Neoadjuvant Capecitabine Plus Temozolomide in Atypical Lung NETs

Summary

Neoadjuvant and adjuvant remedy in lung neuroendocrine tumors (NETs) is a subject that has not been explored in-depth, with little data on the influence on disease-free survival. This case research highlights the effectiveness of neoadjuvant remedy with capecitabine plus temozolomide (CAPTEM) in a girl with well-differentiated atypical carcinoid. The affected person was asymptomatic at prognosis and was referred to the outpatient NET clinic at Sotiria Hospital in Athens, following an incidental discovering on a chest x-ray. ¹⁸F-fluorodeoxyglucose (FDG) PET/CT and ⁶⁸Ga-Dotatoc PET/CT revealed one other mass within the pancreas, with avidity in each imaging research. The affected person underwent remedy for six months with CAPTEM with a response within the lung NET and mediastinal lymph nodes. Nevertheless, the mass within the pancreas barely elevated and was eliminated with a central pancreatectomy. The affected person continued remedy with CAPTEM for six extra months. There was additional response in accordance with RECIST 1.1 standards (partial response within the mediastinal lymph nodes and a 21% regression within the main tumor measurement). Pathology report after lobectomy with lymph node dissection confirmed a pathologic full response within the mediastinal lymph nodes. Twenty-four months after surgical procedure, the affected person stays disease-free and has a great high quality of life. Though giant medical trials are wanted, this case research underlines the worth of preoperative chemotherapy in atypical carcinoids.

Background

Lung neuroendocrine tumors (NETs) are uncommon malignancies, accounting for 1% to 2% of all lung cancers.¹ They’re sporadic tumors with an unclear affiliation with smoking, and a minority are associated to MEN1 pathogenic variants.² There’s a paucity of proof for managing totally different medical situations in sufferers recognized with these tumors, together with the indications for adjuvant and neoadjuvant remedy. Surgical procedure is the really helpful strategy within the native/domestically superior stage with out typically accepted standards defining what constitutes a resectable illness. On this case report, a girl with MEN1 pathogenic variant, an atypical lung NET within the decrease lobe of her left lung with confirmed metastases to mediastinal lymph nodes with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy, and a synchronous main grade 2 NET within the physique of the pancreas underwent remedy with capecitabine plus temozolomide (CAPTEM). After 6 months of remedy, the pancreatic NET (panNET) was eliminated with a central pancreatectomy. The affected person continued remedy with CAPTEM for one more 6 months and underwent lobectomy with lymph node dissection (together with stations 12, 11, 10, 9, 8, and seven); there was full pathologic remission within the mediastinal lymph nodes, with a main tumor shrinkage of roughly 21%.

Case Presentation

A 62-year-old White lady with a recognized historical past of hypercalcemia handled with parathyroidectomy 8 years in the past offered with fever and productive cough to her normal practitioner (GP). She was a never-smoker and had a historical past of dyslipidemia on remedy with a statin. Her GP ordered a chest x-ray, revealing a mass within the left decrease lobe. The GP prescribed antibiotics and referred the affected person to the outpatient NET clinic of Sotiria Common Hospital of Thoracic Ailments in Athens, Greece, to handle the lung mass. There was no household historical past of most cancers; her older son obtained a prognosis of hypercalcemia at age 30 years. On the outpatient clinic, the affected person appeared in good normal well being; signs from the current an infection had subsided, and she or he was anxious in regards to the mass within the chest x-ray. There was no stridor on auscultation, and respiratory sounds have been regular in each lungs. She reported no adjustments in her skill to handle on a regular basis duties or weight reduction over the previous 12 months. She had no breathlessness, ache, or different signs over the earlier 12 months in addition to coughing and fever within the first days of the an infection, which had resolved.

Imaging and Laboratory Outcomes

• A chest CT scan confirmed a mass of three.8 x 3.2 cm in
  the left decrease lobe and enlarged subcarinal lymph nodes (2.4 x 1.9 cm). Bronchoscopic biopsy of the mass revealed atypical bronchial NET.
• Ki-67 of 20%
• Thyroid transcription factor-1 unfavourable
• Orthopedia homeobox protein (OTP) unfavourable
  Somatostatin receptor subtype 2 + 3 (Determine 1)
• EBUS-TBNA confirmed metastasis of the NET to
  lymph nodes in station 7.

An ¹⁸F-fluorodeoxyglucose (FDG) PET/CT scan confirmed the findings and, as well as, confirmed an FDG-avid mass within the physique of the pancreas, 1.2×1 cm (Figures 2 and three). The cytology from the endoscopic ultrasound–guided fine-needle aspiration biopsy of the pancreatic mass confirmed a NET. Nevertheless, due to insufficient materials, there was no additional characterization of the tumor’s main origin and grade. A ⁶⁸Ga-PET/CT scan revealed avidity within the mass of the left decrease lobe, subcarinal lymph nodes, and pancreatic mass (Figures 4 and 5).

FIGURE 4. Dotatoc PET-CT exhibiting avidity of the first tumor within the left decrease lobe (customary uptake worth 15.9).

FIGURE 5. Dotatoc PET-CT exhibiting avidity in mediastinal lymph nodes (station 7; customary uptake worth 8.8).

Therapy

The affected person was referred to a geneticist because of a household historical past of hypercalcemia and NET prognosis. The genetic evaluation revealed 4 members within the genealogic tree with early-onset hyperparathyroidism, and genetic testing within the affected person confirmed a pathologic variant in MEN1 gene c.959C>G (p.Pro320Arg) in exon 7 (Determine 6). Consequently, members of her household tree have been knowledgeable and screened for a similar variant, though some refused to endure the check. Her older son, was additionally a service of the pathogenic variant, and additional investigations revealed no indicators of MEN1 syndrome manifestations. Despite the fact that surgical remedy was an possibility for each lung and pancreatic lesions at this level, a stepwise strategy was thought of extra acceptable. The investigators determined to begin remedy with CAPTEM and observe the responsiveness of the illness and its organic habits. If there was illness development following 3 to six months of remedy with CAPTEM, the risk-benefit ratio of surgical resection of each the lung and the pancreatic lesions could be of doubtful worth for the affected person primarily based on knowledge extrapolated from different neoplasms reminiscent of oligometastatic non–small cell lung most cancers (NSCLC) and colon most cancers liver metastases.^3,4

FIGURE 6. Sufferers’ genealogic tree. The affected person’s older son was recognized with hypercalcemia at 30 years previous. Each he and the affected person are carriers of the pathologic variant in MEN1 gene c.959CG (p.Pro320Arg) in exon 7.

Quite the opposite, illness management or tumor shrinkage with CAPTEM would render surgical resection a extra favorable possibility with probably higher probabilities for extended disease-free survival. The affected person tolerated CAPTEM effectively, with primary complaints of nausea and exhaustion on the times the two medication have been taken collectively. There was additionally grade 1 leukopenia and anemia that didn’t require medical intervention. Following 6 months of remedy, there was a minor quantity discount of the mass within the left decrease lobe from 3.8 x 3.2 cm to three.7 x 3.0 cm and subcarinal lymph node from 2.4 x 1.9 cm to 2.2 x 1.8 cm however a rise within the measurement of the pancreatic mass from 1.2 x 1 cm to 1.4 x 1 cm. Therapy with CAPTEM was discontinued for 1 month, and the mass was excised with a central pancreatectomy. Pathology reported a grade 2 panNET, islet cell antibody constructive, 2 to three mitoses per mm2, Ki-67 of three%, with out lymph node metastases. The affected person recovered with out issues and continued remedy with CAPTEM for six weeks after the operation. After one other 6 months of remedy with CAPTEM, an additional discount was noticed within the mass measurement in left decrease lobe from 3.7 x 3.0 cm to three.1 x 3.0 cm and within the subcarinal lymph node from 2.2 x 1.8 cm to 2.0 x 1.6 cm. Due to the response to remedy, the affected person underwent left decrease lobe resection with hilar and mediastinal lymph node excision. The pathology report confirmed the preliminary prognosis of atypical carcinoid, Ki-67 of 20%, OTP unfavourable, 4 mitoses per 2 mm², and no most cancers cells recognized within the subcarinal lymph nodes.

Outcomes and Comply with-Up

The affected person recovered with no vital issues. Nevertheless, returning to her typical actions took 5 to six months. She misplaced 7% of her weight within the first 4 months and has been secure ever since. FDG PET/CT and ⁶⁸Ga PET/CT scans publish surgical procedure confirmed no avid lesions. The affected person is on follow-up with CT scans each 6 months with no indicators of recurrence 24 months following the lobectomy. The affected person stories occasional ache within the space across the surgical wound, which she correlates with climate adjustments. Concerning her older son, an MRI of the pituitary gland confirmed an enlarged gland (1.8×1.5×1.7 cm) with no particular indications of a lesion with a light shift of the stalk of the gland. He stays asymptomatic and has common follow-ups in accordance with revealed pointers by the neurosurgeon and within the NET clinic.⁵

Dialogue

The case research highlights the efficacy of neoadjuvant remedy in a affected person with atypical carcinoid, which might considerably have an effect on the administration of those tumors. There are restricted potential knowledge for the effectiveness of neoadjuvant or adjuvant remedy for these uncommon tumors, and due to this fact medical administration depends on consensus pointers and revealed case collection. As well as, MEN1 pathogenic variants are uncommon findings in sufferers with atypical carcinoids, and this report contributes to a greater understanding of the organic habits of those uncommon circumstances.

Within the research by Daddi et al, a retrospective evaluation of 247 sufferers with atypical carcinoids, just one affected person had the MEN1 pathogenic variant (0.4%), indicating that these tumors are principally sporadic.⁶ Neoadjuvant chemotherapy was chosen as a remedy plan in 6 of 247 sufferers (2.8%), reflecting the clinicians’ insecurity within the effectiveness of neoadjuvant remedy. Quite the opposite, adjuvant remedy with both chemotherapy, radiotherapy, or each was chosen in 27% of sufferers, with nodal metastasis being the primary choice criterion. This evaluation illustrates the bias in decision-making for managing these tumors principally from practices utilized in NSCLC or SCLC.

Neoadjuvant chemotherapy has been evaluated in retrospective research, principally domestically superior and oligometastatic gastroenteropancreatic NETs (GEP-NETs). In 662 sufferers with GEP-NETs handled in European and Asian facilities, chemotherapy was administered within the neoadjuvant setting in 1.4% of the sufferers,6 whereas in one other collection, this proportion was 4%.^7,8 Totally different regimens have been examined within the preoperative setting with no head-to-head comparability of their effectiveness. Outcomes of a research by Dumont et al confirmed improved charges of R0 resection and better charges of tumor downstaging following neoadjuvant remedy, which led to surgical resection in low to intermediate panNETs.⁹ Opposite to those outcomes, different research confirmed no vital downstaging in localized panNETs with preoperative remedy when totally different regimens have been used.^10,11 Moreover tumor shrinkage, a current research by Xie et al investigated the usage of neoadjuvant remedy within the largest group of sufferers with pancreatic neuroendocrine neoplasms (pNENs).¹² The research included 4892 sufferers who underwent surgical procedure with the intent of curing their most cancers. The researchers discovered no vital enchancment in total survival, even in sufferers with grade 1 and a pair of pNENs. These findings counsel that neoadjuvant remedy ought to be used with warning in sufferers with pNENs, as there’s a lack of conclusive proof to assist its use.

Restricted proof exists on the effectiveness of preoperative chemotherapy in lung NETs. In a collection of 45 sufferers with typical and atypical carcinoids, 2 sufferers underwent neoadjuvant remedy with fluorouracil, cisplatin, and streptozocin, and each sufferers had good response and tumor downstaging.13 Peptide receptor radionuclide remedy (PRRT) has additionally been evaluated within the preoperative setting in sufferers with midgut and lung NETs with reasonable response charges.^14-16 In a meta-analysis of 468 sufferers with pNENs, each PRRT and chemotherapy confirmed efficacy in tumor shrinkage, with PRRT having a major benefit over chemotherapy concerning total response charge.¹⁷ In sufferers with lung NETs, tumor shrinkage was considerably lower than in these with panNETs.

CAPTEM is a chemotherapy routine with a reasonable toxicity profile and response charges starting from 21% to 44%.^18-20 It’s efficient each in typical and atypical carcinoids in addition to GEP-NETs and can be utilized in first or later traces of remedy.²¹ In a research the place CAPTEM was used within the preoperative setting in sufferers with panNETs, 43% of sufferers had a partial response and 54% had secure illness.²² These sufferers had a median progression-free survival of ^28.2 months and 5-year total survival of 63%.

The outcomes of most research present that adjuvant chemotherapy has no clear profit in typical and atypical carcinoids, even in confirmed nodal metastasis.^23,24 These outcomes ought to be interpreted cautiously due to their retrospective nature and contemplating that many variables may have an effect on the findings, reminiscent of staging with each FDG PET/CT and [⁶⁸Ga]- PET/CT, sort of chemotherapy administered, standards for affected person choice, and sort of surgical resection. These variables can range considerably between research, significantly influencing the outcomes.

A case report revealed in 2021 underlies the effectiveness of CAPTEM in a affected person with unresectable atypical carcinoid tumor of the mediastinum.²⁵ The affected person underwent remedy for six months earlier than the tumor was thought of resectable. Though the authors report that the tumor was primarily mediastinal and never a lung carcinoid, this case exhibits profitable tumor shrinkage because of neoadjuvant chemotherapy. Downstaging was achieved following 6 months of remedy, indicating that outcomes seem after extended preoperative remedy administration, as within the affected person with the atypical carcinoid we current, and never after 3 months, as, for instance, in sufferers with NSCLC. Though there are not any accepted protocols for response reevaluation in lung NETs on remedy with chemotherapy, reevaluation ought to be carried out each 6 months together with a resectability evaluation of the illness, on condition that the remedy is effectively tolerated throughout this era.

The opportunity of disagreement between preoperative biopsy prognosis and the ultimate surgical specimen provides to the issue in decision-making for sufferers with superior lung NETs. It’s estimated that discordance may be as frequent as 57% of sufferers with resectable illness, and thus bronchoscopic biopsies ought to be interpreted cautiously when forming remedy plans.²⁶ Contemplating the findings from each FDG PET/CT and [⁶⁸Ga]- PET/CT helps to extend accuracy within the staging of the illness and alleviate, to some extent, the bronchoscopic biopsy shortcomings.²⁷ The choice for neoadjuvant remedy in lung NETs ought to make use of FDG PET/CT and [⁶⁸Ga]- PET/CT and never rely totally on the pathology report of the bronchoscopic biopsy and CT scans.

The popular remedy for lung NETs is lobectomy with systematic nodal dissection in each typical and atypical carcinoids, though parenchyma-sparing approaches could be thought of for the previous. A typical problem in medical observe is the extent of lung parenchyma removing when these tumors are centrally situated. A bronchoplasty is usually employed, and when this process will not be indicated, a sleeve resection may be carried out to keep away from pneumonectomy.²⁸ Tumor downstaging might provide fewer ablative surgical excisions in these tumors and probably enhance survival and R0 resections, though medical trials will reply these questions.

One other difficulty that have to be addressed in lung NETs is the resectability standards. Clinicians could be prejudiced by the really helpful observe in NSCLC, the place N2 illness is usually thought of a relative resection contraindication until neoadjuvant remedy results in tumor downstaging. In 2019, Yoon et al revealed their paper on the prognostic significance of TNM staging in lung NETs.²⁹ Prognosis within the superior T or N phases is significantly higher in lung NETS than in NSCLC Primarily based on these findings, resectability standards ought to be broader in typical and atypical carcinoids, and clinicians mustn’t observe the paradigm of NSCLC administration.

The limitation of this case research is the truth that this isn’t a sporadic atypical carcinoid case for the reason that affected person is a service of a recognized pathologic variance within the MEN1 gene. As well as, there are not any pointers to explain the pathology findings of neoadjuvant remedy in these tumors, and solely imaging standards are offered for response within the main tumor. With these limitations, it’s a case research exhibiting that preoperative remedy can profit chosen sufferers with lung carcinoids when tumor burden discount is the first purpose.

In conclusion, typical and atypical carcinoids can typically be very difficult to handle as a result of the prognosis is significantly higher than both NSCLC or SCLC, and the influence of medical interventions have to be weighed rigorously in opposition to the quick or late opposed results. There are restricted knowledge for managing totally different medical situations, and clinicians typically base their selections on extrapolating proof from both NSCLC or SCLC and GEP-NETs. A typical state of affairs is a necessity for downstaging when tumors are centrally situated and lobectomy will not be an possibility, or when adjoining constructions are invaded. Neoadjuvant remedy with CAPTEM with reevaluation each 6 months may be proposed in such a state of affairs, as in our case research. There may also be a profit in survival, though giant medical trials will reply this query.

Affected person’s Perspective

The affected person’s main concern in the course of the remedy was whether or not the profit/threat ratio could be favorable for her in the long term, regardless of the preliminary discomfort and restoration interval. She tolerated remedy with CAPTEM effectively with out vital opposed results (grade 3/4) and didn’t have to alter her day by day actions. She describes that her temper adjustments in the course of the remedy oscillated between hope and concern that the remedy may not be enough or might need opposed results. Twenty-four months following the lobectomy, she finds that the concern of recurrence impacts her day by day life, notably when experiencing occasional ache in any space of her physique. She is below periodic surveillance by a clinic psychiatrist and isn’t taking any remedy for anxiousness or melancholy. She can be involved about the opportunity of her older son growing MEN1-related ailments and the way this may have an effect on the remainder of his life. She is glad that each operations didn’t have an effect on her high quality of life in the long run and that she is 2 years disease-free.

Funding Assertion

This analysis didn’t obtain any particular grant from any funding company within the public, business, or not-for-profit sectors.

Declaration of Curiosity

The authors declare that there isn’t any battle of curiosity that may very well be perceived as prejudicing the impartiality of the analysis reported.

Affected person Consent

Written knowledgeable consent has been obtained from the affected person for publication of the submitted article and accompanying photos.

REFERENCES

1. Dasari, A. et al. Tendencies within the Incidence, Prevalence, and Survival Outcomes in Sufferers With Neuroendocrine Tumors in america. JAMA Oncology 3, 1335-1342, doi:10.1001/jamaoncol.2017.0589 (2017).
2. de Laat, J. M. et al. Pure course and survival of neuroendocrine tumors of thymus and lung in MEN1 sufferers. J Clin Endocrinol Metab 99, 3325-3333, doi:10.1210/jc.2014-1560 (2014).
3. Gomez, D. R. et al. Native consolidative remedy versus upkeep remedy or statement for sufferers with oligometastatic non-small-cell lung most cancers with out development after first-line systemic remedy: a multicentre, randomised, managed, section 2 research. The Lancet Oncology 17, 1672-1682, doi:10.1016/S1470-2045(16)30532-0 (2016).
4. Chan, G. & Chee, C. E. Perioperative Chemotherapy for Liver Metastasis of Colorectal Most cancers. Cancers (Basel) 12, doi:10.3390/cancers12123535 (2020).
5. Thakker, R. V. et al. Medical observe pointers for a number of endocrine neoplasia sort 1 (MEN1). J Clin Endocrinol Metab 97, 2990-3011, doi:10.1210/jc.2012-1230 (2012).
6. Daddi, N. et al. Prognostic elements in a multicentre research of 247 atypical pulmonary carcinoids. Eur J Cardiothorac Surg 45, 677-686, doi:10.1093/ejcts/ezt470 (2014).
7. Loosen, S. H. et al. Medical traits of 662 sufferers with pancreatic neuroendocrine tumors receiving antitumoral remedy. Drugs (Baltimore) 101, e32044, doi:10.1097/md.0000000000032044 (2022).
8. Titan, A. L. et al. Analysis of Outcomes Following Surgical procedure for Domestically Superior Pancreatic Neuroendocrine Tumors. JAMA Netw Open 3, e2024318, doi:10.1001/jamanetworkopen.2020.24318 (2020).
9. Dumont, F. et al. Therapeutic Methods for Superior Pancreatic Neuroendocrine Tumors with Segmental Portal Hypertension. World J Surg 39, 1974-1980, doi:10.1007/s00268-015-3030-8 (2015).
10. Prakash, L. et al. Function of Fluorouracil, Doxorubicin, and Streptozocin Remedy within the Preoperative Therapy of Localized Pancreatic Neuroendocrine Tumors. J Gastrointest Surg 21, 155-163, doi:10.1007/s11605-016-3270-4 (2017).
11. Reher, D. et al. Localization Defines Streptozotocin/5-FU Response in Major Pancreatic Neuroendocrine Tumours. Neuroendocrinology 112, 595-605, doi:10.1159/000518895 (2022).
12. Xie, H. et al. The Function of Perioperative Systemic Remedy in Localized Pancreatic Neuroendocrine Neoplasms. Neuroendocrinology 110, 234-245, doi:10.1159/000501126 (2020).
13. Srirajaskanthan, R. et al. Surgical administration and palliative remedy in bronchial neuroendocrine tumours: A medical research of 45 sufferers. Lung Most cancers 65, 68-73, doi:https://doi.org/10.1016/j.lungcan.2008.10.025 (2009).
14. Parghane, R. V. et al. Surgical Feasibility, Determinants, and General Efficacy of Neoadjuvant (177)Lu-DOTATATE PRRT for Domestically Superior Unresectable Gastroenteropancreatic Neuroendocrine Tumors. J Nucl Med 62, 1558-1563, doi:10.2967/jnumed.120.258772 (2021).
15. Opalińska, M. Worth of Peptide Receptor Radionuclide Remedy as Neoadjuvant Therapy within the Administration of Major Inoperable Neuroendocrine Tumors. Entrance Oncol 11, 687925, doi:10.3389/fonc.2021.687925 (2021).
16. Chiapponi, C. et al. Peptide receptor radionuclide remedy as a two-step technique for initially unresectable liver illness from neuroendocrine tumors: a single-center expertise. Endocrine 70, 187-193, doi:10.1007/s12020-020-02341-1 (2020).
17. Li, Y. et al. Neoadjuvant remedy in pancreatic neuroendocrine neoplasms: A scientific evaluate and meta-analysis. Entrance Oncol 12, 981575, doi:10.3389/fonc.2022.981575 (2022).
18. Thomas, Ok. et al. Outcomes of Capecitabine and Temozolomide (CAPTEM) in Superior Neuroendocrine Neoplasms (NENs). Cancers (Basel) 12, doi:10.3390/cancers12010206 (2020).
19. Bongiovanni, A. et al. Temozolomide Alone or Mixed with Capecitabine for the Therapy of Metastatic Neuroendocrine Neoplasia: A “Actual-World” Information Evaluation. Neuroendocrinology 111, 895-906, doi:10.1159/000513218 (2021).
20. Al-Toubah, T., Morse, B. & Strosberg, J. Capecitabine and Temozolomide in Superior Lung Neuroendocrine Neoplasms. Oncologist 25, e48-e52, doi:10.1634/theoncologist.2019-0361 (2020).
21. Arrivi, G. et al. Capecitabine and Temozolomide (CAPTEM) in Superior Neuroendocrine Neoplasms (NENs): A Systematic Assessment and Pooled Evaluation. Most cancers Manag Res 14, 3507-3523, doi:10.2147/cmar.S372776 (2022)
22. Squires, M. H. et al. Neoadjuvant Capecitabine/Temozolomide for Domestically Superior or Metastatic Pancreatic Neuroendocrine Tumors. Pancreas 49, 355-360, doi:10.1097/mpa.0000000000001500 (2020).
23. Sobash, P. T. Survival Advantage of Adjuvant Chemotherapy in Pulmonary Carcinoid Tumors. Cancers (Basel) 14, doi:10.3390/cancers14194730 (2022).
24. Wegner, R. E. et al. The function of adjuvant remedy for atypical bronchopulmonary carcinoids. Lung Most cancers, 90-94, doi:10.1016/j.lungcan.2019.03.022 (2019).
25. Testori, A. et al. Domestically superior main mediastinal atypical carcinoid efficiently resected after neoadjuvant remedy: A case report. Thorac Most cancers 12, 2415-2419, doi:10.1111/1759-7714.14091 (2021).
26. Moonen, L. et al. Preoperative Biopsy Analysis in Pulmonary Carcinoids, a Shot within the Darkish. J Thorac Oncol 16, 610-618, doi:10.1016/j.jtho.2020.12.004 (2021).
27. Deleu, A. L. et al. Worth of [(68)Ga]Ga-somatostatin receptor PET/CT within the grading of pulmonary neuroendocrine (carcinoid) tumours and the detection of disseminated illness: single-centre pathology-based evaluation and evaluate of the literature. EJNMMI Res 12, 28, doi:10.1186/s13550-022-00900-3 (2022).
28. Wurtz, A. Outcomes of systematic nodal dissection in typical and atypical carcinoid tumors of the lung. J Thorac Oncol 4, 388-394, doi:10.1097/JTO.0b013e3181951aa6 (2009).
29. Yoon, J. Y. et al. Analysis of the Prognostic Significance of TNM Staging Tips in Lung Carcinoid Tumors. J Thorac Oncol 14, 184-192, doi:10.1016/j.jtho.2018.10.166 (2019).