Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. MATERIAL AND METHODS: TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. RESULTS: From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was <1%. CONCLUSIONS: The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov, registration number: NCT0064660.

Phase III trial comparing 3-6 months of adjuvant FOLFOX4/XELOX in stage II-III colon cancer: safety and compliance in the TOSCA trial.

BACKGROUND: Six months of oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. A shorter duration of therapy, if equally efficacious, would be advantageous for patients and Health-Care Systems. PATIENTS AND METHODS: TOSCA ['Randomized trial investigating the role of FOLFOX-4 or XELOX (3 versus 6 months) regimen duration and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer] is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months (arm 3 m) versus 6 months (arm 6 m) of FOLFOX4/XELOX. Primary end-point was relapse-free survival. We present here safety and compliance data. RESULTS: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Treatment completion rate without any modification was 35% versus 12% and with delays or dose reduction 52% versus 44% in arm 3 and 6 m. Treatment was permanently discontinued in 8% (arm 3 m) and 33% (arm 6 m). In arm 6 m, 50% of patients discontinuing treatment did so after completing 80% of planned program. Grade 3+ toxicities were higher in arm 6 m than that in 3 m. Grade 2+ neuropathy was 31.2% versus 8.8% (P < 0.0001) while grade 3+ was 8.4 versus 1.3 (P < 0.0001), in arm 3 and 6 m. Seven deaths within 30 days from last treatment administration in arm 6 m and three deaths in arm 3 m were observed (0.3% versus 0.1%, P = 0.34). CONCLUSIONS: TOSCA is the first trial comparing 3 versus 6 months of adjuvant chemotherapy completing accrual within the international initiative of treatment duration evaluation (International Duration Evaluation of Adjuvant, IDEA). High compliance to treatment in control arm will allow a correct assessment of potential differences between the two treatment durations. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT00646607.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.

BACKGROUND: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01640782.

[A full economic evaluation of extensive vaccination against rotavirus with RIX4414 vaccine at National and Regional level in Italy]. / Una valutazione economica completa della vaccinazione estensiva contro i rotavirus con il vaccino RIX4414 a livello nazione e regionale in Italia.

Vaccination of all healthy children against rotavirus (RV) has been recommended, since the availability of vaccines, both in Europe (PIDJ) and Italy (pediatricians). The aims of universal vaccination against RV include the protection of children against moderate/severe gastroenteritis forms by RV (GARV), prevent hospitalizations, reduce the severity and duration of the disease, and reduce morbidity and socioeconomic costs. Payers need to informed regarding the efficacy and the healthcare utilization related to RV vaccination in order to decide in favour of its extensive implementation. The aim of this paper is to assess the clinical and financial impact of the extensive vaccination aganist RV both at National and Regional level. Particular attention, compared to the previous analysis (Standaert et al, 2008) has been given to the influence of herd immunity (HI) on cost-utility results of vaccination against-RV. Methods. The analysis was conducted with the Markovian model previously used by Standaert B et al and updated for comparing costs and benefits associated with a situation of vaccination anti-RV that includes efficacy data due to HI, with a situation without vaccination. For the base case is assumed an annual coverage of 90%, where the effect of HI is present in the population at risk (0-5 years) and extended to children who have not been vaccinated, adding as conservative assumption, a further 10% to the efficacy of the vaccine, compared to 15% determined by several published studies. Two analysis have been made based on this model: a cost-utility analysis that compared vaccination with two doses of RIX441410 administered at 2 and 3 months after birth compared with no vaccination from National Health Service and Society perspective; a budget impact analysis at National and Regional level. The evaluation has as its main element the reduction of cases of infection through universal vaccination and consequent reduction of Garv events and nosocomial infections. Results. From the NHS perspective, in a cohort of 555,791 born in Italy in 2011, the annual number of hospitalizations due to RV infections in the absence of vaccination is estimated to be 14,550 units. Assuming that 90% of newborns receive two doses of the vaccine, and including an additional effect of HI to the efficacy of the vaccine, vaccination would lead to a reduction of 71% of cases of Garv (176,804 cases in less) and a 86% of hospitalizations due to Garv (12,913 fewer cases), with an impact on quality of life and mortality as a consequence of vaccination. The introduction of the vaccine would lead to a gain of 0.0014 QALYs and 0.0022 life-years gained per child compared to a situation without vaccination (assuming a discount rate of 3% on future benefits). The reduction of GARV also would lead to a strong economic impact. The introduction of the vaccine would lead to a saving of € 25.41 per child or a saving of more than € 14 million for the whole population included in the analysis. Cost reduction increase significantly from the perspective of society and introducing the indirect costs due to lost productivity. In this case, the savings due to the introduction of vaccination would increase to € 67,747,654 in the total cohort, or € 121.89 per child. In an alternative scenario, where HI is excluded, RIX4414 remains dominant (0.0013 QALYs gained and € 22.14 per child saved). The budget impact analysis shows that, as early as the second year, the additional cost of the vaccine is more than offset by a reduction in costs of the disease, which leads to savings for the NHS, which increases from year 3. In a time horizon of 5 years (without the discount rate), the savings for the NHS amount to € 34,440,314. These savings would amount to a cost reduction of € 4.64 per child over 5 years (€ 0.93 per year). The savings due to the introduction of the vaccine were mainly due to a reduction in costs associated with hospitalizations. The budget impact analysis at regional level, has taken a vaccine cost of € 30.00 per dose. Cases of diarrhoea before after vaccination are reduced in each region, based on the number of births, ranging from a minimum of 399 cases avoided for Valle d'Aosta to a maximum of 31,116 cases avoided in Lombardy. In a similar way, the number of hospitalizations due to GARV are reduced considerably, from a minimum of 36 cases in Valle d'Aosta to a maximum of 3,096 in Lombardy. Obviously, these reductions are greater in regions with 30,000 or more births per year. Conclusions. This study suggests that a universal vaccination anti-RV with 2 doses of RIX4414 brings significant clinical and economic benefits both at National and Regional level. The indirect effects of the vaccine (HI) could generate protection even in unvaccinated children with health gain and a number of cases by GARV much less than those that would vaccinating small groups of children and with a cost of illness, for NHS, which would be reduced significantly, despite the additional costs of the vaccine as early as the second year of vaccination. Productivity losses due to absence from work of a parent, as well as all other costs included in the model, show that is precisely the society to pay the consequences, from economic and social point of view. Considering the citizen in the role of private payer, we must stress as for him, the savings generated by vaccination, whether universal or with demand for cost-sharing by the health service, prove significant with a major health gain for the population under study.

Phase I study of a weekly schedule of oxaliplatin, high-dose leucovorin, and infusional fluorouracil in pretreated patients with advanced colorectal cancer.

PURPOSE: To identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oxaliplatin (L-OHP) given on a weekly schedule including fixed doses of leucovorin (LV) and infusional 5-fluorouracil (5-FU), to define the toxicity profile of this regimen and to find preliminary evidence of its activity in pretreated patients with metastatic colorectal cancer (MCRC). PATIENTS AND METHODS: Twenty-one patients with progressive disease, treated with fluoropyrimidines and with histologically measurable MCRC entered into this phase I study. Fixed doses of LV (500 mg/m2) followed by a 48-hour 5-FU 2600 mg/m2 infusion (5-FU48h) were administered with escalating doses of L-OHP, starting from 60 mg/m2 and with stepwise increments of 5 mg/m2. No intra-patient dose escalation was allowed. Treatment was given once a week for four consecutive weeks, followed by a one-week rest period. RESULTS: Three dose levels were tested. The MTD was L-OHP 70 mg/m2 since two of the three patients showed dose-limiting diarrhea and the third developed neutropenia during the first cycle of chemotherapy. Most patients complained of mild peripheral sensitive neurotoxicity, which was related to the cumulative dose of L-OHP. Treatment delays were necessary for a total of 42 cases, but only in II of 42 after the pre-arranged 10% dose reduction of 5-FU (2300 mg/m2). Sixteen patients were evaluable for response: seven (33%; 95% confidence interval (CI): 14.6%-57.0%) were considered to show a major response (one complete), six showed a stable disease, and in addition progressive disease was observed in three patients. CONCLUSIONS: Our results show that L-OHP, LV and 5-FU can be administered safely and repetitively using a weekly schedule. Diarrhea and neutropenia are the DLT of this regimen. Its activity and its manageable toxicity profile deserve further evaluation in chemotherapy-naïve MCRC patients. The doses recommended for phase II trials are: L-OHP 65 mg/m2, LV 500 mg/m2 and 5-FU48h 2300 mg/m2 infusion given on a weekly-times-four schedule followed by a one-week rest period.

Long latency evoked potentials in a case of corpus callosum agenesia.

Following monoaural stimulation, long latency auditory evoked potentials (LLAEPs) recorded from contralateral temporal areas have a shorter latency and larger amplitude than those recorded from the ipsilateral temporal areas. This observation agrees with the operational model drawn up in 1967 by Kimura, which assumes that only anatomically prevailing crossed auditory pathways are active during dichotic hearing, while direct pathways are inhibited. The inputs may then be conveyed to the contralateral cortex, from where they finally reach the ipsilateral temporal areas by means of interhemispheric commissures. It is this mechanism which may underline the right ear advantage for verbal stimuli and the left ear advantage for melodies observed when administering dichotic listening tasks. With the aim of verifying this hypothesis, we recorded temporal LLAEPs in a 21 year-old woman suffering from complex partial seizures, whose CT scan and MRI showed corpus callosum agenesia. Our data support the hypothesis that ipsilateral pathways are greatly inhibited by the contralateral pathways, and therefore auditory stimuli can be supposed to reach the contralateral auditory cortex from where they are transferred through the corpus callosum to the ipsilateral auditory cortex.