Nodal Irradiation Research Articles

Impact of the G8 Score on Treatment Strategies and Outcome in Definitive Radiotherapy for the Elderly Esophageal Cancer Patients

Although chemoradiotherapy (CRT) is widely used as a curative treatment for esophageal cancer, it is often difficult to perform standard CRT for the elderly in the real world. This study aimed to investigate the impact of the Geriatric 8 (G8) score on treatment strategies and outcome in definitive radiotherapy (RT) for elderly esophageal cancer patients. We analyzed 81 esophageal cancer patients aged ≥65 years who received definitive RT between 2018 and 2021. The G8 score was acquired at the first visit to the radiation oncology department. The treatment strategy was decided by a multi-disciplinary conference, and the G8 score was not used to determine the treatment strategy. Standard treatment (standard CRT) was defined as RT with elective nodal irradiation and a total dose ≥50 Gy, and chemotherapy with two cycles of platinum (70 mg/m2) and 5FU (700 mg/m2 for 4 days) concurrently. The Kaplan-Meier method was used to generate actual survival curves. The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used to assess toxicities. The Mann-Whitney U test was used to compare the two groups, and statistical significance was set at p<0.05. The Receiver Operating Characteristic (ROC) curve was used to calculate the cutoff value. The Median follow-up time was 30 months (range: 8-51) for survivors. The mean G8 scores by treatment strategy were 13.9 (range: 9-17) for standard CRT group (n = 26), 12.1 (range: 7-16) for reduced CRT group (n = 30), and 9.7 (range: 4.5-14) for RT alone group (n = 25). G8 score was significantly higher for standard CRT (p = 0.017) and significantly lower for RT alone (p<0.01). The cut-off value of the G8 score for standard treatment, calculated by the ROC curve, was 12.5 points. In the non-standard treatment group, the cut-off value of the G8 score for RT alone, calculated by the ROC curve, was 10.5 points. The 2-year overall survival (OS) rates for standard CRT, reduced CRT and RT alone were 74%, 71% and 35%, respectively, and significantly lower in RT alone (p<0.001). The 2-years OS rates for G8 score >10.5 points and ≤10.5 points were 69% and 48%, respectively (p = 0.039). Grade 3 or higher acute toxicities were observed in 33 patients (41%); 14 (54%) in standard CRT, 17 (57%) in reduced CRT and 2 (8%) in RT alone. Grade 5 acute toxicity was not observed. G8 scores tended to be higher in the patients with grade 3 or higher acute toxicities, but the difference was not statistically significant (p = 0.057). Grade 3 or higher late toxicities were observed in 7 patients. Our results suggest that there is an association between the G8 score and clinicians' treatment decisions. Although RT alone could be safely performed even in patients with low G8 scores, administration of chemotherapy strongly affected prognosis. These results suggest the importance of developing less toxic systemic therapy regimens for patients with low G8 scores.

Quality Assurance in a Phase III, Multicenter, Randomized Trial of POstmastectomy radioThErapy in Node posiTive Breast Cancer with or without Internal mAmmary nodaL Irradiation (POTENTIAL): A Planning Dummy Run

To report the planning dummy run results of the POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL) trial-a multicenter, randomized, phase 3 trial-to evaluate postmastectomy radiotherapy, with or without internal mammary nodal irradiation, for patients with high-risk breast cancer. All participating institutions were provided the contours of the dummy run case, and they generated radiotherapy (RT) plans per protocol guidelines. The plans were reviewed and feedback were provided by the quality assurance team, after which the institutions resubmitted revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed both in the primary and final submission. Theplans from 26 institutions were included in the analysis. A number of major deviations were found in the primary submission, such as less strict constraint on organs at risk (OARs) V5Gy, and no application of chest wall skin flash. The protocol compliance rates of the dose coverage for the planning target volume of the chest wall (PTVcw), PTV of supra/infraclavicular fossa plus axilla levels I, II, III (PTVsc+ax), and PTV of the IMN region (PTVim) were all significantly improved in the final submission compared with those in the primary submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8, respectively. For OARs, the protocol compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. All major deviations were corrected and protocol compliance was significantly improved and of high level in the final submission. Moreover, the variations were reduced. Therefore, a planning dummy run was essential to guarantee good RT plan quality and inter-institutional consistency for multicenter trials.

Cardiopulmonary Protection for Bilateral Breast Irradiation: A Dosimetric Comparison between Proton and Photon Plans

Recent advances in cancer treatment improve cancer survivorship. Cardiovascular disease has become the leading cause of non-cancer death in breast cancer survivors. Therefore, risk of cardiopulmonary toxicities during multimodality treatment should be assessed carefully. It remains to be defined the best scenario for proton therapy to confer meaningful cardiovascular protection in the setting of breast irradiation. We hypothesized proton therapy plan provides optimal cardiopulmonary protection during bilateral breast irradiation. The study aimed to compare cardiopulmonary dosimetric parameters of proton and photon radiotherapy plans. We conducted a retrospective study and patients with bilateral breast cancer indicated for radiotherapy between January 01, 2010 and December 31, 2020 were included. All patients received whole breast or chest wall irradiation with or without regional nodal irradiation. The dose scheme was 50-50.4 Gy in 25-28 fractions. Boost was allowed if patients receiving breast conserving surgery or known risk factors. The dosimetric parameters included planning target volume, mean dose to the heart, the volume of whole lung receiving 5 Gy, 10 Gy, and 20 Gy. For photon therapy, volumetric modulated arc therapy using double partial arc plans was generated with Pinnacle 9.8, Elekta Synergy and tomotherapy helical plan was generated with Tomo Hi-Art planning system. For proton therapy, treatment planning was generated with Ray station 9A. All data was managed using SAS v.9.4 software. Analysis of variance (α = 0.05) was used to compute the dosimetry of different treatment modalities. The statistical significance was considered with a p-value <0.05. Thirty-one patients with bilateral breast cancer were included, including 12 bilateral breast irradiation patients and 6 bilateral chest wall irradiation patients. The mean dose of heart was 53.0±43.3 cGy in proton therapy while 736.6±225.1 cGy and 869.67±241.0 cGy in Tomotherapy and volumetric modulated arc therapy respectively. The volume of whole lung receiving 5 Gy was 15.4±7.91% in proton therapy while 46.1±10.8% and 46.3±2.5% in Tomotherapy and volumetric modulated arc therapy respectively. The volume of whole lung receiving 20 Gy was 7.7±4.3% in proton therapy while 15.4±5.6% and 19±3.5% in Tomotherapy and volumetric modulated arc therapy respectively. The effects of cardiopulmonary protection were more significant for chest wall irradiation over breast irradiation. Proton radiotherapy provided significant dose reduction for bilateral breast irradiation. The benefit is more significant is patients receiving bilateral chest wall irradiation. Further clinical validations will be warranted to confirm the clinical relevance of the finding.

Standardizing Breast Adjuvant Radiation Therapy Practices in a Diverse Health System through Development of a Delphi Consensus Supported Clinical Algorithm

Adjuvant radiation therapy (RT) for early breast cancer is a highly effective treatment option. However, the multitude of available techniques backed by strong clinical evidence can result in a lack of consistency in treatment approaches, even within a single healthcare organization. This presents challenges for both providers and patients in making informed decisions. To address this issue, our radiation department, which serves a large and diverse health system, developed a clinical algorithm for adjuvant RT for breast cancer. This algorithm was created to enhance the quality and standardization of care delivered across our network. A modified Delphi technique was used. A panel of eight experienced breast radiation oncologists from our institution was assembled. The panel first identified the common clinical scenarios encountered in treating patients with adjuvant breast RT, and then made recommendations for the primary and alternative approaches for each scenario. NCCN guidelines, ASTRO executive summaries, and published national and international randomized trials were used for reference. In case of disagreements, the final recommendation was reached through a majority vote. The draft algorithm was also shared with medical oncologists, surgeons, and patient advocates to gather their input prior to final approval by the expert panel. Consensus was reached for three broad clinical scenarios for patients who have undergone lumpectomy or mastectomy: Ductal Carcinoma in Situ (DCIS), Invasive Cancer Node Negative (ICN0), and Invasive Cancer Node Positive (ICN+). The panel agreed subdivision of the scenarios into three risk groups (low, intermediate, and high) and three age groups, based on guidelines and consensus statements. For DCIS patients, size, grade, margin status, hormone receptor status, and tumor focality were used for further stratification. For ICN0 patients, HER2 receptor status and lymphovascular space invasion were also included. For ICN+ patients, nodal status (negative versus 1-3 positive nodes versus more than 3 positive nodes) was used for stratification. Additionally, DCIS and ICN0 patients were further divided into age groups. The panel reached consensus recommendations for RT, including whole breast RT, partial breast RT, chest wall RT, regional nodal irradiation, or omission of RT for each sub-group. Clinical trial enrollment was also recommended where appropriate. A breast cancer adjuvant RT algorithm was developed with the aim of standardizing care for patients with breast cancer. Implementation is expected to standardize treatment recommendations in our health system and to streamline the shared decision-making process with patients.

Involved Site Radiotherapy in HPV Positive Oropharyngeal Cancer: Patterns of Failure Analysis Across Prospective De-Escalation Trials

HPV-associated oropharyngeal cancers (HPV+OPC) have a favorable prognosis with ongoing efforts to reduce long term toxicity while maintaining oncologic outcomes. One method under investigation includes lowering the elective radiation dose or in some cases omitting radiation to elective lymphatic nodal stations. Furthermore, pre-clinical evidence demonstrates that elective nodal irradiation blunts the anti-tumor immune response in head and neck cancer. This is a pooled secondary analysis reporting patterns of failure in patients (pts) with HPV+OPC enrolled on consecutive induction chemo- or chemoimmunotherapy (IC) based response-adaptive de-escalation trials and treated with involved-site radiotherapy (ISRT). Pts treated on two prospective phase II trials as well as on a prospective cohort registry were included for analysis. Pts with ≥ 50% response to IC based on RECIST 1.1 who received de-escalated definitive radiotherapy (RT) or concurrent chemoradiation (CRT) with ISRT were evaluable. Pts with locally advanced low risk or high-risk HPV+OPC (LR and HR, respectively) were eligible for enrollment. Pts were considered to have HR if at least one of the following criteria was met: T4 primary, N2c-N3 disease (AJCC 7th ed.), or > 10-20 pack years smoking. In the first trial, pts with ≥ 50% response to IC received RT to gross disease plus a 1.5 cm margin (PTV1) and to the next echelon of uninvolved nodes (PTV2). Pts with LR received 50 Gy in 2 Gy daily fractions without chemotherapy; pts with HR received 30 Gy in 1.5 Gy BID fractions to PTV2 with a 15 Gy sequential boost to PTV1 with CRT. In the subsequent trial, pts with ≥ 50% response received RT to PTV1 alone to 50 Gy in 2 Gy daily fractions; concurrent CRT was included if pts had HR. Survival was estimated using the Kaplan Meier method for progression free survival (PFS), locoregional PFS (LRPFS), and overall survival (OS). Patterns of failure analysis was performed by comparing RT plans to radiographic surveillance scans. Of 172 evaluable pts, 119 (69.2%) achieved a ≥ 50% response to IC and received definitive ISRT. 45 (37.8%) pts evaluated received RT to gross disease only plus margin without the next nodal echelon included. With a median follow up of 46 (IQR 34-65) months, 3-year PFS, LRPFS, and OS with their 95% confidence intervals were 96.2% (90.1-98.5%), 97.1% (91.1-99.0%), and 96.2% (90.3-98.6%), respectively. All locoregional failures were in-field and in the high dose region. No failures were observed in the RT omitted neck. This prospective experience demonstrates feasible volume de-escalation using IC response-based selection with progressively smaller elective volumes over time. Notably, despite a marked reduction in elective treatment volume, there were no regional out-of-field failures. IC may allow for selection of pts with favorable tumor biology and microscopic disease sterilization in the regional nodes. Further efforts at elective nodal de-escalation are needed.

A Phase II Randomized Clinical Trial to Assess Toxicity and Quality of Life of Breast Cancer Patients with Hypofractionated vs. Conventional Fractionation Radiotherapy with Regional Nodal Irradiation

To compare acute toxicity between conventional fractionated radiation therapy (CFRT) and hypofractionated radiation therapy (HFRT) for patients undergoing breast-conserving surgery or mastectomy with breast or chest wall and regional nodal irradiation (RNI). The secondary endpoints were acute and subacute toxicity, cosmesis, quality of life, and lymphedema features. Unblinded randomized trial with a total of 86 patients treated with CFRT (n = 33; 50 Gy/25 fractions ± sequential boost [10 Gy/5 fractions]) versus HFRT (n = 53; 40 Gy/15 fractions ± concomitant boost [8 Gy/15 fractions]). Women included for enrollment were 18 years or older and diagnosed with breast carcinoma, staging T1-4, with at least one positive lymph node (American Joint Committee on Cancer - AJCC 8th). The surgery performed was mastectomy or breast-conservative surgery with the investigation of sentinel lymph node or axillary dissection. Toxic effects and cosmesis evaluation used the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE) and the Harvard/NSABP/RTOG scale. Patients-reported QoL was determined using the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and the breast cancer-specific supplementary questionnaire (QLQ-BR23). The comparative analysis of categorical variables between the control and experimental groups used the Chi-square test and Fisher's exact test, while numerical variables basing on the Mann-Whitney U test. The intergroup comparison of the EORTC QLQ-C30 used the Generalized Equations Estimating method. All analyses used 2-sided α = 0.05 with R software version 4.1.2. Lymphedema determination compared volume differences between the affected and contralateral arms using the Casley-Smith volume formula. Grade 2 and grade 3 skin rash dermatitis were lower with HFRT than with CF-RT (28% vs. 52%, 0% vs. 6%; p = 0.022, respectively). HFRT vs. CFRT had lower rate of grade 2 hyperpigmentation (23% vs. 55%; p = 0.005). Overall rates of any physician-assessed grade ≥ 2 and grade ≥ 3 acute toxicities were no different between HFRT vs. CFRT arms. There was no statistical difference between the CFRT and the HFRT regarding cosmesis, lymphedema rate (13% vs. 12% HFRT vs. CFRT; p = 1.000, respectively), and functional and symptom scales during irradiation and after six months of treatment. HF-RT showed lower rates of acute toxicity, with no changes in quality-of-life outcomes.

Prospective Clinical Trial of Premastectomy Radiotherapy Followed by Immediate Breast Reconstruction for Operable Breast Cancer

Radiation delivered prior to mastectomy and autologous breast reconstruction may avoid the adverse effects of radiation on autologous donor tissue while providing the psychologic benefit of immediate reconstruction. We aimed to study the feasibility of premastectomy radiation therapy (PreMRT). A total of 50 women enrolled in a prospective trial of preoperative radiation to the breast and regional nodes followed by mastectomy with axillary evaluation and immediate breast reconstruction. The trial was embedded in a randomized trial of hypofractionated versus conventionally fractionated regional nodal irradiation (NCT02912312). Eligible women enrolled from 2018-22, had cT0-T3 N0-3 breast cancer, and a pre-operative recommendation for radiation. The primary outcome was frequency of complete free flap loss. Mastectomy skin flap necrosis was assessed by validated SKIN grading score. The Satisfaction with Breast Cosmetic Outcomes Scales evaluated patient satisfaction with cosmetic result. Descriptive statistics and 95% exact confidence intervals were calculated. One patient withdrew prior to any treatment and one elected not to have breast reconstruction. Median age of the 48 women completing PreMRT and reconstruction was 48 [range 31-72]. Most had ER-positive HER2-negative (77%), cT3 (54%) or cT2 (38%), cN1 (79%) disease and received 50 Gy in 25 fractions (n = 24) or 40.05 Gy in 15 fractions (n = 23). Four received 10-16 Gy internal mammary or infraclavicular boost. 35% VMAT, 48% matched photon-electron, and 17% partially-wide-tangent technique. Median time to surgery was 23 days [14-85]. Skin reaction delayed surgery for one patient. Most had skin-sparing mastectomy (92%) and axillary lymph node dissection (67%). 12 surgeons performed the reconstructions: 35 deep inferior epigastric perforators; 4 profunda artery perforator; 2 muscle-sparing transverse rectus abdominis myocutaneous; 1 latissimus dorsi (LD); 2 LD/implant; 2 LD/tissue expander (TE); and 2 subpectoral (SP) TE. There were no complete flap losses. Two patients (4.4%, 95% CI 0.5%-14.8%) with free flaps had partial flap loss with revision surgery. Both patients with SP TEs had infections and unplanned reoperation. The protocol was subsequently amended to not allow SP TE reconstruction. Eight patients had skin flap necrosis: 5 partial and 3 full thickness necrosis; only 1 required operative debridement. Seven had pathologic complete response. At six months 19/31 (61%) reported being "quite a bit" or "very much" satisfied with how they looked in the mirror clothed. There are no recurrences with a median follow up of 33 months [5-119]. Radiation treatment of the breast and lymph node basins prior to mastectomy with immediate autologous reconstruction is feasible. There were no autologous flap loses and complication rates are similar to reconstruction after radiation series. This promising strategy reduces time to autologous reconstruction and merits further prospective study.

Evaluation of Metastatic Potential in Esophageal and Gastroesophageal Junction (GEJ) Cancer with Adherence to Elective Nodal Volume Guidelines: A Retrospective Analysis of Elective Nodal Irradiation

In 2015, expert guidelines on esophageal/GEJ cancer contouring for intensity-modulated radiation therapy (IMRT) were published in IJROBP, which delineate recommended elective nodal basins (celiac, para-aortic, gastrohepatic ligament, supraclavicular) to be irradiated depending on the primary tumor location. We hypothesize that incomplete coverage of these areas increases the risk of the development of distant failures. Patients treated for non-metastatic esophageal or GEJ cancer with chemoradiotherapy pre-operatively or definitively from 2012 to 2021 were retrospectively identified from a single institution database. Radiation plans of eligible patients were then analyzed by tumor location. Plans were deemed guideline-compliant if radiation dose coverage, between 41.4 to 45 Gy, encompassed nodal basins recommended by the 2015 guidelines. The primary endpoint of this study was the overall rate of distant disease. Other endpoints included locoregional failures, defined as failures within the radiation field but outside of the primary tumor, and local failures within the gross tumor volume. Summary and descriptive statistics were used to define collected variables. Differences were measured using chi-square and Fisher's exact test for categorical variables and two-sided t-tests for continuous measures. Assessment of distant, locoregional, and local failures were assessed using univariate logistic regression with statistical significance at p < 0.05. With a median follow-up of 25.0 months, 37 patients, with a median age of 66, were included in the study. Most patients were male (94.6%) with cT3 (54.1%), cN0 (43.2%), moderately differentiated (47.1%) adenocarcinoma (75.7%) located at the GEJ (56.8%). The median radiation dose used was 50.4 Gy, with the majority of patients receiving concurrent carboplatin and paclitaxel (83.8%). Four patients received induction chemotherapy and 20 (55.6%) underwent esophagectomy. When examining guideline compliance, 17 (46.0%) radiation plans demonstrated adequate ENI. The most common improperly covered nodal basin was para-aortic (65.0%), followed by gastrohepatic (30.0%). No patients with sufficient ENI coverage (0/17) developed distant failure compared to 45.0% (9/20) with insufficient coverage (p = 0.001). There were inappreciable differences in locoregional or local failure rates between those with and without complete ENI. Patients with complete ENI were more likely to be of larger craniocaudal length (p = 0.007) or have N2 disease (p = 0.003). When examining other tumor characteristics (histologic subtype, location, HER2 status, esophagectomy rate) of patients with and without complete ENI, no further differences were noted. These results suggest that proper coverage of nodal basins, when indicated by expert guidelines, could improve distant metastasis. ENI analysis of previous prospective CRT studies for esophageal cancer could validate these findings.

Long Term Evaluation of Cardiac Events and Outcomes Following Breast Cancer Irradiation

Although whole heart dose has been associated with cardiac toxicity in patients receiving radiation therapy for breast cancer, data detailing the clinical significance of cardiac substructures, particularly the left anterior descending artery (LAD), are limited. We investigated whether dose to the LAD correlates with adverse cardiac events and death. We identified 190 female patients treated from 2002 to 2019 who received breast or chest wall irradiation, with or without regional nodal irradiation. Ninety-three patients were treated on their right side, 95 on their left, and two were bilateral. Medical records were queried in healthcare software to identify cardiac events after radiation therapy. Mean and maximum LAD and heart doses, as well as V15LAD, were calculated. Univariate and multivariate Cox regression analyses were performed to determine their association with cardiac toxicity as well as death. Cumulative incidence curves for death and cardiac toxicity were also calculated for the patient population. Median follow-up time was 68 months. Thirty patients experienced a cardiac event (15.7%), with three of these being grade 3 or higher. On univariate analyses, left side (hazard ratio 8, P<0.001), increased Mean LAD Dose per cGy (1.001, P = 0.01), Mean Heart Dose (1.16, P = 0.01), and anatomic stage (3.5, P = 0.003) were statistically significant predictors of death but not of adverse cardiac events. Statistically significant predictors of adverse cardiac events were the receipt of chemotherapy (2.68, p = 0.046) which remained significant even after adjusting for radiation parameters. There was no association with hormonal therapy use. Cumulative incidence curves predicted a 14.11% probability of a cardiac event 5 years after treatment and a 25.7% probability at 10 years after treatment. They also predicted a 9.43% probability of death at both 5- and 10-years post-treatment. On this long-term analysis, doses to the heart seemed to negatively impact survival, but did not have a clear association between cardiac events. In contrast, utilizing cytotoxic systemic therapy seemed have an association, even when adjusted for on multivariable models for cardiac events.

Establishing a Risk Stratification Model to Identify Clinically High-Risk N0 Breast Cancer Who Could Benefit from Regional Nodal Irradiation: A Single Institute Analysis

The adverse clinical features for pN0 BC patients significantly varies and there is no established clinical risk stratification system to identify those "high-risk" pN0 BC patients who might benefit from RNI. The purpose of this real-world study was to investigate the risk factors for developing recurrence among patients with pathological T1-3N0 breast cancer (BC) treated with breast-conserving surgery (BCS) followed by whole breast irradiation alone (WBI) and identify those clinically high-risk BCs who could benefit from regional nodal irradiation (RNI). Female BC patients treated from 2009 to 2016 were retrospectively reviewed. The disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and survival differences were compared with the log-rank test. Univariate and multivariate analysis was performed using Cox logistic regression analysis. An external validation was conducted by using SEER database. A total of 622 BC patients treated with BCS+WBI alone were included. With a median follow-up of 82 months, the 7-year OS and DFS for the entire cohort was 97% and 91%, respectively. Multivariable Cox analysis indicated that tumor size (p = 0.006), tumor location (p = 0.033), lymphovascular invasion (LVI) status (p = 0.0028) and Ki-67 index (p = 0.051) were independent risk factors for DFS, while only tumor size was the only independent risk factors for OS (p = 0.029). A scoring system was developed using these four factors and the 7-year DFS and OS were 97% and 96% for patients with 0-1 risk factors, 95% and 82% for patients with ≥2 risk factors (p<0.0001 for DFS, and p = 0.0063 for OS). Based on tumor size and tumor location, an external validation by demonstrated that the 7-year OS was 90% and 88% for patients with 0-1 risk factor, which was significantly better than those defined as high-risk BC patients (82%, p<0.0001). By using our institute database, we establish a risk stratification system for identifying sub-group of pN0 BC patients, who are at high risk for developing recurrence. The results of our study support tailored RT decision-making according to individual risks, which needed to be confirmed in further studies.

Challenging the Role of Subtotal Resection Following Proton Radiotherapy for Adenoid Cystic Carcinoma of the Head and Neck

To report long-term outcomes of patients with adenoid cystic carcinoma (ACC) of the head and neck treated with proton radiotherapy. On this IRB-approved, single institutional prospective outcomes registry, 56 patients were included with de novo, nonmetastatic adenoid carcinoma of the head and neck treated with primary (n = 9) or adjuvant proton therapy from June 2007 to December 2021. The cohort had 30 women and 26 men with a median age of 57 years (range, 10-81 years). Twenty-nine percent (n = 16) had intracranial extension, 23% (n = 13) had orbital extension, and 55% (n = 31) had clinical cranial nerve involvement at the time of radiotherapy. Thirty patients underwent gross total resection (GTR), 26 had gross disease at the time of treatment undergoing a subtotal resection (STR) (n = 17) or biopsy alone (n = 9). The median dose to the primary site was 72.6 GyRBE (range, 64-74.4 GyRBE) delivered in either once (n = 19) or twice (n = 37) daily treatments. Thirty patients received either elective nodal irradiation (ENI) in a node negative neck or concurrent chemotherapy. With a median follow-up of 6.2 years (range, 0.9 - 14.7 years), the 5-year local-regional control (LRC), disease free survival (DFS), cause-specific survival (CCS) and overall survival (OS) were 88%, 85%, 89%, and 89%, respectively. Cranial extension (p = 0.003) and gross residual tumor (p = 0.0388) were factors associated with decreased LRC. While LRC for those with a GTR was 96%, those with STR or biopsy alone were 81% and 76%, respectively. T-stage (p = 0.0154), cranial extension (p = 0.0056), extent of resection (p = 0.0355), and gross residual tumor (p = 0.0094) were associated with decreased DFS. T-stage (p = 0.0099), extent of surgery (p = 0.029) and gross residual tumor (p.0071) were associated with decreased CCS. The 5-year cumulative incidence of clinically significant late grade ³3 toxicity was 15% and the crude incidence at most recent follow-up was 23% (n = 13). There was no LRC benefit with ENI (p = 0.94). Proton therapy provides excellent disease control for head and neck ACC with acceptable toxicity. Gross residual disease at the time of treatment and intracranial involvement were significant prognostic features for worse outcomes. STR did not confer benefit over biopsy only at 5-years and may question the role of extensive and morbid operations if GTR is not technically feasible.

Toxicity and Efficacy of Hypofractionated Regional Nodal Irradiation

Hypofractionated whole-breast irradiation (HF-WBI) has been widely adopted. However, there are still limited data on whether hypofractionated regional nodal irradiation (HF-RNI) is safe and effective. We report toxicity and cancer outcomes with our HF-RNI approach. This retrospective study included 154 patients with node-positive or high-risk node-negative breast cancer treated with HF-RNI with curative intent at a single academic institution from 2008-2020. Median dose to the breast or chest wall/reconstructed breast was 40 Gy in 16 fractions (interquartile range [IQR], 40-45 Gy in 16-18 fractions). Median dose to the regional nodes was 40 Gy in 16 fractions (IQR, 40-40 Gy in 16-16 fractions). The primary end-point was the rate of chronic toxicity. Secondary endpoints were local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), disease-free survival (DFS), and overall survival (OS). Toxicities were scored using the Common Terminology Criteria for Adverse Events v5.0 and Radiation Therapy Oncology Group scale where appropriate. This study was approved by the Institutional Review Board. Median follow-up was 46 months (IQR 33-63 mo). Median age at diagnosis was 58 years. Sentinel lymph node biopsy (SLNB) was performed in 49% of patients, 16% underwent both SLNB and axillary lymph node dissection (ALND), 32% underwent ALND alone, and 3% had no axillary surgery; 79% had partial mastectomy and 21% had total mastectomy with or without reconstruction. The nodal target included the supraclavicular and axillary Level 1-3 nodes in 66% of patients and supraclavicular and Level 3 nodes in 34%. The crude incidence of grade 1 chronic brachial plexopathy was 2%, grade 1 chronic limited range of motion (LROM) of the upper extremity was 3%, and chronic upper extremity lymphedema was 8% (11 patients with grade 1 toxicity and 1 patient with grade 2 toxicity). The only grade 3+ chronic toxicity was hyperpigmentation (1%). The median time to the development of the highest-grade toxicity was 10 months for brachial plexopathy, 10 months for LROM, and 11 months for lymphedema, respectively. Five-year actuarial rates of LRFS, RRFS, DFS, and OS were 98%, 99%, 90%, and 88%, respectively. HF-RNI resulted in low rates of chronic toxicities and excellent disease control in this study. Results of randomized trials of HF-RNI are needed for definitive evidence, but these retrospective data support wider adoption of HF-RNI.

Long-Term Results of a Phase II Study of Accelerated Hyperfractionated Thoracic Radiotherapy with Dose Escalation to 54 Gy for Limited-Stage Small-Cell Lung Cancer

The combination of accelerated hyperfractionated thoracic radiotherapy (AHF-TRT) of 45 Gy and concurrent chemotherapy is the standard treatment for limited-stage small-cell lung cancer (LS-SCLC). However, the optimal dose and fractionation remain controversial. We herein report the results of a phase II study investigating the utility of dose escalation to 54 Gy on AHF-RT for LS-SCLC. We enrolled patients ≤80 years old with treatment-naïve confirmed LS-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The radiation dose was 54 Gy delivered in 36 fractions in 18 treatment days over 3.6 weeks. The chemotherapy regimens were PE (cisplatin and etoposide)- or CE (carboplatin and etoposide)-based. AHF-TRT was given in 2 phases: patients initially received 36 Gy to the gross tumor plus uninvolved mediastinal nodes, followed by a boost to the gross tumor of 18 Gy. All patients were treated with three-dimensional conformal radiation therapy with multiple fields to reduce the elevated dose volume to the surrounding tissues, such as the lungs and esophagus, as much as possible. All patients were evaluated for the overall survival (OS), progression-free survival (PFS), and non-hematological toxicity. Between 2013 and 2016, a total of 13 patients were enrolled in the present study. All the patients were assessable for the response and toxicity. The median age was 67 (range, 54-78) years old, and 9 patients were male, while 4 were female. Twelve patients had a ECOG performance status of 0. The numbers of patients with Stage IIA, IIB, IIIA, and IIIB disease were one, one, eight, and three, respectively. The median follow-up for all patients was 79 (range, 13-107) months, and that for surviving patients was 90 (range, 79-107) months. The patterns of failure were locoregional-only recurrence in 0% (0 patients), both locoregional and distant in 15.4% (2 patients), and distant-only in 30.8% (4 patients). Recurrence from the elective nodal irradiation area was seen in 0% (0 patients). The 1-, 3-, 5-, and 7-year OS rates were 100%, 76.9%, 53.9%, and 44.9%, respectively, and the median OS was 83.0 months. The 1-, 3-, 5-, and 7-year PFS rates were 76.9%, 53.9%, 53.9%, and 44.9%, respectively, and the median PFS was 83.0 months. No patient experienced a grade ≥3 non-hematological adverse effect, such as esophagitis or pneumonitis, during treatment or follow-up. Grade 2 pneumonitis was observed in 2 patients (15.4%), Grade 2 esophagitis was observed in 12 patients (92.3%), and Grade 2 esophageal pain was observed in 2 patients (15.4%). In this study, AHF-TRT of 54 Gy with concurrent PE- or CE-based regimens resulted in a good OS and PFS without increasing severe toxicity. Although this regimen needs to be evaluated in more patients to fully confirm its efficacy, these outcomes suggest that dose escalation to 54 Gy may be a promising radical treatment for LS-SCLC.

Phase I-II Study of Prone Hypofractionated Accelerated Breast and Nodal Intensity Modulated Radiation Therapy

In patients (pts) with breast cancer, prone radiation therapy (RT) has been shown to reduce heart and lung dose which may decrease late toxicity. Routinely used for whole breast irradiation, its use to treat regional lymph nodes (LNs) is not widespread. In this phase I-II study, pts treated with partial mastectomy or mastectomy with 1-5 pathologically involved LNs underwent whole breast or post-mastectomy RT plus regional nodal irradiation using IMRT to the supraclavicular and level III axillary LNs. Pts who underwent sentinel LN biopsy (SLNB) alone (no axillary dissection) had the level I and II axillary LNs included in the RT field. 40.5Gy in 15 daily 2.7Gy fractions with daily concomitant 0.5Gy tumor bed boost was prescribed. Normal tissue dose constraints included heart V5Gy<5%, ipsilateral lung V10Gy<20%, contralateral lung V5Gy<15%, ipsilateral brachial plexus (BP) maximal dose (Dmax)<43Gy, spinal cord Dmax≤37.5Gy, spinal cord + 0.5cm Dmax<41Gy, thyroid contralateral lobe Dmax<16Gy, esophagus V30Gy<50% and Dmax≤40.5Gy. The primary endpoints were dosimetric feasibility and incidence of >grade 2 acute toxicity according to CTCAE, v3.0. The secondary endpoint was late toxicity. Exploratory outcomes were local recurrence, disease free survival (DFS), and overall survival (OS). Between January 2011 to December 2016, 97 pts with stage IB-IIA breast cancer were enrolled. 66 pts underwent partial mastectomy and 31 pts underwent mastectomy. 16 pts had SLNB alone. 33% (95% CI: 23.8%, 43.3%) met all protocol dose constraints. Heart, contralateral lung, spinal cord and esophagus V30Gy constraints were met by all pts. The ipsilateral lung constraint was met in 95% (95% CI: 88.6%, 98.4%) of plans with a mean V10Gy of 9.44% (SD: 6.08). The BP Dmax constraint was exceeded in 31.6% (95% CI: 22.4%, 41.9%) of plans with a mean increase of 2.86 Gy (SD: 7.92 Gy) over target. The esophageal Dmax<40.5Gy constraint was exceeded in 6 plans with an increase in 0.74 Gy (SD: 0.46 Gy) over target. There were no grade 3 acute toxicities meeting the primary toxicity endpoint. Common acute low-grade toxicities by pt included fatigue (grade 1: 54 [56%]; grade 2: 2 [2%]), esophagitis (grade 1: 8 [8%]; grade 2: 2 [2%]), dermatitis (grade 1: 81 [84%]; grade 2: 6 [6%]). At median and maximum follow up of 8.02 (IQR: 3.31) and 13.3 years, respectively, there were 2 local recurrences (2.1%). DFS and OS were 86.6% (95% CI: 78.2%, 92.7%) and 90.7% (95% CI: 83.1%, 95.7%), respectively. The incidence of pts with maximum grade 1, 2 and 3 late toxicities were 39 (40%), 14 (14%), and 2 (2%), respectively. The maximum grade late toxicities included 1 grade 3 retraction and 2 grade 3 asymmetries. There was no brachial plexopathy or pneumonitis. Patients treated with prone hypofractionated hybrid breast/chest wall tangents and IMRT to the regional LNs demonstrate excellent dosimetry to the heart, lungs and spinal cord, minimal acute and late toxicity and excellent clinical outcomes. PMID: 26723552.

Treatment Outcomes and Toxicity Profile of MRI-Guided Gated-Real Time Online Adaptive Stereotactic Body Radiotherapy to Patients with Pancreatic Tumors

Stereotactic body radiation therapy (SBRT) to patients with inoperable pancreas cancer has shown promising outcomes. Dose escalation is challenging given the associated risks to nearby organs at risk and requires treatment plan adaptation and motion management. This study reports the treatment related adverse events and treatment outcomes of MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy to patients with pancreatic tumors. This is a single institution retrospective IRB approved study and included patients with pancreatic tumors who were treated with MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy, consecutively between 2019 and 2022. All patients were treated with 0.35T MRI linear accelerator. All patients' charts and radiation plans were reviewed for this study. The study included 25 patients treated consecutively to 125 radiation fractions with MRI-guided SBRT. The study included 15 females and 10 males, 19 white, 2 Asians, 1 Latin American and 2 African Americans. The median age was 74, and all patients had pancreatic adenocarcinoma (92%) except two patients who had biopsy proven renal cell carcinoma metastatic to the pancreas without evidence of disease elsewhere. Most patients (68%) received chemotherapy (FOLFIRINOX or Gemcitabine / Protein-bound paclitaxel) prior to SBRT. The median dose to gross target volume (GTV) was 50 Gy, and to planning target volume (PTV) was 35 Gy. All patients were treated in 5 radiation fractions. Thirteen patients (52%) received elective nodal irradiation (ENI). All patients had at least a single real-time online adaptive replanning (median 3 fractions, range 1-5 fractions). All treatment fractions were gated (100%) with MRI guidance. The 1-, 2-, & 3- year local-regional control (LRC) were 81%, 57%, & 57% respectively (Median 16 months). The 1-, 2-, & 3- year Distant Control (DC) were 81%, 74%, & 56% respectively (Median 14 months). The 1-, 2-, 3-year overall survival (OS) were 77%, 35%, & 24% (Median 21 months). Planning Target Volume (PTV) dose ≥40Gy was significantly associated with improved local-regional control (p = 0.02). Gross Target Volume (GTV) dose <50Gy was significantly associated with lower DC (p = 0.03). ENI showed a trend towards improved local-regional control but was not statistically significant (p = 0.1). None of the patients experienced ≥ grade 3 toxicities. Most common adverse event were grades 1 or 2 fatigue (24%), nausea (16%), and abdominal discomfort (12%). In this cohort, MRI-guided SBRT utilizing gated-real time online adaptive radiotherapy was a safe and effective approach for patients with pancreatic tumors who are not surgical candidates. In this study, dose escalation was significantly associated with improved local-regional (PTV ≥40 Gy) and distant control (GTV ≥50Gy). None of the patients experienced grade ≥3 radiation induced adverse events.

Definitive Radiotherapy in Patients with Clinical T1N0M0 Esophageal Squamous Cell Carcinoma: A Multicenter Retrospective Study

In this study, we aimed to assess the failure pattern and survival outcomes and to analyze the optimal treatment field of definitive RT for T1N0M0 esophageal squamous cell carcinoma (ESCC). We performed a retrospective analysis in a multi-institutional cohort of patients with histologically confirmed T1N0M0 ESCC. We included patients who underwent RT with definitive aim from 2010 to 2019. Patterns of failure were demonstrated as in-field locoregional, out-field locoregional and distant metastasis. In the survival analysis, freedom from locoregional recurrence and their association with clinicopathologic risk factors were analyzed. We performed a propensity score matching in the cT1b patients to adjust for the heterogeneity of radiation technique, radiation dose and the use of concurrent chemotherapy. A total of 168 patients were included with a median follow-up of 34.0 months, and there were 20 cT1a, 94 cT1b and 24 cT1x, (cT1, not otherwise specified) patients. The rates of all and locoregional failure were 26.9% and 23.1% for cT1a and 25.0% and 22.4% for cT1b patients. 10 (10.6%) patients experienced grade ≥ 3 adverse events. Among 116 cT1b patients, 69 patients received elective nodal irradiation (ENI) and 47 patients received involved field irradiation (IFI). After propensity score matching, the 3-year FFLRR rate was 84.5% (95% Confidence Interval, 71.0 - 92.1%). There was no significant difference between the ENI and IFI patients in FFLRR (Log-rank P = 0.831). In the multivariate analysis, the use of concurrent chemotherapy was the only factor marginally associated with FFLRR (Hazard ratio, 0.17; 95% CI, 0.02 - 1.13; P = 0.067). cT1a patients who cannot receive endoscopic resection, showed similar rates of failure compared with cT1b patients, which questioned the accuracy of the staging and raised the need for through treatment such as chemoradiotherapy. In cT1b patients, IFI using dose of 50 to 60 Gy with concurrent chemotherapy could be a reasonable treatment option.

Posterior Neck Coverage in Patients Receiving Regional Nodal Irradiation for Breast Cancer

Patterns-of-failure studies suggest the posterior neck (PN) may harbor microscopic disease in patients with locally advanced breast cancer. We compared target coverage, lung dose, and toxic effects in patients treated with either an anterior oblique field (AO) or opposed oblique fields (OO) to address the superior axillary and supraclavicular nodal (SCV) regions. We identified 119 consecutively treated patients who received regional nodal irradiation, including a "third field," to address the superior axillary and supraclavicular nodal regions with a monoisocentric technique in our institution. Coverage of the axillary clinical target volume (CTV), SCV CTV and PN CTV was determined based on the delivered treatment plan. Wilcoxon rank-sum test and Fisher's exact test were used to compare coverage of the axillary, SCV, and PN CTVs, lung dosimetry, and toxic effects (graded by the Common Terminology Criteria for Adverse Events v4.0) between patients receiving an AO or OO. There were 29 patients in the AO group and 80 in the OO group. All patients in the AO group received conventionally fractionated radiation versus 61% in the OO group. Modestly hypofractionated plans were delivered to 39% of the OO group. The body mass index and anterior-posterior separation at the matchline (measured at the center of the carotid artery) were similar in both groups. The median volume (%) of the SCV CTV receiving at least 90% of the prescription dose (V90%) was 91% (85, 99) in the AO group and 93% (91, 95) in the OO group (P = 0.2). The median V90% of the PN CTV was 30% (12, 49) in the AO group and 100% (100, 100) in the OO group (P<0.001). The median V90% in the axillary levels I, II and III CTVs were 98%, 95% and 90%, respectively, in the AO group and all 100% in the OO group (P<0.001). Maximum dose and heterogeneity in the SCV CTV were similar in both groups. Including only patients who received conventionally fractionated plans, the mean lung dose (cGy) was 1216 in the AO group and 1328 in the OO group (P = 0045). The lung V5 Gy, V10 Gy and V20 Gy were similar in both groups. Ipsilateral upper extremity lymphedema (all grade 1) was 3.4% in the AO group and 2.5% in the OO group (p>0.9). Moist desquamation in the neck was 0% in the AO group and 1.2% in the OO group (p>0.9). Pneumonitis (all grade 1) was 0% in the AO group and 1.2% in the OO group (p>0.9). Compared to a single anterior field, opposed oblique fields provide superior axillary and posterior neck coverage without increasing toxicity.

Real-World Experience of Intensity Modulated Radiation Therapy and Concurrent Chemotherapy for Anal Cancer with Long-Term Follow up and Clinical Outcomes

The standard treatment for epidermoid anal cancer (AC) is concurrent chemoradiation (CRT). Here we present real world evidence of the safety and outcomes of AC patients managed by IMRT and concurrent chemotherapy at a single academic cancer center. We retrospectively reviewed the outcomes of 180 AC patients treated with definitive CRT between 2011 and 2018. Patients were managed according to a prospectively designed protocol of IMRT with radiation dose escalated according to tumor stage: 50.4, 55.8 and 63 Gy for T1, T2 and T3/T4 disease respectively, and 36 Gy for elective nodal RT. Involved nodes were given the same dose based on T category. Concurrent chemotherapy consisted of two cycles of mitomycin C (MMC, 12 mg/m2) and 5-fluorouracil (5FU, 1000 mg/m2/day x 4 days) given on week 1 and 5. There was no planned treatment break. Univariate and multivariate analysis for outcomes were performed using Cox proportional hazard method and likelihood ratio statistics. Overall survival (OS) disease free (DFS), colostomy-free survival (CFS) and local failure rates (LFR) were described by Kaplan-Meier methods. There were 128 female and 52 male patients with a median age of 64 (IQR 55-74). The median size of the primary was 4.0 cm (0.6-11.0 cm). There were 18 T1, 91 T2, 38 T3 and 33 T4 lesions; 50.6% (91/180) of the patients had N0 disease. Thirteen (7.2%) did not receive concurrent chemotherapy, and 16 (8.9%) failed to complete treatment as planned. Forty-three (23.9%) patients had a treatment gap >5 (6-33) days. Eighteen of 147 (12%) with T1-3 disease failed locally, LF was observed in 13/33 (39%) T4 lesions (P = 0.0002). The 5-year OS, DFS, CFS and LFR were 85.1%, 75.6%, 87.6% and 15.5% respectively. On multivariate analysis, increasing age and N+ disease were significant for worse OS, and increasing size of the primary tumor was the only significant factor for worse DFS, CFS and LFR. Grade ≥3 acute toxicities were observed in 42.8% of patients, with grade ≥3 neutropenia and febrile neutropenia observed in 18.9% and 13.9% of patients respectively. Six patients (3.3%) died of acute toxicities. Thirteen (7%) patients experienced grade ≥3 late toxicities. Size of the primary appears to be the most important determinant of outcome following standard CRT using IMRT for AC. Despite IMRT, almost 1 in 4 patients required a treatment break, and over 40% experienced grade ≥3 acute toxicities including neutropenia and febrile neutropenia. Future studies with RT dose escalation or de-escalation, stratifying patients based on tumor size, HPV status and molecular markers are necessary to improve outcomes and decrease treatment related toxicity.

Clinicopathologic Features of Prostate Cancer with Mesorectal Lymph Node Involvement on PSMA or Fluciclovine PET/CT

Advanced PET imaging has shown more prevalent mesorectal lymph node (LN) involvement in prostate cancer than previously appreciated. The clinical features predicting risk for mesorectal involvement are not well established and the prognostic impact is unclear. This may have implications on management including radiotherapy field design. This study aims to identify clinical and pathologic characteristics associated with mesorectal involvement identified on PSMA or fluciclovine PET/CT. We conducted a single institution retrospective review of prostate cancer patients with F-18 fluciclovine, F-18 piflufolastat, or Ga-68 gozetotide PET between January 2020 and 2023 demonstrating tracer-avid mesorectal LN in the setting of newly diagnosed disease (ND) or biochemical failure after curative-intent therapy (BF). Clinical characteristics, pathologic findings, and early clinical outcomes were reviewed. We identified 16 ND and 34 BF patients with uptake in at least one mesorectal LN on PET. For ND patients, clinical features at initial diagnosis were median PSA of 35.2 (range 9.6-659), median grade group 5, and 87% with clinical or radiographic T3/T4 disease. Radiographic PET staging among ND patients (excluding mesorectal LNs) were 19% N0M0, 25% N1M0, 56% as N1M1. For BF patients, clinical features at initial diagnosis were median PSA 9.2 (range 4.1-90) and median grade group 4. Primary treatment was prostatectomy in most (91%), with a high rate of high-risk features: 68% pT3-4, 28% pN1, and 32% had persistent detectable postop PSA. Radiographic PET staging among BF patients (excluding mesorectal LNs) were 29% N0M0, 38% N1M0, 12% N0M1, and 21% as N1M1. High-risk histologic features (cribriform, intraductal, ductal, or neuroendocrine) were identified in 88% of ND and 48% BF patients. Of these patients, 86% had cribriform pattern. Median PSA prior to PET for ND and BF patients was 37.0 (range 8.5-659) and 1.9 (0.2-11.1). Median interval from initial therapy to PET for BF patients was 4.4yr (range 0.2-19.7). Median follow-up post-PET was 8.7mo (range 3.4-29) for ND and 8.8mo (range 0-76) for BF patients. Of patients with M0 PET staging, none of the 7 ND patients developed DMs, and 1 of 23 BF patients developed DM after 4 yrs. In this analysis of prostate cancer patients with mesorectal involvement, we found a high incidence of high grade, T3-4 disease, and cribriform pattern, especially in ND patients. For BF patients, there was a high incidence of pT3-4 and pN1 disease at time of initial treatment. Overall, most patients had concurrent regional nodal disease on PET. Longer follow up of clinical outcomes and comparison to high-risk patients without mesorectal LN involvement is needed to understand the prognostic significance and predictors of mesorectal LN spread. Additional studies are needed to identify patients at highest risk in whom elective coverage of mesorectal lymphatics with elective pelvic nodal RT may be warranted.

Characterization of Objective Skin Color Changes during and after Breast and Chest Wall Radiotherapy and Correlation with Radiation-Induced Skin Toxicity in Breast Cancer Patients, Including Patients with Skin of Color

Radiation dermatitis (RD) is common among women undergoing breast and chest wall radiotherapy (RT); however, existing scales to assess the severity of RD are subjective and do not account for variability in skin of color (SOC). For instance, the Common Terminology Criteria for Adverse Events (CTCAE) criteria do not include hyperpigmentation in the grading scale. There is data indicating worse RD in African American and Hispanic patients; however, the rate and severity in SOC remains unknown given the lack of data using objective measures of RD. Spectrophotometry is one method to quantify the appearance of color by measuring spectral characteristics without the bias associated with subjective clinical scoring. We present a phase I prospective non-therapeutic clinical trial to objectively define SOC at baseline and evaluate spectrophotometric skin changes during and after breast or chest wall RT in parallel with physician-graded RD using CTCAE criteria. We hypothesize that there will be greater discrepancy between physician graded RD and objective measures of RD in patients with SOC in whom hyperpigmentation will be undercaptured by physician-grading. This is the first study intending to correlate SOC with objective changes after RT as a reliable indicator of RD. We offer a novel system for evaluating RD that is applicable to SOC. A total of 60 patients with localized breast cancer (stage 0-III) undergoing conventional whole breast or chest wall RT (50Gy/ 25 fx), hypofractionated whole breast RT (40.5Gy/15 fx) or ultrahypofractionated partial breast RT (6Gy x5), with or without regional nodal RT were enrolled. 3 skin color readouts using the Commission International de l'Eclairage 3D color system (l*, a*, b*) were measured within the radiation field using a spectrophotometer at baseline, once weekly during RT, 10 days post RT, 4 weeks and 12 months post RT. The spectrophotometer is a non-invasive, hand-held device that is used in the clinic room with no additional equipment or setup requirements. Data is automatically exported to a spreadsheet organized by timepoint and patient. The l* axis is a gray scale (0 = black, 100 = white) correlating with skin pigmentation and the a* axis describes red and green values correlating with erythema. The primary objective is to evaluate the changes from baseline in skin color readouts in the quadrant of tumor location during and after RT based on fractionation. The secondary objective is to evaluate changes within and across groups defined by baseline skin color. Exploratory objectives include evaluating the association of baseline color readouts and changes after RT with acute and late grade > 2 clinician-rated skin and subcutaneous tissue effects according to the CTCAE, v5.0, physician graded cosmesis and clinical interventions to treat RD, such as use of topical steroids and oral analgesics. As of January 2023, we have enrolled 100% of the planned patients. To be determined. To be determined. Clinical Study Identifier: S22-00192.