Version May 2024
INTRODUCTION — Well-differentiated lung neuroendocrine (bronchial carcinoid) tumors (NETs) are a rare group of pulmonary neoplasms that are often characterized by indolent clinical behavior. Like other carcinoid tumors, lung NETs are thought to derive from peptide- and amine-producing neuroendocrine cells. NETs can arise at a number of sites throughout the body, including the thymus, lung, gastrointestinal (GI) tract, and ovary. The GI tract is the most frequently involved site for NETs, while the lung is the second most common. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
Lung NETs are characterized by strikingly heterogeneous pathological features and clinical behavior. At one end of the spectrum are the so-called typical carcinoids, which are well-differentiated, low-grade, slowly growing neoplasms that seldom metastasize to extrathoracic structures. At the other end of the spectrum are the poorly differentiated and high-grade neuroendocrine carcinomas, as typified by small cell lung cancer, which behaves aggressively, with rapid tumor growth and early distant dissemination. The biologic behavior of intermediate-grade (atypical) NETs, which are of intermediate grade and differentiation, is intermediate between low-grade NETs and small cell lung cancer. The terms "typical" and "atypical" carcinoid of the lung correspond roughly to the terms "grade 1" and "grade 2," which are used more commonly in extrathoracic NETs. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Classification, histology, and histochemistry' and "Pathobiology and staging of small cell carcinoma of the lung" and "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)
Multifocal disease is relatively common in patients with low-grade lung NETs. An extreme example is diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a condition characterized by diffuse hyperplasia of pulmonary neuroendocrine cells and formation of multiple tumorlets and invasive NETs. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia'.)
The treatment and prognosis of both low-grade (typical) and intermediate-grade (atypical) lung NETs (carcinoid tumors) will be discussed here. The epidemiology, classification, clinical features, diagnosis, and staging of these tumors is discussed elsewhere, as is treatment of well-differentiated NETs arising in other sites and poorly differentiated neuroendocrine cancers arising in the lung. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging" and "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors" and "Extensive-stage small cell lung cancer: Initial management" and "Limited-stage small cell lung cancer: Initial management".)
LOCALIZED DISEASE — For patients with localized lung neuroendocrine tumors (NETs), surgical resection is the preferred treatment approach, assuming adequate pulmonary reserve. For patients whose condition does not permit complete resection and for exceptional low-grade cases where the lesion is entirely endobronchial, transbronchoscopic resection may be an alternative. (See 'Endobronchial management' below.)
Surgical resection — For patients with either a low- or intermediate-grade lung NET whose medical condition and pulmonary reserve will tolerate it, we recommend surgical resection, and mediastinal lymph node sampling or dissection.
Surgery is the treatment of choice for lung NETs and the therapeutic option offering the best chance of cure. In general, anatomic resections, such as segmentectomy, are superior to wedge resections in preventing tumor recurrence, even for low-grade tumors [1]. For small, peripheral tumors, the surgeon can attempt to preserve lung parenchyma by using lung-sparing techniques (eg, sleeve resection); however, lobectomy, bilobectomy, and pneumonectomy are justified and appropriate for more extensive low-grade lung NETs, especially those located proximally [2-4].
Standard oncologic resection as is performed for a non-small cell lung cancer (eg, lobectomy or even pneumonectomy when necessary) is appropriate for intermediate-grade (atypical) or poorly differentiated tumors.
Since low-grade (typical) lung NETs, unlike bronchogenic carcinomas, tend not to spread submucosally, an endobronchial surgical margin as narrow as 5 mm is considered adequate, but a >2 cm histologically negative lung parenchymal margin is preferred. Intraoperative frozen section analysis is critical to the success of this approach. Although long-term survival has been reported in patients with positive margins [3,5], reresection is preferred in this setting [2,6].
Proximal tumors — For polypoid low-grade (typical) tumors of the mainstem bronchus or bronchus intermedius, a bronchotomy with wedge or sleeve resection of the bronchial wall and complete preservation of distal lung parenchyma could be performed [7]. However, such completely parenchyma-sparing procedures are only rarely possible because of the frequency of "iceberg" lesions (in which the tumor appears entirely intraluminal bronchoscopically but has a significant extraluminal component that is evident with high-resolution computed tomography [CT] scanning). (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Cross-sectional imaging'.)
Tumors with more extensive central parenchymal involvement, those that are associated with severe distal parenchymal disease (ie, nonfunctioning lung parenchyma), and intermediate-grade (atypical) lung NETs require more extensive surgery (eg, lobectomy or pneumonectomy).
Peripheral tumors — For peripheral lesions in the outer one-third of the lung, the ideal surgical approach is debated, and there is no consensus. Segmental resections are preferred, unless there is a safety concern or anticipated significant concern about quality of life. A wedge resection of small, peripheral <2 cm diameter, low-grade lung NETs is acceptable if an adequate tumor-free margin can be obtained [8]. Most advocate lobectomy in the case of a more central tumor involving the orifice of a segmental bronchus, while others suggest that a more limited resection (eg, segmentectomy) is acceptable for a low-grade (typical) lung NET because of the low likelihood of a local recurrence [9].
Role of lymph node dissection — Between 5 and 20 percent of low-grade (typical) lung NETs and 30 to 70 percent of intermediate-grade (atypical) tumors metastasize to lymph nodes [10,11]. A complete mediastinal lymph node sampling or dissection at the time of initial treatment is indicated [12,13], with complete resection of nodal metastasis if at all possible. Metastatic involvement of mediastinal lymph nodes does not preclude a complete (R0) surgical resection or long-term cure.
Prognosis
Low-grade (typical) lung neuroendocrine tumors — Localized low-grade (typical) lung NETs have an excellent prognosis following surgical resection. Reported five-year survival rates are 87 to 100 percent; the corresponding rates at 10 years are 82 to 87 percent (table 1) [9-11,14-22]. A contemporary large series with long-term follow-up and expert pathology review reported a 3 percent (9 of 291) recurrence rate for resected low-grade lung NETs [23].
The prognostic impact of nodal involvement for low-grade lung NETs is controversial, but most studies show a worse outcome compared with cases without nodal involvement [11,23-28]. Besides nodal involvement [23], incomplete resection is the only widely accepted feature with negative prognostic significance. A nomogram to predict survival for low-grade lung NETs has been developed that is based on age; gender; prior malignancy; tumor site (central versus peripheral); Tumor, Node, Metastasis (TNM) stage; and performance status [29].
Intermediate-grade (atypical) lung neuroendocrine tumors — Intermediate-grade (atypical) lung NETs have a worse prognosis than do low-grade tumors. Five-year survival rates range widely from 30 to 95 percent; the corresponding rates at 10 years are 35 to 56 percent (table 1) [10,15,18,20,21,25,27,30-34]. Intermediate-grade tumors have a greater tendency to both metastasize (16 and 23 percent in three large series [22,23,35]) and recur locally (3 and 25 percent in the same series [22,23,35]). Distant metastases to the liver or bone are more common than local recurrence [23]. Most series report an adverse influence of nodal metastases on prognosis that is more profound than for low-grade tumors (table 1) [17,20,31,35,36]. This is best illustrated by the experience at the Mayo Clinic [17]. Nineteen of 23 patients with low-grade lung NETs and lymph node involvement (83 percent) remained alive and well, while four failed distantly, two of whom died. In contrast, only 4 of the 11 patients with intermediate-grade tumors and lymph node involvement were alive without disease, while seven developed distant metastases and six died.
Role of adjuvant therapy — Although some disagree, we suggest not administering postoperative adjuvant therapy for most R0 resected lung NETs, even in the setting of positive lymph nodes. Adjuvant platinum-based chemotherapy with or without radiation therapy (RT) is a reasonable option for patients with histologically aggressive-appearing, stage III (table 2), intermediate-grade (atypical) lung NETs (ie, relatively high mitotic rate, extensive necrosis, etc), although there is no evidence to support this practice. RT is a reasonable option for intermediate-grade lung NETs if gross residual disease remains after surgery, although whether this improves outcomes is unproven.
The role of adjuvant therapy after complete resection of a lung NET is undefined due to the total lack of prospective randomized trials. Patients with low-grade (typical) tumors (which are generally considered chemoresistant) are unlikely to benefit from adjuvant systemic treatment, even in the setting of lymph node metastases. On the other hand, intermediate-grade (atypical) tumors represent a relatively broad spectrum of disease, with a higher rate of recurrence.
The benefit of adjuvant therapy has been addressed in retrospective reports, most of which have not found a benefit from adjuvant therapy [11,16,37-41].
As examples:
●MD Anderson reported their experience in 73 surgical patients with lung NETs (of the 63 patients with tumor blocks available for review, there were 14 atypical and 49 typical NETs), seven of whom received adjuvant RT and/or chemotherapy because of positive margins, local invasion, and/or lymph node involvement [41]. Only one of the seven patients who underwent surgery followed by RT was alive without evidence of disease 10 years later.
●In an Italian series of 42 patients with lung NETs (26 typical, 16 atypical), RT and/or systemic therapy (four cycles of cisplatin and etoposide) was administered to all seven patients with stage III disease and to one patient who had a T3N1 tumor as assessed by the older sixth edition of the American Joint Committee on Cancer (AJCC) staging system [16]. Five of the seven patients who had received adjuvant therapy recurred and died of their disease despite receiving adjuvant therapy, all of whom had atypical histology.
●A lack of benefit for adjuvant therapy in node-positive typical lung NETs was also seen in a retrospective analysis of 629 patients in the National Cancer Database who underwent lobectomy and had metastatic nodal disease; adjuvant chemotherapy was used in 37 (5.9 percent) who were matched by baseline demographic and clinical characteristics with similar patients who did not receive adjuvant treatment [42]. The use of chemotherapy was not associated with a survival advantage, and in fact, outcomes in this group were worse than in those who did not receive chemotherapy (survival at five years 69.7 versus 81.9 percent).
It should be noted that many of the series that purport to show a benefit for adjuvant therapy included patients with large cell neuroendocrine carcinomas, whose outcome is significantly worse than that of patients with intermediate-grade (atypical) lung NETs [20]. These tumors are treated according to guidelines for intrathoracic small cell and large cell neuroendocrine cancer. (See "Limited-stage small cell lung cancer: Initial management" and "Extensive-stage small cell lung cancer: Initial management".)
Recommendations of expert groups — The recommendations from expert groups regarding adjuvant therapy are variable, and there is no consensus as to the optimal approach. The following consensus-based guidelines are available:
●The National Comprehensive Cancer Network (NCCN) panel recommends consideration of adjuvant cisplatin or carboplatin plus etoposide with or without RT for patients with completely resected, stage IIIA (table 2), intermediate-grade (atypical) NETs [43]. For patients with unresectable or margin-positive low-grade (typical) NETs, there is no consensus regarding the benefit of adjuvant therapy; however, radiation with or without chemotherapy can be considered. For patients with unresectable or margin-positive intermediate-grade (atypical) NETs, the recommendation is RT with or without adjuvant chemotherapy. The NCCN emphasizes that the benefits of platinum/etoposide-based chemotherapy are higher as tumor grade increases.
●Recommendations from the European Neuroendocrine Tumor Society (ENETS) state that only patients with intermediate-grade (atypical) tumors with positive lymph nodes, especially if there is a high proliferative index, should be considered for adjuvant therapy and discussed individually in the context of a multidisciplinary tumor board meeting [44].
●A later Best Practice consensus statement on lung NETs from the Commonwealth Neuroendocrine Tumour Research Collaboration (CommNETs) and the North American Neuroendocrine Tumor Society (NANETs), which updated the 2015 ENETS recommendations, states that there is no consensus on adjuvant therapy in lung NETs after complete resection, but that it might be considered in a patient with an atypical NET of high proliferative index [13].
●Year 2021 guidelines from the European Society of Medical Oncology (ESMO) suggest consideration of systemic therapy with or without RT for patients with a particularly high risk of relapse (eg, intermediate-grade [atypical] lung NETs with N2 disease [ipsilateral mediastinal and/or subcarinal lymph node(s)]) after multidisciplinary discussion [45].
Endobronchial management
Resection — Endobronchial resection is a suboptimal method of definitive treatment, thus definitive surgical resection is preferred for most patients. Endobronchial laser resection is best reserved for palliative treatment of patients with central airway occlusion who are poor surgical candidates (eg, older adults, debilitated).
In some cases, a polypoid lung NET may appear entirely intraluminal and amenable to bronchoscopic resection. For highly selected patients with a central, polypoid, low-grade (typical) lung NET, transbronchoscopic resection with a neodymium-doped yttrium aluminium garnet (Nd:YAG) laser alone may provide prolonged recurrence-free survival [18,25,46-48]. In the largest series of 112 patients (83 typical, 29 atypical NETs) undergoing initial bronchoscopic management, who were all followed for a minimum of five years, initial bronchoscopic treatment was successfully used to avoid surgery in 47 cases (42 percent, including 42 of 83 typical but only 5 of 29 atypical NETs) [48]. Residual intraluminal disease after a second bronchoscopic resection or residual or recurrent extraluminal disease prompted surgical resection in 62 cases (including 24 of the 29 atypical lung NETs). Metastatic disease developed in four cases, and two died; all had been treated with rescue surgery. At a median follow-up of 112 months, 100 patients remained alive, and only three of the deaths were tumor related (one perioperative); disease-specific survival was 97 percent.
Close posttreatment follow-up is an integral component of bronchoscopic resection. In the series described above, patients underwent high-resolution CT and flexible bronchoscopy with endobronchial ultrasonography within six weeks after endobronchial resection and were then referred for surgery for any evidence of residual disease [46]. Repeat evaluation was performed every six months for two years and annually thereafter.
In our view, the most appropriate candidates for endobronchial resection are patients who present with a polypoid intraluminal tumor, who have good bronchoscopic visualization of the distal tumor margin, and who have no evidence of bronchial wall involvement or suspicious lymphadenopathy by high-resolution CT. However, we do not consider bronchoscopic resection to represent a standard potentially curative treatment for the vast majority of patients with central lesions because, even in the setting of a negative CT, most tumors extend into or through the wall of the bronchus, and endobronchial resection risks leaving substantial tumor behind, either within or beyond the endobronchial lumen. Because of the slow-growing nature of lung NETs, it may take years before a recurrence develops. Until more data are available, transbronchoscopic laser resection is best reserved for palliative treatment of patients with central airway occlusion who are poor surgical candidates (eg, older adults, debilitated) [49-51]. Laser bronchoscopic removal of an obstructing lesion may also be useful preoperatively to allow the surgeon to plan the most appropriate surgical procedure [52].
Cryotherapy — The utility of transbronchoscopic cryotherapy was addressed in a small series of 18 isolated, endoluminal, low-grade (typical) NETs [53]. There was only a single recurrence seven years after initial treatment, and the procedure was safe and not associated with later development of bronchial stenosis. As with endobronchial laser resection, this procedure (where available) is best reserved for palliative management of patients with central airway occlusion who are poor surgical candidates (eg, older adults, debilitated).
Inoperable and locally advanced unresectable disease — Definitive RT can provide effective palliation of a locally unresectable primary lung NET [37,54,55]. It is not a curative option, however.
Some recommend that patients with locally advanced unresectable lung NETs undergo chemotherapy plus RT in a manner similar to treatment for intrathoracic neuroendocrine small cell lung cancer [56]. However, response rates seem to be lower than are seen with small cell lung cancer, and whether this approach is superior to RT alone remains uncertain. The use of platinum-based chemotherapy is likely to be most appropriate in patients with histologically aggressive tumors with relatively high proliferative activity (eg, a Ki-67 index >20 percent). (See "Limited-stage small cell lung cancer: Initial management" and "Extensive-stage small cell lung cancer: Initial management".)
For a small, peripheral, low-grade (typical) lung NET in a patient who is not a physiologic candidate for surgical resection, stereotactic body radiation is another reasonable therapeutic option and is likely effective, although this is an unusual situation and there are no clinical series in this tumor subset to verify benefit.
Posttreatment surveillance — There is very little evidence regarding the benefits of postoperative surveillance. In one large series, scheduled imaging failed to detect most recurrences, and the rate of recurrence was very low (<3 percent) in patients with node-negative low-grade (typical) lung NETs [23]. Distant metastases predominated (95 percent). These data suggest that patients with node-negative low-grade lung NETs are highly unlikely to benefit from any type of postoperative surveillance. Updated guidelines from CommNETs and NANETS suggest no surveillance for most patients, although exceptions could be made for tumor size >3 cm, close margins, or multifocality [13].
For patients with node-positive low-grade lung NETs or intermediate-grade tumors, the risk of recurrence is higher, and posttreatment surveillance is reasonable. The optimal posttreatment surveillance strategy is not defined, and there is no consensus on what tests should be ordered. We perform a history and physical examination and chest/abdomen CT every six months for the first two years, then annually for at least 10 years. The duration of yearly CT scans is undefined, although nearly all recurrences occur within 10 years. This recommendation is consistent with updated guidelines from CommNETs/NANETS [13].
Although some authors recommend somatostatin-receptor-based imaging (eg, somatostatin receptor scintigraphy using indium-111 pentetreotide, or integrated positron emission tomography [PET]/CT using gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC) in the follow-up of patients with lung NETs [57], we do not routinely order somatostatin-receptor-based imaging unless there is suspicion for metastatic disease. This recommendation is consistent with updated guidelines from CommNETs/NANETS [13].
Chromogranin A (CgA) is insufficiently sensitive or specific to be useful as a tumor marker during post-treatment surveillance. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A (CgA)' and "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Role of nonhormonal tumor markers in clinical practice'.)
MANAGEMENT OF CARCINOID SYNDROME — Lung neuroendocrine tumors (NETs) produce lesser quantities of serotonin than do midgut NETs, accounting for a lower rate of carcinoid syndrome. Among patients with localized disease (the vast majority of cases of typical lung NETs), carcinoid syndrome is encountered uncommonly and most often with tumors of large size (>5 cm) [58]. Although it is encountered more often in patients with liver metastases, carcinoid syndrome is uncommon overall. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Carcinoid syndrome and carcinoid crisis'.)
Potentially resectable locoregional disease — Surgical resection represents the preferred strategy for patients with locoregional lung NETs producing carcinoid syndrome. (See 'Surgical resection' above.)
Unresectable disease
Somatostatin analogs — For patients with an unresectable lung NET and carcinoid syndrome, we recommend treatment with a somatostatin analog (SSA), such as octreotide or lanreotide.
SSAs bind to somatostatin receptors on the tumor cells, and they are highly effective at inhibiting the release of bioactive amines. Flushing and diarrhea are significantly improved in over 80 percent of patients with carcinoid syndrome. (See "Treatment of the carcinoid syndrome", section on 'Somatostatin-analog therapy'.)
Refractory symptoms — Treatment options for patients with symptoms of carcinoid syndrome that do not respond to SSA therapy include ablative treatments for liver metastases, systemic antiproliferative therapy with cytotoxic agents, peptide receptor radiation therapy (for patients with somatostatin-receptor-positive advanced disease), or telotristat, a tryptophan hydroxylase inhibitor. (See "Treatment of the carcinoid syndrome", section on 'Management of refractory symptoms'.)
ANTITUMOR THERAPY FOR ADVANCED DISEASE — The most frequent site of distant metastatic disease is the liver; other sites include bone, adrenal glands, and brain. The risk of distant metastases is higher for atypical lung neuroendocrine tumors (NETs) compared with typical NETs (21 versus 3 percent in one series of approximately 142 lung NETs [14]).
The rarity of lung NETs has prevented the design of prospective trials, and few data are available regarding treatment for relapsed or advanced disease. In most cases, treatment principles are extrapolated from experience with the more common gastrointestinal (GI) NETs. However, even among patients with GI tract NETs, optimal management, particularly in the setting of advanced unresectable disease, is not established.
Initial therapy for slowly progressive disease — For patients who have slowly progressive, metastatic, somatostatin-receptor-positive lung NETs (as determined by somatostatin-receptor-based diagnostic imaging), we suggest initiating therapy with a somatostatin analog (SSA).
SSAs have been shown to inhibit tumor growth in patients with advanced gastroenteropancreatic NETs. Randomized studies of SSAs versus placebo have not been completed in lung NETs. Two phase III trials demonstrating the antiproliferative effects of SSAs in gastroenteropancreatic NETs specifically excluded patients with lung NETs [59,60]. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Control of tumor growth' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)
A limited amount of data support antiproliferative activity for SSAs in patients with metastatic lung NETs that express somatostatin receptors. In a retrospective review of 61 patients with progressive, metastatic lung NETs (67 percent atypical, 48 percent with functioning tumors) who were treated with an SSA, the best overall response was stable disease in 77 percent [61]. With a median follow-up of 5.8 years, the median progression-free survival (PFS) and overall survival durations were 17.4 and 58.4 months, respectively. Patients with functioning tumors had significantly longer PFS (28.7 versus 8.7 months), as did those with slowly rather than rapidly progressive disease (with rapid progression defined as an at least 20 percent increase in the sum of the longest diameter of the target lesions or the appearance of one or more new lesions within six months), with a median PFS 26 versus 4.5 months.
The randomized phase III SPINET trial of lanreotide versus placebo in advanced, unresectable lung NETs (NCT02683941) was stopped early due to slow accrual; 77 patients were randomized to receive lanreotide (n = 51) or placebo (n = 26) [62]. In a preliminary report, median PFS was not significantly longer with lanreotide (16.6 versus 13.6 months, HR 0.90, 95% CI 0.46-1.88). Firm conclusions cannot be drawn due to the limited accrual.
Liver-dominant metastatic disease — For patients who have limited, potentially resectable, liver-dominant, metastatic NETs, surgical resection is often recommended. The liver is the predominant site of metastatic disease. As with gastroenteropancreatic NETs, hepatic resection is indicated for the treatment of selected patients with isolated, limited-volume, metastatic liver disease. Although the vast majority of cases will not be cured by surgery, symptoms of hormone hypersecretion (when present) are effectively palliated, and prolonged survival is often possible. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic-predominant metastatic disease'.)
Other liver-directed therapies for hepatic-predominant disease include hepatic artery embolization (bland particle embolization, chemoembolization, radioembolization) and radiofrequency ablation. Fewer data are available on the efficacy of these modalities in patients with lung as compared with gastroenteropancreatic NETs [63-65]. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Nonsurgical liver-directed therapy'.)
Progressive, disseminated, or SSA-refractory disease — Systemic therapy is appropriate for patients with progressive, disseminated, or SSA-refractory disease. Options include everolimus, cytotoxic chemotherapy, or for patients with somatostatin-receptor-positive tumors, peptide receptor radioligand therapy using the radiolabeled somatostatin analog (SSA) Lutetium Lu-177 dotatate (177Lu-dotatate), where available.
Everolimus — Based upon data from the RADIANT 4 trial, we suggest everolimus for treatment of progressive metastatic lung NETs. In some cases, everolimus may be an appropriate first-line option for patients with tumors that are somatostatin receptor negative on somatostatin-receptor-based imaging. Although the RADIANT 4 trial excluded concomitant SSA use, combination of everolimus with an SSA is safe and commonly prescribed in patients with GI NETs; it represents a reasonable choice for second-line therapy of slowly progressive lung NETs after failure of an SSA alone (particularly in patients with carcinoid syndrome). (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Everolimus'.)
Support for the benefit of everolimus in lung NETs comes from the RADIANT-4 trial, a phase III study in which 302 patients with advanced, nonfunctional, lung (30 percent) or GI tract NETs were randomized to receive everolimus or placebo [66]. Everolimus was associated with a significant improvement in median PFS, the primary endpoint (11 versus 3.9 months, hazard ratio 0.48, 95% CI 0.35-0.67). There was an overall objective response rate of 2 percent for everolimus compared with 1 percent for placebo, but the disease control rate was 81 percent for patients assigned to everolimus compared with 64 percent for placebo. Among the 90 patients in the trial who had lung NETs, the hazard ratio for PFS was 0.5 (95% CI 0.28-0.88). Adverse events (AEs) were mainly grade 1 or 2 and included stomatitis, diarrhea, peripheral edema, fatigue, and rash. The most-frequent severe (grade 3 or 4) AEs that were more common with everolimus were diarrhea (7 versus 2 percent), stomatitis (9 versus 0 percent), and anemia (4 versus 1 percent). Based on these results, everolimus was approved in February 2016 by the US Food and Drug Administration (FDA) for the treatment of adults with progressive, well-differentiated, nonfunctional NETs of lung origin with unresectable locally advanced or metastatic disease.
Cytotoxic chemotherapy — For patients with initially rapidly progressive disease or those who have failed therapy with everolimus, we suggest cytotoxic chemotherapy. We utilize cisplatin- or carboplatin-based chemotherapy regimens, such as those used for small cell lung cancer, for patients with highly aggressive atypical lung NETs, and we use temozolomide-based chemotherapy for patients with typical or atypical lung NETs with more indolent growth, although the level of evidence supporting use of these drugs in this setting is low. In our view, participation in clinical trials testing new strategies is the preferred approach.
For metastatic NETs as a group, multiple cytotoxic drugs have been tried in various combinations, but randomized trials have revealed only minor activity. As a result, there is no standard regimen, and the role of chemotherapy continues to be debated. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Cytotoxic chemotherapy'.)
There are some data to suggest that lung NETs are less chemosensitive than pancreatic NETs but more sensitive than midgut NETs.
●Patients with metastatic disease from lung NETs are often treated with regimens that are typically used for small cell lung cancer. Although chemotherapy responsiveness is not as predictable as it is with small cell lung cancer, objective partial responses have been documented using cisplatin plus etoposide [67,68]. It is likely that platinum-based regimens are more active in atypical NETs that have relatively aggressive pathological features than in relatively low-grade tumors.
●Some data suggest activity with single-agent temozolomide. In a retrospective study of 31 patients with progressive metastatic lung NETs (14 typical, 15 atypical, 2 unclassifiable), all received oral temozolomide for five consecutive days every 28 days [69]. Three (14 percent) had a partial response, and 11 others had stable disease (52 percent). The median PFS and overall survival durations were 5.3 and 23.2 months, respectively. Grade 3 or 4 toxicities included thrombocytopenia in three and neutropenia in one.
Although these results seem promising, activity for temozolomide monotherapy in advanced lung NETs has not yet been confirmed in prospective studies.
●A few objective responses have also been reported in case reports and small series of patients treated with temozolomide plus capecitabine, fluorouracil plus dacarbazine and epirubicin, capecitabine plus oxaliplatin, and capecitabine plus pegylated liposomal doxorubicin [70-74].
Lutetium Lu-177 dotatate — Another option for treatment of somatostatin-receptor-positive advanced disease is peptide receptor radioligand therapy using radiolabeled SSAs such as lutetium Lu-177 dotatate (177Lu-dotatate).
177Lu-dotatate has been studied mainly for the treatment of gastroenteropancreatic NETs. Among patients with advanced midgut NET, the benefits of 177Lu-dotatate were shown in the NETTER-1 trial, which demonstrated significant improvement in objective response rate, PFS, and overall survival with 177Lu-dotatate compared with high-dose long-acting octreotide in patients whose disease had progressed on standard-dose SSA therapy (median PFS not reached versus 18 months) [75]. These data are discussed in detail elsewhere. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs'.)
Although the experience is more limited, responses are reported in lung NETs [76-82]:
●In one of the largest series, in which 48 patients with progressive lung NETs were treated with 177Lu-dotatate, the disease control rate was 64 percent (partial response 20 percent, stable disease 44 percent), and the median PFS and overall survival were 23 and 59 months, respectively [82].
●Efficacy results are also available from a large series of Dutch patients treated with 177Lu-dotatate, of whom 23 had a lung NET [81]. The objective response rate in the lung cohort was 30 percent, and an additional 30 percent had stable disease. At a median follow-up of 78 months, median PFS was 20 months, and median overall survival was 52 months. The safety analysis included 610 patients with either gastroenteropancreatic or lung NETs who had received a cumulative dose of at least 100 millicuries (3.7 gigabecquerels [GBq]). Long-term toxicity included acute leukemia in four patients (0.7 percent, three fatal) and myelodysplastic syndrome in nine (1.5 percent, five fatal). There was no therapy-related long-term renal or hepatic failure.
Largely based upon data from the NETTER-1 trial, in January 2018, the US FDA approved 177Lu-dotatate for the treatment of somatostatin-receptor-positive gastroenteropancreatic NETs in adults [83]. While the approval did not cover bronchial NETs, off-label use could be considered in appropriate patients with somatostatin receptor-expressing tumors.
Painful bone metastases — Radiation can provide useful pain relief for patients with bone metastases [54,84].
Recommendations from expert groups — There are recommendations for management of advanced disease from expert groups, including the National Comprehensive Cancer Network (NCCN) [43], European Neuroendocrine Tumor Society (ENETS) [44], Commonwealth Neuroendocrine Tumour Research Collaboration (CommNETs), ESMO [45], and the North American Neuroendocrine Tumor Society (NANETS), which largely endorsed the 2015 ENETs recommendations [13]. However, there is no consensus as to the optimal approach for individual patients.
MANAGEMENT OF PATIENTS WITH DIPNECH — Most patients with symptomatic diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) have chronic cough, dyspnea, and bilateral multifocal involvement with neuroendocrine cell hyperplasia and neuroendocrine tumorlets. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia'.)
Many cases remain stable over many years. However, in general, DIPNECH is a chronic, slowly progressive disease, with progression of both respiratory symptoms and tumor growth.
At least some evidence suggests that somatostatin analogs (SSAs) can improve respiratory symptoms as well as pulmonary function. In a series of 42 patients with chronic cough or dyspnea due to proven or suspected DIPNECH and were treated with SSAs, 33 patients (79 percent) experienced symptomatic improvement. Additionally, 14 of 15 patients in whom pulmonary function tests were checked were noted to have an improvement in the forced expiratory volume in one second after treatment [85]. Although fewer data are available, SSAs may also stabilize tumor growth [86].
Although neuroendocrine tumorlets in this condition are typically benign and indolent, progression of individual lesions into invasive, low-grade, malignant neuroendocrine tumors (NETs) can occur rarely, and radiographic surveillance is appropriate, usually no more often than once a year.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●Resectable localized disease
•For patients with either a low- or intermediate-grade resectable lung NET whose medical condition and pulmonary reserve are adequate, we recommend surgical resection including mediastinal lymph node sampling or dissection (Grade 1B). (See 'Surgical resection' above.)
•For most patients, endobronchial resection is suboptimal, and we suggest not pursuing this approach over definitive surgical resection (Grade 2C). Endobronchial laser resection is best reserved for palliative treatment of patients with central airway occlusion who are poor surgical candidates (eg, older adults, debilitated). (See 'Endobronchial management' above.)
•Although some disagree, we suggest not routinely administering postoperative adjuvant therapy for resected lung NETs, even in the setting of positive lymph nodes (Grade 2C).
Adjuvant platinum-based chemotherapy with or without radiation therapy (RT) is a reasonable option for patients with histologically aggressive-appearing, stage III (table 2), intermediate-grade lung NETs (ie, relatively high mitotic rate, extensive necrosis, etc), although there is only limited evidence to support this.
RT is a reasonable option for intermediate-grade lung NETs if gross residual disease remains after surgery, although whether this improves outcomes is unproven. (See 'Role of adjuvant therapy' above.)
•We pursue posttreatment surveillance after resection of node-positive low-grade lung NETs and for all intermediate-grade tumors. CT of the chest and abdomen every six months for two years followed by annual scans for a total of 5 to 10 years represents a reasonable surveillance schedule. (See 'Posttreatment surveillance' above.)
●Inoperable locally advanced
•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.
•For a small, peripheral, low-grade lung NET in a patient who is not a physiologic candidate for surgical resection, stereotactic body radiation is a reasonable option. (See 'Inoperable and locally advanced unresectable disease' above.)
●Carcinoid syndrome
•Carcinoid syndrome, while uncommon, can occur in patients with locoregional or disseminated disease. Surgical resection represents the preferred strategy for patients with locoregional lung NETs producing carcinoid syndrome. For unresectable disease, we recommend initiation of long-acting somatostatin analog (SSA) therapy with either octreotide or lanreotide rather than surgical debulking (Grade 1B). (See 'Management of carcinoid syndrome' above.)
•Treatment options for patients with refractory symptoms include ablative treatments for liver metastases, systemic antiproliferative therapy with cytotoxic agents, peptide receptor RT (for patients with somatostatin-receptor-positive advanced disease), or the tryptophan hydroxylase inhibitor telotristat. (See 'Refractory symptoms' above.)
●Antitumor therapy, advanced disease
•For patients with initially slowly progressive, metastatic, somatostatin-receptor-positive (as determined by somatostatin-receptor-based diagnostic imaging) lung NETs, we suggest initiating therapy with an SSA for disease control (Grade 2C). (See 'Initial therapy for slowly progressive disease' above.)
•For patients who have limited, potentially resectable, liver-dominant, metastatic NETs, surgical resection may extend survival. (See 'Liver-dominant metastatic disease' above and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)
•Local treatment options for patients with unresectable, hepatic-dominant, metastatic disease include embolization (bland particle embolization, chemoembolization, radioembolization) and radiofrequency ablation. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Nonsurgical liver-directed therapy'.)
•For patients with progressive or disseminated SSA-refractory disease, everolimus is an option. In some cases, everolimus may be an appropriate first-line option (eg, for patients with tumors that are somatostatin receptor [SSR] negative on SSR-based imaging). (See 'Everolimus' above.)
For patients with initially rapidly progressive disease, and/or for those who progress while receiving, or are intolerant of everolimus, cytotoxic chemotherapy is reasonable. We utilize cisplatin- or carboplatin-based chemotherapy regimens, such as those used for small cell lung cancer, for patients with highly aggressive atypical lung NETs, and we use temozolomide-based chemotherapy for patients with more indolent, typical or atypical lung NETs, although the level of evidence supporting use of these drugs in this setting is low. (See 'Cytotoxic chemotherapy' above.)
Another option for treatment of SSR-positive advanced disease, is peptide receptor radioligand therapy with lutetium Lu-177 dotatate (177Lu-dotatate), where available. (See 'Lutetium Lu-177 dotatate' above.)
•RT can provide useful pain relief for patients with bone metastases. (See 'Painful bone metastases' above.)
●Patients with DIPNECH – Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a chronic, slowly progressive disease, with progressive dyspnea and enlarging tumors. SSA therapy may improve respiratory symptoms and stabilize tumor growth. (See 'Management of patients with DIPNECH' above.)
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