Surveillance imaging for non-small cell lung cancer: mounting evidence that less is more

Lung cancer is the leading cause of death in both men and women in the United States (1). With increasing implementation of low dose computed tomography (CT) screening in high-risk populations, more patients should be diagnosed with early stage disease in the coming years, amenable to curative intent therapy (2). However, no firm consensus yet guides the frequency and modality of surveillance imaging following definitive treatment, with variable guidelines from large national and international oncologic societies. This largely results from a lack of high-quality data to guide surveillance decisions, and current post-treatment surveillance imaging guidelines from national and international oncologic societies are based on lower-level evidence and expert opinion. The National Comprehensive Cancer Network (NCCN) surveillance guidelines for non-small cell lung cancer (NSCLC) treated definitively recommends a chest CT with or without contrast every 6 months for 2–3 years followed by annual low-dose non-contrast enhanced chest CT for patients with NSCLC stages I–II treated with surgery with or without chemotherapy (3). The American Academy of Chest Physicians (AACP) suggests bi-annual chest CT for 2 years followed by annual chest CT for patients treated with resection (4). The American Association for Thoracic Surgery guidelines for surveillance recommends bi-annual chest CT for the first 4 years after surgical resection of NSCLC stages IA–IIIA followed by annual low-dose chest CT until the age of 79 (5). The European Society of Medical Oncology recommends at least annual chest CT after treatment or bi-annual chest CT if the patient is a candidate for future salvage therapy (6).

Efforts to establish evidence to support a specific modality and frequency for surveillance imaging have led to multiple small retrospective studies with conflicting results. Several retrospective studies have suggested a survival advantage to more frequent imaging (7,8) while others have shown no benefit (9,10). A systematic review by Srikantharajah et al. identified 5 relevant studies that investigated the impact of chest CT surveillance in patients who had undergone surgical resection for NSCLC. The authors found conflicting results, with 3 studies that showed a survival benefit and two that did not (11). One prospective trial, the Intergroupe Francophone de Cancerologie Thoracique (IFCT)-0302, randomized patients to Q6 month CT, exam, and chest X-ray (with or without bronchoscopy) to exam and chest X-ray alone. At a median follow up of 8.7 years, no significant survival benefit was identified with the addition of CT, although longer follow up is ongoing.

Still fewer studies have investigated the role of surveillance imaging in NSCLC patients treated with definitive radiation. The available studies suggest more frequent imaging (12,13) or imaging with positron emission tomography (PET)/CT (14) leads to definitive intent treatment in very few patients. One small prospective study enrolled 24 patients who had undergone either definitive radiation therapy or chemoradiation for NSCLC and surveillance PET/CT every 3 months detected 24 patients at 3 months with recurrence but only 3% were amenable for curative therapy (15).

In aggregate, the available studies addressing frequency of imaging have been largely retrospective, variable in terms of imaging modality, and have shown conflicting results, leading to challenges in creating evidence-based guidelines for practitioners. Most population-based databases do not include whether imaging was performed for surveillance or in response to symptoms, creating challenges in interrogating such databases to better understand the impact of surveillance on outcomes. However, McMurry et al. (16), as part of a special study of the National Cancer Database, provide an analysis of a unique population-based dataset that provides fairly robust evidence that more intensive surveillance strategies are not associated with improved survival following surgery for lung cancer. This study analyzed the first surveillance CT imaging for 4,463 patients who had undergone curative surgical resection for stages I–III NSCLC, classified by the interval to scan (3, 6 or 12 months). The dataset included indication, whether imaging was obtained as surveillance or in response to symptoms. The authors of this study conclude that there was not an associated improvement of overall survival with any particular surveillance schedule. This analysis provides additional evidence that more frequent cross-sectional imaging does not affect survival following surgical resection of lung cancer. The general finding that more aggressive surveillance does not impact survival is concordant with the results of the only completed prospective randomized phase III trial to address surveillance imaging in lung cancer, the IFCT-0302. At a median follow-up of 8.7 years, the IFCT-0302 identified no significant survival benefit with the addition of CT to exam and chest X-ray.

The lack of survival benefit to more aggressive surveillance imaging suggests that expedient initiation of salvage therapy does not measurably improve survival, and is congruent with the currently poor prognosis of recurrent lung cancer. Based on available evidence, there is no clear role for frequent cross-sectional imaging in the absence of symptoms in surgically treated lung cancer patients. However, as treatment options improve, the role and impact of surveillance may evolve. New systemic options, most notably immune checkpoint inhibitors, have markedly improved outcomes for the subset of patients who respond. As systemic salvage options continue to improve, early detection of recurrence may have greater impact on survival. Recent randomized phase II trials also suggest that local ablative therapy with stereotactic radiation may improve survival for patients with limited metastatic disease (17-19). Surveillance guidelines will need continual reassessment as salvage options evolve and improve so that patients who may benefit from more aggressive salvage are identified.

Notably, the McMurry study included only surgically resected patients and the results are not applicable to patients treated with definitive radiation, particularly given the challenges of interpreting post-radiation CT scans. Another limitation is that the dataset included only the first surveillance study, rather than capturing ongoing surveillance. The McMurry study also does not address surveillance modality. While the IFCT-0302 suggests the addition of CT to exam and chest X-ray does not improve survival, there is also interest in the role of PET/CT in surveillance, particularly for patients treated with radiation therapy, given the difficulty of differentiating recurrence versus post radiation changes (20), although PET/CT is not currently recommended by any major guidelines as a surveillance modality. The use of blood-based biomarkers in surveillance has also emerged as an area of interest and active investigation. Several studies have sought to elucidate the utility of screening for circulating free tumor DNA and circulating tumor cells (21,22). Such strategies remain investigational at this time, but in the future may supplant or even replace cross sectional imaging for routine surveillance. The impact of surveillance on patient anxiety and quality-of-life is also an important and understudied area in need of investigation.

In summary, a paucity of prospective trials and high-quality population-based data has led to a lack of consensus on the appropriate surveillance strategy following definitive treatment of lung cancer. The McMurry study, using a unique, population-based dataset that includes scan indication, adds to the available evidence that frequent imaging does not affect survival with current treatment approaches and should not be routinely used in asymptomatic patients. However, novel approaches that could replace imaging-based surveillance, such as blood-based biomarkers, may emerge in the upcoming years. Improvements to both local and systemic salvage options may also eventually increase the importance of surveillance and early detection of recurrence.

Acknowledgments

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. American Cancer Society. Cancer Facts & Figures 2019. Atlanta: American Cancer Society; 2019.
2. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. [Crossref] [PubMed]
3. NCCN Clinical Practice Guidelines in Oncology, Non-Small Cell Lung Cancer. Version 3.2019.
4. Colt HG, Murgu SD, Korst RJ, et al. Follow-up and surveillance of the patient with lung cancer after curative-intent therapy: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e437S-e454S.
5. Jaklitsch MT, Jacobson FL, Austin JH, et al. The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg 2012;144:33-8. [Crossref] [PubMed]
6. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv1-21. [Crossref] [PubMed]
7. Gourcerol D, Scherpereel A, Debeugny S, et al. Relevance of an extensive follow-up after surgery for nonsmall cell lung cancer. Eur Respir J 2013;42:1357-64. [Crossref] [PubMed]
8. Westeel V, Choma D, Clement F, et al. Relevance of an intensive postoperative follow-up after surgery for non-small cell lung cancer. Ann Thorac Surg 2000;70:1185-90. [Crossref] [PubMed]
9. Lamont JP, Kakuda JT, Smith D, et al. Systematic postoperative radiologic follow-up in patients with non-small cell lung cancer for detecting second primary lung cancer in stage IA. Arch Surg 2002;137:935-8. [Crossref] [PubMed]
10. Backhus LM, Farjah F, Liang CK, et al. Imaging surveillance and survival for surgically resected non-small-cell lung cancer. J Surg Res 2016;200:171-6. [Crossref] [PubMed]
11. Srikantharajah D, Ghuman A, Nagendran M, et al. Is computed tomography follow-up of patients after lobectomy for non-small cell lung cancer of benefit in terms of survival? Interact Cardiovasc Thorac Surg 2012;15:893-8. [Crossref] [PubMed]
12. Daly ME, Beckett LA, Chen AM. Does early posttreatment surveillance imaging affect subsequent management following stereotactic body radiation therapy for early-stage non-small cell lung cancer? Pract Radiat Oncol 2014;4:240-6. [Crossref] [PubMed]
13. Ho QA, Harandi NK, Daly ME. Clinical Impact of Frequent Surveillance Imaging in the First Year Following Chemoradiation for Locally Advanced Non-small-cell Lung Cancer. Clin Lung Cancer 2017;18:410-4. [Crossref] [PubMed]
14. Ebright MI, Russo GA, Gupta A, et al. Positron emission tomography combined with diagnostic chest computed tomography enhances detection of regional recurrence after stereotactic body radiation therapy for early stage non-small cell lung cancer. J Thorac Cardiovasc Surg 2013;145:709-15. [Crossref] [PubMed]
15. van Loon J, Grutters J, Wanders R, et al. Follow-up with 18FDG-PET-CT after radical radiotherapy with or without chemotherapy allows the detection of potentially curable progressive disease in non-small cell lung cancer patients: a prospective study. Eur J Cancer 2009;45:588-95. [Crossref] [PubMed]
16. McMurry TL, Stukenborg GJ, Kessler LG, et al. More Frequent Surveillance Following Lung Cancer Resection Is Not Associated With Improved Survival: A Nationally Representative Cohort Study. Ann Surg 2018;268:632-9. [Crossref] [PubMed]
17. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet 2019;393:2051-8. [Crossref] [PubMed]
18. Gomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:1672-82. [Crossref] [PubMed]
19. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2018;4:e173501. [Crossref] [PubMed]
20. Dunlap NE, Yang W, McIntosh A, et al. Computed tomography-based anatomic assessment overestimates local tumor recurrence in patients with mass-like consolidation after stereotactic body radiotherapy for early-stage non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2012;84:1071-7. [Crossref] [PubMed]
21. Perez-Callejo D, Romero A, Provencio M, et al. Liquid biopsy based biomarkers in non-small cell lung cancer for diagnosis and treatment monitoring. Transl Lung Cancer Res 2016;5:455-65. [Crossref] [PubMed]
22. Chinniah C, Aguarin L, Cheng P, et al. Prospective Trial of Circulating Tumor Cells as a Biomarker for Early Detection of Recurrence in Patients with Locally Advanced Non–Small Cell Lung Cancer Treated with Chemoradiation Therapy. Int J Radiat Oncol Biol Phys 2017;98:221. [Crossref]