Simultaneous integrated boost intensity-modulated radiotherapy post breast-conserving surgery: clinical efficacy, adverse effects, and cosmetic outcomes in breast cancer patients

Background Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) is an innovative technique delivering a higher dose to the tumor bed while irradiating the entire breast. This study aims to assess the clinical outcomes, adverse effects, and cosmetic results of SIB-IMRT following breast-conserving surgery in breast cancer patients. Methods We conducted a retrospective analysis of 308 patients with stage 0–III breast cancer who underwent breast-conserving surgery and SIB-IMRT from January 2016 to December 2020. The prescribed doses included 1.85 Gy/27 fractions to the whole breast and 2.22 Gy/27 fractions or 2.20 Gy/27 fractions to the tumor bed. Primary endpoints included overall survival (OS), local–regional control (LRC), distant metastasis-free survival (DMFS), acute and late toxicities, and cosmetic outcomes. Results The median follow-up time was 36 months. The 3-year OS, LRC, and DMFS rates were 100%, 99.6%, and 99.2%, respectively. Five patients (1.8%) experienced local recurrence or distant metastasis, and one patient succumbed to distant metastasis. The most common acute toxicity was grade 1–2 skin reactions (91.6%). The most common late toxicity was grade 0–1 skin and subcutaneous tissue reactions (96.7%). Five patients (1.8%) developed grade 1–2 upper limb lymphedema, and three patients (1.1%) had grade 1 radiation pneumonitis. Among the 262 patients evaluated for cosmetic outcomes at least 2 years post-radiotherapy, 96.9% achieved excellent or good results, while 3.1% had fair or poor outcomes. Conclusions SIB-IMRT after breast-conserving surgery in breast cancer patients demonstrated excellent clinical efficacy, mild acute and late toxicities, and satisfactory cosmetic outcomes in our study. SIB-IMRT appears to be a feasible and effective option for breast cancer patients suitable for breast-conserving surgery.


Introduction
Breast cancer has become the most prevalent cancer among women, accounting for 11.7% of all global cancer cases [1].This increase emphasizes the necessity for effective and efficient treatment strategies.The evolution of diagnostic and therapeutic technologies has facilitated the early detection of breast cancer, particularly in its early stages.With the development of diagnosis and treatment technology, more and more early-stage breast cancer patients can be detected in time.Breast-conserving surgery (BCS) followed by wholebreast irradiation (WBI) has become the main treatment method, as it has been proven to provide at least equal effects in local control rate and overall survival time as mastectomy [2,3].However, the traditional whole-breast radiotherapy (RT) regimen, which spans approximately 5 weeks with an additional 1-2 weeks for tumor bed boost, presents challenges such as prolonged treatment duration and increased risk of local tumor recurrence [4].
Despite the established benefits of post-BCS radiotherapy, a significant proportion of patients opt out of this treatment due to various reasons including the length of treatment, perceived discomfort, and economic factors [5].This highlights an urgent need to refine breast radiotherapy approaches to make them more patient-friendly by reducing treatment duration, lowering costs, and minimizing both acute and late toxicities, thereby making this essential treatment more accessible to a broader patient population [6][7][8][9].
The advent of Intensity-modulated radiation therapy (IMRT) has revolutionized radiotherapy by optimizing the dose distribution to the target while sparing surrounding normal tissues, thus mitigating some extent of radiotherapy-induced toxicity.In tandem with the development of IMRT, Simultaneous integrated boost (SIB) technology has been introduced.SIB offers several treatment enhancements such as increased efficacy via higher single-dose irradiation to high-risk areas, optimal and uniform dose distribution within the target area, and a reduction in the number of radiotherapy sessions required [10,11].However, the effectiveness and safety of SIB as an adjuvant radiotherapy approach have not been comprehensively established due to the lack of extensive randomized controlled trials, leading to some controversies in clinical guidelines [12,13].
In light of these considerations, there is a pressing need to evaluate the clinical efficacy, early and late radiotherapyrelated adverse reactions, and cosmetic outcomes of SIB in the context of breast cancer treatment.This study aims to fill this gap by conducting a comprehensive retrospective analysis of stage 0-III breast cancer patients who underwent breast-conserving surgery at our institution.We endeavor to provide robust data and analysis to inform future guidelines and clinical practices in the treatment of breast cancer.

Patient selection
This retrospective study analyzed 308 breast cancer patients treated from January 2016 to December 2020.The median age was 45.1 years, ranging from 24 to 72 years.We included patients diagnosed with stage 0-III breast cancer who underwent breast-conserving surgery followed by radiation therapy.The radiotherapy protocols were in line with the standards set by the Radiation Therapy Oncology Group (RTOG) and the European Society for Radiotherapy & Oncology (ESTRO).Systemic treatments were administered according to the National Comprehensive Cancer Network (NCCN) guidelines.Patients were excluded if they had positive surgical margins, bilateral breast cancer, any other malignancy within the past 5 years, non-adherence to radiotherapy or chemotherapy protocols, insufficient followup data, concurrent organ dysfunction, or incomplete clinical records.The radiotherapy regimen involved delivering 59.4-59.94Gy in 2.20-2.22Gy fractions to the tumor bed volume and 49.95 Gy in 1.85 Gy fractions to the planning target volume, spread over 27 fractions.Radiation therapy was administered using the multibeam IMRT technique, ensuring the prescribed dose covered 95% of the Planning Target Volume (PTV).All IMRT plans utilized 6 MV flattening filter-free photon beams from the Precise linear accelerator (Elekta, Stockholm, Sweden), with the maximum dose rate set to 600 MU/min.Constraints for the Organs at Risk (OARs) were defined as follows: the spinal cord: maximum dose (Dmax) < 3,000 cGy; ipsilateral lung: volume receiving 5% of the dose (V5) < 50%, volume receiving 20% of the dose (V20) < 25%, and mean dose (Dmean) < 1,500 cGy; contralateral lung: V5 < 15% and Dmean < 300 cGy; heart: Dmean < 400 cGy (right side) or Dmean < 600 cGy (left side); the contralateral breast: Dmean < 300 cGy.Regional lymph node radiotherapy was administered to 35.4% of patients, and almost all hormone receptor-positive patients (98.7%) underwent endocrine therapy.Among the HER-2 positive patients, a significant majority (84.8%) received targeted anti-HER-2 therapy.These diverse treatment modalities reflect the tailored approach to breast cancer management based on individual patient and tumor characteristics.

Adverse effects assessment
Throughout the course of radiotherapy, patients were monitored through weekly consultations, physical examinations, and blood tests to identify and manage any adverse reactions.These reactions were classified and assessed according to the criteria established by the Radiation Oncology Collaborative Group (RTOG) and the European Organization for Research on Cancer Therapy (EORTC) [14].This thorough and systematic approach ensured the comprehensive recording and management of treatment-related adverse effects, facilitating the evaluation of the therapy's tolerability and safety.

Cosmetic outcome evaluation
Cosmetic outcomes, an important consideration in breastconserving therapy, were evaluated using the Harris criteria.This evaluation, conducted during the follow-up visits, categorized outcomes as excellent, good, fair, or poor [15].This assessment was crucial to understanding the aesthetic results of the treatment, which is a significant factor in patient satisfaction and quality of life.

Statistical analysis
For statistical analyses, Kaplan-Meier survival plots were generated using SPSS 25.0 software.These plots were utilized to calculate local regional control rates, distant metastasis-free survival rates, and overall survival rates.The choice of statistical methods was aimed at providing a robust and comprehensive analysis of the efficacy of the treatment in terms of disease control and patient survival.

Basic patient characteristics
In this cohort of 308 breast cancer patients, the distribution of cancer subtypes was as follows: 21.4% Luminal A, 52.9% Luminal B, 7.5% HER-2 over-expressing, and 18.2% triple-negative.A small subset (2.6%) received neoadjuvant chemotherapy, with half achieving complete remission and the other half partial remission.Axillary debulking was performed in 34.1% of patients, while the majority (84.4%) received adjuvant chemotherapy (Table 1).

Clinical outcomes
The median follow-up was 42 months, ranging from 11 to 78 months.By November 2022, the follow-up compliance was notably high, with 11.0% lost to follow-up.At 1-year, 3-year, and 5-year milestones, the follow-up rates were 99.7%, 75.6%, and 10.4%, respectively.The study found exceedingly high rates of 3-year local control (99.6%), distant metastasis-free survival (99.2%), and overall survival (100%).These figures underscore the efficacy of the treatment modalities used in this cohort.Survival curves (Fig. 1A-C) illustrate these outcomes.
Local regional recurrence was infrequent, occurring in only 1.09% of patients, and primarily affected axillary and interstitial pectoral muscle lymph nodes, and ipsilateral breast.Distant metastasis was reported in 0.73% of cases, while the mortality rate was also low (0.73%), with one death attributed to distant metastasis from breast cancer and another due to unrelated causes (Table 2).

Late radiotherapy response and cosmetic outcome
Late reactions in the skin and subcutaneous tissue were predominantly mild, with 84.8% experiencing no late reactions (grade 0).Grades 1-3 late reactions occurred in 15.3% of patients.Upper limb lymphedema and radiation pneumonia were rare, observed in 1.8% and 1.1% of patients, respectively.Notably, the cosmetic outcomes post-radiotherapy were predominantly positive, with 96.9% achieving excellent results, affirming the treatment's effectiveness in preserving aesthetic appearance (Table 4).[27][28][29].
The diverse response of different molecular subtypes to IMRT-SIB treatment observed in our study suggests that personalized treatment strategies are essential.Understanding the nuances of how various subtypes, especially more aggressive forms like triple-negative breast cancer, respond to treatment will be crucial in optimizing therapeutic approaches for individual patients.Particularly in understanding and overcoming treatment resistance in this subgroup.This is in line with other studies that have reported higher rates of distant metastases in luminal and triple-negative subtypes [30,31].
In terms of treatment safety, our study reports a significantly lower incidence of radiation pneumonitis (1.1%) compared to the broader range documented in other studies (4.5-63%) [32,33].These patients had only slight imaging changes of pneumonia, but no respiratory symptoms.The radiation dose to the heart is relatively small, so there is no ischemic cardiomyopathy occurred [34].The reduction of such adverse effects reactions may be mainly attributed to the accuracy of IMRT-SIB radiotherapy dose and the use of advanced improved irradiation technology.This indicates that IMRT-SIB has made great progress in reducing the side effects of radiotherapy [35,36].
The late cosmetic effect of the whole breast combined with tumor bed concurrent IMRT-SIB has always been the focus of attention.The comprehensive publication of longterm cosmetic results and longer follow-up data for several large randomized controlled phase III trials investigating the application of SIB in adjuvant WBI is still pending [37,38].Our findings had a high rate of excellent cosmetic outcomes (96.9% at 2 years) highlight the patient-centric benefits of IMRT-SIB, better than some studies [39,40].However, the reliance on subjective assessments by patients and physicians raises questions about the consistency and objectivity of these evaluations.Our study highlights the necessity of incorporating more objective measures in assessing cosmetic outcomes.These detailed analyses of toxicity and cosmetic outcomes could offer new insights into patient experiences and long-term satisfaction with IMRT-SIB, potentially influencing future treatment choices and patient care strategies.Future research should aim to include more standardized and objective measures, such as those employed in the IMRT-MC2 trial, to provide a more comprehensive evaluation of cosmetic outcomes [25,26,41].During the follow-up of this study, it was also found that 5 patients had upper limb lymphedema, which may be caused by comprehensive factors such as local regional radiotherapy and axillary lymph node dissection [42].
In this study, most patients (89.6%) had grade 0-1 acute radiodermatitis, and 10.4% had grade 2. No patients with grade 3 or above skin toxicity were found.This is similar to the findings of Krug et al. [38], but lower than the results reported by Xia et al. [43].This may be because that most of the patients in this study are hospitalized for radiotherapy, and the skin care during radiotherapy is better, thus reducing the occurrence of higher-level skin toxicity.In addition, relevant studies have shown that the increase of wet desquamation is related to the larger breast volume, and the breast sizes of patients after breast conserving surgery are different in each study, which may be one of the factors that have different incidence of acute skin toxicity in the same type of study [44].
The occurrence of radiation esophagitis is directly related to the radiation dose.Therefore, in the IMRT-SIB for breast cancer, the esophagus must be taken as an OAR for strict dose limit.Our results found that 147 patients (47.4%) had grade 1 acute laryngopharyngitis/ esophagitis, which was consistent with the observation of 59.6% grade 1-2 esophageal toxicity after radiotherapy reported by Pasqueer et al. [45], which is slightly lower than that reported by Wang et al. [46].The reason for this discrepancy might be that their study involved patients who underwent total breast mastectomy and had pathologically positive axillary lymph nodes.The tumor target area in their study is closer to the entrance of the esophagus, resulting in a higher radiation dose to the esophagus.However, our analysis focuses on patients who have undergone breast-conserving surgery, where the target area is relatively farther away, leading to a lower radiation dose to the esophagus.
While our study presents substantial evidence supporting the efficacy and safety of SIB, it is not without limitations.The relatively short follow-up period limits our ability to assess long-term outcomes comprehensively.Although these short-term results are promising, the need for extended follow-up to ascertain long-term efficacy and safety remains paramount [47].Moreover, the lack of photographic documentation for cosmetic assessments introduces an element of subjectivity that might affect the reliability of these outcomes.The longevity of treatment benefits, potential late adverse effects, and long-term quality of life outcomes are critical components of comprehensive cancer care that require further exploration.To address these limitations, future studies should incorporate longer follow-up durations and objective methods for cosmetic assessment, such as photographic records.
In light of these considerations, our study contributes significantly to the existing body of knowledge, supporting the use of IMRT-SIB in the treatment of breast cancer post-conserving surgery.We advocate for further research to validate these findings in a larger cohort over a more extended period, ensuring that the promising results observed in our study are sustainable and universally applicable.Additionally, patient-reported outcomes and quality of life assessments could be incorporated to provide a more holistic view of the treatment impact.These outcomes are crucial for understanding the patient experience and the broader implications of treatment beyond clinical efficacy.

Conclusion
In conclusion, our study provides compelling evidence that intensity-modulated radiation therapy with simultaneous integrated boost (IMRT-SIB) following breast-conserving surgery is not only effective in the short term but also yields favorable cosmetic outcomes.The impressive rates of local control, distant metastasis-free survival, and overall survival observed in our cohort are indicative of the potential of IMRT-SIB as a reliable adjuvant therapy in breast cancer management.Furthermore, the high rate of excellent cosmetic outcomes emphasizes the patient-centric advantages of this approach, which are increasingly vital in cancer care.

Table 1
Patient and tumor characteristics

Table 1
(continued) DCIS ductal carcinoma in situ, SLNB sentinel lymph node biopsy, ALND Axillary lymph node dissection Fig. 1 Survival curves (A Local area control rate; B Distant metastasis free survival; C Overall survival rate)

Table 2
Pattern of failures among patients

Table 3
Acute radiotherapy adverse reactions

Table 4
Late radiotherapy adverse reactions and cosmetic