Simron Singh

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.

Exploring the rising incidence of neuroendocrine tumors: A population-based analysis of epidemiology, metastatic presentation, and outcomes

An increased incidence of neuroendocrine tumors (NETs) has been reported worldwide, but the reasons underlying this rise have not been identified. By assessing patterns of metastatic presentation, this study sought to examine the epidemiologic characteristics of NETs and the contribution of early‐stage detection to the rising incidence.

Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial

BACKGROUND Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m(2)) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2)) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00500760. FINDINGS Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54-78) in the chemoradiotherapy group and 61% (50-71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3-4 adverse events were dysphagia (17 [27%] of 63 patients in the chemoradiotherapy group vs 35 [40%] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24%] vs 48 [55%]), and radiation skin injury (eight [13%] vs 27 [31%]). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. INTERPRETATION In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. FUNDING Amgen.

Influence of Sex on Toxicity and Treatment Outcome in Small-Cell Lung Cancer

PURPOSE Female sex has been shown consistently to be a favorable prognostic factor in small-cell lung cancer (SCLC). Studies have shown that women with other tumor types experience greater treatment toxicity, but there have been few studies of sex-related toxicity in SCLC. PATIENTS AND METHODS This was a sex-based retrospective analysis of four SCLC trials conducted by the National Cancer Institute of Canada Clinical Trials Group between 1987 and 1999. The 1,006 patients (648 males and 358 females) received similar chemotherapy consisting of cyclophosphamide-doxorubicin-vincristine and etoposide-cisplatin. Toxicities examined included myelosuppression, stomatitis, vomiting, and infection. Other end points included dose reductions and omissions, response, and survival. RESULTS Women experienced significantly more hematologic toxicity than men (grade 3 and 4 anemia, 16.3% v 7.6%, respectively, P < .001; grade 3 and 4 leukopenia, 80.4% v 69.2%, respectively, P = .0001). However, toxic death rates were similar for men and women (1.5% v 1.1%, respectively, P = .58). Women also had significantly more stomatitis and vomiting of all grades. Despite increased toxicity, 76% of females versus 73.4% of males received all six treatment cycles (P = .38), but 52% of females versus 43.4% of males had treatment delayed for 2 weeks or more (P = .022). Only 31.8% of females and 28.2% of males had at least one cycle of chemotherapy dose reduction (P = .23). The overall response rate was 80.3% for females and 66.9% for males (P < .0001), and the median survival time was 1.31 years for females compared with only 0.91 year for males (P < .0001). CONCLUSION Women experience more chemotherapy-related toxicity in the treatment of SCLC, but they also have increased response rates and survival.

A systematic review of surgery for non-curative gastric cancer

BackgroundMost gastric cancer patients present with advanced stage disease precluding curative surgical treatment. These patients may be considered for palliative resection or bypass in the presence of major symptoms; however, the utility of surgery for non-curative, asymptomatic advanced disease is debated and the appropriate treatment strategy unclear.PurposeTo evaluate the non-curative surgical literature to better understand the limitations and benefits of non-curative surgery for advanced gastric cancer.MethodsA literature search for non-curative surgical interventions in gastric cancer was conducted using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases from 1 January 1985 to 1 December 2009. All abstracts were independently rated for relevance by a minimum of two reviewers. Outcomes of interest were procedure-related morbidity, mortality, and survival.ResultsFifty-nine articles were included; the majority were retrospective, single institution case series. Definitions describing the treatment intent for gastrectomy were incomplete in most studies. Only five were truly performed with relief of symptoms as the primary indication for surgery, while the majority were considered non-curative or not otherwise specified. High rates of procedure-related morbidity and mortality were demonstrated for all surgeries across the majority of studies and treatment-intent categories. Median and 1-year survival were poor, and values ranged widely within surgical approaches and across studies.ConclusionsA lack of transparent documentation of disease burden and symptoms limits the surgical literature in non-curative gastric cancer. Improved survival is not evident for all patients receiving non-curative gastrectomy. Further prospective research is required to determine the optimal intervention for palliative gastric cancer patients.

Matrix Metalloproteinase 1, 3, and 12 Polymorphisms and Esophageal Adenocarcinoma Risk and Prognosis

The matrix metalloproteinase (MMP) family degrade extracellular matrix and mediate pathways including apoptosis, angiogenesis and immunity. We studied the association between four MMP polymorphisms within three MMP genes and esophageal adenocarcinoma (EA) risk and prognosis. A total of 313 EA cases and 455 age and gender frequency-matched controls were genotyped for MMP1 1G/2G, MMP3 6A/5A, MMP12 -82A/G and MMP12 1082A/G. The association between individual MMP polymorphisms and EA risk was evaluated using regression models and adjusted for age, gender, adult body mass index and smoking status. Haplotype analysis was performed to investigate the combined effect of all four linked MMP polymorphisms and EA risk. The MMP1 and MMP3 polymorphisms were associated with increased EA risk: MMP1 1G/2G and 2G/2G had adjusted odds ratios of 1.46 [95% confidence interval 1.0-2.1; P = 0.04] and adjusted odds ratio 1.83 (1.2-2.8; P = 0.005), respectively, whereas MMP3 6A/5A had adjusted odds ratio 1.40 (95% confidence interval 1.0-2.1; P = 0.09) and MMP3 5A/5A had 1.61 (95% confidence interval 1.0-2.5; P = 0.03). Two MMP haplotypes [MMP1-MMP3-MMP12 (-82) 2G-5A-A (adjusted odds ratio 1.36, 95% confidence interval 1.0-1.8; P = 0.03) and 2G-5A-G (adjusted odds ratio 1.70, 95% confidence interval 1.1-2.6; P = 0.01)] were also associated with increased EA risk. The relationship between BE cases with the same set of controls was similar. No association was identified between the MMP polymorphisms and overall survival or progression free survival of patients with EA. MMP1, MMP3 and possibly MMP12 -82A/G polymorphisms and their haplotypes are associated with increased EA risk.

Chromogranin A: a sensitive biomarker for the detection and post-treatment monitoring of gastroenteropancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are a heterogeneous group of neoplasms that arise from neuroendocrine cells of the GI tract and pancreas. Due to the lack of symptoms in the early stage of the disease and the frequency of nonspecific gastrointestinal symptoms, GEP-NET are difficult to diagnose. This delay in diagnosis often results in patients presenting with advanced disease and thus a poor prognosis. There is an unmet medical need for earlier, more definitive GEP-NET diagnosis. Identification of effective biomarkers to improve GEP-NET diagnosis, as well as to assess treatment efficacy, relapse and prognosis, is important for improving outcomes in GEP-NET. Chromogranin A is currently the most useful general biomarker for the assessment of GEP-NET. This review summarizes the biochemical characteristics of chromogranin A, its specificity and sensitivity for GEP-NET diagnosis, and its use in monitoring treatment effectiveness, disease progression and prognosis.

Shared decision making in oncology: assessing oncologist behaviour in consultations in which adjuvant therapy is considered after primary surgical treatment

Introduction  Shared decision making (SDM) is now considered a desirable goal in health care, yet little is known about current practice in cancer care, and its impact on patient outcomes. This study aimed to develop an oncology‐specific coding system for SDM, explore variations in SDM according to patient and disease characteristics, determine the relationship between SDM and patient satisfaction with the consultation, and explore the impact of SDM on patient anxiety.

Consensus Recommendations for the Diagnosis and Management of Pancreatic Neuroendocrine Tumors: Guidelines from a Canadian National Expert Group

Pancreatic neuroendocrine tumors (pNETs) are rare heterogeneous tumors that have been steadily increasing in both incidence and prevalence during the past few decades. Pancreatic NETs are categorized as functional (F) or nonfunctional (NF) based on their ability to secrete hormones that elicit clinically relevant symptoms. Specialized diagnostic tests are required for diagnosis. Treatment options are diverse and include surgical resection, intraarterial hepatic therapy, and peptide receptor radionuclide therapy (PRRT). Systemic therapy options include targeted agents as well as chemotherapy when indicated. Diagnosis and management should occur through a collaborative team of health care practitioners well-experienced in managing pNETs. Recent advances in pNET treatment options have led to the development of the Canadian consensus document described in this report. The discussion includes the epidemiology, classification, pathology, clinical presentation and prognosis, imaging and laboratory testing, medical and surgical management, and recommended treatment algorithms for pancreatic neuroendocrine cancers.

Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease.

BACKGROUND The Ki67-LI is a valid surrogate for biologic behavior of neuroendocrine tumors (NETs), with higher levels associated with aggressive behavior. The World Health Organization (WHO) classifies NETs according to Ki67-LI (G1: <3%; G2 : 3-20%; G3: >20%). Little is known about the evolution of NETs histologic characteristics over the disease course. We sought to evaluate variations in Ki67-LI throughout NETs disease course. METHODS We retrospectively reviewed the Sunnybrook Odette Cancer Center NET database for patients with multiple pathology specimens. Primary outcome was the WHO NET class based on Ki67-LI for each specimen. We assessed change in WHO class between specimens. RESULTS Forty-three patients were retrieved, of which 39 had specimens from the primary tumor and a metastatic focus, and 4 had specimens from multiple metastatic foci. Sixteen (37.0%) were identified with Ki67-LI falling in different WHO classes on distinct biopsies. For 12 (75.0%) of those 16 patients, Ki67-LI showed enough variability for WHO class to be upstaged: 5 (31%) from G1 to G2, 2 (13%) from G2 to G3, and 5 (31%) from G1 to G3. CONCLUSION When multiple pathology specimens were available, Ki67-LI varied throughout NETs disease course, with a majority of cases upgraded to a higher WHO class. If confirmed, this finding may have implications in how neuroendocrine tumors are monitored and treated. Further research is warranted to confirm these findings, understand better the underlying mechanisms of Ki67 variability, and define its relationship to prognosis.