Catherine Lombard-Bohas

Sunitinib malate for the treatment of pancreatic neuroendocrine tumors

BACKGROUND The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

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.

Rapid and Sustained Relief from the Symptoms of Carcinoid Syndrome: Results from an Open 6-Month Study of the 28-Day Prolonged-Release Formulation of Lanreotide

This 6-month, open, non-controlled, multicenter, dose-titration study evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome. Eligible patients had a carcinoid tumor with ≧3 stools/day and/or ≧1 moderate/severe flushing episodes/day. Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection. The dose for the first two injections was 90 mg. Subsequent doses could be titrated (60, 90, 120 mg) according to symptom response. Seventy-one patients were treated. Flushing decreased from a mean of 3.0 at baseline to 2.3 on day 1, and 2.0 on day 2, with a daily mean of 2.1 for the first week post-treatment (p < 0.05). Diarrhea decreased from a mean of 5.0 at baseline to 4.3 on day 1 (p < 0.05), and 4.5 on day 2, with a daily mean of 4.4 for the first week post-treatment (p < 0.001). Symptom frequency decreased further after the second and third injections, and reached a plateau after the fourth injection. By month 6, flushing and diarrhea had significantly decreased from baseline by a mean of 1.3 and 1.1 episodes/day, respectively (both p ≤ 0.001); 65% of patients with flushing as the target symptom and 18% of diarrhea-target patients achieved ≧50% reduction from baseline. Median urinary 5-hydroxyindoleacetic acid and chromogranin A levels decreased by 24 and 38%, respectively. Treatment was well tolerated. 28-day PR lanreotide was effective in reducing the symptoms and biochemical markers associated with carcinoid syndrome.

Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases.

Cystic endocrine tumors of the pancreas are rare and raise difficult clinical problems. Our aims were to reevaluate the diagnostic and therapeutic strategy and to assess their histopathologic characteristics. Thirteen cystic endocrine tumors diagnosed in 10 patients were included. Clinical, radiologic, and pathologic data were reviewed. There were 6 male and 4 female patients (median age, 46 yrs). Six patients had evidence of multiple endocrine neoplasia type 1 (MEN1) disease. Four had a functional endocrine syndrome. Ten tumors were visible on imaging studies. The most suggestive radiologic features were the existence of a peripheral hypervascular rim (10 cases) and images of cyst into cyst (two cases). On gross and histologic examinations, two distinct types were present. Macrocystic tumors (six cases) were unilocular and limited by a thick wall containing nests of tumor cells. Microcystic tumors (seven cases) were characterized by the presence of multiple cystic spaces directly lined by tumor cells. Surgical resection was performed in all cases. Three patients had lymph node metastases at the time of diagnosis. One patient is dead with metastatic dissemination. The others are alive without recurrence or metastasis. The diagnosis of endocrine tumor must be considered for any pancreatic cyst discovered in a patient with a history of MEN1 syndrome or with clinical features suggestive of this syndrome. Cystic pancreatic endocrine tumors must be treated by surgical resection because of their possible malignant evolution.

Low Microvessel Density Is an Unfavorable Histoprognostic Factor in Pancreatic Endocrine Tumors

BACKGROUND AND AIMS In many malignant tumors, intratumoral microvascular density (MVD) has been suggested to be a prognostic parameter. We aimed to provide a quantitative evaluation of intratumoral microvascular density in a large series of resected endocrine tumors of the pancreas and to evaluate the potential prognostic significance of this parameter. METHODS Eighty-two tumors from 77 patients have been studied. MVD was evaluated by 2 observers after CD34 immunostaining and correlated with the following parameters: WHO classification, hormonal profile, tumor size, vascular endothelial growth factor expression, occurrence of metastasis, duration of survival. RESULTS MVD ranged from 5 to 92 vessels/field. MVD was significantly higher in well-differentiated benign endocrine tumors than in tumors of uncertain behavior and in carcinomas. No close correlation was found between MVD and the hormonal profile. MVD was significantly higher in tumors characterized by the following histoprognostic parameters: size <2 cm, proliferation index <2%, no evidence of metastasis. No close correlation was observed between MVD and VEGF expression. Finally, a MVD <30 vessels/field was associated with the occurrence of metastasis in tumors <2 cm and/or with a proliferation index <2% and with a significantly shorter survival after surgery. CONCLUSIONS The quantitative analysis of microvessel density in pancreatic endocrine tumors may identify patients who, despite favorable conventional histoprognostic factors, are at risk of unfavorable evolution.

Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000–05): an open-label, randomised, phase 3 trial

BACKGROUND The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer. METHODS In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256. FINDINGS 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0·0001) and non-haematological adverse events (26 events vs 186 events; p<0·0001) occurred in the sequential group than in the combination group. INTERPRETATION Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer. FUNDING Sanofi-Aventis France.

Molecular and Clinical Differences between Adenocarcinomas of the Esophagus and of the Gastric Cardia

Adenocarcinoma of the esophagus (ADCE) with Barretts mucosa and adenocarcinoma of the cardia (ADCC) are often reported as a single pathological entity. In this study we have used strict anatomical-pathological criteria to distinguish between these two lesions and we have investigated their differences in TP53 mutations, MDM2 gene amplification, and cytokeratin expression. DNA was extracted from the tumor areas of formalin-fixed, paraffin-embedded sections in 26 ADCC and 28 ADCE patients. TP53 mutations were detected by temporal temperature gradient electrophoresis and identified by sequencing. MDM2 amplification was assessed by differential polymerase chain reaction. The expression of cytokeratins 4, 7, and 13 was examined by immunohistochemistry. In ADCC, the male to female ratio was 1.8:1, compared to 27:1 in ADCE. Five ADCC patients had a history of other neoplasms, compared to only one ADCE patient. The two types of tumor differed in the prevalence of TP53 mutations (31% in ADCC and 50% in ADCE) and of MDM2 gene amplification (19% in ADCC and 4% in ADCE), and in the pattern of expression of cytokeratin 7 (positive in 100% of ADCE and in 41% of ADCC) and cytokeratin 13 (positive in 81% of ADCE and in 36.5% of ADCC). ADCE and ADCC differ in their clinical characteristics, in the prevalence of TP53 mutations and MDM2 amplifications, and in the patterns of cytokeratin expression. These results support the notion that ADCC and ADCE are distinct pathological entities.

Value of CT enteroclysis in suspected small-bowel carcinoid tumors.

OBJECTIVE The purpose of this study was to evaluate the value of CT enteroclysis in depicting small-bowel carcinoid tumors in symptomatic patients with surgical, histologic, or clinical follow-up findings as a reference standard. SUBJECTS AND METHODS At our institution, 44 patients with symptoms of suspected gastrointestinal carcinoid tumors underwent CT enteroclysis. Clinical symptoms were as follows: carcinoid syndrome (n = 3), abdominal pain with diarrhea (n = 24), hypervascular liver metastases (n = 7), subileus condition (n = 1), hypervascular peritoneal lesion (n = 3), abnormal ileal stenosis on optical colonoscopy (n = 3), and follow-up extraintestinal carcinoid lesion (n = 3). Positive CT enteroclysis findings were compared with pathology results after surgical procedures (n = 19). Negative examinations were compared with surgery results (n = 3) or clinical follow-up (n = 22). RESULTS CT enteroclysis findings were positive in 19 patients and negative in 25 patients. The sizes of the carcinoid tumors identified were 5-30 mm in axial diameter. These tumors were depicted as focal nodular lesions located in the small-bowel wall or as intraluminal polypoid masses with marked enhancement. Twenty-two patients underwent only clinical follow-up, with a mean clinical follow-up time of 20 months. The overall sensitivity and specificity of CT enteroclysis in identifying patients with small-bowel carcinoid tumors were 100% and 96.2%, respectively. The negative predictive value of CT enteroclysis was 100% and the positive predictive value, 94.7%. Pathologic findings confirmed small-bowel carcinoid tumors in 18 patients. CONCLUSION CT enteroclysis should be considered an excellent tool for the diagnosis of the carcinoid tumor before any surgical procedures.

Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia

BACKGROUND Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option. METHODS Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to the first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded. RESULTS Twelve patients with metastatic insulinoma and refractory hypoglycemia who were treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/day, except in one patient, 5 mg/day) was given after a median of four previous therapeutic lines. Medication aimed at normalizing blood glucose levels in 11 patients. After a median duration of 6.5 months (range 1-35+ months), median time to the first recurrence of symptomatic hypoglycemia was 6.5 months (range 0 to 35+ months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to two deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia. CONCLUSION Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.