BMC Cancer 2009, 9:153 http://www.biomedcentral.com/1471-2407/9/153 Background Cancer chemotherapy produces variable and unpredicta- ble toxicities, which can cause significant morbidity, occa- sional mortality and result in substantial healthcare costs due to increased requirement for toxicity-related hospital- isation [1-3]. Non-Hodgkin lymphoma (NHL) is the fifth most common cancer by incidence in both men and women in the developed world [4] and is usually treated with combination chemotherapy. Although regarded as a chemotherapy-sensitive disease, over 50% of patients with the diffuse large B cell variant will die of their disease. The effective use of cancer chemotherapy is a balance between adequate anti-tumour effect and manageable normal tissue toxicities. There is evidence that dose reduc- tion and delay for toxicity in NHL results in inferior response rates and survival than when dose intensity is maintained [5]. An improved ability to predict and/or prevent toxicity would substantially improve outcomes in NHL, and other malignancies. The presence or absence of inflammatory or B symptoms (fever > 38°C, weight loss > 5% or night sweats) is an established negative prognostic factor in patients with NHL. B symptoms are associated with increased plasma levels of inflammatory proteins including C-reactive pro- tein (CRP) [6] and cytokines such as interleukin-6 (IL-6) [7]. Elevated inflammatory proteins have been shown to correlate with other prognostic markers in NHL including ECOG performance status, β2-microglobulin levels and International Prognostic Index (IPI) [7,8]. In addition, NHL patients with elevated plasma inflammatory markers have lower response rates to chemotherapy and worse sur- vival than those with normal levels [7-10]. The impact of inflammation on toxicity in NHL has not been extensively investigated. Chemotherapy induced toxicity is particularly relevant in NHL as many of the patients are older and relatively frail, and toxicities may lead to treatment interruption, dose reduction, major morbidity necessitating hospitalization, and even treat- ment-related death. There is evidence that loss of relative dose intensity in NHL can compromise treatment out- comes. For example, Kwak and colleagues reported that NHL patients who received > 75% of planned doxoru- bicin doses had markedly superior survival to those receiving lesser doses [5]. Improved dose individualiza- tion and avoidance of or reduction in the severity of tox- icity would assist in maintaining dose intensity. There is increasing evidence that a systemic inflammatory response occurs frequently in patients with malignancy, and is generally associated with worse clinical outcomes (reviewed in [11]). Furthermore, the presence of raised pro-inflammatory cytokines, including IL-6, has been shown to negatively impact on hepatic drug metabolism (reviewed in [12] and [13]). This concept is supported by data which demonstrated that reductions in CYP3A4 activity in patients with advanced cancer were correlated with increased plasma concentrations of IL-6 and CRP [14]. This was associated with reduced clearance and increased toxicity from docetaxel, a well-characterized substrate for CYP3A4 [14,15]. Most cancer drugs are metabolized by CYP3A4, including those used to treat NHL. These data suggested the hypothesis that cancer patients with evidence of a tumour-induced inflammatory response would experience greater chemotherapy-related toxicity and worse treatment outcomes than patients without such an inflammatory response. An obvious cir- cumstance in which to test such an hypothesis is NHL, due to the frequent presence and documentation of inflammatory symptoms, and because reduced dose intensity has an adverse prognostic impact in this condi- tion. It is also timely to evaluate such a relationship as a number of anti-inflammatory treatments have been devel- oped recently, including monoclonal antibodies to cytokines and cytokine receptors. These treatments could potentially be used to reverse impaired cytotoxic drug metabolism prior to commencement of chemotherapy. A British National Lymphoma Investigation (BNLI) phase III study compared the efficacy and safety of two chemo- therapy regimens (cyclophosphamide, doxorubicin, vinc- ristine and prednisone (CHOP) or mitoxantrone, cyclophosphamide, etoposide, vincristine, bleomycin and prednisolone (PMitCEBO)) with or without granulocyte colony stimulating factor (G-CSF) in patients aged over 60 years with aggressive NHL [16]. This trial enrolled 784 patients of whom approximately 50% per arm had B symptoms. In the current study we have reanalysed these data to determine the prognostic impact of B symptoms on toxicity. Methods The study procedures have been published previously [16]. Briefly, consenting patients over 60 years of age diag- nosed with diffuse large B cell lymphoma who had ade- quate organ function and performance status were randomised in a two by two fashion to receive chemother- apy with either CHOP or PMitCEBO with or without G- CSF. The study was approved by the human research eth- ics committees of all participating centres. Prediction of toxicity Toxicity was recorded during all cycles of treatment in regard to the worst grade of anaemia, leucopenia and thrombocytopenia and the symptoms of nausea/vomit- ing, diarrhoea, alopecia, mucositis, neuropathy and skin rashes according to standard criteria (National Cancer Page 2 of 10 (page number not for citation purposes)