Chronic radiation dermatitis in breast cancer patients: pathophysiology, prevention and management strategies, and clinical impact

Introduction

Breast cancer is the most commonly diagnosed non-cutaneous malignancy worldwide, with radiation therapy (RT) often delivered as a key component of the definitive multidisciplinary treatment paradigm (1,2). Acute radiation dermatitis (ARD), defined as occurring during or within 90 days of RT, is the most common acute adverse effect of breast RT and is characterized by symptoms such as tenderness, erythema, change in pigmentation, pruritus, and desquamation (3,4). In contrast, chronic radiation dermatitis (CRD) is defined as beginning or extending beyond 90 days following the completion of RT. CRD can be progressive and irreversible, and manifests as fibrosis, atrophy, hypo- or hyper-pigmentation, hyperkeratosis, dysfunction of sweat and sebaceous glands, telangiectasia and permanent ulcers. CRD can additionally contribute to the development of cutaneous malignancy (5-8). Despite an increasingly positive prognosis related to breast cancer given advances in treatment, changes associated with CRD include susceptibility to late treatment complications, poor cosmetic outcomes, and a negative impact on patient’s quality of life (9,10).

Although there is a lack of consensus on how best to prevent and treat ARD, rates of ARD are commonly reported, with an abundance of research and discussion published in recent years on ARD management strategies (3,11-16). The rates of CRD are much less commonly reported, with significantly less current research and discussion on prevention and treatment strategies (6). In this article, we aim to provide a comprehensive review of the existing literature on the current landscape of the understanding of the pathophysiology, prevention and management techniques of CRD, as well as its impact on patients’ quality of life.

Pathophysiology representing progression of ARD to CRD

Radiation injures cells by both direct DNA damage and by the generation of reactive oxygen species (ROS) (6). Skin is particularly susceptible to the effects of radiation due to rapid cell proliferation, with keratinocytes, melanocytes, fibroblasts and vascular endothelial cells being the most susceptible to radiation-induced injury. Death of these cells subsequently triggers an inflammatory response, resulting in the release of inflammatory cytokines, chemokines, and adhesion molecules by infiltrating lymphocytes and macrophages (5,6). Damage to vascular endothelial cells leads to erythema and edema, while death of epidermal cells leads to desquamation and blistering associated with ARD (6). In addition to direct damage by these inflammatory processes, wound healing is impaired due to damage to basal keratinocytes (5). Additional radiation exposure through higher doses and greater numbers of fractions may also lead to ARD of increasing severity (5-7).

The persistent production of acute pro-inflammatory cytokines, in particular TNF-α, IL-1 and IL-6, creates a chronic inflammatory state. This environment of chronic inflammation stimulates the production of TGF-β, which promotes fibroblast activation and proliferation. TGF-β also leads to the production of extracellular matrix proteins, including collagen, leading to skin hardening and stiffness associated with fibrosis. This transition to the sustained production and release of TGF-β is a key step in the transition from acute skin injury to chronic skin injury (5-7). The chronic inflammatory and fibrotic environment also leads to vascular damage, resulting in a reduced number of capillaries and development of telangiectasias. The decrease in capillaries leads to hypoxia, and in combination with the ROS produced from RT, further contributes to fibrosis (6,17). Damage to structures such as sweat glands and hair follicles also contributes to poor skin appearance and function, which makes the skin more vulnerable to additional damage (6).

ARD and CRD manifestations

ARD is characterized first by the development of erythema, which may progress to dry desquamation, which may then progress to moist desquamation, and in the most severe cases may lastly progress to ulceration and necrosis (4,5). Generally, ARD resolves within three months. CRD may be progressive and irreversible, and is characterized by clinical manifestations such as xerosis, hyperkeratosis, atrophy, telangiectasia, pain, pigmentation change, alopecia, decreased sweat production, nail damage, erosions and ulcerations, fibrosis, and limited range of motion (Figure 1). Most severely, CRD can increase the risk of development of skin cancer, including squamous cell carcinoma, basal cell carcinoma, and rarely, angiosarcoma (5-8). It is important to note that there is currently limited understanding of which patients will go on to develop the different manifestations of CRD, when they will develop symptoms, and how severe their presentation will be. This contrasts with ARD, in which the time sequence of symptom development is well understood.

Figure 1 Representative photo of patient with chronic skin telangiectasias (arrow) 36 months after completion of breast radiotherapy.

Up to 95% of patients undergoing RT may develop some degree of ARD (18). Areas of the body with a greater number of folds, such as the breast, are especially prone to the development of radiation dermatitis due to likelihood of high dose RT exposure and increased susceptibility to infection (16). However, as regimens involving increasing hypofractionation of RT for breast cancer become more common, rates and severity of ARD may currently be or eventually become lower as acute skin reactions are less sensitive to fraction size (19,20).

Existing studies demonstrate a wide variety of results regarding the rates of the various clinical manifestations associated with CRD, but interpretation is limited by the use of different toxicity evaluation methodologies, grading scales, study endpoints, inclusion of quality of life assessments, and varying follow-up durations, making direct comparison between studies difficult (21). Additionally, variations in the rates of CRD likely exist due to differences in patient populations studied, radiation modalities and techniques used, total dose delivered, use of boost and boost technique, and fractionation scheme.

Rates of CRD by RT fractionation schemes and boosts

Indeed, different rates of CRD have been reported by studies depending on fractionation scheme and use of a boost. The 20-year results of the EORTC 22881-10882 boost or no boost trial found that the cumulative incidence of any degree of fibrosis was 71.4% in breast cancer patients receiving a boost and 57.2% in those not receiving a boost. The rate of moderate to severe fibrosis was 30.4% and 15.0%, respectively, and the rate of severe fibrosis was 5.2% and 1.8%, respectively. Patients in this study all received conventionally fractionated whole breast RT (WBRT) (22). In the 10-year results of the UK START-B trial, of the patients in the group receiving a hypofractionated regimen of 40 Gy in 15 fractions, 22.0% experienced moderate to marked breast shrinkage, 12.8% experienced moderate to marked breast induration, and 3.1% experienced telangiectasia (23). In the 5-year results of the UK FAST-Forward trial, the following rates of moderate to marked CRD related effects were reported for the ultra-hypofractionated regimen of 26 Gy in 5 fractions and the standard of care (40 Gy in 15 fractions) groups, respectively: 1.6% vs. 1.0% experienced telangiectasia, 1.6% vs. 0.8% experienced breast induration outside of the tumor bed, 4.0% vs. 3.2% experienced breast induration in the tumor bed, and 6.2% vs. 5.8% experienced breast shrinkage, respectively (24).

Rates of CRD manifestations may also vary by WBRT technique and boost technique utilized. A Canadian trial with 10 years of follow-up comparing patients treated with conventionally fractionated intensity-modulated RT (IMRT) and 3-dimensional conformal radiotherapy (3DCRT) demonstrated rates of telangiectasia of 7.8% vs. 12.2% and fibrosis of 17.0% vs. 24.0%, respectively (25). Another trial comparing patients receiving conventionally fractionated breast IMRT with simultaneously integrated boost (SIB) and 3DCRT with sequential boost found that after two years, 28.2% vs. 30.7% experienced fibrosis, 13.0% vs. 8.9% experienced telangiectasia, and 26.4% vs. 23.8% experienced retraction/atrophy, respectively. Additionally, 0.5% of patients experienced ulceration in both groups (26). A study investigating once-weekly ultra-hypofractionated IMRT vs. 3DCRT reported that 16.7% vs. 7.2% experienced grade ≥2 late fibrosis, 1.4% vs. 1.4% experienced grade 2 late telangiectasia, 4.3% vs. 0.0% experienced late grade 2 pigmentation changes, 1.4% vs. 0.0% experienced grade 2 late atrophy, and 11.6% vs. 8.3% experienced grade ≥2 late breast retraction, respectively (27). A phase III trial investigating patients receiving conventionally fractionated field-in-field IMRT (FiF-IMRT) vs. helical tomotherapy IMRT (HT-IMRT) with 5-year follow-up demonstrated that 75% vs. 67% experienced skin induration/fibrosis, 78% vs. 63% experienced hyperpigmentation, 61% vs. 59% experienced hypopigmentation, 9% vs. 5% experienced skin atrophy, and 32% vs. 25% developed telangiectasia, respectively (28). The two-year results of a phase II trial investigating hypofractionated volumetric modulated arc therapy (VMAT) with SIB reported that only 14% of patients experienced late grade 1 dermatitis at one year, and this decreased to 4% at the time of last follow-up (29).

Interest in partial breast irradiation (PBI) for breast cancer patients have increased in recent years. There have been mixed results in the rates of CRD manifestations in patients receiving photon PBI compared to WBRT. For example, one trial comparing photon PBI and WBRT reported that 22.9% vs. 4.6% experienced grade ≥2 induration or fibrosis and that 9.3% vs. 3.7% experienced grade ≥2 telangiectasia, respectively, suggesting that PBI resulted in worse late toxicities, including CRD (30). Notably, this trial used PBI twice per day. A study comparing once per day photon PBI and WBRT found that PBI was associated with lower rates of late toxicities and reported that 2.9% vs. 7.0% experienced grade ≥2 late dermatitis, 9.2% vs. 12.3% experienced grade ≥1 fibrosis, and 3.5% vs. 4.3% experienced grade ≥1 telangiectasia. respectively (31). A systematic review concluded that there is likely no difference between the incidence of late toxicities for patients receiving photon PBI vs. WBRT (32).

The use of proton therapy for breast cancer has also significantly increased over the past decade (33,34). Limited data exist on the rates of CRD manifestations after proton therapy, with the majority to date focusing on proton PBI (35). As the physical properties of protons allow for lower entrance dose, protons could be hypothesized to result in a lower rate of skin toxicities (36). Indeed, recent studies of proton PBI have reported low rates of late toxicities. For example, a phase II study of proton PBI at MD Anderson Cancer Center found that 17% of patients developed grade 1 telangiectasia, and 7% of patients developed tumor bed retraction, but there were no cases of fibrosis or breast shrinkage (37). Similarly, a study of pencil beam scanning proton PBI found that the only late toxicities at 12 months were one case of breast edema and one seroma (38). Further study on the incidence of CRD manifestations after whole breast or chest wall proton therapy will be informative.

Grading

The RT Oncology Group (RTOG) and European Organization for Research and Treatment of Cancer (EORTC) published a grading system for chronic effects of RT, including chronic effects on skin and subcutaneous tissue (Table 1) (39). Higher grading of late effects most often represents progression of CRD over time from manifestations such as fibrosis and telangiectasia to more severe manifestations such as ulceration and necrosis; however, it is important to note that higher grade toxicities (grades 3–5) can also occur within 90 days of RT completion.

The Common Terminology Criteria for Adverse Events (CTCAE v5.0) is commonly used to grade other adverse effects, including ARD, but it does not specifically mention CRD. The CTCAE v5.0 does include “dermatitis radiation” and includes grading systems for the various clinical manifestations associated with CRD, including fibrosis, skin ulceration, telangiectasia, dry skin, pain of skin, skin atrophy, skin induration, and hypo/hyperpigmentation (Table 2) (40). Similar to the RTOG/EORTC grading scale, in the CTCAE grading system, increase in grade may represent progression from ARD manifestations to CRD manifestations over time, although grade 3–5 toxicities can also occur acutely. As some studies use the RTOG/EORTC grading system, while others use the CTCAE v5.0 grading system, direct comparison between different existing studies can be challenging. A standardized consensus on the grading of CRD is crucial to ensure equitable comparisons when assessing new strategies for the prevention and treatment of this condition.

A disadvantage to the use of the RTOG/EORTC and CTCAE grading scales is that they are dependent on clinical evaluation and palpation, which is subjective. Objective methods of measuring the manifestations of CRD, such as ultrasound elastography for fibrosis or spectrophotometry for skin discoloration, may be valuable in allowing for better comparison of CRD rates between studies (41,42). Additionally, the RTOG/EORTC and CTCAE grading scales are clinician-reported and do not take into account evaluation by the patients themselves. Patient-reported outcome measures (PROMs) are being used in the clinical setting more frequently, and studies suggest that there can be great discrepancies between clinical reported and patient reported toxicities, such as for ARD (43). Thus, the development of PROMs to evaluate CRD will be useful for understanding the true incidence of this condition and permitting better comparison between studies.

ARD and CRD risk factors

Patients who experience severe ARD, especially moist desquamation, may be more likely to develop manifestations of CRD months to years later (25). Thus, strategies that reduce ARD may also prevent CRD, and risk factors for ARD may also be those contributing to the later development of CRD. Risk factors for increased severity of ARD in breast cancer patients include greater body mass index (BMI), greater breast size, being a smoker, African American race, undergoing mastectomy rather than breast conserving surgery, node positive disease, greater RT dose, conventionally fractionated RT regimens, heterogeneous dose distribution, boost receipt, greater boost volume, supine positioning, and bolus use (25,44-48). It is important to note, however, that although some association has been observed between the development of severe acute toxicity and CRD, correlation is overall limited. For example, some patients will develop severe acute toxicity with only limited CRD in the future. Thus, it is difficult to predict which patients may be most affected by CRD.

Factors impacting the development of CRD may include age, total RT dose, total volume irradiated, fractionation, RT technique, use of bolus, concurrent targeted therapies, connective tissue disorders, skin disorders, and genetic factors, such as polymorphisms in TGF-β1, GSTP1, and GSTA1 (7,49-52).

Studies on radiation dermatitis prevention

In general, avoiding unnecessary irradiation of healthy skin through the use of techniques such as IMRT may reduce late complications (53). Prone positioning for large-breasted patients has been shown to reduce the risk of ARD and has also translated into the reduction of some CRD (54,55). Massage therapy and physical activity can also reduce acute symptoms such as erythema, pain, pruritus, and induration of skin, and they may additionally have the potential to break down fibrotic tissue, thus preventing CRD (56,57). The use of sunscreen after RT to protect against UV-light and the avoidance of smoking may also help prevent the development of CRD (58).

As increasingly severe manifestations of ARD have been associated with increased risk of manifestations of CRD, methods that have been studied to prevent ARD may also help prevent CRD. The application of corticosteroid creams such as mometasone and betamethasone currently has the greatest consensus for use by experts in the prevention of ARD in breast cancer patients (4,14,59-61). For example, Hindley et al. conducted a randomized double-blind comparison of mometasone furoate and diprobase emollient cream for the prevention of ARD in breast cancer patients (n=62 and 58, respectively). The mean and maximum RTOG skin dermatitis score and the mean erythema score was significantly lower for the mometasone furoate group compared to the control group (P=0.046, P=0.018, and P=0.012, respectively) (59). A randomized trial of Ulff et al. compared betamethasone cream to two other control moisturizing creams. There were 104 participants randomized in a 2:1:1 ratio. RTOG clinical scoring was used as well as colorimeter quantitative scoring. The study results demonstrated a significant benefit to betamethasone when evaluating skin changes using the RTOG scale (P=0.01 at 5 weeks post-treatment), but did not demonstrate any difference when evaluating with colorimetry, patients also reported lesser symptoms of itching, burning, and irritation in the betamethasone group (P=0.048) (61).

Various barrier films have also been studied in the prevention of ARD. Mepitel Film is a silicone-based film that patients can apply for the duration of their RT. Although studies have shown some evidence of benefit for all breast cancer patients, Mepitel Film has the most promising data for breast cancer patients at high risk for ARD (12,62-66). For example, Behroozian et al.’s phase III clinical trial of 376 patients receiving either Mepitel Film or standard aqueous cream after chest wall RT or WBRT for patients with a band size of 36+ or a cup size of C+. The incidence of clinician assessed grade 2+ ARD was significantly lower in the Mepitel Film group (P<0.0001), and patients reported significantly lower scores using the Radiation-Induced Skin Reaction Assessment Scale (RISRAS) (P<0.0001) (62). Other barrier films with promising evidence include Hydrofilm, a polyurethane film, and StrataXRT, a silicone gel that transforms into a film (3,15,67-70). Schmeel et al. conducted an intra-patient randomized trial in which Hydrofilm was used prophylactically on either the medial or lateral half of the breast in 62 patients. The mean RTOG/EORTC skin dermatitis score was 1.33 in the control half of the breast, and 0.35 in the Hydrofilm half (P<0.001). Patients also reported a significantly lower mean itching and pain score according to the modified RISRAS (P<0.001 and 0.04, respectively) (70). Ahn et al. conducted a randomized trial investigating 56 patients who prophylactically received StrataXRT or a standard moisturizer. There was a significantly lower erythema index score in the StrataXRT group (P<0.001) at 6 weeks and a significantly lower melanin index score at 2 weeks (P<0.001) (67).

CRD management

Cutaneous fibrosis

A variety of methods have been proposed to help treat cutaneous fibrosis related to RT, however data are overall limited. Several clinical trials have shown that vitamin E and pentoxifylline can prevent the development of CRD as well as cause it to regress after it has developed. These compounds have antioxidant effects and have been hypothesized to interfere with TGF-β signaling (71-74). Jacobson et al. (2013) conducted a randomized trial of 53 patients who were randomized to receive pentoxifylline 400 mg three times daily and vitamin E 400 IU daily for 6 months after RT or standard follow-up. Tissue compliance meter measurements were used to assess fibrosis. The study reported that the mean difference in tissue compliance meter measurements was 0.88 mm (P=0.0478) (73). Delanian et al. (2003) conducted a randomized controlled trial of 24 patients with 29 fibrosis areas. Patients received either 800 mg/day of pentoxifylline and 1,000 IU/day of vitamin E, pentoxifylline only, vitamin E only, or placebo only. Mean fibrosis regression was 60% in the combined pentoxifylline and vitamin E group, and 43% in the placebo group (P=0.038) (72).

Delanian et al. (1994) conducted a clinical trial of 34 patients with 42 palpable zones of skin fibrosis that received liposomal Cu/Zn superoxide dismutase (Lipsod) after RT. Softening of fibrosis tissue was significant to pronounced in 86% of patients, and a complete response was observed in 17% of patients. All patients showed evidence of some clinical regression (75). Of note, a recent systematic review concluded that the benefit to using vitamin E, pentoxifylline, or superoxide dismutase could not be determined based on evidence in current studies due to overall small sample sizes and high risk of bias. Additionally, the review pointed out that all of the studies investigating vitamin E and pentoxifylline demonstrated clinically relevant adverse effects (76).

Hyperbaric oxygen therapy has also been suggested as a method of treating CRD, however, similarly to vitamin E, pentoxifylline and superoxide dismutase, a systematic review concluded that there is not enough evidence to draw a conclusion on effectiveness (77). Of note, van der Molen et al.’s (2024) recently published clinical trial (not included in the above systematic review) that investigated the use of 30–40 hyperbaric oxygen therapy sessions over 6–8 consecutive weeks to treat 125 patients with moderate to severe breast, chest wall, and/or shoulder pain in combination with edema, fibrosis, or movement restriction following breast RT. The study concluded that hyperbaric oxygen therapy is effective at reducing fibrosis (33% of patients reported fibrosis in the intervention arm, 51% of patients reported fibrosis in the control arm; P=0.02. However, a significant number of patients were reluctant to engage in this therapy due to the intensity of the treatment (78).

Fat grafting may also improve cutaneous fibrosis, as adipose cells release proangiogenic and antiapoptotic growth factors that may help regenerate damaged tissues. One study of 20 patients showed that fat grafting resulted in symptomatic improvement in all included patients with fibrosis, including those who were considered otherwise untreatable with significant functional impairment (79). Receipt of fat grafting in patients undergoing breast reconstruction after RT has also been shown to reduce capsular contracture and result in better reconstruction outcomes (56,80).

In a recent small study of 5 patients, 10,600 nm carbon dioxide laser therapy resulted in improved range of motion and increased skin elasticity for all included patients with chronic radiation fibrosis (81). Surgery, such as partial mastectomy with latissimus dorsi reconstruction, may also be used to manage fibrosis not responding to other therapies, such as in one study that showed that 8 out of 9 patients with severe CRD experienced improvements in their complaints and the shape of their breast after undergoing surgical intervention (82). Although the results of these studies are encouraging, it is important to note that evidence is overall limited for both laser therapy and surgical intervention and higher quality studies are needed.

Telangiectasia

Laser therapy is a technology that treats telangiectasia by targeting endogenous chromophore oxyhemoglobin, resulting in vessel clearance due to photothermolysis (83). Nymann et al. (2009) conducted a randomized trial of 13 patients that compared long-pulse dye laser (LPDL) vs. intense pulsed light laser therapy (IPL) in treating telangiectasia. The study found median vessel clearance of 90% in the LPDL group, and a median vessel clearance of 50% in the IPL group. Of note, two patients withdrew from the study due to hypopigmentation (83). Lanigan et al. (2003) conducted a study of 8 patients treated with pulsed dye laser therapy every 8 weeks until satisfaction of result (maximum number of treatments was three). Of the 6 patients who were able to be reviewed at the end of treatment, all showed 100% vessel clearance in the treated areas (84). Rossi et al. (2014) included 11 patients who were treated with pulsed dye laser therapy for telangiectasia. All 11 patients experienced clinical improvement, and the mean percent clearance was 72.7%. No adverse effects were reported (85).

Ulceration

Li et al. (2019) described the results of a study of 10 breast cancer patients with chest wall ulcers who received negative pressure wound therapy with chest wall debridement followed by a latissimus dorsi myocutaneous flap transplantation. Ulcers ranged in size from 1×2 cm to 5×7 cm. At a median follow-up of 25.9 months, all flaps survived with satisfactory appearance and there was no recurrence of ulcers (86). Dong et al. (2023) presented a study of 13 patients with radiation-induced ulcers, 3 of whom had ulcers of the chest. The mean ulcer size was 33.1 cm². Among 15 regional flaps, at a median follow-up of 23.3 months, there were no ulcer recurrences but there were significant morbidities, including wound dehiscence (6.7%) and localized necrosis requiring re-operation (26.7%) (87). Zhou et al. (2019) reported on a study comparing 50 breast cancer patients with radiation-induced ulcers who either underwent single-stage reconstruction or two-stage reconstruction. Single-stage treatment consisted of debridement and reconstruction with a tissue flap in one procedure. Two-stage reconstruction included debridement and omentum majus tamping in the first stage, followed by reconstruction with skin grafting or flap placement two weeks later. Ulcer area ranged from 3×5 cm to 8×10 cm. Two-stage reconstruction was concluded to be safer, as six patients developed flap infection with four progressing to necrosis in the single-stage group. Additionally, one patient in the single-stage group died of septicemia 5 days after surgery (88).

Hyperpigmentation

A particularly common manifestation of CRD is hyperpigmentation, and this may disproportionately impact patients with darker skin tones. Q-switched lasers may represent a potential treatment option for this condition (58,89).

Necrosis

Unfortunately, there is a lack of quality research on the most effective method of treating radiation-induced skin necrosis in breast cancer patients. Koppert et al. conducted a study that included 8 patients who underwent sternal resection for radiation-induced necrosis, 7 of whom were previously treated for breast cancer. Among the 8 patients, there were two severe complications, and one patient died post-operatively. Two patients had unexpected tumor tissue in the resected specimen and thus likely gained survival time (90). Flap reconstruction may represent another method of managing radiation induced necrosis after treatment of breast cancer, but data are very limited (91).

Clinical impact

Most severely, CRD may contribute to an increased risk of secondary cutaneous malignancy (5,8). Secondary cancers may be life threatening, emotionally distressing, and require that the patient undergo further treatment, reducing quality of life. Ulceration, skin necrosis and fibrosis associated with CRD can be cosmetically displeasing, painful, and limit range of motion, thus reducing patient ability to engage in daily activities. Skin atrophy and ulceration additionally predispose patients to infection, which can be painful, slow to heal, and possibly lead to superinfection. Radiation necrosis is particularly difficult to manage, as it often results in impaired healing and superinfection (92).

A study that surveyed patients before and after RT and the subsequent development of radiation dermatitis found that patients reported worsening in every domain of the survey, including how much they worry about their skin condition, how much they worry about the appearance of their skin, how frustrated, annoyed, depressed and embarrassed they feel about their skin, their desire to be with other people, their ability to show affection, and their ability to engage in work and other daily activities (9). One study showed that patients treated for their telangiectasias with pulsed dye laser were all highly satisfied with the cosmetic improvement resulting from this intervention, suggesting that even less severe manifestations of CRD can reduce patient quality of life (84).

Conclusions

CRD development is associated with pathological activation of TGF-β and can manifest as fibrosis, skin atrophy, changes in pigmentation, ulceration, and necrosis, and could predispose patients to secondary cutaneous malignancies. Studies report widely varying incidence rates of CRD, with difficulty in comparison due to differences in how CRD manifestations are graded and due to differences in the delivery of RT. Existing studies reporting CRD incidence mainly consist of photon studies; as proton therapy becomes more common for treating breast cancer patients, data on the incidence of CRD following proton therapy, especially for whole breast and chest wall treatment, will be valuable. As hypofractionated and ultra-hypofractionated radiotherapy could theoretically be associated with greater late normal tissue effects, longer term follow-up of studies using these fractionation regimens on the incidence of CRD-associated symptoms, such as fibrosis, will also be informative.

There has also been significantly less research on methods of prevention and management of CRD compared to ARD, mainly stemming from uncertainty in the time course of development of CRD, the lack of PROMs related to CRD, and variability of study endpoints making comparisons between interventions difficult. As severe ARD reactions are associated with increased risk of development of CRD, methods for preventing ARD likely can also prevent CRD. Currently, corticosteroid creams such as betamethasone and mometasone have the most compelling evidence, but there is also recent evidence for barrier films such as Mepitel Film, StrataXRT, and Hydrofilm. Additionally, although some relationship between ARD severity and risk of CRD has been observed, the relationship is overall not well understood as some patients may have severe ARD without significant CRD in the future. Thus, further research is needed to better characterize the relationship between ARD and CRD.

Pulsed dye laser therapy has shown efficacy in treating telangiectasias associated with CRD. Some methods with evidence to support application in the treatment of CRD-associated fibrosis include vitamin E and pentoxifylline therapy, superoxide dismutase supplementation, hyperbaric oxygen, and fat grafting. Surgical interventions such as debridement, resection, and flap reconstruction may be efficacious in treating radiation induced ulcers and necrosis. Q-switched lasers may represent a possible intervention for hyperpigmentation. A standardized scoring scale for CRD, common study endpoints, and further research to better understand the incidence of CRD and methods of prevention and management are critical, as CRD can be associated with significant morbidity, including secondary cutaneous malignancies, along with a negative impact on patient quality of life across multiple domains.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine for the series “Supportive Care After Breast Cancer: Challenges and Opportunities”. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-158/prf

Funding: This research was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) Memorial Sloan Kettering Cancer Center Support Grant (Core Grant No. P30-CA008748).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-158/coif). The series “Supportive Care After Breast Cancer: Challenges and Opportunities” was commissioned by the editorial office without any funding or sponsorship. H.C.Y.W., C.B.S., and J.I.C. served as the unpaid Guest Editors of the series. C.B.S. serves as the Editor-in-Chief of Annals of Palliative Medicine. S.F.L. serves as an unpaid Chair of Palliative Radiotherapy Subcommittee of Annals of Palliative Medicine from October 2023 to September 2025. The authors have no other conflicts of interest to disclose.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All clinical procedures described in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this article and the accompanying image.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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