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study [17] described, in 42 metastatic patients treated by severe kidney toxicity was observed in 4.2% of patients,
octreotide long-acting repeatable (LAR) 30 mg, a median a toxicity not reported in the regulatory trials, where no
progression-free survival (PFS) of 14.3 months vs. 6 patients pre-treated with PRRT had been enrolled. To date,
months of the 43 cases enrolled in the placebo group. The no conclusive data on the optimal therapeutic sequence
more recent CLARINET trial [18] showed, in 101 patients involving PRRT is available and caution should be used
with digestive NET using lanreotide 120 mg, a median when considering everolimus therapy in patients who have
PFS not reached vs. 18 months of the 103 included in the previously received PRRT.
placebo group. Both studies highlight the increased anti-
proliferative activity of these drugs in patients with low Targeted therapies: everolimus or sunitinib
Ki67 (G1 NETs or G2 NETs with Ki67 < 10%), stable first?
slow-growing disease, and high somatostatin receptor Another relevant option for digestive NETs is targeted
expression as assessed by functional imaging. Alternative therapy. Recent trials have demonstrated the activity of
medical treatments should be considered if these criteria the mTOR inhibitor everolimus (RAD001, Afinitor ,
®
are not satisfied. Novartis Oncology) against tumor growth. In the
RADIANT-3 trial, [25] a phase III placebo-controlled
Peptide receptors radionuclide therapy (PRRT): study enrolling advanced pNETs, everolimus provided a
is there a place as a first-line approach? significant prolongation in median PFS vs. placebo (11
PRRT acts with the same molecular mechanism as SSAs, and 4.6 months; 207 and 203 patients, respectively). The
but the somatostatin analog is radiolabeled with Y90 or results of this trial led to approval by the U.S. Food and
Lu177, performing an “in loco” radiotherapy. This well- Drug Administration (FDA) and the European Medicines
tolerated treatment is able to inhibit tumor growth in up to Agency (EMA) for the treatment of locally advanced,
50-70% of digestive NETs. [19-21] metastatic or unresectable pNETs. [24] Its activity has also
been reported in progressive, well-differentiated, non-
Results from the first Phase III, multicenter randomized functioning lung and non-pancreatic digestive NETs,
clinical trial (RCT) comparing Lutathera vs. Octreotide based on the findings of the RADIANT-4 RCT. [26] This
®
in patients with inoperable, progressive, somatostatin study showed a significant benefit with everolimus in
receptor-positive G1-G2 small intestinal NETs these patients, with median PFS being 11 months in the
(NETTER-1 trial) have been recently presented at the treatment arm (n = 205) vs. 3.9 months in the placebo
last ECC (Vienna, September 2015) (www.clinicaltrials. group (n = 97) (HR: 0.64, P = 0.037). [26] The most
gov NCT01578239). [21] They showed that, in 230 patients common adverse events reported in the phase III RCTs
enrolled, the median PFS was not reached in the PRRT- (Radiant 3-4) (> 30%) were stomatitis (62%, 64%),
treated group vs. 8.4 months obtained by SSA [hazard rash (37%, 49%), fatigue (31%, 31%) and diarrhea
ratio (HR): 0.21, P < 0.0001]. This data supports the (27%, 34%), while grade 3/4 treatment-related adverse
benefit of this therapy in metastatic small intestinal NETs, events were stomatitis (7%, 7%), anemia (1%, 6%), and
and hopefully will help achieve official registration of hyperglycemia (5%, 5%). Overall, grade 3-4 toxicity
this drug. [21] was reported in approximately 5-8% of patients. This
data suggests caution when using everolimus in patients
All international guidelines (ENETS, NANETS, ESMO, with diabetes, in whom an optimal glucose control is
and NCCN) consider PRRT as a valid option in patients mandatory before beginning the treatment.
with advanced NETs; however, there are no solid
data supporting where PRRT should be placed in the Sunitinib (Sutent , Pfizer) is another targeted therapy,
®
therapeutic sequence. A recent multicenter Italian study effective for the treatment of advanced pNETs. It is an
on the compassionate use of everolimus in advanced antiangiogenic, pan-receptor tyrosine kinase inhibitor,
NETs highlighted the increasing risk of severe toxicity in acting against multiple targets including VEGFR,
patients who had been previously treated with PRRT or PDGFR, c-KIT, Flt-3 and RET. In the phase III RCT
chemotherapy, thus suggesting the early use of everolimus published in 2011, it prolonged PFS to 10.2 months vs.
in patients with advanced NETs. Furthermore, Bajetta et 5.4 with placebo. The most common adverse events
[27]
[22]
al. treated patients with everolimus in combination with reported in the sunitinib trial were diarrhea (59%),
[23]
octreotide LAR as first line approach in advanced NETs nausea, fatigue, vomiting (35%) and fatigue (32%), while
and showed that in this setting, this combination treatment the most frequent grade 3/4 treatment-related included
is very effective with disease control being reached in neutropenia (12%), hypertension (10%), and palmar-
92% of patients. This therapy also has an excellent safety plantar erythrodysesthesia (6%). Notably, because
profile, with only one single grade 4 adverse event in patients with severe cardiac comorbidities had not been
the population of 50 patients enrolled. Conversely enrolled in this study, caution should be exercised when
[23]
in a relatively small series of NET patients treated with using sunitinib in patients with a significant cardiac
everolimus after previous failure of PRRT, Kamp et al. history (e.g., arrhythmia, coronary artery disease,
[24]
reported an overall safety profile similar to that presented cardiomyopathy, uncontrolled hypertension). Grade 3-4
in the randomized clinical trials. However in this trial, toxicity was present in up to 12% of patients.
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦