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Delineation of treatment targets and organs-at-risk (OAR) for treatment planning is the standard of care across all disease sites for curative radiation therapy. However, this approach has been variably adopted for breast cancer with significant variation amongst experts regarding contouring breast cancer target volumes. In order to create a framework for the contouring of breast cancer cases, particularly within the context of clinical trials, the Radiation Therapy Oncology Group (RTOG) Breast Atlas was created in 2009. Since that time, numerous other atlases have been developed and several retrospective studies since 2015 have called into question the adequacy of clinical target volume delineation as defined by the RTOG atlas and other atlases based on patterns of failure. Here, we will review the existing atlases, highlighting the differences between them and potential opportunities for improvement based on these patterns of failure studies. Ultimately, the results of recently completed and ongoing prospective clinical trials, which included contouring guidelines based on current atlases, will provide important information regarding patterns of failure and toxicity in patients treated with modern radiotherapy using a systematic target volume delineation and OAR-driven approach to treatment planning.

Using evidence-based radiation therapy to direct care for patients with breast cancer is critical to standardizing practice, improving safety, and optimizing outcomes. To address this need, the Veterans Affairs (VA) National Radiation Oncology Program (NROP) established the VA Radiation Oncology Quality Surveillance Program (VAROQS) to develop clinical quality measures (QM). The VA NROP contracted with the American Society for Radiation Oncology (ASTRO) to commission five Blue-Ribbon Panels for breast, lung, prostate, rectal, and headneck cancers.The Breast Cancer Blue-Ribbon Panel experts worked collaboratively with NROP to develop consensus QM for use throughout the VA system. establishing a set of quality measures for patients in several areas including: 1) consultation and work up, 2) simulation, treatment planning and treatment, and 3) follow up care. As part of this initiative, consensus dose volume histogram (DVH) constraints were outlined.In total, 36 quality measures were established. Herein we review the process utilized to develop QM and final consensus QM pertaining to all aspects of radiation patient care as well as DVH constraints.The QM and expert consensus DVH constraints are intended for ongoing quality surveillance within the VA system, centers providing community care for Veterans, and also available for use by the greater non-VA community measures of quality care for breast cancer patients receiving radiation.

Regional nodal irradiation (RNI) improves disease outcome in breast cancer patients, but the contribution of internal mammary node irradiation (IMNI) in the context of modern systemic treatment is still controversial. The aim of our study is to evaluate the effect of IMNI in patients with modern systemic treatment in real-world setting. We retrospectively analyzed patients with primary breast cancer treated with surgery followed by adjuvant chemotherapy and adjuvant chestwall/breast irradiation and RNI from 5/2007-12/2010. RNI was delivered to the ipsilateral supraclavicular region and infraclavicular region + / − IMNs. We separated two groups based on the presence and the absence of IMNI. The primary end point was disease-free survival (DFS). DFS and overall survival (OS) were evaluated with Kaplan–Meier method. Differences between two groups were compared with the log-rank test (p

Purpose Quantitative changes in positron emission tomography with computed tomography imaging metrics over serial scans may be predictive biomarkers. We evaluated the relationship of pretreatment metabolic tumor growth rate (MTGR) and standardized uptake value velocity (SUVV) with disease recurrence or death in patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy (SABR). Methods and Materials Under institutional review board approval, we retrospectively identified patients who underwent positron emission tomography with computed tomography at diagnosis and staging and simulation for SABR. Two cohorts underwent SABR between November 2005 to October 2012 (discovery) and January 2012 to April 2016 (validation). MTGR and SUVV were calculated as the daily change in metabolic tumor volume and maximum standardized uptake value, respectively. Cox proportional hazard models identified predictors of local, regional, and distant recurrence and death for the combined cohort. MTGR and SUVV thresholds dichotomizing risk of death in the discovery cohort were applied to the validation cohort. Results A total of 152 lesions were identified in 143 patients (92 lesions in 83 discovery cohort patients). In multivariable models, increasing MTGR trended toward increased hazard of distant recurrence (hazard ratio, 6.98; 95% confidence interval, 0.67-72.61; P = .10). In univariable models, SUVV trended toward risk of death (hazard ratio, 11.8, 95% confidence interval, 0.85-165.1, P = .07). MTGR greater than 0.04 mL/d was prognostic of decreased survival in discovery (P = .048) and validation cohorts (P Conclusions MTGR greater than 0.04 mL/d is prognostic of death in patients with non-small cell lung cancer treated with SABR. Increasing SUVV trends, nonsignificantly, toward increased risk of recurrence and death. MTGR and SUVV may be candidate imaging biomarkers to study in trials evaluating systemic therapy with SABR for patients at high risk of out-of-field recurrence.

PURPOSE/OBJECTIVE(S) The excellent survival and locoregional outcomes from the APT trial in predominantly stage I HER2+ breast cancer (BC) treated with upfront surgery (∼75% breast conservation surgery [BCS]) and adjuvant paclitaxel/trastuzumab has raised optimism that radiation (RT) may be de-escalated in this setting. Our initial analysis using the National Cancer Database (NCDB) instead demonstrated an association between RT omission and worse overall survival (OS) in these patients. Patients with HER2+ disease that receive neoadjuvant systemic therapy (NST) demonstrate great outcomes for patients with a pathologic complete response (pCR). This suggests that pCR may be used to de-escalate RT in early-stage HER2+ patients treated with NST+BCS. We used the NCDB to test the hypothesis that RT omission results in equivalent OS in cT1-2 (< 3 cm) N0 HER2+ patients treated with NST+BCS with pCR. MATERIALS/METHODS We identified patients with cT1-T2 (< 3 cm) N0 HER2+ BC treated with anti-HER2 based NST and BCS +/- RT from 2013-2015. We identified factors associated with RT omission using logistic regression analysis. We evaluated OS in the subset of patients with pCR stratified by receipt of RT. We used a propensity score matched (PSM) analysis to compare OS between the groups. Patients were matched on clinical and demographic factors. The effect of RT omission was evaluated with a Cox proportional hazards model with robust standard errors to account for clustering in matched pairs. RESULTS We identified 4,842 patients (4,505 RT; 337 no RT): 31.7% ER-/PR-; 48.5% with pCR. On multivariate analysis, age≥70 (OR = 2.88, P < 0.0001), Black race (OR = 1.43, P = 0.03), and use of single-agent cytotoxic chemotherapy (OR = 1.47, P = 0.02) were associated with RT omission. There was a trend towards RT omission in patients with pCR (OR = 1.21, P = 0.11). OS data was available in 1,581 (1,471 RT; 110 no RT) of the 2,348 patients with pCR. Median follow-up was 27.1 months (IQR = 19.7-37.0 months) with 14 deaths (3 RT; 11 RT omission). The 2-year OS was significantly worse for patients with RT omission (96.9% vs. 99.7%, P = 0.02). The PSM cohort consisted of 103 (of a possible 110) pairs of patients with 6 deaths (3 RT; 3 RT omission) and median follow-up 25.6 months (IQR, 17.9-35.9 months). In the PSM cohort, RT omission was not significantly associated with an increased risk of death (2-year OS 96.7% vs. 98.5%; HR = 1.12, 95% CI 0.23-5.41, P = 0.89). CONCLUSION We did not find an association between RT omission and increased risk of death in patients with cT1-T2 (< 3 cm) N0 HER2+ BC treated with NST+BCS with pCR. Patients that did not receive RT tended to be older, of Black race, and to have received single-agent cytotoxic chemotherapy. These data support prospective evaluation of RT omission in this patient population in a randomized controlled trial.

In the modern era, highly effective anti-HER2 therapy is associated with low local-regional recurrence (LRR) rates for early-stage HER2+ breast cancer raising the question of whether local therapy de-escalation by radiation omission is possible in patients with small-node negative tumors treated with lumpectomy. To evaluate existing data on radiation omission, we used the National Cancer Database (NCDB) to test the hypothesis that RT omission results in equivalent overall survival (OS) in stage 1 (T1N0) HER2+ breast cancer. We excluded patients that received neoadjuvant systemic therapy. We stratified the cohort by receipt of adjuvant radiation. We identified 6897 patients (6388 RT; 509 no RT). Patients that did not receive radiation tended to be ≥70 years-old (odds ratio [OR] = 3.69, 95% CI: 3.02–4.51, p p = 0.0154), to be Hispanic (OR = 1.49, 95% CI: 1.00–2.22, p = 0.049), and to live in lower income areas (OR = 1.32, 95% CI: 1.07–1.64, p = 0.0266). Radiation omission was associated with a 3.67-fold (95% CI: 2.23–6.02, p

Rates of acute esophagitis in breast cancer patients undergoing regional nodal irradiation (RNI) are under-reported. We set to identify esophageal dose-volume constraints associated with grade 2 esophagitis (G2E). We hypothesized that the G2E rate was higher with intensity modulated radiation therapy (IMRT) vs. 3D conformal radiation therapy (3DCRT).We identified patients that received RNI (50 Gy/25 fractions) from 1/2013 to 6/2019. We retrospectively contoured the esophagus in a consistent manner and recorded esophageal mean dose, max dose, and V10-V50. Our primary endpoint was the G2E rate. Receiver operating characteristics curves analysis (e.g., Youden's J statistic) were used to determine the cutpoints for the dosimetric parameters which were then tested in logistic regression models.We identified 531 patients (50% left-sided; 41% IMRT; 16.2% G2E). G2E was significantly higher in IMRT vs. 3DCRT patients (23.6% vs. 10.9%, p 0.0001). All esophageal dosimetric parameters were significantly associated with G2E after adjusting for age and laterality. The cutpoints for esophageal mean dose, V10 and V20 were 11 Gy, 30%, and 15%, respectively. The associations between the dichotomized dose-volume parameters and G2E were OR = 3.82 (95% CI 2.28-6.40, p 0.0001) for esophageal mean dose, OR = 5.37 (95% CI 3.01-9.58, p 0.0001) for esophageal V10, and OR = 3.23 (95% CI 1.93-5.41, p 0.0001) for esophageal V20.In patients receiving RNI with modern techniques, we found that G2E occurs in15%, and more frequently with IMRT. These data strongly support the routine contouring of the esophagus in RNI planning, and our constraints should be incorporated in future prospective protocols of RNI.

Purpose Clinical trials support adjuvant regional nodal irradiation (RNI) after breast-conserving surgery or mastectomy for patients with lymph node–positive breast cancer. Advanced treatment planning techniques (eg, intensity modulated radiation therapy [IMRT]) can reduce dose to organs at risk (OARs) in this situation. However, uncertainty persists about when IMRT is clinically indicated (vs 3-dimensional conformal radiation therapy [3DCRT]) for RNI. We hypothesized that an adaptive treatment planning algorithm (TPA) for IMRT adoption would allow OAR constraints for RNI to be met when 3DCRT could not without significantly changing toxicity and locoregional recurrence (LRR) patterns. Methods and Materials Since 2013, all RNI patients also underwent an adaptive TPA that began with 3DCRT and then changed to IMRT when OAR constraints (mean heart dose ≤500 cGy; ipsilateral lung V20 ≤35%) could not be met. Patients received 2 Gy/d to the prospectively contoured target volumes (including internal mammary nodes). We retrospectively evaluated the dosimetry and clinical outcomes of the treatment groups (IMRT vs 3DCRT). The primary endpoint was the cumulative incidence of LRR as the site of first recurrence, and we specifically address patterns of failure based on dose to the posterior supraclavicular nodal region (SCL-post). Results Two hundred forty patients (60% stage III; mean 4.0 + nodes) underwent an adaptive-TPA for RNI after mastectomy (74%) or breast-conserving surgery (26%), resulting in 168 patients treated with 3DCRT and 72 patients treated with IMRT. There were 7 LRRs (2 IMRT, 5 3DCRT) resulting in 4-year LRR of 2.8% for IMRT versus 1.8% for 3DCRT (P = .99). Three patients (2 IMRT, 1 3DCRT) had SCL nodal failures (1 in the SCL-post). Conclusions An adaptive TPA for use of IMRT when 3DCRT does not meet critical OAR constraints resulted in rare high-grade toxicity and no difference in failure patterns between patients treated with IMRT and 3DCRT. These data should provide reassurance that IMRT maintains the therapeutic ratio by preserving cancer control outcomes without excess toxicity when 3DCRT fails to meet OAR constraints.

PURPOSE: To test the hypothesis that increasing radiation therapy (RT) dose to the thoracic vertebral bodies (TVBs) contributes to the development of hematologic toxicities (HTs) in patients with lung cancer. METHODS AND MATERIALS: Cases of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated with definitive chemoradiation with concurrent platinum-based doublet chemotherapy at our institution from 2007 to 2016 were identified. Mean TVB dose and the volume of TVBs receiving at least 5 to 60 Gy (V(5)-V(60)) were retrospectively recorded. Logistic regression was used to test associations between grade ≥3 HT (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability was evaluated using the Lyman-Kutcher-Burman (LKB) model for HT3+, and receiver operating characteristics analysis was used to determine dosimetric cut-points. RESULTS: We identified 201 patients, the majority having NSCLC (n = 162, 81%) and stage III to IV disease (n = 179, 89%). All patients received either cisplatin/etoposide (n = 107, 53%) or carboplatin/paclitaxel (n = 94, 47%). Median RT dose was 60 Gy (range, 60–70 Gy). The rate of HT3+ was 49% (n = 99). Increasing mean TVB dose (per Gy) was associated with higher odds of developing HT3+ (odds ratio 1.041, 95% confidence interval 1.004–1.080, P = .032), as were increasing TVB V(5) to V(20).These dosimetric correlates to HT3+ persisted on multivariate analysis. Constrained optimization of the LKB model for HT3+ yielded the parameters: n = 1, m = 1.79, and TD(50) = 21.4 Gy. Optimal cut-points identified were V(5) = 65%, V(10) = 60%, V(20) = 50%, and mean dose = 23.5 Gy. Patients with values above these cut-points had an approximately 2-fold increased risk of HT3+. CONCLUSIONS: We found that mean TVB dose and low-dose parameters (V(5)-V(20)) were associated with HT3+ in chemoradiation for lung cancer. Per the LKB model, bone marrow behaves like a parallel organ (n = 1), implying that mean TVB dose is a useful predictor for toxicity. These data suggest that efforts to spare dose to the TVBs may reduce rates of severe HT.

Purpose/objective(s) Breast angiosarcoma (AS) is an uncommon malignancy that is either secondary to prior radiation therapy (RT) or can occur in the primary setting in the absence of prior RT. Since these malignancies are rare, there are scant prospective data to guide the optimal use and timing of surgery, chemotherapy and RT. Here, we set to focus on details of RT use for primary AS and secondary AS with a focus on the dose, fractionation and timing of RT relative to surgery using the National Cancer Database (NCDB). We hypothesized that RT use would be more frequent in primary AS compared to secondary AS. In addition, we hypothesized that when RT is used, hyperfractionated schedules and preoperative RT would be more common in secondary AS compared to primary AS. Materials/methods We identified patients with a histologic diagnosis of AS from the NCDB from 2004-2016. Patients that were coded as having a prior malignancy were used as a surrogate to denote secondary AS whereas the rest were classified as primary AS. RT use was defined as conventional fractionation (1.8-2.0 Gy/fraction given daily); hypofractionated (> 2.0 Gy/fraction given daily); accelerated hyperfractionated (≤1.5 Gy/fraction given 2-3 times/day); palliative (total dose≤30 Gy); or unknown (insufficient RT details provided). Comparisons between the primary AS and secondary AS groups were performed using the chi-square test with P Results We identified 1,174 patients with non-metastatic AS: 864 secondary AS, 310 primary AS. Radiation was used in 211 patients (18.0%) and was significantly more common in primary AS compared to secondary AS (36.1% [N = 113] vs. 11.4% [N = 98], P Conclusion Radiation use for the treatment of breast AS is uncommon, even for patients with primary AS. When RT is used, conventional fractionation schedules predominate. However, accelerated hyperfractionation is used more frequently in secondary AS with 1.5 Gy BID to doses≥45 Gy as the most common regimen. Preoperative RT is rarely used for AS based on this analysis. The under-utilization of RT and wide variations in RT dose/fractionation schedules emphasize the need for more standardized consensus guidelines for this rare but aggressive malignancy.

PURPOSE/OBJECTIVE(S) In women with early-stage breast cancer, lumpectomy and breast radiation achieve comparable cancer control as mastectomy. After whole breast irradiation (WBI), a lumpectomy cavity directed supplemental dose ("boost') reduces ipsilateral breast recurrences yet can be associated with worse cosmesis. Moreover, identifying the lumpectomy cavity precisely is a practical challenge in radiation treatment planning. We hypothesized that the 3D marker would reduce Lumpectomy Gross volume (GTV) and clinical target volumes (CTV) and improve cosmesis. MATERIALS/METHODS After IRB approval, 248 charts of women with a pathological ductal carcinoma in situ or invasive carcinoma treated with post lumpectomy WBI between January 2016 and December 2017 were reviewed. All cases had delineation of gross lumpectomy volume (GTV), clinical (CTV) and planning (PTV) target volumes and as well Breast CTV and PTV for standard RT planning. Every case met dose goals and OAR constraints for approval. Pathological lumpectomy volume (PLV) was calculated from specimen dimensions in the gross portion of the pathology report. Median follow up is 27.33 months (range 4.1 - 45 months). Data was analyzed using linear regression to predict the clinical and dosimetric variables associated with target volumes and cosmetic outcomes. RESULTS The mean age was 57.8 years. Twelve women (4.8%) underwent oncoplastic lumpectomy, 237 (95.2%) underwent lumpectomy only. Sixteen (6.27%) received neoadjuvant chemotherapy. Mean lumpectomy GTV was 31.45ml with the use of surgical clips (n = 99), 23.59 cm3 with the use of 3D Marker (n = 58), and 16.8 cm3 without any demarcation (n = 98) (P = 0.0001) and highly correlated with PLV (P = < 0.0001.) PLV was significantly associated with individual surgeon after adjustment for surgical marker used and overall pathological stage (P < 0.05). Surgical marker was not associated with PLV on univariate or multivariate analysis. Individual surgeons predicted the use of a surgical marker during surgery (P < 0.0001). Overall Breast cosmesis was Excellent/Good (EG) in242 (98%) and in 233 (93.3%) women at 6- and 12-months, respectively. A 3D marker was not associated with breast cosmesis; however, a negative association with Breast PTV Eval Structure Volume (P < 0.04) was observed after adjustment for surgeon, marker, overall pathologic stage, breast and boost dose, age at radiation, PLV and lump GTV. CONCLUSION In this analysis, the presence of a 3D marker significantly increases the size of a lumpectomy GTV compared to no demarcation and less than surgical clips. The lack of demarcation is worrisome for potential marginal misses - especially for partial breast irradiation. The usage of clips and/or 3D marker is strongly associated with the individual surgeon. The marker used did not influence cosmetic outcome but very few patients had less than EXC-good outcomes. A collaboration between radiation oncologists and surgeons may lead to increased usage of markers and improved lumpectomy delineation.

Purpose/Objective(s) Primary tumor failure is common in patients treated with chemoradiation (CRT) for unresectable LA-NSCLC. Stereotactic body radiation therapy (SBRT) yields high rates of primary tumor control in Stage I NSCLC. This trial tested an SBRT boost to the primary tumor prior to the start of CRT to improve primary tumor control (PTC). Materials/Methods Patients with LA-NSCLC with primary tumor ≤10 cm were enrolled on a prospective phase II trial testing an SBRT boost in 2 fractions (central 6 Gy x 2, peripheral 8 Gy x 2) immediately followed by standard concurrent CRT (60 Gy in 30 fractions). Patients were staged with PET-CT, brain MRI, and underwent 4D-CT simulation for radiation planning using a customized immobilization device that enabled radiation planning for the sequential delivery of the SBRT boost and conventionally-fractionated radiation from the same CT dataset. Chemotherapy was carboplatin/paclitaxel (C/P) or cisplatin/etoposide. For patients receiving C/P, consolidation C/P for 2 cycles was given at the discretion of the medical oncologist. The trial was later amended to allow for consolidation durvalumab. The primary objective was to estimate PTC rate at 1-year with a hypothesis that the 1-year PTC rate is ≥90%. Secondary objectives were to establish the safety, feasibility, objective response rate (ORR; RECISTv1.1), and rates of regional & distant control, disease-free survival (DFS), and overall survival (OS). Exploratory functional MRI (fMRI) scans before and within the first 30 hrs of the first SBRT fraction were performed in 11 patients. Results The study enrolled 21 patients (10 male, 11 female), with median age 62 years (range 52-78). 16 patients received 6 Gy x 2 SBRT boost, while 5 patients received 8 Gy x 2 SBRT boost. 18 patients received C/P chemotherapy, of whom 9 patients received consolidation C/P. Six patients received consolidation durvalumab. Median pre-treatment primary tumor size was 5.0 cm (range 1.0-8.3). Median and mean follow-up were17.9 and 20.2 months, respectively. The most common toxicities were fatigue, neutropenia, leukopenia, lymphopenia, anemia, pneumonitis, fibrosis, dyspnea and esophagitis. Five grade 4 toxicities related to treatment occurred [lymphopenia (3), neutropenia (1), and leukopenia (1)], but no grade 5 toxicities related to treatment occurred. ORR at 3 and 6 months was 72.7% and 80.0%. The PTC rate was 100% and 92.3% at 1 and 2 years, respectively. The 2-year regional and distant control were 81.6% and 70.3%, respectively. Disease-free survival and overall survival at 2 yrs were 46.1% and 50.3%, respectively. Median survival was 37.8 months. fMRI detected a mean relative decrease in BOLD signal of -87.1% (P = 0.05). Conclusion Dose escalation to the primary tumor utilizing upfront SBRT appears feasible and safe. PTC was high and other oncologic endpoints compared favorably with the literature. Through the use of 1 CT simulation dataset, accurate calculation of the planned dose through the 2 sequentially-delivered plans is achievable.

PURPOSE/OBJECTIVE(S) Chest radiation therapy (RT) has been associated with increased cardiac morbidity and mortality in a number of retrospective studies, including the landmark Darby study published in 2013 that demonstrated a linear increase in cardiac mortality with increasing mean heart radiation dose. The adverse effects of RT on the heart have led to an increased focus on minimizing radiation dose to the heart or its substructures during radiation planning. However, the extent to which cardiotoxicity has been incorporated as an endpoint in prospective RT studies remains unknown. We hypothesized that cardiotoxicity has increased in frequency as an endpoint in oncology trials involving thoracic RT since publication of the Darby study in 2013, and we sought to quantify this change in trial design. MATERIALS/METHODS We queried clinicaltrials.gov for all phase II/III interventional studies conducted from 1/1/2006 until 2/1/2021 which included RT for breast, esophageal, lymphoma, mesothelioma, thymoma, or lung cancer with a planned enrollment of ≥100 patients. Studies were categorized into the pre-Darby era (enrollment started prior to 1/1/2014) or the post-Darby era (enrollment after 1/1/2014). We determined whether each eligible study included cardiotoxicity as a specific primary or secondary endpoint. The primary endpoint was to compare the rate of studies with a cardiotoxicity endpoint in the pre-Darby versus post-Darby era using the Chi-square test (P < 0.05 considered significant). RESULTS Overall, 1,822 trials were reviewed and 256 met the study criteria. Of the trials included, 32% were for esophageal cancer, 31% for lung cancer, 28% for breast cancer, and 7% lymphoma/thymoma/mesothelioma. Overall, 5% (N = 13) included cardiotoxicity as an endpoint: 6 breast cancer, 3 lung cancer, 3 esophageal cancer, and 1 lymphoma study. There was no statistically significant increase in the inclusion of cardiotoxicity as an endpoint in the pre-Darby versus post-Darby era (3.9% vs. 5.9%, P = 0.46). The greatest absolute increase in inclusion of cardiotoxicity as an endpoint was seen for lung cancer (0% vs. 6%, P = 0.17) and breast cancer (5.7% vs. 10.8%, P = 0.43) studies, though these increases remained insignificant. CONCLUSION Among prospective clinical trials involving chest RT, cardiotoxicity remains an uncommon endpoint despite its prevalence as a primary source of toxicity following treatment. Breast cancer RT trials had the highest rates of including cardiotoxicity endpoints in the pre- and post-Darby era, though this rate remained low at 10%. Despite increased recognition that cardiac toxicity is prevalent after chest RT, there has been no detectable increase in the inclusion of cardiotoxicity endpoints in prospective clinical trials. In order to better characterize cardiac toxicities, future prospective studies involving chest RT should include cardiotoxicity endpoints.

Purpose Pelvic bone marrow (BM) constraints may offer a means to reduce the toxicity commonly associated with chemoradiation for anal cancer. We conducted a bi-institutional analysis of dose-volume metrics in a time-sensitive fashion to devise practical metrics to minimize hematologic toxicity. Methods and Materials Fifty-six anal cancer patients from 2 institutions received definitive radiation therapy (median primary dose of 54 Gy) using intensity modulated radiation therapy (IMRT, n=49) or 3-dimensional (3D) conformal therapy (n=7) with concurrent 5-fluorouracil (5-FU) and mitomycin C. Weekly blood counts were retrospectively plotted to characterize the time course of cytopenias. Dose-volume parameters were correlated with blood counts at a standardized time point to identify predictors of initial blood count nadirs. Results Leukocytes, neutrophils, and platelets reached a nadir at week 3 of treatment. Smaller volumes of the pelvic BM correlated most strongly with lower week 3 blood counts, more so than age, sex, body mass index (BMI), or dose metrics. Patients who had ≥750 cc of pelvic BM spared from doses of ≥30 Gy had 0% grade 3+ leukopenia or neutropenia at week 3. Higher V40 Gy to the lower pelvic BM (LP V40) also correlated with cytopenia. Patients with an LP V40 >23% had higher rates of grade 3+ leukopenia (29% vs 4%, P =.02), grade 3+ neutropenia (33% vs 8%, P =.04), and grade 2+ thrombocytopenia (32% vs 7%, P =.04) at week 3. On multivariate analysis, pelvic BM volume and LP V40 remained associated with leukocyte count, and all marrow subsite volumes remained associated with neutrophil counts at week 3 ( P Conclusions Larger pelvic BM volumes correlate with less severe leukocyte and neutrophil nadirs, suggesting that larger total "marrow reserve" can mitigate cytopenias. Sparing a critical marrow reserve and limiting the V40 Gy to the lower pelvis may reduce the risk of hematologic toxicity.

Purpose To investigate patterns of failure in institutional credentialing submissions to NRG/RTOG 1005 with the aim of improving the quality and consistency for future breast cancer protocols. Methods and Materials NRG/RTOG 1005 allowed the submission of 3-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), and simultaneous integrated boost (SIB) breast plans. Credentialing required institutions to pass a 2-step quality assurance (QA) process: (1) benchmark, requiring institutions to create a plan with no unacceptable deviations and ≤1 acceptable variation among the dose volume (DV) criteria, and (2) rapid review, requiring each institution's first protocol submission to have no unacceptable deviations among the DV criteria or contours. Overall rates, number of resubmissions, and reasons for resubmission were analyzed for each QA step. Results In total, 352 institutions participated in benchmark QA and 280 patients enrolled had rapid review QA. Benchmark initial failure rates were similar for 3DCRT (18%), IMRT (17%), and SIB (18%) plans. For 3DCRT and IMRT benchmark plans, ipsilateral lung most frequently failed the DV criteria, and SIB DV failures were seen most frequently for the heart. Rapid review contour initial failures (35%) were due to target rather than organs at risk. For 29% of the rapid review initial failures, the planning target volume boost eval volume was deemed an unacceptable deviation. Conclusions The review of the benchmark and rapid review QA submissions indicates that acceptable variations or unacceptable deviations for the ipsilateral lung and heart dose constraints were the most commonly observed cause of benchmark QA failure, and unacceptable deviations in target contouring, rather than normal structure contouring, were the most common cause of rapid review QA failure. These findings suggest that a rigorous QA process is necessary for high quality and homogeneity in radiation therapy in multi-institutional trials of breast cancer to ensure that the benefits of radiation therapy far outweigh the risks.

When surgery is the first line of breast cancer treatment, numerous randomized clinical trials and meta-analyses have demonstrated that postmastectomy radiation therapy (PMRT) improves locoregional control and survival for many women with axillary lymph node-positive disease. In contrast, there are no randomized data regarding the use of PMRT in women who receive neoadjuvant chemotherapy (NAC) first followed by mastectomy. This has led to controversy regarding which patient with breast cancer will benefit from PMRT after NAC, particularly in women with clinically node-positive axillary disease that responds well and is down staged to pathologically negative disease at surgery (ypN0). We review the current evidence on this topic, which forms the underlying basis for the ongoing phase III clinical trial-National Surgical Adjuvant Breast and Bowel Project (NSABP) B51/RTOG 1304-that is examining the role of regional nodal irradiation in patients with clinical N1 disease that responds to NAC and becomes ypN0 at surgery.

Background To compare patterns of care for elderly patients versus non-elderly patients with non-surgically treated stage III non-small cell lung cancer (NSCLC) using the National Cancer Database (NCDB). We hypothesize that elderly patients are less likely to receive curative treatments, including concurrent chemoradiation (CCRT), compared to non-elderly patients. Methods We identified patients from the NCDB between 2003 and 2014 with non-surgically treated stage III NSCLC. We defined elderly as ≥70 years old and non-elderly

Purpose To identify a panel of radiation-responsive plasma proteins that could be used in a point-of-care biologic dosimeter to detect clinically significant levels of ionizing radiation exposure. Methods and Materials Patients undergoing preparation for hematopoietic cell transplantation using radiation therapy (RT) with either total lymphoid irradiation or fractionated total body irradiation were eligible. Plasma was examined from patients with potentially confounding conditions and from normal individuals. Each plasma sample was analyzed for a panel of 17 proteins before RT was begun and at several time points after RT exposure. Paired and unpaired t tests between the dose and control groups were performed. Conditional inference trees were constructed based on panels of proteins to compare the non-RT group with the RT group. Results A total of 151 patients (62 RT, 41 infection, 48 trauma) were enrolled on the study, and the plasma from an additional 24 healthy control individuals was analyzed. In comparison with to control individuals, tenascin-C was upregulated and clusterin was downregulated in patients receiving RT. Salivary amylase was strongly radiation responsive, with upregulation in total body irradiation patients and slight downregulation in total lymphoid irradiation patients compared with control individuals. A panel consisting of these 3 proteins accurately distinguished between irradiated patients and healthy control individuals within 3 days after exposure: 97% accuracy, 0.5% false negative rate, 2% false positive rate. The accuracy was diminished when patients with trauma, infection, or both were included (accuracy, 74%-84%; false positive rate, 14%-33%, false negative rate: 8%-40%). Conclusions A panel of 3 proteins accurately distinguishes unirradiated healthy donors from those exposed to RT (0.8-9.6 Gy) within 3 days of exposure. These findings have significant implications in terms of triaging individuals in the case of nuclear or other radiologic events.

Purpose To identify various dosimetric parameters of bone marrow cavity that correlate with acute hematologic toxicity (HT) in patients with anal squamous cell carcinoma treated with definitive chemoradiation therapy (CRT). Methods and materials We analyzed 32 patients receiving CRT. The whole pelvic bone marrow (PBM) and the lumbosacral spine (LSS) subregion were contoured for each patient. Marrow cavities were contoured using the Hounsfield units (HUs) of 100, 150, 200, and 250 as maximum density threshold levels. The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. The endpoint was grade ≥3 HT (HT3+). Normal-tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Maximal likelihood estimate was used to compare the parameter set. Logistic regression was used to test associations between HT and both dosimetric and clinical parameters. Results Ten patients (31%) experienced HT3+. While dose to both LSS and PBM significantly predicted for HT3+, LSS was superior to PBM by logistic regression and LKB modeling. Constrained optimization of the LKB model for HT3+ yielded the parameters m=0.21, n=1, and TD 50 = 32 Gy for LSS. The NTCP fits were better with the whole bone than with marrow cavity using any HU threshold. Mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3+, respectively. Mean dose and low-dose radiation parameters (V5, V10, V15, V20) of whole bone or bone cavities of LSS were correlated most significantly with HT3+. Conclusions For predicting the risk of HT3+, whole-bone contours were superior to marrow cavity and LSS was superior to PBM by LKB modeling. The results confirm PBM and LSS as parallel organs when predicting hematologic toxicity. Recommended dose constraints to the LSS are V10 ≤80%. An LSS mean dose of 23.5 Gy is associated with a 10% risk of HT.

To determine whether higher pre-treatment metabolic tumor volume (tMTV-pre) is associated with worse overall survival (OS) in patients with inoperable NSCLC treated with definitive chemoradiation (CRT).This is a secondary analysis of the American College of Radiology Imaging Network (ACRIN) 6668/Radiation Therapy Oncology Group 0235 trial. Pre-treatment PET scans were performed on ACRIN-qualified scanners. Computer-aided MTV measurement was performed using RT_Image. Kaplan-Meier curves and Cox proportional hazards regression models were used to assess the association between tMTV and OS.Of the 250 patients enrolled on the study, 230 were evaluable for tMTV-pre. Patients with MTV-pre32 mL (median value) vs. ≤32 mL had worse median OS (14.8 vs. 29.7 months, p 0.001). As a continuous variable, higher tMTV-pre (per 10-mL increase) remained associated with worse OS (HR = 1.03, p 0.001) after controlling for other variables. A significant interaction between radiation dose and tMTV-pre occurred for OS (p = 0.002), demonstrating that the negative prognostic impact of tMTV-pre decreased as radiotherapy dose increased. Among patients with tMTV-pre ≤32 mL, there was no difference in survival according to radiotherapy dose delivered (p = 0.694). However, median OS was inferior in patients with tMTV-pre32 mL who received ≤60 Gy compared with those who received 61-69 Gy or ≥70 Gy (p = 0.001).Higher tMTV-pre is associated with significantly worse OS in inoperable stage III NSCLC treated with definitive CRT. Our findings suggest that for patients with large tMTV-pre, achieving a therapeutic radiation dose may help maximize OS. Prospective studies are needed to confirm this finding.

PET imaging has become a useful diagnostic tool in patients with anal cancer. We evaluated the prognostic value of metabolic tumor volume (MTV) in patients with anal cancer treated with definitive chemoradiotherapy. Methods: Patients with anal cancer who underwent PET imaging for pretreatment staging or radiation therapy planning from 2003 to 2011 were included. PET parameters included MTV and maximum standardized uptake value (SUVmax). Total MTV (MTV-T) was defined as the sum of the volumes above a standardized uptake value 50% of the SUVmax within the primary tumor and involved nodes. Kaplan–Meier and Cox regression models were used to test for associations between metabolic or clinical endpoints and overall survival (OS), progression-free survival (PFS), and event-free survival (EFS). Results: Thirty-nine patients were included. Median follow-up for the cohort was 22 mo. Overall, 6 patients died and 9 patients had disease progression. The 2-y OS, PFS, and EFS for the entire cohort were 88%, 74%, and 69%, respectively. Higher MTV-T was associated with worse OS (P = 0.04), PFS (P = 0.004), and EFS (P = 0.002) on univariate analysis. Patients with an MTV greater than 26 cm3 had worse PFS than did those with an MTV of 26 cm3 or less (33% vs. 82%, P = 0.003). SUVmax was not prognostic for any outcome. Higher T classification (T3/T4 vs. T1/T2) was associated with worse PFS and EFS. When adjusting for T classification, MTV-T remained a significant predictor for PFS (P = 0.01) and EFS (P = 0.02). Conclusion: MTV-T yields prognostic information on PFS and EFS beyond that of established prognostic factors in patients with anal cancer.

To identify dosimetric parameters that correlate with acute hematologic toxicity (HT) in patients with squamous cell carcinoma of the anal canal treated with definitive chemoradiotherapy (CRT).We analyzed 33 patients receiving CRT. Pelvic bone (PBM) was contoured for each patient and divided into subsites: ilium, lower pelvis (LP), and lumbosacral spine (LSS). The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. Endpoints included grade ≥3 HT (HT3+) and hematologic event (HE), defined as any grade ≥2 HT with a modification in chemotherapy dose. Normal tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT and dosimetric/clinical parameters.Nine patients experienced HT3+ and 15 patients experienced HE. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.175, n = 1, and TD(50) = 32 Gy. With this model, mean PBM doses of 25 Gy, 27.5 Gy, and 31 Gy result in a 10%, 20%, and 40% risk of HT3+, respectively. Compared with patients with mean PBM dose of30 Gy, patients with mean PBM dose ≥30 Gy had a 14-fold increase in the odds of developing HT3+ (p = 0.005). Several low-dose radiation parameters (i.e., PBM-V10) were associated with the development of HT3+ and HE. No association was found with the ilium, LP, or clinical factors.LKB modeling confirms the expectation that PBM acts like a parallel organ, implying that the mean dose to the organ is a useful predictor for toxicity. Low-dose radiation to the PBM was also associated with clinically significant HT. Keeping the mean PBM dose22.5 Gy and25 Gy is associated with a 5% and 10% risk of HT, respectively.