SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018)

Surgery is the only potentially curative therapeutic strategy in these patients. Radical oncological surgery, even in cases with metastatic disease if complete resection is deemed feasible, is indicated except for small (< 1 cm) carcinoids of the stomach, duodenum, appendix or rectum, and small pancreatic insulinomas, in which more conservative surgical or endoscopic resections may be appropriate given their low risk of metastasis [9]. No adjuvant therapy is recommended after complete resection of well-differentiated (G1/G2) NETs (IV, C).

Major cytoreductive surgery with palliative purposes may be indicated when resection of > 90% tumor burden is feasible, especially for patients with hormonal syndrome refractory to medical therapy. Besides the significant clinical benefit in cases with functioning tumors, there are some retrospective data that suggest an impact in terms of survival [10] (IV, B).

In patients with unresectable metastatic disease, palliative surgery may be considered in cases with symptomatic primary tumor, mainly in patients with small bowel NETs. Perioperative prophylactic therapy with somatostatin analogues (SSA) is mandatory in functional tumors to prevent carcinoid crisis. Finally, liver transplantation is still controversial (44–52% 5-year overall survival (OS) rates) but may be considered in highly selected young patients (< 55 years) with well-differentiated liver-only metastases, resected primary tumor and low ki67 index (< 5%), who demonstrated a stable disease status for at least 6 months before organ transplantation [11] (IV, C).

In patients who are not suitable candidates for surgery, regional control of liver metastases may be achieved (50–80% 5-year OS in small retrospective series) by different ablative techniques such as laparoscopic or percutaneous radiofrequency or laser ablation, and cryotherapy, among others [12, 13]. Other locoregional approaches include embolization of the hepatic artery by particles with or without cytotoxic agents (TACE/TAE) or radioactive microspheres (TARE). These therapies may be considered as an alternative approach to systemic therapies, especially for patients with symptomatic/functioning high liver tumor burden. Doxorubicin and mitomycin C are commonly used agents in this context, although adequately sized randomized studies that properly evaluate the benefit–risk ratio of chemoembolization with that of mechanical embolization are still lacking. Clinical responses have been reported in up to 80% of the patients, and radiological responses in about 50%. Embolization is contraindicated in patients with portal-vein thrombosis, liver insufficiency, biliary obstruction or prior Whipple procedure. Radioembolization is an alternative technique of liver-directed therapy (most commonly with yttrium-90 microspheres) with similar clinical results, but prospective randomized trials comparing it to the other liver-directed modalities are lacking [14] (III, C).

SSAs are the first choice of therapy for symptom control in functional GEP–NETs (70–80% of patients experience resolution of diarrhea or flushing, and about 40% achieve biochemical response) (III, A) and they also have antiproliferative activity as demonstrated in two placebo-controlled randomized trials. (I, A) The PROMID study enrolled 85 patients with G1 metastatic midgut NETs, which were randomized to receive octreotide LAR (30 mg/28 days) or placebo. Time to tumor progression was significantly longer in the octreotide LAR group (14.3 months) as compared to patients treated with placebo (6 months) [HR 0.34; 95% confidence interval (CI) 0.20–0.59, p < 0.001]. The greatest effect was observed in patients with low hepatic tumor load and resected primary tumor [15]. No difference was observed, however, in OS among study arms. More recently, the CLARINET study [16] included 204 patients with non-functioning GEP–NETs and ki67 < 10% (45% pancreatic, 36% midgut, 7% hindgut and 13% of unknown primary), that were randomly allocated to receive lanreotide autogel (120 mg/28 days) or placebo [16]. Treatment with lanreotide significantly prolonged progression-free survival (PFS) over placebo (median not reached with lanreotide vs. 18 months with placebo, HR 0.47, p < 0.001). Of note, patients with high liver involvement (> 25%) also benefited from lanreotide. Currently recommended antiproliferative doses are octreotide LAR 30 mg or lanreotide autogel 120 mg every 28 days. Lower starting doses may be used for syndrome control, and then be titrated as needed. Short-acting subcutaneous octreotide may be necessary as rescue treatment for carcinoid syndrome exacerbations. Doses above 120 mg for lanreotide autogel or 30 mg for octreotide LAR are off-label but can sometimes be needed in selected cases. Adverse effects of SSA include malabsorption, hypo or hyperglycemia, hypothyroidism, pain and erythema at the site of injection, hypersensitivity reactions and cholelithiasis on long-term use.

Interferon has some activity in terms of symptomatic control of the hormonal syndrome, but adverse effects limit its widespread use (particularly fatigue, depression, liver toxicity, flu-like syndrome and myelosuppression). Although it may have some antiproliferative activity too, this has not been definitively proven [17], and it is therefore generally indicated after failure of other therapeutic options (III, C).

Systemic chemotherapy is indicated in progressive or bulky advanced panNETs and in G3 NENs. Chemotherapy may be considered in NETs of other sites (lung, thymus, stomach, colon, and rectum) in certain circumstances (e.g., ki67 in the upper G2 range, rapidly progressive disease and/or after failure of other therapies, particularly if somatostatin receptor imaging is negative). In patients with small intestinal primaries, chemotherapy plays a minor role and is generally reserved for patients with progressive disease along with other strategies (III, D).

Chemotherapy combinations most frequently used include streptozocin with either 5-FU or doxorubicin, with overall response rates (ORRs) of 45–69% in older trials (II,B) and 28–42% in more recent ones, and PFS ranging from 16 to 23 months [18]. Other active agents include dacarbazine or temozolomide, Recently, results of a randomized phase II trial showed an increase in progression-free survival (PFS) (from 14.4 to 22.7 months, HR 0.58, p = 0.023) and in survival (38 months vs. not reached, HR 0.41, p = 0.012) with similar response rates (27.8% vs. 33.3%) for the combination of temozolamide and capecitabine as compared to temozolamide alone in panNETs [19] (II, B).

No biomarkers may be currently recommended for routine clinical practice to predict response to chemotherapy. The use of MGMT deficiency as a predictive biomarker of temozolomide activity has not been demonstrated in prospective studies and is not considered standard.

No randomized studies have been performed in lung NETs (typical and atypical carcinoids). Chemotherapy is an option after failure of SSA and everolimus, or in patients with rapidly growing tumors. Temozolomide has been explored in non-randomized studies as well as in combination with oxaliplatin, with PFS ranging from 5 to 20 months [20] (III, B).

Everolimus and sunitinib are approved worldwide for the treatment of advanced well-moderately differentiated NETs based on positive results of placebo-controlled phase III clinical trials. Sunitinib has demonstrated in an international, placebo-controlled phase III clinical study, significantly increased PFS in patients with advanced panNETs (median PFS 11.4 vs. 5.5 months; HR 0.42; 95% CI 0.26–0.66, p < 0.001) (I, A). Recent updated data showed a trend towards an improved OS in favor of sunitinib, with almost 10 months median survival increase compared with placebo (38.6 vs. 29.1 months, HR 0.73; 95% CI 0.50–1.06, p = 0.094) [21]. The RADIANT-3 trial randomized patients with advanced well-moderately differentiated panNETs to receive everolimus or placebo demonstrating an increase of PFS in favor of everolimus (11.0 vs. 4.6 months; HR 0.35; 95% CI 0.27–0.45, p < 0.001). A follow-up reported no significant improvement in OS, but this may be attributed to the fact that > 70% of patients in the placebo arm crossed over to everolimus upon disease progression [22]. The RADIANT-4 trial confirmed the everolimus effectiveness in non-functioning NETs of lung or gastrointestinal origin. PFS was significantly increased with everolimus as compared to placebo (11.0 vs. 3.9 months, respectively, HR 0.48; 95% CI 0.35–0.67, p < 0.00001) [23]. The results obtained by the RADIANT-3 and -4 trials led to the approval of everolimus by regulatory authorities for the treatment of advanced and progressive, well-moderately differentiated, functioning and non-functioning panNETs and for non-functioning gastrointestinal and lung NETs (I, A).

Patients with advanced disease and a positive somatostatin-receptor imaging may be considered for peptide receptor radionuclide therapy (PRRT). PRRT primarily utilizes one of two radioisotopes, yttrium-90 (⁹⁰Y) or lutetium 177(¹⁷⁷Lu), linked to a SSA via the chelating agent 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA).

The phase III NETTER-1 study, conducted in patients with midgut NETs progressive to standard-dose SSA, has shown that lutetium (¹⁷⁷Lu)-DOTATATE, compared to high doses of octreotide, significantly increases the ORR (18 vs. 3%; p < 0.001) and PFS (28.4 vs. 8.5 months; HR 0.21, 95% CI 0.14–0.33, p < 0.0001), with a trend towards improved OS, although data are still immature for definitive conclusions in this regard (median not achieved vs. 27.4 months, HR 0.46, 95% CI 0.14–1.5). In addition, 177Lu-DOTATATE was able to improve the subjective measurement of patient’s quality of life in multiple relevant domains, such as global health status, physical functioning, role functioning, fatigue, diarrhea, pain, disease-related worries and body image. With limited median follow-up, 14 months, the most common grade 3–4 toxicities were lymphopenia (9%) and emesis (7%), with no renal toxicity detected [24].

Large series from reference European centres have reported significant PRRT activity in NETs of primary tumor sites other than the midgut. In this series, the ORR was 30%, PFS was 40 months, OS was 46 months. ORRs were higher in patients with gastrinomas, insulinomas, VIPomas and non-functioning panNETs than in carcinoid tumors. In multivariate analysis, uptake on the OctreoScan (p < 0.01), and Karnofsky performance status > 70% (p < 0.05) were prognostic factors for predicting tumor remission [25].

Therefore, PRRT is indicated in patients with well-differentiated, metastatic, unresectable midgut NETs, in progression to SSA and with positive somatostatin receptors (grade 2–4 scale Krenning). It is also required for the patient to have a good performance status (ECOG < 2), and an adequate renal, hepatic and bone marrow function. (I, A) Its administration to tumors of other primary sites may also be considered although the evidence to support it is not derived from randomized trials (II, B). The appropriate timing of this therapeutic intervention remains to be elucidated.