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Table 2: Principal studies with inhibitors of mTOR
Author/trials Regimen Patients enrolled Results Adverse reactions
(grade > 3)
Yao et al. RADIANT-1 Stratum 1: everolimus Metastatic P-NETs after Stratum 1: mPFS: 9.7 Stomatitis, diarrhea
[64]
Stratum 2: everolimus progression months
plus octreotide LAR Stratum 2: mPFS:
(Phase II) 16.7 months
Pavel et al. [66] RADIANT-2 Everolimus plus Advanced NETs with carcinoid mPFS: 16.4 vs. 11.3 Stomatitis, diarrhea,
(Phase III) octreotide LAR vs. syndrome after progression months fatigue
placebo plus octreotide
LAR
Fazio et al. [67] Everolimus plus Low- to intermediate-grade mPFS: 13.6 vs. 5.6 Stomatitis, rash,
octreotide LAR vs. advanced lung NETs months diarrhea, fatigue
RADIANT-2 (Phase III)- placebo plus octreotide
exploratory analysis LAR

Yao et al. RADIANT-3 Everolimus vs. placebo Advanced P-NETs after mPFS: 11.0 vs. 4.6 Stomatitis, diarrhea,
[65]
(Phase III) progression months fatigue, nausea, rash
mTOR : mammalian target of rapamycin; P-NETs: primitive neuroendocrine tumors; mPFS: median progression free survival;
LAR: long-acting release
Table 3: Anti-IGF-R1 drugs in NETs

Author/trials Regimen Patients enrolled Results Adverse reactions
(grade > 3)
Naing et al. [99] Cixutumumab plus Advanced solid tumors pre- SD = 47% Hyperglycemia,
(Phase I) temsirolimus treated (neuroendocrine tumors) hypertriglyceridemia,
hypercholesterolemia,
thrombocytopenia,
mucositis
Rothenberg et al. [100] Ganitumumab Advanced solid tumors pre- PR = 20% Diarrhea
(Phase I) treated (neuroendocrine tumors) SD = 80%

Strosberg et al. [101] Ganitumumab Metastatic progressive No objective responders Hyperglycemia,
(Phase II) carcinoid or P-NETs by RECIST. mPFS = 6.3 neutropenia,
months: 10.5 months for thrombocytopenia,
carcinoid patients, and 4.2 infusion reaction
months for P-NET patients.
OS rate at 12 months =
66%: mOS = NR
IGF: insulinlike growth factor; NETs: neuroendocrine tumors; SD: stable disease; PR: partial response; P-NETs: primitive
neuroendocrine tumors; RECIST: response evaluation criteria in solid tumors; mPFS: median progression free survival; OS: overall
survival; mOS: median overall survival; NR: not reached
[49]
If presented on tumor cells’ surface, the blockage of shown by Rinke et al. in the PROMID study, advanced
SSTRs operates directly on cell proliferation, stimulating midgut NENs gained an advantage in time to progression,
antimitotic and apoptotic activities. SSAs also induce cell response rate, and risk reduction of tumor progression
growth inhibition with indirect activities (not requiring from use of octreotide long-acting release (LAR)
SSTR neoplasm expression), [40-44] such as angiogenesis compared to placebo. Furthermore, octreotide LAR also
inhibition and immunomodulation mechanism, mediated extends overall survival (OS), but only in the subgroup of
by stimulation of the production of natural-killer cells and patients with metastatic midgut NETs and a low hepatic
[51]
blockage of growth factors. [45-48] load (≤ 10% at study entry) . [Table 1a]
The results of two international studies (PROMID, Recently, the CLARINET trial enrolled nonfunctioning
using octreotide, and CLARINET trial, using lanreotide) GEP-NENs randomized to receive depot lanreotide
represent the principal reason for using SSAs as first- or placebo and demonstrated an improvement in PFS
line medical and systemic therapy in GEP tumors or for patients in the treatment arm [Table 1a]. Due these
neuroendocrine tumors of unknown origin, especially significant data, octreotide LAR and depot lanreotide
for data about progression-free survival (PFS). [49,50] As have been approved as treatment for patients with newly
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦