Table 1 A summary of currently used therapy modalities (systemic and liver loco-regional) for advanced GEP NETs, indicating reference studies for each one, and frequent side effects

Octreotide LAR

Rinke et al. 2009 [10], PROMID study

Intestinal NETs F/NF (85)

Randomized phase III

PFS

14.3 months vs 6 months with placebo

Diarrhea, flatulence, cholelithiasis

Lanreotide autogel

Caplin et al. 2014 [11], CLARINET study

NF Intestinal/ Pancreatic NETs (204)

Randomized phase III

PFS

Median not reached vs 18 months with placebo

Diarrhea, flatulence, cholelithiasis, hyperglycemia

Interferon

Oberg et al. 2012 [15]

GEP NETs, carcinoid syndrome

Review

Clinical and biochemical response, tumor effect

Symptoms relief up to 70%, biochemical response 50–60%, SD up to 70%

Flu-like symptoms, chronic fatigue, liver toxicity, bone marrow suppression, depression, autoimmune-related conditions

Everolimus

Yao et al., 2008 [21], RADIANT-1 study

PNET (160)

Single-arm (± sandostatin) phase II

Response rate

8.7% objective response rate; 84.7% stable disease

Pavel et al., 2011 [23], RADIANT-2 study

Intestinal NETs (420)

Randomized phase III

PFS

16.4 months vs 11.3 months with placebo

Stomatitis, rash, fatigue, diarrhea, nausea, infections, fever, cytopenia, edema, hyperglycemia, dyspnea, pneumonitis

Yao et al., 2011 [23], RADIANT-3 study

PNETs (410)

Randomized phase III

PFS

11 months vs 4.6 months with placebo

Yao et al. 2016 [24], RADIANT-4 study

Lung/Intestinal NETs (302)

Randomized phase III

PFS

11 months vs 3.9 months with placebo

Sunitinib

Raymond et al. 2011

Pancreatic NETs (171)

Randomized phase III

PFS

11.4 months vs 5.5 months with placebo

Diarrhea, nausea, asthenia, vomiting, fatigue, HTN, neutropenia, stomatitis, palmar-plantar erythrodysesthesia

Telotristat ethyl

Pavel et al. 2015 [16], TELESTAR study

Carcinoid syndrome (135)

Randomized phase III

Reduction in daily bowel movements

Mean reduction of 1.7–2.1 BM/day (dose dependent) vs 0.9 with placebo

Nausea, abdominal pain, vomiting, fatigue, infections, increased LFTs

PRRT

Strosberg et al. 2017 [33], NETTER-1 trial

Intestinal NETs (229)

Randomized phase III

PFS

PFS at 20 months 65.2% vs 10.8% with SSA alone

Nausea, vomiting, renal impairment, marrow toxicity

STZ-5FU

Dilz et al. 2015 [40];

Clewemar et al. 2016 [41]

pNETs (96)

pNETs (133)

Retrospective

PFS

19.4 months

23 months

Nausea, fatigue, kidney toxicity, bone marrow suppression

CAPTEM

Strosberg et al. 2011 [45];

Fine et al. 2013 [46]

pNETs (30)

GEP NETs (18)

Retrospective

PFS

18 months

14 months

Fatigue, nausea, myelosuppression, palmar-plantar erythrodysesthesia

TACE

Grozinsky-Glasberg et al. 2018 [54]

NETs (57)

Retrospective

PFS

14 months

Fever, leukocytosis, abdominal pain, nausea, elevated liver enzymes (post embolization syndrome), carcinoid crisis, liver failure, cholecystitis, liver abscess

SIRT

Kennedy et al. [55]

NETs (158)

Retrospective

Imaging response

SD 22.7%, PR 60.5%, CR 2.7%, PD 4.9%

Fatigue, nausea, pain, ascites,