Whole-breast Irradiation Research Articles

Assessing the Relationship between Residual Cancer Burden and the Tumor Immune-Microenvironment in Early-Stage, Hormone Receptor-Positive Breast Cancer Following Preoperative Radiation Therapy in MC1732 Clinical Trial

<h3>Purpose/Objective(s)</h3> Tumor-infiltrating lymphocytes (TILs) and ectopic lymphoid formations known as tertiary lymphoid structures (TLS) are prognostically significant in triple-negative breast cancer (TNBC). However, there is a paucity of data on this matter in hormone receptor-positive (HR+) breast cancer and whether these immunological parameters are impacted by preoperative radiation therapy (RT). The purpose of this work is to assess the relationship between residual cancer burden (RCB) and TILs/TLS in HR+ early-stage breast cancer following preoperative radiation therapy. <h3>Materials/Methods</h3> During 2019-2020, patients with cT0-T2, N0, M0 breast cancer were enrolled in a clinical trial (MC1732) in which they received hypofractionated whole-breast RT in 25 Gy in 5 fractions 4-8 weeks prior to breast-conserving surgery (BCS). RCB (determined per MD Anderson calculator), estimated % cellularity, TILs, and TLS were assessed in the surgical tissues. Low TIL was defined as < 10%, intermediate TIL as 11-49%, and high TIL as > 50%. The relationships between RCB class, numerical RCB values, and immunological parameters were explored using Kruskal-Wallace/Wilcoxon Rank Sum Test, linear regression, and Kendall's tau correlations. TILs and TLS were log-transformed to overcome extreme distributions. Lastly, a predictive model for pathologic outcomes was developed using backward elimination. <h3>Results</h3> Among the 22 patients analyzed for RCB, all were ER/PR positive. One patient was HER2 positive, and 13/22 had Grade 1 disease. Pathologic complete response (pCR) was noted in 18%, RCB-I in 60%, and RCB-II in 22%. In post-treatment samples, low, intermediate, and high TIL were found in 77%, 18%, and 5% of patients, respectively. Approximately 36% of patients had at least one TLS present after radiation. Kruskal-Wallace/Wilcoxon Rank Sum Test indicated a significant association between RCB class and % TILs and TLS (p = 0.010 and 0.003, respectively.) Kendall's tau correlation indicated a statistically significant positive correlation between RCB values and % TILs (p = 0.02) and TLS (p = 0 .001). Linear regression revealed that for every one-unit increase in RCB value, there was a statistically significant 4.3 unit increase in the % TILs (p <0.001), and a 2.48 unit increase in TLS (p <0.001). Finally, per the backward selection model, the number of TLS was associated with increased % cellularity at the time of surgery. <h3>Conclusion</h3> Our data suggest that increases in TILs and TLS following preoperative radiation are associated with increased residual disease in HR+ early-stage breast cancer. Given the fact that there are multiple types of potential immune infiltrates, further work is needed to elucidate the mechanisms behind these findings and specific types of immune infiltration.

Clinical Trials of Curative Partial Breast Irradiation for Early-Stage Breast Cancer Using Carbon Ion Radiotherapy

<h3>Purpose/Objective(s)</h3> Our institute conducted clinical trials of curative partial breast irradiation using carbon ion radiotherapy (CIRT) to patients with stage 0 and I breast cancer since 2013. The purpose of this report is to evaluate treatment outcomes up to now. <h3>Materials/Methods</h3> To date, we have conducted three clinical trials and one advanced medical treatment (NIRS9404: AMT). The first study (UMIN000010848: known as Breast I) was 4 fractions partial breast CIRT for stage I luminal patients aged 60 years or older. The AMT protocol was provided in parallel with Breast I in same manner for stage I breast cancer patients who was difficult to register due to minor variant or reject to participate in Breast I. In principle, these patients received maintenance hormone therapy. The next clinical trial (UMIN000029478: known as Breast II) enrolled patients aged 20 years and older without 2 mm or more metastasis in sentinel lymph node for all types of Tis-1N0M0, tumor size 2 cm or less. In this study, 4 fractions CIRT partial breast irradiations were combined with standard systemic therapy and x-ray whole-breast irradiation. And the latest clinical trial (UMIN000046859: known as Breast III) is a single dose of CIRT for luminal Tis-1N0M0 patients aged 50 years and older. All Breast III patients received maintenance hormone therapy. In all trials, Phase I was a dose-escalation study and Phase II was treated with the recommended dose determined in Phase I. <h3>Results</h3> By December 2021, 56 cases have been enrolled. A total of 19 were enrolled In Breast I, 7 in Phase I, 12 in Phase II with a recommended dose of 60.0 Gy (RBE), and total of 14 were enrolled in AMT. A total of 17 were enrolled In Breast II, 5 in Phase I, 12 in Phase II with a recommended dose of 60.0 Gy (RBE). A total of 6 were enrolled in Breast III, 3 in Phase I, 3 in Phase II with a recommended dose of 50.0 Gy (RBE). As acute adverse effects, acute radiation dermatitis (grade 2 in 1, Grade1 in 37), mastitis (grade 1 in 6) and myositis (grade 1 in 7) were observed. As late adverse effects, grade 3 pneumonia of unknown causality were observed in 1 case. The cosmetic results of breast were excellent in all cases. Tumor disappearance after CIRT took 3 to 24 months. Local recurrence with axillary lymph node metastasis was observed in one high-risk AMT patient who refused any systemic therapy, but no other recurrences or metastases have been observed. <h3>Conclusion</h3> CIRT for early-stage breast cancer is expected to be effective with mild adverse events, and it is considered meaningful to continue research.

Ultrahypofractionated Adjuvant Proton Therapy for Localized Stage Breast Cancer: Early Toxicity Report

<h3>Purpose/Objective(s)</h3> To report early toxicity and dosimetry data in breast cancer patients treated with ultrahypofractionated proton therapy (Ultra-HF-PT). <h3>Materials/Methods</h3> Patients with localized breast cancer (Tis-T2, N0) who required postoperative whole-breast radiotherapy were eligible. The prescribed dose was 26 Gy in 5 daily fractions ± single fraction 5,2 Gy boost. Treatment planning was performed with 1 or 2 anterior fields (0°±40°) using multi-field optimization. Robust optimization was performed on the CTV structure with a 3- mm setup uncertainty and a 3.5% range uncertainty. For 69% of patients with left-sided cancer deep inspiration breath hold technique (DIBH) was used. The target coverage was defined as V_100%>98% (>98% of volume receiving 100% of the prescribed dose). Patients were seen weekly while on treatment, at 1 month after radiation therapy completion, and at 3-month intervals thereafter. Toxicity was scored using CTCAE ver. 5.0. <h3>Results</h3> From July 2020 to November 2021, 63 patients were treated with intensity-modulated proton therapy. Median follow-up was 9 months (2 to 18). During radiotherapy Grade 1 and 2 dermatitis occurred in 45 (71%) and 4 (6%) patients respectively. After the end of treatment Grade 1 or 2 dermatitis occurred in all patients, resolving in 4 weeks. Mean dose to the left anterior descending coronary artery (LAD) was 1,28 Gy (0,12-8,2) for left-sided breast cancer patients. Mean ipsilateral lung dose was 2,66 Gy (0,55-5,8). Compared to free breathing DIBH significantly reduced mean dose to the heart (0,4 to 0,1 Gy, p=0,03) and LAD (2,5 to 1,2 Gy, p=0,03) in patients with left-sided cancer. <h3>Conclusion</h3> Limited data exists demonstrating the clinical benefit of proton radiotherapy (PRT) in breast cancer. This study is the first report of clinical data for Ultra-HF-PT in patients with localized breast cancer. Treatment was well tolerated, with acceptable rates of skin toxicity, providing low dose to normal tissue without compromising target coverage. Dose reduction to organs at risk might translate into the reduction of late toxicities.

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.

The case against IORT in the management of early stage breast cancer

Since the development of breast conserving therapy (BCT) that incorporated standard fractionation whole breast irradiation (WBI) delivered daily over 5–7 weeks, there has been a concerted effort to shorten the duration of adjuvant radiation therapy as a way to improve convenience and compliance, reduce costs, and potentially reduce toxicities. Over the past decade, an unprecedent shift in breast radiation techniques and regimens has led to the emergence of shorter courses of WBI (5–15 fractions) as well as partial breast approaches which also reduce treatment duration to 1–3 weeks.

Optimizing Preventive Adjuvant Linac-Based (OPAL) Radiation: A Phase 2 Trial of Daily Partial Breast Irradiation

Evidence supports use of partial-breast irradiation (PBI) in the management of early breast cancer, but the optimal dose-fractionation remains unsettled. We conducted a phase 2 clinical trial (OPAL trial) to evaluate a novel PBI dosing schedule of 35 Gy in 10 daily fractions. Patients with close (<2 mm) margins also received a boost of 9 Gy in 3 fractions. Eligible patients underwent margin-negative lumpectomy for ductal carcinoma in situ or estrogen receptor-positive invasive breast cancer, up to 3 cm, pTis-T2 N0. The primary outcome was any grade ≥2 toxic effect occurring from the start of radiation through 6 months of follow-up. Secondary outcomes included patient-reported cosmesis, breast pain, and functional status, measured using the Breast Cancer Treatment Outcomes Scale, and physician-reported cosmesis, measured using the Radiation Therapy and Oncology Group scale. The Cochran-Armitage trend test and multivariable mixed-effects longitudinal growth curve models compared outcomes for the OPAL study population with those for a control group of similar patients treated with whole-breast irradiation (WBI) plus boost. All 149 patients enrolled on the OPAL trial received the prescribed dose, and 17.4% received boost. The median age was 64 years; 83.2% were White, and 73.8% were overweight or obese. With median follow-up of 2.0 years, 1 patient (0.7%) experienced in-breast recurrence. Prevalence of the primary toxicity outcome was 17.4% (26 of 149 patients) in the OPAL trial compared with 72.7% (128 of 176 patients) in the control WBI-plus-boost cohort (P < .001). In longitudinal multivariable analysis, treatment on the OPAL trial was associated with improved patient-reported cosmesis (P < .001), functional status (P=.004), breast pain (P=.004), and physician-reported cosmesis (P < .001). Treatment with daily PBI was associated with substantial reduction in early toxicity and improved patient- and physician-reported outcomes compared with WBI plus boost. Daily external-beam partial-breast irradiation with 13 or fewer fractions merits further prospective evaluation.

Knowledge-based multi-institution plan prediction of whole breast irradiation with tangential fields.

To quantify inter-institute variability of Knowledge-Based (KB) models for right breast cancer patients treated with tangential fields whole breast irradiation (WBI). Ten institutions set KB models by using RapidPlan (Varian Inc.), following previously shared methodologies. Models were tested on 20 new patients from the same institutes, exporting DVH predictions of heart, ipsilateral lung, contralateral lung, and contralateral breast. Inter-institute variability was quantified by the inter-institute SDint of predicted DVHs/Dmean. Association between lung sparing vs PTV coverage strategy was also investigated. The transferability of models was evaluated by the overlap of each model's geometric Principal Component (PC1) when applied to the test patients of the other 9 institutes. The overall inter-institute variability of DVH/Dmean ipsilateral lung dose prediction, was less than 2% (20%-80% dose range) and 0.55Gy respectively (1SD) for a 40Gy in 15 fraction schedule; it was < 0.2Gy for other OARs. Institute 6 showed the lowest mean dose prediction value and no overlap between PTV and ipsilateral lung. Once excluded, the predicted ipsilateral lung Dmean was correlated with median PTV D99% (R2=0.78). PC1 values were always within the range of applicability (90th percentile) for 7 models: for 2 models they were outside in 1/18 cases. For the model of institute 6, it failed in 7/18 cases. The impact of inter-institute variability of dose calculation was tested and found to be almost negligible. Results show limited inter-institute variability of plan prediction models translating in high inter-institute interchangeability, except for one of ten institutes. These results encourage future investigations in generating benchmarks for plan prediction incorporating inter-institute variability.

The comparison of transforming growth factor beta-1 serum levels in early-stage breast cancer patients treated with external beam whole breast irradiation plus boost versus interstitial brachytherapy accelerated partial breast irradiation

PURPOSETransforming growth factor beta-1 (TGF-β1) is a profibrotic cytokine used as an early biomarker to develop radiation-induced fibrosis (RIF). This study aimed to compare TGF-β1 serum levels in early-stage breast cancer patients treated with whole-breast radiation therapy (WBRT) plus boost versus accelerated partial breast irradiation (APBI) using multicatheter interstitial brachytherapy. METHODS AND MATERIALSThis clinical trial study was conducted on 20 women with early-stage breast cancer after breast-conserving surgery candidate for adjuvant radiotherapy in Golestan hospital, Ahvaz, in 2021. In one group APBI with high-dose-rate brachytherapy (n = 10), the other group WBRT with external beam radiation plus boost (n = 10) was performed. Serum level of TGF-β1 was evaluated before radiotherapy, immediately after the end of radiotherapy and three months after the end of radiotherapy by Enzyme-linked immunosorbent assay technique (ELISA). ResultsMedian serum TGF-β1 level before radiotherapy was not significantly different between the two groups (p = 0.971). In both APBI and WBRT groups, serum TGF-β1 levels significantly decreased immediately after radiotherapy compared to before treatment (p = 0.005 and p = 0.007, respectively); But three months after radiotherapy, serum TGF-β1 levels increased significantly in the WBRT group (40.50 to 77.41 pg/mL; p = 0.017), while no significant change was observed in the APBI group (24.75 to 30.50 pg/mL; p = 0.332). ConclusionSHigher TGF-β1 values in the WBRT group after radiotherapy can be used as an early and vital biomarker in this treatment, and this data may corroborate links between TGF-beta1 and fibrosis and fibrosis rates between APBI and WBRT; It also shows the preference for using the brachytherapy technique in this group of patients. However, due to the small number of samples, definitive conclusions require further prospective studies.

A Meta-Analysis of Trials of Partial Breast Irradiation

Partial breast irradiation (PBI) is the delivery of radiation therapy (RT) limited to the tumor bed after breast conserving surgery. The results of recent trials of PBI compared with whole breast irradiation (WBI) have suggested conflicting results with respect to local control and toxicity. The purpose of this meta-analysis was to assess effectiveness of PBI and to compare the different techniques. A meta-analysis of aggregate data from published randomized trials was performed to examine the effectiveness of PBI compared with WBI in patients with invasive breast cancer and ductal carcinoma in situ. Relevant data were extracted. The primary outcome was any ipsilateral breast event (invasive or noninvasive). Secondary outcomes included acute and late toxicity. The results of randomized trials were pooled using a fixed effects model and the inverse variance method. Fifteen trials involving 16,474 patients were identified. The majority of enrolled patients were >60 years of age and had T1N0 grade 1 to 2 disease treated with hormone therapy. The percent of ipsilateral breast events was higher in patients treated with PBI compared with WBI (5.0% vs 2.8%; risk ratio [RR], 1.72; 95% confidence interval [CI], 1.47-2.02). Heterogeneity (P=.0002) was observed between the 4 PBI techniques: external beam RT without computed tomography (CT) planning (RR, 2.06; 95% CI, 1.36-3.12); brachytherapy (RR, 1.21; 95% CI, 0.65-2.25); intraoperative RT (RR, 2.79; 95% CI, 2.08-3.73); and external beam RT with CT planning (RR, 1.25; 95% CI, 0.99-1.58). When external beam RT without CT planning and intraoperative RT trials were excluded, the percent of ipsilateral breast events was 3.3% versus 2.6%, respectively (RR, 1.25; 95% CI, 1.00-1.55; P=.05), and no heterogeneity was observed (P=.92). Overall, acute toxicity was less with PBI, and the effect on late toxicity varied by technique. Overall, WBI was more effective than PBI, but the effectiveness of PBI was technique related. PBI was less effective when given by external beam RT without CT planning or intraoperative therapy. Although PBI given by multicatheter brachytherapy or external beam RT with CT planning tended to be statistically less effective than WBI, the absolute difference between groups for ipsilateral breast events was very small (<1%), supporting these approaches for women considering PBI.

Four irradiation and three positioning techniques for whole-breast radiotherapy: Is sophisticated always better?

We report on a dosimetrical study of three patient positions (supine, prone dive, and prone crawl) and four irradiation techniques for whole-breast irradiation (WBI): wedged-tangential fields (W-TF), tangential-field intensity-modulated radiotherapy (TF-IMRT), multi-beam IMRT (MB-IMRT), and intensity-modulated arc therapy (IMAT). This is the first study to evaluate prone crawl positioning in WBI and the first study to quantify dosimetrical and anatomical differences with prone dive positioning. We analyzed five datasets with left- and right-sided patients (n=51). One dataset also included deep-inspiration breath hold (DIBH) data. A total of 252 new treatment plans were composed. Dose-volume parameters and indices of conformity were calculated for the planning target volume (PTV) and organs-at-risk (OARs). Furthermore, anatomical differences among patient positions were quantified to explain dosimetrical differences. Target coverage was inferior for W-TF and supine position. W-TF proved overall inferior, and IMAT proved foremost effective in supine position. TF-IMRT proved competitive to the more demanding MB-IMRT and IMAT in prone dive, but not in prone crawl position. The lung-sparing effect was overall confirmed for both prone dive and prone crawl positioning and was largest for prone crawl. For the heart, no differences were found between prone dive and supine positioning, whereas prone crawl showed cardiac advantages, although minor compared to the established heart-sparing effect of DIBH. Dose differences for contralateral breast were minor among the patient positions. In prone crawl position, the ipsilateral breast sags deeper and the PTV is further away from the OARs than in prone dive position. The prone dive and prone crawl position are valid alternatives to the supine position in WBI, with largest advantages for lung structures. For the heart, differences are small, which establishes the role of DIBH in different patient positions. These results may be of particular interest to radiotherapy centers with limited technical resources.

Partial breast irradiation: An updated consensus statement from the American brachytherapy society

PurposeIn recent years, results with mature follow-up have been reported for several Phase III trials randomizing women to receive whole breast irradiation (WBI) versus varying modalities of partial breast irradiation (PBI). It is important to recognize that these methods vary in terms of volume of breast tissue treated, dose per fraction, and duration of therapy. As such, clinical and technical guidelines may vary among the various PBI techniques. MethodsMembers of the American Brachytherapy Society with expertise in PBI performed an extensive literature review focusing on the highest quality data available for the numerous PBI options offered in the modern era. Data were evaluated for strength of evidence and published outcomes were assessed. ResultsThe majority of women enrolled on randomized trials of WBI versus PBI have been age >45 years with tumor size <3 cm, negative margins, and negative lymph nodes. The panel also concluded that PBI can be offered to selected women with estrogen receptor negative and/or Her2 amplified breast cancer, as well as ductal carcinoma in situ, and should generally be avoided in women with extensive lymphovascular space invasion. ConclusionsThis updated guideline summarizes published clinical trials of PBI methods. The panel also highlights the role of PBI for women facing special circumstances, such as history of cosmetic breast augmentation or prior breast irradiation, and discusses promising novel modalities that are currently under study, such as ultrashort and preoperative PBI. Updated consensus guidelines are also provided to inform patient selection for PBI and to characterize the strength of evidence to support varying PBI modalities.

A Novel Nomogram for Predicting Prognosis and Tailoring Local Therapy Decision for Ductal Carcinoma In Situ after Breast Conserving Surgery.

Purpose: We sought to explore the role of nomogram-combined biomarkers, mammographic microcalcification and inflammatory hematologic markers in guiding local therapy decisions in ductal carcinoma in situ (DCIS) subgroups with different ipsilateral breast tumour recurrence (IBTR) risk. Methods: Between January 2009 and December 2018, consecutive patients with DCIS and breast conserving surgery (BCS) were enrolled and randomly assigned to a training cohort (n = 181) and internally validation cohort (n = 78). Multivariate analyses were performed to identify predictors of IBTR. Model performance was evaluated by the concordance index (C-index) and calibration plot. The time-to-event curves were calculated by the Kaplan–Meier methods and compared by the log-rank test. Results: In total, 259 patients were enrolled and 182 of them received whole breast irradiation (WBI). After a median follow-up of 51.02 months, 23 IBTR events occurred in the whole cohort. By multivariate analyses of training cohort, presence of microinvasion, Ki67 index >14%, mammographic-clustered fine linear microcalcifications and neutrophil/lymphocyte ratio before BCS (preop-NLR), >1.1 remained independent risk factors of IBTR to develop a nomogram. The C-indexes of the nomogram were 0.87 and 0.86 in the training and internal validation set, respectively. Calibration plots illustrated good agreement between the predictions and actual observations for 5-year IBTR. Cut-off values of nomogram point were identified as 53 and 115 points, which divided all patients into low-, intermediate- and high-risk groups. Significant differences in IBTR existed between low-, intermediate- and high-risk subgroups (p < 0.01). For the whole cohort and ER-positive tumours, the benefit of WBI was found only in the intermediate-risk subgroup, but not in those with low or high risk. Fourteen out of 23 IBTRs occurred outside the original quadrant and all occurred in the high-risk group. Conclusions: The novel nomogram demonstrated potential to separate the risk of IBTR and locations of IBTR. For the whole cohort and ER-positive tumours, the benefit of WBI was restricted to an intermediate-risk subgroup.

Thermal Boost Combined with Interstitial Brachytherapy in Early Breast Cancer Conserving Therapy-Initial Group Long-Term Clinical Results and Late Toxicity.

(1) In breast-conserving therapy (BCT), adjuvant radiation, including tumor bed boost, is mandatory. Safely delivered thermal boost (TB) based on radio-sensitizing interstitial microwave hyperthermia (MWHT) preceding standard high-dose-rate (HDR) brachytherapy (BT) boost has the potential for local control (LC) improvement. The study is to report the long-term results regarding LC, disease-free survival (DFS), overall survival (OS), toxicity, and cosmetic outcome (CO) of HDR-BT boost ± MWHT for early breast cancer (BC) patients treated with BCT. (2) In the years 2006 and 2007, 57 diverse stages and risk (IA-IIIA) BC patients were treated with BCT ± adjuvant chemotherapy followed by 42.5–50.0 Gy whole breast irradiation (WBI) and 10 Gy HDR-BT boost. Overall, 25 patients (group A; 43.9%) had a BT boost, and 32 (group B; 56.1%) had an additional pre-BT single session of interstitial MWHT on a tumor bed. Long-term LC, DFS, OS, CO, and late toxicity were evaluated. (3) Median follow-up was 94.8 months (range 1.1–185.5). LC was 55/57, or 96.5% (1 LR in each group). DFS was 48/57, or 84.2% (4 failures in group A, 5 in B). OS was 46/57, or 80.7% (6 deaths in group A, 5 in B). CO was excellent in 60%, good in 36%, and satisfactory in 4% (A), and in 53.1%, 34.4%, and 9.4% (B), respectively. One poor outcome was noted (B). Late toxicity as tumor bed hardening occurred in 19/57, or 33.3% of patients (9 in A, 10 in B). In one patient, grade 2 telangiectasia occurred (group A). All differences were statistically insignificant. (4) HDR-BT boost ± TB was feasible, well-tolerated, and highly locally effective. LC, DFS, and OS were equally distributed between the groups. Pre-BT MWHT did not increase rare late toxicity.

Non-Invasive Physical Plasma for Preventing Radiation Dermatitis in Breast Cancer: A First-In-Human Feasibility Study.

Radiation dermatitis (RD) is the most common acute side effect of breast irradiation. More than a century following the therapeutic utilisation of X-rays, potent preventative and therapeutic options are still lacking. Non-invasive physical plasma (NIPP) is an emerging approach towards treatment of various dermatological disorders. In this study, we sought to determine the safety and feasibility of a NIPP device on RD. Thirty patients undergoing hypofractionated whole-breast irradiation were included. Parallel to radiation treatment, the irradiated breast was treated with NIPP with different application regimens. RD was assessed during and after NIPP/radiation, using clinician- and patient-reported outcomes. Additionally, safety and feasibility features were recorded. None of the patients was prescribed topical corticosteroids and none considered the treatment to be unpleasant. RD was less frequent and milder in comparison with standard skin care. Neither NIPP-related adverse events nor side effects were reported. This proven safety and feasibility profile of a topical NIPP device in the prevention and treatment of RD will be used as the framework for a larger intrapatient-randomised double-blind placebo-controlled trial, using objective and patient-reported outcome measures as an endpoint.

Patterns of Care and Utilization of Radiation for Women With Good-Risk Ductal Carcinoma In Situ: A National Cancer Database Analysis.

Purpose/objective(s)Lumpectomy followed by whole-breast radiation therapy (WBRT) provides a 50% recurrence rate reduction in ductal carcinoma in situ (DCIS) patients when compared to lumpectomy alone. Certain factors increase the risk of recurrence, including higher nuclear grade, large size, age less than 50, and close margins. RTOG 9804 demonstrated a reduction in local failure after WBRT with the use of adjuvant radiation in women with "good-risk disease" (mammographically detected, measuring less than or equal to 2.5 cm, with a predominant nuclear grade of 1 or 2, and a margin of greater than or equal to 1 cm, or a negative re-excision). The purpose of this study is to retrospectively identify the patterns of care in women with low-risk DCIS utilizing the National Cancer Database (NCDB). We hypothesize that with the utilization of hypofractionation, there may be an increase in the delivery of RT for these "good-risk" patients.Materials/methodsThe National Cancer Database was queried to identify women treated with lumpectomy for <2.5 cm, nuclear grade 1 or 2 DCIS of the breast from 2004 to 2016. Data were collected regarding age, tumor size, endocrine therapy use, ER receptor status, race, insurance type, and distance from the treatment center. The distance was stratified into quartiles consisting of 0-3.9, 4-8, 8.1-15.8, and > 15.8 miles, respectively. Radiation fractionation was collected and categorized as hypofractionation, standard fractionation, or other if fractionation could not be ascertained. Clinical and patient-related factors were compared between patients who received radiation and those who received no radiation. The frequency distributions between categorical variables were compared using the Chi-square test. Multivariable logistic regression was used to identify covariables that impacted the receipt of radiation.ResultsThe eligibility criteria were met by a total of 12,846 patients. Of those, 6,600 (51.4%) received adjuvant WBRT. On multivariable regression, patients whose tumors were ER (OR 1.24, P<0.001) and those who had not received endocrine therapy (OR 2.24, P<0.001) were more likely to receive WBRT. Factors less likely to receive WBRT included increasing age over 50 (age 50-65 OR 0.83, P<0.001; age>65 OR 0.58, P<0.001), and distance of >15.8 miles (OR 0.78, P<0.001). The fractionation technique was categorized as standard or hypofractionated in 52.2% of patients. Of those, the use of hypofractionation increased from 0.4% in 2004 to 8.9% in 2010 and to 53.8% in 2016.ConclusionThis NCDB analysis demonstrated that patients who meet the RTOG 9804 criteria for "good-risk" DCIS are less likely to receive RT as time progresses despite an increase in the utilization of hypofractionation techniques. Overall, slightly more than half of these patients receive adjuvant RT.

Global adoption of single-shot targeted intraoperative radiotherapy (TARGIT-IORT) for breast cancer-better for patients, better for healthcare systems.

Micro abstractTargeted intraoperative radiotherapy (TARGIT-IORT) is delivered immediately after lumpectomy for breast cancer. We estimated its impact. At least 44,752 patients with breast cancer were treated with TARGIT-IORT in 260 centres in 35 countries, saving >20 million miles of travel and preventing ~2,000 non–breast cancer deaths. The TARGIT-IORT website (https://targit.org.uk/travel) provides maps and tools to find the nearest centre offering TARGIT-IORT and travel savings.BackgroundTargeted intraoperative radiotherapy (TARGIT-IORT) delivers radiotherapy targeted to the fresh tumour bed exposed immediately after lumpectomy for breast cancer. TARGIT-A trial found TARGIT-IORT to be as effective as whole-breast radiotherapy, with significantly fewer deaths from non–breast cancer causes. This paper documents its worldwide impact and provides interactive tools for clinicians and patients.MethodCentres using TARGIT-IORT provided the date of the first case and the total number of patients. We plotted these data on a customised Google Map. An interactive web-based tool provided directions to the closest centre. Using the data from the TARGIT-A trial, we estimated the total savings in travel miles, carbon footprint, and the number of non–breast cancer deaths that might be prevented.ResultsData from 242 (93%) of the 260 centres treating patients from 35 countries were available. From the first patient treated in 1998 to early 2020, at least 44,752 women with breast cancer have been treated with TARGIT-IORT. The TARGIT-IORT website (https://targit.org.uk/travel) displays the Google Map of centres with number of cases and an interactive tool for patients to find the nearest centre offering TARGIT-IORT and their travel savings. Scaling up to the already treated patients, >20 million miles of travel would have been saved and about 2,000 deaths prevented.ConclusionOne can ascertain the number of patients treated with a novel treatment. These data show how widely TARGIT-IORT has now been adopted and gives an indication of its beneficial worldwide impact on a large number of women with breast cancer.

Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The Danish Breast Cancer Group Partial Breast Irradiation Trial.

On the basis of low risk of local recurrence in elderly patients with breast cancer after conservative surgery followed by whole breast irradiation (WBI), the Danish Breast Cancer Group initiated the noninferiority external-beam partial breast irradiation (PBI) trial (ClinicalTrials.gov identifier: NCT00892814). We hypothesized that PBI was noninferior to WBI regarding breast induration. Patients operated with breast conservation for relatively low-risk breast cancer were randomly assigned to WBI versus PBI, and all had 40 Gy/15 fractions. The primary end point was 3-year grade 2-3 breast induration. In total, 865 evaluable patients (434 WBI and 431 PBI) were enrolled between 2009 and 2016. Median follow-up was 5.0 years (morbidity) and 7.6 years (locoregional recurrence). The 3-year rate of induration was 9.7% for WBI and 5.1% for PBI (P = .014). Large breast size was significantly associated with induration with a 3-year incidence of 13% (WBI) and 6% (PBI) for large-breasted patients versus 6% (WBI) and 5% (PBI) for small-breasted patients. PBI showed no increased risk of dyspigmentation, telangiectasia, edema, or pain, and patient satisfaction was high. Letrozole and smoking did not increase the risk of radiation-associated morbidity. Sixteen patients had a locoregional recurrence (six WBI and 10 PBI; P = .28), 20 patients had a contralateral breast cancer, and eight patients had distant failure (five WBI and three PBI). A nonbreast second cancer was detected in 73 patients (8.4%), and there was no difference between groups. External-beam PBI for patients with low-risk breast cancer was noninferior to WBI in terms of breast induration. Large breast size was a risk factor for radiation-associated induration. Few recurrences were detected and unrelated to PBI.

Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3–07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study

Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS. The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236). Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001). In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

Breast radiotherapy for ductal carcinoma in situ: could less be more?

We congratulate Boon H Chua and colleagues1 on their high-quality randomised, unmasked, phase 3 trial addressing tumour bed boost and dose fractionation in non-low-risk ductal carcinoma in situ (DCIS) in the breast (BIG 3–07/TROG 07.01). They recruited 1608 women from 136 participating centres in 11 countries and report results with a median follow-up of 6·6 years. The primary endpoint was the 5-year free-from-local-recurrence rate. The rationale for the study was that, despite mounting evidence for moderately hypofractionated whole-breast radiotherapy (~2·7 Gy in 15–16 fractions) and a tumour bed boost for invasive breast cancer, few data exist for DCIS.

Comparison of Breast Cancer Radiotherapy Techniques Regarding Secondary Cancer Risk and Normal Tissue Complication Probability - Modelling and Measurements Using a 3D-Printed Phantom.

BackgroundRadiotherapy after breast-conserving therapy is a standard postoperative treatment of breast cancer, which can be carried out with a variety of irradiation techniques. The treatment planning must take into consideration detrimental effects on the neighbouring organs at risk—the lung, the heart, and the contralateral breast, which can include both short- and long-term effects represented by the normal tissue complication probability and secondary cancer risk.Patients and MethodsIn this planning study, we investigate intensity-modulated (IMRT) and three-dimensional conformal (3D-CRT) radiotherapy techniques including sequential or simultaneously integrated boosts as well as interstitial multicatheter brachytherapy boost techniques of 38 patients with breast-conserving surgery retrospectively. We furthermore develop a 3D-printed breast phantom add-on to allow for catheter placement and to measure the out-of-field dose using thermoluminescent dosimeters placed inside an anthropomorphic phantom. Finally, we estimate normal tissue complication probabilities using the Lyman–Kutcher–Burman model and secondary cancer risks using the linear non-threshold model (out-of-field) and the model by Schneider et al. (in-field).ResultsThe results depend on the combination of primary whole-breast irradiation and boost technique. The normal tissue complication probabilities for various endpoints are of the following order: 1%–2% (symptomatic pneumonitis, ipsilateral lung), 2%–3% (symptomatic pneumonitis, whole lung), and 1%–2% (radiation pneumonitis grade ≥ 2, whole lung). The additional relative risk of ischemic heart disease ranges from +25% to +35%. In-field secondary cancer risk of the ipsilateral lung in left-sided treatment is around 50 per 10,000 person-years for 20 years after exposure at age 55. Out-of-field estimation of secondary cancer risk results in approximately 5 per 10,000 person-years each for the contralateral lung and breast.ConclusionsIn general, 3D-CRT shows the best risk reduction in contrast to IMRT. Regarding the boost concepts, brachytherapy is the most effective method in order to minimise normal tissue complication probability and secondary cancer risk compared to teletherapy boost concepts. Hence, the 3D-CRT technique in combination with an interstitial multicatheter brachytherapy boost is most suitable in terms of risk avoidance for treating breast cancer with techniques including boost concepts.