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Pre-Treatment CBC and the Prediction of Myelotoxicity
Abstract & commentary
By William B. Ershler, MD
Synopsis: Capitalizing on data from a rather homogenous population of breast cancer patients treated with a single chemotherapy regimen (FEC), Jenkins and Freeman found that pretreatment absolute neutrophil and absolute lymphocyte counts, examined together, were highly predictive of risk for all neutropenic events, including febrile neutropenia, dose delays, and overall reduced dose intensity over the six cycle course of treatment.
Source: Jenkins P, Freeman S. Pretreatment haematological laboratory values predict for excessive myelosuppression in patients receiving adjuvant FEC chemotherapy for breast cancer. Ann Oncology. 2009;20: 34-40.
Neutropenia and associated neutropenic events (NE), such as febrile neutropenia (FN) and treatment delays, are a major untoward effect of many chemotherapy regimens. In addition to the life-threatening aspect of infection in a myelosuppressed patient, there is also the issue of delays or reduction in chemotherapy dose, both of which diminish the intensity of a planned chemotherapy regimen, and such reduced intensity has been associated with reduced treatment effectiveness.1 Thus, identifying factors that might predict NE prior to treatment might prove of clinical value, such that prophylactic measures could be undertaken.
The current research was undertaken to determine if the pretreatment complete blood count (CBC) might be used to predict NE. Jenkins and Freeman analyzed a large cohort (n = 741) of breast cancer patients who received adjuvant or neo-adjuvant FEC (5-fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 intravenously every three weeks) for a planned six cycles. Capitalizing on an electronic database patient management information system employed at the Gloucestershire Cancer Center, all FEC-treated breast cancer patients were identified between the years 2001-2005 and because a dose-banding algorithm was employed by the Center's pharmacy; the actual doses employed were within 5% of those calculated based upon body surface area (BSA). Each cycle of treatment was delivered if the absolute neutrophil count (ANC) was > 1.5 x 109/l and the platelet count > 100 x 109/l. If not, chemotherapy was delayed for one week. If chemotherapy had to be delayed on two occasions due to inadequate blood counts, a dose reduction of 20% was made for all agents and maintained for the rest of the treatment course. Greater dose reductions were instituted if the patient experienced further myelosuppression despite these modifications. After an episode of FN, doses were also reduced by 20%. Granulocyte colony-stimulating factors (G-CSFs) were not employed as either primary or secondary prophylaxis during the period of this study. No patient received concomitant radiotherapy, and endocrine treatment was only commenced after completion of chemotherapy. A NE was defined as either an episode of FN or a dose delay > 1 week caused by prolonged myelosuppression. Dose intensity was defined as (dose received/dose planned)/(overall treatment time/planned treatment time) over six cycles of treatment.2 This was considered to be suboptimal if it fell < 0.85 (DI < 85%).3
Of the 741 consecutively treated patients, 192 had a schedule interruption on the basis of myelotoxicity. Of these, 53 had an episode of FN (three patients had two episodes) and 160 experienced one or more treatment delays due to myelosuppression. In total, 104 (17.3%) patients had a dose intensity (DI) of < 85% and 10 (1.6%) a DI < 65% due to myelosuppression. While treatment delays were evenly spread throughout the planned six cycles of chemotherapy, FN was most common in cycle 1 (25 of 53, 47%). Of note, 83% of patients who experienced a neutropenic event in cycle 1 went on to receive a DI of < 85%, whereas, of the 29 patients with FN in cycles 2-6, only two (7%) had experienced a previous treatment delay due to neutropenia.
Regarding the pretreatment CBC as a predictor of neutropenic events (NEs), it was found that both the absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were strongly associated with the risk of febrile neutropenia (FN), dose delays, and receiving suboptimal chemotherapy dose intensity (DI < 85%). On the basis of ANC and ALC, the total population was divided into quintiles, and it was found that the risk of any NE varied by 2.8-fold (from 18% to 52%) between the separate groups, the risk for a DI of < 85% varied four-fold (9% to 36%), and the risk for FN by 5.3-fold (4% to 21%) between the groups.
FEC chemotherapy at these doses is not considered a high risk for producing myelotoxicity, but 26% of patients still had scheduled interruptions, and 13% had dose reductions because of NEs. Using pretreatment differential white blood cell count to identify patients at an increased risk of significant myelosuppression, whether such a model can be extrapolated to other chemotherapy regimens or other clinical settings, will require additional investigation. Certainly, the concept is a good one and, if substantiated, would provide an inexpensive method of predicting those patients at risk for neutropenic events and for whom primary prophylaxis with granulocyte colony stimulation factor (G-CSF) would be warranted.
1. Budman DR, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998;90: 1205-1211.
2. Longo DL, et al. The calculation of actual or received dose intensity: a comparison of published methods. J Clin Oncol. 1991;9: 2042-2051.
3. Bonadonna G, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332: 901-906.