ORIGINAL ARTICLE Year : 2022  |  Volume : 18  |  Issue : 7  |  Page : 1903-1909

Analysis of risk factors related to acute radiation dermatitis in breast cancer patients during radiotherapy

Di Liu1, Zhewen Zheng2, Shuyuan Zhang2, Chunmei Zhu2, Hongyan Zhang3, Yunfeng Zhou3
1 Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province; Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
2 Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China
3 Department of Radiation and Medical Oncology; Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China

Date of Submission10-Jul-2022Date of Acceptance15-Jul-2022Date of Web Publication11-Jan-2023

Correspondence Address:
Hongyan Zhang
No. 169, Donghu Road, Wuchang District, Wuhan - 430071, Hubei Province
China
Yunfeng Zhou
No. 169, Donghu Road, Wuchang District, Wuhan - 430071, Hubei Province
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jcrt.jcrt_1203_22

Aims: To investigate the incidence and influencing factors of acute radiation dermatitis (ARD) induced by radiotherapy in postoperative patients with breast cancer.
Methods and Materials: A retrospective analysis was conducted on 598 patients with breast cancer who received postoperative radiotherapy from November 18, 2014 to September 14, 2019. The radiotherapy technology included two-dimensional radiotherapy, three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and tomotherapy. The occurrence of ARD in patients was then followed up and recorded. The independent risk factors for radiation-induced dermatitis were analyzed by using an orderly logistic regression model.
Results: Of the 598 patients, 431 had mild skin reactions, including pigmentation and dry desquamation (grade 1), 151 developed wet desquamation and tender erythema (grade 2), and 16 had severe skin reactions, including flaky wet scaling and erosion (grade 3). There were no grade 4 skin reactions. The severity of ARD was independent of the following factors: Age, diabetes, allergy, quadrant, pathological type, the clinical stage, the tumor stage, triple-negative breast cancer, ki-67 expression, adjuvant chemotherapy, endocrine therapy, targeted therapy, radiotherapy area, and boost irradiation. However, it was found to be dependent on the body mass index, surgery type, radiotherapy technique, node stage, and the prophylactic use of topical agents.
Conclusions: ARD in response to postoperative radiotherapy in patients with breast cancer is common and mild. Clinicians and patients need to cultivate awareness of the potential risk factors involved and then intervene to alleviate skin reactions and improve the quality of life.

Keywords: Acute radiation dermatitis, breast cancer, factor analysis, radiotherapy

How to cite this article:
Liu D, Zheng Z, Zhang S, Zhu C, Zhang H, Zhou Y. Analysis of risk factors related to acute radiation dermatitis in breast cancer patients during radiotherapy. J Can Res Ther 2022;18:1903-9
How to cite this URL:
Liu D, Zheng Z, Zhang S, Zhu C, Zhang H, Zhou Y. Analysis of risk factors related to acute radiation dermatitis in breast cancer patients during radiotherapy. J Can Res Ther [serial online] 2022 [cited 2023 Jan 13];18:1903-9. Available from: https://www.cancerjournal.net/text.asp?2022/18/7/1903/367455

Authors Di Liu, Zhewen Zheng, Hongyan Zhang, Yunfeng Zhou contributed equally.

 > Introduction 

Breast cancer has the highest morbidity and mortality rate among women and has a severe impact on women's health.[1] Radiation therapy (RT) has become standard treatment of breast cancer to improve the local control rate and the overall survival rate.[2],[3] Radiation can destroy tumor cells as well as damage the surrounding normal tissues. Acute radiation dermatitis (ARD) is the most common side effect; 95% of the patients with cancer treated with radiation develop some form of radiation dermatitis. These radiation-induced skin reactions often negatively affect the patients' quality of life and make the treatment schedule get delayed or terminated.[4]

ARD refers to an adverse reaction of the irradiated area within 90 days after radiation. The injury mechanisms of ARD may be such that the damage to the skin epithelial cells, dermis, and subcutaneous blood vessels to varying degrees destroys the epidermal basal stem cells.[5],[6] In addition, it may be associated with cytokine-mediated inflammatory cascades.[7] Because of the impaired skin barrier function and the immune system, the skin gradually becomes more susceptible to chemicals, allergens, and ultraviolet light radiation.[8]

New treatments and RT techniques have successfully decreased these side effects, but have not yet eliminated them. Based on the existing research reports, the ARD-related risk factors may be associated with age, nutritional status, body mass index (BMI), breast size, radiation dose, dose fractionation, and other synchronous treatments.[9],[10],[11] Intensity-modulated RT (IMRT) has been demonstrated to reduce cutaneous toxicity and significantly improve the dose distribution.[12],[13],[14] In addition, it has been demonstrated that the prophylactic application of steroids reduces ARD.[15],[16] However, there is insufficient evidence to demonstrate the effectiveness of other therapies in preventing and managing radiation-induced skin damage.[9] Although the abovementioned study has been published, the risk factors for ARD remain controversial with no unified standard.

Consequently, we conducted this retrospective study to analyze the factors influencing the occurrence of ARD in patients who underwent postoperative radiotherapy for breast cancer at our center. Comparison and integration with the existing research outcomes have provided some evidence to support the prevention and management of ARD.

 > Materials and Methods 

Clinical data

This retrospective study included 598 patients with breast cancer who were treated at our institute between November 18, 2014 and September 14, 2019. Patients were treated with surgery by either modified radical mastectomy (MRM) (378 cases) or breast-conserving surgery (220 cases), followed by postoperative radiotherapy. There were 364 patients with early breast cancer (stages I and II) and 234 patients with advanced breast cancer (stages III and IV).

Inclusion criteria

The following were the inclusion criteria: Patients with primary breast cancer who underwent MRM or breast-conserving surgery in the surgical department and showed pathological evidence after surgery. Continuous, well-defined standard adjuvant radiotherapy was administered to the entire breast or chest wall (with or without draining the lymph node, including supraclavicular, axillary, and internal mammary lymph nodes).

Exclusive criteria

Patients with bilateral breast cancer, metastatic breast cancer from another tumor, reirradiation at the same site, and infection in the irradiated area were excluded from the study.

Therapeutic regimen

Based on the recommendations of the guidelines, the clinician developed the radiotherapy plan and delineated the treatment target according to the patient's condition, while the medical physicist formulated the dose distribution. The results were then reported to the clinician for verification and implementation. The radiotherapy program included traditional two-dimensional radiotherapy (2DRT), three-dimensional conformal radiotherapy (3DCRT), IMRT, and tomotherapy (TOMO). All patients in this study received a conventional segmentation regimen, namely, a daily segmentation dose of 2.0 Gy, with a total radiation dose of 50 Gy (with or without dose boost).[5],[11] Patients with validated lymph node metastasis underwent irradiation of the regional lymph nodes. The clinician individually administered tumor boost irradiation, which was composed of an additional 10–16 Gy on the tumor bed.[17]

Health education was provided by clinicians before RT. The patients were advised to wear loose clothes to avoid rubbing on the irradiated site, use alcohol disinfectants, eat a high protein diet including more fresh fruits and vegetables, and avoid spicy foods. Patients could opt for the use of either triethanolamine cream (Biafine) or human-like collagen dressing (Mepiform) for local skin support care.[18]

Assessment of ARD

Accurate assessment and classification of ARD are critical. At present, the most widely used evaluation standard is the Acute Radioactive Dermatitis Grading Scale for the Radiotherapy Oncology Group (RTOG). The scale classifies the clinical symptoms of dermatitis into five grades, ranging from no skin changes (grade 0) to severe ulcerative tissue necrosis or hemorrhage (grade 4).[19],[20] The participants' skin responses were assessed according to the RTOG grading scale, and the most severe dermal toxicity incident within 90 days after RT was recorded.

Statistical analysis

Data were analyzed using the Statistical Package for Social Sciences version 22.0 (IBM Corporation, Armonk, NY, USA). The numerical data were directly recorded, and the categorical data were recorded into different categories. The statistical software was used to conduct multivariate analyses using a forward stepwise binary logistic regression model on the potential influencing factors for all patients, including the breast-conserving therapy group and the MRM group. The test of parallel lines was performed before using the model. Statistical significance was defined as P < 0.05.

 > Results 

Incidence of ARD

A total of 598 patients with breast cancer were included in the study between November 2014 and September 2019. The detailed medical records of all patients from the beginning of the radiotherapy program until the end of the treatment as well as the details of skin changes at the irradiated sites were collected. At the end of the radiotherapy session, the skin of the patients exposed to radiation was observed, evaluated, and recorded. All patients were followed up for at least 90 days after discharge to collect updates regarding the subsequent skin changes. Finally, ARD was graded according to the RTOG grading scale. Grade 1 dermatitis after RT occurred in 431 patients who demonstrated local erythema, pigmentation, and dry desquamation. Grade 2 dermatitis (i.e., tender erythema, patchy wet desquamation, or moderate edema) was observed in 151 patients. There were 16 patients with grade-3 ARD, which mainly manifested as skin ulceration, purulent exudation, and pitting edema. No patients with grade 4 dermatitis were recorded in this study. The incidence rates of grades 1, 2, and 3 dermatitis were 72.07%, 25.25%, and 2.68%, respectively [Table 1], [Figure 1].

Figure 1: Representative images of grades 1, 2, and 3 dermatitis after postoperative radiotherapy. Notes: Grade 1: Blisters, pale red, hair loss, dry desquamate, and sweat reduced; Grade 2: Skin touch pain, erythema, moist flake peeling, and moderate edema; and Grade 3: Additional skin folds in the fusion of wet peeling and severe edema

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Variable assignment

For the convenience of statistical analysis, variable assignments for all parameters in this article have been defined in [Table 2] and [Table 3].

Table 2: Variable assignment of the analyses parameters (patient factors)

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Table 3: Variable assignment of the analyses parameters (treatment factors)

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Analysis of ARD-related factors in all patients

We analyzed the potential risk factors for the severity of radiation skin injury in all patients and found that the severity of ARD was independent of the patient's age, diabetes, allergy, quadrant, pathological type, clinical stage, tumor stage, node stage, TNBC, ki-67 expression, adjuvant chemotherapy, endocrine therapy, targeted therapy, radiotherapy site, and dose-boosted irradiation. The P values for BMI, type of surgery, radiotherapy technique, and drug intervention were statistically significant (P < 0.05). Patients with BMI ≥24 were more likely to develop dermatitis than other patients with BMI <24. Patients who underwent lumpectomy showed more severe dermatitis than those who underwent a mastectomy. Patients who underwent the traditional 2DRT and 3DCRT exhibited more serious dermatitis than those who underwent TOMO, albeit no significant difference was recorded between IMRT and TOMO. Dermatitis was most severe in patients who did not use any dermatitis medications, and no difference was noted in dermatitis lesions between the cream group and the dressing only group [Table 4].

Subgroup analysis of different types of surgery

Considering the influence of surgical methods on the patients' choice of radiotherapy technique, we further categorized the patients into two subgroups (breast-conserving surgery group and MRM group). Based on the differences between the abovementioned radiotherapy techniques, 2DRT and 3DCRT were combined into the conventional radiotherapy group, and IMRT and TOMO were combined into the precision radiotherapy group for comparative analyses.

Analysis of ARD-related factors in the breast-conserving surgery group

In 220 breast-conserving patients, the severity of ARD was associated with node stage, radiotherapy techniques, and drug intervention. Patients with positive regional lymph node metastasis were found to be more susceptible to dermatitis (P = 0.009). Dermatitis that developed in response to traditional radiotherapy was more severe than that developed in response to precision radiotherapy (P = 0.001); this result was consistent for all patients. ARD was more likely to occur in patients who did not use any drug for skin intervention (P = 0.018), showing a tendency that ARD is associated with adjuvant-targeted therapy (because the P value is 0.052) [Table 5].

Table 5: Multivariate logistic regression analysis for the breast-conserving surgery group

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Analysis of ARD-related factors in the MRM group

In 378 patients undergoing MRM, the potential risk factors for the severity of radioactive skin damage were only related to the use of prophylactic skin protection drugs. ARD was found to be more severe in patients who did not use any medication (P = 0.000), followed by those who used triethanolamine cream (P = 0.038), and a slight difference was noted between those who used dressings and those who used both the drugs. This result suggested that the effect of humanoid collagen dressing may be superior to that of the cream. In addition, our article considered that the choice of radiotherapy techniques may be a patient-associated risk factor (because the P value was 0.056) [Table 6].

 > Discussion 

With the increasing incidence and the overall survival of breast cancer, there is an increasing concern regarding the quality of life during and after cancer therapy. ARD, which is one of the common complications of RT, reduces the patient's quality of life, causes pain and discomfort, and limits their daily activities.[13]

The basic precautions for ARD include hygiene, clothing, and diet.[21] Individual conditions of patients such as diabetes, skin disease, obesity, and breast volume can also affect the skin response.[22] Indeed, the severity of ARD was most relevant to the details of the treatment plan, such as the irradiated skin area, total radiation dose, fraction dose, radiotherapy technique, chemotherapy, and local medication.[23],[24],[25]

The results of this retrospective analysis indicated that the ARD in patients who underwent postoperative radiotherapy for breast cancer is common and widely tolerated. The incidence and severity of ARD were lower in the present study than those reported elsewhere,[25],[26] possibly because most patients were treated with drug intervention during radiotherapy. A multivariate analysis of all 598 patients indicated that ARD is related to BMI, surgery, radiotherapy techniques, and the type of prophylactic medication. Consistent with previous observations, BMI served as a prognostic factor in the findings. BMI and breast size were strongly correlated, as patients with higher BMI tended to have a larger breast volume. A greater dose inhomogeneity and field separation in patients with larger breasts as well as self-bolusing of the inframammary fold could be the reasons for this association.[27],[28] Goldsmith et al.[29] suggested that the inhomogeneity of the dose is insufficient to explain this association and that other factors such as the presence of a greater amount of adipose tissues may play a role in this case.

In our study, the skin response of patients undergoing MRM was less severe than that of patients who underwent breast-conserving surgery, possibly because of the dose inhomogeneity caused by breast preservation and the other factors that were not excluded. Therefore, in this study, we conducted a subgroup analysis based on the type of surgery. In addition, more advanced and sophisticated techniques could reduce the skin dose, make the dose distribution more uniform, and reduce the inflammatory response of the irradiated skin. Multiple studies have demonstrated that the incidence, severity, and duration of skin reactions in patients with breast cancer receiving IMRT are reduced compared with conventional RT.[13],[14],[30] The present results were similar, albeit there was no statistical difference between TOMO and IMRT.

A large number of topical agents such as moisturizer,[31] marigold,[32] aminophosptin,[33] and corticosteroids[34],[35],[36] are known interventions to reduce radiation dermatitis. The topical drugs used in our study included triethanolamine cream (Biafen) and humanoid collagen dressing (Mepiform). The former is a compound preparation with a deep hydration effect and it can increase microcirculation and the skin blood-flow velocity as well as reduce the inflammatory response. In addition, it can stimulate the proliferation of fibroblasts and increase the synthesis of collagen.[37],[38] The main ingredients in humanoid collagen dressing are collagen solution and non-woven cloth, which can provide a moist environment for the skin, inhibit the production of melanin and reduce pigmentation, promote wound healing, and reduce the risk of scar formation.[39],[40] ARD was most severe in patients who did not use either of the abovementioned two drugs. No difference was noted in dermatitis injury among patients with a single-drug intervention. Therefore, the choice of cream or dressings remains necessary in the absence of standardized and continuous supportive care.

The present results demonstrated that ARD was associated with positive lymph node metastasis, which, in turn, is associated with changes in the surgical coverage because of regional lymph node metastasis and skin and soft tissue changes resulting from irradiation.[26] The expansion of the surgical scope can cause more damage to the surrounding tissues, resulting in greater difficulty in wound healing and aggravated dermatitis.[41]

Notably, some treatments combined with radiotherapy aggravate the occurrence of dermatitis, such as concurrent chemotherapy, which can increase the incidence and severity of ARD. Other published studies have demonstrated a trend toward increased skin toxicity after adjuvant chemotherapy,[42],[43] whereas patients treated with anthracyclines reported greater experience of skin reactions after radiotherapy.[44] However, our results did not show this difference, and some other studies also reported no significant association between chemotherapy and ARD.[14],[30] In the future, it will, therefore, be necessary to further distinguish the type and duration of chemotherapy drugs as well as the relationship between them and radiotherapy.

Furthermore, the effects of synchronous targeted therapy and hormone therapy on cutaneous toxicity are controversial; our results did not show any relationship between them. It has also been reported that hormone therapy may affect breast fibrosis. A retrospective study of patients with breast-conserving RT revealed an increase in breast fibrosis in patients treated with both tamoxifen and radiation when compared with patients who were treated with sequential radiation and tamoxifen.[45] However, two other retrospective studies did not notice any difference in the incidence of radiation toxicity in breast cancer that developed from the use of concurrent or sequential tamoxifen.[46],[47] Some studies have demonstrated that trastuzumab has a protective effect on the skin after RT,[26] whereas others reported that it was an important risk factor for radiation dermatitis.[48] Regardless of the abovementioned effects, there is no reasonable explanation reported yet for the pathological mechanisms, making it urgent and essential to maintaining an objective attitude on this subject.

 > Conclusion 

ARD caused by postoperative adjuvant RT is common but acceptable in patients with breast cancer. The degree of dermatitis can be reduced by the use of new precise radiotherapy techniques and topical interventions. However, there are some limitations to our study, mainly owing to its retrospective nature. Patients with breast cancer undergoing radiation treatment should receive appropriate intervention depending on their circumstances and they should not abandon treatment for the fear of radiation-induced acute skin reactions.

Ethics approval

This study was approved by Medical Ethics Committee (approval no. 2020071K). The study protocol is in accordance with the Declaration of Helsinki. All patients informed consent from telephone interview had been obtained before their participation in this study.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

The National Natural Science Foundation of China (81472799).

Conflicts of interest

There are no conflicts of interest.

 

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]