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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 491-495
 

Management of febrile neutropenia in malignancy using the MASCC score and other factors: Feasibility and safety in routine clinical practice


Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Feb-2016

Correspondence Address:
J Bajpai
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175340

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 » Abstract 

Background: The current standards for empirical broad-spectrum intravenous antibiotic (AB) treatment, combined with hospitalization, are cautious and safe, but lead to over-treatment of a substantial group of patients. We need to validate parameters to identify these low-risk febrile-neutropenia (FN) patients, who could then be safely treated in an outpatient setting with minimal/no AB treatment. Materials And Methods: A retrospective analysis for validation of a risk-assessment model in FN patients was done on a patient population from January 2007 to December 2008. Inclusion criteria were a histological diagnosis of malignancy, FN secondary to chemotherapy, absolute-neutrophil-count of ≤500/μl, axillary temperature of ≥38°C, and age ≥14 years. Other clinical and laboratory parameters were explored for risk stratification during the FN episodes. Receiver-operating characteristic curves were used to find the threshold value, an Chi-square analysis was done to find the association between the outcome and the parameters. Results: A total of 178 FN episodes were documented; 22 in solid tumors and 156 in hematolymphoid malignancies. Culture positivity was documented in 59 episodes; peripheral blood was the most common source, with Escherichia coli being the most common organism identified. Risk stratification was done using the Multinational Association of Supportive Care in Cancer (MASCC) risk-index score. The association between the MASCC score and risk stratification could not be established (P = not significant) at a score of ≤21; however, it was found to be significant at a score of ≤18. The total number of complications was 23 (sepsis 22, mortality 23). Other factors found to be significantly associated with a high risk of complications in the univariate analysis were, mucositis (P = 0.03), maximum temperature ≥103°F (P = 0.01), tachycardia (P < 0.001), tachypnea (P = <0.001), age (P = 0.006), high dose of steroid (P < 0.001), total duration of fever (≥2.5 days (for which sensitivity (S) and specificity (Sp) were 87 and 81%, respectively), serum-creatinine (≥0.45 mg%, S = 100%, Sp = 97%), serum-bilirubin (≥0.5 mg/dl, S = 100%. Sp = 90%), requirement of second-line antibiotics (P = 0.02), intensive-care (P ≤ 0.001), ventilatory support (P < 0.001), and requirement of packed cell (PC) transfusion (P = 0.02). In the multivariate analysis, mucositis (P = 0.02), HD steroid use (P = 0.026), and PC requirement (0.026) were identified as independent variables. Conclusions: The MASCC risk-index score was found to be meaningful at a score of ≤18. Other clinical and laboratory parameters were found to have a strong association with risk stratification in cancer patients during FN episodes.


Keywords: Feasibility, febrile neutropenia, multinational association for supportive care score, safety


How to cite this article:
Kumar P, Bajpai J, Shetty N, Medekar A, Kurkure P A, Ghadyalpatil N, Gupta S, Noronha V, Kanujia A, Parikh P, Banavali S D. Management of febrile neutropenia in malignancy using the MASCC score and other factors: Feasibility and safety in routine clinical practice. Indian J Cancer 2014;51:491-5

How to cite this URL:
Kumar P, Bajpai J, Shetty N, Medekar A, Kurkure P A, Ghadyalpatil N, Gupta S, Noronha V, Kanujia A, Parikh P, Banavali S D. Management of febrile neutropenia in malignancy using the MASCC score and other factors: Feasibility and safety in routine clinical practice. Indian J Cancer [serial online] 2014 [cited 2019 Dec 8];51:491-5. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/491/175340



 » Introduction Top


Cytotoxic chemotherapies used in the treatment of malignancies are generally myelosuppressive and result in a variable duration and severity of neutropenia. As a result, infections remain one of the most common causes of morbidity and mortality in these patients. There has been a change in the management of febrile neutropenia (FN) in recent times with the increasing realization that the previous standard of care of in-patient treatment with intravenous broad-spectrum antibiotics until resolution is neither necessary nor appropriate for all patients. It has been established that FN represents a spectrum of severity, with a large majority of patients with FN being at 'low-risk' of developing significant medical complications. These are the ones in whom alternative treatment strategies, including the use of oral antibiotics and early hospital discharge are appropriate.[1],[2],[3] These newer treatment strategies are still not widely practiced in general clinical practice, due to the lack of an agreed definition of low-risk; different investigators use different sets of criteria, some of which may be difficult to assess in a clinical setting.[4],[5],[6],[7],[8] In the year 2000, the Multinational Association for Supportive Care in Cancer (MASCC) published a risk index [Table 1], based on more than 1000 patients with FN, in 15 participating countries.[9] This index is a weighted scoring system of seven clinical characteristics assessed at presentation with neutropenic fever. A score of ≥21 was recommended as the threshold for definition of low risk, 7% developing serious medical complications compared to 49% of those scoring <21. Since then, this scoring system was validated in both single-center and multi-center settings for predicting the risk of serious complications.[10],[11] However, the value of the MASCC risk assessment in routine clinical practice and in defining patients for oral antibiotics and early hospital discharge is yet to be established. Recently, Klastersky et al., published their single-center experience of combining a policy of early hospital discharge in low-risk patients receiving oral antibiotics after the first episode of neutropenia.[12] The findings support the feasibility and safety of such a policy, although the eligible group only represented 20.6% of the low-risk febrile episodes analyzed.
Table 1: MASCC risk-index score

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The present study attempts to risk-stratify the patients with solid and hematological malignancies using the MASCC scoring system, to assess the predictability of the outcome in febrile neutropenia patients and to evaluate the feasibility of the MASCC system in our local setting. Furthermore, we tried to incorporate other variables, which might have their own contribution as risk-stratification tools in this population.


 » Materials and Methods Top


This was a retrospective study on adult (≥14 years) patients admitted in our center from January 2007 to December 2008. Data was collected from the patient's hospital inpatient and outpatient notes. The inclusion criteria were as follows:

  1. Fever, defined as a single oral temperature of 38.3°C or an oral temperature of 38°C lasting for more than one hour
  2. Neutropenia, defined as a neutrophil count of <500 cells/mm 3 or a count of <1,000 cells/mm 3 with a predicted decrease to <500 cells/mm 3 within the next 48-72 hours
  3. Had received a course of chemotherapy prior to the episode of febrile neutropenia.


Exclusion criteria were fever and neutropenia as a result of an underlying disease process and patients who had not received chemotherapy. Subsequent episodes of febrile neutropenia in the same patient were included as separate febrile neutropenia events. The choice of an empirical antibiotic regimen on the use of antimicrobial agents in neutropenic patients with cancer was guided by the Infectious Diseases Society of America (IDSA) and our institutional guidelines.[7],[13] The 2002 IDSA guidelines for the treatment of febrile neutropenia recommended dual therapy initially, with third generation cephalosporin or antipseudomonal penicillin combined with an aminoglycoside, and this practice was followed at our center, with conversion to a carbapenem by day three if the patient's clinical condition deteriorated. Antifungal therapy with amphotericin-B and gram-positive coverage with vancomycin was added to the regimen if clinically indicated or a gram-positive organism was cultured. The dependent variable of interest was the final outcome of each febrile neutropenic episode, designated as 'favorable' or 'not favorable'. 'Favorable' was defined as a resolution of fever without development of serious medical complications or the modification of an initial antibiotic therapy. 'Not favorable' was defined as resolution of fever, but with at least one serious medical complication, including death.

'Serious medical complications' were defined as:

  1. Hypotension: Systolic blood pressure less than 90 mmHg or a need for inotropic support to maintain blood pressure
  2. Respiratory failure: Arterial oxygen pressure less than 60 mmHg while breathing room air or a need for mechanical ventilation
  3. Intensive care unit admission
  4. Disseminated intravascular coagulation
  5. Congestive cardiac failure seen on chest x-ray and requiring treatment
  6. Severe bleeding (requiring transfusion)
  7. Arrhythmia or electrocardiogram changes requiring treatment
  8. Renal failure requiring investigation and/or treatment with intravenous fluids, dialysis or any other intervention
  9. Confusion or altered mental state
  10. Other complications judged serious and clinically significant by the investigator.


These definitions of the outcome were adapted from the Klastersky study from which the MASCC risk-score index was derived so as to compare the prediction capacity of their model in our population [Table 1]. The maximum theoretical score was 26 and a score ≥21 was designated as a low-risk episode.[14] Other clinical parameters recorded at the start of the febrile neutropenia episode were, the hemoglobin level, serum albumin, site of infection, mucositis, maximum temperature (≥103°F), tachycardia, tachypnea, age, high dose of steroid, total duration of fever (≥8 days), serum-creatinine, serum-bilirubin, requirement of second-line antibiotics, intensive-care, ventilatory support, and requirement of packed cell (PC) transfusion. In our clinical practice, a hemoglobin level of less than 8 g/dl usually required red blood cell transfusion unless deemed unnecessary by the attending physicians. Therefore, the hemoglobin level was included in the analysis.

Statistical analysis

The SPSS version 18 was used for statistical analysis. The data were summarized using the descriptive method. The Chi square test or Fisher test was used to test the variables as predictors of the outcome, when appropriate. Sensitivity and specificity with positive and negative predictive values were calculated for the MASCC-risk score. Logistic regression analysis was performed by using the forward stepwise method. Variables considered significant in univariate analysis were further analyzed using logistic regression analysis. A P < 0.05 was considered statistically significant.


 » Results Top


Between January 2007 and December 2008, a total of 137 patients who satisfied the inclusion criteria were included. There were a total of 178 febrile neutropenic admissions fulfilling the inclusion criteria, 22 with solid tumors and 156 with hematolymphoid malignancies. Subsequent febrile neutropenic episodes in the same patient were included in the study and considered as a separate episode. The median age of patients was 30 years, with a range of 16-65 years. There were 101 males and 58 females. Out of these, 17 patients had two episodes and one patient had three episodes. The majority of the febrile episodes (70%) had an infective focus, blood cultures were positive in 59 episodes; peripheral blood was the most common source, with E. coli being the most common organism identified. Of the 178 episodes of febrile neutropenia, 87.08% had favorable outcomes. Serious medical complications occurred in 12.92% (23/178, Sepsis 22, Mortality 23) of the cases [Table 2].
Table 2: Patient characteristics

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Predicting the outcome using the MASCC risk-index score

The findings are shown in [Table 3] and [Table 4]. Utilizing the Multinational Association of Supportive Care in Cancer (MASCC) scoring system, with a threshold of 21, had a poor sensitivity and specificity (P = 0.407 − not significant) in identifying patients likely to have a favorable outcome; however, it was found significant at a score of ≤18 (P = 0.005 − significant).
Table 3: MASCC score versus outcome

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Table 4: MASCC score versus outcome

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The characteristics predicting a statistically significant (P< 0.05) higher rate of unfavorable outcome on univariate analysis in this study were, mucositis (P = 0.03), maximum temperature ≥103°F (P = 0.01), tachycardia (P < 0.001), tachypnea (P ≤0.001), age (P = 0.006), high dose of steroid (P < 0.001), total duration of fever (≥2.5 days (for which sensitivity (S) and specificity (Sp) were 87 and 81%, respectively), serum-creatinine (≥0.45 mg%, S = 100%, Sp = 97%), serum-bilirubin (≥0.5 mg/dl, S = 100%, Sp = 90%), requirement of second-line antibiotics (P = 0.02), intensive-care (P = <0.001), ventilatory support (P < 0.001), and requirement of packed cell (PC) transfusion (P = 0.02). In multivariate analysis mucositis (P = 0.02), HD steroid use (P = 0.026), and PC requirement (0.026) were identified.


 » Discussion Top


The objective of this study was to determine the usefulness of the MASCC scoring system in predicting low-risk cancer patients with FN in our local setting. There is sparse literature available from the developing countries to attempt to validate the MASCC scoring system. In this study of 178 cases of febrile neutropenia episodes, 84 episodes were low-risk FN (47.19% patients were low-risk FN cases). In a study, Innes et al., found that 90% of all FN episodes were of low risk. This was somewhat higher than in other studies.[9],[12] This is attributed to the difference in patient population, as only patients with solid tumors and lymphomas were treated in that center.

We have found that the MASCC index, although not suitable at the score of ≥21, was highly suitable for initial patient assessment in the routine clinical setting at a score of ≥18. Due to its reliance on the basic clinical parameters, at the initial assessment of a patient with FN it allows accurate evaluation by less experienced junior medical staff, who do not have a detailed knowledge of the specific chemotherapy regimens or predicted neutrophil nadir timing or the expected duration of neutropenia. In many clinical settings this is essential, as the initial attending physician may not be familiar with either the patient or the expert management of FN, as the MASCC index is used to determine the primary antibiotic regimen as well as the potential eligibility, for early discharge of those patients who are deemed to be at low-risk. Consequently, the most important measure of the value of the MASCC score is its positive predictive value (PPV). In our data, if we have considered a score >21 as low risk, then the PPV is 89.29%, whereas, if we take a score >18, it is 89.74%. In the study by Innes et al., the PPV is 96.7% (i.e., there is a very low likelihood of a patient with a score ≥21 developing serious complications);This However, is even better than the validation set of the initial study by Klastersky et al., wherein it is reported as 91%[9]. Innes et al. has only included solid tumors and lymphomas, and their study findings are consistent with a recent multi-center prospective validation study of the MASCC index in solid tumors by Paesmans et al.[11]

In contrast to Klastersky et al., we present data on all episodes of FN, which include 17 episodes of the second and one episode of the third admission. In the study by Innes et al., 100 episodes of FN have been analyzed, which occurred in 83 patients (71 patients had one, seven had two, and five had three episodes of FN).[9] Although the MASCC index has not yet been validated on more than one episode of FN per patient, our preliminary experience suggests that similar risk-directed policies using oral antibiotics and early discharge may be relevant to any episode of FN.

Variables that were not included in the MASCC score, but had an influence on the outcome of this study were, mucositis, maximum temperature ≥103°F, tachycardia, tachypnea, age, high dose of steroid, total duration of fever, serum-creatinine, serum-bilirubin, requirement of second-line antibiotics, intensive care, ventilatory support, and requirement of packed cell (PC) transfusion. In multivariate analysis mucositis, HD steroid use and PC requirement were identified.

In previous studies other factors found to be significant were duration of neutropenia and the presence of an infective focus.[15],[16],[17] However, these were not evident after multivariate analysis in this study. In our study, serum albumin level was not significantly correlated with the outcome of patients. It is contrary to the two reports that identified low serum albumin as having an impact on survival and on the prognosis of patients with gastrointestinal tumors.[18],[19] In the two other studies conducted in Taiwan, low levels of serum albumin were also noted to have a significant effect on the mortality rate of patients who had septicemia due to Acinetobacter baumannii and Stenotrophomonas maltophilia.[20],[21] The underlying disease was not found to be significantly associated with a better outcome after multivariate analysis. The age of the patient did not influence the outcome of this study, unlike the findings from Klastersky's study.[22] This could be due to several factors; the patients in our study were younger (median 30) compared to Klastersky's patients (median 52) and in our study, subsequent episodes in the same patient were included, which could also influence the outcome.

The MASCC score is currently a relatively reliable method to stratify cancer patients who have undergone chemotherapy and have developed febrile neutropenic episodes. However, it must be remembered that it is a continuous scale and validation of the score as a risk stratification tool may be obtained at different score values in different populations. This risk stratification is useful in our setting, for identifying high-risk patients with febrile neutropenia and allowing outpatient treatment for those identified as low risk. However, other factors, including mucositis, HD steroid use, and PC requirement are also important. A new risk-index score for cancer patients with FN can be coined by conducting a prospective study using these factors to predict the outcome. However, we have demonstrated that the MASCC score is both feasible and safe when used in standard clinical practice and can inform management strategies for FN; our patient's understanding of the risks involved in receiving outpatient treatment is very important and must be assessed before this treatment modality can be implemented in our setting.

 
 » References Top

1.
Freifeld A, Marchigiani D, Walsh T, Chanock S, Lewis L, Hiemenz J, et al. A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy. N Engl J Med 1999;341:305-11.  Back to cited text no. 1
    
2.
Kern WV, Cometta A, De Bock R, Langenaeken J, Paesmans M, Gaya H. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy: International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 1999;341:312-8.  Back to cited text no. 2
    
3.
Innes HE, Smith DB, O'Reilly SM, Clark PI, Kelly V, Marshall E. Oral Antibiotics with early discharge compared with inpatients intraveneous antibiotics for low-risk febrile neutropenia in patients with cancer: A prospective randomized controlled single center study. Br J Cancer 2003;89:43-9.  Back to cited text no. 3
    
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Elting LS, Rubenstein EB, Rolston KV, Bodey GP. Outcomes of bacteremia in patients with cancer and neutropenia: Observations from two decades of epidemiological and clinical trials. Clin Infect Dis 1997;25:247-59.  Back to cited text no. 4
    
5.
Rubin M, Hathorn JW, Pizzo PA. Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 1998;6:167-84.  Back to cited text no. 5
    
6.
Talcott JA, Finberg R, Mayer RJ, Goldman L. The medical course of cancer patients with fever and neutropenia. Clinical identification of a low-risk subgroup at presentation. Arch Intern Med 1998;148:2561-8.  Back to cited text no. 6
    
7.
Talcott JA, Siegel RD, Finberg R, Goldman L. Risk assessment in cancer patients with fever and neutropenia: A prospective, two-center validation of a prediction rule. J Clin Oncol 1992;10:316-22.  Back to cited text no. 7
    
8.
Viscoli C, Bruzzi P, Castagnola E, Boni L, Calandra T, Gaya H, et al. Factors associated with bacteraemia in febrile, granulocytopenic cancer patients: The International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer 1994;30A: 430-7.  Back to cited text no. 8
    
9.
Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038-51.  Back to cited text no. 9
    
10.
Uys A, Rapoport BL, Anderson R. Febrile neutropenia: A prospective study to validate the Multinational Association of Supportive care of Cancer (MASCC) risk-index score. Support Care Cancer 2004;8:556-60.  Back to cited text no. 10
    
11.
Paesmans M, Rapoport B, Maertens J, Slabbeer C, Ferrant A, Wingard J, et al. Multicentric prospective validation of the MASCC risk-index score for identification of febrile neutropenic cancer patients at low-risk for serious medical complications. Proc Am Soc Clin Oncol 2000;22:22-35.  Back to cited text no. 11
    
12.
Klastersky J, Paesmans M, Georgala A, Muanza F, Plehiers B, Dubreucq L, et al. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol 2006;24:4129-34.  Back to cited text no. 12
    
13.
Marshall E, Smith DB, O'Reilly SM, Murray A, Kelly V, Clark PI. Low-dose continuous-infusion ceftazidime monotherapy in low-risk febrile neutropenic patients. Support Care Cancer 2000;8:198-202.  Back to cited text no. 13
    
14.
Talcott JA, Siegel RD, Finberg R, Goldman L. Risk assessment in cancer patients with fever and neutropenia: A prospective, two-center validation of a prediction rule. J Clin Oncol 1992;10:316-32.  Back to cited text no. 14
    
15.
Klastersky J, Ameye L, Maertens J, Georgala A, Muanza F, Aoun M, et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents 2007;30:S51-9.  Back to cited text no. 15
    
16.
Viscoli C, Castagnola E. Treatment of febrile neutropenia: What is new. Curr Opin Infect Dis 2002;15:377-82.  Back to cited text no. 16
    
17.
Yadegarynia D, Tarrand J, Raad I, Rolston K. Current spectrum of bacterial infections in patients with cancer. Clin Infec Dis 2003;37:1144-5.  Back to cited text no. 17
    
18.
Cengiz O, Kucer B, Sürmeli S, Santicky MJ, Soran A. Are pretreatment serum albumin and cholesterol levels prognostic tools in patients with colorectal carcinoma. Med Sci Monit 2006;12:CR240-7.  Back to cited text no. 18
    
19.
Alici S, Kaya S, Izmirli M. Analysis of survival factors in patients with advanced stage gastric adenocarcinoma. Med Sci Monit 2006;12:CR221-9.  Back to cited text no. 19
    
20.
Chen HP, Chen TL, Lai CJ, Fung CP, Wong WW, Yu KW, et al. Predictors of mortality in Acinetobacter baumanii bacteremia. J Microbial Immunol Infect 2005;38:127-36.  Back to cited text no. 20
    
21.
Lai CH, Chi CY, Chen HP, Chen TL, Lai CJ, Fung CP, et al. Clinical characteristics and prognostic factors for patients with Stenotrophomonas maltophilia bacteremia. J Microbial Immunol Infect 2004;37:350-8.  Back to cited text no. 21
    
22.
Klastersky J, Paesmans M, Rubenstein EB. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038-51.  Back to cited text no. 22
    



 
 
    Tables

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

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