Identifying Patients at Low Risk for FN Complications:
Development and Validation of the MASCC Risk Index Score

Febrile neutropenia (FN) is a life-threatening complication of cancer chemotherapy and is considered a medical emergency. The classic treatment strategy is broad-spectrum antibiotics administered intravenously in a hospital setting, and most patients respond promptly with no complications.

Several instruments have been developed to identify patients at high risk for FN complications. One was the tool developed and validated by Talcott and colleagues (Talcott et al., 1988). However, it depended on patients’ hospitalization status, a measure that varies from country to country or institution to institution and can change with the development of new anticancer treatments. Kern et al. (1999) and Freifeld et al (1999) proposed other methods, but neither gained consensus.

Klastersky et al. conducted a survey between 1994 and 1997 to identify independent predictive factors that could be assessed at fever onset in adult febrile neutropenic cancer patients being treated with chemotherapy. The research team also aimed to develop an internationally validated scoring system. The identified factors were combined to produce a score indicating the probability of resolution of FN without serious medical complications. Secondary objectives of this research included assessing response to empiric therapy, infection documentation, bacteremia development, and fever duration.

This effort resulted in the MASCC Risk Index, a scoring system for identifying low-risk cancer patients with febrile neutropenia. Further research, published by Klastersky et al. in the Journal of Clinical Oncology (2000), showed that the Risk Index could accurately identify patients at low risk for complications and that it could be used to select patients for testing more convenient or cost-effective therapies. The MASCC Risk-Index Score comprises the following factors.

Table 1. MASCC Risk Index Factors and Weights


Burden of febrile neutropenia refers to general clinical status as influenced by the febrile neutropenic episode. It is evaluated in accordance with the following scale: no symptoms (5), mild symptoms (5), moderate symptoms (3), severe symptoms (0), moribund (0).
 
Chronic obstructive pulmonary disease means active chronic bronchitis, emphysema, decrease in FEVs, need for oxygen therapy and/or steroids and/or bronchodilators.
 
Previous fungal infection means demonstrated fungal infection or empirically treated suspected fungal infection.
 

The points attributed to the variable "burden of febrile neutropenia" are not cumulative. Thus, the maximum theoretical score is therefore 26. A score of ≥ 21 is considered low risk and a score of < 21 as high risk (positive predictive value of 91%, specificity of 68%, and sensitivity of 71%). 

This tool was endorsed in 2002 by the Infectious Diseases Society of America and has also been adopted by the European Society of Medical Oncology. This work also led to the development and publication of updated methodology guidelines for clinical trials involving patients with cancer and FN. The guidelines, jointly issued by MASCC and the Immunocompromised Host Society, suggest that response to empirical antibiotic therapy be determined after 72 hours and again on day 5, and the reasons for modification stated. The guidelines further specified that patients enrolled in outpatient studies be selected by use of a validated risk model and that they be carefully monitored after discharge from the hospital. Recommendations are included for blinding and stratification, as well as statistical consideration of trials specifically designed for showing equivalence, recording of response, safety parameters, and readmission rates. The guidelines were intended to simplify and improve comparisons between studies with the ultimate goal of improving therapy.

The publication and endorsement of the MASCC Risk Index was followed by numerous external validations. These are discussed by Klastersky and Paesmans (2013) in their review of 10 years of research using the MASCC index. The authors also discuss antimicrobial empiric therapy for FN, early hospital discharge of low-risk FN patients, and prediction and management of non-low-risk patients. Alternatives to the MASCC scoring system have been proposed — for example methods combining clinical and biological parameters — but these have not been validated in a prospective study or compared with the MASCC score. One proposed model (Eun Ha et al, 2011) would incorporate prediction of bacteremia, but such prediction remains uncertain at this time. Another recent model for predicting risk of neutropenic complications (Lyman et al., 2011) includes clinical and biological parameters as well as chemotherapy characteristics. Klastersky et al. point out that this would be difficult to use in many clinical settings, thus limiting its acceptance.

The MASCC Risk Index has been shown to be a reliable tool for identifying patients at low risk for complications of FN. As such, it is a valuable part of the selection of patients who can safely be treated at home. Specificity of prediction could still be improved, especially for patients with hematological tumors. There have been attempts to improve the MASCC score by incorporating biological variables (e.g., measurement of various interleukins TNF, procalcitonin, and CRP) or by incorporating a prediction of bacteremia. But these do not appear to improve predictive accuracy of the score. Patient characteristics, tumor characteristics, anticancer therapies, and management of FN continue to change over time, so it is important to continue monitoring predictive accuracy and searching for ways to improve it. Klastersky et al. point out that a prediction rule for high-risk patients is still needed and should be developed.


References 

Eun Ha Y, Song JH, Kang WK et al Clinical factors predicting bacteremia in low-risk febrile neutropenia after anti-cancer chemotherapy. Support Care Cancer 2011;19:1761–1767.
 
Feld R, Paesmans M, Freifeld AG, Klastersky J, Pizzo PA, Rolston KV, Rubenstein E, Talcott JA, Walsh TJ. Immunocompromised Host Society; Multinational Association for Supportive Care in Cancer. Methodology for clinical trials involving patients with cancer who have febrile neutropenia: updated guidelines of the Immunocompromised Host Society/Multinational Association for Supportive Care in Cancer, with emphasis on outpatient studies. Clin Infect Dis. 2002;15;35(12):1463-8.
 
Freifeld A, Marchigiani D, Walsh T 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;341:305–3011.
 
Kern WV, Cometta A, De Bock R et al. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. N Engl J Med 1999;314:312–318.
 
Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, Gallagher J, Herrstedt J, ,Rapoport B, Rolston K, Talcott J. 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. 2002;Aug;18(16):3038-51.
 
Klastersky J and Paesmans M. The Multinational Association for Supportive Care in Cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. Support Care Cancer 2013;May;21(5):1487-95.
 
Lyman G, Kuderer N, Crawford B et al. Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer 2011;117:1917–1927.
 
Talcott JA, Finberg R, Mayer RJ, et al. The medical course of cancer patients with fever and neutropenia: Clinical identification of a low-risk subgroup at presentation. Arch Intern Med 1988;148:2561-2568.