Margot Tesselaar

Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study

BACKGROUND 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. METHODS 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. FINDINGS 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], p<0·00001). 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). INTERPRETATION 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. FUNDING Novartis Pharmaceuticals Corporation.

Microparticle‐associated tissue factor activity in cancer patients with and without thrombosis

2 Rodeghiero F, Castaman G, Tosetto A, Batlle J, Baudo F, CappellettiA, Casana P, De Bosch N, Eikenboom JC, Federici AB, Lethagen S,Linari S, Srivastava A. The discriminant power of bleeding history forthe diagnosis of type 1 von Willebrand disease: an international, mul-ticenter study. JThrombHaemost2005; 3: 2619–26.3BowmanM,MundellG,GrabellJ,HopmanWM,RapsonD,LillicrapD, James P. Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease . J ThrombHaemost 2008; 6: 2062–6.4BissTT, Blanchette VS, Bowman M, Clark DS, Silva M, Lillicrap D,James P, Rand ML. Quantitation of bleeding symptoms in childrenwith von Willebrand disease or a pla telet function disorder: use of astandardized pediatric bleeding score . Blood 2007; 110: 636a.

Risk of venous thromboembolism in lung cancer.

Purpose of review To evaluate venous thromboembolism (VTE) risk factors in lung cancer patients. Recent findings VTE incidence is around 40–100 cases per 1000 person-years in lung carcinoma patients vs. an estimated 1–2 cases per 1000 person-years in the general population. Patients with adenocarcinoma have higher risk of VTE than patients with squamous cell lung carcinoma. VTE risk appears two-fold higher in nonsmall-cell lung cancer than in small-cell lung cancer patients. Other risk factors are pneumonectomy, metastatic disease, use of specific chemotherapeutic drugs in combination with novel targeted drugs, such as antiangiogenic agents, and elevated prechemotherapy platelet counts. Tissue factor (TF), the initiator of the clotting cascade, may be (over)expressed in lung carcinoma cells. Active TF-bearing microparticles, which may originate from the tumour cells themselves, have been found in the circulation of cancer patients. Microparticle-associated TF activity may provide a link between cancer and thrombosis and play a decisive role in the pathogenesis of the prothrombotic state in cancer patients. Summary Risk factors of VTE in lung cancer patients are adenocarcinoma, metastatic disease, pneumonectomy and anticancer therapy including chemotherapy and anti-VEGF targeted drugs. Other risk factors include pretreatment platelet counts and active TF-expressing circulating microparticles.

Reirradiation for head-and-neck cancer: delicate balance between effectiveness and toxicity.

PURPOSE To analyze the effectiveness and toxicity of reirradiation (re-RT) for head-and-neck cancer. METHODS AND MATERIALS A retrospective data analysis was performed of 58 patients who underwent re-RT with curative intent. Re-RT was given as definitive treatment in 53% of patients, whereas salvage surgery preceded reirradiation in 47%. The median cumulative RT dose was 119 Gy (range, 76-140). Concurrent chemotherapy was administered with re-RT (CRT) in 57% of patients. Event-free survival was defined as survival without recurrence and without serious toxicity (≥Grade 3). RESULTS Median follow-up was 57 months (range, 9-140). Locoregional (LR) control was 50% at 2 and 5 years. The 2-year and 5-year overall survival (OS) was 42% and 34%. The following factors were associated with improved OS: postoperative re-RT (vs. primary re-RT), treatment with RT only (vs. CRT) and interval >3 years between previous RT and re-RT. For patients treated with postoperative re-RT and definitive re-RT, the 5-year OS was 49% and 20%, respectively. Patients treated with CRT had a 5-year OS of 13%. Serious (late) toxicity ≥Grade 3 was observed in 20 of 47 evaluable patients (43%). Three cases of treatment-related death were recorded. The 2- and 5-year serious toxicity-free interval was 59% and 55%, respectively. Associated with increased risk of serious toxicity were CRT and higher re-RT dose. The event-free survival rates at 2 and 5 years were 34% and 31%, respectively. CONCLUSIONS Re-RT in head-and-neck cancer is associated with poor survival rates of 13-20% in patients with inoperable disease treated with primary (chemo-) re-RT. For this subgroup, however, no other curative options are available. Long-term disease control and survival can be achieved in patients who receive re-RT as an adjunct to surgical resection. The rates of serious toxicity after re-RT are high, with an incidence of approximately 45% at 5 years. Approximately 1 in 3 patients survived re-RT without recurrence and severe complications.

A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

Induction chemotherapy with docetaxel/cisplatin/5-fluorouracil followed by randomization to two cisplatin-based concomitant chemoradiotherapy schedules in patients with locally advanced head and neck cancer (CONDOR study) (Dutch Head and Neck Society 08-01): A randomized phase II study

PURPOSE To study the feasibility of induction chemotherapy added to concomitant cisplatin-based chemoradiotherapy (CRT) in patients with locally advanced head and neck cancer (LAHNC). PATIENTS AND METHODS LAHNC patients were treated with 4 courses of docetaxel/cisplatin/5-fluorouracil (TPF) followed by randomization to either cisplatin 100 mg/m(2) with conventional radiotherapy (cis100 + RT) or cisplatin 40 mg/m(2) weekly with accelerated radiotherapy (cis40 + ART). Primary endpoint was feasibility, defined as receiving ≥ 90% of the scheduled total radiation dose. Based on power analysis 70 patients were needed. RESULTS 65 patients were enrolled. The data safety monitoring board advised to prematurely terminate the study, because only 22% and 41% (32% in total) of the patients treated with cis100 + RT (n = 27) and cis40 + ART (n = 29) could receive the planned dose cisplatin during CRT, respectively, even though the primary endpoint was reached. Most common grade 3-4 toxicity was febrile neutropenia (18%) during TPF and dehydration (26% vs 14%), dysphagia (26% vs 24%) and mucositis (22% vs 57%) during cis100 + RT and cis40 + ART, respectively. For the patients treated with cis100 + RT and cis40 + ART, two years progression free survival and overall survival were 70% and 78% versus 72% and 79%, respectively. CONCLUSION After TPF induction chemotherapy, cisplatin-containing CRT is not feasible in LAHNC patients, because the total planned cisplatin dose could only be administered in 32% of the patients due to toxicity. However, all but 2 patients received more than 90% of the planned radiotherapy. Clinical Trials Information: NCT00774319.

Bevacizumab combined with docetaxel, oxaliplatin, and capecitabine, followed by maintenance with capecitabine and bevacizumab, as first-line treatment of patients with advanced HER2-negative gastric cancer: A multicenter phase 2 study.

The current study was a multicenter, single‐arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B‐DOC) in patients with advanced human epidermal growth factor receptor 2 (HER2)‐negative, previously untreated, gastric or gastroesophageal adenocarcinoma.

Tissue factor-bearing microparticles and CA19.9: two players in pancreatic cancer-associated thrombosis?

Background:Cancer-related venous thromboembolism (VTE) heralds a poor prognosis, especially in pancreatic adenocarcinoma (PAC). Tissue factor (TF) is implicated as one of the main culprits in PAC-associated VTE and disease progression.Methods:In a prospective cohort study of 79 PAC patients, we measured plasma CA19–9 and microparticle-associated TF activity (MP-TF activity). In addition, we enumerated TF+MPs and MUC1+MPs in plasma (n=55), and studied the expression of TF, MUC1, CD31 and CD68 in tumour tissue (n=44).Results:Plasma MP-TF activity was markedly elevated in PAC patients with VTE compared with those without (median: 1925 vs 113 fM Xa min−1; P<0.001) and correlated with the extent of thromboembolic events, metastatic disease and short survival. Similar results were found for CA19–9. Patients with massively progressing thrombosis and cerebral embolisms despite anticoagulant therapy (n=3) had the highest MP-TF activities (12 118–40 188 fM Xa min−1) and CA19–9 (40 730–197 000 kU l−1). All tumours expressed MUC1 and TF. MP-TF activity did not correlate with intensity of TF expression in adenocarcinoma cells, but corresponded with numbers of TF+ macrophages in the surrounding stroma.Conclusions:Circulating TF+MPs and mucins may concertedly aggravate coagulopathy in PAC. Understanding of underlying mechanisms may result in new treatment strategies for VTE prevention and improvement of survival.

GEP-NETs UPDATE: Secreting gastro-enteropancreatic neuroendocrine tumours and biomarkers

Neuroendocrine tumours (NETs) are rare tumours with an annual incidence in the population in a range of 2-5 new cases per 100,000 inhabitants. NETs are widely variable in terms of anatomical location, hormone production, clinical behaviour and syndromes they can cause. This article reviews the many localizations and clinical presentations of NETs with a main focus on clinical biomarkers and their use in medical practice.

Grading of Neuroendocrine Neoplasms: Mitoses and Ki-67 Are Both Essential

Background: The current WHO classification for neuroendocrine neoplasms (NEN) of the gastrointestinal tract requires Ki-67 and mitotic index for grading. However, both indexes might be conflicting as far as grade is concerned. In this study, we investigate which of the two indexes is most informative to predict survival. Methods: We assessed 362 patients with NEN of gastrointestinal (n = 148), pancreatic (n = 29), lung (n = 77), unknown primary site (n = 102) and of miscellaneous (n = 6) origin. Follow-up and proliferative indexes were recorded. Results: Survival was clearly correlated with both proliferative indexes (p < 0.001). One hundred and nineteen samples (34%) showed discordance in grading between the Ki-67 and the mitotic index, of which 74 (62%) were biopsies and 45 (38%) resection specimens (p = 0.001). In 86% of these cases, survival matched with the highest proliferative index, which was the Ki-67 index in 87% of these cases. Seventeen cases had a mitotic index of 2 (threshold grade 2) and a Ki-67 index of <3% (grade 1). For these cases, survival curve matched that of patients with concordant indexes of grade 1. Conclusion: Grading NEN using two proliferative markers results in discordance between these indexes in one third of cases, more often in biopsy material than in resection specimens. If results are discordant, survival is for the most part associated with the grade of the highest index, for the most part Ki-67. Thus, grading with two proliferative indexes is useful as it highlights cases where one of these indexes may be incongruent.