Research Article: Early neutropenia on day 8 treated with adjuvant Docetaxel-based chemotherapy in early breast cancer patients: Putative mechanisms within the neutrophil pool system

Date Published: April 18, 2019

Publisher: Public Library of Science

Author(s): Yoshihiko Furuya, Giandomenico Roviello.

http://doi.org/10.1371/journal.pone.0215576

Abstract

Most chemotherapy regimens cause neutropenic nadirs between days 10 and 14, and administration of granulocyte colony-stimulating factor (G-CSF) support relies on this timing. In docetaxel (DOC)-based chemotherapy, the frequency of febrile neutropenia (FN) and the G-CSF dose administered varied greatly between studies. Our study goal was to forecast the necessary dose of G-CSF by comparing day 8 neutropenia with putative changes within the neutrophil pool. We conducted a retrospective observational analysis of 242 early breast cancer patients who had received adjuvant DOC-based chemotherapy (DOC group) compared with 43 patients who had received FEC chemotherapy (FEC group). Patients who were given a standard dose and had a blood test on day 8 in the 1st cycle were eligible. In the DOC group, patients routinely received prophylactic administration of G-CSF (150 μg/body) on day 3 and received additional G-CSF based on a blood test on day 8. Results of the day 8 blood test showed that severe neutropenia (<500/mm3, average 494/mm3) was observed in 152 out of 242 (62.8%) patients in the DOC group, while in the FEC group (n = 43), neutropenia was ambiguous (average 1,741/mm3). In the FEC group, 9 out of 43 patients (20.9%) and in the DOC group, 27 out of 242 patients (11.1%) experienced FN. In the DOC group, day 8 neutropenia was predictive for FN in a logistic regression model (OR 0.79 [95% CI: 0.655–0.952], p = 0.013). Among 214 patients under 70 years old, the planned chemotherapy cycle was completed in 190 (88.8%) patients who also received the maximum dose of G-CSF (150 μg/body) four times, while 23 patients could not complete the planned chemotherapy cycle, but only five because of FN-related complications. Patients treated with DOC should be treated for primary prophylaxis with G-CSF support at an earlier time starting with a relatively small dose.

Partial Text

Severe neutropenia caused by myelosuppressive chemotherapy predisposes patients to serious infections. Febrile neutropenia (FN), generally defined as fever with grade 3/4 neutropenia (neutrophil count <1000/mm3 and <500/mm3, respectively) [1], is associated with substantial morbidity and represents an oncologic emergency [2, 3]. The study was approved by the institutional review board of the Saiseikai Osaka Nakatsu Hospital and written informed consent was obtained from all patients prior to surgery or primary chemotherapy. This retrospective analysis included all consecutive patients in an electronic database who were treated with TC, FEC-DOC, and FEC chemotherapy with standard doses for breast cancer at the Saiseikai Osaka Nakatsu Hospital, Osaka, Japan from May 2008 to March 2018. The regimen employed TC (DOC 75 mg/m2 and cyclophosphamide 600 mg/m2 administered i.v. every 3 weeks), FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 administered i.v. every 3 weeks), and DOC (100 mg/m2 i.v. every 3 weeks after completion of three cycles of FEC), as described in the NCCN Guidelines. Doses prescribed were within 5% of the calculated doses based on body surface area. The semi-mechanistic models for neutropenia generally used consist of three compartments [20]. Anticancer drugs affect each compartment and evoke a change in duration of each compartment and its respective interactions. The first is a proliferating compartment that is sensitive to chemotherapy drugs. Destruction of neutrophil progenitors in the bone marrow, known as the most rapidly proliferating cells in the body by a chemotherapy drug, is considered diagnostic of antiproliferative activity. A proliferating compartment sensitive to a chemotherapeutic agent then forms the hematopoietic niche. The second is a transit compartment that represents maturation. Postmitotic bone marrow neutrophils constitute 95% of the neutrophils in the body and this reserve is easily mobilized and recruited rapidly to sites of infection [21, 22]. Transit compartments predict the time delay that mimics the maturation chain in the bone marrow. Studies in healthy volunteers employing tritiated thymidine have shown that postmitotic transit time is ~6.5 days [23]. When recombinant G-CSF is administered, this is reduced to 2.9 days [24]. These durations of transit time between compartments have not been investigated in chemotherapy-treated patients in whom DNA damage to neutrophil progenitor cells can trigger a stop at the G2 to M-phase transition in the cell cycle. The third is a compartment of circulating mature neutrophils. Mature neutrophils had been thought to be remarkably short-lived with a circulating half-life of 6–8 h, but recent studies indicated that their lifespan was in the order of several days [25]. Neutrophil progenitors are diversely differentiated and their fate and lifespan are also known to vary.   Source: http://doi.org/10.1371/journal.pone.0215576

 

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