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(GEP NETs) are classified on the basis of their proliferation (RR) was similar between NECs (40%) and NETs (33%).
[57]
rate as assessed by either mitotic index (MI) and/or nuclear In a more recent Eastern retrospective analysis, 21
Ki67 (WHO 2010). Low-grade or G1 are those with untreated patients with NECs of hepato-biliary-pancreatic
[53]
0-2% Ki67 and/or < 2 MI per 10 high power fields (HPF), tract (with 10 pancreatic NECs), CDDP was administered
intermediate-grade or G2 those with 3-20% Ki67 and/or at 80 mg/m day 1 and VP-16 at 100 mg/m per day for 3
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2-20 MI per 10 HPF, high-grade or G3 those with > 20% days, every 3 weeks. RR was 14%, but with a short PFS
Ki67 and/or > 20 MI per 10 HPF. G1 and G2 are called (1.8 months) and OS (5.8 months) and high toxicity. To
[58]
neuroendocrine tumors (NETs) and G3 neuroendocrine date, some questions still remain: first, the potential role of
carcinomas (NECs). This terminology is only valid alternative regimens to platinum-based chemotherapy, and
for GEP NETs. According to the WHO classification then the homogeneity of the category of NECs in terms
(2004), lung NETs are classified as: typical carcinoids, of biological aggressiveness and chemosensitivity. About
[54]
with < 2 mitoses per 10 HPF and lacking necrosis; atypical any alternative regimens, the experts have suggested
carcinoids, with 2-10 mitoses per 10 HPF and/or punctate that carboplatin instead of cisplatin or irinotecan instead
necrosis; large cell neuroendocrine carcinomas, with > 10 of etoposide are acceptable options for extrapulmonary
mitoses per 10 HPF (median 70), coarse nuclear chromatin NECs. This is based on data from small cell lung cancer
[18]
and extensive necrosis; and small cell carcinomas with > rather than experiences in the NECs, although in a recent
10 mitoses per 10 HPF (median 80), even chromatin and Scandinavian retrospective analysis of over 200 patients
extensive necrosis. Therapeutic options include local with advanced GEP NECs treated with chemotherapy, the
treatments such as surgery, as well as interventional platinum-based regimens (particularly cisplatin versus
radiology and systemic treatments, such as chemotherapy, carboplatin) did not influence the response and survival in
SSAs, interferon α2b, peptide receptor radionuclide a statistically significant way. In this analysis the patients
[19]
therapy and, as only for pancreatic NETs, molecular with Ki67 < 55% were less responsive (15% vs. 42%; P =
targeted agents including everolimus and sunitinib. 0.001) but lived longer (14 vs. 10 months; P < 0.001) than
those with Ki67 > 55 %. On this basis, in patients with
Chemotherapy in neuroendocrine carcinomas NEC and Ki67 < 55% it is possible to consider alternative
Chemotherapy is the most common treatment approach chemotherapy regimens than those which are platinum-
in advanced NECs. Although these neoplasms appear based. Such observations, while respecting the existing
relatively chemosensitive their prognosis is dismail. classifications, could be a starting point for research to
Cisplatin [Compound Danshen Dripping Pills (CDDP)]/ define, within the NECs group, a different category of
etoposide [vepeside-16 (VP-16)] is the most often proposed neoplasms, less aggressive and that, therefore, could be
regimen chemotherapy based on the assumption that the treated in a different way from that usually proposed. A
clinical behavior of NECs is similar to that of lung small recent retrospective publication reported the results about
cell carcinomas. The literature, however, is rather scant in the treatment with CDDP + Irinotecan in 16 patients
this regard and is limited to studies rather dated. In 1991, with advanced GEP NECs. The response rate was 51%,
Moertel et al. treated 45 metastatic NENs patients, 14 median PFS 5.5 months, and OS 10.6 months. A further
[55]
[59]
of which derived from GEP tract. The regimen consisted subgroup of patients with GEP NENs G3 (WHO 2010)
of VP-16 130 mg/m per day for 3 days and CDDP 45 mg/m is represented by morphologically well-differentiated
2
2
per day for 2 days, on days 2 and 3, every 3 weeks. Only 18 neuroendocrine neoplasms while having Ki67 > 20% and/
patients had a NEC. The rate of objective tumor responses or mitosis > 20/10 HPF. Recent reports suggest that these
was clearly different between NECs (67%) and NETs tumors have a better prognosis than other GEP NECs and
(7%). In NECs the time to tumor progression (TTP) was are less responsive to conventional chemotherapies. [60,61]
11 months and OS 19 months, reflecting a still unfavorable Second-line chemotherapy after platinum-containing
prognosis. Since then, CDDP/VP-16 has been considered regimens has not been well defined. Reports of literature
the standard regimen in NEC. In 1999, in a retrospective are very scarce. FOLFIRI regimen was administered in a
[55]
French analysis, 53 patients with advanced NENs received series of 19 patients with GEP NECs who had received
CDDP 100 mg/m per day + VP-16 100 mg/m per day for platinum-based chemotherapy as first-line. Objective
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3 days, every 3 weeks. Forty-one patients had NEC and response rate (ORR) was 31% and tumor control was
20 a neoplasm arising from the GEP tract (13 pancreatic). 62%. In another published experience, temozolomide
[62]
This was first-line chemotherapy in 70% of NEC. The was used as second line, alone or in combination with
response rate, once again, was clearly different between capecitabine +/- bevacizumab. Response rate was 33%,
NECs (42%) and NETs (9%). Median PFS survival was with a median duration of 19 months, PFS 6 months and
9 months in NECs and 2 months in NETs. However, OS OS 22 months. [63]
was 15 months in NECs and 18 months in NETs. A third
[56]
study included 36 patients with advanced NEN of which Chemotherapy in neuroendocrine tumors
only 9 were NECs, while the remaining 27 NENs were In NETs, chemotherapy may be considered in therapeutic
included only due to their rapid clinical progression. The strategy because it can contribute to tumor and symptom
regimen was VP-16 100 mg/m per day for 3 days + CDDP control by reducing extent of disease. Therapy based on a
2
45 mg/m per day for 2 days, every 4 weeks. Response rate single-agent chemotherapy have shown ORR usually not
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦