Surgical management of neuroendocrine tumour (NET) liver metastases

Abstract

Neuroendocrine tumours (NETs) usually have an indolent course, developing slowly over many years, and when there is a lack of overt hormonal symptoms they may have been present for a considerable period of time before diagnosis. Therefore, NETs are commonly found with metastatic disease at diagnosis, especially in the most common variant small-intestinal NETs (SI-NETs). Surgical treatment of NETs varies somewhat according to site of origin and extent of disease. Surgical treatment of liver metastases is generally indicated if there are less than about five tumours, if they are confined to one lobe or in the case of large tumours as a debulking option to reduce hormonal release. However, there are several alternative options. First of all, stabilisation of disease is important, usually achieved by offering biotherapy (SI-NETs) or chemotherapy (pancreatic or pulmonary NETs). In addition, treatment with 177luthetium-labelled somatostatin analogues in tumours expressing somatostatin receptors has emerged as a possible option for initial treatment. After stabilisation of the disease, or even reduction of the tumour burden, often achieved by these treatments, surgery may become an option. A likewise targeted metastasis-directed therapy is ablation by radiofrequency (RFA), microwave (MW) or recently also irreversible electroporation (IRE). Another available option is hepatic artery embolisation. Therefore, surgical management of liver metastases may be offered at different stages of the disease. In some cases the goal is total eradication of metastases from the liver, in other cases as another method to keep the disease ‘under control’ or as a debulking procedure to reduce hormonal levels. RFA or MW for SI-NETs has been evaluated and found to be safe, to reduce hormonal levels, and to reduce symptoms such as diarrhoea and abdominal pain. However, there seems to be no improvement on survival, although no randomised trial to test this has yet been conducted. Surgery has classically involved standard resections such as segmentectomies or hemihepatectomy, but recently a more local approach has been utilised as an alternative to the likewise local RFA or MW. No studies have compared liver surgery for NETs with the alternatives, but studies have demonstrated the safety of – and clear benefit as a result of – surgery as a debulking procedure. Studies in SI-NET have shown that the recurrence rate of liver metastases is very high. In careful microscopic evaluations of resected liver specimens it is clear that there are almost always several previously unrecognised metastases present, perhaps indicating the impossible goal of reaching microscopic R0. In pancreatic NETs the situation may be different. Unless diffusely spread, R0 may be achieved in the liver, and if combined with proper chemotherapy an impressively stable disease may be achieved compared with previously. Liver transplantation has been advocated in patients with pancreatic NETs, Ki67 20 years, raising doubts about whether liver transplant is an option. Indeed, the metastases in SI-NETs commonly also occur at other sites than in the liver – but may still be controlled with the appropriate biotherapy treatment, as well as with 177Lu in certain cases. Indeed, there are reports of very successful liver transplant case series, but also cases with recurrence of disease in the new liver associated with short survival. Overall, no comparative or randomised studies are available to support any evidence-based recommendations. There are several patient case series describing long survival and improvement of symptoms after liver surgery, but these are of small value because of lack of comparisons. On the other hand, liver surgery or ablative procedures may still be chosen by the individual patient when offered, as a variant of personalised medical care.