**13. Management of neutropenia**

#### **13.1. Granulocyte colony stimulating factors**

Granulocyte colony stimulating factors are glycoproteins that regulate the proliferation, differentiation, functional activity and survival of myeloid cells, which help in reducing the duration and neutropenia severity as a result of chemotherapy [8]. Moreover, G-CSF treatment can significantly reduce hospitalization period and frequency neutropenic patients, and reduce the amount of antibiotics used [8]. G-CSF such as Filgrastim (Neupogen®) can be used to prevent, reduce, or palliate neutropenia in patients treated with chemotherapy. Filgrastim has also been shown to decrease the incidence of febrile neutropenia and to improve survival. Moreover, G-CSF have also been shown to decrease neutropenia severity. Both G-CSF and granulocyte-macrophage colony stimulation factors (GM-CSF) (Sargramostim®) have been approved by the United States Food and Drug Administration for the treatment of neutropenia [2, 8]. But G-CSF use is preferred as it is more effective and has a lower side-effect [8]. A study on the efficacy of the G-CSF in reducing neutropenia among solid tumor and lymphoma patients receiving chemotherapy was carried out by Lyman *et al*. (2002). In their study, G-CSF was administered before the occurrence of fever and neutropenia. There were 1144 patients with eight trials, five with filgrastim and three with lenograstim. The results showed that G-CSF reduced the risk of febrile neutropenia (odd ratio [OR] 0.38, 95% [CI]: 0.29 - 0.49). However, the reduction of infection-related mortality was insignificant (OR= 0.6, 95% CI 0.3 - 1.22). There were no differences in treatment effect by cancer type. The study demonstrated that there was a significant association between the G-CSF and the reduction of neutropenia risk [58].

Juan *et al*. (2001) carried out a prospective study in Spain on 44 solid cancer patients between 1997 and 1999. The aim of the study was to compare the effectiveness of different doses of G-CSF (lenograstim) on neutropenia. The doses used were 263 micrograms/day (full dose) and 131.5 micro grams/ day (half dose). Of the 44 patients, 39 (88.6%) developed neutropenia after chemotherapy. A total of 120 courses of chemotherapy were given to the patients, full doses were given in 61 courses and half a dose of lenograstim was given in 59 courses. The results of the study showed that severe neutropenia was more common among patients who received low doses of lenograstim (20%) as compared to the full dose of lenograstim (12%), but the difference was not significant (*P*= 0.1). The frequency of fever and hospital admission was not affected. The mean ANC with full doses of lenograstim was higher than with half doses, but was again not significant (*P*= 0.324). Juan concluded that both doses of lenograstim had a similar efficacy in reducing neutropenia severity [59].

All the above studies showed that G-CSF should be the primary treatment for severe and febrile neutropenia. This is also in accordance with Malaysian treatment guidelines for febrile neutropenia (i.e., severe neutropenia) treatment [60], which indicate that G-CSF should be considered in patients with febrile neutropenia with high risk features. In the case of severe febrile neutropenia (ANC less than 0.1× 109 cells/L), or in the presence of signs and symptoms of infection, antibiotics, must, be used with G-CSF [8].

#### **13.2. Antimicrobial therapy**

cryptococcus). Moreover, therapeutic interventions such as corticosteroids, chemotherapy, stem cell transplant, and radiation also produce deficiencies in the host immune defense [57].

Neutropenia due to chemotherapy is the most common risk factor for severe bacterial infections in hematological malignancies. Impaired T-cell function in patients undergoing allogenic stem cell transplant is associated with an increased susceptibility to invasive viral infections. It can also induce alterations in host colonization, such as disruption of natural skin and mucosal barriers, and can interfere with nutrition, which can cause an increase in the risk of infection. Therefore, the degree of neutropenia either as a consequence of the disease or the therapy, is directly related to the incidence of serious bacterial and fungal infection in patients with hematological malignancies. There is a significant increase in the incidence of serious infection once ANC falls below 500 cells/µl. Patients with ANC below 100 cells/µl are at the highest risk of infection. The duration of neutropenia also contributes significantly to the risk of serious infections. Qualitative defects in neutrophil function have been described in hematological malignancies. These include defects in chemotaxis, phagocytosis, bactericidal capacity, and the absence of respiratory burst that accompanies phagocytosis. Additionally, chemotherapeutic regimens used in association with corticosteroids can decrease phagocytosis

Granulocyte colony stimulating factors are glycoproteins that regulate the proliferation, differentiation, functional activity and survival of myeloid cells, which help in reducing the duration and neutropenia severity as a result of chemotherapy [8]. Moreover, G-CSF treatment can significantly reduce hospitalization period and frequency neutropenic patients, and reduce the amount of antibiotics used [8]. G-CSF such as Filgrastim (Neupogen®) can be used to prevent, reduce, or palliate neutropenia in patients treated with chemotherapy. Filgrastim has also been shown to decrease the incidence of febrile neutropenia and to improve survival. Moreover, G-CSF have also been shown to decrease neutropenia severity. Both G-CSF and granulocyte-macrophage colony stimulation factors (GM-CSF) (Sargramostim®) have been approved by the United States Food and Drug Administration for the treatment of neutropenia [2, 8]. But G-CSF use is preferred as it is more effective and has a lower side-effect [8]. A study on the efficacy of the G-CSF in reducing neutropenia among solid tumor and lymphoma patients receiving chemotherapy was carried out by Lyman *et al*. (2002). In their study, G-CSF was administered before the occurrence of fever and neutropenia. There were 1144 patients with eight trials, five with filgrastim and three with lenograstim. The results showed that G-CSF reduced the risk of febrile neutropenia (odd ratio [OR] 0.38, 95% [CI]: 0.29 - 0.49). However, the reduction of infection-related mortality was insignificant (OR= 0.6, 95% CI 0.3 - 1.22). There were no differences in treatment effect by cancer type. The study demonstrated that there was a significant association between the G-CSF and the reduction of neutropenia risk [58].

and neutrophil migration [57].

212 Updates on Cancer Treatment

**13. Management of neutropenia**

**13.1. Granulocyte colony stimulating factors**

Empirical antibiotic therapy is required in neutropenia especially, when it is combined with gram-negative bacterial infection, as this combination is associated with high mortality. This point is supported by Schimpff (2001), who mentioned that if fever is not taken seriously and the neutropenic patient is suffering from a bacterial infection, 40% will die within the first 48 hours [61]. This is because there are no reliable methods to determine whether neutropenic fever is due to bacterial infection or not. Thus, antimicrobial therapy must be started either as mono antibiotic therapy or a combination antibiotic therapy. This reduces the mortality of gram-negative infection by 10% [62]. Any empirical antibiotic used must have a wide range of activity, enough to cover the majority of potential pathogens. There are three different universal strategies for using antibiotics in the treatment of febrile neutropenia: (i) a combi‐ nation of either beta-lactam with aminoglycoside, (ii) monotherapy with wide range betalactam, and (iii) both of the above strategies combined [62]. Most neutropenic patients are treated with a beta-lactam antibiotic such as ceftazidime which is widely used as a single empirical antibiotic for neutropenic fever because its effectiveness is very similar to combina‐ tion therapy. Other beta-lactam antibiotics such as imipenem, ticarcillin and cefepime may also be used as monotherapy or in combination with metronidazole or aminoglycoside (amikacin and gentamicin) to overcome bacterial infection, especially gram-negative bacteria. Penicillin derivatives such as piperacillin and tazobactam can also be used alone or in combi‐ nation with beta-lactam derivatives such as imipenem to overcome anaerobe bacterial infection. The new generations of beta-lactam antibiotics have shown wide protection against both gram-positive and gram-negative bacteria such as cefepime [63]. Therefore, ceftazidime or imipenem could be used as first-line treatment while awaiting the results of a culture and sensitivity test [2]. This is also in accordance with Malaysian antibiotic guidelines for febrile neutropenia (i.e., severe neutropenia) treatment [61, 64]. According to the United States Food and Drug Administration, there are many types of antibiotics that could be used to treat neutropenic patients. However, there are only a limited number of antibiotics that are effective for the treatment of febrile neutropenia (i.e., severe neutropenia). Ceftazidime is considered one of the most effective antibiotics and has been approved for the treatment of febrile neutropenic patients at different ages [65].

Combination therapy is also used when there is a need, when there is resistant bacteria in neutropenic patients, or even because of neutropenia severity [62]. In the United States, cephalosporin (mainly ceftazidime) is frequently used as an initial single empirical antibiotic for the treatment of febrile neutropenia. The combinations of cephalosporin plus vancomycin, third generation cephalosporin plus penicillin, or carbapenem plus aminoglycoside are also used. These combinations have been recommended for patients who were suspected to be or are suffering from resistance gram-negative bacterial infection [8]. The same result was found by De Pauw *et al*. (1994) who conducted a study on 692 cancer patients suffering from febrile neutropenia. In their study the patients either received 2g ceftazidime every 8 hours, or 14 - 16 g/ day of piperacillin, in 4 - 6 divided doses plus tobramycin 1.7 - 2 mg/kg of body weight every 8 hours. Their results showed that mortality due to infections was 6% with ceftazidime and 8% with piperacillin plus tobramycin. Adverse effects of ceftazidime occurred in 8% of patients, compared to 20% who received combination antibiotics. The main conclusion made by De Pauw and his colleagues was that ceftazidime as monotherapy was as effective as piperacillin plus tobramycin, and that ceftazidime was much safer in the treatment of febrile/ severe neutropenic patients [65].

Another study in Japan by Yano and Nakano (1996) looked at the use of antibiotic monotherapy in 43 patients suffering from hematological toxicity. Eighteen of these patients suffered from severe neutropenia (ANC < 500 cells/µl). The patients were treated with cefpirome or a combination of two beta-lactam antibiotics. The results showed that 89.5% of patients on cefpirome had a better quality of life, a decreased number of infusions, and a decrease in the frequency of antibiotic administration. Cefpirome use also led to a reduction in night urination, a low cost/benefit ratio and a reduction in nursing responsibil‐ ities. Due to this high efficacy rate, cefpirome monotherapy is therefore considered a first line treatment for patients with hematological diseases, and especially those with severe neutropenia, suffering from infection [66].

The effectiveness of antibiotic monotherapy was again supported by Tamura *et al*. (2001), who compared the effectiveness of antibiotic monotherapy and combination antibiotics in neutro‐ penic patients. One hundred sixty five patients were enrolled in the study, with an average age of 52 years. Severe febrile neutropenia was found in the 60% of patients (ANC < 100 cells/ µl). The patients were divided into two groups. One group was treated with antibiotic monotherapy (either cefepime or carbapenem) and the other was treated with a combination of cefepime and aminoglycoside. Two- thirds of the patients from both groups showed that infection was overcome with antibiotic treatment. The conclusion was that the use of antibiotic monotherapy is as good and effective as combination antibiotics in the treatment of febrile neutropenic patients. As mentioned the use of antibiotic monotherapy (ceftazidime or cefepime) was also emphasized by the Malaysian Ministry of Health. Indeed, while the uses of dual therapy may be preferred in cases with severe neutropenia, a prolonged duration should be expected, as should complications, such as sepsis, hypotension, mucositis and recurrent episodes [67].

#### **13.3. Antibiotics schedule**

sensitivity test [2]. This is also in accordance with Malaysian antibiotic guidelines for febrile neutropenia (i.e., severe neutropenia) treatment [61, 64]. According to the United States Food and Drug Administration, there are many types of antibiotics that could be used to treat neutropenic patients. However, there are only a limited number of antibiotics that are effective for the treatment of febrile neutropenia (i.e., severe neutropenia). Ceftazidime is considered one of the most effective antibiotics and has been approved for the treatment of febrile

Combination therapy is also used when there is a need, when there is resistant bacteria in neutropenic patients, or even because of neutropenia severity [62]. In the United States, cephalosporin (mainly ceftazidime) is frequently used as an initial single empirical antibiotic for the treatment of febrile neutropenia. The combinations of cephalosporin plus vancomycin, third generation cephalosporin plus penicillin, or carbapenem plus aminoglycoside are also used. These combinations have been recommended for patients who were suspected to be or are suffering from resistance gram-negative bacterial infection [8]. The same result was found by De Pauw *et al*. (1994) who conducted a study on 692 cancer patients suffering from febrile neutropenia. In their study the patients either received 2g ceftazidime every 8 hours, or 14 - 16 g/ day of piperacillin, in 4 - 6 divided doses plus tobramycin 1.7 - 2 mg/kg of body weight every 8 hours. Their results showed that mortality due to infections was 6% with ceftazidime and 8% with piperacillin plus tobramycin. Adverse effects of ceftazidime occurred in 8% of patients, compared to 20% who received combination antibiotics. The main conclusion made by De Pauw and his colleagues was that ceftazidime as monotherapy was as effective as piperacillin plus tobramycin, and that ceftazidime was much safer in the treatment of febrile/

Another study in Japan by Yano and Nakano (1996) looked at the use of antibiotic monotherapy in 43 patients suffering from hematological toxicity. Eighteen of these patients suffered from severe neutropenia (ANC < 500 cells/µl). The patients were treated with cefpirome or a combination of two beta-lactam antibiotics. The results showed that 89.5% of patients on cefpirome had a better quality of life, a decreased number of infusions, and a decrease in the frequency of antibiotic administration. Cefpirome use also led to a reduction in night urination, a low cost/benefit ratio and a reduction in nursing responsibil‐ ities. Due to this high efficacy rate, cefpirome monotherapy is therefore considered a first line treatment for patients with hematological diseases, and especially those with severe

The effectiveness of antibiotic monotherapy was again supported by Tamura *et al*. (2001), who compared the effectiveness of antibiotic monotherapy and combination antibiotics in neutro‐ penic patients. One hundred sixty five patients were enrolled in the study, with an average age of 52 years. Severe febrile neutropenia was found in the 60% of patients (ANC < 100 cells/ µl). The patients were divided into two groups. One group was treated with antibiotic monotherapy (either cefepime or carbapenem) and the other was treated with a combination of cefepime and aminoglycoside. Two- thirds of the patients from both groups showed that infection was overcome with antibiotic treatment. The conclusion was that the use of antibiotic monotherapy is as good and effective as combination antibiotics in the treatment of febrile

neutropenic patients at different ages [65].

214 Updates on Cancer Treatment

severe neutropenic patients [65].

neutropenia, suffering from infection [66].

According to the guidelines from the Infectious Society of America, neutropenic patients who remained febrile but showed recovery in ANC on the third day of antibiotic therapy can either continue with antibiotic treatment for 7 days, or antibiotic treatment can be stopped on the fourth or fifth day. For those febrile neutropenic patients with no recovery in ANC, antibiotics should be continued, and can be discontinued after 2 weeks if examinations and cultures show no bacterial growth [68]. Hughes *et al*. (2002) reported that antibiotic schedule for neutropenic patients is mainly determined and controlled by ANC (i.e., neutropenia severity). Antibiotic treatment can be stopped after 3 days if there is no infection. Indeed, continuing antibiotic treatment until the neutropenia is resolved is not preferred as it could lead to increased drug toxicity and bacterial resistance. Thus, Hughes and his colleagues suggested a preferred treatment of antibiotics for 5 - 7 days; antibiotics could be stopped before 5 days if there is evidence of hematological recovery [69].

In Canada, a study by Tomiak *et al*. (1994) looked at the antibiotic schedule used in 134 febrile neutropenic patients and its effect on duration of hospital stay. The study showed that antibiotics can be stopped within 4 - 5 days especially for patients whose culture shows no bacterial infection. The association between neutropenia and antibiotic reduction was signif‐ icant (*P*<0.001) [70].
