Annals of Oncology Advance Access originally published online on March 5, 2008
Annals of Oncology 2008 19(5):1019-1020; doi:10.1093/annonc/mdn053
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letters to the editor |
Reply to Letter to the editor, by Ishiguro et al. (Ann Oncol)
Referring to our recent publication, Ishiguro and colleagues raise concerns about the use of pegfilgrastim 6 mg per cycle to support dose-dense (dd) chemotherapy. While we welcome debate, we would like to correct an inaccuracy in the interpretation of our study. The suggestion that hematological toxicity led to more discontinuations in the pegfilgrastim-supported dd epirubicin+cyclophosphamide
docetaxel (ddECT) and ddTEC arms compared with patients receiving conventional TEC (also with pegfilgrastim support) is incorrect. Neutropenia was the most common adverse event, with grade 4 neutropenia occurring more frequently in patients receiving ddECT than in the other two arms. Adverse events leading to discontinuation were also most frequent with ddECT, but no withdrawals in either dd arm resulted from hematological toxicity. We are unable to comment extensively on the patient reported by your correspondents. This 48-kg Japanese breast cancer patient is described as having a ‘prolonged neutropenia’ after receiving dose dense doxorubicin plus cyclophosphamide supported by pegfilgrastim, yet severe neutropenia was not actually observed until day 26. The hypothesis that this delayed event was linked to prolonged presence of pegfilgrastim seems unlikely. There is some evidence of increased myelosuppression when colony-stimulating factors are given concurrently with chemotherapy [1], but this was not the case here. Dr Ishiguro indicates that some patients receiving pegfilgrastim 6 mg in the study by Green et al. [2] (weight range: 46–125 kg) had elevated levels of the drug at day 14. Yang et al. [3] defined the lowest pegfilgrastim serum concentration to elicit a meaningful clinical effect as 2 ng/ml. They analyzed data from patients (N = 187) in six breast cancer and lymphoma studies, including Green. Over 50% of these patients received pegfilgrastim 6 mg. Serum pegfilgrastim levels dropped sharply from day 7 and, assuming a log-normal distribution of serum concentrations in the population, the proportion of patients with pegfilgrastim levels >2 ng/ml at day 12 was 0.2%. Moreover, in their study of elderly lymphoma patients receiving dd chemotherapy with pegfilgrastim support, Mey et al. [4] reported no accumulation of pegfilgrastim.
Although no large-scale clinical trials of pegfilgrastim with dd chemotherapy have been conducted by the manufacturer, there are increasing reports of its use in this setting (e.g. by Burstein et al. [5]). Consequently, the recommendation that the European Society of Medical Oncology warns against pegfilgrastim use with dd chemotherapy is not supported by the weight of current evidence. Undoubtedly, the patient described was at the lower end of the weight range for which pegfilgrastim 6 mg has been studied (
46 kg). Furthermore, pegfilgrastim has not been specifically studied in Japanese patients. The use of pegfilgrastim in dd regimens is supported by pharmacokinetic/pharmacodynamic data. Nevertheless, physicians must use their clinical judgement in individual cases.
1 Department of Oncology, Hôpital Henri Mondor, Créteil, France
2 Department of Oncology, Institut Sainte Catherine, Avignon
3 Department of Oncology, Hôpital Départemental, La Roche Sur Yon
4 Department of Oncology, Clinique Saint-Come et Saint-Damien, Blois
5 Department of Oncology, Clinique de l'Espérance, Hyères, France
* (E-mail: pascal.piedbois{at}hmn.aphp.fr)
References
1. Neulasta®. Summary of Product Characteristics. Breda, Netherlands: Amgen Europe BV. http://www.amgen.co.uk/pdfs/Neulasta_SPC_Jul_07.pdf (July 2007, date last accessed).
2. Green MD, Koelbl H, Baselga J, for the International Pegfilgrastim 749 Study Group. A randomized, double-blind, multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol (2003) 14:29–35.
3. Yang BB, Kido A, Shibata A. Serum pegfilgrastim concentrations during recovery of absolute neutrophil count in patients with cancer receiving pegfilgrastim after chemotherapy. Pharmacotherapy (2007) 27:1387–1393.[CrossRef][Web of Science][Medline]
4. Mey UJM, Maier A, Schmidt-Wolf IGH, et al. Pegfilgrastim as hematopoietic support for dose-dense chemoimmunotherapy with R-CHOP-14 as first line therapy in elderly patients with diffuse large B cell lymphoma. Support Care Cancer (2007) 15:877–884.[CrossRef][Web of Science][Medline]
5. Burstein HJ, Parker LM, Keshaviah A, et al. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol (2005) 33:8340–8347.
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