Reference: February 2025 | Issue 2 | Vol 11 | Page 28
At University College Dublin’s Charles Institute seminar in July 2024, Prof Ohsang Kwon, Professor and Chairman of the Department of Dermatology at Seoul National University College of Medicine in Korea, delivered a presentation on progress in the prevention of chemotherapy-induced alopecia (CIA), and the challenges that remain.
Prof Kwon specialises in male and female alopecia, scalp diseases, and hair restoration surgery, and has more than 160 publications to date.
He described the challenges and progress in the management of CIA in a presentation that encompassed the mechanisms of damage to rapidly proliferating hair follicle cells caused by anti-cancer agents, the available evidence in managing CIA, and clinical realities of the disorder.
Unmet need
Prof Kwon began by describing two major “unmet needs of cancer survivors that are very hard to overcome”, namely infertility and permanent hair loss. Presenting a patient case, he emphasised that CIA “causes severe psychosocial problems for cancer survivors”, before moving on to discuss the condition itself. “CIA is a type of anagen effluvium, a type of hair loss in the growing follicles, and generally hair recovers after the chemotherapy,” attendees heard.
Prof Kwon said that permanent CIA occurs “when no hair growth is observed, even six months after the final chemotherapy”. Noting the absence of an optimal experimental model, he went on to say that “two questions need to be answered” – whether the quiescent chemotherapy-resistant hair follicle stem cell (HFSC) pool is truly depleted, or whether permanent CIA is, in fact, potentially reversible.
Prof Kwon delivered an overview of the pathogenesis of transient CIA to explore the recovery mechanisms of hair loss after chemotherapy, as well as the pathomechanisms of stem cell depletion in permanent CIA, and outlined the eukaryotic cell cycle and cell cycle checkpoints that monitor the health, integrity, and progression of the cell. Describing “mitotic catastrophe”, Prof Kwon said the “G2M checkpoint is decisive in whether to progress or exit the cell cycle”.
He then went on to detail the anagen, catagen, and telogen phases of the HFSC cycle, highlighting that cells are at the highest risk and most susceptible to damage in the anagen growth phase.
“HFSCs are progenitors for all epithelial lineages in the hair follicle. They are quiescent, therefore very resistant to DNA damage to ensure genomic integrity for tissue homeostasis and regeneration. However, when DNA damage happens, the adult stem cells have to decide whether to stop and repair, fade into senescence, or cell death to avoid leaving inaccurate genetic information. On the other hand, hair matrix cells are short-lived, highly proliferative cells that terminally differentiate into the hair fibre and are very sensitive to genotoxicity.”
Prof Kwon then presented a large body of his work, and said “we were able to establish a permanent CIA model using human hair follicle xenografts”. He described creating the model using cycling human hair follicles treated with the alkylating agents busulfan followed by cyclophosphamide to uncover the underlying mechanisms by which HFSCs lose their pool.
The seminar heard that quiescent HFSCs showed “unexpected massive reactive proliferation”, after busulfan, and “became vulnerable to DNA damage-induced cell death, resulting in stem cell depletion and permanent loss of regeneration” following cyclophosphamide.
Prof Kwon also said that HFSC proliferation is activated through the PI3K/Akt pathway, and depletion is driven by p53/p38-induced cell death. “RNA-seq analysis showed that HFSCs experience mitotic catastrophe with G2/M checkpoint activation,” he added.
“We now have answers to our two questions. The quiescent HFSC pool was truly depleted after chemotherapy and permanent CIA is, in fact, permanent and not reversible.”
Treatment of CIA
Prof Kwon presented the methodology and findings from research carried out to quantify the efficacy of existing interventions for the prevention of CIA, including scalp cooling, catagen inducers, and pharmacological treatment.
“The scientific rationale for scalp cooling is vasoconstriction of the vessels and a reduction in biochemical activity,” he said, and described the intervention itself with accompanying images of a scalp cap in situ.
“It’s important to maintain intradermal hypothermia of the scalp, therefore post-infusion cooling time after chemotherapy is very important,” Prof Kwon emphasised, before acknowledging the variable results, limitations, and challenges associated with scalp cooling.
“Some patients cannot endure this procedure,” he noted as a primary barrier and challenge.
Moving on to present data from mouse models analysing pre-treatment with epidermal growth factor (EGF) to promote hair recovery post-cancer treatment, Prof Kwon returned to the mitotic activity of the hair follicle, describing it as “critical at the moment of insult”.
“Hair follicles are at their highest mitotic rate in early anagen, so they become seriously injured, whereas those in mitotically inactive phases of catagen or telogen are not that affected. Therefore, we thought it would be possible to prevent CIA via a hair cycle shift from anagen to catagen-telogen during scheduled chemotherapy. We selected EGF, DKK1, and interleukin-6 as candidates for catagen inducers.”
Prof Kwon described both the cell growth stimulation and catagen-inducing effects of EGF on hair follicles and said the results of the study suggest that catagen-inducers “could prevent CIA damage”.
With reference to more of his previous work, Prof Kwon then outlined findings from a retrospective cohort study of breast cancer patients that evaluated the efficacy of low-dose minoxidil in the management of CIA. He noted the high prevalence of breast cancer in females and that alopecia rates are also high in view of the cytotoxic and endocrine therapies used to treat the disease.
Prof Kwon also stressed the psychological impacts of both the cancer and the CIA for these women. He outlined the study methodology and said “there were notable differences between the three groups that had either cytotoxic chemotherapy, endocrine therapy, or a combination of cytotoxic and endocrine treatment”.
The seminar heard that diffuse alopecia was significantly higher in those receiving cytotoxic or combined therapy than those receiving endocrine treatment alone. “The endocrine therapy showed an androgenic alopecia-like pattern, relatively mild alopecia” compared to the other groups, Prof Kwon said.
“We tried topical minoxidil or a combination of low-dose oral minoxidil plus topical. Low doses ranged from 1.25 to 5mg per day. Low-dose and topical minoxidil showed significant results compared to topical alone, especially for hair density, which was significantly increased. The combination group did report a slight increase in adverse events such as hypertrichosis, oedema, and palpitations, but these adverse events were not statistically significant.”
Minoxidil was also a major element of Prof Kwon’s research into childhood CIA, which was the final component of the talk. He presented data from a retrospective cohort study he and his colleagues carried out to investigate the efficacy of topical minoxidil and L-cystine, medicinal yeast, and pantothenic acid complex-based dietary supplements (CYP) in managing CIA in childhood. Study participants had undergone high-dose conditioning chemotherapy followed by haematopoietic stem cell transplantation, and received either topical minoxidil, CYP, or combination therapy for CIA between January 2011 and January 2022.
“We can see better treatment outcomes in the combination group, especially in hair thickness, than in the topical monotherapy group,” he concluded, and stressed the importance of adhering to the treatment.
Questions and answers
During the post talk questions and answers session, Prof Tobin and Prof Kwon discussed a range of issues, including alternative treatments to scalp cooling, such as an Irish development that applies a tolerable amount of pressure to the patient’s scalp for reduced blood flow to hair follicles, and magnet-based interventions.
Prof Tobin noted that, in contrast to these treatments, minoxidil is a vasodilator that encourages blood flow to the area and asked if the timing of administration was a factor in its efficacy. “Timing of minoxidil is important,” Prof Kwon replied, “It’s better to apply minoxidil 24 hours at least after treatment, otherwise it can provoke more damage on the hair follicles.”
Prof Tobin also addressed “the tragedies of trying to treat cancers with chemotherapy and radiotherapy”, including DNA damage and increased risk of secondary disease, as well as the diverse range of side effects associated with variable classes of cancer therapies.
“People are now using immune checkpoint inhibitors that are trying to release the body’s innate immune power,” he said, and asked Prof Kwon if he felt alopecia rates will decline as “we move away from cytotoxic chemical use and towards more immune response leveraging treatment”.
Prof Kwon agreed, saying “alopecia is provoked by conventional chemotherapy”, and alopecia rates are “much lower” in immune checkpoint and targeted therapies.
Finally, Prof Tobin and Prof Kwon discussed the fact that “all aspects of modulation of hair follicle growth are limited by delivery challenges because of the scalp”, and the difficulties in “moving the follicle into the catagen-telogen phase”, noting that unlike other mammals, human hair follicles are 80-85 per cent in anagen, “the highly proliferative and highly vulnerable phase”.
Prof Tobin also emphasised that some patients decide against chemotherapy “because they are so concerned about the impact it will have on their hair”. Prof Kwon agreed psychological treatment is a vital part of any approach and must be a factor for consideration when managing these patients.
