Chemotherapy is the cornerstone in the treatment of NECs. As the biological characterization is similar to that of small cell lung cancer (SCLC), the European Neuroendocrine Tumor Society guidelines [53, 54] recommend that metastatic gastric NECs, as well as all other gastroenteropancreatic NECs, should be treated in a similar way to SCLC, i.e., with etoposide or irinotecan in combination with platinum compounds such as cisplatin or carboplatin, which is the standard therapy. Although objective remission rates are high (40–67%), median progression-free survival is limited to 4–6 months. These results are difficult to interpret due to the heterogeneity of the treatments and the low number of patients enrolled in the study.

The WHO 2010 classification defines NEC as a poorly differentiated neuroendocrine neoplasm when Ki-67 is >20% and the grade is G3, but this neuroendocrine cancer can be further subclassified on the basis of the Ki-67 value less than or greater than 55%, since it shows different response rates to chemotherapy, as reported in the largest cohort of advanced gastrointestinal-NEC patients ever studied.

NEC patients with Ki-67 index >55% vs. 20–55% responded better to platinum-based chemotherapy (42% vs. 15%, respectively; p <0.05) but nevertheless had a median survival of 10 vs. 14 months. Thirty months after chemotherapy was started, 23% of patients with a Ki-67 <55% were alive, compared with only 7% of those with a Ki-67 ≥55% (p <0.001) [55]. Patients with a primary site in the esophagus, stomach and pancreas responded better than those with a primary site in the colon and rectum (complete response/partial response 44%, 50%, 30%, vs. 16%, 23%, respectively) and showed a better overall survival (median 14, 11, 15, and 8, 10 months, respectively). Cox regression on prognostic baseline factors for survival in patients treated with first-line chemotherapy demonstrated that gastric localization had a better odds ratio [56].

Other agents — such as taxanes, gemcitabine, pemetrexed, and topotecan in very small phase II single-agent studies — have not been encouraging, with global response rates less than 10% [57–61].

Increasing the number of chemotherapic agents (triplet versus doublet therapy, particularly with paclitaxel, etoposide plus carboplatin), although feasible, does not lead to clinical benefits.

Amrubicin has demonstrated to be active with a 22% of response rate in patients with platinum-refractory metastatic NEC and MANEC of the gastrointestinal tract [62].

There is no standard of treatment for second-line chemotherapy in NEC patients. With 29% and 31% response rates, the FOLFOX regimen (folinic acid, 5-fluorouracil and oxaliplatin) [63] and FOLFIRI regimen (folinic acid, 5-fluorouracil and irinotecan) [64] could be considered as a second-line option in poorly differentiated NEC patients after cisplatin-based first-line treatment, but they necessitate further confirmation in future larger prospective studies. Welin et al. reported similar results in a series of 25 patients with mainly gastrointestinal NEC, who had progressed on first-line platinum-based chemotherapy and were treated with temozolomide alone or in combination with capecitabine with or without bevacizumab, with a response rate of 33% [65].

Even though platinum-based treatment has historically shown interesting results in terms of response rate in undifferentiated forms, the real impact on overall survival is minimal, so these results remain controversial and the question of what is the best treatment schedule is still debated. Therefore etoposide plus cisplatin remains a virtual standard of therapy, and its traditional use stems from old studies, with small statistical evidence due to the small number of patients enrolled in clinical trials.

Given the paucity of adequately powered definitive phase III studies incorporating modern response assessments and up-to-date histological subtyping aimed to reducing patient heterogeneity, patients themselves and clinicians should be encouraged to participate in well-designed, prospective clinical trials of chemotherapy or novel targeted therapies [66].