Re: Article: “Skin problems associated with pegylated liposomal doxorubicin – more than palmoplantar erythrodysesthesia syndrome” by Mangana et al., Eur J Dermatol 2008; 18 (5): 566-70

ARTICLE

Auteur(s) : Roger Von Moos, Richard Cathomas

Medical Oncology, Kantonsspital Graubünden, Loestrasse 170, CH-7000 Chur, Switzerland

With interest we have read the article by Mangana et al. [1] on skin toxicities associated with pegylated liposomal doxorubicin (PLD, Caelyx^®/Doxil^®). They report six cases of severe palmar-plantar erythrodysesthesia (PPE, hand-foot syndrome). Three of these patients experienced classical PPE, while one patient had PPE with extensive bullous disease; one patient developed an eruption of lymphocyte recovery syndrome and one patient showed intertrigo-like dermatitis with stomatitis. The authors concluded that PLD can cause more than just classical PPE. While this is true for the reported case series, we would like to point out that in three of the patients (50%) described, PLD was administered either in single doses above the dose-limiting toxicity or in too short dose intervals, leading to unusually high corresponding weekly doses.

The registered dose of PLD is 50 mg/m² every 4 weeks for patients with ovarian and metastatic breast cancer [2, 3]. However, expert committees recommend the use of pegylated liposomal doxorubicin at corresponding doses of 10 mg/m²/week [4]. Various studies have shown that, with doses of 40 mg/m² every 4 weeks [5, 6], or doses of 20 mg/m² every 2 weeks [7], toxicity, especially regarding PPE, was clearly reduced without compromising therapeutic effectiveness.

In the case report series by Mangana et al., patient number 6 was treated with 85 mg/m2 PLD every 4 weeks for 2 cycles (corresponding weekly dose 21 mg/m²). In comparison, the dose-limiting toxicity in phase I studies was reached at single doses of 70 mg/m² of PLD [8]. Patient number 2 received a weekly dose equivalent to 25mg/m² and patient number 4 one of 20 mg/m² of PLD. Therefore these three patients clearly received PLD doses that are greater than 100% above the recommended dose levels. From a present-day perspective, it would even be advisable to reduce the doses of patients 1 and 5 to 40 mg/m² every 4 weeks or 20 mg/m² every 2 weeks, respectively. Therefore out of the six patients in the case series this leaves only one patient who was treated at current standard doses.

We conclude from the article by Mangana et al. that overdosing of PLD may indeed be associated with the manifestation of skin toxicity in other areas than palms and soles. This is also demonstrated in another case report of a patient treated with 50 mg/m² every 3 weeks who developed severe PPE after 2 cycles but nonetheless received a third cycle and then developed more extensive skin manifestations [9].

By using evidence-based initial dosing of PLD and monitoring of the treatment by an experienced oncologist with attentive dosage- and interval adaptation, together with instructions regarding patient behaviour [4], the skin toxicity of PLD can in many cases be prevented, in others at least markedly alleviated.

Acknowledgements

References

2 O’Brien MER, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (Caelyx/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 2004; 15: 440-9.

3 Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent Epithelial Ovarian Carcinoma: A Randomized Phase III Study of Pegylated Liposomal Doxorubicin versus Topotecan. JCO 2001; 19: 3312-22.

4 von Moos R, Thuerlimann BJ, Aapro M, et al. Pegylated liposomal doxorubicin-associated hand-foot syndrome: recommendations of an international panel of experts. Eur J Cancer 2008; 44: 781-90.

5 Salzberg M, Thurlimann B, Hasler U, et al. Pegylated liposomal doxorubicin (caelyx) in metastatic breast cancer: a community-based observation study. Oncology 2007; 72: 147-51.

6 Al-Batran SE, Meerpohl HG, von Minckwitz G, et al. Reduced incidence of severe palmar-plantar erythrodysesthesia and mucositis in a prospective multicenter phase II trial with pegylated liposomal doxorubicin at 40 mg/m² every 4 weeks in previously treated patients with metastatic breast cancer. Oncology 2006; 70: 141-6.

7 Sehouli J, Oskay-Ozcelik G, Kuhne J, et al. Biweekly pegylated liposomal doxorubicin in patients with relapsed ovarian cancer: results of a multicenter phase-II trial. Ann Oncol 2006; 17: 957-61.

8 Uziely B, Jeffers S, Isacson R, et al. Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 1995; 13: 1777-85.

9 Ziemer M, Goetze S, Kaatz M, et al. Chemotherapy-induced toxic erythema under treatment with pegylated liposomal doxorubicin: No restriction to palms and soles. J Am Acad Dermatol 2008; 58: S44-S46.