Annals of Oncology Advance Access originally published online on April 27, 2005
Annals of Oncology 2005 16(7):1210-1211; doi:10.1093/annonc/mdi204
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© 2005 European Society for Medical Oncology
Letter to the Editor |
Release of doxorubicin in sweat: first step to induce the palmar-plantar erythrodysesthesia syndrome?
Doxorubicin, one of the most potent single chemotherapeutic agents against solid and angiomatous tumors, is encapsulated in highly stable Stealth® liposomes so that its toxicity is significantly reduced [1
]. The efficacy and toxicity of doxorubicin is affected by the different liposomal leakage rates; liposomes with the slowest rate of drug leakage showed the best therapeutic activity [2]. Nevertheless, severe and dose-limiting mucocutaneous reactions occur [3], mostly the palmar-plantar erythrodysesthesia syndrome (PPE). This syndrome is mainly located on the palms and plantae, but it may also affect intertrigeneous sites. A better understanding of the pathogenesis of PPE could provide the basis for its prevention and effective treatment. Fifteen patients were observed for six cycles of their therapy with encapsulated doxorubicin (Caelyx, Essex Pharma GmbH, Munich, Germany) against carcinoma. Cutaneous side-effects that occurred during this period were documented (Table 1). Five women, who discontinued treatment for unknown reasons, were excluded from the study. Five patients developed PPE, mainly localized on the palms and plantae. These patients also demonstrated palmar and plantar hyperhidrosis (5 from 5 and 4 from 5, respectively). The two patients with PPE with a high grade 3 developed PPE on intertrigeneous sites, i.e. the axilla. Toxic effluvium (n=4) and atopic eczema (n=2) were also observed.
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In addition, the fluorescence of the drug was qualitatively determined in vivo in the uppermost part of the skin using a dermatological laser scanning microscope (Stratum, Optiscan Ltd., Melbourne, Australia) [4
]. The measurements were performed on a male patient (no. 10) before and after intravenous treatment of the flexor forearm, the palm, the sole, the axilla and the forehead. Three hours after injection, fluorescence was detected on the skin surface of all sites and in the uppermost part of the skin on the plantae and palms. The fluorescence signal on the palm was detected deep in a sweat duct (Figure 1A) and around its opening in the upper skin layers (Figure 1B).
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The observed results indicate a possible relationship between the hyperhidrosis on the palms and plantae and the development of PPE on these skin sites during therapy. Both skin sites are characterized by the highest number of eccrine sweat glands which continuously excrete serous fluid [5
]. Similar apoeccrine and eccrine sweat glands are located in the axillae [5], which are also frequently affected by PPE. Indeed, the drug was observed in the sweat inside the excretory ducts of sweat glands (Figure 1A). This result indicates that the sweat functions as a carrier of doxorubicin to the skin surface, presumably favoured by the hydrophilic coating of the liposomes. After excretion on the skin surface, the sweat containing the drug may penetrate into the stratum corneum (Figure 1B). The stratum corneum could be functioning as a reservoir for the penetration of doxorubicin into deeper skin layers, where its radicals will be formed and react with epidermal cells. In conclusion, the induction of PPE during therapy with encapsulated doxorubicin could be avoided by the prevention of hyperhidrosis. Routinely used antihidrotic treatments, such as ionotophoresis or topically applied aluminum chloride, may help to reduce PPE and should be investigated in prospective trials. The reproducibility of the results obtained by laser scanning microscopy should also be investigated.
Department of 1Dermatology and 2 Gynecology and Obstetrics, Medical Faculty Charité, Berlin, Germany
(*Email: ute.jacobi{at}charite.de).
References
1. Berry G, Billingham M, Alderman E et al. The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal doxorubicin. Ann Oncol 1998; 9: 711–716.
2. Charrois GJ, Allen TM. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta 2004; 1663: 167–177.[Medline]
3. Lotem M, Hubert A, Lyass O et al. Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 2000; 136: 1475–1480.
4. Jacobi U, Waibler E, Bartoll J et al. In vivo determination of doxorubicin and its metabolites within the skin using laser scanning microscopy. Laser Phys Lett 2004; 1: 100–104.[CrossRef]
5. Sato K, Leidal R, Sato F. Morphology and development of an apoeccrine sweat gland in human axillae. Am J Physiol 1987; 252: R166–R180.
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