Outcomes of patients with metastatic neuroendocrine lung neoplasms: typical versus atypical carcinoids

ABSTRACT

Introduction: Well-differentiated neuroendocrine pulmonary tumours (NETp) are morphologically classified as typical carcinoid (TC) and atypical carcinoid (AC). There are limited data on systemic treatment for metastatic disease. Objective: Our study evaluated the median progression-free survival of patients with metastatic tumours, comparing TC and AC status for different treatments. Methods: Retrospective series of patients with metastatic NETp treated from 2002 to 2019 in a large cancer centre were analysed. Our primary endpoint was progression-free survival according to morphological classification (TC vs. AC). All patients received at least one treatment modality (e.g., somatostatin analogue [SSA], chemotherapy [ChP], and everolimus [Eve]). Variables were analysed using the chi-square test, median progression-free survival (mPFS) rates (months), with comparisons evaluated by the log-rank test. Results: Twenty-seven patients were included: 44% with TC and 56% with AC. TC patients were on average 58-years-old, 83.3% were female, and 33.3% received more than one treatment. AC patients were on average 61-years-old, 66.7% were female, and 20% received more than one treatment. All patients were treated more frequently with SSA (TC: 75% vs. AC: 80%, p=0.756). Cisplatin and etoposide were the most frequent ChP regimen (TC: 75% vs. AC: 30%, p=0.248). Patients with TC and AC treated with SSA had higher mPFS in months (TC mPFS SSA: 14.5, Eve: 2.50, ChP: 4.0, SSA + Eve: 4.50; AC mPFS SSA: 7.50, Eve: 4.50, ChP: 7.50, SSA + Eve: 7.00). Conclusion: Although the statistical analyses did not show a significant difference between treatment, numerically, more patients with TC or AC experienced tumor control with SSAs, where the mPFS pairs showed a possible tendency to differentiate themselves from the other regimes (Eve and ChP).

RESUMO

Introdução:Os tumores neuroendócrinos pulmonares bem diferenciados (TNPs) são morfologicamente classificados como carcinoide típico (CT) e carcinoide atípico (CA). Os dados são limitados sobre o tratamento sistêmico para a doença metastática. Objetivo: Nosso estudo avaliou a sobrevida livre de progressão mediana de pacientes com tumores metastáticos, comparando o TC e o status de AC para diferentes tratamentos. Métodos: Foram analisadas séries retrospectivas de pacientes com TNPs metastático tratados, de 2002 a 2019, em um grande centro de câncer. Nosso endpoint primário foi a sobrevida livre de progressão de acordo com a classificação morfológica (CT vs. CA). Todos os pacientes receberam pelo menos uma modalidade de tratamento (por exemplo, análogo de somatostatina [SSA], quimioterapia [QT] e everolimus [Eve]). As variáveis foram analisadas pelo teste do qui-quadrado, taxas da mediana da sobrevida livre de progressão (SLPm) (meses), com comparações avaliadas pelo teste de log-rank. Resultados: Vinte e sete pacientes foram incluídos: 44% com CT e 56% com CA. Os pacientes com CT tinham em média 58 anos, 83,3% eram mulheres e 33,3% receberam mais de um tratamento. Os pacientes com CA tinham em média 61 anos, 66,7% eram mulheres e 20% receberam mais de um tratamento. Todos os pacientes foram tratados com maior frequência com SSA (CT: 75% vs. CA: 80%, p=0,756). A cisplatina e o etoposídeo foram os regimes de QT mais frequentes (CT: 75% vs. CA: 30%, p=0,248). Pacientes com CT e CA tratados com SSA tiveram maior mPFS em meses (TC SLPm SSA: 14,5, Eve: 2,50, QT: 4,0, SSA + Eve: 4,50; CA SLPm SSA: 7,50, Eve: 4,50, QT: 7,50, SSA + Eve: 7,00). Conclusão: Embora as análises estatísticas não tenham mostrado uma diferença significativa entre os tratamentos, numericamente, mais pacientes com CT ou CA tiveram controle do tumor com SSAs, onde os pares de mPFS mostraram uma possível tendência de se diferenciar dos outros regimes (Eve e QT).

Keywords:

Carcinoid tumor - Typical carcinoid - Atypical carcinoid - Everolimus - Somatostatin analogue - Chemotherapy - Adjuvant/ Neuroendocrine tumor.

Descritores:

Carcinoma espinocelular de cabeça e pescoço - Sobrevivência - Polimorfismo Genético - DNA - Gene.

Publication History

Received: 07 April 2020

Accepted: 10 September 2020

Article published online:
18 January 2021

• REFERENCES

• Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E. et al A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 2018; Aug; 31: 1770-1786 https://doi.org/10.1038/s41379-018-0110-y
• Travis WD.. The concept of pulmonary neuroendocrine tumours. Travis WD, Brambilla E, Burke A, Muller-Hermelink HK, Harris CC. Pathology and genetics of tumors of the lung, pleura, thymus, and heart. Lyon (France): IARC Press; 2004
• Hung YP.. Neuroendocrine tumors of the lung: updates and diagnostic pitfalls. Surg Pathol Clin 2019; Dec; 12 (01) 1055-1071
• Travis WD.. Lung tumours with neuroendocrine differentiation. Eur J Cancer 2009; 45 (Suppl 1): 251-266
• Travis WD, Gal AA, Colby TV, Klimstra DS, Falk R, Koss MN.. Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 1998; Mar; 29 (03) 272-279
• Ferolla P, Daddi N, Urbani M, Semeraro A, Ribacchi R, Giovenali P. et al Tumorlets, multicentric carcinoids, lymph-nodal metastases, and longterm behavior in bronchial carcinoids. J Thorac Oncol 2009; Mar; 4 (03) 383-387
• Chong CR, Wirth LJ, Nishino M, Chen AB, Sholl LM, Kulke MH. et al Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors. Lung Cancer 2014; Nov; 86 (02) 241-246
• Quinn AM, Chaturvedi A, Nonaka D.. High-grade neuroendocrine carcinoma of the lung with carcinoid morphology: a study of 12 cases. Am J Surg Pathol 2017; Feb; 41 (02) 263-270
• Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E. et al Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016; Mar; 387 (10022): 968-977
• Beasley MB, Thunnissen FB, Brambilla E, Hasleton P, Steele R, Hammar SP. et al Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000; Oct; 31 (10) 1255-1265
• Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M. et al Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001; Jun; 119 (06) 1647-1651
• Scott WJ.. Surgical treatment of other bronchial tumors. Chest Surg Clin N Am 2003; Feb; 13 (01) 111-128
• Modlin IM, Lye KD, Kidd M. A. 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; Feb; 97 (04) 934-959
• Stueven AK, Kayser A, Wetz C, Amthauer H, Wree A, Tacke F. et al Somatostatin analogues in the treatment of neuroendocrine tumors: past, present and future. Int J Mol Sci 2019; Jun; 20 (12) 3049
• Rai U, Thrimawithana TR, Valery C, Young SA.. Therapeutic uses of somatostatin and its analogues: current view and potential applications. Pharmaco Therapeut 2015; Aug; 152: 98-110
• Tsoukalas N, Baxevanos P, Aravantinou-Fatorou E, Tolia M, Galanopoulos M, Tsapakidis K. et al Advances on systemic treatment for lung neuroendocrine neoplasms. Ann Transl Med 2018; Apr; 6 (08) 146 https://doi.org/10.21037/atm.2018.04.03
• Gosain R, Mukherjee S, Yendamuri S, Iyer R.. Management of typical and atypical pulmonary carcinoids based on different established guidelines. Cancers 2018; Dec; 10 (12) 510
• Aparicio T, Ducreux M, Baudin E, Sabourin JC, Baere T, Mitry E. et al Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. Eur J Cancer 2001; May; 37 (08) 1014-1019
• Sullivan I, Le Teuff G, Guigay J, Caramella C, Berdelou A, Leboulleux S. et al Antitumour activity of somatostatin analogues in sporadic, progressive, metastatic pulmonary carcinoids. Eur J Cancer 2017; Apr; 75: 259-267
• Grozinsky-Glasberg S, Shimon I, Korbonits M, Grossman AB.. Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms. Endocr Relat Cancer 2008; Sep; 15 (03) 701-720
• Yau H, Kinaan M, Quinn SL, Moraitis AG.. Octreotide long-acting repeatable in the treatment of neuroendocrine tumors: patient selection and perspectives. Biol Targets Ther 2017; Dec; 11: 115-122
• Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE. et al Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; Dec; 378 (9808) 2005-2012
• Hendifar AE, Marchevsky AM, Tuli R.. Neuroendocrine tumors of the lung: current challenges and advances in the diagnosis and management of well- differentiated. J Thorac Oncol 2017; Mar; 12 (03) 425-436
• Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE. 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; Jun; 26 (18) 3063-3072
• Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P. et al Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010; Jan; 28 (01) 69-76
• Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E. et al Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; Feb; 364 (06) 514-523
• Fjällskog ML, Granberg DP, Welin SL, Eriksson C, Oberg KE, Janson ET. et al Treatment with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer 2001; Sep; 92 (05) 1101-1107
• Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H. et al Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 2007; May; 13 (10) 2986-2991
• Crona J, Fanola I, Lindholm DP, Antonodimitrakis P, Öberg K, Eriksson B. et al Effect of temozolomide in patients with metastatic bronchial carcinoids. Neuroendocrinology 2013; 98 (02) 151-155
• Ito M, Niho S, Nihei K, Yoh K, Ohmatsu H, Ohe Y.. Risk factors associated with fatal pulmonary hemorrhage in locally advanced non-small cell lung cancer treated with chemoradiotherapy. BMC Cancer 2012; Jan; 12: 27 https://doi.org/10.1186/1471-2407-12-27
• Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlácková E. et al Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; Jul; 371 (03) 224-233