Abstract
Background/Aim: Patients with breast cancer receiving adjuvant radiotherapy may experience grade ≥2 dermatitis. In the Interreg-project HeAT, a mobile application (app) reminding patients to perform skin care will be prospectively tested with the goal of decreasing clinically significant radiation dermatitis. This study aimed to identify the prevalence of grade ≥2 dermatitis and risk factors, required for designing the prospective trial. Patients and Methods: In a retrospective study of 327 patients with breast cancer irradiated during 2022-2023, the prevalence of grade ≥2 dermatitis and 23 potential risk factors were investigated. Results: The prevalence of grade ≥2 dermatitis was 31.2%. On multivariate analysis, it was significantly associated with chronic inflammatory disease (p=0.001), significant cardiovascular disease (p<0.001), smoking history >10 pack years (p<0.001), advanced T-stage (p=0.017), normo-fractionation (p<0.001), and radiation boost (p<0.001). Conclusion: The prevalence of grade ≥2 dermatitis and independent risk factors during adjuvant radiotherapy for invasive breast cancer were identified that contribute to improved patient care and the design of a prospective trial.
The majority of patients with non-metastatic breast cancer receive adjuvant radiotherapy following breast conserving surgery or mastectomy (1, 2). Depending on risk factors of local or loco-regional recurrence, the treatment volume includes breast or chest wall plus/minus regional lymph nodes. Adjuvant radiotherapy for breast cancer may be associated with grade ≥2 dermatitis, which can be painful and impair the patients’ quality of life (3, 4). In order to reduce the risk of grade ≥2 radiation dermatitis, the patients are asked to perform specific skin care several times per day during the course of radiotherapy and one or two weeks following the treatment. Sometimes, this can be challenging.
In the Interreg-project HeAT, a mobile application (app) will be developed and prospectively tested that reminds the patients to perform the required skin care. The hypothesis of the prospective trial is that the use of the app will decrease the rate of grade ≥2 radiation dermatitis. For designing that trial, it is mandatory to know the prevalence of grade ≥2 radiation dermatitis and corresponding risk factors. The present study was performed to define both in patients with breast cancer irradiated in 2022 and 2023. We have already investigated these endpoints in a previous retrospective study (5). However, to allow for most precise calculation of the required sample size of the planned prospective trial, it is helpful to perform an additional study in patients treated more recently. Moreover, the present study is important, because the use of systemic therapies prior to or during adjuvant radiotherapy for breast cancer has increased (6-8).
Patients and Methods
In a retrospective study, 327 female patients treated with adjuvant radiotherapy for invasive breast cancer in the years 2022 and 2023 were evaluated at the end of their radiotherapy course for grade ≥2 radiation dermatitis (9). The study was approved by the ethics committee of the University of Lübeck, Germany (file number 2024-148). Prior to radiotherapy, 272 patients (83.2%) underwent breast conserving surgery and 55 patients (16.8%) underwent mastectomy. Moreover, 229 patients (70.0%) were treated with systemic treatment prior to irradiation. Eighty-seven of these patients received endocrine therapy alone (48 letrozole, 32 tamoxifen, 7 other), 66 patients chemotherapy including epirubicin, cyclophosphamide and paclitaxel (plus endocrine therapy in 12 of these patients), 37 patients treatment with docetaxel, carboplatin and trastuzumab plus/minus pertuzumab (plus endocrine therapy in seven of these patients), 18 patients epirubicin, cyclophosphamide, paclitaxel/carboplatin and pembrolizumab, and 21 patients other regimens. During the radiotherapy course, 220 patients received systemic treatment, which included tamoxifen in 56 patients, letrozole in 88 patients, other aromatase inhibitors in 15 patients, pembrolizumab in 15 patients, trastuzumab alone or combined with emtansine (TDM-1) or pertuzumab in 26 patients, endocrine therapy combined with trastuzumab, TDM-1 or trastuzumab/pertuzumab in 16 patients, and other regimens in four patients.
Radiotherapy was performed with linear accelerators using either intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). Treatment volumes included whole breast alone in 204 patients (62.4%), whole breast plus regional lymph nodes in 68 patients (20.8%), chest wall alone in eight patients (2.4%), and chest wall plus regional lymph nodes in 47 patients (14.4%). In the 115 patients receiving radiotherapy of regional lymph nodes, treatment volumes included supraclavicular plus internal mammary nodes in 82 patients, axillary nodes alone in 17 patients (including high tangent in 13 patients), supraclavicular plus internal mammary and axillary nodes in eight patients, supraclavicular nodes alone in seven patients, and supraclavicular plus axillary nodes in one patient. Dose-fractionation regimens included conventional hypo-fractionated radiotherapy with 40 Gy in 15 fractions of 2.666 Gy in 228 patients (69.7%) and normo-fractionated radiotherapy in 99 patients (30.3%). Of the latter group, 97 patients received 50.4 Gy in 28 fractions of 1.8 Gy, and one patient each received 45 Gy in 25 fractions of 1.8 Gy or 30 Gy in 15 fractions of 2.0 Gy followed by 19.8 Gy in 11 fractions of 1.8 Gy. In addition to irradiation of the breast or the chest wall, 198 patients (60.6%) received a radiation boost to the tumor bed. Most of these patients (n=190) received a sequential boost with 10 Gy in 5 fractions. In one patient the sequential boost was terminated after 6 Gy. Seven patients received a simultaneous integrated boost with 8.4 Gy in 28 fractions or 9.8 Gy in 28 fractions. The deep-inspiration breath hold (DIBH) technique was used in 207 patients (63.3%), of which 142 patients had left-sided breast cancer.
In addition of evaluation of the prevalence of grade ≥2 radiation dermatitis, 23 potential risk factors plus the year of treatment (2022 vs. 2023) were analyzed for associations with grade ≥2 dermatitis (Table I). The risk factors included age at radiotherapy (<65 vs. ≥65 years; ≥65 years=elderly patients), Eastern Cooperative Oncology Group (ECOG) performance score (0 vs. 1 or 2), history of another malignancy (no vs. yes), history of chronic inflammatory disease (no vs. yes), history of significant cardiovascular disease (no vs. yes), history of hypertension (no vs. yes), history of diabetes mellitus (no vs. yes), history of smoking (0-10 vs. >10 pack years), systemic treatment (no vs. prior to radiotherapy only vs. during radiotherapy only vs. prior to and during radiotherapy), main histology (no special type vs. lobular vs. other), primary tumor stage (T1 or T2 vs. T3 or T4), nodal stage (N0 or N1mi vs. N1 vs. N2 or N3), grading (G1 or G2 vs. G3), Ki-67 labeling index (≤15% vs. >15%), hormone receptor status (negative vs. positive), triple negativity (no vs. yes), side of affected breast (right vs. left), tumor localization (central vs. inner and outer quadrant vs. inner quadrant vs. outer quadrant), fractionation of radiotherapy (hypo-fractionation vs. normo-fractionation), treatment volume (breast plus regional lymph nodes vs. breast alone vs. chest wall plus regional lymph nodes vs. chest wall alone), radiation technique (IMRT vs. VMAT), radiation boost (no vs. yes), and DIBH technique (no vs. yes). In the four patients with synchronous bilateral breast cancer, the more advanced tumor was considered for the analyses. Other malignancies included breast cancer in 17 patients, skin cancer or melanoma in seven patients, gynecological cancer in four patients, lymphoma or myeloma in four patients, colon cancer in three patients, lung cancer in two patients, thyroid cancer in two patients, sarcoma in one patient, and hepatocellular carcinoma in one patient. Chronic inflammatory diseases included mainly Hashimoto’s thyroiditis (n=10), bronchial asthma (n=9) and rheumatoid arthritis (n=8) and psoriasis plus/minus arthritis (n=7). Significant cardiovascular disease included mainly history of cerebral apoplexy or transient ischemic attack (n=10), coronary heart disease with coronary stents or cardiac infarction (n=7), and cardiomyopathy or heart failure (n=7).
Associations between patient characteristics and the prevalence of acute radiation dermatitis grade ≥2.
Univariate analyses were performed with the Chi-square test. For multivariate analysis, logistic regression models were fitted. A stepwise selection approach was applied to identify the final parsimonious model that still explains the data and consists of the subset of most relevant factors. The criteria for including a variable in a model may vary from one problem to the next and from one scientific discipline to another. The traditional approach to statistical model building involves seeking the most parsimonious model that still explains the data. A significance level of 0.15 was required to allow a variable into the model, and a significance level of 0.20 was required for a variable to stay in the model. Statistical analyses were performed using SAS 9.4 (SAS Institute Inc, Cary, NC, USA). p-Values <0.05 were considered indicating significance and p-Values <0.07 indicating a trend.
Results
The prevalence of grade ≥2 radiation dermatitis was 31.2% (95% confidence interval=26.2-36.2%). On univariate analyses, the occurrence of grade ≥2 dermatitis was significantly associated with history of chronic inflammatory disease (p=0.028), history of significant cardiovascular disease (p<0.001), smoking history of >10 pack years (p<0.001), advanced T-stage (T3 or T4, p=0.023), normo-fractionated radiotherapy (p<0.001), larger treatment volume (including regional lymph nodes, p=0.034), and administration of a radiation boost (p=0.006). In addition, trends were found for history of another malignancy (p=0.060) and history of diabetes mellitus (p=0.069). Complete results of the univariate analyses are given in Table I.
In the multivariate analysis (final parsimonious model), history of chronic inflammatory disease (p=0.001), history of significant cardiovascular disease (p<0.001), smoking history of >10 pack years (p<0.001), advanced T-stage (T3 or T4, p=0.017), normo-fractionated radiotherapy (p<0.001), and administration of a radiation boost (p<0.001) were significant. The results of the multivariate analysis are shown in Table II.
Multivariate analysis (stepwise logistic regression model - parsimonious model after stepwise regression).
Discussion
Radiation dermatitis is a common adverse event of adjuvant radiotherapy for breast cancer, which is most frequently limited to mild erythema (grade 1). However, a considerable number of patients may experience grade ≥2 dermatitis, which can have a negative effect on the patients’ quality of life (3, 4). The prevalence of grade ≥2 radiation dermatitis in breast cancer patients was reported by other groups to range between 3% and 76% (10-30). In our previous study investigating patients irradiated for breast cancer between 2016 and 2019, the prevalence of grade ≥2 radiation dermatitis was 25.3% (5).
Because of the wide range of the grade ≥2 dermatitis rates, additional studies appear reasonable to better define the real prevalence. These studies should consider the increasing use of systemic therapies prior to or during adjuvant radiotherapy for breast cancer, which may lead to a higher prevalence of grade ≥2 dermatitis (6-8). In our previous study, the prevalence of grade ≥2 dermatitis was significantly higher in patients who had received systemic treatment prior and/or during their radiotherapy course on univariate analysis (32.0 vs. 19.5%, p=0.002). Therefore, the present study was conducted, which included patients who were treated more recently, namely in 2022 and 2023. As supposed, a greater proportion of these patients received systemic treatment prior and/or during their radiotherapy course when compared to our previous study (82.9% vs. 46.4%) (5). In the present study, the prevalence of grade ≥2 dermatitis was higher than in our previous cohort of patients treated between 2016 and 2019 (5). Administration of systemic therapies prior to and/or during the radiotherapy course was non-significantly higher than that in patients not receiving systemic treatment (32.1% vs. 26.8%).
For optimal treatment personalization and patient care, the knowledge of risk factors of grade ≥2 radiation dermatitis would be helpful. In addition to determining the prevalence of grade ≥2 dermatitis in patients receiving adjuvant radiotherapy for breast cancer, this study aimed to define risk factors for this adverse event. History of chronic inflammatory disease, history of significant cardiovascular disease, smoking history of >10 pack years, advanced T-stage, normo-fractionation of radiotherapy, and administration of a boost were identified as independent risk factors on multivariate analysis. In addition, history of another malignancy and diabetes mellitus showed trends for an association with grade ≥2 dermatitis on univariate analysis.
Some of these risk factors have been described before. Normo-fractionated radiotherapy was associated with a higher risk of acute dermatitis in several studies and review articles (4, 5, 13, 15-17, 21-23, 31-33). So were the administration of a radiation boost (4, 5, 19, 32, 34) and the history of smoking prior to or during the course of radiotherapy (4, 12, 16, 29, 35, 36). Diabetes mellitus was associated with an increased risk of acute dermatitis in one prospective cohort study and a meta-analysis (4, 29). In addition, a prospective trial showed a trend for an association between diabetes mellitus and radiation dermatitis (37), and another study found an association between diabetes mellitus and late radiation-related skin toxicity (19). An association between radiation dermatitis and chronic inflammatory disease was described in a review article (36), and a trend for such an association was observed in our previous study (5). Moreover, an impact of a history of chronic inflammatory disease was found for another toxicity related to adjuvant radiotherapy of breast cancer, i.e., radiation pneumonitis (38). In the study of Kraus-Tiefenbacher et al., investigating 211 patients receiving adjuvant radiotherapy for breast cancer, development of radiation dermatitis was significantly associated with larger tumor size (12). Moreover, in another study, acute dermatitis showed a significant positive correlation with the boost volume, which is larger in more advanced tumors (19). To our knowledge, no studies so far have investigated the prognostic role of significant cardiovascular disease or history of another malignancy regarding radiation dermatitis in patients with breast cancer. In a previous study of our group, history of another malignancy showed a trend for a correlation with radiation pneumonitis in breast cancer patients (38). This may be a consequence of a reduced DNA repair capacity, which was reported for different primary tumor types (39-41). In another study, breast cancer was associated with a reduced DNA repair capacity and consequently increased radiosensitivity and higher rates of radiation toxicity (42). Regarding the history of significant cardiovascular disease, Kobat et al. identified this characteristic as a risk factor for cardiotoxicity in patients receiving systemic treatment for non-small-cell lung cancer (43).
The accordance with the findings of previous studies suggest consistency of our present data. During the interpretation of our results, the retrospective study design should be considered, which bears the risk of hidden selection biases. However, the major goals of this study, namely identification of the prevalence of grade ≥2 dermatitis and corresponding risk factors were achieved. These data are mandatory for designing the planned prospective trial within the Interreg-project HeAT that will test a reminder app.
In summary, the prevalence of grade ≥2 dermatitis in patients receiving adjuvant radiotherapy for breast cancer and independent risk factors were identified. The results will contribute to improved personalized patient care by identifying patients who require closer monitoring during and following their course of radiotherapy. Moreover, our results will help designing a prospective trial.
Footnotes
Authors’ Contributions
All Authors participated in the design of the study. D.R. collected the data that were analyzed by a professional statistician. D.R. drafted the article, which was reviewed and approved by all Authors.
Conflicts of Interest
The Authors declare no conflicts of interest related to this study.
- Received February 7, 2024.
- Revision received February 20, 2024.
- Accepted February 21, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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