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appears promising. Even though Y-90 radio-embolization a promising strategy to enhance resectability of metastatic
[60]
may achieve a survival benefit, especially in patients lesions. 5-FU or capecitabine has been used in many of
presenting with significant tumor shrinkage, however, this the numerous trials investigating the effects of external
technique is not easily available, especially in outlying beam radiotherapy with chemotherapy. Also, Y-90 labeled
hospitals. [51] antibody radioimmunotherapy in combination with 5-FU
as radiosensitizer was found to be feasible and safe.
[18]
Long-term outcome analysis after SIRT indicated treatment The combination therapy of PRRT and oral everolimus
response in 62.7% of the patients, disease stabilization in was less effective than 177-Lu-DOTATATE only in the
32.5%, and a survival rate of 45.0% at 3 years. Findings rat pancreatic CA20948 tumor model. Despite the low
[61]
from an international multicenter prospective treatment toxicity, a caveat is the limited access to this therapy in
registry showed that safety and response rates of SIRT Europe, the USA, and Japan. Rare side effects of treatment
[52]
and TACE were similar when evaluated at 6 months. At can adversely affect the kidney and bone marrow.
12 months, the group receiving SIRT had a significantly
lower response rate than the group receiving TACE SYSTEMIC TREATMENT
(46% vs. 66%). It should be noted that portal vein
[46]
thrombosis and impaired liver function are not considered Immunotherapy
contraindications to SIRT, as they are for TACE and A potential role of interferon alpha (IFNα) has been
TA. Adverse events associated with SIRT included lung explored in several studies: an older comprehensive
shunting of beads, radiation gastritis, duodenal ulceration, review reported an overall response rate of 20%,
[62]
and hepatic fibrosis. Finally, the SIRT procedure is not whereas some small-sized retrospective and randomized
considered pharmaco-economically advantageous. [53] trials have reported an improvement of PFS and OS. [63-65]
However, these benefits in outcome were not confirmed in
PRRT other studies. The combination of IFNα with continuous
[66]
infusion of 5-fluorouracil was explored in a phase-II study
PRRT is a form of molecular targeted therapy which uses a of patients with rapidly progressive NETs, and an overall
small peptide (a somatostatin analog similar to octreotide) response rate of 41.6 was achieved. Other studies
[67]
coupled with a radionuclide emitting beta radiation. This enrolling limited patient series have demonstrated the role
therapy can be proposed only to patients with somatostatin of immunotherapy/immunochemotherapy in obtaining a
receptor expressing NETs. In phase II studies PRRT was significant shrinkage of LM from NETs. [68-70] However,
demonstrated to obtain objective response rates in 20-35% further investigations are needed to better define whether
of treated patients. [54-57] Thus, it could have a potential role immunotherapy or immunochemotherapy could have a
as a cytoreductive preoperative therapy, as demonstrated role as a neoadjuvant strategy in NETs.
by several case reports in patients with GEP-NETs. [55-57]
The most important positive predictive factor for response Biotherapy
to PRRT was the ratio of radiolabel uptake on diagnostic In well- and moderately differentiated somatostatin
scans (normal to tumor). In a retrospective analysis, receptor expressing NETs, the mainstay of treatment
complete and partial tumor remission was reported in consists of somatostatin analogue (SSA) administration,
2% and 28% of 310 patients, respectively, who received made manageable with long-acting repeatable (LAR)
177Lu-DOTATATE treatment for various histologic types formulations. [71] Therapy with SSAs represents
of metastasized NETs. Of those patients, 89% had the standard of care in patients with metastasized,
[58]
hepatic metastases, with extensive and moderate liver nonresectable midgut NETs, pancreatic NETs, or NETs of
involvement in 27% and 62%, respectively. The median unknown origin, whether associated or not with hormone
time to progression was 40 months, and the median OS hypersecretion and regardless of the hepatic tumor burden.
from the first treatment cycle was 46 months. The OS from Randomized phase-III, multicenter trials demonstrated
initial diagnosis was 128 months, yielding a survival benefit that LAR octreotide and lanreotide depot can significantly
of 40 to 72 months compared with historical cohorts. prolong PFS in a heterogeneous population of patients
[58]
Extensive hepatic metastatic involvement is a significant with GEP-NETs. [72,73] Therapy with SSAs, however,
negative predictive factor for progression-free survival did not demonstrate reduction of tumor load. The best
(PFS) or OS with PRRT. A phase-3 trial comparing PRRT clinical response obtained in all these studies was disease
[58]
and octreotide was presented at the 2015 18th-ECCO-40th- stabilization.
ESMO Congress. In this first prospective randomized
[59]
study in patients with progressive metastatic midgut NETs, PROMID trial enrolled 85 treatment-naive patients with
177Lu-DOTATATE was superior to octreotide 60 mg in well-differentiated G1 advanced midgut or unknown
terms of PFS (not reached vs. 8.4 months, P < 0.0001) and origin NETs, randomizing them to receive either
overall response rate (19% vs. 3%, P < 0.0004). Interim placebo or intramuscular octreotide LAR every 4 weeks
analysis suggests increased OS (13 vs. 22 deaths), to be (Sandostatin LAR ). Patients treated with octreotide LAR
TM
confirmed by final analysis. The combination of PRRT presented a longer time to tumor progression (14.3 vs. 6
with radiosensitizing chemotherapy has been considered months) and a higher disease stabilization rate (66.7%
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦ 297