PRQG N OSlS

Study devises risk index to identify people with cancer who are at low risk of complication if treated with empiric antibiotics for febrile neutropenia Klastersky], Paesmans M, Rubenstein E, Boyer M, Eltin L, Feld R, Gallagher], Herrstedt], Rapoport B, Rolston K, Talcott] for MASCC (Study Section on Infections of Multinational Association of Supportive Care in Cancer). The multinational association for supportive care in cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. ] Clin Oncol 2000; 18: 3038-305 I

QUESTION Febrile neutropenia is common in people being treated for cancer. Traditional treatment requires admission, close monitoring and intensive treatment. Less intensive treatment may be possible in people at low risk of complications. T h s study designs and validates a scoring system to identify people with cancer at low risk of complications following febrile neutropenia.

DESIGN Multicenter prospective observational study.

SETTING Twenty centers in 15 countries.

PATIENTS Adults with malignancy and a first episode of febrile neutropenia attributable to chemotherapy; developed a fever over 38°C; and were treated with an appropriate empiric antibiotic regmen (antipseudomonal beta-lactam with aminoglycoside; two beta-lactams together; or monotherapy with a thrd-generation cephalosporin or carbapenem) . At least 20 subjects were enrolled from each center (n = 1139).

INTERVENTIONS Two-thrds of centers were randomly assigned to create the Multinational

Association of Supportive Care in Cancer (MASCC) preQction model (n = 756), using logstic regression analysis. The remaining centers were used to compare the validity of the model versus the Talcott prediction rule (total number of participants for validation = 383).

MAIN OUTCOME MEASURES Comparison of the predicted and actual outcome of subjects (no fever for 5 consecutive days without serious complication; or with serious complication or death).

MAIN RESULTS The best, independent predictors associated with low risk are presented in Table 1. These were weighted according to predictive value. The total score was calculated as the sum of the weights; any score 2 21 was recommended for low-risk classification. With a cutoff score of 21, the MASCC rule was more sensitive, but less specific than the Talcott rule (see Table 2). The MASCC rule identified more people as low risk than the Talcott rule (243/383 with MASCC vs 99/383 with Talcott). Bleeding and hypotension were the most common complications in people falsely identified as low risk by MASCC. Four deaths occurred in the group identified as low risk by the MASCC rule (of whom 3 were at hgh risk by the

Table I . Factors predicting high probability of a favorable outcome*

Factor Odds ratio 95% CI Weight

Burden of disease: no o r mild symptoms Absence of hypotension Absence of chronic pulmonary obstructive disease Solid tumor o r no previous fungal infection if hematologic tumor Absence of dehydration Burden of disease: moderate symptoms Outpatient status Age < 60

8.2 I 7.62 5.35 5.07 3.8 I 3.70 3.5 I 2.45

4.15- 16.38 2.9 I - 19.89 I .86- 15.46 I .97- 12.95 I .89-7.73 2.18-6.29 2.02-6.04 I .5 1-4.0 I

*Weights are based on the coefficients (multiplied by the same factor) from a logistic regression analysis in which factors with P-value 0.05 were included.

@3 Evidence-based Oncology (200 I) 2, I + I 6 doi: 10. I054/ebon.2000.0088, available online at http://www.idealibrary.com on IBEkL

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Table 2. Comparison of the new prediction rule with the Talcott prediction rule based on the validation set

Performance MASCC risk index score 2 2 I * Talcott prediction rule

Sensitivity Specificity Negative predictive value Misclassification rate

71% 68% 36% 30%

30% 90% 23% 59%

* MASCC score is the sum of individual factor weights listed in Table I for a maximum of 26 (burden of disease has a maximum score of 5; the mild and moderate symptom weights are not cumulative). Higher scores indicate lower risk.

Talcott rule). Three deaths occurred in the group identified as low risk by the Talcott rule (of whom one had a MASCC score of 21 or greater).

CONCLUSION The MASCC prediction rule may be used to accurately identify people at low risk of complications following febrile neutropenia due to chemotherapy for malignancy. The MASCC index outperformed the Talcott rule on misclassification and sensitivity with comparable positive predictive value,

although specificity with a cutoff score of 21 was lower. The study’s external validity is enhanced by the participation of over 1100 subjects in 15 different countries.

Sources o f funding: not listed.

Correspondence to: J Klasterskj, MD, Service o f Medicine, Institute Jules Bordet, I rue Heger-Bordet, B 1000 Brussels, Belgu~;~ean.klasterskj@bordet. be

Commentary

Significant progress has been made in the management of patients who are neutropenic and develop fever. The standard-of-care for such patients includes: immediate hospitalization at the first sign of infection o r the development of fever; empiric intravenous broad-spectrum antibiotics; close monitoring for the development of potentially fatal and non-fatal complications; and an inpatient assessment of the response t o treatment.’,’ This treatment strategy has dramatically lowered infection-associated mortality.

It is now accepted that patients with fever and neutropenia are a heterogeneous population. Risk factors for the development of infection-associated complications include disease type; disease status; treatment intensity; patient age; hospitalization status when fever develops (inpatient vs outpatient); duration of profound neutropenia; concomitant co-morbid illness; physiologic status; and the site of infection o r infecting pathogen(s). Patient heterogeneity has provided an incentive t o explore new treatment strategies for patients with fever and neutropenia. Some of these newer approaches propose t o eliminate o r curtail hospitalization and manage patients in an ambulatory treatment setting. If these new approaches are t o provide the same level of success we have come t o expect, then clinicians will need compliant patients; supportive caregivers; and an outpatient infrastructure that provides specialized care 24 hours per day, 7 days a week. Also, critical t o the success of these new treatment approaches will be the development and validation of indices that prospectively predict an individual’s risk of infection-associated complications. These risk models must be simple, employ objective measures and be reliable.

The ‘MASCC Risk Index for Febrile Neutropenia’ is an important step forward, but this risk-assessment model should still be viewed with caution. The index lacks objective parameters t o classify the burden of illness. The severity of

chronic obstructive pulmonary disease o r degree of dehydration that justifies inclusion in this model is not specified. The model assesses the presence of hypotension at the initiation of the febrile episode. This later factor may actually be more predictive if i t were assessed several hours after administration of the first dose of antibiotic(s).

The authors report that a risk index score of 2 I o r greater defines a low-risk patient group, with a positive predictive value of 0.91, a test sensitivity of 0.71, and a frequency of false positive results (patients classified as low risk when they are truly high risk) of 0.06. When the risk index was applied t o only outpatients, the positive predictive value increased t o 0.94. This reported level of discrimination is quite good, but clinicians and investigators must remember that the positive and negative predictive values are highly dependent on the prevalence of the target disorder being assessed? The prevalence of ‘low-risk‘ patients in both the derivation and validation study patient sets was very high, and thus the use of this index for a patient population where low-risk patients are less prevalent may be less accurate. The authors do note that the model’s reliability is improved when applied t o only patients who were outpatients at the beginning of their febrile episode. This suggests that the optimal role for this model may be for patients with neutropenia who develop fever as an outpatient.

The authors recommend a numerical score of 2 I o r greater as the threshold t o differentiate low-risk, from high-risk patients. The authors acknowledge that implementing a higher score, ‘while potentially safer’, may not increase the index’s reliability enough t o justify the number of patients that would be inappropriately excluded from the low-risk population. However, patient safety must remain paramount. Increasing the numerical threshold t o 22 o r greater would seem t o be a justified trade-off, until the treatment strategies that may employ this index are fully tested.

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The goal of developing new treatment approaches for patients with fever and neutropenia requires future refinement of models, like the MASCC index that predict risk. However, safe and successful patient outcome is not just dependent upon reliable assessment of infection risks. I t also requires effective broad-spectrum antibiotics; specialized care and treatment available 24 hourslday, 7 days/week compliant patients; and willing caregivers.

Ranking score (scale 1-4): relevance 4; validity 2; applicability 3; feasibility I ; impact 2.5; knowledge context 2.

James c. Wade, MD MPH Fred Hutchinson Cancer Research Center, Seattle,

Washington, DC, USA

Literature cited

I. Rubenstein E, Wade JC et al. National Comprehensive Cancer Network practice guidelines for fever and neutropenia. Oncology 1999; 13: 197-257.

2. Hughes WT, Armstrong D, Bodey GP et al. 1997 Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Inf Dis 1997; 25: 55 1-573.

3. Sackett D, Haynes B, Guyatt P, Tugwell (eds). Clinical Epidemiology: A Basic Science for Clinical Medicine, 2nd edn. N e w York, NY: Chapman & Hall, 1993.

Level and quality of evidence (See Table A): I a

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