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INTRODUCTION — Alopecia is a transient and usually (although not always) reversible consequence of cancer chemotherapy that can be psychologically devastating . For some patients, the emotional trauma may be so severe as to lead to refusing or delaying treatment that might otherwise be beneficial [2-8]. Recovery generally requires a period of several months to a year, amplifying the psychological impact of the disease and its treatment.
A general overview of the anatomy and physiology of hair growth, the effects of chemotherapy on the hair follicle, and possible means for preventing or minimizing chemotherapy-induced alopecia are discussed here.
ANATOMY AND PHYSIOLOGY — The hair shaft is a layered structure that consists of three major components. The medulla, the innermost layer, is surrounded by the cortex and cuticle. The hair fiber is the product of the hair follicle, which is composed of three main parts when viewed in longitudinal section (figure 1) :
●The lower portion, which extends from the base of the hair follicle to the insertion of the arrector pili muscle. This lower portion, in turn, is comprised of several major components:
•The hair bulb, which contains the dermal papilla and hair matrix. The dermal papilla controls the number of matrix cells, which determines hair fiber size . Melanocytes, which are responsible for hair color, are present among the matrix cells of the hair bulb.
•The hair itself, consisting of medulla, cortex, and hair cuticle (inside to outside).
•The inner root sheath, which consists of the inner root sheath cuticle, Huxley layer, and Henle layer (inside to outside). The inner root sheath is rigid, with its shape determining whether hair is curly or straight.
•The outer root sheath.
Damage to the lower portion of the hair follicle, as occurs in autoimmune alopecia areata, can result in a nonscarring alopecia. Immune-mediated alopecia areata can also be induced by immune checkpoint inhibitors that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) . (See "Evaluation and diagnosis of hair loss", section on 'Nonscarring alopecia' and "Clinical manifestations and diagnosis of alopecia areata", section on 'Autoimmunity' and "Toxicities associated with checkpoint inhibitor immunotherapy".)
●The middle portion (isthmus), which extends from the insertion of the arrector pili muscle to the entrance of the sebaceous duct. This portion contains the "bulge" of the hair follicle, where the epithelial stem cells reside . Damage to the bulge of the hair follicle results in irreversible scarring alopecia, as is seen clinically in disorders such as discoid lupus and lichen planopilaris.
●The upper portion (infundibulum), which extends from the entrance of the sebaceous duct to the follicular orifice.
Once formed, hair follicles undergo lifelong cycling characterized by periods of growth (anagen), regression (catagen), and rest (telogen), after which time the hair is shed (also known as exogen). Approximately 80 to 90 percent of follicles at any given time are in the active growth phase (anagen). During anagen, mitotically active matrix cells in the hair bulb differentiate and divide, resulting in a rate of hair growth of approximately 0.35 mm per day. Approximately 5 to 10 percent of follicles are in telogen (dormancy), during which all mitotic activity is arrested (figure 2). The remaining 1 to 3 percent are in catagen, the involution phase. (See "Evaluation and diagnosis of hair loss", section on 'Hair cycle'.)
The final step of the hair cycle, exogen, is when the hair is released from the follicle. The scalp is estimated to contain on average 100,000 hairs, of which 100 to 150 are lost daily as part of the normal hair cycle. This loss typically occurs after washing and brushing the hair, so patients who wash their hair less frequently may note a greater number of hairs falling out at each instance.
Multiple signaling molecules have been implicated in the initial development and subsequent cycling of the hair follicle, including Wnt, sonic hedgehog, notch, and bone morphogenic proteins, among others . In a mouse model of chemotherapy-induced alopecia, transient overexpression of sonic hedgehog accelerated hair follicle regrowth .
EFFECTS OF CHEMOTHERAPY
Pathophysiology — Cytotoxic chemotherapy attacks rapidly dividing cells in the body, including the dividing hair matrix cells . This can result in hair loss by either of two mechanisms (figure 3):
●If proliferation of the hair follicle matrix keratinocytes is severely inhibited, the hair may separate at the bulb and shed, a process referred to as anagen effluvium. Depending on the degree of toxicity on hair matrix keratinocytes, agents or schedules with lower toxicity will result in a dystrophic anagen effluvium, resulting in less alopecia and delayed hair regrowth; conversely, agents with greater toxicity will lead to severe alopecia but more rapid hair regrowth . (See "Evaluation and diagnosis of hair loss", section on 'Nonscarring alopecia'.)
●Thinning of the hair shaft can occur at the time of maximal chemotherapy effect, resulting in Pohl-Pinkus constrictions. As a result, the hair shaft may break at the follicular orifice during the resting phase of the hair cycle. (See "Evaluation and diagnosis of hair loss", section on 'Trichoscopy'.)
Reversibility of alopecia is related to the degree of damage to the hair follicle stem cells . Because chemotherapy effects are typically specific for proliferating cells, which reside in the bulb, sparing the quiescent stem cells in the bulge (figure 1) that are responsible for reinitiating follicle growth, hair loss from chemotherapy is usually, but not always, completely reversible. (See 'Recovery and reversibility' below.)
Clinical characteristics — The term alopecia refers to the partial or complete absence of hair from any area of the body where it normally grows. Chemotherapy-induced alopecia is most prominent on the scalp, with a predilection for areas with low total hair densities, in particular the crown and frontal areas of the scalp [16,17], where there is also slower hair recovery. Total scalp alopecia is most common, but hair loss can be diffuse or patchy.
Loss of eyebrows and eyelashes, as well as axillary and pubic hair, is variable, and may even occur after the last dose of chemotherapy has been administered. However, recovery is generally more rapid than on the scalp.
The timing of hair loss depends on the type(s) of chemotherapy agents, dose, and schedule. For most regimens that are given every two to three weeks, hair loss starts around two weeks and is completely lost by the end of the second cycle of chemotherapy. Weekly chemotherapy generally results in slower and occasionally incomplete hair loss, and hair may actually start to grow back with continuing treatment. High-dose chemotherapy used in the setting of hematopoietic cell transplantation leads to rapid and complete hair loss .
Some chemotherapy agents may cause prolonged or permanent alopecia, including docetaxel given at doses of 75 mg/m2 or higher per cycle, although the true incidence is unknown (see 'Recovery and reversibility' below). It is important to advise patients about this risk before starting treatment with a specific regimen, as treatment alternatives may be available if patients are bothered by the possibility of permanent alopecia [19-21].
Chemotherapy may have effects on the hair other than alopecia:
●Methotrexate and some targeted biologic agents may temporarily affect the follicle melanocytes, resulting in a depigmented band of hair (the so-called "flag sign") and, in some cases, general depigmentation. (See "Cutaneous side effects of conventional chemotherapy agents", section on 'Hair'.)
●Small molecule inhibitors and monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), BRAF, Bruton tyrosine kinase (BTK), Bcr/Abl, CTLA-4, programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1), and platelet-derived growth factor receptor (PDGFR)/vascular endothelial growth factor receptor (VEGFR) may result in hair curling and discoloration [11,22]. (See "Cutaneous complications of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Other reactions'.)
Quantitation — An alopecia grading scale for treatment-related alopecia is provided in National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 (table 1).
Risk factors — The ability of chemotherapy agents to cause hair loss depends upon the specific agent and the route, dose, and schedule of drug administration.
●Risk differs substantially between chemotherapy agents, with a number of agents causing little to no hair loss (table 3).
●High-dose, intermittent, intravenous chemotherapy regimens are associated with a high incidence of complete alopecia.
●Low-dose therapy, oral administration, and weekly intravenous regimens are less likely to induce total or complete alopecia [2,3]. As an example, every-three-week, high- or moderate-dose, intravenous cyclophosphamide almost universally causes alopecia, while oral cyclophosphamide-containing regimens are less likely to do so.
●Combination chemotherapy regimens (depending on the individual agents) are more likely to result in alopecia than single agents. Unfortunately, the incidence of alopecia with common regimens has been inconsistently documented in the literature. (See "Acute side effects of adjuvant chemotherapy for early-stage breast cancer".)
Concomitant factors that can affect the risk and phenotype of chemotherapy-induced alopecia include poor drug metabolism, exposure to scalp irradiation, older age, the presence of androgenetic alopecia, prior chemotherapy use, and the presence of graft versus host disease in those patients who have undergone hematopoietic cell transplantation [15,25,26]. In contrast, hair type, ethnicity, and race have not been associated with variations in either loss or regrowth. (See "Female pattern hair loss (androgenetic alopecia in women): Pathogenesis, clinical features, and diagnosis" and "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis".)
Agents with highest risk
Conventional cytotoxic agents — Of the commonly used single cytotoxic agents, those most likely to cause complete alopecia (dose and schedule dependent) include alkylating agents (cyclophosphamide, ifosfamide), antitumor antibiotics (dactinomycin, doxorubicin, idarubicin), antimicrotubule agents (paclitaxel, docetaxel, ixabepilone, eribulin), and topoisomerase inhibitors (etoposide, irinotecan) (table 3). Hair loss is less common or incomplete with bleomycin, epirubicin (especially <30 mg/m2), fluorouracil, gemcitabine, melphalan, methotrexate, mitomycin C, mitoxantrone, the platinums (oxaliplatin, cisplatin, and carboplatin), topotecan, and the vinca alkaloids.
Molecularly targeted agents — Small molecule inhibitors of the EGFR, as well as monoclonal antibodies targeting the EGFR, can induce a constellation of cutaneous symptoms, which include an acneiform rash, abnormal hair growth, pruritus, and dry skin; together, this symptom complex is referred to by the acronym PRIDE (papulopustules and/or paronychia, regulatory abnormalities of hair growth, itching, dryness due to EGFR inhibitors). (See "Cutaneous complications of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'EGFR inhibitors'.)
In addition, diffuse alopecia is described as a side effect of these drugs (4 percent with cetuximab). The alopecia is typically nonscarring and, therefore, reversible. However, at least two reports describe patients on long-term therapy who developed scarring alopecia [27,28]. Interestingly, mice with a targeted deletion in the EGFR gradually develop scarring alopecia .
Diffuse, reversible alopecia is also described in up to 50 percent of patients receiving treatment with the orally active, multitargeted tyrosine kinase inhibitor sorafenib [30-35] and in 65 percent of patients treated with vismodegib, an orally active agent approved for advanced basal cell cancer that inhibits sonic hedgehog signaling . Fifteen percent of patients treated with palbociclib, an orally active inhibitor of cyclin-dependent kinase (CDK) 4 and 6 that is used for treatment of advanced hormone receptor-positive breast cancer and is given in combination with hormone therapy, had mild alopecia beyond that seen with hormone therapy alone, while an additional 2 percent had diffuse hair loss . A similar degree of hair loss has been described with the related agent ribociclib . (See "Cutaneous complications of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Small molecule kinase inhibitors' and "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas", section on 'Vismodegib' and "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy", section on 'Aromatase inhibitors plus CDK 4/6 inhibitors'.)
Alopecia is also reported in up to 45 percent of patients treated with vemurafenib, an agent targeting the BRAF V600E mutation ; it is less common (approximately 22 percent) with dabrafenib, another BRAF inhibitor used for treatment of advanced melanoma. (See "Molecularly targeted therapy for metastatic melanoma".)
Recovery and reversibility — Because chemotherapy effects are typically specific for proliferating cells, which reside in the bulb, sparing the quiescent stem cells in the bulge that are responsible for reinitiating follicle growth, hair loss from chemotherapy is usually completely reversible. The hair follicle resumes normal cycling within a few weeks of treatment cessation, and visible regrowth becomes apparent within three to six months. The new hair frequently has different characteristics from the original; 65 percent of patients experience a graying, rejuvenating, curling, or straightening effect, which is likely due to differential effects of chemotherapy on hair follicle melanocytes and inner root sheath epithelia, and may resolve over time .
Permanent alopecia following chemotherapy is uncommon; most cases have followed the use of high-dose chemotherapy (usually busulfan and cyclophosphamide, thiotepa) and hematopoietic cell transplantation [42-46]. However, there is now convincing evidence of permanent or prolonged alopecia after standard-dose chemotherapy for breast cancer (particularly with docetaxel, which is dose and duration dependent [19,47,48]) and germ cell tumors [43,49]; and long-term use of small molecule EGFR inhibitors, such as gefitinib and erlotinib, can also cause permanent scarring alopecia (picture 1) [50-52]. (See 'Anatomy and physiology' above.)
The impact of hair loss and potential alternative chemotherapy approaches should be discussed with each patient before the initiation of therapy that may lead to alopecia. This preemptive approach is important for minimizing the emotional distress associated with hair loss. For patients with breast cancer who are receiving docetaxel at doses higher than 75 mg/m2 per infusion, it is important to advise patients about the risk of prolonged or permanent alopecia.
PREVENTION OF ALOPECIA — Therapeutic approaches include physically decreasing the amount of drug delivered to the dividing hair bulb by reducing scalp blood flow, and pharmacologic or biologic interventions to block the effects of the chemotherapy on the hair follicle.
Scalp hypothermia (scalp cooling) — For women with breast cancer who are receiving chemotherapy that is expected to result in significant alopecia and who place a high value on avoiding chemotherapy-induced alopecia, we suggest the use of a scalp hypothermia device. Two such automated devices, the DigniCap and Paxman scalp hypothermia systems, have been used extensively outside of the United States, and the DigniCap device is now also US Food and Drug Administration (FDA) cleared in the United States for this use. Manual caps are also available. (See 'Available devices and mechanism of benefit' below.)
Although the evidence base is less robust, scalp hypothermia could also be discussed as a potential option for patients with other solid tumors who are receiving chemotherapy that is expected to result in significant alopecia. Patients considering scalp hypothermia should be counseled on the variable success of scalp hypothermia. In particular, rates of success are highly variable, and overall, less than 50 percent of patients keep at least 50 percent of their hair when receiving anthracyclines. In addition, there is a financial burden from scalp hypothermia that should be discussed with each patient, as well as the side effects of feeling cold and having mild headaches. (See 'Efficacy and safety' below.)
We do not discuss the option of scalp hypothermia for patients with diseases associated with high levels of circulating tumor cells, such as leukemia and some types of lymphoma. Patients with solid tumors receiving continuous-infusion chemotherapy regimens over one day or longer that result in hair loss, and those undergoing cranial irradiation are also not good candidates for scalp hypothermia. Individuals with extreme sensitivity to cold or cold-induced migraines may not tolerate the cooling process. Scalp hypothermia is contraindicated in patients with cold agglutinin disease, cryoglobulinemia, and posttraumatic cold dystrophy  and should be used with caution in patients with liver dysfunction. (See 'Indications and contraindications' below.)
Available devices and mechanism of benefit — Two primary approaches to scalp hypothermia are currently available: automated systems that circulate coolant through cooling caps, and manual cooling with frozen cold caps that must be replaced with a new frozen cap as the cap warms (table 4). Automatic devices use a portable cooling unit that circulates a coolant in a flexible cap so that temperature is maintained within a narrow range. The current devices are able to cool two patients at the same time. Manual cooling involves insulated gel caps that are frozen in a cooler with dry ice or in a freezer (if available in the chemotherapy infusion center), fitted to the head, and then changed every 30 minutes as the temperature increases.
Regardless of the specific device that is used, cooling is started approximately 30 minutes before the chemotherapy infusion starts. Cooling is maintained for a period of time after the end of the chemotherapy infusion, generally between 90 and 120 minutes, although efficacy has been demonstrated with shorter post-cooling times [54,55]. Generally, an insulating cap is placed over the cold cap, and a protective covering is placed over the head between the scalp and cold cap.
Scalp hypothermia is thought to work by several mechanisms, including local vasoconstriction of blood vessels, resulting in reduced delivery of chemotherapy to the scalp, decreased follicle cell metabolic rate, and reduced cellular drug uptake [2,56-58].
The optimal scalp temperature for successful cooling is debated; although some suggest that a scalp temperature of less than 22ºC is required [53,59], others attribute therapeutic success to obtaining a subcutaneous scalp temperature below 15ºC . The type of cooling device determines the temperature, as manual caps are colder when initially applied to the scalp to account for their gradual increase in temperature before a new cap is applied.
Efficacy and safety — Scalp hypothermia has been used in more than 30 countries as a mechanism to prevent chemotherapy-induced alopecia, with variable success reported depending on the specific cooling device and type of chemotherapy [53,61]. In general, cooling has been overall less effective when used with combination anthracycline-containing chemotherapy regimens, although this is dependent on dose and schedule [25,26,62-65].
Results of many older studies are difficult to interpret secondary to the use of multiple cooling systems (ice turban, gel packs, cool caps, thermocirculator, room air conditioner), variable chemotherapy regimens (single versus combined agents), small study populations, retrospective evaluations, and varying definitions of alopecia [2,3,61,66,67]. Nevertheless, several older randomized trials reported significantly less hair loss with scalp hypothermia [62,68-70]. In general, between 50 and 80 percent of patients are reported to have a good to excellent response (defined variably as the degree of hair loss or not using a head covering) to scalp hypothermia [2,62,68-74]. A meta-analysis in 2015 concluded that scalp hypothermia was the only intervention that significantly reduced the risk of chemotherapy-induced alopecia (10 studies, including three randomized trials, relative risk 0.38, 95% CI 0.32-0.45) . No significant adverse events associated with scalp hypothermia were reported in the meta-analysis. Although subgroup analysis suggested a similar degree of efficacy for scalp hypothermia regardless of the underlying cancer, the majority of patients in the included trials had breast cancer, and most of the trials that included other patients did not provide the detailed diagnosis.
These benefits have been confirmed in two more recent prospective trials evaluating the efficacy of two different automated scalp hypothermia devices in women with early stage breast cancer [75,76]:
●In one multicenter, prospective cohort study, 101 patients receiving non-anthracycline taxane-based chemotherapy who used the DigniCap cooling device were compared with 16 concurrently treated controls who did not use the cooling device . Hair loss was measured using the Dean Scale, with success defined as hair loss of 50 percent or less (Dean score 0 to 2 (table 2)) one month after the last chemotherapy infusion, and was graded by the patients using photographs compared with baseline.
Hair loss was 50 percent or less in 66.3 percent of the intervention group compared with none of the control group (p<0.001). Three of five quality of life measures were significantly better one month after the end of chemotherapy, including perception of hair loss, feeling upset over hair loss, and feeling less physically attractive as a result of the disease or its treatment. The primary toxicity was mild headache, and three patients stopped cooling due to feeling cold. Preliminary results of this study led to FDA clearance of this scalp hypothermia device for patients with breast cancer in December of 2015. Approval was expanded to cover all solid tumors in July 2017 .
●The second trial randomly assigned 182 patients in a 2 to 1 ratio to use of the Paxman cooling device or no scalp hypothermia during chemotherapy for breast cancer; 36 percent received anthracycline-based chemotherapy, while the remainder received a taxane, either alone or combined with carboplatin, cyclophosphamide, pertuzumab, and/or trastuzumab . Successful hair preservation was defined as less than 50 percent hair loss not requiring a wig, using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria (grade 0 to 1 (table 1)), and was graded by a clinician unaware of treatment assignment at the end of four cycles of chemotherapy.
The initial report included 142 participants who were evaluable at the time of interim analysis. Scalp hypothermia was graded as successful in 50.5 percent of patients compared with none in the control group (p = 0.0061). Adverse events were all grade 1 and 2, including primarily headache and feeling cold. Interestingly, in this study, there were substantial differences in the success of cooling by site and by drug group. An exploratory post hoc analysis indicated that only 16 percent of patients receiving anthracycline-based chemotherapy met criteria for success, compared with 59 percent of those receiving taxanes, although the confidence intervals were very wide. Seven patients discontinued cooling early, primarily due to feeling cold. The Paxman device is currently under FDA review in the United States.
Scalp hypothermia using the DigniCap automated device is now available in a number of centers, and the manual caps are available to rent. Some infusion centers have freezers available to assist with freezing the caps. Manual caps have the disadvantage of needing to be refrozen (as well as being stored in a refrigerator in between freezing sessions), and the need for an additional person to change the cap every 30 minutes during and after chemotherapy.
Side effects of scalp hypothermia are generally mild and include patient discomfort from feeling cold, headache, nausea, dry skin, scalp thermal injury with manual caps, and claustrophobia [69,73,75,76,78-81]. It has been suggested that use of scalp hypothermia may result in faster regrowth of hair following the end of chemotherapy . Although this is not well documented, certainly retaining some hair at the end of chemotherapy could simply be associated with a shorter time to having "acceptable" hair growth.
Questions remain regarding the cost of scalp hypothermia devices and who will pay for these interventions. The cost of the devices varies depending on the duration of chemotherapy and the type of cooling device used, but the average total cost for scalp hypothermia is estimated to range between USD $1500 and $3000 per patient depending on the number of treatment cycles . In addition, there may be institutional costs associated with extra time in the chemotherapy infusion center and additional personnel costs. In the United States, scalp hypothermia is not yet covered by health insurance, creating financial concerns and variable costs for patients. One philanthropic organization provides some financial assistance to those who cannot afford scalp hypothermia (hairtostay.org), but it is hoped that insurance coverage will change in the near future with the availability of newer efficacy and safety data [83,84].
Indications and contraindications — Scalp hypothermia has been used successfully in patients with a variety of solid tumors receiving potentially curative chemotherapy regimens that are associated with a high risk of complete alopecia, including breast, ovarian, and prostate cancers. In addition, patients with advanced cancer for whom hair loss represents an unacceptable toxicity from palliative chemotherapy that may significantly prolong life and quality of life may be offered the option of scalp hypothermia. However, the evidence for benefit is most robust in patients treated for breast cancer.
In terms of chemotherapy regimens, the success of scalp hypothermia is variable, particularly in patients receiving an anthracycline-based combination; overall, less than 50 percent of patients receiving anthracyclines in combination keep at least 50 percent of their hair. However, this may be acceptable to some patients, and the success may be very good in a minority.
The mechanism underlying the benefit of scalp hypothermia at least in part involves reduced delivery of chemotherapy to the scalp. (See 'Available devices and mechanism of benefit' above.)
Previously, some investigators have raised concerns regarding the possibility of scalp metastasis in association with scalp hypothermia [2,3,56,57,68,70,78,85,86]. The incidence of scalp metastases with use of scalp hypothermia devices has been best studied in breast cancer, where the risk of scalp metastases is very low, and these are often discovered either along with or following a diagnosis of systemic disease. As an example, in one study of 61 patients with disseminated breast cancer receiving chemotherapy using a cooling cap, one patient with underlying liver dysfunction developed cutaneous scalp metastasis . However, larger studies evaluating patients using scalp hypothermia during chemotherapy for early stage breast cancer have shown no association between use of a cooling device and the subsequent development of scalp metastases, and one large study showed no impact of scalp hypothermia on survival [86-88]. In one review, the incidence of scalp skin metastases in breast cancer patients was comparable for scalp-cooled (0.04 to 1 percent) and non-scalp-cooled patients (0.03 to 3 percent) . A systematic review and meta-analysis evaluated 1959 patients using scalp cooling devices over an estimated mean time frame of 43.1 months and 1238 patients who did not use a scalp cooling device over an estimated mean time frame of 87.4 months . The incidence rate of scalp metastasis in the scalp cooling group versus the no scalp cooling group was 0.61 (95% CI 0.32-1.1 percent) versus 0.41 percent (95% CI 0.13-0.94 percent); p = 0.43. In the DigniCap study described above, no patient has developed scalp metastases at a median follow-up of 2.5 years .
We do not recommend scalp hypothermia for patients with diseases associated with high levels of circulating tumor cells, such as leukemia and some types of lymphoma. One group reported the outcome of a patient with mycosis fungoides who used a cooling cap to prevent alopecia . Following chemotherapy, he developed recurrent disease limited to the scalp. Subsequent treatment without a cooling device resulted in complete clinical remission. Although mycosis fungoides is a disease that is primarily manifested in skin, there remains concern about treating patients with diseases associated with high levels of circulating tumor cells, such as leukemia and some types of lymphoma . In addition, these diseases are usually treated with high doses of chemotherapy, where scalp hypothermia is unlikely to be effective.
Patients with solid tumors receiving continuous-infusion chemotherapy regimens over one day or longer that result in hair loss are also not good candidates for scalp hypothermia.
Finally, it does not appear that scalp hypothermia can prevent radiation-induced hair loss, and these patients are not good candidates .
Scalp hypothermia is contraindicated in patients with cold agglutinin disease, cryoglobulinemia, and posttraumatic cold dystrophy  and should be used with caution due to reported poorer efficacy in patients with liver dysfunction [2,3,56,58,66,70,78]. This is likely related to delayed drug metabolism, thereby allowing persistence of therapeutic drug levels beyond the protective period. In addition, patients should be screened for other causes of hair loss, such as hypothyroidism. Those with extreme sensitivity to cold or cold-induced migraines may not tolerate the cooling process.
Pharmacologic interventions — Preliminary studies, mainly conducted in animal models, have suggested that a variety of both small molecules and biologic agents may reduce or prevent alopecia by protecting the hair bulb from the damaging effects of chemotherapy. The only interventions tested in human beings are topical treatment with bimatoprost, topical minoxidil, and calcitriol. However, to date, there are no specific pharmacologic interventions that have demonstrated consistent enough activity in randomized trials to justify their general use to prevent chemotherapy-induced alopecia.
Topical bimatoprost — Topical bimatoprost 0.03 percent, a prostaglandin analog, has been used successfully on the upper eyelid margin to enhance eyelash growth in patients with eyelash alopecia. (See "Management of alopecia areata", section on 'Eyelash alopecia'.)
Benefit for patients with chemotherapy-induced eyelid alopecia was suggested in a randomized controlled trial in 130 patients with idiopathic or chemotherapy-induced alopecia . Eligible patients had completed chemotherapy within 4 to 16 weeks with documented eyelash alopecia, and applied one drop to the upper eyelid margin of each eye once daily. The primary endpoint of at least a one‐grade improvement in investigator‐assessed Global Eyelash Assessment (GEA) and at least a three‐point improvement in patient‐reported Eyelash Satisfaction Questionnaire (ESQ) domain 2 at month 4 was met in the chemotherapy group (37.5 percent for bimatoprost versus 18.2 percent for vehicle), and benefits were more pronounced at month 12.
While topical bimatoprost could be considered for the treatment of chemotherapy-induced eyelash alopecia in patients who are bothered by this temporary side effect, there are no data supporting a preventive benefit or risk from use.
Topical minoxidil — Minoxidil is thought to modify the hair cycle by prolonging the anagen phase. It may also increase hair follicle size, thereby counteracting miniaturization of the hair follicle, which is the characteristic histologic finding of androgenetic alopecia. Minoxidil has been used for the treatment of androgenetic alopecia and as a second-line therapy for alopecia areata. (See "Androgenetic alopecia in men: Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis' and "Female pattern hair loss (androgenetic alopecia in women): Pathogenesis, clinical features, and diagnosis" and "Female pattern hair loss (androgenetic alopecia in women): Treatment and prognosis" and "Treatment of androgenetic alopecia in men" and "Management of alopecia areata", section on 'Minoxidil'.)
Two randomized trials suggest that the effects of minoxidil in preventing or treating chemotherapy-induced alopecia are, at best, very limited:
●In a randomized trial of 48 patients with varying solid tumors receiving doxorubicin-containing regimens, topical minoxidil (2 percent solution applied twice daily) did not prevent the development of severe alopecia compared with placebo .
●A second trial in 22 women receiving chemotherapy after surgery for breast cancer also found that treatment with topical minoxidil did not prevent alopecia, but it did shorten the time to maximal regrowth and the time from maximal hair loss to first regrowth, and lengthen the time to maximal hair loss .
Topical calcitriol — Pretreatment with topical calcitriol (1,25(OH)2D3; the most active metabolite of vitamin D) protects rats from cyclophosphamide-, etoposide-, and doxorubicin-induced alopecia . Effects may be mediated by direct biological activity or modulation of other factors. Specific receptors for calcitriol are present in rat, murine, and human skin cells, and calcitriol induces differentiation of murine epidermal keratinocytes. When human cultured keratinocytes are incubated with calcitriol, there is a dose- and time-dependent stimulation of differentiation and inhibition of DNA synthesis.
One study found that pretreatment with calcitriol did not alter the cytotoxic effects of the chemotherapy but did prevent significant alopecia . However, a phase I trial of 12 patients receiving anthracycline- and cyclophosphamide-containing chemotherapy for breast cancer failed to demonstrate any benefit in preventing chemotherapy-induced alopecia . Furthermore, concerns about potential protection of the cancer cells from the effects of chemotherapy have been raised [94,95,97].
Experimental approaches — Several experimental treatments have demonstrated efficacy in animal models.
●Alpha tocopherol – Alpha tocopherol was initially reported to reduce the incidence of alopecia in a study of patients given high doses of alpha tocopherol (1600 international units daily) for cardioprotection during doxorubicin therapy . Subsequently, two prospective studies were unable to replicate this observation [99,100]. In one trial of 25 female patients with breast cancer, there was no difference in significant alopecia between controls and a study group that received alpha tocopherol (1600 international units daily for seven days prior to therapy) . In the second report, 18 of 20 women with solid tumors receiving various doxorubicin-containing regimens developed significant alopecia despite seven days of pretreatment with high-dose alpha tocopherol .
●Inhibitors of cyclin-dependent kinases – Inhibitors of cyclin-dependent kinase 2 (CDK2), a regulator of cell cycle progression, may reduce the sensitivity of the hair follicle epithelium to cell cycle active cytotoxic agents. In one preclinical report, topical application of small molecule inhibitors of CDK2 reduced chemotherapy-related hair loss in rats by 33 to 50 percent .
●Inhibitors of p53 – Mice deficient for p53 expression do not develop chemotherapy-induced alopecia . The mechanism for protection is thought to be inhibition of hair follicle apoptosis, due to down-regulation of Fas expression and increased expression of Bcl-2. This observation suggests that local pharmacologic inhibition of p53 might be useful to prevent chemotherapy-associated hair loss. However, to date, no therapeutic trials of any strategy have been reported.
●EGF, FGF, and keratinocyte growth factor – There have been several studies evaluating the efficacy of epidermal growth factor (EGF) and fibroblast growth factor (FGF) in preventing hair loss in animal models . Systemically administered EGF protected rats from cytarabine-induced but not cyclophosphamide-induced alopecia, while topical application of EGF prevented alopecia at the site of administration only. Injectable FGF prevented hair loss at the local injection site. The biological mechanism of this action is unclear as epidermal growth factor receptor (EGFR) inhibition with cetuximab has been associated with both alopecia and trichomegaly (picture 2) . Conversely, the combined use of EGFR inhibitors with cytotoxic agents results in less alopecia, likely due to a slowing down of hair matrix proliferation and a decreased sensitivity to chemotherapy .
●Topical cyclosporine – Selected immunophilin ligands, such as cyclosporine A (CsA) and FK 506, are not only potent immunosuppressants, but they also modulate hair growth. In murine models, topical application of CsA and FK 506 induced hair growth and inhibited cyclophosphamide-induced hair loss [107,108]. In another in vivo model, topical CsA protected rat models from site-specific alopecia when coadministered with etoposide, cyclophosphamide, cytarabine, and doxorubicin .
The mechanism of this benefit is unknown. Drugs that act at the hair bulb are assumed to protect the hair follicle keratinocytes against the effects of chemotherapy, possibly through the expression of p-glycoprotein. Topical cyclosporine has been studied in rat models and has been found to inhibit p-glycoprotein and protect the animals from local alopecia induced by a variety of agents . Cyclosporine also increases interleukin-1 (IL-1) receptor expression , which may further enhance its ability to prevent alopecia.
●IL-1 – IL-1 mediates a variety of activities involved in host defense and disease processes. Mononuclear phagocytes, keratinocytes, glial cells, and endothelial cells are all known to produce IL-1 . Dermal and epidermal cells possess IL-1 receptors and are capable of secreting the cytokines thought to play a role in inflammation in the skin.
Administration of IL-1 protects against the alopecia related to chemotherapy and radiation therapy in animals [111-113]. In one study, 48 rats were randomly assigned into four groups that received either cyclophosphamide or cytarabine, with or without IL-1 . The rats treated with cytarabine, a cell cycle-specific agent, were protected against significant alopecia by the addition of IL-1. However, the rats who received cell cycle-nonspecific chemotherapeutic agents were not protected. These results led to the hypothesis that cell cycle-specific and cell cycle-nonspecific agents induce alopecia via different mechanisms.
These data suggest that IL-1 functions at the level of the hair follicle to protect against alopecia. However, evidence is lacking as to whether IL-1 directly or indirectly stimulates the cytokines involved in hair follicle growth [111,112].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hair loss from cancer treatment (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Hair loss is a transient and usually (although not always) completely reversible consequence of cancer chemotherapy that can be psychologically devastating. A wide range of chemotherapy agents can affect the growing cells of the hair follicle. The frequency and severity of alopecia varies depending upon the specific chemotherapy agent or combination regimen administered (table 3), the dose of the drugs, and the treatment schedule. The majority of chemotherapy-induced alopecia is reversible once therapy is discontinued, with the possible exception of some molecularly targeted therapies. (See 'Effects of chemotherapy' above.)
●Hair loss is generally most prominent on the scalp, and there is a predilection for areas that show low total hair densities, in particular the crown and vertex. All patients who will receive chemotherapy that may result in alopecia should be informed of the side effect of hair loss. Options such as head wraps, hats, or wigs should be discussed in advance so that the patient can be more physically and emotionally prepared. For patients who are receiving docetaxel at doses higher than 75 mg/m2 per dose, it is important to advise patients about the risk of prolonged or permanent alopecia. (See 'Clinical characteristics' above and 'Recovery and reversibility' above.)
●Scalp hypothermia minimizes delivery of chemotherapeutic agents to the scalp and reduces metabolism of the hair follicle cell, thereby decreasing the risk of hair loss. Prospective studies in breast cancer confirm that several devices can reduce or prevent hair loss in a majority of patients receiving taxane-based chemotherapy, with lower success rates seen in those receiving anthracycline-based regimens. Although previous concerns arose regarding the potential risk of scalp metastases, newer studies and a review of all available published data have failed to substantiate this concern. (See 'Scalp hypothermia (scalp cooling)' above.)
For women with breast cancer who are receiving chemotherapy that is expected to result in significant alopecia and who place a high value on avoiding chemotherapy-induced alopecia, we suggest the use of a scalp hypothermia device (Grade 2A). Two such automated devices, the DigniCap and Paxman scalp hypothermia systems, have been used extensively outside of the United States, and the DigniCap device is now also US Food and Drug Administration (FDA) cleared in the United States for this use. Manual caps are also available. (See 'Available devices and mechanism of benefit' above.)
Although the evidence base is less robust, scalp hypothermia could also be discussed as a potential option for patients with other solid tumors who are receiving chemotherapy that is expected to result in significant alopecia. Patients considering scalp hypothermia should be counseled on the variable success of this approach. In particular, rates of success in patients receiving anthracycline-based combination therapy are highly variable, and overall, less than 50 percent of patients keep at least 50 percent of their hair. In addition, there is a financial burden from scalp hypothermia that should be discussed with each patient, as well as the side effects of feeling cold and having mild headaches. (See 'Efficacy and safety' above.)
We do not discuss the option of scalp hypothermia for patients with diseases associated with high levels of circulating tumor cells, such as leukemia and some types of lymphoma. Patients with solid tumors receiving continuous infusion chemotherapy regimens over one day or longer that result in hair loss, and those undergoing cranial irradiation are also not good candidates for scalp hypothermia. Individuals with extreme sensitivity to cold or cold-induced migraines are also not ideal candidates. Scalp hypothermia is contraindicated in patients with cold agglutinin disease, cryoglobulinemia, and posttraumatic cold dystrophy and should be used with caution in patients with liver dysfunction. (See 'Indications and contraindications' above.)
●Preliminary studies suggest that a variety of both small molecules and biologic agents may reduce or prevent alopecia by protecting the hair bulb from the damaging effects of chemotherapy. However, to date, there are no specific pharmacologic interventions that have demonstrated consistent enough activity in randomized trials in humans to justify their general use to prevent chemotherapy-induced alopecia. (See 'Pharmacologic interventions' above.)
While topical bimatoprost could be considered for the treatment of chemotherapy-induced eyelash alopecia in patients who are bothered by this temporary side effect, there are no data supporting a preventive benefit and no data to suggest there is risk associated with use. (See 'Topical bimatoprost' above.)
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