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Prolonged neutropenia after dose-dense chemotherapy with pegfilgrastim
- Hiroshi Ishiguro, Toshiyuki Kitano, Hiroshi Yoshibayashi, Masakazu Toi, Takayuki Ueno, Hiroyasu Yasuda, Kazuhiro Yanagihara, Charles L. Garbo, Masanori Fukushima (2 January 2008)
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Hiroshi Ishiguro, Medical Oncologist Outpatient Oncology Unit, Kyoto University Hospital, 606-8507, Japan, Toshiyuki Kitano, Hiroshi Yoshibayashi, Masakazu Toi, Takayuki Ueno, Hiroyasu Yasuda, Kazuhiro Yanagihara, Charles L. Garbo, Masanori Fukushima
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In the dose-dense (DD) adjuvant chemotherapy trial result reported by Piedbois and colleagues in this issue of the Annals of Oncology, they found more grade 3-4 hematological toxicity leading to treatment discontinuation in one of the dose-dense chemotherapy arm supported by pegfilgrastim [1]. The manufacturer’s product information for pegfilgrastim indicates that it should be used once per chemotherapy cycle and should not be used in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy, which is not practically possible in DD chemotherapy. Although ｔhis pegylated formulation of filgrastim has not been approved by the Ministry of Health, Labour and Welfare in Japan, we observed an episode of prolonged severe neutropenia in a Japanese patient who had undergone DD doxorubicin plus cyclophosphamide (AC) neoadjuvant chemotherapy in the United States before being referred to Kyoto University Hospital (Kyoto, Japan) to continue neoadjuvant chemotherapy then perform surgical resection. The patient was a 48-kg Japanese female in her mid-thirties who presented at the Ithaca Medical Group clinic (New York, US) with locally advanced breast cancer. She initially underwent 4 cycles of DD AC chemotherapy, with 6 mg (125 μg/kg) pegfilgrastim administered subcutaneously on day 2 of each cycle. Her absolute neutrophil count (ANC) was 2350/mm3 at the start of the 1st cycle and 3650/mm3, 4150/mm3, and 7300/mm3 at the start of the subsequent AC cycles. After the 4th cycle of DD AC, she was referred to Kyoto University Hospital for further neoadjuvant chemotherapy. ANC at day 20 of the 4th cycle of AC was 3,300/mm3 and we planned to start docetaxel (100 mg/m2) 26 days after completion of the AC regimen. However, her ANC was 500/mm3 on the day that docetaxel treatment was scheduled to begin and we had to postpone chemotherapy. Two weeks later (1 week after the last dose of filgrastim), the patient’s ANC recovered to 1,500/mm3 and she received the 1st cycle of docetaxel (100 mg/m2). She had received a total of 14 administrations of filgrastim starting from day 3 of the 1st cycle of docetaxel, and had been severely neutropenic from day 7 (300/mm3) to day 22 (300/mm3). Her ANC on days 29 and 36 were 600/mm3 and 1100/mm3, respectively. Due to prolonged severe neutropenia, we decided to proceed to surgery instead of continuing neoadjuvant chemotherapy. At the time of writing, the patient is receiving weekly paclitaxel as adjuvant chemotherapy, begun 3 months after the last treatment of neoadjuvant docetaxel, with no major hematological toxicity evident. Broxmeyer and colleagues reported that 50% of bone marrow hematopoietic progenitor cells remained in S-phase at 48 hours after cessation of G-CSF therapy [2], although the manufacturer’s product information for filgrastim recommends a non-use period of just 24 hours before chemotherapy is administered. Furthermore, in a relatively small trial, Tjan-Heijnen and colleagues found that G-CSF administration 48 hours before chemotherapy increases chemotherapy-associated leukocytopenia and thrombocytopenia [3]. Thus, it seems that administration of chemotherapy while hematopoietic progenitor cells are still in S-phase may very well cause more bone marrow suppression. Furthermore, in a clinical trial, serum pegfilgrastim remained elevated in some patients even 14 days after administration of a 6 mg fixed-dose [4] and this residual amount of pegfilgrastim seems dependent on weight-adjusted dose[5]. It is possible that a 6 mg dose of pegfilgrastim is too large for Japanese patients in general, since this dose is also effective in patients weighing 80 to 132 kg, which is approximately twice the weight of the typical Japanese patient population [4]. In our patient, the elevated ANC (3,300/mm3) on day 20 after DD AC treatment and grade 4 neutropenia on day 26 suggest that the effect of pegfilgrastim lasted at least 3 weeks. We therefore caution against the routine use of pegfilgrastim in DD chemotherapy until its safety is established and an optimal dose in this setting is ascertained, especially for low-weight patients. A well-designed clinical trial is needed in order to address these issues. We strongly recommend that the European Society of Medical Oncology warns clinical oncologists against the routine use of pegfilgrastim in DD chemotherapy, which is not an indication approved, and in which situation the drug has never been formally tested for safety and optimal dosage. We believe that such a recommendation would be particularly effective if made through the Annals of Oncology, given that this journal is the most well-known and influential publication for clinical oncologists worldwide. References 1. Piedbois P, Serin D, Priou F et al. Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study. Ann Oncol 2007; 18: 52-57. 2. Broxmeyer HE, Benninger L, Patel SR et al. Kinetic response of human marrow myeloid progenitor cells to in vivo treatment of patients with granulocyte colony-stimulating factor is different from the response to treatment with granulocyte-macrophage colony-stimulating factor. Exp Hematol 1994; 22: 100-102. 3. Tjan-Heijnen VC, Biesma B, Festen J et al. Enhanced myelotoxicity due to granulocyte colony-stimulating factor administration until 48 hours before the next chemotherapy course in patients with small-cell lung carcinoma. J Clin Oncol 1998; 16: 2708-2714. 4. Green MD, Koelbl H, Baselga J et al. 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. 5. Johnston E, Crawford J, Blackwell S et al. Randomized, dose- escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol 2000; 18: 2522-2528. Conflict of Interest:None declared |
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