BMC Cancer 2009, 9:153 http://www.biomedcentral.com/1471-2407/9/153 Table 3: Association between B symptoms and clinical variables. Variable Sex Age Stage LDH Performance status Bone marrow aspirate Bone marrow trephine who experienced early disease progression. Furthermore, multiple previous investigators have established that B symptoms are associated with worse progression free and overall survival in NHL [6-10]. As discussed above, B symptoms are indicators of a sys- temic inflammatory response and have been associated with elevated plasma concentrations of CRP and pro- inflammatory cytokines [6,9,10]. Moreover, clinical stud- ies with anti IL-6 monoclonal antibody in patients with lymphoproliferative conditions resulted in reductions in CRP concentrations and improved clinical outcome [17]. There is substantial pre-clinical and clinical evidence from cancer and other inflammatory diseases, that hepatic drug clearance is reduced in the presence of a systemic inflam- matory response [18-20]. A number of agents used in the management of NHL are metabolized by the liver includ- ing doxorubicin, cyclophosphamide and vincristine. As over 50% of all prescribed medications, including many cytotoxic agents, are metabolized by CYP3A4, this may be a significant source of pharmacokinetic and toxicity varia- bility to anticancer agents [13,21-24]. The effects of cancer on hepatic drug metabolism have been recently clarified. Rivory and colleagues demon- strated that cancer patients with elevated acute phase pro- teins, including CRP and alpha-1 acid glycoprotein (AAGP), had reduced CYP3A4 function as determined by the erythromycin breath test [14]. The elevated plasma CRP concentrations were associated with increased plasma concentrations of IL-6. In addition, elevated levels of CRP were associated with reduced plasma clearance Category Female Male < 75 years GE 75 years Stage 0–2 Stage 3–4 Level 0–1 Level 2–4 Normal Elevated Negative Positive Negative Positive n 311 353 496 168 246 418 470 183 216 381 508 57 487 89 B symptoms present 169 (54.3) 184 (52.1) 261 (52.6) 92 (54.8) 94 (38.2) 259 (62.0) 210 (44.7) 137 (74.9) 95 (44.0) 223 (58.5) 266 (52.4) 38 (66.7) 246 (50.5) 62 (69.7) p 0.577 0.631 < 0.001 < 0.001 < 0.001 0.040 < 0.001 and increased toxicity following treatment with docetaxel, a CYP3A4 substrate [15]. By utilising a regulatory trans- genic reporter mouse model of human CYP3A4, Charles and colleagues demonstrated that the presence of tumour resulted in down-regulation of the CYP3A4, which corre- lated with a systemic acute phase response. Furthermore, IL-6 expression was localised within the tumour, suggest- ing that the tumour or its associated stroma was the source of the increased circulating IL-6 noted in this model. As a result of this study a mechanistic link was suggested between tumour-derived cytokines and impaired drug metabolism [25]. Furthermore, in data from the same models, Sharma and colleagues demonstrated significant reductions in the expression of a number of drug trans- porters in the livers of tumour bearing mice compared to control animals, suggesting a global reduction in hepatic drug handling in the presence of malignancy. These data make it likely that cytokines responsible for the B symptoms in NHL are also causing reduced hepatic drug clearance, resulting in the increased toxicity documented in the current study. This finding has a number of impor- tant clinical and research implications for NHL and cancer in general. Firstly, it means that we have a useful marker for increased toxicity in NHL. Although a number of prog- nostic indices have been used in NHL most have been used to predict for response and survival rather than tox- icity. The ability to identify patients at increased risk of myelosuppression and infection will permit increased sur- veillance and possibly increased use of prophylactic anti- biotics. Furthermore, the prognostic utility of B symptoms could be enhanced by measuring plasma proteins includ- Page 6 of 10 (page number not for citation purposes)