Cancer Science & Research Open Access

Objective: This study was aimed to evaluate the frequency of febrile neutropenia between genders and find out its association with haematological parameters.

Methodology: This was an observational study conducted in the Oncology Department of Jinnah Postgraduate Medical Centre, Karachi Pakistan for 1 year. Data was collected using non-probability convenient sampling technique after taking informed consent from 316 patients diagnosed as having cancer on histopathology, undergoing treatment with chemotherapeutic agent and having neutropenia along with fever as a single oral temperature of >38.3 ºC. Patients who had co-morbid conditions such as diabetes, heart disease, or psychiatric illness were excluded from this study. The variables recorded were age, gender, chemotherapy protocol, number of days of chemotherapy, haemoglobin, total leukocyte count, neutrophils, monocytes, platelets and creatinine. Patients were divided into 2 groups based on gender receiving the chemotherapeutic regimen, Group 1 consisted of male and Group 2 consisted of female patients. SPSS version 20.0 was used for data analysis. Chi-square test and t-test was used to assess the association. P-value was calculated to find association.

Results: The mean age of Group 1 patients was 41.90±14.90 years while that of group 2 was 42.35±13.17years. In our study, males had total leukocyte count 2076.30±1207.72 cells/cum, neutrophil count 29.91±20.68/mm³ and females had total leukocyte count 2862.36±1970.80 cells/ cum, neutrophil count 38.56±21.87/mm³ which is significantly different among two groups (p-value< 0.05). Febrile neutropenia was found to be present in 96(57.1%) of males and 70(47.3%) of female patients in our study which was not statistically significant(p-value=0.080).

Conclusion: Our study showed that among male and female cancer patients on chemotherapy, more than half of males were found to have febrile neutropenia, while fewer females had febrile neutropenia. There was no significant difference in occurrence of febrile neutropenia between two genders.

Keywords: Febrile Neutropenia; Genders;

Febrile neutropenia’s one of the most prominent complication of cancer chemotherapy and leads to decreased efficacy of treatment due to reduction in dosage of chemotherapy. The mortality rate from febrile neutropenia remains on higher side [1]. In patients having solid tumours, the incidence of febrile neutropenia ranges from 10%-50% and is apparently ≥80% in patients having haematological malignancies [2]. The mortality associated with Febrile Neutropenia require prompt hospitalization and aggressive antimicrobial treatment [3]. In patients having Gram-negative and Gram-positive bacteremia, mortality rates of 18% and 5% have been stated respectively [4]. The definition of Febrile Neutropenia according to the European Society for Medical Oncology (ESMO) is: ‘An oral temperature of >38.5°C or two consecutive readings of >38.0°C for 2 h and an absolute neutrophil count (ANC) of < 0.5 × 10⁹/l, or expected to fall < 0.5 × 10⁹/l’ [5]. They are the most numerous circulating white blood cells that are the first line of the defense for infections [6]. Several symptoms are related to neutropenia; and the occurrence of fever is typically because of an infection as the patients are immune-compromised and are more prone to progress to infections [7]. Neutrophils are the most frequently affected cells by chemotherapy acting on bone marrow and suppressing cell lineages [8]. The risk of infection as well as mortality increases as the severity and duration of neutropenia increases along with the persistence of fever wherein the duration of neutropenia is typically 7–10 days, with variations depending upon the type and strength of the chemotherapeutic regimen [9]. Febrile neutropenic patients have heterogeneous grouping; therefore, the development of the infection and outcome is related to individual patient factors such as age, tumour type and stage, previous hospitalizations, or severe comorbidities [10]. Neutropenic patients are prone to suffer from infections, with respiratory tract infection(35%–40%), bloodstream infections (15%–35%) and urinary tract infections (5%–15%) being most common [11]. Moreover, Febrile neutropenia commonly compromises the chemotherapeutic treatment being administered by necessitating a reduction in dose and/ or interruption of treatment cycles, thereby directly affecting treatment efficacy, patient survival and quality of life [12]. Since it is common to develop febrile neutropenia during the initial cycles of chemotherapy, European and US guidelines recommend the use of colony stimulating growth factors in patients having >20% risk of developing febrile neutropenia [13,14]. Metastatic diseases are usually seen in elderly patients who have associated co-morbid conditions and hence poor performance status in comparison to the younger patients with less-severe disease. Treatment in the metastatic setting is often less aggressive, and alternative approaches to managing these toxicities such as the use of less myelosuppressive regimens or scheduled dose modifications in line of prophylaxis using colony-stimulating factors have been recommended in several literatures, especially when the intent of such care is palliative [15,16].

It is observed that there are variations of haematological parameters in normal individuals on gender basis. Therefore, this study was aimed to focus on genders of patients receiving chemotherapy and having febrile neutropenia. Purpose of this study was to determine the frequency of febrile neutropenia among genders so that an appropriate chemotherapeutic plan can be devised to manage the patients accordingly. This may help decrease mortality and morbidity in future.

This was an observational study conducted in the Oncology Department of Jinnah Postgraduate Medical Centre, Karachi Pakistan. The study was done for duration of 6 months from November 2017 till April 2018 by utilizing non-probability convenient sampling technique. The study comprised of a total of 316 patients after receiving informed consent. The Ethical approval was taken from Ethical Review Board of Jinnah Postgraduate Medical Centre.

Patients diagnosed as having cancer on histopathology, undergoing treatment with chemotherapeutic agent were included in this study. The different chemotherapeutic agents used were antibiotics like bleomycin, duanorubicin, alkyl ting agents like cyclophophamide, dacarbazine and micro tubular inhibitors like docitexal, paclitexal, vincristine, vinblastitne, steroids like prednisone and other agents like cisplatin, asparaginase and etoposide. Patients who had comorbid conditions such as diabetes, ischemic heart disease, or psychiatric illness and incomplete data were excluded from this study. The patients were divided into 2 groups based on gender receiving the chemotherapeutic regimen, Group 1 consisted of male patients (n=168) and Group 2, female patients (n=148). The variables including age, weight, height, gender and body surface area, type of cancer, chemotherapy protocol, number of days of chemotherapy, haemoglobin, total leukocyte count, neutrophils, monocytes, platelets and creatinine were recorded.

Data was analysed using SPSS version 20. Demographic and haematological variables were presented as mean, standard deviation. Qualitative data was expressed as frequency and percentages. T-test was applied to find significant difference between quantitative variables. Chi-square test was applied to find significant difference in febrile neutropenia between genders. P-value < 0.05 was considered to be significant.

Our study comprised of 316 patients in total, out of which Group 1 had 168 patients and Group 2 had 148 patients. The mean age of Group 1 patients was 41.90±14.90 years while that of group 2 was 42.35±13.17years. Group 1 had mean weight of 59.51±12.63 kg, mean height of 162.89±9.95 cm, Haemoglobin level of 162.89±9.95 gm/dl, platelet count of 144454.09±106076.47 cells/cum, total leukocyte count of 2076.30±1207.72 cells/cum, neutrophil count of 29.91±20.68/mm³, monocytes of 7.16±7.28/mm³, absolute neutrophil count of 785.50±989.59/mm³ and duration of chemotherapy was 10.98±3.56 days. Group 2 had mean weight of 54.50±10.82 kg, height of 153.79±8.29 cm, Haemoglobin level 9.89±1.68 gm/dl, platelet count 190087.83±120316.52 cells/cum, total leukocyte count 2862.36±1970.80 cells/mm³, neutrophil count 38.56±21.87/mm³, monocytes 9.03±9.78/mm³, absolute neutrophil count 1367.58±1408.94/mm³ and duration of chemotherapy 10.42±2.79 days. There was a significant difference (p-value< 0.05) in weight, height, monocyte count, total leukocyte count and absolute neutrophil count between the two groups (Table 1). The most common type of carcinoma found in the patients on chemotherapy was carcinoma of breast observed in 72(22.8%) and the least common was carcinoma of pancreas found in 10(3.2%) of cases.(Figure 1) In group 1, more than half of the patients 96(57.1%) had febrile neutropenia after chemotherapy, while in group 2, 78(52.3%) patients were not having febrile neutropenia while on chemotherapy regimen (Table 2, Figure 2). The difference in frequency of febrile neutropenia between two genders was insignificant (p-value=0.080).

In our study total 316 cancer patients receiving chemotherapeutic agents were divided into 2 groups depending on the gender of patients. In a study to determine febrile neutropenia, among the 215 patients who participated in that study, the mean age was reported to be 51.53 years [17]. In another study by Younus J et al, the mean age of febrile neutropenia patients was 61.5 years [18]. Patients aged 65 years or above were associated with greater (66%) chances of having febrile neutropenia after 1 cycle of chemotherapy [19]. In an Indian study to comprehend safety and tolerability of febrile neutropenia treatment, the mean age was reported to be 54 years [20]. On the contrary in our study, the mean age of febrile neutropenia patients was reported to be 41.90±14.90 years in Group 1 patients and 42.35±13.17yearsin Group 2, which is younger age than in the studies mentioned above.

In a study to identify patients at risk of developing febrile neutropenia, total leukocyte count 6.90x10⁹/mm³ (3.8-19.5x10⁹/ mm³) and absolute neutrophil count 4.3 x10⁹/mm³ (1.6-17.0 x10⁹/ mm³) pre-treatment were found to be at greater risk to encounter episodes of febrile neutropenia [21]. After adjusting for age and cancer type, the most important independent risk factor in multi variant analysis were found to be prior chemotherapy, abnormal liver and renal function and low leukocyte count [22,23]. In another study, the risk factor for developing febrile neutropenia included advanced age, first cycle of chemotherapy and absolute neutrophil count < 2.0x10⁹/mm³ [24]. In our study, males had total leukocyte count 2076.30±1207.72x10⁹/mm³, neutrophil count 29.91±20.68/mm³ and females had total leukocyte count 2862.36±1970.80x10⁹/mm³, neutrophil count 38.56±21.87/ mm³ which was significantly different among two groups(pvalue< 0.05).

The studies done on non-Hodgkin lymphoma and small cell lung cancer patients have discovered that female gender is prone to develop febrile neutropenia or get admitted to hospital for management of febrile neutropenia [25,26]. In a study to determine occurrence of febrile neutropenia in patients receiving chemotherapy, the risk factors showed no significant difference (p -value=0.931) between two genders [27]. Febrile neutropenia was found to be present in 96(57.1%) of males and 70(47.3%) of female patients in our study which was insignificant (p-value=0.080).

This study is one of its kind in making an effort to determine the difference in occurrence of febrile neutropenia between two genders. However, the findings may have observer bias. Considering the observations of our study and to what extent febrile neutropenia may be consistent with the different chemotherapy regimens would be revealing to expedite more facts about the development of disease.

Our study predicted that among male and female cancer patients on chemotherapy, more than half of males were found to have febrile neutropenia, while less females had febrile neutropenia. There was no significant difference observed in frequency of febrile neutropenia between two genders. However, the neutrophil count and absolute neutrophil count in male and female febrile neutropenia patients had significant difference.

1. Clark OA, Lyman GH, Castro AA, Clark LG, Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol. 2005;23(18):4198-4214.
2. Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect Dis. 2004;39 Suppl 1:S32-7.
3. Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10):2258-2266.
4. Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Annals of Oncology. 2016;27(5):111-118.
5. de Naurois J, Novitzky-Basso I, Gill MJ, Marti FM, Cullen MH, Roila F. ESMO Guidelines Working Group. Management of febrile neutropenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2010;21 Suppl 5:v252-256. doi: 10.1093/annonc/mdq196
6. Kristjanson M. Febrile neutropenia: the empirical strikes back. Cancer Care Manitoba. 2015;6(25):1-6.
7. Andrès E, Mourot-Cottet R, Maloisel F, Keller O, Vogel T, Séverac F, et al. History and Outcome of Febrile Neutropenia Outside the Oncology Setting: A Retrospective Study of 76 Cases Related to Non-Chemotherapy Drugs. J Clin Med. 2017;6(10). pii: E92. doi: 10.3390/jcm6100092
8. Lustberg MB. Management of neutropenia in cancer patients. Clinical advances in hematology& oncology. 2012;10(12):825-826.
9. Hoggatt J, Tate TA, Pelus LM. Role of lipegfilgrastim in the management of chemotherapy-induced neutropenia. Int J Nanomedicine. 2015;10:2647-2652. doi: 10.2147/IJN.S55796
10. Gala Peralta S, Cardesa Salzman T, García García JJ, Estella Aguado J, Gené Giralt A, Luaces Cubells C. Bacteraemia risk criteria in the paediatric febrile neutropenic cancer patient. Clin Transl Oncol. 2005;7(4):165-168.
11. Nesher L, Rolston KV. The current spectrum of infection in cancer patients with chemotherapy related neutropenia. Infection. 2014;42(1):5-13. doi: 10.1007/s15010-013-0525-9
12. Cairo MS. Dose reductions and delays: limitations of myelosuppressive chemotherapy. Oncology (Williston Park). 2000;14(9 Suppl 8):21-31.
13. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205.
14. Carrato A, Paz-Ares Rodríguez L, Rodríguez Lescure A, Casas Fernández de Tejerina AM, Díaz Rubio García E, Pérez Segura P, et al. Spanish Society of Medical Oncology consensus for the use of haematopoietic colony-stimulating factors in cancer patients. Clin Transl Oncol. 2009;11(7):446-454.
15. DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64(4):252-271. doi: 10.3322/caac.21235
16. Bennett CL, Djulbegovic B, Norris LB, Armitage JO. Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med. 2013;368(12):1131-1139. doi: 10.1056/NEJMct1210890
17. Shaikh AJ, Bawany SA, Masood N, Khan AA, Abbasi AN, Niamutullah SN, et al. Incidence and impact of baseline electrolyte abnormalities in patients admitted with chemotherapy induced febrile neutropenia. J Cancer. 2011;2:62-66.
18. Younus J, Vandenberg T, Jawaid M, Jawaid MA. Febrile neutropenia rates with adjuvant docetaxel and cyclophosphamide chemotherapy in early breast cancer: discrepancy between published reports and community practice—an updated analysis. Curr Oncol. 2012;19(6):332–334. doi:  10.3747/co.19.1174
19. Chrischilles E, Delgado DJ, Stolshek BS, Lawless G, Fridman M, Carter WB. Impact of age and colony-stimulating factor use on hospital length of stay for febrile neutropenia in CHOP-treated non-Hodgkin's lymphoma. Cancer Control. 2002;9(3):203-211.
20. Talwar V, Nirni SS, Mallavarapu KM, Ramkumar A, Sinha N. Safety and tolerability of Peg-grafeel™, a pegfilgrastim, for the prophylactic treatment of chemotherapy-induced neutropenia and febrile neutropenia: A prospective, observational, postmarketing surveillance study in India. South Asian J Cancer. 2017;6(1):20-24. doi: 10.4103/2278-330X.202560
21. Jenkins P, Scaife J, Freeman S. Validation of a predictive model that identifies patients at high risk of developing febrile neutropaenia following chemotherapy for breast cancer. Ann Oncol. 2012 ;23(7):1766-1771. doi: 10.1093/annonc/mdr493
22. Lyman GH, Kuderer NM, Crawford J, Wolff DA, Culakova E, Poniewierski MS, et al. Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer. 2011;117(9):1917-1927. doi: 10.1002/cncr.25691
23. Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: a systematic review. Crit Rev Oncol Hematol. 2014;90(3):190-199. doi: 10.1016/j.critrevonc.2013.12.006
24. Dranitsaris G, Rayson D, Vincent M, Chang J, Gelmon K, Sandor D, et al. Identifying patients at high risk for neutropenic complications during chemotherapy for metastatic breast cancer with doxorubicin or pegylated liposomal doxorubicin: The development of a prediction model. Am J Clin Oncol. 2008;31(4):369-374. doi: 10.1097/COC.0b013e318165c01d
25. Lyman GH, Delgado DJ. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer. 2003;98(11):2402-2409.
26. Crawford J, Glaspy JA, Stoller RG, Tomita DK, Vincent ME, McGuire BW, et al. Final results of a placebo-controlled study of filgrastim in small-cell lung cancer: exploration of risk factors for febrile neutropenia. Support Cancer Ther. 2005;3(1):36-46. doi: 10.3816/SCT.2005.n.023
27. Imran Ahmad, Jamal Zekri, Katib Abdel Rahman, Syed Karim, Haleem Rasool , Ehab Abdelghany. Incidence and Risk Factors for Breakthrough Febrile Neutropenia in Cancer Patients Receiving Chemotherapy and Prophylactic Pegfilgrastim. IJSR. 2017;6(2):2017-2019.