Persistent Radiation-Induced Alopecia Has Distinctive Features and May Benefit from Treatment

Dr. Mario Lacouture

Persistent radiation-induced alopecia in patients with primary central nervous system (CNS) tumors or head and neck sarcomas is dose-dependent and has distinctive clinical and trichoscopic features, according to our findings published recently in JAMA Dermatology. This distressing adverse effect of cancer therapy may benefit from treatment.

We conducted a retrospective cohort study of 71 patients with primary CNS tumors or head and neck sarcomas treated at Memorial Sloan Kettering Cancer Center and St. Jude Children’s Research Hospital from 2011 to 2019. Using standardized clinical photographs of the scalp, trichoscopic images, and radiotherapy treatment plans, we evaluated clinical and trichoscopic features, the scalp radiation dose-response relationship, and response to topical minoxidil and procedural interventions. (1)

A higher radiation dose (odds ratio (OR) 1.15; 95% CI, 1.04–1.28) and proton irradiation (OR 5.7; 95% CI, 1.05–30.8) were associated with greater alopecia severity (p < 0.001). The dose at which 50 percent of patients had severe (grade 2) alopecia was 36.1 Gray (Gy) (95% CI; 33.7–39.6). (1)

The most common trichoscopic features were white patches in 16 of 28 patients (57 percent). In 15 patients, hair-shaft caliber was negatively correlated with scalp dose (correlation coefficient –0.624; p = 0.01). (1)

Interventions to address persistent radiation-induced alopecia may be beneficial. With topical minoxidil, 28 of 34 patients responded (82 percent), and four of 25 patients with clinical images available improved in severity grade. Two patients responded to hair transplantation, and one patient experienced a good outcome with plastic surgical reconstruction. (1)

Despite the high incidence of persistent radiation-induced alopecia and severe impact on quality of life, to our knowledge, our study is the first to systematically describe the clinical and trichoscopic phenotype of the condition and its response to dermatologic therapy. We hope our findings will inform patient counseling and treatment planning and guide future randomized controlled clinical trials among cancer survivors with alopecia.

Despite the high incidence of persistent radiation-induced alopecia and severe impact on quality of life, to our knowledge, our study is the first to systematically describe the clinical and trichoscopic phenotype of the condition and its response to dermatologic therapy.
Mario E. Lacouture Director, Oncodermatology Program; Research Director, Dermatology Service

Alopecia and Radiation Therapy

An estimated 80,000 primary CNS tumors and 1,500 head and neck sarcomas are diagnosed annually in the United States. (2), (3) The five-year survival rate reaches 33 percent in adults and 75 percent of children with CNS tumors, and 66 percent of adults and 73 percent of children with head and neck sarcomas. (4), (5), (6) Sixty percent of CNS cancer survivors and 30 percent of patients with head and neck sarcomas undergo cranial radiotherapy (CRT), often as part of multimodality therapy including surgery and chemotherapy. (7), (8)

Patients and clinicians alike recognize the risk of acute alopecia with CRT: 75 to 100 percent of patients who undergo CRT have noticeable hair loss of the scalp with radiation doses greater than 2 Gy, with hair usually growing back within two to four months. By contrast, persistent radiation-induced alopecia is incomplete hair growth six months after completing CRT. The condition affects about 60 percent of patients and has a long-lasting impact on psychosocial functioning and quality of life. (4), (5), (6) Pathologic hair loss can result in psychological distress (9)(10) since it plays an essential role in identity, social interactions, and self-image. (11), (12) Alopecia is often cited as one of the most distressing adverse events of cancer therapy. (13), (14), (15)

The mechanisms of persistent radiation-induced alopecia are not well understood. However, studies show that substantial insults from radiotherapy or cytotoxic chemotherapy can damage epithelial hair follicle stem cells in the bulge region and the rapidly dividing hair matrix cells in the hair follicle bulb, causing damage that is histologically consistent with nonspecific scarring alopecia. (5), (6), (16), (17), (18), (19), (20), (21), (22) Hair follicle radiosensitivity also depends on hair cycle stage: anagen matrix cells are more radiosensitive than telogen matrix cells as they have different proliferation rates.

Despite proton radiation’s dosimetric advantage, it does not spare skin compared to CRT. Proton radiation has an added range uncertainty that augments the exit skin dose, and the lack of build-up results in higher skin surface doses for targets located near the surface. (16), (23)

The dose threshold for transient epilation is low, from 0.75 to 2.0 Gy, (24), (25), (26) and the single-fraction lethal dose for a hair follicle has historically been considered to be seven to 16 Gy. (5), (27), (28) However, the risk factors and dose thresholds for persistent radiation-induced alopecia have been unclear.

Study Design

We identified 71 patients diagnosed with a primary CNS tumor or head and neck sarcoma and persistent radiation-induced alopecia treated at MSK or St. Jude between 2011 and 2019. Our team of collaborating researchers evaluated standardized clinical photographs of the vertex, frontal, lateral, and occipital views of the scalp with the hair parted and combed in the center, plus overt patches of alopecia.

We evaluated clinical photographs using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0: Grade 1 alopecia is hair loss of less than 50 percent of normal and does not require camouflage, and grade 2 alopecia is hair loss of 50 percent or more compared to normal that requires camouflage or is associated with psychosocial issues. (29) We categorized alopecia distribution as localized, diffuse, or mixed localized plus diffuse. A researcher analyzed blinded trichoscopic images for 28 patients obtained at a 50-times magnification of frontal scalp, occipital scalp, or other areas of alopecia.

For 25 patients who were prescribed twice daily application of topical minoxidil, 5 percent, we evaluated clinical images at baseline and follow-up. Complete response was defined as a reduction in severity by one or more CTCAE grades, and partial response was defined as improved scalp coverage with no improvement in grade. We assessed quality of life in 13 patients using the Hairdex Questionnaire, a validated 48-item tool for evaluating alopecia-specific quality of life. (30) The maximum scalp radiation dose was estimated retrospectively based on isodose curves corresponding to about 5 mm deep to the skin’s outer surface (35 patients received photon therapy, and two patients received proton therapy).

Study Results

The median age of patients in our study was 27 years (95% CI, 22–37 years; range 4–75 years). The most common brain tumors were medulloblastoma in 22 patients (31 percent) and glioblastoma multiforme in 18 patients (25 percent). Five of seven patients (71 percent) with head and neck sarcomas had rhabdomyosarcoma. Most patients had surgery and chemotherapy, in addition to radiotherapy. (1)

The median duration between radiotherapy and evaluation for persistent radiation-induced alopecia was 100 weeks (95% CI, 67–27 weeks). Alopecia severity was grade 1 in 40 of 70 patients (56 percent) and grade 2 in 30 patients (43 percent). Alopecia presented in three variants: localized, diffuse, and mixed patterns, which could be categorized by demographic and disease factors that determined cancer surgery, radiotherapy, and chemotherapy. (1)

The median cumulative scalp radiation dose was 39.6 Gy (95% CI, 30–42; range, 15.1–50.0 Gy), and the dose per fraction was 1.3 Gy (95% CI, 1.0–1.4; range 0.54–1.79) for 37 patients with evaluated radiotherapy plans. The median scalp dose of 41.5 Gy was significantly higher for patients with grade 2 alopecia than 31.9 Gy for patients with grade 1 alopecia (p = 0.001). (1)

Scalp dose and whether patients received proton or photon therapy remained statistically significant factors associated with alopecia severity after controlling for sex, age on receipt of radiotherapy, and concurrent chemotherapy. The odds of having grade 2 alopecia increased by 16 percent for every 1-Gy increase in scalp dose (OR 1.16; 95% CI, 1.03–1.29). The probability of grade 2 alopecia was 50 percent or higher at 36.1 Gy (95% CI, 33.7–39.6 Gy). (1)

Among 54 patients with available clinical images, persistent radiation-induced alopecia was distributed as follows: localized (54 percent), diffuse (24 percent), and mixed (22 percent). Persistent radiation-induced alopecia was attributed to radiotherapy alone for 74 percent of patients and radiotherapy plus chemotherapy for the remaining 26 percent. Alopecia distribution was associated with age, cancer type, radiotherapy field, and attribution (p < 0.01). (1)

Trichoscopy findings were evaluated for 28 of 71 patients. The median hair shaft density at a representative area of alopecia at diagnosis was 96 hairs/cm2 (95% CI, 84–144; IQR, 78–166 hairs/cm.2 Median hair shaft diameter was 46.7 μm (95% CI, 42.2–56.0; IQR, 40.3–58.3 μm). Most follicular units consisted of a single hair shaft. The most common features were white patches (57 percent), thin arborizing vessels (36 percent), and milky red areas (32 percent). (1)

At the microscopic level, hair caliber was negatively associated with estimated scalp radiation dose in 15 patients with trichoscopy and radiotherapy treatment plans. The association between hair density and scalp radiation dose was not statistically significant. Median hair density was lower for patients who received concurrent chemotherapy. Diffuse-field radiotherapy correlated with smaller hair diameter. (1)

Regarding quality of life, the median overall Hairdex Questionnaire score was 26.6 (95% CI, 12.2–34.9, IQR, 11.8–35.7). Note: total and subscale scores go from zero to 100, with higher indicating worse quality of life. Quality of life burden was higher in the emotions subscale than functioning, stigmatization, and symptoms subscales. (1)

A five percent solution of topical minoxidil was prescribed to 53 patients. Twenty-eight of 34 evaluable patients (82 percent) responded with a median follow-up time of 61 weeks. Among 25 of these patients who had clinical images, four patients had a complete response, 13 patients had a partial response, seven patients remained stable, and one patient progressed. (1)

Three patients underwent procedural intervention: two patients received hair transplantation with partial and complete responses, and one patient underwent scalp expansion and plastic surgical reconstruction with a complete response. Results from these three cases suggest that these procedures have potential for improving long-term well-being and social functioning, especially among childhood cancer survivors. (1)

Reducing Persistent Radiotherapy-Induced Alopecia

Newer treatment modalities, including intensity-modulated radiotherapy and volumetric-modulated arc therapy, are preferable to traditional radiotherapy for sparing hair. (24), (31), (32) Other tactics for decreasing skin dose include margin adjustment, blocking devices, limiting fixation materials, scalp cooling, and topical agents, but their utility is uncertain. (16), (33), (34), (35), (36), (37)

Radiation oncologists should counsel patients on the risks of alopecia with the planned radiotherapy dosing scheme. Our study serves as a proof of concept that trichoscopic metrics correlate with radiotherapy dose, which may be of use to dosimetrists and radiation oncologists during treatment planning and patient counseling.

Specialists in the Oncodermatology Program at MSK are dedicated to reducing the adverse effects of cancer treatments on skin. The SERIES (Skin and Eye Reactions to Inhibitors of EGFR and kinases) Clinic provides pre-treatment counseling and preventive efforts to minimize side effects and rapid attention to patients who develop skin issues. Close collaboration with treating oncologists ensures that interventions for side effects do not reduce the effectiveness of cancer treatments.

Investigators at MSK are currently conducting the following clinical trials testing new approaches for reducing skin-related side effects and quality of life:

This research was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support grants P30 CA008748 and R25CA020449.

Dr. Lacouture reported serving as a consultant for Legacy Healthcare Services, Adgero BioPharmaceuticals, Amryt Pharmaceuticals, Celldex Therapeutics, Debiopharm, Galderma, Johnson and Johnson, Novocure, Lindi, Merck, Helsinn Healthcare, Janssen, Menlo Therapeutics, Novartis, F. Hoffmann-La Roche, Abbvie, Boehringer Ingelheim, Allergan, Amgen, ER Squibb & Sons, EMD Serono, AstraZeneca, Genentech, Leo Pharma, Seattle Genetics, Bayer, Manner SAS, Lutris, Pierre Fabre, Paxman Coolers, Adjucare, Dignitana, Biotechspert, Teva Mexico, Parexel, OnQuality Pharmaceuticals, Oncoderm, Novartis, Our Brain Bank, and Takeda Millenium. Dr. Lacouture receives institutional research grants from Veloce, US Biotest, Berg, Bristol-Myers Squibb, Lutris, Paxman, Novocure, and Johnson and Johnson. For disclosures from other study authors, please refer to the paper.

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