Hypofractionated Whole Breast Irradiation Research Articles

Increase in Hypofractionated Radiation Therapy Among Patients with Invasive Breast Cancer or Ductal Carcinoma In Situ: Who is Left Behind?

We aimed to update the trend of hypofractionated whole-breast irradiation (HF-WBI) use over time in the US and examine factors associated with lack of HF-WBI adoption for patients with early-stage invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) undergoing a lumpectomy. Among patients who underwent a lumpectomy, we identified 928,034 early-stage IBC patients and 330,964 DCIS patients in the 2004-2020 National Cancer Database. We defined HF-WBI as 2.5-3.33 Gy/fraction to the breast and conventional fractionated whole-breast irradiation as 1.8-2.0 Gy/fraction. We evaluated the trend of HF-WBI utilization using a generalized linear model with the log link and binomial distribution. Factors associated with HF-WBI utilization were assessed using multivariable logistic regression in patients diagnosed between 2018 and 2020. Among IBC patients, HF-WBI use has significantly increased from 0.7% in 2004 to 63.9% in 2020. Similarly, HF-WBI usage among DCIS patients has also increased significantly from 0.4% in 2004 to 56.6% in 2020. Black IBC patients were less likely than White patients to receive HF-WBI (adjusted odds ratio [AOR] 0.81, 95% CI: 0.77-0.85). Community cancer programs were less likely to administer HF-WBI to IBC patients (AOR 0.80, 95% CI: 0.77-0.84) and to those with DCIS (AOR 0.87, 95% CI: 0.79-0.96) than academic/research programs. Younger age, positive nodes, larger tumor size, low volume programs, and facility location were also associated with lack of HF-WBI adoption in both patient cohorts. HF-WBI utilization among post-lumpectomy patients has significantly increased from 2004-2020 and can finally be considered standard of care in the US. We found substantial disparities in adoption within patient and facility subgroups. Reducing disparities in HF-WBI adoption has the potential to further alleviate healthcare costs while improving patients' quality of life.

Geographic and Physician-Level Variation in the Use of Hypofractionated Radiation Therapy for Breast Cancer in the U.S.: A Cross-Classified Multilevel Analysis

We aimed to assess geographic and physician-level variation for hypofractionated whole-breast irradiation (HF-WBI) use for early-stage breast cancer patients in the United States. We further evaluated the association between HF-WBI use and demographic factors after accounting for these variations. We performed a retrospective study of early-stage breast cancer patients using private employer-sponsored insurance claims from 2008 to 2017. Patients were clustered according to geographic level and by radiation oncologist. Bayesian cross-classified multilevel logistic models were used to examine the geographic heterogeneity and variation of radiation oncologists simultaneously. Intracluster correlation coefficient (ICC) and median odds ratios (MOR) were calculated to quantify the variation at different levels. We also used the cross-classified model to identify patient demographic factors associated with receiving HF-WBI. The study included 79,747 women (74.0%) who received conventionally fractionated whole-breast irradiation (CF-WBI) and 27,999 women (26.0%) who underwent HF-WBI. HF-WBI adoption increased significantly across time (2008-2017). The variation in HF-WBI utilization was attributed mostly to physician-level variability (MOR = 2.59). The variability of HF-WBI utilization across core-based statistical areas (CBSAs) (MOR = 1.55) was found to be the strongest among all geographic classifications. After accounting for variability in both CBSAs and radiation oncologists, age, receiving chemotherapy, and several community-level factors, including distance from home to facility, community education level, and racial composition, were found to be associated with HF-WBI utilization. This study demonstrated geographic and physician-level heterogeneity in the use of HF-WBI among early-stage breast cancer patients. HF-WBI utilization was also found to be associated with patient and community-level characteristics. Given observed physician-level variability, intervention through continuing medical education could help doctors to better understand the advantages of HF-WBI and promote the adoption of HF-WBI in the U.S. Influence of physician-level characteristics on HF-WBI utilization merits further study.

Are We Missing Acute Toxicities Associated With Hypofractionated Breast Irradiation? A Report From a Large Multicenter Cohort Study

The efficacy and long-term safety of hypofractionated whole breast irradiation (HF-WBI) have been established through multiple randomized trials, yet data about acute toxicities remain more limited. Since 2013, our group has prospectively collected acute toxicity data from weekly treatment evaluations and additional assessment after completion. In 2016, we intentionally shifted the posttreatment assessment follow-up visit from 1 month to 2 weeks to evaluate for missed acute toxicity occurring in that immediate posttreatment window. Here, we report whether 2-week follow-up has resulted in increased detection of acute toxicities compared with 4-week follow-up. We prospectively compared acute toxicity for patients treated with HF-WBI between January 1, 2013, and August 31, 2015 (4 week follow-up cohort) to patients treated between January 1, 2016, and August 31, 2018 (2 week follow-up cohort). Analyses included a multivariable model that adjusted for other factors known to correlate with toxicity. We prospectively defined acute toxicity as maximum breast pain (moderate or severe rating) and/or occurrence of moist desquamation reported 7 days before the completion of radiation therapy (RT) until 42 days after completion. A total of 2689 patients who received postlumpectomy radiation and boost were analyzed; 1862 patients in the 2-week follow-up cohort and 827 in the 4-week follow-up cohort. All acute toxicity measures assessed were statistically similar between follow-up cohorts when compared in an unadjusted fashion. Overall acute composite toxicity was 26.4% and 27.7% for patients in the 4-week follow-up and 2-week follow-up cohorts, respectively. Overall acute composite toxicity remained similar between follow-up cohorts in a multivariable, adjusted model and was significantly related to patient's age, body mass index, smoking status, and treatment technique (intensity-modulated RT vs 3-dimensional conformal radiation therapy) but not follow-up cohort. An earlier posttreatment follow-up for HF-WBI patients did not reveal a significant increased incidence of acute toxicities at 2 weeks compared with 4 weeks. This study provides physicians and patients with additional data on the safety and tolerability of HF-WBI for early stage breast cancer.

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.

Ten-year results of hypofractionated whole breast radiotherapy and intraoperative electron boost in premenopausal women

AimTo evaluate outcome of intraoperative electron boost (IOERT) and hypofractionated whole breast irradiation (HWBI) for breast cancer (BC) in young women. Methods and MaterialsWomen aged ≤ 48 with pT1-2 N0-1 BC received 12 Gy IOERT boost during conservative surgery followed by 3-dimensional conformal HWBI in 13 fractions (2.85 Gy/die). Local relapses (LR) and survival (disease-free, DFS; specific, BCSS; overall, OS) were analyzed. Results481 consecutive BC patients, mostly node negative, with median age of 42 were treated between 2004 and 2014. Median tumor size was 1.48 cm and median IOERT collimator was 4 cm. After 25-day mean interval, HWBI was delivered. At a median follow-up of 9.6 years, there were 23 LRs (4.8 %, 9 of which were in the boost region). Ten-year LR cumulative incidence was 4.1 % (95 %CI, 2.5–6.3). Over time, local control rate decreased for Luminal A and HER2 positive with negative hormonal receptors, while remained steady for triple negative. At multivariate analysis, LR predictors included age < 40, extensive intraductal component and the use of 4-cm IOERT collimator size. Ten-year survival outcomes were as follows: DFS 80.0 % (95 % CI, 75.8–83.5), BCSS 97.5 % (95 % CI, 95.5–98.6 %), OS 96.5 % (95 % CI, 94.3–97.9). Luminal B HER2 negative had the worse survival outcomes. Perioperative complications were uncommon (16.4 %), acute toxicity was mild (<2% Grade 3), but moderate/severe fibrosis was described in 40.8 % of the cases. Cosmesis was scored as excellent/good in 86 % of the cases. ConclusionsELIOT boost and HWBI achieved an excellent local control at the cost of tumor bed fibrosis. IOERT boost dose lower than 12 Gy is advisable.

NRG RTOG 1005: A Phase III Trial of Hypo Fractionated Whole Breast Irradiation with Concurrent Boost vs. Conventional Whole Breast Irradiation Plus Sequential Boost Following Lumpectomy for High Risk Early-Stage Breast Cancer

<h3>Purpose/Objective(s)</h3> Randomized trials support a supplemental radiation dose (Boost) to the lumpectomy (L) cavity region after whole breast irradiation (WBI), providing a 20-30% relative reduction of in-breast recurrence (IBR); with the disadvantage that it extends treatment duration ⁓ 1 week. Hypofractionated WBI (H-WBI) in ≤ 3 weeks is used after L to deliver adjuvant WBI with acceptable toxicity and comparable IBR as conventional WBI (C-WBI) 50 Gy in 2 Gy fractions (F). NRG RTOG 1005 sought to determine whether a boost delivered concomitantly with H-WBI over 15 F is non-inferior for IBR compared to boost delivered sequentially after C-WBI in patients (pts) considered at High Risk of IBR. <h3>Materials/Methods</h3> Protocol-specified High Risk pts post L with stages 0, I & II breast cancer were randomized to C-WBI 50 Gy in 25 F or 42.7 Gy in 16 F plus sequential boost of 12 Gy in 6 F or 14 Gy in 7 F (Arm I) or H-WBI 40 Gy in 15 F plus concomitant boost of 8 Gy in 15 F of 0.53 Gy per day (Arm II). Radiation was target based 3-dimensional conformal radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT) and quality review (QA) was required. Stratification was by age (<50 vs ≥ 50), adjuvant chemotherapy (Y vs N), ER status (+ vs -) and histologic grade (1, 2 v 3). The primary endpoint is IBR. Assuming Arm I 5‐year IBR of 1.59%, 90% CI upper bound hazard ratio (HR) of 2.12 and 1‐sided significance level = 0.05, 2150 pts with at least 46 IBR events provide >80% power to conclude non‐inferiority. IBR was analyzed comparing the cause-specific hazards. Adverse Events (AE) were graded with NCI CTCAE v4. Physician-reported NRG-RTOG Global Cosmetic Score (GCS) was grouped as excellent/good vs fair/poor, and arms compared with chi-square. <h3>Results</h3> 2262 of 2354 randomized pts were eligible (Arm I n=1124; Arm II n=1138). Median age 55 years, 34% Stage II, 52% grade 3, 30% ER-, 17% close/+ margins consistent with a "High Risk" population. Radiation was 3DCRT 81%, IMRT 19%, and the QA was per protocol 81% and 88% on Arm I vs II, respectively. With a median follow-up of 7.3 years and 56 IBR events, the 5 and 7-year IBR were 2.0% and 2.2% on Arm I and 1.9% and 2.6% on Arm II. The non-inferiority comparison (Arm I reference level) resulted in a HR (90% CI): 1.32 (0.84, 2.05) and p = 0.039, thus meeting non-inferiority. No differences in AEs noted between arms, with low rates of ≥ grade 3 treatment-related AEs, 3.3% vs 3.5% for Arm I vs II, respectively (p=0.79). No difference in 3-year excellent/good cosmesis by arm: 86% for Arm I vs 84% Arm II (p=0.61). <h3>Conclusion</h3> Concomitant boost with H-WBI results in non-inferior IBR compared to sequential boost after C-WBI in high-risk cases and reduces overall treatment time. Using target based 3DCRT or IMRT, there are no differences in toxicity or cosmetic outcome for concomitant v sequential boost or the WBI fractionation regimen.

Hypofractionated Regional Nodal Irradiation in Breast Cancer: Initial Results of a Prospective Clinical Trial

<h3>Purpose/Objective(s)</h3> Randomized clinical trials have validated the efficacy and safety of hypofractionated whole breast irradiation (HWBI) in patients with early-stage breast cancer. Toxicities associated with hypofractionated treatment in patients requiring regional nodal irradiation are less well described, and the utilization of hypofractionation in these patients is uncommon in the United States. We report an interim analysis of acute toxicity of a prospective trial of hypofractionated regional nodal irritation (H-RNI). <h3>Materials/Methods</h3> This is a prospective, single-arm trial at a single institution. Eligible patients comprised those with locally advanced, non-metastatic breast cancer and required adjuvant radiation therapy to the regional lymphatics in addition to the breast or chest wall. Patients were stratified into two groups based on extent of axillary surgery: ≤ 5 lymph nodes (Group 1) and > 5 lymph nodes removed (Group 2). We enrolled 31 patients (23 in Group 1, 8 in Group 2) from 11/2018 to 12/2021. Patients received a dose of 42.56 Gy in 16 fractions to the breast/chest wall and regional lymphatics with a sequential boost of 10-12.5 Gy in 4-5 fractions to the surgical cavity or mastectomy scar. Circumferential arm measurements at 10 cm intervals were taken at baseline and predefined intervals following treatment. The primary endpoint is clinically significant lymphedema, defined as a ≥ 10% difference in ipsilateral arm, forearm, or both, compared to the contralateral side. Additional toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. <h3>Results</h3> The median follow up was 19 months and the median age was 59 years. Acute lymphedema and CTCAE toxicities were analyzed in 27 and 31 patients, respectively. One patient (3.2%) in Group 2 met the predetermined criteria for clinically significant lymphedema. One patient experienced symptomatic lymphedema, requiring a compression sleeve. However, her measurements did not meet the threshold for clinically significant lymphedema. The most prevalent Grade 1 toxicities were hyperpigmentation (66.7%), fatigue (66.7%), breast pain (63.3%), and radiation dermatitis (63.3%). The most prevalent Grade 2 toxicities were radiation dermatitis (26.7%) and hyperpigmentation (20%). The incidence of any ≥ Grade 3 toxicity was 6.5% (n=2) related to hyperpigmentation. One patient (3.2%) developed grade 2 pneumonitis. All cosmetic outcomes were rated as good or excellent at 3 months. There were no grade 4 or 5 toxicities. <h3>Conclusion</h3> Our preliminary data suggest that H-RNI is well tolerated. The rates of acute lymphedema and acute toxicity were very low. A matched comparison with patients treated with conventionally fractionated RNI at our institution is ongoing.

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.

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.

Clinical Outcomes of Hypofractionated Whole Breast Irradiation in Early Stage, Biologically High-Risk Breast Cancer

PurposeAdoption of hypofractionated whole breast irradiation (HWBI) for patients with early-stage, biologically high-risk breast cancer remains relatively low. We compared clinical outcomes of conventionally fractionated whole breast irradiation (CWBI) versus moderate HWBI in this patient population. Methods and MaterialsWe queried a prospectively maintained database for patients with early-stage (T1-2, N0, M0) breast cancer who received whole breast irradiation with either CWBI or moderate HWBI at a single institution. We included only patients with biologically high-risk tumors (defined as either estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 negative, human epidermal growth factor receptor 2 amplified, and/or patients with a high-risk multigene assay) who received systemic chemotherapy. Inverse probability of treatment weighting was used to compare treatment cohorts and to estimate 5-year time to event endpoints. Hazard ratios (HR) and 95% confidence interval (CI) were determined based on Cox proportional hazards model. ResultsWe identified 300 patients, of whom 171 received CWBI and 129 received HWBI. There was a statistically significant difference in median age at diagnosis, 59 years for CWBI versus 63 years for HWBI (P = .004), and in median follow-up time, 97 months for CWBI versus 55 months for HWBI (P < .001). After accounting for differences in patient and tumor characteristics with inverse probability of treatment weighting, we found similar 5-year freedom from local recurrence (HR, 0.76; 95% CI, 0.14-4.1), freedom from regional recurrence (HR, 3.395% CI 0.15-69), freedom from distant metastasis (HR 3.9, 95% CI 0.86-17), and disease-free survival (HR 0.84; 95% CI, 0.3-2.4), between those treated with CWBI and those treated with HWBI. Results were similar among each of the 3 high-risk subtypes. ConclusionsOur data support the use of moderate HWBI in patients with early-stage, biologically high-risk breast cancer.

Favorable safety profile of moderate hypofractionated over normofractionated radiotherapy in breast cancer patients: a multicentric prospective real-life data farming analysis

BackgroundModerately hypofractionated whole-breast radiotherapy (HFRT) has proven to be as safe and efficient as normofractionated radiotherapy (NFRT) in randomized trials resulting in major changes in clinical practice. Toxicity rates observed in selected clinical trial patients may differ from those observed in unselected patients with possible comorbidities and frailty in real-life. This study aimed to examine the influence of HFRT versus NFRT on acute toxicity and identify risks factors of dermatitis in real-life patients.Materials and methodsProspective data from breast cancer patients, treated with locoregional radiotherapy were collected between November 2015 and February 2020 in 3 comprehensive cancer centers. Through a systematic data-farming strategy, acute toxicity evaluation forms (CTCAEv4.0) were prospectively completed and extracted electronically. The results from each center were then anonymously merged into a single database for analysis. A Chi-2 test was used to compare HFRT and NFRT. Furthermore, risk factors of dermatitis were identified in a sub-study (622 patients) by multivariate logistic regression analysis.ResultsIn total, 3518 T0-4 N0-3 mostly M0 (85.8%) breast cancer patients with a median age of 60.7 (24–96 years old) were analyzed. Acute grade 2–3 dermatitis, grade 1–3 breast oedema, and grade 1–2 hyperpigmentation were less frequent with HFRT versus NFRT: respectively 8.9% versus 35.1% (Chi-2 = 373.7; p < 0.001), 29.0% versus 37.0% (Chi-2 = 23.1; p < 0.001) and 27.0% versus 55.8% (Chi-2 = 279.2; p < 0.001). Fewer patients experienced pain with HFRT versus NFRT: 33.4% versus 53.7% respectively (Chi-2 = 137.1; p < 0.001). Factors such as high BMI (OR = 2.30 [95% CI, 1.28–4.26], p < 0.01), large breast size (OR = 1.88 [95% CI, 1.07–3.28], p < 0.01) and lumpectomy over mastectomy (OR = 0.52 [95% CI, 0.27–0.97], p < 0.05) were associated with greater risk factors of grade 2–3 dermatitis in multivariate analysis regardless of NFRT or HFRT.ConclusionThe results of this study suggests that breast HFRT may be a better option even for patients with a high BMI or large breast size. Acute toxicity was low to mild, and lower with HFRT compared to NFRT. Results from real-life data were robust, and support the use of HFRT beyond randomized study populations. Long-term real-life data awaits further investigation.

Hypofractionated Whole-Breast Irradiation Focus on Coronary Arteries and Cardiac Toxicity-A Narrative Review.

Breast cancer is the most common cancer among women worldwide, which is often treated with radiotherapy. Whole breast irradiation (WBI) is one of the most common types of irradiation. Hypo-fractionated WBI (HF-WBI) reduces the treatment time from 5 to 3 weeks. Recent radiobiological and clinical evidence recommended the use of HF-WBI regardless of the age or stage of disease, and it is proven that hypo-fractionation is non-inferior to conventional fractionation regimen irradiation. However, some studies report an increased incidence of heart-related deaths in the case of breast irradiation by hypo-fractionation, especially in patients with pre-existing cardiac risk factors at the time of treatment. Due to the new technical possibilities of radiotherapy techniques, HF-WBI can reduce the risk of cardiac toxicity by controlling the doses received both by the heart and by the anatomical structures of the heart. The radiobiological “double trouble”, in particular “treble trouble”, for hypo-fractionated regimen scan be avoided by improving the methods of heart sparing based on image-guided irradiation (IGRT) and by using respiration control techniques so that late cardiac toxicity is expected to be limited. However, long-term follow-up of patients treated with HF-WBI with modern radiotherapy techniques is necessary considering the progress of systemic therapy, which is associated with long-term survival, and also the cardiac toxicity of new oncological treatments. The still unknown effects of small doses spread in large volumes on lung tissue may increase the risk of second malignancy, but they can also be indirectly involved in the later development of a heart disease. It is also necessary to develop multivariable radiobiological models that include histological, molecular, clinical, and therapeutic parameters to identify risk groups and dosimetric tolerance in order to limit the incidence of late cardiac events. MR-LINAC will be able to offer a new standard for reducing cardiac toxicity in the future, especially in neoadjuvant settings for small tumors.

Hypofractionated Whole Breast Irradiation and Boost-IOERT in Early Stage Breast Cancer (HIOB): First Clinical Results of a Prospective Multicenter Trial (NCT01343459).

Simple SummaryIntraoperative electron radiation therapy (IOERT) has repeatedly demonstrated its power to yield high local control rates in all risk constellation of patients with invasive breast cancer when given as tumor bed boost prior to conventional whole breast irradiation (WBI) after breast conserving surgery (BCS). Since the standard for WBI continuously moved towards hypofractionation, we initiated a prospective trial in 2011 where we combined a high precision IOERT boost with a “moderate” hypofractionation schedule (15 × 2.7 Gy), the HIOB-trial [NCT01343459], as clinical evidence for this combination was scarce. Our results demonstrated a low five-year local recurrence rate (overall two events in a population of 1119 patients), which undershot such best evidences in two age groups (41–50 y and >50 y). As acute and late toxicity were mild with no impaired cosmetic outcome, the HIOB-concept seems to be a viable treatment option for patients who underwent BCS and intended WBI.Background and purpose: To investigate intraoperative electron radiation therapy (IOERT) as a tumor bed boost during breast conserving surgery (BCS) followed by hypofractionated whole breast irradiation (HWBI) on age-correlated in-breast recurrence (IBR) rates in patients with low- to high-risk invasive breast cancer. Material and methods: BCS and IOERT (11.1 Gy) preceded a HWBI (40.5 Gy) in 15 fractions. Five-year IBR-rates were compared by a sequential ratio test (SQRT) with best evidences in three age groups (35–40 y and 41–50 y: 3.6%, >50 y: 2%) in a prospective single arm design. Null hypothesis (H0) was defined to undershoot these benchmarks for proof of superiority. Results: Of 1445 enrolled patients, 326 met exclusion criteria, leaving 1119 as eligible for analysis. After a median follow-up of 50 months (range 0.7–104), we detected two local recurrences, both in the age group >50 y. With no observed IBR, superiority was demonstrated for the patient groups 41–50 and >50 y, respectively. For the youngest group (35–40 y), no appropriate statistical evaluation was yet possible due to insufficient recruitment. Conclusions: In terms of five-year IBR-rates, Boost-IOERT followed by HWBI has been demonstrated to be superior in patients older than 50 and in the age group 41–50 when compared to best published evidence until 2010.

Hypofractionated Radiation Therapy for Breast Cancer: Financial Risk and Expenditures in the United States, 2008 to 2017

Rising cancer care expenditures and technological advancement of shorter radiation therapy regimens have drawn significant attention to the use of hypofractionated radiation therapy in clinical care. We examine the costs of hypofractionated whole breast irradiation (HF-WBI) compared with conventional whole breast irradiation (CF-WBI) in the United States and investigate the influences of patient characteristics and commercial insurance on HF-WBI use. In a retrospective study using private employer-sponsored insurance claims, a pooled cross-sectional evaluation of radiation therapy in patients with commercial insurance was performed from 2008 to 2017. The study population included female patients with early-stage breast cancer treated with lumpectomy and whole breast irradiation. A total of 15,869 women received HF-WBI, and 59,328 received CF-WBI. HF-WBI use increased from 2008 to 2017. Community-level factors such as a higher proportion of college graduates and greater mixed racial composition were associated with increased HF-WBI use. Mean insurer-paid radiation therapy expenditures were significantly lower for HF-WBI versus CF-WBI (adjusted difference, $6375; 95% confidence interval, $6147-$6603). Mean patient out-of-pocket expenditure for HF-WBI was $139 less than that for CF-WBI. Geographic variation existed across the United States in HF-WBI use (range, 9.6%-36.2%), with no consistent relationship between HF-WBI use and corresponding average cost differences between HF-WBI and CF-WBI. If trends continue, HF-WBI will soon become the dominant form of radiation treatment in the United States. Although HF-WBI represents significant savings to the health care system and individual patients, no evidence indicated that a financial disincentive had slowed adoption of HF-WBI. Therefore, multilevel approaches, including individuals, the community, and health policy, should be used to promote cost-effective cancer care. Innovations to policies on cost-effective radiation therapy treatment might consider non-financial incentives to promote HF-WBI use.

Five-Year Longitudinal Analysis of Patient-Reported Outcomes and Cosmesis in a Randomized Trial of Conventionally Fractionated Versus Hypofractionated Whole-Breast Irradiation.

There are limited prospective data on predictors of patient-reported outcomes (PROs) after whole-breast irradiation (WBI) plus a boost. We sought to characterize longitudinal PROs and cosmesis in a randomized trial comparing conventionally fractionated (CF) versus hypofractionated (HF) WBI. From 2011 to 2014, women aged ≥40 years with Tis-T2 N0-N1a M0 breast cancer who underwent a lumpectomy with negative margins were randomized to CF-WBI (50 Gray [Gy]/25 fractions plus boost) versus HF-WBI (42.56 Gy/16 fractions plus boost). At baseline (pre-radiation), at 6 months, and yearly thereafter through 5 years, PROs included the Breast Cancer Treatment Outcome Scale (BCTOS), Functional Assessment of Cancer Therapy-Breast (FACT-B), and Body Image Scale; cosmesis was reported by the treating physician using Radiation Therapy Oncology Group cosmesis values. Multivariable mixed-effects growth curve models evaluated associations of the treatment arm and patient factors with outcomes and tested for relevant interactions with the treatment arm. A total of 287 patients were randomized, completing a total of 14,801 PRO assessments. The median age was 60 years, 37% of patients had a bra cup size ≥D, 44% were obese, and 30% received chemotherapy. Through 5 years, there were no significant differences in PROs or cosmesis by treatment arm. A bra cup size ≥D was associated with worse BCTOS cosmesis (P < .001), BCTOS pain (P=.001), FACT-B Trial Outcome Index (P=.03), FACT-B Emotional Well-being (P=.03), and Body Image Scale (P=.003) scores. Physician-rated cosmesis was worse in patients who were overweight (P=.02) or obese (P < .001). No patient subsets experienced better PROs or cosmesis with CF-WBI. Both CF-WBI and HF-WBI confer similar longitudinal PROs and physician-rated cosmesis through 5 years of follow-up, with no relevant subsets that fared better with CF-WBI. This evidence supports broad adoption of hypofractionation with boost, including in patients receiving chemotherapy and in a population with a high prevalence of obesity. The associations of large breast size and obesity with adverse outcomes across multiple domains highlight the opportunity to engage at-risk patients in lifestyle intervention strategies, as well as to consider alternative radiation treatment regimens.

A comparative study on hypofractionated whole-breast irradiation with sequential or simultaneous integrated boost on different positions after breast-conserving surgery

This study explored the dosimetric difference between hypofractionated whole-breast irradiation (HFWBI) with sequential boost (SEB) and simultaneous integrated boost (SIB) based on supine and prone positions to identify the superior boost mode and superior position. Thirty breast cancer patients eligible for HFWBI after breast-conserving surgery were enrolled. All patients underwent 3DCT simulation scanning in both supine and prone positions. For the SEB-HFWBI plan, the dose prescribed for the planning target volume (PTV) of whole breast (WB) was 2.67 Gy per fraction with a total of 15 fractions, followed by a sequential boost of 3.2 Gy per fraction to the PTV of tumor bed (TB) in 3 fractions. For the SIB-HFWBI plan, the dose prescribed for the PTV of WB was 2.67 Gy per fraction with a total of 15 fractions, with a simultaneously integrated boost of 3.2 Gy per fraction to the PTV of TB with a total of 15 fractions. Regardless of the position, for the PTV of TB, the conformal index (CI) in the SIB-HFWBI plans was greater than those in the SEB-HFWBI plans (T = − 8.114, − 8.114; both P < 0.05). The CI for the PTV of WB increased significantly in the prone position relative to the supine position in both two plans(Z = − 3.340, − 3.501; all P < 0.05). The study suggested that prone SIB-HFWBI might be more suitable for postoperative radiotherapy after breast-conserving surgery for early-stage breast cancer patients.

Photobiomodulation therapy for the prevention of acute radiation dermatitis in breast cancer patients undergoing hypofractioned whole‐breast irradiation (LABRA trial)

To evaluate the efficacy of photobiomodulation therapy in breast cancer patients post-lumpectomy undergoing hypofractionated whole-breast irradiation (HF-WBI) for the prevention and management of acute radiodermatitis (ARD). A randomized, multicentric clinical trial (LABRA trial, NCT03924011) was set up at the Limburg Oncology Center, including the Jessa Hospital (Hasselt, BE) and Ziekenhuis Oost-Limburg (Genk, BE). A total of 71 breast cancer patients planned to undergo HF-WBI were randomized to one of the two study arms: the control group (n = 32) or the PBM group (n = 39). The PBM group received the standard institutional skincare combined with PBM (2×/week) during the complete radiotherapy (RT) course. Patients in the control group received the standard skincare combined with placebo treatment (2x/week). Patients' skin reactions were evaluated weekly during the RT treatment by using the modified version of the Radiation Therapy Oncology Group (RTOG) criteria. At week 3 of RT, one patient presented a grade 2 and one patient a grade 3 skin reaction in the control group, while in the PBM group, all patients still presented grade 1 ARD. At the final RT session 28% of the patients presenting grade 2-3 ARD, while in the PBM group 10% presented grade 2 and no grade 3 ARD. PBM reduced the incidence of severe ARD by 18%. However, the difference was not significant (p = 0.053). Based on the LABRA trial results, PBM seems not able to reduce the incidence of severe ARD in breast cancer patients undergoing HF-WBI. Research in a larger patient population is recommended.

Partial breast irradiation versus whole breast radiotherapy for early breast cancer.

Breast-conserving therapy for women with breast cancer consists of local excision of the tumour (achieving clear margins) followed by radiotherapy (RT). Most true recurrences occur in the same quadrant as the original tumour. Whole breast radiotherapy (WBRT) may not protect against the development of a new primary cancer developing in other quadrants of the breast. In this Cochrane Review, we investigated the delivery of radiation to a limited volume of the breast around the tumour bed (partial breast irradiation (PBI)) sometimes with a shortened treatment duration (accelerated partial breast irradiation (APBI)). To determine whether PBI/APBI is equivalent to or better than conventional or hypofractionated WBRT after breast-conserving therapy for early-stage breast cancer. On 27 August 2020, we searched the Cochrane Breast Cancer Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and three trial databases. We searched for grey literature: OpenGrey (September 2020), reference lists of articles, conference proceedings and published abstracts, and applied no language restrictions. Randomised controlled trials (RCTs) without confounding, that evaluated conservative surgery plus PBI/APBI versus conservative surgery plus WBRT. Published and unpublished trials were eligible. Two review authors (BH and ML) performed data extraction, used Cochrane's risk of bias tool and resolved any disagreements through discussion, and assessed the certainty of the evidence for main outcomes using GRADE. Main outcomes were local recurrence-free survival, cosmesis, overall survival, toxicity (subcutaneous fibrosis), cause-specific survival, distant metastasis-free survival and subsequent mastectomy. We entered data into Review Manager 5 for analysis. We included nine RCTs that enrolled 15,187 women who had invasive breast cancer or ductal carcinoma in-situ (6.3%) with T1-2N0-1M0 Grade I or II unifocal tumours (less than 2 cm or 3 cm or less) treated with breast-conserving therapy with negative margins. This is the second update of the review and includes two new studies and 4432 more participants. Local recurrence-free survival is probably slightly reduced (by 3/1000, 95% CI 6 fewer to 0 fewer) with the use of PBI/APBI compared to WBRT (hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.03 to 1.42; 8 studies, 13,168 participants; moderate-certainty evidence). Cosmesis (physician/nurse-reported) is probably worse (by 63/1000, 95% CI 35 more to 92 more) with the use of PBI/APBI (odds ratio (OR) 1.57, 95% CI 1.31 to 1.87; 6 studies, 3652 participants; moderate-certainty evidence). Overall survival is similar (0/1000 fewer, 95% CI 6 fewer to 6 more) with PBI/APBI and WBRT (HR 0.99, 95% CI 0.88 to 1.12; 8 studies, 13,175 participants; high-certainty evidence). Late radiation toxicity (subcutaneous fibrosis) is probably increased (by 14/1000 more, 95% CI 102 more to 188 more) with PBI/APBI (OR 5.07, 95% CI 3.81 to 6.74; 2 studies, 3011 participants; moderate-certainty evidence). The use of PBI/APBI probably makes little difference (1/1000 less, 95% CI 6 fewer to 3 more) to cause-specific survival (HR 1.06, 95% CI 0.83 to 1.36; 7 studies, 9865 participants; moderate-certainty evidence). We found the use of PBI/APBI compared with WBRT probably makes little or no difference (1/1000 fewer (95% CI 4 fewer to 6 more)) to distant metastasis-free survival (HR 0.95, 95% CI 0.80 to 1.13; 7 studies, 11,033 participants; moderate-certainty evidence). We found the use of PBI/APBI in comparison with WBRT makes little or no difference (2/1000 fewer, 95% CI 20 fewer to 20 more) to mastectomy rates (OR 0.98, 95% CI 0.78 to 1.23; 3 studies, 3740 participants, high-certainty evidence). It appeared that local recurrence-free survival is probably worse with PBI/APBI; however, the difference was small and nearly all women remain free of local recurrence. Overall survival is similar with PBI/APBI and WBRT, and we found little to no difference in other oncological outcomes. Some late effects (subcutaneous fibrosis) may be worse with PBI/APBI and its use is probably associated with worse cosmetic outcomes. The limitations of the data currently available mean that we cannot make definitive conclusions about the efficacy and safety or ways to deliver PBI/APBI. We await completion of ongoing trials.

Has Hypofractionated Whole-Breast Radiation Therapy Become the Standard of Care in the United States? An Updated Report from National Cancer Database

Introduction/BackgroundWe aimed to update the previous evaluation of hypofractionated whole-breast irradiation (HF-WBI) use over time in the United States and factors related to its adoption for patients undergoing a lumpectomy from 2004 to 2016. Materials and MethodsAmong the patients who underwent a lumpectomy, we identified 688,079 patients with early-stage invasive breast cancer and 248,218 patients with ductal carcinoma in situ in the National Cancer Database from 2004 to 2016. We defined HF-WBI as 2.5 to 3.33 Gy/fraction to the breast and conventional fractionated whole-breast irradiation as 1.8 to 2.0 Gy/fraction. We evaluated the trend of HF-WBI use and examined factors associated with HF-WBI use using logistic regression models. ResultsAmong invasive cancer patients, the use of HF-WBI increased exponentially from 0.7% in 2004 to 15.6% in 2013 and then to 38.1% in 2016. Among patients with ductal carcinoma in situ, the use of HF-WBI has increased significantly from 0.42% in 2004 to 13.4% in 2013 and then to 34.3% in 2016. Factors found to be associated with HF-WBI use included age, patient geographical location, race/ethnicity, tumor stage, grade, treating facility type, and volume. ConclusionHF-WBI use in the United States has more than doubled from 2013 to 2016. Although its use is close to that of conventional fractionated whole-breast irradiation, HF-WBI is still far from the preferred standard of care in the United States. We identified several patient and facility factors that can impact the uptake of HF-WBI treatment.MicroabstractUsing the National Cancer Database from 2004 to 2016, we evaluated the trend of hypofractionated whole-breast radiation therapy use and factors associated with use. Use in the United States has more than doubled from 2013 to 2016, but it has not become the standard of care. We identified several patient and facility factors that impact the uptake of hypofractionated whole-breast radiation therapy treatment.

Abstract GS2-04: A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01)

Abstract Background: Wholebreast irradiation (WBI) after breast conserving surgery for DCIS reduces therisk of local recurrence including invasive recurrence. The objective of BIG3-07/TROG 07.01 is to test radiation dose escalation to the tumor bed (tumorbed boost) and fractionation sensitivity of whole breast irradiation (WBI) inpatients with non-low risk DCIS treated with breast conserving therapy. Methods: BIG3-07/TROG 07.01 is an international, multicenter, randomized, controlled, phase 3 trial. Eligible women were ≥18 years ofage with completely resected non-low risk DCIS defined as age &amp;lt;50 years orage ≥50 years plus at least one of the risk factors for local recurrence (palpable tumor,multifocal disease, tumor size ≥ 1.5cm, intermediate or high nuclear grade, central necrosis, comedo histologyand/or surgical margin &amp;lt;10 mm). Patients were randomized to have tumor bedboost (16 Gy in 8 daily fractions) or no boost following conventional WBI (50Gy in 25 daily fractions) or hypofractionated WBI (42.5 Gy in 16 dailyfractions) in one of three randomization categories selected by centers priorto study activation. Randomization A was a 4-arm randomization of no boost vs. boostfollowing conventional WBI vs. hypofractionated WBI. Patients in RandomizationB and Randomization C were assigned no boost or boost following conventional WBIand hypofractionated WBI, respectively. The primary endpoint was time to localrecurrence, analyzed by intention to treat. The trial was designed to detect a3% difference in 5-year free-from- local recurrence rates between the no boostand boost groups (93% vs 96%; hazard ratio, 0.56) with 90% power and 2-sidedalpha level of 5%. The primary effect of boost was assessed on all randomizedpatients. The secondary effect of WBI dose-fractionation and the interactionbetween boost and WBI dose-fractionation were assessed on patients in RandomizationA and additionally on all patients. Results: BetweenJune 2007 and June 2014, 1608 patients were randomized to have no boost (805patients) or boost (803 patients) after WBI. Conventional WBI was given in 831 patients(no boost in 416 patients; boost in 415 patients). Hypofractionated WBI wasgiven in 777 patients (no boost in 389 patients; boost in 388 patients). Adjuvantendocrine therapy was planned in 106 patients (13%) in the no boost group and105 patients (13%) in the boost group. Median follow-up was 6.6 years. The 5-yearfree-from- local recurrence rates were 93% in the no boost group and 97% in theboost group (hazard ratio, 0.47; 95% confidence interval [CI], 0.31 to 0.72;P&amp;lt;0.001). Forty-four percent and 45% of LRs were invasive in the no boostgroup and boost group, respectively. The effect of boost did not vary significantlyby age, tumor size, nuclear grade, surgical margin or endocrine therapy. Therewere no significant differences in the 5-year free-from- local recurrence ratesbetween the conventional WBI group and hypofractionated WBI group inRandomization A (94% vs. 94%, P=0.84) and in all randomized patients (95% vs.95%, P=0.89). The test for interaction between boost and dose-fractionation wasnot significant in Randomization A or in all randomized patients (both P=0.89).The rates of grade ≥2 breastpain (12% vs. 16%, P=0.84) and skin and subcutaneous tissue fibrosis (6% vs.15%, P=0.14) did not differ significantly between the groups. Conclusions: Inwomen with non-low risk DCIS treatedwith breast conserving surgery, the addition of tumor bed boost followingconventional or hypofractionated WBI reduced local recurrence rates. There wasno difference in local recurrence rates between conventional WBI andhypofractionated WBI. (Registered with ClinicalTrials.gov, NCT00470236.) Citation Format: Boon Hui Chua, Emma Link, Ian Kunkler, Ivo Olivotto, Antonia Helen Westenberg, Timothy Whelan, Guenther Gruber, Breast International Group (BIG)-aisbl, Trans Tasman Radiation Oncology Group, Scottish Cancer Trials Breast Group, Canadian Cancer Trials Group, European Organization for Research and Treatment of Cancer, International Breast Cancer Study Group, Cancer Trials Ireland. A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-04.