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vs. 37.2%). CLARINET trial, a double-blind, phase-III III RADIANT-4 trial. The study evaluated everolimus
[72]
study, randomized 204 patients with well- or moderately efficacy in patients with advanced, well-differentiated
differentiated, Octreoscan-positive, nonfunctioning GEP- NETs of different origin and with nonfunctional disease.
NETs to receive lanreotide depot 120 mg monthly versus Patients in the everolimus arm of the study presented a
placebo. SSAs therapy obtained a significant improvement significant improvement in PFS (11.0 vs. 3.9 months).
[81]
in PFS, with a median time not reached in the experimental Interestingly, according to subgroup analysis, the positive
arm versus 18 months in the placebo group. The estimated treatment effect was confirmed irrespective of the extent
rates of PFS at 24 months were 65.1% in the lanreotide of liver metastasis. Objective responses were recorded in
group and 33% in the placebo group. No information on four (2%) patients receiving everolimus and in one patient
disease control rate was reported. [73] (1%) receiving placebo. Disease stabilization was the best
overall response in 165 patients (81%) in the everolimus
Recently, the clinical activity of the new SSA pasireotide group, compared with 62 patients (64%) in the placebo
has been evaluated in an open-label, phase-II study group. The findings of these three studies were consistent
enrolling advanced pancreatic and extrapancreatic Grade with the role of everolimus in prolonging PFS and not in
1 and 2 NETs. Median PFS of the 29 treated patients achieving tumor shrinkage. Thus, everolimus cannot be
[74]
was the primary endpoint of the study and was 11 months. proposed as a preferred therapy in the neoadjuvant setting.
According to the RECIST criteria, one patient obtained a
partial response and 17 experienced disease stabilization, The activity of sunitinib, a multityrosine kinase inhibitor
for a disease control rate of 64%. In all the above-reported of vascular endothelial and platelet-derived growth factor
trials, treatment with SSAs resulted in low cytoreductive receptors, was explored in a double-blind, placebo-
activity as demonstrated by the low objective response controlled, phase-III trial enrolling 171 patients with
rates reported (around 5%). This finding was recently advanced, well-differentiated progressing pancreatic
[82]
confirmed in an extensive review. Thus, while SSAs NETs. The study met its primary endpoint, as median
[75]
can be considered the mainstay of treatment in well- or PFS of patients receiving sunitinib was significantly longer
moderately well-differentiated NETs, both functioning or than that of patients treated with placebo (11.4 vs. 5.5
not, when a disease control is needed, there is no evidence months). In contrast to what was observed in patients with
[83]
to support the use of SSAs in the “neoadjuvant” setting. renal cell carcinoma, tumor shrinkage rate in patients
with pancreatic NET was low; only 9% of those treated
Targeted therapies with sunitinib achieved an objective response according to
Recently, novel targeted therapies such as everolimus and the RECIST criteria.
sunitinib have been introduced in the clinical management
of G1 and G2 NETs. The high rate of vascularization of NETs led to initial
interest in angiogenesis inhibition as a promising field
Following exciting preclinical data demonstrating mTOR of research. Furthermore, an overexpression of vascular
signaling pathway activation in NET cells, everolimus was endothelial growth factor (VEGF) has been observed in
extensively studied in cancer patients. [76-78] both carcinoid and p-NET (either in serum or in tissue),
thus making VEGF and VEGFR excellent targets to be
A randomized, phase-III, double-blind study (RADIANT-3) inhibited. The anti-angiogenetic agent bevacizumab has
[84]
enrolled 410 patients with locally advanced or metastatic been investigated combined with IFNα in a randomized
well- to moderately differentiated pancreatic NETs, phase-II trial of 44 patients with advanced (unresectable
comparing the PFS of patients treated with everolimus or metastatic) carcinoid tumors. Patients were randomized
10 mg/day to that of patients receiving placebo. The to receive 18 weeks of single agent bevacizumab or IFN.
study met its primary endpoint as patients treated with At disease progression or after 18 weeks of treatment,
everolimus presented a longer median PFS (11.0 vs. 4.6 patients were allowed to receive the combination of these
months). Response rate was low, with only 5% of the two treatments. The results obtained in the bevacizumab
patients randomized to receive everolimus achieving a arm were encouraging; a partial response was achieved in
[79]
partial response. Similar encouraging results have been 18% of the patients, with a better 18-week PFS than in the
obtained in the phase-III placebo-controlled RADIANT-2 IFN group (95% vs. 67%, respectively). However, even
[85]
study enrolling patients with well- and moderately though bevacizumab monotherapy has been associated
differentiated locally advanced or metastatic NETs and with improvement in response rate and survival, the
carcinoid syndrome. Patients receiving everolimus plus results obtained in terms of tumor shrinkage were not
SSA (octreotide LAR) presented a longer PFS than those encouraging, probably because of the cytostatic rather than
treated with octreotide LAR plus placebo (16.4 vs. 11.3 cytotoxic effect of antiangiogenic therapies. Therefore,
months, P = 0.026). Overall response rate was similar in the role of bevacizumab-based combination therapy has
both groups, with 2% of patients achieving a partial response been evaluated, mostly with chemotherapy agents or with
and 82% disease stabilization. The advantages of treating mTOR inhibitors in the management of advanced GEP-
[80]
patients with everolimus have recently been confirmed in NETs. In the randomized phase-II study CALGB80701
a randomized, double-blind, placebo-controlled, phase- (Alliance), patients with metastatic pNETs were randomly
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦