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The choice of which targeted agent should be used first Locoregional therapies: is there an impact on
still remains a challenge for physicians dealing with patients’ survival?
advanced pNETs. No comparative study of everolimus In some cases (especially with a functional syndrome)
versus sunitinib in this setting is available yet. Thus, when a complete resection is not possible, debulking
since phase III trials have demonstrated a similar surgery can be performed to improve prognosis and quality
efficacy in terms of PFS, the choice is mainly based on of life. This approach can be based on the combination
the evaluation of other elements, including the toxicity of surgery on primary and secondary tumors and loco-
profile, patients’ comorbidity, and physician’s expertise regional treatments (i.e., trans-arterial liver embolization,
with these drugs. An additional point of interest that TAE; trans-arterial chemoembolization, TACE;
should be considered, besides the physician’s personal radiofrequency ablation). Embolization is contraindicated
clinical experience when managing these drugs, is the in patients with portal vein thrombosis, liver insufficiency,
larger population of NET patients treated with everolimus biliary obstruction or prior Whipple procedure. The
in comparison with sunitinib reported in the literature. In presence of portal vein occlusion or ascites hepatic tumor
fact, more than 600 advanced NET patients have been burden > 75% of the total liver are considered relative
[32]
treated in the RADIANT trials, [25,26,28] in comparison with contraindications. In a retrospective study in patients
the 86 patients included in the sunitinib trial. [27] with pNETs, chemoembolization showed better results
when compared with bland embolization (response: 50%
G3 NECs: is platinum-based chemotherapy vs. 25%, respectively). However, no clear difference
[33]
always required? between TAE and TACE in terms of clinical outcome has
According with the WHO 2010 classification, the been reported so far.
[1]
group of G3 NECs were identified with a proliferation
index (Ki67) > 20% (or > 20 mitotic count per 10 HPF). Another experimental approach to metastatic disease is
International guidelines [29] suggest the use of platinum- selective internal radiation therapy (SIRT), based on the
based systemic chemotherapy in G3 NEC patients due intra-arterial deliver of Yttrium-90 microspheres to the
to the rapidly metastatic behavior of these tumors, and lesions. Although results seem appealing, they are from
the extremely poor prognosis in comparison with other retrospective series, and a recent study comparing this
NETs with lower proliferative activity (G1 and G2). technique to TAE and TACE over a 10-year period did
However, this category constitutes a heterogeneous not show any advantages of SIRT in terms of time to
[34]
group of diseases, including both well-differentiated and disease progression.
poorly differentiated tumors based on morphological The wide range in response rates and survival duration
features, with different implications in terms of patients’ in various studies in terms of patient population and
prognosis and therapeutic approach. [30,31] Overall, tumor profile, the extent of liver involvement, and
median PFS reported with platinum-based first-line the presence of extra-hepatic metastases is reflection
approach ranges from 4 to 9 months. [31] However, this of the heterogeneous tumor biology of this disease.
data mostly derives from non-randomized trials, with Gupta et al. [33] found that patients treated with liver
small series of patients evaluated by a retrospective embolization with carcinoid tumors had a higher
design approach, and usually enrolling a heterogeneous response rate (66.7% vs. 35%; P < 0.0001), longer time
series of patients in terms of therapeutic schedules and to progression (TTP) (22.7 months vs. 16.1 months, P
biological features of the tumor (primary site, staging, < 0.046), and better OS (33.8 months vs. 23.2 months;
Ki67 index). P < 0.012) compared to patients with pNETs. Roche et
al. [35] found non-pancreatic NETs (P < 0.006), absence
Data reported by the Nordic group study proposes to of extra-hepatic lesions (P < 0.03), unresected primary
[31]
consider G3 NECs with Ki67 < 55%, as a different entity (P < 0.012) and TACE as first-line (P < 0.028) were
that exhibits less aggressive behavior and responds well significant for complete response to liver emoblization,
to platinum-based chemotherapy, in comparison with and less hepatic involvement (< 30%) significantly
other G3 NECs. This specific subgroup of patients might improved morphological response (P < 0.016). There
be considered as a separate disease in which therapeutic is no conclusive evidence in the literature that the loco-
approaches other than platinum-based should be tested. regional therapies improve survival rate.
Indeed, the role of everolimus in G3 NECs is under
investigation in phase II trials in several different clinical CONCLUSION
settings (MAVERIC- EudraCT: 2014-003951-72, www.
clinicaltrials.gov, NCT0211380, www.clinicaltrials.gov Despite recent advances in the knowledge of digestive
NCT02248012). NETs, there are still many controversial aspects about
the management of these patients. There is a dire need
Further prospective studies are required before for further multicenter studies designed to clarify gray
considering therapeutic options based on targeted agents areas such as the sequence of medical therapies in patients
as the standard treatments in G3 NECs. with advanced disease, the opportunity for a conservative
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦ 307