Clinical research in febrile neutropenia in cancer patients: Past achievements and perspectives for the future

Table 1 Complications and death rates in patients with febrile neutropenia

	Complications (%)		Mortality (%)
	Hemopathies	Solid tumors	Hemopathies	Solid tumors
No bacteremia	17	11	4	3
Bacteremia	30	35	9	13

Adapted from Klastersky et al[10].

Table 2 Multinational Association for Supportive Care in Cancer scoring system

Characteristic	Weight
Burden of illness: No or mild symptoms	5
No hypotension	5
No chronic obstructive pulmonary disease	4
Solid tumor or no previous fungal infection	4
No dehydration	3
Burden of illness: Moderate symptoms	3
Outpatient status	3
Age < 60 yr	2

Points attributed to the variable “burden of illness” are not cumulative. The maximum theoretical score is therefore 26.

Table 3 Validation studies of Multinational Association for Supportive Care in Cancer score for predicting low-risk

Ref.	N episodes	Patients with hema-tological malignancy (%)	Predicted at low-risk (%)	Se (%)	Sp (%)	PPV (%)	NPV (%)
Klastersky et al[24], 2006	1003	55	72	79	56	88	40
Stratum of hematological tumors	549	100	70	77	51	84	40
Stratum of solid tumor patients	454	0	74	81	64	93	38
Uys et al[22], 2004	80	30	73	95	95	98	86
Cherif et al[23], 2006	279	100	38	59	87	85	64
Klastersky et al[24], 2006	611	43	72	78	54	88	36
Innes et al[25], 2008	100	6	90	92	40	97	20
Baskaran et al[26], 2008	116	100	71	93	67	83	85
Hui et al[27], 2011	227	20	70	81	60	86	52
Carmona-Bayonas et al[28], 20111	169	0	?	94	36	NA	NA

¹Selected patients population (“apparently” stable patients). The characteristics were calculated for a test aiming to identify low-risk patients and may then differ from the original publications. Due to the case-control design of the study, the rate of patients predicted at low risk as well as the negative and positive predictive values are meaningless. Se: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value.

Table 4 CISNE score

Characteristic	Weight
ECOG performance status ≥ 2	2
Stress induced hyperglycemia	2
Chronic obstructive pulmonary disease	1
Chronic cardiovascular disease	1
Mucositis NCI grade ≥ 2	1
Monocytes < 200/μL	1

ECOG: Electrocorticogram; NCI: National cancer institute.

Table 5 Characteristics of CISNE score and Multinational Association for Supportive Care in Cancer score for predicting high-risk

	CISNE	MASCC
Predicting high risk, complications	118	53
Predicting low risk, no complications	747	853
Predicting high risk, no complications	234	128
Predicting low risk, complications	34	99
	1133	1133
Se	0.78	0.35
Sp	0.76	0.87
PPV	0.34	0.29
NPV	0.96	0.90
Miscl rate	0.24	0.20

High-risk of prediction: CISNE > 2, MASCC < 21. Se: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; MASCC: Multinational Association for Supportive Care in Cancer.

Table 6 Major elements of the management of febrile neutropenia over time

60’s	High mortality (> 90%) in FN with gram-negative bacilli bacteremia Establishing the concept of empiric antibiotic therapy
70’s	Anti-pseudomonal penicillins plus aminoglycoside combination as empiric therapy of choice Oral non resorbable antimicrobials (aminoglycosides, glycopeptides, polymyxines, colimycin, in different combinations with nystatin), for intestinal flora suppression
80’s	Establishing empirical antifungal therapy Oral trimethoprim-sulfamethoxazole (or nalidixic acid and fluoroquinoles for prophylaxis in HM Assessment of risk factors predicting complications: Talcott’s criteria
90’s	Monotherapy supplanted combination Ambulatory management first with IV antibiotics (ceftriaxone + aminoglycoside) and then with oral fluoroquinolones
2000’s	Refinement of risk assessment: MASCC score Risk-adapted therapy

FN: Febrile neutropenia; HM: Hematologic malignancies; MASCC: Multinational Association for Supportive Care in Cancer.

Table 7 Possible causes of fever in high risk neutropenic patients unresponsive to broad spectrum antimicrobials[139]

Infectious causes	Frequency
Fungal infections responding (40%)/resistant (5%) to empiric ATB	45%
Bacterial Infections (cryptic foci, biofilm, resistant organism)	10%
Toxoplasma gondii, mycobacteria, legionella, mycoplasma, chl.pneumoniae	5%
Viral infections (HSV, CMV, EBV, HHV6, VZ, parainfluenza, RSV, influenza)	5%
Graft vs host disease in hematopoietic stem cell transplantation	10%
Undefined (drug, toxic effects of chemotherapy, antitumor response, undefined pathogens)	25%

HSV: Herpes simplex virus; CMV: Cytomegalovirus; EBV: Epstein-Barr virus; HHV6: Human herpesvirus 6; RSV: Respiratory syncytial virus.

Table 8 Usual sensitivity and resistances of fungi against the different antifungals[149-151]

Antifungal classes	Antifungal agent	Common resistances	Common sensitivity
Polyenes	Amphotericine B:	Candida lusitaniae	Candida
	Deoxycolate	Trichosporon	Aspergillus
	Liposomal	Fusarium	Zygomycetes
	Lipid complex	Scedosporium
	Colloidal dispersion	Aspergillus terreus
	5 Fluorocytosine	Zygomycetes	Candida
		Scedosporium	Torulopsis
		Fusarium	T. glabrata
		Cryptococcus	Cryptococcus
		Candida	Phialophora
			Cliadosporium
			Exophiala
Triazoles	Fluconazoles	Aspergillus	Candida albicans and others
		Candida kruzei	Candida glabrata1
		Candida glabrata	Cryptococcus neoformans
		Zygomycetes	Blastomyces dermatitidis
			Coccidioides
			Histoplasma capsulatum
	Itraconazole	Aspergillus niger	As itraconazole + Aspergillus flavus
		Aspergilus terreus	Aspergillus fumigatus
		Zygomycetes	Candida kruzei
		Mucor	Trichophyton
		Fusarium solani
		Penicillium
	Voriconazole	Zygomycetes	As itraconazole + Aspergillus niger
		Sisyrinchium inflatum	Aspergillus tereus
		Fusarium oxysporum, penicillium, Schedosporium apiospermum
	Posaconazole	Trichosporon asahii	As voriconazole + Trichophyton
			Zygomycetes
Echinocandins	Caspofungin	Cryptococcus
	Micafungin	Zygomycetes
	Anidulafungin	Fusarium
		Paecilomyces lilacinus
		Trichosporon
		Schedosporium
		prolificans
		Schedosporium inflatum
		Candida parapsilosis

¹Are not always sensible to the antifungals.