Mortality , Length of Stay , and Cost Associated with Hospitalized Adult Cancer Patients with Febrile Neutropenia

Febrile neutropenia (FN) is a serious and lifethreatening condition after administration of intravenous chemotherapy. In 1966, Bodey observed that the mortality of most patients who had infection and neutropenia was 90% or 100% if the bone marrow was unable to recover (Bodey et al., 1966). Nowadays, with the improvement of antibiotics and the use of colony-stimulating growth factor, the mortality rate has been lowered to about 10%. Nevertheless, invasive fungal infections still carry a significant rate of mortality (Kuderer et al., 2006). FN in turn is a major dose-limiting toxicity of chemotherapy, often requiring prolonged hospitalization and broad-spectrum antibiotic use. These measures can prompt dose reductions or treatment delay in subsequent chemotherapy cycles and compromise clinical outcome (Ellis, 2008). Development of FN often leads to a longer hospital stay and an increase in diagnostic and treatment costs. The expenses include intravenous antibiotics, myeloid growth


Introduction
Febrile neutropenia (FN) is a serious and lifethreatening condition after administration of intravenous chemotherapy.In 1966, Bodey observed that the mortality of most patients who had infection and neutropenia was

Data source
The hospitalization database is derived from inpatient Medical Expensing Forms from the National Health Security Office (NHSO), Thailand, and inpatient data from the Civil Servants Benefit System from the Comptroller General's Department and the Social Security Office in the fiscal year 2010.Health institutions across the country from all provinces were included.Laboratory data, radiological studies, and cause of death are not in the database.Hospital costs were derived from charges reported on the patient's insurance scheme.

Patient population
All adult cancer patients (≥15 years old) hospitalized with FN between October 1, 2009and September 30, 2010(fiscal year 2010) were included in the study.Clinical and cost data were analyzed.Data received by the analyst team was checked for accuracy by looking for (a) overlapping information (b) visit dates (c) missing items (d) incorrect coding and (e) dating with the correct fiscal year.
Inclusion criteria were based on the tenth revision of the International Classification of Diseases (ICD-10).All subjects had to have at least one diagnosis for malignancy (ICD-10 C00-C85 and C91-C95) and agranulocytosis (ICD-10 D70).Bone marrow transplant patients were excluded from the study.Some of the patients admitted with FN do not receive the principal diagnosis of FN, instead, they usually receive a diagnosis of other infections if the source could be identified such as pneumonia, fungal infections or complication such as septic shock.Hence, patients with either a principal or secondary diagnosis of FN were included.

Patient demographics and clinical characteristics
Baseline characteristics of FN patients including age, gender, type of cancer, and comorbidities were captured from enrollment data.

Outcome measures
Inpatient mortality, length of stay and hospital costs were the primary outcomes.Bivariate and multivariate analysis of clinical factors predicting longer length of stay (≥5 days) and mortality were conducted.

Statistical analysis
The explanation of variables, tables of frequency enumeration and interrelationships were written using the SPSS program and checked before analyzing.After analyzing the data, the research team passed the primary analysis to ten medical specialists in order to check the validity of the information.Upon confirmation of validity, the data were compared to the Ministry of Public Health's Statistics Report 2010 for trend congruence as well as the hospital's mortality reporting for each age and disease group for comparison with the national Death Registration of the Registry Administration, Ministry of Interior Affairs (Hollenberg, 1996).
Ethics approval was provided by the Ethics Committee of the Faculty of Medicine, Khon Kaen University, under the guidelines of the Helsinki Declaration and Good Clinical Practice.

Patient population
A total of 5,809 adult cancer patients with FN were reported in 2010 in the nationwide hospitals of Thailand.The sample consisted of 3,485 (60%) female and 2,324 (40%) male patients.In the study population, 3,687 (63.5%) were adults between the ages of 15 and 60 years, and 2,122 (36.5%) subjects were older than 60 years.

Length of stay (LOS)
The median LOS was 8.67 days (1-320 days).There were 1,822 (31%) patients with a LOS of 5 days or less and 3,987 (69%) patients with a LOS longer than 5 days (Table 1).Gender of subjects hospitalized for more than 5 days was significantly different from those with a shorter LOS.Men required a longer admission time than women.Age group was also a risk factor for longer LOS.Patients aged less than 40 years were more likely to need hospitalization for more than 5 days as compared with those aged 40-80 years.Acute leukemia was the greatest risk of longer LOS compared with other cancer diagnoses.Patients who suffered from pneumonia, bacteremia/sepsis, fungal infections, and hypotension were found to have a significant likelihood of being hospitalized for longer than 5 days as compared with those without these diagnoses (Table 1).

Mortality
The mortality rate was 14.0% from 815 deaths reported in the study time.Male patients were more likely to die compared with females.Subjects who were older than 70 years old were at higher risk of death than those younger patients.Acute leukemia was the greatest risk of death compared with other cancer types (Table 2).Renal disease, COPD, and congestive heart failure significantly increased the risk of death.A diagnosis of hypotension significantly increased the risk of death: 37% of patients with hypotension died, as compared with 7.8% mortality rate among patients without hypotension.The incidence of hypotension among patients who died was 56% as compared with 15% among survivors.Likewise, pneumonia, bacteremia/sepsis, and fungal infections were significantly associated with an increased risk of death (Table 2).

Multivariate analysis
Table 3 presents the results of a multivariate logistic regression analysis for inpatient mortality and longer length of stay (>5 days).Age group and cancer type significantly increased risk for both mortality and longer length of stay.Bacteremia/sepsis, hypotension, pneumonia, renal disease and congestive heart failure were all found to be significantly associated with the risk of death, while diabetes mellitus, pneumonia, bacteremia/ sepsis, fungal infection and hypotension increased the risk for longer LOS significantly.
Older adults (≥70 years old) were at a significantly higher risk for death as compared with young adults (15-40 years) with the OR of 1.71 in 70-79 year-old group and 1.90 in ≥80 year-old group, but the length of stay was not DOI:http://dx.doi.org/10.7314/APJCP.2013APJCP. .14.2.1115 Mortality and Costs Associated with Febrile Neutropenia in Hospitalized Adult Cancer Patients higher in elderly (Table 3).
Patients with esophageal, testicular and bladder cancers were at higher risk for death as compared with subjects with acute leukemia, but not statistically significantly, while patients with breast and cervical cancer were at a significantly lower risk of death.Acute leukemia patients were at higher risk for longer LOS as compared to other cancer patients.
The complications of bacteremia/sepsis, hypotension, and pneumonia were all significantly associated with death and these three conditions along with fungal infections increased the risk of longer LOS significantly.Patients with hypotension had an almost 6-fold increase in the risk of death as compared to those without hypotension.And patients with fungal infections had an increase in the risk of longer LOS for 4.5 times compared with those without fungal complications.

Cost of treatment
Overall, the mean and median costs of hospitalization were THB 76,484 (USD 2,549) and THB 33,686 (USD 1,122).There was a wide range of hospital costs among various types of cancer.Acute leukemia was associated with the highest hospitalization cost with the median of THB 90,239 (USD 3,008) and cervical cancer

Discussion
Among 5,809 cancer patients who were hospitalized with FN during Oct 2009 to September 2010 at all hospitals in Thailand, the overall inpatient mortality was 14%.This figure is similar to the study from the United Kingdom (Schelenz et al., 2012) but slightly higher than the result from a few studies (Kuderer et al., 2006;Jin et al., 2010) mainly due to the higher proportion of the elderly and acute leukemia patients and the inclusion of all levels of hospital, not only tertiary hospital.
In addition to type of cancer, infectious complications, age group, and underlying disease increased mortality significantly.Hypotension, bacteremia/sepsis, and pneumonia were the most significant risk factors for inpatient mortality.Patients with hypotension were at 5-fold and those with pneumonia were at 2-fold increase in mortality.The elderly (>70 years) and those with renal disease were also at an increased risk for mortality but not longer LOS.The results are similar to other studies from various countries (Kuderer al., 2006;Lal et al., 2008).
However, invasive fungal infection did not increase mortality as opposed to the study from Kuderer et al.The difficulty to obtain an accurate diagnosis was, since fungal cultures were not available in every hospital in Thailand, resulting in lower rates of diagnosis with only 5% of patients with fungal infection compared to 9% of patients from Kuderer et al study.The under report would explain the different results.
A diagnosis of acute leukemia was associated with longer LOS and mortality while breast cancer was associated with a significant reduction in the risk of both.This also corresponds to other published studies (Lal et al., 2008;Schelenz et al., 2012).The chemotherapy dose for acute leukemia is very high in order to completely eradicate cancer cells for the goal of complete remission, and as a result, the neutropenic period is prolonged and patients are at greater risk for developing infectious complications.Breast cancer patients, however, receive a lower dose of adjuvant and palliative chemotherapy compared to hematologic malignancy.Early diagnosis of breast cancer may lead to the reduction of the administration of high dose chemotherapy e.g.TAC (docetaxel, doxorubicin, and cyclophosphamide) regimen which contributed to a more than 20% risk of FN.
The LOS for all FN patients was 8.7 days, which collaborates with other studies of 6.5-9.2 days (Courtney et al., 2007;Innes et al., 2008;Schelenz et al., 2012).Surprisingly, patients who were younger than 40 years old were more likely to need longer hospitalization period compared to the older groups.A lower mortality rate and intensive treatment for infectious complications might contribute to the increased LOS.
FN results in a considerable burden on patients, caregivers, and payers.The median cost of FN was THB 33,686 (USD 1,122) per inpatient episode.Although it is much lower than other studies from the US and UK (Courtney et al., 2007;Liou et al., 2007;Innes et al., 2008;Schelenz et al., 2012), it is a huge burden for the payers, the Thai government.The three main reimbursement programs for Thai citizens are national coverage, government welfare for government officers, and social welfare for workers.In general, the government is responsible for more than two-thirds of the burden (Chindaprasirt et al., 2012).According to recent studies, outpatient management of low-risk FN patients is safe and effective with a low failure rate in western countries (Elting et al., 2008;Teuffel et al., 2011).Thus, identifying patients who are low-risk is important.Nevertheless, outpatient management in the Thai setting is yet to be validated for effectiveness.
There are limitations of the present study.Firstly, there is the potential for misclassification of data collection wherein some patients were either inappropriately included or excluded based on ICD-10 codes.Secondly, some data associated with risk factors of death associated with FN were unavailable.The results of the present study need to be interpreted in the context of its limitations.Finally, the impact of FN on some aspects is lacking, such as long-term survival, caregiver burden, and posthospital costs.
In conclusion, FN remains a serious cause of substantial morbidity, mortality, and cost as a whole.Elderly patients (>70 years), invasive fungal infection, bacteremia/sepsis, pneumonia, hypotension, multiple comorbid diseases, and acute leukemia should be considered as high risk factors in adults with FN.In order to improve the outcome and reduce the financial burden, risk stratification should be implemented in management of FN patients.

Figure 1 .
Figure 1.Median Cost of FN by Cancer Type hospitalization cost was the lowest with the median of THB 15,931 (USD 531) (Figure 1).

Table 1 . Bivariate Association between Each Predictor Variable and Length of Stay
*HL: Hodgkin lymphoma, NHL: non-Hodgkin lymphoma, CUP: cancer of unknown primary, LOS: length of stay, OR: Odds ratio, CI: confidence interval, p-value significant<0.05