Guillaume Cadiot

Daily Oral Everolimus Activity in Patients With Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial

PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

Preoperative detection of duodenal gastrinomas and peripancreatic lymph nodes by somatostatin receptor scintigraphy. Groupe D'etude Du Syndrome De Zollinger-Ellison

BACKGROUND & AIMSnDuodenal gastrinomas and peripancreatic lymph nodes are difficult to localize. The aim of this study was to evaluate the ability of Octreoscan scintigraphy to detect such tumors.nnnMETHODSnResults of Octreoscan scintigraphy in 21 consecutive patients with Zollinger-Ellison syndrome were compared with those of conventional imaging techniques, including endoscopic ultrasonography, and with the surgical findings.nnnRESULTSnSurgical exploration found 27 duodenal and/or lymph node gastrinomas in 19 patients. None had pancreatic gastrinoma. Octreoscan scintigraphy was the only positive preoperative technique in 32% of the patients. The sensitivities of conventional techniques, Octreoscan scintigraphy, and their association were 58%, 58%, and 90%, respectively, for all resected gastrinomas. The smallest duodenal gastrinoma detected by Octreoscan scintigraphy measured 3 mm. Endoscopic ultrasonography detected all the tumors visualized by any other conventional technique and was considered falsely positive, as was Octreoscan scintigraphy, in 1 patient. Follow-up and comparison between the number of resected gastrinomas and the number of preoperative hot spots suggested that surgeons should find at least as many tumors as the number of hot spots.nnnCONCLUSIONSnOctreoscan scintigraphy improved the preoperative detection of extrapancreatic gastrinomas, mainly by endoscopic ultrasonography. Surgeons should find at least as many gastrinomas as the number of hot spots.

Multivariate analysis of pathophysiological factors in reflux oesophagitis.

BACKGROUND: Reflux oesophagitis is considered a multifactorial disease, but the respective roles of the main factors involved in its pathophysiology have not been clearly established. AIMS: To attempt to assign these roles by means of a multivariate logistic regression analysis of the main parameters associated with reflux oesophagitis. PATIENTS: Eighty seven patients with gastro-oesophageal reflux disease were studied: 41 without oesophagitis and 46 with reflux oesophagitis grade 1 to 3. METHODS: (1) Monovariate comparison of patients characteristics and of parameters derived from in hospital 24 hour oesophageal pH monitoring, oesophageal manometry, double isotope gastric emptying studies, and basal and pentagastrin stimulated gastric acid and pepsin output determinations, between patients with and without oesophagitis. (2) Multivariate logistic regression analysis including the parameters significant in the monovariate analysis. RESULTS: Among the 16 significant parameters from monovariate analysis, three significant independent parameters were identified by multivariate logistic regression analysis: number of refluxes lasting more than five minutes, reflecting oesophageal acid clearance (p = 0.002); basal lower oesophageal sphincter pressure (p = 0.008); and peak acid output (p = 0.012). These three parameters were not correlated with each other. The multivariate model was highly discriminant (correct classification of 81.3% of the cases (95% confidence intervals 0.723, 0.903). Risk for oesophagitis increased as a function of the tercile threshold values of the three parameters. Odds ratios of the three parameters for oesophagitis risk were similar, regardless of whether they were calculated when the patients were compared as a function of oesophagitis grade or the presence or absence of oesophagitis. CONCLUSIONS: This multivariate approach adds evidence that impaired oesophageal acid clearance and hypotonic lower oesophageal sphincter are the two major independent pathophysiological factors of oesophagitis, but also showed that the acid secretion level is an independent pathophysiological factor.

Usefulness of somatostatin receptor scintigraphy in the management of patients with Zollinger-Ellison syndrome. Groupe de Recherche et d'Etude du Syndrome de Zollinger-Ellison (GRESZE).

BACKGROUND: Management of patients with Zollinger-Ellison syndrome (ZES) depends on the presence of multiple endocrine neoplasia type 1 (MEN 1) or liver metastases, or both. Somatostatin receptor scintigraphy (SRS) detects previously unknown endocrine tumours. AIM AND METHODS: To evaluate SRS findings susceptible to modifying the management of patients with ZES-that is, relevant findings, and the specificity of these findings. The latter were defined according to our current therapeutic strategy in three subgroups of patients (sporadic, MEN 1, and liver metastases). PATIENTS: 85 consecutive patients without known extra-abdominal metastases were studied between September 1991 and March 1996. RESULTS: Relevant findings were found in 41% of 49 patients with sporadic disease but without liver metastases, in 22% of 18 patients with MEN 1 but without liver metastases, and in 17% of 18 patients with liver metastases. Follow up was available for 20 (74%) of 27 patients who had 23 relevant findings. Nineteen relevant findings (83%) were confirmed at a median of three (range 0.25-45) months of follow up; four (17%) were not confirmed at 30 (range 12-52) months (p = 0.025). Findings located in the duodenopancreatic area (90%), chest (100%), bone (100%), and liver (60%) were confirmed. Most findings for patients with MEN 1 involved the chest. CONCLUSION: SRS detects many anomalies susceptible to modifying management of patients with ZES, especially in those with sporadic disease. The specificity of hot spots located outside the liver seems very high. By contrast, the specificity of hot spots located in the liver remains to be evaluated when conventional imaging is negative.

Exérèse du primitif et des adénopathies mésentériques chez les malades ayant des métastases hépatiques non résécables de tumeur neuroendocrine de l’intestin grêle : quel est l’état de nos connaissances ?

Les tumeurs neuroendocrines de l’intestin grele (TNEig) presentent des metastases hepatiques (MH) non resecables dans pres d’un tiers des cas. Dans la strategie de prise en charge de ces malades, la question de la resection de la tumeur primitive et des adenopathies mesenteriques metastatiques n’est pas reglee. Des donnees de la litterature suggerent un possible benefice de la resection du primitif et des adenopathies mesenteriques chez des malades ayant des MH non resecables, mais ces donnees sont pauvres en elements factuels. En effet, toutes les series sont retrospectives et comparent des groupes de patients heterogenes. Lorsque la tumeur primitive et/ou les adenopathies sont symptomatiques, l’exerese est de facto necessaire. De meme, chez les malades ayant des MH resecables, l’exerese de la tumeur primitive et la lymphadenectomie appropriee semble ameliorer la survie tout en evitant la survenue de complications evolutives (occlusion, hemorragie). En revanche, chez les malades ayant des MH non resecables de TNEig avec une tumeur primitive et des metastases ganglionnaires mesenteriques asymptomatiques (hormis le syndrome carcinoide), aucune etude n’a pu clairement demontrer l’interet de l’exerese de la tumeur primitive et des ganglions. De ce fait, chez ces malades selectionnes, nous pensons qu’une etude prospective randomisee est le meilleur moyen de repondre a cette question.