GMKA
Support

Early-Stage Non-Small Cell Lung Cancer

Oncology
Read in Ukrainian

Introduction

Lung cancer is considered the leading cause of cancer related mortality, the most common cancer in men and the second commonest malignancy in women with approximately 2,200,000 newly diagnosed cases and 1,800,000 deaths worldwide per year.[1,2]
The most common histology of lung cancer is non-small-cell lung cancer (NSCLC), accounting for 85% of cases.[1] Typically, the diagnosis of NSCLC is made at advanced stages due to the lack of universal screening programs.
Early-stage NSCLC management involves either resection of the primary tumor or radiotherapy in non-operable patients. Chemotherapy and recently adjuvant chemoimmunotherapy and neoadjuvant chemoimmunotherapy have specific roles for stage 2 disease. The aim of this chapter is to summarize the diagnostic and treatment approaches for early-stage NSCLC.

Presentation

Patients with lung cancer are typically asymptomatic, and even if some symptoms emerge while the disease progresses, they can mimic a plethora of other health conditions. Particularly early-stage lung cancer is mainly found incidentally or on screening chest CT scans in asymptomatic patients. Patients with centrally located masses could occasionally present with respiratory symptoms such as dyspnea, wheezing or hemoptysis.
Constitutional symptoms such as fatigue, weight loss and diffuse pain may also co-exist at the time of lung cancer diagnosis. Lastly, paraneoplastic symptoms such as Syndrome of Antidiuretic Hormone (SIADH) production, Cushing’s syndrome and paraneoplastic neurological syndromes are linked mostly with small cell lung cancers and are very rare in early-stage NSCLC.

Screening

According to the 2022 National Comprehensive Cancer Network instructions, patients aged 50-80 with ≥20 years of smoking and ≤15 years from smoking cessation are considered “high-risk” and are considered eligible for lung cancer screening.[3]
Screening should not be recommended for individuals with functional status or comorbidity that would prohibit curative-intent therapy and it should be discontinued once the individual has not smoked for 15 years or has a limited life expectancy.[3,4]

Evaluation

A detailed history and physical examination are the first steps in assessing a patient for lung cancer. Attention should be given to constitutional symptoms and laboratory findings that might indicate metastases, including focal neurological sings, papilledema, bone tenderness, elevated ALP, GGT, SGOT or findings that indicate primary adrenal insufficiency.
Endoscopic examination of the airways with bronchoscopy can be used for central lesions. When available, advanced bronchoscopy techniques including navigation bronchoscopy and endobronchial ultrasound (EBUS) are often utilized to diagnose, stage, or even treat lung cancer that is located centrally.[5–7]
CT-guided transthoracic FNA is another safe alternative to diagnose lung cancer especially for masses that are located in the periphery.[8,9] A diagnostic thoracoscopic procedure is usually opted if both bronchoscopy and CT-guided transthoracic FNA cannot be conducted safely or the lesion is peripheral and anticipated to require anatomic resection.[10]
Additional imaging may be used to further stage the disease. MRIs are usually performed supplementary to CT scans when there are concerns about invasion of the mass into the chest wall, the superior vena cava, the brachial plexus, or the spinal cord. MRIs are especially useful in diagnosing brain metastasis. Because brain metastases are uncommon in neurologically asymptomatic patients, MRI scans are reserved only for patients with new onset of neurological symptoms.[11]
Whole-body positron emission tomography (PET) with 18F-flurodeoxyglucose (FDG) is another imaging modality that plays a crucial role in NSCLC diagnosis and staging. A PET can be accompanied by a CT scan or be performed alone, although the combination of PET and CT is most commonly performed as it is associated with higher sensitivity and specificity for disease staging.[12–14]
Several studies have reported that the addition of PET/CT in the diagnostic algorithm of lung cancer patients led to disease up- or down-staging and consequently resulted in changing the initial management plan.[15–20]
Current guidelines recommend using PET/CT in all patients in whom lung cancer is confirmed or suspected and when PET/CT cannot be utilized conventional chest and abdominal CT with bone scintigraphy is the best available alternative.[3,21]
If enlarged or avid mediastinal or hilar nodal stations are identified with the imaging techniques described above, there are several invasive staging modalities including mediastinoscopy and (EBUS) that are used to optimize clinical staging.[22] EBUS with transbronchial needle aspiration (TBNA) is credited to be more sensitive and safer than mediastinoscopy and thus it is a first line strategy.[25]

Staging

Lung cancer is staged with the American Joint Committee on Cancer (AJCC) staging manual. Based on the 8th edition of AJCC, early disease NSCLC includes malignancies that are classified as stage IA (T1miN0M0 or T1N0M0), IB (T2aN0M0), IIA (T2bN0M0) and IIB (T1-2N1M0 or T3N0M0).
The T- and N- stages for early disease NSCLC are explained in more detail in the following tables.
Table 1: AJCC 8th edition T categories for early-stage lung cancer
T stageDescription
T1• Size <3cm
• Main bronchi not affected
• No visceral pleura invasion
  T1mi• Minimally invasive adenocarcinoma with size <3 cm
• Lung invasion <0.5cm
  T1a• Size <=1cm
  T1b• Size >1, <=2cm
  T1c• Size >2, <=3cm
T2Tumor has one or more of the following:
• Size >3, <=5cm
• Main bronchi involvement but not the carina
• Visceral pleura invasion
• Tumor obstructing airways
 T2a• Size >3, <=4cm
  T2b• Size >4, <=5cm
T3Tumor has one or more of the following:
• Size >5 <=7cm
• Invasion in the chest wall/ parietal pleura/ phrenic nerve/ parietal pericardium >=2 tumors in the same lobe
Table 2: AJCC 8th edition N categories and descriptions
N stageDescription
N0No regional lymph nodes
N1Involvement of ipsilateral intrapulmonary, peribronchial, or hilar lymph nodes
  N1aSingle station metastasis
  N1bMultiple station metastasis

Treatment

Pulmonary resection continues to be the mainstay of treatment for early-stage NSCLC patients.[21] If physical functioning and pulmonary function testing is adequate based on guidelines (American College of Chest Physicians (ACCP)[26], the European Respiratory Society, the European Society of Thoracic Surgeons (ERS/ESTS)[27], and the British Thoracic Society), surgery may be recommended. Surgery may include a wedge with adequate margins, segmentectomy, or lobectomy, depending on the size and location of the tumor.[28]
The advantage of surgery over biopsy only with radiation is a complete mediastinal lymph node sampling and/or dissection. Stereotactic body radiation therapy (SBRT), also referred to as stereotactic ablative radiotherapy (SABR), is the first line of treatment for patients who are ineligible for surgery or who prefer non-operative management.
Contemporary randomized clinical trials have supported the comparability of segmentectomy and sublobar resection for small (<2cm) lung masses. [29–31] Regarding centrally located tumors where lobectomy is not feasible, bilobectomy or sleeve lobectomy are some alternatives. Pneumonectomy can also be considered, however, it has been associated with higher morbidity and mortality compared to sleeve lobectomy.[32]
Finally, extended pulmonary resections are utilized in cases where the primary tumor has invaded the surrounding tissues (chest wall, pericardium, diaphragm) and can also be accompanied by reconstruction of the invaded tissues with the use of surgical mesh. [33,34]
Finally, it is worth noting that resected patients with Stage IB and Stage II disease and negative surgical margins are considered for adjuvant chemotherapy.
Surgical approach
Over the past decades the open approaches to pulmonary resection are steadily decreasing due to their inherent association with painful postoperative periods and long hospitalizations.[35] Open thoracotomy has been largely replaced by video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracic surgery (RATS) which are two contemporary minimally invasive surgical approaches credited to offer similar oncologic results compared to open thoracotomy with far less postoperative morbidity.[36]
More specifically, both RATS and VATS have been associated with optimal postoperative pain, shorter hospitalizations, less morbidity and quicker overall recovery compared to their open counterpart, however, the literature is still conflicting on whether RATS is superior compared to VATS and further evidence is warranted to make solid conclusions.[37]

Surveillance

The current consensus recommends that patients that have received definitive treatment for NSCLC should have surveillance imaging with chest CT scan that includes the adrenals, with contrast (preferred) or without contrast, every six months for two years to evaluate for disease recurrence.[38]
After that patients should receive a low dose CT scan once a year to check for new primary lung malignancies. Patients who are clinically ineligible for or unwilling to accept additional treatment may not be given surveillance imaging, however, age should not prohibit further surveillance imaging.[38]

Summary

  • Patients aged 50-80 with ≥20 years of smoking and ≤15 years from smoking cessation are considered “high-risk” and are considered eligible for screening with yearly low dose CT scans.
  • Diagnosis and clinical staging of lung cancer are typically made via navigational bronchoscopic techniques or via CT-guided transthoracic FNA for peripheral lesions and/or diagnostic VATS.
  • Lung cancer is staged using a TNM classification system and according to the 8th edition of AJCC, early disease NSCLC includes malignancies that are classified as stage IA (T1miN0M0 or T1N0M0), IB (T2aN0M0), IIA (T2bN0M0) and IIB (T1-2N1M0 or T3N0M0).
  • Pulmonary resections are the treatment of choice for early-stage NSCLC in patients who are deemed eligible for surgery.
  • Lobectomy is still considered the mainstay definitive treatment for NSCLC; however, contemporary evidence supported that sublobar resections might offer equivalent outcomes in patients with early-stage NSCLC and small tumor size.
  • Adjuvant chemotherapy may be offered for improved survival rates for stage 2 resected lung cancer.
  • Neoadjuvant chemoimmunotherapy is emerging as standard of care for operable stage 2 lung cancer.
  • SBRT is considered an alternative definitive treatment and it is typically utilized in patients who are not operative candidates or who elect to undergo non-operative management.
  • Patients who received a definitive treatment for NSCLC should have surveillance CT scans every six months for two years to check for disease recurrence, and then once a year to check for new primary lung malignancies.

References

  1. Lung Cancer Statistics | How Common is Lung Cancer? n.d. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html (accessed October 8, 2022).
  2. Lung cancer statistics | World Cancer Research Fund International n.d. https://www.wcrf.org/cancer-trends/lung-cancer-statistics/ (accessed January 4, 2023).
  3. Wood DE, Kazerooni EA, Aberle D, Berman A, Brown LM, Eapen GA, et al. NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2022: Featured Updates to the NCCN Guidelines. Journal of the National Comprehensive Cancer Network 2022;20:754–64. https://doi.org/10.6004/JNCCN.2022.0036.
  4. Krist AH, Davidson KW, Mangione CM, Barry MJ, Cabana M, Caughey AB, et al. Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2021;325:962–70. https://doi.org/10.1001/JAMA.2021.1117.
  5. El-Bayoumi E, Silvestri GA. Bronchoscopy for the diagnosis and staging of lung cancer. Semin Respir Crit Care Med 2008;29:261–70. https://doi.org/10.1055/S-2008-1076746/ID/42.
  6. Dooms C, Seijo L, Gasparini S, Trisolini R, Ninane V, Tournoy KG. Diagnostic bronchoscopy: state of the art. European Respiratory Review 2010;19:229–36. https://doi.org/10.1183/09059180.00005710.
  7. Maldonado F, Edell ES, Barron PJ, Yung RC, Gilbert C, Akulian J, et al. Novel bronchoscopic strategies for the diagnosis of peripheral lung lesions: Present techniques and future directions. Respirology 2014;19:636–44. https://doi.org/10.1111/RESP.12301.
  8. Gould MK, Donington J, Lynch WR, Mazzone PJ, Midthun DE, Naidich DP, et al. Evaluation of individuals with pulmonary nodules: When is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2013;143:e93S-e120S. https://doi.org/10.1378/CHEST.12-2351/ATTACHMENT/62CD9F06-7D2E-4FCF-A041-2B5F781CEFFE/MMC4.XLS.
  9. Wiener RS, Schwartz LM, Woloshin S, Gilbert Welch H. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: An analysis of discharge records. Ann Intern Med 2011;155:137–44. https://doi.org/10.7326/0003-4819-155-3-201108020-00003.
  10. Giroux DJ, Rami-Porta R, Chansky K, Crowley JJ, Groome PA, Postmus PE, et al. The IASLC lung cancer staging project data elements for the prospective project. Journal of Thoracic Oncology 2009;4:679–83. https://doi.org/10.1097/JTO.0b013e3181a52370.
  11. Silvestri GA, Gonzalez A v., Jantz MA, Margolis ML, Gould MK, Tanoue LT, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2013;143:e211S-e250S. https://doi.org/10.1378/CHEST.12-2355/ATTACHMENT/19E9A976-6185-4CE8-AAEE-B4A713FEACCA/MMC1.DOCX.
  12. de Wever W, Vankan Y, Stroobants S, Verschakelen J. Detection of extrapulmonary lesions with integrated PET/CT in the staging of lung cancer. European Respiratory Journal 2007;29:995–1002. https://doi.org/10.1183/09031936.00119106.
  13. Wever W, Ceyssens S, Mortelmans L, Stroobants S, Marchal G, Bogaert J, et al. Additional value of PET-CT in the staging of lung cancer: comparison with CT alone, PET alone and visual correlation of PET and CT. Eur Radiol 2007;17:23–32. https://doi.org/10.1007/S00330-006-0284-4.
  14. Gould MK, Kuschner WG, Rydzak CE, Maclean CC, Demas AN, Shigemitsu H, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med 2003;139. https://doi.org/10.7326/0003-4819-139-11-200311180-00013.
  15. Morgensztern D, Goodgame B, Baggstrom MQ, Gao F, Govindan R. The effect of FDG-PET on the stage distribution of non-small cell lung cancer. J Thorac Oncol 2008;3:135–9. https://doi.org/10.1097/JTO.0B013E3181622C2C.
  16. Heo EY, Yang SC, Yoo CG, Han SK, Shim YS, Kim YW. Impact of whole-body 18F-fluorodeoxyglucose positron emission tomography on therapeutic management of non-small cell lung cancer. Respirology 2010;15:1174–8. https://doi.org/10.1111/J.1440-1843.2010.01790.X.
  17. Margery J, Milleron B, Vaylet F, Grahek D, Lebeau B, Mangiapan G, et al. [Impact of positron emission tomography on clinical management of potentially resectable non-small-cell lung cancer: a French prospective multicenter study]. Rev Pneumol Clin 2010;66:313–20. https://doi.org/10.1016/J.PNEUMO.2010.07.015.
  18. Subedi N, Scarsbrook A, Darby M, Korde K, Mc Shane P, Muers MF. The clinical impact of integrated FDG PET-CT on management decisions in patients with lung cancer. Lung Cancer 2009;64:301–7. https://doi.org/10.1016/J.LUNGCAN.2008.09.006.
  19. Maziak DE, Darling GE, Inculet RI, Gulenchyn KY, Driedger AA, Ung YC, et al. Positron emission tomography in staging early lung cancer: a randomized trial. Ann Intern Med 2009;151:221–8. https://doi.org/10.7326/0003-4819-151-4-200908180-00132.
  20. Fischer B, Lassen U, Mortensen J, Larsen S, Loft A, Bertelsen A, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009;361:32–9. https://doi.org/10.1056/NEJMOA0900043.
  21. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 1.2023 n.d. https://www.nccn.org/guidelines/recently-published-guidelines (accessed September 12, 2022).
  22. Mentzer SJ. Mediastinoscopy, thoracoscopy, and video-assisted thoracic surgery in the diagnosis and staging of lung cancer. Hematol Oncol Clin North Am 1997;11:435–47. https://doi.org/10.1016/S0889-8588(05)70442-1.
  23. Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest 2009;136:260–71. https://doi.org/10.1378/CHEST.08-0978.
  24. Detterbeck F, Puchalski J, Rubinowitz A, Cheng D. Classification of the thoroughness of mediastinal staging of lung cancer. Chest 2010;137:436–42. https://doi.org/10.1378/CHEST.09-1378.
  25. Annema JT, van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM, et al. Mediastinoscopy vs Endosonography for Mediastinal Nodal Staging of Lung Cancer: A Randomized Trial. JAMA 2010;304:2245–52. https://doi.org/10.1001/JAMA.2010.1705.
  26. Brunelli A, Kim AW, Berger KI, Addrizzo-Harris DJ. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143. https://doi.org/10.1378/CHEST.12-2395.
  27. Brunelli A, Charloux A, Bolliger CT, Rocco G, Sculier JP, Varela G, et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). European Respiratory Journal 2009;34:17–41. https://doi.org/10.1183/09031936.00184308.
  28. Armstrong P, Congleton J, Fountain SW, Jagoe T, McAuley DF, Macmahon J, et al. BTS guidelines: guidelines on the selection of patients with lung cancer for surgery. Thorax 2001;56:89–108. https://doi.org/10.1136/THORAX.56.2.89.
  29. Altorki NK, Kamel MK, Narula N, Ghaly G, Nasar A, Rahouma M, et al. Anatomical Segmentectomy and Wedge Resections Are Associated with Comparable Outcomes for Patients with Small cT1N0 Non-Small Cell Lung Cancer. J Thorac Oncol 2016;11:1984–92. https://doi.org/10.1016/J.JTHO.2016.06.031.
  30. Altorki NK, Wang X, Wigle D, Gu L, Darling G, Ashrafi AS, et al. Perioperative mortality and morbidity after sublobar versus lobar resection for early-stage non-small-cell lung cancer: post-hoc analysis of an international, randomised, phase 3 trial (CALGB/Alliance 140503). Lancet Respir Med 2018;6:915–24. https://doi.org/10.1016/S2213-2600(18)30411-9.
  31. Saji H, Okada M, Tsuboi M, Nakajima R, Suzuki K, Aokage K, et al. Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Lancet 2022;399:1607–17. https://doi.org/10.1016/S0140-6736(21)02333-3.
  32. Ferguson MK, Lehman AG. Sleeve Lobectomy or Pneumonectomy: Optimal Management Strategy Using Decision Analysis Techniques. Annals of Thoracic Surgery 2003;76:1782–8. https://doi.org/10.1016/S0003-4975(03)01243-8.
  33. Oka S, Matsumiya H, Shinohara S, Kuwata T, Takenaka M, Chikaishi Y, et al. Total or partial vertebrectomy for lung cancer invading the spine. Annals of Medicine and Surgery 2016;12:1. https://doi.org/10.1016/J.AMSU.2016.10.002.
  34. Borri A, Leo F, Veronesi G, Solli P, Galetta D, Gasparri R, et al. Extended pneumonectomy for non-small cell lung cancer: morbidity, mortality, and long-term results. J Thorac Cardiovasc Surg 2007;134:1266–72. https://doi.org/10.1016/J.JTCVS.2007.01.021.
  35. Dezube AR, Hirji S, Shah R, Axtell A, Rodriguez M, Swanson SJ, et al. Pre-COVID-19 National Mortality Trends in Open and Video-Assisted Lobectomy for Non-Small Cell Lung Cancer. J Surg Res 2022;274:213–23. https://doi.org/10.1016/J.JSS.2021.12.047.
  36. Lim EKS, Batchelor TJP, Dunning J, Shackcloth M, Anikin V, Naidu B, et al. Video-assisted thoracoscopic versus open lobectomy in patients with early-stage lung cancer: One-year results from a randomized controlled trial (VIOLET). https://DoiOrg/101200/JCO20213915_suppl8504 2021;39:8504–8504. https://doi.org/10.1200/JCO.2021.39.15_SUPPL.8504.
  37. Yang HX, Woo KM, Sima CS, Bains MS, Adusumilli PS, Huang J, et al. Long-term Survival Based on the Surgical Approach to Lobectomy For Clinical Stage I Nonsmall Cell Lung Cancer: Comparison of Robotic, Video-assisted Thoracic Surgery, and Thoracotomy Lobectomy. Ann Surg 2017;265:431–7. https://doi.org/10.1097/SLA.0000000000001708.
  38. Schneider BJ, Ismaila N, Aerts J, Chiles C, Daly ME, Detterbeck FC, et al. Lung Cancer Surveillance After Definitive Curative-Intent Therapy: ASCO Guideline. J Clin Oncol 2020;38:753–66. https://doi.org/10.1200/JCO.19.02748.
Early-Stage Non-Small Cell Lung Cancer Lung Cancer - GMKA - Global Medical Knowledge Alliance