Treatment options of metastatic and nonmetastatic VIPoma: a review

Obviously, adequate symptomatic therapies, including rebalancing electrolytes, sufficient intravenous fluid substitution and diarrhoea treatment, are the first measures to be taken. Due to the possible cardiac effects of electrolyte deregulation [15], close monitoring (e.g. in the ICU) should be considered. In many cases, treatment with somatostatin analogues improves the patient’s situation by decreasing VIP plasma levels and, as a consequence, reducing the high ileal fluid flow [16, 17]. Somatostatin and somatostatin analogues (SSAs), such as octreotide, are a common treatment for all kinds of well-differentiated NENs (as most NEN cells, including VIPoma, express somatostatin receptors on their surface). The application of steroids, clonidine, loperamide or tincture of opium is usually reserved for patients with diarrhoea and those with no response to SSAs. In some patients, the administration of cinacalcet can be used as a treatment for cystic fibrosis transmembrane conductance regulator (CTFR)-mediated secretory diarrhoea. Chemotherapy and targeted therapy are also part of a symptomatic therapy and are described below.

The combination of streptozotocin (STZ) and 5-FU was established as an effective chemotherapeutic option in patients with well-differentiated and moderately differentiated neuroendocrine neoplasia from the pancreas several decades ago [18, 19]. STZ and its combinations have thereby been described as beneficial in oncological tumour growth as well as hormone symptom control. Consistently, these regimens show efficacy in patients suffering from VIPoma and played a central role in treatment strategies in locally advanced or metastatic diseases [20]. Additionally, other combinations of 5-FU with immunomodulatory agents, such as interferon-alpha, have also been described as effective in both tumour growth and hormone symptom control [21]. Nevertheless, the reported median progression-free survival was between 12 [22] and 16.5 months [23], which is not satisfactory, considering the young median age of the patients. The antisecretory effects of chemotherapy are limited and often delayed. For frail patients in whom other antisecretory treatments fail and who are not suitable for surgery, chemotherapy might be a possible course of treatment.

Recent developments in targeted therapeutics have improved medical treatment options in advanced VIPoma. In 2013, Bourcier and Vinik reported improved symptoms and partial response of tumour masses in a 12-year-old boy with metastatic VIPoma after treatment with sunitinib [24], an inhibitor of multiple receptor tyrosine kinases. In 2015, De Mestier et al. described two more cases in which somatostatin-refractory metastatic VIPoma patients were treated with sunitinib [25]. In general, SSA show both antisecretory effects and antitumoural effects in metastatic NET [26]. The discontinuation of the treatment, however, resulted in a sudden recurrence of symptoms, although the exact underlying mechanism remained unclear. Other therapeutics, such as everolimus, cetuximab and rituximab, have been indicated in case reports as possible effective therapeutic options [27]. In a clinical trial for advanced pancreatic neuroendocrine tumours in general, everolimus showed a antisecretory and tumour stabilising effect (in tumours with ≤ 20% proliferation rate) with a median progression-free survival of 11 months (vs. 4.5 months in placebo group) [28]. The most recent case published by Marquez et al. reported a complete response in a 48-year-old female with metastatic VIPoma and insulin cosecretion to a therapy regimen of lanreotide, temozolomide and capecitabine [29]. Others have reported the successful application of this therapy regimen in metastatic NETs in general [22, 23, 30].

PRRT remains a newly introduced therapeutic option for NEN patients that targets somatostatin receptor 2 and 5 on the surface of the tumour cells. As shown in the NETTE-1 trial, treatment with ¹⁷⁷Lu-Dotatate resulted in a significantly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR in patients with metastatic neuroendocrine tumours of the small intestine [31]. Due to the remarkable objective response rate, PRRT has the potential to reduce tumour load, subsequently hormone-level and finally hormone-dependent clinical symptoms in patients with hormonally active neuroendocrine tumours [32]. Zandee et al. reported an immediate symptom control rate of 80% [33]. Therefore, PRRT remains a potentially valuable therapeutic option in patients suffering from VIPoma.

In general, surgical resection is considered the only curative therapy for nonmetastatic VIPoma [8, 34]. Many case reports have described successful treatment of VIPoma patients via oncological resection of the tumour [35‐38], mostly as distal pancreatectomy or pancreatic head resection. Somatostatin or somatostatin analogues are used perioperatively to prevent cardiovascular complications [39]. For metastatic VIPoma, surgical approaches are considered a possible option but not a standard procedure [8]. The ENETS (European Neuroendocrine Tumor Society) guidelines for functional pancreatic neuroendocrine tumours with metastasis state ‘Surgery is generally contraindicated for locally advanced PanNETs when a macroscopic radical resection cannot be achieved’ [40]. However, the recommendations concern functional pancreatic neuroendocrine tumours, which is a very heterogenous group. Regardless, some publications about the resection of metastatic VIPoma reported promising results. For example, Ueda et al. described successful resection of a VIPoma in the pancreatic tail with paraaortic lymph node metastasis in a 72-year-old female [41]. They performed distal pancreatectomy and paraaortic lymphadenectomy, and no recurrence of the disease was detected at the 11-month follow-up. In another case, a 47-year-old male with one hepatic metastasis of a pancreatic tail VIPoma underwent distal pancreatectomy with splenectomy, the resection of the single hepatic lesion and lymph node dissection [42]; the authors also performed radiofrequency ablation for the hepatic lesion postoperatively. During surveillance, the patient was described as being in better health than before surgery. However, residual hepatic lesions were shown on MRI after 6 months, but the patient was still in good health without tumour progression at more than 18 months after the surgery.

In a recent review focusing on clinicopathological data and treatment modalities for pancreatic VIPoma, which included case reports and case series of 65 patients in total, approximately 50% of all patients showed hepatic metastasis; of those, 23.5% received no treatment of the metastasis, 47.1% underwent surgery, and approximately 30% were treated via ablation [34]. Interestingly, among all included patients, the liver was the only site of metastasis. Nonetheless, lung, lymph node, kidney and bone metastases have been reported [10]. Regarding surgical treatment as an option, some authors support surgical resection in metastatic situations with curative intent if the metastasis is completely resectable (e.g. limited to one liver lobe) [8] or as a tumour debulking procedure with palliative intent [43]. A recent case series of 15 VIPoma patients, including 9 with hepatic metastasis at diagnosis, showed that patients who underwent surgery had a longer overall survival than patients who were treated with other therapeutic modalities (44 vs. 33 months) [44].

It is crucial to separate between cases in which all metastases and the primary tumour are resectable and cases in which complete resection of all lesions is not possible (debulking surgery). Brugel et al. showed in a retrospective analysis of liver metastasis resection (n = 14) immediate symptom control in 100% of cases, with a median progression-free survival (PFS) of 15.3 months. In n = 4 cases, a debulking surgery with palliative intent was performed. Here, an immediate symptom control rate of 75% was achieved with a median PFS of 21.1 months [45].

In general, locoregional treatments are used in addition to surgical resection of the tumour. Locoregional treatments seem to be promising options for hepatic lesions smaller than 3 cm. Usage of transarterial chemoembolisation (TACE) for hepatic metastasis of VIPoma is reported in a few case reports [46, 47]. It seems to be a possible alternative to surgery (in frail patients) or as combination with surgery in a two-step approach (first TACE than surgery). In addition to standard locoregional treatments such as TACE and radiofrequency ablation [42, 48, 49], a case report from 2017 suggested the use of percutaneous irreversible electroporation (IRE) as a treatment option [50].