JONT Journal

Multiple sections of hair shafts from a cohort of 52 patients were scanned to ensure uniformity of observed changes. The focus was on evaluating the degree 0 to 4 of intrinsic damage to the hair shaft surface as a result of the therapeutic intervention.

Results

Objectives – descriptive aspects:

Hair Retention (HMI post) and Avoidance of visible Alopecia (HMI post ≥50): The study evaluated 81 patients with a median pre-treatment HMI-score of 75 (IQR 58-92), which decreased to a median of 51 (IQR 17-58) post-treatment. Following treatment, 53% of patients retained an HMI-score of 50 or higher, indicating no visible hair loss.

Hair Loss During Therapy (HMI difference post-pre): In individuals with low baseline hair density, stabilization of the HMI proved to be of particular clinical relevance, underscoring the importance of relative HMI preservation as a meaningful success criterion. The median reduction in HMI-score from pre- to posttreatment was -27, IQR (-45,-10). For patients with an initial HMIscore below 50, the median change was -20.

Possible influencing or even predictive factors: Factors potentially influencing outcomes comprise general health conditions such as age, comorbidities, alopecia-inducing medications e.g. hypertensives, smoking status, and menopausal condition, also individual hair characteristics, such as original color, structure, and length and hair treatment. Additional variables include neutrophil nadirs and specific trichologic parameters, encompassing bulb and shaft diameter, anagen rate, shaft surface condition and hair pigment density.

In the category of general health, neutrophil nadirs and hair treatment, comorbidity tends to be associated with poorer hair retention HMI post (p= 0.060, ß= -0,55). This trend is also observed in the prevention of visible alopecia by comorbidity (p= 0.053, OR -0,27) and elevated nadir neutrophil count (p=0,055, OR 1,97).

The use of alopecia-inducing medications predictably leads to greater hair loss during therapy (p=0,033, ß=-0,54). Other mentioned potential influencing factors, including hair treatment do not affect hair loss over the time.

Light Microscopy Results: Correlational analysis demonstrated that pre- and post-therapeutic factors significantly impacted hair retention. Post-treatment factors had a stronger influence, with a stable anagen rate showing a strong correlation with hair retention (HMI post) (r = 0.41, p = 0.007). A stable shaft diameter was also significantly linked to better hair retention (r = 0.41, p = 0.008). Post-treatment shaft diameter had the strongest association with hair retention (r = 0.62, p < 0.001), followed by post-treatment anagen rate (r = 0.59, p < 0.001) and bulb diameter (r = 0.40, p = 0.016) demonstrating a more substantial impact on hair retention.

Therapeutic Effects on Melanosomes

Multivariate analysis indicates a link between stable melanosome density during therapy and reduced hair loss. A smaller decrease in pheomelanosomes correlates with less hair loss (p=0.013, ß=+0,35), while less pronounced changes in eumelanosomes show a positive, though borderline significant, effect (p=0.061, ß= +0,26) (Table 1).

A Fisher test was carried out and no relationship between original hair color and prevention of visible hair loss (HMI 50) was shown.

Melanosome clustering defined as more than five touching pigments exhibits a consistent pattern across all hair colors, showing no correlation with hair retention or the avoidance of visible hair loss (see table 2).

Table 2:  Statistical analysis reveals the following correlation coefficients (r) and p-values.

Results SEM:

Descriptive analyses:  pre-treatment evaluation exhibits a low median shaft surface damage of grade 1, post-treatment median shaft surface damage shows grade 2

In the univariate analysis the pre-treatment damage grade of the hair shaft significantly influences hair preservation (p= 0.012, correlation coefficient = -0.37); though it is surpassed by the impact of the post-therapeutic damage grade (p = 0.0006, correlation coefficient = -0.50)

Specifically, the greater the degree of damage to the shaft surface post-treatment, the lower the probability of avoiding visible hair loss (p=0,007, cc=-0,41).

The two highly meaningful surrogate parameters like melanosome density and low shaft surface damage, do not exhibit a statistically important context among themselves (r = -0.10, p = 0.564).

Surrogate Parameters for Hair Preservation as BEST of BEST

From all parameters previously tested with each HMI outcome variable, we included every significant one in overall regression analyses. We used linear regression to predict HMI post and difference and logistic regression to predict HMI ≥ 50.

When predicting HMI difference (Table 1), the difference of Pheomelanosomes (β = 0.35, p = 0.019) and the difference of Eumelanosomes (β = 0.25, p = 0.061) showed an effect. The less melanosomes were lost the more hair could be preserved. No medication results in better hair preservation (p=0,017, ß= -0,31). The model explained 32% variance (adj. R² = 0.32) and contained 46 patients with complete data.

When predicting HMI post (Table 3), less post-therapeutic damage degree of shaft surface led to better hair preservation (β = -0.30, p = 0.034). Having no comorbidities (β = -0.28, p = 0.073) and elevated nadir neutrophil count (β = 0.21, p = 0.083) were related to better hair preservation. The model explained 33% variance (adj. R² = 0.33) and contained 51 patients with complete data.

Table 3: Hair retention post treatment and influencing factors as every significant one from all categories in overall regression analysis as BEST of BEST.

When predicting HMI ≥ 50 (Table 4), an increased pre-treatment shaft diameter (OR = 1.11, p = 0.012), presenting no comorbidities (OR = 0.12, p = 0.024) and to be medication free were related to prevention of alopecia. The model explained a high amount of variance (Nagelkerke R² = 0.47) and contained 52 patients with complete data.

Pragmatic approach to evaluate the efficacy of scalp-cooling:

For prediction purposes we conducted a logistic regression with HMI≥50 as outcome and pre-HMI alongside comorbidity and medication as predictors. The model fit was moderately strong (Nagelkerke R² = 0.22). The analysis found that in the absence of comorbidities and medication a pre-HMI-score of 69 was a critical threshold for a significant prediction of hair loss prevention (OR = 6.98, 95% CI [1.01; 48.33]).

In a similar prediction-focused regression we entered posttherapeutic shaft surface damage and total melanosome difference as binary median-split variables (cut-off 2 and -12.9) alongside comorbidity and medication. The model contained only 37 patients due to missing data but showed a strong model fit (Nagelkerke R² = 0.37). Using favourable values for all predictors indicated at least a two-fold increased chance of preventing alopecia (OR = 137.50, 95% CI [2.12; 8911.32]) and effectively even much higher though wide confidence intervals reflecting small sample size.

Discussion

Visible hair loss (HMI < 50) was avoided in 53% of patients, though the median HMI dropped significantly from 75 pre-treatment to 51 post-treatment, indicating varied scalp-cooling effectiveness. Beside pre-treatment reduced hair density, this decline requires an analysis of the underlying factors contributing to this outcome in this patient cohort. Individual scalp temperature differences of up to 11.7 °C [10] may alter chemotherapy exposure at hair follicles, affecting cell biologic activity in the pigmentary unit influencing alopecia prevention. Pharmacodynamic responses to residual cytostatics in follicular cells may contribute to these variations.

Firstly, this evaluation aimed at investigating significant effects on hair preservation across various parameters concerning general health, hair characteristics based on light and electron microscopy.

High and stable anagen rates and increased pre-therapeutic shaft diameter emerge as a red flag in statistical efficiency evaluation, exerting substantial influence on hair preservation assessed by light microscopy. Scanning electron microscopy show that better initial hair conditions including shaft surface integrity and stable pigment density correlate strongly with effective scalpcooling. This points to the follicular unit as central determinant for the success of scalp cooling. The pigmentary unit, comprising fibroblasts, melanocytes, and keratinocytes, produces and transfers pigments during the anagen phase, influenced by both intrinsic factors (released by fibroblasts of the dermal papilla, melanocytes, keratinocytes, inflammatory and endocrine cells) and extrinsic (as UV radiation or drugs), being critical for hair retention under chemotherapy and cooling [11-14].

Alongside the anagen rate, bulb and shaft diameter and shaft surface condition, the components of the follicular pigmentary unit, particularly melanosomes, significantly impact hair preservation. Electron microscopy identified pheomelanosomes and eumelanosomes, with hair color diversity based on their ratio [15-19]. The role of melanosomes in hair retention under scalpcooling and chemotherapy warrants further exploration.

Preclinical studies show that cyclophosphamide induces changes in mouse hair follicles besides the apoptosis of proliferating matrix keratinocytes, especially affecting melanocytes and potentially causing premature disordered or even disrupted melanogenesis. These pigment changes including quantity and type of melanosomes may act as surrogate markers for chemotherapyinduced follicular alterations, aligning with the study’s focus on efficiency parameters [5,14 20].

In the context of hair pigment alterations, functional aspects of the follicular pigmentary unit’s function must be considered, going beyond pigment transfer. Melanosomes are positioned around keratinocyte nuclei providing photoprotection and reducing oxidative stress, subsequently stabilizing keratinocyte proliferation which forms the hair shaft [21-23]. Stable melanosome density, as shown in electron microscopy, strongly correlates with reduced hair loss. Despite scalp-cooling, disordered melanogenesis may occur due to chemotherapy-induced oxidative stress, leading to melanin clumping and disrupted pigment production, particularly affecting pheomelanin. This is likely due to increased antioxidant defence mechanism by incorporation of cysteine into glutathione, thereby leading to decreased availability of cysteine for the formation of cysteinyldopa indispensible for pheomelanogenesis, shifting melanin synthesis toward eumelanogenesis. Post-treatment, a reduced pheomelanosome density and a higher eumelanin-topheomelanin ratio were observed [24-28].

Scale: appr. 6.000:1

Photo 1: Example for clustering (more than five touching pigments).

Similar to cutaneous keratinocytes in light-skinned individuals, pigment clustering in light-colored hair may serve as a UVprotective mechanism [29, 30], though its occurrence during treatment is rare and does not significantly correlate with hair retention.

Chemotherapy-induced alterations in melanogenesis, along with other changes in the follicular pigmentary unit, are critical for evaluating scalp-cooling efficacy.

Light microscopy identifies stable anagen rate, consistent shaft diameter, and bulb diameter as key factors for hair preservation.

Ultrastructural analysis reveals increased shaft surface damage following treatment, exacerbating the hair´s susceptibility to breakage, primarilary due to its limited antioxidant defenses. Multivariate analysis confirms that minimal post-treatment shaft surface damage and stable melanogenesis are independently significant for hair preservation, marking them as essential parameters for scalp-cooling success confirmed as Best of Best.

Despite extensive research on chemotherapy’s damaging effects on hair follicles and the protective role of scalp-cooling, additional measures are being considered to enhance efficacy. Follicular targeting could support scalp-cooling by providing localized protection to the follicular pigmentary unit without systemic side effects. Topical melatonin and vitamin C nanovesicles, which have shown antioxidant benefits in androgenetic alopecia, a protypical ROS-related follicular pathology may improve hair shaft integrity and hair density [35].

Cytostatic agents such as anthracyclines also target sebocytes by increasing ROS levels thereby impairing their function. This can lead to hindered shaft protrusion, hair breakage and glandular apoptosis and follicular cornification while also reducing UV protection and weakening antimicrobial properties [31,39, 40].

Additionally, Paclitaxel as the final component of this CTX regime contributes to hair loss by targeting mitotically active matrix keratinocytes and potentially impacting non-dividing melanocytes and fibroblasts by increased oxidative cell stress, both crucial for melanosome transfer and follicle health [25].

Stem and progenitor cells residing in the bulge of the hair follicle’s outer root sheath, vital for hair growth and cycling, are vulnerable to chemotherapy-induced damage, potentially leading to permanent alopecia in case of prolonged retention of taxanes [32,33].

Paclitaxel primarily impacts actively proliferating cells like matrix keratinocytes. This raises the possibility that temporary G1 cell cycle arrest could shield these cells. Topical Palbociclib, a CDK 4/6 inhibitor, has shown promise in preclinical studies by inducing a brief G1 arrest in hair follicle cultures followed by activation of anagen phase without promoting hair shedding. This approach may allow hair growth to resume post-treatment, offering a way to protect hair follicles without safeguarding tumor cells from chemotherapy effects by topical application [34].

Remarkably, in the discussion of elevated ROS levels as chemotherapy-induced damaging factors to the cellular structures of the follicular pigmentary unit, it is crucial to consider the aspect that the dose makes the poison. Elevated ROS levels, indicative of oxidative stress, have been proven to cause damage to hair follicles [36].

Interestingly, Zhang and colleagues demonstrated at the preclinical level that mild oxidative stress may confer protection against chemotherapy-induced hair loss [37]. Subcutaneous application of peroxide induces cell cycle arrest through p53 activation, thereby shielding hair follicles from the cytotoxic effects of chemotherapy on actively dividing cells.

This is underscored at clinical level by Chen and colleagues revealing that cooling mitigates chemotherapy-induced alopecia by decelerating the cell cycle in hair follicles, thereby making them more resistant to chemoterapy’s cytotoxic effects. This provides further evidence that cell cycle arrest enhances the resistance of hair follicles to cytotoxic chemotherapy [38].

In light of these findings, it might be advantageous to combine scalp-cooling with pre-treatment-induced mild oxidative stress for example via topical peroxid application.

Discussing red flags of efficacy, alongside hair health as a key factor but also broader health parameters, such as comorbidity and medication use, has proven to be statistically significant.

After identifying significant variables from each parameter domain, joint regression models are created for hair mass index outcome as a prognostic approach. For patients with a pre-treatment Hair Mass Index (HMI) of 69, no comorbidities, and no alopecia-inducing medications, the odds of avoiding alopecia increases 6.98-fold. With additional favourable factors like no post-treatment shaft damage and minimal melanosome difference (<20 units), the odds of hair preservation increased up to 137 fold under anthracyclinetaxane chemotherapy.

These findings suggest that, while baseline parameters such as a high pre-treatment Hair Mass Index and the absence of comorbidities or alopecia-inducing medications contribute to hair retention, the most pronounced effect is observed when post-treatment shaft integrity and stable melanosome density are present. The substantial increase in predictive power—reflected in an odds ratio rising from 6.98 to 137—highlights melanogenic stability together with intact hair shaft surface as a key determinant of follicular resilience. This underscores the importance of preserving the structural and functional integrity of the pigmentary follicular unit as a central target in mitigating chemotherapy-induced hair loss.

Limitations include the study’s single-center design, a small cohort of 81, and only 52 patients with REM-analyzed follicles, which could introduce bias.

Gonadal profiling was performed exclusively in female participants through assessment of menopausal status based on serum levels of FSH, LH, and estradiol. As no significant association was found between menopausal status and hair retention, further sex-specific hormonal analyses were not extended to the male cohort. This approach was guided by both biological relevance and observed data patterns.

Crucially, no increased risk of scalp metastases supports scalpcooling as a safe option in cancer treatment.

Conclusion

Scalp-cooling has demonstrated efficacy in preventing visible hair loss in 53% of patients undergoing chemotherapy. Assuming optimal application of scalp-cooling beyond considerations of comorbidity and medications, its effectiveness is constrained by the integrity of the follicular pigmentary unit. Chemotherapy primarily induces hair loss by causing apoptosis in rapidly dividing matrix keratinocytes and by damaging hair follicle components through elevated oxidative stress. Achieving optimal hair health in combination with scalp-cooling could significantly improve hair retention.

Due to the multifaceted damage inflicted on hair follicles by reactive oxygen species, follicular targeting emerges as a promising approach to counteract these significant damaging factors. For example, topical applications of melatonin and vitamin C encapsulated in nanovesicles could provide targeted protection. Research represents an unmet need to establish protocols integrating follicular targeting within the existing framework of scalp-cooling systems. Optimizing these aspects is essential to maximize patients’ comfort and satisfaction, holistically addressing the multidimensional challenges of managing chemotherapy-induced alopecia as one of the most distressing periods of patients´ lives.

Statements and Declarations

Funding:  The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing interests: The authors have no relevant financial or non-financial interests to disclose.

Author contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Dörthe Schaffrin-Nabe, Anke JostenNabe, Andrea Tannapfel, Merle Schaffrin, Adrian Heinze and Rudolf Voigtmann. The first draft of the manuscript was written by Dörthe Schaffrin-Nabe and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval:This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Münster, Germany, Northrhine-Westfalia on April 15, 2024 under code 2016-011-f-s.

Consent to participate: Informed consent was obtained from all individual participants included in the study.

Consent to publish: The authors affirm that human research participants provided informed consent for publication of all fotos and figures.

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