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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 10  |  Page : 565-570

The change in peripheral blood monocyte count: A predictor to make the management of chemotherapy-induced neutropenia


1 Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, China
2 Department of Radiation and Medical Oncology; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuchang District, Wuhan, China

Date of Web Publication24-Sep-2018

Correspondence Address:
Dr. Conghua Xie
Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuchang District, Wuhan 430071
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.177502

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 > Abstract 


Purpose: The occurrence of neutropenia following chemotherapy makes the management of myelosuppression important. The main objective of this study was to evaluate whether the decrease of peripheral blood monocytes was a potential indicator to predict the occurrence of neutropenia.
Patients and Methods: We retrospectively reviewed the medical records of 103 chemotherapy patients who underwent neutropenia. A paired sample t-test was used to assess whether the number of days when monocyte initial decrease/are in nadir/final increase was significantly less than that of the neutrophils. The baseline of monocyte percentage and the decrease rate of neutrophil were analyzed by the bivariate correlation (two-tailed). Moreover, the grade of neutropenia and the baseline of monocyte percentage (divided into <5% and ≥5%) were examined by the Chi-square test for correlations.
Results: Our study showed that the change trend of monocyte count was the same as that of neutrophil count and that the number of days when monocytes initial decrease/are in nadir/final increase was significantly less than that of neutrophils, respectively. The time of initial decrease in monocyte count was 1.39 days earlier; the nadir in monocyte count occurred 3.81 days earlier, and the final increase in monocyte count was 2.36 days earlier than that in neutrophil count. In addition, there was an inverse correlation between the decrease rate of neutrophil and the baseline of monocyte percentage according to the analysis of bivariate correlation (Pearson correlation = –0.241, P = 0.0142). Unfortunately, there was no significant correlation between the baseline of monocyte percentage and the grade of neutropenia examined with the Chi-square test (P = 0.7401).
Conclusion: Our study shows the increase or decrease in monocyte count is a significant potential indicator to predict the occurrence of neutropenia, and it is also a predictor to guide the next monitoring time of neutrophil count and the treatment of granulocyte-colony stimulating factor.

Keywords: Granulocyte-colony stimulating factor, monocyte, neutropenia, neutrophil


How to cite this article:
Ouyang W, Liu Y, Deng D, Zhou F, Xie C. The change in peripheral blood monocyte count: A predictor to make the management of chemotherapy-induced neutropenia. J Can Res Ther 2018;14:565-70

How to cite this URL:
Ouyang W, Liu Y, Deng D, Zhou F, Xie C. The change in peripheral blood monocyte count: A predictor to make the management of chemotherapy-induced neutropenia. J Can Res Ther [serial online] 2018 [cited 2018 Dec 14];14:565-70. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/565/177502




 > Introduction Top


The occurrence of neutropenia following the administration of cytotoxic anticancer drugs is a frequently adverse effect. Neutropenia and resultant infection not only discontinue chemotherapy but also are potentially life-threatening.[1],[2] It has been increasingly important to make the management of myelosuppression.[3] Recombinant granulocyte-colony stimulating factor (G-CSF) are known to stimulate the proliferation of mitotic cells, to reduce the maturation time of nonmitotic cells in the bone marrow, to prolong the lifespan and enhance the function of mature neutrophils.[4],[5] Therefore, these agents are frequently employed with therapeutic intent in patients with established neutropenia after chemotherapy. Furthermore, several clinical trials also show the prophylactic administration of G-CSF can reduce the incidence of febrile neutropenia and the number of days of hospitalization.[6],[7],[8],[9],[10],[11],[12],[13],[14]

Continuous monitoring of neutrophil count following chemotherapy is only adequate for inpatients. During outpatients' chemotherapy, blood sampling is often just conducted on treatment days. The probability of developing neutropenia is currently predicted on the basis of the physician's experience according to various chemotherapy regimens. Therefore, physicians may ignore numerous cases of Grade 4 neutropenia, which probably leads to dosage reduction or schedule delay in following cycle of chemotherapy or both. It may reduce treatment outcome, also may lead to severe infection, even threaten life.[15] Consequently, in order to offer a safer chemotherapy, it is significant to find a marker which is capable of predicting the occurrence of neutropenia.

In daily clinical practice, we discovered an increase or decrease in monocyte count was prior to changes in the neutrophil count following chemotherapy. Hence, we retrospectively aimed to confirm whether the change of monocyte count is a potential indicator to predict the occurrence of neutropenia, and to further guide the time of blood collection and the administration of G-CSF.


 > Patients and Methods Top


Patients

One hundred and three patients who underwent neutropenia following chemotherapy were reviewed on the basis of electronic medical records, and all of their blood samples were retrospectively analyzed, including neutrophil count, monocyte count, neutrophil percentage, monocyte percentage, the number day of blood collection, and so on. These patients with lung, breast, esophagus, or nasopharynx cancer, were treated with a combined chemotherapy regimen including docetaxel, gemcitabine, cisplatin, or vinorelbine, and so on, from September 1, 2010 to April 12, 2013, at the Department of Radiation and Medical Oncology of Zhongnan hospital of Wuhan University. The backgrounds of the included patients are shown in [Table 1]. Approval of our study was obtained from the Ethics Committee of Zhongnan hospital of Wuhan University. Ethics Committee approved oral informed consent, as the data were reviewed and analyzed anonymously. Informed consent was obtained orally from the included patients by telephone, and all samples were collected for the purposes of research.
Table 1: Characteristics of the included 103 patients

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Treatment

Neutropenia was assessed using the Common Terminology Criteria for Adverse Events Version 4.0. Blood samples were obtained for monitoring the occurrence of neutropenia (<2.0 × 109/L neutrophils). On the basis of the blood sample data, each patient received G-CSF treatment following the occurrence of neutropenia. When neutrophil count rose to normal/above normal, G-CSF administration would be discontinued. If neutrophil count dropped below normal level again, G-CSF would continue to be administrated until neutrophil count return to normal/above normal and no longer drop. The therapeutic dosage range of G-CSF was 100–600 μg/day on the basis of severity of neutropenia.

Information collection and assessment

Blood samples obtained from each patient were analyzed. Before chemotherapy, the count of peripheral blood neutrophil and monocyte detected was defined as its respective baseline. The 1st day of chemotherapy was defined as day zero, the 2nd day of chemotherapy was defined as day one and so on. Following chemotherapy, blood samples were obtained between days 1 and 27. When peripheral blood neutrophil/monocyte count detected was first found to be below its baseline level at the first time, it was considered as the initial decrease, and the number of days after the first day of chemotherapy was calculated, respectively. When the absolute count of neutrophil/monocyte decreased to nadir point, it was considered as the minimal level, and the number of days after the first day of chemotherapy was also calculated, respectively. Similarly, when the absolute count of neutrophil/monocyte begin to increase from its nadir point, and following detection of the absolute neutrophil/monocyte count would not decrease to below normal again, we called it the final increase and, respectively, calculated the number of days after the first day of chemotherapy above definitions are shown in [Figure 1]. Patients were classified as with the baseline percentage of monocyte <5% and ≥5%, and Grades 1–4 neutropenia. The rate of neutrophil decrease was calculated using the equation: (The neutrophil count baseline-the nadir of neutrophil count)/the difference between the number of days. For example, if the neutrophil count baseline was 2 × 109/L detected at day 1 and the nadir of neutrophil count was 1.0 × 109/L detected at day 4, the decrease rate was calculated as (2 × 109/L–1.0 × 109/L)/(4−[−1]) =0.2 × 109/L.
Figure 1: One typical patient's neutrophil/monocyte count variation depended on time. This figure indicates the initial decrease/nadir/final increase point of neutrophil/monocyte. Moreover, the normal level of neutrophil count is 2.0 × 109/L. The patient would be treated with granulocyte-colony stimulating factor (100–600 μg/day) once the neutrophil count below the normal level. It was again confirmed that the change trend of monocyte count was similar with the neutrophil count, and the change of monocyte count was prior to neutrophil count. However, it was also observed that if the monocyte count sharply dropped again, even the absolute count of neutrophil had recovered to normal level, the decrease of neutrophil count probably occurred again

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Statistical analysis

The Statistical Package for Social Scientists (SPSS/Windows, Version 13.0, SPSS Inc., Chicago, USA) was used for all analyses, a two-sided P < 0.05 was considered statistically significant. A paired sample t-test was used to assess whether the number of days when monocyte occurs initial decrease/nadir/final increase after chemotherapy was significantly less than the number of days when neutrophil occur initial decrease/nadir/final increase, respectively. The baseline of monocyte percentage and the decrease rate of neutrophil were analyzed by the bivariate correlation. Moreover, the grade of neutropenia and the baseline of monocyte percentage (divided into <5% and ≥5%) were examined by the Chi-square test for correlations.


 > Results Top


The decrease in monocyte was prior to neutrophil following chemotherapy.

As shown in [Figure 2]a and [Table 2], the initial decrease in monocyte count occurred between days 1 and 11 (mean 4.04, median 4), and the initial decrease in neutrophil count occurred between days 1 and 16 (mean 5.44, median 5). It was evidenced that the initial decrease in monocyte occurred prior to neutrophil following chemotherapy, and the difference was significant (P < 0.001, mean difference = −1.39, 95% confidence interval of the difference: −1.84–−0.96).
Figure 2: The number days of initial decrease/minimal level/final increase in monocyte and neutrophil count. X axis is the number days of initial decrease/minimal level/final increase in monocyte count, and Y axis is number days of initial decrease/minimal level/final increase in neutrophil count. The diagonal line indicates the number days of initial decrease/minimal level/final increase in monocyte count is identical with that in neutrophil count. The point above the diagonal line means the number days in neutrophil is more than that in monocyte. In another word, the point above the diagonal line indicates the occurrence of initial decrease/minimal level/final increase in one patient's monocyte count is prior to neutrophil count. (a) The number days of initial decrease in monocyte and neutrophil count. (b) The number days of minimal level in monocyte and neutrophil count. (c) The number days of final increase in monocyte and neutrophil count. Because our study was retrospective, if the time of blood collection was later than the time of first change in monocyte count, it would probably lead to some points on or below the diagonal line

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Table 2: The number of days of initial decrease/minimal level/final increase in monocyte/neutrophil count

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In the same way, the nadir point of monocyte count was detected between days 2 and 23 (mean 5.65, median 5), and the nadir point of neutrophil count was detected between days 3 and 26 (mean 9.46, median 8). It was also evidenced that the minimum of monocyte occurred prior to neutrophil following chemotherapy as shown in [Figure 2]b and [Table 2], and the difference was significant (P < 0.001, mean difference = −3.81, 95% confidence interval of the difference: −4.38–−3.23), too. Consequently, it was suggested that the decrease of monocyte count could predict the occurrence of neutropenia.

The final increase in monocyte was prior to neutrophil following the administration of G-CSF.

It was observed that after the neutrophil count started to increase from nadir, it might drop again, especially after it had returned to normal and administration of G-CSF had been discontinued. It was found that the neutrophil count of seven patients decreased again except for the initial decrease in this study as shown in [Figure 1] and [Table 3], which presented one of the abovementioned seven patients' neutrophil/monocyte count variation depended on time. In another words, the cell count initial increase is not always its final increase.
Table 3: The time of blood sampling and neutrophil/monocyte count variation of one patient

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As shown in [Figure 2]c and [Table 2], the monocyte count final increase occurred between days 5 and 24 (mean 9.11, median 8), and the neutrophil count final increase occurred between days 6 and 27 (mean 11.49, median 10) after the 1st day of chemotherapy. As a result, it was proved that the final increase of monocyte count occurred prior to neutrophil count following administration of G-CSF, and the difference was significant (P < 0.001, mean difference = −2.36, 95% confidence interval of the difference: −2.78–−1.93). Hence, it was suggested that the increase of monocyte count could predict the final increase of neutrophil.

Besides, as shown in [Figure 1] and [Table 3], when the neutrophil count increased from nadir and returned to normal level, administration of G-CSF discontinued. Next, monocyte count was found the second drop on days 14 and 16, whereas neutrophil count was still above normal level. However, the neutrophil count rapidly decreased to 1.0 × 109/L. This result warned that if the absolute count of monocyte remained at a lower level or sharply dropped again, even the absolute count of neutrophil had recovered to normal level, the decrease of neutrophil count probably occurred again. Therefore, under the condition above, it was still necessary to continue the administration of G-CSF and monitoring of blood sample. All of the results above confirmed that the change trend of monocyte count was similar with the neutrophil count, and the change of monocyte count was prior to neutrophil count.

The decrease rate of neutrophil was inversely correlated with the baseline of monocyte percentage.

As shown in [Figure 3], there was an inverse correlation between the decrease rate of neutrophil and the baseline of monocyte percentage according to the analysis of bivariate correlation (Pearson correlation = −0.241), and the difference was significant (P = 0.0142). However, there was no significant correlation between the baseline of monocyte percentage (divided into <5% and ≥5%) and the grade of neutropenia (P = 0.7401), which was analyzed by the Chi-square test. As shown in [Table 4] and [Figure 4], the frequency of ≥5% monocytes in patients with Grade 3 or 4 neutropenia was similar with that in the patients with Grade 1 or 2 neutropenia, and <5% monocytes group showed a similar trend.
Figure 3: The correlation analysis of the neutrophil decrease rate and the monocyte baseline percentage. There was an inverse correlation between the decrease rate of neutrophil and the baseline of monocyte percentage according to the analysis of bivariate correlation (Pearson correlation = −0.241), and the difference was significant (P = 0.0142)

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Table 4: Cross tabulation of the monocyte percentage and the grade of neutropenia

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Figure 4: Correlation between the fraction of monocytes and the grade of neutropenia. The monocyte baseline percentage was divided into 0% ≤ monocyte percentage <5% group and monocyte percentage p5 group. Moreover, there was no significant correlation between the baseline of monocyte percentage and the grade of neutropenia (P = 0.7401), which was analyzed by the Chi-square test

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 > Discussion and Conclusion Top


The incidence of high-grade neutropenia varies with the dosage, schedule, drug of chemotherapy, and patient-related factors,[16] such as patient age >65 years; poor performance status; poor nutritional status; bone marrow involvement by tumor and so on.[14] It has been reported that patients with high-grade neutropenia (<0.5 × 109/L neutrophils) are at high risk of serious infections,[17] and that once the patient has fever, there is a longer recovery period from neutropenia, even if G-CSF is administered.[3]

The results of our study showed that the trend of change in monocyte count was the same as that in neutrophil count, and the increase or decrease in monocyte count was prior to changes in neutrophil count. For example, the initial decrease in monocyte count occurred 1.39 days earlier than that in neutrophil count; the nadir in monocyte count occurred 3.81 days earlier than that in neutrophil count, and the final increase in monocyte count occurred 2.36 days earlier than that in neutrophil count. Especially, our study suggested that if the absolute count of monocyte remained at a lower level or sharply dropped again, even the absolute count of neutrophil had recovered to normal level, the decrease of neutrophil count probably occurred again. Hence, the increase or decrease of monocyte count can be a useful and significant predictor to guide the next monitoring time of neutrophil count and administration of G-CSF. Consequently, when the peripheral monocyte count of patients following chemotherapy significantly decreased, even if the peripheral neutrophil count remained at normal level, the prophylactic administration of G-CSF could effectively prevent the occurrence of high-grade neutropenia. Conversely, once the significant increase of monocyte count was observed following the administration of G-CSF, even if the neutrophil count remained near the nadir point, the dosage reduction or discontinuation of G-CSF administration should be considered, especially for patients who are high-responsive for the treatment of G-CSF, in case the neutrophil count increased too much, resulting in unintentional overmedication. In addition, we should approve that even if G-CSF is administered, Grades 3–4 neutropenia may persist if the monocyte count remains near the nadir point, which suggested the monitoring of neutropenic patients and the treatment of G-CSF should be continued.

At the same time, there was an inverse correlation between the decrease rate of neutrophil and the baseline of monocyte percentage according to the analysis of bivariate correlation, which suggested that patients with a lower level monocyte percentage baseline should be accepted more frequently blood sampling. Unfortunately, there was no significant correlation between the baseline of monocyte percentage (divided into <5% and ≥5%) and the grade of neutropenia. Therefore, predicting the decrease rate of neutrophil count, rather than the grade of neutropenia, on the basis of the baseline percentage of monocytes is considered to be feasible. The correlation above can also guide the monitoring of blood sample and treatment of G-CSF to some extent.

Unfortunately, our study was conducted retrospectively. In addition, type of carcinoma, type and dosage of chemotherapy regimen, dosage and schedule of G-CSF, and the days of blood sampling varied among the participants. Therefore, we should not regard the results of this study to be absolute. More finely devised prospective study is needed to confirm the conclusion.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (No. 81502308) and the Youth Science Foundation of Zhongnan Hospital, Wuhan University (No. 2014A07).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Matsui K, Mori T, Sawada M, Kuroboshi H, Tatsumi H, Yoshioka T, et al. Evaluation of primary prophylaxis with granulocyte colony-stimulating factor for epithelial ovarian cancer. Eur J Gynaecol Oncol 2014;35:48-51.  Back to cited text no. 13
    
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Quartino AL, Karlsson MO, Lindman H, Friberg LE. Characterization of endogenous G-CSF and the inverse correlation to chemotherapy-induced neutropenia in patients with breast cancer using population modeling. Pharm Res 2014;31:3390-403.  Back to cited text no. 15
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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