were subsequently re-tested.Passing scores were achieved on 19 of 30 organs evaluated. These scores were correlated to organ volume. For organ volumes8 cc, the average DSC was 0.61 vs organ volumes ≥8 cc, for which the average DSC was 0.91 (P=.005). Normal tissues that had the lowest scores included the lenses, optic nerves, chiasm, cochlea, and esophagus. Of the 11 organs that were considered for re-testing, 10 showed improvement in the average score, and statistically significant improvement was noted in more than half of these organs after education and re-assessment.The results of this study indicate the feasibility of applying the PDCA cycle to assess competence in the delineation of individual organs, and to identify areas for improvement. With testing, guidance, and re-evaluation, contouring consistency can be obtained across multiple dosimetrists. Our expectation is that continual quality improvement using the PDCA approach will ensure more accurate treatments and dose assessment in radiotherapy treatment planning and delivery.

Purpose To evaluate disease outcomes and toxicity in cervical cancer patients treated with pelvic intensity-modulated radiation therapy (IMRT). Methods and Materials We included all patients with Stage I–IVA cervical carcinoma treated with IMRT at three different institutions from 2000–2007. Patients treated with extended field or conventional techniques were excluded. Intensity-modulated radiation therapy plans were designed to deliver 45 Gy in 1.8-Gy daily fractions to the planning target volume while minimizing dose to the bowel, bladder, and rectum. Toxicity was graded according to the Radiation Therapy Oncology Group system. Overall survival and disease-free survival were estimated by use of the Kaplan-Meier method. Pelvic failure, distant failure, and late toxicity were estimated by use of cumulative incidence functions. Results The study included 111 patients. Of these, 22 were treated with postoperative IMRT, 8 with IMRT followed by intracavitary brachytherapy and adjuvant hysterectomy, and 81 with IMRT followed by planned intracavitary brachytherapy. Of the patients, 63 had Stage I–IIA disease and 48 had Stage IIB–IVA disease. The median follow-up time was 27 months. The 3-year overall survival rate and the disease-free survival rate were 78% (95% confidence interval [CI], 68–88%) and 69% (95% CI, 59–81%), respectively. The 3-year pelvic failure rate and the distant failure rate were 14% (95% CI, 6–22%) and 17% (95% CI, 8–25%), respectively. Estimates of acute and late Grade 3 toxicity or higher were 2% (95% CI, 0–7%) and 7% (95% CI, 2–13%), respectively. Conclusions Intensity-modulated radiation therapy is associated with low toxicity and favorable outcomes, supporting its safety and efficacy for cervical cancer. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT vs. conventional techniques.

Purpose To test the hypothesis that increased pelvic bone marrow (BM) irradiation is associated with increased hematologic toxicity (HT) in cervical cancer patients undergoing chemoradiotherapy and to develop a normal tissue complication probability (NTCP) model for HT. Methods and Materials We tested associations between hematologic nadirs during chemoradiotherapy and the volume of BM receiving ≥10 and 20 Gy (V 10 and V 20 ) using a previously developed linear regression model. The validation cohort consisted of 44 cervical cancer patients treated with concurrent cisplatin and pelvic radiotherapy. Subsequently, these data were pooled with data from 37 identically treated patients from a previous study, forming a cohort of 81 patients for normal tissue complication probability analysis. Generalized linear modeling was used to test associations between hematologic nadirs and dosimetric parameters, adjusting for body mass index. Receiver operating characteristic curves were used to derive optimal dosimetric planning constraints. Results In the validation cohort, significant negative correlations were observed between white blood cell count nadir and V 10 (regression coefficient (β) = −0.060, p = 0.009) and V 20 (β = −0.044, p = 0.010). In the combined cohort, the (adjusted) β estimates for log (white blood cell) vs. V 10 and V 20 were as follows: −0.022 ( p = 0.025) and −0.021 ( p = 0.002), respectively. Patients with V 10 ≥ 95% were more likely to experience Grade ≥3 leukopenia (68.8% vs. 24.6%, p 20 > 76% (57.7% vs. 21.8%, p = 0.001). Conclusions These findings support the hypothesis that HT increases with increasing pelvic BM volume irradiated. Efforts to maintain V 10 20

Purpose To experimentally validate how temporal modification of the applied dose pattern within a single fraction of radiation therapy affects cell survival. Method and Materials Using the linear-quadratic model, we have previously demonstrated that the greatest difference in cell survival results from comparing a temporal dose pattern delivering the highest doses during the middle of a fraction and the lowest at the beginning and end ("Triangle") to one with the lowest doses at the middle and the highest at the beginning and end ("V-shaped"). Also, these differences would be greatest in situations with low α/β and large dose/fraction and fraction length. Two low (WiDr, PC-3) and one high (SQ-20B) α/β cell lines were irradiated in six-well plates with 900 cGy over 20 min (900 cGy/20 min), one each with a Triangle and V-shaped dose pattern. WiDr cells were subjected to the same experiments with first 180 cGy/20 min, then 900 cGy/5 min. Cell survival was assessed using the clonogenic assay. Results At 900 cGy/20 min, irradiation with a V-shaped pattern resulted in an increased survival compared with use of a Triangle pattern of 21.2% for WiDr ( p p p > 0.05). For WiDr cells at 180 cGy/20 min, this increase reduced to 2.7% ( p > 0.05) and to −0.8% ( p > 0.05) at 900 cGy/5 min. Conclusions These results verify the assertions of the modeling study in vitro , and imply that the temporal pattern of applied dose should be considered in treatment planning and delivery.

Purpose: To compare bone marrow-sparing intensity-modulated pelvic radiotherapy (BMS-IMRT) with conventional (four-field box and anteroposterior‐posteroanterior [AP‐PA]) techniques in the treatment of cervical cancer. Methods and Materials: The data from 7 cervical cancer patients treated with concurrent chemotherapy and IMRTwithout BMS were analyzed and compared with data using four-field box and AP‐PA techniques. All plans were normalized to cover the planning target volume with the 99% isodose line. The clinical target volume consisted of the pelvic and presacral lymph nodes, uterus and cervix, upper vagina, and parametrial tissue. Normal tissues included bowel, bladder, and pelvic bone marrow (PBM), which comprised the lumbosacral spine and ilium and the ischium, pubis, and proximal femora (lower pelvis bone marrow). Dose‐volume histograms for the planning target volume and normal tissues were compared for BMS-IMRT vs. four-field box and AP‐PA plans. Results: BMS-IMRT was superior to the four-field box technique in reducing the dose to the PBM, small bowel, rectum, and bladder. Compared with AP‐PA plans, BMS-IMRT reduced the PBM volume receiving a dose >16.4 Gy. BMS-IMRT reduced the volume of ilium, lower pelvis bone marrow, and bowel receiving a dose >27.7, >18.7, and >21.1 Gy, respectively, but increased dose below these thresholds compared with the AP‐PA plans. BMS-IMRT reduced the volume of lumbosacral spine bone marrow, rectum, small bowel, and bladder at all dose levels in all 7 patients. Conclusion: BMS-IMRTreduced irradiation of PBM compared with the four-field box technique. Compared with theAP‐PAtechnique,BMS-IMRTreduced lumbosacral spine bonemarrowirradiationand reduced thevolumeof PBM irradiated to high doses. ThereforeBMS-IMRT might reduce acute hematologic toxicity comparedwith conventional techniques. 2008 Elsevier Inc. Bone marrow, Bone marrow-sparing, Intensity-modulated radiotherapy, IMRT, Cervical cancer.

Total body irradiation (TBI) has been used as a form of systemic therapy for the treatment of hematological malignancies and as a pre-conditioning regimen prior to bone marrow transplant. However, standard techniques are associated with both acute and chronic toxicities due to the large volumes of normal tissue irradiated. Intensity modulated radiation therapy (IMRT), with its ability to conform the high dose region to the shape of the target, offers a method to reduce radiation related sequelae and potentially allow for the delivery of higher than conventional doses. The goal of this study is to investigate the feasibility of a linac-based approach to intensity modulated total marrow irradiation (IM-TMI) and to discuss the challenges associated with its clinical implementation. The successful development of linac-based IM-TMI would represent advancement in the field of radiotherapy and potentially reduce the incidence and severity of complications associated with current TBI techniques.