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Granberg, D.; Juhlin, C.C.; Falhammar, H.; Hedayati, E. Treatment for Lung Carcinoids. Encyclopedia. Available online: https://encyclopedia.pub/entry/52264 (accessed on 07 July 2024).
Granberg D, Juhlin CC, Falhammar H, Hedayati E. Treatment for Lung Carcinoids. Encyclopedia. Available at: https://encyclopedia.pub/entry/52264. Accessed July 07, 2024.
Granberg, Dan, Carl Christofer Juhlin, Henrik Falhammar, Elham Hedayati. "Treatment for Lung Carcinoids" Encyclopedia, https://encyclopedia.pub/entry/52264 (accessed July 07, 2024).
Granberg, D., Juhlin, C.C., Falhammar, H., & Hedayati, E. (2023, December 01). Treatment for Lung Carcinoids. In Encyclopedia. https://encyclopedia.pub/entry/52264
Granberg, Dan, et al. "Treatment for Lung Carcinoids." Encyclopedia. Web. 01 December, 2023.
Treatment for Lung Carcinoids
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15225440

Lung carcinoids are divided into typical and atypical. Most tumors are slow-growing yet have malignant potential, which is more common in patients harboring atypical carcinoids. Most patients with lung carcinoids are diagnosed before the occurrence of distant metastases. Surgery is curative in most of these cases. In individuals with distant metastases, the treatment is more controversial. A watch-and-wait policy has been proposed in asymptomatic individuals with a low proliferative rate. Possible treatment options include somatostatin analogues, chemotherapy, mTOR inhibitors, and radionuclide therapy with 177Lu-DOTA-octreotate, depending on somatostatin receptor expression, proliferative rate, bone marrow and kidney function, and the patient’s general health.

lung carcinoids symptoms diagnosis treatment

1. Introduction

Neuroendocrine tumors may arise in many organs in the body, including the gastrointestinal tract, lungs, and sympathetic and parasympathetic ganglia. The presence of neuroendocrine cells in the lungs was first described by Frölich in 1949 [1] and confirmed by Feyrter in 1954 [2]. These cells may be solitary or occur in clusters, termed neuroepithelial bodies [3][4]. Neuroendocrine cells in the lungs are believed to be the origin of neuroendocrine lung tumors [5][6][7][8]. Neuroendocrine lung tumors are divided into typical and atypical carcinoids, large cell neuroendocrine carcinomas, and small cell lung carcinomas. Arrigoni et al. were the first to introduce the division of pulmonary neuroendocrine tumors into typical and atypical carcinoids and small-cell lung carcinomas [9]. More recently, several other classifications have been suggested. For a long time, lung carcinoids were considered relatively benign neoplasms, and patients were often monitored with chest X-rays for a few years before being discharged.

2. Surgery

For patients with typical and atypical lung carcinoids without distant metastases, surgery involving the complete removal of the primary tumor and a systematic lymph node dissection, which eliminates all affected lymph nodes, is recommended as the sole curative treatment. It is essential to preserve as much healthy lung parenchyma as possible. Surgical methods include bronchotomy with excision of the tumor and bronchoplasty, sleeve resection where the part of the bronchus containing the tumor is resected and an end-to-end anastomosis is performed, wedge or segmental resection, lobectomy, bilobectomy, and pneumonectomy. When deciding the surgical procedure, the type of tumor (typical/atypical), presence of lymph node metastases and surrounding tumorlets, and the age and lung function of the patient must all be taken into account. In contrast to lung cancer, carcinoids do not require wide resection margins. Peripheral tumors can be removed by wedge resection, segmentectomy, or lobectomy/bilobectomy. Small central tumors can be treated with bronchotomy with resection of the tumor and bronchoplasty, sleeve resection of the bronchus, or segmentectomy [10][11][12], while larger central tumors may require lobectomy or bilobectomy. An advantage of sleeve resection is that the hospital morbidity and mortality are very low [10] and more lung function is preserved. Pneumonectomy is reserved for large invasive central tumors. In older patients and patients with reduced lung function, great efforts should be made to preserve maximum lung parenchyma. Intra-operative biopsies with examination of frozen sections are warranted. Individuals diagnosed with atypical carcinoids should undergo at least a lobectomy as a basic surgical intervention [13][14][15]. Nowadays, most surgeries for lung carcinoids are performed by video-assisted thoracoscopic surgery (VATS) [16], which leads to better quality of life as well as better-preserved lung and shoulder function compared with open surgery [17]. Even if there is a small risk for conversion to open surgery, especially in larger tumors, this does not result in more postoperative complications [18].

3. Interventional Pulmonology

Since lung carcinoids often grow profoundly into the surrounding tissue, endoscopic excision of the mass by YAG laser is usually not recommended. Two studies, however, found that bronchoscopic laser therapy was a safe and effective treatment option for approximately 54–64% of individuals with typical intrabronchial carcinoids; open surgery had to be performed later for the remaining patients [19][20]. If possible, a sleeve resection may instead be performed to avoid a lobectomy and repeated surgery [11]. Open surgery is not recommended for individuals with a high risk of cardiopulmonary complications. Instead, their obstructive symptoms may be palliated by YAG-laser-mediated removal or reduction of an intrabronchial carcinoid. Moreover, in a few patients, laser treatment to reduce the tumor mass may enable surgery after post-obstructive infiltrates have resolved. There is no scientific evidence for adjuvant chemotherapy after radical surgery [21][22].

4. Radiotherapy

External radiotherapy is mainly performed to alleviate pain from bone metastases and treat brain metastases but is also recommended as a complementary treatment modality after incomplete resection or palliative treatment in inoperable tumors. Peptide receptor radionuclide therapy (PRRT) is a possibility in individuals with metastatic or inoperable tumors showing high expression of somatostatin receptors on 68Ga-DOTATOC or 68Ga-DOTATATE PET. In one small study, a radiological response was observed among 5/9 patients receiving 177Lu-DOTA-octreotate for a median of 31 months [23], and in another study, 29% (24/84) treated with 90Y-DOTA-octreotide responded objectively [24]. Since 9.5% of all patients treated with the 90Y-DOTA-octreotide experienced a serious permanent worsening of the kidney function, 177Lu-DOTA-octreotate may be preferable. Ianniello et al. treated 34 patients having progressive lung carcinoids (15 typical, 19 atypical) with four to five cycles of 177Lu-DOTA-octreotate up to a cumulated activity of 18.5 or 27.8 GBq. Individuals with typical carcinoids achieved a disease control rate of 80% (6% complete response, 27% partial response, and 47% stable disease) with a median PFS of 20.1 months, while individuals with atypical carcinoids had a disease control rate of 47.5% (no objective response) with a median PFS of 15.7 months [25]. Sabet et al. reported 22 patients that received four cycles of 7.8 GBq 177Lu-DOTATATE with three-month intervals; partial response occurred in 6 (27.3%) and stable disease in 9 (40.9%). Median PFS was 27 months, and median overall survival (OS) was 42 months [26]. Another, more extensive, retrospective study encompassing 114 patients compared three protocols: 90Y-DOTATOC, 177Lu-DOTATATE, and 90Y-DOTATOC + 177Lu-DOTATATE. Median OS was 58.8 months, and median progression-free survival (PFS) was 28.0 months. In that study, 15 patients (13.3%) had objective response and 61 (53.5%; including 15 individuals with minor response) had stable disease. Individuals treated with the combination of 90Y-DOTATOC and 177Lu-DOTATATE showed the best objective response rate (38.1%) [27].

5. Somatostatin Analogues

The somatostatin analogues octreotide and lanreotide have previously demonstrated antitumoral activity in gastrointestinal and pancreatic neuroendocrine tumors [28][29]. Sullivan et al. evaluated 61 patients with lung carcinoids (20 typical, 41 atypical) receiving octreotide long-acting release (LAR) 20 or 30 mg intramuscularly every four weeks or lanreotide LAR 90 or 120 mg subcutaneously every four weeks. Forty-one patients were slowly progressing before the start of somatostatin analogue treatment. The best response was stable disease seen in 47 patients (77%). Median PFS and median OS were 17.4 months and 58.4 months, respectively. Individuals with slowly progressive disease before the somatostatin analogue and patients with functioning tumors had significantly longer PFS [30]. In a more recent report, 31 consecutive individuals, 14 with typical and 17 with atypical lung carcinoids, used first-line octreotide LAR or lanreotide depot every four weeks. A majority (60%) had Ki67 ≤ 10%. Partial response was observed in 2 individuals (6.5%), stable disease in 24 (77.4%), and progressive disease in 5 (16.1%) individuals. Median PFS was 28.6 months, and median OS was not achieved. Median PFS was longer, yet not significantly, in individuals with typical carcinoids and Ki67 ≤ 10% [31]. The double-blind SPINET trial, randomizing individuals with somatostatin-receptor-positive typical and atypical carcinoids 2:1 to lanreotide LAR 120 mg s.c. or placebo every four weeks, was ended early due to slow accrual after inclusion of 77 individuals (52 lanreotide, 26 placebo). Results were presented at the 2021 ESMO meeting. PFS was 21.9 months for lanreotide vs 13.9 months for placebo in individuals with typical carcinoids and 13.8 months for lanreotide vs 11.0 months for placebo in atypical carcinoids. The authors concluded that lanreotide 120 mg every 4 weeks could be an appropriate treatment especially for individuals with typical carcinoids [32].

6. Chemotherapy

In individuals with metastatic lung carcinoids, several chemotherapy regimens have shown to have limited response rates. The modalities that have been studied are single cisplatin and docetaxel, carboplatin + etoposide, paclitaxel ± doxorubicin, streptozotocin + 5-fluorouracil or doxorubicin, oxaliplatin + capecitabine, 5-fluorouracil + dacarbazine + epirubicin, and 5-fluorouracil + cisplatin + streptozotocin [33][34][35][36][37][38][39]. The best results were observed with temozolomide. In one report encompassing 31 individuals with typical or atypical carcinoids, objective tumor response was demonstrated in 14% and stabilization of progressive disease in 52%. All individuals with partial response were found to have atypical carcinoids, but stabilization was noted in both typical and atypical carcinoids [40]. Combining temozolomide with capecitabine has yielded similar results. Papaxoinis et al. treated 33 individuals with well-differentiated lung carcinoids (10 typical, 20 atypical, 3 not specified) with capecitabine 750 mg/m2 twice daily day 1–14 and temozolomide 200 mg/m2 day 10–14, repeated every four weeks for at most six cycles, followed by maintenance therapy with octreotide LAR 30 mg intramuscularly every four weeks. Partial response was found in 6 (18%) and stable disease in 19 (58%) patients. The median response duration was 21.7 months, median PFS was 9.0 months, and median OS was 30.4 months [41].

7. Targeted Therapies

Several medications targeting signal pathways or membrane receptors have shown activity in individuals with neuroendocrine neoplasia. In 2011, two reports were published demonstrating that both everolimus, an inhibitor of mammalian target of rapamycin (mTOR), and sunitinib, inhibiting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-kit, prolong PFS in persons with pancreatic endocrine tumors [42][43].

8. mTOR Inhibitors

Everolimus was also studied in individuals with lung carcinoids. In a subanalysis from the randomized, placebo-controlled RADIANT-2 study, PFS in lung carcinoid patients treated with everolimus + octreotide LAR was 13.6 months vs 5.6 months in the group with placebo + octreotide LAR. However, no significant difference was found. A small response was observed in 67% and 27% in the everolimus and placebo groups, respectively [44]. In another subanalysis from the randomized phase 3 RADIANT-4 study, encompassing 90 individuals with well-differentiated lung carcinoids, everolimus 10 mg od (n = 63) was compared with placebo (n = 27). Median PFS was 9.2 months (95% CI 6.8–10.9) in the everolimus group and 3.6 months (95% CI 1.9–5.1) in the placebo group. The risk for disease progression or death was reduced by 50% in the everolimus group. Tumor shrinkage was observed in 58% of the individuals receiving everolimus vs 13% among those that were on placebo [45]. In the LUNA study, everolimus (n = 42) was compared with long-acting pasireotide (n = 41) and everolimus + pasireotide (n = 41) in persons with well-differentiated lung and thymic carcinoids. Disease control rate (complete response + partial response + stable disease) after 9 months was 33.3% in the everolimus group, 39.0% in the pasireotide group, and 58.5% in the combination group [46]. These data suggest that everolimus has antitumor activity in individuals with lung carcinoids. According to recommendations in the Commonwealth Neuroendocrine Tumor Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines, everolimus should be considered in progressing lung NETs, both non-functional and functional [47].

9. Anti-Angiogenic Drugs

The tyrosine kinase receptors PDGFRα, PDGFRβ, c-kit, and EGFR are expressed in most lung carcinoids [48]. However, neither sunitinib nor pazopanib, an inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFRα, PDGFRβ, and c-kit, has been studied in lung carcinoids except as small parts of more extensive studies, with no convincing results [49][50].

10. Immune Therapy

Immune checkpoint inhibitor antibodies target the interaction between programmed death receptor 1 (PD-1) and its ligand PD-L1. Examples are pembrolizumab, nivolumab and atezolizumab. Antitumoral activity has been shown in several tumor types. There are few clinical data for patients with lung carcinoids. Spartalizumab, a humanized anti-PD-1 antibody blocking PD-L1 and PD-L2, was investigated in a phase 2 study with advanced non-functioning neuroendocrine tumors progressing on prior therapy. In 30 patients with thoracic NET, partial response was observed in 5 (16.7%), all harboring atypical tumors. In addition, 17 (56.7%) had stable disease [51]. In the KEYNOTE-028 study, individuals with advanced PD-L1-positive carcinoid or pancreatic neuroendocrine neoplasia were treated with pembrolizumab 10 mg/kg every fortnight for up to 2 years. Nine patients with lung carcinoids were included, of whom one had a partial response lasting seven months [52]. Although Tsuruoka et al. found no expression of PD-L1 in typical and atypical carcinoids [53], further testing of immune checkpoint inhibitors in persons with lung carcinoids would be highly interesting since antitumoral activity has been observed in other tumor types regardless of PD-L1 expression [54].

11. Local Treatment

Patients with progressing liver metastases and stable or no disease outside the liver or uncontrollable hormonal symptoms from liver metastases may benefit from debulking of the liver metastases. This may be performed by embolization of the hepatic arteries with particles causing ischemia in the metastases, 90Y-labeled microspheres (SIR-Spheres® or TheraSpheres®) causing a local radiation effect in the metastases, or chemotherapeutic agents. Although radiofrequency or microwave ablation of liver metastases has not been shown to prolong survival in individuals with liver metastases from ileal neuroendocrine tumors [55], this can be an alternative for individuals with a limited number of liver metastases or patients in whom only one liver metastasis is progressing and the other remains stable.

12. Adjuvant Treatment

There are no data supporting prolonged survival with adjuvant chemotherapy or radiotherapy after surgical resection either of typical or atypical carcinoids [22][56][57].

13. Symptomatic Treatment

The primary symptomatic treatment for classical carcinoid syndrome is somatostatin analogues [14][58]. Patients with diarrhea and high 5-HIAA levels may in addition benefit from telotristate ethyl [59][60]. Bilateral adrenalectomy is the most efficient symptomatic therapy in persons with ectopic Cushing syndrome and metastatic disease [61]. Other options include ketoconazole, metyrapone [58], somatostatin analogues [62], and mitotane [61], which can also be used to correct the metabolic disturbances before surgery in patients without distant metastases.

14. Treatment of DIPNECH

There is no accepted treatment for patients with DIPNECH, but bronchodilators or inhaled corticosteroids could be tried in addition to surgical excision of the largest lesion(s). Systemic therapy with somatostatin analogues was shown to stabilize the condition [63]. DIPNECH is stable in approximately half of individuals, and the remaining half will develop progressive disease [64][65].

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Dan Granberg
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Carl Christofer Juhlin
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Henrik Falhammar
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Elham Hedayati
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Update Date: 04 Dec 2023
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