Skip to main content

Advertisement

SpringerLink
Log in

Managing Metastatic Extrapulmonary Neuroendocrine Carcinoma After First-Line Treatment

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a rare, aggressive malignancy that can arise from any organ and frequently presents with distant metastases. Advanced disease has a poor prognosis with median overall survival (OS) rarely exceeding 1 year even with systemic therapy. The management paradigm of advanced/metastatic EP-NEC has been extrapolated from small cell lung cancer (SCLC) and commonly consists of 1st line therapy with etoposide and platinum (cisplatin or carboplatin), followed by alternative cytotoxic regimens at the time of progression. Only a minority of patients are able to receive 2nd line therapy, and cytotoxics derived from the SCLC paradigm such as topotecan or lurbinectedin have very limited activity. We aimed to evaluate emerging therapeutic options in the 2nd and later lines and survey potential future developments in this space.

Recent Findings

After a long period of stagnation in treatment options and outcomes, more promising regimens are gradually being utilized in the 2nd line setting including systemic therapy combinations such as FOLFIRI, FOLFOX, modified FOLFIRINOX, CAPTEM, and, more recently, novel checkpoint inhibitors such as nivolumab and ipilimumab. Simultaneously, advances in the understanding of disease biology are helping to refine patient selection and identify commonalities between NEC and their sites of origin which may eventually lead to additional targeted therapy options.

Summary

While many questions remain, contemporary developments give grounds for optimism that improved outcomes for EP-NEC will soon be within reach.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Smith JD, Reidy DL, Goodman KA, Shia J, Nash GM. A retrospective review of 126 high-grade neuroendocrine carcinomas of the colon and rectum. Ann Surg Oncol. 2014;21:2956–62.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: a SEER database analysis of 162,983 cases. Cancer. 2018;124:807–15.

    Article  PubMed  Google Scholar 

  3. Alheraki SZ, Almquist DR, Starr JS, Halfdanarson TR, Sonbol MB. Treatment landscape of advanced high-grade neuroendocrine neoplasms. Clin Adv Hematol Oncol. 2023;21:16–26.

    PubMed  Google Scholar 

  4. Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39:683–90.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657–64.

    Article  CAS  PubMed  Google Scholar 

  6. Coriat R, Walter T, Terris B, Couvelard A, Ruszniewski P. Gastroenteropancreatic well-differentiated grade 3 neuroendocrine tumors: review and position statement. Oncologist. 2016;21:1191–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kloppel G. Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2011;18(Suppl 1):S1–16.

    Article  PubMed  Google Scholar 

  8. . Eads JR, Halfdanarson TR, Asmis T, Bellizzi AM, Bergsland EK, Dasari A, et al. Consensus recommendations for management of high grade neuroendocrine tumors. Endocr Relat Cancer. 2023;1 Very recent consensus statement from the North American Neuroendocrine Tumor Society concerning gynecologic and gastroenteropancreatic G3 NEN, with detailed discussion of NEC management

  9. Feola T, Centello R, Sesti F, Puliani G, Verrico M, Di Vito V, et al. Neuroendocrine carcinomas with atypical proliferation index and clinical behavior: a systematic review. Cancers (Basel). 2021:13.

  10. Moertel CG, Kvols LK, O'Connell MJ, 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;68:227–32.

    Article  CAS  PubMed  Google Scholar 

  11. Rossi A, Di Maio M, Chiodini P, Rudd RM, Okamoto H, Skarlos DV, et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol. 2012;30:1692–8.

    Article  CAS  PubMed  Google Scholar 

  12. Mitry E, Baudin E, Ducreux M, Sabourin JC, Rufie P, Aparicio T, et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer. 1999;81:1351–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ohmoto A, Fujiwara Y, Horita N, Nakano K, Takahashi S. Platinum-doublet chemotherapy for advanced gastroenteropancreatic neuroendocrine carcinoma: a systematic review and meta-analysis. Discov Oncol. 2022;13:40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Morizane C, Machida N, Honma Y, Okusaka T, Boku N, Kato K, et al. Effectiveness of etoposide and cisplatin vs irinotecan and cisplatin therapy for patients with advanced neuroendocrine carcinoma of the digestive system: the TOPIC-NEC phase 3 randomized clinical trial. JAMA Oncol. 2022;8:1447–55.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhang P, Li J, Li J, Zhang X, Zhou J, Wang X, et al. Etoposide and cisplatin versus irinotecan and cisplatin as the first-line therapy for patients with advanced, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma: a randomized phase 2 study. Cancer. 2020;126(Suppl 9):2086–92.

    Article  CAS  PubMed  Google Scholar 

  16. McGarrah PW, Leventakos K, Hobday TJ, Molina JR, Finnes HD, Westin GF, et al. Efficacy of second-line chemotherapy in extrapulmonary neuroendocrine carcinoma. Pancreas. 2020;49:529–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sorbye H, Welin S, Langer SW, Vestermark LW, 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;24:152–60.

    Article  CAS  PubMed  Google Scholar 

  18. McNamara MG, Frizziero M, Jacobs T, Lamarca A, Hubner RA, Valle JW, et al. Second-line treatment in patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma: a systematic review and meta-analysis. Ther Adv Med Oncol. 2020;12:1758835920915299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9:389–93.

    Article  CAS  PubMed  Google Scholar 

  20. Hadoux J, Walter T, Kanaan C, Hescot S, Hautefeuille V, Perrier M, et al. Second-line treatment and prognostic factors in neuroendocrine carcinoma: the RBNEC study. Endocr Relat Cancer. 2022;29:569–80.

    Article  CAS  PubMed  Google Scholar 

  21. Yeung HM, Sreekrishnanilayam K, Meeker C, Deng M, Agrawal S, Abdullah H, et al. Comparative outcomes of second-line topoisomerase-I inhibitor therapies on neuroendocrine carcinoma. J Gastrointest Cancer. 2022;

  22. Patel SP, Mayerson E, Chae YK, Strosberg J, Wang J, Konda B, et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: high-grade neuroendocrine neoplasm cohort. Cancer. 2021;127:3194–201.

    Article  CAS  PubMed  Google Scholar 

  23. Klempner SJ, Gershenhorn B, Tran P, Lee TK, Erlander MG, Gowen K, et al. BRAFV600E mutations in high-grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov. 2016;6:594–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yamaguchi T, Machida N, Morizane C, Kasuga A, Takahashi H, Sudo K, et al. Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system. Cancer Sci. 2014;105:1176–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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;19:751–7.

    Article  CAS  PubMed  Google Scholar 

  26. . McNamara MG, Swain J, Craig Z, Sharma R, Faluyi OO, Wadsley J, et al. NET-02: A multicenter, randomized, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC). J Clin Oncol. 2022;40:4005. A recently reported comparative trial of 5-fluorouracil/folinic acid/nal-IRI vs. docetaxel in platinum-refractory NEC

    Article  Google Scholar 

  27. . Walter T, Lievre A, Coriat R, Malka D, Elhajbi F, Di Fiore F, et al. Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet Oncol. 2023;24:297–306. A newly published comparative trial of FOLFIRI vs. FOLFIRI + bevacizumab in platinum-refractory NEC

    Article  CAS  PubMed  Google Scholar 

  28. Hadoux J, Malka D, Planchard D, Scoazec JY, Caramella C, Guigay J, et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocr Relat Cancer. 2015;22:289–98.

    Article  CAS  PubMed  Google Scholar 

  29. Walter T, Tougeron D, Baudin E, Le Malicot K, Lecomte T, Malka D, et al. Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: are they really heterogeneous? Insights from the FFCD-GTE national cohort. Eur J Cancer. 2017;79:158–65.

    Article  CAS  PubMed  Google Scholar 

  30. Zhu J, Strosberg JR, Dropkin E, Strickler JH. Treatment of high-grade metastatic pancreatic neuroendocrine carcinoma with FOLFIRINOX. J Gastrointest Cancer. 2015;46:166–9.

    Article  PubMed  Google Scholar 

  31. Hadoux J, Afchain P, Walter T, Tougeron D, Hautefeuille V, Monterymard C, et al. FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin. Dig Liver Dis. 2021;53:824–9.

    Article  CAS  PubMed  Google Scholar 

  32. Eads JR, Catalano PJ, Fisher GA, Rubin D, Iagaru A, Klimstra DS, et al. Randomized phase II study of platinum and etoposide (EP) versus temozolomide and capecitabine (CAPTEM) in patients (pts) with advanced G3 non-small cell gastroenteropancreatic neuroendocrine neoplasms (GEPNENs): ECOG-ACRIN EA2142. J Clin Oncol. 2022;40:4020.

    Article  Google Scholar 

  33. Chan DL, Bergsland EK, Chan JA, Gadgil R, Halfdanarson TR, Hornbacker K, et al. Temozolomide in grade 3 gastroenteropancreatic neuroendocrine neoplasms: a multicenter retrospective review. Oncologist. 2021;26:950–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Olsen IH, Sorensen JB, Federspiel B, Kjaer A, Hansen CP, Knigge U, et al. Temozolomide as second or third line treatment of patients with neuroendocrine carcinomas. Sci World J. 2012;2012:170496.

    Article  Google Scholar 

  35. 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;117:4617–22.

    Article  CAS  PubMed  Google Scholar 

  36. Kobayashi N, Takeda Y, Okubo N, Suzuki A, Tokuhisa M, Hiroshima Y, et al. Phase II study of temozolomide monotherapy in patients with extrapulmonary neuroendocrine carcinoma. Cancer Sci. 2021;112:1936–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bongiovanni A, Liverani C, Pusceddu S, Leo S, Di Meglio G, Tamberi S, et al. Randomised phase II trial of CAPTEM or FOLFIRI as SEcond-line therapy in NEuroendocrine CArcinomas and exploratory analysis of predictive role of PET/CT imaging and biological markers (SENECA trial): a study protocol. BMJ Open. 2020;10:e034393.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhang P, Li S, Li J, Shen L, Lu M. Nab-paclitaxel plus bevacizumab for patients with previously treated, metastatic neuroendocrine carcinomas (NEC): a multicenter, open-label, phase II trial interim results. Eur Neuroendocr Tumor Soc (ENETS). 2023;2023

  39. Apostolidis L, Bergmann F, Jager D, Winkler EC. Efficacy of topotecan in pretreated metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma. Cancer Med. 2016;5:2261–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Olsen IH, Knigge U, Federspiel B, Hansen CP, Skov A, Kjaer A, et al. Topotecan monotherapy in heavily pretreated patients with progressive advanced stage neuroendocrine carcinomas. J Cancer. 2014;5:628–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Longo-Munoz F, Castellano D, Alexandre J, Chawla SP, Fernandez C, Kahatt C, et al. Lurbinectedin in patients with pretreated neuroendocrine tumours: results from a phase II basket study. Eur J Cancer. 2022;172:340–8.

    Article  CAS  PubMed  Google Scholar 

  42. Desai A, Tella S, McGarrah P, Kommalapati A, Halfdanarson T, Leventakos K. Lurbinectedin in extrapulmonary metastatic neuroendocrine carcinomas. North Am Neuroendocr Tumor Soc (NANETS). 2021;2021

  43. Araki T, Takashima A, Hamaguchi T, Honma Y, Iwasa S, Okita N, et al. Amrubicin in patients with platinum-refractory metastatic neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma of the gastrointestinal tract. Anticancer Drugs. 2016;27:794–9.

    Article  CAS  PubMed  Google Scholar 

  44. Hattori Y, Takasaki H, Ishiyama Y, Aoki J, Numata A, Watanabe R, et al. Amrubicin therapy for platinum-refractory extrapulmonary neuroendocrine carcinoma: retrospective single-center analysis. Ann Oncol. 2015;26:vii112.

    Article  Google Scholar 

  45. Kasahara N, Wakuda K, Omori S, Nakashima K, Ono A, Taira T, et al. Amrubicin monotherapy may be an effective second-line treatment for patients with large-cell neuroendocrine carcinoma or high-grade non-small-cell neuroendocrine carcinoma. Mol Clin Oncol. 2017;6:718–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ebata T, Shimoi T, Bun S, Yunokawa M, Yonemori K, Ishiwata T, et al. Efficacy of amrubicin monotherapy after platinum chemotherapy for non-gastrointestinal extrapulmonary neuroendocrine carcinoma. Ann Oncol. 2016;27:vi147.

    Article  Google Scholar 

  47. Munker S, Vogelhuber M, Bornschein J, Stroszczynski C, Evert M, Schlitt H, et al. EpiCO (epirubicin, cyclophosphamide and vincristine) as treatment for extrapulmonary high-grade neuroendocrine neoplasms. Z Gastroenterol. 2020;58:133–6.

    Article  CAS  PubMed  Google Scholar 

  48. Apostolidis L, Winkler EC, Jäger D. Efficacy and toxicity of combination chemotherapy with cyclophosphamide, vincristine and an anthracycline in patients with metastatic extrapulmonary neuroendocrine carcinoma. Ann Oncol. 2019;30:v571.

    Article  Google Scholar 

  49. Okuyama H, Ikeda M, Okusaka T, Furukawa M, Ohkawa S, Hosokawa A, et al. A phase ii trial of everolimus in patients with advanced pancreatic neuroendocrine carcinoma refractory or intolerant to platinum-containing chemotherapy (NECTOR Trial). Neuroendocrinology. 2020;110:988–93.

    Article  CAS  PubMed  Google Scholar 

  50. Pellat A, Dreyer C, Couffignal C, Walter T, Lombard-Bohas C, Niccoli P, et al. Clinical and biomarker evaluations of sunitinib in patients with grade 3 digestive neuroendocrine neoplasms. Neuroendocrinology. 2018;107:24–31.

    Article  CAS  PubMed  Google Scholar 

  51. Trikalinos N, Pedersen K, Tan B, Amin M, Rama S, Park H, et al. Cabozantinib in high-grade neuroendocrine neoplasms: interim results from a phase II study. Eur Neuroendocr Tumor Soc (ENETS). 2023;2023

  52. Dai Q, Zhang J, Long W, Haybaeck J, Yang Z. Genetic alterations of GI-NECs involving three main signaling pathways. Cancer Med. 2023;

  53. Sun TY, Zhao L, Van Hummelen P, Martin B, Hornbacker K, Lee H, et al. Exploratory genomic analysis of high-grade neuroendocrine neoplasms across diverse primary sites. Endocr Relat Cancer. 2022;29:665–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yachida S, Totoki Y, Noe M, Nakatani Y, Horie M, Kawasaki K, et al. Comprehensive genomic profiling of neuroendocrine carcinomas of the gastrointestinal system. Cancer Discov. 2022;12:692–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Puccini A, Poorman K, Salem ME, Soldato D, Seeber A, Goldberg RM, et al. Comprehensive genomic profiling of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Clin Cancer Res. 2020;26:5943–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. . Capdevila J, Arques O, Hernandez Mora JR, Matito J, Caratu G, Mancuso FM, et al. Epigenetic EGFR gene repression confers sensitivity to therapeutic BRAFV600E blockade in colon neuroendocrine carcinomas. Clin Cancer Res. 2020;26:902–9. A pioneering report of BRAF inhibition in NEC

    Article  CAS  PubMed  Google Scholar 

  57. . Venizelos A, Elvebakken H, Perren A, Nikolaienko O, Deng W, Lothe IMB, et al. The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2021;29:1–14. An important genomic study, providing extensive information on molecular alterations commonly encountered in NEC

    Article  PubMed  PubMed Central  Google Scholar 

  58. Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021;39:273–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. . Sorbye H, Grande E, Pavel M, Tesselaar M, Fazio N, Reed NS, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma. J Neuroendocrinol., The recently published ENETS guidelines provide comprehensive guidance on the management of digestive NEC. 2023;35:e13249.

  60. Elvebakken H, Hjortland GO, Garresori H, Andresen PA, Janssen EAM, Vintermyr OK, et al. Impact of KRAS and BRAF mutations on treatment efficacy and survival in high-grade gastroenteropancreatic neuroendocrine neoplasms. J Neuroendocrinol. 2023:e13256.

  61. Elvebakken H, Venizelos A, Perren A, Couvelard A, Lothe IMB, Hjortland GO, et al. Treatment response and survival according to molecular alterations in 229 patients with high grade gastroenteropancreatic neuroendocrine neoplasms (HG GEP NEN). Eur Neuroendocr Tumor Soc (ENETS). 2022;2022

  62. Knappskog S, Grob T, Venizelos A, Amstutz U, Hjortland GO, Lothe IM, et al. Mutation spectrum in liquid versus solid biopsies from patients with advanced gastroenteropancreatic neuroendocrine carcinoma. JCO Precis Oncol. 2023;7:e2200336.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zakka K, Nagy R, Drusbosky L, Akce M, Wu C, Alese OB, et al. Blood-based next-generation sequencing analysis of neuroendocrine neoplasms. Oncotarget. 2020;11:1749–57.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sorbye H, Kong G, Grozinsky-Glasberg S. PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Endocr Relat Cancer. 2020;27:R67–77.

    Article  CAS  PubMed  Google Scholar 

  65. Zhang J, Kulkarni HR, Singh A, Niepsch K, Muller D, Baum RP. Peptide receptor radionuclide therapy in grade 3 neuroendocrine neoplasms: safety and survival analysis in 69 patients. J Nucl Med. 2019;60:377–85.

    Article  CAS  PubMed  Google Scholar 

  66. Carlsen EA, Fazio N, Granberg D, Grozinsky-Glasberg S, Ahmadzadehfar H, Grana CM, et al. Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study. Endocr Relat Cancer. 2019;26:227–39.

    Article  CAS  PubMed  Google Scholar 

  67. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9.

    Article  CAS  PubMed  Google Scholar 

  68. Paz-Ares L, Chen Y, Reinmuth N, Hotta K, Trukhin D, Statsenko G, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022;7:100408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhen DB, Mayerson E, Chiorean EG, Burgess EF, Swisher EM, Gay CM, et al. SWOG S2012: Randomized phase II/III trial of first line platinum/etoposide (P/E) with or without atezolizumab (NSC#783608) in patients (pts) with poorly differentiated extrapulmonary small cell neuroendocrine carcinomas (NEC). J Clin Oncol. 2022;40 TPS4179-TPS

  70. Riesco Martinez MC, Capdevila Castillon J, Alonso V, Jimenez-Fonseca P, Teule A, Grande E, et al. 496MO Final overall survival results from the NICE-NEC trial (GETNE-T1913): a phase II study of nivolumab and platinum-doublet chemotherapy (CT) in untreated advanced G3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or unknown (UK) origin. Ann Oncol. 2022;33:S769.

    Article  Google Scholar 

  71. Gile JJ, McGarrah PW, Leventakos K, Sonbol MB, Starr JS, Eiring RA, et al. Efficacy of checkpoint inhibitors in combination with chemotherapy in patients with high-grade extrapulmonary neuroendocrine carcinoma. North Am Neuroendocr Tumor Soc (NANETS). 2022;2022

  72. Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37:318–27.

    Article  PubMed  Google Scholar 

  73. Vijayvergia N, Dasari A, Deng M, Litwin S, Al-Toubah T, Alpaugh RK, et al. Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. Br J Cancer. 2020;122:1309–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mulvey C, Raj NP, Chan JA, Aggarwal RR, Cinar P, Hope TA, et al. Phase II study of pembrolizumab-based therapy in previously treated extrapulmonary poorly differentiated neuroendocrine carcinomas: Results of Part A (pembrolizumab alone). J Clin Oncol. 2019;37:363.

    Article  Google Scholar 

  75. Chan DL, Rodriguez-Freixinos V, Doherty M, Wasson K, Iscoe N, Raskin W, et al. Avelumab in unresectable/metastatic, progressive, grade 2-3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials. Eur J Cancer. 2022;169:74–81.

    Article  CAS  PubMed  Google Scholar 

  76. Fottner C, Apostolidis L, Ferrata M, Krug S, Michl P, Schad A, et al. A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC). J Clin Oncol. 2019;37:4103.

    Article  Google Scholar 

  77. Lu M, Zhang P, Zhang Y, Li Z, Gong J, Li J, et al. Efficacy, Safety, and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms: a multiple-center phase ib trial. Clin Cancer Res. 2020;26:2337–45.

    Article  CAS  PubMed  Google Scholar 

  78. Yao JC, Strosberg J, Fazio N, Pavel ME, Bergsland E, Ruszniewski P, et al. Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neoplasms. Endocr Relat Cancer. 2021;

  79. Gile JJ, Liu AJ, McGarrah PW, Eiring RA, Hobday TJ, Starr JS, et al. Efficacy of checkpoint inhibitors in neuroendocrine neoplasms: mayo clinic experience. Pancreas. 2021;50:500–5.

    Article  CAS  PubMed  Google Scholar 

  80. Marcus L, Fashoyin-Aje LA, Donoghue M, Yuan M, Rodriguez L, Gallagher PS, et al. FDA approval summary: pembrolizumab for the treatment of tumor mutational burden-high solid tumors. Clin Cancer Res. 2021;27:4685–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Andreatos N, Iyer G, Grivas P. Emerging biomarkers in urothelial carcinoma: challenges and opportunities. Cancer Treat Res Commun. 2020;25:100179.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, Singh PP, et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors. Clin Cancer Res. 2020;26:2290–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS, et al. Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers. Clin Cancer Res. 2020;26:4454–9.

    Article  CAS  PubMed  Google Scholar 

  84. . Girard N, Mazieres J, Otto J, Lena H, Lepage C, Egenod T, et al. LBA41 Nivolumab (nivo) +/- ipilimumab (ipi) in pre-treated patients with advanced, refractory pulmonary or gastroenteropancreatic poorly differentiated neuroendocrine tumors (NECs) (GCO-001 NIPINEC). Ann Oncol. 2021;32:S1318. The largest and only comparative (vs. nivolumab) trial on the use of ipilimumab + nivolumab in platinum-refractory NEC reported so far

    Article  Google Scholar 

  85. Al-Toubah T, Halfdanarson T, Gile J, Morse B, Sommerer K, Strosberg J. Efficacy of ipilimumab and nivolumab in patients with high-grade neuroendocrine neoplasms. ESMO Open. 2022;7:100364.

    Article  CAS  PubMed  Google Scholar 

  86. Mohamed A, Vijayvergia N, Kurian M, Liu L, Fu P, Das S. Exploring real world outcomes with nivolumab plus ipilimumab in patients with metastatic extra-pulmonary neuroendocrine carcinoma (EP-NEC). Cancers (Basel). 2022:14.

  87. Capdevila J, Teule A, López C, García-Carbonero R, Benavent M, Custodio A, et al. A multi-cohort phase II study of durvalumab plus tremelimumab for the treatment of patients (pts) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic or lung origin: the DUNE trial (GETNE 1601). Ann Oncol. 2020;31(suppl_4):S711–S24.

    Google Scholar 

  88. Uboha NV, Milhem MM, Kovacs C, Amin A, Magley A, Purkayastha DD, et al. Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies. J Clin Oncol. 2019;37:2553.

    Article  Google Scholar 

  89. Shen L, Yu X, Lu M, Zhang X, Cheng Y, Zhang Y, et al. Surufatinib in combination with toripalimab in patients with advanced neuroendocrine carcinoma: results from a multicenter, open-label, single-arm, phase II trial. J Clin Oncol. 2021;39:e16199-e.

    Article  Google Scholar 

  90. Frizziero M, Kilgour E, Simpson KL, Rothwell DG, Moore DA, Frese KK, et al. Expanding therapeutic opportunities for extrapulmonary neuroendocrine carcinoma. Clin Cancer Res. 2022;28:1999–2019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ho KJ, Herrera GA, Jones JM, Alexander CB. Small cell carcinoma of the esophagus: evidence for a unified histogenesis. Hum Pathol. 1984;15:460–8.

    Article  CAS  PubMed  Google Scholar 

  92. Bergsland EK, Roy R, Stephens P, Ross JS, Bailey M, Olshen A. Genomic profiling to distinguish poorly differentiated neuroendocrine carcinomas arising in different sites. J Clin Oncol. 2016;34:4020.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Nikolaos Andreatos, Patrick W. McGarrah & Thorvardur R. Halfdanarson

  2. Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA

    Mohamad Bassam Sonbol

  3. Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA

    Jason S. Starr

  4. Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain

    Jaume Capdevila

  5. Department of Oncology, Haukeland University Hospital, Bergen, Norway

    Halfdan Sorbye

  6. Department of Clinical Science, University of Bergen, Bergen, Norway

    Halfdan Sorbye

Authors
  1. Nikolaos Andreatos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick W. McGarrah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamad Bassam Sonbol
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jason S. Starr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaume Capdevila
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Halfdan Sorbye
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thorvardur R. Halfdanarson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thorvardur R. Halfdanarson.

Ethics declarations

Conflict of Interest

Nikolaos Andreatos and Patrick W. McGarrah declare no conflict of interest. Mohamad Bassam Sonbol is the recipient of research grants from Eli Lilly and Taiho (paid to institution) and has received compensation for consulting services from Novartis. Jason S. Starr has received compensation for consulting services from TerSera, Advanced Accelerator Applications, Pfizer, Taiho, Ipsen, Natera, Tempus, Cancer Expert Now, and Helsinn Therapeutics and support for attending meetings/travel from Camurus. Jaume Capdevila is the recipient of grants/contracts from Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Amgen, and Bayer, has received compensation for consulting services from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Hutchinson Pharma, ITM, Advanz, Merck Serono, Esteve, and Roche and payment or honoraria for lectures/presentations/speakers’ bureaus/manuscript writing/educational events from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Hutchinson Pharma, ITM, Advanz, Merck Serono, Esteve, and Roche. Halfdan Sorbye has received compensation for consulting services from Hutchinson and Advanced Accelerator Applications, payment or honoraria for lectures/presentations/speakers’ bureaus/manuscript writing/educational events from Novartis, Ipsen, Bayer, SAM Nordic, and Pierre Fabre, and has participated on Data Safety Monitoring/Advisory Boards for ITM and Bayer. Thorvardur R. Halfdanarson has received compensation for consulting services from TerSera and Terumo, payment or honoraria for lectures/presentations/speakers’ bureaus/manuscript writing/educational events from OncLive, and has participated on Data Safety Monitoring/Advisory Boards for ITM and Camurus. He currently serves as the Vice President of the North American Neuroendocrine Tumor Society without financial compensation. He has performed consulting services without personal compensation (all fees paid to Mayo Clinic) for Ipsen, Advanced Accelerator Applications, Crinetics, Camurus, TerSera, and Viewpoint Molecular Imaging. Funding for research has been provided to Mayo Clinic on his behalf from Advanced Accelerator Applications, Crinetics, Camurus, and Thermo Fisher Scientific.

Human and Animal Rights and Informed Consent

Not applicable as the study constitutes a literature review.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Andreatos, N., McGarrah, P.W., Sonbol, M.B. et al. Managing Metastatic Extrapulmonary Neuroendocrine Carcinoma After First-Line Treatment. Curr Oncol Rep 25, 1127–1139 (2023). https://doi.org/10.1007/s11912-023-01438-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-023-01438-w

Keywords

Search

Navigation