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Purpose: Esophageal cancer (EC) is an aggressive malignancy and is often resistant to currently available therapies. Inhibition of ribonucleotide reductase small subunit M2 (RRM2) in tumors is speculated to mediate chemosensitization. Previous studies have reported that Osalmid could act as an RRM2 inhibitor. We explored whether RRM2 was involved in radioresistance and the antitumor effects of Osalmid in EC., Methods and Materials: RRM2 expression was detected by immunohistochemistry in EC tissues. The effects of Osalmid on cell proliferation, apoptosis, and cell cycle were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphhenyl tetrazolium, colony formation, and flow cytometry assays. DNA damage, cell apoptosis, and senescence induced by Osalmid or ionizing radiation (IR) alone, or both, were detected with immunofluorescence, flow cytometry, Western blot, and β-galactosidase staining. A xenograft mouse model of EC was used to investigate the potential synergistic effects of Osalmid and IR in vivo., Results: The expression of RRM2 in treatment-resistant EC tissues is much higher than in treatment-sensitive EC, and strong staining of RRM2 was correlated with shorter overall survival. We observed direct cytotoxicity of Osalmid in EC cells. Osalmid also produced inhibition of the ERK1/2 signal transduction pathway and substantially enhanced IR-induced DNA damage, apoptosis, and senescence. Furthermore, treatment with Osalmid and IR significantly suppressed tumor growth in xenograft EC models without additional toxicity to the hematologic system and internal organs., Conclusions: Our study revealed that RRM2 played a vital role in radioresistance in EC, and Osalmid synergized with IR to exert its antitumor effects both in vitro and in vivo., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To construct a tumor voxel dose response matrix (DRM) and dose prescription function (DPF) for adaptive dose painting by number (DPbN) based on treatment feedback of fluoro-2-deoxyglucose (FGD) positron emission tomography (PET)/computed tomography (CT) imaging., Methods and Materials: FDG-PET/CT images obtained before and after chemoradiation therapy and at weekly chemoradiation therapy sessions for each of 18 patients with head and neck cancer, as well as the treatment outcomes, were used in the modeling. All weekly and posttreatment PET/CT images were registered voxel-to-voxel to the corresponding pretreatment baseline PET/CT image. Tumor voxel DRM was created using serial FDG-PET imaging of each patient with respect to the baseline standardized uptake value (SUV 0 ). A tumor voxel control probability (TVCP) lookup table was created using the maximum likelihood estimation on the tumor voxel (SUV 0 , DRM) domain of all tumors. Tumor voxel DPF was created from the TVCP lookup table and used as the objective function for DPbN-based inverse planning optimization., Results: Large intertumoral and intratumoral variations on both tumor voxels (SUV 0 , DRM) were identified. Tumor voxel dose resistance did not show correlation with its baseline SUV 0 value and was the major cause of the tumor local failures. Tumor voxel DPF as the function of tumor voxel (SUV 0 , DRM) values also showed a very large intertumoral and intratumoral heterogeneity. Most human papillomavirus-negative tumors require a treatment dose >100 Gy to certain local tumor regions. These treatment doses, which are most unlikely to be implementable in conventional radiation therapy, can be achieved using adaptive DPbN treatment. Clinical feasibility was evaluated by comparing the adaptive DPbN treatment plan with the conventional intensity modulated radiation therapy plan., Conclusions: Tumor voxel (SUV 0 , DRM) provides an intratumoral prognostic map to target tumor locoregional-resistant regions. The corresponding TVCP or DPF provides a quantitative objective to optimize the intratumoral dose distribution for the individuals. The adaptive DPbN with FDG-PET/CT imaging feedback is feasible to implement in clinics., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Four-dimensional (4D) adaptive radiation therapy (ART) treatment planning is an alternative to the conventional margin-based treatment planning approach. In 4D ART, interfraction patient geometric variations, gathered from computed tomography (CT) or cone beam CT (CBCT) images acquired during the patient treatment course, are directly incorporated into the adaptive plan optimization using a probabilistic treatment planning method. The goal of the present planning study was to evaluate the dosimetric differences between 4D ART and conventional margin-based adaptive planning strategies for head and neck cancers. In addition, we examined whether the dose differences achieved with 4D ART would translate into clinically relevant toxicity reductions using the existing normal tissue complication probability (NTCP) models., Methods and Materials: For 18 head and neck cancer patients, the treatment plans were retrospectively generated for 4 different treatment strategies, including a solely image guided radiation therapy (IGRT) strategy (IGRT-only), 2 conventional adaptive treatment planning strategies using 3- and 0-mm planning target volume (PTV) margins, and the 4D ART strategy. In the IGRT-only strategy, a conventional 3-mm PTV margin treatment plan was applied for the entire treatment course. In the 2 conventional adaptive strategies, 2 new treatment plans were generated during the treatment course using diagnostic planning CT scans acquired after the 10th and 22nd fractions. The 4D ART followed the same adaptive schedule, except that the 4D adaptive plan was generated using 5 CBCT images acquired during the 5 most recent treatment fractions. For each strategy, the actual delivered dose for the entire treatment course was constructed by calculating the daily doses on 35 CBCT scans, deforming back to the pretreatment planning CT scan, and accumulating over all 35 fractions. The target coverage was evaluated using the percentage of target volume receiving ≥100% of the prescription dose (V 100% ) and the minimum dose to 99% of the target volume (D 99 ). It was considered adequate if the V 100% was ≥95% and the dose deficit in D 99 was ≤2 Gy (with respect to the prescription dose). For each strategy, the dose received by the organs at risk (OARs) was also evaluated, and the corresponding NTCP values were subsequently calculated using 3 NTCP models., Results: Adequate target coverage was achieved for the primary clinical target volume (CTV1) and elective nodal CTV (CTV2) with a 3-mm PTV margin, regardless of adaptation. The 3-mm ART plan reduced the OAR mean dose by 1 to 2 Gy compared with the IGRT-only plan. The 0-mm ART plan further reduced the OAR dose by another 2 to 3 Gy at the expense of target coverage: 3 and 1 patient had V 100% <95%, and 6 and 5 patients had a >2 Gy dose deficit in D 99 for the CTV1 and CTV2, respectively. Use of 4D ART improved target coverage and attained OAR sparing similar to that with 0-mm ART. The number of patients with V 100% <95% and >2 Gy D 99 deficit decreased to 0 and 0 for CTV1 and 0 and 2 for CTV2, respectively. The NTCP calculations suggested that 4D ART could benefit a substantial portion of patients compared with IGRT-only because 17 and 12 patients had ≥5% and ≥10% NTCP reductions for parotid toxicity and 18 and 3 patients had ≥5% and ≥10% NTCP reductions for swallowing toxicity, respectively., Conclusions: Compared with margin-based adaptive planning strategies, 4D ART provides a better balance between target coverage and OAR sparing. NTCP estimation predicted for theoretical clinical benefits that warrant further clinical validation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To present a novel robust and delivery-efficient spot-scanning proton arc (SPArc) therapy technique., Methods and Materials: A SPArc optimization algorithm was developed that integrates control point resampling, energy layer redistribution, energy layer filtration, and energy layer resampling. The feasibility of such a technique was evaluated using sample patients: 1 patient with locally advanced head and neck oropharyngeal cancer with bilateral lymph node coverage, and 1 with a nonmobile lung cancer. Plan quality, robustness, and total estimated delivery time were compared with the robust optimized multifield step-and-shoot arc plan without SPArc optimization (Arc multi-field ) and the standard robust optimized intensity modulated proton therapy (IMPT) plan. Dose-volume histograms of target and organs at risk were analyzed, taking into account the setup and range uncertainties. Total delivery time was calculated on the basis of a 360° gantry room with 1 revolutions per minute gantry rotation speed, 2-millisecond spot switching time, 1-nA beam current, 0.01 minimum spot monitor unit, and energy layer switching time of 0.5 to 4 seconds., Results: The SPArc plan showed potential dosimetric advantages for both clinical sample cases. Compared with IMPT, SPArc delivered 8% and 14% less integral dose for oropharyngeal and lung cancer cases, respectively. Furthermore, evaluating the lung cancer plan compared with IMPT, it was evident that the maximum skin dose, the mean lung dose, and the maximum dose to ribs were reduced by 60%, 15%, and 35%, respectively, whereas the conformity index was improved from 7.6 (IMPT) to 4.0 (SPArc). The total treatment delivery time for lung and oropharyngeal cancer patients was reduced by 55% to 60% and 56% to 67%, respectively, when compared with Arc multi-field plans., Conclusion: The SPArc plan is the first robust and delivery-efficient proton spot-scanning arc therapy technique, which could potentially be implemented into routine clinical practice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate online/offline image-guided/adaptive treatment techniques for prostate cancer radiation therapy with daily cone-beam CT (CBCT) imaging., Methods and Materials: Three treatment techniques were evaluated retrospectively using daily pre- and posttreatment CBCT images on 22 prostate cancer patients. Prostate, seminal vesicles (SV), rectal wall, and bladder were delineated on all CBCT images. For each patient, a pretreatment intensity modulated radiation therapy plan with clinical target volume (CTV) = prostate + SV and planning target volume (PTV) = CTV + 3 mm was created. The 3 treatment techniques were as follows: (1) Daily Correction: The pretreatment intensity modulated radiation therapy plan was delivered after online CBCT imaging, and position correction; (2) Online Planning: Daily online inverse plans with 3-mm CTV-to-PTV margin were created using online CBCT images, and delivered; and (3) Hybrid Adaption: Daily Correction plus an offline adaptive inverse planning performed after the first week of treatment. The adaptive plan was delivered for all remaining 15 fractions. Treatment dose for each technique was constructed using the daily posttreatment CBCT images via deformable image registration. Evaluation was performed using treatment dose distribution in target and critical organs., Results: Treatment equivalent uniform dose (EUD) for the CTV was within [85.6%, 100.8%] of the pretreatment planned target EUD for Daily Correction; [98.7%, 103.0%] for Online Planning; and [99.2%, 103.4%] for Hybrid Adaptation. Eighteen percent of the 22 patients in Daily Correction had a target dose deficiency >5%. For rectal wall, the mean ± SD of the normalized EUD was 102.6% ± 2.7% for Daily Correction, 99.9% ± 2.5% for Online Planning, and 100.6% ± 2.1% for Hybrid Adaptation. The mean ± SD of the normalized bladder EUD was 108.7% ± 8.2% for Daily Correction, 92.7% ± 8.6% for Online Planning, and 89.4% ± 10.8% for Hybrid Adaptation., Conclusions: Both Online Planning and Hybrid Adaptation can achieve comparable target coverage and normal tissue sparing and are superior to the Daily Correction technique. The Daily Correction technique using a 3-mm target margin in the pretreatment plan is not appropriate to compensate for residual variations in CBCT image-guided prostate cancer radiation therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: This study compared normal tissue complication probability (NTCP) modeling of chronic gastrointestinal toxicities following prostate cancer treatment for 2 treatment modalities. Possible factors causing discrepancies in optimal NTCP model parameters between 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated RT (IMRT) were analyzed and discussed, including the impact of patient characteristics, image guidance, toxicity scoring bias, and NTCP model limitations., Methods and Materials: Rectal wall dose-volume histograms of 1115 patients treated for prostate cancer under an adaptive radiation therapy protocol were used to model gastrointestinal toxicity grade ≥2 (according to Common Terminology Criteria for Adverse Events). A total of 457 patients were treated with 3D-CRT and 658 with IMRT. 3D-CRT patients were matched to IMRT patients based on various patient characteristics, using a propensity score-based algorithm. Parameters of the Lyman equivalent uniform dose and cut-off dose logistic regression NTCP models were estimated for the 2 matched treatment modalities and the combined group., Results: After they were matched, the 3D-CRT and IMRT groups contained 275 and 550 patients with a large discrepancy of 28.7% versus 7.8% toxicities, respectively (P<.001). For both NTCP models, optimal parameters found for the 3D-CRT groups did not fit the IMRT patients well and vice versa. Models developed for the combined data overestimated NTCP for the IMRT patients and underestimated NTCP for the 3D-CRT group., Conclusions: Our analysis did not reveal a single definitive cause for discrepancies of model parameters between 3D-CRT and IMRT. Patient characteristics and bias in toxicity scoring, as well as image guidance alone, are unlikely causes of the large discrepancy of toxicities. Whether the cause was inherent to the specific NTCP models used in this study needs to be verified by future investigations. Because IMRT is increasingly used clinically, it is important that appropriate NTCP model parameters are determined for this treatment modality., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate whether radiation treatment influences the expression of glucose metabolism genes and compromises the potential use of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a tool to monitor the early response of head and neck cancer xenografts to radiation therapy (RT)., Methods and Materials: Low passage head and neck squamous cancer cells (UT14) were injected to the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm(3) they were treated with either sham RT or 15 Gy in 1 fraction. At different time points, days 3, 9, and 16 for controls and days 4, 7, 12, 21, 30, and 40 after irradiation, 2 to 3 mice were assessed with dynamic FDG-PET acquisition over 2 hours. Immediately after the FDG-PET the tumors were harvested for global gene expression analysis and immunohistochemical evaluation of GLUT1 and HK2. Different analytic parameters were used to process the dynamic PET data., Results: Radiation had no effect on key genes involved in FDG uptake and metabolism but did alter other genes in the HIF1α and glucose transport-related pathways. In contrast to the lack of effect on gene expression, changes in the protein expression patterns of the key genes GLUT1/SLC2A1 and HK2 were observed after radiation treatment. The changes in GLUT1 protein expression showed some correlation with dynamic FDG-PET parameters, such as the kinetic index., Conclusion: (18)F-fluorodeoxyglucose positron emission tomography changes after RT would seem to represent an altered metabolic state and not a direct effect on the key genes regulating FDG uptake and metabolism., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the influence of tumor size, prescription dose, and dose to the lungs on posttreatment pulmonary function test (PFT) changes after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC)., Methods and Materials: The analysis is based on 191 patients treated at 5 international institutions: inclusion criteria were availability of pre- and post-SBRT PFTs and dose-volume histograms of the lung and planning target volume (PTV); patients treated with more than 1 SBRT course were excluded. Correlation between early (1-6 months, median 3 months) and late (7-24 months, median 12 months) PFT changes and tumor size, planning target volume (PTV) dose, and lung doses was assessed using linear regression analysis, receiver operating characteristics analysis, and Lyman's normal tissue complication probability model. The PTV doses were converted to biologically effective doses and lung doses to 2 Gy equivalent doses before correlation analyses., Results: Up to 6 months after SBRT, forced expiratory volume in 1 second and carbon monoxide diffusion capacity changed by -1.4% (95% confidence interval [CI], -3.4% to 0) and -7.6% (95% CI, -10.2% to -3.4%) compared with pretreatment values, respectively. A modest decrease in PFTs was observed 7-24 months after SBRT, with changes of -8.1% (95% CI, -13.3% to -5.3%) and -12.4% (95% CI, -15.5% to -6.9%), respectively. Using linear regression analysis, receiver operating characteristic analysis, and normal tissue complication probability modeling, all evaluated parameters of tumor size, PTV dose, mean lung dose, and absolute and relative volumes of the lung exposed to minimum doses of 5-70 Gy were not correlated with early and late PFT changes. Subgroup analysis based on pre-SBRT PFTs (greater or equal and less than median) did not identify any dose-effect relationship., Conclusions: This study failed to demonstrate a significant dose-effect relationship for changes of pulmonary function after SBRT for early-stage non-small cell lung cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Hypofractionated stereotactic body radiation therapy (SBRT) has emerged as an effective treatment option for early-stage non-small cell lung cancer (NSCLC). Using data collected by the Elekta Lung Research Group, we generated a tumor control probability (TCP) model that predicts 2-year local control after SBRT as a function of biologically effective dose (BED) and tumor size., Methods and Materials: We formulated our TCP model as follows: TCP = e([BED10 - c ∗ L - TCD50]/k) ÷ (1 + e([BED10 - c ∗ L - TCD50]/k)), where BED10 is the biologically effective SBRT dose, c is a constant, L is the maximal tumor diameter, and TCD50 and k are parameters that define the shape of the TCP curve. Least-squares optimization with a bootstrap resampling approach was used to identify the values of c, TCD50, and k that provided the best fit with observed actuarial 2-year local control rates., Results: Data from 504 NSCLC tumors treated with a variety of SBRT schedules were available. The mean follow-up time was 18.4 months, and 26 local recurrences were observed. The optimal values for c, TCD50, and k were 10 Gy/cm, 0 Gy, and 31 Gy, respectively. Thus, size-adjusted BED (sBED) may be defined as BED minus 10 times the tumor diameter (in centimeters). Our TCP model indicates that sBED values of 44 Gy, 69 Gy, and 93 Gy provide 80%, 90%, and 95% chances of tumor control at 2 years, respectively. When patients were grouped by sBED, the model accurately characterized the relationship between sBED and actuarial 2-year local control (r=0.847, P=.008)., Conclusion: We have developed a TCP model that predicts 2-year local control rate after hypofractionated SBRT for early-stage NSCLC as a function of biologically effective dose and tumor diameter. Further testing of this model with additional datasets is warranted., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To investigate the metabolic information provided by (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) during the early response of head-and-neck squamous cell carcinoma (HNSCC) xenografts to radiotherapy (RT)., Methods and Materials: Low-passage HNSCC cells (UT14) were injected into the rear flanks of female nu/nu mice to generate xenografts. After tumors grew to 400-500 mm(3), they were treated with either 15 Gy in one fraction (n = 18) or sham RT (n = 12). At various time points after treatment, tumors were assessed with 2-h dynamic FDG-PET and immediately harvested for direct histological correlation. Different analytical parameters were used to process the dynamic PET data: kinetic index (Ki), standard uptake value (SUV), sensitivity factor (SF), and retention index (RI). Tumor growth was assessed using the specific growth rate (SGR) and correlated with PET parameters using the Pearson correlation coefficient (r). Receiver operating characteristic (ROC) and the area under the ROC curve (AUC) were used to test PET parameters for their ability to predict for radiation necrosis and radiation change., Results: Tumor growth was arrested for the first 20 days after RT and recovered thereafter. Histologically, radiation change was observed in the peripheral regions of tumors between days 7 and 23 after RT, and radiation necrosis were observed in the central regions of tumors between days 7 and 40. Ki provided the best correlation with SGR (r = 0.51) and was the optimal parameter to predict for early radiation necrosis (AUC = 0.804, p = 0.07). SUV(30 min) was the strongest predictor for late radiation necrosis (AUC = 0.959, p = 0.004). Both RI(30-60 min) and SF(12-70 min) were very accurate in predicting for radiation change (AUC = 0.891 and 0.875, p = 0.009 and 0.01, respectively)., Conclusions: Dynamic FDG-PET analysis (such as Ki or SF) may provide informative assessment of early radiation necrosis or radiation change of HNSCC xenografts after RT., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To identify dosimetric predictors for the development of gastrointestinal (GI) toxicity in patients with locally advanced pancreatic adenocarcinoma (LAPC) treated with concurrent full-dose gemcitabine and radiotherapy (GemRT)., Methods and Materials: From June 2002 to June 2009, 46 LAPC patients treated with definitive GemRT were retrospectively analyzed. The stomach and duodenum were retrospectively contoured separately to determine their dose-volume histogram (DVH) parameters. GI toxicity was defined as Grade 3 or higher GI toxicity. The follow-up time was calculated from the start of RT to the date of death or last contact. Univariate analysis (UVA) and multivariate analysis (MVA) using Kaplan-Meier and Cox regression models were performed to identify risk factors associated with GI toxicity. The receiver operating characteristic curve and the area under the receiver operating characteristic curve (AUC) were used to determine the best DVH parameter to predict for GI toxicity., Results: Of the patients, 28 (61%) received concurrent gemcitabine alone, and 18 (39%) had concurrent gemcitabine with daily erlotinib. On UVA, only the V(20Gy) to V(35Gy) of duodenum were significantly associated with GI toxicity (all p ≤ 0.05). On MVA, the V(25Gy) of duodenum and the use of erlotinib were independent risk factors for GI toxicity (p = 0.006 and 0.02, respectively). For the entire cohort, the V(25Gy) of duodenum is the best predictor for GI toxicity (AUC = 0.717), and the 12-month GI toxicity rate was 8% vs. 48% for V(25Gy) ≤ 45% and V(25Gy) > 45%, respectively (p = 0.03). However, excluding the erlotinib group, the V(35Gy) is the best predictor (AUC = 0.725), and the 12-month GI toxicity rate was 0% vs. 41% for V(35Gy) ≤ 20% and V(35Gy) > 20%, respectively (p = 0.04)., Conclusions: DVH parameters of duodenum may predict Grade 3 GI toxicity after GemRT for LAPC. Concurrent use of erlotinib during GemRT may increase GI toxicity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Rectal distension has been shown to decrease the probability of biochemical control. Adaptive image-guided radiotherapy (IGRT) corrects for target position and volume variations, reducing the risk of biochemical failure while yielding acceptable rates of gastrointestinal (GI)/genitourinary (GU) toxicities., Methods and Materials: Between 1998 and 2006, 962 patients were treated with computed tomography (CT)-based offline adaptive IGRT. Patients were stratified into low (n = 400) vs. intermediate/high (n = 562) National Comprehensive Cancer Network (NCCN) risk groups. Target motion was assessed with daily CT during the first week. Electronic portal imaging device (EPID) was used to measure daily setup error. Patient-specific confidence-limited planning target volumes (cl-PTV) were then constructed, reducing the standard PTV and compensating for geometric variation of the target and setup errors. Rectal volume (RV), cross-sectional area (CSA), and rectal volume from the seminal vesicles to the inferior prostate (SVP) were assessed on the planning CT. The impact of these volumetric parameters on 5-year biochemical control (BC) and chronic Grades ≥2 and 3 GU and GI toxicity were examined., Results: Median follow-up was 5.5 years. Median minimum dose covering cl-PTV was 75.6 Gy. Median values for RV, CSA, and SVP were 82.8 cm(3), 5.6 cm(2), and 53.3 cm(3), respectively. The 5-year BC was 89% for the entire group: 96% for low risk and 83% for intermediate/high risk (p < 0.001). No statistically significant differences in BC were seen with stratification by RV, CSA, and SVP in quartiles. Maximum chronic Grades ≥2 and 3 GI toxicities were 21.2% and 2.9%, respectively. Respective values for GU toxicities were 15.5% and 4.3%. No differences in GI or GU toxicities were noted when patients were stratified by RV., Conclusions: Incorporation of adaptive IGRT reduces the risk of geometric miss and results in excellent biochemical control that is independent of rectal volume/distension while maintaining very low rates of chronic GI toxicity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Prolonged delivery times during daily cone-beam computed tomography (CBCT)-guided lung stereotactic body radiotherapy (SBRT) introduce concerns regarding intrafraction variation (IFV) of the mean target position (MTP). The purpose of this study was to evaluate the magnitude of the IFV-MTP and to assess target margins required to compensate for IFV and postonline CBCT correction residuals. Patient, treatment, and tumor characteristics were analyzed with respect to their impact on IFV-MTP., Methods and Materials: A total of 126 patients with 140 tumors underwent 659 fractions of lung SBRT. Dose prescribed was 48 or 60 Gy in 12 Gy fractions. Translational target position correction of the MTP was performed via onboard CBCT. IFV-MTP was measured as the difference in MTP between the postcorrection CBCT and the posttreatment CBCT excluding residual error., Results: IFV-MTP was 0.2 ± 1.8 mm, 0.1 ± 1.9 mm, and 0.01 ± 1.5 mm in the craniocaudal, anteroposterior, and mediolateral dimensions and the IFV-MTP vector was 2.3 ± 2.1 mm. Treatment time and excursion were found to be significant predictors of IFV-MTP. An IFV-MTP vector greater than 2 and 5 mm was seen in 40.8% and 7.2% of fractions, respectively. IFV-MTP greater than 2 mm was seen in heavier patients with larger excursions and longer treatment times. Significant differences in IFV-MTP were seen between immobilization devices. The stereotactic frame immobilization device was found to be significantly less likely to have an IFV-MTP vector greater than 2 mm compared with the alpha cradle, BodyFIX, and hybrid immobilization devices., Conclusions: Treatment time and respiratory excursion are significantly associated with IFV-MTP. Significant differences in IFV-MTP were found between immobilization devices. Target margins for IFV-MTP plus post-correction residuals are dependent on immobilization device with 5-mm uniform margins being acceptable for the frame immobilization device., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To investigate the impact of primary tumor and involved lymph node (LN) geometry (centroid, shape, volume) on internal target volume (ITV) throughout treatment for locally advanced non-small cell lung cancer using weekly four-dimensional computed tomography (4DCT)., Methods and Materials: Eleven patients with advanced non-small cell lung cancer were treated using image-guided radiotherapy with acquisition of weekly 10-Phase 4DCTs (n = 51). Initial ITV was based on planning 4DCT. Master-ITV incorporated target geometry across the entire treatment (all 4DCTs). Geographic miss was defined as the % Master-ITV positioned outside of the initial planning ITV after registration is complete. Registration strategies considered were bony (B), primary tumor soft tissue alone (T), and registration based on primary tumor and involved LNs (T&#95;LN)., Results: The % geographic miss for the primary tumor, mediastinal, and hilar lymph nodes based on each registration strategy were (1) B: 30%, 30%, 30%; (2) T: 21%, 40%, 36%; and (3) T&#95;LN: 26%, 26%, 27%. Mean geographic expansions to encompass 100% of the primary tumor and involved LNs were 1.2 ± 0.7 cm and 0.8 ± 0.3 cm, respectively, for B and T&#95;LN. Primary and involved LN expansions were 0.7 ± 0.5 cm and 1.1 ± 0.5 cm for T., Conclusion: T is best for solitary targets. When treatments include primary tumor and LNs, B and T&#95;LN provide more comprehensive geographic coverage. We have identified high % geographic miss when considering multiple registration strategies. The dosimetric implications are the subject of future study., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Different cavity expansions are used to define the clinical target volume (CTV) for accelerated partial breast irradiation (APBI) delivered via balloon brachytherapy (1 cm) vs. three-dimensional conformal radiotherapy (3D-CRT) (1.5 cm). Previous studies have argued that the CTVs generated by these different margins are effectively equivalent. In this study, we use deformable registration to assess the effective CTV treated by balloon brachytherapy on clinically representative 3D-CRT planning images., Methods and Materials: Ten patients previously treated with the MammoSite were studied. Each patient had two computed tomography (CT) scans, one acquired before and one after balloon implantation. In-house deformable registration software was used to deform the MammoSite CTV onto the balloonless CT set. The deformed CTV was validated using anatomical landmarks common to both CT scans., Results: The effective CTV treated by the MammoSite was on average 7% ± 10% larger and 38% ± 4% smaller than 3D-CRT CTVs created using uniform expansions of 1 and 1.5 cm, respectively. The average effective CTV margin was 1.0 cm, the same as the actual MammoSite CTV margin. However, the effective CTV margin was nonuniform and could range from 5 to 15 mm in any given direction. Effective margins <1 cm were attributable to poor cavity-balloon conformance. Balloon size relative to the cavity did not significantly correlate with the effective margin., Conclusion: In this study, the 1.0-cm MammoSite CTV margin treated an effective volume that was significantly smaller than the 3D-CRT CTV based on a 1.5-cm margin., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: We analyzed variables associated with long-term toxicity using three-dimensional conformal external beam radiation therapy (3D-CRT) to deliver accelerated partial breast irradiation., Methods and Materials: One hundred patients treated with 3D-CRT accelerated partial breast irradiation were evaluated using Common Terminology Criteria for Adverse Events version 4.0 scale. Cosmesis was scored using Harvard criteria. Multiple dosimetric and volumetric parameters were analyzed for their association with worst and last (W/L) toxicity outcomes., Results: Sixty-two patients had a minimum of 36 months of toxicity follow-up (median follow-up, 4.8 years). The W/L incidence of poor-fair cosmesis, any telangiectasia, and grade ≥2 induration, volume reduction, and pain were 16.4%/11.5%, 24.2%/14.5%, 16.1%/9.7%, 17.7%/12.9%, and 11.3%/3.2%, respectively. Only the incidence of any telangiectasia was found to be predicted by any dosimetric parameter, with the absolute breast volume receiving 5% to 50% of the prescription dose (192.5 cGy-1925 cGy) being significant. No associations with maximum dose, volumes of lumpectomy cavity, breast, modified planning target volume, and PTV, dose homogeneity index, number of fields, and photon energy used were identified with any of the aforementioned toxicities. Non-upper outer quadrant location was associated with grade ≥2 volume reduction (p = 0.02 W/p = 0.04 L). A small cavity-to-skin distance was associated with a grade ≥2 induration (p = 0.03 W/p = 0.01 L), a borderline significant association with grade ≥2 volume reduction (p = 0.06 W/p = 0.06 L) and poor-fair cosmesis (p = 0.08 W/p = 0.09 L), with threshold distances ranging from 5 to 8 mm., Conclusions: No dose--volume relationships associated with long-term toxicity were identified in this large patient cohort with extended follow-up. Cosmetic results were good-to-excellent in 88% of patients at 5 years., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To assess the adequacy of dose delivery to the clinical target volume (CTV) using external beam (EB) accelerated partial breast irradiation (APBI)., Methods and Materials: Sixteen patients treated with EB APBI underwent cone beam CT (CBCT) before each fraction and daily helical CT (HCT) scans to determine setup errors and calculate the dose per fraction. For 12 patients, an in-house image-intensity-based deformable registration program was used to register the HCTs to the planning CT and generate the cumulative dose. Treatment was 38.5 Gy in 10 fractions. EB APBI constraints from the National Surgical Adjuvant Breast and Bowel Project B39/Radiation Therapy Oncology Group 0413 Phase III protocol were used., Results: The mean setup error per CBCT registration was 9 ± 5 mm. Dose-volume histogram analysis showed only one patient (8%) with a decrease in the CTV V90 (8% underdosage). All other patients demonstrated adequate target coverage. PTV&#95;EVAL V90 was on average 3% (range, 0%-16%) less than planned. For the ipsilateral breast, four patients had an increase in V50 (≤ 1% increase) and three patients had an increase in V100 (≤ 9% increase). Only one patient showed an increase >5%. Four patients had an increase in ipsilateral lung V30 (maximum 3%), and one had an increase in heart V5 (1%). Four patients had an increase in MaxDose (maximum 89 cGy)., Conclusions: The current CTV-to-PTV margin of 10 mm appears sufficient for ∼92% of patients treated with EB APBI. Although expansion of the population PTV margin to 14 mm would provide ∼97% confidence level for CTV coverage, online image guidance should be considered., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: We present a novel form of arc therapy: continuous arc rotation of the couch (C-ARC) and compare its dosimetry with three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and volumetric-modulated arc therapy (VMAT) for accelerated partial breast irradiation (APBI). C-ARC, like VMAT, uses a modulated beam aperture and dose rate, but with the couch, not the gantry, rotating., Methods and Materials: Twelve patients previously treated with APBI using 3D-CRT were replanned with (1) C-ARC, (2) IMRT, and (3) VMAT. C-ARC plans were designed with one medial and one lateral arc through which the couch rotated while the gantry was held stationary at a tangent angle. Target dose coverage was normalized to the 3D-CRT plan. Comparative endpoints were dose to normal breast tissue, lungs, and heart and monitor units prescribed., Results: Compared with 3D-CRT, C-ARC, IMRT, and VMAT all significantly reduced the ipsilateral breast V50% by the same amount (mean, 7.8%). Only C-ARC and IMRT plans significantly reduced the contralateral breast maximum dose, the ipsilateral lung V5Gy, and the heart V5%. C-ARC used on average 40%, 30%, and 10% fewer monitor units compared with 3D-CRT, IMRT, and VMAT, respectively., Conclusions: C-ARC provides improved dosimetry and treatment efficiency, which should reduce the risks of toxicity and secondary malignancy. Its tangent geometry avoids irradiation of critical structures that is unavoidable using the en face geometry of VMAT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To quantify the dosimetric effect and margins required to account for prostate intrafractional translation and residual setup error in a cone beam computed tomography (CBCT)-guided hypofractionated radiotherapy protocol., Methods and Materials: Prostate position after online correction was measured during dose delivery using simultaneous kV fluoroscopy and posttreatment CBCT in 572 fractions to 30 patients. We reconstructed the dose distribution to the clinical tumor volume (CTV) using a convolution of the static dose with a probability density function (PDF) based on the kV fluoroscopy, and we calculated the minimum dose received by 99% of the CTV (D(99)). We compared reconstructed doses when the convolution was performed per beam, per patient, and when the PDF was created using posttreatment CBCT. We determined the minimum axis-specific margins to limit CTV D(99) reduction to 1%., Results: For 3-mm margins, D(99) reduction was ≤5% for 29/30 patients. Using post-CBCT rather than localizations at treatment delivery exaggerated dosimetric effects by ~47%, while there was no such bias between the dose convolved with a beam-specific and patient-specific PDF. After eight fractions, final cumulative D(99) could be predicted with a root mean square error of <1%. For 90% of patients, the required margins were ≤2, 4, and 3 mm, with 70%, 40%, and 33% of patients requiring no right-left (RL), anteroposterior (AP), and superoinferior margins, respectively., Conclusions: For protocols with CBCT guidance, RL, AP, and SI margins of 2, 4, and 3 mm are sufficient to account for translational errors; however, the large variation in patient-specific margins suggests that adaptive management may be beneficial., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the dosimetric impact of online cone-beam computed tomography (CBCT) guided correction in lung stereotactic body radiation therapy (SBRT)., Methods and Materials: Twenty planning and 162 CBCT images from 20 patients undergoing lung SBRT were analyzed. The precorrection CBCT (CBCT after patient setup, no couch correction) was registered to planning CT using soft tissue; couch shift was applied, with a second CBCT for verification (postcorrection CBCT). Targets and normal structures were delineated on CBCTs: gross tumor volume (GTV), clinical target volume (CTV), cord, esophagus, lung, proximal bronchial tree, and aorta. Dose distributions on all organs manifested on each CBCT were compared with those planned on the CT., Results: Without CBCT guided target position correction, target dose reduced with respect to treatment plan. Mean and standard deviation of treatment dose discrepancy from the plan were -3.2% (4.9%), -2.1% (4.4%), -6.1% (10.7%), and -3.5% (7%) for GTV D(99%), GTV D(95%), CTV D(99%), and CTV D(95%), respectively. With CBCT correction, the results were -0.4% (2.6%), 0.1% (1.7%), -0.3% (4.2%), and 0.5% (3%). Mean and standard deviation of the difference in normal organ maximum dose were 2.2% (6.5%) before correction and 2.4% (5.9%) after correction for esophagus; 6.1% (14.1%) and 3.8% (8.1%) for cord; 3.1% (17.5%) and 6.2% (9.8%) for proximal bronchial tree; and 17.7% (19.5%) and 14.1% (17%) for aorta., Conclusion: Online CBCT guidance improves the accuracy of target dose delivery for lung SBRT. However, treatment dose to normal tissue can vary regardless of the correction. Normal tissues should be considered during target registration, according to target proximity., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: Previous studies have shown that lumpectomy cavity volumes can change significantly in the weeks following surgery. The effect of this volume change on the surrounding tissue that constitutes the clinical target volume (CTV) for accelerated partial breast irradiation and boost treatment after whole breast irradiation has not been previously studied. In the present study, we used deformable registration to estimate the effect of lumpectomy cavity volume changes on the CTV for accelerated partial breast irradiation and discuss the implications for target construction., Methods and Materials: The data from 13 accelerated partial breast irradiation patients were retrospectively analyzed. Deformable registration was used to propagate contours from the initial planning computed tomography scan to a later computed tomography scan acquired at the start of treatment. The changes in cavity volume and CTV, distance between cavity and CTV contours (i.e., CTV margin), and CTV localization error after cavity registration were determined., Results: The mean ± standard deviation change in cavity volume and CTV between the two computed tomography scans was -35% ± 23% and -14% ± 12%, respectively. An increase in the cavity-to-CTV margin of 2 ± 2 mm was required to encompass the CTV, and this increase correlated with the cavity volume change. Because changes in the cavity and CTV were not identical, a localization error of 2-3 mm in the CTV center of mass occurred when the cavity was used as the reference for image guidance., Conclusion: Deformable registration suggested that CTV margins do not remain constant as the cavity volume changes. This finding has implications for planning target volume and CTV construction., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: To present treatment planning case studies for several treatment sites for which volumetric modulated arc therapy (VMAT) could have a positive impact; and to share an initial clinical experience with VMAT for stereotactic body radiotherapy (SBRT)., Methods and Materials: Four case studies are presented to show the potential benefit of VMAT compared with conformal and intensity-modulated radiotherapy (IMRT) techniques in pediatric cancer, bone marrow-sparing whole-abdominopelvic irradiation (WAPI), and SBRT of the lung and spine. Details of clinical implementation of VMAT for SBRT are presented. The VMAT plans are compared with conventional techniques in terms of dosimetric quality and delivery efficiency., Results: Volumetric modulated arc therapy reduced the treatment time of spine SBRT by 37% and improved isodose conformality. Conformal and VMAT techniques for lung SBRT had similar dosimetric quality, but VMAT had improved target coverage and took 59% less time to deliver, although monitor units were increased by 5%. In a complex pediatric pelvic example, VMAT reduced treatment time by 78% and monitor units by 25% compared with IMRT. A double-isocenter VMAT technique for WAPI can spare bone marrow while maintaining good delivery efficiency., Conclusions: Volumetric modulated arc therapy is a new technology that may benefit different patient populations, including pediatric cancer patients and those undergoing concurrent chemotherapy and WAPI. Volumetric modulated arc therapy has been used and shown to be beneficial for significantly improving delivery efficiency of lung and spine SBRT., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer., Methods and Materials: Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to develop a cutoff-dose normal tissue complication probability (NTCP) model., Results: There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001)., Conclusion: The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.

Purpose: Significant anatomic and volumetric changes occur in head and neck cancer patients during fractionated radiotherapy, and the actual dose can be considerably different from the original plan. The purposes of this study were (1) to evaluate the differences between planned and delivered dose, (2) to investigate margins required for anatomic changes, and (3) to find optimal replanning strategies., Methods and Materials: Eleven patients, each with one planning and six weekly helical CTs, were included. Intensity-modulated radiotherapy plans were generated using the simultaneous integrated boost technique. Weekly CTs were rigidly registered to planning CT before deformable registration was performed. The following replanning strategies were investigated with different margins (0, 3, 5 mm): midcourse (one replan), every other week (two replans), and every week (six replans). Doses were accumulated on the planning CT for comparison of various dose indices for target and critical structures., Results: The cumulative doses to targets were preserved even at the 0-mm margin. Doses to cord, brainstem, and mandible were unchanged. Significant increases in parotid doses were observed. Margin reduction from 5 to 0 mm led to a 22% improvement in parotid mean dose. Parotid sparing could be preserved with replanning. More frequent replanning led to better preservation; replanning more than once a week is unnecessary., Conclusion: Shrinkage does not result in significant dosimetric difference in targets and critical structures, except for the parotid gland, for which the mean dose increases by approximately 10%. The benefit of replanning is improved sparing of the parotid. The combination of replanning and reduced margins can provide up to a 30% difference in parotid dose.

Purpose: Intensity-modulated radiotherapy with photons (IMRT) and protons (IMPT) produces dose distributions that have high conformality to the planning target volume and sufficient sparing of the organs at risk if calculated on a single static computed tomography (CT) scan. For prostate cancer patients, organ movement with related changes to the density distribution in the irradiated volume occurs during the treatment course. We evaluated the sensitivity of IMPT and IMRT plans to organ movement., Methods and Materials: IMPT and IMRT treatment plans were evaluated for 4 patients with an average of 16 CT data sets per patient. The treatment plans were recalculated on all treatment CT scans, and the dose was accumulated in the reference geometry using a deformable registration algorithm. Accurate dose calculation methods were applied for both IMPT and IMRT., Results: With IMPT, unacceptably low total doses in the gross tumor volume were observed for patients with gas in the rectum on the planning CT scan. To achieve a total equivalent uniform dose (EUD) and EUD spread similar to that with IMRT, two methods were crucial for IMPT-a rectal gas water-equivalent density overwrite in the original planning CT scan and initial beam weight setting to achieve a homogeneous dose distribution for the whole planning target volume for each field separately. An improvement in the total EUD for the prostate and rectal wall was also observed for IMRT with the water-equivalent density overwrite of the rectal cavities., Conclusion: The sensitivities of IMPT and IMRT to organ movement are of the same order if appropriate planning strategies are applied. The latter is especially crucial for IMPT.

Purpose: To calculate the generic planning target margin (GPTM) for patients receiving radiation therapy (RT) for rectal cancer placed in a prone position with a customized cradle for small-bowel exclusion., Methods and Materials: A total of 25 consecutive rectal cancer patients were treated for 25 or 28 fractions in a prone position using a cradle to maximize small bowel exclusion. Treatment planning computed tomography (CT) scans were used to create orthogonally digitally reconstructed radiographs (DRRs) for portal image registration, which were compared with daily portal images from an electronic portal-imaging device (EPID). Translation values needed to align the DRRs and EPIDs were recorded for the superior to inferior (SI), right to left (RL), and anterior to posterior (AP) directions, and used to calculate the GPTM using the four-parameter model. Age, weight, and body mass index were tested compared with the setup variation using a Pearson correlation and a t test for significance. Gender versus setup variation was compared with a t test., Results: A total of 1,723 EPID images were reviewed. The GPTM was 10 mm superior, 8 mm inferior, 7 mm RL and 10 mm AP. Age and gender were unrelated to setup variation. Weight was significantly associated with systematic AP variation (p < 0.05). BMI was significantly associated with systematic SI (p < 0.05) and AP (p < 0.01) variation and random RL variation (p < 0.05)., Conclusions: The GPTM for rectal cancer is asymmetric with a maximum of 10 mm in the superior, anterior and posterior dimensions. Body mass index may effect setup variation. Research using advanced treatment planning should include these margins in the planning target volume definition.

Purpose: To evaluate patient parameters that may predict for relative differences in cumulative four-dimensional (4D) lung dose among several motion management strategies., Methods and Materials: Deformable image registration and dose accumulation were used to generate 4D treatment plans for 18 patients with 4D computed tomography scans. Three plans were generated to simulate breath hold at normal inspiration, target tracking with the beam aperture, and mid-ventilation aperture (control of the target at the mean daily position and application of an iteratively computed margin to compensate for respiration). The relative reduction in mean lung dose (MLD) between breath hold and mid-ventilation aperture (DeltaMLD(BH)) and between target tracking and mid-ventilation aperture (DeltaMLD(TT)) was calculated. Associations between these two variables and parameters of the lesion (excursion, size, location, and deformation) and dose distribution (local dose gradient near the target) were also calculated., Results: The largest absolute and percentage differences in MLD were 1.0 Gy and 21.5% between breath hold and mid-ventilation aperture. DeltaMLD(BH) was significantly associated (p < 0.05) with tumor excursion. The DeltaMLD(TT) was significantly associated with excursion, deformation, and local dose gradient. A linear model was constructed to represent DeltaMLD vs. excursion. For each 5 mm of excursion, target tracking reduced the MLD by 4% compared with the results of a mid-ventilation aperture plan. For breath hold, the reduction was 5% per 5 mm of excursion., Conclusions: The relative difference in MLD among different motion management strategies varied with patient and tumor characteristics for a given dosimetric target coverage. Tumor excursion is useful to aid in stratifying patients according to appropriate motion management strategies.

Purpose: For patients with intermediate- and high-risk prostate cancer, the seminal vesicles (SVs) are included in the clinical target volume (CTV). The purposes of this study are to investigate interfraction motion characteristics of the SVs and determine proper margins for online computed tomography image guidance., Methods and Materials: Twenty-four patients, each with 16 daily helical computed tomography scans, were included in this study. A binary image mask was used for image registration to determine daily organ motion. Two online image-guided radiotherapy strategies (prostate only and prostate + SVs) were simulated in a hypofractionated scheme. Three margin designs were studied for both three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT). In prostate-only guidance, Margin A was uniformly applied to the whole CTV, and Margin B was applied to the SVs with a fixed 3-mm prostate margin. In prostate plus SV guidance, Margin C was uniformly applied to the CTV. The minimum margins were sought to satisfy the criterion that minimum cumulative CTV dose be more than those of the planning target volume in the plan for greater than 95% of patients., Results: The prostate and SVs move significantly more in the anterior-posterior and superior-inferior than right-left directions. The anterior-posterior motion of the prostate and SVs correlated (R(2) = 0.7). The SVs move significantly more than the prostate. The minimum margins found were 2.5 mm for three-dimensional conformal radiotherapy and 4.5, 4.5, and 3.0 mm for Margins A, B, and C for IMRT, respectively. Margins for IMRT were larger, but the irradiated volume and doses to critical structures were smaller. Minimum margins of 4.5 mm to the SVs and 3 mm to the prostate are recommended for IMRT with prostate-only guidance., Conclusions: The SVs move independently from the prostate gland, and additional margins are necessary for image-guided radiotherapy.

Purpose: Real-time target tracking (RT-TT) and four-dimensional inverse planning (4D-IP) are two potential methods to manage respiratory target motion. In this study, we evaluated each method using the cumulative dose-volume criteria in lung cancer radiotherapy., Methods and Materials: Respiration-correlated computed tomography scans were acquired for 4 patients. Deformable image registration was applied to generate a displacement mapping for each phase image of the respiration-correlated computed tomography images. First, the dose distribution for the organs of interest obtained from an idealized RT-TT technique was evaluated, assuming perfect knowledge of organ motion and beam tracking. Inverse planning was performed on each phase image separately. The treatment dose to the organs of interest was then accumulated from the optimized plans. Second, 4D-IP was performed using the probability density function of respiratory motion. The beam arrangement, prescription dose, and objectives were consistent in both planning methods. The dose-volume and equivalent uniform dose in the target volume, lung, heart, and spinal cord were used for the evaluation., Results: The cumulative dose in the target was similar for both techniques. The equivalent uniform dose of the lung, heart, and spinal cord was 4.6 +/- 2.2, 11 +/- 4.4, and 11 +/- 6.6 Gy for RT-TT with a 0-mm target margin, 5.2 +/- 3.1, 12 +/- 5.9, and 12 +/- 7.8 Gy for RT-TT with a 2-mm target margin, and 5.3 +/- 2.3, 11.9 +/- 5.0, and 12 +/- 5.6 Gy for 4D-IP, respectively., Conclusion: The results of our study have shown that 4D-IP can achieve plans similar to those achieved by RT-TT. Considering clinical implementation, 4D-IP could be a more reliable and practical method to manage patient respiration-induced motion.

Purpose: To determine treatment accuracy and margins for stereotactic lung radiotherapy with and without cone-beam CT (CBCT) image guidance., Methods and Materials: Acquired for the study were 308 CBCT of 24 patients with solitary peripheral lung tumors treated with stereotactic radiotherapy. Patients were immobilized in a stereotactic body frame (SBF) or alpha-cradle and treated with image guidance using daily CBCT. Four (T1) or five (T2/metastatic) 12-Gy fractions were prescribed to the planning target volume (PTV) edge. The PTV margin was >or=5 mm depending on a pretreatment estimate of tumor excursion. Initial daily setup was according to SBF coordinates or tattoos for alpha-cradle cases. A CBCT was performed and registered to the planning CT using soft tissue registration of the target. The initial setup error/precorrection position, was recorded for the superior-inferior, anterior-posterior, and medial-lateral directions. The couch was adjusted to correct the tumor positional error. A second CBCT verified tumor position after correction. Patients were treated in the corrected position after the residual errors were

Purpose: This study compares multiple planning techniques designed to improve accuracy while allowing reduced planning target volume (PTV) margins though image-guided radiotherapy (IGRT) with four-dimensional (4D) cone-beam computed tomography (CBCT)., Methods and Materials: Free-breathing planning and 4D-CBCT scans were obtained in 8 patients with lung tumors. Four plans were generated for each patient: 3D-conformal, 4D-union, 4D-offline adaptive with a single correction (offline ART), and 4D-online adaptive with daily correction (online ART). For the 4D-union plan, the union of gross tumor volumes from all phases of the 4D-CBCT was created with a 5-mm expansion applied for setup uncertainty. For offline and online ART, the gross tumor volume was delineated at the mean position of tumor motion from the 4D-CBCT. The PTV margins were calculated from the random components of tumor motion and setup uncertainty., Results: Adaptive IGRT techniques provided better PTV coverage with less irradiated normal tissues. Compared with 3D plans, mean relative decreases in PTV volumes were 15%, 39%, and 44% using 4D-union, offline ART, and online ART planning techniques, respectively. This resulted in mean lung volume receiving > or = 20Gy (V20) relative decreases of 21%, 23%, and 31% and mean lung dose relative decreases of 16%, 26%, and 31% for the 4D-union, 4D-offline ART, and 4D-online ART, respectively., Conclusions: Adaptive IGRT using CBCT is feasible for the treatment of patients with lung tumors and significantly decreases PTV volume and dose to normal tissues, allowing for the possibility of dose escalation. All analyzed 4D planning strategies resulted in improvements over 3D plans, with 4D-online ART appearing optimal.

Purpose: To compare localization of the lumpectomy cavity by using breast surface matching vs. clips for image-guided external beam accelerated partial breast irradiation., Methods and Materials: Twenty-seven patients with breast cancer with two computed tomography (CT) scans each had three CT registrations performed: (1) to bony anatomy, (2) to the center of mass (COM) of surgical clips, and (3) to the breast surface. The cavity COM was defined in both the initial and second CT scans after each type of registration, and distances between COMs (DeltaCOM(Bone), DeltaCOM(Clips), and DeltaCOM(Surface)) were determined. Smaller DeltaCOMs were interpreted as better localizations. Correlation coefficients were calculated for DeltaCOM vs. several variables., Results: The DeltaCOM(Bone) (mean, 7 +/- 2 [SD] mm) increased with breast volume (r = 0.4; p = 0.02) and distance from the chest wall (r = 0.5; p = 0.003). Relative to bony registration, clip registration provided better localization (DeltaCOM(Clips) < DeltaCOM(Bone)) in 25 of 27 cases. Breast surface matching improved cavity localization (DeltaCOM(Surface) < DeltaCOM(Bone)) in 19 of 27 cases. Mean improvements (DeltaCOM(Bone) - DeltaCOM(Clips or Surface)) were 4 +/- 3 and 2 +/- 4 mm, respectively. In terms of percentage of improvement ([DeltaCOM(Bone) - DeltaCOM(Clips or Surface)]/DeltaCOM(Bone)), only surface matching showed a correlation with breast volume. Clip localization outperformed surface registration for cavities located superior to the breast COM., Conclusions: Use of either breast surface or surgical clips as surrogates for the cavity results in improved localization in most patients compared with bony registration and may allow smaller planning target volume margins for external beam accelerated partial breast irradiation. Compared with surface registration, clip registration may be less sensitive to anatomic characteristics and therefore more broadly applicable.

Purpose: Previous work has found a highly significant relationship between the irradiated small-bowel volume and development of Grade 3 small-bowel toxicity in patients with rectal cancer. This study tested the previously defined parameters in a much larger group of patients., Methods and Materials: A total of 96 consecutive patients receiving pelvic radiation therapy for rectal cancer had treatment planning computed tomographic scans with small-bowel contrast that allowed the small bowel to be outlined with calculation of a small-bowel dose-volume histogram for the initial intended pelvic treatment to 45 Gy. Patients with at least one parameter above the previously determined dose-volume parameters were considered high risk, whereas those with all parameters below these levels were low risk. The grade of diarrhea and presence of liquid stool was determined prospectively., Results: There was a highly significant association with small-bowel dose-volume and Grade 3 diarrhea (p < or = 0.008). The high-risk and low-risk parameters were predictive with Grade 3 diarrhea in 16 of 51 high-risk patients and in 4 of 45 low-risk patients (p = 0.01). Patients who had undergone irradiation preoperatively had a lower incidence of Grade 3 diarrhea than those treated postoperatively (18% vs. 28%; p = 0.31); however, the predictive ability of the high-risk/low-risk parameters was better for preoperatively (p = 0.03) than for postoperatively treated patients (p = 0.15). Revised risk parameters were derived that improved the overall predictive ability (p = 0.004)., Conclusions: The highly significant dose-volume relationship and validity of the high-risk and low-risk parameters were confirmed in a large group of patients. The risk parameters provided better modeling for the preoperative patients than for the postoperative patients.

Quality assurance has long been implemented in radiation treatment as systematic actions necessary to provide adequate confidence that the radiation oncology service will satisfy the given requirements for quality care. The existing reports from the American Association of Physicists in Medicine Task Groups 40 and 53 have provided highly detailed QA guidelines for conventional radiotherapy and treatment planning. However, advanced treatment processes recently developed with emerging high technology have introduced new QA requirements that have not been addressed previously in the conventional QA program. Therefore, it is necessary to expand the existing QA guidelines to also include new considerations. Image-guided adaptive radiation therapy (IGART) is a closed-loop treatment process that is designed to include the individual treatment information, such as patient-specific anatomic variation and delivered dose assessed during the therapy course in treatment evaluation and planning optimization. Clinical implementation of IGART requires high levels of automation in image acquisition, registration, segmentation, treatment dose construction, and adaptive planning optimization, which brings new challenges to the conventional QA program. In this article, clinical QA procedures for IGART are outlined. The discussion focuses on the dynamic or four-dimensional aspects of the IGART process, avoiding overlap with conventional QA guidelines.

Purpose: To compare two "four-dimensional" methods for image-guided target localization in the presence of respiration., Methods and Materials: Four-dimensional image guidance was performed with two methods. A respiration-correlated computed tomography (RCCT) was acquired on a CT simulator, and an average CT (AVG-CT) image was generated from the RCCT. A respiration-correlated cone-beam CT (RC-CBCT) and a free-breathing cone-beam CT (FB-CBCT) were acquired. The "RCCT method" consisted of calculating the mean target position on both the RCCT and RC-CBCT, registering the RCCT to the RC-CBCT, and determining the shift in the mean target position from the planned mean position. The "AVG-CT method" consisted of registering the AVG-CT to the FB-CBCT. The ability of each to measure the shift in the mean target position was compared, both in a respiratory phantom and in 8 patients., Results: In phantom, the RCCT and AVG-CT methods were able to measure the true mean target position to within 0.15 cm and 0.10 cm, respectively. In the patient study, the mean error between the methods was 0.13 cm (left-right), 0.14 cm (anterior-posterior), and 0.10 cm (cranio-caudal). The error was not observed to vary with tumor position or magnitude of tumor motion., Conclusions: Respiration may impact the on-line image guidance process. The RCCT method enables localization of the mean tumor position and measurement of changes in the motion pattern, whereas the AVG-CT method is simple, fast, and easily implemented. We found the methods to be nearly equivalent in detecting shifts in the mean tumor position.

Purpose: To identify factors predictive for chronic urinary toxicity secondary to high-dose adaptive three-dimensional conformal radiation., Methods and Materials: From 1999 to 2002, 331 consecutive patients with clinical Stage II-III prostate cancer were prospectively treated (median dose, 75.6 Gy). The bladder was contoured, and the bladder wall was defined as the outer 3 mm of the bladder solid volume. Toxicity was quantified according to the National Cancer Institute Common Toxicity Criteria 2.0. Median follow-up was 1.6 years., Results: The 3-year rates of Grade > or =2 and Grade 3 chronic urinary toxicity were 17.0% and 3.6%, respectively. Prostate volume, confidence-limited patient-specific planning target volume, bladder wall volume, and acute urinary toxicity were all found to be accurate predictors for chronic urinary toxicity. The volume of bladder wall receiving > or =30 Gy (V30) and > or =82 Gy (V82), along with prostate volume, were all clinically useful predictors of Grade > or =2 and Grade 3 chronic urinary toxicity and chronic urinary retention. Both Grade > or =2 (p = 0.001) and Grade 3 (p = 0.03) acute urinary toxicity were predictive for the development of Grade > or =2 (p = 0.001, p = 0.03) and Grade 3 (p = 0.05, p < 0.001) chronic urinary toxicity. On Cox multivariate analysis the development of acute toxicity was independently predictive for the development of both Grade > or =2 and Grade 3 chronic urinary toxicity., Conclusions: Acute urinary toxicity and bladder wall dose-volume endpoints are strong predictors for the development of subsequent chronic urinary toxicity. Our recommendation is to attempt to limit the bladder wall V30 to <30 cm(3) and the V82 to <7 cm(3) when possible. If bladder wall information is not available, bladder solid V30 and V82 may be used.

Purpose: To present an on-line image guidance procedure for external beam accelerated partial breast irradiation based on cone-beam computed tomography (CBCT) imaging of surgical clips; and to estimate the possible clinical target volume (CTV) to planning target volume (PTV) margin reduction allowed by this technique., Methods and Materials: Clips in the CBCT image are detected automatically using in-house software. The treatment couch is translated according to the shift in the clips' center of mass between the planning and CBCT images. Three components for the PTV margin are considered: (1) breathing, (2) surrogate error (i.e., error in cavity position after perfect setup to clips), and (3) residual error (i.e., error arising from the inability to execute a perfect setup to clips due to technological limitations, such as couch travel precision). These factors were input into a standard formula for CTV-to-PTV margin calculation., Results: The average magnitude of clip-based corrections was 7 +/- 2 mm (10 patients, 44 fractions). After localization, the residual error magnitude was 1.6 +/- 1.3 mm, justifying an isotropic CTV-to-PTV margin of approximately 6 mm, including breathing and surrogate error., Conclusions: On-line localization of the lumpectomy cavity using surgical clips is technically feasible from the standpoint of equipment, time, and process, making possible a decreased CTV-to-PTV margin for accelerated partial breast irradiation. Because the procedure is exclusively target based, additional monitoring of critical structures may be advisable.

Purpose: To determine the gross tumor volume (GTV) to clinical target volume margin for non-small-cell lung cancer treatment planning., Methods: A total of 35 patients with Stage T1N0 adenocarcinoma underwent wedge resection plus immediate lobectomy. The gross tumor size and microscopic extension distance beyond the gross tumor were measured. The nuclear grade and percentage of bronchoalveolar features were analyzed for association with microscopic extension. The gross tumor dimensions were measured on a computed tomography (CT) scan (lung and mediastinal windows) and compared with the pathologic dimensions. The potential coverage of microscopic extension for two different lung stereotactic radiotherapy regimens was evaluated., Results: The mean microscopic extension distance beyond the gross tumor was 7.2 mm and varied according to grade (10.1, 7.0, and 3.5 mm for Grade 1 to 3, respectively, p < 0.01). The 90th percentile for microscopic extension was 12.0 mm (13.0, 9.7, and 4.4 mm for Grade 1 to 3, respectively). The CT lung windows correlated better with the pathologic size than did the mediastinal windows (gross pathologic size overestimated by a mean of 5.8 mm; composite size [gross plus microscopic extension] underestimated by a mean of 1.2 mm). For a GTV contoured on the CT lung windows, the margin required to cover microscopic extension for 90% of the cases would be 9 mm (9, 7, and 4 mm for Grade 1 to 3, respectively). The potential microscopic extension dosimetric coverage (55 Gy) varied substantially between the stereotactic radiotherapy schedules., Conclusion: For lung adenocarcinomas, the GTV should be contoured using CT lung windows. Although a GTV based on the CT lung windows would underestimate the gross tumor size plus microscopic extension by only 1.2 mm for the average case, the clinical target volume expansion required to cover the microscopic extension in 90% of cases could be as large as 9 mm, although considerably smaller for high-grade tumors. Fractionation significantly affects the dosimetric coverage of microscopic extension.

Purpose: The variability of dose-volume histogram (DVH) shapes in a patient population can be quantified using principal component analysis (PCA). We applied this to rectal DVHs of prostate cancer patients and investigated the correlation of the PCA parameters with late bleeding., Methods and Materials: PCA was applied to the rectal wall DVHs of 262 patients, who had been treated with a four-field box, conformal adaptive radiotherapy technique. The correlated changes in the DVH pattern were revealed as "eigenmodes," which were ordered by their importance to represent data set variability. Each DVH is uniquely characterized by its principal components (PCs). The correlation of the first three PCs and chronic rectal bleeding of Grade 2 or greater was investigated with uni- and multivariate logistic regression analyses., Results: Rectal wall DVHs in four-field conformal RT can primarily be represented by the first two or three PCs, which describe approximately 94% or 96% of the DVH shape variability, respectively. The first eigenmode models the total irradiated rectal volume; thus, PC1 correlates to the mean dose. Mode 2 describes the interpatient differences of the relative rectal volume in the two- or four-field overlap region. Mode 3 reveals correlations of volumes with intermediate doses ( approximately 40-45 Gy) and volumes with doses >70 Gy; thus, PC3 is associated with the maximal dose. According to univariate logistic regression analysis, only PC2 correlated significantly with toxicity. However, multivariate logistic regression analysis with the first two or three PCs revealed an increased probability of bleeding for DVHs with more than one large PC., Conclusions: PCA can reveal the correlation structure of DVHs for a patient population as imposed by the treatment technique and provide information about its relationship to toxicity. It proves useful for augmenting normal tissue complication probability modeling approaches.

Purpose: To develop and validate a fully automatic region-of-interest (ROI) delineation method for on-line adaptive radiotherapy., Methods and Materials: On-line adaptive radiotherapy requires a robust and automatic image segmentation method to delineate ROIs in on-line volumetric images. We have implemented an atlas-based image segmentation method to automatically delineate ROIs of head-and-neck helical computed tomography images. A total of 32 daily computed tomography images from 7 head-and-neck patients were delineated using this automatic image segmentation method. Manually drawn contours on the daily images were used as references in the evaluation of automatically delineated ROIs. Two methods were used in quantitative validation: (1) the dice similarity coefficient index, which indicates the overlapping ratio between the manually and automatically delineated ROIs; and (2) the distance transformation, which yields the distances between the manually and automatically delineated ROI surfaces., Results: Automatic segmentation showed agreement with manual contouring. For most ROIs, the dice similarity coefficient indexes were approximately 0.8. Similarly, the distance transformation evaluation results showed that the distances between the manually and automatically delineated ROI surfaces were mostly within 3 mm. The distances between two surfaces had a mean of 1 mm and standard deviation of <2 mm in most ROIs., Conclusion: With atlas-based image segmentation, it is feasible to automatically delineate ROIs on the head-and-neck helical computed tomography images in on-line adaptive treatments.

Purpose: Accurate modeling of rectal complications based on dose-volume histogram (DVH) data are necessary to allow safe dose escalation in radiotherapy of prostate cancer. We applied different equivalent uniform dose (EUD)-based and dose-volume-based normal tissue complication probability (NTCP) models to rectal wall DVHs and follow-up data for 319 prostate cancer patients to identify the dosimetric factors most predictive for Grade > or = 2 rectal bleeding., Methods and Materials: Data for 319 patients treated at the William Beaumont Hospital with three-dimensional conformal radiotherapy (3D-CRT) under an adaptive radiotherapy protocol were used for this study. The following models were considered: (1) Lyman model and (2) logit-formula with DVH reduced to generalized EUD, (3) serial reconstruction unit (RU) model, (4) Poisson-EUD model, and (5) mean dose- and (6) cutoff dose-logistic regression model. The parameters and their confidence intervals were determined using maximum likelihood estimation., Results: Of the patients, 51 (16.0%) showed Grade 2 or higher bleeding. As assessed qualitatively and quantitatively, the Lyman- and Logit-EUD, serial RU, and Poisson-EUD model fitted the data very well. Rectal wall mean dose did not correlate to Grade 2 or higher bleeding. For the cutoff dose model, the volume receiving > 73.7 Gy showed most significant correlation to bleeding. However, this model fitted the data more poorly than the EUD-based models., Conclusions: Our study clearly confirms a volume effect for late rectal bleeding. This can be described very well by the EUD-like models, of which the serial RU- and Poisson-EUD model can describe the data with only two parameters. Dose-volume-based cutoff-dose models performed worse.

Purpose: To compare the planning target volume (PTV) definitions for computed tomography (CT) vs. positron emission tomography (PET) in non-small-cell lung cancer (NSCLC)., Methods and Materials: A total of 21 patients with NSCLC underwent three-dimensional conformal radiotherapy planning. All underwent a staging F-18 fluorodeoxyglucose-position emission tomography (18FDG-PET) scan and underwent treatment simulation using CT plus a separate planning 18FDG-PET scan. Three sets of target volumes were defined: Set 1, CT volumes (CT tumor + staging PET nodal disease); Set 2, PET volumes (planning PET tumor {gross tumor volume (GTV) = [(0.3069 x mean standardized uptake value) + 0.5853])}; Set 3, composite CT-PET volumes (fused CT-PET tumor). Sets 1 and 2 were compared using a matching index. Three-dimensional conformal radiotherapy plans were created using the Set 1 (CT) volumes; and coverage of the Set 3 (composite) volumes was evaluated. Separate three-dimensional conformal radiotherapy plans were designed for the Set 3 volumes., Results: For the primary tumor GTV, the Set 1 (CT) volume was larger than the Set 2 (PET) volume in 48%, smaller in 33%, and equal in 19%. The mean matching index was 0.65 (35% CT-PET mismatch). Although quantitatively similar, the volumes differed qualitatively. The Set 3 (composite) volume was larger than either CT or PET alone in 62%, smaller in 24%, and equal in 14%. The dose-volume histogram parameters did not differ among the plans for Set 1 (CT) vs. Set 3 (composite) volumes. Small portions of the Set 3 PTV were significantly underdosed in 40% of cases using the CT-only plan., Conclusion: Computed tomography and PET are complementary and should be obtained in the treatment position and fused to define the GTV for NSCLC. Although the quantitative absolute target volume is sometimes similar, the qualitative target locations can be substantially different, leading to underdosage of the target when planning is done using CT alone without PET fusion.

Purpose: We performed a complete pathologic analysis examining extracapsular extension (ECE) and microscopic spread of malignant cells beyond the prostate capsule to determine whether and when clinical target volume (CTV) expansion should be performed., Methods and Materials: A detailed pathologic analysis was performed for 371 prostatectomy specimens. All slides from each case were reviewed by a single pathologist (N.S.G.). The ECE status and ECE distance, defined as the maximal linear radial distance of malignant cells beyond the capsule, were recorded., Results: A total of 121 patients (33%) were found to have ECE (68 unilateral, 53 bilateral). Median ECE distance=2.4 mm [range: 0.05-7.0 mm]. The 90th-percentile distance = 5.0 mm. Of the 121 cases with ECE, 55% had ECE distance>or=2 mm, 19%>or=4 mm, and 6%>or=6 mm. ECE occurred primarily posterolaterally along the neurovascular bundle in all cases. Pretreatment prostrate-specific antigen (PSA), biopsy Gleason, pathologic Gleason, clinical stage, bilateral involvement, positive margins, percentage of gland involved, and maximal tumor dimension were associated with presence of ECE. Both PSA and Gleason score were associated with ECE distance. In all 371 patients, for those with either pretreatment PSA>or=10 or biopsy Gleason score>or=7, 21% had ECE>or=2 mm and 5%>or=4 mm beyond the capsule. For patients with both of these risk factors, 49% had ECE>or=2 mm and 21%>or=4 mm., Conclusions: For prostate cancer with ECE, the median linear distance of ECE was 2.4 mm and occurred primarily posterolaterally. Although only 5% of patients demonstrate ECE>4 to 5 mm beyond the capsule, this risk may exceed 20% in patients with PSA>or=10 ng/ml and biopsy Gleason score>or=7. As imaging techniques improve for prostate capsule delineation and as radiotherapy delivery techniques increase in accuracy, a posterolateral CTV expansion should be considered for patients at high risk.

Purpose: To address glucose sensitivity in lung cancers before and after radiation treatment (Tx)., Methods and Materials: Twelve patients were each studied with two pre-Tx positron emission tomography (PET) scans and 3 patients each with one post-Tx PET scan, with glucose concentration [Glc] and maximum standard uptake value (SUV) recorded. The pre-Tx glucose sensitivity, g from SUV1/SUV2= {[Glc]1/[Glc]2}g and Tx index, tau from SUVpost-Tx/SUVpre-Tx = {[Glc]post-Tx/[Glc]pre-Tx}tau was calculated by linear regression. Pre-Tx SUVs were corrected to post-Tx Glc with g (SUV'pre-Tx) for a pure Tx effect, R = ln(SUVpost-Tx/SUV'pre-Tx)., Results: There were no significant differences in SUV but [Glc] were different (96.4 +/- 10.9 vs. 88.3 +/- 10.5, p = 0.015) between two pre-Tx PET scans. Linear regression yielded g = -0.79 and tau = -1.78 to -2.41 (p < 0.0005 in all). The %DeltaSUV after Tx for 3 patients without vs. with g correction were different by -12%, 0%, and + 7%, suggesting varying effects from glucose. R values were also different and mean R (-0.81 +/- 0.38) was significantly different from zero (p = 0.03), consistent with successful Tx as confirmed by clinico-radiologic follow-up., Conclusions: The extra dimension of glucose sensitivity, g besides SUV incorporated in the combined Tx-derived tau may be a useful global Tx evaluation index even with differing [Glc].

Purpose: To evaluate an online image-guidance strategy for conformal treatment of prostate cancer and to estimate margin-reduction benefits., Methods and Materials: Twenty-eight patients with at least 16 helical computed tomography scans were each used in this study. Two prostate soft-tissue registration methods, including sagittal rotation, were evaluated. Setup errors and rigid organ motion were corrected online; non-rigid and intrafraction motion were included in offline analysis. Various clinical target volume-planning target volume (CTV-PTV) margins were applied. Geometrical evaluations included analyses of isocenter shifts and rotations and overlap index. Dosimetric evaluations included minimum dose and equivalent uniform dose (EUD) for prostate and gEUD for rectum., Results: Average isocenter shift and rotation were (dX,dY,dZ,theta) = (0.0 +/- 0.7,-1.1 +/- 4.0,-0.1 +/- 2.5,0.7 degrees +/- 2.0 degrees ) mm. Prostate motion in anterior-posterior (AP) direction was significantly higher than superior-inferior and left-right (LR) directions. This observation was confirmed by isocenter shift in perspectives AP (1.8 +/- 1.8 mm) and RL (3.7 +/- 3.0 mm). Organ motion degrades target coverage and reduces doses to rectum. If 2% dose reduction on prostate D(99) is allowed for 90% patients, then minimum 3 mm margins are necessary with ideal image registration., Conclusions: Significant margin reduction can be achieved through online image guidance. Certain margins are still required for nonrigid and intrafraction motion. To further reduce margin, a strategy that combines online geometric intervention and offline dose replanning is necessary.

Purpose: In our Phase II prostate cancer Adaptive Radiation Therapy (ART) study, the highest possible dose was selected on the basis of normal tissue tolerance constraints. We analyzed rectal toxicity rates in different dose levels and treatment groups to determine whether equivalent toxicity rates were achieved as hypothesized when the protocol was started., Methods and Materials: From 1999 to 2002, 331 patients with clinical stage T1 to T3, node-negative prostate cancer were prospectively treated with three-dimensional conformal adaptive RT. A patient-specific confidence-limited planning target volume was constructed on the basis of 5 CT scans and 4 sets of electronic portal images after the first 4 days of treatment. For each case, the rectum (rectal solid) was contoured in its entirety. The rectal wall was defined by use of a 3-mm wall thickness (median volume: 29.8 cc). The prescribed dose level was chosen using the following rectal wall dose constraints: (1) Less than 30% of the rectal wall volume can receive more than 75.6 Gy. (2) Less than 5% of the rectal wall can receive more than 82 Gy. Low-risk patients (PSA < 10, Stage < or = T2a, Gleason score < 7) were treated to the prostate alone (Group 1). All other patients, intermediate and high risk, where treated to the prostate and seminal vesicles (Group 2). The risk of chronic toxicity (NCI Common Toxicity Criteria 2.0) was assessed for the different dose levels prescribed. HIC approval was acquired for all patients. Median follow-up was 1.6 years., Results: Grade 2 chronic rectal toxicity was experienced by 34 patients (10%) (9% experienced rectal bleeding, 6% experienced proctitis, 3% experienced diarrhea, and 1% experienced rectal pain) at a median interval of 1.1 year. Nine patients (3%) experienced grade 3 or higher chronic rectal toxicity (1 Grade 4) at a median interval of 1.2 years. The 2-year rates of Grade 2 or higher and Grade 3 or higher chronic rectal toxicity were 17% and 3%, respectively. No significant difference by dose level was seen in the 2-year rate of Grade 2 or higher chronic rectal toxicity. These rates were 27%, 15%, 14%, 17%, and 24% for dose levels equal to or less than 72, 73.8, 75.6, 77.4, and 79.2 Gy, respectively (p = 0.3). Grade 2 or higher chronic rectal bleeding was significantly greater for Group 2 than for Group 1, 17% vs. 8% (p = 0.035)., Conclusions: High doses (79.2 Gy) were safely delivered in selected patients by our adaptive radiotherapy process. Under the rectal dose-volume histogram constraints for the dose level selection, the risk of chronic rectal toxicity is similar among patients treated to different dose levels. Therefore, rectal chronic toxicity rates reflect the dose-volume cutoff used and are independent of the actual dose levels. On the other hand, a larger PTV will increase the rectal wall dose and chronic rectal toxicity rates. PTV volume and dose constraints should be defined, considering their potential benefit.

Purpose: We analyzed our experience treating localized prostate cancer with image-guided off-line correction with adaptive high-dose radiotherapy (ART) in our Phase II dose escalation study to identify factors predictive of chronic rectal toxicity., Materials and Methods: From 1999-2002, 331 patients with clinical stage T1-T3N0M0 prostate cancer were prospectively treated in our Phase II 3D conformal dose escalation ART study to a median dose of 75.6 Gy (range, 63.0-79.2 Gy), minimum dose to confidence limited-planning target volume (cl-PTV) in 1.8 Gy fractions (median isocenter dose = 79.7 Gy). Seventy-four patients (22%) also received neoadjuvant/adjuvant androgen deprivation therapy. A patient-specific cl-PTV was constructed using 5 computed tomography scans and 4 sets of electronic portal images by applying an adaptive process to assure target accuracy and minimize PTV margin. For each case, the rectum (rectal solid) was contoured from the sacroiliac joints or rectosigmoid junction (whichever was higher) to the anal verge or ischial tuberosities (whichever was lower), with a median volume of 81.2 cc. The rectal wall was defined using the rectal solid with an individualized 3-mm wall thickness (median volume = 29.8 cc). Rectal wall dose-volume histogram was used to determine the prescribed dose. Toxicity was quantified using the National Cancer Institute Common Toxicity Criteria 2.0. Multiple dose-volume endpoints were evaluated for their association with chronic rectal toxicity., Results: Median follow-up was 1.6 years. Thirty-four patients (crude rate = 10.3%) experienced Grade 2 chronic rectal toxicity at a median interval of 1.1 years. Nine patients (crude rate = 2.7%) experienced Grade > or =3 chronic rectal toxicity (1 was Grade 4) at a median interval of 1.2 years. The 3-year rates of Grade > or =2 and Grade > or =3 chronic rectal toxicity were 20% and 4%, respectively. Acute toxicity predicted for chronic: Acute Grade 2-3 rectal toxicity (p < 0.001) including any acute rectal Grade 2-3 tenesmus (p = 0.02) and pain (p = 0.008) were significant predictors of chronic Grade > or =2 rectal toxicity. Any acute rectal toxicity (p = 0.001), any acute tenesmus (p = 0.03), and any acute diarrhea (p < 0.001) were also found to be predictive for chronic toxicity, as continuous variables. Dose-volume histogram predicted for chronic toxicity: Rectal wall absolute and relative V50, V60, V66.6, V70, and V72 and rectal solid relative V60-V72 were significantly associated with chronic Grade > or =2 rectal toxicity both as categorical and continuous variables (t test, linear regression) and when divided into subgroups (chi-square table). The chronic rectal toxicity Grade > or =2 risk was 9%, 18%, and 25% for the rectal wall relative V70 <15%, 25%-40%, and >40% respectively. The volume of rectum or rectal wall radiated to > or =50 Gy was a strong predictor for chronic rectal toxicity. Nonpredictive factors: Rectal solid/wall absolute or relative volumes irradiated to < or =40 Gy, dose level, and use of androgen deprivation were not found predictive., Conclusions: In our ART dose escalation study, rectal wall or rectum relative > or =V50 are closely predictive for chronic rectal toxicity. If rectal dose-volume histogram constraints are used to select the dose level, the risk of chronic rectal toxicity will reflect the risk of toxicity of the selected constraint rather than the dose selected as found in our study using an adaptive process. To select the prescribed dose, different dose-volume histogram constraints may be used including the rectal wall V70. Patients experiencing acute rectal toxicity are more likely to experience chronic toxicity.

Purpose: Kilovoltage cone-beam CT (CBCT) implemented on board a medical accelerator is available for image-guidance applications in our clinic. The objective of this work was to assess the magnitude and stability of the residual setup error associated with CBCT online-guided prostate cancer patient setup. Residual error pertains to the uncertainty in image registration, the limited mechanical accuracy, and the intrafraction motion during imaging and treatment., Methods and Materials: The residual error for CBCT online-guided correction was first determined in a phantom study. After online correction, the phantom residual error was determined by comparing megavoltage portal images acquired every 90 degrees to the corresponding digitally reconstructed radiographs. In the clinical study, 8 prostate cancer patients were implanted with three radiopaque markers made of high-winding coils. After positioning the patient using the skin marks, a CBCT scan was acquired and the setup error determined by fusing the coils on the CBCT and planning CT scans. The patient setup was then corrected by moving the couch accordingly. A second CBCT scan was acquired immediately after the correction to evaluate the residual target setup error. Intrafraction motion was evaluated by tracking the coils and the bony landmarks on kilovoltage radiographs acquired every 30 s between the two CBCT scans. Corrections based on soft-tissue registration were evaluated offline by aligning the prostate contours defined on both planning CT and CBCT images., Results: For ideal rigid phantoms, CBCT image-guided treatment can usually achieve setup accuracy of 1 mm or better. For the patients, after CBCT correction, the target setup error was reduced in almost all cases and was generally within +/-1.5 mm. The image guidance process took 23-35 min, dictated by the computer speed and network configuration. The contribution of the intrafraction motion to the residual setup error was small, with a standard deviation of +/-0.9 mm. The average difference between the setup corrections obtained with coil and soft-tissue registration was greatest in the superoinferior direction and was equal to -1.1 +/- 2.9 mm., Conclusion: On the basis of the residual setup error measurements, the margin required after online CBCT correction for the patients enrolled in this study would be approximatively 3 mm and is considered to be a lower limit owing to the small intrafraction motion observed. The discrepancy between setup corrections derived from registration using coils or soft tissue can be due in part to the lack of complete three-dimensional information with the coils or to the difficulty in prostate delineation and requires further study.