Febrile neutropenia: A critical review of the initial management

Critical Reviews in Oncology/Hematology 78 (2011) 185–194

Febrile neutropenia: A critical review of the initial management Jean Klastersky ∗ , Ahmad Awada, Mariane Paesmans, Mickael Aoun Department of Medicine, Institut Jules Bordet, Centre des Tumeurs de l’Université Libre de Bruxelles, 1, rue Héger-Bordet, 1000 Brussels, Belgium Accepted 24 March 2010

Contents 1.

2.

3.

4.

5. 6.

7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Present achievements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Possible future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of febrile neutropenic episodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Febrile neutropenic episodes and bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The significance of MASCC scoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Complicated bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The issue of bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Prediction of bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Management of low-risk patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Limitations of the MASCC score predictive value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antimicrobial regimens used in febrile neutropenic cancer patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Optimal regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Discussion of the potential choices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biomarker predictors of the risk of complications in febrile neutropenic patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The management of non-low-risk patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Traditional approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Novel possible orientations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Stratification of the risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Strategies for the future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Final conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

186 186 186 187 187 187 188 188 188 189 189 189 189 190 190 191 191 191 191 191 192 192 192 192 192 194

Abstract The present state of the art for management of patients with febrile neutropenia has been reviewed as well as potential ways to improve it in the future. A major advance has been the possibility to predict, accurately and early, the risk of complications and death in those patients. While the algorithm for therapy in low-risk patients is presently straightforward, significant progresses are needed for patients who are at higher risk of presenting severe complications. © 2010 Elsevier Ireland Ltd. All rights reserved. Keywords: Febrile neutropenia; Bacteremia; Prediction of complications; Prediction of mortality; Predictive biomarkers; Epidemiology; Microbiology

∗

Corresponding author. Tel.: +32 25413201; fax: +32 25413202. E-mail addresses: [email protected], [email protected] (J. Klastersky).

1040-8428/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2010.03.008

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1. Introduction 1.1. Present achievements Although infection has been recognized as a complication of leukemia in case reports dating back at least in 1845 [1], the importance of neutropenia, as a predisposing factor for infection in patients with malignancies, was not clearly appreciated until effective therapeutic agents became available. A long series of efforts led to the foundation of a standard clinical approach of the syndrome “febrile neutropenia” (FN) (Table 1) which still represents the most common and potentially most lethal complication of cancer chemotherapy administration [2]. Strategies for minimizing complications of neutropenia – prophylactic myeloid growth factors or antibiotics – have recently been reviewed comprehensively [3]. The requirement of an empirical approach, both in patients with a low and high risk of complications, has been endorsed in international recommendations [4]. The tailoring of empirical therapy to the risk of complications is now feasible through validated instruments, such as the MASCC (Multinational Association for Supportive Care in Cancer) score [5]. Since, overall, the low-risk patients represent at least two thirds of the population with FN, simplified management, i.e. oral antibiotics and possibly out patient treatment, may contribute to substantial improvement of patient’s quality of life and results in substantial cost savings [6,7], in significant numbers of patients. Meta-analyses have suggested that empirical monotherapy was as effective, or even more effective, than combination therapy [8]. The current success of monotherapy is related, in part, to the breadth and efficacy of the third generation cephalosporins and carbapenems against the microorganisms responsible for the infections in the febrile neutropenic population. However, this can be negatively impacted if the spectrum of microorganisms associated today with FN would change. Notably, if P. aeruginosa re-emerges, or if the incidence of Enterobacter sp. or Acinetobacter sp., methicillin-resistant Staph. aureus or enterococci increases significantly, current monotherapies would almost certainly prove insufficient for empirical therapy. These considerations are an incentive for periodically appraising the distribution of pathogens responsible for infection in neutropenic patients.

Table 1 Standard approaches for the management of febrile neutropenia. (1) (2) (3) (4) (5)

Prevention (antibiotics and/or CSFs) is essential Empirical therapy remains a basic rule Antimicrobial therapy and overall management can be adjusted to the risk of complications Antimicrobial monotherapy is adequate in most cases but early and rational changes are often needed Occult fungal infection must be suspected in patients with protracted febrile neutropenia and be managed with empirical or pre-emptive anti-fungal therapy

The lessons from these surveys are important, not only for designing the optimal initial regimens, but also for making adequate decisions regarding the rational modifications of the initial approaches. Overall, today, empirical therapy with antimicrobials is associated with a survival rate of more than 90% in patients with FN, even if the latter cannot be microbiologically documented, which suggests that most cases are indeed associated with bacterial infections. However, in patients with prolonged FN, especially in those who present concomitantly a severe immunodepression, as those receiving hematopoietic cell transplants, emergence of invasive fungal pathogens has been frequently documented [9] and requires early empirical or pre-emptive use of antifungals [10,11]. 1.2. Possible future directions Where do we go from here? (Table 2) [12]. The changing nature and sensitivity of the offending pathogens may require the development of broader and more potent antibiotics, although there is little evidence that this will happen in a near future. As some of the complications and deaths in febrile neutropenic patients do occur in spite of an adequate microbiological control of the infection, it might be essential to pay attention to the pathophysiology of severe infection, especially in patients at high risk of bacteremia or those who present initially with severe sepsis, and treat them accordingly. Another approach might be the development of cancer therapies that are less inductive of neutropenia and immunodepression; the more frequent use of biologics with limited hematological toxicity may be a step into that direction. Finally, as the use of empirical approaches reflects to some extent our limited ability to rapidly and precisely diagnose the microbiological causes of fever in neutropenic and/or immunosuppressed patients, progresses in microbiological diagnosis might lead to a more selective approach and a more timely use of antimicrobials and other anti-infective drugs. Newer laboratory markers might also improve our capability of coping with FN, especially in high-risk patients. The issue of procalcitonin and various cytokines for the diagnosis and prognosis will be discussed later. In addition, imaging techniques with HR-CT or MRI may help with early and more specific diagnosis as well as with better evaluation of response to therapy [13]. Table 2 Future possible avenues to cope with febrile neutropenia in the future. (1) (2) (3) (4) (5) (6)

Development of more potent antibiotics Intensive care of severe sepsis Less aggressive anti-cancer regimens More specific and earlier laboratory microbiological diagnosis Use of bio-markers for infection Imaging techniques

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Table 3 Pathogens isolated from blood cultures in 499 patients with febrile neutropenia (from 2 multicentric studies). Nrs.

Incidence (%)

Complications (%)

Deaths (%)

Gram-positives Staph. coagulase negative Staph. aureus Streptococcus sp. Pneumococcus Others

283 138 25 73 1 46

57 50 9 27 <1 15

20 15 24 26 – –

5 6 0 4 – –

Gram-negatives Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Proteus sp. Acinetobacter Enterobacter sp. Others

168 72 20 42 2 4 7 21

34 41 11 24 1 2 4 12

23 26 30 19 – – – –

18 18 10 31 – – – –

48 29 19

9 60 40

22 28 16

13 17 5

Polymicrobial At least one Gram− Only Gram+ Adapted from Klastersky et al. (2007) [19].

2. Epidemiology of febrile neutropenic episodes 2.1. Febrile neutropenic episodes and bacteremia In four recent studies of the microbiological causes of FN in which, however, microbiologically documented and bacteremic cases were not clearly separated [14–17], the incidence of Gram-negative infections was superior to that of Gram positive in 2 series [14,15], in which no prophylaxis has been used. On the other hand, in the two other studies, in which prophylaxis with cotrimoxazole [16] or norfloxacin [17] had been given, the Gram-positive infections outnumbered the Gram negative. Among Gram-negative pathogens, E. coli followed by P. aeruginosa and/or K. pneumoniae were the most common. Among the Gram positives the most frequent pathogens were coagulase-negative staphylococci followed by Staph. aureus and streptococci. The mortality rate, given in 3 of these series, ranged from 5% to 11% and most deaths were caused by Gram-negative infections. In one of these studies [17], the resistance of bacteria species to commonly used antibiotics was analyzed in two time periods, 1994–2000 and 2001–2005, and was not found to be significantly different. However, other recent studies point clearly to an increase of the emergence of resistant strains, namely fluoroquinolone-resistant bacteria in patients receiving prophylaxis with these agents [18]. Another recent paper [19] analyzed the characteristics and outcomes of 499 patients with FN in whom bacteremia has been documented (Table 3). There were 168 patients (34%) with bacteremia caused by a single Gram-negative organism. The mortality observed was 18%, 10% and 31% when the bacteremia was caused by E. coli, Klebsiella sp. and P. aeruginosa, respectively. Eighty-two (49%) had bacteremia due to a single Gram-

positive pathogen, with a 5% mortality rate, which was significantly lower than the 18% mortality in bacteremia caused by Gram-negative organisms (P < 0.001). Coagulasenegative staphylococci were associated with a mortality rate of 5%, and a mortality rate of 4% was noted among the 73 streptococcal bacteremias. There were 48 polymicrobial bacteremias, with a 13% mortality rate; but only 1/9 of these patients died if the pathogens consisted of a mixture of Gram-positives with no Gram-negatives, compared with 5/29 (17%) if at least one Gram-negative pathogen was present. The authors examined the possible effects of the administration of prophylactic antibiotics or granulopoiesisstimulating factors. The use of prophylactic antibiotics affected the type of pathogens causing bacteremia, with only 25% caused by Gram-negative organisms compared with 75% caused by Gram-positive organisms in patients receiving prophylactic antibiotics; if no prophylactic antibiotics had been given the rates were 52% and 48% respectively (P < 0.001). There did not appear to be any difference in the distribution of pathogens whether granulopoiesis agents were administered or not. The administration of either antibiotics or granulopoiesis-stimulating factors did not affect mortality or overall complications rates in these series. 2.2. The significance of MASCC scoring The authors looked also at the possible significance of the MASCC score, at the beginning of FN, in relation to bacteremia. The MASCC scoring system is shown in Table 4 [5]. A relatively low rate of overall complications (18%) and death (3%) was seen in low-risk patients with bacteremia and MASCC scores of >21; but if the MASCC score was <21 the corresponding figures were 49% and 19% (P < 0.001).

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Table 4 Score derived from the logistic equation of the MASCC predictive model. Characteristic

Points

Burden of illness No or mild symptoms Moderate symptoms

5 3

No hypotension No chronic obstructive pulmonary disease Solid tumor or no previous fungal infection in hematological cancer Outpatient status No dehydration Aged <60 years

5 4 4 3 3 2

Threshold: score ≥21 (maximum 26) predicts <5% of severe complications Klastersky et al. [5].

If the score was <15, overall complications (79%) and mortality (36%) were even higher, with 15–20 being intermediate in risk (40% and 14% respectively) (Table 5). This is an interesting observation that requires confirmation. Using this score it might be possible to identify low-risk and high-risk patients with bacteremia, and perhaps a different approach to therapy might be used in the high-risk patients (MASCC score <15) to try to lower the very high overall complication and mortality rates seen in these patients. It was also found that, even with Gram-positive bacteremia, a low MASCC score (<15) predicted a high mortality (28%). These data are not ideal because the number of very high-risk patients in this study (MASCC score <15) was quite small. However, the data still suggest that patients with low MASCC scores and bacteremia have a very poor prognosis and might require a different and more urgent therapeutic approach. As pointed out by Feld [20] in developing countries the situation may be different. The predominant pathogens causing bacteremia are frequently the Gram-negatives because there is less routine use of prophylactic oral antibiotics, such as quinolones, and because it is more difficult to afford central lines, with both of these approaches contributing to the emergence of Gram-positive organisms causing more frequent bacteremia in developed countries. However, the emergence of fluoroquinolone-resistant Gram-negative bacteria, namely E. coli, has been well documented, as a result of extensive use of the quinolones for prophylaxis in patients with hematological malignancies [18]. Such a trend by itself, as well as the discontinuation of the prophylaxis policy by fear Table 5 Mortality rate in bacteremic patients stratified by MASCC score values and type of bacteremia. MASCC score

<15 15–20 ≥21

Gram+

Gram−

Total (Nr.)

Deaths (%)

Total (Nr.)

Deaths (%)

18 89 176

28 6 2

23 64 81

43 23 6

Adapted from Klastersky et al. (2007) [19].

resistance, might increase the risk of resistant Gram-negative infections in neutropenic patients, in the future. Thus, we might, also in developed countries, face the re-emergence of Gram-negatives as the major cause of infection during febrile neutropenia. 2.3. Complicated bacteremia The presence of clinically apparent sites of infection (e.g. pneumonia, urinary-tract infections, neutropenic enteracolitis, peri-rectal infections) which are usually polymicrobial or predominantly Gram-negative, are often considered to have a higher morbidity/mortality than simple bacteremia. This was not the case in our review [19]. Bacteremia associated with a clinical site of infection (mucositis, lower respiratory tract, skin/soft tissue, vascular access device, urinary-tract infection with or without drainage device, upper respiratory tract, and others, including gastro-intestinal sites and multiple sites) was seen in 235 patients, 48 (20%) of whom presented a non-lethal complication and 29 (12%) died. In 264 bacteremic patients with no clinical site of infection identified, 58 (21%) presented with severe complications and 20 (8%) died. However, the mortality for patients with Gam-negative bacteremia was 13% without a clinical site of infection and 23% in those with a clinical site of infection identified.

3. The issue of bacteremia 3.1. Prediction of bacteremia The preceeding discussion has stressed the very highmortality rate in bacteremic patients, especially in those with Gram-negative bacteremia. It has also indicated that, in patients presenting with a high-risk FN (i.e. MASCC score <21), the mortality associated with bacteremia was higher, even for Gram-positive infections, compared to those with a low risk of complications. Thus, the question can be asked whether it is important to detect early, or even better, predict the occurrence of bacteremia, in order to possibly modify the outcome of the patients. Earlier studies to identify factors associated with bacteremia in febrile neutropenic patients have been disappointing [21]. Although a few predictive factors such as antifungal prophylaxis, duration of granulocytopenia before fever, platelet count, the highest fever, shock and presence and location of initial signs of infection, could be identified, when tested in a validation set, the model was poorly predictive. More recently, attempts to predict bacteremia associated with multi-resistant Gram-negative bacilli in hematopoietic stem cell transplant recipients has been also unsuccessful [22]. Although predictive models for bacteremia, based on five easily accessible clinical variables (more intensive chemotherapy, shorter time since diagnosis, bone marrow involvement, central vensus access device, and prior febrile neutropenia), have been proposed, recently, in febrile neu-

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tropenic children, they need to be validated by prospective studies before clinical application [23]. As will be discussed later, some sophisticated biological markers (procalcitonin, interleukins, etc.) have been used for the prediction of bacteremia and/or severe sepsis in febrile neutropenic patients. Nonetheless, the question regarding the importance of predicting bacteremia remains open. We found recently, in a study assessing FN with the MASCC score [24], a significant association between the predicted risk of complications and bacteremia documentation: patients at low risk of complications had also a lower risk of bacteremia and, namely, Gram-negative bacteremia was significantly more frequent (13%) in the non-low-risk patients compared to the low-risk group (5%). We further found that the risk of complications and death was increased in bacteremic patients in both strata of predicted low and high-risk patients and, especially in patients with Gram-negative bacteremia. However, looking at the predictive value of the MASCC score in strata defined by bacteremic status, we did not detect any statistically significant difference in odds ratios estimates comparing complications rates in patients predicted at low risk or high risk which led us to the conclusion that the MASCC score was discriminant in both bacteremic and non-bacteremic patients. Thus, attempts to improve the MASCC score, using the documentation of bacteremia, do not appear very promising. However, it might be an interesting theoretical issue and a potential area for further research. 3.2. Management of low-risk patients Moreover, that analysis suggested that the occurrence of bacteremia, namely Gram-negative bacteremia, is still unpredictable with the covariates that we today assess. As will be discussed later, it is possible that, in the future, we might have some laboratory parameters to be used as markers for bacteremia like CRP or various interleukins levels. However, for the time being, the MASCC score, which use has been recommended by ESMO (European Society of Medical Oncology) and others to evaluate the risk of complications in febrile neutropenic patients [5], remains a standard to guide, in clinical practice, the management of febrile neutropenia in patients with solid tumors and lymphomas. Its main interest today lies in the observation that patients predicted to have low risk can be managed safely with oral antibiotics and early hospital discharge [25,26]. However, the prediction of the risk during FN and the prediction of a safe early discharge are somewhat different issues. In a recent study, we found that 9% of the patients who were not sent back home after a 24-h observation within the hospital developed serious complications [25]. The in-hospital observation is probably very important to selecting those patients to be discharged early. However it is clear that many centers will send low-risk patients home after a 4–8 h observation period, after ensuring that the first dose of the prescribed regimen has been

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safely administered. Equally important – and this applies to all patients who are being treated as out patients, whatever the duration of the in-hospital observation is – is the careful further monitoring of these patients. Those patients should be given specific instructions to return to the hospital if they fell worse or develop serious symptoms. They also should be encouraged to record their temperature several times a day as well as their weight and to list their problems. Those patients should be reviewed in follow-up clinics at regular intervals and, in the intervals, be contacted by telephone to review clinical and laboratory data and to make decisions regarding response failure, drug toxicity and other adverse events [27]. As far as oral antimicrobial therapy is concerned, it can be given to the majority of low-risk patients but some do not tolerate oral agents or may have mucositis or nausea making this route suboptimal. This should not lead necessarily to the decision not to send the patient home as parenteral out patient therapy has also been shown to be safe and effective in low-risk patients who are unable or unwilling to receive oral therapy [28]. 3.3. Limitations of the MASCC score predictive value In our initial study, we found that the MASCC score was less predictive in patients with hematological malignancies than in patients with solid tumors. It is therefore not surprising that attempts have been made to adapt the MASCC score to the more complex conditions found in patients with hemopathies [29]. In an evaluation of 354 such patients, it was found that the following nine risk factors: age, type of hematological disease, leukocyte count, reduction in leukocyte count, prophylaxis with antimycotics, sterilization of the gut, urine albumin, serum creatinine and C reactive protein levels could be used as a risk predictive score. However, the exact sensitivity and specificity of this new scoring index has not been established. Febrile neutropenic children with cancer have also specific characteristics that justify adaption of predictive models that are used in adults. These aspects have been recently reviewed [30] and, upon this review, general recommendations have been proposed. On the other hand, if elderly patients with leukemia do not appear to be significantly more susceptible to infections than younger ones [31], the comorbidities that are frequent in those patients increase the risk of complications and the burden of cost [32]; therefore risk-based treatment and preventive strategies are particularly important in the elderly population.

4. Antimicrobial regimens used in febrile neutropenic cancer patients 4.1. Optimal regimens A systematic review and meta-analysis of randomized trials of antibiotic monotherapy for FN was presented by Yahav

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et al. [33]. It was found that cefepime was associated with higher all-cause mortality at 30 days than other beta-lactams (RR 1.44, 95% CI 1.06–1.94). This requires confirmation, as cefepime has been successfully used patients with highrisk FN. The meta-analysis published by Yahav et al. [33] was based on 41 studies which comprised a subset of our trial-level data, but not patient-level data. The conclusions of significantly higher mortality rate in the cefepime group compared to the comparator group were not confirmed in a FDA analysis. The FDA analysis was based on a broader spectrum of data sources and found that the majored risk difference in the cefepime group was greater, but this increase was not found to be statistically significant in both trial-level and patient-level analyses [34]. In the Yahav’s meta-analysis, carbapenems were associated with fewer treatment modifications, including addition of glycopeptides, than ceftazidime or other comparators, but adverse effects were significantly more frequent, specifically pseudomembranous colitis (RR 1.94, 95% CI 1.24–3.04). Piperacillin–tazobactam was compared recently with cefepime or carbapenems in seven randomized trials and no significant differences were demonstrated [35]. Although there may be variations in study design and definitions, the clinical outcomes with piperacillin–tazobactam were generally similar to comparator agents as monotherapy (or in combination with an aminoglycoside) for empiric management of FN. An EORTC (European Organisation for Research and Treatment of Cancer) evaluation of piperacillin–tazobactam monotherapy, with or without concomitant vancomycin, noted no difference in resolution of fever, time to defervescence, treatment modification or mortality between the 2 groups and confirmed, through an intention to treat and per protocol analysis, the use of piperacillin–tazobactam monotherapy for empiric treatment of FN [36]. In addition, that study clearly indicated that the empiric use of glycopeptides, as initial therapy, was not needed. Adverse events, probably or definitely related to piperacillin–tazobactam, were uncommon, confirming the favorable therapeutic index of piperacillin–tazobactam; out of 468 adverse events, only 24 (5%) were considered to be definitely or probably related to piperacillin–tazobactam therapy. Importantly in children with FN, piperacillin–tazobactam may also be safely used as empiric therapy [37,38]. 4.2. Discussion of the potential choices Actually, it may be concluded that probably ceftazidime, cefepime, carbapenems and piperacillin–tazobactam can be safely used for empiric therapy of FN. Specific choices should be based on local microbiological epidemiology and it may be wise not to use as primary therapy those antibiotics that can be of particular usefulness in infections with highly resistant bacteria. Although monotherapy is probably safe in most cases [8], the use of combination of beta-lactams or carbapen-

ems with aminoglycosides might be considered for infections caused by relatively resistant organisms, such as P. aeruginosa, or in patients with a high risk of complications, as already discussed. For patients with a low risk of infection, oral administration of amoxicillin–clavulanate combined with ciprofloxacin has been found effective and safe [6]. More recently, oral moxifloxacin was found also highly effective and safe [27,28]. Both approaches make possible early discharge from the hospital. Actually, as shown in a recent investigation, the implementation of a critical pathway for the management of FN, might have a major impact on clinical outcomes, whatever would be the selected antimicrobial regimen [39]. In that study, evaluating the compliance with an institutional approach, the MASCC score was used to select initial antibiotic therapy. For the low-risk neutropenic patients, the critical pathway recommended cefepime or oral ciprofloxacin combined with amoxicillin–clavulanate; for high-risk patients (e.g. patients with signs of clinical instability) the recommendation was cefepime plus amikacin. After protocol implementation, the all-cause mortality decreased from 24% to 14% (P = 0.017) and there was an overall reduction of use of cephalosporins and quinolones.

5. Biomarker predictors of the risk of complications in febrile neutropenic patients As the risk stratification appears essential for orienting therapy in patients with FN, it is not surprising that attempts have been made to improve the accuracy of that prediction by combining to clinical characteristics some biomarkers, although the latter may not be accessible at the onset of fever and/or patient’s presentation to the hospital for medical advice. Among these biological parameters, procalcitonin (PCT) and C-reactive protein (CRP) have been evaluated as potentially useful markers of severe infection in febrile neutropenic patients. In recipients of allogenic hematopoietic stem cell transplantation, a CRP ≥ 90 mg/L or a PCT ≥ 0.7 ng/mL had a high specificity and negative predictive value for the diagnosis of invasive bacterial infections [40]. In another study, in patients with hematological malignancies, PCT but not CRP was found predictive of severe infection [41]. In a similar population, the predictive value of PCT was confirmed for Gram-negative bacteremia, while there was no significant differences in CRP, neopterin, IL-6 or IL-8 levels, according to the source and the etiology of infection [42]. A literature review concluded also that PCT might be an useful predictive tool in FN [43]. In another study, in oncology patients, IL-6 and IL-8 allowed to define a group of patients with a short duration of the febrile episode and a group with severe infection or blood culture positive sepsis; IL-6 was the best predictive parameter [44].

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Uys et al. attempted to combine all these biological markers with the MASCC risk index [45]. Multivariate analysis revealed that the MASCC score, but none of the laboratory parameters, was an accurate and independent variable (P < 0.0001) for prediction of resolution of FN, with or without complications or death. Of the various laboratory parameters, PCT had the strongest association with the MASCC risk index score. This clinical study concluded that the MASCC risk index score was a useful predictor of outcome, while measurement of PCT, CRP, IL-6 or IL-8 was of limited value. Santolaya et al. evaluated predictive factors of severe sepsis, at the onset of FN, in 601 febrile neutropenic episodes children. They found that age ≥12 years and admission or 24hours values of CRP ≥ 90 mg/L and IL-8 ≥ 200–300 pg/mL were predictors of sepsis [46], not clinically apparent during the first 24 h of hospitazation. They also identified early clinical and laboratory findings significantly associated with death occurring at a later stage (low absolute neutrophil and monocyte counts, higher blood urea nitrogen and high CRP values); in those children, bacteremia was also more frequent (79%) [47].

6. The management of non-low-risk patients 6.1. Traditional approaches Now, the question is what to do for these patients who are predicted at a higher risk of sepsis, complications and death via any of these predictive models. It is uncertain whether the sole full control of the infection would be sufficient for an optimal outcome; as a matter of facts, the antimicrobial coverage is adequate is most cases. Whether the final issue could be improved by the use of synergistic combinations of antimicrobials remains to be demonstrated. However, a meta-analysis does not suggest a benefit from combination therapy [8] but most studies have not been conducted specifically in high-risk patients, as defined by a validated predictive tool. The use of myeloid colony-stimulating agents, as a therapy, might be associated with a limited benefit in terms of mortality [48]; however, it must be recognized that many of the high-risk patients, namely those having hematological malignancies, already would be receiving some myeloid colony-stimulating factors by the time of the onset of febrile neutropenia. Actually, one has to take into account the impressive pathophysiological turmoil associated with sepsis [49], the understanding of which might lead to novel, biologically based approaches. As an example, it has been recently reported that activated protein C administration could shorten the duration of FN and improve the clinical outcome in pediatric patients during cancer therapy, without serious complications [50]; these preliminary data certainly require

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confirmation from larger studies, conducted in adequately selected patients, as recently discussed in an exhaustive review [49]. 6.2. Novel possible orientations Another possible approach to an improved management of high-risk neutropenic patients might be the early use of intensive care management. It seems, indeed, that the optimal time of admission to the intensive care unit plays a major role for the outcome [51]. Therefore, it might be necessary to revise our traditional attitude towards intensive care unit admissions which is usually considered only when organ failure(s) and/or refractory hypotension has developed; it is possible that earlier admission for surveillance of otherwise asymptomatic febrile neutropenic patients who have a high-risk predictive score would be worth to be considered and might require carefully designed controlled studies. Relatively to other high-mortality disease processes, such as cardiac or traumatic emergencies, FN is still not always considered much as a medical emergency, justifying early admission to the intensive care unit [52]. While in these other situations one is aware of the need not to loose the “golden hour”, this is still not the case in many patients with FN. It may thus be possible that a more protocolized approach, including the early admission to the intensive care unit should be recommended, at least in those patients, predicted at a high risk of complications and death.

7. Conclusions 7.1. Stratification of the risk FN is the most frequent and potentially lethal complication of cancer therapy. As it occurs in about 10–20% of patients receiving chemotherapy for solid tumors (in those with hematological malignancies, the incidence is much higher) and carries a mortality rate of at least 5%, one can easily appreciate the magnitude of the problem, given the rising numbers of patients receiving cancer chemotherapy. A series of achievements have made FN less frequent and less severe over the recent years; among them the development of the myeloid growth factors for its prevention and that of potent broad spectrum antibiotics for its empirical therapy. Possibly, one of the most important addition to our strategy to cope with FN has been the tailoring of management to the level of risk of complications of individual patients. Such a risk stratification of the febrile neutropenic population allows a simplified therapy (e.g. oral antibiotics and early discharge from hospital) in a significant proportion (approximately 50%) of patients with solid tumors who present with FN. The direct consequence is an improved quality of life

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for the patient and a reduction of the cost for the health care providers. It remains, nonetheless, that a small proportion of patients, both among those with solid tumors and hematological malignancies, have a high risk of complications and death during an episode of FN. The possibility to identify those patients, through validated predictive instruments, both in children and adults, permits to envision more specific and earlier therapies for these high-risk patients. 7.2. Strategies for the future What can these strategies consist of? There lies the main challenge we are now facing to make a further step towards a more comprehensive control of the complications of FN. The empiric use of more active antibiotics (e.g. synergistic combinations) and therapeutic use of myeloid growth factors in high-risk febrile neutropenic patients will not, probably, change much the present situation; although empirical management remains a corner stone of the overall strategy. Actually, the empiric approach reflects our relative inability to early diagnose the type of offending microorganisms which are involved in the febrile neutropenic episodes. Progresses in early microbiological diagnosis might considerably help the clinician, especially with difficult and unexpected pathogens during the initial phase of febrile neutropenia. Although we can predict who are the patients at high risk of complications and death, we can still not predict the individual patient who is at risk of severe sepsis. The use of biomarkers such as C reactive protein, procalcitonin, various interleukins and other markers have not clearly changed, so far, our ability to predict the risk in individual patients. It is now recognized that sepsis is actually a cascade of events, triggered and mediated by numerous biological events which, at the end, result in hypotension and coagulopathy. It may be logical to look at these pathophysiological steps, in order to interfere with this potentially lethal cascade, with agents that can selectively inhibit or reverse the action of cytokines and other biologicals involved with the progression of the sepsis process. Finally, from the clinician’s point of view, it may be important to provide to the patients, who are predicted at high risk of complications during FN, an intensive care environment, as soon as possible, even before the appearance of any organ failure or other ominous symptoms. 7.3. Final conclusion To conclude, it is clear that, after about half a century of dedicated efforts to improve the control of infectious complications in cancer patients – namely in those with FN – the

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Biographies Professor Jean Klastersky has been Head of the Department of Medicine at the Institut Jules Bordet in Brussels and Professor of Medicine, Medical Oncology and Physical Diagnosis at the Université Libre de Bruxelles since 1977. He retired from these positions in 2005. Currently, he is the Coordinator of the “Programme des Soins Oncologiques” for the Public Hospitals in Brussels and Consultant in Medical Oncology at the Institut Jules Bordet. Professor Klastersky was a founder member of the European Lung Cancer Working Party and has been his President since 1978 until 2003. He was President (and founder member) of the International EORTC Antimicrobial Therapy Project Group between 1979 and 1987 and the Group’s Secretary General from 1987 to 2000. He was President (and founder member) of the Multinational Association for Supportive Care in Cancer (MASCC) from 1990 to 2000. He is Visiting Professor of Medical Oncology at the Charles University in Prague, since 1994. Professor Klastersky is a member of the American Society of Clinical Oncology, the American Association of Cancer Research, the European Society of Medical Oncology, the American Society of Microbiology, the Infectious Diseases Society of America, the International Association for the Study of Lung Cancer, the “Royale Académie de Médecine” of Belgium and various other international and national medical and/or oncological societies. Professor Klastersky is the author of over 500 original articles, nearly 400 review articles and 17 scientific books. He is the Editor of Current Opinion in Oncology. Professor Ahmad Awada was born in Lebanon and studied Medicine at the Free University in Brussels (ULB), Belgium. He did a specialisation in Internal Medicine and Medical Oncology at Jules Bordet Institute, in Brussels, until 1992. During his specialisation, he also followed trainings in the clinical development of new therapies and new anticancer drugs, As a research fellow, he stayed in the Netherlands (New Drug Development Office, Free University, Amsterdam;) and in San Antonio, USA (Institute for Drug Development). He focused on the clinical development of new anticancer agents. Back from the USA at the beginning of 1994, Dr. Awada became Assistant Head of Medical Oncology Clinic, and Head of the New Drugs Development Unit at Jules Bordet Institute, Brussels. Since April 2005, he is the Head of the Medical Oncology Clinic. He has an important clinical activ-

ity in the treatment of solid tumors. Dr. Awada took an active part in the development of new drugs, some of them already widely used, namely molecular-targeted therapies. Dr. Awada is membership of several international scientific (ASCO, EORTC, ESMO) societies and and Professor of Medicine at the Université Libre de Bruxelles. He published 24 book chapters and, 154 articles in international publications. Marianne Paesmans has a diploma in mathematical sciences and in actuarial sciences, both delivered by the Free University of Brussels and works as statistician at Institut Jules Bordet since 1988; she is currently head of Data Centre, an unit at Institut Jules Bordet having as mission among others, to participate to clinical research with respect to methodology, statistical methods, statistical analysis and data managing. She is member of various international associations active in the conduct of clinical research in cancer (European Lung Cancer Working Party, European Organization for Research and Treatment of Cancer Infectious Diseases Group, Multinational Association for Supportive Care in Cancer) and of various scientific societies (International Society of Clinical Biostatistics, American Society of Clinical Oncology, European Society of Medical Oncology, European Respiratory Society, International Association for the Study of Lung Cancer). She has authored or co-authored more than 200 scientific publications and 8 book chapters. Dr. Mickael Aoun is a consultant in infectious diseases at Institut Jules Bordet, Brussels, Belgium. He is a specialist in internal medicine, oncology and infectious diseases; he graduated from the Free University of Brussels. He is Head of the Infectious Diseases Department at the Institut Jules Bordet in Brussels. He is a member of ASM (American Society of Microbiology), ESCMID (European Society of Clinical Microbiology and Infectious Diseases), EBMT (European Group for Bone & Marrow Transplantation), MASCC (Multinational Association for Supportive Care in Cancer), EORTC IDG Group (European Organisation for Research and Treatment of Cancer – Infectious Diseases Group). His main research topics are febrile neutropenia and infection in immunocompromised patients. He is the author or co-author of more than 100 publications including several book chapters and peer-reviewed original articles.