Back to Journals » Lung Cancer: Targets and Therapy » Volume 7

Optimal delivery of follow-up care following pulmonary lobectomy for lung cancer

Authors Chen Y, Huang T, Chang H, Lee S

Received 24 October 2015

Accepted for publication 7 January 2016

Published 30 March 2016 Volume 2016:7 Pages 29—34

DOI https://doi.org/10.2147/LCTT.S85112

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Pan-Chyr Yang



Ying-Yi Chen, Tsai-Wang Huang, Hung Chang, Shih-Chun Lee

Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

Introduction: The rationale for oncologic surveillance following pulmonary lobectomy is to detect recurrent disease or a second primary lung cancer early enough so that an intervention can increase survival and/or improve quality of life. Therefore, we reviewed literature for international guidelines and reorganized these useful factors associated with non-small-cell lung cancer (NSCLC) recurrence as remedies in postoperative follow-up.
Method: The population of interest for this review was patients who had been treated with complete resection for primary NSCLC and were in follow-up.
Result: Guidelines on follow-up care for NSCLC vary internationally. Because of the production of progressive medical modalities, the current follow-up care should be corrected.
Conclusion: The specific follow-up schedule for computed tomography imaging may be more or less frequent, depending upon risk factors for recurrence. Many different predictors of postoperative recurrence may help to optimize the patient selection for specified surveillance guidelines and personalized adjuvant therapies to prevent possibly occult micrometastases and to get a better outcome.

Keywords: lung cancer, follow-up, surveillance, recurrence

Introduction

Lung cancer is the most commonly diagnosed cancer worldwide, with incidence rates continuing to increase in developing countries.1 Optimal follow-up care following pulmonary lobectomy for non-small-cell lung cancer (NSCLC) includes close surveillance for early detection of disease recurrence or second primary lung cancer and proper management for recurrence or second primary lung cancer. The majority of deaths in postresectional treatment of NSCLC are related to the development of recurrence.2,3 Close surveillance is required for survivors of lung cancer who have received definitive therapy but are at risk for recurrence of their disease and for the development of second primary lung cancers.4,5 There is a paucity of evidence for different follow-up strategies for patients with lung cancer as well as information about their cost effectiveness. International recommendations for follow-up after curative intent treatment for lung cancer are systematically reviewed comparing follow-up regimes in lung cancer.6 Multiple factors influence survival following disease recurrence. Risk factors of postoperative recurrence and/or metastatic disease in patients with NSCLC may enable us to optimize the patient selection for proper management with better outcome. However, few recent studies integrated the relationship of clinicopathologic variables and recurrence of NSCLC after pulmonary lobectomy in patients into the follow-up guiding principle. Therefore, we reviewed literature for international guidelines and reorganized these useful factors associated with NSCLC recurrence as remedies in postoperative follow-up.

Methods

Search strategy

We aimed at identifying all literature related to follow-up of patients with lung cancer. Searches were conducted in September and October 2015. Relevant articles were identified and retrieved from Ovid Medline and PubMed by internet search. The selected articles were staged according to the seventh edition of the American Joint Committee on Cancer adopted in 2009.7

Inclusion and exclusion criteria

The population of interest for this review was patients older than 18 years (with no upper age limit) who had been treated with complete resection for primary NSCLC and were in follow-up. All stages of lung cancer were included in the review. In line with previous reviews and published guidance, lung cancer follow-up is defined as care after treatment, which is planned and multifaceted. Primary outcomes included overall survival. Secondary outcomes were time to detection of recurrence or death. Only studies that reported at least one of the primary outcomes were included. Because of limited reported data, cost was not included as a formal outcome measure.

Recurrences in this review included locoregional recurrences and distant metastases. Although randomized controlled trials are widely regarded as the most appropriate design to evaluate efficacy of an intervention, a scoping review identified a paucity of studies using this design. This approach may potentially result in less robust studies being used for the development of evidence but provides the best evidence currently available in this underresearched area.

Results

Guidelines on follow-up care for NSCLC vary internationally and are listed in Table 1. There are five guidelines, including different follow-up frequency, clinical evaluation, and medical modality. Because of the production of progressive medical modalities, the current follow-up care should be corrected. Low-dose computed tomography (LDCT)8 or minimal-dose computed tomography (MnDCT)9 without contrast may be a reasonable option over chest X-ray for detection of pulmonary lesions. The surveillance imaging frequency would be 3, 6, 12, 18, and 24 months and then annually after curative-intent therapy. Diagnostic chest CT with contrast plus upper abdomen scan is suggested to detect local recurrence or new primary lung cancer. If the patient is symptomatic, imaging modality specific to the patient’s symptoms is recommended.

Table 1 Comparison of international guidelines for follow-up after curative intent treatment for lung cancer
Abbreviations: CXR, chest X-ray; NSCLC, non-small-cell lung cancer; CT, computed tomography; NCCN, National Comprehensive Cancer Network; NICE, National Institute for Health and Clinical Excellence; ACCP, American College of Chest Physicians; ESMO, European Society for Medical Oncology.

Table 2 lists the comparison of common clinicopathologic variables for recurrence of NSCLC following pulmonary lobectomy. These predictors included poor differentiation, squamous cell carcinoma (SCC), smoking history, tumor location, lymphovascular space invasion (LVSI), tumor maximum standard uptake value (SUVmax), carcinoembryonic antigen (CEA) value, epidermal growth factor receptor (EGFR), and tumor size. The most common risk factor for recurrence of NSCLC following pulmonary lobectomy is poor differentiation.

Table 2 Comparison of common clinicopathologic variables for recurrence of NSCLC following pulmonary lobectomy
Abbreviations: SCC, squamous cell carcinoma; LVSI, lymphovascular space invasion; SUVmax, maximum standard uptake value; CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor.

Table 3 lists the comparison of uncommon risk factors for postoperative recurrence of NSCLC. These factors were total lesion glycolysis (TLG), survivin overexpression, glucosylceramide synthase, fibroblast growth factor 9, expression of Id-1 and VEGF, reactive oxygen species modulator 1 (Romo1) expression, FoxM1, preoperative peripheral lymphocyte count, Ki-67 labeling index, CD66b-positive neutrophil-to-CD8-positive lymphocyte ratio (iNTR), p53R2, preoperative plasma d-dimer, the significance and handling of microscopic invasion of NSCLC into hilar peribronchovascular soft tissue (SHEATH+), and tumor necrosis.

Table 3 Comparison of uncommon risk factors for postoperative recurrence of NSCLC
Abbreviations: TLG, total lesion glycolysis; OS, overall survival; NSCLC, non-small-cell lung cancer; Romo1, reactive oxygen species modulator 1; DFS, disease-free survival; iNTR, CD66b-positive neutrophil-to-CD8-positive lymphocyte ratio; SHEATH+, the significance and handling of microscopic invasion of NSCLC into hilar peribronchovascular soft tissue; LI, labeling index; TNM, tumor-node-metastasis.

Discussion

The rationale for oncologic surveillance following initial treatment of lung cancer is to detect recurrent disease or a second primary lung cancer early enough so that an intervention can increase survival and/or improve quality of life. Even with completely resected early stage lung cancer, recurrence rates are high. Unfortunately, the majority of recurrences present at distant sites and have a poor prognosis, but a small proportion of patients do present with localized and potentially salvageable relapses. The majority of locoregional and distant recurrences occur within the first 2 years.10 When planning posttreatment surveillance, care should be taken to limit the number of CT scans if possible, particularly in younger individuals. There are no randomized trials comparing different surveillance strategies in patients with NSCLC. The evidence from observational studies and a systematic review of the literature6 does not establish a clear-cut benefit for aggressive surveillance following treatment with curative intent. There are no data comparing full-dose, diagnostic, contrast-enhanced CT with LDCT and MnDCT. Given the desire to minimize radiation exposure and the potential for continued screening for many years, some physicians use LDCT even in the initial period after NSCLC treatment. In view of new imaging modalities, such as LDCT8 and MnDCT scan,9 the radiation injury for patients with NSCLC after surgery could be enormously decreased. Patients who have had lung cancer are also at increased risk of a second primary, particularly of the lung, and may benefit from early detection of a second primary as well as from detection of a local recurrence. Therefore, annual LDCT8 may be continued beyond 3 years for patients who have no evidence of disease since these individuals are at risk for a second primary lung cancer as well as for recurrence. The specific follow-up schedule for CT imaging may be more or less frequent, depending upon risk factors for recurrence.

In a series of 1,073 patients who underwent a complete resection, recurrent NSCLC was identified in 445 patients (41%).11 The median time to recurrence following surgery was 11.5 months, and the median survival following recurrence was 8.1 months. Multivariate analysis identified several factors that predicted shorter survival following recurrence. These included poor performance status, disease-free interval of 1 year or less, prior use of neoadjuvant chemotherapy or adjuvant radiotherapy, and distant metastases (as opposed to intrathoracic recurrence alone). In our previous research,3 261 patients with clinical Stage I NSCLC after complete resection and dissection of mediastinal lymph nodes were reviewed. Only 17 patients (6.5%) had locoregional recurrences, and 20 (7.66%) of the same population had distant metastases. We found that tumor differentiation and serum CEA were independent predicators of postoperative relapse for clinical Stage I NSCLC after surgical resection. Risk factors of postoperative recurrence in patients with NSCLC may enable us to optimize the patient selection for postoperative adjuvant therapies to prevent possibly occult micrometastases.12 One of the purposes of this study is to get together all possible predictors of postoperative recurrences in patients with NSCLC (Tables 2 and 3). However, what kind of surveillance duration and follow-up modalities could really benefit these selected patients with specific risk factors of postoperative recurrence of NSCLC? Prospective multi-institutional studies or randomized clinical trials are mandatory to further validate the predictors of recurrence in NSCLC and specially designated surveillance guidelines for these selected patients.

Currently there is no established indication for targeted agents as adjuvant therapies outside of a clinical trial setting for patients with resectable NSCLC, and its use in this setting is controversial. There is suggestive evidence that EGFR mutation- positive early stage patients have a superior recurrence-free survival with erlotinib, particularly patients with resected Stage IIIA N2 disease.13,14 Whether this translates to an improvement in overall survival or merely delays recurrence is unknown. Randomized clinical trials are evaluating the role of EGFR- or ALK-targeted therapies in the adjuvant setting for molecularly selected patients. The rapid progression of molecular biology and genetic technique provide clinicians with tools to diagnose and treat diseases more precisely. EGFR mutation test can sieve out suitable cases, who are sensitive to EGFR TKIs, from patients with recurrences of NSCLC after adjuvant erlotinib therapy.13,14 Besides, immune checkpoint inhibitors, which unleash a patient’s own T-cells to kill tumors, are revolutionizing cancer treatment. Rizvi et al15 used whole-exome sequencing of NSCLC samples treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1) to unravel the genomic determinants of response to this therapy. The results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy.

Conclusion

Annual LDCT, which causes less radiation harm, may be continued beyond 3 years for patients who have no evidence of disease since these individuals are at risk for a second primary lung cancer as well as for recurrence. The specific follow-up schedule for CT imaging may be more or less frequent, depending upon risk factors for recurrence. Many different predictors of postoperative recurrence in patients with NSCLC may enable us to optimize the patient selection for specified surveillance guidelines and design personalized adjuvant therapies to prevent possibly occult micrometastases and to get better outcome.

Disclosure

There was no substantial direct or indirect commercial financial incentive associated with publishing this article. The authors report no conflicts of interest in this work.


References

1.

Alberg AJ, Ford JG, Samet JM, et al. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132:29S–55S.

2.

Taylor MD, Nagji AS, Bhamidipati CM, et al. Tumor recurrence after complete resection for non-small cell lung cancer. Ann Thorac Surg. 2012;93:1813–1820; discussion 1820–1821.

3.

Chen YY, Huang TW, Tsai WC, et al. Risk factors of postoperative recurrences in patients with clinical stage I NSCLC. World J Surg Oncol. 2014;12:10.

4.

Clark MM, Novotny PJ, Patten CA, et al. Motivational readiness for physical activity and quality of life in long-term lung cancer survivors. Lung Cancer. 2008;61:117–122.

5.

Yang P. Epidemiology of lung cancer prognosis: quantity and quality of life. Methods Mol Biol. 2009;471:469–486.

6.

Calman L, Beaver K, Hind D, et al. Survival benefits from follow-up of patients with lung cancer: a systematic review and meta-analysis. J Thorac Oncol. 2011;6:1993–2004.

7.

American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010.

8.

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.

9.

Brouwers MC, Kho ME, Browman GP, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182:E839–E842.

10.

Lou F, Sima CS, Rusch VW, et al. Differences in patterns of recurrence in early-stage versus locally advanced non-small cell lung cancer. Ann Thorac Surg. 2014;98:1755–1760; discussion 1760–1761.

11.

Sugimura H, Nichols FC, Yang P, et al. Survival after recurrent nonsmall-cell lung cancer after complete pulmonary resection. Ann Thorac Surg. 2007;83:409–417; discussion 417–418.

12.

Chen YY, Huang TW, Tsai WC, et al. Lymphovascular space invasion and tumor differentiation are predictors for postoperative recurrence in patients with pathological stage I nonsmall cell lung cancer. J Chin Med Assoc. 2014;77:416–421.

13.

Pennell NA, Neal JW, Chaft JE, et al. SELECT: a multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. J Clin Oncol. 2014;32:5s.

14.

Shepherd FA, Altorki NK, Eberhardt WE, et al. Adjuvant erlotinib (E) versus placebo (P) in non-small cell lung cancer (NSCLC) patients (pts) with tumors carrying EGFR-sensitizing mutations from the RADIANT trial. J Clin Oncol. 2014;32:5s.

15.

Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–128.

16.

David SEDE, Wallace A, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 7. Fort Washington, PA: National Comprehensive Cancer Network; 2015.

17.

Saunders M, Sculier JP, Ball D, et al. Consensus: the follow-up of the treated patient. Lung Cancer. 2003;42 (Suppl 1):S17–S19.

18.

National Institute for Health and Clinical Excellence. The Diagnosis and Treatment of Lung Cancer. London, UK: National Institute for Health and Clinical Excellence; 2011.

19.

Crino L, Weder W, van Meerbeeck J, et al. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v103–v115.

20.

Zhang Y, Sun Y, Xiang J, et al. A clinicopathologic prediction model for postoperative recurrence in stage Ia non-small cell lung cancer. J Thorac Cardiovasc Surg. 2014;148:1193–1199.

21.

Kuo SW, Chen JS, Huang PM, et al. Prognostic significance of histologic differentiation, carcinoembryonic antigen value, and lymphovascular invasion in stage I non-small cell lung cancer. J Thorac Cardiovasc Surg. 2014;148:1200–1207, e1203.

22.

Park SY, Cho A, Yu WS, et al. Prognostic value of total lesion glycolysis by 18F-FDG PET/CT in surgically resected stage IA non-small cell lung cancer. J Nucl Med. 2015;56:45–49.

23.

Jiang W, Pang X, Xi J, et al. Clinical outcome of subcentimeter non-small cell lung cancer after surgical resection: single institution experience of 105 patients. J Surg Oncol. 2014;110:233–238.

24.

Tao H, Hayashi T, Sano F, et al. Prognostic impact of lymphovascular invasion compared with that of visceral pleural invasion in patients with pN0 non-small-cell lung cancer and a tumor diameter of 2 cm or smaller. J Surg Res. 2013;185:250–254.

25.

Izar B, Sequist L, Lee M, et al. The impact of EGFR mutation status on outcomes in patients with resected stage I non-small cell lung cancers. Ann Thorac Surg. 2013;96:962–968.

26.

Kobayashi N, Toyooka S, Soh J, et al. Risk factors for recurrence and unfavorable prognosis in patients with stage I non-small cell lung cancer and a tumor diameter of 20 mm or less. J Thorac Oncol. 2007;2:808–812.

27.

Kozu Y, Maniwa T, Takahashi S, et al. Risk factors for both recurrence and survival in patients with pathological stage I non-small-cell lung cancer. Eur J Cardiothorac Surg. 2013;44:e53–e58.

28.

Choi PJ, Jeong SS, Yoon SS. Prognosis of recurrence after complete resection in early-stage non-small cell lung cancer. Korean J Thorac Cardiovasc Surg. 2013;46:449–456.

29.

Cho S, Park TI, Lee EB, et al. Poor prognostic factors in surgically resected stage I non-small cell lung cancer: histopathologic and immunohistochemical analysis. Korean J Thorac Cardiovasc Surg. 2012;45:101–109.

30.

Guo NL, Tosun K, Horn K. Impact and interactions between smoking and traditional prognostic factors in lung cancer progression. Lung Cancer. 2009;66:386–392.

31.

Nguyen XC, Lee WW, Chung JH, et al. FDG uptake, glucose transporter type 1, and Ki-67 expressions in non-small-cell lung cancer: correlations and prognostic values. Eur J Radiol. 2007;62:214–219.

32.

He L, Hou M, Zhang J, et al. [Subcellular localization of survivin in non-small cell lung cancer.] Ai Zheng 2009;28:955–960. Chinese.

33.

Zhang C, Lin X, Song Y, et al. Overexpression of glucosylceramide synthase and its significance in the clinical outcome of non-small cell lung cancer. Chin Med J (Engl). 2014;127:3071–3076.

34.

Ohgino K, Soejima K, Yasuda H, et al. Expression of fibroblast growth factor 9 is associated with poor prognosis in patients with resected non-small cell lung cancer. Lung Cancer. 2014;83:90–96.

35.

Kim MS, Park TI, Lee YM, et al. Expression of Id-1 and VEGF in non-small cell lung cancer. Int J Clin Exp Pathol. 2013;6:2102–2111.

36.

Lee SH, Min JW, Lee JS, et al. Reactive oxygen species modulator 1 (Romo1) overexpression is an independent predictor of poor survival in NSCLC patients who undergo surgical resection. Lung Cancer. 2015;87:45–52.

37.

Xu N, Wu SD, Wang H, et al. Involvement of FoxM1 in non-small cell lung cancer recurrence. Asian Pac J Cancer Prev. 2012;13:4739–4743.

38.

Zhang J, Huang SH, Li H, et al. Preoperative lymphocyte count is a favorable prognostic factor of disease-free survival in non-small-cell lung cancer. Med Oncol. 2013;30:352.

39.

Yamashita S, Moroga T, Tokuishi K, et al. Ki-67 labeling index is associated with recurrence after segmentectomy under video-assisted thoracoscopic surgery in stage I non-small cell lung cancer. Ann Thorac Cardiovasc Surg. 2011;17:341–346.

40.

Ilie M, Hofman V, Ortholan C, et al. Predictive clinical outcome of the intratumoral CD66b-positive neutrophil-to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer. Cancer. 2012;118:1726–1737.

41.

Hsu NY, Wu JY, Liu X, et al. Expression status of ribonucleotide reductase small subunits hRRM2/p53R2 as prognostic biomarkers in stage I and II non-small cell lung cancer. Anticancer Res. 2011;31:3475–3481.

42.

Wang Z, Fu J, Diao D, et al. [Pre-operative plasma D-dimer level may predict the poor prognosis within one year after the surgery for non-small cell lung cancer.] Zhongguo Fei Ai Za Zhi. 2011;14:534–537. Chinese.

43.

Sakai Y, Ohbayashi C, Kanomata N, et al. Significance of microscopic invasion into hilar peribronchovascular soft tissue in resection specimens of primary non-small cell lung cancer. Lung Cancer. 2011;73:89–95.

44.

Park SY, Lee HS, Jang HJ, et al. Tumor necrosis as a prognostic factor for stage IA non-small cell lung cancer. Ann Thorac Surg. 2011;91:1668–1673.

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.