Definitive chemoradiation or radiation therapy alone for the management of vulvar cancer.

Vulvar cancer is rare, and unresectable disease provides a therapeutic conundrum. Although definitive surgery remains the mainstay for curative treatment of vulvar cancer, a minority of patients present with advanced disease for which surgical resection would be extraordinarily morbid. Pre-operative and definitive radiation with radiosensitizing systemic therapy allows such patients an opportunity for cure. In this review, we explore the origins of pre-operative radiation, current treatment standards for pre-operative and definitive chemoradiation, and future directions.

Dose-escalated intensity modulated radiation therapy in patients with locally-advanced vulvar cancer - does it increase response rate?

PURPOSE: GOG 205 safely increased clinical (cCR) and pathologic complete response (pCR) in locally-advanced vulvar cancer through dose escalation using three-dimensional radiotherapy (RT). The aim of this study is to assess the response of dose-escalated intensity modulated radiotherapy (IMRT) in locally-advanced vulvar cancer. METHODS: A retrospective review of patients treated with dose-escalated (≥ 55Gy) IMRT from 2012 to 2018 for locally-advanced vulvar cancer was performed. Patients treated with preoperative or definitive intent were included. Rates of cCR and pCR were assessed, and predictors of disease-free survival (DFS) were analyzed using the Kaplan Meier method with log rank test between groups and a parsimonious multivariate Cox model. RESULTS: Median dose to the vulva was 66.0 Gy (Interquartile Range [IQR]: 66.0-68.0) for definitive and 59.4 Gy (IQR: 58.0-59.4) for preoperative IMRT. The overall rates of cCR and pCR were 76% and 70%, respectively. DFS at two years was 65% (95% Confidence Interval [CI] 50-80%) for all patients, 81% (95% CI 63% - 98%) for definitive IMRT, and 55% (95% CI 35% - 76%) for preoperative IMRT. On multivariate analysis, cCR predicted for disease-free survival (HR 0.21; 95% CI 0.06-0.76; p = 0.02), and pCR predicted for OS (HR 0.12; 95% CI 0.02-0.60; p = 0.01). Grade 3 acute and late RT toxicity was seen in 14 (29%) and 3 (6%) of patients, respectively. CONCLUSION: Dose-escalated IMRT for locally-advanced vulvar cancer is well tolerated, with rates of cCR and pCR that compare favorably with published data.

Outcomes after definitive re-irradiation with 3D brachytherapy with or without external beam radiation therapy for vaginal recurrence of endometrial cancer.

BACKGROUND: Limited outcome data exists on salvage re-irradiation for vaginal relapse of previously-irradiated endometrial cancer. We report our 10-year experience with management of vaginal recurrence using definitive intent re-irradiation brachytherapy with or without EBRT. METHODS: A retrospective review was performed on 22 patients treated with definitive-intent re-irradiation brachytherapy ±â€¯EBRT for vaginal recurrence of endometrial cancer. The cumulative rectosigmoid and bladder D2cc (EQD2) were limited to <75 Gy and <90 Gy, respectively. Kaplan-Meier and Cox proportional hazards modeling were used to estimate survival. Severe (grade 3 or higher) radiation-related toxicities, defined according to CTCAE v4, were recorded. RESULTS: Prior radiation therapy consisted of vaginal brachytherapy (54.5%), pelvic EBRT (22.7%), or combination pelvic EBRT and brachytherapy (22.7%). Median re-irradiation interval was 26.6 months. Salvage re-irradiation consisted of EBRT with brachytherapy in 50.0% and brachytherapy alone in 50.0%. Median HR-CTV D90 (EQD2) was 64.5 Gy (IQR: 49.6-75.8). Median cumulative D2cc for bladder, rectum, and sigmoid were 72.1 Gy (range: 30.3-81.8), 70.6 Gy (range: 32.0-80.5), and 52.7 Gy (range: 29.6-75.3), respectively. At a median follow-up of 27.6 months, 3-year local control, regional control, disease-free survival, and overall survival rates were 65.8%, 76.6%, 40.8%, and 68.1%, respectively. There were no grade ≥ 3 acute or late rectosigmoid or bladder toxicities. CONCLUSION: Re-irradiation with 3D conformal brachytherapy for vaginal recurrence is feasible and safe as long as cumulative dose to surrounding normal organs is limited, and offers a chance to potentially salvage 40% of patients presenting with vaginal recurrence in the setting of prior pelvic radiation.

Contrast-Enhanced Liver Magnetic Resonance Image Synthesis Using Gradient Regularized Multi-Modal Multi-Discrimination Sparse Attention Fusion GAN.

PURPOSES: To provide abdominal contrast-enhanced MR image synthesis, we developed an gradient regularized multi-modal multi-discrimination sparse attention fusion generative adversarial network (GRMM-GAN) to avoid repeated contrast injections to patients and facilitate adaptive monitoring. METHODS: With IRB approval, 165 abdominal MR studies from 61 liver cancer patients were retrospectively solicited from our institutional database. Each study included T2, T1 pre-contrast (T1pre), and T1 contrast-enhanced (T1ce) images. The GRMM-GAN synthesis pipeline consists of a sparse attention fusion network, an image gradient regularizer (GR), and a generative adversarial network with multi-discrimination. The studies were randomly divided into 115 for training, 20 for validation, and 30 for testing. The two pre-contrast MR modalities, T2 and T1pre images, were adopted as inputs in the training phase. The T1ce image at the portal venous phase was used as an output. The synthesized T1ce images were compared with the ground truth T1ce images. The evaluation metrics include peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), and mean squared error (MSE). A Turing test and experts' contours evaluated the image synthesis quality. RESULTS: The proposed GRMM-GAN model achieved a PSNR of 28.56, an SSIM of 0.869, and an MSE of 83.27. The proposed model showed statistically significant improvements in all metrics tested with p-values < 0.05 over the state-of-the-art model comparisons. The average Turing test score was 52.33%, which is close to random guessing, supporting the model's effectiveness for clinical application. In the tumor-specific region analysis, the average tumor contrast-to-noise ratio (CNR) of the synthesized MR images was not statistically significant from the real MR images. The average DICE from real vs. synthetic images was 0.90 compared to the inter-operator DICE of 0.91. CONCLUSION: We demonstrated the function of a novel multi-modal MR image synthesis neural network GRMM-GAN for T1ce MR synthesis based on pre-contrast T1 and T2 MR images. GRMM-GAN shows promise for avoiding repeated contrast injections during radiation therapy treatment.

Single projection driven real-time multi-contrast (SPIDERM) MR imaging using pre-learned spatial subspace and linear transformation.

Objective.To develop and test the feasibility of a novel Single ProjectIon DrivEn Real-time Multi-contrast (SPIDERM) MR imaging technique that can generate real-time 3D images on-the-fly with flexible contrast weightings and a low latency.Approach.In SPIDERM, a 'prep' scan is first performed, with sparse k-space sampling periodically interleaved with the central k-space line (navigator data), to learn a subject-specific model, incorporating a spatial subspace and a linear transformation between navigator data and subspace coordinates. A 'live' scan is then performed by repeatedly acquiring the central k-space line only to dynamically determine subspace coordinates. With the 'prep'-learned subspace and 'live' coordinates, real-time 3D images are generated on-the-fly with computationally efficient matrix multiplication. When implemented based on a multi-contrast pulse sequence, SPIDERM further allows for data-driven image contrast regeneration to convert real-time contrast-varying images into contrast-frozen images at user's discretion while maintaining motion states. Both digital phantom andin-vivoexperiments were performed to evaluate the technical feasibility of SPIDERM.Main results.The elapsed time from the input of the central k-space line to the generation of real-time contrast-frozen 3D images was approximately 45 ms, permitting a latency of 55 ms or less. Motion displacement measured from SPIDERM and reference images showed excellent correlation (R2≥0.983). Geometric variation from the ground truth in the digital phantom was acceptable as demonstrated by pancreas contour analysis (Dice ≥ 0.84, mean surface distance ≤ 0.95 mm). Quantitative image quality metrics showed good consistency between reference images and contrast-varying SPIDREM images inin-vivostudies (meanNMRSE=0.141,PSNR=30.12,SSIM=0.88).Significance.SPIDERM is capable of generating real-time multi-contrast 3D images with a low latency. An imaging framework based on SPIDERM has the potential to serve as a standalone package for MR-guided radiation therapy by offering adaptive simulation through a 'prep' scan and real-time image guidance through a 'live' scan.

Quality of Regional Nodal Irradiation Plans in Breast Cancer Patients Across a Large Network-Can We Translate Results From Randomized Trials Into the Clinic?

PURPOSE: Regional nodal irradiation (RNI) improved disease-free survival by 3% to 5% in 2 large randomized trials, but this small absolute advantage relies on accurate contouring and dose delivery. We audited our network to determine compliance on regional nodal coverage, contouring, and dosimetric parameters with respect to accepted guidelines. METHODS AND MATERIALS: In our network, we have established a clinical pathway for patients with node-positive breast cancer that guides indications for RNI and dosimetric goals. We reviewed records of 183 patients with nodal macrometastases after upfront surgery or involved nodes of any size after neoadjuvant chemotherapy. Radiation treatment plans were examined to determine lymph node volumes treated, whether nodes were contoured, quality of nodal contours, and whether target coverage and normal organ dosimetric constraints were met when RNI was delivered. RESULTS: Despite the presence of macrometastases on sentinel lymph node biopsy, no lymph nodes were treated in 2.2% (4 of 183). Of 179 patients who received nodal irradiation, 18 received radiation to axillary levels 1 and 2 only, and 161 patients received RNI. Overall, regional nodes were not treated despite strong indications in 7.6% (14 of 183). Treated nodes were not contoured for 2.2% (4 of 179), and lymph node contours were unacceptable in 15.4% (27 of 175). Of patients receiving RNI, 14.9% (24 of 161) did not have adequate nodal target volume coverage, mean heart dose was >4 Gy for 3.1% (5 of 161), and lung V20 Gy was >35% for 8.7% (14 of 161). CONCLUSIONS: Adherence to indications for regional nodal treatment was high, but nodes were either not contoured or had unacceptable contour quality in 18% of plans, and coverage was inadequate in 15%. Because the small disease-free survival advantage seen in trials may be decreased with these deviations, routine clinical practice requires detailed peer review to fully translate results of clinical trials.

Hypofractionated Prostate Radiation Therapy: Adoption and Dosimetric Adherence Through Clinical Pathways in an Integrated Oncology Network.

PURPOSE: Updates to consensus guidelines in October 2018 recommending moderately hypofractionated external beam radiotherapy (mHF-EBRT) in prostate cancer lagged several years after publication of evidence supporting its efficacy. In January 2018, we amended our prostate cancer clinical pathway (CP) to facilitate adoption of mHF-EBRT. Herein, we analyze patterns of care and changes in mHF-EBRT use after the CP modification. METHODS: Our prostate CP was amended in January 2018 to make mHF-EBRT the recommended treatment for patients with low- and intermediate-risk prostate cancer pursuing curative EBRT monotherapy. Normal-tissue dose constraints accompanied the CP modification to guide planning. Use of mHF-EBRT from 2015 to 2017 was compared with use in 2018 after the CP modification, using the Cochran-Armitage test for trend. Predictors of mHF-EBRT use and adherence to dose constraints were analyzed with binary logistic regression. RESULTS: In 560 patients treated with EBRT monotherapy, mHF-EBRT use increased from 3.7% in 2015-2017 to 85.6% in 2018 (P < .001), whereas conventionally fractionated EBRT (CF-EBRT) use decreased from 96.3% to 14.4% (P < .001). Consultation year of 2018 (odds ratio [OR], 214.6; 95% CI, 94.5 to 484.6; P < .001), treatment at an academic facility (OR, 4.5; 95% CI, 1.8 to 11.3; P = 0.001), and having a smaller prostate (OR, 0.99; 95% CI, 0.97 to 1.00; P = .028) predicted for mHF-EBRT use. At least five of six recommended bladder and rectal dose constraints were met in 89.4% of patients. CONCLUSION: Modification of our prostate cancer CP, in concert with institutional policies to monitor and audit CP compliance, facilitated rapid adoption of mHF-EBRT in our large, integrated cancer center with good adherence to dosimetric constraints.

Ureteral stenosis after 3D MRI-based brachytherapy for cervical cancer - Have we identified all the risk factors?

BACKGROUND AND PURPOSE: Ureteral stenosis (US) is a known complication from image-guided brachytherapy (IGBT); however, no dosimetric parameter has been associated with ureteral toxicity. We aimed to report the rate of late grade ≥3 US after MRI-based IGBT, and to identify clinical factors and dosimetric parameters predictive for US. MATERIALS AND METHODS: A retrospective review was performed on all cervical cancer patients treated with MRI-based IGBT between 2007 and 2017. Late grade ≥3 US was recorded according to CTCAE 4.03. The minimum dose to the maximally irradiated 0.1 cm3 of ureter (D0.1cm3) was extracted from dose-volume histograms. Binary logistic regression was performed to identify predictors of late grade ≥3 US. RESULTS: 242 patients with a median follow-up of 35.8 months (IQR, 19.2-60.8) were identified. Late grade ≥3 US occurred in 18 patients, and the actuarial 3-year rate was 7.3% (95% CI 3.3-11.3). After excluding patients with pre-existing hydronephrosis, late grade ≥3 US occurred in 11 patients with an actuarial 3-year rate of 4.4% (95% CI 1.7-7.1). Ureters with D0.1cm3 ≥77 Gy had a 28.6% incidence of late grade ≥3 US compared to 7.5% in those with D0.1cm3 <77 Gy (OR 2.39; 95% CI 1.23-4.65; p = 0.01). The incidence of late grade ≥3 US was 33.3%, and 40.0% for ureters receiving ≥85 and ≥90 Gy, to D0.1cm3, respectively. CONCLUSION: After MRI-based IGBT, there is an estimated 4.4% risk of developing late grade ≥3 US among patients without pre-existing hydronephrosis. Ureteral dose ≥77 Gy to D0.1cm3 correlates with development of late grade ≥3 US.

Initial Data Pooling for Radiation Dose-Volume Tolerance for Carotid Artery Blowout and Other Bleeding Events in Hypofractionated Head and Neck Retreatments.

PURPOSE: Dose-volume data for injury to carotid artery and other major vessels in stereotactic body radiation therapy (SBRT)/SABR head and neck reirradiation were reviewed, modeled, and summarized. METHODS AND MATERIALS: A PubMed search of the English-language literature (stereotactic and carotid and radiation) in April 2018 found 238 major vessel maximum point doses in 6 articles that were pooled for logistic modeling. Two subsequent studies with dose-volume major vessel data were modeled separately for comparison. Attempts were made to separate carotid blowout syndrome from other bleeding events (BE) in the analysis, but we acknowledge that all except 1 data set has some element of BE interspersed. RESULTS: Prior radiation therapy (RT) dose was not uniformly reported per patient in the studies included, but a course on the order of conventionally fractionated 70 Gy was considered for the purposes of the analysis (with an approximately ≥6-month estimated interval between prior and subsequent treatment in most cases). Factors likely associated with reduced risk of BE include nonconsecutive daily treatment, lower extent of circumferential tumor involvement around the vessel, and no surgical manipulation before or after SBRT. CONCLUSIONS: Initial data pooling for reirradiation involving the carotid artery resulted in 3 preliminary models compared in this Hypofractionated Treatment Effects in the Clinic (HyTEC) report. More recent experiences with alternating fractionation schedules and additional risk-reduction strategies are also presented. Complications data for the most critical structures such as spinal cord and carotid artery are so limited that they cannot be viewed as strong conclusions of probability of risk, but rather, as a general guideline for consideration. There is a great need for better reporting standards as noted in the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic introductory paper.

Regional Recurrence Rates With or Without Complete Axillary Dissection for Breast Cancer Patients with Node-Positive Disease on Sentinel Lymph Node Biopsy after Neoadjuvant Chemotherapy.

PURPOSE: Current standard of care for patients with breast cancer with a positive node on sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy is axillary dissection with irradiation of the regional nodes, but it is unknown whether axillary lymph node dissection (ALND) can be safely omitted if complete axillary radiation is delivered instead. METHODS AND MATERIALS: We identified 161 patients found to have a positive sentinel lymph node on SLNB after neoadjuvant chemotherapy for breast cancer between December 2006 and October 2017, who were treated with or without completion ALND. Local, regional, and distant recurrence and overall survival were analyzed using the Kaplan-Meier method. Patient, disease, and treatment factors potentially predictive of each outcome were entered into Cox regression analysis. RESULTS: Median follow-up was 28.8 months (range, 2.5-137.0). The 3-year regional control rate did not differ according to extent of axillary surgery (92.6% for SLNB alone vs 96.4% for SLNB with ALND, P = .616). Regional recurrence occurred as part of first recurrence in 9 patients (5.6%). Five patients failed in axillary levels 1 or 2, 6 failed in axillary level 3 or supraclavicular nodes, and 2 failed in internal mammary nodes, with some patients failing in multiple regional nodal areas. Extent of axillary dissection (SLNB only vs SLNB plus ALND) did not predict for disease control or survival. Patients who underwent ALND were significantly more likely to have lymphedema (25.0% vs 9.4%, P = .021). CONCLUSIONS: Careful selection of patients with a positive sentinel node on SLNB after neoadjuvant chemotherapy for omission of completion ALND in favor of irradiation of the undissected axilla does not compromise local, regional, or distant control or overall survival and results in lower rates of lymphedema.

External validation of life expectancy prognostic models in patients evaluated for palliative radiotherapy at the end-of-life.

BACKGROUND: The TEACHH and Chow models were developed to predict life expectancy (LE) in patients evaluated for palliative radiotherapy (PRT). We sought to validate the TEACHH and Chow models in patients who died within 90 days of PRT consultation. METHODS: A retrospective review was conducted on patients evaluated for PRT from 2017 to 2019 who died within 90 days of consultation. Data were collected for the TEACHH and Chow models; one point was assigned for each adverse factor. TEACHH model included: primary site of disease, ECOG performance status, age, prior palliative chemotherapy courses, hospitalization within the last 3 months, and presence of hepatic metastases; patients with 0-1, 2-4, and 5-6 adverse factors were categorized into groups (A, B, and C). The Chow model included non-breast primary, site of metastases other than bone only, and KPS; patients with 0-1, 2, or 3 adverse factors were categorized into groups (I, II, and III). RESULTS: A total of 505 patients with a median overall survival of 2.1 months (IQR: 0.7-2.6) were identified. Based on the TEACHH model, 10 (2.0%), 387 (76.6%), and 108 (21.4%) patients were predicted to live >1 year, >3 months to ≤1 year, and ≤3 months, respectively. Utilizing the Chow model, 108 (21.4%), 250 (49.5%), and 147 (29.1%) patients were expected to live 15.0, 6.5, and 2.3 months, respectively. CONCLUSION: Neither the TEACHH nor Chow model correctly predict prognosis in a patient population with a survival <3 months. A better predictive tool is required to identify patients with short LE.

Physician-Predicted Prognosis and Palliative Radiotherapy Treatment Utilization at the End of Life: An Audit of a Large Cancer Center Network.

CONTEXT: At our institution, clinical pathways capture physicians' prognostication of patients being evaluated for palliative radiotherapy. We hypothesize a low utilization rate of long-course radiotherapy (LCRT) and stereotactic ablative radiotherapy (SAbR) among patients seen at the end of life, especially those with physician-predicted poor prognosis. OBJECTIVE: To analyze utilization rates and predictors of LCRT and SAbR at the end of life. METHODS: A retrospective review was conducted on patients who were evaluated for palliative radiotherapy between January 2017 and August 2019 and died within 90 days of consultation. Binary logistic regression was used to identify predictors for utilization of LCRT (≥10 fractions) and SAbR. RESULTS: A total of 1608 patients were identified, of which 1038 patients (64.6%) were predicted to die within a year. Six hundred ninety-three patients (66.8%) out of 1038 were prescribed LCRT or SAbR. On a multivariate analysis, patients were less likely to be prescribed LCRT if treated at an academic site (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.23-0.39; P < 0.01) and treated for bone metastases (OR, 0.08; 95% CI, 0.05-0.11; P < 0.01) or other nonbrain/nonbone metastases (OR, 0.19; 95% CI, 0.13-0.30; P < 0.01). SAbR was less likely to be prescribed among patients predicted to die within a year (OR, 0.09; 95% CI, 0.06-0.16; P < 0.01), treated for bone metastases (OR, 0.13; 95% CI, 0.07-0.22; P < 0.01), with poor performance status (OR, 0.51; 95% CI, 0.31-0.85; P = 0.01), and with a breast primary (OR, 0.35; 95% CI, 0.15-0.82; P = 0.02). CONCLUSION: Although most patients were predicted to have a limited prognosis, LCRT and SAbR were commonly prescribed at the end of life.

Dose-response model for severe late laryngeal toxicity after stereotactic body radiation therapy for previously-irradiated head and neck cancer.

We sought to evaluate the association between larynx dose and risk of severe late laryngeal toxicity in patients undergoing re-irradiation SBRT for recurrent HNC. Fifty-five patients with an intact larynx underwent re-irradiation SBRT to a median dose of 44 Gy in 5 fractions. Five (41.7%) patients treated for a laryngeal/hypopharyngeal recurrence experienced late grade ≥3 laryngeal toxicity, compared to 0.0-7.1% for other sites. Logistic dose-response models were created to predict risk of severe late laryngeal toxicity, including dysphagia and airway compromise. According to the model, the risk of severe laryngeal toxicity with a larynx D5cc of 5 Gy is 5.8% (95% CI 2.9-9.9%) and rises to 11.4% with a D5cc of 20 Gy and 25.3% with a D5cc of 40 Gy. In patients with a laryngeal/hypopharyngeal recurrence, SBRT planning should carefully assess the dose to laryngeal structures given these dose findings, and SBRT should be approached with significant caution in such patients.

Cost-Effectiveness Analysis of Upfront SBRT for Oligometastatic Stage IV Non-Small Cell Lung Cancer Based on Mutational Status.

OBJECTIVES: Current National Comprehensive Cancer Network (NCCN) guidelines support systemic therapy based on mutational status in stage IV non-small cell lung cancer (NSCLC), with stereotactic body radiation therapy (SBRT) reserved for oligoprogression. We aimed to evaluate the cost-effectiveness of the routine addition of SBRT to upfront therapy in stage IV NSCLC by mutational subgroup. MATERIALS AND METHODS: A Markov state transition model was constructed to perform a cost-effectiveness analysis comparing SBRT plus maintenance therapy with maintenance therapy alone for oligometastatic NSCLC. Three hypothetical cohorts were analyzed: epidermal growth factor receptor or anaplastic lymphoma kinase mutation-positive, programmed death ligand-1 expressing, and mutation-negative group. Clinical parameters were obtained largely from clinical trial data, and cost data were based on 2018 Medicare reimbursement. Strategies were compared using the incremental cost-effectiveness ratio with effectiveness in quality-adjusted life years (QALYs) and evaluated with a willingness to pay threshold of $100,000 per QALY gained. RESULTS: SBRT plus maintenance therapy was not cost-effective at a $100,000/QALY gained threshold, assuming the same survival for both treatments, resulting in an incremental cost effectiveness ratio of $564,186 and $299,248 per QALY gained for the epidermal growth factor receptor or anaplastic lymphoma kinase positive and programmed death ligand-1 positive cohorts, respectively. Results were most sensitive to the cost of maintenance therapy. A large overall survival gain with SBRT could potentially result in upfront SBRT becoming cost-effective. For the mutation-negative cohort, upfront SBRT was nearly cost-effective, costing $128,424 per QALY gained. CONCLUSION: Adding SBRT to maintenance therapy is not a cost-effective strategy for oligometastatic NSCLC compared with maintenance therapy alone for mutation-positive groups. However, this should be validated via randomized trials.

Long-Term Patient-Reported Rectal Bleeding and Bowel-Related Quality of Life After Cs-131 Prostate Brachytherapy.

PURPOSE: There is limited long-term data on outcome and side effects of Cs-131 prostate brachytherapy and minimal patient-reported data on rectal bleeding with any isotope. We aimed to describe the incidence, prevalence, and predictors of late patient-reported rectal bleeding after Cs-131 brachytherapy. METHODS AND MATERIALS: We reviewed a prospectively collected database of 620 men treated with Cs-131 prostate brachytherapy. Of 620 patients, 390 (62.9%) received brachytherapy as monotherapy; the remainder received combination therapy with external beam radiation therapy (EBRT). Patients were administered Expanded Prostate Cancer Index Composite questionnaires preoperatively and postoperatively at each follow-up visit. The primary outcome was late rectal bleeding, defined as rectal bleeding reported at the 6-month follow-up or later. Clinically significant rectal bleeding was defined as occurring more than "rarely," and clinically significant bother from rectal bleeding was defined as considering bleeding more than a "very small problem." Univariate and multivariate Cox regression were performed to identify factors predictive for rectal bleeding. RESULTS: With a median follow-up time of 48 months, the cumulative incidence of clinically significant late rectal bleeding was 12.4%, with 15.2% reporting clinically significant bother from bleeding. At the time of last follow-up, the prevalence of clinically significant rectal bleeding and bother were 4.0% and 4.7%, respectively. On univariate analysis, acute clinically significant rectal bleeding, defined as occurring within the first 6 months (P = .001) and combination therapy with EBRT (P = .001) predicted for clinically significant late rectal bleeding. On multivariate analysis, both EBRT (P = .001; hazard ratio, 2.50; 95% confidence interval, 1.58-3.94) and acute rectal bleeding (P < .001; hazard ratio, 3.11; 95% confidence interval, 1.75-5.53) remained significant predictors for late rectal bleeding. CONCLUSIONS: Prostate brachytherapy with Cs-131 is well tolerated in the long term. Although the incidence of clinically significant patient-reported late rectal bleeding was 12.4%, the prevalence at last follow-up was only 4.0%, suggesting that this problem tends to resolve.

Lag Time Between Evidence and Guidelines: Can Clinical Pathways Bridge the Gap?

PURPOSE:: The 2018 American Society for Radiation Oncology guidelines state that hypofractionated whole-breast irradiation (HF-WBI) may be used for early-stage breast cancer regardless of age, although evidence to support this became available years ago. Before guideline publication, we sought to change the practice pattern within an integrated, comprehensive radiation oncology network using clinical pathways. METHODS:: The breast clinical pathway was amended in January 2016 to allow HF-WBI as a pathway-concordant option for women younger than 50 years of age. In December 2016, the pathway was amended to mandate HF-WBI as the only pathway-concordant option. Women younger than 50 years of age treated for stage 0 to IIA breast cancer, without irradiation of regional nodes, were included. Potential predictors of hypofractionation use were analyzed using binary logistic regression. RESULTS:: We identified 305 patients treated between 2013 and 2017. From 2013 to December 2015, HF-WBI use was 4.2%. After the first and second amendments, use increased to 53.1% ( P < .001) and 96.5% ( P < .001), respectively. Before amendment 1, there was no difference in use of hypofractionation at academic (2.6%) versus community (4.7%) sites ( P = .568). After amendment 1, academic practices were more likely to use hypofractionation (72.0% v 44.6%; P = .026). After amendment 2, there was, again, no difference between academic (100.0%) and community (95.3%) practices ( P = .999). CONCLUSION:: With implementation of a clinical pathway that mandated use of HF-WBI regardless of age, HF-WBI use for women younger than 50 years of age rapidly increased from 4.2% to greater than 95%. Clinical pathways effectively standardize patterns of care to reflect the most up-to-date clinical evidence, independently of guideline publication.

Salvage Curative-Intent Reirradiation Stereotactic Body Radiation Therapy for Isolated Pelvic and/or Paraortic Recurrences of Gynecologic Malignancies.

PURPOSE: To determine the feasibility of stereotactic body radiation therapy (SBRT) for isolated nodal recurrences of gynecologic malignancies within a previously irradiated area. METHODS AND MATERIALS: A retrospective review was performed on 20 patients who underwent 21 curative-intent reirradiation SBRT treatments for locoregional recurrences of gynecologic malignancies. Disease control and survival outcomes were analyzed with the Kaplan-Meier method and log-rank test. Treatment toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.03. RESULTS: All patients had an isolated pelvic, paraortic, or intra-abdominal nodal recurrence, with the exception of 1 patient who had a concurrent paraortic and right acetabulum metastasis, both of which were irradiated with SBRT. Primary sites included cervix (30.0%), uterus (55.0%), vulva (5.0%), vagina (5.0%), and ovary (5.0%). Median prior external beam radiation therapy dose was 45 Gy. Recurrences were in field in 14 (66.7%) and marginal in 7 (33.3%). SBRT was directed to the pelvis in 13 cases (61.9%) and to paraortic or celiac nodes in 8 (38.1%). The most common SBRT regimen was 40 to 45 Gy in 5 fractions (n = 12). At a median follow-up of 31.2 months, 3-year actuarial in-field local control, distant progression-free survival, and overall survival were 61.4%, 44.0%, and 51.9%, respectively. At the time of last follow-up, 9 (45.0%) patients remained alive without evidence of disease. Actuarial 3-year risk of grade ≥2 and grade ≥3 late toxicities was 38.1% and 14.3%, respectively. CONCLUSIONS: SBRT for isolated pelvic or intra-abdominal recurrences of gynecologic malignancies within a previously irradiated field is feasible with an acceptable toxicity rate. With this approach, about half of patients achieved durable disease-free survival.

Hypofractionated Whole-Breast Irradiation in Large-Breasted Women-Is There a Dosimetric Predictor for Acute Skin Toxicities?

PURPOSE: Underutilization of hypofractionated whole-breast irradiation (HF-WBI) in large-breasted women may be partially explained by concerns about dose heterogeneity. Although modern planning may mitigate this issue, validated dosimetric guidelines are lacking. Our clinical pathway mandates hypofractionation, guided by institutional dosimetric criteria for plan evaluation. We examined acute radiation dermatitis rates with HF-WBI in large-breasted patients when our guidelines are followed and evaluated factors predictive for dermatitis. METHODS AND MATERIALS: Patients with whole-breast clinical target volumes (WB-CTV) of ≥1000 cm3 treated with HF-WBI were reviewed. WB-CTV V105, V107, and V110 were assessed. Our guidelines recommend limiting V105 to <10% to 15% and V110 to 0%. The highest grade of acute dermatitis was recorded. Potential clinical and dosimetric predictors of dermatitis were analyzed using logistic regression. RESULTS: From 2012 to 2017, 505 breasts in 502 patients were treated with HF-WBI. The median WB-CTV was 1261.3 cm3 (interquartile range [IQR], 1115.3-1510.0). Most plans (99%) delivered 42.56 Gy in 16 fractions. A cavity boost of 10 Gy in 4 fractions was delivered in 99% of plans. Electrons were used in 69% of boost plans. Three-dimensional field-in-field technique was used in 68% of plans and inverse-planned intensity modulated radiation therapy in 32%. The median WB-CTV V105 was 9.7% (IQR, 5.6%-13.3%); the median WB-CTV V107 was 0.8% (IQR, 0.0%-2.5%). The WB-CTV V110 was 0% in 97.4% of plans (median, 0.0%; IQR, 0.0%-0.0%). Grade 1, 2, and 3 dermatitis rates were 55.0%, 40.8%, and 3.4%, respectively. On multivariate analysis, age >64 years (P = .016; odds ratio [OR] 4.0; 95% confidence interval [CI], 1.3-12.3), WB-CTV >1500 cm3 (P = .006; OR, 4.3; 95% CI, 1.5-12.3), body mass index ≥34 (P = .044; OR, 3.9; 95% CI, 1.0-14.5), and WB-CTV V105 >10% (P = .011; OR, 5.3; 95% CI, 1.5-19.3) predicted for grade 3 dermatitis. CONCLUSIONS: With our institutional dosimetric guidelines, grade 3 dermatitis rates with HF-WBI in large-breasted women was <5%. WB-CTV V105 should be optimized to <10% to keep grade 3 dermatitis rates <2%.

Dose-response modeling the risk of carotid bleeding events after stereotactic body radiation therapy for previously irradiated head and neck cancer.

Given the lack of clear dose constraints for the carotid artery, we created dose-response models to better quantify the risk of carotid bleeding events following re-irradiation stereotactic body radiation therapy (SBRT) for head and neck cancer (HNC). We performed a retrospective analysis on 75 patients treated with SBRT for recurrent, previously irradiated HNC. Logistic dose-response models were created to predict the risk of a carotid bleeding event, defined as any mucosal bleeding event or bleeding resulting from rupture of the carotid artery or its major branches in the setting of controlled disease. According to the models, the risk of a carotid bleeding event with a cumulative D0.1cc of 20 Gy from SBRT is 0.8% (95% CI 0.1%-3.9%), and rises to 5.0% with a D0.1cc of 50 Gy. No patient experienced a carotid bleeding event with D0.1cc < 39.4 Gy, and none experienced carotid blowout syndrome with a cumulative D0.1cc < 47.6 Gy.

Is Multifocal Regression a Risk Factor for Ipsilateral Breast Tumor Recurrence in the Modern Era After Neoadjuvant Chemotherapy and Breast Conservation Therapy?

PURPOSE: Multifocal pattern of regression after neoadjuvant chemotherapy has been identified as a risk factor for ipsilateral breast tumor recurrence (IBTR). We aimed to determine the significance of multifocal regression as a predictor of IBTR after neoadjuvant chemotherapy and breast conservation therapy in the modern era. METHODS AND MATERIALS: We retrospectively reviewed 346 patients treated between November 2009 and June 2017. Pattern of regression was categorized as pathologic complete response (pCR), unifocal (tumor present as a cohesive mass), limited multifocal (single cells or clusters of cells concentrated in 1 portion of the fibrotic area), or diffuse multifocal (cells spread over entire fibrotic area). IBTR was defined as new ipsilateral invasive or noninvasive breast tumor after breast conservation therapy. Predictive factors were analyzed using Cox regression. RESULTS: Incidence of multifocal regression was 25.7% for the overall cohort and 12.2% for estrogen receptor (ER) negative/progesterone receptor (PR) negative/human epidermal growth factor receptor 2 (HER2) positive, 17.5% for triple-negative, 36.9% for ER+ or PR+/HER2-, and 38.5% for triple-positive (P < .001). With a median follow-up of 41.1 months, 4-year IBTR-free survival after pCR or unifocal regression versus multifocal regression was 94.1% versus 90.9% (P = .411). Pattern of regression (P = .010; compared to pCR, hazard ratio [HR] of 11.2 for diffuse multifocal regression, 1.65 for limited multifocal regression, and 3.81 for unifocal regression), phenotype (P = .001; compared to ER+ or PR+/HER2-, HR of 30.67 for ER-/PR-/HER2+, 25.30 for triple-negative, and 1.60 for triple-positive), and lack of nodal pCR (P = .004; HR of 3.78) predicted for IBTR on multivariate Cox regression. On multivariate subset analysis, pattern of regression and lymphovascular space invasion predicted for IBTR in hormone receptor-negative patients, but pattern of regression was not associated with IBTR for hormone receptor-positive patients. CONCLUSIONS: Multifocal regression, hormone receptor-negative phenotype, and lack of nodal pCR predict for increased risk of IBTR after neoadjuvant chemotherapy. Although more common in hormone receptor-positive disease, multifocal regression was associated with worse outcome only in hormone receptor-negative patients.