Interventions for Preventing Chemotherapy-Induced Alopecia

A Systematic Review and Network Meta-analysis of Randomized Controlled Trials

Abstract

Background 

Chemotherapy-induced alopecia (CIA) is a common adverse effect among patients undergoing chemotherapy. Patients experiencing CIA suffer psychological distress and even refuse or discontinue chemotherapy. A variety of interventions have been applied to prevent CIA. However, the best intervention option remains unknown.

Objective 

To evaluate and determine the comparative effects of all available interventions for preventing CIA.

Methods 

A comprehensive literature search of four English and 3 Chinese electronic databases was performed to identify potential studies from database inception to August 2018. Two reviewers conducted data selection, data extraction, and risk of bias assessment independently. The consistency model was used to conduct a network meta-analysis based on a frequentist framework to evaluate the relative effects of different interventions. Rankings of interventions were evaluated by the surface under the cumulative ranking curve values.

Results 

Seventeen eligible trials including 1378 patients were included. Scalp cooling (odds ratio, 0.13; 95% confidence interval, 0.07–0.25) and scalp compression (odds ratio, 0.13; 95% confidence interval, 0.03–0.52) had significant effects relative to usual care. Ranking of efficacy indicated that scalp cooling was the most effective, followed by scalp compression with tourniquets, topical Chinese medicinal herbs, oral Chinese medicinal herbs, minoxidil, and usual care.

Conclusion 

The results of this study indicate that scalp cooling is the most effective method to prevent CIA during chemotherapy.

Implications for Practice 

Our results could provide a reference to prevent CIA. Updated studies with high quality, sufficient sample sizes, and direct comparison between interventions are needed in the future.

Chemotherapy-induced alopecia (CIA) is a common and highly distressing adverse effect among patients undergoing chemotherapy.¹ An estimated 65% of patients undergoing chemotherapy will experience CIA.² The occurrence and severity of CIA depend on the specific agent, the dose and duration of therapy, the route by which it is administered, and the response of the individual.³ Various cytotoxic drugs used in chemotherapy, including anthracycline antibiotics (doxorubicin, epirubicin), microtubule antagonists (paclitaxel, docetaxel), and alkylating agents (ifosfamide, cyclophosphamide, etoposide), may cause CIA.⁴ Chemotherapy-induced alopecia usually starts at 1 to 3 weeks after the first cycle of chemotherapy and continues throughout subsequent cycles.³

Although most patients suffering from CIA gradually recover within 6 to 8 weeks after chemotherapy ends, patients experiencing CIA suffer psychological distress, with negative consequences regarding body image, sexual behavior, and self-esteem and deterioration of social relationships.⁵ Some patients even refuse or discontinue chemotherapy because of the fear of hair loss and the associated distress.⁶ Approximately 50% of patients considered hair loss to be the most traumatic aspect of chemotherapy, and approximately 8% reported that they would decline chemotherapy because of this concern.^7,8

Over the past few decades, clinical professionals have applied a variety of methods to prevent CIA, including pharmacological and nonpharmacological interventions, such as scalp cooling, scalp compression with tourniquets, Chinese medicinal herbs (CMHs), and minoxidil.^9–11 Among these methods, the most widely used intervention is scalp cooling with a cooling device. Scalp cooling was first introduced in the 1970s and has shown significant benefits in preventing CIA.^12,13 Scalp compression is another early method and involves an inflatable tourniquet used to reduce the blood supply to the scalp during the time of peak plasma concentration of chemotherapeutics.⁹ The efficacy of scalp compression was demonstrated in 1979 and supported by some subsequent studies.¹⁴ Minoxidil is an effective and safe drug approved by the US Food and Drug Administration for the treatment of patterned alopecia; however, its effect on preventing CIA is still controversial.^15,16 In addition, CMHs, including CMH oral liquids and topical CMHs, have also been used for the prevention of CIA and have resulted in significant differences in CIA between the CMH groups and the control groups.^10,11

Several systematic review studies have examined the efficacy of scalp cooling for preventing CIA during chemotherapy,^9,17 but data from direct head-to-head comparisons of other interventions are lacking. Efficacy ranking of these interventions has not been performed. Traditional meta-analysis methods do not allow adequate assessment of the comparative effectiveness of all therapies. Network meta-analysis (NMA) is an evidence synthesis method that allows for simultaneous comparisons of the clinical effectiveness of all available interventions.¹⁸ Therefore, we performed this systematic review and NMA of all relevant randomized clinical trials (RCTs) to synthesize all available interventions for the prevention of CIA and compare the efficacy of the interventions. The results of this study provide evidence-based recommendations for preventing CIA.

Materials and Methods

We used an NMA approach to conduct a systematic review of RCTs, adhering to the Cochrane Handbook¹⁹ and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines for the NMA checklist.²⁰

Search Strategies

An initial limited search of PubMed and Web of Science was performed to identify relevant keywords that could be used in the comprehensive search. Then, a comprehensive search was conducted in 7 databases, namely, PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, China Biology Medicine, Chinese Journal of Full-text Database, and Chinese Science Periodical Database, from their inception to August 2018. To search all relevant studies, a combination of various key words was applied, including chemotherapy, cancer, neoplasm, tumor, carcinoma, alopecia, baldness, hair loss, clinical trial, and randomized. The search strategy for PubMed (MEDLINE) is (drug therapy[MeSH] or pharmacotherapy* or chemotherapy[MeSH] or chemotherapy-induced or chemotherapy-related or cancer or neoplasms[MeSH] or tumor* or carcinoma*) AND (alopecia[MeSH] or baldness or hair loss or chemotherapy-induced alopecia or CIA), with filters of Randomized Controlled Trial. Finally, references from reviews and included studies were further screened manually.

Inclusion and Exclusion Criteria

Randomized clinical trials that investigated the efficacy of any type of intervention for preventing CIA in patients receiving chemotherapy were eligible for review. The RCT inclusion criteria were as follows: (1) published in English or Chinese; (2) the study population was definitively diagnosed with cancer and was undergoing chemotherapy; (3) included at least one intervention for the prevention of CIA; and (4) the primary RCT outcome was the occurrence, level or severity of CIA during or after chemotherapy. Secondary outcomes included patient-reported comfort, wig use rate, anxiety, depression, body image, and quality of life. The RCT exclusion criteria were as follows: (1) the study included laboratory animals, (2) a duplicate publication, and (3) insufficient data for analysis, such as the criteria of CIA, the number of participants, or the number of patients with and without alopecia in the different groups.

Data Selection and Extraction

The titles and abstracts of all relevant studies were independently screened by 2 reviewers (T.Z. and S.H.). Full texts of potential studies were obtained and assessed according to the eligibility criteria. Any disagreement between the 2 reviewers was resolved by the third reviewer (W.X.). Data from the included studies were extracted by 1 reviewer (S.H.) and validated by the second reviewer (T.Z.) by using standardized data abstraction forms. The following data were extracted: name of first author, publication year, country, participants, intervention and control methods, baseline demographics, and clinical outcomes at follow-up.

Risk-of-Bias Assessment

The Cochrane Collaboration tool for assessing risk of bias was applied to assess the risk of bias of the included studies by 2 reviewers independently (T.Z. and S.H.).¹⁹ Seven domains are addressed in the tool, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. Bias was assessed as a judgment (high, unclear, or low) for individual domain. The overall risk of bias of the study was also summarized as high (high risk of bias for 1 or more key domains), unclear (unclear risk of bias for 1 or more key domains), or low risk of bias (low risk of bias for all key domains). Any disagreements between the 2 reviewers were resolved by a third reviewer (W.X.).

Data Analysis

The traditional meta-analysis was performed using Stata software 14.0 (StataCorp, College Station, Texas). A random-effects model was selected to calculate pooled effect sizes, which are presented as odds ratios (ORs) for dichotomous variables with 95% confidence intervals (CIs). Heterogeneity between studies was estimated by the I² statistic, with a value >50% indicating significant heterogeneity.

The NMA was also performed with Stata software 14.0 (StataCorp, College Station, TX, USA) by using the network family of commands.²¹ The implementation of the NMA was based on a frequentist framework. A consistency model was used to draw conclusions about the relative effects of different interventions. Direct and indirect evidence from any pair of interventions was combined to generate pooled effect sizes, presented as ORs for dichotomous variables with 95% CIs. The plot of a network consisted of nodes representing the interventions being compared and edges representing the available direct comparisons between pairs of interventions.²¹ The ranking probabilities for all included interventions were obtained by surface under the cumulative ranking curve (SUCRA) values and cumulative ranking plots.²² The SUCRA value indicates the cumulative probability that a treatment method is among the most efficacious interventions. Publication bias was assessed using a funnel plot.

Results

Literature Search and Study Selection

A total of 17 380 articles were identified from 7 databases. After excluding 6134 duplicate articles, 2 investigators (T.Z. and S.H.) independently reviewed the titles and abstracts and excluded an additional 11 107 articles. The full texts of the remaining 139 articles were reviewed, and another 123 articles were excluded. In addition, one study was added through a manual search of the bibliographies of the relevant articles. Finally, seventeen studies met the inclusion criteria and were eligible for review (Figure 1).

Figure 1: Flowchart of the search strategy and results.

General Characteristics of the Included Studies

Among the 17 studies, ten studies were conducted in China,^{10,11,23–30} 3 studies were conducted in the United States,^14,31,32 and the remaining studies were conducted in Argentina,¹⁶ Ireland,³³ Italy³⁴ and the United Kingdom.³⁵ Eleven studies were published between 2003 and 2017,^{10,11,23,25–31,35} with the remaining published before 2000.^{14,16,24,32–34} The participants included patients with breast cancer,^{10,11,16,23,25–27,30–32,34,35} lung cancer,^11,23,24,30 ovarian cancer,^11,30,32,34 colorectal cancer,^11,25,30 gastric cancer,^25,30,32 lymphoma,^11,32 liver cancer,³² esophageal cancer,³⁰ and one study focused on young children with cancer.²⁹ The total number of participants included in this review was 1378, with sample sizes ranging from 6 to 220.^14,24 Doxorubicin,^{11,16,24–27,29–35} docetaxel,^23,31,35 and platinum-based^11,26,30 drugs were the commonly used drugs (Table 1).

Table 1 - Characteristics of Trials Included in the Final Network Meta-analysis (n = 17)

Study	Country	Participants	Intervention Group	Control Group	Intervention Time	Outcome of Interests	Time of Outcome Measurement
Edelstyn et al, 197733	Ireland	Cancer patients receiving chemotherapy (doxorubicin) n = 77 n (treatment) = 40 n (control) = 37	Cryogel bag (−15°C) secured by a stockingnette bandage	Usual care	10 min before chemotherapy administration and until 30 min after the treatment ends	Hair loss—total, severe, slight, or none	Not clear
Giaccone et al, 198834	Italy	Cancer patients (most of them with breast cancer) receiving chemotherapy (doxorubicin) n = 39n (treatment) = 23 n (control) = 16	Hypothermia cap (−18°C) placed directly on the patient’s head	Usual care	10 min prior to, during, and 30 min after intravenous bolus injection of cytotoxic drugs	Hair loss: grade 0 (no hair loss); grade 1 (minimal hair loss <25%); grade 2 (moderate hair loss 25%–50%) or grade 3 (severe alopecia >50% requiring used of a wig)	Before each cycle of chemotherapy
Li et al, 200710	China	Cancer patients (breast cancer) receiving chemotherapy n = 60 n (treatment) = 30 n (control) = 30	External application of CMH	Usual care	2 d prior to each chemotherapy infusion, wice daily, last for 10 d	Hair loss: WHO scale for hair loss with slight modification (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss; complete hair loss)	At baseline; after every circle of chemotherapy; after 6 circles of chemotherapy
Li et al, 200923	China	Cancer patients (breast cancer, lung cancer) receiving chemotherapy (docetaxel) n = 100 n (treatment) = 50 n (control) = 50	Scalp hypothermia with cap	Usual care	60 min for each chemotherapy infusion (15 min before infusion, 30 min during infusion, 15 min after infusion)	Hair loss: WHO scale for hair loss (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss; complete hair loss) Patient-reported comfort: level of satisfaction	3–4 wk
Liu et al, 199524	China	Lung cancer patients receiving chemotherapy (adriamycin, cyclophosphamide) n = 220 n (treatment) = 110 n (control) = 110	scalp compression with tourniquets 6-cm-wide elastic band	Usual care	15–20 min prior to and during and 30 min after each chemotherapy infusion	Hair loss: minimal hair loss (about 30%), moderate (50%–70%), severe (>70%)	3–4 wk after chemotherapy
Lovejoy, 197914	the United States	Patients receiving chemotherapy (adriamycin) n = 6 n (treatment) = 3 n (control) = 3	Scalp compression with tourniquets scalp tourniquet inflated to a pressure of 50 mm Hg above systolic blood pressure	Usual care	Prior to, during, and for 15 min after chemotherapy	Hair loss: percentages of hair loss (accessed on scales marked in 5% intervals)	Approximately 3 wk after chemotherapy
MacDuff et al, 200335	the United Kingdom	Cancer patients (breast cancer) receiving chemotherapy (epirubicin and docetaxel) n = 30 n (treatment) = 16 n (control) = 14	Gel cooling cap Caps were previously cooled to −25°C. Replace caps for 4 times each during chemotherapy treatment	Usual care	15 min prior to, during, and 45 min after chemotherapy	Hair loss: WHO scale for hair loss with slight modification (no hair loss, Minimal hair loss, moderate hair loss, extensive hair loss; complete hair loss)	At baseline; 3–4 wk after chemotherapy
Nangia et al, 201731	the United States	Cancer patients (stage I or II breast cancer) receiving chemotherapy (doxorubicin, paclitaxel) n = 182 n (treatment) = 119 n (control) = 63	Orbis Paxman Hair Loss Prevention Scalp Cooling System	Usual care	30 min prior to and during and 90 min after each chemotherapy infusion	Hair loss: measured by CTCAE v4.0: grade 0 (no hair loss); grade 1 (<50% hair loss not requiring a wig); grade 2 (>50% hair loss, requiring use of a wig). Quality of life: assessed by EORTC QLQ-30 Anxiety and depression: evaluated by HADS Body image: measured by BIS Adverse device effects (discomfort, headache, forehead pain, dizziness, nausea) Patient-reported comfort: 5 levels	At baseline and after each cycle of chemotherapy
Rodriguez et al, 199416	Argentina	Female patients (breast carcinoma, soft-tissue sarcomas, and endometrial carcinoma) receiving chemotherapy(doxorubicin) n = 48 n (treatment) = 24 n (control) = 24	Minoxidil 2% topical solution	Placebo	twice a day starting 24 h before the first course of chemotherapy	Hair loss: grade 1 (no hair loss), grade 2 (minor hair loss not requiring the use of a wig), grade 3 (hair loss requiring the use of a wig)	before each cycle of therapy
Satterwhite et al, 198432	the United States	Cancer patients (breast, stomach, lung, liver, non-Hodgkin lymphoma, others) receiving chemotherapy (doxorubicin) n = 25 n (treatment) = 12 n (control) = 13	Scalp hypothermia with chemo cap	Usual care	15 min prior to chemo infusion, left in place during chemo and remained in place 60 min after chemo. Chemo cap was placed each time patient received chemo	Hair loss: minimal hair loss (<25%), moderate (<25%–50%), severe (>50%)	at baseline and after each the intervention (the patients were followed and treated until they either stopped receiving doxorubicin or had “severe” hair loss)
Shi et al, 200826	China	Cancer patients (breast cancer) receiving chemotherapy (CTF) n = 60 n (treatment) = 30 n (control) = 30	Scalp hypothermia with cap	Usual care	10–15 min prior to, during, and 50–60 min after each chemotherapy infusion	Hair loss: WHO scale hair loss with slight modification (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss; complete hair loss).	After 3 cycles of chemotherapy
Song et al, 200611	China	Cancer patients (lung cancer, breast cancer, lymphoma, colorectal cancer, Ovarian cancer) receiving chemotherapy n = 120 n (treatment) = 60 n (control) = 60	CMH oral liquids (sequential therapy of 2 comprehensive formula)	Usual care	Last for 2 cycles of chemotherapy	Hair loss- WHO scale for hair loss with slight modification (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss; complete hair loss).	After 2 cycles of chemotherapy
Sun et al, 201625	China	Cancer patients (breast cancer, gastric cancer, colon cancer) receiving chemotherapy n = 80 n (treatment) = 40 n (control) = 40	Scalp hypothermia with cap	Usual care	20 min prior to and during and 1–2 h after each chemotherapy infusion	Hair loss: WHO scale for hair loss with slight modification (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss; complete hair loss).	At baseline, 6–8 wk after the first time of chemotherapy
Xiao et al, 200928	China	Cancer patients receiving chemotherapy (anthracycline) n = 168 n (treatment) = 82 n (control) = 86	Scalp hypothermia with cap Keep scalp temperature at 21°C–27°C	Usual care	10 min prior to and during and 30 min after each chemotherapy infusion	Hair loss- WHO scale for hair loss (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss).	At baseline; After 3 wk
Xiao et al, 201327	China	Cancer patients (breast cancer) receiving chemotherapy n = 100 n (treatment) = 50 n (control) = 50	Scalp hypothermia with cap	Usual care	10 min prior to and during and 30 min after each chemotherapy infusion Total 2 mo	Hair loss-WHO scale for hair loss (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss).	At baseline; 2 mo
Yu et al, 200629	China	Young children with cancer receiving chemotherapy (adriamycin) n = 40 n (treatment) = 20 n (control) = 20	Scalp hypothermia with cap	Usual care	20 min prior to and during and 30 min after each chemotherapy infusion	Hair loss: WHO scale for hair loss (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss).	3–4 wk after the first time of chemotherapy
Zhu, 200730	China	Cancer patients (lung cancer, breast cancer, colorectal cancer, ovarian cancer, gastric cancer, esophagus cancer) receiving chemotherapy (CPA) n = 80 n (treatment) = 38 n (control) = 42	Scalp hypothermia with cap	Usual care	15–20 min prior to and during and 45–60 min after each chemotherapy infusion	Hair loss—WHO scale for hair loss with slight modification (no hair loss, minimal hair loss, moderate hair loss, extensive hair loss; complete hair loss)	At baseline, 3 mo

Abbreviations: BIS, Body Image Scale; CMH, Chinese medicinal herb; CPA, cyclophosphamide, cisplatin, adriamycin regimen; CTF, cyclophosphamide, pirarubicin, 5-fluorouracil regimen; CTCAE, Common Terminology Criteria for Adverse Events; EORTC QLQ-30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; WHO, World Health Organization.

Interventions Being Evaluated

Six interventions were evaluated, including scalp cooling in 12 studies,^23,25–35 scalp compression in 2 studies,^14,24 topical minoxidil in one study,¹⁶ CMHs in oral liquid form in one study,¹¹ topical CMHs in one study¹⁰ and usual care in 17 studies.^{10,11,14,16,23–35}

Scalp cooling Scalp cooling was performed by wearing an electrically cooled cap, cooling cap or ‘Cryogel’ bag. The cooling cap was fully refrigerated, reaching a temperature below 0°C before application, and applied to the scalp 10–30 min before chemotherapeutic agent administration until 0–120 min (mostly 30–60 min) after treatment. Most of the included articles did not describe the intervention time. During the scalp cooling process, the cooling bags were usually secured by a bandage.

Scalp compression Scalp ischemia was induced just prior to, during, and after chemotherapeutic agent injection by means of a tourniquet inflated above the systolic blood pressure level.¹⁴ Some researchers used head bands made from 6-cm wide elastic bands to ensure that the looseness was appropriate for the patients’ heads and did not cause numbness.²⁴

Minoxidil One study tested the efficacy of 2% topical minoxidil. Five milliliters of minoxidil 2% topical solution was applied twice daily starting 24 hours prior to the first chemotherapy cycle through the end of the study.¹⁶ Treatment was administered continuously until the occurrence of hair loss or of dose-limiting toxicity.

CMH oral liquids Patients in the treatment group received sequential therapy with 2 comprehensive CMH formulas every day.¹¹

Topical CMHs In the one efficacy study of the external application of CMHs, the intervention group applied a homemade herbal lotion at the roots of the hair twice per day starting 2 days before chemotherapy and lasting for 10 days.¹⁰

Treatment Comparisons

Most of the included studies were compared with usual care, which did not receive devices, drugs or guidance for preventing CIA. One was a placebo-controlled study.¹⁶

Risk-of-Bias Assessment

All the included trials were RCTs. Most of the included studies had a high or unclear risk of bias. The results of the risk of bias assessment are presented in Table 2. Five studies reported a low risk of bias for random sequence generation.^{16,26,31,32,35} Two studies reported a low risk of bias for allocation concealment.^31,32 All included studies were considered to have low risk of bias for blinding of participants and personnel. Four studies had a low risk of bias for blinding of outcome assessors.^14,16,31,35 Most of the included studies had a low risk of incomplete outcome data.^{10,11,14,16,23–33} One study was assessed as having low risk of bias for selective reporting because it was preregistered and provided the protocol link.³¹ Seven studies were assessed to have unclear risk of other bias due to small sample sizes or incomplete reporting.^{16,23,24,26,29,32,33}

Table 2 - Risk-of-Bias Assessment (n = 17)

Study	Random Sequence Generation	Allocation Concealment	Blinding of Participants and Personnel	Blinding of Outcome Assessment	Incomplete Outcome Data	Selective Reporting	Other Bias	Overall Risk of Biasa
Edelstyn et al, 197733	Unclear	Unclear	Low	Unclear	Low	Unclear	Unclear	Unclear
Giaccone et al, 198834	Unclear	Unclear	Low	Unclear	High	Unclear	Low	High
Li et al, 200710	Unclear	Unclear	Low	Unclear	Low	Unclear	Low	Unclear
Li et al, 200923	Unclear	Unclear	Low	Unclear	Low	Unclear	Unclear	Unclear
Liu et al, 199524	Unclear	Unclear	Low	Unclear	Low	Unclear	Unclear	Unclear
Lovejoy, 197914	Unclear	Unclear	Low	Low	Low	Unclear	Low	Unclear
MacDuff et al, 200335	Low	Unclear	Low	Low	High	Unclear	Low	High
Nangia et al, 201731	Low	Low	Low	Low	Low	Low	Low	Low
Rodriguez et al, 199416	Low	Unclear	Low	Low	Low	Unclear	Unclear	Unclear
Satterwhite et al, 198432	Low	Low	Low	Unclear	Low	Unclear	Unclear	Unclear
Shi et al, 200826	Low	Unclear	Low	Unclear	Low	Unclear	Unclear	Unclear
Song et al, 200611	Unclear	Unclear	Low	Unclear	Low	Unclear	Low	Unclear
Sun et al, 201625	Unclear	Unclear	Low	Unclear	Low	Unclear	Low	Unclear
Xiao et al, 200928	High	Unclear	Low	Unclear	Low	Unclear	Low	High
Xiao et al, 201327	Unclear	Unclear	Low	Unclear	Low	Unclear	Low	Unclear
Yu et al, 200629	Unclear	Unclear	Low	Unclear	Low	Unclear	Unclear	Unclear
Zhu, 200730	High	Unclear	Low	Unclear	Low	Unclear	Low	High

^aOverall risk of bias of the study.

High—high risk of bias for 1 or more key domains; unclear—unclear risk of bias for 1 or more key domains; low—low risk of bias for all key domains.

Intervention-Control Pairwise Meta-analyses

Seventeen studies (n = 1378) were included in the NMA. All articles reported the primary outcome of occurrence or severity of CIA. Due to the various durations of follow-up periods, we estimated the overall OR based on the data after the intervention. Compared with usual care, the pooled ORs (random-effects model) for the occurrence of CIA were estimated for scalp cooling (OR, 7.10; 95% CI, 4.93–10.23), scalp compression (OR, 7.19; 95% CI, 3.59–14.38), oral CMHs (OR, 2.25; 95% CI, 0.78–6.46), topical CMHs (OR, 7.76; 95% CI, 0.38–157.14), and minoxidil (OR, 1.57; 95% CI, 0.24–10.37). No RCTs reported direct comparisons among these interventions.

Results of NMA

Figure 2 shows the network geometry of the available interventions among the included studies. The sizes of the nodes represent each intervention plus a control. A large node size indicates a large number of participants included in each trial. The thickness of the lines connecting 2 nodes represents the number of studies. Usual care was the common comparator and had the largest sample size among the 6 treatment regimens.

Figure 2: Network plot of eligible comparisons.

The relative effects of the different treatments are presented in Figure 3. Scalp cooling (OR, 0.13; 95% CI, 0.07–0.25) and scalp compression (OR, 0.13; 95% CI, 0.03–0.52) had significant effects relative to usual care. There were no significant differences among the other comparators.

Figure 3: Network meta-analysis of chemotherapy-induced alopecia.

Figure 4 displays the distribution of probabilities for each treatment ranked by efficacy in preventing CIA according to the SUCRA values. On the horizontal axis is the possible rank of each treatment (from the first best rank to worse according to the outcome). On the vertical axis is the cumulative probability for each treatment to be the best option among these treatments. The overall ranking of treatments is estimated by the SUCRA. A high SUCRA value suggested a low probability of the occurrence of CIA. The ranking showed that scalp cooling (76.6%) had a higher probability of being more effective than scalp compression with tourniquets (74.5%), topical CMHs (68.1%), oral CMHs (38.3%), minoxidil (29.7%), and usual care (12.8%).

Figure 4: Surface under the cumulative ranking curve for the cumulative probabilities.

Publication Bias

The funnel plot (Figure 5) of the included articles showed asymmetry, which may have resulted from small-sample effects and heterogeneity between studies.

Figure 5: Funnel plot.

Secondary Outcomes

One study reported secondary outcomes including quality of life, body image perception, anxiety and depression.³¹ The changes in emotional functioning, social functioning, body image summary scores, and anxiety and depression summary scores were not different between the treatment and control groups. One study reported adverse events related to cooling.³¹ Fifty-four mild adverse events (grade 1 or 2), including chills, dizziness, headache, nausea, paresthesia, pruritus, sinus pain, skin and subcutaneous tissue disorders, skin ulceration, headache, scalp pain and dry skin, were reported in the cooling group. Two studies measured patient-reported comfort.^23,31 Most patients were comfortable while wearing the device; however, among these 2 studies, 1 participant withdrew because the device was too cold.^23,31

Discussion

Principal Findings

The result of the NMA of the 17 RCTs showed that scalp cooling was the most effective intervention, followed by scalp compression with tourniquets, topical CMHs, oral CMHs, minoxidil, and usual care. To our knowledge, this is the first NMA to compare and rank the efficacy of all available interventions for the prevention of CIA.

Methodological Quality of Included Trials

The risk of bias of the included studies was high or unclear. In a large portion of studies, the reporting of sequence generation, allocation concealment, and blinding of outcome assessment were unclear. In addition, the risk of selective reporting was high because almost all studies were not preregistered. With regard to heterogeneity, the cancer types and chemotherapy regimens varied. The method of cold therapy and the time and frequency of the intervention also differed. The measurement time and tools to assess the primary outcome were also inconsistent. All of these factors may decrease the overall methodological quality of the study.

Efficacy of Interventions

Scalp cooling was demonstrated to be one of the most effective interventions to prevent CIA. The efficacy of scalp cooling for CIA has been previously reported in numerous studies and systematic reviews.^9,13,17 The mechanism of scalp cooling for CIA can be explained by the fact that the cold temperature induces vasoconstriction and therefore limits the cellular uptake of cytotoxic agents, and the cold temperature reduces metabolic activity and therefore decreases the effect of chemotherapy on follicular cells.³⁶ Considering the high efficacy and low rate of adverse effects, patients undergoing chemotherapy with the following agents are the most suitable candidates for scalp cooling: cyclophosphamide, daunorubicin, docetaxel, doxorubicin, epirubicin, and paclitaxel.³⁷ However, the use of scalp cooling devices requires additional equipment fees, nurse work hours, and patient chair time.³⁸ Therefore, the feasibility of large-scale application should be evaluated in the future.

Scalp compression with tourniquets is one of the earliest proposed methods for preventing CIA. The external carotid artery is the source of blood supply to the scalp tissue and can be blocked by external pressure.⁹ In this study, scalp compression with tourniquets was also found to be an effective method for preventing CIA. However, there were only 2 relevant studies included in the analysis, and both of them were published several decades ago.^14,24 Additional updated studies are needed to confirm its effect.

Chinese medicinal herbs in oral liquid forms and topical CMHs are traditional methods in China to prevent or treat the adverse effects of chemotherapy.³⁹ Chinese medicinal herb oral liquids may alleviate chemotherapy-induced short-term adverse effects, improve the overall state of cancer patients’ well-being, and improve their ability to resist the disease.³⁹ The external application of CMHs may penetrate hair follicles, giving them nutrients that can protect against the damage caused by chemotherapy drugs. Some CMHs may help preserve hairs and make them easy to comb. In this NMA, the effect of oral CMHs and topical CMHs ranked third and fourth according to the SUCRA values, respectively. However, the number and quality of the included studies were very limited.

In mouse models, minoxidil modulates the hair cycle by prolonging the anagen stage.¹⁶ This study demonstrated a slight effect on CIA in cancer patients.¹⁶ However, the result was concluded from only 1 study.

Limitations

There were several limitations in this study. First, most of the included studies generally had a high or unclear risk of bias, which may lead to an underestimation or overestimation of the true effects of interventions and decrease the recommendation level of the results. Second, because of the lack of direct comparisons between interventions, it was difficult to verify the inconsistency assumptions. Therefore, additional updated studies with high quality, sufficient sample sizes, and direct comparisons between interventions are needed in the future.

Conclusion

The results of this study indicate that scalp cooling is the most effective method to prevent CIA during chemotherapy. Additional updated studies with high quality, sufficient sample sizes, and direct comparison between interventions are needed in the future. Our results could provide a reference to prevent CIA. Updated studies with high quality, sufficient sample sizes, and direct comparison between interventions are needed in the future.