Onycholysis secondary to multiple paclitaxel 1-hour infusions: possible role for its vehicle (Cremophor EL)

U. De Giorgi*,1, G. Rosti1, M. Monti1, G. L. Frassineti2 and M. Marangolo1

1 Istituto Oncologico Romagnolo, Department of Oncology, Santa Maria delle Croci Hospital, Ravenna; 2 Istituto Oncologico Romagnolo, Department of Oncology, Pierantoni Hospital, Forli, Italy

*E-mail: ugo_degiorgi@yahoo.com

We read with interest the clinical cases describe by Minisini et al. and their review of the literature related to nail toxicity associated with taxane therapy [1]. Nail changes are reported with docetaxel given as 3-weekly or weekly schedules, and with weekly paclitaxel. The authors suggested that nail changes were based on taxane-induce vascular abnormalities (hematoma, hemorrhagic lesions) and neurotoxic damage (onycholysis). Previous reports focusing on onycholysis after prolonged weekly paclitaxel hypothesized direct toxicity to the nail bed, inhibition of angiogenesis, a possible role of ultra-violet light in nail damage, higher paclitaxel dose density and cumulative doses reached with weekly schedules [25]. Overall, onycholysis was reported in 15–25% patients after prolonged weekly paclitaxel treatment, but it was not observed under the standard 3-weekly regimen [15].

We are currently conducting a study of high dose density chemotherapy in high-risk breast cancer patients. The protocol requires a mobilizing course consisting of epirubicin 150 mg/m2, preceded by dexrazoxane (day 1), and paclitaxel 175 mg/m2 plus filgrastim (day 2); followed by three courses of epirubicin 150 mg/m2, preceded by dexrazoxane (day 1), and paclitaxel 400 mg/m2 (day 2), with peripheral blood progenitor cell support and filgrastim every 16–19 days. Paclitaxel was given as a 6-h infusion in the first 24 evaluable patients (P6h patients), then as a 24-h infusion in the next 15 evaluable patients (P24h patients). The infusion time of paclitaxel 400 mg/m2 was modified in order to reduce the neurotoxicity of this regimen. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0 (NCI-CTC 2.0), which describe two grades of nail changes: discoloration, ridging (koilonychia) or pitting (grade 1); and partial or complete nail loss (onycholysis) or pain in nailbeds (grade 2) [6].

In our experience, ridging has been reported in six (25%) of 24 P6h patients and four (27%) of 15 P24h patients, and hyperpigmentation of the hyponychia was reported in eight (33%) of 24 P6h patients and two (13%) of 15 P24h patients. Hyperpigmentation of the hyponychia is known to be regularly induced by anthracyclines and taxanes [2]. No cases of grade 2 nail toxicity have been observed, despite the very high paclitaxel total cumulative dose and dose density (1375 mg/m2 and 137 mg/m2/week, respectively), and patients receiving not only high-dose paclitaxel, but also high-dose epirubicin that potentially may also induce onychopathy. The suggestion that use of dose-intensified paclitaxel schedules may induce relevant toxicities to the nails by itself cannot be supported by our experience.

We propose to focus on the 1-h infusion that is peculiar to the weekly paclitaxel administration. Unbound paclitaxel (pharmacologically active form) and paclitaxel vehicle Cremophor EL disposition are subject to considerable variability depending on the paclitaxel infusion duration [7]. The systemic exposure, i.e. area under the curve (AUC), to Cremophor EL is significantly higher with the 1-h than the standard 3-h schedule. In contrast, the AUC of unbound paclitaxel is substantially reduced after 1-h infusion. Because the AUC of unbound paclitaxel is related to the neutrophil survival fraction, these findings explain, at least in part, observations that 1-h infusion schedules lack significant myelotoxicity, whereas potentially Cremophor EL-related side-effects, including acute hypersensitivity reactions and peripheral neuropathy, are augmented [7, 8]. Furthermore, weekly oral paclitaxel, without the absorption of Cremophor EL, is associated with no hypersensitivity reactions, only grade 1 neurotoxicity in <5% of cases, and no nail changes [9].

We believe that these findings are convincing enough to consider that onycholysis, presenting after multiple paclitaxel 1-h infusions only, might represent a side-effect related to the paclitaxel vehicle Cremophor EL, possibly through neurotoxic damage. In addition, docetaxel was administered with the same infusion time (1 h) in every schedule, and its vehicle (Tween 80), which shares some constituents and in part some side-effects with Cremophor EL [8], might be involved in the docetaxel-related nail toxicity.

U. De Giorgi1*, G. Rosti1, M. Monti1, G. L. Frassineti2 & M. Marangolo1

1Istituto Oncologico Romagnolo, Department of Oncology, Santa Maria delle Croci Hospital, Ravenna; 2Istituto Oncologico Romagnolo, Department of Oncology, Pierantoni Hospital, Forli, Italy (*E-mail: ugo_degiorgi@yahoo.com)

References

1. Minisini AM, Tosti A, Sobrero AF et al. Taxane-induced nail changes: incidence, clinical presentation and outcome. Ann Oncol 2003; 14: 333–337.[Abstract/Free Full Text]

2. Hussain S, Anderson DN, Salvatti ME et al. Onycholysis as a complication of systemic chemotherapy. Report of five cases associated with prolonged weekly paclitaxel therapy and review of the literature. Cancer 2000; 88: 2367–2371.[CrossRef][ISI][Medline]

3. Lüftner D, Flath B, Akrivakis C et al. Dose-intensified weekly paclitaxel induces multiple nail disorders. Ann Oncol 1998; 9: 1139–1141.[CrossRef][ISI][Medline]

4. Flory SM, Solimando DA Jr, Webster CJ et al. Onycholysis associated with weekly administration of paclitaxel. Ann Pharmacother 1999; 33: 584–586.[Abstract/Free Full Text]

5. Spazzapan S, Crivellari D, Lombardi D et al. Nail toxicity related to weekly taxanes: an important issue requiring a change in common toxicity criteria grading? J Clin Oncol 2002; 20: 4404–4405.[Free Full Text]

6. Cancer Therapy Evaluation Program. Common toxicity criteria manual: common toxicity criteria, version 2.0. Bethesda, MD: National Cancer Institute 1999 [on-line] http://ctep.cancer.gov/forms/CTCv20_4-30-992.pdf (date last accessed, 10 April 2003).

7. Gelderblom H, Mross K, ten Tije AJ et al. Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions. J Clin Oncol 2002; 20: 574–581.[Abstract/Free Full Text]

8. van Zuylen L, Verweij J, Sparreboom A. Role of formulation vehicles in taxane pharmacology. Invest New Drugs 2001; 19: 125–141.[CrossRef][ISI][Medline]

9. Kruijtzer CM, Boot H, Beijnen JH et al. Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer. Ann Oncol 2003; 14: 197–204.[Abstract/Free Full Text]





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