Search

Purpose: To update outcome and toxicity results of a prospective trial of 19-Gy single-fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer., Methods and Materials: Patients were treated on a prospective study of single-fraction HDR brachytherapy. All patients had low- or intermediate-risk prostate cancer. Patients with prostate volumes >50 cm 3 , taking alpha-blockers for urinary symptoms, or with baseline American Urologic Association symptom scores >12 were ineligible. Patients underwent transrectal ultrasound-guided interstitial implant of the prostate followed by single-fraction HDR brachytherapy to a prescription dose of 19 Gy., Results: Sixty-eight patients were enrolled with a median follow-up of 3.9 years. Median age was 62 years. Median gland volume at the time of treatment was 35 cm 3 , 92.6% of patients had T1 disease, 63.2% had a Gleason score of 6, and median pretreatment prostate-specific antigen was 5.0 ng/mL. Chronic grade 2 genitourinary toxicity was 14.7%. No grade 3 urinary toxicity occurred. A single patient experienced grade 2+ rectal toxicity (grade 3 diarrhea) that was transient and resolved with medical management. The 5-year estimated disease-free survival was 77.2% with no significant difference between low- and intermediate-risk patients. A single patient developed distant metastases during the follow-up period. Biopsy-proven local failure at 5 years was 18.8%, occurring at a median interval of 4.0 years posttreatment. No deaths occurred during follow-up., Conclusions: With extended follow-up, toxicity rates after single-fraction 19-Gy HDR brachytherapy remain low. Higher-than-expected rates of biochemical and local failure, however, raise concerns regarding the adequacy of this dose. Additional investigation to define the optimal single-fraction HDR brachytherapy dose is warranted, and single-fraction treatment currently should not be offered outside the context of a clinical trial., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To report the toxicity and preliminary clinical outcomes of a prospective trial evaluating 19-Gy, single-fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer., Methods and Materials: A total of 63 patients were treated according to an institutional review board-approved prospective study of single-fraction HDR brachytherapy. Eligible patients had tumor stage ≤T2a, prostate-specific antigen level ≤15 ng/mL, and Gleason score ≤7. Patients with a prostate gland volume >50 cm 3 and baseline American Urologic Association symptom score >12 were ineligible. Patients underwent transrectal ultrasound-guided transperineal implantation of the prostate, followed by single-fraction HDR brachytherapy. Treatment was delivered using 192 Ir to a dose of 19 Gy prescribed to the prostate, with no additional margin applied., Results: Of the 63 patients, 58 had data available for analysis. Five patients had withdrawn consent during the follow-up period. The median follow-up period was 2.9 years (range 0.3-5.2). The median age was 61.4 years. The median gland volume at treatment was 34.8 cm 3 . Of the 58 patients, 91% had T1 disease, 71% had Gleason score ≤6 (29% with Gleason score 7), and the median pretreatment prostate-specific antigen level was 5.1 ng/mL. The acute and chronic grade 2 genitourinary toxicity incidence was 12.1% and 10.3%, respectively. No grade 3 urinary toxicity occurred. No patients experienced acute rectal toxicity grade ≥2, and 2 experienced grade ≥2 chronic gastrointestinal toxicity. Three patients experienced biochemical failure, yielding a 3-year cumulative incidence estimate of 6.8%., Conclusions: Single-fraction HDR brachytherapy is well-tolerated, with favorable preliminary biochemical and clinical disease control rates., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy of pulsed low-dose radiation therapy (PLRT) combined with temozolomide (TMZ) as a novel treatment approach for radioresistant glioblastoma multiforme (GBM) in a murine model., Methods and Materials: Orthotopic U87MG hGBM tumors were established in Nu-Foxn1(nu) mice and imaged weekly using a small-animal micropositron emission tomography (PET)/computed tomography (CT) system. Tumor volume was determined from contrast-enhanced microCT images and tumor metabolic activity (SUVmax) from the F18-FDG microPET scan. Tumors were irradiated 7 to 10 days after implantation with a total dose of 14 Gy in 7 consecutive days. The daily treatment was given as a single continuous 2-Gy dose (RT) or 10 pulses of 0.2 Gy using an interpulse interval of 3 minutes (PLRT). TMZ (10 mg/kg) was given daily by oral gavage 1 hour before RT. Tumor vascularity and normal brain damage were assessed by immunohistochemistry., Results: Radiation therapy with TMZ resulted in a significant 3- to 4-week tumor growth delay compared with controls, with PLRT+TMZ the most effective. PLRT+TMZ resulted in a larger decline in SUVmax than RT+TMZ. Significant differences in survival were evident. Treatment after PLRT+TMZ was associated with increased vascularization compared with RT+TMZ. Significantly fewer degenerating neurons were seen in normal brain after PLRT+TMZ compared with RT+TMZ., Conclusions: PLRT+TMZ produced superior tumor growth delay and less normal brain damage when compared with RT+TMZ. The differential effect of PLRT on vascularization may confirm new treatment avenues for GBM., (Copyright © 2013 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 assess the prognostic value of the percentage of positive biopsy cores (PPC) and perineural invasion in predicting the clinical outcomes after radiotherapy (RT) for prostate cancer and to explore the possibilities to improve on existing risk-stratification models., Methods and Materials: Between 1993 and 2004, 1,056 patients with clinical Stage T1c-T3N0M0 prostate cancer, who had four or more biopsy cores sampled and complete biopsy core data available, were treated with external beam RT, with or without a high-dose-rate brachytherapy boost at William Beaumont Hospital. The median follow-up was 7.6 years. Multivariate Cox regression analysis was performed with PPC, Gleason score, pretreatment prostate-specific antigen, T stage, PNI, radiation dose, androgen deprivation, age, prostate-specific antigen frequency, and follow-up duration. A new risk stratification (PPC classification) was empirically devised to incorporate PPC and replace the T stage., Results: On multivariate Cox regression analysis, the PPC was an independent predictor of distant metastasis, cause-specific survival, and overall survival (all p < .05). A PPC >50% was associated with significantly greater distant metastasis (hazard ratio, 4.01; 95% confidence interval, 1.86-8.61), and its independent predictive value remained significant with or without androgen deprivation therapy (all p < .05). In contrast, PNI and T stage were only predictive for locoregional recurrence. Combining the PPC (≤50% vs. >50%) with National Comprehensive Cancer Network risk stratification demonstrated added prognostic value of distant metastasis for the intermediate-risk (hazard ratio, 5.44; 95% confidence interval, 1.78-16.6) and high-risk (hazard ratio, 4.39; 95% confidence interval, 1.70-11.3) groups, regardless of the use of androgen deprivation and high-dose RT (all p < .05). The proposed PPC classification appears to provide improved stratification of the clinical outcomes relative to the National Comprehensive Cancer Network classification., Conclusions: The PPC is an independent and powerful predictor of clinical outcomes of prostate cancer after RT. A risk model replacing T stage with the PPC to reduce subjectivity demonstrated potentially improved stratification., (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: To determine 20-year rates of local control and outcome-associated factors for ductal carcinoma in situ (DCIS) after breast-conserving therapy (BCT)., Methods and Materials: All DCIS cases receiving BCT between 1980 and 1993 were reviewed. Patient demographics and pathologic factors were analyzed for effect on outcomes, including ipsilateral breast tumor recurrence (IBTR) and survival., Results: One hundred forty-five cases were evaluated; the median follow-up time was 19.3 years. IBTR developed in 25 patients, for 5-, 10-, 15-, and 20-year actuarial rates of 9.9%, 12.2%, 13.7%, and 17.5%, respectively. One third of IBTRs were elsewhere failures, and 68% of IBTRs occurred <10 years after diagnosis. Young age and cancerization of lobules predicted for IBTR at <10 years, and increased slide involvement and atypical ductal hyperplasia were associated with IBTR at later time points., Conclusions: Patients with DCIS treated with BCT have excellent long-term rates of local control. Predictors of IBTR vary over time, and the risk of recurrence seems highest within 10 to 12 years after diagnosis., (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: High-dose-rate (HDR) brachytherapy used as the only treatment (monotherapy) for early prostate cancer is consistent with current concepts in prostate radiobiology, and the dose is reliably delivered in a prospectively defined anatomic distribution that meets all the requirements for safe and effective therapy. We report the disease control and toxicity of HDR monotherapy from California Endocurietherapy (CET) and William Beaumont Hospital (WBH) in low- and intermediate-risk prostate cancer patients., Methods and Materials: There were 298 patients with localized prostate cancer treated with HDR monotherapy between 1996 and 2005. Two biologically equivalent hypofractionation protocols were used. At CET the dose was 42 Gy in six fractions (two implantations 1 week apart) delivered to a computed tomography-defined planning treatment volume. At WBH the dose was 38 Gy in four fractions (one implantation) based on intraoperative transrectal ultrasound real-time treatment planning. The bladder, urethral, and rectal dose constraints were similar. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3., Results: The median follow-up time was 5.2 years. The median age of the patients was 63 years, and the median value of the pretreatment prostate-specific antigen was 6.0 ng/mL. The 8-year results were 99% local control, 97% biochemical control (nadir +2), 99% distant metastasis-free survival, 99% cause-specific survival, and 95% overall survival. Toxicity was scored per event, meaning that an individual patient with more than one symptom was represented repeatedly in the morbidity data table. Genitourinary toxicity consisted of 10% transient Grade 2 urinary frequency or urgency and 3% Grade 3 episode of urinary retention. Gastrointestinal toxicity was <1%., Conclusions: High disease control rates and low morbidity demonstrate that HDR monotherapy is safe and effective for patients with localized prostate cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Patients treated with radiation therapy (RT) for prostate cancer were evaluated to estimate the length of time required to document biochemical cure (BC) after treatment and the variables associated with long-term treatment efficacy., Patients and Methods: 2,100 patients received RT alone for localized prostate carcinoma (external-beam RT, n = 1,504; brachytherapy alone, n = 241; or brachytherapy + pelvic radiation, n = 355). The median external-beam dose was 68.4 Gy, and the median follow-up time was 8.6 years. Biochemical failure (BF) was defined according to the Phoenix definition., Results: Biochemical failure was experienced by 685 patients (32.6%). The median times to BF for low-, intermediate-, and high-risk groups were 6.0, 5.6, and 4.5 years respectively (p < 0.001). The average annual incidence rates of BF for years 1-5, 5-10,11-15, and 16-20 in low-risk patients were 2.0%, 2.0%, 0.3%, and 0.06% (p < 0.001); for intermediate-risk patients, 4%, 3%, 0.3%, and 0% (p < 0.001); and for high-risk patients, 10.0%, 5.0%, 0.3%, and 0.3% (p < 0.001). After 5 years of treatment, 36.9% of all patients experienced BF. The percentage of total failures occurring during years 1-5, 5-10, 11-15, and 16-20 were 48.7%, 43.5%, 6.5%, and 1.3% for low-risk patients; 64.0%, 32.2%, 3.8%, and 0% for intermediate-risk patients; and 71.9%, 25.9%, 1.1%, and 1.1% for high-risk patients, respectively. Increasing time to nadir was associated with increased time to BF. On multivariate analysis, factors significantly associated with 10-year BC included prostate-specific antigen nadir and time to nadir., Conclusions: The incidence rates for BF did not plateau until later than 10 years after treatment, suggesting that extended follow-up time is required to monitor patients after treatment. Prostate-specific antigen nadir and time to nadir have the strongest association with long-term BC., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To determine the prognostic significance of neuroendocrine differentiation (NED) in Gleason score 8-10 prostate cancer treated with primary radiotherapy (RT)., Methods and Materials: Chromogranin A (CgA) staining was performed and overseen by a single pathologist on core biopsies from 176 patients from the William Beaumont prostate cancer database. A total of 143 had evaluable biopsy material. Staining was quantified as 0%, <1%, 1-10%, or >10% of tumor cells. Patients received external beam RT alone or together with high-dose-rate brachytherapy. Cox regression and Kaplan-Meier estimates determined if the presence/frequency of neuroendocrine cells correlated with clinical endpoints., Results: Median follow-up was 5.5 years. Forty patients (28%) had at least focal positive CgA staining (<1% n = 21, 1-10% n = 11, >10% n = 8). No significant differences existed between patients with or without staining in terms of age, pretreatment prostate-specific antigen, tumor stage, hormone therapy administration, % biopsy core involvement, mean Gleason score, or RT dose/modality. CgA staining concentration independently predicted for biochemical and clinical failure, distant metastases (DM), and cause-specific survival (CSS). For patients with <1% vs. >1% staining, 10-year DM rates were 13.4% vs. 55.3%, respectively (p = 0.001), and CSS was 91.7% vs. 58.9% (p < 0.001). As a continuous variable, increasing CgA staining concentration predicted for inferior rates of DM, CSS, biochemical control, and any clinical failure. No differences in outcomes were appreciated for patients with 0% vs. <1% NED., Conclusions: For Gleason score 8-10 prostate cancer, >1% NED is associated with inferior clinical outcomes for patients treated with radiotherapy. This relates most directly to an increase in distant disease failure., (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: Glioblastoma multiforme (GBM) is an aggressive tumor that typically causes death due to local progression. To assess a novel low-dose radiotherapy regimen for treating GBM, we developed an orthotopic murine model of human GBM and evaluated in vivo treatment efficacy using micro-positron-emission tomography/computed tomography (microPET/CT) tumor imaging., Methods: Orthotopic GBM xenografts were established in nude mice and treated with standard 2-Gy fractionation or 10 0.2-Gy pulses with 3-min interpulse intervals, for 7 consecutive days, for a total dose of 14 Gy. Tumor growth was quantified weekly using the Flex Triumph (GE Healthcare/Gamma Medica-Ideas, Waukesha, WI) combined PET-single-photon emission CT (SPECT)-CT imaging system and necropsy histopathology. Normal tissue damage was assessed by counting dead neural cells in tissue sections from irradiated fields., Results: Tumor engraftment efficiency for U87MG cells was 86%. Implanting 0.5 × 10(6) cells produced a 50- to 70-mm(3) tumor in 10 to 14 days. A significant correlation was seen between CT-derived tumor volume and histopathology-measured volume (p = 0.018). The low-dose 0.2-Gy pulsed regimen produced a significantly longer tumor growth delay than standard 2-Gy fractionation (p = 0.045). Less normal neuronal cell death was observed after the pulsed delivery method (p = 0.004)., Conclusion: This study successfully demonstrated the feasibility of in vivo brain tumor imaging and longitudinal assessment of tumor growth and treatment response with microPET/CT. Pulsed radiation treatment was more efficacious than the standard fractionated treatment and was associated with less normal tissue damage., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the 10-year outcomes of intermediate- and high-risk prostate cancer patients treated with a prospective dose escalation hypofractionated trial of pelvic external beam radiation therapy (P-EBRT) with a high-dose-rate (HDR) brachytherapy boost., Methods and Materials: From 1992 to 2007, 472 patients were treated with a HDR boost at William Beaumont Hospital. They had at least one of the following: a prostate-specific antigen (PSA) level of >10 ng/ml, a Gleason score of ≥7, or clinical stage ≥T2b. Patients received 46-Gy P-EBRT and an HDR boost. The HDR dose fractionation was divided into two dose levels. The prostate biologically equivalent dose (BED) low-dose-level group received <268 Gy, and the high-dose group received >268 Gy . Phoenix biochemical failure (BF) definition was used., Results: Median follow-up was 8.2 years (range, 0.4-17 years). The 10-year biochemical failure rate of 43.1% vs. 18.9%, (p < 0.001), the clinical failure rate of 23.4% vs. 7.7%, (p < 0.001), and the distant metastasis of 12.4% vs. 5.7%, (p = 0.028) were all significantly better for the high-dose level group. On Cox multivariate analysis, higher BED levels (p = 0.017; hazard ratio [HR] = 0.586), pretreatment PSA assays (p < 0.001, HR = 1.022), and Gleason scores (p = 0.004) were significant variables for reduced biochemical failure. Higher dose levels (p, 0.002; HR, 0.397) and Gleason scores (p < 0.001) were significant for clinical failure. Grade 3 genitourinary complications were 2% and 3%, respectively, and grade 3 gastrointestinal complication was <0.5%., Conclusions: This prospective trial using P-EBRT with HDR boost and hypofractionated dose escalation demonstrates a strong dose-response relationship for intermediate- and high-risk prostate cancer patients. The improvement at 10 years for locoregional control with higher radiation doses (BED, > 268 Gy) has significantly decreased biochemical and clinical failures as well as distant metastasis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To examine the combination of radiation and the multikinase inhibitor sorafenib in human colorectal cancer cell lines and xenografts., Methods and Materials: HT29 and SW48 colorectal cancer cells were studied in vitro using MTT assays to establish the optimal timing of radiation and sorafenib. This optimal timing was then investigated in clonogenic survival assays. Xenografts were established, and the effect of a 3-week schedule of daily radiation and sorafenib was studied by growth delay., Results: Sorafenib predominantly had minimal effects on cell growth or radiation response in MTT growth assays, though growth inhibition was significantly enhanced in HT29 cells when sorafenib was administered after radiation. The highest dose of sorafenib altered the alpha component of the cell survival curve in clonogenic assays. The combination of radiation and sorafenib was synergistic in SW48 xenografts, with a mean time to threshold tumor size of 11.4 +/- 1.0 days, 37.0 +/- 9.5 days, 15.5 +/- 3.2 days, and 98.0 +/- 11.7 days in the control, radiation, sorafenib, and combined treatment group, respectively. The effect on HT29 tumors was additive, with mean time to threshold volume of 12.6 +/- 1.1 days, 61.0 +/- 4.3 days, 42.6 +/- 11.7 days, and 100.2 +/- 12.4 days., Conclusions: Sorafenib had little effect on radiation response in vitro but was highly effective when combined with radiation in vivo, suggesting that inhibition of proliferation and interference with angiogenesis may be the basis for the interaction., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Purpose: Prostate-specific health products (dietary supplements) are taken by cancer patients to alleviate the symptoms linked with poor prostate health. However, the effect of these agents on evidence-based radiotherapy practice is poorly understood. The present study aimed to determine whether dietary supplements radiosensitized normal prostate or prostate cancer cell lines., Methods and Materials: Three well-known prostate-specific dietary supplements were purchased from commercial sources available to patients (Trinovin, Provelex, and Prostate Rx). The cells used in the study included normal prostate lines (RWPE-1 and PWR-1E), prostate tumor lines (PC3, DU145, and LNCaP), and a normal nonprostate line (HaCaT). Supplement toxicity was assessed using cell proliferation assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and cellular radiosensitivity using conventional clonogenic assays (0.5-4Gy). Cell cycle kinetics were assessed using the bromodeoxyuridine/propidium iodide pulse-labeling technique, apoptosis by scoring caspase-3 activation, and DNA repair by assessing gammaH2AX., Results: The cell growth and radiosensitivity of the malignant PC3, DU145, and LNcaP cells were not affected by any of the dietary prostate supplements (Provelex [2 microg/mL], Trinovin [10 microg/mL], and Prostate Rx [50 microg/mL]). However, both Trinovin (10 microg/mL) and Prostate Rx (6 microg/mL) inhibited the growth rate of the normal prostate cell lines. Prostate Rx increased cellular radiosensitivity of RWPE-1 cells through the inhibition of DNA repair., Conclusion: The use of prostate-specific dietary supplements should be discouraged during radiotherapy owing to the preferential radiosensitization of normal prostate cells., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Purpose: Rectal toxicity remains a serious complication affecting quality of life for prostate cancer patients treated with radiotherapy. We began an investigational trial injecting hyaluronic acid (HA) in the perirectal fat to increase the distance between the prostate and the anterior rectal wall. This is the first report using HA injection in oncology., Methods and Materials: This is a trial of external beam radiation therapy with HDR brachytherapy boosts in prostate cancer. During the two high-dose-rate (HDR) fractions, thermoluminescent dosimeter dosimeters were placed in the urethra and in the rectum. Before the second HDR fraction, 3-7 mL (mean, 6 mL) of HA was injected under transrectal ultrasound guidance in the perirectal fat to systematically create a 1.5-cm space. Urethral and rectal HDR doses were calculated and measured. Computed tomography and magnetic resonance imaging were used to assess the stability of the new space., Results: Twenty-seven patients enrolled in the study. No toxicity was produced from the HA or the injection. In follow-up computed tomography and magnetic resonance imaging, the HA injection did not migrate or change in mass/shape for close to 1 year. The mean distance between rectum and prostate was 2.0 cm along the entire length of the prostate. The median measured rectal dose, when normalized to the median urethral dose, demonstrated a decrease in dose from 47.1% to 39.2% (p < 0.001) with or without injection. For an HDR boost dose of 1150 cGy, the rectum mean Dmax reduction was from 708 cGy to 507 cGy, p < 0.001, and the rectum mean Dmean drop was from 608 to 442 cGy, p < 0.001 post-HA injection., Conclusion: The new 2-cm distance derived from the HA injection significantly decreased rectal dose in HDR brachytherapy. Because of the several-month duration of stability, the same distance was maintained during the course of external beam radiation therapy.

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: Minimal data are available regarding selection of an optimal biochemical failure (BF) definition for patients treated with brachytherapy, external beam radiotherapy (EBRT), and combinations of these treatments with or without androgen deprivation (AD). We retrospectively analyzed our institution's experience treating localized prostate cancer in an attempt to determine a BF definition that could be applied for these various treatment modalities., Methods and Materials: A total of 2376 patients with clinical stage T1-T3 N0 M0 prostate cancer were treated with conventional dose (median, 66.6 Gy) EBRT (n = 1201), high-dose (median, 75.6 Gy) adaptive radiation therapy (n = 465), EBRT + high-dose-rate brachytherapy boost (n = 416), or brachytherapy alone (n = 294) between 1987 and 2003. A total of 496 patients (21%) received neoadjuvant AD with radiation therapy. There were 21924 posttreatment prostate-specific antigen (PSA) measurements. Multiple BF definitions were tested for their sensitivity, specificity, positive predictive value (+PV), and negative PV (-PV) in predicting subsequent clinical failure (CF) (any local failure or distant metastasis), overall survival (OS), and cause-specific survival (CSS). Median follow-up was 4.5 years. The date of BF was the date BF criteria were met (e.g., date of third rise)., Results: A total of 290 patients (12%) experienced CF at a median interval of 3.6 years (range, 0.2-15.2 years). The 5- and 10-year CF rates were 12% and 26%, respectively. Three consecutive rises yielded a 46% sensitivity and 84% specificity for predicting CF. The 10-year CF for those 475 patients who experienced three rises (BF) was 37% vs. 17% for those patients who did not meet these criteria (biochemically controlled [BC]). For all patients, the following definitions were superior to three rises for predicting CF for both +PV, and -PV: n + 1 (> or =1 ng/mL above nadir), n + 2, n + 3, threshold 2 (any PSA > or =2.0 ng/mL at or after nadir), threshold 3, threshold 4, and threshold 5. For the subset of patients treated with EBRT alone, the n + k definitions and threshold k definitions maintained superior predictive capacity. However, the threshold k definitions seemed to maintain a slightly greater separation in 10-year CF rates (43% for BF vs. 13% for BC = 30% difference for threshold 3). Surprisingly, all definitions generally had better predictive capacity for those patients who received brachytherapy or neoadjuvant AD vs. EBRT alone. The endpoints appeared similar for n + 1 vs. threshold 3 and n + 2 vs. threshold 4 in EBRT alone patients, but for brachytherapy or neoadjuvant AD patients, there were similarities for n + 2 vs. threshold 3 and n + 3 vs. threshold 4. This may be a reflection of the lower nadir levels in patients receiving AD (median <0.1 ng/mL vs. 0.2 ng/mL for brachytherapy vs. 0.8 ng/mL for EBRT alone, p < 0.01). When examining CF correlation for the various classes of BF definitions, the threshold k definitions clearly demonstrated the greatest area under the receiver operating characteristic curve, followed by the n + k definitions. For OS, the threshold k definitions again demonstrated the greatest area under the curve, followed by definitions based on specific nadir cutoffs (nadir > or =k ng/mL)., Conclusions: Biochemical failure definitions applying a PSA threshold at or after the nadir (e.g., threshold 3) demonstrated the highest association with CF, OS, and CSS for all assessed treatment modalities. Definitions incorporating a PSA increase above the nadir value (e.g., nadir + 2 ng/mL) were also superior for all modalities. In general, BF definitions have greater predictive capacity for clinical outcome with brachytherapy or neoadjuvant AD than EBRT alone, possibly because of less "noise" from production of background PSA.

Objective: To evaluate outcomes of intermediate- and high-risk prostate cancer patients on a prospective dose-escalation study of pelvic external-beam radiation therapy (EBRT) combined with high-dose-rate (HDR) brachytherapy boost., Methods: From November 1991 to April 2003, 197 patients were treated for intermediate- and high-risk disease features. All patients had prostate-specific antigen>10 ng/ml, Gleason score>or=7, or clinical stage>or=T2b, and all received pelvic EBRT (46 Gy) while receiving either two or three HDR boost treatments. HDR dose fractionation increased progressively and was divided into two dose levels. The mean prostate biologic equivalency dose was 88.2 Gy for the low-dose group and 116.8 Gy for the high-dose group (alpha/beta=1.2). Clinical failure was either local failure or distant metastasis; clinical event-free survival (cEFS) was defined as patients who lived free of clinical failure., Results: Median follow-up was 4.9 years. The 5-year rates were as follows: biologic failure (BF), 18.6%, clinical failure (CF), 9.8%, cEFS 84.8%, cause-specific survival (CSS), 98.3%, and overall survival (OS), 92.9%. Five-year biochemical failure (68.7% vs. 86%, p<0.001), CF (6.1% vs. 15.6%, p=0.04), cEFS (75.5% vs. 91.7%, p=0.003), CSS (95.4% vs. 100%, p=0.02), and OS (86.2% vs. 97.8%, p=0.002) were significantly better for the high-dose group. Multivariate analysis showed that high-dose group (p=0.01, HR 0.35) and Gleason score (p=0.01, HR 1.84) were significant variables for cEFS. Multivariate analysis showed that high-dose group (p=0.01, HR 0.14) and age (p=0.03, HR 1.09 per year) were significant variables for overall survival., Conclusion: There is a strong dose-response relationship for intermediate- to high-risk prostate cancer patients. Improved locoregional control with higher radiation doses alone can significantly decrease biochemical and clinical failures.

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: The aim of this study was to investigate effect of increasing dose on risk groups for clinical failure (CF: local failure or distant failure or hormone ablation or PSA>or=25 ng/ml) in patients with T1-T2 prostate cancer treated with external beam radiotherapy., Methods and Materials: Patients (n=4,537) were partitioned into nonoverlapping dose ranges, each narrow enough that dose was not a predictor of CF, and risk groups for CF were determined using recursive partitioning analysis (RPA). The same technique was applied to the highest of these dose ranges (70-76 Gy, 1,136 patients) to compare risk groups for CF in this dose range with the conventional risk-group classification., Results: Cutpoints defining low-risk groups in each dose range shifted to higher initial PSA levels and Gleason scores with increasing dose. Risk groups for CF in the dose range 70-76 Gy were not consistent with conventional risk groups., Conclusions: The conventional classification of risk groups was derived in the early PSA era, when total doses<70 Gy were common, and it is inconsistent with risk groups for patients treated to doses>70 Gy. Risk-group classifications must be continuously re-examined whenever the trend is toward increasing total dose.

Purpose: To determine the significance of prostate-specific antigen (PSA) nadir (nPSA) and the time to nPSA (T(nPSA)) in predicting biochemical or clinical disease-free survival (PSA-DFS) and distant metastasis-free survival (DMFS) in patients treated with definitive external beam radiotherapy (RT) for clinical Stage T1b-T2 prostate cancer., Methods and Materials: Nine participating institutions submitted data on 4839 patients treated between 1986 and 1995 for Stage T1b-T2cN0-NxM0 prostate cancer. All patients were treated definitively with RT alone to doses > or =60 Gy, without neoadjuvant or planned adjuvant androgen suppression. A total of 4833 patients with a median follow-up of 6.3 years met the criteria for analysis. Two endpoints were considered: (1) PSA-DFS, defined as freedom from PSA failure (American Society for Therapeutic Radiology and Oncology definition), initiation of androgen suppression after completion of RT, or documented local or distant failure; and (2) DMFS, defined as freedom from clinically apparent distant failure. In patients with failure, nPSA was defined as the lowest PSA measurement before any failure. In patients without failure, nPSA was the lowest PSA measurement during the entire follow-up period. T(nPSA) was calculated from the completion of RT to the nPSA date., Results: A greater nPSA level and shorter T(nPSA) were associated with decreased PSA-DFS and DMFS in all patients and in all risk categories (low [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level < or =10 ng/mL], intermediate [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level >10 but < or =20 ng/mL, or Stage T2b or T2c, Gleason score < or =6, and PSA level < or =20 ng/mL, or Gleason score 7 and PSA level < or =20 ng/mL], and high [Gleason score 8-10 or PSA level >20 ng/mL]), regardless of RT dose. The 8-year PSA-DFS and DMFS rate for patients with nPSA <0.5 ng/mL was 75% and 97%; nPSA > or =0.5 but <1.0 ng/mL, 52% and 96%; nPSA > or =1.0 but <2.0 ng/mL, 40% and 91%; and nPSA > or =2.0 ng/mL, 17% and 73%, respectively. The 8-year PSA-DFS and DMFS rate for patients with T(nPSA) <6 months was 27% and 66%; T(nPSA) > or =6 but <12 months, 31% and 85%; T(nPSA) > or =12 but <24 months, 42% and 94%; and T(nPSA) > or =24 months, 75% and 99%, respectively. A shorter T(nPSA) was associated with decreased PSA-DFS and DMFS, regardless of the nPSA. Both nPSA and T(nPSA) were significant predictors of PSA-DFS and DMFS in multivariate models incorporating clinical stage, Gleason score, initial PSA level, and RT dose. The significance of nPSA and T(nPSA) was supported by landmark analysis, as well as by analysis of nPSA and T(nPSA) as time-dependent covariates. A dose > or =70 Gy was associated with a lower nPSA level and longer T(nPSA) in all risk categories, and a greater dose was significantly associated with greater PSA-DFS and DMFS in multivariate analysis. Regression analysis confirmed that higher clinical stage, Gleason score, and initial PSA were associated with a greater nPSA level., Conclusion: The results of this large, multi-institutional analysis of 4833 patients have provided important evidence that nPSA and T(nPSA) after definitive external beam RT are not only predictive of a predominantly PSA endpoint (PSA-DFS), but are also predictive of distant metastasis in all clinical risk categories. Greater RT doses were associated with lower nPSA, longer T(nPSA), and improved PSA-DFS and DMFS.

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: High-dose radiotherapy, delivered in an accelerated hypofractionated course, was utilized to treat prostate cancer. Therapy consisted of external beam radiotherapy (EBRT) and transrectal ultrasound (TRUS)-guided conformally modulated high-dose rate (HDR) brachytherapy. The purpose of this report is (1) to assess long-term comparative outcomes from three trials using similar accelerated hypofractionated regimes; and (2) to examine the long-term survival impact of a short course of < or =6 months adjuvant/concurrent androgen deprivation when a very high radiation dose was delivered., Methods and Materials: Between 1986 and 2000, 1,260 patients were treated at three institutions with pelvic EBRT (36-50 Gy) integrated with HDR prostate brachytherapy. The total dose including brachytherapy was given over 5 weeks. The biologic equivalent EBRT dose ranged between 90 and 123 Gy (median, 102 Gy) using an alpha /beta of 1.2. Patient eligibility criteria included a pretreatment prostate-specific antigen > or =10, Gleason score > or =7, or clinical stage > or =T2b. A total of 1,260 patients were treated, and 934 meet the criteria. Kiel University Hospital treated 198 patients; William Beaumont Hospital, 315; and California Endocurietherapy Cancer Center, 459 patients. Brachytherapy dose regimes were somewhat different between centers and the dose was escalated from 5.5 x 3 to 15 Gy x 2 Gy. Patients were divided for analysis between the 406 who received up to 6 months of androgen deprivation therapy and the 528 patients who did not. All patients had a minimum follow-up of 18 months (3 times the exposure to androgen deprivation therapy). The American Society for Therapeutic Radiology and Oncology biochemical failure definition was used., Results: Mean age was 69 years. Median follow-up time was 4.4 years (range, 1.5-14.5); 4 years for androgen deprivation therapy patients and 4.9 for radiation alone. There was no difference at 5 and 8 years in overall survival, cause-specific survival, or biochemical control among the three institutions. The corresponding 8-year rates with and without androgen deprivation therapy were biochemical control 85% and 81%; overall survival 83% and 78%; cause-specific survival 89% and 94%; and metastatic rates of 16.6% and 7.3%. A multivariate analysis revealed androgen deprivation therapy did not predict for biochemical failure for either the entire group or the subset of 177 patients harboring all three poor prognostic factors. Moreover, adding androgen deprivation therapy strongly correlated with higher rates of both metastasis (p = 0.09; hazard ratio, 2.08) and cancer-related deaths (p = 0.02, hazard ratio 3.25). These negative results for the most unfavorable group led us to question if androgen deprivation therapy might have a deleterious impact through delay in delivery of the potentially curative radiation or whether there may be a biologic basis by fixing the cycling cells in G0., Conclusions: Accelerated hypofractionated pelvic EBRT integrated with TRUS-guided conformally modulated HDR administered to 1,260 patients in three institutions was an excellent method of delivering very high radiation dose to the prostate in 5 weeks. Similar high overall, cause-specific, and biochemical no evidence of disease survival rates achieved show that prostate HDR can be successfully delivered in academic and community settings. At 8 years, the addition of a course of < or =6 months of neoadjuvant/concurrent androgen deprivation therapy to a very high radiation dose did not confer a therapeutic advantage but added side effects and cost. Furthermore, for the most unfavorable group, there was a higher rate of distant metastasis and more prostate cancer-related deaths. We question the value of a short course of androgen deprivation therapy when used with high-dose radiation.

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.

Purpose: To quantify prostate motion during a radiation therapy treatment using cine-magnetic resonance imaging (cine-MRI) for time frames comparable to that expected in an image-guided radiation therapy treatment session (20-30 min)., Materials and Methods: Six patients undergoing radiation therapy for prostate cancer were imaged on 3 days, over the course of therapy (Weeks 1, 3, and 5). Four hundred images were acquired during the 1-h MRI session in 3 sagittal planes through the prostate at 6-s intervals. Eleven anatomic points of interest (POIs) have been used to characterize prostate/bony pelvis/abdominal wall displacement. Motion traces and standard deviation for each of the 11 POIs have been determined. The probability of displacement over time has also been calculated., Results: Patients were divided into 2 groups according to rectal filling status: full vs. empty rectum. The displacement of POIs (standard deviation) ranged from 0.98 to 1.72 mm for the full-rectum group and from 0.68 to 1.04 mm for the empty-rectum group. The low standard deviations in position (2 mm or less) would suggest that these excursions have a low frequency of occurrence. The most sensitive prostate POI to rectal wall motion was the mid-posterior with a standard deviation of 1.72 mm in the full-rectum group vs. 0.79 mm in the empty-rectum group (p = 0.0001). This POI has a 10% probability of moving more than 3 mm in a time frame of approximately 1 min if the rectum is full vs. approximately 20 min if the rectum is empty., Conclusion: Motion of the prostate and seminal vesicles during a time frame similar to a standard treatment session is reduced compared to that reported in interfraction studies. The most significant predictor for intrafraction prostate motion is the status of rectal filling. A prostate displacement of <3 mm (90%) can be expected for the 20 min after the moment of initial imaging for patients with an empty rectum. This is not the case for patients presenting with full rectum. The determination of appropriate intrafraction margins in radiation therapy to accommodate the time-dependent uncertainty in positional targeting is a topic of ongoing investigations for the on-line image guidance model.

Purpose: Heart dose-volume analysis using computed tomography (CT) is limited because of motion artifact and poor delineation between myocardium and ventricular space. We used dedicated cardiac magnetic resonance imaging (MRI) to quantify exclusion of left ventricular (LV) myocardium via active breathing control (ABC) during left breast irradiation and to determine the correlation between irradiated whole heart and LV volumes., Methods and Materials: Fifteen patients who completed adjuvant irradiation for early-stage left breast cancer participated. Treatment consisted of 45 Gy to the entire breast using ABC followed by a 16-Gy electron boost to the lumpectomy cavity. Patients underwent planning CT scans in free breathing (FB) and moderate deep inspiration breath hold (mDIBH). Electrocardiogram-gated cardiac MRI was performed in the treatment position using alpha-cradle immobilization. MRI scans were acquired in late diastole (LD), mid-diastole (MD), and systole (S) for both FB and mDIBH. After image fusion with the patients' radiation therapy planning CT scan, MRI LV volumes were defined for the three examined phases of the cardiac cycle, and comparative dose-volume analysis was performed., Results: Cardiac volume definition was found to differ significantly because of combinations of respiratory and intrinsic heart motion. The fraction of LV myocardium receiving 50% (22.5 Gy) of the prescribed whole breast dose (V(22.5)) was reduced by 85.3%, 91.8%, and 94.6% via ABC for LD, MD, and S, respectively. Linear regression revealed strong correlation between MRI-defined whole heart and LV V(22.5) reduction via ABC, suggesting that LV myocardium accounts for up to approximately 50% of the excluded heart volume through this technique. Significant but weaker correlations were noted between CT-defined whole heart and LV V(22.5) reductions with marked variability in the measurements of patients with larger amounts of heart in the treatment field., Conclusions: Cardiac MRI demonstrated a significant reduction in LV myocardium irradiated with the use of ABC. The correlation between reduction in V(22.5) values for LV wall and CT-defined whole heart suggests that CT is adequate for determining which patients are likely to benefit from ABC treatment, but inaccuracies inherent to standard CT dictate that more detailed imaging studies such as MRI are required for accurate cardiotoxicity assessment.

Purpose: The indications for adjuvant external beam radiotherapy (EBRT) after radical prostatectomy (RP) are poorly defined. We performed a retrospective comparison of our institution's experience treating prostate cancer with RP vs. RP followed by adjuvant EBRT., Methods and Materials: Between 1987 and 1998, 617 patients with clinical Stage T1-T2N0M0 prostate cancer underwent RP. Patients who underwent preoperative androgen deprivation and those with positive lymph nodes were excluded. Of the 617 patients, 34 (5.5%) with an undetectable postoperative prostate-specific antigen (PSA) level underwent adjuvant prostatic fossa RT at a median of 0.25 year (range, 0.1-0.6) postoperatively because of poor pathologic features. The median total dose was 59.4 Gy (range, 50.4-66.6 Gy) in 1.8-2.0-Gy fractions. These 34 RP+RT patients were compared with the remaining 583 RP patients. Biochemical failure was defined as any postoperative PSA level > or =0.1 ng/mL and any postoperative PSA level > or =0.3 ng/mL (at least 30 days after surgery). Administration of androgen deprivation was also scored as biochemical failure when applying either definition. The median clinical follow-up was 8.2 years (range, 0.1-11.2 years) for RP and 8.4 years (range, 0.3-13.8 years) for RP+RT., Results: Radical prostatectomy + radiation therapy patients had a greater pathologic Gleason score (mean, 7.3 vs. 6.5; p < 0.01) and pathologic T stage (median, T3a vs. T2c; p < 0.01). Age (median, 65.7 years) and pretreatment PSA level (median, 7.9 ng/mL) were similar between the treatment groups. Extracapsular extension was present in 72% of RP+RT patients vs. 27% of RP patients (p < 0.01). The RP+RT patients were more likely to have seminal vesicle invasion (29% vs. 9%, p < 0.01) and positive margins (73% vs. 36%, p < 0.01). Despite these poor pathologic features, the 5-year biochemical control (BC) rate (PSA <0.1 ng/mL) was 57% for RP+RT and 47% for RP (p = 0.28). For patients with extracapsular extension, the 5-year BC rate was 52% for RP+RT vs. 30% for RP (p < 0.01). The 5-year BC rate for patients with seminal vesicle invasion was 60% for RP+RT vs. 18% for RP (p < 0.01). For those with positive margins, the 5-year BC rate was 64% for RP+RT vs. 27% for RP (p < 0.01). The use of adjuvant RT remained statistically significant on multivariate analysis when applying either biochemical failure definition. Adjuvant RT also remained statistically significant when including the postoperative PSA level (>30 days after surgery) in the multivariate analyses. In addition, 99 (17%) of the 583 RP patients required salvage prostatic fossa RT (median dose, 59.4 Gy) at a median interval of 1.3 years after surgery (range, 0.1-8.4) for a palpable recurrence (n = 10) or a detectable/rising postoperative PSA level (n = 89). The median PSA level before salvage RT was 0.8 ng/mL (mean, 3.2 ng/mL). The 5-year and 8-year BC rate, using the PSA <0.1 ng/mL definition, from the date of salvage RT was 41% and 35%, respectively. The 5-year and 8-year BC rate, using the PSA <0.3 ng/mL definition, was 46% and 36%, respectively. The 8-year local recurrence rate after salvage RT was 4%., Conclusion: Adjuvant RT demonstrated improved efficacy against prostate cancer. For patients with poor pathologic features (extracapsular extension, seminal vesicle invasion, positive margins), adjuvant RT improved the biochemical outcome independent of other prognostic factors.

Purpose: F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is now considered the most accurate clinical staging study for non-small-cell lung cancer (NSCLC) and is also important in the staging of multiple other malignancies. Gross tumor volume (GTV) definition for radiotherapy, however, is typically based entirely on computed tomographic data. We performed a series of phantom studies to determine an accurate and uniformly applicable method for defining a GTV with FDG-PET., Methods and Materials: A model-based method was tested by a phantom study to determine a threshold, or unique cutoff of standardized uptake value based on body weight (standardized uptake value [SUV]) for FDG-PET based GTV definition. The degree to which mean target SUV, background FDG concentration, and target volume influenced that GTV definition were evaluated. A phantom was constructed consisting of a 9.0-L cylindrical tank. Glass spheres with volumes ranging from 12.2 to 291.0 cc were suspended within the tank, with a minimum separation of 4 cm between the edges of the spheres. The sphere volumes were selected based on the range of NSCLC patient tumor volumes seen in our clinic. The tank and spheres were filled with a variety of known concentrations of FDG in several experiments and then scanned using a General Electric Advance PET scanner. In the initial experiment, six spheres with identical volumes were filled with varying concentrations of FDG (mean SUV = 1.85 approximately 9.68) and suspended within a background bath of FDG at a similar concentration to that used in clinical practice (0.144 muCi/mL). The second experiment was identical to the first, but was performed at 0.144 and 0.036 muCi/mL background concentrations to determine the effect of background FDG concentration on sphere definition. In the third experiment, six spheres with volumes of 12.2 to 291.0 cc were filled with equal concentrations of FDG and suspended in a standard background FDG concentration of 0.144 muCi/mL. Sphere images in each experiment were auto-contoured (simulating a GTV) using the threshold SUV that yielded a volume matching that of the known sphere volume. A regressive function was constructed to represent the relationship between the threshold SUV and the mean target SUV. This function was then applied to define the GTV of 15 NSCLC patients. The GTV volumes were compared to those determined by a fixed image intensity threshold proposed by other investigators., Results: There was a strong linear relationship between the threshold SUV and the mean target SUV. The linear regressive function derived was: threshold SUV = 0.307 x (mean target SUV) + 0.588. The background concentration and target volume indirectly affect the threshold SUV by way of their influence on the mean target SUV. We applied the linear regressive function, as well as a fixed image intensity threshold (42% of maximum intensity) to the sphere phantoms and 15 patients with NSCLC. The results indicated that a much smaller deviation occurred when the threshold SUV regressive function was utilized to estimate the phantom volume as compared to the fixed image intensity threshold. The average absolute difference between the two methods was 21% with respect to the true phantom volume. The deviation became even more pronounced when applied to true patient GTV volumes, with a mean difference between the two methods of 67%. This was largely due to a greater degree of heterogeneity in the SUV of tumors over phantoms., Conclusions: An FDG-PET-based GTV can be systematically defined using a threshold SUV according to the regressive function described above. The threshold SUV for defining the target is strongly dependent on the mean target SUV of the target, and can be uniquely determined through the proposed iteration process.

Purpose: The purpose of this analysis was to evaluate patterns and rates of ipsilateral breast tumor recurrence (IBTR) over time based on the type of failure (true recurrence/marginal miss [TR/MM] vs. elsewhere [E]) and to compare these to rates of contralateral failure in women with Stages I/II breast cancer treated with conservative surgery (CS) and radiation therapy (RT)., Methods and Materials: Between 1980 and 1997, 1448 patients with Stages I/II invasive breast carcinoma were treated with CS and RT to a median total dose of >60 Gy. IBTRs were analyzed in terms of their location as follows: TR/MM, referring to those occurring in the same quadrant, and E, referring to the development of a malignancy remote from the index lesion. Outcomes were characterized in terms of their temporal recurrence patterns and correlated with rates of contralateral breast failure (CL). The median follow-up was 8.5 years., Results: A total of 79 ipsilateral and 98 contralateral failures were observed during the follow-up period corresponding to 5-, 10-, and 15-year actuarial rates of 2%, 7%, and 10% and 4%, 9%, and 12% respectively. Fifty-nine ipsilateral failures (74.7%) were designated as TR/MM and 20 (25.3%) as E. The corresponding 5-, 10-, and 15-year actuarial rates of TR/MM and E failures were 2%, 5%, and 8% and 0.1%, 2%, and 3%, respectively. The median times to total ipsilateral, TR/MM, E, and contralateral failure were 6.5, 5.7, 7.4, and 5.2 years, respectively. Between 0 and 5 years of follow-up, E failures represented 7% of the total ipsilateral failures observed. From 5-10 and 10-15 years, E failures represented 39% and 27% of the total, respectively (p = 0.01). Contralateral failure was significantly more likely to occur in the first 5 years of follow-up than IBTR, accounting for 50 (63.3%) of the 79 failures in that interval (p = 0.02). No significant differences in survival rates were detected between any of the various failure types. On multivariate analysis, only reduced time to tumor recurrence was found to be adversely associated with overall survival., Conclusions: The rates and patterns of IBTR vary with time and, after 5 years, approach the rates of development of a contralateral breast cancer. E failures are, overall, less frequent than TR/MM but contribute increasingly to the IBTR rate after 5 years. Time to tumor recurrence is the most reliable predictor of prognosis after IBTR.

Purpose: We hypothesize that surgical clips placed in the biopsy cavity during lumpectomy can be used as radiographic markers to facilitate image-guided external beam accelerated partial breast irradiation., Methods and Materials: We evaluated 28 patients with surgically placed clips in the lumpectomy cavity and two CT scans on different days. To establish whether the clips remain predictive of the lumpectomy cavity throughout therapy, we analyzed the motion of both cavities with repeat volumetric CT scans. The three-dimensional (3D) locations of each lumpectomy cavity and the associated clips were defined as individual regions of interest (ROIs). A single point of interest (POI) was defined for each ROI. The calculated movements of the lumpectomy cavity POIs between different scans were compared to those of the clip POIs. The second CT data set was then moved in accordance to the calculated clip POI's movement. The volume of the (second) lumpectomy cavity associated with the second scan outside of the (first) cavity of the first scan was measured. In addition, the required amount of a radial margin expansion around the first lumpectomy cavity to ensure coverage of the second lumpectomy cavity both before and after moving the second lumpectomy according to the clip POI movement was calculated., Results: The two CT scans were obtained on average 27 days apart, and the mean lumpectomy size decreased from 35 to 16 cc. The clip and lumpectomy cavity POIs moved a mean of 3 mm along the three principal Cartesian axes. In moving the second lumpectomy cavity according to the clip POI displacement from its original position, the volume of the second lumpectomy cavity outside of the volume of the first decreased from 2.6 cc to 1.0 cc after correction, and the required radial margin on the first lumpectomy cavity to include the second lumpectomy cavity decreased from 5.5 mm vs. 3.8 mm., Conclusion: The surgically placed clips after lumpectomy are strong radiographic surrogates for the biopsy cavity. If the clips were used to guide accelerated partial breast irradiation, a planning target volume margin of the order of 5 mm could be used, significantly smaller than the 10-mm margin currently employed.

Purpose: We analyzed our experience treating localized prostate cancer to determine the impact of androgen deprivation (AD) on clinical outcome if administered at the time of isolated biochemical failure (BF) vs. after clinical failure (clinical failure), and the associated impact of various BF definitions., Methods: A total of 1,201 patients with stage T1-T3N0M0 prostate cancer were treated with external beam radiotherapy (EBRT) to a median dose of 66.6 Gy. Early AD was defined as administration of AD after BF, without evidence of clinical failure. Delayed AD was defined as administration of AD after clinical failure. Multiple BF definitions were tested for capacity to predict subsequent clinical failure. For each BF definition, outcome was compared for BF patients receiving early AD vs. no or delayed AD., Results: Five-year clinical failure (from date of BF) was 60% for patients who experienced a prostate-specific antigen rise to >/=3 ng/mL above nadir. For these patients, early AD was associated with decreased 5-year local failure (4% vs. 33%), distant metastasis (13% vs. 44%), cause-specific death (9% vs. 24%), and death due to any cause (32% vs. 48%), despite poorer prognostic factors in patients receiving early AD. On multivariate analysis, early AD remained independently significant for each of these end points., Conclusion: The efficacy of AD after BF varies depending on the BF definition. When an optimal BF definition is applied, early AD decreases distant metastasis and improves survival. Prostate-specific antigen elevation to >/=2 or >/=3 ng/mL above nadir seems optimal in establishing clinically significant BF and the timing of AD intervention.

Purpose: The active breathing control (ABC) apparatus was used to quantify the effect of breathing motion on whole breast radiotherapy (RT) with standard wedges and intensity-modulated RT (IMRT)., Methods and Materials: Ten patients with early-stage breast cancer underwent routine free-breathing (FB) CT simulations for whole breast RT. An ABC apparatus was used to obtain two additional CT scans with the breath held at the end of normal inhalation and normal exhalation. The FB scan was used to develop both a standard treatment plan using wedged coplanar tangents and an IMRT plan using multiple static multileaf collimator segments. To simulate breathing, each plan was copied and applied to the normal inhalation and normal exhalation CT scans., Results: The medial field border (defined by a radiopaque catheter) for the normal inhalation and normal exhalation scans moved an average of 0.6 cm anteriorly and 0.3 cm posteriorly compared with the FB position, respectively. The corresponding movement of the lateral field border was an average of 0.4 cm anteriorly and 0.2 cm posteriorly compared with the FB position. For both the wedged and the IMRT techniques, the dose delivered to breast tissue, biopsy cavity, and ipsilateral lung was similar for each of the three CT scan positions. However, the internal mammary node dose varied significantly with breathing., Conclusions: The dose delivered to breast using standard wedges or step-and-shoot IMRT is relatively insensitive to the effects of breast motion during normal breathing. However, an appreciable portion of the internal mammary nodes are irradiated during normal inhalation, contributing to the uncertainty in the analysis of the efficacy of internal mammary nodal RT in breast treatment.

Purpose: A CT-based three-dimensional (3D) method was used to analyze the intra- and interfraction reproducibility of lung immobilization during moderate deep inspiration breath hold (mDIBH), defined as 75% of the maximal inspiration using an active breathing control (ABC) apparatus., Methods and Materials: The ABC apparatus was used to immobilize the breathing motion with a computer-controlled valve. Immobilization of the lungs in breast cancer patients was used as a model to evaluate the reproducibility of mDIBH using the ABC apparatus. CT scans were acquired twice at mDIBH in the same session for 30 breast cancer patients. Twenty-three of them were immobilized with an alpha-cradle, of which 14 had a repeat scan at mDIBH 1-4 weeks later. Twelve of those patients received intensity-modulated radiotherapy to the left breast at mDIBH to displace the heart from the beam. The remaining patients were treated at free breathing, with either intensity-modulated irradiation to the whole breast or conformal partial breast irradiation. To remove the component of setup error, mDIBH scans were registered with respect to the vertebrae. The lungs and carina were auto-contoured to form 3D surfaces for each data set. The closest distance-to-agreement (DTA) for each point between the 3D surfaces of the corresponding CT scans was displayed on a 3D surface map. For analysis, each lung was divided along its inferior to superior extent into six regions, from the basal 10%, the next four consecutive 20% sections in height, to the last apical 10%. Likewise, the carina was divided into regions of the trachea and bifurcation. The mean and standard deviation (SD) of the DTA for each of these regions was computed., Results: With the patient positioned in an alpha-cradle, the mean +/- SD intrafraction DTA was 1.5 +/- 1.4 mm for the left lung and 1.0 +/- 1.4 mm for the right lung. The corresponding values without the use of an alpha-cradle were significantly greater, with 1.9 +/- 2.1 mm and 2.2 +/- 2.2 mm for the left and right lung, respectively (p <0.005 for the SD of the left lung and p <0.0003 for the SD of the right lung). The interfraction DTA for the left and right lungs was 1.4 +/- 1.7 mm and 1.4 +/- 1.6 mm, respectively. The regional analysis demonstrated better immobilization for the upper two-thirds of the chest wall compared with that for the lung base. The DTA values obtained for the tracheal bifurcation were 0.9 +/- 0.8 mm for intrafraction and 1.4 +/- 1.0 mm for interfraction., Conclusion: The ABC device can be used to reduce respiratory motion at mDIBH in breast cancer patients or those patients who can perform the maneuver. This device demonstrated excellent intra- and interfraction reproducibility of chest wall and carina immobilization, especially when combined with alpha-cradle immobilization. Internal margins for suspended breathing can be extrapolated from these data for various anatomic regions within the lung and chest wall.

Purpose: To report the long-term outcome for patients with Stage T1-T2 adenocarcinoma of the prostate definitively irradiated in the prostate-specific antigen (PSA) era., Methods and Materials: Nine institutions combined data on 4839 patients with Stage T1b, T1c, and T2 adenocarcinoma of the prostate who had a pretreatment PSA level and had received >or=60 Gy as definitive external beam radiotherapy. No patient had hormonal therapy before treatment failure. The median follow-up was 6.3 years. The end point for outcome analysis was PSA disease-free survival at 5 and 8 years after therapy using the American Society for Therapeutic Radiology and Oncology (ASTRO) failure definition., Results: The PSA disease-free survival rate for the entire group of patients was 59% at 5 years and 53% at 8 years after treatment. For patients who had received >or=70 Gy, these percentages were 61% and 55%. Of the 4839 patients, 1582 had failure by the PSA criteria, 416 had local failure, and 329 had distant failure. The greatest risk of failure was at 1.5-3.5 years after treatment. The failure rate was 3.5-4.5% annually after 5 years, except in patients with Gleason score 8-10 tumors for whom it was 6%. In multivariate analysis for biochemical failure, pretreatment PSA, Gleason score, radiation dose, tumor stage, and treatment year were all significant prognostic factors. The length of follow-up and the effect of backdating as required by the ASTRO failure definition also significantly affected the outcome results. Dose effects were most significant in the intermediate-risk group and to a lesser degree in the high-risk group. No dose effect was seen at 70 or 72 Gy in the low-risk group., Conclusion: As follow-up lengthens and outcome data accumulate in the PSA era, we continue to evaluate the efficacy and durability of radiotherapy as definitive therapy for early-stage prostate cancer. Similar studies with higher doses and more contemporary techniques will be necessary to explore more fully the potential of this therapeutic modality.

Purpose: To systematically evaluate four different techniques of radiation therapy (RT) used to treat non-small-cell lung cancer and to determine their efficacy in meeting multiple normal-tissue constraints while maximizing tumor coverage and achieving dose escalation., Methods and Materials: Treatment planning was performed for 18 patients with Stage I to IIIB inoperable non-small-cell lung cancer using four different RT techniques to treat the primary lung tumor +/- the hilar/mediastinal lymph nodes: (1) Intensity-modulated radiation therapy (IMRT), (2) Optimized three-dimensional conformal RT (3D-CRT) using multiple beam angles, (3) Limited 3D-CRT using only 2 to 3 beams, and (4) Traditional RT using elective nodal irradiation (ENI) to treat the mediastinum. All patients underwent virtual simulation, including a CT scan and (18)fluorodeoxyglucose positron emission tomography scan, fused to the CT to create a composite tumor volume. For IMRT and 3D-CRT, the target included the primary tumor and regional nodes either > or =1.0 cm in short-axis dimension on CT or with increased uptake on PET. For ENI, the target included the primary tumor plus the ipsilateral hilum and mediastinum from the inferior head of the clavicle to at least 5.0 cm below the carina. The goal was to deliver 70 Gy to > or =99% of the planning target volume (PTV) in 35 daily fractions (46 Gy to electively treated mediastinum) while meeting multiple normal-tissue dose constraints. Heterogeneity correction was applied to all dose calculations (maximum allowable heterogeneity within PTV 30%). Pulmonary and esophageal constraints were as follows: lung V(20) < or =25%, mean lung dose < or =15 Gy, esophagus V(50) < or =25%, mean esophageal dose < or =25 Gy. At the completion of all planning, the four techniques were contrasted for their ability to achieve the set dose constraints and deliver tumoricidal RT doses., Results: Requiring a minimum dose of 70 Gy within the PTV, we found that IMRT was associated with a greater degree of heterogeneity within the target and, correspondingly, higher mean doses and tumor control probabilities (TCPs), 7%-8% greater than 3D-CRT and 14%-16% greater than ENI. Comparing the treatment techniques in this manner, we found only minor differences between 3D-CRT and IMRT, but clearly greater risks of pulmonary and esophageal toxicity with ENI. The mean lung V(20) was 36% with ENI vs. 23%-25% with the three other techniques, whereas the average mean lung dose was approximately 21.5 Gy (ENI) vs. 15.5 Gy (others). Similarly, the mean esophagus V(50) was doubled with ENI, to 34% rather than 15%-18%. To account for differences in heterogeneity, we also compared the techniques giving each plan a tumor control probability equivalent to that of the optimized 3D-CRT plan delivering 70 Gy. Using this method, IMRT and 3D-CRT offered similar results in node-negative cases (mean lung and esophageal normal-tissue complication probability [NTCP] of approximately 10% and 2%-7%, respectively), but ENI was distinctly worse (mean NTCPs of 29% and 20%). In node-positive cases, however, IMRT reduced the lung V(20) and mean dose by approximately 15% and lung NTCP by 30%, compared to 3D-CRT. Compared to ENI, the reductions were 50% and >100%. Again, for node-positive cases, especially where the gross tumor volume was close to the esophagus, IMRT reduced the mean esophagus V(50) by 40% (vs. 3D-CRT) to 145% (vs. ENI). The esophageal NTCP was at least doubled converting from IMRT to 3D-CRT and tripled converting from IMRT to ENI. Finally, the total number of fractions for each plan was increased or decreased until all outlined normal-tissue constraints were reached/satisfied. While meeting all constraints, IMRT or 3D-CRT increased the deliverable dose in node-negative patients by >200% over ENI. In node-positive patients, IMRT increased the deliverable dose 25%-30% over 3D-CRT and 130%-140% over ENI. The use of 3D-CRT without IMRT increased the deliverable RT dose >80% over ENI. Using a limited number of 3D-CRT beams decreased the lung V(20), mean dose, and NTCP in node-positive patients., Conclusion: The use of 3D-CRT, particul mean dose, and NTCP in node-positive patients. The use of 3D-CRT, particularly with only 3 to 4 beam angles, has the ability to reduce normal-tissue toxicity, but has limited potential for dose escalation beyond the current standard in node-positive patients. IMRT is of limited additional value (compared to 3D-CRT) in node-negative cases, but is beneficial in node-positive cases and in cases with target volumes close to the esophagus. When meeting all normal-tissue constraints in node-positive patients, IMRT can deliver RT doses 25%-30% greater than 3D-CRT and 130%-140% greater than ENI. Whereas the possibility of dose escalation is severely limited with ENI, the potential for pulmonary and esophageal toxicity is clearly increased.

Introduction: We present our initial clinical experience using moderate deep-inspiration breath hold (mDIBH) with an active breathing control (ABC) device to reduce heart dose in the treatment of patients with early-stage, left-sided breast cancer using external beam radiation therapy (EBRT) limited to the whole breast., Methods and Materials: Between February and August 2002, 5 patients with Stages I/II left-sided breast cancer received EBRT limited to the whole breast using an ABC device. After standard virtual simulation, patients with >2% of the heart receiving >30 Gy in free breathing were selected. All patients underwent a training session with the ABC apparatus to determine their ability to comfortably maintain mDIBH at 75% of the maximum inspiration capacity. Three patients received 45 Gy to the whole breast in 25 fractions, and 2 patients received 50.4 Gy in 28 fractions. For each of the medial and lateral tangential beams, radiation was delivered during 2 or 3 breath hold durations that ranged from 18 to 26 s. "Step-and-shoot" intensity modulation was employed to achieve uniform dose distribution. Open beam segments were purposely delivered over 2 breath hold sessions and captured on electronic portal images to allow intra- and interfraction setup error analysis. All electronic portal images of the tangential beams were analyzed off-line using an in-house treatment verification tool to assess the anteroposterior, craniocaudal, and rotational uncertainties. Corrections were applied if necessary., Results: A comparison of treatment plans performed on breath-hold and free-breathing CTs showed that ABC treatments achieved a mean absolute reduction of 3.6% in heart volume receiving 30 Gy (heart V(30)) and 1.5% in the heart normal tissue complication probability. A total of 134 ABC treatment sessions were performed in the 5 patients. The average number of breath holds required per beam direction was 2.5 (4-6 per treatment) with a median duration of 22 s per breath hold (range: 10-26 s). Patients tolerated mDIBH well. The median treatment time was 18.2 min (range: 13-32 min), which was progressively shortened with increasing experience. A total of 509 portal images were analyzed. Combining measurements for all patients, the interfraction setup errors (1 SD) in the lateral and craniocaudal directions and in rotation were 2.4 mm, 3.2 mm, and 1 degrees, respectively, for the medial beam and 2.3 mm, 3.1 mm, and 1 degrees, respectively, for the lateral beam. For all patients, the intrafraction setup errors were about 1 mm and always less than 2 mm (1 SD)., Conclusion: Reduction in heart V(30) can be achieved in patients with left-sided breast cancer using mDIBH assisted with an ABC device. With increasing experience, ABC treatments were streamlined and could be performed within a 15-min treatment slot. Our results suggest that mDIBH using an ABC device may provide one of the most promising methods of improving the efficacy of EBRT in patients with left-sided breast cancer, particularly when wide tangential beams are employed. Breast cancer; Breath hold; Radiation therapy; Intensity modulated radiation therapy

Purpose: To evaluate the heart and lung sparing effects of moderate deep inspiration breath hold (mDIBH) achieved using an active breathing control (ABC) device, compared with free breathing (FB) during treatment with deep tangents fields (DT) for locoregional (LR) irradiation of breast cancer patients, including the internal mammary (IM) nodes (IMNs). To compare the DT-mDIBH technique to other standard techniques and to evaluate the dosimetric effect of intensity-modulated radiation therapy (IMRT)., Methods and Materials: Fifteen patients (9 left-sided and 6 right-sided lesions) with Stages 0-III breast cancer underwent standard FB and ABC computed tomographic (CT) scans in the treatment position. A dosimetric planning study was performed. In FB, the 9 left-sided patients were planned with a 5-field technique where electron fields covering the IM region were matched to shallow tangents using wedges (South West Oncology Group [SWOG] protocol S9927 technique A). This method was compared with a 3-field DT technique covering the breast and the IMNs (SWOG S9927 technique B). Compensation with IMRT was then compared with wedges for each technique. For the 15 total patients, dosimetric planning using DT with IMRT was then reoptimized on the mDIBH CT data set for comparison. Dose-volume histograms for the clinical target volume (CTV) (including the IMNs), planning target volume (PTV), ipsilateral and contralateral breast, and organs at risk (OAR) were analyzed. In addition, normal tissue complication probabilities (NTCP) for lung and heart, mean lung doses, and the number of monitor units (MUs) for a 1.8 Gy fraction were compared., Results: For the 9 left-sided patients, the mean percentage of heart receiving more than 30 Gy (heart V30) was lower with the 5-field wedged technique than with the DT wedged technique (6.8% and 19.1%, respectively, p < 0.004). For the DT technique, the replacement of wedges with IMRT slightly diminished the mean heart V30 to 16.3% (p < 0.51). The introduction of mDIBH to the DT-IMRT technique reduced the heart V30 by 81% to a mean of 3.1% (p < 0.0004). Compared with 5-field IMRT, DT-IMRT with mDIBH reduced the heart V30 for 6 of the 9 patients, entirely avoiding heart irradiation in 2 of these 6 patients. For DT-IMRT, mDIBH reduced the mean lung dose and NTCP to levels obtained with the 5-field IMRT technique. For the 15 patients planned with DT-IMRT in FB, the use of mDIBH reduced the mean percentage of both lungs receiving more than 20 Gy from 20.4% to 15.2% (p < 0.00007). With DT-IMRT, more than 5% of the contralateral breast received more than 10 Gy for 6 of the 9 left-sided patients in FB, 3 of those 9 patients in mDIBH, and only 1 of those 9 patients planned with 5 fields. The mean % of the PTV receiving more than 55 Gy (110% of the prescribed dose) was 36.4% for 5-field wedges, 33.4% for 5-field IMRT, 28.7% for DT-wedges, 12.5% for DT-IMRT, and 18.4% for DT-IMRT mDIBH. The CTV remained covered by the 95% isodose in all the DT plans but one (99.1% of the volume covered). DT-wedges required more MUs than DT-IMRT (mean of 645 and 416, respectively, p < 0.00004)., Conclusion: mDIBH significantly reduces heart and lung doses when DT are used for LR breast irradiation including the IMNs. Compared with shallow tangents matched with electrons, DT with mDIBH reduces the heart dose (in most patients) and results in comparable lung toxicity parameters, but may increase the dose to the contralateral breast. IMRT improves dose homogeneity, slightly reduces the dose to the heart, and diminishes the number of MUs required.

Purpose: We present a novel three-dimensional conformal radiation therapy (3D-CRT) technique to treat the lumpectomy cavity, plus a 1.5-cm margin, in patients with early-stage breast cancer and study its clinical feasibility., Methods and Materials: A 3D-CRT technique for partial-breast irradiation was developed using archived CT scans from 7 patients who underwent an active breathing control study. The clinical feasibility of this technique was then assessed in 9 patients who were prospectively enrolled on an Investigational Review Board-approved protocol of partial-breast irradiation. The prescribed dose was 34 Gy in 5 patients and 38.5 Gy in 4 patients, delivered in 10 fractions twice daily over 5 consecutive days. The impact of both breathing motion and patient setup uncertainty on clinical target volume (CTV) coverage was studied, and an appropriate CTV-to-PTV (planning target volume) margin was calculated., Results: By adding a CTV-to-PTV "breathing-only" margin of 5 mm, 98%-100% of the CTV remained covered by the 95% isodose surface at the extremes of normal inhalation and normal exhalation. The "total" CTV-to-PTV margin employed to accommodate organ motion and setup error (10 mm) was found to be sufficient to accommodate the observed uncertainty in the delivery precision. Patient tolerance was excellent, and acute toxicity was minimal. No skin changes were noted during treatment, and at the initial 4-8-week follow-up visit, only mild localized hyperpigmentation and/or erythema was observed. No instances of symptomatic radiation pneumonitis have occurred., Conclusions: Accelerated partial-breast irradiation using 3D-CRT is technically feasible, and acute toxicity to date has been minimal. A CTV-to-PTV margin of 10 mm seems to provide coverage for most patients. However, more patients and additional studies will be needed to validate the accuracy of this margin, and longer follow-up will be needed to assess acute and chronic toxicity, tumor control, and cosmetic results.

Purpose: To evaluate the long-term results of treatment using adjuvant whole abdominal irradiation (WAPI) with a pelvic/vaginal boost in patients with Stage I-III endometrial carcinoma at high risk of intra-abdominopelvic recurrence, including clear cell (CC) and serous-papillary (SP) histologic features., Methods and Materials: In a prospective nonrandomized trial, 119 patients were treated with adjuvant WAPI between November 1981 and April 2000. All patients were analyzed, including those who did not complete therapy. The mean age at diagnosis was 66 years (range 39-88). Thirty-eight patients (32%) had 1989 FIGO Stage I-II disease and 81 (68%) had Stage III. The pathologic features included the following: 64 (54%) with deep myometrial invasion, 48 (40%) with positive peritoneal cytologic findings, 69 (58%) with high-grade lesions, 21 (18%) with positive pelvic/para-aortic lymph nodes, and 44 (37%) with SP or CC histologic findings., Results: The mean follow-up was 5.8 years (range 0.2-14.7). For the entire group, the 5- and 10-year cause-specific survival (CSS) rate was 75% and 69% and the disease-free survival (DFS) rate was 58% and 48%, respectively. When stratified by histologic features, the 5- and 10-year CSS rate for adenocarcinoma was 76% and 71%, and for serous papillary/CC subtypes, it was 74% and 63%, respectively (p = 0.917). The 5- and 10-year DFS rate for adenocarcinoma was 60% and 50% and was 54% and 37% serous papillary/CC subtypes, respectively (p = 0.498). For surgical Stage I-II, the 5-year CSS rate was 82% for adenocarcinoma and 87% for SP/CC features (p = 0.480). For Stage III, it was 75% and 57%, respectively (p = 0.129). Thirty-seven patients had a relapse, with the first site of failure the abdomen/pelvis in 14 (38%), lung in 8 (22%), extraabdominal lymph nodes in 7 (19%), vagina in 6 (16%), and other in 2 (5%). When stratified by histologic variant, 32% of patients with adenocarcinoma and 30% with the SP/CC subtype developed recurrent disease. Most failures for either histologic group occurred within the abdominopelvic region. However, one-third of the adenocarcinoma recurrences were in the lung. Multivariate regression analysis (age, surgical stage, grade, myometrial invasion, histologic type, lymph node status, and peritoneal cytology) demonstrated age (p = 0.019) and surgical stage (p = 0.036) to be of prognostic significance for CSS; age (p = 0.036) was the only significant prognostic factor for DFS. Grade 1-2 gastrointestinal and hematologic acute toxicities were common. Asymptomatic bibasilar scarring on chest X-ray and mild elevation of liver enzymes were seen in almost 50% of the patients. Even though chronic toxicities were less frequent, 12% developed Grade 3-4 gastrointestinal and 2% Grade 3 renal toxicities., Conclusion: Adjuvant WAPI is very effective treatment with excellent 10-year results for Stage I-III endometrial carcinoma with risk factors for intra-abdominopelvic recurrence, including SP or CC histologic variants, deep myometrial invasion, high grade, nodal involvement, and positive peritoneal cytology. The low long-term complication rate with high CSS rate makes WAPI the treatment of choice for these patients with significant comorbidities.

Purpose: The clinical significance of postradiotherapy (RT) prostate biopsy characteristics is not well understood relative to the known prognostic factors. We performed a detailed pathologic review of posttreatment biopsy specimens in an attempt to clarify their relationship with clinical outcome and radiation dose., Methods and Materials: Between 1991 and 1998, 78 patients with locally advanced prostate cancer were prospectively treated with external beam RT in combination with high-dose-rate brachytherapy at William Beaumont Hospital and had post-RT biopsy material available for a complete pathologic review. Patients with any of the following characteristics were eligible for study entry: pretreatment prostate-specific antigen level > or =10.0 ng/mL, Gleason score > or =7, or clinical Stage T2b-T3cN0M0. Pelvic external beam RT (46.0 Gy) was supplemented with three (1991-1995) or two (1995-1998) ultrasound-guided transperineal interstitial (192)Ir high-dose-rate implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy per implant. Post-RT prostate biopsies were performed per protocol at a median interval of 1.5 years after RT. All pre- and post-RT biopsy specimen slides from each case were reviewed by a single pathologist (N.S.G.). The presence and amount of residual cancer, most common RT-effect score, and least amount RT-effect score were analyzed. The median follow-up was 5.7 years. Biochemical failure was defined as three consecutive prostate-specific antigen rises., Results: Forty patients (51%) had residual cancer in the post-RT biopsies. The 7-year biochemical control rate was 79% for patients with negative biopsies vs. 62% for those with positive biopsies with marked RT damage vs. 33% for those with positive biopsies with no or minimal RT damage. A greater percentage of positive pre-RT biopsy cores (p = 0.01), lower total RT dose (p = 0.001), lower dose per implant (p = 0.001), and greater percentage of positive post-RT biopsy cores (p = 0.01) were each associated with biochemical failure (Cox regression, univariate analysis). For patients with <25% positive post-RT biopsy cores, the 7-year biochemical control rate was 81% vs. a 62% biochemical control rate for those with 25-49% positive cores and only 32% for those with > or =50% positive cores (p = 0.01). On Cox multiple regression analysis, only the percentage of positive pre-RT biopsy cores and RT dose remained significantly associated with biochemical failure. Of all the factors analyzed, only the pretreatment cancer volume and lower RT dose were significantly associated with residual cancer and/or residual cancer with no or minimal RT damage. A greater percentage of positive pre-RT biopsy cores was associated with both a positive post-RT biopsy (p = 0.08) and a greater percentage of positive post-RT biopsy cores (p = 0.04). A lower total RT dose was associated with both a positive post-RT biopsy (p = 0.08) and a greater percentage of positive post-RT biopsy cores (p = 0.02). For patients who received <80 Gy (equivalent in 2-Gy fractions), 73% had positive post-RT biopsies vs. a 56% biopsy positivity rate for those who received 84-90 Gy and only 39% for those who received > or =92 Gy (p = 0.07)., Conclusion: Patients with positive post-RT biopsies are more likely to experience biochemical failure, especially when the RT damage is minimal. Patients who have a larger pretreatment tumor volume or receive a lower RT dose are more likely to demonstrate post-RT biopsy positivity and biochemical failure.

Purpose: Geometric uncertainties in the process of radiation planning and delivery constrain dose escalation and induce normal tissue complications. An imaging system has been developed to generate high-resolution, soft-tissue images of the patient at the time of treatment for the purpose of guiding therapy and reducing such uncertainties. The performance of the imaging system is evaluated and the application to image-guided radiation therapy is discussed., Methods and Materials: A kilovoltage imaging system capable of radiography, fluoroscopy, and cone-beam computed tomography (CT) has been integrated with a medical linear accelerator. Kilovoltage X-rays are generated by a conventional X-ray tube mounted on a retractable arm at 90 degrees to the treatment source. A 41 x 41 cm(2) flat-panel X-ray detector is mounted opposite the kV tube. The entire imaging system operates under computer control, with a single application providing calibration, image acquisition, processing, and cone-beam CT reconstruction. Cone-beam CT imaging involves acquiring multiple kV radiographs as the gantry rotates through 360 degrees of rotation. A filtered back-projection algorithm is employed to reconstruct the volumetric images. Geometric nonidealities in the rotation of the gantry system are measured and corrected during reconstruction. Qualitative evaluation of imaging performance is performed using an anthropomorphic head phantom and a coronal contrast phantom. The influence of geometric nonidealities is examined., Results: Images of the head phantom were acquired and illustrate the submillimeter spatial resolution that is achieved with the cone-beam approach. High-resolution sagittal and coronal views demonstrate nearly isotropic spatial resolution. Flex corrections on the order of 0.2 cm were required to compensate gravity-induced flex in the support arms of the source and detector, as well as slight axial movements of the entire gantry structure. Images reconstructed without flex correction suffered from loss of detail, misregistration, and streak artifacts. Reconstructions of the contrast phantom demonstrate the soft-tissue imaging capability of the system. A contrast of 47 Hounsfield units was easily detected in a 0.1-cm-thick reconstruction for an imaging exposure of 1.2 R (in-air, in absence of phantom). The comparison with a conventional CT scan of the phantom further demonstrates the spatial resolution advantages of the cone-beam CT approach., Conclusions: A kV cone-beam CT imaging system based on a large-area, flat-panel detector has been successfully adapted to a medical linear accelerator. The system is capable of producing images of soft tissue with excellent spatial resolution at acceptable imaging doses. Integration of this technology with the medical accelerator will result in an ideal platform for high-precision, image-guided radiation therapy.

Purpose: The posttreatment prostate-specific antigen (PSA) profile can often be difficult to interpret after external beam radiotherapy for prostate cancer. We performed an extensive analysis of post-radiotherapy PSA measurements to determine the clinical significance of biochemical failure (BF) and the correlation of BF with clinical failure (CF) and cause-specific death (CSD)., Materials and Methods: Between 1987 and 1997, 727 patients with clinical stage T1-T3 N0 M0 prostate cancer were treated with definitive external beam radiotherapy at William Beaumont Hospital and had at least five post-radiotherapy PSA levels and did not receive hormonal therapy for post-radiotherapy PSA elevations only (before evidence of CF). All patients received external beam radiotherapy alone (no adjuvant hormonal therapy) to a median total prostate dose of 66.6 Gy. More than 20 BF definitions were tested for their correlation with CF (any local failure or distant metastasis) and CSD. All BF definitions were tested for sensitivity, specificity, accuracy, and positive and negative value of predicting subsequent CF and CSD. The median follow-up was 5.0 years., Results: Three consecutive PSA rises yielded a 73% sensitivity, 76% specificity, and 75% overall accuracy for predicting CF. The 10-year CF rate (from the completion of radiotherapy) for those 251 patients demonstrating three consecutive rises (BF) was 64% vs. 14% for those patients who did not have three rises (biochemically controlled). Defining BF as a post-nadir increase to >or=3 ng/ml above the nadir yielded the highest accuracy of 87%. In addition, this definition also seemed to provide the greatest separation in CF rates: 82% for BF vs. 5% for biochemically controlled at 10 years after radiotherapy. CF rates were also calculated from the date of BF (e.g., date of third rise). The CF rates at 6 months and 2 years after the third PSA rise were 9% and 27%, respectively. The CF rates at 6 months and 2 years after an increase to >or=3 ng/ml above the nadir were 23% and 54%, respectively. Once a patient was classified as a BF, regardless of the BF definition, the CF rate varied markedly, depending on the pretreatment characteristics. For each BF definition, younger age at diagnosis, higher pretreatment PSA, and higher Gleason score independently predicted for CF after BF on Cox multiple regression analysis. For instance, patients with a pretreatment PSA <4.0 ng/ml demonstrated an 11% CF rate at 2 years after the third PSA rise vs. 46% after three rises with a pretreatment PSA >or=20.0 ng/ml. Similarly, patients with Gleason 2-4 had a 2-year CF rate of only 3% after a nadir >or=1.0 ng/ml vs. 47% for Gleason 8-10 at 2 years after a nadir >or=1.0 ng/ml. Although the CF rate also coincided with pretreatment characteristics when using >or=3 ng/ml above the nadir, CF rates remained high even for low-risk patients (e.g., 2-year CF of 48% for PSA <10.0 ng/ml, 41% for Gleason 2-4). In addition, a shorter time interval from nadir to nadir + 1 ng/ml or from nadir to nadir + 3 ng/ml (corresponding to a steeper slope in the PSA profile) independently predicted for CF., Conclusion: Once the post-radiotherapy PSA profile reaches >or=3 ng/ml above the nadir, there is a high risk of clinical failure within a relatively short time period, for which treatment intervention may be considered, regardless of pretreatment characteristics. After a nadir >or=1.0 ng/ml or three consecutive rises, some patients (especially with low-risk pretreatment characteristics) may be considered for further PSA observation before treatment intervention.

Purpose: To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed., Methods and Materials: Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure., Results: The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%., Conclusion: Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Purpose: To demonstrate a new interactive Internet-ready database for prospective clinical trials in high-dose-rate (HDR) brachytherapy for prostate cancer., Methods and Materials: An Internet-ready database was created that allows common data acquisition and statistical analysis. Patient anonymity and confidentiality are preserved. These data forms include all common elements found from a survey of the databases. The forms allow the user to view patient data in a view-only or edit mode. Eight linked forms document patient data before and after receiving HDR therapy. The pretreatment forms are divided into four categories: staging, comorbid diseases, external beam radiotherapy data, and signs and symptoms. The posttreatment forms separate data by HDR implant information, HDR medications, posttreatment signs and symptoms, and follow-up data. The forms were tested for clinical usefulness., Conclusion: This Internet-based database enables the user to record and later analyze all relevant medical data and may become a reliable instrument for the follow-up of patients and evaluation of treatment results.

Purpose: A new device has been developed with the goal of making breast-conserving therapy more widely available, by making breast brachytherapy as monotherapy simpler and more accurate. This is the first published report on the dosimetric characteristics of this device., Materials and Methods: The experience of a single institution participating in a multi-institutional trial is reported. Twelve patients were enrolled, of whom 8 were treated. Computed tomography scans of all 12 patients were obtained before initiation of treatment. A commercial three-dimensional planning system was used for retrospective detailed analysis of dosimetry, including dose-volume histograms and, in selected patients, skin dose distributions. These data were compared to those of a similar group of patients, analyzed previously, that was treated with interstitial high-dose-rate brachytherapy., Results: Compared with interstitial brachytherapy, the MammoSite device resulted in a treatment dose that was less uniform, with a mean dose homogeneity index of 0.77 vs. 0.93. Coverage and reproducibility were improved, with a mean D90 (minimum dose to 90% of target volume) of 90.0% of prescribed dose (SD 0.5, range: 89.2-90.8%) vs. 69.8% (SD 7.3, range: 61.1-83.5%) for interstitial brachytherapy., Conclusions: Reproducible placement was easily achieved in this very early experience, indicating a much smaller "learning curve" than for interstitial brachytherapy. Because skin doses can be increased with the use of this device, caution is indicated, although simple maneuvers can significantly reduce skin dose.

Purpose: A direct relationship between the volume of small bowel irradiated and the degree of acute small bowel toxicity experienced during concurrent 5-fluorouracil (5-FU)-based chemoradiotherapy for rectal carcinoma is well recognized but poorly quantified. This study uses three-dimensional treatment-planning tools to more precisely quantify this dose-volume relationship., Methods and Materials: Forty patients receiving concurrent 5-FU-based chemotherapy and pelvic irradiation for rectal carcinoma had treatment-planning CT scans with small bowel contrast. A median isocentric dose of 50.4 Gy was delivered using a posterior-anterior and opposed lateral field arrangement. Bowel exclusion techniques were routinely used, including prone treatment position on a vacuum bag cradle to allow anterior displacement of the abdominal contents and bladder distension. Individual loops of small bowel were contoured on each slice of the planning CT scan, and a small bowel dose-volume histogram was generated for the initial pelvis field receiving 45 Gy. The volume of small bowel receiving each dose between 5 and 40 Gy was recorded at 5-Gy intervals., Results: Ten patients (25%) experienced Common Toxicity Criteria Grade 3+ acute small bowel toxicity. A highly statistically significant association between the development of Grade 3+ acute small bowel toxicity and the volume of small bowel irradiated was found at each dose level. Specific dose-volume threshold levels were found, below which no Grade 3+ toxicity occurred and above which 50-60% of patients developed Grade 3+ toxicity. The volume of small bowel receiving at least 15 Gy (V15) was strongly associated with the degree of toxicity. Univariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicity., Conclusions: A strong dose-volume relationship exists for the development of Grade 3+ acute small bowel toxicity in patients receiving concurrent 5-FU-based chemoradiotherapy for rectal carcinoma.

Purpose: A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low alpha/beta ratio), more typical of the surrounding late-responding normal tissue., Methods and Materials: Earlier estimates of alpha/beta for prostate cancer have relied on comparing results from external beam radiotherapy (EBRT) and brachytherapy, an approach with significant pitfalls due to the many differences between the treatments. To circumvent this, we analyze recent data from a single EBRT + high-dose-rate (HDR) brachytherapy protocol, in which the brachytherapy was given in either 2 or 3 implants, and at various doses. For the analysis, standard models of tumor cure based on Poisson statistics were used in conjunction with the linear-quadratic formalism. Biochemical control at 3 years was the clinical endpoint. Patients were matched between the 3 HDR vs. 2 HDR implants by clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, length of follow-up, and age., Results: The estimated value of alpha/beta from the current analysis of 1.2 Gy (95% CI: 0.03, 4.1 Gy) is consistent with previous estimates for prostate tumor control. This alpha/beta value is considerably less than typical values for tumors (> or =8 Gy), and more comparable to values in surrounding late-responding normal tissues., Conclusions: This analysis provides strong supporting evidence that alpha/beta values for prostate tumor control are atypically low, as indicated by previous analyses and radiobiological considerations. If true, hypofractionation or HDR regimens for prostate radiotherapy (with appropriate doses) should produce tumor control and late sequelae that are at least as good or even better than currently achieved, with the added possibility that early sequelae may be reduced.