Prevention of chemotherapy-induced hair loss by scalp cooling
JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT
Effectiveness of Cold
Cap in the Prevention of Docetaxel-induced Alopecia
PREVENTION OF CHEMOTHERAPY-INDUCED HAIR LOSS BY SCALP COOLING
G. Grevelman1 and W. P. M. Breed2*
University of Maastricht, Nassaulaan 11a, 6224 JT Maastricht; 2Department of
Internal Medicine, Catharina Hospital, Eindhoven, The Netherlands Received 22
June 2004; accepted 26 October 2004
Background: Chemotherapy-induced temporary hair loss is one of the most common
and distressing side-effects of cancer therapy. Scalp cooling to reduce this
hair loss is a controversial issue for many doctors and nurses. This may be due
to inadequate knowledge.
Methods: This review from 53 publications and three personal communications
focuses on the efficacy of the treatment, side-effects, possible disadvantages
and the controversies in these areas.
Results: Scalp cooling has become an increasingly effective
method to prevent hair loss, especially when anthracyclines or taxanes are
used. Unfortunately, many studies were small and badly designed and are
therefore difficult to compare. There is a considerable variation in the
success rates in the various studies. This remains unexplained, but the cooling
time, the chemotherapy used and the temperature seem to be influential. Scalp
cooling should not be used if chemotherapy is given with a curative intent in
patients with generalized haematogenic metastases. The majority of patients
tolerate cooling very well.
Conclusion: Scalp cooling is effective but not for all chemotherapy patients.
Further psychological, clinical and biophysical research is needed to determine
exact indications for cooling and to improve the effect, tolerance,
side-effects and the cooling procedure. Multi-center trials should be carried
out to gather this information.
Key words: alopecia, chemotherapy-induced hair loss, cold cap, hair
preservation, hypothermia, scalp cooling Introduction Chemotherapy-induced
temporary hair loss is one of the most common and emotionally distressing
side-effects of cancer therapy [1-3]. Since about 1970, many preventive
measures have been tried to reduce chemotherapy-induced alopecia: the
tourniquet , medicaments  and scalp cooling. Currently, preventive
measures mainly focus on scalp cooling. This is done either by procedures in
which the cooling agent (ice cap, or gel cap) must be changed several times or
by continuous cooling of the scalp with cold air or cold liquid. There are two
scientific rationales for scalp cooling. The first is vasoconstriction, which
reduces the blood flow to the hair follicles during peak plasma concentrations
of the chemotherapeutic agents and so reduces cellular uptake of these agents.
This was demonstrated by Bu¨low et al. . The second rationale is reduced
biochemical activity, which makes hair follicles less susceptible to the damage
of chemotherapeutic agents. The latter may be more important than
vasoconstriction . A lower glucose/lactate was demonstrated in a hypothermic
scalp than in the normothermic scalp . This review of literature will focus
on the following areas: the efficacy of the treatment, side-effects, possible
disadvantages and the controversies in these areas.
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Effectiveness of Cold Cap in the Prevention of Docetaxel-induced Alopecia
M. Lemenager,¹ S. Lecomte,¹ M.E. Bonneterre,¹ E. Bessa, ² J.
Dauba ¹ and J. Bonneterre¹
¹ Centre Oscar Lambret, BP 307, F.59020 Lille Cedex; and ²Laboratoire Bellon,
Docetaxel is a new taxoid antineoplastic agent with clinical efficacy
especially in breast cancer. One of the most distressing side-effects induced
by docetaxel is alopecia. We studied the prevention of alopecia by using a cold
cap in 98 patients receiving 100 mg/m² docetaxel by 1 h i.v. infusion every 3
weeks. One patient was lost to follow-up. 83 patients (86%) were evaluated as a
success to the cold cap, as they presented WHO grade alopecia ≤ 2 and no need
to wear a wig. 14 patients (14%) had to wear a wig; among them, 7 patients
withdrew before the evaluation at three cycles. The cold cap is a very
effective technique with minimal side-effects for docetaxel-treated patients. ©
1997 Elsevier Science Ltd. All rights reserved.
Key words: alopecia, chemotherapy, toxicity
Eur 'J Cancer, Vol. 33, No. 2, pp. 297-300, 1997
DOCETAXEL (TAXOTERE) is a new antineoplastic agent from the taxoid family,
which promotes the assembly of microtubules, stabilizing them and preventing
their depolymerisation. Several phase II trials have demonstrated that this
drug has significant and consistent anti-tumor activity in metastatic breast
and non-small-cell lung cancers. It has also produced significant results in
other tumors among which include ovarian cancer [1, 2]. Currently, the
recommended dose of docetaxel for phase II or III studies is 100 mg/m²
administered as a 1-h i.v. infusion repeated every 21 days. Phase I trials have
demonstrated the toxicity of docetaxel: dose-limiting neutropenia,
paresthesias, asthenia, oral mucositis, fluid retention, nail changes and
alopecia . Alopecia is common at doses higher than 55 mg/m², and has been
observed in over two-thirds of patients at doses higher than 70 mg/m² during
phase I trials . Alopecia occurs in over 80% of patients receiving docetaxel
at the dose of 100 mg/m²  and represents a major psychological drawback for
the patients, especially for women. Although mostly transient, alopecia is one
of the most distressing side-effects of anticancer chemotherapy. In a study on
patient perception of the side-effects of chemotherapy, patients chose alopecia
as the second worst physical side-effect after nausea and vomiting . Another
study showed that 88% of the women who received pre-operative chemotherapy for
breast cancer considered alopecia the most burdensome aspect of the treatment
. Hair loss can induce a negative body image, alter interpersonal
relationships, reduce the quality of life and generated enough anxiety to cause
some patients to reject potentially curative treatments, particularly women.
In our day-care hospital, the prevention of alopecia is an important endpoint
for nurses and physicians. We use the cold cap for the prevention of
anthracyclin-induced alopecia: 85% of female patients have no, minor or
moderate alopecia and they do not need to wear a wig or a hat . Due to
differences in chemotherapy administration schedules (10-min bolus for
epirubicin versus 1 h for docetaxel), the research nurses modified the cold cap
technique and adapted it to docetaxel chemotherapy . Preliminary results
showed good protection from hair loss in 39 patients receiving docetaxel 100
mg/m² for metastatic breast cancer as second- or third-line chemotherapy. 21
patients had no alopecia, grade 1 was observed in 15 patients, grade 2 in two
patients, and one patient had grade 3 alopecia, who had to wear a wig .
The following study reports the full data which confirm these promising results
and promotes the cold cap safety and efficacy for the prevention of
Patients and Methods
All patients were treated as out-patients. 98 patients received docetaxel alone
(100 mg/m² i.v., every 21 days) after failure of one or more previous
chemotherapy regimen during a compassionate use program or ongoing clinical
trials from April 1992 to October 1995.
Patients were offered a cold cap technique aimed at the prevention of
docetaxel-induced alopecia and were informed by the oncologists. The patients
(93 females and 5 males) received docetaxel chemotherapy for metastatic breast
cancer (n=88), advanced ovarian cancer (n=3) and advanced pancreatic cancer
(n=7). Previous chemotherapy regimens were either epirubicin-based or contained
mitoxantrone, vinorelbine, cisplatin, cyclophosphamide or 5-fluorouracil. Some
patients had previously worn a cold cap or had already experienced hair loss
during their cancer treatment.
Patients were ineligible if they had scalp metastases, prior radiation to the
scalp, presence of baldness or significant hair loss. Clinical and biochemical
signs of liver metastases or impairment of the liver function were recorded at
admission. Patients with transaminase enzyme levels below 2.5 times the upper
normal limit were eligible to receive docetaxel chemotherapy. Patients with
significant liver metastases were eligible for docetaxel chemotherapy and cold
cap if they had only a minor impairment of their liver function.
Scalp hypothermia was achieved with the Spenco Hypothermia Cap filled with
cryogel. The cold cap was placed in the freezer for a minimum of 12 h prior to
use. The temperature of the cap had to be below -25°C. First, a wet single-use
mobcap was placed on the patients' hair. To apply the cap as tightly as
possible, it was kept in place by bandages wrapped around the head. Cotton
protected the nape, forehead and ears. The cold cap was applied 15 min. before
the administration of docetaxel and left in place for 30 min. after the
beginning of the infusion; then the second cap was worn for 45 min. Two cold
caps were successively used (45 min. for each); the cap changing was done
quickly by two nurses. To improve the hair protection, the research nurses gave
some advice to the patients: no hair brushing during the treatment day, no
shampoo for one week, no permanent wave or hair coloring during chemotherapy
treatment, and to have a short haircut. This was done every time the patient
received docetaxel. The patients were followed and treated until they either
stopped receiving docetaxel, or had total hair loss.
Measurement of the degree of hair loss was determined by the nurse. Alopecia
was assessed before each docetaxel cycle and during at least three consecutive
cycles. Hair loss was evaluated using the World Health Organization (WHO)
criteria for alopecia (grade 0, no hair loss; grade 1, minimal hair loss; grade
2, moderate hair loss, patchy alopecia; grade 3, complete but reversible hair
loss; grade 4, complete and irreversible alopecia).
Success was defined as WHO alopecia grade ≤ 2 and no need to wear a wig,
according to patient's decision. If the patient wore a wig whatever the grade
of alopecia, this was considered a failure.
98 patients received docetaxel chemotherapy in combination with the cold cap.
All patients but one were able to be evaluated for the results; one patient was
not able to be evaluated, as she refused to continue chemotherapy and was lost
to follow-up. The median age was 49 years (range 29-73). The median number of
previous chemotherapy regimens was 2 (range 0-5). 83 female patients had
previously received epirubicin-based regimen as adjuvant or metastatic
treatment. All patients except one received at least 3 docetaxel chemotherapy
cycles, the median number was 5 cycles (range 2-11).
The results are shown in Table 1. 14 (14%) patients were evaluated as a failure
to the cold cap: 7 of them refused to go on through the three cycles with the
caps (one at cycle 1, two at cycle 2 and 4 at cycle 3); the other 7 patients
had to wear a wig, 3 had presented with grade 2 alopecia and 4 patients had
grade 3 alopecia. 83 (86%) patients were successful responders to the cap as
they had both grade ≤ 2 alopecia and did not need to wear a wig.
When considering prior treatment, 83 out of the 97 patients able to be
evaluated had previously received anthracyclin-based chemotherapy (mostly
epirubicin). Information on the results of alopecia prevention (with a cold
cap) at the time of anthracyclin chemotherapy was available for 50 of these
patients: 20 grade 0, 20 grade 1, 9 grade 2, 1 grade 3, and no grade 4. These
same patients had the following results for docetaxel-induced alopecia
prevention: 25 grade 0, 15 grade 1, 6 grade 2, 4 grade 3 and no grade 4. 14
patients had not previously received an anthracyclin-based regimen, and their
results of docetaxel-induced alopecia prevention were 3 grade 0, 5 grade 1, 4
grade 2, and 2 grade 3.
The cold cap was well tolerated. Its side-effects were mild headaches and
unpleasant cold sensations. Only 7 patients refused to go on with the cold cap
(ad were considered as failures): 5 complained of headaches and 2 were not
satisfied because of hair thinning. None of the patients treated with scalp
hypothermia developed scalp metastases, with a median follow-up after the end
of the treatment of 9 months (range 4-12).
Despite the fact that alopecia is one of the most common side-effects of
chemotherapy, especially with anthracyclins and taxoids, with a major social
and psychological impact, relatively few trials evaluating different prevention
approaches have been reported. A literature review has recently been published
. Four studies showed failure of hair loss prevention, but most series
showed good hair preservation in 50-80% of patients with a scalp-cooling
method. Several techniques were used to induce hypothermia: simple bags with
crushed ice or frozen cryogel packs, caps containing cryogel and an insulation
layer, caps connected to a cooling device using air or fluid and equipped with
a thermostat . Our studies, conducted with the Spenco Hypothermia Cap,
containing cryogel, gave good hair preservation (between 80 and 85% with
epirubicin 50 mg/m² and docetaxel 100 mg/m²).
The rationale for the use of cold caps is that scalp hypothermia causes
cutaneous vasoconstriction with a reduced blood flow, leading to a reduction in
the quantity of drugs reaching the hair follicles . The pharmacokinetics of
docetaxel fit a tri-exponential curve; the α, β, and γ half-lives with a 115
mg/m² 1-h infusion are 4 min., 36 min., and 22 h, respectively . This means
that the drug is present at high concentrations in the capillary circulation
for a duration which is shorter than that of hypothermia. Cellular uptake by
the hair follicles may also be reduced because of the lower temperature .
finally, a reduction in the metabolism of local tissue, in response to low
temperature rather than reduced blood flow, is the most significant factor in
preventing alopecia [8, 11].
Limited data are available on the degree of the cooling temperature that must
be obtained. Hair conservation could be obtained when scalp temperature is
reduced to a level ≤ 24°C  or < 22°C . In our experience, assessment
of scalp hypothermia was not done. Clinical experiences have revealed that hair
preservation is improved when the temperature of the cap is around -25°C after
remaining at least 12 h in the freezer. The cold caps are always placed in the
freezer on the evening prior to use. A cap is used only once per day.
The precooling time ranges from 5 to 20 min. (15 min. in our study) . Most
of the reviewed series use a post-injection cooling time of 30 min. (range
15-60) probably taking the doxorubicin pharmacokinetics as their guidelines
. The post-injection cooling time with docetaxel (1-h infusion) was 15 min.
in our study.
Various chemotherapy drugs have been used, with several dosages, to evaluate
the efficacy of the cold cap. The degree of protection against alopecia is both
drug and dose-dependent. Scalp hypothermia resulted in 100% (5/5) minor or no
hair loss when a dose of < 50 mg. . Our experience shows the same
difference between the FEC 50 regimen (epirubicin 50 mg/m², 5-fluorouracil 500
mg/m², cyclophosphamide 500 mg/m²) and the FEC 100 regimen (epirubicin 100
mg/m²) in larger studies. Hair preservation (alopecia grade ≤ 2 and no wig) was
85% (64/73) with the cold cap during FEC 50 chemotherapy and fell to 64%
(25/39) with FEC 100 chemotherapy and increased epirubicin doses (J.
Bonneterre, Centre Oscar Lambret, France). No evident difference seems to exist
between the results obtained in the prevention of epirubicin-induced alopecia
and docetaxel-induced alopecia: 85% hair preservation was achieved in both
series. In addition, previous epirubicin treatments do not seem to decrease the
efficacy of the cold cap in the prevention of docetaxel-induced alopecia.
Most physicians recommend that the cold cap should not be used in
haematological malignancies or solid tumors which could spread to the scalp.
One study reported scalp recurrence in a patient with mycosis fungoides who was
treated with a cold cap . In two series [14, 15], 5 cases of scalp
metastases after cold cap use in a series of 96 patients, treated for
metastatic breast cancer, were also reported. No report of scalp metastasis
after the cold cap in adjuvant breast cancer chemotherapy was found in the
literature . In another study, no scalp metastasis was observed . In our
experience, we have been using the cold cap for about 15 years and no increase
in the rate of scalp metastases has been observed.
The influence of liver metastases in decreasing the effectiveness of the cold
cap has been raised by several authors [16, 17]; impaired liver function could
reduce the excretion of the drug. There is no evidence that liver function
decreased the efficacy of the cold cap. In one study , all patients
receiving adjuvant chemotherapy had normal liver function and failed to benefit
from cold caps. Conversely, despite a high rate of liver metastasis in our
patients, we obtained very good hair preservation.
The cold cap is well tolerated. The side-effects are headaches, unpleasant cold
sensation and occasional complaints of a 'heavy' cap [11,17]. Tolerability is
very good and comparable to other studies [11-17]. Few patients refused the
cold cap without having tried it, mostly because they were more anxious and
fearful of losing their hair than of the temporary discomfort of the cold cap.
However, 10 patients refused the cold cap during the docetaxel regimen; putting
the cold cap on and changing it is a very time-consuming process for the
nursing staff. In our experience, there is no necessity to measure the scalp
temperature during treatment.
Other techniques to prevent chemotherapy-induced alopecia are being studied
with limited success to date. A phase I trial of intracutaneous interleukin 1
to prevent cytarabine-induced alopecia showed no significant protection .
Minoxidil is known to induce hair growth in men with male pattern baldness. A
minoxidil topical solution was not effective in the prevention of
doxorubicin-induced alopecia in a placebo-controlled study .
Alopecia is one of the most distressing side-effects of chemotherapy.
docetaxel, a taxoid with a broad range of anti-tumor activity, often induces
complete and reversible alopecia. The simple technique of scalp cooling appears
to be as useful in preventing alopecia induced by docetaxel as it is for
epirubicin. The cold cap is safe, well accepted by patients and with no major
side-effects. The cold cap can be recommended for routine use in docetaxel
chemotherapy, to improve the quality of life of cancer patients.
Cortes JE, Pazdur R. Docetaxel. F Clin Oncol 1995, 13,
Gelmon K. Th taxoids: paclitaxel and docetaxel. Lancet 1994,
Chevalier B, Fumoleau P, Kerbrat P, et al. Docetaxel is a
major cytotoxic drug for the treatment of advanced breast cancer: a phase II
trial of the clinical screening cooperative group of the European Organization
for Research and Treatment of Cancer. J Clin Oncol 1995, 13, 314-322.
Coates A, Abraham S, Kaye SB, et al. On the receiving end
- patient perception of the side-effects of cancer chemotherapy, Eur F Cancer
Clin Oncol 1983, 19, 203-208.
Kiebert GM, Haes JCJM de, Kievit J, et al. Effect of
perioperative chemotherapy on the quality of life of patients with early breast
cancer. Eur J Cancer 1990, 26, 1038-1042.
Bonneterre J, Wartel C, Bachelet H, et al. Efficacy of
scalp hypothermia in patients receiving anthracycline chemotherapy. 1st
International Symposium on Supportive Care in Cancer Patients. St
Gallen, Switzerland, February 1987, 18-21.
Lemenager M, Genouville C, Bessa EH, et al. Docetaxel-induced
alopecia can be prevented. Lancet 1995, 346, 371-372.
Tollenaar R, Liefers GJ, Repelaer van Driel OJ, et al. Eur J
Cancer 1994, 30A, 1448-1453.
Bulow J, Friberg L, Gaardsting O, Hansen M. Frontal subcutaneous
blood flow, and epi- and subcutaneous temperatures during scalp cooling in
normal man. Scand F Clin Lab Invest 1985, 45, 505-508.
Gregory RP, Cooke T, Middleton J, et al. Prevention of
doxorubicin-induced alopecia by scalp hypothermia: relation to degree of
cooling. Br Med F 1982, 284, 1674.
Satterwhite B, Zimm S. The use of scalp hypothermia in the
prevention of doxorubicin-induced hair loss. Cancer 1984, 54, 34-37.
Cooke T, Gregory RP, Middleton J, et al. Prevention of
doxorubicin-induced alopecia. Br Med F 1981, 282, 734-735.
Witman G, Cadman Ed, Chen M. Misuse of scalp hypothermia. Cancer
Treat Rep 1981, 65, 507-508.
Vendelbo Johansen L. Scalp hypothermia in the prevention of
chemotherapy-induced alopecia. Acta Radiol 1985, 24, 113-116.
Middleton J, Franks D, Buchanan RB, et al. Failure of
scalp hypothermia to prevent hair loss when cyclophosphamide is added to
doxorubicin and vincristine. Cancer Treat Rep 1985, 69, 373-375.
Anderson JE, Hunt JM, Smith IE. Prevention of
doxorubicin-induced alopecia by scalp cooling in patients with advanced breast
cancer. Br Med F 1981, 282, 423-424.
Wheelock JB, Myers MB, Krebs HB, et al. Ineffectiveness
of scalp hypothermia in the prevention of alopecia in patients treated with
doxorubicin and cisplatin combinations. Cancer Treat Rep 1984, 68,
Daghistani D, Jimenez JJ, Maharaj D, et al. A phase I
trial of intracutaneous interleukin-1 (IL-1) for the prevention of
chemotherapy-induced alopecia. Proc Am Soc Clin Oncol 1994, 13, A1545.
Rodriguez R, Machiavelli M, Leone B, et al. Minoxidil
(Mx) as a prophylaxis of doxorubicin-induced alopecia. Ann Oncol 1994,
Acknowledgments - The authors express their gratitude to the
Oncology Research Nursing Staff of the Department: Danièle Bauwens, Delphine
Boidin, Laurence Dewiite, Christine Janicki, Nathalie Marechal, Anne-Bérangè
Noirot, Frédérique Renart and Florence Trache.
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VOLUME 23 - NUMBER 19 -
JULY 1 2005
JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT
Multi-center Study of a Frozen Glove to Prevent
Docetaxel-Induced Onycholysis and Cutaneous Toxicity of the Hand
Scotte, Jean-Marc Tourani, Eugeniu Banu, Michel Peyromaure, Eric Levy, Sandrine
Marsan, Emmanuelle Magherini, Elisabeth Fabre-Guillevin, Jean-Marie Andrieu,
and Stephane Oudard
From the Department of Medical Oncology, Georges Pompidou European Hospital;
Urology Department Cochin Hospital, Paris; and Medical Oncology Department,
Submitted February 10, 2005; accepted March 18, 2005.
Authors’ disclosures of potential conflicts of interest are found at the end of
reprint requests to Florian Scotte, MD, Department of Medical Oncology. Georges
Pompidou European Hospital, 20 rue Leblanc, 75908, Paris Cedex 15, France,
© 2005 by American Society of Clinical Oncology
A B S T R A C T
Onycholysis and skin toxicity occur in approximately 30% of patients treated
with docetaxel. We investigated the efficacy and safety of (84400 APT Cedex,
Akromed, France) frozen glove (FG) for the prevention of docetaxel-induced
onycholysis and skin toxicity.
Patients and Methods
Patients receiving docetaxel 75 mg/m2 alone or in combination chemotherapy were
eligible for this case-control study. Each patient wore an FG for a total of 90
minutes on the right hand. The left hand was not protected and acted as the
control. Onycholysis and skin toxicity were assessed at each cycle by National
Cancer Institute Common Toxicity Criteria and documented by photography.
Wilcoxon matched-pairs rank test was used.
Between August 2002 and September 2003, 45 patients were evaluated. Onycholysis
and skin toxicity were significantly lower in the FG-protected hand compared
with the control hand (P= .0001). Onycholysis was grade (G) 0 in 89% v49% and
G1 to 2 in 11 % v51 % for the FG-protected hand and the control hand,
respectively. Skin toxicity was GO in 73% v41 % and G1 to 2 in 27% v 59% for
the FG-protected and the control hand, respectively. Median time to nail and
skin toxicity occurrence was not significantly different between the
FG-protected and the control hand, respectively (106 v 58 days for nail
toxicity; 57 v 58 days for skin toxicity). Five patients (11 %) experienced
discomfort due to cold intolerance.
FG significantly reduces the nail and skin toxicity associated with docetaxel
and provides a new tool in supportive care management to improve a patient's
quality of life.
J Clin Oncol 23:4424-4429. © 2005 by American Society of Clinical
Docetaxel and paclitaxel are part of the taxane group, which has emerged as one
of the most powerful classes of chemotherapeutic agents and exhibits a wide
range of activity against a variety of solid tumors. 1-4 Taxanes act by
disrupting the normal microtubule network essential for mitotic and interphase
cellular functions.5 In general, the toxicity profile of each taxane is
predictable and can be managed with prophylactic measures and supportive care.6
Cutaneous toxicity manifested as erythema and desquamation of the skin of the
extremities (hand-foot syndrome [HFS] ) and nail changes have been reported
with taxane treatment, but both toxicities have been associated more frequently
with docetaxel.7-9 Although HFS does not appear to be a common adverse event
with docetaxel treatment,7 a recent review of published studies by Minisini et
al8 showed that the overall incidence of taxane-induced nail changes is as high
Frozen Glove to Prevent Nail Changes
Nail changes include hyperpigmentation, splinter hemorrhage, subungual
hematoma, subungual hyperkeratosis, orange discoloration, Beau-Reil lines
(indicating the cessation of nail growth), acute paronychia, and onycholysis
(the loosening or separation of a fingernail or toenail from its nail bed).
Usually, several or all nails are involved. Some nail changes are asymptomatic
and cause only cosmetic problems, whereas others can be accompanied by either
discomfort or pain, and negatively affect a patient's ability to perform manual
activities and ambulate. Nail changes are usually transitory and disappear with
drug withdrawal, but may persist in some patients.10 Application of local
topical antibiotics or antifungal treatments may be required to treat nail bed
infections, which seem to be a complication of nail's detachment. Onycholysis
is manifested in 2% to 3% of patients.11 The brown discoloration associated
with nail toxicity is indicative of bleeding beneath the nails. Dermatologic
examination may show no evidence that an infection was the origin of the nail
change.12 The type of nail change is related to the number of chemotherapy
cycles administered, and to date no effective preventive measures are
The flexible frozen glove.
The physiopathology of nail toxicity is unknown. Drug-induced nail
abnormalities result from toxicity arising in the various nail constituents,
such as the matrix, nail bed, periungual tissues, or blood vessels in the
fingers.14 Several studies have suggested that the antiangiogenic properties of
taxanes may be involved in nail toxicity,15, 16 whereas another study suggests
the existence of a neurogenically mediated inflammatory process.17
Docetaxel-induced HFS presents as a discoloration of the skin that progresses
to blisters and desquamation, and may be accompanied by nail changes that
progress to onycholysis.7 The hands are usually more frequently affected than
the feet. The cause of HFS is also unknown, but it appears to be a direct
cytotoxic effect on keratinocytes associated with peak drug concentrations and
Although nail and skin toxicity are not life threatening, they should be
managed effectively to prevent early discontinuation of chemotherapy; the
toxicities often do not
Scotte et al
resolve between cycles. Cold temperature applied to the scalp before, during,
and after chemotherapy reduces the incidence of chemotherapy-induced
alopecia.18-20 This effect is related to a cold-induced vasoconstriction, which
reduces the amount of drug reaching the hair follicles, and causes a decrease
in follicular metabolism. In addition, oral cryotherapy has been administered
with efficacy in patients receiving bolus-dose fluorouracil therapy.21 This
concept was extended to the present study of a frozen glove (FG) for the
prevention of nail and skin toxicity associated with docetaxel treatment. The
primary end point was efficacy in onycholysis prevention, and secondary end
points were the assessment of efficacy in the prevention of skin toxicity, the
median time to occurrence of nail and skin toxicity, and patient
PATIENTS AND METHODS
In this phase II, multi-center, matched case-control study, we evaluated the
applicability and efficacy of FG therapy in the prevention ofdocetaxel-induced
onycholysis and skin toxicity during a 14-month period extending from 2002 to
2003. Each patient wore the protective glove on the right hand and had no
Fig 2. Nail toxicity grade 2 (onycholysis) present on the left hand (control)
but absent on the protected right hand.
on the left hand, which was considered to be the control side. By this method,
we could obtain a comparative incidence of nail and skin disorders with and
without cold protection.
Patients enrolled onto this study were undergoing treatment for a variety of
tunum types with docetaxel 75 mg/m2 as a 1-hour intravenous infusion every 3
weeks either alone or in combination with other cytotoxic agents. Inclusion
criteria included no prior treatment with taxanes, the absence of skin and nail
disorders at the start of treatment, a life expectancy of at least 3 months,
and an Eastern Cooperative Oncology Group performance status of 0 to 2.
Patients were excluded if they had Raynaud's phenomenon, distal metastases,
Original pathology, arteriopathy, cold intolerance, or peripheral neuropathy
grade 2 or higher. All patients provided written informed consent.
Patients wore (84400 APT Cedex, Akromed, France) flexible glove (Fig 1). This
patented glove contains glycerin, which has thermal properties, allowing its
use in hot or cold therapies. The gel-filled glove covers the hand to the wrist
and separates the thumb from the rest of the hand. Before use, it must be
refrigerated for at least 3 hours at -25 to -30°C. With every docetaxel
infusion, each patient wore an FG for a total of 90 minutes on the right hand
(15 minutes before the administration of docetaxel, during the 1-hour docetaxel
infusion, and 15 minutes after the end of infusion). Because of the duration of
the infusion, two FG's were used successively (for 45 minutes each) to maintain
a consistently low temperature of the hand. The left hand was not protected by
the FG and acted as the control.
Frozen Glove to Prevent Nail Changes
Onycholysis and skin toxicity were assessed at each cycle by the medical
investigator (F.S. or E.L. in Paris and J.M.T. in the Poitiers centers) and
assessment was repeated by a second different observer, using National Cancer
Institute Common Toxicity Criteria (Version 2); that is, grade 1, indicated by
discoloration, ridging (koilonychia), or pitting; and grade 2, indicated by
partial or complete onycholysis or pain in the nail bed. Changes were
photographically documented by the medical investigator. Patients' comfort
level was assessed using a 4-point rating system that determined whether
patients were dissatisfied (0), not very satisfied (1), satisfied (2), or very
satisfied (3). The results were expressed as two patient groups: those
satisfied with the FG (2 and 3) and those dissatisfied with the FG (0 and I).
Treatment was stopped when patients showed intolerance to the FG, had a serious
adverse event, or withdrew consent.
Analyses of toxicity were carried out on the intent-to-treat population. The
Wilcoxon matched-pairs rank test was used to determine the magnitude of
difference between the control hands and the FG-protected hands. The
Kaplan-Meier and log-rank methods were used to estimate and compare differences
in time to toxicity occurrence.
Forty-five patients (10 women, 35 men; median age of 65 years) undergoing
treatment for lung, breast, prostate, Fig 3. Nail toxicity grade 1
(dyschromia), showing the difference between the left hand (control) and the
protected right hand.
and other cancers were enrolled onto the study (Table 1). Docetaxel was
administered either as monotherapy (71%) or in combination with other cytotoxic
drugs (29(%), such as carboplatin, vinorelbine, and anthracyclines. This was
first-line chemotherapy for 76% of patients. The median number of docetaxel
cycles administered was six (range, one to nine cycles) and the median
cumulative docetaxel dose was 810 mg (range, 150 to 1,275 mg; Table 1).
Nail and Skin Toxicity
Forty-five patients who received docetaxel chemotherapy in combination with FG
treatment were evaluated for nail toxicity. The application of FG significantly
reduced the overall occurrence of nail toxicity from 51% to 11% (P = .0001),
with grade 2 nail toxicity (onycholysis) occurring in none of the FG-protected
hands compared with 22% of the control hands (Fig 2). Grade 1 toxicity
(dyschromia; Fig 3) was observed in 11% of the FG-protected hands and in 29%,
of the control hands (Table 2).
Forty-one patients receiving docetaxel chemotherapy in combination with FG
treatment were assessed for skin toxicity; the remaining four patients
presented with incomplete data. Overall, skin toxicity occurred in 24% of the
FG-protected hands versus 53% of the control hands (P = .0001; Table 3).
Although the appearance of nail toxicity was delayed with FG protection, no
difference was observed in the median time to appearance of skin toxicity
Assessment of patients' global comfort included factors such as glove contact,
temperature tolerance, and immobilization constraints. Forty-three patients
were assessable (two patients refused FG protection). Using the ad-hoc rating
scale, 37 patients (86%) were satisfied with the treatment, whereas six were
dissatisfied, including five (11%) who withdrew from the study because of cold
intolerance during glove contact (Table 5).
Chemotherapy-induced toxicity adversely affects patients' quality of life and
limits the dose of chemotherapy that can be administered. The dermatologic
complications of cancer chemotherapy can result in significant morbidity,
cosmetic disfigurement, and psychological distress. In this study, the use of
an FG reduced the incidence of nail and skin toxicity associated with docetaxel
75 Mg/m2 administered every 3 weeks, either alone or in combination with other
cytotoxic agents. Eleven percent of the FG-protected hands developed nail
toxicity with dyschromia, but no onycholysis; this result compared favorably
with the unprotected hands, 29% of which developed dyschromia (grade 1) and 22%
of which developed onycholysis (grade 2). The FG delayed the median time to
occurrence of nail toxicity (106 days) compared with non-FG-protected hands (58
days). Similarly, the incidence of skin toxicity of the FG-protected hand
reduced by half. The incidence of nail changes observed in the unprotected
hands in this study are consistent with those reported for docetaxel.8,11-13,22
Although taxane-induced nail toxicity has been observed in patients using the
regimen administered weekly and every 3 weeks,8 the risk of developing nail
reactions may be related more to the dosing interval and the cumulative dose
than to the dose administered.7-9 The temperature of the FG in this study (-25
to -30°C) was in the same range as that used in a study of the cold cap to
prevent docetaxel-induced alopecia,19 in which 86% of patients presented with
no worse than grade 2 alopecia, and had no need to wear a wig.
In this study, the simple FG technique reduced the incidence of nail and
cutaneous toxicity. The FG is easy to apply, is well accepted by most patients,
and has no major adverse effects. Thus, it may be considered a new tool in
supportive care and may be recommended for routine use with chemotherapy
agents. These favorable results warrant additional studies to assess the
efficacy of FG protection with other doses or schedules of docetaxel, either
alone or in combination, and with other chemotherapeutic agents, such as free
or liposomal doxorubicin.7-9,23 Future applications can also include the feet.
A logical development of our study is the administration of three-fold therapy
using a cold cap, gloves, and socks in a blinded manner for the investigator,
and random hand and foot allocation.
In August 2004, the US Food and Drug Administration approved docetaxel for use
in combination with doxorubicin and cyclophosphamide for the adjuvant treatment
of patients with operable, node-positive breast cancer,24 and in May 2004,
approval was obtained for the use of docetaxel in combination with prednisone
as a treatment for men with hormone-refractory metastatic prostate cancer.25 In
addition, docetaxel is being studied extensively in clinical trials for safety
and efficacy in head and neck and gastric cancers. A new era is beginning in
the field of interventional measures. Such measures might be capable of
preserving the duality of life for thousand of patients.
We thank the men and women who entered onto this study. We also thank Sarah
Guyon for her valuable work.
Authors' Disclosures of Potential Conflicts of Interest.
The authors indicated no potential conflicts of interest.
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