Systemic treatment for lung carcinoids: from bench to bedside

Abstract

In the huge spectrum of lung neuroendocrine neoplasms, typical and atypical carcinoids should be considered as a separate biological entity from poorly differentiated forms, harboring peculiar molecular alterations. Despite their indolent behavior, lung carcinoids correlate with a worse survival. To date, only limited therapeutic options are available and novel drugs are strongly needed. In this work, we extensively reviewed scientific literature exploring available therapeutic options, new molecular targets and future perspectives in the management of well differentiated neoplasms of bronchopulmonary tree. Systemic therapy represents the main option in advanced and unresectable disease; accepted choices are somatostatin analogs, peptide receptor radionuclide therapy, everolimus and chemotherapy. To date, an univocal treatment strategy has not been identified yet, thus tailored therapeutic algorithms should consider treatment efficacy as well as safety profiles. Several molecular alterations found in carcinoid tumors might act as molecular targets leading to development of new therapeutic options. Further studies are necessary to identify new potential “druggable” molecular targets in the selected subset of low-grade lung carcinoids. Furthermore, evaluating the available therapies in more homogeneous population might improve their efficacy through a perfect tailoring of treatment options.

Australian experience of peptide receptor radionuclide therapy in lung neuroendocrine tumours

“…Systemic therapy is the mainstay of treatment for advanced lung NETs, though there is no univocal treatment strategy [10]. NETs as a whole are less responsive to chemotherapy, with limited efficacy and further evaluation needed for drugs including temozolomide, capecitabine, 5-fluorouracil, doxorubicin, etoposide and platinum agents [10,11]. Somatostatin analogues (SSA) are commonly used for advanced lung NETs, without specific evidence until very recently, with publication of the LUNA trial [12].…”

Heterogeneous tumor‐immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti‐PD‐L1 antibody therapy

“…Typical and atypical carcinoids are classified as highly differentiated malignant neuroendocrine tumors (NET) 1 . Due to their rarity, pulmonary carcinoids lack a validated therapeutic approach for unresectable disease 2,3 .…”

“…Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non‐small cell lung cancer (NSCLC), their impact on small cell lung cancer, which is in the same spectrum with typical and atypical carcinoids, is limited 4,5 . Drug development of immunotherapy targeting pulmonary NET including carcinoids is ongoing 1,3,6 . However, there is only very limited evidence for immunotherapy in patients with pulmonary carcinoids, with early trials suggesting a low‐level activity in patients treated with single agent therapy, 3,6 highlighting the importance of investigating the heterogeneity of tumor‐immune microenvironments (TIME) in carcinoids.…”

Treatment of atypical pulmonary carcinoid with combination ipilimumab and nivolumab

“…It has been shown to have some efficacy in these tumours, yet is limited by nephrotoxicity in ~50% of patients 12 13. Beyond these current treatments, research for future therapeutics has focused on Epidermal Growth Factor Receptor (EGFR) signalling and Vascular Endothelial Growth Factor (VEGF) binding to prevent hypervascularisation 14. Initial studies were not optimistic about the efficacy of immunotherapy in NENs, due to their lack of CD8 infiltration or Programmed Death-Ligand 1 (PD-L1) expression 14.…”

“…Beyond these current treatments, research for future therapeutics has focused on Epidermal Growth Factor Receptor (EGFR) signalling and Vascular Endothelial Growth Factor (VEGF) binding to prevent hypervascularisation 14. Initial studies were not optimistic about the efficacy of immunotherapy in NENs, due to their lack of CD8 infiltration or Programmed Death-Ligand 1 (PD-L1) expression 14. Given the rarity of atypical carcinoids, bulk of data in literature are composed of case reports and case series.…”