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Cryotherapy for the prevention of high-dose melphalan-induced oral mucositis

Bone Marrow Transplantation volume 38, pages 637–638 (2006)Cite this article

High-dose melphalan (⩾140 mg/m2) alone or in combination with other chemotherapeutic agents or total body irradiation has been frequently used as conditioning for autologous or allogeneic hematopoietic stem cell transplantation (HSCT).1, 2, 3 Severe mucositis, however, remains as one of the major complications of high-dose melphalan. We read with great interest the recent article by Lilleby et al.,4 in which they reported the results of a prospective, randomized study of cryotherapy for the prevention of high-dose melphalan (200 mg/m2)-induced oral mucositits in patients undergoing autologous peripheral blood stem cell transplantation. They showed that oral cryotherapy contributes significantly to a decrease in the incidence and duration of grades 3–4 oral mucositis, as do the uses of narcotics and total parenteral nutrition.4 In their study, patients were instructed to continue cryotherapy for 7 h (30 min before, 30 min during and 6 h after the infusion of melphalan), but compliance with the cryotherapy was not universal owing to complaint(s) regarding the cold. In addition, the authors could not describe the exact mean or median duration of cryotherapy performed because of missing data. We have previously reported the efficacy of oral cryotherapy in the prevention of high-dose melphalan (140 mg/m2)-induced oral mucositis in patients undergoing allogeneic HSCT.5 In the present study, 18 patients underwent cryotherapy for 120 min (15 min before, 15 min during and for 90 min after the infusion of melphalan), and only two patients (11.1%) developed grades 2–3 oral mucositis. The incidence was significantly lower than that of historical group (85.7%; P=0.001). This cryotherapy was well-tolerated, although 39% of the patients complained of coldness or chills. We have recently attempted to shorten the duration of cryotherapy to 60 min (15 min before, 15 min during and for 30 min after the infusion of melphalan), and have succeeded in reducing the unpleasant symptoms associated with cryotherapy without increasing the incidence and severity of oral mucositis.6 In our studies, the duration of cryotherapy was determined based on the pharmacokinetics of high-dose melphalan. A high dose of melphalan shows a biphasic plasma half-life (t1/2); a distribution phase t1/2, 6–16 min and an elimination phase t1/2, 40–83 min (Gouyete et al.,7 and an internal report of GlaxoSmithKein Inc.). We hypothesized that a higher concentration of melphalan in the distribution phase would play a more important role in causing oral mucositits, and therefore set a shorter duration of cryotherapy than that of Lilleby's study. The results of our latest study confirm that cryotherapy during the distribution phase is as effective as cryotherapy of longer duration.6 Two previous studies demonstrating the efficacy of cryotherapy (during and 5 or 30 min after melphalan infusion) for preventing melphalan-induced oral mucositits also reinforce our results.8, 9

Because a variety of differences do exist between the report of Lilleby et al. and our two reports, including the dose of melphalan and stem cell sources, it is difficult to draw firm conclusions by simply comparing the results. Nevertheless, we think that the pharmacokinetics of high-dose melphalan and the results of our studies strongly suggest that 6 h of oral cryotherapy after the infusion of melphalan for the prevention of oral mucositis seems excessive, and additional study should attempt to determine the optimal duration of cryotherapy.

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  1. Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

    T Mori, Y Aisa, R Yamazaki, A Mihara, Y Ikeda & S Okamoto

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  1. T Mori
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Mori, T., Aisa, Y., Yamazaki, R. et al. Cryotherapy for the prevention of high-dose melphalan-induced oral mucositis. Bone Marrow Transplant 38, 637–638 (2006). https://doi.org/10.1038/sj.bmt.1705494

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