What Is the Appropriate Management of Nonfunctioning Pancreatic Neuroendocrine Tumours Disclosed on Screening in Adult Patients With Multiple Endocrine Neoplasia Type 1?

Benjamin G. Challis; Ruth T. Casey; Ashley Grossman; John Newell-Price; Paul Newey; Rajesh V. Thakker


Clin Endocrinol. 2019;91(6):708-715. 

In This Article

What are the Treatment Options for Nonmetastatic MEN-1 NF-pNETs?

Surgical excision is the only potentially curative treatment for nonmetastatic NF-pNETs in MEN1. The surgical approach offered is dependent on tumour location and tumour size, and options include distal pancreatectomy, tumour enucleation, pylorus-preserving pancreaticoduodenectomy or total pancreatectomy.[45] The aims of surgery include prevention of disease progression through complete tumour resection, whilst preserving pancreatic function and avoiding early and late surgical complications such as diabetes mellitus and pancreatic exocrine insufficiency. The main criteria for recommending surgical excision are tumour size and, in some guidelines, tumour growth rate (ie tumour doubling over a 6-month period). However, the size threshold above which surgery should be undertaken remains contentious. Given the correlation between increased tumour size and presence of liver metastases, surgical resection is recommended for MEN1 NF-pNETs >3 cm and probably 2–3 cm; however, future clinical studies are required to clearly establish the benefit-to-risk ratio of surgery for the latter tumour subgroup. In MEN1 patients with NF-pNETS ≤2 cm, data from several studies support a 'watch and wait' approach because most of these tumours have low oncological risk.[12,14,46] For example, the Dutch MEN1 study group suggested that surgery should be reserved for NF-pNETs >2 cm because they found no difference in metastasis-free survival or mortality in patients who were actively surveyed compared with patients who underwent surgery for NF-pNETs <2 cm.[12] In addition to oncological safety, a noninterventional strategy for small NF-pNETs also mitigates against the high rate of major early post-operative complications, irrespective of tumour size, that has been reported for MEN1 patients undergoing pancreatic surgery[47] (Figure 2D,E). For example, an analysis of the early and late complications of surgical resection of NF-pNETs in a study of 63 patients with MEN1 found that: 33% of patients had major early surgical complications, most commonly due to severe pancreatic fistulas, which were associated with prolonged length of hospital attendance and significant readmission rates; 20% developed several major early complications; and 23% suffered from long-term complications.[47] Collectively, these data highlight the risk of significant post-operative morbidity associated with pancreatic surgery in MEN1.[47]

The timing and extent of surgery in MEN1 are further complicated by the occurrence of multiple NF-pNETs in many patients and the formation of new tumours within the pancreatic remnant following previous surgery, rendering subsequent resections more challenging and probably further increasing the risk of complications[35] (Figure 2F,G). In these situations, surgical options are limited to aggressive approaches, including total pancreatectomy. Finally, it is noteworthy that in patients with MEN1, synchronous duodenal and pancreatic NETs may be present and should always be considered since their occurrence may influence the decision for surgical versus conservative management.

Given the significant morbidity associated with surgical resection of NF-pNETs in MEN1, there remains an unmet medical need for antiproliferative medical therapies that may delay, or even prevent, the need for pancreatic surgery in MEN1 patients with single or multiple NF-pNETs. In this regard, somatostatin analogues (SSAs) have proven efficacy with respect to progression-free survival in non-MEN1 patients with advanced gastro-enteropancreatic neuroendocrine tumours.[48,49] In the CLARINET study, which excluded patients with MEN1, lanreotide treatment reduced disease progression and prolonged progression-free survival in patients with advanced metastatic pNETs.[48] Despite inherent clinical and biological differences between non-MEN1 and MEN1 pNETs and an absence of supportive clinical trial evidence, lanreotide is a recognised treatment option for MEN1 patients with unresectable pNETs or advanced metastatic disease. However, given the frequency of post-operative complications associated with surgical resection of small NF-pNETs, it was postulated that somatostatin analogues may have potential as 'chemoprophylactic' agents against pNETs. Indeed, the somatostatin analogue pasireotide was shown to have a chemopreventive action in the development of pNETs in a mouse model for MEN1,[50] thereby suggesting that somatostatin analogues may have a role in slowing the growth of early NF-pNETs (<2 cm) and/or preventing the formation of new pNETs in MEN1 patients. Proof-of-concept evidence for this notion has been provided by one uncontrolled retrospective clinical study of 20 MEN1 patients with early pNETs (<2 cm) (NF-pNETs [n = 14], Zollinger-Ellison syndrome [n = 5] and insulinoma [n = 1]) who were treated with octreotide LAR (30 mg intramuscularly every 28 days) over 12–75 months.[51] In this study, the investigators found that octreotide LAR resulted in an objective tumour response in 10% of patients, stable disease in 80% of patients and disease progression in 10% of patients.[51] However, it is notable that this study had several limitations, including the absence of a control arm, small sample size and retrospective design. Thus, a well-powered, prospective, placebo-controlled clinical trial is required to clearly establish whether SSAs may attenuate tumour growth and new tumour formation of early NF-pNETs in MEN1. However, such a clinical trial will be difficult to deliver given that the majority of MEN1 patients possess small and slow-growing NF-pNETs and in the absence of robust prognostic biomarkers associated with MEN1 NF-pNETs, identifying the patients most likely to derive benefit from this treatment will be challenging.