The role of antifungal treatment in hematology

Invasive fungal diseases, especially those caused by molds, show many similarities with lymphomas and other hema tologic cancers. Indeed, unequivocal proof for the pres ence of these life-threatening diseases relies on histopatho logical evidence or on the demonstration of malignant cells or fungi by microscopic examination or culture. In general, if left untreated, these diseases will disseminate and prove fatal. Before adequate treatment is started, a staging workup in search of metastatic lesions needs to be performed, usually involving (but not limited to) whole body computed tomog raphy (CT) scanning, with or without positron emission tomography, and a thorough examination of sanctuary sites. In addition, prognostic scores are constructed at baseline and immunophenotypic profiles, cytogenetic, molecular or sero logic markers are identified. The latter may have prognostic value or later serve as surrogate markers for detecting residual disease or for guiding further therapy. First-line therapy typically consists of a single drug or combination of drugs, includ ing the use of monoclonal antibodies or immunomodulatory drugs. Moreover, successful first-line therapy is frequently followed by maintenance therapy for several months, with or without adjunctive radiotherapy or surgery. In case of refrac tory disease or relapse, salvage treatment is started using drugs with different modes of action. Finally, the crude mor tality rate of invasive fungal disease is not that different from the mortality rate of most malignant blood disorders, being around 40%. However, assessing the role of the underlying malignant disease or of invasive fungal disease remains difficult, especially when a postmortem examination is not car ried out. Despite the obvious similarities, clinicians seem to accept different thresholds for initiating diagnostic workups and for starting treatment. Virtually no hemato-oncologist would consider starting antineoplastic chemotherapy, immunother apy or radiotherapy to prevent the development of malignant disease in a population at risk, or to ‘treat’ a strong clinical suspicion that the patient may have malignant disease, even if their decision is based on a marker in the absence of histopathological evidence. However, a large majority of these physicians are apparently willing to start expensive broad-spectrum antifungal agents for these exact indications, irrespective of the immediate and long-term consequences, be they in terms of cost, the development of resistance or tox icity. This liberal approach developed in the early 1980s and was fueled by the lack of reliable non-invasive diagnostic tools, a reluctance to look for tissue-based evidence in cytopenic patients, and the impression that early treatment would result in better outcome. Over the last few decades, four basic strategies have been developed and investigated in clinical studies to deal with invasive fungal disease, particularly in neutropenic patients. As far as invasive mold disease is concerned, it is possible to delineate various patterns that are encountered in the neu tropenic population (Table 1) based on radiological signs and clinical symptoms that might be consistent with invasive fun gal disease, and on mycology results, with a view to assessing whether or not they are consistent with infection, disease or both. Each pattern is evaluated for its compatibility with infection and disease, and whether or not it meets the current EORTC/MSG definitions. 1 Management options are also assigned to each pattern. The diagnosis is predicated from a CT scan, and also by testing for evidence of infection directly by culture, and indirectly by testing for galactomannan, though PCR and beta-d-glucan might be included as well. Categories from A through to E each progress along an axis of certainty of diagnosis of invasive fungal disease. Whilst category A represents no invasive fungal disease at all, cate gory E represents proven invasive fungal disease according to current EORTC/MSG definitions. Categories B, C and D rep resent the spectrum in between these two extremes. Category A is made up of patients who might be considered suitable candidates for prophylaxis, 2