Acute Skin Toxicity Research Articles

HDR brachytherapy in keratinocyte skin carcinomas - Single center experience with analysis of clinical, dosimetric, and radiobiological factors in acute skin toxicity

PURPOSERadiotherapy techniques have been utilized to treat keratinocyte skin carcinoma (KSC). The objective of this study was to report the results of patients with KSC treated with HDR brachytherapy, with a variety of techniques and applicators. A statistical analysis of clinical, radiobiological, and technical factors has been made to analyze those factors related to skin acute toxicity, focused on acute epithelitis G3. METHODS AND MATERIALSBetween February 2005 and August 2020, 93 patients with 120 histologically proven KSC have been treated in our Institution. BT treatment has been performed using superficial BT/plesiotherapy (Valencia applicator (22%), flaps (48%), customized molds (4%) or interstitial techniques (26%)). The indications of BT were primary/definitive in 38 treatments (32%) or adjuvant/postoperative in 82 (68%). In 14 (17%) of the 82 operated patients a skin graft. Mean comparison t tests were performed for quantitative variables, and percentage comparison Chi2 tests for qualitative. Multivariate binomial logistic regression models were done. RESULTSMedian follow-up was 36.5 months (range 5–141). Local control was achieved in 110 treatments (92%). Acute toxicity, dermatitis, was G1 7%; G2, 57% and G3 38%. The main factors statistically associated to the appearance of dermatitis G3 were the total dose, the volume treated, and the use of manufactured flaps. The main protective factor against dermatitis G3 was implant of skin graft. CONCLUSIONSIn KSC BT the use of manufactured flap is accompanied by greater EG3, only with a relationship with the volume of treatment and total dose.

Radiobiological modelling of radiation-induced acute skin toxicity (dermatitis): A single institutional study of breast carcinoma.

The purpose of the study was to estimate the fitting parameters of the sigmoidal dose response (SDR) curve of radiation-induced acute dermatitis in breast cancer patients treated with intensity-modulated radiation therapy for calculation of normal tissue complication probability (NTCP). Twenty-five breast cancer patients were enrolled to model the SDR curve for acute dermatitis. The acute radiation-induced (ARI) dermatitis toxicity was assessed weekly for all the patients, and their scores were determined using the common terminology criterion adverse events version 5.0. The radiobiological parameters n, m, TD50, and γ50 were derived using the fitted SDR curve obtained from breast cancer Patient's clinical data. ARI dermatitis toxicity in carcinoma of breast patients was calculated for the end point of acute dermatitis. The n, m, TD50, and γ50 parameters from the SDR curve of Grade-1 dermatitis are found to be 0.03, 0.04, 28.65 ± 1.43 (confidence interval [CI] 95%) and 1.02 and for Grade-2 dermatitis are found to be 0.026, 0.028, 38.65 ± 1.93 (CI. 95%) and 1.01 respectively. This research presents the fitting parameters for NTCP calculation of Grade-1 and Grade-2 acute radiation-induced skin toxicity in breast cancer for the dermatitis end point. The presented nomograms of volume versus complication probability and dose versus complication probability assist radiation oncologists in establishing the limiting dose to reduce acute toxicities for different grades of acute dermatitis in breast cancer patients.

Prediction of radiation-induced acute skin toxicity in breast cancer patients using data encapsulation screening and dose-gradient-based multi-region radiomics technique: A multicenter study.

Radiation-induced dermatitis is one of the most common side effects for breast cancer patients treated with radiation therapy (RT). Acute complications can have a considerable impact on tumor control and quality of life for breast cancer patients. In this study, we aimed to develop a novel quantitative high-accuracy machine learning tool for prediction of radiation-induced dermatitis (grade ≥ 2) (RD 2+) before RT by using data encapsulation screening and multi-region dose-gradient-based radiomics techniques, based on the pre-treatment planning computed tomography (CT) images, clinical and dosimetric information of breast cancer patients. 214 patients with breast cancer who underwent RT between 2018 and 2021 were retrospectively collected from 3 cancer centers in China. The CT images, as well as the clinical and dosimetric information of patients were retrieved from the medical records. 3 PTV dose related ROIs, including irradiation volume covered by 100%, 105%, and 108% of prescribed dose, combined with 3 skin dose-related ROIs, including irradiation volume covered by 20-Gy, 30-Gy, 40-Gy isodose lines within skin, were contoured for radiomics feature extraction. A total of 4280 radiomics features were extracted from all 6 ROIs. Meanwhile, 29 clinical and dosimetric characteristics were included in the data analysis. A data encapsulation screening algorithm was applied for data cleaning. Multiple-variable logistic regression and 5-fold-cross-validation gradient boosting decision tree (GBDT) were employed for modeling training and validation, which was evaluated by using receiver operating characteristic analysis. The best predictors for symptomatic RD 2+ were the combination of 20 radiomics features, 8 clinical and dosimetric variables, achieving an area under the curve (AUC) of 0.998 [95% CI: 0.996-1.0] and an AUC of 0.911 [95% CI: 0.838-0.983] in the training and validation dataset, respectively, in the 5-fold-cross-validation GBDT model. Meanwhile, the top 12 most important characteristics as well as their corresponding importance measures for RD 2+ prediction in the GBDT machine learning process were identified and calculated. A novel multi-region dose-gradient-based GBDT machine learning framework with a random forest based data encapsulation screening method integrated can achieve a high-accuracy prediction of acute RD 2+ in breast cancer patients.

151 (PB-064) Poster - First results on acute skin toxicity in model-based selected breast cancer patients treated with adjuvant intensity modulated proton therapy

Background: Several studies have reported on acute skin toxicity outcomes in breast cancer (BC) patients treated with proton therapy (PT). However, limited data is available on (1) acute skin toxicity outcomes of mildly hypofractionated intensity modulated PT, and (2) on PT outcomes of model-based selected BC patients. Therefore, the primary objective of this study was to assess the incidence and severity of acute skin toxicity in these BC patients, and the secondary objectives were to assess predictive factors and dose-effect relationships.

Anal squamous cell carcinoma: Impact of radiochemotherapy evolution over years and an explorative analysis of MRI prediction of tumor response in a mono-institutional series of 131 patients.

Radiochemotherapy (RCHT) for the treatment of anal squamous cell carcinoma (ASCC) has evolved dramatically, also thanks to intensity-modulated RT (IMRT) and 3D image guidance (3D IGRT). Despite most patients presenting fair outcomes, unmet needs still exist. Predictors of poor tumor response are lacking; acute toxicity remains challenging; and local relapse remains the main pattern of failure. Between 2010 and 2020, ASCC stages I-III treated with 3D conformal radiotherapy or IMRT and CDDP-5FU or Mytomicine-5FU CHT were identified. Image guidance accepted included 2D IGRT or 3D IGRT. The study endpoints included freedom from locoregional recurrence (FFLR), colostomy free survival (CFS), freedom from distant metastasis (FFDM), overall survival (OS), and acute and late toxicity as measured by common terminology criteria for adverse events (CTCAE) version 5.0. An exploratory analysis was performed to identify possible radiomic predictors of tumor response. Feature extraction and data analysis were performed in Python™, while other statistics were performed using SPSS® v.26.0 software (IBM®). A total of 131 patients were identified. After a median FU of 52 months, 83 patients (63.4%) were alive. A total of 35 patients (26.7%) experienced locoregional failure, while 31 patients (23.7%) relapsed with distant metastasis. Five year FFLR, CFS, DMFS and PS resulted 72.3%, 80.1%, 74.5% and 64.6%. In multivariate analysis, 2D IGRT was associated with poorer FFLR, OS, and CFS (HR 4.5, 4.1, and 5.6, respectively); 3DcRT was associated with poorer OS and CFS (HR 3.1 and 6.6, respectively). IMRT reduced severe acute gastro-intestinal (GI) and severe skin acute toxicity in comparison with 3DcRT. In the exploratory analysis, the risk of relapse depended on a combination of three parameters: Total Energy, Gray Level Size Zone Matrix's Large Area High Gray Level Emphasis (GLSZM's LAHGLE), and GTV volume. Advances in radiotherapy have independently improved the prognosis of ASCC patients over years while decreasing acute GI and skin toxicity. IMRT and daily 3D image guidance may be considered standard of care in the management of ASCC. A combination of three pre-treatment MRI parameters such as low signal intensity (SI), high GLSZM's LAHGLE, and GTV volume could be integrated in risk stratification to identify candidates for RT dose-escalation to be enrolled in clinical trials.

Caloric Restriction Decreases Radiation-Induced Normal Tissue Toxicity

<h3>Purpose/Objective(s)</h3> Improvements in radiation delivery are limited by normal tissue toxicity. Studies show that the patient's metabolic state affects radiation toxicity. It has previously been shown that caloric restriction can be used to induce radiation sensitivity in treating breast and prostate tumors. Here we investigate the effect of caloric restriction on radiation induced normal tissue toxicity in two murine models. <h3>Materials/Methods</h3> To determine the role of diet on radiation induced normal tissue toxicity two toxicity models were used to assess mice fed either an ad libitum (AL), caloric restriction (CR: 30% reduction of calories) or ketogenic diet (KD: 60mg fat). A leg shortening model was used to assess acute and long-term skin toxicity by treating one leg of 9-week old Balb/c mice with a single- fraction of 30Gy of irradiation (320kV) with the rest of the body shielded and the contralateral leg serving as an unirradiated control. Measurements of leg length of irradiated compared with control leg length were performed. To assess differences in bone marrow, gastrointestinal and cardiac toxicity, total body radiation was administered to Balb/c mice using a dose of 6.5Gy (LD 50/30) with cohorts from each experimental diet. Histologic evaluation of small intestines and bone marrow was performed after tissue collection at 0, 1, 72 hours as well as 16-18 days post TBI. Small intestinal histology was reviewed by a gastrointestinal pathologist. Serum was evaluated for cardiac troponin 1 levels using ELISA at the same time points. Statistical comparisons were made using students t-test. <h3>Results</h3> The leg shortening model revealed radiation acute skin toxicity at 2 weeks post an ad libitum or ketogenic diet with skin peeling, hair loss, and moist desquamation that lasted 3 weeks compared to the mice treated with CR that had a delayed acute skin toxicity that only lasted 1 week. Long term, the irradiated leg was notably shortened and decreased by 22% and 20% relative to the contralateral leg in the AL and KD groups with 14% leg shortening and decreased fibrosis at 120 days post treatment in the CR groups (p<0.01). Gastrointestinal toxicity was decreased after TBI in mice on CR diet with less denuded villi epithelium and less obvious change in villi length at 72 hours compared to AL diet. The CR mice at 72 hours also had less variation in nuclear size within the epithelium and less changes in Paneth cells. Bone marrow was more hypocellular in the TBI mice on ad libitum diet compared with mice in the CR cohort. Acute cardiac toxicity was evaluated with serum troponin and was less elevated 72 hours post radiation in the CR group, 0.16ng/ml compared to 0.25ng/ml in the AL mice (p=0.03). <h3>Conclusion</h3> Dietary changes impact radiation induced toxicity. Our data show that caloric restriction decreases acute skin toxicity, fibrosis, gastrointestinal and cardiac toxicity. Future research is warranted to translate this strategy to decrease radiation induced normal tissue toxicity.

Clinical Introduction of a Volumetric-Based Skin-Sparing Planning Technique for Breast and Chest Wall Patients Treated with PBS Proton Therapy: A Review on Feasibility and Impact on Target Coverage and Robustness

<h3>Purpose/Objective(s)</h3> Acute and late skin toxicities are common and bothersome for patients undergoing breast or chest wall (CW) irradiation. There is clinical concern that acute skin toxicity may be higher with proton radiation compared with photon radiation because of differences in their energy deposition properties. Limited literature exists on dosimetric strategies to mitigate skin toxicity for patients treated with intensity modulated proton therapy (IMPT). We characterize the outcomes of a volumetric-based skin-sparing planning technique for IMPT treated breast and CW patients. <h3>Materials/Methods</h3> Prior to a consensus strategy, skin dose evaluation in IMPT Breast and CW plans was heterogeneous across physicians and dosimetrists. Uniformly, clinical targets were delineated by cropping off the skin surface by 3 mm for CW and 5 mm for intact breast; however, further skin-sparing strategies were previously restricted to limiting hot spots. In January 2022 our center established a consensus strategy to mitigate skin toxicity that added volumetric-based skin sparing objectives in addition to hot-spot evaluation. To start, a consistent skin evaluation structure (skin-eval) was defined within 5 mm of the CTV and included a rind of 3 mm for CW and 5 mm for intact breast, bound by the patient's surface. IMPT planning incorporated an objective to limit the volume of skin-eval receiving 95% of the prescription dose or more (V95%) to ideally less than 40% (goal of less than 50%) of the volume of the skin-eval structure, Skin-eval V95%Rx<40% (goal 50%), while still prioritizing CTV coverage and robustness. We report the early dosimetric experience with this volumetric-based objective. Boost plans were not included in this study. <h3>Results</h3> Ten patients underwent IMPT planning incorporating the described skin-eval objective, including 6 with intact breasts and 4 CW. Median skin-eval V95%Rx=36.4% (range, 20.3-49.9%). Median skin-eval max dose to 0.03cc, 0.3cc, and 1cc was 102.8% (range 101.4%-103.9%), 101.8% (range 100.5%-102.9%), and 101.1% (range 99.5%-102.3%), respectively. Median CTV V97.5%Rx was 98.2% (range, 94.9%-99.5%). 9 of the 10 plans passed all robust evaluation scenarios at V95%Rx receiving at least 95% (median 97.7%, range 96.1%-98.5%). Only 1 plan did not meet CTV goal coverage in all robust scenarios, failing only 1 scenario. This plan uniquely incorporated a couch kick to address atypical setup challenges. <h3>Conclusion</h3> A volumetric-based objective of skin-eval V95%Rx<50% appears consistently achievable while still maintaining excellent nominal and robustly optimized target coverage in patients receiving IMPT to the breast and CW. Future studies with both retrospective and prospective designs can validate dose constraints that may be more relevant for toxicity mitigation with IMPT.

Dosimetric Variables and Clinical Correlation of Toxicities and Breast Cosmesis in Adjuvant Hypofractionated Whole Breast Irradiation Using Field in Field 3DCRT

<h3>Purpose/Objective(s)</h3> The objective of our study was to assess the change in breast cosmesis, Acute skin toxicity, Late Skin Toxicity, Late Subcutaneous Tissue Toxicity at different points of time in patients receiving adjuvant Hypofractionated Whole Breast Radiotherapy schedule (HF-WBRT) and to find out any existing relation with any other dosimetric variables responsible for their outcomes. <h3>Materials/Methods</h3> The START B protocol for dose fractionation was followed. The cosmetic outcome of the patients was assessed using the Harvard Breast Cosmesis Grading Scale. Similarly, Acute toxicities, Late skin toxicities, Late subcutaneous tissue toxicities were recorded using the RTOG/EORTC scoring scheme. Data was generated on the different volumes of tissue receiving 95%,102%,105% and 107% of the prescribed dose respectively. Further, all these volumes were divided into two subgroups – dose volumes within the Whole Breast PTV and dose volumes outside the Whole Breast PTV. Multivariate Analysis of variables were done. Bivariate Correlations of differences were performed and outcomes were analyzed using Spearman's rho correlation coefficient test. We also ran the Binary Logistic Regression Analysis test for predicting the outcomes of interest with the different variables. <h3>Results</h3> 125 patients were accrued and analyzed for this study. For acute skin toxicity, significant positive correlations existed with the volume of tissue within the PTV receiving 95% (0.695) and 102% (0.430) and with the volume of tissue outside the PTV receiving 95% (0.333) of the prescribed dose. The volume of tissue outside the PTV receiving 102% had a significant predictive probability for acute skin toxicity [p=0.001, OR 1.056 (1.024-1.029)]. For late skin toxicity, a significant positive correlation existed with the volume of tissue within the PTV receiving 95% (0.465). For late subcutaneous tissue toxicity, there was a significant positive correlation with the volume of tissue within the PTV receiving 95% (0.516). Significant predictive associations were found with the volume of tissue within the PTV receiving 105% [p=0.014, OR 1.014(1.003-1.026)] and volume of tissue outside the PTV receiving 102 % [p=0.00, OR 1.052(1.025-1.080)]. For a change in breast cosmesis, Significant predictive associations were found with volume of tissue within the PTV receiving 95% [p=0.00, OR 1.006(1.004-1.009)] and 102% [p=0.02, OR 1.003(1.001-1.005)]. <h3>Conclusion</h3> The volume of tissue receiving more than 105% was found to be a factor for the development of late toxicities The volume of tissue outside the breast PTV receiving more than 102% also should be kept at a minimum as it had a significant association with both changes in breast cosmesis and with acute and late toxicities. Therefore, newer variables like excess dose above the prescribed dose received by tissue, outside the PTV, also needs to be looked into. This study thus hypothesizes use of more conformal planning techniques in whole breast irradiation.

Clinical Toxicity in Hypofractionated and Conventionally Fractionated Radiation in Breast Cancer Patients with Germline ATM Mutations

<h3>Purpose/Objective(s)</h3> The ataxia telangiectasia mutated (ATM) gene has significant roles in DNA double-strand break repair, and homozygous deficiency in ATM is known to cause significant sensitivity to ionizing radiation. Multigene panel testing has increasingly identified patients with ATM variants raising the question if those patients with heterozygous ATM variants are at increased risk of radiation toxicity. We hypothesize that there will be no significant difference in toxicity between hypofractionated (Hypo-RT) or conventionally fractionated (CRT) radiation treatments after breast conserving surgery (BCS) or mastectomy in patients with heterozygous germline ATM pathogenic variants or variants of uncertain significance (VUS). <h3>Materials/Methods</h3> Between 2004 and 2016, breast cancer patients treated with radiation were consented for peripheral blood sequencing (PBS). ATM variants detected by high-throughput PBS were designated benign, pathogenic, VUS, or with conflicting interpretations of pathogenicity using the ClinVar database. Variants designated benign or likely benign were excluded and those with conflicting interpretations of pathogenicity or variants of uncertain significance were classified as VUS. Toxicities were abstracted from medical records and were graded per Common Terminology Criteria for Adverse Events v5. Additional clinicopathologic information was abstracted from the medical records. Fisher's exact test was used to compare Grade 2 or 3 acute skin toxicity among patients with pathogenic variants or VUS treated with Hypo-RT versus CRT. <h3>Results</h3> A total of 400 patients were sequenced. After excluding benign ATM variants, 23 were included in this analysis, 2 (8%) were pathogenic and 21 (91%) were VUS. Median tumor size was 1.5cm and median age at diagnosis was 54 years (range: 33–74). Among these patients 91% had invasive disease, 72% were ER+, and 39% received chemotherapy; 86% elected for BCS with 78% undergoing sentinel lymph node dissection. All patients received photon based external beam radiation, 10 (43%) were treated with Hypo-RT, 12 (52%) with CRT, one (4%) with accelerated partial breast irradiation, and 4 (17%) with nodal irradiation. Median follow up was 5.04 years. Grade 2 acute radiation dermatitis (ARD) was noted in 8 patients (34%) and grade 3 in 2 patients (8%). There was no difference in Grade 2 or 3 ARD between patients receiving Hypo-RT or CRT (P= 0.4). Late grade 2 fibrosis was recorded in 1 patient (4%) and there were no events of any late grade 3 toxicity. Contralateral breast cancer occurred in 2 patients (8%) at 6 months and 9 years after the initial diagnosis. <h3>Conclusion</h3> Radiation treatment in patients with heterozygous ATM germline pathogenic or VUS appears well tolerated. In our study, there was no statistical difference in toxicity between Hypo-RT or CRT.

Development of gRADient: An Inclusive Tool for Objective Measurement of Radiation Acute Skin Toxicity across Skin Tones in Breast Cancer

<h3>Purpose/Objective(s)</h3> Existing tools for grading radiation acute skin toxicity (RAST) primarily rely on subjective interpretation of erythema and desquamation, potentially limiting validity for patients of color (POC). Yet, more objective tools like in-lab colorimetry are not readily available for use in clinical practice. We report the development and preliminary testing of a novel digital photograph-based tool (gRADient) for RAST assessment in hypofractionated whole breast irradiation (hWBI) by: (1) validating the tool against colorimetry, and (2) testing its ability to detect skin changes over the course of hWBI across a range of skin tones. <h3>Materials/Methods</h3> Women ≥18 years undergoing unilateral hWBI to 40.5-42.6 Gy, +/- boost, were prospectively enrolled at 2 facilities (N=39). ≥2 physicians rated Fitzpatrick skin phenotype. Multiple photos of the treated and untreated (control) breast were taken weekly during hWBI (N=15 photos per time point). We mapped pixel-level RBG values to 2 corresponding color spaces: 3-item L*a*b* and Prism model (12 colors, shade, and tint on an increasing 0-1 scale). 13 patients also underwent in-lab colorimetry, collected in 4 quadrants of each breast. Patient PRO-CTCAE and Skindex-16, and provider CTCAEv.5 and RTOG tools were completed weekly. Spearman's rho assessed in-lab colorimetry vs. photo-based L*a*b*, and paired t-tests evaluated changes in Prism values between the treated and control breast at the first and last assessment. <h3>Results</h3> We evaluated 1,815 photos from 30 patients who underwent ≥3 photo sessions at the time of analysis. Patient-reported race was 43% White, 40% Black, and 17% other, corresponding to Fitzpatrick skin types of I-II (44%), III-IV (20%), and V (37%). For the colorimetry cohort, all 3 values of L*a*b* were significantly correlated for in-lab colorimetry vs. photos (all p<0.005). Across all photos, there was a significant increase in red, pink, and orange hues as well as in shading [mean ∆ of differences (dod) 0.023, 0.0004, 0.023, and 0.033, respectively, all p<0.05] for Prism in the treated vs. control breast over time. In exploratory analyses, a composite of these variables detected significant changes in time across all skin types (mean dod 0.047). While RTOG and CTCAE responses correlated with color space changes, more granular variations could be detected with gRADient. Inter-patient Skindex-16 results varied widely. <h3>Conclusion</h3> In a preliminary analysis, our novel photo-based tool yielded measurements that correlated with in-lab colorimetry, supporting its validity. Moreover, gRADient detected increases in red and pink (corresponding to erythema) as well as orange hues and shading (corresponding to increased pigmentation) across a range of skin tones. Next steps include continued prospective evaluation of gRADient, with the goal of building a web-based photo application to facilitate clinical use in RAST grading and patient education.

Factors on development and severity of acute radiodermatitis: prospective single-center study

Aim: Although prior literature has examined the treatment and patient-associated factors affecting the development and severity of acute radiodermatitis, there are relatively few prospective studies evaluating both. This study was prospectively designed to evaluate factors affecting the development and extent of radiation-induced acute skin toxicity called radiodermatitis (RD). &#x0D; Material and Method: A total of 63 patients who underwent radiotherapy (RT) in Ankara Atatürk Research and Education Hospital between July 2017 and October 2018 were evaluated. Patients’ demographic status, disease/treatment details, hemoglobin, ferritin, folic acid, Vit B12, and hemoglobin A1c values were recorded. The development and grade of RD were evaluated weekly by the same radiation oncologist using the Radiation Therapy Oncology Group (RTOG) radiation toxicity guideline.&#x0D; Results: There was no significant relationship between the development of any degree of RD and gender, concomitant chemotherapy (CT), pre-RT CT, comorbid disease, RT technique and blood parameters (Hb, Hba1c, ferritin, folic acid and B12). The development of grade 2-3 RD was significantly affected by the number of operations (p=0.032) and total dose of RT (p=0.008). In patients with grade 2/3 RD, the RT dose at which RD first appeared was 20 Gy (range, 14-36); in patients with grade 1 RD, this value was 32 Gy (range, 16-56) (p=0.018).&#x0D; Conclusion: There is no significant relationship between the development of acute radiodermatitis and Hba1c, hemoglobin, ferritin, B12 and folic acid levels. There was a significant correlation between grade of RD and repeated surgery, increase in total RT dose and early onset of RD.

Comparison of Overall Response to Neoadjuvant Short Course Radiotherapy Followed by Consolidation Chemotherapy with Long Course Chemoradiotherapy in Locally Advanced Rectal Cancer

<h3>Purpose/Objective(s)</h3> Primary objective of this study was to compare the clinical and radiological response rates between patients receiving pre-operative Short Course Radiotherapy (SCRT) followed by chemotherapy versus conventional long course CRT in patients with locally advanced rectal cancer. secondary objectives included comparison of rates of pCR and acute toxicities among the 2 groups of patients. <h3>Materials/Methods</h3> 33 patients with locally advanced rectal cancer were randomized to standard long course CTRT arm (arm A) and SCRT followed by sequential chemotherapy (arm B) arm (17 and 16 patients respectively). Patients in arm A received long course RT at dose 45 Gy in 25 fractions over 5 weeks with concurrent oral capecitabine on days of radiotherapy. Patients in arm B was prescribed short course radiotherapy at dose 25 Gy in 5 fractions over 1 week. 3 cycles of 3 weekly CAPOX chemotherapy was followed. Patients were planned with 3DCRT technique in Versa HD with 6 MV and 15 MV photons. Clinical response assessment was done by comparing the 2 arms in terms of per rectal examination findings before starting radiotherapy and after completion of RT, right before surgery. The parameters used for assessment were palpability of lesion, tone, mobility, distance from anal verge and location of the lesion. Radiological response assessment was done by comparing 5-point tumor regression grades (TRG) post treatment in the 2 treatment arms. <h3>Results</h3> Radiological tumor regression showed statistically non-significant trend favoring the experimental arm (rates of complete tumor regression 35.7% in SCRT followed by chemotherapy arm versus 23.1% in long course CTRT arm, higher percent of patients with greater tumor regression in SCRT+CT arm). pathological tumor regression also favored experimental arm without showing statistical significance (pCR rates 20% in long course CTRT versus 30% in SCRT+CT). Most of patients in the interventional arm presented with higher pathological tumor regression (TRG 0 and TRG 1) while the most common TRG in the long-course CTRT arm was TRG 3. Higher rate of acute grade 3 bowel toxicities was seen in the interventional arm. Grade 3 acute skin toxicity occurred in the standard arm compared no skin toxicity in the interventional arm. This difference was also not statistically significant. <h3>Conclusion</h3> Short course radiotherapy followed by 3 cycles of CAPOX chemotherapy is comparable to Long-course CTRT in terms of tumor regression. In resource limited setting, short course radiotherapy and chemotherapy is favored due to smaller radiotherapy duration and lesser chances of treatment interruption

Physician Rated Cosmesis and Patient Reported Outcomes after Concomitant Boost (CB) vs. Sequential Boost (SB) for Adjuvant Treatment of Breast Cancer: A Prospective Randomized Study

<h3>Purpose/Objective(s)</h3> The aim of the current study was to compare toxicity, cosmesis and patient reported outcomes after sequential radiation therapy boost vs. concomitant boost in the adjuvant setting of breast cancer treatment. <h3>Materials/Methods</h3> One hundred and forty-five breast cancer patients who underwent breast conserving surgery and were candidates for tumor bed boost following whole breast irradiation (WBI) were randomized to receive either concomitant boost (CB) (n=71) or sequential boost (SB) (n=74). All patients received WBI to a total dose of 40.05 Gy/15 F/3 weeks. Patients in the SB arm received 10 Gy/5 F / 1 week to the boost volume following WBI. Patients in the CB arm received 7.95 Gy/15 F/3 weeks to the boost volume concomitant with the WBI. All treatments were carried out using 3D conformal radiation therapy. Physicians rated cosmesis prior to starting radiation and at 6 and 12 months after end of treatment. All patients filled a validated quality of Life questionnaire 12 months after end of treatment. <h3>Results</h3> Median follow-up 30 months (range, 18-48). G III or higher acute skin toxicity was observed in 12 (16.4%) patients in the SB arm and in 4 (6.3%) patients in the CB arm (p 0.042). GII or higher late skin toxicity developed in 4 (5.4%) patients in the SB arm and in 1 (1.4%) patient in the CB arm (p 0.18). GII subcutaneous fibrosis was observed in 3 (4%) patients in the SB arm and in none of the patients in the CB arm. Prior to radiation treatment, 50 (67.5%) patients had Excellent/good cosmesis in the SB arm vs. 47 (66.2%) patients in the CB arm (p 0.59). At 6 months after radiation, 44 (59.4%) patients had Excellent/good cosmesis in the SB arm vs. 40 (56.3%) patients in the CB arm (p 0.83). At 12 months after radiation, 50 (67.5%) patients in the SB arm had Excellent/good cosmesis vs 42 (59.2%) patients in the CB arm (p 0.57). twelve months after radiation, 50 (78.1%) patients in the SB arm reported very satisfied/satisfied with their cosmetic outcomes compared to 44 (72.1%) patients in the CB arm (p 0.43). <h3>Conclusion</h3> Concomitant boost radiation therapy is non-inferior to sequential boost in terms of late toxicity, cosmesis and patient satisfaction with slightly more favorable outcome in the acute toxicity and shorter overall treatment time.

Prospective Single-Arm Trial of Preoperative 42.75 Gy in 15 Fractions for Soft Tissue Sarcoma of the Extremity/Trunk

<h3>Purpose/Objective(s)</h3> The standard pre-operative radiation therapy (RT) dose of 50 Gy in 25 daily fractions for soft tissue sarcoma (STS) contributes to excellent local control and is associated with major wound complications (MWC) in approximately 35% of patients. We sought to prospectively investigate whether a radiobiologically equivalent dose given in a 3-week course of 42.75 Gy in 15 daily fractions confers a higher risk of MWC. <h3>Materials/Methods</h3> We conducted a prospective, single-arm, non-randomized trial of hypofractionated pre-operative RT consisting of 42.75 Gy in 15 once-daily fractions followed by surgery 4-8 weeks after RT completion for adult patients with biopsy-confirmed, non-metastatic, previously un-irradiated STS of the extremity or superficial trunk. Patients (n=120) were enrolled from December 2018 to January 2021. The primary outcome of the study was to determine the rate of MWC within 120 days of surgery among patients treated with the trial regimen. Safety was monitored using a Bayesian stopping rule One-Arm Time-To-Event Simulator which compared development of MWC at 120 days post-surgery among patients on study to the historical rate of 35%. The Kaplan-Meier method was used to estimate outcomes. <h3>Results</h3> Median follow-up from surgery was 23 months (interquartile range [IQR] 15-29). Median age was 60 years (IQR 48-69) and median maximum tumor size was 7.6 cm (IQR 4.5-12.8). A majority of the patients had lower extremity (LE) tumors (n=78, 65%; upper extremity (UE), n=20, 17%; trunk, n=22, 18%). Tumor grade was: high in 51% (n=61), intermediate in 23% (n=27), low in 8% (n=9), or not gradable in 19% (n=23). All patients received 42.75 Gy (or CGE) in 15 once-daily fractions with either: IMRT (n=57, 48%), 3D-RT (n=55, 46%), electrons (n=5, 4%), or protons (n=3, 3%). None experienced acute skin toxicity of CTCAE v4.0 > or = grade 3. Thirty-seven (31%, 95% CI: 24-40%) patients developed MWC within 120 days of surgery (median, 37 days (IQR 25-59)). Six patients (5%) developed local recurrence at a median 16 mos (IQR 7-17); 4 in the RT field, 1 at the field margin, and 1 wide of field. Actuarial 2-year local control is 93% (95% CI: 85-97%). <h3>Conclusion</h3> Our prospective non-randomized clinical trial revealed that a hypofractionated pre-operative radiotherapy dosing regimen of 42.75 Gy in 15 once-daily fractions resulted in a MWC rate that was not higher than accepted historical rates. Early analyses show rates of local recurrence that are consistent with those observed with standard fractionation. These data support that this 3-week regimen may offer a safe, effective, and more convenient alternative to 50 Gy in 25 daily fractions for patients undergoing pre-operative RT for STS.

Ultra-Hypofractionation for Whole-Breast Irradiation in Early Breast Cancer: Interim Analysis of a Prospective Study.

We report on the early clinical outcomes of a prospective series of early breast cancer (EBC) patients treated with ultra-hypofractionated post-operative whole-breast irradiation (WBI) after breast-conserving surgery (BCS) and axillary management. Primary endpoints were patient’s compliance and acute toxicity. Secondary endpoints included physician-rated cosmesis and ipsilateral breast tumour recurrence (IBTR). Acute toxicity was evaluated at the end of WBI, 3 weeks and 6 months thereafter, according to the Common Terminology Criteria for Adverse Events (v. 5.0). Patients were treated between September 2021 and May 2022. The treatment schedule for WBI consisted of either 26 Gy in 5 fractions over one week (standard approach) or 28.5 Gy in 5 fractions over 5 weeks (reserved to elders). Inverse planned intensity-modulated radiation therapy (IMRT) was used employing a static technique. A total of 70 patients were treated. Fifty-nine were treated with the 26 Gy/5 fr/1 w and 11 with the 28.5 Gy/5 fr/5 ws schedule. Median age was 67 and 70 in the two groups. Most of the patients had left-sided tumours (53.2%) in the 26 Gy/5 fr/1 w or right-sided lesions (63.6%) in the 28.5 Gy/5 fr/5 ws group. Most of the patients had a clinical T1N0 disease and a pathological pT1pN0(sn) after surgery. Ductal invasive carcinoma was the most frequent histology. Luminal A intrinsic subtyping was most frequent. Most of the patients underwent BCS and sentinel lymph node biopsy and adjuvant endocrine therapy. All patients completed the treatment program as planned. Maximum detected acute skin toxicities were grade 2 erythema (6.7%), grade 2 induration (4.4%), and grade 2 skin colour changes. No early IBTR was observed. Ultra-hypofractionated WBI provides favourable compliance and early clinical outcomes in EBC after BCS in a real-world setting.

Incidence and predictors of toxicity in the management of vulvar squamous cell carcinoma treated with radiation therapy

Purpose/ObjectiveGiven the rarity of vulvar cancer, data on the incidence of acute and late severe toxicity and patients’ symptom burden from radiotherapy (RT) are lacking. Materials/MethodsThis multi-center, single-institution study included patients with vulvar squamous cell carcinoma treated with curative intent RT between 2009 and 2020. Treatment-related acute and late grade ≥ 3 toxicities and late patient subjective symptoms (PSS) were recorded. ResultsForty-two patients with predominantly stage III/IV disease (n = 25, 59.5 %) were treated with either definitive (n = 25, 59.5 %) or adjuvant (n = 17, 40.5 %) external beam RT to a median dose of 64 Gy and 59.4 Gy, respectively. Five patients received a brachytherapy boost with a median total dose of 84.3 Gy in 2 Gy-equivalent dose (EQD2). Intensity-modulated RT was used in 37 (88.1 %) of patients, and 25 patients (59.5 %) received concurrent chemotherapy. Median follow-up was 27 months. Acute grade ≥ 3 toxicity occurred in 17 patients (40.5 %), including 13 (31.0 %) acute grade 3 skin events. No factors, including total RT dose (p = 0.951), were associated with acute skin toxicity. Eleven (27.5 %) patients developed late grade ≥ 3 toxicity events, including 10 (23.8 %) late grade ≥ 3 skin toxicity events. Patients with late grade ≥ 3 skin toxicity had a higher mean body-mass index (33.0 vs 28.2 kg/m2; p = 0.009). Common late PSS included vaginal pain (n = 15, 35.7 %), skin fibrosis (n = 10, 23.8 %), and requirement of long-term opiates (n = 12, 28.6 %). ConclusionRT for vulvar cancer is associated with considerable rates of severe acute and late toxicity and PSS burden. Larger studies are needed to identify risk factors, explore toxicity mitigation strategies, and assess patient-reported outcomes.

3D-printed bolus ensures the precise postmastectomy chest wall radiation therapy for breast cancer.

PurposeTo investigate the values of a 3D-printed bolus ensuring the precise postmastectomy chest wall radiation therapy for breast cancer.Methods and materialsIn the preclinical study on the anthropomorphic phantom, the 3D-printed bolus was used for dosimetry and fitness evaluation. The dosimetric parameters of planning target volume (PTV) were assessed, including Dmin, Dmax, Dmean, D95%, homogeneity index (HI), conformity index (CI), and organs at risk (OARs). The absolute percentage differences (|%diff|) between the theory and fact skin dose were also estimated, and the follow-up was conducted for potential skin side effects.ResultsIn preclinical studies, a 3D-printed bolus can better ensure the radiation coverage of PTV (HI 0.05, CI 99.91%), the dose accuracy (|%diff| 0.99%), and skin fitness (mean air gap 1.01 mm). Of the 27 eligible patients, we evaluated the radiation dose parameter (median(min–max): Dmin 4967(4789–5099) cGy, Dmax 5447(5369–5589) cGy, Dmean 5236(5171–5323) cGy, D95% 5053(4936–5156) cGy, HI 0.07 (0.06–0.17), and CI 99.94% (97.41%–100%)) and assessed the dose of OARs (ipsilateral lung: Dmean 1341(1208–1385) cGy, V5 48.06%(39.75%–48.97%), V20 24.55%(21.58%–26.93%), V30 18.40%(15.96%–19.16%); heart: Dmean 339(138–640) cGy, V30 1.10%(0%–6.14%), V40 0.38%(0%–4.39%); spinal cord PRV: Dmax 639(389–898) cGy). The skin doses in vivo were Dtheory 208.85(203.16–212.53) cGy, Dfact 209.53(204.14–214.42) cGy, and |%diff| 1.77% (0.89–2.94%). Of the 360 patients enrolled in the skin side effect follow-up study (including the above 27 patients), grade 1 was the most common toxicity (321, 89.2%), some of which progressing to grade 2 or grade 3 (32, 8.9% or 7, 1.9%); the radiotherapy interruption rate was 1.1%.ConclusionA 3D-printed bolus can guarantee the precise radiation dose on skin surface, good fitness to skin, and controllable acute skin toxicity, which possesses a great clinical application value in postmastectomy chest call radiation therapy for breast cancer.

Hypofractionated radiotherapy after breast-conserving surgery: Clinical and dosimetric factors predictive of acute skin toxicity.

The purpose of this study was to evaluate acute skin toxicity in early breast cancer patients treated with hypofractionated radiotherapy (HFRT) after breast-conserving surgery and to identify factors predictive for grade ≥ 2 acute skin toxicity. Amonocentric retrospective study was carried out using cases treated between December 2017 and November 2020. We analyzed data from 202patients with early breast cancer treated with 3D hypofractionated RT (40.05 Gy in 15fractions) to the whole breast with or without regional lymph nodes, followed by 13.35 Gy in 5fractions to the tumor bed. Acute skin toxicity was monitored during RT according to CTCAE (common toxicity criteria for adverse events) scale. Univariate and multivariate analyses were performed to assess predictive factors of acute skin toxicity. Overall, there was no erythema in 9%, grade1 erythema in 64.5%, grade2 in 24%, and grade3 in 2.5%. No grade4 erythema was seen. Median delay between RT initiating and maximum skin reaction was 22days (range 4-44days). No patient interrupted treatment. In univariate analysis, the rate of acute skin toxicity grade 2---3 (G2-3) was significantly higher for patients with larger tumor size (p = 0.02), body mass index > 27 (p = 0.04), and time between chemotherapy (CT) and RT less than 20days (p = 0.01). Dosimetric risk factors for acute skin toxicity G2‑3 were breast volume > 800 cc (p = 0.000), boost volume > 18 cc (p = 0.002), V105% > 40 cc (p = 0.03), and Dmax > 56 Gy (p = 0.007). CT, trastuzumab, regional lymph node radiation, and age were not correlated with increased skin toxicity. In multivariate analysis, acute skin toxicity correlated with Tstage (p = 0.032), breast volume > 800 cc (p = 0.012), boost volume > 18 cc (p = 0.04), and Dmax > 56 Gy (p = 0.035). Our results confirm that whole breast with or without lymph nodes hypofractionated RT is safe and well tolerated. The factors strongly associated with adecreased risk of G2‑3 skin toxicity are T1, breast volume < 800 c, boost volume < 18 cc, and Dmax < 56 Gy. Long-term follow-up is needed to evaluate late toxicity.

Minimizing the Risk of Acute Skin Toxicity Due to Hip Prosthesis Avoidance in Prostate Radiation Therapy

Limiting the entrance dose through hip prostheses to improve dosimetric accuracy can result in unfavorable skin toxicity. We propose a volumetric modulated arc therapy solution that strikes a better balance between dose accuracy and skin dosimetry. Our current planning strategy limits the entrance dose through hip prostheses using stringent optimization objectives on an avoidance structure. Avoidance efficiency is evaluated by recalculating the plan with prosthesis density set at 20 g/cc, and evaluating the loss of target coverage from increased attenuation. We require this loss to be ≤5% of the original values. This approach has resulted in an uncommon skin toxicity for a prostate-bed patient with bilateral hip prostheses. Thus, the dosimetric tradeoffs between skin dose and prosthesis avoidance were investigated by incrementally reducing prosthesis avoidance to achieve maximum skin doses (Dmax) between 30 and 50 Gy. When prosthesis avoidance is prioritized, the skin dose increases and the target dose coverage and conformity decrease. A large degradation in target coverage for plans with the lowest skin Dmax of 30 to 35 Gy indicates that a significant proportion of the target dose arises from beams entering the prostheses. The plan with a skin Dmax of 40 Gy provides a better compromise between skin and prosthesis entrance doses, with a <20% reduction in target coverage at an increased prosthesis density of 20 g/cm3. Skin dose needs to be considered when using prosthesis avoidance planning strategies. Allowing for a minimal dose through the prosthesis may be required to restrict skin dose and reduce the risk of toxicity.

Validation of a Patient-Reported Outcome Measure for Moist Desquamation among Breast Radiotherapy Patients.

There has been an increasing interest in patient-reported outcome (PRO) measures in both the clinical and research settings to improve the quality of life among patients and to identify when clinical intervention may be needed. The primary purpose of this prospective study was to validate an acute breast skin toxicity PRO measure across a broad sample of patient body types undergoing radiation therapy. Between August 2018 and September 2019, 134 women undergoing adjuvant breast radiotherapy (RT) consented to completing serial PRO measures both during and post-RT treatment and to having their skin assessed by trained trial radiation therapists. There was high patient compliance, with 124 patients (92.5%) returning to the clinic post-RT for at least one staff skin assessment. Rates of moist desquamation (MD) in the infra-mammary fold (IMF) by PRO were compared with skin assessments completed by trial radiation therapists. There was high sensitivity (86.5%) and good specificity (79.4%) between PRO and staff-reported presence of MD in the IMF, and there was a moderate correlation between the peak severity of the MD reported by PRO and assessed by staff (rho = 0.61, p < 0.001). This prospective study validates a new PRO measure to monitor the presence of MD in the IMF among women receiving breast RT.