The use of a scalp hypothermia device that has been approved by the United
States (U.S.) Food and Drug Administration (FDA) for the prevention of
chemotherapy-induced alopecia (CIA) shall be considered reasonable and
necessary for patients with solid tumors.

The device is contraindicated for pediatric patients, patients with certain
cancers and patients undergoing specific chemotherapy treatments. Usage of the
device is contraindicated in:

  * Central nervous system malignancies (either primary or metastatic)
  * Squamous cell carcinoma and small cell carcinoma of the lung
  * Skin cancers including melanoma, squamous cell carcinoma, and Merkel cell carcinoma
  * Patients who are scheduled for bone marrow ablation chemotherapy
  * Patients who are scheduled to undergo skull irradiation or have previously received skull irradiation
  * Patients with a history of scalp metastases, or in whom scalp metastases are suspected
  * Patients with cold sensitivity, cold agglutinin disease, cryoglobulinemia, cryofibrinogenemia, and post-traumatic cold dystrophy
  * Patients with severe liver or renal disease from any etiology who may not be able to metabolize or clear the metabolites of the chemotherapeutic agent
  * Patients with hematologic malignancies (leukemia, non-Hodgkin and other generalized lymphomas)

CIA is a common and well-known side effect of chemotherapy, affecting
approximately 65% of patients who undergo chemotherapy for cancer. Total scalp
alopecia is most common, but alopecia can also be diffuse or patchy. CIA is
most prominent on the scalp, with a predilection for areas with low total hair
density, in particular the crown and frontal areas of the scalp, where there
is slower hair recovery. CIA is attributed to the cytotoxic effects of
chemotherapy drugs on the matrix cells of the hair follicles during hair
growth phases.1,2 Alopecia is usually, although not always, reversible but can
be psychologically and socially devastating. CIA has been cited as the most
disturbing anticipated side effect by up to 58% of women preparing for
chemotherapy, with 8% being at risk for avoiding treatment altogether due to
those fears. CIA has been associated with reduced quality of life (QOL),
depression, and poor body image, which may endure for months after
chemotherapy is completed.3 A prospective, multi-center study was performed in
13 hospitals to look at the effects of CIA on QOL and associated distress.4
Breast cancer patients treated with (N=98) and without (N=168) scalp cooling
completed questionnaires before chemotherapy, and 3 weeks and 6 months after
the last chemotherapy cycle. Scalp cooling was effective in 52% of the cases.
Alopecia was considered among the most distressing problems at all 3 moments
of measurement. A trend towards higher well-being was found in successfully
scalp-cooled patients, as indicated by a general better health-related QOL and
better body image, whereas unsuccessfully scalp-cooled patients reported
lowest well-being. Recovery generally requires a period of several months to a
year, worsening the impact of the disease.

The timing of alopecia depends on the type(s) of systemic therapy agent, dose,
and schedule.5 For most regimens that are given every 2 to 3 weeks, alopecia
starts around 2 to 3 weeks, and hair is completely lost by the end of the
second cycle of chemotherapy. High-dose, intermittent, intravenous (IV)
chemotherapy regimens are associated with a high incidence of  grade 2
alopecia. Weekly chemotherapy generally results in slower and occasionally
incomplete alopecia, and hair may start to grow back during treatment. Of the
commonly used IV single cytotoxic agents, those most likely to cause complete
alopecia (dose and schedule dependent) include alkylating agents
(cyclophosphamide, ifosfamide, busulfan, thiotepa), antitumor antibiotics
(dactinomycin, doxorubicin, epirubicin, idarubicin), antimicrotubule agents
(paclitaxel, docetaxel, ixabepilone, eribulin), and topoisomerase inhibitors
(etoposide, irinotecan).6 Alopecia is less common or incomplete with
bleomycin, low-dose epirubicin or doxorubicin (especially < 30 mg/m2), oral
cyclophosphamide, fluorouracil, gemcitabine, melphalan, methotrexate,
mitomycin, mitoxantrone, platinum agents (oxaliplatin, cisplatin, and
carboplatin), topotecan, and vinca alkaloids. Antibody-drug conjugates are
also associated with variable hair loss (HL), which is agent specific. In
addition, diffuse or partial alopecia may occur with a number of targeted
agents. A new class of targeted agents, termed cyclin-dependent kinase (CDK)
4/6 inhibitors, has demonstrated marked efficacy in combination with endocrine
therapy in patients with metastatic hormone receptor-positive breast cancer.
Three agents have FDA-approval: palbociclib, ribociclib, and abemaciclib.
Given in combination with aromatase inhibitors, these agents increase all-
grade and grade 2 alopecia compared with that observed with endocrine therapy
alone. There is approximately a doubling of all-grade alopecia, from 10-16% to
25-33%, and approximately a 1.5% increased incidence of grade 2 alopecia.7

Hair regrowth generally begins by 6 months after the last chemotherapy
session; however, HL may be permanent in some patients.8,9 Regrowth to a
normal appearance can take up to 1 year. The new hair frequently has different
characteristics from the original; 65% of patients experience a graying,
curling, or straightening effect, which is likely due to differential effects
of chemotherapy on hair follicle melanocytes and inner root sheath epithelia,
and these effects often resolve over time. Once CIA occurs, treatment to
regrow scalp hair may include topical minoxidil. Minoxidil prolongs the anagen
phase and may increase hair follicle size counteracting miniaturization of
follicle by androgenic alopecia. Two randomized trials suggest that the
effects of topical minoxidil in preventing or treating CIA are limited, at
best. In a randomized trial of 48 patients with varying solid tumors receiving
doxorubicin-containing regimens, topical minoxidil (2% solution applied twice
daily) did not prevent the development of severe alopecia compared with
placebo.10 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 alopecia to first regrowth, and lengthened the time to maximal
alopecia.11

Although permanent alopecia is uncommon after standard-dose chemotherapy,
there is now convincing evidence of permanent or prolonged alopecia after
standard-dose chemotherapy for breast cancer (particularly with docetaxel and
clearly related to both dose per infusion and duration of exposure).8

HL is quantifiable via various rating systems. Most commonly used is the
Modified Dean's Alopecia Scale for Hair Loss, which has multiple grades
stratified by percentage of HL12: grade 0: no HL, grade 1: > 0% to  25% HL,
grade 2: > 25% to  50% HL, grade 3: > 50% to  75% HL, and grade 4: > 75% HL.
Also utilized is the World Health Organization (WHO) Criteria guidelines for
determining degree of alopecia: degree 1: no significant HL, degree 2: minor
HL, degree 3: severe HL, and degree 4: total alopecia.13

The mechanism of action of scalp hypothermia includes local vasoconstriction
of blood vessels, resulting in reduced delivery of chemotherapy to the scalp,
decreased follicle cell metabolic rate, and reduced cellular drug uptake.
Older studies employ ice packs secured to the scalp with bandages, or ice
packs fashioned into caps that fit over the scalp. Commercially available
precooled nonautomated caps include PenguinTM Cold Caps and Chemo Cold CapsTM
(Chemotherapy Cold Caps Inc.). These older technologies can be heavy to wear,
require replacement approximately every 20 minutes per treatment session due
to thawing, and have been associated with cold thermal burns (e.g.,
frostbite).1 These caps are not subject to FDA regulation or prescription, and
patients can rent them directly from the manufacturers and take the caps to
their chemotherapy sessions.

The National Comprehensive Cancer Network (NCCN) has updated the Clinical
Practice Guidelines in oncology for breast cancer (Version 1.2019) to include
scalp cooling as a Category 2A recommendation to reduce the incidence of CIA
for patients receiving chemotherapy.14 Newer technologies for scalp cooling
systems are self-contained, with built-in temperature sensors that cool and
circulate a glycol-based fluid through channels in a cap, allowing for
continuous, uninterrupted cooling throughout the treatment session.15 These
have purported advantages of greater ease of use for clinical personnel and
greater comfort for patients. In December 2015, the FDA cleared the DigniCap
Scalp Cooling System (Dignitana AB, Sweden) for marketing, and the Orbis from
Paxman Coolers Ltd. received clearance in 2017.1 Automated caps include the
DigniCap (Dignitana Inc.) and Paxman Scalp Cooling System (Paxman Coolers
Ltd.). According to its FDA summary, the DigniCap computer-controlled system
is touchscreen operated and circulates liquid coolant between a tank that
refrigerates the coolant and the DigniCap, a silicone cap with separate
cooling circuits for the front and back of the head. The cap and tank
temperature are computer-controlled and automatically regulated. During
treatment, a neoprene cap fits over the DigniCap to insulate it and keep it
in place. Coolant can be chilled to -15C to 5C. A new device from Dignitana
("Delta") provides a cap that can be shaped to the individual head (similar to
the design of the frozen PenguinTM cap, but with an automated circulating
coolant).16 According to its FDA summary, the Paxman system is substantially
equivalent to the DigniCap System. Paxman provides an additional extra-small
size cap in addition to small, medium, and large. Each patient has a personal
scalp cooling cap, and the systems are designed to treat 1 or 2 patients at a
time. A pay-for-use token is scanned at the beginning of the cooling
session.17

Regardless of the specific device that is used, cooling is started
approximately 30 minutes before the chemotherapy infusion starts in order to
allow gradual cooling of the scalp to the desired temperature. Cooling is
maintained for a period of time after the end of the chemotherapy infusion,
generally at least 90 minutes and as long as 3 to 4 hours in some cases.18,19
The duration of post-infusion cooling is determined at least in part by the
clearance of high levels of chemotherapy, but also by the severity of the
expected alopecia.

The optimal scalp temperature for successful cooling is thought to be 22C,
although data regarding this specific number is quite limited, and it is
difficult to accurately measure. Indeed, others attribute therapeutic success
to obtaining a subcutaneous scalp temperature below 15C. However, the caps
themselves must be much colder in order to bring the scalp to the desired
temperature. The type of cooling device determines the temperature, as manual
caps must be much colder when initially applied to the scalp to account for
their gradual increase in temperature before a new cap is applied. The
automated units are usually set around 0C. There is currently no consensus in
the literature with regard to the best cooling device, duration and frequency
of application, or temperature of cooling.18,20

Contraindications18 to scalp cooling appear to be nonspecific to a particular
device. The use of a cooling cap is contraindicated in all children, and in
adults with:

  * Central nervous system malignancies (either primary or metastatic)
  * Squamous cell carcinoma and small cell carcinoma of the lung
  * Skin cancers including melanoma, squamous cell carcinoma, and Merkel cell carcinoma
  * Patients who are scheduled for bone marrow ablation chemotherapy
  * Patients who are scheduled to undergo skull irradiation or have previously received skull irradiation
  * Patients with a history of scalp metastases, or in whom scalp metastases are suspected
  * Patients with cold sensitivity, cold agglutinin disease, cryoglobulinemia, cryofibrinogenemia, and post-traumatic cold dystrophy
  * Patients with severe liver or renal disease from any etiology who may not be able to metabolize or clear the metabolites of the chemotherapeutic agent
  * Patients with hematologic malignancies (leukemia, non-Hodgkin and other generalized lymphomas)

Ultimately, the primary measure of scalp cooling's efficacy is whether it
prevents HL, as compared with controls. Additional considerations are if hair
regrowth also occurs more rapidly in those that do lose hair, compared to no
scalp cooling. Both the benefits of and minimal-to-modest adverse events (AEs)
from scalp cooling have been confirmed in 3 prospective trials evaluating the
efficacy of 2 scalp hypothermia devices in women with early-stage breast
cancer.

A prospective cohort study was conducted between August 2013 and October 2014,
with ongoing annual follow-up for 5 years, at 5 U.S. medical centers. One
hundred one women with stage I or II breast cancer receiving adjuvant or
neoadjuvant chemotherapy regimens excluding sequential or combination
anthracycline and taxane, used the DigniCap scalp cooling device and were
compared with 16 concurrently treated controls who did not use the cooling
device. Alopecia was measured using the Dean Scale, with success defined as
alopecia of 50% or less (Dean score 0 to 2 [table 3]) 1 month after the last
chemotherapy infusion and was graded by the patients themselves using
photographs compared with their own baseline hair. The rate of significant
alopecia (>2 on the Dean Scale) was 50% or less in 66.3% of the intervention
group compared with none of the control group (p < 0.001). Three of 5 QOL
measures were significantly better 1 month after the end of chemotherapy,
including perception of HL, feeling upset over HL, and feeling less physically
attractive as a result of the disease or its treatment. The primary toxicity
was mild headache, and 3 patients stopped cooling due to feeling cold.21

From July 2014 to November 2016, 139 consecutive breast cancer patients
receiving an anthracycline containing adjuvant chemotherapy were enrolled and
received at least 1 treatment with scalp cooling utilizing DigniCap. HL was
evaluated by patient self-assessment and by the physician according to the
Dean's Scale at baseline and after each cycle of chemotherapy. The primary
efficacy endpoint was the patient self-assessment HL score evaluated at least
3 weeks after completing chemotherapy. A Dean's Scale score of 0-2 (i.e., HL 
50%) was considered a success. Fifty-six out of 131 evaluated patients
successfully prevented HL (43%, 95% confidence interval (CI): 34-51%). Twenty-
four patients (32%) discontinued the scalp cooling because of alopecia or
scalp cooling-related AEs, 3 patients had missing information on CIA, and 48
patients (64%) had a HL greater than 50% after chemotherapy. No serious AEs
were reported.22

A different trial conducted at 7 sites in the U.S. from December 9, 2013 to
September 30, 2016, enrolled 182 patients. Participants were randomized in a
2:1 ratio to scalp cooling (n = 119) utilizing the Paxman scalp cooling device
or control (n = 63) with no scalp hypothermia during chemotherapy for breast
cancer; 36% received anthracycline-based chemotherapy, while the remainder
received a taxane, either alone or in combination with carboplatin,
cyclophosphamide, pertuzumab, and/or trastuzumab. Successful hair preservation
was defined as less than 50% HL not requiring a wig and was graded by a
clinician unaware of treatment assignment at the end of 4 cycles of
chemotherapy. The mean (standard deviation [SD]) age of the patients was 52.6
(10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64%
(n = 91) received taxane-based chemotherapy. Successful hair preservation was
found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared
with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate
difference, 50.5%; 95% CI, 40.5%-60.6%). Only AEs related to device use were
collected; 54 AEs were reported in the cooling group, all grades 1 and 2.
There were no serious adverse device events. Scalp hypothermia was graded as
successful in 50.5% of patients compared with none of the control group (p =
0.0061). AEs were all grade 1 and 2, primarily headache and feeling cold.
Seven patients discontinued cooling early, primarily due to feeling cold.
There were substantial differences in the success of cooling by drug group. An
exploratory post hoc analysis indicated that only 16% of patients receiving
anthracycline-based chemotherapy met criteria for success, compared with 59%
of those receiving taxanes, although the CIs were very wide.23

A meta-analysis in 2015 concluded that scalp hypothermia was the only
intervention that significantly reduced the risk of CIA (10 studies, involving
818 patients and including 3 randomized trials; relative risk 0.38 compared
with no cooling, 95% CI 0.32-0.45). No significant AEs associated with scalp
hypothermia were reported in this meta-analysis, although the reported studies
did not always track toxicity.24 Two of the authors independently searched
PubMed, Embase and the Cochrane Library, from June 20, 2013 through August
31, 2013, and selected clinical trials that reported the efficacy of any
intervention for prevention of CIA compared with that of controls. Out of 691
articles retrieved, a total of 8 randomized controlled trials (RCTs) and 9
controlled clinical trials (CCTs) involving 1,098 participants (616
interventions and 482 controls), were included in the final analyses. Scalp
cooling, scalp compression, a combination of cooling and compression, topical
minoxidil and Panicum miliaceum were used as interventions. The participants
were mainly breast cancer patients receiving doxorubicin- or epirubicin-
containing chemotherapy. Scalp cooling, which is the most popular preventive
method, significantly reduced the risk of CIA (relative risk [RR] = 0.38, 95%
CI = 0.32-0.45), whereas topical 2% minoxidil and other interventions did not
significantly reduce the risk of CIA. No serious AEs associated with scalp
cooling were reported.

Another review and meta-analysis looked at 654 patients. There were 10 studies
included in the review that met the criteria for eligibility. Six of the
studies were performed in Europe and 4 were performed in the U.S. Two of these
studies were a multi-center study with the remainder being single-center. All
these studies except for 2, used older scalp cooling technology (e.g., frozen
caps) rather than the more recent technologies such as DigniCap Scalp Cooling
System (Dignitana) or Orbis (Paxman). Two studies used the Paxman system. Most
patients in all these studies were treated with anthracyclines (doxorubicin,
epirubicin or taxanes). For the binary outcome of < 50% versus > 50% alopecia,
the use of scalp cooling reduced RR of alopecia by 43% (RR, 0.57; 95% CI,
0.45-0.72; I(2) = 11%; P < 0.00001). For ordinal outcomes (alopecia on a scale
of 0-3), use of scalp cooling significantly reduced alopecia (MD, -0.80; 95%
CI, -1.19 to -0.41; I(2) = 0%; P < 0.0001). The quality of the evidence was
graded as moderate. This systematic review and meta-analysis support the use
of scalp cooling to prevent alopecia in patients with solid tumors undergoing
chemotherapy.15

A later meta-analysis of 27 studies (3 randomized trials, 12 cohort, and 12
cross-sectional studies) was performed looking at breast cancer patients
undergoing chemotherapy who used a variety of scalp cooling devices. The
effectiveness rate of using a scalp cooling device to protect hair was 61%
(95% CI: 55 to 67%, I(2) = 88%, P = 0.000). Estimates of adverse reactions
that were reported in 4 or more studies included headache (28%), scalp pain
(25%), feeling cold (50%), neck pain (22%), and heaviness of the head (53%).
Review authors noted that the comparison of scalp cooling studies to attempt
to determine which caps and protocols work best is limited by the substantial
variability in chemotherapy (e.g., drugs, dosages, number of cycles, and mode
of administration) and scalp cooling treatment (e.g., device, procedures,
evaluation method, scalp temperatures) among studies. Scalp temperature and
duration of application were associated with statistically heterogeneous
outcomes. Review authors note that in other studies in the literature,
temperatures of 22C or lower have been associated with better hair retention.
However, since every study in their meta-analysis had a different treatment
protocol, it is not possible to determine from the meta-analysis which, if
any, works best.25

The risk of scalp metastases was a concern when the technology was first used.
There were no scalp metastases in 952 patients treated with scalp cooling in
the reviewed RCTs or CCTs, but Shah1 and colleagues noted that the follow-up
duration was short, and metastases were not routinely documented. Given the
importance of the issue, they reviewed additional literature from other
published sources. They noted that a 2006 series of 227 breast cancer patients
reported scalp metastases in 2 patients who used scalp cooling (0.88%). A 2009
study of 640 breast cancer patients reported that 6 of 553 scalp cooling
patients (1.1%) had scalp metastases, compared with 1 of 87 (1.2%) control
group patients (P = 0.40). A 2005 systemic review (SR) included 56 studies and
identified 9 reported cases of scalp metastases among approximately 2500
patients. Martin, et al.9 followed patients for a median of 8 years and found
no scalp metastases in patients with breast cancer who had scalp cooling.

Ross, et al.26 reviewed 40 years of efficacy, safety, and tolerability
literature on scalp cooling to prevent CIA. Forty articles were reviewed, with
12 articles demonstrating high levels of evidence and meeting inclusion
criteria. Comparative trials, systematic reviews, and 1 large single-arm trial
were included. The conclusion was that scalp cooling efficacy is dependent on
many factors but demonstrates better hair preservation than no cooling. No
increase in scalp metastases or statistically significant difference in
overall survival was seen in retrospective safety data when cooling was used.
Few patients discontinued cooling early because of adverse experiences.
Further, it demonstrates a high level of qualitative consistency among
studies, which found that scalp cooling is more effective than no cooling for
hair preservation, even though no quantitative conclusion about the size of
that benefit is currently possible due to heterogeneity. The overall evidence
suggests that there are no major complications related to scalp cooling and
that most side effects are tolerable.

Initial data, as well as more recent meta-analysis, support the efficacy and
safety of scalp cooling devices for patients with solid tumors who are
receiving chemotherapy that is expected to result in significant alopecia. Two
such devices, the DigniCap and Paxman scalp hypothermia systems, have been
used extensively outside of the U.S., and both are now also FDA cleared in the
U.S. for this use. Manual caps are also available, although these caps are
unregulated, and there are risks associated with their use. Because they are
unregulated, their use is not considered reasonable and necessary. Overall,
the literature is of moderate quality, limited by heterogeneity of
chemotherapy protocols and associated cooling times.

Given the NCCN recommendations, the significant deleterious effect that CIA
has on QOL, as well as the safety of the devices, the use of devices that have
been cleared by the FDA to prevent CIA will be covered as reasonable and
necessary. Scalp hypothermia for patients who have the previously described
contraindication(s) will not be considered to be reasonable and necessary.