Patients with advanced EP-NECs are usually treated with platinum-based chemotherapy regimens in first-line setting. However, many options have been evaluated in second-line setting, but none with robust literature evidence, with data mainly coming from several small retrospective studies in which amrubicin , temozolomide  , S-1 , oxaliplatin , irinotecan , EpiCO (epirubicin, cyclophosphamide, and vincristine)  and taxanes  have been tested.
Hentic et al described the efficacy of irinotecan in this setting of patients retrospectively analyzing a population of 19 patients affected by PD-NEC and observing DCR of 62% with 31% partial response, 31% of stable disease, PFS and OS of 4 and 18 months, respectively. However, in that context, only 5 patients presented a Ki-67 ≥ 55%, while the majority of the population (14 patients, 74%) had a Ki-67 < 55% . A recent analysis demonstrated Ki-67 = 55% as the best cut-off value concerning response rate and survival. Besides, data from the NORDIC NEC trial showed that patients with Ki-67 < 55% had a lower response rate (15% versus 42%, P < 0.001), but paradoxically better survival than those with Ki-67 ≥ 55% . Based on this evidence, no consistent data concerning the impact of IRI-CT on EP-NECs with higher Ki-67 are available in the second-line setting.
To the best of our knowledge, this is the largest study aiming at evaluating the efficacy and feasibility of IRI-CT in a cohort of patients with pretreated NEC. In the last 12 years, in the four cancer centers that participated in this retrospective analysis, 34 patients affected by EP-NECs received IRI-CT after progression to first-line platinum plus etoposide chemotherapy. Twenty-seven of them had a Ki-67 ≥ 55% while four had Ki-67 < 55% (for three patients data was not available). Our population showed a DCR of 44.1% with 17.6% PR and 26.5% SD with median PFS and OS of 4.4 months and 5.9 months respectively. According to the retrospective nature of this study, survival outcomes appear significantly worse than literature evidence . This difference should be probably attributed to the different populations of patients enrolled, with a higher proliferative index and probably a more aggressive disease. Nevertheless, our results show the anti-tumor activity of irinotecan also in patients with higher Ki-67, but without an important gain in OS, underling the worse prognosis of this subgroup of patients.
Besides the Ki-67 value, also liver involvement and colorectal primary location tend to negatively impact survival: data showed a moderately difference in OS between patients with and without liver metastases and worse prognosis in patients with NEC arising from the colorectal district, as already demonstrated by Sorbye et al. . However, data did not reach statistical significance, probably due to an exiguous sample of patients analyzed.
This is the first study in which the prognostic significance of serum inflammatory biomarkers is evaluated in patients with NECs. While PLR and NLR did not impact OS and PFS, in our casuistry, lower LMR seems to be associated with poorer PFS, although it did not correlate with poorer OS. This data must be deeply explored in a larger and dedicated trial in order to assess possible major impact on outcome and clinical medical history.
As far as safety is concerned, adverse events were predominantly graded 1–2, and no treatment-related deaths were observed. As described by Sugiyama et al , our data support the good tolerance of IRI-CT with only minor treatment delay.
An interesting point is that, despite a cohort of patients affected by such an aggressive disease, 66% of patients received further systemic treatments, thus demonstrating the feasibility of a third-line treatment.
We have also to outline that the limitation of our study may be related to the retrospective nature of the analysis with relatively small sample size and without an independent pathological review.
However, we presume the reported data may have value due to the rarity of the disease prompting larger studies on irinotecan as second-line treatment for PD-NECs, particularly in those patients with high Ki-67 which still have an unacceptable prognosis.
Currently, there are several ongoing prospective trials aiming at evaluating the most efficacious chemotherapy schedule for second-line PD-NEC: SENECA trial (ClinicalTrials.gov Identifier: NCT03387592) in which FOLFIRI is compared to a combination of capecitabine and temozolomide; BEVANEC trial (ClinicalTrials.gov Identifier: NCT02820857) testing the efficacy of bevacizumab in combination with FOLFIRI vs FOLFIRI alone; NET-02 trial (ClinicalTrials.gov Identifier: NCT03837977) in which the standard second-line for SCLC (docetaxel) is compared to liposomal irinotecan (nal-IRI) and 5-fluorouracil/folinic acid; the EVINEC trial (ClinicalTrials.gov Identifier: NCT02113800) designed to test everolimus in NEC and NET G3 after the failure of first-line platinum-based chemotherapy; cabozantinib in combination with nivolumab/ipilimumab (ClinicalTrials.gov Identifier: NCT04079712) and avelumab (AVENEC ClinicalTrials.gov Identifier: NCT03147404) have been recently evaluated. Final data of the above studies should clarify the best clinical approach to such aggressive carcinomas.