引言：
肺減容手術是一種對於嚴重肺氣腫患者有幫助的新型治療方式。但是，這類隨機對照試驗往往需要花費很多的資源，來追蹤病人的併發症與死亡狀況。因此，通過Prentice criteria，我們的研究旨在驗證運動能力和肺功能是否可以替代接受肺減容手術患者的死亡率

方法：
本研究使用美國國家肺氣腫治療試驗（NETT）的數據進行次要分析。NETT研究原本的目的，在比較接受肺減容手術的患者和僅接受藥物治療患者的後續差別。本研究會使用Prentice criteria來驗證6分鐘行走測試（6MWT）、腳踏車最大功率、用力呼氣一秒量（FEV1）和用力呼氣肺活量（FVC）的變化是否能作為5年死亡率的替代終點。此外，也會評估各替代終點的治療成效解釋率（proportion of treatment effect explained, PTE），藉此獲得最佳替代終點。

結果：
499位患者被納入分析，這些患者皆有5年死亡狀況、肺減容手術前、肺減容手術後6、12及24個月的6MWT、腳踏車最大功率、FEV1和FVC數據。發現6、12及24個月後6MWT、FEV1和FVC的變化，及12及24個月後腳踏車最大功率的變化，可以作為5年死亡率的替代終點。此外，最佳的替代終點是24個月後腳踏車最大功率的變化，因為該替代終點治療成效解釋率為最大的65%。

結論：
這項研究證實了運動能力和肺功能的變化可以做為死亡率的替代終點。未來的研究可以據此使用它們來減少研究的成本和時間。

Introduction:
Lung volume reduction surgery (LVRS) is one of the novel treatment which had shown survival benefits for patients with severe emphysema. However, this kind of randomized controlled trails would take years and cost massively before primary outcomes, morbidity or mortality are shown. Therefore, by using the concept of Prentice criteria, our study aimed to validate whether exercise capacity and lung functions could be surrogate endpoints for mortality in patients who received LVRS

Methods:
The study is a secondary analysis from the data of the National Emphysema Treatment Trial (NETT). The randomized controlled trial aimed to compare the outcomes between the patients who received LVRS and others receiving medical treatment only. Prentice criteria are used to validate changes of 6-min walk test (6MWT), maximal ergometry workload, FEV1 and FVC as surrogate outcomes for 5-year mortality. In addition, proportion of treatment effect explained (PTE) would be evaluated for optimal surrogacy.

Results:
499 patients with intact data of 5-year mortality, 6MWT, maximal ergometry workload, FEV1 and FVC before, 6, 12, and 24 months after randomization were recruited. The changes of 6MWT, FEV1 and FVC after 6, 12, and 24 months, and the changes of maximal ergometry workload after 12 and 24 months were validated surrogate outcomes for 5-year mortality. In addition, the best surrogate endpoint is the change of maximal ergometry workload after 24 months due to its highest PTE.

Conclusion:
The study validated the changes of exercise capacity and pulmonary function could be surrogate endpoints for mortality. Future studies can use them to reduce the cost and duration.

1. Collaborators, G.B.D.C.R.D., Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med, 2017. 5(9): p. 691-706.
2. Cheng, S.L., et al., COPD in Taiwan: a National Epidemiology Survey. Int J Chron Obstruct Pulmon Dis, 2015. 10: p. 2459-67.
3. COPD Mortality. [cited 2020 March 6th]; Available from: https://www.lung.org/research/trends-in-lung-disease/copd-trends-brief/copd-mortality.
4. Geddes, D., et al., Effect of lung-volume-reduction surgery in patients with severe emphysema. N Engl J Med, 2000. 343(4): p. 239-45.
5. Fishman, A., et al., A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med, 2003. 348(21): p. 2059-73.
6. Yusen, R.D., et al., A prospective evaluation of lung volume reduction surgery in 200 consecutive patients. Chest, 2003. 123(4): p. 1026-37.
7. Hillerdal, G., et al., Comparison of lung volume reduction surgery and physical training on health status and physiologic outcomes: a randomized controlled clinical trial. Chest, 2005. 128(5): p. 3489-99.
8. Miller, J.D., et al., Lung volume reduction surgery vs medical treatment: for patients with advanced emphysema. Chest, 2005. 127(4): p. 1166-77.
9. Lederer, D.J., et al., Lung-volume reduction surgery for pulmonary emphysema: Improvement in body mass index, airflow obstruction, dyspnea, and exercise capacity index after 1 year. J Thorac Cardiovasc Surg, 2007. 133(6): p. 1434-8.
10. Pompeo, E. and T.C. Mineo, Two-year improvement in multidimensional body mass index, airflow obstruction, dyspnea, and exercise capacity index after nonresectional lung volume reduction surgery in awake patients. Ann Thorac Surg, 2007. 84(6): p. 1862-9; discussion 1862-9.
11. Ciccone, A.M., et al., Long-term outcome of bilateral lung volume reduction in 250 consecutive patients with emphysema. J Thorac Cardiovasc Surg, 2003. 125(3): p. 513-25.
12. Rationale and design of the National Emphysema Treatment Trial (NETT): A prospective randomized trial of lung volume reduction surgery. J Thorac Cardiovasc Surg, 1999. 118(3): p. 518-28.
13. Gandhi, G.Y., et al., Patient-important outcomes in registered diabetes trials. JAMA, 2008. 299(21): p. 2543-9.
14. Buyse, M., et al., Statistical evaluation of surrogate endpoints with examples from cancer clinical trials. Biom J, 2016. 58(1): p. 104-32.
15. Prentice, R.L., Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med, 1989. 8(4): p. 431-40.
16. Lin, D.Y., T.R. Fleming, and V. De Gruttola, Estimating the proportion of treatment effect explained by a surrogate marker. Stat Med, 1997. 16(13): p. 1515-27.
17. Ciani, O., et al., Validation of Exercise Capacity as a Surrogate Endpoint in Exercise-Based Rehabilitation for Heart Failure: A Meta-Analysis of Randomized Controlled Trials. JACC Heart Fail, 2018. 6(7): p. 596-604.
18. Biomarkers Definitions Working, G., Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther, 2001. 69(3): p. 89-95.
19. De Gruttola, V.G., et al., Considerations in the evaluation of surrogate endpoints in clinical trials. summary of a National Institutes of Health workshop. Control Clin Trials, 2001. 22(5): p. 485-502.
20. Yetley, E.A., D.L. DeMets, and W.R. Harlan, Jr., Surrogate disease markers as substitutes for chronic disease outcomes in studies of diet and chronic disease relations. Am J Clin Nutr, 2017. 106(5): p. 1175-1189.
21. Ellenberg, S. and J.M. Hamilton, Surrogate endpoints in clinical trials: cancer. Stat Med, 1989. 8(4): p. 405-13.
22. Fokas, E., et al., Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial. Ann Oncol, 2018. 29(7): p. 1521-1527.
23. Rodel, C., et al., Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol, 2012. 13(7): p. 679-87.
24. Royce, T.J., et al., Surrogate End Points for All-Cause Mortality in Men With Localized Unfavorable-Risk Prostate Cancer Treated With Radiation Therapy vs Radiation Therapy Plus Androgen Deprivation Therapy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol, 2017. 3(5): p. 652-658.
25. Kerem, E., et al., Prediction of mortality in patients with cystic fibrosis. N Engl J Med, 1992. 326(18): p. 1187-91.
26. Milla, C.E. and W.J. Warwick, Risk of death in cystic fibrosis patients with severely compromised lung function. Chest, 1998. 113(5): p. 1230-4.
27. Montgomery, A.B., T. Abuan, and M.A. Yeager, Regulatory aspects of Phase 3 endpoints for new inhaled antibiotics for cystic fibrosis patients with chronic Pseudomonas aeruginosa infections. J Aerosol Med Pulm Drug Deliv, 2012. 25(4): p. 198-203.
28. van Agteren, J.E., et al., Lung volume reduction surgery for diffuse emphysema. Cochrane Database Syst Rev, 2016. 10: p. CD001001.
29. Kishaba, T., Evaluation and management of Idiopathic Pulmonary Fibrosis. Respir Investig, 2019. 57(4): p. 300-311.
30. du Bois, R.M., et al., Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference. Am J Respir Crit Care Med, 2011. 183(9): p. 1231-7.
31. Cote, C.G., et al., The 6-min walk distance, peak oxygen uptake, and mortality in COPD. Chest, 2007. 132(6): p. 1778-85.
32. Ciani, O., et al., Time to Review the Role of Surrogate End Points in Health Policy: State of the Art and the Way Forward. Value Health, 2017. 20(3): p. 487-495.