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Roberto Buzzoni,1 Carlo Carnaghi,2 Jonathan Strosberg,3 Nicola Fazio,4 Simron Singh,5 Fabian Herbst,6 Antonia Ridolfi,7 Marianne E Pavel,8 Edward M Wolin,9 Juan W Valle,10 Do-Youn Oh,11 James C Yao,12 Rodney Pommier13 1IRCCS Foundation, National Institute of Tumors, Milan, Italy; 2Humanitas Clinical and Research Center, Rozzano, Italy; 3Moffitt Cancer Center, Tampa, FL, USA; 4European Institute of Oncology, Milan, Italy; 5Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 6Novartis AG, Basel, Switzerland; 7Novartis Pharma S.A.S., Rueil-Malmaison, France; 8Medizinische Klinik 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 9Montefiore Einstein Center for Cancer Care, Bronx, NY, USA; 10Institute of Cancer Sciences, University of Manchester, The Christie Hospital, Manchester, UK; 11Seoul National University Hospital, Seoul, Republic of Korea; 12University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 13Oregon Health & Science University, Portland, OR, USA Background: Recently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35–0.67; P

This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436).In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1.As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%).BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.

Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population.In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783.Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0).Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract.Novartis Pharmaceuticals Corporation.

276 Background: NET are malignant tumors arising from neuroendocrine cells throughout the body. Everolimus (EVE), a mammalian target of rapamycin inhibitor, is approved for the treatment of advanced, well-differentiated pancreatic NET. There is an unmet medical need in GI and lung NET; targeted therapies, such as everolimus, are of particular interest. Methods: Patients with advanced nonfunctional NET of GI or lung origin with progressive disease (PD) within the past 6 months were randomized (2:1) to EVE 10 mg/d or placebo, both with best supportive care. Concomitant use of somatostatin analogue (SSA) was not allowed during the study, except for control of emergent carcinoid symptoms not manageable by standard therapy. Patients were stratified based on tumor sites, prior SSA exposure, and WHO performance status (PS) at baseline. Primary endpoint was progression-free survival (PFS) as assessed by central radiology review using modified RECIST 1.0 criteria. Primary analysis is planned after ~176 PFS events. Crossover to open label EVE after progression would not be allowed prior to the primary analysis. Overall survival was the key secondary endpoint. Results: Recruitment is completed. Of 388 patients screened, 302 were randomized (planned, 285). Median age was 63 years, 53% were females, and majority of them (76.2%) were white. The most common tumor sites were lung (29.8%), ileum (23.5%), and rectum (13.2%). WHO PS was 0 in 219 (72.5%) patients and 1 in 82 (27.2%) patients; 52% had received SSA prior to study entry. As of Sep 16, 2013, 173 (57.3%) patients remain on treatment, 127 (42.1%) discontinued treatment and 2 (0.7%) were not treated. PD (24.2%) and adverse events (10.6%) were the most common reasons for treatment discontinuation. Results of primary analysis are expected by early 2015. Conclusions: RADIANT-4 is the first phase III study to assess the efficacy and safety of EVE in patients with nonfunctional NET of GI or lung origin. Non-crossover design and prospective stratification of the population based on known prognostic factors should minimize confounding in the estimation of the treatment effect. Clinical trial information: NCT01524783.

PurposeBreast cancer follow-up procedures after primary treatment are still a controversial issue. Aim of this study was to investigate, through a web-based survey, surveillance methodologies selected by Italian oncologists in everyday clinical practice.MethodsReferents of Italian medical oncology units were invited to participate to the study via e-mail through the SurveyMonkey website. Participants were asked how, in their institution, exams of disease staging and follow-up are planned in asymptomatic women and if surveillance continues beyond the 5th year.ResultsBetween February and May 2013, 125 out of 233 (53.6%) invited referents of Italian medical oncology units agreed to participate in the survey. Ninety-seven (77.6%) referents state that modalities of breast cancer follow-up are planned according to the risk of disease progression at diagnosis and only 12 (9.6%) oncology units apply the minimal follow-up procedures according to international guidelines. Minimal follow-up is never applied in high risk asymptomatic women. Ninety-eight (78.4%) oncology units continue follow-up in all patients beyond 5 years.ConclusionsOur survey shows that 90.4% of participating Italian oncology units declare they do not apply the minimal breast cancer follow-up procedures after primary treatment in asymptomatic women, as suggested by national and international guidelines. Interestingly, about 80.0% of interviewed referents performs the so called "tailored follow-up", high intensity for high risk, low intensity for low risk patients. There is an urgent need of randomized clinical trials able to determine the effectiveness of risk-based follow-up modalities, their ideal frequency and persistence in time.

Background Persons living after a cancer diagnosis represent 4% of the whole population in high income Countries. The study aim was to provide estimates of indicators of long-term survival and cure for 26 cancer types, presently lacking. Patients and Methods Data on 818,902 Italian cancer patients diagnosed at age 15-74 years in 1985-2005 were included. Proportions of patients with the same death rates of the general population (cure fractions) and those of prevalent patients who were not at risk of dying as a result of cancer (cure prevalence) were calculated, using validated mixture cure models, by cancer type, sex, and age group. We also estimated complete prevalence, conditional relative survival (CRS), time to reach five- and ten-year CRS>95%, and proportion of patients living longer than those thresholds. Results The cure fractions ranged from >90% for patients aged 95% after 19 and 25 years, respectively, and in 15 and 18 years for prostate cancer patients. Five-year CRS remained 25 years after cancer diagnosis in patients with liver and larynx cancers, non-Hodgkin lymphoma, myeloma, and leukaemia. Overall, the cure prevalence was 67% for men and 77% for women. Therefore, 21% of male and 31% of female patients had already reached five- year CRS>95%, while 18% and 25% had reached ten-year CRS>95%. Conclusions A quarter of Italian cancer patients can be considered cured. This observation has a high potential impact on health planning, clinical practice, and patients perspective.

BACKGROUND The aim of the current randomized Phase II study was to investigate the efficacy and safety of capecitabine combined with irinotecan as first-line treatment in metastatic colorectal carcinoma (CRC). METHODS A total of 140 patients received capecitabine at a dose of 1250 mg/m2 twice daily on Days 2–15 and irinotecan at a dose of either 300 mg/m2 on Day 1 (Arm A) or 150 mg/m2 on Days 1 and 8 (Arm B) every 3 weeks. During the course of the study, enrollment was continued using lower doses of capecitabine (1000 mg/m2 twice daily) and irinotecan (Arm A: 240 mg/m2; Arm B: 120 mg/m2) to improve the safety profile of the combinations. RESULTS Efficacy was evaluable in 134 patients (68 in Arm A, 66 in Arm B). Objective responses were observed in 46% of the patients (8% complete response [CR]), including 47% in Arm A (9% CR; 38% partial response [PR]) and 44% in Arm B (8% CR; 36% PR). The median progression-free survival was 8.3 months in Arm A and 7.6 months in Arm B. Among the first 52 patients treated with the higher doses, the most frequent Grade 3–4 adverse event was diarrhea (27%). The lower doses adopted in the subsequent 88 patients led to better diarrhea control, particularly in Arm A, and significant reductions in the incidence of all-grade hand-foot syndrome and abdominal pain. CONCLUSIONS The capecitabine and irinotecan combination was a highly active first-line therapy in metastatic CRC. An acceptable safety profile was observed after dose reduction, particularly when irinotecan was administered on 1 day. Cancer 2004;100:279–87. © 2003 American Cancer Society.

It has been suggested that tamoxifen may improve the efficacy of medical castration with luteinising hormone-releasing hormone analogues, but very few data have so far been published concerning the clinical and endocrinological activity of this therapeutic modality. In this phase II multicentre trial conducted by the Italian Trials in Medical Oncology group (ITMO), 64 premenopausal patients with hormone receptor-positive or unknown breast cancer were treated with monthly s.c. injections of goserelin 3.6 mg, in association with a tamoxifen daily dose of 20 mg, as first-line therapy for their advanced disease. All of the patients were evaluable for efficacy and there was an overall response rate of 41% (95% confidence interval 28-52%), with 7 of the 26 responders achieving complete remission. The median time to response was 4 months (range 2-17), and the median response duration was 13 months (range 6-37 +). Better responses were observed in soft tissues (51%); the response in visceral and bone metastases was respectively 19% and 37%. Serum concentrations of gonadotrophins and oestradiol were significantly decreased by the treatment, oestrogen levels being constantly suppressed to within the range observed in post-menopausal women. No significant change was detected in serum testosterone levels. In our experience, although it was not associated with any increased clinical efficacy, the concurrent use of goserelin and tamoxifen proved to be a feasible approach in the management of premenopausal advanced breast cancer.