Bronchial carcinoids are a rare group of well-differentiated lung neuroendocrine tumors (NETs) with an incidence in western countries ranging from 0.2 to 2/100 000 persons/year (1). They are distinguished from neuroendocrine large and small cell lung carcinomas by histologic features as well as clinical, epidemiologic, genetic and prognostic parameters (2–8). According to WHO histologic criteria (9), lung NETs are divided in typical (low-grade, <2 mitoses/10 HPF and no necrosis) or atypical (intermediate grade, 2-10 mitosis/10HPF and/or foci of necrosis) carcinoids. Surgery is the mainstay of therapy for patients with disease at an early stage. Typical lung NETs have an excellent prognosis following surgical resection while atypical carcinoids are associated with a higher risk of disease relapse and a worse prognosis (10–12).

In patients with unresectable locally advanced or metastatic disease the goals of medical management are to control both hormone-related symptoms and tumor growth (13). Lung NETs frequently express somatostatin receptors, therefore somatostatin analogs (SSAs), such as lanreotide autogel (LAN) and octreotide long-acting release (LAR), are frequently used therapies and recommended by available guidelines (2, 13, 14). These drugs are well tolerated and have demonstrated both anti-secretory and anti-proliferative effects in NET patients. However, the data regarding the efficacy of SSAs in the management of lung carcinoids are very limited and refer to retrospective series (15–19). No prospective study data is currently available. The SPINET trial (NCT02683941), a placebo-controlled randomised phase III study, which was designed to evaluate lanreotide 120 mg in advanced lung carcinoids, was early stopped for insufficient enrolment (20). Most of the published retrospective studies are heterogeneous and included patients with NET of different primaries (21–28). Only 2 studies evaluated patients with lung carcinoids only. One of them enrolled patients undergoing SSAs both as first, and second line approach (21), only one study retrospectively evaluated patients treated with first line SSAs (22).

More data on the efficacy of SSAs in patients with advanced lung carcinoids, not previously submitted to systemic antineoplastic therapies, are therefore needed.

This retrospective study was designed to provide additional data on the efficacy of SSAs as first line therapy in patients with metastatic lung carcinoids.

We retrospectively reviewed data of consecutive patients with metastatic lung NET, treated with first line SSA monotherapy, from January 2014 to December 2019, at the Medical Oncology Unit of ASST Spedali Civili di Brescia and at the Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors of the European Institute of Oncology of Milan (IEO). To be included in the study the patients had to meet the following inclusion criteria: histopathological confirmed diagnosis of Lung NET according to 2015 WHO criteria (22), locally advanced or metastatic disease not amenable to radical surgery, absence of prior systemic therapy, at least three months of SSA therapy. Poorly differentiated morphology was an exclusion criterion. A single investigator (EL) collected clinical data from medical records. Database included the following data at baseline conditions: age, gender, tobacco exposure, surgery of primary tumor, histological subtype according 2015 WHO criteria, Ki- 67 index, mitotic count, hereditary or sporadic, primary tumor site, TNM/AJCC (tumor-node-metastasis/American Joint Committee on Cancer 2010 stage) (9), site of metastasis, functional tumor status. The following data were collected before and during the SSA therapy: ECOG PS, disease response at imaging according to RECIST criteria, type of SSA used and dose, date of initiation and completion of SSAs, adverse effects, any local therapies before SSA initiation or during SSA treatment. The study was approved by the institutional review board.

Follow-up visits during SSA therapy were performed approximately every 3 months and included a physical examination, complete blood count and biochemical profile. The evaluation of tumor response was assessed approximately every 6 months. Computed tomography [CT] scan or Positron emission tomography [PET] with Gallium 68 were the imaging techniques employed. The best overall response was defined according to the RECIST 1.1 criteria. Adverse events were evaluated over the whole duration of SSA administration and classified according to CTCAE v4.0.

Treatment with SSAs consisted in an intramuscular injection of octreotide long-acting release (LAR) (at dose of 20 mg or 30 mg every 4 weeks, or 30 mg every 3 weeks) or a subcutaneous injection of lanreotide depot (at dose of 60 mg or 120 mg every 4 weeks).

The primary study end point was progression free survival (PFS), defined as the time elapsing from SSA initiation to disease progression or death whichever occurred first. Patients with no event and alive were censored at the date of the last follow-up. Secondary endpoints were: overall survival (OS), defined as the time from SSA initiation to death from any cause. Survivors were censored at the date of their last follow-up; best overall response under SSA; toxicity.

Data of thirty-one consecutive patients, meeting the eligibility criteria, were analyzed. The clinical and pathological and characteristics and type of SSAs administered are summarized in Table 1 .

Thirteen (41.9%) patients were male, median age at SSA initiation was 62 years (range 20-82 years). The majority of patients (93.5%) had an ECOG PS 0.

Fourteen patients (45.2%) had a typical carcinoid, 17 (54.8%) an atypical carcinoid. Six patients had a carcinoid syndrome. One tumor, classified as atypical carcinoid, had Ki-67≥20%. This latter tumor was classified as an atypical carcinoid due to the well-differentiated phenotype. Necrosis was described in only one patient (3.2%). Radiological staging at diagnosis was performed with thoracic and abdominal CT in 17 (55%) patients. PET Gallium or Octreoscan were performed in 16 (51.6%) patients. All disease lesions displayed great uptake of the radiotracers.

Metastases were synchronous in 18 (58.1%) patients and metachronous in 13 (41.9%). Eighteen (58.1%) patients underwent surgery of the primary tumor which consisted in lobectomy in 3 patients (9.7%), lobectomy plus lymphadenectomy in 11 patients (35.5%) and atypical resection in 4 others. Liver was the most frequent metastatic site (61.3%). The other metastatic sites were bone (38.7%), contralateral lung (19.4%), extra-regional nodes (19.4%) and peritoneum (9.7%).

Somatostatin analogs are standard treatment in the management of well-differentiated neuroendocrine tumors of the gastro-entero-pancreatic tract, both functioning and non-functioning. On the basis of the results of the two prospective randomized studies (29, 30), their administration as first line approach is recommended to patients whose tumor expresses ki-67 in less than or equal to 10% of cancer cells (2). No prospective studies of first-line SSA have been conducted in patients with lung NET.

In this retrospective series the 2 SSAs: octreotide and lanreotide, were shown to be active as first line therapy in patients with advanced/metastatic lung NET with a proportion of partial responses and stable diseases not different from that obtained in the GEP NET setting. The good overall survival should be interpreted considering the short follow-up and the few events observed, that limit the generalization of this result. The 28-month PFS is promising, considering that lung carcinoids, in particular atypical ones, generally have a worse prognosis than GEP NET patients (2). The PFS of the present case series is superior to that of a published retrospective study of lung carcinoids submitted to front line SSAs (22). The difference can be attributed to the patient selection and in particular the higher proportion of typical carcinoids in our series, as compared to that of Bongiovanni A et al. (22).

As expected, atypical carcinoid was associated with a lower PFS than typical carcinoid, although not statistically significant. However, the 19 month PFS of patients with atypical carcinoid is a better outcome compared with historical reports (6). As mentioned in the introduction, the efficacy of SSAs was demonstrated in GEP NETs with Ki67 ≤10%. The observed median PFS of 27 months in lung carcinoid patients with Ki67<10% in the present paper is suggestive of efficacy of these drugs also in this subset. This series however included 9 patients whose lung carcinoid had a ki67 ranging between 11 and 20% and 1 patient with ki67 >20%. The median PFS of 19.9 months in patients with ki67 >10% is noteworthy and suggests that also selected patients with ki67 >10% could benefit from SSAs administered as frontline therapy. This observation needs confirmation in future prospective studies.

In our series the PFS was negatively influenced by the functional status (although without attaining the statistical significance) confirming a previous observation (22). However, it did not change dividing patients according to the tumor burden and the presence of liver metastases, suggesting that these parameters could not be considered a deterrent in the prescription of SSAs as first-line therapy.

In summary, the long PFS obtained in this patient series with progressive, metastatic pulmonary NET, uniformly submitted to first line SSAs suggest that these drugs could be potentially efficacious in this patient setting, confirming previous observations (21, 22). These findings are relevant in patients with Ki67 ≤10% and typical carcinoids, but are encouraging also patients with greater Ki67 expression and atypical hystotype. Although no definitive conclusions can be drawn from our series of patients and that all our outcomes should be interpreted with caution, the results of our analysis are encouraging and should be considered as hypothesis-generating for further prospective studies.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by ethics committee of European Institute of Oncology. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

EL, ABe, NF, and FS contributed to conception and design of the study. EL organized the database. PM and AA performed the statistical analysis. AA, EL, and ABe wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.

This study was in part supported by The Italian Ministry of Health with Ricerca Corrente and 5 × 1000.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.