Y-90-Ibritumomab Tiuxetan (Zevalin (R)) Consolidation of First Remission In Advanced-Stage Follicular Non-Hodgkin's Lymphoma: Updated Results After a Median Follow-up of 66.2 Months From the International, Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients

The FIT trial was conducted to evaluate the safety and efficacy of 90Y-ibritumomab tiuxetan (0.4 mCi/kg; maximum dose 32 mCi) when used as consolidation of first complete or partial remission in patients with previously untreated, advanced-stage follicular lymphoma (FL). Patients were randomly assigned to either 90Y-ibritumomab treatment (n = 207) or observation (n = 202) within 3 months (mo) of completing initial induction therapy (chemotherapy only: 86%; rituximab in combination with chemotherapy: 14%). Response status prior to randomization did not differ between the groups: 52% complete response (CR)/CR unconfirmed (CRu) to induction therapy and 48% partial response (PR) in the 90Y-ibritumomab arm vs 53% CR/CRu and 44% PR in the control arm. The primary endpoint was progression-free survival (PFS) of the intent-to-treat (ITT) population. Results from the first extended follow-up after a median of 3.5 years revealed a significant improvement in PFS from the time of randomization with 90Y-ibritumomab consolidation compared with control (36.5 vs 13.3 mo, respectively; P < 0.0001; Morschhauser et al. JCO. 2008; 26:5156-5164). Here we report a median follow-up of 66.2 mo (5.5 years). Five-year PFS was 47% in the 90Y-ibritumomab group and 29% in the control group (hazard ratio (HR) = 0.51, 95% CI 0.39-0.65; P < 0.0001). Median PFS in the 90Y-ibritumomab group was 49 mo vs 14 mo in the control group. In patients achieving a CR/CRu after induction, 5-year PFS was 57% in the 90Y-ibritumomab group, and the median had not yet been reached at 92 months, compared with a 43% 5-year PFS in the control group and a median of 31 mo (HR = 0.61, 95% CI 0.42-0.89). For patients in PR after induction, the 5-year PFS was 38% in the 90Y-ibritumomab group with a median PFS of 30 mo vs 14% in the control group with a median PFS of 6 mo (HR = 0.38, 95% CI 0.27-0.53). Patients who had received rituximab as part of induction treatment had a 5-year PFS of 64% in the 90Y-ibritumomab group and 48% in the control group (HR = 0.66, 95% CI 0.30-1.47). For all patients, time to next treatment (as calculated from the date of randomization) differed significantly between both groups; median not reached at 99 mo in the 90Y-ibritumomab group vs 35 mo in the control group (P < 0.0001). The majority of patients received rituximab-containing regimens when treated after progression (63/82 [77%] in the 90Y-ibritumomab group and 102/122 [84%] in the control group). Overall response rate to second-line treatment was 79% in the 90Y-ibritumomab group (57% CR/CRu and 22% PR) vs 78% in the control arm (59% CR/CRu, 19% PR). Five-year overall survival was not significantly different between the groups; 93% and 89% in the 90Y-ibritumomab and control groups, respectively (P = 0.561). To date, 40 patients have died; 18 in the 90Y-ibritumomab group and 22 in the control group. Secondary malignancies were diagnosed in 16 patients in the 90Y-ibritumomab arm vs 9 patients in the control arm (P = 0.19). There were 6 (3%) cases of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) in the 90Y-ibritumomab arm vs 1 MDS in the control arm (P = 0.063). In conclusion, this extended follow-up of the FIT trial confirms the benefit of 90Y-ibritumomab consolidation with a nearly 3 year advantage in median PFS. A significant 5-year PFS improvement was confirmed for patients with a CR/CRu or a PR after induction. Effective rescue treatment with rituximab-containing regimens may explain the observed no difference in overall survival between both patient groups who were - for the greater part - rituximab-naïve.

The management of brain metastases

Brain metastases occur in 20-50% of NSCLC and 50-80% of SCLC. In this review, we will look at evidence-based medicine data and give some perspectives on the management of BM. We will address the problems of multiple BM, single BM and prophylactic cranial irradiation. Recursive Partitioning Analysis (RPA) is a powerful prognostic tool to facilitate treatment decisions. Dealing with multiple BM, the use of corticosteroids was established more than 40 years ago by a unique randomized trial (RCT). Palliative effect is high (_80%) as well as side-effects. Whole brain radiotherapy (WBRT) was evaluated in many RCTs with a high (60-90%) response rate; several RT regimes are equivalent, but very high dose per fraction should be avoided. In multiple BM from SCLC, the effect of WBRT is comparable to that in NSCLC but chemotherapy (CXT) although advocated is probably less effective than RT. Single BM from NSCLC occurs in 30% of all BM cases; several prognostic classifications including RPA are very useful. Several options are available in single BM: WBRT, surgery (SX), radiosurgery (RS) or any combination of these. All were studied in RCTs and will be reviewed: the addition of WBRT to SX or RS gives a better neurological tumour control, has little or no impact on survival, and may be more toxic. However omitting WBRT after SX alone gives a higher risk of cerebro-spinal fluid dissemination. Prophylactic cranial irradiation (PCI) has a major role in SCLC. In limited disease, meta-analyses have shown a positive impact of PCI in the decrease of brain relapse and in survival improvement, especially for patients in complete remission. Surprisingly, this has been recently confirmed also in extensive disease. Experience with PCI for NSCLC is still limited, but RCT suggest a reduction of BM with no impact on survival. Toxicity of PCI is a matter of debate, as neurological or neuro-cognitive impairment is already present prior to PCI in almost half of patients. However RT toxicity is probably related to total dose and dose per fraction. Perspectives : Future research should concentrate on : 1) combined modalities in multiple BM. 2) Exploration of treatments in oligo-metastases. 3) Further exploration of PCI in NSCLC. 4) Exploration of new, toxicity-sparing radiotherapy techniques (IMRT, Tomotherapy etc).

Perioperative nutrition is still a surgical orphan: results of a Swiss-Austrian survey.

Background/Objectives:There is strong evidence for the beneficial effects of perioperative nutrition in patients undergoing major surgery. We aimed to evaluate implementation of current guidelines in Switzerland and Austria.Subjects/Methods:A survey was conducted in 173 Swiss and Austrian surgical departments. We inquired about nutritional screening, perioperative nutrition and estimated clinical significance.Results:The overall response rate was 55%, having 69% (54/78) responders in Switzerland and 44% (42/95) in Austria. Most centres were aware of reduced complications (80%) and shorter hospital stay (59%). However, only 20% of them implemented routine nutritional screening. Non-compliance was because of financial (49%) and logistic restrictions (33%). Screening was mainly performed in the outpatient's clinic (52%) or during admission (54%). The nutritional risk score was applied by 14% only; instead, various clinical (78%) and laboratory parameters (56%) were used. Indication for perioperative nutrition was based on preoperative screening in 49%. Although 23% used preoperative nutrition, 68% applied nutritional support pre- and postoperatively. Preoperative nutritional treatment ranged from 3 days (33%), to 5 (31%) and even 7 days (20%).Conclusions:Although malnutrition is a well-recognised risk factor for poor post-operative outcome, surgeons remain reluctant to implement routine screening and nutritional support according to evidence-based guidelines.

Perioperative nutrition is still a surgical orphan

Objective: To assess if screening programs and treatment of preoperative malnutrition have been implemented into surgical practice to decrease morbidity. There is strong evidence that postoperative morbidity can be minimized by early identifying and treating patients at nutritional risk before major surgery.The validated nutritional risk score (NRS) is recommended by the European Society of Parenteral and Enteral Nutrition for nutritional screening. It remains unclear whether routine preoperative nutritional assessment and perioperative nutrition is widely implemented.Methods: A survey was conducted in 173 Swiss and Austrian surgical departments. Implementation of nutritional screening, perioperative nutrition, and estimated impact on clinical outcome were assessed. Non-responders were repeatedly contacted by the authors.Results: The overall response rate was 55%, whereby 69% (54/78) of Swiss and 44% (42/95) of Austrian centers responded. Despite 80% and 59% of the responding centers are aware of a reduced complication rate and shortened hospital stay, respectively, only 20% of them implemented routine nutritional screening. Financial (49%) and logistic restrictions (33%) are the predominant reasons against the routine clinical use. Screening is mainly performed either in the outpatient's clinic (52%) or during admission (54%). The NRS is only used by 14%. Instead, various clinical (78%), e.g. BMI and laboratory findings (56%), e.g. albumine, are used. Indication for perioperative nutrition is based on preoperative screening in 49%.While 23% use preoperative nutrition, 68% apply nutritional support pre- and postoperatively. Preoperative nutritional treatment ranged from three days (33%), to five days (31%) and even seven days (20%).Conclusion: Despite malnutrition is well recognized as major risk factor for increased postoperative morbidity, the majority of surgeons are reluctant to implement routine screening and nutritional support. If nutritional assessment is performed, local institutional screening parameters are still preferred. It remains difficult to overcome traditions, and to change surgeon's mind.

Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.

Background In angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20(+) large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. DESIGN AND METHODS: Twenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. RESULTS: A complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median follow-up of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/μg DNA) was associated with shorter progression-free survival (P=0.06). Conclusions We report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20(+) B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted.

Exposure of the Swiss population by medical x-rays: 2008 review.

Nationwide surveys on radiation dose to the population from medical radiology are recommended in order to follow the trends in population exposure and ensure radiation protection. The last survey in Switzerland was conducted in 1998, and the annual effective dose from medical radiology was estimated to be 1 mSv y(-1) per capita. The purpose of this work was to follow the trends in diagnostic radiology between 1998 and 2008 in Switzerland and determine the contribution of different modalities and types of examinations to the collective effective dose from medical x-rays. For this reason, an online database (www.raddose.ch) was developed. All healthcare providers who hold a license to run an x-ray unit in the country were invited to participate in the survey. More than 225 examinations, covering eight radiological modalities, were included in the survey. The average effective dose for each examination was reassessed. Data from about 3,500 users were collected (42% response rate). The survey showed that the annual effective dose was 1.2 mSv/capita in 2008. The most frequent examinations are conventional and dental radiographies (88%). The contribution of computed tomography was only 6% in terms of examination frequency but 68% in terms of effective dose. The comparison with other countries showed that the effective dose per capita in Switzerland was in the same range as in other countries with similar healthcare systems, although the annual number of examinations performed in Switzerland was higher.

Sickness certification in primary care: a survey on views and practices among Swiss physicians.

QUESTIONS UNDER STUDY: Studies from several countries (Scandinavia, United Kingdom) report that general practitioners (GPs) experience problems in sickness certification. Our study explored views of Swiss GPs towards sickness certification, their practice and experience, professional skills and problematic interactions with patients. METHODS: We conducted an online survey among GPs throughout Switzerland, exploring behaviour of physicians, patients and employers with regard to sickness certification; GPs' views about sickness certification; required competences for certifying sickness absence, and approaches to advance their competence. We piloted the questionnaire and disseminated it through the networks of the five Swiss academic institutes for primary care. RESULTS: We received 507 valid responses (response rate 50%). Only 43/507 GPs experienced sickness certification as problematic per se, yet 155/507 experienced problems in sickness certification at least once a week. The 507 GPs identified estimating a long-term prognosis about work capacity (64%), handling conflicts with patients (54%), and determining the reduction of work capacity (42%) as problematic. Over 75% would welcome special training opportunities, e.g., on sickness certifications during residency (93%), in insurance medicine (81%), and conflict management (80%). CONCLUSION: Sickness certification as such does not present a major problem to Swiss GPs, which contrasts with the experience in Scandinavian countries and in the UK. Swiss GPs did identify specific tasks of sickness certification as problematic. Training opportunities on sick-leave certification and insurance medicine in general were welcomed.