Publications by authors named "Catherine Lombard-Bohas"

106 Publications

Renal function in patients receiving streptozocin for locally advanced or metastatic digestive neuroendocrine tumours: results of the Streptotox-FFCD 0906 study.

Clin Res Hepatol Gastroenterol 2021 Mar 19;45(5):101572. Epub 2021 Mar 19.

Department of Nephrology Dialysis and Transplantation, and INSERM UMR 1088, Centre Hospitalier Universitaire, Amiens, France.

Introduction: Streptozocin can impair renal function. The purpose of this study was to evaluate the evolution of renal function in patients receiving this anti-mitotic for the treatment of locally advanced/metastatic digestive well differentiated neuroendocrine tumours.

Methods: A prospective and a retrospective cohort of patients with normal baseline renal function were analysed. The primary endpoint was the incidence of a decrease in the estimated glomerular filtration rate ≥ 25% during treatment. Secondary endpoints were the evaluation of glomerular filtration rate changes, the impact of combined nephrotoxic treatments, other toxicities, compliance, and the objective response rate.

Results: After screening 142 patients, 27 were included in the prospective and 84 in the retrospective cohort. A decrease in estimated glomerular filtration rate ≥ 25% was observed in 32 patients (30%): respectively four (15.4%) and 28 patients (34.1%) among respectively 26 and 82 patients with numerous measures (P = 0.0097). Altogether, 39 patients (35%) experienced grade 1-2 renal toxicity, while no grade 3-4 occurred in the prospective and 1 occurred in the retrospective cohort. Renal toxicity was more frequent in the retrospective cohort with a less careful follow up. As best responses, objective response was achieved in 27% of patients with pancreatic primary tumours, disease control in 78.9% of patients with pancreatic primary tumours, in 87% of those with small bowel tumours and in 72.7% of patients with other primary locations.

Conclusions: Strongly recommended for pancreatic NET, streptozocin is associated with frequent mild renal toxicity but low occurrence of renal impairment in patients with baseline normal renal function and under adequate hydration.
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http://dx.doi.org/10.1016/j.clinre.2020.10.014DOI Listing
March 2021

Value of a patient-reported-outcome measure of carcinoid syndrome symptoms.

Eur J Endocrinol 2021 May;184(5):711-722

Service d'Oncologie Médicale et Hépatogastroentérologie, Hospices Civil de Lyon, Lyon, France.

Objective: Literature on patient-reported outcomes (PRO) of carcinoid syndrome symptoms (CSS) is scarce. We used a patient-reported outcome measure (PROM) to evaluate CSS, the domains of daily life impacted by CSS, the main symptoms that affect daily life, its change according to clinical, biological and morphological evolution, and the risk factors for a poor PRO-CSS score.

Methods: Patients completed the PRO-CSS, EORTC-QLQ30, and GI-NET21 questionnaires at the time of their clinical, laboratory, and morphological assessments in a multicentre French cohort study from February 2019 to May 2020.

Results: In total, 147 patients with metastatic ileal (n =126), lung (n =20), or unknown primitive neuroendocrine tumour but high 5-hydroxyindole-3-acetic acid level (n =1) were included; 42 (32%) received an above-label dose of somatostatin analogues. Fifty-one (35%) patients had a poor PRO-CSS score. Travelling and food restriction were the two main domains affected. Diarrhoea (mean: 2.3/5 on Likert scale), imperiousness (mean of 2.5/5), fatigue (2.2/5), abdominal pain (1.7/5), and flushing episodes (1.5/5) were the main symptoms affecting daily life. The PRO-CSS score was not correlated to the clinical assessment performed by physicians at the baseline and during the follow-up. Patients with a poor PRO-CSS score had a higher tumour burden.

Conclusions: PROM-CSS may help physicians make an objective assessment of CSS and its impact in daily practice; this tool could become a key evaluation criterion in clinical trials focusing on CSS.
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http://dx.doi.org/10.1530/EJE-20-1138DOI Listing
May 2021

Phase II study evaluating the association of gemcitabine, trastuzumab and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1).

Int J Cancer 2021 Feb 2;148(3):682-691. Epub 2020 Sep 2.

Medical Oncology Department, Institut du Cancer de Montpellier (ICM), Univ. Montpellier, Montpellier, France.

In a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second-line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first-line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression-free (PFS), overall (OS) survival and toxicity (NCI-CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty-three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35-77), 59.7% men. The median treatment duration was 16.1 weeks (2.1-61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8-85.0; 44/59 patients). After a median follow-up of 23.3 months (0.6-23.6), median PFS was 3.5 months (95%CI: 2.4-3.8) and median OS 7.9 months (95%CI: 5.1-10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0-1 toxicities (HR = 0.55, 95%CI: 0.33-0.92, P = .020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed.
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http://dx.doi.org/10.1002/ijc.33225DOI Listing
February 2021

ctDNA in neuroendocrine carcinoma of gastroenteropancreatic origin or of unknown primary: the CIRCAN-NEC pilot study.

Neuroendocrinology 2020 Oct 23. Epub 2020 Oct 23.

Introduction: Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterised by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations, to assess their predictive value for response to chemotherapies, and their change according to disease progression.

Methods: The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary, scheduled to begin first or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation, at first evaluation, and during disease progression. ctDNA were sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction (MAF).

Results: All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post first-line regimen. Twenty-two patients had at least one driver mutation: TP53 (n=21), RB1 (n=2), KRAS (n=4), BRAF (n=3). Ten (42%) had a "adenocarcinoma-like" profile. Five of six patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA-mutation/immunohistochemistry-profile was 64% (7/11) for TP53/p53+ and 14% (1/7) for RB1/pRb-. In this pilot study including few patients by subgroups, patients with KRAS (HR=3.60, 95%CI [1.06-12.04]) and BRAF (HR=4.25, 95%CI [1.11-16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide, while the two patients with RB1 mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response), which was associated with longer PFS (HR=0.37, 95%CI [0.15; 0.91]).

Conclusion: This pilot study shows a high sensitivity of ctDNA assessment, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).
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http://dx.doi.org/10.1159/000512502DOI Listing
October 2020

Unifocal versus multiple ileal neuroendocrine tumors location: an embryological origin.

Neuroendocrinology 2020 Sep 30. Epub 2020 Sep 30.

Introduction: Small-intestinal neuroendocrine tumors (SI-NET) are situated preferentially within the ileum. The aim was to describe a potential difference in location between unifocal and multiple ileal-NET.

Methods: Between December 2010 and December 2019, all consecutive patients who underwent resection in our European Neuroendocrine Tumor Society Center of Excellence, of at least one non-duodenal SI-NET, were retrospectively included. The main objective was to prove that multiple ileal-NET were mostly located on the left side of the superior mesenteric artery (SMA) axis (defined as 40cm from the ileocecal valve), and unifocal ones on the right-side.

Results: Ninety-four patients were included, six with unifocal jejunal-NET located 35cm (range, 10-60) from the duodenojejunal angle (DJA), 44 (47%) with unifocal ileal-NET, and 44 (47%) with multiple ileal-NET. The median number of tumors in multiple ileal-NET was 7 (range, 2-95), within a median small bowel segment of 105cm (10-240). The median length between the proximal tumor and the DJA was 428cm (300-635) and 540cm (350-725) for the distal one; 40 (91%) of them were located on the left side of the SMA axis. In contrast, unifocal ileal-NET were located at a median distance of 577cm (305-820) from the DJA (p<0.001, compared to multiple ileal-NET); 30 (68%) of them were on the right side of the SMA axis (p<0.001).

Conclusion: Multiple ileal-NET are mostly located on the left side of the SMA axis. Further studies are warranted to explore the embryological origin of unifocal versus multiple ileal-NET.
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http://dx.doi.org/10.1159/000511849DOI Listing
September 2020

Solitary myocardial metastasis from neuroendocrine tumor: surgical resection as curative surgery.

Gen Thorac Cardiovasc Surg 2021 Jan 18;69(1):126-129. Epub 2020 Jun 18.

Department of Thoracic Surgery and Pulmonary Transplantation, Louis Pradel Hospital, 28, Avenue du Doyen Jean Lépine, 69500, Bron (Lyon), France.

We present the case of a 70-year-old man with intramyocardial solitary metastasis from a carcinoid bowel tumor. One year previously, he had undergone distal ileum resection for a neuroendocrine tumor. Asymptomatic recurrence was diagnosed with the combination of elevated chromogranin A serum level and somatostatin receptor scintigraphy. The tumor was located on the right ventricle free wall, without obstruction of the right ventricular outflow tract and absence of carcinoid syndrome or liver involvement. Complete resection was obtained under cardiopulmonary bypass. The patient is currently alive without disease 2 years after surgery. Oncologists should be aware of the heart as a possible site of neuroendocrine metastatic disease. This case highlights the value of positron emission tomography with somatostatin analogs for earlier and more frequent metastasis detection. Persistent remission can be obtained with complete surgical resection when the metastatic tumor is localized in the right ventricle without evidence of carcinoid heart disease.
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http://dx.doi.org/10.1007/s11748-020-01409-zDOI Listing
January 2021

Baseline Splenic Volume as a Prognostic Biomarker of FOLFIRI Efficacy and a Surrogate Marker of MDSC Accumulation in Metastatic Colorectal Carcinoma.

Cancers (Basel) 2020 May 31;12(6). Epub 2020 May 31.

Department of Medical Oncology, Georges François Leclerc Cancer Center-UNICANCER, 1 rue Professeur Marion, 21000 Dijon, France.

Background: Predictive biomarkers of response to chemotherapy plus antiangiogenic for metastatic colorectal cancer (mCRC) are lacking. The objective of this study was to test the prognostic role of splenomegaly on baseline CT scan.

Methods: This study is a sub-study of PRODIGE-9 study, which included 488 mCRC patients treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab in first line. The association between splenic volume, and PFS and OS was evaluated by univariate and multivariable Cox analyses. The relation between circulating monocytic Myeloid derived suppressor cells (mMDSC) and splenomegaly was also determined.

Results: Baseline splenic volume > 180 mL was associated with poor PFS (median PFS = 9.2 versus 11.1 months; log-rank = 0.0125), but was not statistically associated with OS (median OS = 22.6 versus 28.5 months; log-rank = 0.1643). The increase in splenic volume at 3 months had no impact on PFS (HR 0.928; log-rank = 0.56) or on OS (HR 0.843; log-rank = 0.21). Baseline splenic volume was positively correlated with the level of baseline circulating mMDSC ( = 0.48, -value = 0.031).

Conclusion: Baseline splenomegaly is a prognostic biomarker in patients with mCRC treated with FOLFIRI and bevacizumab, and a surrogate marker of MDSC accumulation.
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http://dx.doi.org/10.3390/cancers12061429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352427PMC
May 2020

Post first-line dacarbazine or temozolomide in neuroendocrine carcinoma.

Endocr Connect 2020 Jun;9(6):498-505

Service d'Oncologie Médicale, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.

Objective: First-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment.

Material And Methods: This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS).

Results: Twenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments.

Conclusion: LV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.
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http://dx.doi.org/10.1530/EC-20-0192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354717PMC
June 2020

Management and prognosis of localized duodenal neuroendocrine neoplasms.

Neuroendocrinology 2020 Apr 24. Epub 2020 Apr 24.

Introduction: The characteristics, prognostic factors, and management of duodenal neuroendocrine neoplasms (dNEN) are ill-defined given their rarity. Whether non-surgical management could be appropriate in good-prognosis non-metastatic dNEN, as for pancreatic NEN (pNEN), is unknown. We aimed to describe the management and prognosis of non-metastatic dNEN patients.

Methods: All consecutive patients with non-metastatic dNEN managed between 1981 and 2018 in two expert centers were included. Recurrence-free survival (RFS) and factors associated with recurrence were estimated.

Results: A total of 145 patients with dNEN were included. Twenty-eight sporadic, non-functioning, small (median size: 7mm), dNEN underwent endoscopic resection, with a 5-year recurrence-free survival rate of 89.4%. Local recurrence occurred in two patients, who underwent surgery without new event. The 5-year recurrence-free rate was 87.9% in patients who underwent surgery. In univariate analysis, age, size, Ki67, and lymph-node involvement were significantly associated with worse RFS for all treated (endoscopy/surgery) dNEN; multivariate analysis found age, size, and lymph-node involvement were associated with worse RFS.

Conclusion: Selected non-metastatic dNEN had a favorable outcome and appear suitable for a less invasive therapeutic strategy than oncological surgery.
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http://dx.doi.org/10.1159/000508102DOI Listing
April 2020

Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).

Dig Liver Dis 2020 05 28;52(5):473-492. Epub 2020 Mar 28.

Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France. Electronic address:

Introduction: This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org).

Methods: All French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019.

Results: The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET.

Conclusion: These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
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http://dx.doi.org/10.1016/j.dld.2020.02.011DOI Listing
May 2020

Metformin and everolimus in neuroendocrine tumours: A synergic effect?

Clin Res Hepatol Gastroenterol 2020 11 4;44(6):954-960. Epub 2020 Mar 4.

Service d'oncologie médicale, hôpital Edouard-Herriot, hospices civils de Lyon, Pavillon E, UJOMM, 69437 Lyon, France; University of Lyon, Univsersité de Lyon 1, Lyon, France. Electronic address:

Objective: To explore potential synergy in effectiveness between metformin and everolimus, 2 inhibitors of the mTOR pathway, for neuroendocrine tumours (NET).

Design And Methods: A cohort of patients with advanced gastroenteropancreatic or lung NETs treated by everolimus were stratified in to those without diabetes, those with diabetes and without metformin, and those with diabetes with metformin. The primary endpoint was the median progression-free survival (PFS).

Results: A total of 213 patients were included, 165 of which were non-diabetic; among diabetic patients, 19 were treated with metformin and 29 with others anti-diabetic drugs. No significant difference in median PFS [95%CI] was found between the three groups: 10.05 months [8.27;11.83] for non-diabetic patients, 15.24 [19.88;49.43] for diabetic w/metformin, and 9.03 months [4.01;14.06] for diabetic w/o metformin group. In univariate analysis, factors significantly associated with longer PFS was a functioning NET, a number of metastatic sites<3, the absence of lung metastasis, and an uptake on Octreoscan®, but not the absence of metformin use; only uptake on Octreoscan® remained significant in multivariate analysis.

Conclusions: In contrast with the literature, we did not find a synergy between everolimus and metformin in NET. Prospective studies are underway to improve the comprehension of the potential synergy regarding population and tumour type.
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http://dx.doi.org/10.1016/j.clinre.2020.02.011DOI Listing
November 2020

Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients.

Int J Cancer 2020 08 22;147(4):967-977. Epub 2020 Jan 22.

Department of Oncology, Saint Antoine Hospital, APHP, Paris, France.

Small bowel adenocarcinoma (SBA) is a rare tumour. We conducted a prospective cohort to describe the prevalence, survival and prognostic factors in unselected SBA patients. The study enrolled patients with all stages of newly diagnosed or recurrent SBA at 74 French centres between January 2009 and December 2012. In total, 347 patients were analysed; the median age was 63 years (range 23-90). The primary tumour was in the duodenum (60.6%), jejunum (20.7%) and ileum (18.7%). The prevalence of predisposing disease was 8.7%, 6.9%, 1.7%, 1.7% and 0.6% for Crohn disease, Lynch syndrome, familial adenomatous polyposis, celiac disease and Peutz-Jeghers syndrome, respectively. At diagnosis, 58.9%, 5.5% and 35.6% of patients had localised and resectable, locally advanced unresectable and metastatic disease, respectively. Crohn disease was significantly associated with younger age, poor differentiation and ileum location, whereas Lynch syndrome with younger age, poor differentiation, early stage and duodenum location. Adjuvant chemotherapy (oxaliplatin-based in 89.9%) was performed in 61.5% of patients with locally resected tumours. With a 54-months median follow-up, the 5-year overall survival (OS) was 87.9%, 78.2% and 55.5% in Stages I, II and III, respectively. The median OS of patients with Stage IV was 12.7 months. In patients with resected tumours, poor differentiation (p = 0.047) and T4 stage (p = 0.001) were associated with a higher risk of death. In conclusion, our study showed that the prognosis of advanced SBA remains poor. Tumour characteristics differed according to predisposing disease. In SBA-resected tumours, the prognostic factors for OS were grade and T stage.
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http://dx.doi.org/10.1002/ijc.32860DOI Listing
August 2020

Everolimus after hepatic arterial embolisation therapy of metastases from gastrointestinal neuroendocrine tumours: The FFCD 1104-EVACEL-GTE phase II study.

Eur J Cancer 2019 12 31;123:92-100. Epub 2019 Oct 31.

Interventional Radiology Department, Gustave Roussy Villejuif & UFR Medecine Kremlin Bicetre Paris Sud University, Villejuif, France.

Background: Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity.

Methods: This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7-30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%.

Results: Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5-43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14-23), 17 (13-22), and 51 (33-60) months. The most common grade III-IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%).

Conclusions: The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease.

Trial Registration: NCT01678664 (clinicaltrials.gov).
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http://dx.doi.org/10.1016/j.ejca.2019.09.021DOI Listing
December 2019

Elderly Patients with Metastatic Neuroendocrine Tumors Are Undertreated and Have Shorter Survival: The LyREMeNET Study.

Neuroendocrinology 2020 7;110(7-8):653-661. Epub 2019 Oct 7.

Service de Gastroentérologie et d'Oncologie Médicale, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France,

Introduction: The incidence of neuroendocrine tumors (NETs) is rising, especially in elderly patients. The elderly cancer population presents considerable challenges, yet little is known about the characteristics, treatment patterns, and outcomes of metastatic NET (mNET) patients.

Methods: The Lyon Real-life Evidence in Metastatic NeuroEndocrine Tumors study (LyREMeNET, NCT03863106) included consecutive mNET patients, diagnosed between January 1990 and December 2017. The exclusion criteria were nonmetastatic NET, poorly differentiated neuroendocrine carcinoma, and mixed neuroendocrine-nonneuroendocrine neoplasms. We aimed to compare patients ≥70 years old to patients <70 years old.

Results: A total of 866 patients were included, 198 (23%) were ≥70 years old. There was no significant difference in characteristics except that elderly patients had synchronous metastasis more frequently. Elderly patients received significantly fewer treatments (median of 2.0 vs. 3.0 lines, respectively, p < 0.0001), were significantly less frequently treated by chemotherapy (32 vs. 54%), targeted therapy (16 vs. 30%), peptide receptor radionuclide therapy (5 vs. 16%), and they underwent significantly less frequently locoregional intervention. Median overall survival was significantly shorter in elderly patients (5.2 vs. 9.6 years). The most frequent cause of death was related to disease progression (71%). Multivariate analysis found that, after adjustment for tumor location, tumor grade, and number of metastatic sites, age remained significantly associated with overall survival (HR 1.66, 95% CI 1.26-2.18), indicating a poorer survival in patients ≥70 years old in comparison with younger patients (p = 0.0003).

Conclusion: Patients ≥70 years old have a worse survival, die frequently from their disease, and are undertreated compared to younger patients.
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http://dx.doi.org/10.1159/000503901DOI Listing
October 2019

Temozolomide Alone or Combined with Capecitabine for the Treatment of Advanced Pancreatic Neuroendocrine Tumor.

Neuroendocrinology 2020 10;110(1-2):83-91. Epub 2019 May 10.

Department of Pancreatology and Gastroenterology, ENETS Centre of Excellence, Beaujon Hospital, and Paris University, Clichy, France.

Background: The combination of capecitabine (CAP) with temozolomide (TEM) chemotherapy in advanced pancreatic neuroendocrine tumors (PanNET) relies on limited evidence. We compared TEM-CAP to TEM alone in patients with advanced PanNET.

Methods: Consecutive patients with advanced PanNET treated with TEM or TEM-CAP between 2004 and 2017 in three expert centers were included. Progression-free survival (PFS), tolerance, tumor response, and overall survival were compared between the two groups. Propensity-based analyses were performed to reduce confounding bias due to the nonrandomized setting.

Results: TEM and TEM-CAP were administered to 38 patients and 100 patients, respectively, with a median age of 58 years. The patients in the TEM group more often had hormonal syndromes (p = 0.03), a longer median delay to diagnosis (p = 0.001), and a higher number of pretreatment lines (p < 0.001). The performance status was 0 in 58% versus 65% of the patients, and tumor's median Ki-67 index was 8% versus 11%, respectively. Tolerance was similar, except that there were more cases of asthenia in the TEM group (p = 0.017) and more cases of hand-foot syndrome in the TEM-CAP group (p = 0.025). The objective response rate was 34% versus 51% (p = 0.088). The raw median PFS was similar with TEM and with TEM-CAP (21.4 vs. 19.8 months, p = 0.84). Although CAP tended to decrease the risk of progression in Cox multivariate analysis (HR 0.65, p = 0.12), it had no effect after adjustment for the propensity score (HR 1.06, p = 0.80).

Conclusions: TEM-CAP might not prolong PFS but might achieve a higher response rate than TEM alone. Hence, TEM-CAP might be preferred when tumor shrinkage is the main therapeutic objective. Otherwise, TEM might be adequate for patients with an impaired performance status or in case of extrahepatic metastases.
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http://dx.doi.org/10.1159/000500862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979423PMC
February 2021

O6-methylguanine-DNA methyltransferase (MGMT) status in neuroendocrine tumors: a randomized phase II study (MGMT-NET).

Dig Liver Dis 2019 04 14;51(4):595-599. Epub 2019 Feb 14.

Department of Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France. Electronic address:

Introduction: Neuroendocrine tumors (NETs) are rare, but their incidence is rising. Alkylating agents (ALKY), temozolomide and streptozotocin, are the main chemotherapies used for advanced pancreatic NETs. According to retrospective data, O6-methylguanine-DNA methyltransferase (MGMT) status appears to be a predictive factor of the response to ALKY.

Aims: The main objective is to evaluate the value of tumor MGMT promoter (pMGMT) methylation in the prediction of the objective response (OR) at 3 months in patients treated with ALKY. Secondly, we will evaluate the value of MGMT immunohistochemistry and the efficacy of treatment with ALKY vs. oxaliplatin-based chemotherapy (Ox).

Materials And Methods: A national, prospective, open-label, randomized, controlled and multicenter trial was designed. Main inclusion criteria are: adult patients with well-differentiated advanced duodeno-pancreatic, lung, or unknown primitive NETs with a validated indication for chemotherapy. pMGMT methylation will be assessed by pyrosequencing, but an ancillary study will compare this technique with others ones including MGMT immunohistochemistry.

Results: A total of 104 patients will be randomly assigned (1:1 for unmethylated or 2:1 for methylated pMGMT NETs) to either the ALKY arm or to the Ox arm.

Conclusion: Recruitment started on October 16, 2018 (NCT03217097) and will be open in 21 centers in France.
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http://dx.doi.org/10.1016/j.dld.2019.02.001DOI Listing
April 2019

Characterization, Prognosis, and Treatment of Patients With Metastatic Lung Carcinoid Tumors.

J Thorac Oncol 2019 06 13;14(6):993-1002. Epub 2019 Feb 13.

Service d'Oncologie Médicale, Groupement Hospitalier Centre, Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France; University of Lyon, Lyon, France. Electronic address:

Introduction: Metastatic lung carcinoids (MLCs) remain poorly characterized and no prognostic stratification exists.

Methods: We conducted a retrospective study including patients with MLCs in two European expert centers. The aims were to characterize these cases and to identify prognostic factors of survival and effectiveness of their treatments.

Results: A total of 162 patients with MLC were included: 50% were women, and the median age was 61 years. Half of the patients had synchronous metastases, mainly located in the liver (75%), bone (42%), and lung (25%). According to WHO classification, MLCs were typical (28%), atypical (60%), or unspecified (12%). A functioning syndrome was observed in 43% of cases and an uptake at somatostatin receptor scintigraphy in 76% of cases. The 5-year overall survival rate was 60% and at 10 years this was 25%. In multivariate analysis, Eastern Cooperative Oncology Group performance status of 0-1 (hazard ratio [HR]: 5.81, 95% confidence interval [CI]: 2.10-16.11), uptake on SRS (HR: 0.38, 95% CI: 0.22-0.66), low serum chromogranin A (HR: 2.27, 95% CI: 1.36-3.81), and typical carcinoid (HR: 1.87, 95% CI: 1.26-2.78) were associated with better survival. According to Response Evaluation Criteria in Solid Tumors version 1.0, the highest objective response rates were obtained after radiofrequency ablation of metastases (86%), liver embolization (56%), peptide receptor radionuclide therapy (27%), and oxaliplatin-based chemotherapy (18%).

Conclusions: MLCs are characterized by a high frequency of atypical carcinoids, functioning syndrome, and liver/bone metastases. WHO classification, performance status, somatostatin receptor scintigraphy, and chromogranin A were associated with longer survival. Partial response was more frequent with locoregional therapies, peptide receptor radionuclide therapy, or oxaliplatin-based chemotherapy.
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http://dx.doi.org/10.1016/j.jtho.2019.02.002DOI Listing
June 2019

Comparison of Temozolomide-Capecitabine to 5-Fluorouracile-Dacarbazine in 247 Patients with Advanced Digestive Neuroendocrine Tumors Using Propensity Score Analyses.

Neuroendocrinology 2019 13;108(4):343-353. Epub 2019 Feb 13.

Department of Hepato-Gastroenterology and Digestive Oncology and Reims-Champagne-Ardennes University, Reims, France.

Introduction: Although chemotherapy combining 5-fluorouracil (5FU)-dacarbazine (DTIC) or temozolomide (TEM)-capecitabine (CAP) is extensively used in patients with neuroendocrine tumors (NET), they were never compared. We compared their tolerance and efficacy in advanced NET.

Methods: We evaluated the records of consecutive patients with pancreatic or small-intestine advanced NET who received 5FU-DTIC or TEM-CAP between July 2004 and December 2017 in 5 French centers. Tolerance, tumor response and progression-free survival (PFS) were compared. Factors associated with PFS were analyzed using Cox multivariate regression model. To reduce the confounding bias of the nonrandomized design, PFS was compared using propensity score analyses.

Results: Ninety-four (5FU-DTIC) patients and 153 (TEM-CAP) patients were included. Pancreatic NET represented 82.3% of cases and 17.1, 61.8 and 10.9% of patients had G1, G2 or G3 NET respectively. Progression at baseline was reported in 92.7% of patients with available data. Grades 3-4 adverse events occurred in 24.7 and 8.5% of TEM-CAP and 5FU-DTIC patients respectively (p = 0.002). The overall response rate was 38.3 and 39.2% respectively (p = 0.596). Median PFS on raw analysis was similar to 5FU-DTIC and TEM-CAP (13.9 vs. 18.3 months, respectively p = 0.86). TEM-CAP was associated with an increased risk of progression on the raw multivariate analysis (hazard ratio [HR] 1.90, 95% CI [1.32-2.73], p = 0.001) and when adjusted on propensity score (HR 1.65, 95% CI [1.18-2.31], p = 0.004).

Conclusion: PFS may be longer with 5FU-DTIC than TEM-CAP in patients with advanced NET. Although patients often prefer oral chemotherapy, 5FU-DTIC is a relevant alternative. A randomized comparison is needed to confirm these results.
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http://dx.doi.org/10.1159/000498887DOI Listing
December 2019

Quality of life and cost of strategies of two chemotherapy lines in metastatic colorectal cancer: results of the FFCD 2000-05 trial.

Expert Rev Pharmacoecon Outcomes Res 2019 Oct 15;19(5):601-608. Epub 2019 Feb 15.

Department of Biostatistic and Epidemiology, Gustave Roussy , Villejuif , France.

: This study compared the cost and quality of life (QoL) of 407 advanced colorectal cancer patients, randomly assigned to receive LV5FU2 followed by FOLFOX6 (sequential strategy) or FOLFOX6 followed by FOLFIRI (combination strategy). : Costs were compared from the French health insurance perspective, until the end of the second line of treatment. Consumed resources, collected during the trial, included medicines, hospitalizations, examinations, and transportation. Valuations were made using 2009 and 2016 tariffs. QoL was assessed using the QLQ-C30 questionnaire and clinically significant variations were searched. : In 2009, the mean cost per patient was significantly lower for the sequential strategy compared to the combination strategy (18,061€ and 23,119€, p = 0.001). In 2016, the difference was no longer significant (16,876€ and 18,090€, p = 0.41) because oxaliplatin and irinotecan became generics. The QoL analysis (292 patients) showed that there was significantly less improvement of global health status in the sequential strategy than in the combination strategy (29% and 42%; p = 0.02) during first-line therapy. No significant differences were observed for emotional functioning (p = 0.45) and physical functioning (p = 0.07) or during second-line therapy. : The choice to treat patients with advanced colorectal cancer using one or the other strategy cannot be based on costs or QoL.
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http://dx.doi.org/10.1080/14737167.2019.1580573DOI Listing
October 2019

Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.

J Clin Oncol 2019 03 1;37(8):658-667. Epub 2019 Feb 1.

24 Centre Hospitalier Universitaire St Etienne, St Etienne, France.

Purpose: No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection.

Patients And Methods: We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m on day 1 and oxaliplatin 85 mg/m infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL.

Results: Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001).

Conclusion: There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.
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http://dx.doi.org/10.1200/JCO.18.00050DOI Listing
March 2019

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome.

Clin Ther 2018 06 1;40(6):952-962.e2. Epub 2018 May 1.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival.

Methods: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan.

Findings: In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status.

Implications: Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910.
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http://dx.doi.org/10.1016/j.clinthera.2018.04.006DOI Listing
June 2018

An onco-geriatric approach to select older patients for optimal treatments of pancreatic adenocarcinoma.

J Geriatr Oncol 2018 07 9;9(4):373-381. Epub 2018 Jun 9.

Department of Digestive Oncology, Edouard Herriot University Hospital, Lyon, France; Department of Gastroenterology, Lyon-Sud Hospital, Lyon, France.

Introduction: Pancreatic adenocarcinoma affects mainly older patients. Surgery is indicated for localized tumors while chemotherapy alone is proposed in advanced or metastatic tumors.

Objective: To evaluate the feasibility of standard of care oncologic treatments in this population, the accuracy of the geriatric evaluation to predict the ability of patients to tolerate the recommended treatments and to identify specific geriatric prognosis factors.

Methods: We included, between 2007 and 2014, all consecutive patients over 70 years of age with a pathologically diagnosed pancreatic cancer. The patients underwent a comprehensive geriatric assessment before therapeutic decision in a multidisciplinary team meeting. We analyzed factors independently associated with all-cause mortality with Cox survival analysis.

Results: Seventy-three patients (median age = 77.9 years) were prospectively included. Among them, 42 patients underwent surgery whereas the 31 other patients not eligible for surgical treatment received chemotherapy (n = 22) or best supportive care alone (n = 9). Almost 62% of operated patients received adjuvant chemotherapy. In the non-surgical group, a mean of 9 cycles of palliative chemotherapy per patients were administrated. Median overall survival was 21.3 months in the surgical group and 6.1 months in the palliative group (p = 0.0001). Most of oncologic parameters were found to be independent survival predictors. Age was not associated with the survival, but a significant impact of Lawton's Instrumental Activities of Daily Living (IADL) impairment (IADL<4) (HR = 5.0, p = 0.047), Cumulative Index Rating Scale-Geriatric (CIRS-G) ≥2 (HR = 19, p = 0.035) and weight loss >10% (HR = 4.6, p = 0.03) on survival was detected. Surgery was the only factor independently predictive of survival in multivariate analysis (p < 0.001).

Conclusion: Almost 90% of selected older pancreatic patients with cancer (64 out of 73 patients) may benefit from the same standard treatments as younger patients. IADL impairment of patients, CIRS-G ≥2, and weight loss >10% constitute survival prognostic factors which should be added to the oncological criteria in the therapeutic decision-making process.
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http://dx.doi.org/10.1016/j.jgo.2018.03.007DOI Listing
July 2018

Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms.

Neuroendocrinology 2018 8;107(1):24-31. Epub 2018 Mar 8.

Medical Oncology, Hôpital Saint Joseph, AP-HP, Paris, France.

Background/aims: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3.

Methods: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRβ, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1.

Results: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89-0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET.

Conclusion: Sunitinib showed evidence of activity in patients with GEPNEN-G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3.
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http://dx.doi.org/10.1159/000487237DOI Listing
January 2019

Evaluating bevacizumab in combination with FOLFIRI after the failure of platinum-etoposide regimen in patients with advanced poorly differentiated neuroendocrine carcinoma: The PRODIGE 41-BEVANEC randomized phase II study.

Dig Liver Dis 2018 Feb 6;50(2):195-198. Epub 2017 Dec 6.

Gastrointestinal Oncology Department, Gustave Roussy Institute, Villejuif, France; Gastroenterology & Digestive Oncology, University Hospital Le Bocage, Dijon, France.

Introduction: Patients with gastroenteropancreatic (GEP), metastatic or locally advanced, non-resectable, grade 3 poorly-differentiated neuroendocrine carcinoma (NEC) are treated with cisplatin (or carboplatin)-etoposide in first-line palliative chemotherapy (CT1). However, nearly all patients will develop resistance and there is no standard second-line treatment.

Aim: PRODIGE 41-BEVANEC is an academic randomized, phase II study designed to evaluate the efficacy of bevacizumab in combination with FOLFIRI after failure of CT1 in unknown primary NEC and GEP-NEC.

Materials And Methods: The main eligibility criteria are age ≥18 years, metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 3 GEP-NEC, and documented progressive disease during or after CT1 therapy.

Results: A total of 124 patients will be randomly assigned (1:1) to receive either 5 mg/kg bevacizumab with FOLFIRI, or FOLFIRI alone, every 14 days until disease progression or unacceptable toxicity. The hypothesis is to demonstrate a 6-month overall survival for at least 50% of the patients in bevacizumab arm versus 35% in the control arm (FOLFIRI alone). Secondary endpoints are objective response, response duration, progression-free survival, toxicity, and biochemical response.

Conclusion: The study is currently opened in France (NCT02820857). The first patient was randomized on September 6, 2017.
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http://dx.doi.org/10.1016/j.dld.2017.11.020DOI Listing
February 2018

Phase II Study of BEZ235 versus Everolimus in Patients with Mammalian Target of Rapamycin Inhibitor-Naïve Advanced Pancreatic Neuroendocrine Tumors.

Oncologist 2018 07 14;23(7):766-e90. Epub 2017 Dec 14.

The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Lessons Learned: Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents.

Background: This phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy.

Methods: Patients with advanced pNET were randomized (1:1) to oral BEZ235 400 mg twice daily or oral everolimus 10 mg once daily on a continuous dosing schedule. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), and time to treatment failure.

Results: Enrollment in this study was terminated early (62 enrolled of the 140 planned). The median PFS was 8.2 months (95% confidence interval [CI]: 5.3 to not evaluable [NE]) with BEZ235 versus 10.8 months (95% CI: 8.1-NE) with everolimus (hazard ratio 1.53; 95% CI: 0.72-3.25). The most commonly reported all-grade adverse events (>50% of patients regardless of study treatment relationship) with BEZ235 were diarrhea (90.3%), stomatitis (74.2%), and nausea (54.8%).

Conclusion: BEZ235 treatment in mTOR inhibitor-naïve patients with advanced pNET did not demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.
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http://dx.doi.org/10.1634/theoncologist.2017-0144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058330PMC
July 2018

Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

Br J Cancer 2018 01 21;118(2):181-188. Epub 2017 Nov 21.

Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester M20 4BX, UK.

Background: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent.

Methods: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib.

Results: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg '4-weeks on/2-weeks off' schedule; n=86 '37.5 mg continuous daily dosing (CDD)')) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P<0.001). A PR was seen in 19 patients (13%) on sunitinib; the median change in the sum of the lesions (vs baseline) was -12.8% (range -100 to +36.4). Month 7 was the most informative time-point (AUC 0.78 (95% CI 0.66-0.9); odds ratio 1.05 (95% CI 1.01-1.08), P=0.002). Reduction of 10% (vs baseline) achieved the highest sensitivity (50%) and specificity (82%), amongst cut-offs tested. A 10% reduction in marker lesions was associated with improved PFS in the whole sunitinib population (HR 0.55 (95 CI 0.3-0.9); P=0.04); mostly in patients on sunitinib CDD (HR 0.33 (95% CI 0.2-0.7); P=0.005). A 10% reduction in marker lesions (P=0.034) and sunitinib treatment (P=0.012) independently impacted on PFS (multivariable analysis).

Conclusions: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design.
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http://dx.doi.org/10.1038/bjc.2017.402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785750PMC
January 2018

Patient-reported tolerance in treatments approved in neuroendocrine tumors: A national survey from the French Group of Endocrine Tumors.

Clin Res Hepatol Gastroenterol 2018 04 20;42(2):153-159. Epub 2017 Nov 20.

Service d'hépatogastroentérologie et d'oncologie, hospices civils de Lyon, hôpital Edouard-Herriot, 5, place d'Arsonval, 69437 Lyon, France. Electronic address:

Background: Patients with advanced neuroendocrine tumors (NETs) benefit from an increasing number of treatments. The patient's preference could help physicians to choose among these options. Our patient-reported survey aims to compare the perceived tolerance of NETs treatments.

Methods: Patients treated by at least three different therapeutic options have evaluated their perceived tolerance from one (very good) to five (very poor) for each single treatment. Referent physician confirmed the type and ranking over time of each treatment.

Results: Two hundred and fourty two treatments have been evaluated by 54 patients. Among patients and NETs characteristics, only a female gender was associated with poor perceived tolerance. Median perceived tolerance increased from 1 (somatostatin analogs, peptide receptor radionuclide therapy (PRRT)), 2 (surgery, radiofrequency ablation and oral chemotherapy), 3 (interferon and everolimus), to 4 (liver embolization, sunitinib and intravenous chemotherapy). In taking somatostatin analogs as reference, the odd ratios for poor perceived tolerance were 1.7 [0.6-5.1] for oral chemotherapy, 2.2 [0.9-5.3] for surgery of the primary tumor, 2.4 [0.6-9.5] for radiofrequency ablation, 2.8 [1.1-7.3] for surgery of metastasis, 3.4 [1.4-7.9] for everolimus, 3.7 [1.6-8.5] for liver embolization, 4.9 [2.2-10.7] for intravenous chemotherapy and 5.9 [2.6-13.1] for sunitinib. Only PRRT had negative odd ratio.

Conclusion: Our retrospective analysis suggests that perceived tolerance differ in between therapeutic options and may help physicians to sequence the therapeutic strategy.
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http://dx.doi.org/10.1016/j.clinre.2017.10.003DOI Listing
April 2018

Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial.

Lancet Oncol 2017 12 23;18(12):1652-1664. Epub 2017 Oct 23.

Endocrine Oncology and Nuclear Medicine, Institut Gustave Roussy, Villejuif, France.

Background: There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.

Methods: LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.

Findings: Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.

Interpretation: The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.

Funding: Novartis Pharma AG.
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http://dx.doi.org/10.1016/S1470-2045(17)30681-2DOI Listing
December 2017

Management of gastric neuro-endocrine tumours in a large French national cohort (GTE).

Endocrine 2017 Sep 29;57(3):504-511. Epub 2017 Jun 29.

Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims, France.

Introduction: Gastric neuro-endocrine tumours are rare. European guidelines for the management of neuro-endocrine tumours have been published in 2012. The aim of our survey was to study the management of gastric neuro-endocrine tumours registered in the national cohort. A prospective national cohort registers the Neuro-endocrine tumours in France since January 2003 (GTE network). We reviewed all the individual medical reports of gastric neuro-endocrine tumours in order to collect data on treatment.

Results: One hundred and ninety seven gastric neuro-endocrine tumours diagnosed between 1964 and 2013 in 20 centres were registered. For 181 cases data were considered complete for our survey. Eighty four tumours were type 1 (46.4%); five types 2 (2.8%); 52 types 3 (28.7%) and 40 types 4 (22.1%). Types 1 and 2 were first endoscopically managed in 93 and 60% of cases, respectively, whereas surgery was first done in 45 and 42%, respectively, of types 3 and 4. Systemic treatment, chemotherapy and/or somatostatin analogue, was first administered exclusively for types 3 and 4. Near 3% of types 1 and 40% of types 2 received at a time somatostatin analogue treatment. Five-year survival rates were 98.3, 100, 63.2 and 31.8% for types 1, 2, 3 and 4, respectively.

Conclusion: The great majority of gastric neuro-endocrine tumours registered in this national cohort are treated in accordance with the current guidelines. The survival rates we reported must be interpreted with caution, because this cohort registered preferentially selected patients eligible for treatment. The registration of all the gastric neuro-endocrine tumours, in particular type 1 considered as benign and type 4 not eligible for specific anti-cancer treatment must be encouraged.
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http://dx.doi.org/10.1007/s12020-017-1355-9DOI Listing
September 2017