Oxaliplatin and 5-Fluorouracil in Advanced Well-Differentiated Digestive Neuroendocrine Tumors: A Multicenter National Retrospective Study from the French Group of Endocrine Tumors.

INTRODUCTION: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs); however, the available data are limited. Our aim was to assess the efficacy of FOLFOX (association of 5-fluorouracil with oxaliplatin) in a large series of patients with advanced digestive NETs. METHODS: All patients with advanced digestive well-differentiated NETs treated with at least 3 cycles of FOLFOX between January 2004 and December 2018 in 12 centers from the French Group of Endocrine Tumors were included. Tumor response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, progression free survival (PFS), and overall survival, as well as prognostic factors, were analyzed retrospectively. RESULTS: One hundred fifty-five patients were included. Primary tumor locations were pancreas (n = 89), small intestine (n = 40), unknown with no evidence for lung primary (n = 13), stomach (n = 7), and rectum (n = 6). Median Ki-67 was 10%, and 65% of the tumors were grade 2. The partial response rate was 30% for pancreatic NETs, 12.5% for small intestine NETs, 38.5% for unknown primary NETs, 14% for gastric NETs, and 17% for rectal NETs. Significant prognostic factors for poor PFS after FOLFOX were progressive disease at the beginning of treatment (hazard ratio [HR] = 1.83, p = 0.007), hepatic involvement superior to 50% (HR = 2.67, p = 0.0001), and rectal primary tumor location (HR = 2.6, p = 0.0036). Among pancreatic NETs, insulinomas had a better median PFS (22 months) than other pancreatic NETs (9 months, p = 0.026) and showed a high rate (8/9) of serum glucose normalization. CONCLUSIONS: FOLFOX shows a promising antitumor activity in advanced digestive NETs. Rapid symptomatic response is observed in metastatic insulinomas.

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.

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.

Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma.

INTRODUCTION: Use of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC). METHODS: This was a bicentric retrospective study including all patients ≥75years and treated with sorafenib for advanced HCC between January 2010 and March 2014. RESULTS: Of the 51 patients included (median age: 78 years, range: 75-92; performance status (PS) 0-1: 98%; cirrhosis: 88.2%; Child-Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3-4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients ≥80 years were associated with severe AE (OR: 13.3; p=0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS ≥1 at baseline (OR: 10.4; p=0.01), or other cardiovascular histories (OR: 30.9; p=0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p<0.0001). CONCLUSION: Tolerance of Sorafenib seems to be low in elderly, especially for patients aged ≥80 years or with PS ≥1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival.

The level of epidermal growth factor receptors expression is correlated with the advancement of colorectal adenoma: validation of a surface biomarker.

INTRODUCTION: Data about the expression of Epidermal Growth Factor Receptors (EGFRs) in colorectal adenomas remain scarce. RESULTS: 101 patients were enrolled including 53 controls. All adenomas (n = 38) and CRC (n = 5) were EGFR positive. Hyperplastic polyps (HP) (n = 8) and control colons (n = 53) were EGFR negative in half of cases (p < 0.0001). A well significant gradient of increased EGFR expression was observed between adjacent mucosa, hyperplastic lesions, low grade dysplasia (LGD) (n = 30), high grade dysplasia (HGD) adenomas (n = 9) and cancers (p < 0.0001). EGFR overexpression was reported in 100% of cancers, 77.8% of HGD, and 10% of LGD adenomas. By multivariate analysis in adenomas, associated factors with EGFR overexpression were HGD and tubulo-villous feature. MATERIALS AND METHODS: All patients undergoing colonoscopy in the university center of Saint-Etienne were eligible to the study from December 2015 to March 2016. In patients with colorectal neoplasia (lesions group), biopsies were performed on the lesion before its resection, and on the adjacent and distal colon mucosa. In control group, biopsies were performed in the right and left side colon. The EGFR expression was assessed by immunohistochemical scores (Goldstein grade, intensity of staining, composite score), using a primary mouse monoclonal antibody (EGFR, clone 113, Novocastra). Outcomes were compared using Kruskal-Wallis and/or Mann-Whitney-U tests, appropriately. The associated clinical, endoscopic and histological factors with EGFR overexpression (composite score ≥ 6) were assessed for adenomas by logistic regression. CONCLUSIONS: EGFR are early involved in colorectal carcinogenesis, and their expression is strongly correlated to the neoplasia stage, leading to validate EGFR as an interesting surface biomarker of adenomas.

Evaluating lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours.

INTRODUCTION: Patients with metastatic or locally advanced, non-resectable, grade 1 or 2 well-differentiated duodeno-pancreatic (WDDP) NETs are treated following European guidelines. Patients (Pts) with aggressive disease, i.e. progressive and/or symptomatic metastases and/or with significant hepatic invasion (>30-50%), and/or bone metastases, anti-tumour therapy should receive systemic combination of chemotherapy once disease control is obtained. AIM(S): The aim is to stop chemotherapy until progression. REMINET is an academic randomized, double-blind, placebo-controlled, phase II/III study designed to evaluate lanreotide (LAN) as maintenance treatment after L1 chemotherapy in G1-G2 WDDP NET. MATERIALS AND METHODS: Main eligibility criteria: adults pts with a metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 1 or 2 WDDP NETs and documented control disease after L1 therapy at least 4 weeks prior to randomization. RESULTS: 222 patients will be randomly assigned in a 1:1 ratio to receive 120mg LAN or placebo, every 28 days, until disease progression or unacceptable toxicity. The aim of the phase II part is to demonstrate a 6-months PFS >45% in LAN arm. Secondary endpoints are PFS according to central review, overall survival, safety and quality of life. A bio-bank of frozen blood will be constituted. CONCLUSION: The study is currently open in France, Germany, Belgium, United Kingdom and Ireland. A total of 25 patients are randomized (NCT02288377).

Squamous cell carcinoma of middle rectum: Literature review.

INTRODUCTION: Squamous cell carcinoma SCC of the rectum is a distinct entity. We report a very rare case of squamous cell carcinoma of the middle rectum. PRESENTATION OF CASE: The patient was a 62-year-old woman who presented with a history of rectal bleeding and discomfort. Colonoscopy revealed a polypoid tumour of the middle rectum. Biopsies of this mass revealed a poorly differentiated SCC of the rectum. CT scan of the chest, abdomen and pelvis was negative for distal metastases. The patient received combined chemo-radiation followed by surgical excision. The postoperative period was uncomplicated. DISCUSSION: The pathogenesis of rectal SCC remains unclear and diagnosis is often delayed. Diagnostic criteria have been proposed. MRI of the rectum and trans-rectal endoscopic ultrasound R-EUS provide essential information to plan a therapeutic approach. The squamous cell carcinoma antigen level is not suitable for initial diagnosis of rectal SCC. Most authors conclude that the surgery is the gold standard treatment. Tumour stage is the most important prognostic predictor of SCC. CONCLUSION: Squamous cell carcinoma of the rectum is a distinct entity. Before the final choice of treatment is made, digestive surgeons should bear in mind this rare tumour.

A mini geriatric assessment helps treatment decision in elderly patients with digestive cancer. A pilot study.

UNLABELLED: Comprehensive geriatric assessment (CGA) is advocate to improved care of elderly with cancer but is not available in every hospital within a short delay. Therefore, a tool allowing gastroenterologist to detect rapidly specific abnormalities in elderly is needed. PATIENTS AND METHODS: the aim of our pilot study was to evaluate feasibility of a mini geriatric assessment (MGA) to adapt the anticancer treatments. MGA was done by a gastroenterologist and was taken into account during the cancer multidisciplinary team meeting for making decision. Then, CGA was realised and suggested adaptation of care. RESULTS: 21 patients over 75 years treated for different digestive cancers were enrolled. The treatments recommended by the cancer multidisciplinary team meeting after the GMA were: standard treatments in 9 (41%); modified in 10 (47%) and best supportive care in 2 (12%) patients. CGA led to an adaptation of the non-oncological treatment in 15 (72%) and of the social care in 8 (38%) patients, but never modified the oncological strategy. CONCLUSIONS: MGA could help gastroenterologists for adaptation of anticancer treatment. The characteristics of the patients that should subsequently have a geriatric follow-up remain to be defined.

Half of elderly patients routinely treated for colorectal cancer receive a sub-standard treatment.

BACKGROUND: Several database studies report a lack of care in elderly patients with colorectal cancer. PURPOSE: To describe the management of elderly patients admitted for colorectal cancer; to identify factors associated with standard management according to recommendations and to study factors influencing the survival. PATIENTS AND METHODS: All consecutive patients over 75 years managed for a colorectal adenocarcinoma in our hospital from 1995 to 2000 and followed until 2006 were retrospectively included. The appropriateness of the management of their disease according to the recommendations available at that time was assessed. Several risk factors in receiving the standard cancer treatment were tested using univariate and then multivariate logistic regression. Risk factors of survival were studied using univariate and then multivariate survival analysis. RESULTS: One hundred and ten patients were included. Median age was 82 years (range: 75-96). A surgical treatment was performed in 96 patients. The median overall survival was 32 (1-108) months. A standard cancer treatment according to recommendations was performed in 53 (48%) patients: adjuvant chemotherapy in 6/23 patients with stage III tumour, palliative chemotherapy in 3/18 patients with stage IV tumour and adjuvant radiotherapy in 4/14 patients who had a rectal tumour resection. Multivariate analysis retains tumour stage I or II (OR=7.6, 95% C.I.=[2.9-19.9], p<0.0001) as the only factor associated with standard treatment and presence of metastasis (HR=3.9, 95% C.I. [1.4-10.8], p=0.005), and Charlson's score >3 (HR=28.9, 95% C.I. [2.5-335.6], p=0.001) as independent risk factors of poor survival. CONCLUSIONS: Fifty two percent of elderly patients have had a sub-standard cancer treatment. The majority had a surgical treatment, but only a few received chemotherapy or radiotherapy. Metastasis, older age and Charlson's comorbidity score are the main prognosis factors of poor survival.