Advertisement

Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: Are they really heterogeneous? Insights from the FFCD-GTE national cohort

      Highlights

      • Large cell type GEP-NEC and advanced stage at diagnosis are predominant.
      • Prognosis is mainly impacted by performance status, NSE and tumour burden.
      • First-line platinum-etoposide allows 50% of response and 6.2 months of PFS.
      • Second-line treatment has low efficacy and must be improved.

      Abstract

      Background

      Diagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC.

      Patients and methods

      All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded.

      Results

      253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0–1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20–100). Median overall survival was 15.6 (13.6–17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE>2 upper limit of normal [ULN]; HR = 3.2), CgA>2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72).

      Conclusions

      We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bosman F.T.C.F.
        • Hruban R.H.
        WHO Classification of tumours of the digestive system.
        IARC, 2010, Lyon2010
        • Sobin L.H.G.M.
        • Wittekind C.
        TNM Classification of malignant tumours.
        7th ed. Wiley-Blackwell, 2010
        • Yao J.C.
        • Hassan M.
        • Phan A.
        • Dagohoy C.
        • Leary C.
        • Mares J.E.
        • et al.
        One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States.
        J Clin Oncol. 2008; 26: 3063-3072
        • Lepage C.
        • Bouvier A.M.
        • Phelip J.M.
        • Hatem C.
        • Vernet C.
        • Faivre J.
        Incidence and management of malignant digestive endocrine tumours in a well defined French population.
        Gut. 2004; 53: 549-553
        • Korse C.M.
        • Taal B.G.
        • van Velthuysen M.L.
        • Visser O.
        Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry.
        Eur J Cancer. 2013; 49: 1975-1983
        • Sorbye H.
        • Strosberg J.
        • Baudin E.
        • Klimstra D.S.
        • Yao J.C.
        Gastroenteropancreatic high-grade neuroendocrine carcinoma.
        Cancer. 2014; 120: 2814-2823
        • Mitry E.
        • Baudin E.
        • Ducreux M.
        • Sabourin J.C.
        • Rufie P.
        • Aparicio T.
        • et al.
        Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin.
        Br J Cancer. 1999; 81: 1351-1355
        • Moertel C.G.
        • Kvols L.K.
        • O'Connell M.J.
        • Rubin J.
        Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms.
        Cancer. 1991; 68: 227-232
        • Hadoux J.
        • Malka D.
        • Planchard D.
        • Scoazec J.Y.
        • Caramella C.
        • Guigay J.
        • et al.
        Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma.
        Endocr Relat Cancer. 2015; 22: 289-298
        • Hentic O.
        • Hammel P.
        • Couvelard A.
        • Rebours V.
        • Zappa M.
        • Palazzo M.
        • et al.
        FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3.
        Endocr Relat Cancer. 2012; 19: 751-757
        • Welin S.
        • Sorbye H.
        • Sebjornsen S.
        • Knappskog S.
        • Busch C.
        • Oberg K.
        Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy.
        Cancer. 2011; 117: 4617-4622
        • Heetfeld M.
        • Chougnet C.N.
        • Olsen I.H.
        • Rinke A.
        • Borbath I.
        • Crespo G.
        • et al.
        Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms.
        Endocr Relat Cancer. 2015; 22: 657-664
        • Brenner B.
        • Tang L.H.
        • Klimstra D.S.
        • Kelsen D.P.
        Small-cell carcinomas of the gastrointestinal tract: a review.
        J Clin Oncol. 2004; 22: 2730-2739
        • Velayoudom-Cephise F.L.
        • Duvillard P.
        • Foucan L.
        • Hadoux J.
        • Chougnet C.N.
        • Leboulleux S.
        • et al.
        Are G3 ENETS neuroendocrine neoplasms heterogeneous?.
        Endocr Relat Cancer. 2013; 20: 649-657
        • Faggiano A.
        • Sabourin J.C.
        • Ducreux M.
        • Lumbroso J.
        • Duvillard P.
        • Leboulleux S.
        • et al.
        Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas: diagnostic and prognostic features.
        Cancer. 2007; 110: 265-274
        • Garcia-Carbonero R.
        • Sorbye H.
        • Baudin E.
        • Raymond E.
        • Wiedenmann B.
        • Niederle B.
        • et al.
        Consensus guidelines for high grade gastro-entero-pancreatic (GEP) neuroendocrine tumours and neuroendocrine carcinomas (NEC).
        Neuroendocrinology. 2016; 103: 186-194
        • Strosberg J.R.
        • Coppola D.
        • Klimstra D.S.
        • Phan A.T.
        • Kulke M.H.
        • Wiseman G.A.
        • et al.
        The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas.
        Pancreas. 2010; 39: 799-800
        • Sorbye H.
        • Welin S.
        • Langer S.W.
        • Vestermark L.W.
        • Holt N.
        • Osterlund P.
        • et al.
        Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.
        Ann Oncol. 2013; 24: 152-160
        • Olsen I.H.
        • Sorensen J.B.
        • Federspiel B.
        • Kjaer A.
        • Hansen C.P.
        • Knigge U.
        • et al.
        Temozolomide as second or third line treatment of patients with neuroendocrine carcinomas.
        ScientificWorldJournal. 2012; 170496
        • Strosberg J.R.
        • Fine R.L.
        • Choi J.
        • Nasir A.
        • Coppola D.
        • Chen D.T.
        • et al.
        First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas.
        Cancer. 2011; 117: 268-275