Grade 3 poorly differentiated neuroendocrine carcinomas (G3 NEC) are rare diseases. The
      diagnosis is often done at the metastatic stage and the prognosis is poor. The standard
      first-line treatment is the platinum-etoposide chemotherapy regimen, mostly based on
      retrospective studies .With this regimen, response rate (RR) is 40 to 70% but the median
      progression-free survival is between 4 and 9 months. Disease progression almost always occurs
      during or just after treatment and median overall survival (OS) is only about 12-15 months
      for gastro-entero-pancreatic (GEP) NEC with similar efficacy of either cisplatin or
      carboplatin in the NORDIC study and of 8 to 10 months for pulmonary NEC. After progression,
      only 40 to 45% of patients will receive a second line chemotherapy which will include
      5-fluoro-uracil (5FU) and irinotecan (FOLFIRI or oxaliplatin (XELOX, FOLFOX).This second line
      treatment can provide around 30% of responses and a median progression-free survival of 4
      months. Taken together, these data indicate a major medical need for improving G3 NEC
      treatments.

      Few trials have tried to challenge the standard platinum-etoposide first-line treatment.
      Clinical trials challenging the platinum-etoposide combination in the first-line setting
      feasibility has already been demonstrated with paclitaxel-carboplatin-etoposide combination
      and the cisplatin-irinotecan phase III trials. However, these trials have shown equivalent
      activities between experimental group and platinum-etoposide regimen. Furthermore, the lack
      of randomization precluded any definitive conclusion. Therefore, prospective randomized
      studies aiming at improving first-line chemotherapy remains challenging and clinically
      meaningful. Currently, the only randomized trial in progress in first line treatment of
      metastatic G3 GEP NEC compares platinum-etoposide to temozolomide-capecitabine. Other
      mono-arm phase II studies evaluate carboplatin - nab-paclitaxel and everolimus - temozolomide
      combinations. FOLFIRINOX is also planned to be evaluated in a mono-arm first or subsequent
      line setting at Lee. H Moffit Cancer Institute.

      Although the second-line treatment studies of metastatic G3 NEC of GEP or unknown origin were
      retrospective, they have suggested that both irinotecan and oxaliplatin, in conjunction with
      5FU can have anti-tumor effect in G3 NEC. In recent years, the intensified chemotherapy
      regimen FOLFIRINOX, which associates 5FU, oxaliplatin and irinotecan, has shown great
      efficacy in several digestive cancer such as pancreas or colorectal adenocarcinoma. Tolerance
      of this regimen has improved over the years with better management and dose adaptations that
      has led to the development of the mFOLFIRINOX regimen . mFOLFIRINOX could be a good
      first-line treatment candidate in metastatic GEP NEC because: (i) Oxaliplatin, irinotecan and
      5FU have anti tumor effect in metastatic GEP NEC; (ii) trichemotherapy with a potential high
      RR could be efficient in these chemosensitive cancers; (iii) the degradation of performance
      status following tumor progression after first-line treatment makes access to a second line
      uncertain which argue for the use of an aggressive first-line treatment; (iiii)
      administration on a one-day outpatient basis (day hospital) as well as acceptable and
      manageable side effects, could have an impact on quality of life in these patients with a
      poor prognosis. the hypothesis is that the intensive trichemotherapy mFOLFIRINOX, improves
      the prognosis of patients with metastatic G3 NEC from GEP or unknown primary.

      Little is known on the predictive factors of first-line chemotherapy in metastatic G3 NEC and
      few trials have tried to challenge the platinum-etoposide standard. Among G3 NEC, there are 2
      histological subtypes; eg. small cell NEC (SCNEC) and large cell NEC (LCNEC). These two
      subtypes are treated with the same platinum-etoposide regimen, whatever the primary, although
      RR seem to differ between SCNEC and LCNEC. This difference has been reported for pulmonary G3
      NEC: the RR to platinum-etoposide was 34% in the French phase II trial on LCNEC and 37% in a
      recent retrospective study, while the RR of SCNEC was 50 to 60% in different reports.
      Moreover, the difference in RR to platinum based chemotherapy has also been recently reported
      in a Japanese retrospective study of pancreatic NEC with RR of 68 and 44% for SCNEC and LCNEC
      respectively.

      These results suggest that there could be some biological differences among G3 NEC, which
      could be responsible for the different responses to treatment and that G3 NEC could be a
      heterogeneous group of tumors. While pulmonary SCNEC are fairly homogeneous tumors and are
      characterized by a quasi-constant Rb loss of expression, LCNEC are more heterogeneous. A
      sequencing study of 45 pulmonary LCNEC samples has shown that 40% of the tumors had a
      mutational profile which looks like small cell lung cancer (SCLC) while 58% of the tumors had
      a mutation profile like those found in non-small cell lung cancer (NSCLC) (Rekhtman et al.
      2016). According to their molecular profiles, LCNEC could be divided between "NSCLC-like" and
      "SCLC-like" tumors. "SCLC-like" tumors were characterized by p53 and Rb inactivating
      mutations while "NSCLC-like" tumors were characterized by p53 inactivating mutations but also
      KRAS and STK11 mutations like those found in lung adenocarcinomas. Therefore, when
      considering the pulmonary NEC model, it could be hypothesized that, among LCNEC, some tumors
      may be "adenocarcinoma-like" and some other may be really "SCNEC-like". This hypothesis is
      supported by some data from digestive tract G3 NEC. Rb loss of expression is found in 100% of
      SCNEC of the colon versus 31% of LCNEC of the colon; Rb loss is also found in 89% of SCNEC
      versus 60% of LCNEC of the pancreas . These data seem to parallel the pulmonary NEC data and
      suggest that G3 NEC, especially LCNEC, is a heterogeneous group of tumors with some of them
      being biologically very close to SCNEC with Rb loss and others being more biologically close
      to adenocarcinoma. G3 SCNEC are probably more homogeneous but some heterogeneity is also
      possible within this group because the pathological diagnosis of "large"versus "small cell"
      is challenging. This has led to the hypothesis that LCNEC could arise from different cell of
      origin, i.e; from neuroendocrine precursors and/or from trans-differentiation of
      adenocarcinoma cells as already described in prostate and lung cancer while SCNEC would
      represent the bona fide poorly differentiated NEC.

      Taking together the putative biological heterogeneity of G3 NEC and the need, in clinical
      practice, for more effective chemotherapy regimen, it can be hypothesized that a more
      "tailored" chemotherapy regimen is needed for G3 NEC patients. This is supported by the
      retrospective analysis from the Dutch registry of pulmonary NEC which have suggested that
      "NSCLC-like" chemotherapy regimen without pemetrexed were more effective than "SCLC-like"
      chemotherapy regimen for the treatment of pulmonary LCNEC. Moreover, the same group has
      recently reported that the better efficacy of "NSCLC-like" chemotherapy was observed for
      pulmonary LCNEC without Rb mutation (the so-called "NSCLC-like" tumors in the Rekhtman et al
      study) while Rb mutated LCNEC did not have significantly different response to "SCLC-like"
      and "NSCLC like" chemotherapy regimens. This has also been shown in pancreatic LCNEC with a
      RR to first-line platinum-based chemotherapy of 80% in case of Rb loss of expression, and
      38.4% in case of retained Rb expression.