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higher than 20%, and so these are generally reserved to on a group of heterogeneous NENs in terms of the site
chemonaïve patients when the clinical condition does not of primary tumor and biology (well differentiated,
allow therapy with multiple agents. Poly-chemotherapy progressive on biotherapy, poorly differentiated). This
regimens have shown greater activity as evidenced by study indicates that oxaliplatin may be effective, both in
numerous phase II studies and retrospective analyses. digestive NETs and extra-digestive, especially low-grade.
Drugs with activity in this setting belong to the class of The role of oxaliplatin was studied by another group in
[67]
alkylating agents [streptozotocin dacarbazine (TMZ)], a retrospective analysis of a heterogeneous population in
anti-metabolites (5-fluorouracil, capecitabine) and, terms of primary tumor, biology, and disease progression
more recently, oxaliplatin. Streptozotocin (STZ) is one at baseline. All patients except one had a low-grade
of the drugs most commonly proposed in patients with tumor according to 2000 WHO classification but Ki67
pancreatic NETs (pNETs), but it is not marketed in Italy. was only available in 4 of 20 patients. There was a RR
It has been much criticized due to its toxicity, especially of 84%, 7 months for PFS and 23 months for OS. More
renal and because some studies have reported very high recently, another group explored the activity and toxicity
ORR but based on often questionable evaluation methods of oxaliplatin-based chemotherapy in an Italian muticenter
of response. The most reliable study had 84 pNETs “real world” study. A heterogeneous population of 78
[64]
patients treated with a combination of 5-fluorouracil (5- NENs with well-detailed tumour characterization was
FU), adriamicin, and STZ with a 39% partial response analyzed between 1999-2013 and found that an oxalipatin-
(PR) but 20% had moderate-to-severe toxicity, especially based regimen to be active and well-tolerated, including in
in terms of neutropenia and asthenia. previously treated patients. [68]

Dacarbazine has been used in a mixed population in Italy Metronomic chemotherapy
in combination with 5-FU and epirubycin with 30% partial The various way of chemotherapy administration currently
response rate. The same combination used in a mixed represents an interesting issue. The NENs are highly
[65]
population of patients, predominantly pretreated, with low vascularized neoplasms so angiogenesis plays a key role
grade tumors and an intermediate proliferation index. The in the growth of these tumors. For this reason, metronomic
result was a good disease control and the demonstration chemotherapy, defined as continuous administration
that chemotherapy may also be active in patients with non of a low-dose chemotherapeutic drug, could have an
pNETs, GEP, NETs, and non-GEP NETs. [20] antiangiogenic-reducing effect. One group 5-FU with
octreotide LAR, reaching 23 months TTP in patients
Recently, new combinations have been tested in phase II with GEP NETs. The same group has also shown that
[69]
trials. Temozolomide is an alkylating agent used in NETs due expression of thymidylate synthase, an enzyme involved
to its oral use. There are some retrospective and prospective in the metabolism of 5-FU, reduces time to progression
studies showing activity but, because of the small number (TTP) and OS in patients with GEP NETs treated with
of patients involved and the variety of regimens used, it is 5-FU. A phase II single arm trial with metronomic
[70]
difficult to recommend the best regimen. Interesting results capcitabine in combination with octreotide LAR and
have emerged from a retrospective analysis published bevacizumab has been used in patients with intestinal
in 2011 in association with capecitabine in pNETs naïve NENs. The study was conducted from 2006 to 2009 in
[23]
for any type of chemotherapy. The high response rate 5 centers and included 45 patients with well/moderately
[66]
(70%) and low toxicity led to a prospective phase II differentiated, locally advanced or metastatic disease,
study conducted in the US to validate this combination. from various origins. Some were chemonaive and were
Methylguanine-methyltransferase (MGMT) is an enzyme progressing on SSA or radioreceptor therapy. Metronomic
that acts by methylating oxygen in position 8 of guanine, capecitabine was administered at a fixed dose of 2,000
allowing repair of damage induced on DNA and making mg per day in combination with octreotide LAR 20 mg
the expression of the enzyme inversely proportional to the every 4 weeks and bevacizumab at 5 mg/kg, intravenously,
response to the TMZ itself. In a retrospective analysis of 97 every 2 weeks. There was a > 80% (PR + stable disease),
patients with NETs (pancreatic, intestinal, lung carcinoid especially in patients with GEP NENs, but when responses
tumors) treated with TMZ, the authors showed that the were analyzed for the primary tumor site a higher RR
lack of expression of MGMT is more common in pNETs in patients with pancreatic neuroendocrine neoplasms
than in carcinoids and demonstrated a partial response (pNENs) was observed than those with extrapancreatic
rate of 34% in pNETs and only 2% in carcinoids. These NENs. Temozolomide was used with a metronomic
[21]
observations suggest that the state of MGMT could be schedule as well. The dose was 100 mg daily continuously
a potential predictor of response to alkylating agents in in combination with bevacizumab and octreotide LAR in
NETs and therefore that studies of MGMT in tumor tissue a group of 15 patients with low-grade NEN (Ki67 < 20%)
are needed. of various origins, functioning and non-functioning, and
progressive on at least first-line therapy. Partial responses
As regards the platinum derivatives, in 2006 a clinical were 57% with 9 months TTP. It is noteworthy that 47%
[24]
study conducted by Italian Trials in Medical Oncology of patients had pNEN and 67% had an NEN with Ki67 less
[22]
evaluated the combination of capecitabine and oxaliplatin than or equal to 5%. The authors conclude that the very
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦ 317