Impact of the introduction of rituximab in first-line follicular lymphoma: a retrospective study of 247 unselected patients referred to a single institution with a long-term follow-up.

Rituximab was approved in France in 2004, following randomized trials that demonstrated efficacy in newly diagnosed high tumour burden follicular lymphoma (FL). This retrospective study compared the management and outcome of FL in unselected patients treated in a single institution before and after rituximab approval. Two hundred and forty-seven adult patients were referred with first-line FL between 1996 and 2010 and are included in this study. The 103 pre-rituximab patients comprising cohort 1 were diagnosed between January 1996 and December 2003; cohort 2 includes the 144 patients diagnosed after the approval of rituximab between January 2004 and December 2010. Baseline clinical and biological data, type of therapy, treatment response, progression-free survival (PFS) and overall survival (OS) rates were compared. There were no statistically significant differences between the two cohorts with respect to baseline clinical and disease characteristics, including FL International Prognostic Index score. The major difference between the two cohorts is the use of rituximab in first line. Seventy-one per cent of patients in cohort 2 received rituximab (19% alone, 52% with chemotherapy) versus 10% in cohort 1 (2% alone, 8% with chemotherapy; p < 0.0001). The objective response rate (ORR) was significantly higher for cohort 2 (ORR 84% compared with 72% for cohort 1; p = 0.03). The PFS and OS rates were also significantly better: 3-year PFS 72% [95% confidence interval (CI) 64-80%] versus 55% (95% CI 45-64%), p = 0.0039 and 3-year OS 98% (95% CI 94-99%) versus 83% (95% CI 74-90%), p = 0.0007. Effect of period of study is significant when using multivariate analysis on PFS and OS and lactate dehydrogenase level (PFS and OS) and age (OS). These data from everyday practice confirm the benefit for patients with FL treated in the last decade through availability of rituximab in first line used alone or in association with various chemotherapy regimens.

Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma.

PURPOSE: We examined the utility of post-therapy surveillance imaging in a large, prospectively enrolled cohort of patients with diffuse large B-cell lymphoma (DLBCL) from the United States and confirmed our results in an independent cohort of patients from France. METHODS: Patients with newly diagnosed DLBCL and treated with anthracycline-based immunochemotherapy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence and the Léon Bérard Cancer Center, Lyon, France. In those with relapse, details at relapse and outcomes were abstracted from records. RESULTS: 680 individuals with DLBCL were identified from the MER, 552 (81%) of whom achieved remission after induction. 112 of the 552 patients (20%) suffered a relapse. The majority (64%) of relapses were identified before a scheduled follow-up visit. Surveillance imaging detected DLBCL relapse before clinical manifestations in nine out of 552 patients (1.6%) observed after therapy. In the Lyon cohort, imaging identified asymptomatic DLBCL relapse in four out of 222 patients (1.8%). There was no difference in survival after DLBCL relapse in patients detected at scheduled follow-up versus before scheduled follow-up in both the MER (P = .56) and Lyon cohorts (P = .25). CONCLUSION: The majority of DLBCL relapses are detected outside of planned follow-up, with no difference in outcome in patients with DLBCL detected at a scheduled visit compared with patients with relapse detected outside of planned follow-up. These data do not support the use of routine surveillance imaging for follow-up of DLBCL.

Body weight change in women receiving adjuvant chemotherapy for breast cancer: a French prospective study.

BACKGROUND & AIMS: Adjuvant chemotherapy has frequently been associated with weight gain after breast cancer diagnosis. We aimed to prospectively evaluate body weight variations in French patients with early breast cancer. METHODS: This prospective observational study included 272 breast cancer patients who were candidates for adjuvant chemotherapy. Weight and body mass index were measured at baseline visit, then at 9 and 15 months from baseline (6 and 12-month post-chemotherapy). At baseline visit, information on the benefits of weight gain prevention and healthy diet was given by a dietician. Univariate logistic regression was performed to test the association between weight gain and potential predictive factors. RESULTS: Thirty percent of patients gained weight during the year before diagnosis, 26% were overweight and 15% were obese. At one year, the mean weight change was +1.5kg (SD=4.1) and +2.3% (SD=6.0); 60% of the cohort had gained weight, with a median increase of 3.9kg (SD=3.0) and 5.9% (SD=4.4). Reported weight gain during the year before diagnosis appears to be the only factor associated with the absence of post-chemotherapy weight gain (OR=0.54, 95% CI [0.31-0.95], p=0.034). CONCLUSION: Body weight increased in the post-chemotherapy period in French breast cancer survivors, even when given dietary recommendations. Appropriate weight management interventions with nutritional follow-up and physical activity programs are needed.

Serum cytokines in follicular lymphoma. Correlation of TGF-ß and VEGF with survival.

The prognosis of follicular lymphoma could vary with the tumor immune microenvironment. We evaluated the prognostic value of serum levels of ten cytokines. Our study cohort included 60 follicular lymphoma patients and 20 controls. Serum was available at diagnosis in 31 patients, at first relapse in 18, and complete remission in 11. Bioplex technology was used for determination of nine cytokines [interleukin (IL)-1Ra, IL-6, IL-7, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (b-FGF)]. Transforming growth factor beta (TGF-ß) was measured by sandwich enzyme-linked immunosorbent assay. IL-1Ra, IL-6, IL-7, IL-10, IL-13, TNF-α, VEGF, and PDGF levels were found increased in follicular lymphoma patients compared to controls. Multivariate analysis identified early stage and high TGF-ß levels as independent predictors of overall survival associated with improved outcome. High lactate dehydrogenase and VEGF levels were independently associated with poorer progression-free survival. These results show the prognostic value of TGF-ß and VEGF in follicular lymphoma and suggest their contribution to tumor microenvironment alterations.

Combination of rituximab with chemotherapy in diffuse large B-cell lymphoma. Evaluation in daily practice before and after approval of rituximab in this indication.

Randomized trials have demonstrated improved outcome from adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for patients with diffuse large B-cell lymphoma (DLBCL). This retrospective study compared the outcomes of 224 patients with DLBCL treated in our institution before (Period 1, 1996-2002) and after (Period 2, 2002-2005) approval of rituximab in this indication to evaluate the impact of the drug in daily practice in unselected patients receiving different types of chemotherapy. We treated 131 patients in Period 1 versus 93 in Period 2 (median follow-up, 75 and 29 months, respectively) with no difference in patient characteristics between the two periods. Event-free and overall survivals (EFS and OS) were significantly improved in Period 2 for elderly patients and a significant shift in the selection of regimens was observed at the time when rituximab became available. More patients received the CHOP regimen in Period 2 than in Period 1 (82 vs. 57%, p < 0.007) with CHOP being substituted for epirubicin-based regimens. In younger patients treated mostly with the ACVBP regimen (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) these differences were not observed, suggesting that combination of rituximab with dose-dense chemotherapy may deserve further evaluation in this age group.

Time-to-event analysis with artificial neural networks: an integrated analytical and rule-based study for breast cancer.

This paper presents an analysis of censored survival data for breast cancer specific mortality and disease-free survival. There are three stages to the process, namely time-to-event modelling, risk stratification by predicted outcome and model interpretation using rule extraction. Model selection was carried out using the benchmark linear model, Cox regression but risk staging was derived with Cox regression and with Partial Logistic Regression Artificial Neural Networks regularised with Automatic Relevance Determination (PLANN-ARD). This analysis compares the two approaches showing the benefit of using the neural network framework especially for patients at high risk. The neural network model also has results in a smooth model of the hazard without the need for limiting assumptions of proportionality. The model predictions were verified using out-of-sample testing with the mortality model also compared with two other prognostic models called TNG and the NPI rule model. Further verification was carried out by comparing marginal estimates of the predicted and actual cumulative hazards. It was also observed that doctors seem to treat mortality and disease-free models as equivalent, so a further analysis was performed to observe if this was the case. The analysis was extended with automatic rule generation using Orthogonal Search Rule Extraction (OSRE). This methodology translates analytical risk scores into the language of the clinical domain, enabling direct validation of the operation of the Cox or neural network model. This paper extends the existing OSRE methodology to data sets that include continuous-valued variables.

Development of a rule based prognostic tool for HER 2 positive breast cancer patients.

A three stage development process for the production of a hierarchical rule based prognosis tool is described. The application for this tool is specific to breast cancer patients that have a positive expression of the HER 2 gene. The first stage is the development of a Bayesian classification neural network to classify for cancer specific mortality. Secondly, low-order Boolean rules are extracted form this model using an Orthogonal Search based Rule Extraction (OSRE) algorithm. Further to these rules additional information is gathered from the Kaplan-Meier survival estimates of the population, stratified by the categorizations of the input variables. Finally, expert knowledge is used to further simplify the rules and to rank them hierarchically in the form of a decision tree. The resulting decision tree groups all observations into specific categories by clinical profile and by event rate. The practical clinical value of this decision support tool will in future be tested by external validation with additional data from other clinical centres.

Second autologous transplantation after failure of a first autologous transplant in 18 patients with non-Hodgkin's lymphoma.

High-dose chemotherapy and autologous marrow or peripheral stem cell support offers the best chance of cure in some subgroups of patients with non-Hodgkin's lymphoma (NHL). Less is known about the role of a second course of myeloablative chemotherapy in patients who relapse after a first autologous transplant. The aim of this retrospective study was to evaluate the disease outcome, morbidity and mortality associated with second autologous transplantation in patients with NHL. Between 1985 and 2001, 225 patients who had received autologous transplantation for NHL in two institutions in Lyon relapsed. Of these 225 patients 18 underwent a second autologous transplantation. The median age at second transplant was 41 years. There were six indolent lymphomas and 12 aggressive lymphomas. The median follow-up from the second transplant was 42 months. The OS rate at 2 and 5 years were 58 and 27%, respectively. The PFS rate at 2 and 5 years was 36%. Five patients are alive without disease 20 to 100 months after the second transplant. Seven patients died of disease recurrence. Four (22%) toxic deaths occurred: one of pulmonary fibrosis, one of fungal infection and cardiac failure and two of acute leukaemia. A minority of patients with NHL recurrence after a first transplant can be cured by a second course of myeloablative chemotherapy at the cost however of high-risk toxic death.