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Prevention of chemotherapy-induced hair loss by scalp cooling 1University 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 formany doctors and nurses. This may be due to inadequate knowledge.
Methods: This review from 53 publications and three personal communications focuses on the effi-cacy 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 designedand are therefore difficult to compare. There is a considerable variation in the success rates in thevarious studies. This remains unexplained, but the cooling time, the chemotherapy used and the tem-perature seem to be influential. Scalp cooling should not be used if chemotherapy is given with acurative intent in patients with generalised haematogenic metastases. The majority of patients toler-ate 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 improvethe effect, tolerance, side-effects and the cooling procedure. Multicentre trials should be carried out to gather this information.
Key words: alopecia, chemotherapy-induced hair loss, cold cap, hair preservation, hypothermia,scalp cooling This review of literature will focus on the following areas: the efficacy of the treatment, side-effects, possible disadvan- Chemotherapy-induced temporary hair loss is one of the most tages and the controversies in these areas.
common and emotionally distressing side-effects of cancertherapy [1 – 3]. Since about 1970, many preventive measureshave been tried to reduce chemotherapy-induced alopecia: the tourniquet [4], medicaments [5] and scalp cooling. Currently,preventive measures mainly focus on scalp cooling. This is Between 1973 and 2003, 53 publications and three personal done either by procedures in which the cooling agent (ice cap, communications were found reporting cooling results in more or gel cap) must be changed several times or by continuous than one patient, partially in nursing journals. Seven trials cooling of the scalp with cold air or cold liquid. There are two were randomised and 49 were non-randomised. In 14 of thenon-randomised studies, the results were compared with a scientific rationales for scalp cooling. The first is vasoconstric- (historical) control group. The type of treatment was adjuvant tion, which reduces the blood flow to the hair follicles during in seven studies, palliative in nine, both adjuvant and pallia- peak plasma concentrations of the chemotherapeutic agents tive in 12, and unknown in the remaining 28 studies. Most and so reduces cellular uptake of these agents. This was studies were carried out in Europe, 11 took place outside demonstrated by Bu¨low et al. [6]. The second rationale is Europe. The number of patients varied from six to 180. There reduced biochemical activity, which makes hair follicles less was a great variation in chemotherapeutic regimens and cool- susceptible to the damage of chemotherapeutic agents. The ing methods. The latter varied from ice packs to gel caps or latter may be more important than vasoconstriction [6]. A cooling machines. Methods used to evaluate hair loss also lower glucose/lactate was demonstrated in a hypothermic scalp than in the normothermic scalp [7].
*Correspondence to: Dr W. P. M. Breed, Lissevenlaan 13, 5582 KB In six out of the seven randomised studies, a significant Waalre, The Netherlands. Tel: +31-40-2213807; Fax: +31-40-2214508;E-mail: wpmbreed@planet.nl advantage was seen when scalp cooling was used (Table 1).
q 2005 European Society for Medical Oncology aWHO grade 0, 1, 2 unless in the opinion of the authors the hair preservation in a part of the patients with grade 2 is not good or if the authors mention‘good hair preservation’, or ‘no wig required’.
bDoses not per m2.
cDepending on who rated hair loss: patients, nurses or experts.
dP value calculated for the incidence of alopecia of any grade.
C, cyclophosphamide; Ch, chlorambucil; Cp, cisplatin; D, doxorubicin; DT, docetaxel; E, epirubicin; F, 5-fluorouracil; M, methotrexate; Vc, vincristine; In 13 out of the 14 non-randomised studies with historical stopping the cooling procedure [9, 18, 31, 32]. Dougherty control groups, the authors concluded positive results of scalp even reported that in the group of patients in which cooling cooling for certain indications (Tables 2 and 3). The 35 had been ineffective, 38% of those patients felt they would studies without historic controls showed 31 positive results want the scalp cooling procedure if they needed another The 19 non-randomised studies carried out from 1995 Scalp cooling is contra-indicated in cases of cold sensi- onwards all showed positive results; five of these had (histori- tivity, cold agglutinin disease, cryoglobulinemia and cryo- cal) controls (Table 2). The only randomised study carried out after 1995 showed (marginal) positive results with epirubicinand docetaxel.
The average success rate of the studies carried out before Scalp metastases. In only 24 out of 58 studies (including the 1995 was 56% and from 1995 onwards 73% (Table 4).
two studies with only one patient), was attention paid to the In studies reporting results of several chemotherapy presence of scalp skin metastases after cooling. Sixteen of schedules (e.g. Refs [18, 27, 28, 34, 43]), their mean results those 24 studies mentioned explicitly that no scalp skin metas- were used to calculate the mean and median values in Tables 4 tases were found. In six studies, scalp skin metastases were found in nine patients out of a total of about 2500 patients in The cooling time seems to influence the success rate of the the 56 studies [14, 23, 46, 48, 54, 57, 58]. Both Witman et al.
studies. The median success rate was 76% if, after infusion of and Forsberg had a patient (one with mycosis fungoides, one cytostatics, the cooling time was 90 min or more. When with leukaemia) in whom they thought there was a relation shorter post-infusion cooling times were used, the median suc- between the skin metastases and the cooling [57, 58]. Only cess rate was 71% (Table 5). In the past few years, longer Lemenager et al. [21] and Ridderheim et al. [25] looked sys- post-infusion cooling times have been used. Before 1995, tematically for the incidence of scalp skin metastases after post-infusion cooling for more than 90 min was used in only cooling. In the 15 years that Lemenager et al. used scalp cool- two out of 32 studies, whereas since 1995 this was the case in ing, they did not find increased incidence in scalp metastases nine out of 20 studies. (In four studies the post-infusion cool- after cooling (median post-cooling follow-up of 9 months) [21]. Ridderheim et al. found no scalp metastases during a In 13 studies, liver function or the presence of liver metas- median follow-up period of 15 months among 74 patients [25].
tasis were taken into consideration for the hair protective One study even reported a decrease in size of a scalp skin effect of scalp cooling. In six out of these 13 studies, impaired metastasis despite cooling during chemotherapy [14].
liver function seemed to be related to less benefit from cooling Survival. No research has been carried out to evaluate the influence of scalp cooling on the survival time.
Side-effects. The most often reported side-effects were: head-aches, complaints of coldness and/or uncomfortable sen- sations, among others claustrophobia. These side-effects werein general not serious. There were a few studies in which in Unfortunately, most articles on scalp cooling are of poor value more than 10% of the patients side-effects were a reason for and there are only seven randomised studies. Many studies are Table 2. Results of non-randomised studies after 1994 A.D. Klaren, Albert SchweizerHospital, Dordrecht,The Netherlands aSee Table 1.
ANR, anthracyclines; C, cyclophosphamide; Cp, cisplatin; Ct, cytarabine; D, doxorubicin; DT, docetaxel; E, epirubicin; ET, etoposide; F, 5-fluorouracil; M, methotrexate; Mi, mitoxantrone; P, paclitaxel; TX, taxanes; H, historical control group.
rather small or have no exact description of the duration of similar CMF regimens in two randomised trials: 17% and infusion and the method of scalp cooling. Although the 49 non-randomised studies lack an optimal control group, they The success of cooling is most apparent in the randomised give some relevant clinical information.
studies (Table 1), but in a number of the 49 non-randomised The original idea was to analyse the studies to find the studies, cooling also seems effective (Tables 2 and 3). Table 4 relation between the temperature of the scalp obtained in the suggests better results from 1995 onwards than before that various studies and the effect of scalp cooling; however, tem- period, although this might be influenced by publication bias.
perature measurements were only done in one study.
The wide variation in reported success rates is unexplained.
The success of scalp cooling depends on many factors like type of cytostatics, the doses, the number of chemotherapy It is evident that cooling can prevent hair loss. However, it is courses and the admission method [14, 28, 35, 49]. In parti- very difficult to compare most studies, because of differences cular, when anthracyclines or taxanes were used, the positive in patient characteristics, chemotherapy, cooling and hair loss effect has been proven [7, 14, 21, 45]. If a combination assessment. This is demonstrated in hair preservation with of anthracyclines and taxanes were used, the results were Table 3. Results of the non-randomised studies before 1995 aSee Table 1.
bThe non-cooled patients lost an average of 80% of their hair; the cooled patients lost an average of 30% of their hair.
ANR, anthracyclines; C, cyclophosphamide; Cp, cisplatin; Ct, cytarabine; D, doxorubicin; Dr, daunorubicin; DT, docetaxel; E, epirubicin; ET, etoposide; F, 5-fluorouracil; M, methotrexate; Pr, prednisolone; Sem, semustine; Tg, thioguanin; TX, taxanes; Vc, vincristine; Vd, vindesine; H; historical control group; ns, not specified; p.o., oral.
considerably less positive [9, 14, 18]. As hair loss induced by Few studies have been made to find out which method paclitaxel is considerably increased if patients have undergone of scalp cooling is the most effective [1, 13, 43]. Careful previous chemotherapy [59], it seems likely that the results of application of the cooling cap might be more important cooling will also be influenced by previous chemotherapy.
than the cooling system itself, as the contact between the Therefore previous chemotherapy treatments should always be cold cap and the scalp skin is decisive for scalp tempera- taken into consideration when analysing results of scalp ture as has been suggested in numerical modelling of scalp Table 4. Results of studies before and since 1995 Studies before 1995 [3, 8 – 10, 12, 14, 28 – 46, 48 – 56]; 1563 cases Studies since 1995 [1, 2, 7, 11, 13, 15 – 18, 20 – 27]; personal communication: C. Christodoulou, Athens Medical Centre, Greece;personal communication: A.D. Klaren, AlbertSchweizer Hospital, Dordrecht, The Netherlands; personalcommunication: B. Kolen, Elisabeth Hospital, Tilburg, The Netherlands;[19]b; 1047 cases bThe results of this study are not used for calculation of mean and median values as the patients are part of the Kolen study patients.
Table 5. Results of studies with various post-infusion cooling times Post-infusion cooling time <90 min [1, 7 – 14, 17, 19 – 21, 25, 28 – 31, 33, 35 – 37, 39 – 52, 54 – 56]; personal communication: B. Kolen,Elisabeth Hospital, Tilburg, The Netherlands; [19]b; 1864 cases _ 90 min [2, 16, 18, 22, 23, 26, 27, 32, 53]; personal communication: C. Christodoulou, Athens Medical Centre,Greece; personal communication: A.D. Klaren, Albert Schweizer Hospital,Dordrecht, The Netherlands; 746 cases aSee Table 1.
bThe results of this study are not used for calculation of mean and median values as the patients are part of the Kolen study patients.
Furthermore, the importance of the degree of hypothermia of the scalp skin has hardly been studied. In 1982, in a study In several publications, authors have been concerned about the with a limited number of patients, Gregory et al. found the possible protective effect of cooling on (micro-)metastases of best protective effect against hair loss in the group of patients the scalp skin [9, 12, 14, 25, 45]. Although the findings of with the lowest intradermal temperatures [41]. There have Lemenager et al. and Ridderheim et al. seem to be very reas- been no further studies to confirm this. Although accurate suring, one has to bear in mind that their conclusions were measurement of the scalp skin temperature during cooling is based on only a 9 month follow-up period [21, 25]. A good extremely difficult, temperature measurements or other para- systematic study to look for the influence of cooling on scalp meters for skin temperature are necessary to determine the skin metastases and on survival time of patients would require optimal hypothermia, pre-cooling times and optimal appli- very large numbers of patients and a long-term follow-up. It is clear that in the case of haematological malignancies with Post-infusion cooling time also seems to be relevant for the haematogenic metastases, cooling is contraindicated [57, 58].
results of cooling (Table 5). Theoretically, the cooling period Scalp cooling is controversial in patients with non-haemato- after infusion of cytostatics should be related to the half-life logical malignancies who undergo chemotherapy with a time of the cytostatic used and their active metabolites but this is rarely done and has never been investigated [15, 53].
Fear of undoing the effect of chemotherapy on (micro) The importance of liver function to the success rate of scalp brain metastases by cooling seems unrealistic as the current cooling is controversial. In six out of 13 studies with abnormal cooling techniques do not cause a significant decrease in brain liver function or liver metastasis, less benefit from cooling was observed [29, 35, 45, 50, 52, 54].
Scalp skin cooling is generally well tolerated. Although side- Based on the results of these studies, scalp cooling should be effects are rarely a reason to stop the cooling, further applied more. However, it is not possible to advise on the research to improve tolerance for cooling might improve the optimum application of the cooling methods (system, duration and temperature). Careful application of the cooling cap might be more important than the cooling system itself. We 9. Giaccone G, Di Gulio F, Morandini MP, Calciati A. Scalp hypother- recommend multicentre trials to study the optimal method, mia in the prevention of doxorubicin-induced hair loss. Cancer Nurs temperature and duration of cooling with various chemother- apy regimens. Patient satisfaction should be the most import- 10. Kennedy M, Packard R, Grant M et al. The effect of using Chemocap on occurrence of chemotherapy-induced alopecia. Oncol Nurs Forum ant criteria for success, because efforts to obtain objective measurements are very difficult and less important than the 11. Macduff C, Mackenzie T, Hutcheon A et al. The effectiveness of scalp cooling in preventing alopecia for patients receiving epirubicin and docetaxel. Eur J Cancer Care 2003; 12: 154 – 161.
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