Clinical presentation, diagnosis, and management of typical and atypical bronchopulmonary carcinoid

Given the indolent nature of typical carcinoids, there has been extensive research to evaluate whether a sublobar resection is oncologically appropriate for these tumors. Although there are no comprehensive randomized studies comparing sublobar resection with lobectomy for typical carcinoids, findings from numerous database reviews and single-center studies suggest that sublobar resections are noninferior.^14-17 Due to the higher nodal metastatic rate and the overall poorer prognosis associated with atypical carcinoids, formal anatomic resection is still recommended with atypical histology.¹⁸

An adaptive approach must be taken for patients who undergo wedge resection of pulmonary lesions without a known diagnosis. If intraoperative frozen section is consistent with carcinoid and the margins are negative, mediastinal lymph node dissection should be performed. If the patient is node negative, then completion lobectomy is not required. In node-positive patients with adequate pulmonary reserve, lobectomy should be performed regardless of histology. If atypical features are found during pathologic evaluation, then interval completion lobectomy may be patients with adequate pulmonary reserve.^19,20

As with other pulmonary malignancies, clinical or radiographic suspicion of mediastinal lymph node involvement requires invasive staging before pulmonary resection is considered. If the patient is proven to have mediastinal metastatic disease, then multimodality treatment should be considered.²⁰

Adjuvant therapy. Postoperative adjuvant therapy for most resected bronchial NETs, even in the setting of positive lymph nodes, is generally not recommended.⁷ In clinical practice, adjuvant platinum-based chemotherapy with or without radiation therapy (RT) is a reasonable option for patients with histologically aggressive-appearing or poorly differentiated stage III atypical bronchial NETs, although there is only limited evidence to support this. RT is a reasonable option for atypical bronchial NETs if gross residual disease remains after surgery, although it has not been proven that this improves outcomes.⁷

Nonmetastatic and unresectable disease

For inoperable patients and for those with surgically unresectable but nonmetastatic disease, options for local control of tumor growth include RT with or without concurrent chemotherapy and palliative endobronchial resection of obstructing tumor.²¹

Metastatic and unresectable disease

Everolimus. In February 2016, everolimus was approved by the US Food and Drug Administration (FDA) as first-line therapy for progressive, well-differentiated, nonfunctional NETs of lung origin that are unresectable, locally advanced, or metastatic. The aApproval was based on the RADIANT-4 trial, in which median progression-free survival was 11 months in the 205 patients allocated to receive everolimus (10 mg/day) and 3.9 months in the 97 patients who received placebo. Everolimus was associated with a 52% reduction in the estimated risk of progression or death.²²

Somastatin analogues (SSA). There is lack of comprehensive data on the role of SSA compared with everolimus in lung carcinoid. The National Comprehensive Cancer Network (NCCN) guidelines on NETs and SCLCs recommend the consideration of octreotide or lanreotide as first-line therapies for select patients with symptoms of carcinoid syndrome or octreotide-positive scans.²¹ Guidelines from the European Neuroendocrine Tumor Society (ENETS)¹⁹ also recommend the use of SSAs as a first-line option in patients with: lung carcinoids exhibiting hormone-related symptoms or slowly progressive typical or atypical carcinoid with a low proliferative index (preferably Ki-67 <10%), provided there is a strongly positive SSTR status.

In cases in which metastatic lung NETs are associated with the carcinoid syndrome, initiation of long-acting SSA therapy in combination with everolimus is recommended.

Cytotoxic chemotherapy. According to the NCCN guidelines, cisplatin-etoposide or other cytotoxic regimens (eg, those that are temozolomide based) are recommended for advanced typical and atypical carcinoids, with cisplatin-etoposide being the preferred first-line systemic regimen in stage IV atypical carcinoid.²² ENETS guidelines stipulate that systemic chemotherapy is generally restricted to atypical carcinoid after failure of first-line therapies and only under certain conditions (Ki-67 >15%, rapidly progressive disease, and SSTR-negative disease).¹⁹ Based on a summary of NCCN and ENET guidelines:

n For patients with highly aggressive atypical bronchial NETs, a combination of platinum- and etoposide-based regimens such as those used for small-cell lung cancer has shown better response rate and overall survival data.

n For patients with typical or atypical bronchial NETs, temozolomide can be used as monotherapy or combination with capecitabine, although there are no findings from large randomized controlled trials to support this. Capecitabine-temozolomide has recently shown moderate activity in a small, single-institution study of patients with advanced lung carcinoids (N = 19), with 11 of 17 assessable patients (65%) demonstrating stable disease or partial response.²³

n The following regimens can also be used for advanced disease after failure of somastatin analogues, although there are limited data for objective responses:^24,25fluorouracil plus dacarbazine; epirubicin, capecitabine plus oxaliplatin; and capecitabine plus liposomal doxorubicin.

Participation in a clinical trial should be encouraged for patients with progressive bronchial NETs during any line of therapy. For patients who have a limited, potentially resectable liver-isolated metastatic NET, surgical resection should be pursued. For more extensive unresectable liver-dominant metastatic disease, treatment options include embolization, radiofrequency ablation, and cryoablation.^20,22