Predictive factors associated with acute radiation dermatitis in patients with breast cancer: a retrospective cohort study

Introduction

Breast cancer poses a significant global public health challenge (Wilkinson & Gathani, 2022). It is the leading cause of both cancer incidence and mortality among women, with approximately 2.26 million new cases and nearly 685,000 deaths annually (Wilkinson & Gathani, 2022). In Thailand, breast cancer ranks first in both cancer incidence and mortality rates among women, mirroring global statistics and underscoring its critical impact on both national and international levels (Suwankhong et al., 2023; Virani et al., 2018). At Chulabhorn Hospital, around 200–300 breast cancer patients receive radiation therapy (RT) annually, contributing to thousands of RT sessions each year. The hospital consistently treats breast cancer as the most common cancer in its radiation oncology department.

Breast cancer originates from cellular abnormalities in the terminal duct lobular unit (TDLU) or glands that lead to uncontrolled cell division (Metzger-Filho et al., 2019). Most breast cancers are adenocarcinomas, of which the breast ducts account for 85% of instances and the lobular epithelium for 15% (Feng et al., 2018). A common occurrence of the natural progression of the disease is the spread of carcinomatous cells via the lymphatic system to nearby lymph nodes and distant organs, such as the bones, lungs, liver, and brain (Rahman & Mohammed, 2015). Breast cancer is primarily diagnosed in women; men account for less than 1% of breast cancer cases (Konduri et al., 2020). There is a range of medical treatments available for breast cancer, including surgery, adjuvant chemotherapy, radiation therapy (RT), hormonal therapy, and targeted therapy (Mee et al., 2023). Each modality plays an essential role in controlling disease progression and improving patient outcomes.

Despite the advances made in the development of therapeutic options for breast cancer, treatment-related side effects, particularly acute radiation dermatitis (ARD), remain prevalent and can significantly impact patients’ quality of life (Xie et al., 2021). Acute radiation dermatitis is characterized by edema, endothelial cell changes, and various epidermal and dermal alterations, including inflammation, apoptosis, and necrosis mediated by lymphocytes and cytokines. Cell death typically occurs after one to five cycles of radiation division. Radiation-induced damage to chromosomal DNA leads to cell destruction through apoptosis, necrosis, and mitotic failure (Lee et al., 2009). Up to 95% of postsurgical breast cancer patients experience ARD, which can lead to physical discomfort and emotional distress (Iacovelli et al., 2020; Sherman & Walsh, 2022). The severity of ARD has been found to depend on radiation-related factors, such as the amount of radiation received (total dose of radiation), the number of radiation sessions, the duration of the treatment, and the energy, radiation techniques, and bolus doses applied (Chan et al., 2014). The volume of irradiated tissue and the radiation sensitivity of the involved tissue are also contributing factors (Xie et al., 2021). Other patient-related factors, such as age, smoking, comorbidities, and concurrent chemotherapy treatments, may also influence possible dermatologic reactions to RT (Wei et al., 2019). The consequences of RT and the resultant side effects include discomfort , difficulty sleeping, anxiety, depression, and body image issues, which can lead to discomfort, anxiety about clothing, and disruption of daily routines and the patient’s social life (Almeida et al., 2023). When acute dermatitis progresses to a severe stage, it can cause pain and negatively impact the patient’s quality of life (Bashyam et al., 2021). Some patients may need to pause their treatment due to side effects, and the most serious consequences of side effects are treatment refusal and failure to follow up, which affect cancer survival rates (Spałek, 2016). Hence, researchers and healthcare providers are increasingly focused on understanding and mitigating such side effects to improve patient care.

The severity of ARD varies among patients, even among those with identical conditions and treatment regimens. These factors influencing the severity of ARD have been identified, but there is still controversy regarding the results. Elucidating these factors is crucial to improving breast cancer treatment and optimizing personalized patient care strategies. Thus, the objective of this research was to investigate predictive factors that influence the severity of ARD in breast cancer patients undergoing RT.

Materials and Methods

Results

Discussion

ARD is a prevalent and distressing side effect experienced by breast cancer patients undergoing RT. The results of this retrospective cohort study revealed that there were several predictive factors associated with the development of ARD, which can significantly impact treatment outcomes. The nature of the identified risk factors, which included a higher BMI, the use of radiation boosts, and bolus application, suggests that certain patient and treatment characteristics predispose individuals to more severe ARD. Conversely, the finding that HFRT and hormonal therapy mediated protective effects indicates that these treatment modalities can reduce the severity of ARD.

Numerous studies have established a significant association between BMI and the development of ARD in breast cancer patients undergoing RT (Xie et al., 2021). Our results are consistent with these findings, demonstrating a significant association between a higher BMI and the incidence and severity of ARD among patients undergoing RT. Specifically, we found that a BMI ≥ 30 kg/m² was associated with an increased risk of developing ARD classified as grade ≥ 2 (AOR = 2.33; 95% CI [1.36–3.98]; p-value = 0.002). This aligns with other studies that reported that 80% of patients who presented with wet desquamation (grade 2) had a BMI ≥ 25 kg/m² (Córdoba, Lacunza & Güerci, 2021). In the same study, it was observed that 69% of patients who developed grade ≥ 2 acute radiation dermatitis were classified as overweight or obese (BMI > 25 kg/m²), with obese patients having 2.87 times more risk of manifesting radiodermatitis than those with a normal BMI (AOR = 2.87, p-value = 0.026). Additionally, in a study conducted among 598 patients, those with a BMI ≥ 24 kg/m² were found to be more likely to develop dermatitis than those with a BMI < 24 kg/m² (Liu et al., 2022).

Moreover, Cavalcante et al. (2024) found that for each unit increase in BMI, the likelihood of developing ARD classified as grade ≥2 increases by 1.14 times (AOR = 1.14; 95% CI [1.04–1.26]; p-value = 0.004) (Cavalcante et al., 2024). This trend has also been supported by a larger cohort study involving 3,518 patients, which found BMI to be a statistically significant risk factor for grade 2–3 acute dermatitis (AOR = 2.30; 95% CI [1.28–4.26]; p < 0.01) (Issoufaly et al., 2022). In terms of treatment regimens, both CFRT and HFRT have shown significant associations with ARD and moist desquamation in relation to BMI (p-value = 0.003 and p < 0.001, respectively) (De Langhe et al., 2014). Additionally, factors such as breast volume and comorbidities may further exacerbate the risk of ARD in overweight patients (Xie et al., 2021). In breast cancer patients, particularly those with higher BMI values, the presence of more voluminous skin folds can create a bolus effect during RT, especially in inframammary and axillary regions. This phenomenon occurs because the additional tissue thickness can inadvertently increase the radiation dose delivered to the skin surface, potentially exacerbating the risk of ARD (Liu et al., 2022).

Our results indicate that the incidence of ARD was significantly higher in patients receiving boost irradiation (OR = 2.09; 95% CI [1.08–4.06]; p-value = 0.029). This finding is consistent with those of previous studies that demonstrated that administering boosts to the tumor bed exacerbated skin reactions in breast cancer patients. For instance, a study involving 502 patients treated with IMRT and a simultaneous integrated boost reported that grade ≥ 2 ARD occurred significantly more often in patients who underwent IMRT compared to those who received 3DCRT with a sequential boost (29.1% vs. 20.1%; p-value = 0.02) (Krug et al., 2020). However, without boost irradiation, 3DCRT was found to cause more radiation dermatitis than IMRT because The IMRT technique delivers radiation from multiple directions compared to 3DCRT, resulting in greater skin sparing and, consequently, less dermatitis (Chen et al., 2020). In another study of 75 patients, it was found that boost treatment was significantly associated with an increased risk of ARD (OR = 4.61; 95% CI [1.33–15.93]; p-value = 0.01) (Abdeltawab et al., 2021). Additionally, a cohort study involving 489 breast cancer patients revealed that grade ≥ 2 ARD was significantly more prevalent in those who received a radiation boost compared to those who did not (30.4% vs. 13.5%; p < 0.0001) (Eggert, Yu & Rades, 2023). These findings collectively support the notion that boost treatment is a critical predictor of ARD. However, it is noteworthy that a study involving 1,093 patients found no significant difference in skin outcomes between patients who received simultaneous and sequential boosts; nonetheless, the use of a boost was predictive of edema (p-value = 0.02) (Behroozian et al., 2021). This discrepance more likely highlights the complexity of radiation-induced skin toxicity and suggest that while boosts generally increase the risk of ARD, individual treatment regimens and patient characteristics also contribute to the varied outcomes (Schmeel et al., 2020).

The use of bolus material in post-mastectomy radiation therapy (PMRT) has been a topic of considerable debate due to its dual role in enhancing radiation dose delivery to superficial tissues while simultaneously increasing the risk of ARD (Wong et al., 2020). Our findings align with previous research indicating that the application of a bolus significantly increases the incidence of severe ARD (Parekh et al., 2018). In our study, patients who received RT with bolus had an AOR of 2.08 (95% CI [1.02–4.24]; p-value = 0.044) for developing ARD, reinforcing the notion that bolus use is a critical predictor of this complication. Krug et al. (2020) reported that approximately 80% of breast cancer patients developed grade 2–3 ARD following PMRT, and they identified bolus use as a key contributing factor to this outcome. This finding is supported by our analysis, which indicates that bolus application can exacerbate skin toxicity, leading to higher rates of severe ARD. In another study, PMRT without bolus use resulted in a significantly lower incidence of severe ARD, with only 10% of patients developing grade 2 ARD, and this was achieved without any increase in local recurrence rates (Eggert, Yu & Rades, 2023). Additionally, a cohort study involving 1,093 patients found that bolus use was the only factor significantly associated with bleeding complications (p-value = 0.02), suggesting that while bolus use may enhance treatment efficacy in terms of local control, it also poses risks for acute toxicities that could complicate patient management (Behroozian et al., 2021). Moreover, the advantages of using personalized silicone rubber boluses have been highlighted in other studies; for example, Chen et al. (2024) reported that only 16.6% of patients developed grade 2 ARD when utilizing such materials. This suggests that not all bolus applications are equal and that there is a need for personalized approaches based on patient characteristics and treatment goals (Verma, 2023).

Our analysis supports the hypothesis that using HFRT does not increase the risk of ARD (Sinzabakira et al., 2023), as evidenced by an OR of 0.31 (95% CI [0.16–0.57]; p < 0.001) because HFRT delivers a higher radiation dose per fraction, while the total dose of HFRT is lower than that of CFRT, which is associated with reduced occurrences of breast shrinkage, telangiectasia, and breast edema (Butler-Xu et al., 2019). This finding aligns with those of previous studies that indicated that patients who underwent HFRT experienced significantly lower rates of acute skin toxicity compared to those who received CFRT. For instance, in a cohort of 339 patients, grade 2 and 3 ARD were reported to occur in 42% and 13% of CFRT patients, respectively, compared to 30% and 7.5% of HFRT patients (Tortorelli et al., 2013). The overall acute toxicity rates were notably higher among patients treated with CFRT (81.6%) compared to those treated with moderate HFRT (62.6%), and this difference was statistically significant (p < 0.001). Further supporting these findings, a study involving 377 patients demonstrated that those treated with HFRT developed less ARD than those treated with a normofractionated regimen (p < 0.001) (De Langhe et al., 2014). Additionally, a larger analysis of 1,727 patients found that the incidence of grade ≥ 2 ARD was significantly lower in a group treated with HFRT compared to a group treated with conventional treatment (OR = 0.34; 95% CI [0.29–0.41]) (Bruand et al., 2022). Similarly, another study reported that only 8.9% of patients treated with HFRT experienced grade 2–3 ARD compared to 35.1% of patients treated with CFRT (χ² = 373.7; p < 0.001) (Issoufaly et al., 2022). Despite these consistent findings suggesting that HFRT regimens result in a reduced incidence of ARD, there are instances in which no significant difference was observed in the incidence of ARD between CFRT and HFRT. For example, one study indicated that while CFRT increased the skin dose and was a significant predictor of worse skin reactions, the use of CFRT and HFRT did not yield significant differences in terms of ARD (Sawanee Nirunsiriphol, 2021). This discrepancy may stem from variations in the patient populations, treatment protocols, and dosimetric factors across studies. This highlights the need for further research to clarify the conditions under which HFRT may or may not confer protective benefits against ARD (Parekh et al., 2018).

In this study, the use of hormone therapy, regardless of type, was associated with a significant decrease in ARD (OR = 0.60; 95% CI [0.42–0.86]; p-value = 0.005). This finding contrasts with those of previous studies that investigated the effects of hormone therapy on acute skin reactions during RT. For instance, a study involving 377 patients found that concomitant hormone therapy was associated with an increased risk of ARD (p-value = 0.041), with no significant difference in incidence between the use of aromatase inhibitors and tamoxifen (De Langhe et al., 2014). In another study of 104 women, among those who underwent concomitant hormone therapy alongside HFRT, 70.5% developed some form of skin reaction, primarily erythema (Vieira et al., 2022). These results suggest that there is a complex relationship between hormone therapy and skin toxicity during RT, which may vary based on treatment protocols and patient characteristics. Additionally, a case report noted the occurrence of radiation recall dermatitis (RRD) induced by tamoxifen, although such cases are rare (Rhee et al., 2014). Furthermore, in two retrospective studies, no significant differences were observed in the incidence of radiation toxicity related to the concurrent or sequential use of tamoxifen in breast cancer patients (Liu et al., 2022). These contradictory findings highlight the need for further investigation into the role that hormone therapy plays in ARD. While our data suggest a protective effect, other studies indicate potential risks associated with specific hormonal treatments. Future research should aim to clarify these relationships and explore the underlying mechanisms that may contribute to varying outcomes based on hormone therapy type and treatment context (De Langhe et al., 2014).

Previous studies have shown that patients who receive targeted therapies, particularly trastuzumab treatment, have a decreased risk of ARD. More specifically, in a study involving 377 patients, (De Langhe et al., 2014) demonstrated that those who received trastuzumab had a significantly reduced risk of ARD (p < 0.001). Similarly, in their analysis of 75 patients, (Abdeltawab et al., 2021) revealed that the use of trastuzumab was associated with a decreased risk of ARD (p-value = 0.01). These results suggest that targeted therapies may play a protective role against ARD. However, contrasting evidence exists in the literature. A study involving 598 patients indicated a tendency for ARD to be associated with adjuvant targeted therapy (p-value = 0.052) (Liu et al., 2022). These findings suggest that while targeted therapies (e.g., use of trastuzumab) may reduce the risk of ARD in some cases, there may be specific contexts or patient populations in which these therapies could potentially contribute to increased skin toxicity (Anupama, Anuradha & Maka, 2018). In line with our study’s results, which showed that targeted therapies were not significantly associated with the development of grade ≥ 2 ARD (OR = 0.72, 95% CI [0.43–1.20]; p-value = 0.210), it appears that the protective effect of targeted therapies can vary based on treatment regimens and individual patient factors. This variability highlights the complexity of interactions between cancer treatments and their dermatological effects.

Regarding the effect on ARD of directing RT to regional lymph nodes, our results indicate that there was no significant difference in the severity of ARD between the patients who received RT for primary tumors alone and those who received RT for both primary tumors and regional lymph nodes (OR = 0.81; 95% CI [0.41–1.59]; p-value = 0.538). This finding aligns with those of previous studies that reported no significant differences in ARD incidence between node-negative and node-positive patients, regardless of the fractionation schedule (χ² = 0.24; p-value = 0.62) (Issoufaly et al., 2022). However, contrasting evidence exists regarding the relationship between nodal involvement and ARD severity. For instance, a study involving 220 patients who underwent breast-conserving surgery found that the severity of ARD was associated with lymph node stage and that patients with positive regional lymph node metastasis were more susceptible to ARD (p-value = 0.009) (Liu et al., 2022). This suggests that while we did not observe a significant difference in ARD severity based on nodal involvement, there may be specific contexts in which nodal status influences the occurrence of ARD; for example, it may affect the treatment techniques used, an individual patient’s characteristics, and the overall radiation dose delivered (Bennardo et al., 2021). The results of this study indicate that some factors align with previous research and can be applied in clinical practice by closely monitoring patients with risk factors. However, certain factors show inconsistent results compared to other studies, possibly due to insufficient data and single center. Despite this, the findings remain interesting and beneficial to patients. Therefore, further studies with a larger sample size across multiple centres are needed. Focusing on the differences in the type and dosage of hormonal drugs received by patients may provide valuable insights. These findings could potentially support the role of hormones in reducing acute radiation dermatitis.

Conclusions

The study highlights critical predictive factors for ARD in breast cancer patients undergoing RT, emphasizing the importance of BMI, the treatment modalities applied (e.g., boost and bolus applications), and the effects of fractionation and hormonal therapy on skin outcomes. These findings have implications for clinical practice. They can be used to identify high-risk patients and tailor preventive strategies to mitigate ARD.

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