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Background: Setup reproducibility of the tissue in the proton beam path is critical in maintaining the planned clinical target volume (CTV) dose coverage and sparing the organs at risk (OAR). In this study, we retrospectively evaluated radiation therapy dose reproducibility for proton pencil beam scanning (PBS) treatment of breast cancer patients with and without mask immobilization. Methods: Ninety-four patients treated between January 2019 and September 2022 with at least one verification CT scan (V-CT) in treatment position were included for this study. All patients were set up with arms up using the Orfit AIO patient positioning system, with (69 patients) or without (25 patients) mask immobilization in chin, neck, shoulder, upper arm, and chest areas. Two to three enface or near enface single field uniform dose PBS beams were optimized using a commercial treatment planning system. Prescription doses were 25 to 60 GyRBE in 5 to 45 fractions. Treatment plan doses re-calculated on V-CTs were compared to the corresponding planned doses. Cumulative doses were also calculated for patients with at least 3 V-CTs by deform and weighted sum doses from V-CTs to corresponding P-CTs. CTV D95%, ipsilateral-lung V40%, esophagus D0.01cc, and heart mean dose were evaluated and reported as percentages of prescription doses. Differences were large dose deteriorations (LDD) if: (1) CTV (V-CT/cumulative D95%) – (Planned D95%) < − 5%; or (2) Ipsilateral-lung (V-CT/cumulative V40%) – (Planned V40%) > 5%; or (3) Esophagus (V-CT/cumulative D0.01cc) – (Planned D0.01cc) > 10%; or (4) Heart (V-CT/cumulative mean) – (Planned mean) > 1.5%. Results: On average, V-CT/cumulative and planned CTV/OAR dose parameter differences were less than 2.2%/1.7% and 3.4%/3.7% for masked and maskless patients, respectively. The percentages of patients with at least one CTV or OAR V-CT/cumulative dose LDD were 20.3%/25.0% and 72.0%/54.0% for masked and maskless patients, respectively. Conclusions: On average, masked/maskless setups achieved delivered and planned CTV/OAR dose parameters agreed within 2.2%/3.7% for PBS treatment of breast cancer patients in this study. Maskless patients had higher rate of CTV/OAR LDDs compared to masked patients. Dosimetric differences large enough to raise clinical concerns in either group were able to be addressed with replannings. [ABSTRACT FROM AUTHOR]

Simple Summary: While the definition of the prostate bed clinical target volume (CTV) has been proposed in consensus guidelines, various PTV expansions have been proposed. Depending on the institution, isotropic or non-isotropic expansions on the prostate bed CTV may be considered. This is a preliminary study evaluating PTV margin reduction accounting for inter-fractional uncertainties using high quality iCBCT image guidance. This analysis revealed that 2 mm and 4 mm margins may be considered for margin expansion with and without an endorectal balloon. Purpose: Planning target volume (PTV) expansion for post-prostatectomy radiotherapy is typically ≥5 mm. Recent clinical trials have proved the feasibility of a reduced margin of 2–3 mm for treatments on MRI-linac. We aim to study the minimum PTV margin needed using iterative cone-beam CT (iCBCT) as image guidance on conventional linacs. Materials/Methods: Fourteen patients who received post-prostatectomy irradiation (8 with an endorectal balloon and 6 without a balloon) were included in this study. Treatment was delivered with volumetric modulated radiation therapy (VMAT). Fractional dose delivery was evaluated in 165 treatment fractions. The bladder, rectal wall, femoral heads, and prostate bed clinical tumor volume (CTV) were contoured and verified on daily iCBCT. PTV margins (0 mm, 2 mm, and 4 mm) were evaluated on daily iCBCT. CTV coverage and OAR dose parameters were assessed with each PTV margin. Results: CTV D100% was underdosed with a 0 mm margin in 32% of fractions in comparison with 2 mm (6%) and 4 mm (6%) PTV margin (p ≤ 0.001). CTV D95% > 95% was met in 93–94% fractions for all PTV expansions. CTV D95% > 95% was achieved in more patients with an endorectal balloon than those without: 0 mm—90/91 (99%) vs. 63/74 (85%); 2 mm—90/91 (99%) vs. 65/75 (87%); 4 mm—90/90 (100%) vs. 63/73 (86%). There was no difference in absolute median change in CTV D95% (0.32%) for 0-, 2-, and 4 mm margins. The maximum dose remained under 108% for 100% (0 mm), 97% (2 mm), and 98% (4 mm) of images. Rectal wall maximum dose remained under 108% for 100% (0 mm), 100% (2 mm), and 98% (4 mm) of images. Conclusions: With high-quality iCBCT image guidance, PTV margin accounting for inter-fractional uncertainties can be safely reduced for post-prostatectomy radiotherapy. For fractionated radiotherapy, an isotropic expansion of 2 mm and 4 mm may be considered for margin expansion with and without the endorectal balloon. Future application for margin reduction needs to be further evaluated and considered with the advent of shorter post-prostatectomy radiation courses. [ABSTRACT FROM AUTHOR]

Purpose: To identify factors predictive for chronic urinary toxicity secondary to high-dose adaptive three-dimensional conformal radiation. Methods and Materials: From 1999 to 2002, 331 consecutive patients with clinical Stage II–III prostate cancer were prospectively treated (median dose, 75.6 Gy). The bladder was contoured, and the bladder wall was defined as the outer 3 mm of the bladder solid volume. Toxicity was quantified according to the National Cancer Institute Common Toxicity Criteria 2.0. Median follow-up was 1.6 years. Results: The 3-year rates of Grade ≥2 and Grade 3 chronic urinary toxicity were 17.0% and 3.6%, respectively. Prostate volume, confidence-limited patient-specific planning target volume, bladder wall volume, and acute urinary toxicity were all found to be accurate predictors for chronic urinary toxicity. The volume of bladder wall receiving ≥30 Gy (V30) and ≥82 Gy (V82), along with prostate volume, were all clinically useful predictors of Grade ≥2 and Grade 3 chronic urinary toxicity and chronic urinary retention. Both Grade ≥2 (p = 0.001) and Grade 3 (p = 0.03) acute urinary toxicity were predictive for the development of Grade ≥2 (p = 0.001, p = 0.03) and Grade 3 (p = 0.05, p < 0.001) chronic urinary toxicity. On Cox multivariate analysis the development of acute toxicity was independently predictive for the development of both Grade ≥2 and Grade 3 chronic urinary toxicity. Conclusions: Acute urinary toxicity and bladder wall dose–volume endpoints are strong predictors for the development of subsequent chronic urinary toxicity. Our recommendation is to attempt to limit the bladder wall V30 to <30 cm3 and the V82 to <7 cm3 when possible. If bladder wall information is not available, bladder solid V30 and V82 may be used. [Copyright &y& Elsevier]

Purpose: To describe dose–volume values with the use of water alone vs. a rectal balloon (RB) for the treatment of prostate cancer with proton therapy. Materials and Methods: We analyzed 30 proton plans for 15 patients who underwent CT and MRI scans with an RB or water alone. Simulation was performed with a modified MRI endorectal coil and an RB with 100 mL of water or water alone. Doses of 78–82 gray equivalents were prescribed to the planning target volume. The two groups were compared for three structures: rectum, rectal wall (RW), and rectal wall 7 cm (RW7) at the level of the planning target volume. Results: Rectum and RW volumes radiated to low, intermediate, and high doses were small: rectum V10, 33.7%; V50, 17.3%; and V70, 10.2%; RW V10, 32.4%; V50, 20.4%; and V70, 14.6%. The RB effectively increased the rectal volume for all cases (139.8 ± 44.9 mL vs. 217.7 ± 32.2 mL (p < 0.001). The RB also decreased the volume of the rectum radiated to doses V10–V65 (p ≤ 0.05); RW for V10–V50; and RW7 for V10–V35. An absolute rectum V50 improvement >5% was seen for the RB in 5 of 15 cases, for a benefit of 9.2% ± 2.3% compared with 2.4% ± 1.3% for the remaining 10 cases (p < 0.001). Similar benefit was seen for the rectal wall. No benefit was seen for doses ≥70 gray equivalents for the rectum, RW, or RW7. No benefit of ≤1% was seen with an RB in 46% for the rectum V70 and in 40% for the rectal wall V70. Conclusions: Rectum and rectal wall doses with proton radiation were low whether using water or an RB. Selected patients will have a small but significant advantage with an RB; however, water alone was well tolerated and will be an alternative for most patients. [Copyright &y& Elsevier]

Abstract: Purpose. : Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. Age has been associated with worse outcome in univariate analysis. However, the patterns of failure and associated risk factors in older patients remain unclear. We reviewed our institution''s experience to assess the effect of age in a population of endometrial cancer patients treated with surgery and adjuvant radiation therapy. Methods. : From 1992–2002, 243 endometrial cancer patients underwent a total abdominal hysterectomy and adjuvant radiation. Forty-nine patients with stage I–II (occult) endometrial adenocarcinoma (no clear cell or serous papillary) were treated postoperatively with vaginal intracavitary high-dose rate (HDR) brachytherapy alone using Iridium-192 (median dose 30 Gy) to a median length of 4 cm. Forty-eight patients with stage I–III endometrial adenocarcinoma (no clear cell or papillary serous) were treated with postoperative pelvic RT (median dose 45 Gy) and intracavitary HDR brachytherapy (median dose 20 Gy). One hundred forty-six patients underwent postoperative whole abdomino-pelvic irradiation (WAPI) secondary to unfavorable histology (clear cell or serous papillary) or two of the following: deep myometrial invasion, grade 3, or FIGO stage III. Age was analyzed as a continuous and a categorical variable. The age of 63 year split the age group using various statistical analyses. Results. : Median follow-up of all patients was 4.2 years. Patients grouped by age of ≤63 years or older had similar FIGO stage (P = 0.5), grade (P = 0.09), treatment modality (P = 0.7), and lymphovascular space invasion (LVSI) (P = 0.6). Twenty-five percent (60/243) of patients developed recurrence. Of these failures, 15% (15/102) were age ≤63 years and 32% (45/141) were age >63 years at diagnosis (P = 0.02). For all patients, the 5-year event-free survival (EFS), cause specific survival (CSS), and overall survival (OS) were 64%, 82%, and 72%, respectively. Five-year EFS for patients age ≤63 years and >63 years was 76% vs. 55% (P < 0.001). Five-year OS for age ≤63 years and >63 years was 85% vs. 63% (P < 0.001). Five-year CSS for age ≤63 years and >63 years was 91% vs. 75% (P = 0.003). Various factors were analyzed to determine an association with age. Older patients with stage III–IVA had significantly more failures than patients less than age 63 (P = 0.002). Older patients (>63 years) were found to have serous papillary histology (28%) more often than younger patients (15%) (P = 0.02). Greater depth of invasion was associated with older age (P = 0.01). On univariate analysis, older age (P = 0.003), LVSI (P = 0.002), FIGO stage (P < 0.001), grade (P < 0.001), and depth of invasion (P = 0.03) predicted for failure. On Cox multivariate analysis, older age (P = 0.006, HR 2.83), higher FIGO stage (P = 0.001, HR 1.96), and higher grade (P = 0.002, HR 2.66) were significant prognostic factors for recurrence. No difference was seen between the two age groups from date of surgery and start of radiation. The duration of therapy was not different between the two groups. Conclusions. : Older endometrial cancer (age >63 years) patients have a significantly decreased overall survival, cause-specific survival, and greater risk of recurrence following postoperative RT independent of other prognostic factors and/or treatment technique. The impact of treatment-related variables did not alter the age-related outcome. [Copyright &y& Elsevier]

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 ≥7, or clinical stage ≥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 (α/β = 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. [Copyright &y& Elsevier]

Purpose: We reviewed our institution’s experience treating patients with ductal carcinoma in situ (DCIS) of the breast to determine risk factors for ipsilateral breast tumor recurrence (IBTR) and cause-specific survival (CSS) after breast-conserving therapy (BCT) or mastectomy. Materials and Methods: Between 1981 and 1999, 410 cases of DCIS (405 patients) were treated at our institution; 367 were managed with breast-conserving surgery (54 with lumpectomy alone and 313 with adjuvant radiation therapy (RT) [median dose, 45 Gy]). Of these 313 patients, 298 received also a supplemental boost of RT to the lumpectomy cavity (median dose, 16 Gy). Forty-three patients underwent mastectomy; 2 (5%) received adjuvant RT to the chest wall. A true recurrence/marginal miss (TR/MM) IBTR was defined as failure within or adjacent to the tumor bed in patients undergoing BCT. Median follow-up for all patients was 7 years (mean: 6.1 years). Results: Thirty patients (8.2%) experienced an IBTR after BCT (25 [8%] after RT, 5 [9.3%] after no RT), and 2 patients (4.7%) developed a chest wall recurrence after mastectomy. Of the 32 local failures, 20 (63%) were invasive (18/30 [60%] after BCT and 2/2 [100%] after mastectomy), and 37% were DCIS alone. Twenty-four (80%) of the IBTRs were classified as TR/MM. The 10-year freedom from local failure, CSS, and overall survival after BCT or mastectomy were 89% vs. 90% (p = 0.4), 98% vs. 100% (p = 0.7), and 89% vs. 100% (p = 0.3), respectively. Factors associated with IBTR on Cox multivariate analysis were younger age (p = 0.02, hazard ratio [HR] 1.06 per year), electron boost energy ≤9 MeV (p = 0.03, HR 1.41), final margins ≤2 mm (p = 0.007; HR, 3.65), and no breast radiation (p = 0.002, HR 5.56). On Cox univariate analysis for BCT patients, IBTR, TR/MM failures, and predominant nuclear Grade 3 were associated with an increased risk of distant metastases and a reduced CSS. Conclusions: After treatment for DCIS, 10-year rates of local control, CSS, and overall survival were similar after mastectomy and BCT. Young age (<45 years), close/positive margins (≤2 mm), no breast radiation, and lower electron boost energies (≤9 MeV) were associated with IBTR. Local failure and predominant nuclear Grade 3 were found to have a small (4%–12%) but statistically significantly negative impact on the rates of distant metastasis and CSS. These results suggest that optimizing local therapy (surgery and radiation) is crucial to improve local control and CSS in patients treated with DCIS. [Copyright &y& Elsevier]

Purpose: The use of pelvic radiation for patients with a high risk of lymph node (LN) metastasis (>15%) remains controversial. We reviewed the data at three institutions treating patients with a combination of external-beam radiation therapy and high-dose-rate brachytherapy to address the prognostic implications of the use of the Roach formula and the benefit of pelvic treatment. Methods and Materials: From 1986 to 2003, 1,491 patients were treated with external-beam radiation therapy and high-dose-rate brachytherapy. The Roach formula [2/3 prostate-specific antigen + (Gleason score −6) × 10] could be calculated for 1,357 patients. Group I consisted of patients having a risk of positive LN ≤15% (n = 761), Group II had a risk >15% and ≤30% (n = 422), and Group III had a risk of LN disease >30% (n = 174). A >15% risk of having positive LN was found in 596 patients and was used to determine the benefit of pelvic radiation. The pelvis was treated at two of the cancer centers (n = 312), whereas at the third center (n = 284) radiation therapy was delivered to the prostate and seminal vesicles alone. Average biologic effective dose was ≥100 Gy (αβ = 1.2). Biochemical failure was as per the American Society for Therapeutic Radiology and Oncology definition. Statistics included the log–rank test as well as Cox univariate and multivariate analysis. Results: For all 596 patients with a positive LN risk >15%, median follow-up was 4.3 years, with a mean of 4.8 years. For all cases, median follow-up was 4 years and mean follow-up was 4.4 years. Five-year results for the three groups based on their risk of positive LN were significantly different in terms of biochemical failure (p < 0.001), clinical control (p < 0.001), disease-free survival excluding biochemical failure (p < 0.001), cause-specific survival (p < 0.001), and overall survival (p < 0.001). For all patients with a risk of positive LN >15% (n = 596), Group II (>15–30% risk), or Group III (>30% risk), no benefit was seen in the 5-year rates of clinical failure, cause-specific survival, or overall survival with pelvic radiation. In the Cox multivariate analysis for cause-specific survival, Gleason score (p = 0.009, hazard ratio [HR] 3.1), T stage (p = 0.03, HR 1.8), and year of treatment (p = 0.05, HR 1.1) were significant. A log–rank test for cause-specific survival for all patients (n = 577) by the use of pelvic radiation was not significant (p = 0.99) accounting for high-dose-rate brachytherapy dose, neoadjuvant hormones, Gleason score, prostate-specific antigen, T stage, and year of treatment as covariates. Conclusions: The use of the Roach formula to stratify patients for clinical and biochemical outcomes is excellent. Pelvic radiation added to high prostate radiation doses did not show a clinical benefit for patients at a high risk of pelvic LN disease (>15%) selected using the Roach formula. [Copyright &y& Elsevier]

The optimal treatment of patients with localized prostate cancer remains controversial. Significant clinical data are available, however, demonstrating that patients treated with radiation therapy (RT) have a significantly better outcome as the dose to the gland is increased. What remains debatable, however, is how to best deliver these higher doses of RT without significantly increasing normal tissue toxicities. Conformal high dose rate brachytherapy (C-HDR BT) represents an alternative means of precise dose delivery that offers similar tumoricidal effects as three-dimensional (3D) conformal external beam radiotherapy (EBRT) or permanent interstitial prostate seed implants with potential additional advantages. Since C-HDR BT consists of temporarily placing afterloading needles or catheters directly into the prostate gland under real-time ultrasound guidance, a steep dose gradient between the prostate and adjacent normal tissues can be generated that is minimally affected by organ motion and edema or treatment setup uncertainties. The ability to control the amount of time the single HDR radioactive source "dwells" at each position along the length of each brachytherapy catheter further enhances the conformity of the dose. In addition, recent radiobiological data on prostate cancer treatment suggest that C-HDR BT should produce tumor control and late normal tissue side effects that are at least as good as achieved with conventional fractionation, with the additional possibility that acute side effects might be reduced. Published data from several groups performing C-HDR BT as boosts in patients with locally advanced disease have supported these assumptions. Combined with the physical advantages discussed above, C-HDR BT should provide similar tumor control as 3D conformal EBRT with the added advantages of reduced treatment times, less acute toxicity, and no additional technological requirements to account and correct for treatment setup uncertainties and organ motion. Due to the success of C-HDR BT as boost treatment in locally advanced disease, this form of radiation treatment has recently been applied to low-risk prostate cancer patients as an alternative brachytherapy technique to permanent interstitial seed implantation. Advantages in this setting include an improved ability to define and deliver the prescribed dose, a significantly shortened treatment schedule compared to 3D conformal EBRT, and the fact that patients are not radioactive after implantation. [ABSTRACT FROM AUTHOR]

This study aimed to predict the probability of grade ≥2 pneumonitis or dyspnea within 12 months of receiving conventionally fractionated or mildly hypofractionated proton beam therapy for locally advanced lung cancer using machine learning. Demographic and treatment characteristics were analyzed for 965 consecutive patients treated for lung cancer with conventionally fractionated or mildly hypofractionated (2.2-3 Gy/fraction) proton beam therapy across 12 institutions. Three machine learning models (gradient boosting, additive tree, and logistic regression with lasso regularization) were implemented to predict Common Terminology Criteria for Adverse Events version 4 grade ≥2 pulmonary toxicities using double 10-fold cross-validation for parameter hyper-tuning without leak of information. Balanced accuracy and area under the curve were calculated, and 95% confidence intervals were obtained using bootstrap sampling. The median age of the patients was 70 years (range, 20-97), and they had predominantly stage IIIA or IIIB disease. They received a median dose of 60 Gy in 2 Gy/fraction, and 46.4% received concurrent chemotherapy. In total, 250 (25.9%) had grade ≥2 pulmonary toxicity. The probability of pulmonary toxicity was 0.08 for patients treated with pencil beam scanning and 0.34 for those treated with other techniques (P = 8.97e-13). Use of abdominal compression and breath hold were highly significant predictors of less toxicity (P = 2.88e-08). Higher total radiation delivered dose (P =.0182) and higher average dose to the ipsilateral lung (P =.0035) increased the likelihood of pulmonary toxicities. The gradient boosting model performed the best of the models tested, and when demographic and dosimetric features were combined, the area under the curve and balanced accuracy were 0.75 ± 0.02 and 0.67 ± 0.02, respectively. After analyzing performance versus the number of data points used for training, we observed that accuracy was limited by the number of observations. In the largest analysis of prospectively enrolled patients with lung cancer assessing pulmonary toxicities from proton therapy to date, advanced machine learning methods revealed that pencil beam scanning, abdominal compression, and lower normal lung doses can lead to significantly lower probability of developing grade ≥2 pneumonitis or dyspnea. [ABSTRACT FROM AUTHOR]

Objectives In non-small cell lung cancer (NSCLC), the association between common EGFR mutations (Del EX19/L858R) with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been well established. However, this has not been investigated for rare EGFR mutations or their impact on treatment response and outcome to EGFR TKIs (primary objective) and chemotherapy (secondary objective). Materials and methods In an observational prospective cohort, we analyzed 188 NSCLC patients from Mexico, Colombia and Costa Rica with EGFR mutations. As a first line of treatment, 66.5% received platinum-based chemotherapy. All patients received TKIs in first-line treatment or after progression to chemotherapy. The clinical–pathological characteristics as well as the f of common and rare EGFR mutations associated with treatment response were analyzed. Results Of all patients, 79.5% had common and 20.5% had rare EGFR mutations. Lepidic and acinar adenocarcinomas were associated with common EGFR mutations ( p = 0.010). Patients with common EGFR mutations had higher response rates to EGFR-TKIs than those who had rare EGFR mutations (63.8 vs 32.4%, p < 0.001). Women had increased progression-free survival (PFS) to EGFR-TKIs than men (16.4 vs 9.5 months, p = 0.02). The median PFS and overall survival (OS) were better in patients with common EGFR mutations (15.5 vs 3.9 months, p < 0.001; and 37.3 vs 17.4 months, p < 0.001) respectively. Conclusion Our findings suggested that only patients with rare EGFR mutations could receive platinum-based chemotherapy as a first-line treatment, due to their low response rates and short PFS in response to EGFR-TKIs. Consequently, EGFR-TKIs could be reserved as a second- or third-line treatment. In patients with EGFR mutations, women have better PFS to EGFR-TKIs than men, and rare EGFR mutations are more frequent in high grade adenocarcinomas than in low grade tumors. [ABSTRACT FROM AUTHOR]

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 ≥2 mm, 19% ≥4 mm, and 6% ≥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 ≥10 or biopsy Gleason score ≥7, 21% had ECE ≥2 mm and 5% ≥4 mm beyond the capsule. For patients with both of these risk factors, 49% had ECE ≥2 mm and 21% ≥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 ≥10 ng/ml and biopsy Gleason score ≥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. [Copyright &y& Elsevier]

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 ≤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 α /β of 1.2. Patient eligibility criteria included a pretreatment prostate-specific antigen ≥10, Gleason score ≥7, or clinical stage ≥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 × 3 to 15 Gy × 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 ≤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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]