Partial Breast Irradiation Research Articles

Financial Implications of Evolving Breast Cancer Radiotherapy Treatment Protocols

Adjuvant radiotherapy for breast cancer represents a significant portion of radiotherapy (RT) treatments. The resource implications of evidence-based changes in treatment protocols must be defined to facilitate RT service planning. We designed a study to calculate the impact of past changes and create a model to allow prediction of costs implications for future changes. Changes in RT treatment (shown in table 1) in the past 3 years were identified in consultation with clinical staff and by reviewing institutional treatment guidelines. Resource and infrastructure costs were calculated for each protocol. Staff time was calculated using standard time slots where known (e.g., CT simulation appointment) and estimates based on discussion with staff (e.g., time to plan whole breast RT). Cost / Gy was calculated based on Linac cost of €2.5M, 10% annual service charge over 12-year lifetime, 2.7 patients treated / hour (verified institutional metric) and standard 2Gy fraction, giving €37.72 / Gy. We did not include facilities costs nor account for differing treatment outcomes. We collected relevant data on a consecutive 6-month sample (Jan - Jun 2019) of women receiving adjuvant RT for breast cancer (n = 224). Total costs were calculated by applying costs for each protocol change to the women in this cohort eligible for the changes. Protocol changes and costs are summarized in table 1. The use of DIBH for women <60 years receiving IMN RT (left and right sided) added a cost. The largest cost saving resulted from more selective tumor bed boost, a saving of €462,138. The potential impact of a 5-fraction boost for women with non-low risk DCIS was estimated. In the cohort analyzed, identified changes in adjuvant breast radiotherapy resulted in overall savings due to updated indications for boost and the implementation of ultra-hypofractionated radiotherapy. We are now analyzing the impact of introducing simultaneous integrated boost and partial breast radiotherapy.

Intra-Operative Radiotherapy (IORT) in Breast Conserving Therapy in Early-Stage Breast Cancer and DCIS

Initial breast intra-operative radiotherapy (IORT) results in clinical trials were encouraging though with longer follow up, increased local recurrences have been reported compared with whole breast radiation or other partial breast radiation including accelerated partial breast irradiation (APBI) methods. The goal of the study is to report our prospective single institution IORT breast study outcomes of local recurrence (LR) including true recurrence and breast elsewhere failures, breast cancer specific survival (BCSS), and overall survival (OS) with low energy x-ray IORT in early-stage breast cancer or ductal carcinoma in situ. A total of 480 patients with early-stage breast cancer or DCIS were prospectively enrolled in an IRB approved single institution trial and treated with low energy X-ray IORT 20 Gy at time of breast-conserving surgery. Eligibility criteria included ≥ 45 years of age with unifocal tumors < 3 cm deemed candidates for partial mastectomy. Supplemental external beam radiation was recommended for patients with high-risk surgical pathology including multifocal disease, positive nodes, close margins < 2 mm, or lymphovascular invasion. Ipsilateral breast tumor recurrences were classified as true recurrence versus elsewhere failure by location and histology: same/different quadrant and similar/different histology. Kaplan-Meier methods were used to estimate survival probabilities across time. Median age of enrolled patients was 64 years with the majority of patients having favorable phenotype with 94% ER+ and 93% Her-2 - disease. 110 patients (23%) had supplemental EBRT delivered; 103 to the whole breast and 7 to the breast and regional nodes. At a median follow up of 73 months (range 17 - 131 months), there were 23 (4.8%) ipsilateral breast tumor recurrences, of which 9 were true recurrences (1.9%) and 14 elsewhere failures (2.9%). One patient with true recurrence and 3 patients with elsewhere breast failures synchronously presented with clinical or radiographic regional node involvement. Seven patient developed contralateral breast cancer and 8 patients developed distant metastases during the follow-up period. There were 2 breast cancer related deaths. At 6-years, overall survival rate was 96.8% and breast cancer specific survival was 98.7%. Our study outcomes reflect similar outcomes as other reported IORT studies with electron or low energy X-ray in breast cancer, with higher risk of local failure than historical whole breast and other partial breast radiation techniques. This supports current radiation society guidelines for IORT monotherapy for breast cancer to be optimally considered in the context of prospective clinical trials.

Understanding Treatment Anxiety and Utility of Mixed Media Educational Tools in Radiation Oncology Consultation: A Qualitative Study

Anxiety and adjustment disorders are prevalent in cancer patients, especially at the initiation of treatment, which may be alleviated by improved communication at initial consultation. The purpose of this study is to explore patients' needs in how radiation consultation may improve treatment-related anxiety and the role of multimedia visual tools. Eight patients previously treated with partial or whole breast irradiation at our institution were interviewed in a semi-structured manner at a median of 1.54 months (range 0.13 - 12.42) after they completed radiation. Interview questions included expectations prior to consultation, experience of consultation and treatment, and the role of augmented reality or multimedia tools. Two independent reviewers performed an inductive, thematic analysis to generate themes and subthemes (inter-rater reliability = 0.79). Four main themes were identified in thematic analysis: information expectations, anxiety, personalized education, and visual aids. Patients described preconceptions of radiation, desire for greater volume of information, importance of repetition from providers, benefit of seeing treatment set-up during simulation, and frustrations with the breath-holding process. Anxiety was related to fear of the unknown, difficulty remembering information when anxious, difficulty asking questions, and ambiguity of information worth worrying about. Patients expressed a desire for personalized education, including accounting for prior health conditions, varying health literacy, preference for individualized presentations, and minimizing extraneous input from those not on the healthcare team. Patients desired visuals during consultation, favored 3D technology over 2D mediums, acknowledged differences in learning style, and preferred an interactive component of patient education done in conjunction with visual tools. While verbal consultation process provides valuable education regarding radiation treatment, patients continue to experience anxiety attributed to fear of the unknown. Augmenting the standard initial consultation with interactive visual aids, particularly in the form of a 3D medium, may enhance the patient experience at time of consultation. The results of this study will inform the development of a patient educational tool and clinical study named Curie therapy User eXperience (CurieUx) to be used during radiation oncology consultations.

Early Clinical Experience of Utilizing Online Adaptive Radiotherapy for Accelerated Partial Breast Irradiation with Stereotactic Body Radiation Therapy for Early-Stage Breast Cancer Patients

Accelerated partial breast irradiation (APBI) with stereotactic body radiation therapy (SBRT) is becoming popular for early-stage breast cancer (ESBC) due to decreased treatment time and dose to healthy breast tissue. With variability in lumpectomy cavity size post-surgery, CBCT-guided online adaptive RT (oART) may improve target coverage and reduce normal tissue exposure by accounting for inter- and intrafractional cavity variations. In this study, we report our initial clinical experience utilizing APBI oART for patients with ESBC. A total of 15 patients with 17 ESBC cavities (2 with bilateral disease) were treated with SBRT using oART over one year. Patients were immobilized using standard breast simulation setup with free breathing and breath hold (if left sided). The clinical target volume consisted of an isometric 1 cm expansion off the lumpectomy cavity, which was expanded another 3 mm (cropped 3mm from surface) to create the planning target volume (PTV). 95% of the PTV received prescription dose (30 Gy in 5 fractions). The oART delivery process (supervised by physician and physicist) initially coregisters the daily CBCT to the treatment planning CT with alignment to lumpectomy cavity. Target volumes and organs-at-risk were modified at each treatment and the plan re-optimized. Either the re-optimized oART plan or scheduled plan was chosen for each fraction pending which plan best met prespecified clinical goals. Acute toxicity was assessed at one-month follow-up using CTCAE. Patients were age 56 or older, ECOG 0-1, with no known genetic abnormality, and with anatomic stage 0-1A ESBC. Most tumors were located in the upper outer quadrant (n = 12, 70.6%) at middle or posterior depth (n = 15, 88.2%). Final margins were negative. 88% had tantalum clips placed. One patient had an Oncotype DS score of 34 and received systemic therapy. 82.3% met suitable APBI criteria and 3 met cautionary criteria due to high grade, of which 2 had ipsilateral trimodality treatment 10+ years prior and denied mastectomy at recurrence. Mean time to starting RT after lumpectomy was 2.5 months. Mean PTV to breast ratio was 0.12. From simulation to end of treatment, lumpectomy cavity size decreased a median of 27%. oART plans were chosen 89% of the time. VMAT was utilized 52.9% of the time compared to static-field IMRT (47.1%). Three patients were treated with breath hold. 93% of patients were treated on non-consecutive days with average treatment lasting 9.1 ± 2.2 days. CTCAE grade 1 toxicities were hyperpigmentation (n = 6, 40%), breast pain (n = 2, 13.3%), persistent seroma (n = 1, 6.7%), and fatigue (n = 7, 46.7%). No patients experienced fat necrosis, telangiectasias, breast shrinkage, lymphedema, or CTCAE grade 2+ toxicities. oART for APBI using SBRT for patients with ESBC is clinically feasible and allows for variations in lumpectomy cavity size. Nearly half of patients had no complaints or breast changes at one-month follow-up and the remaining had CTCAE grade 1 toxicities alone.

Clinical Trials of Carbon Ion Radiotherapy for Early-Stage Breast Cancer

Our institute conducted a clinical trial 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. To date, we have conducted three clinical trials and one advanced medical treatment (NIRS 9404 Comprehensive Research). The first study (UMIN000010848: commonly known as Breast I trial) was 4-split irradiation for stage I low-risk patients aged 60 years or older, and the next clinical study (UMIN000029478: commonly known as Breast II trial) was for Tis-1N0M0 cases of 2 cm or less. On the other hand, 4-split irradiation using standard adjuvant drug therapy according to risk combined with whole breast irradiation by X-ray, the latest clinical trial (UMIN000046859: commonly known as Breast III trial) is a single irradiation for Tis-1N0M0 patients aged 50 years or older. be. In each phase I, the dose increase test was performed, and in phase II, treatment was performed with the recommended dose determined in phase I. Advanced medical care was provided in parallel with breast I for stage I breast cancer that was difficult or rejected to participate in breast I trial. By January 2023, 60 cases were enrolled. A total of 19 were enrolled In Breast I, 7 in Phase I, 12 in Phase II of the recommended dose of 60.0 Gy (RBE). A total of 14 were enrolled in the 9404 Comprehensive Research. A total of 17 were enrolled In Breast II, 5 cases in Phase I, 12 cases in Phase II of recommended dose 60.0 Gy (RBE). A total of 10 were enrolled in Breast III, 6 cases in Phase I, and 4 in Phase II of recommended dose 50.0 Gy (RBE). As acute adverse events, grade 2 of acute radiation dermatitis were observed in 1 case, grade 1 of acute radiation dermatitis was observed in 31 cases, and grade 1 of mastitis was observed in 6 cases. As a late adverse event, grade 3 of pneumonia of unknown causality were observed in one case, but there were no other problematic adverse events, and breast cosmetic outcome was excellent in all cases. Tumor disappearance after CIRT took 3 to 24 months. Local recurrence and axillary lymph node metastasis were observed in one high-risk case of advanced medical treatment who refused any other therapy. Two cases had ipsilateral intramammary metachronous breast cancer with different subtypes. To date, no other recurrences or metastases have been observed. CIRT for early-stage breast cancer is expected to be effective with mild adverse events, and it is considered meaningful to continue research.

Multi-Institutional Phase II Trial Using Dose Escalated Five Fraction Stereotactic Partial Breast Irradiation (S-PBI) with GammaPodTM for Early-Stage Breast Cancer

We report on our early experience of a multi-institutional phase II study of dose escalated five fraction stereotactic partial breast irradiation (S-PBI) for early-stage breast cancer after partial mastectomy using the GammaPodTM stereotactic radiation system. Patient eligibility included DCIS or invasive epithelial histologies, AJCC clinical stage 0, I, or II with tumor size < 3 cm, and negative margins. Prior safety of Phase I dose escalation has been reported. Dose was 40 Gy delivered in 5 fractions to the CTV, and minimum dose 30 Gy in 5 fractions to the PTV. CTV margin was 1 cm and PTV margin 3 mm. For PTV cavities larger than 100cc, dose was reduced to 35Gy in 5 fractions to the CTV and 30 Gy in 5 fractions to the PTV. Primary endpoint of the study is to determine the 3-year patient global cosmesis score (4-point scale excellent, good, fair, or poor) and adverse cosmesis using a dose escalated approach with smaller PTV margins than conventional methods. Both patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Treatment related toxicity was graded using the NCI version 4.0 and RTOG/EORTC late radiation scale. From 3/2019-10/2021, 74 patients were treated respectively. Of these, 38 were treated to 40Gy and 36 were treated to 35 Gy. Median follow up (f/u) was 24 months (mo), range (r) 3-39mo. Median age was 63 years (r 43-77). Histology included 28 DCIS, and 46 invasive carcinomas. 45/46 invasive tumors were ER+. 60/74 (81%) patients received endocrine therapy, and 7/74 patient received chemotherapy. There were 221 acute grade 1 toxicities, and 28 Grade 2 toxicities. No grade 3 or higher acute toxicities were reported (< 90 days). The most common Grade 2 toxicities were radiation dermatitis (10), breast pain (8), blister (4), skin infection (2), nipple discharge (2), and fatigue (2). In the late period, there were 54 Grade 1 late toxicities, 4 Grade 2 late toxicities, and no Grade 3 or higher late toxicities. Grade 2 toxicities included fibrosis (2), and pain (2). Two patients developed grade 1 asymptomatic nonpalpable fat necrosis both diagnosed at 12 months after radiation treatments. The most common grade 1 late toxicities were breast pain (14), hyperpigmentation (8), fibrosis (10), and fatigue (5). Physicians scored cosmesis excellent or good 70/73 (95.8%), 58/60 (96.7%), 36/36 (100%),17/17(100%) respectively at baseline, 12 months, 24 months, and 36months post SBRT, while patients scored the same periods 62/71 (83.7%), 53/59 (89.8%), 33/36 (91.6%), 17/18 (94.4%). There have been no reports of disease recurrences. Results at 24-month median follow-up, of our dose escalated stereotactic partial breast 5 fraction regimen, has low acute and late toxicity, while maintaining high proportion of excellent/good cosmetic outcomes. Continued analysis of all cohorts is in progress. gov identifier is NCT03581136.

A Multicenter Study of Clinical to Planning Target Volume Margins for Adjuvant Partial Breast Irradiation Delivered on the 1.5T MR-Linear Accelerator

Adjuvant partial breast irradiation (APBI) for early-stage breast cancer patients delivered on a conventional Linac commonly uses a clinical to planning target volume (CTV-PTV) margin of 10 mm. Published data suggest this margin could be reduced using an MR-guided workflow. This study quantifies the CTV to PTV margin for APBI delivered on the 1.5T MR-Linac (MRL) using an Adapt to Position (ATP) workflow. All target contouring was done as per the IMPORT LOW trial and MRL Consortium guidelines. The CTV is the tumor bed defined by surgical clips including postsurgical changes. A single center cohort of ten patients was used to assess delineation error on ProKnow DS v1.28.0 by measuring CTV contour displacements on the CT planning scans (pCT) delineated by five breast radiation oncologists. All other error components were measured on treatment planning software on another single center cohort of ten patients. Target deformation error was measured as surgical clip displacements between the pCT and daily pre-treatment (pre-Tx) MRI scans. Intrafraction motion was determined by the CTV displacement between pre- and post-treatment MRIs (post-Tx) in available paired images from five patients. Matching error was estimated as the interobserver variation of three MRL radiographers registering the pCT with daily pre-Tx MRI. Technical delivery accuracy was estimated using the results from routine quality assurance measurements. Beam penumbral width (p) was estimated from the clinical treatment plans. The systematic (Σ) and random errors (σ) for each component were calculated in the left/right (X), superior/inferior (Y) and anterior/posterior (Z) directions. The contribution of these errors to the PTV margin, M was calculated using van Herk's formula with α and β being 2.50 and 1.64 respectively. For APBI using an MRL ATP workflow, a CTV-PTV margin of 5.7 to 7.6 mm is required to achieve a 90% confidence of CTV coverage by the 95% isodose. Individual error components are in. Table 1 delineation error remains the largest component of error. A minimum CTV-PTV margin of 6-8 mm is required for APBI using an MRL ATP workflow. Although smaller than margins used in conventional Linacs, the clinical benefits (in terms of fibrosis risk) of treating APBI patients on an MRL are likely to be modest. Further margin reductions may be possible using an "Adapt to Shape" workflow with daily online recontouring.

Early Results of the French Multicenter, Randomized SHARE Trial Comparing Whole Breast Irradiation vs. Accelerated Partial Breast Irradiation in Postmenopausal Women with Early-Stage Breast Cancer

The aim is to report toxicity and cosmetic outcomes at 3 and up to 9 years of follow-up of post-menopausal patients randomized to receive either standard whole breast irradiation (WBI), including hypofractionated options, versus accelerated partial breast irradiation (APBI). From December 2010 to July 2015, 1006 patients were enrolled in 34 French centers. Among the whole population, 28 patients who did not meet the final selection criteria or withdrew consent were excluded leading to a modified intention to treat analysis dataset of 978 patients (WBI: n = 488; APBI: n = 490). Median age (65y) and tumor stage pT1 (99%) rates were similar in both arms. Patients had conservative surgery with clip placement in the tumor bed. Clear margins (> 2mm) were observed in 99% of the patients. In both arms, 96-97% of the patients had negative sentinel lymph node biopsy. The median time interval between surgery and radiotherapy was 57d in WBI vs 62d in APBI. WBI schedules consisted of 50 Gy in 25 fr+16 Gy (n = 212) or 40 Gy in 15 fr (n = 156) or 42.5 Gy in 16 fr (n = 120). APBI arm consisted of 38.5 Gy or 40 Gy in 10 fr, 2 fr/day. Overall, 94 patients from the APBI arm finally received standard WBI. For statistical considerations, SHARE trial, sponsored by UNICANCER (NCT01247233) is a non-inferiority randomized controlled trial comparing APBI versus WBI in terms of local control as primary objective. Secondary endpoints were severe toxicity (NCI-CTCAE v4 grade ≥ 2), and cosmetic results. For both outcomes, we estimated the cumulative incidences (CI) using Kalbfleish and Prentice method, considering disease relapse, secondary cancer or death as competing events. Treatment effect (APBI vs WBI) was estimated by cause-specific Hazard Ratios (cs-HR) from Cox models. Median follow-up was 5.8y (range, 0.13-9.5). The number of deaths was 27, and the number of local relapses was 8. Among the 978 patients, 582 and 396 had finally WBI and APBI, respectively. The rates of post-operative hematoma, edema and infection were low: 8-9%, 2%, 3-2%, respectively. When considering any type of severe toxicity, we observed a significant reduction rate in APBI compared to WBI: cs-HR = 0.73 (95% confidence interval: 0.61-0.88); p = 0.001, and 3-year CI of severe toxicity at 45% in WBI vs 36% in APBI arm. The difference was also in favor of APBI when considering breast skin toxicity alone: cs-HR = 0.55 (0.44-0.70), p<0.001 and 3-year CI at 36% in WBI vs 21% in APBI arm. Conversely, for breast other toxicities, WBI was found less toxic than APBI with a 3-year CI of 8% vs 15%, respectively. When considering cosmetic results, we observed no significant difference between the two arms in both evaluations by physicians and patients. Historically SHARE is the first APBI trial that included hypofractionated schedules in the standard arm. We report increased risk of severe toxicity and skin breast toxicity in standard arm as compared with APBI arm without any difference in terms of cosmetic results. Longer follow-up is needed.

KV-CBCT-Guided Daily Adaptation Improves Target Coverage and Spares Normal Tissue for Accelerated Partial Breast Irradiation

Linear accelerator based accelerated partial breast irradiation (APBI) in early-stage breast cancer necessitates a reduction in non-target breast tissue to decrease long term toxicity and adverse cosmetic outcome. In particular, lumpectomy cavity seromas may decrease in size and deform in shape during the course of short course APBI. Online adaptive RT (oART) offers considerable prospect for treating mobile targets through pendulous breast anatomy. However, there are limited studies outlining the methods and outcomes of CBCT-based oART for APBI. Here we present a retrospective, single institutional study analyzing the treatment process for patients receiving stereotactic kV-CBCT guided oART APBI. Fourteen patients were treated to 30 Gy in 5 fractions for a total of 70 fractions. Time between simulation and treatment, change in gross tumor volume (GTV), and differences in DVH metrics with adaption were analyzed. The Wilcoxon paired, non-parametric test was utilized to test for DVH metric differences between the scheduled plans (initial plans recalculated on daily CBCT anatomy) and treated plans, which were either the scheduled or adapted plan (initial plans re-optimized using daily anatomy), depending on the preference of the treating physician or physicist. Median (inter-quartile range) time from simulation to first treatment was 28 days (21-33 days). During this same time, GTV volume reduced to 72.5% (57.8-87.3%) of the simulation lumpectomy cavity volume. Adaptive treatments required 31.1 min (27.2-37.1 min) from start of CBCT to treatment session end. Table 1 summarizes differences between scheduled and treated plan metrics for 70 fractions, 62 (89%) of which were treated adaptively and 8 (11%) of which were treated using the scheduled plan. Significant improvement in prescription planning target volume coverage (p = 0.003), significant reduction in 5/6 organ-at-risk metrics evaluated (p ≤ 0.003), and significant improvement in conformity index and high dose spillage (p ≤ 0.001) were realized with adaption. Table 1: Scheduled versus treated plan metrics. APBI using oART decreased most organs at risk DVH metrics, improved plan quality metrics, and increased target coverage, justifying the use of kV-CBCT-guided oART for APBI.

Financial Toxicity and Patient Experience Outcomes on a Multi-Institutional Phase I Single Fraction Stereotactic Partial Breast Irradiation Protocol for Early-Stage Breast Cancer

Given the demonstrated financial toxicity (FT) of radiation treatment on breast cancer patients shown in both conventional and our recent 5 fraction stereotactic APBI (S-PBI) study, we assessed the FT, as well as patient-reported utility, quality-of-life and patient experience measures, on patients treated in our phase I single fraction S-PBI trial. A phase I single fraction dose escalation trial of S-PBI for early-stage breast cancer was conducted. Women with in-situ or stage I-II (AJCC 6) invasive breast cancer following breast conserving surgery were treated with S-PBI in 1 fraction to a total dose of 22.5, 26.5 or 30 Gy (Clinical trials.gov ID NCT02685332). At one month follow-up, patients were asked to complete our novel "Patient Perspective Cost and Convenience of Care Questionnaire". Patients also completed the EQ-5D-5L, including the visual analogue scale of overall health (VAS), at enrollment, 6, 12-, 24-, 36-, and 48-month follow-up. Of 29 patients enrolled and treated, questionnaire data was available for all patients. Our trial encompassed a wide range of annual household incomes, education, and employment status. Overall, 44.8% (n = 13/29) of patients reported that radiation treatment presented a financial burden. Interestingly, no demographic information, such as patient race, marital status, education, household income, or employment during treatment predicted perceived FT. Patients reporting FT trended towards younger age (median 64 vs 70.5) and having a cancer related co-pay similar to our 5 fraction S-PBI FT trial; however, due to the small size of this study, this did not reach significance (p = 0.24 and 0.10, respectively). VAS and utility scores were calculated per the EQ-5D-5L and remained unchanged from baseline through 4-year follow-up. Likewise, there was no difference in the utility or VAS between patients who reported FT and those who did not. Interestingly, while patient reported cosmesis was similar for all patients at enrollment, patients who reported FT noted significantly worse cosmesis scores (fair/poor vs good/excellent) at 6 month and 2-year follow-ups (p = 0.01 and 0.04, respectively). Finally, patients were surveyed on treatment related disruption to their daily activities and enjoyment of life. The median values were 0 (scale 0-10, with 0 being no disruption) regardless of perceived FT. Patients were also uniformly satisfied with treatment time with a median score of 10 (scale 0-10, 10 being most satisfied). Here, we show that despite using SPBI in a single fraction, nearly half of the patients treated still reported FT of treatment. Importantly, single fraction S-PBI has no negative impact on patient VAS or utility scores, and all patients were uniformly satisfied with treatment time without significant disruption to their life.

Effectiveness and Toxicity of Five Fraction Prone Accelerated Partial Breast Irradiation

Accelerated partial breast irradiation (APBI) after breast conserving therapy (BCT) is increasingly used to treat women with early stage breast cancer. Our institution was an early adopter of 5-fraction ABPI and delivers APBI primarily to patients in the prone position. This study reports long term oncologic and cosmetic outcome in a large cohort of women treated with 5-fraction external beam APBI. We included patients receiving APBI 600 cGy × 5 fx delivered every other day or every day between 2010 and 2022. Late toxicities and clinician and patient rated cosmesis were evaluated for patients with > 6 month follow up. Univariate and multivariate logistic regression models were used to identify clinical and dosimetric factors associated with development of acute and late toxicities, clinician and patient rated cosmesis. All statistical tests were two-sided, and the null hypothesis was rejected for p<0.05. Kaplan Meier methodology was used to calculate overall survival (OS), disease-free survival (DFS) and locoregional recurrence-free survival (LR-RFS). Four hundred and forty-two patients received APBI either daily (56%) or every other day (44%). Most of the patients (92%) were treated in the prone position. Average mean heart dose was 23 cGy for left-sided and 11 cGy for right-sided breast cancers. Ipsilateral lung V30% ≤ 30%. At a median follow up of 48 months (range: 5.96 - 155 months), 12 (2.7%) patients developed a local recurrence, 14 (3.2%) patients developed a contralateral breast primary, 10 patients (2.3%) developed a distant metastasis and one patient (0.2%) developed a local recurrence followed by a distant metastasis 1 month later. Out of 258 patients with > 6 month follow up, rates of late grade 1-2 telangiectasia, fibrosis, edema, atrophy and hyperpigmentation were 4%, 18%, 1%, 19% and 7% respectively. There was only one late grade 3 event in a patient who developed significant breast atrophy. The rate of good-excellent physician and patient rated cosmesis was 95% and 89% respectively (N = 256 at median follow up of 80 months). On multivariate logistic regression, patients who did not receive any adjuvant endocrine or chemotherapy were at increased risk of developing a local recurrence. Patients with PR negative disease were at increased risk of distant metastasis. Patient who experienced any grade of acute dermatitis during treatment were at increased risk of any high grade (grade ≥ 2) late adverse event and worse physician rated cosmesis. Daily or every other day treatment did not correlate with worse toxicity or clinical outcomes. Plastic surgery involvement, LVI, EIC, lobular histology, and ER negativity did not correlate with an increased risk of recurrence. Five-year LR-RFS, DFS and OS were 98%, 92.5% and 98.6% respectively. Five- fraction APBI delivered primarily in the prone position either daily or every other day was effective with low rates of local recurrence, minimal toxicity and excellent cosmetic scores at long term follow up.

Comparison of Early Outcomes of Stereotactic Accelerated Partial Breast Irradiation vs. Volumetric Modulated Arc Therapy-Based FAST-FORWARD Whole Breast Irradiation for Breast Cancer

Despite evidence supporting APBI from 8 published prospective randomized trials enrolling over 10,000 women, the uptake of APBI in clinical practice is surprisingly low. This is being exacerbated by a new, convenient, and safe shortened WBI schedule. Here, we report the dosimetric and early outcome analyses of the first >1000 patients treated at our institution since the first adoption of stereotactic APBI and the ultra-hypofractionated WBI regimen. From 2016 to 2022, 801 women with breast cancers in the suitable or cautionary categories according to the ASTRO APBI consensus panel guidelines, received 30 Gy in 5 fractions (92%) either using a robotic stereotactic radiation system (83%) or stereotactic volumetric-based arc therapy (VMAT, 17%). Between 2020 and 2022, 468 women, who were not candidates for APBI and not undergoing any regional irradiation received 26 Gy in 5 fractions using VMAT to the whole breast with the addition of cardiac sparing technique in left-sided breast cancer patients. Tumor bed boosts were delivered in 99% of FF-WBI patients. We evaluated dose-volume histogram parameters for target volumes and organs-at-risk and radiation-related toxicities during RT or within 6 months after the end of RT. Target volume coverage was acceptable in both groups, with mean 96% of the target volumes receiving 95% of the prescribed doses and 0 cm3 within target volumes exceeding 105% of the prescribed doses. S-APBI resulted in small, but statistically significant, reductions in the radiation dose delivered to the ipsilateral breast, contralateral breast, lungs, heart, and coronary artery compared with FF-WBI. Comparing WBI to APBI, the mean contralateral breast dose, ipsilateral lung V20 Gy, mean contralateral lung dose, and mean heart dose, were reduced by 89%, 78%, 73%, and 29%, respectively. With median follow-up periods of 32 months for s-APBI and 19 months for FF-WBI, acute toxicity was assessable in all patients. The risks of any grade acute toxicity were 21% for s-APBI and 25% for FF-WBI (p = .117). Among them, grade 2 rates were 1.3% in both groups and no severe toxicity has been reported. We found s-APBI and VMAT-based FF WBI were associated with favorable dosimetric and acute toxicity profiles. However, considering significantly less irradiated volume in the breast, lungs, and heart, APBI with advanced available technique options should be considered over any WBI-based approach for patients at low risk for local recurrence.

Prospective Cohort Study to Evaluate Toxicity and Cosmesis between Interstitial APBI and Ultra-Hypo-Fractionated Whole Breast Irradiation in Patients with Early Breast Cancer

Both interstitial multi-catheter brachytherapy based accelerated partial breast irradiation (APBI) and ultra-hypo-fractionated whole breast irradiation (WBI) with 5 fractions can complete treatment in a short time and result in lower treatment-related costs. Although data are available on their toxicity compared with conventional and hypo-fractionated regimens, there are few data directly comparing these two techniques. This prospective cohort study enrolled early breast cancer patients with negative ink margin, T1 or T2 stage, and tumor size of 3 cm or less, with 0 to 3 positive lymph nodes after adequate axillary dissection or negative sentinel lymph node biopsy (N0-1), regardless of receptor status (ER, PR, HER2neu). Of the total 31 patients, 15 received APBI with multi-catheter interstitial brachytherapy (35 Gy in10 fractions over 5 days with a minimum interval of 6 hours between fractions) and 16 patients received WBI (27 Gy in 5 fractions over 5 days) with either 3DCRT or VMAT technique. Acute toxicity was assessed using the RTOG toxicity grading and breast cosmesis was assessed using the Harvard breast cosmesis score. Toxicity and cosmesis were assessed immediately after treatment, after one month, and after three months of treatment. Results were compared between groups using the Mann Whitney U test. All patients completed a 3-month follow-up after completion of treatment. There was no statistically significant difference between the 2 groups in terms of highest grade toxicity (p = 0.97) and acute toxicity immediately after RT (p = 1.0) and after 1 month of RT (p = 0.91). However, at 3 months, more patients in the WBI group had a residual skin reaction than in the APBI group (p = 0.03). There was no statistically significant difference in breast cosmesis scores at any time point. 53.3%, 6.6% had grade 1 and 2 skin toxicities respectively immediately after RT in the APBI group and 62.5% of patients had grade 1 skin toxicity in WBI group. After 1 month 26.6%, 26.6% & 13.3% patients had grade 2, grade 1 and grade 3 toxicities respectively. In the WBI group, at 1 month, 50%, 18.7% and 12.5% patients had grade 1, 3 and 2 skin toxicities respectively. At 3 months, 42.8% and 7.1% of patients in the APBI group had grade 1 and grade 2 toxicities, respectively. In the WBI group, 78.5% and 7.1% of patients had grade 1 and 2 skin toxicities respectively. In this study, no difference in acute toxicity or breast cosmesis was demonstrated between APBI-based interstitial brachytherapy and ultra-hypo-fractionated WBI. Since both regimens can be administered within 5 days, the decision between them is challenging for both physicians and patients. This study can be considered hypothesis-generating and used for further planning of equivalence or noninferiority studies.

Five-Fraction Accelerated Partial Breast Irradiation [APBI] may Reduce Health Care Disparity in Patients Receiving Adjuvant Radiation Therapy for Breast Cancer by Overcoming Treatment Barriers of Distance to Treatment Center, Age, and Ethnicity

Although changing, breast irradiation is still standard of care in many patients after breast conservation therapy (lumpectomy). Distance from radiation treatment center, Age, and Ethnicity have been shown to be barriers to completing needed adjuvant radiation therapy in breast and other cancers. In this retrospective review, it was hypothesized that the Meattini five-fraction partial breast treatment (APBI) would reduce these barriers to care, and more patients would complete treatment. Data from the radiation planning system was utilized to identify all patients treated with APBI at a single community cancer center from 3/6/2020 to 10/14/2022. The Electronic Medical Record (EMR) was used to identify home addresses and then online navigation software measured patient round trip driving distance to the treatment center. Records in EMR were reviewed to see if each patient completed treatment. Patients were divided into 2 groups for three variables: 1. Distance from clinic- <40 miles round trip vs. >40 miles round trip, 2. Age- 65 and older or less than 65, 3. Ethnicity- Hispanic or Non-Hispanic. Each variable consisting of 2 groups were then evaluated statistically using two proportion Z test. Eighty-one patients were identified who underwent APBI. There were 50 patients living <40 miles round trip and 31 living >40 miles from cancer treatment center. There were 48 patients age 65 and older and 33 patients under 65. Patients self- identified their ethnicity as: Hispanic (26 patients, 32.1%), non-Hispanic (55 patients, 67.9%: European Descent-52 patients, Native American- 2 patients, Asian American- 1 patient). 80/81 APBI patients completed the planned treatment. Using the two proportion Z-test, there was no statistical difference between patients with distance to treatment center less than 40 mi round trip commute vs greater than 40 miles round trip commute (Z score 1.28, p = .20), no statistical difference by age 65 or older vs under 65 (Z score = -.83, p = 0.40), and no statistical difference between ethnicity of Hispanic vs non-Hispanic patients (Z score 0.69, p = 0.49). Shorter course radiation therapy regimens for many reasons are easier to complete than longer treatment regimens. In this single-institution retrospective review, all but one short course five-fraction APBI patient (80/81) completed treatment. APBI short course five-fraction treatment (compared to traditional longer breast radiation therapy regimens) may help increase completion of adjuvant radiotherapy and reduce healthcare disparity in breast cancer patients and may overcome barriers to treatment such as Distance to treatment center, Age, and Ethnicity.

Five Fraction Accelerated Partial Breast Irradiation vs. Intraoperative Radiation Therapy for Early-Stage Breast Cancer

Accelerated partial breast irradiation (APBI) represents an alternative to whole breast irradiation (WBI), reducing the target volume and potentially treatment duration. APBI delivered in 5 fractions with intensity modulated radiation therapy (IMRT) has been shown to have comparable outcomes to WBI with reduced toxicity profiles. In contrast, intraoperative radiation therapy (IORT) offers patients the potential to complete adjuvant radiation therapy in a single treatment. While early data were initially promising, concerns regarding long-term rates of local recurrence exist. We present a comparison of 5 fraction APBI versus IORT. We performed a retrospective review of 473 patients with early-stage breast cancer (Stage 0-IIA) treated at a single institution with 258 receiving APBI and 215 IORT from October 2011 to May 2021. APBI patients received 30 Gy in 5 fractions delivered with IMRT daily or every other day. IORT patients received 20 Gy in 1 fraction prescribed to the applicator surface delivered at the time of surgery. Kaplan-Meier analysis was used to estimate locoregional control rates and overall survival among the 2 groups. Mean age was 70.7 years old (IQR:67-74) for the IORT patients and 66.6 years old (IQR:62-72) for the APBI patients (p<0.001). Median follow up was 5.7 years for IORT patients and 2.4 years for APBI patients (p<0.001). For IORT patients, 11%/83.5%/5.5% of patients and for APBI 17.8%/77.5%/4.7% of patients had Tis/T1/T2 disease (p = 0.005). With regards to adjuvant therapies, 79%/76% of IORT/APBI patients were offered endocrine therapy (p = 0.50) and 1.4%/6.2% chemotherapy (p = 0.008). Recurrence at any time was seen in 7.9% (n = 17) of patients receiving IORT as compared to 0.8% (n = 2) of patients receiving APBI. APBI was however no differences in recurrence free survival (92.6% vs. 98.5%, p = .079) or overall survival were noted (92.8% vs. 95.1%, p = 0.99). In a series of almost 500 patients with stage 0-IIA breast cancer, IORT was associated with higher rates of locoregional recurrence compared to APBI with no survival difference at 5 years. These outcomes, consistent with other series and current guidelines, suggest a limited role for IORT as monotherapy following breast conserving surgery.

Very APBI in 1 or 2 Days: Late Toxicity and Early Oncological Outcomes of the GEC-ESTRO Cohort

To analyze late toxicity after very accelerated partial breast irradiation (VAPBI) for low-risk breast cancer. In this retrospective observational international multicenter study (HDH F20220713143949) from 7 European centers, patients with low-risk breast cancer underwent lumpectomy + adjuvant VAPBI based on high-dose rate (HDR) multicatheter interstitial brachytherapy (MIB). VAPBI was performed with 4 (4 × 6.2 Gy/2 d), 3 (3 × 7.45 Gy/2 d) or 1 fraction (1 × 16 Gy or 1 × 18 Gy/1 d). Primary endpoint was late toxicity. Secondary endpoints were oncological outcome based on cumulative incidence of breast cancer local relapse (LR) and distant metastasis disease (DMD) and cause-specific (CSS) and overall (OS) survival. Prognostic factors for late toxicity were analyzed. From 01/2012 to 06/2022, the GEC-ESTRO VAPBI cohort included 516 pts with an early breast cancer. Median follow-up was 42 months [95% CI = 39 - 44]. Median age was 71 years [40 - 100]. Median tumor size was 12 mm [1 - 46]. Tumor was mainly invasive ductal carcinoma (78%), pN0 (88.5%), with positive hormonal receptors (98.5%) and negative HER2 overexpression (96%). Patients underwent hormonal and chemo-therapy in 93.8% and 2.3% respectively. Catheter placement was performed peri or post-operatively in 50.2% and 49.8% respectively. Median time interval between surgery and VABPI was 10 days [6 - 65]. VAPBI delivered 1, 3 and 4 fractions for 205 pts (39.7%), 167 pts (32.4%) and 144 pts (28%) respectively. Median CTV was 40.7 cc [95% CI = 26.6 - 72], median V100%, V150%, D90% and Dose non-uniformity ratio (DNR) were 90.2% [95% CI = 84.1 - 97.2], 24.2% [95% CI = 18.9 - 31.6], 103.8% [95% CI = 100.1 - 107.4] and 0.28 [95% CI = 0.23 - 0.33] respectively, 211 late toxicity events were observed in 168 pts (32.6%). Fibrosis, dyschromia, pain and telangiectasia were observed in 26.7%, 7.9%, 7.2% and 0.4 respectively. Grade 2 and 3 late toxicities were observed in 7.2 and 0.6% respectively (no G4). Grade ≥2 late toxicity was observed in 8.1%, 16.7% and 3.7% after 1, 3 and 4 fractions, respectively (p = 0.004). CTV > 50 cc (p = 0.007) and V150 > 40% (p = 0.027) were prognostic factors for G≥2 late toxicity. Regarding oncological outcome, 4-year cumulative incidence of LR, RR and DMD were 2% [95% CI = 0 - 3], 1% [95% CI = 0 - 2] and 1% [95% CI = 0 - 2] respectively. CSS and OS were 98% [95% CI = 96 - 100] and 93% [95% CI = 90 - 96] respectively. No significant difference was observed in terms of oncological outcome between the 3-fractionation groups. VAPBI based on 1 or 2 days of HDR MIB represents an attractive de-escalation irradiation approach for low-risk breast cancer. Late toxicity profile appears acceptable while early oncological outcome shows excellent local control. Brachytherapy technique remains a key component of clinical outcome. Longer follow-up is warranted in order to confirm these encouraging preliminary results.

Accelerated Partial Breast Irradiation (APBI) For HER2+ Early-Stage Breast Cancer

Historically, HER2+ breast cancer exhibited poor outcomes and, hence, has not been well-studied among trials of accelerated partial breast irradiation (APBI). We hypothesized that in contemporary practice with effective HER2-targeted agents, patients with HER2+ breast cancer now have excellent disease control and survival outcomes when treated with adjuvant APBI. Using a prospectively-maintained institutional database, we identified all HER2+ breast cancer patients treated with breast conserving surgery (BCS) and adjuvant APBI from 2000 - 2022. Salient clinicopathologic parameters were collected, as were receipt of systemic and endocrine therapies. All patients received external beam APBI to a total dose of 40Gy in 10 daily fractions over 2 weeks. We analyzed outcomes including local recurrence (LR), regional recurrence, distant recurrence, and death. Cumulative incidence functions were calculated to estimate the incidence of LR with the competing risk of death. All statistical analyses were performed in R version 4.2.2. The study cohort comprised 52 patients with HER2+ breast cancer (median age 64 years; range 44-87). Nearly all had T1 tumors (98%; median size 15 mm; range 1 - 21 mm). Approximately 10% had multifocal disease, with one exhibiting suspicion for lymphovascular invasion. Most patients had ER+ disease (88%). All patients had negative final surgical margins. Nearly all underwent sentinel node biopsy (94%), with the remainder undergoing no surgical axillary evaluation. 42 (81%) received chemotherapy, 40 (77%) endocrine therapy, and 42 (81%) HER2-directed therapy, most commonly trastuzumab. At 143.8 person-years of follow-up (range 7 - 226 months for each patient), we observed two LR events, at 14 and 26 months, yielding a 2-year LR rate of 3.8%. No regional or distant recurrences were observed, nor were any contralateral invasive breast cancer events or breast-specific mortality events. Two deaths were noted in the cohort, both without evidence of disease. Among a cohort of HER2+ early-stage breast cancer patients managed with BCS and APBI, we observed a 2-year LR rate of 3.8% with no regional or distant recurrences, and excellent overall survival. These findings merit longer term follow-up among larger cohorts, although are thus far consistent with the results of contemporary randomized trials of APBI unselected for HER2-status.

Dosimetric Comparison of Adaptive Radiotherapy Modalities for Stereotactic Partial Breast Irradiation

An increase in the availability of adaptive radiotherapy (ART) platforms have proven to be effective in the treatment of a variety of sites. In this study, we aim to evaluate the effectiveness of non-adaptive RT and 3 different ART platforms: (1) CBCT-based, (2) CT-based, and (3) MRI-based for stereotactic partial breast irradiation (SPBI). Data were collected from 32 patients (16 left and 16 right breast) treated at a single institution. 16 patients (8 left and 8 right) treated using the non-ART platform were re-planned onto two different ART platforms, CBCT- and MRI-based. The remaining 16 patients treated using CT-based adaptive platform were not re-planned due to the prone patient treatment position (others systems supine). All cases were planned to 30 Gy in 5 fractions. Plan quality was evaluated based on pre-defined planning goals to the OARS: ipsilateral and contralateral lungs (Dmean, Dmax, V20 Gy, V9 Gy), ipsilateral (V15 Gy, V30 Gy) and contralateral breasts (Dmax), heart (Dmean, Dmax, V3 Gy, V1.5 Gy), skin (Dmax, V36.5 Gy), and rib (Dmax, V30 Gy). Target goals were defined by Dmax, Dmin, gradient index, and paddock conformality index. Re-planned cases were compared within the cohort using a paired t-test and a 2-sided t-test was used comparing to the CT-based platform. Comparing the left and right breast cohort across all platforms, the CT-based ART system showed a signification dose reduction in Dmean (p<0.001 for all platforms), Dmax (p<0.001 for left breast, p<0.03 for right breast) and V9 Gy (p<0.004 for left breast, p<0.001 for right breast) to the ipsilateral lung, V15 Gy (p<0.004 for left breast cohort) to the ipsilateral breast, and Dmax to the contralateral breast (p<0.001) and ribs (p = 0.01, p<0.001, p = 0.01 for CBCT-ART, MRI-ART, and non-ART for left breast cohort only). On average, the MR-Linac platform showed the least degree of OAR sparing across nearly all dosimetric parameters evaluated when compared to all modalities, especially for contralateral lung Dmean and Dmax (p<0.05 for all dosimetric parameters for all platforms) and contralateral breast Dmax (p<0.003 for all platforms). The CBCT-based platform showed superior dose reduction in contralateral lung mean (p<0.03 for all platforms) and heart Dmean (p = 0.065, p<0.001, p = 0.045 for non-adaptive, MRI-ART, and CT-ART for left breast and p<0.008 for right breast). PTV coverage was comparable across all platforms, averaging at approximately 95%. The CT-based ART platform showed a significantly reduced gradient index relative to the CBCT- and MRI-based platforms (p<0.001). For SPBI treatments, the CT-based ART platforms displayed a higher degree of OAR sparing for many of the dosimetric parameters recorded relative to the other ART and non-ART platforms presented. The MRI-based system typically showed less reduced OAR sparing; however, the advantage of the system is shown if soft tissue contrast is needed. PTV coverage remained comparable across all platforms.

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

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

Patterns and Longitudinal Changes in The Practice of Breast Cancer Radiotherapy in Korea: Korean Radiation Oncology Group 22-01

To analyze contemporary practice patterns in breast cancer radiotherapy (RT) and to assess longitudinal changes therein over 5 years in Korea. A nationwide survey was conducted among board-certified radiation oncologists in Korea by the Division for Breast Cancer of the Korean Radiation Oncology Group in March 2022. The survey consisted of 44 questions related to six domains: hypofractionated (HypoFx) whole breast RT, accelerated partial breast RT (APBI), regional nodal irradiation (RNI), RT for ductal carcinoma in situ (DCIS), postmastectomy RT (PMRT), and tumor bed boost. In total, 70 radiation oncologists from 61 of 101 (60%) institutions participated in the survey. HypoFx RT was used by 62 respondents (89%), which has significantly increased from 36% in 2017. The HypoFx RT was commonly administered at 40-42.5 Gy in 15-16 fractions. APBI was used by 12 respondents (17%), which has increased from 5% in 2017. The use of RNI did not change significantly: ≥ pN2 (6%), ≥ pN1 (33%), and ≥ pN1 with pathological risk factors (61%). However, the indications for use of internal mammary lymph node (IMN) irradiation have expanded. In particular, the rates of routine treatment of IMN (11% from 6% in 2017) and treatment in cases of ≥ pN2 (27% from 14% in 2017) have doubled; however, the rate of treatment for only IMN involvement, identified on imaging, has decreased to 31% from 47% in 2017. With regard to DCIS, the use of hypoFx RT increased to 75% from 25%, and the rate of omission on of RT after breast-conserving surgery decreased to 38% from 48% in 2017. The use of hypoFx RT for PMRT also increased to 36% from 8% in 2017. The adoption of HypoFx RT after breast-conserving surgery in invasive breast cancer and DCIS has increased significantly, whereas that for PMRT has increased moderately, compared to 2017. Further studies are required to determine the optimal use of RNI.