Randomized Pilot Study of a Keratin-based Topical Cream for Radiation Dermatitis in Breast Cancer Patients

Abstract

Purpose: Radiotherapy (RT) is commonly used in the treatment of breast cancer and often, despite advances in fractionated dosing schedules, produces undesirable skin toxicity. The purpose of this study was to evaluate the feasibility of using a keratin-based topical cream, KeraStat® Cream (KC; KeraNetics, Inc., Winston Salem, NC, USA) to manage the symptoms of radiation dermatitis (RD) in breast cancer patients undergoing RT. Materials and Methods: A total of 24 subjects were enrolled on this single-center, randomized, open-label study. Participants were randomly assigned to KC or standard of care (SOC, patient's choice of a variety of readily available creams or moisturizers). Patients were asked to apply the assigned treatment to the irradiated area twice daily, beginning with day 1 of RT, through 30 days post-RT. The primary outcome was compliance of use. Secondary outcomes included safety and tolerability of KC, as well as RD severity assessed using the Radiation Therapy Oncology Group (RTOG) scale and the patient-reported Dermatology Life Quality Index (DLQI). Results: All subjects in the KC group were assessed as compliant with no adverse events. The rate of RTOG Grade 2 RD was lower in the KC group (30.8%) compared to the SOC group (54.5%, P = .408). At the final RT visit, the mean RTOG RD score was lower in the KC group (1.0) versus the SOC group (1.4). Similarly, patient-reported quality of life measured by the DLQI at the end of RT was improved in the KC group (mean 4.25, small effect) versus the SOC group (mean 6.18, moderate effect, P = .412). Conclusions: KC was safe and well tolerated with no adverse events. Though efficacy measures were not powered to draw definitive conclusions, trends and clinical assessments suggest that there is a benefit of using KC compared to SOC for breast cancer patients treated with RT, and a larger powered study for efficacy is warranted. Trial Registry: This clinical trial is registered as NCT03374995 titled KeraStat(R) Cream for Radiation Dermatitis.

Introduction

Radiotherapy (RT), an effective adjuvant treatment for breast cancer, primarily induces tumor cell death via DNA damage. ¹ Additional RT effects on skin and soft tissues can manifest as radiation dermatitis (RD) that occurs within a treatment field. Historically, up to 95% of patients undergoing breast RT experience moderate-to-severe RD, ² though modern advances have reduced this rate to 35-90%.^3–6 The disturbance of the cutaneous barrier function can significantly impact both health-related quality of life and the ability to tolerate the course of treatment. ⁷ Mitigating the adverse skin effects of RT is necessary to ensure timely completion of RT, reduce pain/discomfort, and increase patient quality of life. ² Due in large part to a lack of standardized guidance, there is significant variability in the treatment options used in clinical practice, and there is no consensus standard of care (SOC). ⁸ Skin care recommendations typically include the use of topical emollients, non-fragrant moisturizers, gentle cleansing, or topical corticosteroids; however, these vary widely among practices. ² A recent review of six published practice guidelines for the treatment of RD (including the Multinational Association for Supportive Care in Cancer (MASCC), British Columbia Cancer Agency (BCCA), Cancer Care Manitoba (CCMB), Oncology Nursing Society (ONS), Society and College of Radiographers (SCoR), and International Society of Nurses in Cancer Care (ISNCC)), recommended 59 specifically different treatment options for RD. ⁹

One potential new option is the FDA-cleared keratin-based topical product, KeraStat® Cream (KC; KeraNetics, Inc., Winston Salem, NC, USA), which is indicated for the treatment of RD. This product is a non-sterile, non-implantable, emulsion-based wound treatment intended to act as a protective covering for the management of RD, as well as a variety of skin wounds, ulcers and first and second degree (partial thickness) burns. KC uses human hair-derived keratin proteins that have been shown to be an effective treatment for burn wounds and thermal stresses. ¹⁰ Proteomic analysis has shown that lower molecular weight keratin proteins regulate cell communication, growth, and migration ¹¹ and can salvage thermally stressed cells by downregulating cell death pathway-related genes. ¹² Higher molecular weight keratin proteins have been shown to be particularly effective in regulating energy metabolism and reactive oxygen scavenging. ¹¹ One potential mechanism for these proteins’ successful use in wound and injury healing involves interdiction of the inflammatory cascade by inducing macrophage polarization to the M2, remodeling anti-inflammatory lineage. ¹³ When undifferentiated macrophages are exposed to a combination of both high and low molecular weight keratin proteins in the presence of lipopolysaccride which preferentially drives macrophages down the M1 (inflammatory) lineage, they preferentially differentiate to the M2 lineage and downregulate pro-inflammatory cytokines such as IL-1 and upregulate anti-inflammatory cytokines such as IL-10. ¹⁴ Given these potential beneficial aspects of KC, we sought to investigate the feasibility and efficacy of KC to prevent and treat RD in patients with breast cancer treated with RT.

Materials and Methods

This randomized, open-label pilot study (NCT03374995) enrolled 24 women ages 18 to 70 with stage 0-II breast carcinoma scheduled to receive 4-6 weeks of adjuvant RT after breast-conserving surgery at the Wake Forest Comprehensive Cancer Center. The study was approved by the Wake Forest Institutional Review Board (IRB, approval IRB00046759) and complied with published CONSORT clinical trial research standards. ¹⁵ Clinical staff were blinded to the randomization table used for patient group assignment. Exclusion criteria included: previous RT to the target region, planned palliative RT, unhealed/infected surgical sites in the target region, plan for concurrent cytotoxic chemotherapy, anti-HER2 or anti-EGFR agents, use of oral corticosteroids or topical corticosteroids in the target region, autoimmune disease in the target region, or allergy to the SOC or any ingredients in KC. Twenty-four eligible patients were randomized to be treated with either KC or SOC and informed consent was completed with each patient prior to enrollment. Group sample sizes were selected based on the Wake Forest IRB recommendations for pilot studies not only to assess product safety, but also to provide adequate secondary outcome efficacy data to power a larger follow-up definitive study. The SOC used was chosen by the subject from a list of readily available commercial emollient creams such as Calendula, Eucerin, Cetaphil, or Aveeno. The instructions for use of either the KC or SOC topical agents were to: “apply the agent to the irradiation area and 1 cm beyond the border of the affected area twice daily. Smooth the product over the target area to cover with a thin layer; do not rub the product in.”

The following activities were performed prior to RT start, weekly during RT, and at 1-month after completion of RT: assessment of compliance to assigned study agent, clinician-rated assessment of RD using the Radiation Therapy Oncology Group (RTOG) scale, patient-reported assessment of skin-related quality of life using the Dermatologic Life Quality Index (DLQI), photographs of the skin in the treated area, and adverse event recording.^16,17 The DLQI measures the impact of skin reaction on quality of life over the preceding week. The composite score ranges from 0 to 30, with a higher score indicating greater impact on quality of life, a score greater than 10 indicating a severe quality of life detriment, and a difference in 4 points representing a clinically meaningful difference. Compliance rate of use for KC was determined based on the average number of applications per week for a participant. Participants who averaged at least 10 applications per week were classified as compliant. Descriptive statistics comparing the two treatment groups were conducted, then a t-test was used for outcomes of effectiveness including RTOG RD grade and DLQI score at each time point. Comparisons between groups for the RTOG RD scale and DLQI score were conducted with 80% power to detect a difference of 1.2 standard deviations. Safety was evaluated by examining the incidence, grade, and type of adverse events from the screening period through study completion.

Results

In total, 25 women were enrolled; one withdrew from the study prior to treatment and was replaced. All remaining 24 patients completed the study, 13 in the KC group, and 11 in the SOC group. The mean age was 62.0 years; 20 (83%) patients self-identified as Caucasian, 3 (13%) as African American, and 1 (4%) as South Asian (Table 1). The total radiation dose was 4256-5256 cGy in 16-25 fractions across an irradiated area of 1-10% of total body surface area. There were no significant differences between the groups in total dose, fractionation regimen, breast volume or smoking history that contribute risk factors for RD.

Table 1.

Patient Characteristics.

	Overall	KeraStat	SOC	P
n	24	13	11
Age	62.0 (9.3)	59.2 (9.9)	65.4 (7.5)	.103
Race				.503
Caucasian	20 (83)	11 (85)	9 (82)
African American	3 (13)	1 (8)	2 (18)
South Asian	1 (4)	1 (8)	0 (0)
Weight	175.3 (27.4)	174.7 (28.0)	175.9 (28.0)	.919
BMI	30.7 (5.2)	31.1 (6.1)	30.2 (4.3)	.681

All 13 subjects in the KC group (100%) were assessed as being compliant. There were no unexpected adverse events attributable to the study intervention recorded. The mean RTOG score over time is shown in Figure 1. There were no significant differences in mean RTOG RD grade at any visit (Table 2), though the mean RTOG RD grade was higher in the SOC (1.4) versus the KC group at the end of RT (1.0; P = .075). All subjects but one (95.8%) experienced RTOG grade 1 RD over the duration of the study. A total of 10 subjects (41.7%) experienced RTOG grade 2 RD over the duration of the study: 6 of 11 (54.5%) in the SOC group and 4 of 13 (30.8%) in the KC group (Fisher's exact P = .408). There was one subject in the KC group who experienced moist desquamation. The mean DLQI score for each subject at each study visit is shown in Figure 2. One baseline score from a subject in the SOC group was removed given it was significantly higher than all other subjects, which was attributed to “anticipatory anxiety” by the patient. The mean DLQI at end of RT (week 6) was 6.18 in the SOC group versus 4.25 KC group (P = .412). There were no significant differences in DLQI between arms (Table 2).

Figure 1.

Average RTOG toxicity scale by treatment group for each study visit.

Figure 2.

Mean DLQI score by treatment group at each study visit.

Table 2.

Mean RTOG Radiation Dermatitis and Dermatology Life Quality Index Outcomes between Standard of Care and KeraStat® Cream.

	Mean RTOG radiation dermatitis grade			Mean DLQI score
Visit	SOC	KeraStat	P-value	SOC	KeraStat	P-value
Pre-RT	0	0	–	2.73	0.31	.132
Week 1	0.09	0.15	0.659	1.64	0.77	.244
Week 2	0.55	0.62	0.743	1.91	2.23	.815
Week 3	0.82	1.00	0.459	2.36	2.85	.690
Week 4	1.00	1.17	0.451	5.27	4.75	.847
Week 5	1.36	1.00	0.075	6.18	4.25	.412
1-month Post-RT	0.30	0.23	0.723	1.00	0.85	.827

RT, radiotherapy.

Discussion

RD is among the most common side effects for patients with breast cancer. ¹⁸ Acute RD can be associated with erythema, tenderness, desquamation (dry and moist), edema, pain, motion limitation or restriction, and prevention of daily activities. ¹⁹ This can have a profound impact on quality of life, which was observed in our cohort through increases in DLQI score over time. The treatment of acute RD is primarily supportive, but it can range from topical emollients with gentle cleansing to topical corticosteroids, hydrogel or colloid dressings, and topical or systemic antibiotics. ²⁰ Considering the reactive nature of the management of acute RD, novel topical agents to prevent, delay the onset of, or effectively treat RD are direly needed.

Here we show the first clinical evidence of the use of KC, a radiation injury treatment originally developed to treat more severe cases of grade 3 cutaneous radiation injury. ²¹ The use of KC was determined to be feasible in breast cancer patients treated with adjuvant RT after breast-conserving surgery. Though there were no significant differences in clinician-rated RTOG RD grade and patient-reported DLQI scores, given that this study was not powered for comparisons with regard to RD reduction, promising signals toward efficacy of KC were identified. Mean DLQI scores at the end of RT for the SOC group can be interpreted as having a moderate effect on quality of life. In the KC group, the mean end-RT DLQI score indicates only a “small effect” on quality of life. These findings, in addition to the lack of adverse effects, provide strong rationale for future study of KC for the prevention and treatment of RD in patients treated with RT.

This study is limited by its small size and nature as a pilot study to assess patient compliance to KC during RT. Thus, efficacy measures are underpowered and no conclusions can be made regarding the benefit of KC compared to SOC for breast cancer patients treated with RT. Additionally, the study could have benefited from the use of an objective measurement such as spectrophotometry, though studies have shown good correlation between these measurements and the RTOG. ²² Despite these limitations, this study provides preliminary data supporting further study of this intervention, ideally in a randomized study powered for efficacy of reduction in RD rates and improvement in quality of life compared to SOC skin care.

Conclusion

This randomized, pilot study of a keratin emulsion-based wound treatment for patients with breast cancer treated with RT demonstrates high levels of compliance with no apparent adverse effects. Statistically non-significant trends toward improved rates of acute RD were observed, as this study was not powered for efficacy. These findings support future comparative effectiveness studies in patients treated with RT and may be applied toward further research in patients with other primary malignancies for which RD is a common adverse effect.