Chemotherapy for gastro-enteropancreatic endocrine tumours

Despite similar histological and morphological aspects, gastro-enteropancreatic (GEP) endocrine tumours represent a heterogeneous group of tumours with varying clinical expression depending on tumour type (functional or not), origin and extension, but also on histological differentiation and proliferative capacity. The natural history of well-differentiated tumours is often favourable without treatment and GEP endocrine tumours may remain indolent for many years. Chemotherapy may however be indicated in the presence of symptomatic non-progressive disease (progression evaluated over 3-6 months). In contrast, poorly differentiated GEP endocrine tumours are frequently aggressive and early treatment is required. Accurate staging is mandatory and where surgery is possible (even in the event of limited metastatic disease), this option should be re-evaluated in a multidisciplinary approach. Approximately 2/3 of malignant GEP tumours are metastatic at discovery and surgery is possible in a minority of patients; therefore, chemotherapy, with/without other strategies (e.g. local ablation), is frequently indicated in patients with symptomatic, bulky or progressive disease. For well-differentiated pancreatic tumours, the reference association is Adriamycin with streptozotocin yielding objective responses (OR) in 40-60% of patients. Prolonged treatment is limited due to potential cardiotoxicity of Adriamycin and standard 2nd-line regimens are not of proven efficacy; thus, other treatment modalities are usually additionally required (e.g. chemo-embolisation). A significant OR may render a small number of patients secondarily amenable to surgery. Published series evaluating chemotherapy for midgut endocrine tumours are outdated and disappointing. Objective response rates with combined associations (including either 5-fluorouracil and/or streptozotocin) rarely exceed 20% and where possible, chemo-embolisation for hepatic metastases combined with somatostatin analogues (+/- interferon) should be preferred. Poorly differentiated GEP tumours are generally aggressive tumours with metastases at diagnosis and tend to progress rapidly. Surgery is rarely possible and ineffective even in locally advanced disease due to a high risk of recurrence. Chemotherapy, using cisplatin and etoposide, is the reference treatment and frequently yields OR rates >50%. However, despite being chemosensitive, disease control is limited (8-10 months). Overall, advances in therapeutic chemotherapeutic options are required in the management of all types of advanced GEP endocrine tumours and evaluation of new drugs (e.g. irinotecan) and combination strategies (chemotherapy with local ablative therapies) are required in the future.