**7. Neutropenia diagnosis**

The diagnosis of neutropenia is usually made by performing the following tests:

#### **7.1. Complete blood count**

The first test to investigate the suspicion of neutropenia presence is to perform complete blood count (CBC) or full blood count (FBC) whereby the neutrophil numbers will be measured. If the results showed a low neutrophil count then these tests will be repeated in order to be certain that neutropenia is actually present [21].

#### **7.2. Bone marrow aspirate/trephine biopsy**

After performing a blood test, a bone examination could be carried out to confirm the results. Bone marrow biopsy is done by obtaining bone marrow aspirates from two sites that are from the middle of the bone and also from solid bonier part of the bone. This bone biopsy is performed with the patient under general anesthesia or local anesthesia with sedation. These bone marrow samples are usually taken from the large bones such as large pelvic bone, the ilium, or sometimes from the flat breastbone (i.e., the sternum) [21].

## **8. Causes of neutropenia**

Neutropenia is usually diagnosed by a complete blood count (CBC) or full blood count (FBC). If the results show a low ANC then these tests are repeated [15]. If the repeated test shows the same results, a bone marrow biopsy is carried out to confirm the diagnosis. Bone marrow aspirate is taken from two sites, one from the middle of the bone and one from the solid, bonier

Febrile neutropenia (i.e., neutropenia with fever) is mostly associated with chemotherapy, but it may also occur after irradiation of the bone marrow. In this chapter, the term febrile neutropenia is usually used to describe the occurrence of neutropenia (body temperature ≥38.3°C or oral temperature ≥38°C for more than hour) and an ANC of ≤ 500 cells/µl at the time

Neutropenia has many negative effects. One of these side effects is dose reduction of chemo‐ therapy. Fifty percent (50%) of cancer patients received less than 85% of the prescribed doses

Neutropenia can also cause delays in chemotherapy treatment, which can lead to increase in cancer cell growth and tumor size. Both dose reduction and delay of chemotherapy can have

Neutropenia also has a dramatic and detrimental effect on the patients' quality of life. Fatigue is the predominant characteristic, which leads to a decrease in the ability to perform daily life activities. Patients describe fatigue as feeling weak and exhausted. Psychological problems were also reported by the patients, such as sadness, anxiety, reduced self-worth, and inability

The first test to investigate the suspicion of neutropenia presence is to perform complete blood count (CBC) or full blood count (FBC) whereby the neutrophil numbers will be measured. If the results showed a low neutrophil count then these tests will be repeated in order to be certain

After performing a blood test, a bone examination could be carried out to confirm the results. Bone marrow biopsy is done by obtaining bone marrow aspirates from two sites that are from

The diagnosis of neutropenia is usually made by performing the following tests:

part of the bone, usually from the large pelvic bone, the ilium, or the sternum [15].

of fever, or in the following 48 hours [2, 14, 15, 16, 17, 18].

serious effects on patients' lives, and may even lead to death [19, 20].

**6. Adverse effects**

204 Updates on Cancer Treatment

because of neutropenia.

to fulfill normal roles [19, 20].

**7. Neutropenia diagnosis**

**7.1. Complete blood count**

that neutropenia is actually present [21].

**7.2. Bone marrow aspirate/trephine biopsy**

Demographic factors, hematological disorders, autoimmune diseases, infections, drugs reactions, and chemotherapy or radiotherapy play a major role in the etiology of neutropenia [2, 13, 17]. Neutrophil production is lower among older people; they are not as able to produce mature neutrophil as younger people, and ANC in White men is higher than that in Black men. Also neutropenia incidence seems to be higher in women than men [2, 13, 14]. Hematological diseases like leukemia, myelodysplastic syndrome, Hodgkin's and non-Hodgkin's diseases, and multiple myeloma have also been shown to cause neutropenia [2]. In these hematological diseases, severe destruction of bone marrow leads to the destruction of stem cells. This will result in the prevention of or decrease in neutrophil production, thus causing neutropenia [2]. Moreover, these hematological diseases can have an effect on the red blood cells (RBC) and platelet production which can lead to severe anemia and thrombocytopenia. Usually the patient will suffer from fever ≥ 38.5°C as well as gingivitis, bleeding, stomatitis, bone chills, and the patient might also collapse [22]. Neutropenia has also been associated with autoim‐ mune diseases like systemic lupus erythromatosis (SLE). Neutropenia following SLE is usually mild and the patient may not suffer from serious bacterial infection. However patients with Sjören syndrome and rheumatoid arthritis may have severe neutropenia, leaving them at higher risk of bacterial or fungal infection [2]. Many drugs such as diuretics, chlorpromazine, and allopurinol have been shown to cause neutropenia, and two mechanisms for this have been suggested. The first postulates that the drug produces dose-dependent toxicity on cell production, protein synthesis, bone marrow, and cell survival. The second suggests a mecha‐ nism of drug-inducing immunological reactions, for example, the binding of drugs with the surface of the neutrophil cell, leading to cell destruction and neutropenia. These two mecha‐ nisms are not always seen; they happen in only a small percentage of patients. These two mechanisms also require a long duration of drug use [2].

## **9. Chemotherapy**

Neutropenia is mostly associated with chemotherapy and radiotherapy. Chemotherapeutic drugs affect the production of folic acid as well as the synthesis of DNA, RNA and protein by acting as anti-metabolites, which lead to bone marrow destruction [2, 13, 14, 22]. Bone marrow destruction in turn leads to a decrease in neutrophil production. Therefore, chemotherapy and radiotherapy are considered to be the main causes of neutropenia and febrile neutropenia. Besides that, chemotherapeutic drugs kill and suppress all the cells that have a high rate of division or affect blood cells, bone cells, and neutrophil cells (Fortner *et al*.*,* 2005). The chemo‐ therapeutic drugs actinomycin, asparaginase, cytarabine, busulfan, cisplatin, daunorubicin, etoposide, fluorouracil, ifosfamide, and methotrexate are highly associated with neutropenia development [2, 14, 23].

The link between chemotherapy and neutropenia was emphasized by Buffoni *et al.* (2006) who looked at the effect and toxicity of chemotherapeutic drugs on 30 non-small lung cancer patients treated with a combination of cisplatin and vinorelbine on day 1 and day 8 and repeated every 21 days. The major toxic effect associated with these chemotherapies was neutropenia 3 and 4 (63%). The treatment also caused three deaths, two of which were due to febrile neutropenia. Hence it can be concluded that even though the combination of cisplatin and vinorelbine was very effective in the treatment of lung cancer, it was also associated with neutropenia, some of which was fatal [24].

Yamanaka *et al*. (2007) conducted a study 1055 patients in Japan with advanced gastric cancer on oral fluoropyrimidine derivatives (S-1). The main important result of the study was that neutropenia incidence was an inadequate predictor of increased survival in these patients. Also the another important point of their study was that the absence of neutropenia indicated that the doses of the chemotherapeutics drugs were not intensive enough to cause neutropenia [25]. This point was also indicated in the observational retrospective study carried out in Penang Hospital on 117 solid tumor patients who were admitted between January 2003 and December 2006, and treated with various types of chemotherapy regimens. The highest chemotherapeutic regimen received in this study was (5-FU + epirubicin + cyclophosphamide) (47, 40.2%), followed by (gemcitabine + cisplatin) (6, 5.1%), and others. The majority of the patients in the study were on a 1-day chemotherapy administration schedule of (90, 76.9%), followed a schedule of more than one day (27, 23.1%). The statistical analysis of Chi-square test results showed insignificant associations between chemotherapy type and neutropenia incidence (*P=*0.798) and neutropenia severity (*P=*0.199). The same results were found between neutropenia incidence and chemotherapy administration schedule and duration (*P=*0.689) and neutropenia severity (*P=*0.434).

The main explanation for these results was that the doses of these drugs were not high enough to cause bone marrow suppression and lead to neutropenia. Moreover, the administration schedule for each drug was long enough to overcome neutropenia, and the high use of G-CSF likely played a major role in reducing the time and neutropenia severity. All these factors likely contributed to the non-significant association observed between neutropenia incidence and severity, and chemotherapeutics drugs and administration schedule [26]. The correct doses of chemotherapeutic drugs must be used in order to prevent the incidence of lethal neutropenia [27].

Another study looking at the association between neutropenia and chemotherapy drugs was conducted by Banerji *et al*. (2006) in the United Kingdom. The study involved 173 patients treated with etoposide and carboplatin. The results obtained from the study showed a significant association between neutropenia and the chemotherapy drugs (*P* <0.0001) [28].

However, different chemotherapy regimens are not associated with the same neutropenia severity. This difference is due to substantial variations in the resiliency of hematopoietic tissues among cancer patients and chemotherapy tolerance. Moreover, severe neutropenia has been reported in patients with solid cancers, especially breast cancer patients, when treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF), suggesting that neutropenia is associated with the intensity of the chemotherapy regimens [8], for example, the doses of cytotoxic drugs such as epirubicin, cisplatin, doxorubicin, vincristine, capecitabine, carbopla‐ tin, and bleomycin were not high or intensive and they do not seem to cause severe neutropenia (i.e., neutropenia is considered a minor side-effect for these chemotherapies). But these low chemotherapy doses can cause other major adverse effects like nausea, vomiting, thrombocy‐ topenia, alopecia, and anemia [29, 30, 31].

#### **9.1. Role of route of chemotherapy administration**

therapeutic drugs actinomycin, asparaginase, cytarabine, busulfan, cisplatin, daunorubicin, etoposide, fluorouracil, ifosfamide, and methotrexate are highly associated with neutropenia

The link between chemotherapy and neutropenia was emphasized by Buffoni *et al.* (2006) who looked at the effect and toxicity of chemotherapeutic drugs on 30 non-small lung cancer patients treated with a combination of cisplatin and vinorelbine on day 1 and day 8 and repeated every 21 days. The major toxic effect associated with these chemotherapies was neutropenia 3 and 4 (63%). The treatment also caused three deaths, two of which were due to febrile neutropenia. Hence it can be concluded that even though the combination of cisplatin and vinorelbine was very effective in the treatment of lung cancer, it was also associated with

Yamanaka *et al*. (2007) conducted a study 1055 patients in Japan with advanced gastric cancer on oral fluoropyrimidine derivatives (S-1). The main important result of the study was that neutropenia incidence was an inadequate predictor of increased survival in these patients. Also the another important point of their study was that the absence of neutropenia indicated that the doses of the chemotherapeutics drugs were not intensive enough to cause neutropenia [25]. This point was also indicated in the observational retrospective study carried out in Penang Hospital on 117 solid tumor patients who were admitted between January 2003 and December 2006, and treated with various types of chemotherapy regimens. The highest chemotherapeutic regimen received in this study was (5-FU + epirubicin + cyclophosphamide) (47, 40.2%), followed by (gemcitabine + cisplatin) (6, 5.1%), and others. The majority of the patients in the study were on a 1-day chemotherapy administration schedule of (90, 76.9%), followed a schedule of more than one day (27, 23.1%). The statistical analysis of Chi-square test results showed insignificant associations between chemotherapy type and neutropenia incidence (*P=*0.798) and neutropenia severity (*P=*0.199). The same results were found between neutropenia incidence and chemotherapy administration schedule and duration (*P=*0.689) and

The main explanation for these results was that the doses of these drugs were not high enough to cause bone marrow suppression and lead to neutropenia. Moreover, the administration schedule for each drug was long enough to overcome neutropenia, and the high use of G-CSF likely played a major role in reducing the time and neutropenia severity. All these factors likely contributed to the non-significant association observed between neutropenia incidence and severity, and chemotherapeutics drugs and administration schedule [26]. The correct doses of chemotherapeutic drugs must be used in order to prevent

Another study looking at the association between neutropenia and chemotherapy drugs was conducted by Banerji *et al*. (2006) in the United Kingdom. The study involved 173 patients treated with etoposide and carboplatin. The results obtained from the study showed a significant association between neutropenia and the chemotherapy drugs (*P* <0.0001) [28].

However, different chemotherapy regimens are not associated with the same neutropenia severity. This difference is due to substantial variations in the resiliency of hematopoietic

development [2, 14, 23].

206 Updates on Cancer Treatment

neutropenia, some of which was fatal [24].

neutropenia severity (*P=*0.434).

the incidence of lethal neutropenia [27].

The route of chemotherapy administration could be either systematic which includes: intra‐ venous (I.V), oral, and intramuscular (I.M) or local intrathecal, intraperitoneal, intra-arterial, and intrapleural. The most commonly used administration routes are the intravenous and the oral route. The advantage of administering chemotherapy by these two routes is that tumor cells throughout the body would be exposed to the chemotherapy. However, the disadvantage is that sensitive tissues such as in the bone marrow and mucosa will also be equally exposed to these chemotherapeutic drugs. So the main goal of I.V administration of chemotherapy is to achieve a systematic chemotherapy concentration that is effective for the cancer treatment of the cancer concerned [32]. When the chemotherapy is administered by the I.V. route, the entire dose of the chemotherapy drug will be in the blood circulation and produce its effect on the cancer cells. This will also lead to an increase in its adverse effect as compared to the oral route whereby the drugs will be slowly absorbed and the concentration will increase gradually thus not producing major side effects. But there will be no difference between the oral and the I.V. route in the part concerned with neutropenia incidence, onset, or severity, since neutro‐ penia is related to chemotherapeutics intensity and effects but not with the route of adminis‐ tration [32, 33].

Jassem *et al*. (2003) focused on the effect of oral and I.V. administration of chemotherapeutic drugs on neutropenia incidence. In their study, 56 patients were treated with vinorelbine and cisplatin for their non-small cell lung cancer (NSCLC). On day 1 both drugs were given via I.V. route, and this was followed by cisplatin I.V. and vinorelbine oral on days 8, 15, and 22. The cycle was repeated every 28 days. The great and the predominant side effect observed was neutropenia, that is, 73% of the patients had grade 3 (severe) and 4 (life threatening) neutro‐ penia and anemia had a lower percentage of incidences. Thus, Jassem and his colleagues' study demonstrated that the route of chemotherapy administration has no significant effect on their pharmacological action, since both routes produced similar efficacy and safety as well as similar side effects. However, the important point of their study was the new approach of I.V. administration on day 1, and oral administration on days 8, 15, and 22 which is more suitable and comfortable to the patients. However, the route of administration had no effect on the chemotherapy toxicity since neutropenia and anemia were still the major side effects produced by these chemotherapeutics drugs [34].

#### **9.2. Impact of chemotherapy cycles and schedule on neutropenia**

It is preferred to administer on a continuous basis for maximal cancer cell killing and to decrease the development of cancer cells resistance. However, chemotherapy toxicity results in the destruction of normal cells, and thus should be stopped for sufficient intervals so as to allow normal cells to recover. The duration of chemotherapy administration is known as chemotherapy cycle. Neutropenia incidence is mainly and highly associated with the first cycle of the chemotherapy more than the other or subsequent cycles. Indeed, the depletion of the bone marrow will lead to decreased production of the neutrophils and neutropenia which mainly occur with the first cycle of chemotherapy.

The association was determined by a study conducted in the United States of America by Crawford *et al*. (2005) The study included more than 4,000 cancer patients age ranged from 18 to 97 years. More than 100 different chemotherapeutic regimens were reported and the most frequently used chemotherapeutics were anthracyclines (35%), platinum compounds (33%) and fluorouracil (20%). Neutropenia occurrence after the first cycle of the chemotherapy was documented in 2,160 patients. Neutropenia with ANC nadir of < 1 × 109 cell/ L was observed in 43% of the patients, while severe neutropenia (ANC nadir < 0.5 × 109 cell/ L) was seen in 24% of the studied population. Fourteen percent of the patients had febrile neutropenia, while severe febrile neutropenia was found in 9% [35].

Another study in the United States conducted by Wolf *et al*. (2005) on 2,222 cancer patients showed that one-third of them were treated with fewer than four cycles of the chemotherapy due to complications. The most important result obtained was that half of the cases of neutropenia occurred during the first cycle of chemotherapy, especially among breast cancer patients [36].

The relationship between chemotherapy and neutropenia was also reported by Schallier *et al*. (2007). He conducted a study in Belgium on 48 non-small lung cancer patients treated with three cycles of paclitaxel, carboplatin, and gemcitabine. Schallier and his colleagues aimed to detect the toxicity of these chemotherapies after each cycle. The results of their study showed that the chemotherapy-induced neutropenia happened on days 8 and 15 of the first cycle. During the second cycle, 34 out of 42 patients developed neutropenia on day 15. Neutropenia was also prominent on day 15 of the third cycle, during which 24 out of 42 patients developed it. Therefore, the study showed that there was a strong relation‐ ship between chemotherapy cycle and neutropenia incidence. However, there was no significant relationship between chemotherapy cycle and neutropenia severity, which remained the same across the three cycles [37].

Neutropenia severity mainly increases due to chemotherapeutic drugs schedules [38]. Chemotherapeutic drugs are usually administered in a manner that will enhance their main benefits and reduce or prevent their toxic effects [32, 33, 39], but the duration of administration is also controlled by the pharmacokinetic and pharmacodynamic characteristics of the drug used, as some chemotherapeutic drugs can cause severe bone marrow suppression, such as the alkylating agent cyclophosphamide. These drugs are usually administered by pulse method, that is, for a short period (usually 1 day) followed by a long interval before the next dose is given. This will give time for both the bone marrow and neutrophils to recover [40]. When given on a longer administration schedule, drugs such as 5-flurouracil will lead to the inhibition of RNA synthesis of the cancer cells, thus killing them. However, when given as a single bolus dose they will lead to the inhibition of thymidylate synthesis, which will result in severe side-effects. On the other hand, paclitaxel, when given for more than 1 day, will mainly lead to severe toxicity and cause more destruction of the bone marrow. However, when given for 1 day, paclitaxel will render the desired anticancer effect, with fewer effects on bone marrow. The standard interval between each cycle, whether the cycle lasts 1 day or more, ranges from 21 to 28 days [32, 33, 39].

## **10. Prevalence and incidence of neutropenia**

Neutropenia generally occurs in one out of three patients treated with chemotherapy. Once neutropenia happens, it may threaten the patient's life, and chemotherapy schedule or dose should be delayed in order to give the body a chance to produce new neutrophils [41, 42, 43, 44]. Although neutropenia is common during chemotherapy, severe neutropenia is not and can cause serious morbidity and mortality due to resulting infections. Epidemiological studies have shown a wide variation in neutropenia incidence according to geographic regions. The average incidence of neutropenia in the United States is 56.4 per million people. There are no, or very few studies that give an exact number of neutropenia prevalence [45].

#### **11. Risk factors for neutropenia**

#### **11.1. Gender**

**9.2. Impact of chemotherapy cycles and schedule on neutropenia**

in 43% of the patients, while severe neutropenia (ANC nadir < 0.5 × 109

mainly occur with the first cycle of chemotherapy.

severe febrile neutropenia was found in 9% [35].

remained the same across the three cycles [37].

patients [36].

208 Updates on Cancer Treatment

It is preferred to administer on a continuous basis for maximal cancer cell killing and to decrease the development of cancer cells resistance. However, chemotherapy toxicity results in the destruction of normal cells, and thus should be stopped for sufficient intervals so as to allow normal cells to recover. The duration of chemotherapy administration is known as chemotherapy cycle. Neutropenia incidence is mainly and highly associated with the first cycle of the chemotherapy more than the other or subsequent cycles. Indeed, the depletion of the bone marrow will lead to decreased production of the neutrophils and neutropenia which

The association was determined by a study conducted in the United States of America by Crawford *et al*. (2005) The study included more than 4,000 cancer patients age ranged from 18 to 97 years. More than 100 different chemotherapeutic regimens were reported and the most frequently used chemotherapeutics were anthracyclines (35%), platinum compounds (33%) and fluorouracil (20%). Neutropenia occurrence after the first cycle of the chemotherapy was documented in 2,160 patients. Neutropenia with ANC nadir of < 1 × 109 cell/ L was observed

of the studied population. Fourteen percent of the patients had febrile neutropenia, while

Another study in the United States conducted by Wolf *et al*. (2005) on 2,222 cancer patients showed that one-third of them were treated with fewer than four cycles of the chemotherapy due to complications. The most important result obtained was that half of the cases of neutropenia occurred during the first cycle of chemotherapy, especially among breast cancer

The relationship between chemotherapy and neutropenia was also reported by Schallier *et al*. (2007). He conducted a study in Belgium on 48 non-small lung cancer patients treated with three cycles of paclitaxel, carboplatin, and gemcitabine. Schallier and his colleagues aimed to detect the toxicity of these chemotherapies after each cycle. The results of their study showed that the chemotherapy-induced neutropenia happened on days 8 and 15 of the first cycle. During the second cycle, 34 out of 42 patients developed neutropenia on day 15. Neutropenia was also prominent on day 15 of the third cycle, during which 24 out of 42 patients developed it. Therefore, the study showed that there was a strong relation‐ ship between chemotherapy cycle and neutropenia incidence. However, there was no significant relationship between chemotherapy cycle and neutropenia severity, which

Neutropenia severity mainly increases due to chemotherapeutic drugs schedules [38]. Chemotherapeutic drugs are usually administered in a manner that will enhance their main benefits and reduce or prevent their toxic effects [32, 33, 39], but the duration of administration is also controlled by the pharmacokinetic and pharmacodynamic characteristics of the drug used, as some chemotherapeutic drugs can cause severe bone marrow suppression, such as the alkylating agent cyclophosphamide. These drugs are usually administered by pulse method, that is, for a short period (usually 1 day) followed by a long interval before the next

cell/ L) was seen in 24%

The female gender is a risk factor for neutropenia and febrile neutropenia. The possible reason for the higher number of females than males with neutropenia is that the incidence of cancer in females is generally higher than that in males by a ratio of 1:1.3 [46]. Moreover, it has also been reported that 49% of the solid cancer patients who developed neutropenia during chemotherapy were diagnosed with breast cancer. Since breast cancer occurs mostly in females, this could also explain the higher number of females with neutropenia [17, 47]. A study by Wolf *et al*. (2005) in the United States looked at the risk factors associated with neutropenia among 2,222 patients. The main results showed that there were significant associations of neutropenia severity and gender (*P*= 0.001) and between complication and gender (*P*= 0.004) [47]. An observational retrospective study was conducted by Bassam *et al*. (2009) on solid cancer patients admitted to Penang Hospital in 2003 - 2006 who became neutropenic during chemotherapy. The results show an insignificant association between incidence and neutropenia severity with patients' demographic data, leading to the conclusion that the demographic data is not a risk factor for neutropenia incidence or severity. However, the main reason for this insignificance was the small sample size [18].

#### **11.2. Age**

Neutropenia is more common among the elderly (i.e., 50 years of age or older). Indeed these individual are already less able to produce mature neutrophil cells [2, 8, 13, 17]. According to the National Cancer Registry of Malaysia (2003), cancer incidence, especially breast cancer incidence, is more predominant at the age of 50 years or more. Yip and Omar Hasan Kasule (2005) reported that neutropenia occurred mostly in people aged 50 - 59 years and 75% of the neutropenic patients in their study were diagnosed with breast cancer [48, 49]. In his study, Crawford (2007) investigated 282 lymphoma cancer patients treated with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP), and said that the incidence of neutropenia was predominant among individuals aged 65 years or more compared to younger than 65 years of age [50]. Moreover, in the United States, Voelker *et al.* (2004) carried out a retrospective study from 1991 to 1999 on 7,238 patients with non-Hodgkin lymphoma (NHL). The main objective was to find the major risk factors associated with initiation and duration of hospi‐ talization among neutropenic patients after chemotherapy. The median age was 75 years (range: 66 to 100 years). About 22% of patients needed hospitalization and half were first admitted within the first 42 days of treatment. The mean duration of hospitalization was 55.7 ± 1.43 days and the median was 34 days. The risk factors found to be associated with hospital admission were patients' age, gender, chemotherapy type, history, and disease stage. The risk of hospitalization due to neutropenia increased with age until the age of 80 years [51]. So the study by Voelker *et al*. (2004) demonstrated a significant association between neutropenia and patients' age and gender. At these advanced ages, chemotherapy doses usually reduced and the administration of G-CSF (Filgrastim) is increased [17, 36].

#### **11.3. Ethnic group**

The ethnic group has been suggested to have a significant effect on ANC and therefore there is a relationship between these variables and neutropenia [13]. However, some specific types of cancers are highly associated with specific races. According to Kaur *et al*. (2007), breast cancer incidence in Penang mostly occurs among the Chinese (62.5%), followed by the Malays (26.7%), and the Indians (10.2%), and breast cancer is most highly associated with neutropenia (Wolf *et al*., 2005), which could indicate that the ethnic group does play a role in the incidence of neutropenia [32, 52].

Moreover, in the United States, another study by Hershman *et al*. (2003) also showed that there is an association between ethnicity and neutropenia (WBC level) in breast cancer survivors. Their study was performed on African American and White American women with breast cancer (stage I and II) treated with chemotherapy. It showed that the WBC level in African American women was significantly lower than that of White American women. There was also a significant difference between the period of chemotherapy treatment of African American (19 women) versus White American women due to neutropenia. The explanation for the difference in period of treatment was said to be due to lower ANC. Besides that, neutropenia occurrence led to a delay in chemotherapy administration. Therefore, their study demonstrated a significant association between neutropenia occurrence and ethnicity [53].
