Update on Therapeutic Strategy in Lung Carcinoids

Sara Pusceddu, Milena Vitali, Eva Haspinger, Luca Tavecchio, Riccardo Giovannetti, Andrea Bille, Laura Concas, Marina Garassino, Massimo Milione, Filippo de Braud, Roberto Buzzoni

Medical Oncology Unit, Fondazione IRCCS—Istituto Nazionale dei Tumori, Milan, Italy.
Pathology Unit, Fondazione IRCCS—Istituto Nazionale dei Tumori, Milan, Italy.
Thoracic Surgery Unit, Fondazione IRCCS—Istituto Nazionale dei Tumori, Milan, Italy.

DOI: 10.4236/jct.2013.410176                

Abstract

An estimated 25% to 30% of all neuroendocrine tumors (NETs) have their origin in the bronchial tree and into the lungs. Although lung NETs account for less than 1% of all pulmonary malignancies, the incidence of these neoplasms has risen precipitously since the mid 1970s. Currently, according to the 2004 World Health Organization categorization, these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Surgery is the treatment of choice for typical and atypical carcinoid lung NETs with loco-regional disease. At diagnosis up to 64% of patients with atypical carcinoid lung NETs present with lymph node metastases, and 5-year survival ranges from 61% to 88%. In contrast, lymph node metastases are present in fewer than 15% of typical carcinoid lung NETs, and 5-year survival exceeds 90%. To date, there is no recognized standard of treatment for advanced carcinoid lung NETs. In recent years only two trials reported intriguing results regarding lung NETs: a phase 2 retrospective study of dacarbazine derivative temozolomide and the phase 3, RADIANT-2 trial in advanced NETs. Successful management requires a multidisciplinary team management. This review is restricted to typical/atypical NETs.

Keywords

Bronchial; Pulmonary; Carcinoids; Neuroendocrine Tumours

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	I. M. Modlin, K. D. Lye and M. A. Kidd, “5-Decade Analysis of 13,715 Carcinoid Tumors,” Cancer, Vol. 97, No. 4, 2003, pp. 934-959.
[2]	W. D. Travis, “Lung Tumours with Neuroendocrine Differentiation,” European Journal of Cancer, Vol. 45, Suppl. 1, 2009, pp. 251-266. http://dx.doi.org/10.1016/S0959-8049(09)70040-1
[3]	J. C. Yao, M. Hassan, A. Phan, et al., “One Hundred Years after ‘Carcinoid’: Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United States.” Journal of Clinical Oncology, Vol. 26, No. 18, 2008, pp. 3063-3072.
[4]	W. D. Travis “Advances in Neuroendocrine Lung Tumors,” Annals of Oncology, Vol. 21, Suppl. 7, 2010, pp. 65-71. http://dx.doi.org/10.1093/annonc/mdq380
[5]	O. Hauso, B. I. Gustafsson, M. Kidd, et al., “Neuroendocrine Tumor Epidemiology: Contrasting Norway and North America,” Cancer, Vol. 113, No. 10, 2008, pp. 2655-2664.
[6]	A. M. Isidori, G. A. Kaltsas and A. B. Grossman, “Ectopic ACTH Syndrome,” Frontiers of Hormone Research, Vol. 35, 2006, pp. 143-56. http://dx.doi.org/10.1159/000094323
[7]	K. ?berg, P. Hellman, P. Ferolla, et al., “Neuroendocrine Bronchial and Thymic Tumors: ESMO Clinical Practice Guidelines for diagnosis, Treatment and Follow-Up. ESMO Guidelines Working Group,” Annals of Oncology, Vol. 23, Suppl. 7, 2012, pp. 120-123.
[8]	L. Righi, M. Volante, V. Tavaglione, et al., “Somatostatin Receptor Tissue Distribution in Lung Neuroendocrine Tumours: A Clinicopathologic and Immunohistochemical Study of 218 ‘Clinically Aggressive’ Cases,” Annals of Oncology, Vol. 21, No. 3, 2010, pp. 548-555. http://dx.doi.org/ 10.1093/annonc/mdp334
[9]	M. Papotti, S. Croce, M. Bello, et al., “Expression of Somatostatin Receptor Types 2, 3 and 5 in Biopsies and Surgical Specimens of Human Lung Tumours. Correlation with Preoperative Octreotide Scintigraphy,” Virchows Archiv, Vol. 439, 2001, pp. 787-797.
[10]	I. M. Modlin, K. Oberg, D. C. Chung, et al., “Gastroenteropancreatic Neuroendocrine Tumours,” The Lancet Oncology, Vol. 9, No. 1, 2008, pp. 61-72. http://dx.doi.org/10.1016/S1470-2045(07)70410-2
[11]	I. J. Virgolini, M. Gabriel, E. von Guggenberg, et al., “Role of Radiopharmaceuticals in the Diagnosis and Treatment of Neuroendocrine Tumours,” European Journal of Cancer, Vol. 45, Suppl. 1, 2009, pp. 274-291. http://dx.doi.org/10.1016/S0959-8049(09)70042-5
[12]	P. Antunes, M. Ginji, H. Zhang, et al., “Are Radiogallium-Labelled DOTA-Conjugated Somatostatin Analogues Superior to Those Labelled with Other Radiometals,” European Journal of Nuclear Medicine and Molecular Imaging, Vol. 34, No. 7, 2007, pp. 982-993. http://dx.doi.org/10.1007/ s00259-006-0317-x
[13]	A. R. Haug, R. Cindea-Drimus, C. J. Auernhammer, et al., “Neuroendocrine Tumor Recurrence: Diagnosis with 68Ga-DOTATATE PET/CT,” Radiology, Vol. 20, 2013.
[14]	T. Binderup, U. Knigge, A. Loft, et al., “Functional Imaging of Neuroendocrine Tumors: A Head-to-Head Comparison of Somatostatin Receptor Scintigraphy, 123IMIBG Scintigraphy, and 18F-FDG PET,” Journal of Nuclear Medicine, Vol. 51, No. 5, 2010, pp. 704-712. http://dx.doi.org/10.2967/ jnumed.109.069765
[15]	W. W. de Herder, V. Mazzaferro, L. Tavecchio, et al., “Multidisciplinary Approach for the Treatment of Neuroendocrine Tumors,” Tumori, Vol. 96, No. 5, 2010, pp. 833-846.
[16]	S. Ekeblad, A. Sundin, E. T. Janson, et al., “Temozolomide as Monotherapy is Effective in Treatment of Advanced Malignant Neuroendocrine Tumors,” Clinical Cancer Research, Vol. 13, No. 10, 2007, pp. 2986-2991. http://dx.doi.org/10.1158/1078-0432.CCR-06-2053
[17]	A. Rinke, H. H. Müller, C. Schade-Brittinger, et al., “Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors: A Report from the PROMID Study Group. PROMID Study Group,” Journal of Clinical Oncology, Vol. 27, No. 28, 2009, pp. 4656-4663.
[18]	M. Caplin, P. Ruszniewski, M. Pavel, et al., “A Randomized Double-Blind Placebo-Controlled Study of Lanreotide Antiproliferative Response in Patients with Enteropancreatic Neuro Endocrine Tumours (CLARINET),” 17th ECCO-38th ESMO-32nd ESTRO European Cancer Congress, Amsterdam, Vol. 49, No. 3, 2013, Abstract E17-7103.
[19]	L. Righi, M. Volante, I. Rapa, et al., “Mammalian Target of Rapamycin Signaling Activation Patterns in Neuroendocrine Tumors of the Lung,” Endocrine-Related Cancer, Vol. 17, No. 4, 2010, pp. 977-987. http://dx.doi.org/10.1677/ERC-10-0157
[20]	M. C. Zatelli, M. Minoia, C. Martini, et al., “Everolimus as a New Potential Antiproliferative Agent in Aggressive Human Bronchial Carcinoids,” Endocrine-Related Cancer, Vol. 17, No. 3, 2010, pp. 719-729. http://dx.doi.org/10.1677/ERC-10-0097
[21]	M. E. Pavel, J. D. Hainsworth, E. Baudin, 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, Vol. 378, No. 9808, 2011, pp. 2005-2012.
[22]	N. Fazio, D. Granberg, A. Grossman, et al., “Everolimus Plus Octreotide Long-Acting Repeatable in Patients with Advanced Lung Neuroendocrine Tumors: Analysis of the Phase 3, Randomized, Placebo-Controlled RADIANT-2 Study,” Chest, Vol. 143, No. 4, 2013, pp. 955-962. http://dx.doi.org/10.1378/chest.12-1108
[23]	E. Gande, et al., “sVEGFR2 and Circulating Tumor Cells to Predict for the Efficacy of Pazopanib in Neuroendocrine Tumors (NETs): PAZONET Subgroup Analysis,” Journal of Clinical Oncology, Vol. 31, Suppl. 15, 2013.