Professional Practices and Diagnostic Issues in Neuroendocrine Tumour Pathology: Results of a Prospective One-Year Survey among French Pathologists (the PRONET Study).

INTRODUCTION: Many changes have recently occurred in the practice of neuroendocrine tumour (NET) pathology. We therefore aimed to evaluate how pathologists have adapted their daily practice to the most recent international guidelines for diagnostic and prognostic evaluation. PROCEDURES: A 12-month prospective study (PRONET) was carried out among French pathologists between August 2010 and July 2011. Data were collected using an anonymous electronic case report form. OBSERVATIONS: Five hundred laboratories were invited, 149 accepted to participate, 80 were active and 59 provided eligible cases. A total of 1,340 cases were collected. The primary tumour was gastroenteropancreatic in 58.1% of cases and thoracic in 18.1%; it was from another site in 9.7%; 12.3% of cases were metastases of unknown origin. Pathological diagnosis was made from the examination of surgical samples in 58.1% of cases, biopsy specimens in 33.5%, endoscopic resections in 3.1% and cytological preparations in 4.2%. For the demonstration of the neuroendocrine nature of the tumour, chromogranin A and synaptophysin were tested in, respectively, 97.1 and 82.8% of cases. The differentiation status was definitely provided in 95.7% of cases. Mitotic count was attempted in 80.1% of cases and Ki67 index in 80.7%. In gastroenteropancreatic (GEP)-NETs, histological grading was available in 95.9% of the cases. WHO classification was available or feasible in 94.1% of GEP-NETs and 93.8% of thoracic NETs. TNM staging was performed according to International Union against Cancer in 74.8% of GEP-NETs and according to European Neuroendocrine Tumour Society in 55.6%. CONCLUSIONS: The PRONET study shows that the current recommendations and diagnostic procedures are satisfactorily respected by most pathologists in daily practice.

Predictive Factors of Somatostatin Receptor Ligand Response in Acromegaly-A Prospective Study.

CONTEXT: Somatostatin receptor ligands (SRLs) are the cornerstone medical treatments for acromegaly; however, many patients remain unresponsive to SRLs. Well-established predictive markers of response are needed. OBJECTIVE: We aimed to explore the relationship between responsiveness to SRLs relative to somatostatin (SST)2A and 5 receptor expression, adenoma granularity, and T2-weighted magnetic resonance imaging (MRI) signal intensity (T2WSI). METHODS: We conducted a multicentric, prospective, observational cohort study, in France. Forty-nine naïve patients (ie, patients without preoperative SRL treatment) with active acromegaly following surgery were treated with octreotide (group 1; n = 47), or pasireotide if uncontrolled under first-generation SRLs (group 2; n = 9). Data were collected at baseline and months 3 and 6. Biochemical measurements, immunohistochemistry studies, and MRI readings were centralized. RESULTS: In group 1, IGF-I decrease from baseline to month 6 positively correlated with SST2A immunoreactive score (IRS), P = 0.01. Densely granulated/intermediate adenomas had a greater IGF-I and GH decrease under octreotide compared with sparsely granulated adenomas (P = 0.02 and P = 0.006, respectively), and expressed greater levels of SST2A (P < 0.001), coupled with lower levels of SST5 (P = 0.004). T2WSI changed between preoperative MRI and month 6 MRI in one-half of the patients. Finally, SST5 IRS was higher in preoperative hyperintense compared with preoperative hypointense adenomas (P = 0.04), and most sparsely granulated and most hyperintense adenomas expressed high SST5 levels. CONCLUSION: We prospectively confirm that SST2A and adenoma granularity are good predictors of response to octreotide. We propose the IRS for scoring system harmonization. MRI sequences must be optimized to be able to use the T2WSI as a predictor of treatment response.

Observational Study in a Real-World Setting of Targeted Therapy in the Systemic Treatment of Progressive Unresectable or Metastatic Well-Differentiated Pancreatic Neuroendocrine Tumors (pNETs) in France: OPALINE Study.

INTRODUCTION: Approval of sunitinib and everolimus for the treatment of progressive, unresectable or metastatic well-differentiated pancreatic neuroendocrine tumors (pNETs) was obtained in France in 2011 and 2012, respectively. OPALINE was set up as an observational study to evaluate the efficacy of sunitinib and everolimus compared to usual pNET treatments of chemotherapies and somatostatin analogues that had been previously recommended by the health authorities. METHODS: The OPALINE study assessed the efficacy of everolimus and sunitinib in terms of survival, disease progression and tolerance. Patients (N = 144) were enrolled from May 2015 to September 2017, and their disease characteristics were analyzed from diagnosis to 2 years post-enrollment. RESULTS: At inclusion most patients had comorbidities, and about 95% presented metastases. Patients received on average 3.2 lines of treatment from diagnosis to inclusion and two lines throughout the 2-year follow-up. Seventy-nine patients (59.0%) received at least one targeted therapy (TT) during their care path. For these patients, the overall survival (OS) was approximatively 176.5 months (95% CI: 97.2-not evaluable), with a 2-year survival rate estimated at 93.6% (SD 2.6%). Similar survival rates were observed whether the TTs were prescribed sooner or later in the treatment path. The main reasons for discontinuation of TTs were disease progression (54 patients) and adverse events (26 patients). Most patients receiving TTs did not change their dose during the follow-up reflecting the good treatment tolerability over time. No new safety alert was reported for everolimus and sunitinib during this study. CONCLUSION: Given their good tolerance and positive impact on estimated OS, the two TTs have an important role to play in the care path of patients with pNETs. GOV NATIONAL CLINICAL TRIAL NUMBER: NCT02264665.

Evaluation of Nurses' and Patients' Overall Satisfaction with New and Previous Formulations of Octreotide Long-acting Release (Sandostatin LAR®): A French Observational Study.

INTRODUCTION: The first long-acting release (LAR) formulation of octreotide was marketed in France in the late 1990s. An injectable formulation of Sandostatin LAR® (Novartis SAS) with a new diluent has been developed to facilitate its preparation and administration and to improve its use in practice. METHODS: We conducted an observational, cross-sectional and multicenter study in France whose main outcome was to compare nurses' satisfaction with the preparation and administration of both previous and new formulations of octreotide LAR. Secondary outcomes included assessment of patient satisfaction (quality of life and pain felt during the injection) and product tolerance. Data were collected at two time points (one for the first formulation group and one for the second formulation group) through paper questionnaires administered to physicians, patients and nurses including a visual analog scale (VAS) from 0 (unsatisfied) to 10 (very satisfied). RESULTS: Results showed that overall nurse satisfaction improved from 5.3 (95% CI 4.9-5.8) with the previous formulation to 7.5 (95% CI 7-7.9) with the new formulation (p < 0.0001). Regarding secondary outcomes, the simplicity of the injection increased (84% for the previous formulation and 94% for the new formulation) and the purge problem disappeared (36% for the previous formulation and 4% for the new formulation). CONCLUSION: The improvement due to the new formulation of Sandostatin LAR® was reported in terms of handling, ease of use and overall nurse satisfaction. The new formulation greatly reduced treatment administration problems associated with the previous formulation, while maintaining low injection site pain and an equivalent safety profile in both indications.

EPIGIST: An observational real-life study on patients with metastatic gastrointestinal stromal tumors receiving imatinib.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. EPIdemiology GIST, is an observational multicenter longitudinal follow-up cohort study reporting the prescribing patterns of imatinib in patients with GIST and the impact of the treatment in a real-world (standard clinical) setting. METHODS: Eligible patients had a confirmed diagnosis of unresectable or metastatic KIT-positive GIST and started treatment with imatinib for the first time between May 24, 2002, and June 30, 2010. During routine visits, annual collection of clinical characteristics was requested, i.e., age, GIST stage at diagnosis, history, imatinib treatment duration and dosage, adherence, and concomitant medications. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analyzed using descriptive statistics. RESULTS: Of 151 patients enrolled, imatinib was initiated for 126 patients before enrollment and for 25 patients on the day of enrollment or soon after. The patient characteristics were similar to those in published prospective trials. The estimated 1-, 2-, 3-, and 4-year overall survival rates were 90.4% (95% confidence interval [CI; 84.8%-94.0%]), 84.7% (95% CI [78.1%-89.4%]), 73.0% (95% CI [65.0%-79.4%]), and 60.7% (95% CI [51.4%-68.8%]), respectively. The most common adverse events (AEs) were diarrhea (39%), asthenia (39%), eyelid or periorbital edema (32%), abdominal pain (23%), and anemia (21%). Eight of 126 serious AEs were possibly related to the treatment as assessed by investigators. CONCLUSIONS: Study results showed that patients in real-life populations are generally treated in accordance with national and international clinical recommendations and have outcomes comparable to those of patients in clinical trials.

SALTO: a randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction.

This phase II, multicenter, randomized, double-blind, non-comparative study assessed the efficacy and safety of immediate-release octreotide and octreotide LAR, in combination with corticosteroids and standard medical care, on the symptoms of inoperable malignant bowel obstruction (MBO) due to peritoneal carcinomatosis. The primary efficacy endpoint was "success" at day 14 defined as a composite endpoint including the absence of a nasogastric tube, and vomiting less than twice per day and no use of anticholinergic agents. Patients in the octreotide arm received octreotide LAR 30 mg intramuscular (im) on days 1, 29 and 57, as well as daily immediate-release octreotide 600 µg per day plus methylprednisolone on days 1 to 6. Placebo-treated patients received methylprednisolone and matched placebo instead of octreotide. Difficulties associated with enrolling patients at palliative-care stage meant only 64 patients (instead of the planned 102 patients) were randomized, 32 to octreotide and 32 to placebo. Despite randomization, more patients in the octreotide arm (46.4%) than in the placebo arm (21.9%) had a baseline Karnofsky score less than 50. An intention-to-treat analysis showed that in the octreotide and placebo arms, 12 (38%) and nine (28%), respectively, patients were successfully treated at day 14, which increased to 9/15 (60%) and 7/25 (28%), respectively, among patients with a baseline Karnofsky score greater or equal to 50. Octreotide-treated patients reported three drug-related adverse events (AEs), and no drug-related serious AEs or deaths. Octreotide LAR may have a key role in treating patients with a MBO due to peritoneal carcinomatosis, particularly in those with moderately severe disease.

Cost-effectiveness model of using zoledronic acid once a year versus current treatment strategies in postmenopausal osteoporosis.

OBJECTIVES: To compare effectiveness, associated cost of outcomes and cost-effectiveness of a single annual infusion of zoledronic acid versus current treatment strategies plans for postmenopausal osteoporosis in France. METHODS: Twelve simulation-based models were built to investigate three types of fractures: vertebral (VF), non-vertebral excluding hip (NVF) and hip (HF), comparing two groups: zoledronic acid and current postmenopausal antiosteoporotic treatment strategies. Two effectiveness comparability assumptions have been tested: specific agent efficacy values, and same standard efficacy values for all active agents. Direct medical costs included drug costs, medical visits, monitoring and fracture management. Adherence levels were integrated into the model under the assumption that non-adherent patients had treatment effects similar to the levels of placebo effectiveness. RESULTS: Using the most conservative assumption (same standard efficacy values for all active agents), zoledronic acid strategy results in less vertebral, non-vertebral and hip fractures than other current antiosteoporotic treatment options over 3 years: 12.04% vs. 14.18%, 10.61% vs. 11.28% and 2.82% vs. 4.64% respectively, (p<0.001). In addition, zoledronic acid is more cost-effective than the current treatment strategies in all types of fractures (p<0.001): 1497 euros vs. 1685 euros per VF avoided, 1337 euros vs. 1404 euros per NVF avoided and 1216 euros vs. 1323 euros per HF avoided. CONCLUSION: Zoledronic acid is a cost-effective treatment strategy regardless of fracture type or effectiveness comparability assumptions.

The estimated incidence of gastrointestinal stromal tumors in France. Results of PROGIST study conducted among pathologists.

UNLABELLED: The aim of this study was to investigate the incidence of gastrointestinal stromal tumors (GISTs) in France. METHOD: This prospective epidemiological study was performed among pathologists who were asked to report exhaustively the cases of GIST over a one-year period. RESULTS: Five hundred ninety-one cases of GISTs were reported, 535 new cases and 56 cases of relapse. So, the estimated incidence of GIST in France was 8.5-10 cases per million inhabitants in 2005. The main characteristics of the new GIST cases were as follows: mean age 65 (+/- 13.2) years; 48.6% men; circumstances of discovery: fortuitous 30.5%, symptomatic 46.5%, and unknown 23%. The primary tumor locations were stomach 63.7%, small intestine 21.5%, mesentery 6.5%, colon and rectum 3.2%, esophagus 0.7%, and 4.3% locations were listed as unknown. Globally, 95.3% of GISTs were cKIT (CD117) positive. Based on tumor size and mitotic rate, among the 490 localized GISTs, 14.7% were considered to have a very low prognostic risk, 25.5% low risk, 23.1% intermediate risk, and 23.1% high risk. CONCLUSIONS: This study provides for the first time an estimation of the incidence of GISTs in France, and the results are comparable to what has been reported in studies in other European countries.

Socio-psychological impact of infused iron chelation therapy with deferoxamine in metropolitan France: ISOSFER study results.

Deferoxamine (DFO) is an iron chelator used to treat iron overload in patients receiving chronic blood transfusions, and is usually administered as overnight subcutaneous infusions. ISOSFER was a prospective, observational, cross-sectional study conducted in metropolitan France that evaluated patient characteristics, quality of life (QoL), compliance and patient satisfaction with DFO monotherapy. Of 70 patients with either thalassemia, sickle cell disease or myelodysplastic syndromes, 30% were 'satisfied' or 'very satisfied' with DFO. Patients' SF-36 scores were lower than those of the general French population, and lower among patients with comorbidities and those dissatisfied with treatment. Although 72% of patients had good compliance to DFO, 57% reported missing at least one infusion in the previous month, and 82% of patients expressed a preference for oral therapy. These results suggest that QoL is severely compromised in patients receiving DFO, and that compliance is not optimal.