Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors

Highlights

• To guide management of pulmonary carcinoid tumors we reviewed patients treated at our institutions.

• Median survival after diagnosis of metastatic atypical pulmonary carcinoid was 3.3 years.

• Treatments include octreotide- or temozolomide-based therapies, and etoposide + platinum.

Abstract

Objectives

The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined.

Materials and methods

A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990 and 2012.

Results

300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stages I–III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4–32), compared to 3 (1%) patients with typical carcinoid (range, 8–12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum–etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5-year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 month median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 month median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6–72 months).

Conclusions

These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy.

Introduction

Patients with pulmonary carcinoid tumors comprise approximately 2% of all primary lung cancers [1], and the relative rarity of these tumors complicates efforts to effectively plan the therapy of patients with locally advanced or metastatic cancer. Pulmonary carcinoid tumors are defined by their typically bland cytomorphology and neuroendocrine features on histologic examination, and immunohistochemical staining for chromogranin, neural cell adhesion molecule (CD56), or synaptophysin [2]. A spectrum of pulmonary neuroendocrine tumors is thought to exist, with carcinoid tumorlets and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) representing less aggressive forms of the neuroendocrine spectrum, and small cell lung cancer the most malignant [2]. Typical carcinoid tumors behave in a more indolent fashion compared to atypical carcinoid tumors, which have a greater propensity for dissemination at the time of presentation and the subsequent development of metastasis. The pathologic criteria that distinguishes typical from atypical carcinoid tumors were proposed by Travis et al., in 1998, and has been widely adopted [3]. Typical carcinoids are distinguished from carcinoid tumorlets by a size larger than 0.5 cm, and have a mitotic rate of <2 mitoses/10 high power field (HPF) with no necrosis [2]. Atypical carcinoids, in contrast, have a mitotic rate of 2–10 mitoses/10 HPF or the presence of necrosis.

Patients with typical carcinoids have an excellent prognosis, with 5- and 10-year survival rates of 85% reported [4]. Atypical carcinoids have a more aggressive course, with 5- and 10-year survival rates in the range of 35–44%, due to a greater frequency of patients presenting with advanced stage and more frequent recurrence [4]. While metastatic disease is rarely reported for typical carcinoid tumors, atypical carcinoid tumors do metastasize in approximately 30–40% of reported cases, with the liver, bone, and brain being the most common sites [4]. Treatment of patients with typical carcinoids has centered on resection, and the vast majority of patients in case-series remain recurrence free for years, and even decades, with little information on systemic treatment [5], [6], [7].

The more aggressive nature of atypical carcinoid tumors compared to typical carcinoid tumors prompted investigators to administer adjuvant chemotherapy for high-risk disease (i.e. stage IIB/IIIA) based on data showing a response rate of 20% to any chemotherapy [8], although this approach has been questioned by others who feel the role of systemic treatment is limited [9]. Regimens showing antitumor activity against pulmonary carcinoid tumors include octreotide [10], doxorubicin/capecitabine [11], everolimus + cisplatin [12], everolimus + octreotide [13], and etoposide + cisplatin [8]. The efficacy of adjuvant treatment for stages II and III resected typical and atypical carcinoid tumors is extrapolated from these response rates in metastatic disease, and the efficacy of adjuvant chemotherapy in resected stage II and III non-small cell lung cancer trials [14], [15], [16]. While patients with pulmonary carcinoid tumors have been included in large-scale studies of neuroendocrine tumors [17], very little data exist on the role of chemotherapy in locally advanced typical or atypical metastatic pulmonary carcinoid tumors.

To further define the role of chemotherapy and adjuvant treatment of pulmonary carcinoid tumors, this retrospective study of patients with atypical and typical carcinoid tumors treated at our institutions between 1990 and 2012 was undertaken. This study updates our 2004 effort which demonstrated that pulmonary carcinoid tumors can respond to chemotherapy [8].