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treated with everolimus or everolimus plus bevacizumab. site. Chemotherapy was well tolerated and outcome results
The overall response rate was 31% and 12% for the were encouraging. Tumor shrinkage was obtained in 44%
combination treatment and everolimus alone, respectively. of the patients, with a median duration of response of 12
The current evidence from this available clinical trial months. Objective response rates recorded in pancreatic,
suggests that combination strategy was more active but not gastrointestinal, and extradigestive NETs were 58%, 25%,
more effective in terms of PFS. [86] and 36%, respectively. Interestingly, disease control was
achieved in 83% of the patients progressing at the time of
Chemotherapy study inclusion. Median PFS was 11 months and OS was
While chemotherapy is the standard of care for aggressive, 21 months. [92]
[87]
poorly differentiated (G3), advanced, or metastatic NECs,
it could represent a therapeutic option in symptomatic Notwithstanding this body of evidence, the number of
and progressive well- or moderately differentiated NETs. patients enrolled in each study was relatively low, thus
Notwithstanding a relatively high number of agents preventing any definitive conclusion on which could be
which have been demonstrated to be active in this latter the best chemotherapeutic strategy for each subset of
tumor setting (platinum salts, 5-fluorouracil, doxorubicin, patients. New multicenter, well designed, randomized
streptozotocin, temozolomide, and capecitabine), the best clinical trials are needed.
chemotherapeutic strategy remains controversial. [88]
CONCLUSION
As far as unresectable or metastatic pancreatic NETs
are concerned, polychemotherapy was more active than About one in seven patients diagnosed with digestive NETs
monotherapy, with a response rate in this latter group presents with metastatic disease at the time of diagnosis,
lower than 20%. A retrospective study evaluating the with the liver being the most frequently involved organ.
combination of streptozotocin (STZ) with doxorubicin Moreover, 25% to 90% of patients who are nonmetastatic
and 5-fluorouracil (5-FU) reported a response rate of at diagnosis are expected to develop metastases during the
39%, with a median response duration of 9.3 months. The course of the disease. In clinical practice, hepatic failure
2-year PFS rate was 41%, and the 2-year OS rate was 74%. represents the primary cause of death in these patients.
Tumor burden clearly affected survival outcomes in both Surgery is the only technique that may permit curability of
univariate and multivariate analyses. In fact, the PFS rate liver involvement. Thus, all treatments should primarily be
at 2 years for patients with LM involving ≤ 75% of the focused on tumor shrinkage, especially when unresectable
parenchyma was 41%, whereas all 12 patients with LM liver lesions could become resectable if reduced in size.
involving more than 75% of the organ had experienced When complete resection is not possible, treatment goals
disease progression by 14.2 months (P = 0.01). At 2 years, should be tumor control and symptom relief.
the OS rate for patients with LM ≤ 75% was 83%, whereas
all 12 patients with LM more than 75% had died at 15.5 Complete resection of primary and metastatic disease (when
months (P = 0.0001). [89] possible) and surgical debulking of symptomatic diseases
are standard procedures for G1 and G2 NETs. To patients
The combination of temozolomide with capecitabine was with Grade 1 or 2 NETs (either pNETs or gastrointestinal
demonstrated to be more active and better tolerated than NETs) with LM and without extra-abdominal metastasis
STZ-based regimens. In a retrospective study enrolling and peritoneal carcinomatosis, surgery permits the best
metastatic pancreatic NETs, objective response rate of results in terms of recurrence-free survival and outcome.
temozolomide combination was reported to be 70%. It Unfortunately only 10-25% of patients can be directly
has to be noted, however, that in this study only 30% of submitted to surgical resection. These considerations
the patients had moderately differentiated (G2) tumors. suggest that “neoadjuvant strategies” should be explored in
[90]
The combination of octreotide LAR 20 mg, metronomic patients with liver-confined metastatic disease. Despite the
capecitabine, and intravenous bevacizumab was explored proven efficacy of different systemic treatment strategies
in the XELBEVOCT phase-II study enrolling 45 patients for metastatic NETs (SSAs, PRRT, chemotherapy, or target
with well- to moderately differentiated NETs from various therapies such as everolimus, sunitinib, and bevacizumab),
primary origins (pancreas, intestinal tract, lungs, and none of these approaches resulted in significant tumor
unknown site). Objective response rate was 17.8% with shrinkage. Few studies have explored systemic therapies
a median PFS of 14.9 months. This study demonstrated in the neoadjuvant setting. Unfortunately, trial designs,
that the combination of SSA plus capecitabine and inhomogeneous inclusion and exclusion criteria, and the
bevacizumab was active and well tolerated in this group relatively low number of patients have hampered definitive
of patients. [91] conclusions in this patient setting.

Finally, a retrospective study evaluated the combination Further research is needed to determine the value of these
of 5-fluorouracil, dacarbazine, and epirubicin in patients medical treatments as a cytoreductive strategy against LM
with well-differentiated NETs originating from pancreas, from NETs. Moreover, loco-regional approaches to LM,
intestine, stomach, gallbladder, kidney, or an unknown such as radiofrequency ablation, laser ablation, or intra-
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦ 299