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Developing and validating utility parameters to establish patient-reported outcome-based postoperative symptom management in patients with lung cancer: a multicentre, prospective, observational cohort study protocol

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-030726

Article Type: Protocol

Date Submitted by the 28-Mar-2019 Author:

Complete List of Authors: Dai, Wei; Sichuan Cancer Hospital and Research Institute, Department of Thoracic Surgery Xie, Shaohua; Chengdu Medical College, Graduate School Zhang, Rui ; The Seventh People's Hospital of Chengdu, Department of Thoracic Surgery Wei, Xing ; Sichuan Cancer Hospital and Research Institute, Department of Thoracic Surgery Wu, Chuanmei ; Sichuan Cancer Hospital and Research Institute, Department of Thoracic Surgery Zhang, Yuanqiang; Zigong First People's Hospital, Department of Cardiothoracic Surgery Feng, Wenhong ; Jiangyou People's Hospital, Department of Thoracic and http://bmjopen.bmj.com/ Cardiovascular Surgery Liao, Xiaoqing ; Dazhu County People's Hospital, Department of Cardiothoracic Surgical Oncology Mu, Yunfei ; The Third People's Hospital of Chengdu, Department of Thoracic Surgery Zhou, Heling ; Sichuan Cancer Hospital and Research Institute, Department of Thoracic Surgery Cheng, Xuemei ; Sichuan Cancer Hospital and Research Institute

Jiang, Yanhua ; Sichuan Cancer Hospital and Research Institute, on September 26, 2021 by guest. Protected copyright. Department of Thoracic Surgery He, Jintao ; Sichuan Cancer Hospital and Research Institute, Department of Thoracic Surgery Li, Qiang; Sichuan Cancer Hospital and Research Institute, Department of Thoracic Surgery Yang, Xiaojun ; Sichuan Cancer Hospital and Research Institute, Department of Thoracic Surgery Shi, Qiuling; University of Texas MD Anderson Cancer Center, Department of Symptom Research

utility parameters, lung cancer, patient-reported outcomes, Keywords: postoperative symptom management, protocol

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29 2 30 Graduate School, Chengdu Medical College, Chengdu, Sichuan, China. 31 3Department of Thoracic Surgery, The Seventh People's Hospital of Chengdu, Chengdu, 32 33 Sichuan, China. 34 4Department of Cardiothoracic Surgery, Zigong First People's Hospital, Zigong, Sichuan, 35 36 China. http://bmjopen.bmj.com/ 37 5 38 Department of Thoracic and Cardiovascular Surgery, Jiangyou People's Hospital, Jiangyou, 39 Sichuan, China. 40 6 41 Department of Cardiothoracic Surgical Oncology, Dazhu County People's Hospital, Dazhu 42 County, Dazhou, Sichuan, China. 43 44 7Department of Thoracic Surgery, The Third People's Hospital of Chengdu, Chengdu, Sichuan, 45 China. on September 26, 2021 by guest. Protected copyright. 46 47 8Department of Symptom Research, The University of Texas MD Anderson Cancer Center, 48 49 Houston, Texas, USA. 50 51 52 Correspondence to 53 Dr Qiuling Shi, Department of Symptom Research, The University of Texas MD Anderson 54 55 Cancer Center, 1515 Holcombe Blvd., Unit 1450 Houston, TX 77030, USA. Telephone: 56 713/745-3504, e-mail: [email protected]. 57 58 59 1 60

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3 Dr Xiaojun Yang, Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 5 Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology 6 of China, No. 55, Section 4, South Renmin Road, Chengdu 610041, Sichuan, China. Telephone: 7 8 +86-028-85420366, e-mail: [email protected]. 9 10 11 #These authors contributed equally to this work. 12 13 14 15 Word count 1737 words 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 5 ABSTRACT 6 7 8 Introduction Patient-reported outcome (PRO)-based symptom monitoring and alerting have 9 10 been attractive for patient care after a tumour-removal surgery. However, the implementation 11 12 parameters of this patient-centred symptom management system in postoperative patients with 13 14 lung cancer are still lacking. We aim to develop a symptom index for monitoring, to determine 15 16 the optimal time points for symptom assessment, and to define alert thresholds for medical 17 intervention. 18 For peer review only 19 20 Methods and analysis The study will prospectively recruit 300 patients with lung cancer 21 22 undergoing surgery in 6 hospitals. The MD Anderson Symptom Inventory-lung cancer module 23 24 will be used to collect longitudinal symptom data within 3 days before surgery, daily 25 26 postoperatively during in-hospital stay, and weekly after discharge until 4 weeks or the start of 27 28 postoperative oncologic treatment. 29 30 31 Ethics and dissemination The study was approved by the Ethics Committee of Sichuan Cancer 32 33 Hospital on October 16, 2017 (No. SCCHEC-02-2017-042). This manuscript is based on the 34 Version 2.0, June 1, 2018 of the protocol. The results of this study will be presented at medical 35 36 conferences and published in peer-reviewed journals. 37 http://bmjopen.bmj.com/ 38 39 Trials registration number NCT03341377. 40 41 42 Keywords utility parameters, lung cancer, patient-reported outcomes, postoperative symptom 43 44 management, protocol.

45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 3 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 ARTICLE SUMMARY 5 6 Strengths and limitations of this study 7 8 9 1. This is a multicentre, prospective, observational cohort study from the real-world clinical 10 11 setting in China. 12 13 2. It focuses on developing and validating utility parameters for future implementation of 14 15 patient-reported outcome (PRO)-based postoperative symptom management in patients with 16 17 lung cancer. 18 For peer review only 19 20 3. It focuses on frequent postoperative longitudinal symptom data collection, including 21 22 preoperatively, daily postoperatively, and weekly after discharge until 4 weeks or the start of 23 24 postoperative oncologic treatment. 25 26 4. The MD Anderson Symptom Inventory-lung cancer module will be used to collect patient- 27 28 reported outcomes. 29 30 31 5. The fact that five sub-centres joined midway through the study may be a limitation. 32 33 34 35 36

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 INTRODUCTION 5 6 Lung cancer is the leading cause of death among all types of cancers,1 2 with surgery as its main 7 8 treatment method. Approximately 150,000 lung cancer operations are performed each year in 9 10 China.3 Thoracotomy or minimally invasive thoracoscopic surgery can lead to severe and 11 12 various postoperative symptoms, such as pain, fatigue, cough, and shortness of breath.4-9 13 14 Adequate perioperative symptom control can accelerate postoperative recovery, improve 15 16 quality of life (QOL), and ensure timely return to intended oncologic therapy, and thus, 17 18 potentially benefitFor survival. peer10 11 Clinical review trials have shown only that the use of patient-reported 19 20 outcome (PRO)-based symptom monitoring in patients receiving chemotherapy can not only 21 22 improve QOL, but also significantly improve survival.12-14 However, very few studies have 23 24 been conducted during the early-phase postoperative care in patients with lung cancer.10 15 25 26 PRO-based symptom management is the key and ideal model for patient-centred care.15-19 27 28 However, there are still a few technical and methodological issues to be resolved before 29 30 implementing PRO tools in postoperative symptom management in patients with lung cancer. 31 32 First, a lung cancer surgery-specific measurement index is lacking. Currently, four commonly 33 34 used lung cancer-specific PRO tools are available: the European Organisation for Research and 35 36 Treatment of Cancer Quality of Life Questionnaire–Lung Cancer Module (EORTC QLQ- 37 http://bmjopen.bmj.com/ 38 LC13), the Functional Assessment of Cancer Therapy–Lung (FACT-L), the Lung Cancer 39 40 Symptom Scale (LCSS), and the MD Anderson Symptom Inventory Lung Cancer Module 41 42 (MDASI-LC).16 20-24 These scales have been primarily generated and validated in patients with 43 44 lung cancer receiving chemotherapy and radiotherapy, but do not include specific symptom and

45 on September 26, 2021 by guest. Protected copyright. 46 function items in patients undergoing surgery. Second, the key symptom monitoring time points 47 48 are undetermined. Usually, PRO data collection for discharged patients who have undergone 49 50 lung cancer surgery is limited to in-clinic visits, and the first clinic visit is approximately 4 51 52 weeks after discharge. During these 4 weeks, the patient’s symptoms and functional status can 53 54 rapidly change,18 and these potential abnormalities are often ignored, leading to negative 55 56 clinical outcomes, for instance, postoperative complications, unplanned clinic visit or 57 58 emergency room visit. In addition, the absence of key PRO information influences the 59 5 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 25 4 evaluation of clinical outcomes. Third, evidence-based alert thresholds for perioperative 5 6 intervention are lacking. A definitive cutpoint of symptom score is the premise of patient 7 8 symptom monitoring and precision medical care. In this study, we aim to solve these 9 methodological issues, via developing and validating a postoperative symptom index, defining 10 11 the optimal symptom monitoring time points and determining alert thresholds for medical 12 13 intervention. 14 15 16 17 18 For peer review only 19 METHODS AND ANALYSIS 20 21 Study design 22 23 24 This is a real-world, ongoing, multicentre, prospective, observational cohort study. A flow 25 26 diagram of this study is shown in Figure 1. 27 28 29 30 31 Setting 32 33 34 The study will be conducted in 6 hospitals in China, namely, Sichuan Cancer Hospital, Zigong 35 36 First People’s Hospital, Jiangyou People’s Hospital, Dazhu County People’s Hospital, The

37 http://bmjopen.bmj.com/ 38 Third People’s Hospital of Chengdu, and The Seventh People’s Hospital of Chengdu. This 39 40 study was initiated by Sichuan Cancer Hospital and started on November 2017. The other five 41 research centres joined midway in January 2019. This study is estimated to be completed before 42 43 March 31, 2020. 44

45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 Study population 50 51 Eligible patients are required to be aged >18 years, have no cognitive impairment or be able to 52 53 understand the study requirements, be pathologically diagnosed as primary lung cancer, and 54 55 undergo a surgical procedure. 56 57 58 59 6 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 Sample size calculation 5 6 This study primarily aims to establish a symptom index that can be used to monitor 7 8 postoperative symptom burden in patients with lung cancer and that requires significant 9 10 changes over time during the early postoperative period. Our preliminary work showed that the 11 12 overall standard deviation of the score of the main postoperative symptom of lung cancer (0– 13 14 10 score) was 2.2 in the first postoperative month. With an average of 5 assessments, the rate 15 16 of symptom score change over time was 0.1 points per assessment according to the general 17 18 linear regression Formodel. In peerorder to reject review the null hypothesis only that the symptom index does not 19 20 significantly change over time, 239 patients with effective symptom data are needed. The type 21 22 I error rate is 5%, and the power is 80%. In consideration of 20% attrition , the final sample 23 24 size is approximately 300 (239/0.8) cases. 25 26 27 28 29 Outcome measures 30 31 32 The primary outcome in this study is postoperative symptom burden in patients with lung 33 34 cancer, as measured by the MDASI-LC. The symptom burden will be presented via a 35 36 postoperative symptom scale, generated from a subgroup of MDASI-LC symptom items that

37 http://bmjopen.bmj.com/ 38 significantly change over the early postoperative phase (from preoperatively to 4 weeks 39 postoperatively). The MDASI-LC will be used to collect preoperative longitudinal symptom 40 41 data (within 3 days preoperatively), daily postoperatively (in-hospital stay of ≤ 14 days), and 42 43 weekly after discharge until 4 weeks (±3 days) or the start of postoperative cancer treatment. 44 45 The MDASI-LC is a lung cancer-specific PRO measurement, which has been translated and on September 26, 2021 by guest. Protected copyright. 46 47 validated in a Chinese setting. Secondary outcomes mainly include QOL measured by a single- 48 49 item QOL scale (UNISCALE)26 and functional status measured by MDASI-LC interference 50 51 items. The measurement time points of QOL are the same as that of the MDASI-LC. We will 52 53 measure patient’s perception of symptom and daily functioning changes via a five- 54 55 point Likert Scale weekly after discharge until 4 weeks (±3 days) or the start of postoperative 56 57 cancer treatment. 58 59 7 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 5 6 Withdrawal criteria 7 8 9 Participants will be withdrawn from this study if they meet the following criteria: (1) 10 11 unexpected cancellation of planned surgery, (2) >24 hours of postoperative endotracheal 12 13 intubation in the ICU, (3) postoperative length of hospital stay of >14 days, (4) severe 14 15 complications interfering with postoperative symptom data collection, (5) the postoperative 16 17 pathological diagnosis is not primary lung cancer, (6) those who do not follow the study 18 For peer review only 19 protocol, (7) those who ask to withdraw from the study, or (8) other conditions that require 20 21 withdrawal as assessed by the investigator. 22 23 24 25 26 Data collection, management, and monitoring 27 28 REDCap,27 28 a web-based software application for data storage and management established 29 30 in our hospital (http://125.71.214.100:888/redcap), will be used to collect and manage data in 31 32 this study. Electronic case report forms (e-CRF) will be designed on the REDCap, consisting 33 34 of 12 domains, such as the demographic characteristics, preoperative characteristics, surgery, 35 36 anaesthesia, postoperative care, perioperative complications, pain management, MDASI-LC, 37 http://bmjopen.bmj.com/ 38 QOL, symptom and daily function changes, completion data, and follow-up. PRO data will be 39 40 collected using a paper questionnaire or an e-questionnaire and then recorded in the REDCap. 41 42 Participants are instructed to fill out the scales independently. If they have difficulties in 43 44 completing the scales, investigators will assist them by reading each item aloud and recording

45 on September 26, 2021 by guest. Protected copyright. 46 their responses. All data will be de-identified and entered into the REDCap platform. Data will 47 48 be entered by a data entry clerk and checked regularly by a quality controller. Data monitoring 49 50 will be regularly carried out by the Ethics Committee of Sichuan Cancer Hospital. 51 52 53 54 55 Quality control 56 57 58 Investigators will receive standard operating procedure training before recruiting the patients. 59 8 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 The sub-centres will receive regular online directions, telephone monitoring, and on-site 5 6 supervision conducted by the principal investigator or international expert from MD Anderson 7 8 Cancer Center. 9 10 11 12 13 Data analysis 14 15 To be included in the analysis, the participants must complete the MDASI-LC assessments 16 17 preoperatively and at least two additional assessments postoperatively. The multiple imputation 18 For peer review only 19 method will be used to impute missing data. Categorical variables will be presented as 20 21 percentages or frequencies. Continuous variables will be presented as mean ± standard 22 23 deviation or median and 25%–75% quartiles. We will use generalised linear mixed effects 24 25 models to describe trajectories of symptom severity, symptom interference, and QOL during 26 27 the entire investigation period. The average score of symptoms that significantly change over 28 29 time will be generated as the postoperative symptom scale (PSS). The optimal time points for 30 31 symptom monitoring will be determined as time points of significantly changes in PSS from 32 33 the previous assessment. The absolute alert thresholds will be generated as cut-off points for 34 35 the PSS with the method proposed by Serlin et al,29 using the 6 MDASI-LC interference items 36

37 as the anchor. We will define the minimally important difference of PSS using anchor-based http://bmjopen.bmj.com/ 38 39 methods,30 with patient’s perception of symptom changes as the anchor. Two-sided P-values of 40 41 <0.05 are considered statistically significant. All data analyses will be performed using the SAS 42 43 9.4. 44

45 on September 26, 2021 by guest. Protected copyright. 46 47 48 Data availability statement 49 50 51 After publishing the results of this study, de-identified data that support the results will be 52 available to applicants from the corresponding author on reasonable request. 53 54 55 56 57 58 Patient and public involvement statement 59 9 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 The patients and the general public were not involved in the design, recruitment, and 5 6 implementation of this study. We have no plans of informing the study participants regarding 7 8 the results of this study. However, the results will be disseminated to the applicants in the form 9 of a published article as requested. 10 11 12 13 14 15 ETHICS AND DISSEMINATION 16 17 This study was approved by the Ethics Committee of Sichuan Cancer Hospital on October 16, 18 For peer review only 19 2017 (No. SCCHEC-02-2017-042). Any amendments to the research protocol will be submitted 20 21 for ethical approval. All participants must provide informed consent. The results in this study 22 23 will be first reported at relevant medical conferences and then will eventually be published in 24 25 peer-reviewed journals. 26 27 28 29 30 Acknowledgements The authors thank all the participants and their advisors involving in this study. 31 32 33 Author contributions WD, YHJ, JTH, QL, XJY, and QLS contributed to the study design. WD, SHX, 34 35 RZ, XW, CMW, YQZ, WHF, XQL, YFM, HLZ, and XMC performed the study. WD, SHX, RZ, XW, 36

37 and CMW drafted the initial manuscript. QL, XJY, and QLS revised the draft. All authors have reviewed http://bmjopen.bmj.com/ 38 39 and approved the final manuscript. 40 41 Funding This work was supported by [Sichuan Science and Technology Program] grant number 42 43 [2011FZ0069], [2019YFH0070], and [National Natural Science Foundation of China] grant number 44 45 [81872506]. on September 26, 2021 by guest. Protected copyright. 46 47 48 Competing interests None declared. 49 50 51 Patient consent Obtained. 52 53 Ethics approval Ethics Committee of Sichuan Cancer Hospital (No. SCCHEC-02-2017-042). 54 55 56 Provenance and peer review Not commissioned; externally peer reviewed. 57 58 59 10 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 5 REFERENCES 6 7 8 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. 2018;68:7-30. 9 10 2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of 11 12 incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394- 13 14 424. 15 16 3. Liao H, Mei JD, Liu CW, et al. [A survey on the current development of thoracic surgery in tertiary 17 hospitals of China]. Zhonghua Wai Ke Za Zhi 2018;56:888-91. 18 For peer review only 19 4. Lowery AE, Krebs P, Coups EJ, et al. Impact of symptom burden in post-surgical non-small cell 20 21 lung cancer survivors. Support Care Cancer 2014;22:173-80. 22 23 5. Oksholm T, Rustoen T, Cooper B, et al. Trajectories of Symptom Occurrence and Severity From 24 25 Before Through Five Months After Lung Cancer Surgery. J Pain Symptom Manage 2015;49:995- 26 27 1015. 28 29 6. Yang P, Cheville AL, Wampfler JA, et al. Quality of life and symptom burden among long-term 30 31 lung cancer survivors. J Thorac Oncol 2012;7:64-70. 32 33 7. Kenny PM, King MT, Viney RC, et al. Quality of life and survival in the 2 years after surgery for 34 35 non small-cell lung cancer. J Clin Oncol 2008;26:233-41. 36

37 8. Li WW, Lee TW, Lam SS, et al. Quality of life following lung cancer resection: video-assisted http://bmjopen.bmj.com/ 38 39 thoracic surgery vs thoracotomy. Chest 2002;122:584-9. 40 41 9. Bendixen M, Jorgensen OD, Kronborg C, et al. Postoperative pain and quality of life after 42 43 lobectomy via video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage 44

45 lung cancer: a randomised controlled trial. Lancet Oncol 2016;17:836-44. on September 26, 2021 by guest. Protected copyright. 46 47 10. Cleeland CS, Wang XS, Shi Q, et al. Automated symptom alerts reduce postoperative symptom 48 49 severity after cancer surgery: a randomized controlled clinical trial. J Clin Oncol 2011;29:994- 50 51 1000. 52 53 11. Miralpeix E, Nick AM, Meyer LA, et al. A call for new standard of care in perioperative 54 55 gynecologic oncology practice: Impact of enhanced recovery after surgery (ERAS) programs. 56 Gynecol Oncol 2016;141:371-8. 57 58 59 11 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 12. Basch E, Deal AM, Kris MG, et al. Symptom Monitoring With Patient-Reported Outcomes 5 6 During Routine Cancer Treatment: A Randomized Controlled Trial. J Clin Oncol 2016;34:557-65. 7 8 13. Basch E, Deal AM, Dueck AC, et al. Overall Survival Results of a Trial Assessing Patient- 9 Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment. JAMA 10 11 2017;318:197-8. 12 13 14. Denis F, Basch E, Septans AL, et al. Two-Year Survival Comparing Web-Based Symptom 14 15 Monitoring vs Routine Surveillance Following Treatment for Lung Cancer. Jama 2019;321:306- 16 17 7. 18 For peer review only 19 15. Khullar OV, Fernandez FG. Patient-Reported Outcomes in Thoracic Surgery. Thorac Surg Clin 20 21 2017;27:279-90. 22 23 16. Bouazza YB, Chiairi I, El Kharbouchi O, et al. Patient-reported outcome measures (PROMs) in 24 25 the management of lung cancer: A systematic review. Lung Cancer 2017;113:140-51. 26 27 17. Basch E. Patient-Reported Outcomes - Harnessing Patients' Voices to Improve Clinical Care. N 28 29 Engl J Med 2017;376:105-8. 30 31 18. Fagundes CP, Shi Q, Vaporciyan AA, et al. Symptom recovery after thoracic surgery: Measuring 32 33 patient-reported outcomes with the MD Anderson Symptom Inventory. J Thorac Cardiovasc Surg 34 35 2015;150:613-9 e2. 36

37 19. Shi Q, Wang XS, Vaporciyan AA, et al. Patient-Reported Symptom Interference as a Measure of http://bmjopen.bmj.com/ 38 39 Postsurgery Functional Recovery in Lung Cancer. J Pain Symptom Manage 2016;52:822-31. 40 41 20. Damm K, Roeske N, Jacob C. Health-related quality of life questionnaires in lung cancer trials: a 42 43 systematic literature review. Health Econ Rev 2013;3:15. 44

45 21. Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a modular supplement on September 26, 2021 by guest. Protected copyright. 46 47 to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. 48 EORTC Study Group on Quality of Life. Eur J Cancer 1994;30a:635-42. 49 50 22. Cella D. The Functional Assessment of Cancer Therapy-Lung and Lung Cancer Subscale assess 51 52 quality of life and meaningful symptom improvement in lung cancer. Semin Oncol 2004;31:11-5. 53 54 23. Hollen PJ, Gralla RJ, Kris MG, et al. Measurement of quality of life in patients with lung cancer 55 56 in multicenter trials of new therapies. Psychometric assessment of the Lung Cancer Symptom Scale. 57 58 59 12 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 Figure legends 5 6 Figure 1 Flow diagram of this study. 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

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Developing and validating utility parameters to establish patient-reported outcome-based perioperative symptom management cohort in patients with lung cancer: a multicentre, prospective, observational cohort study For peer reviewprotocol only Journal: BMJ Open

Manuscript ID bmjopen-2019-030726.R1

Article Type: Protocol

Date Submitted by the 27-Sep-2019 Author:

Complete List of Authors: Dai, Wei; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Department of Thoracic Surgery Xie, Shaohua; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Department of Thoracic Surgery; Chengdu Medical College, Graduate School Zhang, Rui ; The Seventh People's Hospital of Chengdu, Department of Thoracic Surgery

Wei, Xing ; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, http://bmjopen.bmj.com/ School of Medicine, University of Electronic Science and Technology of China, Department of Thoracic Surgery Wu, Chuanmei ; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Department of Thoracic Surgery Zhang, Yuanqiang; Zigong First People's Hospital, Department of Cardiothoracic Surgery Feng, Wenhong ; Jiangyou People's Hospital, Department of Thoracic and Cardiovascular Surgery Liao, Xiaoqing ; Dazhu County People's Hospital, Department of on September 26, 2021 by guest. Protected copyright. Cardiothoracic Surgical Oncology Mu, Yunfei ; The Third People's Hospital of Chengdu, Department of Thoracic Surgery Zhou, Heling ; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Department of Thoracic Surgery Cheng, Xuemei ; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Department of Thoracic Surgery Jiang, Yanhua ; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Department of Thoracic Surgery He, Jintao ; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Department of Thoracic Surgery Li, Qiang; Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of

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1 2 3 China, Department of Thoracic Surgery 4 Yang, Xiaojun ; Sichuan Cancer Hospital & Institute, Sichuan Cancer 5 Center, School of Medicine, University of Electronic Science and 6 Technology of China, Department of Thoracic Surgery 7 Shi, Qiuling; University of Texas MD Anderson Cancer Center, 8 Department of Symptom Research 9 Primary Subject Oncology 10 Heading: 11 12 Secondary Subject Heading: Surgery, Nursing 13 utility parameters, lung cancer, patient-reported outcomes, protocol, Keywords: 14 perioperative symptom management 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 15

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 Title page 5 6 7 Title: Developing and validating utility parameters to establish patient-reported 8 9 10 outcome-based perioperative symptom management cohort in patients with lung cancer: a 11 12 multicentre, prospective, observational cohort study protocol 13 14 15 Authors: Wei Dai1#, Shaohua Xie1,2#, Rui Zhang3, Xing Wei1, Chuanmei Wu1, Yuanqiang 16 17 Zhang4, Wenhong Feng5, Xiaoqing Liao6, Yunfei Mu7, Heling Zhou1, Xuemei Cheng1, 18 For peer review only 19 Yanhua Jiang1, Jintao He1, QiangLi1, Xiaojun Yang1, Qiuling Shi8 20 21 22 Institutions: 23 24 1 25 Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer 26 Center, School of Medicine, University of Electronic Science and Technology of China, 27 28 Chengdu, Sichuan, China. 29 2Graduate School, Chengdu Medical College, Chengdu, Sichuan, China. 30 31 3Department of Thoracic Surgery, The Seventh People's Hospital of Chengdu, Chengdu, 32 33 Sichuan, China. 34 4Department of Cardiothoracic Surgery, Zigong First People's Hospital, Zigong, Sichuan, 35 36 China. 37 5Department of Thoracic and Cardiovascular Surgery, Jiangyou People's Hospital, Jiangyou, http://bmjopen.bmj.com/ 38 39 Sichuan, China.

40 6 41 Department of Cardiothoracic Surgical Oncology, Dazhu County People's Hospital, Dazhu 42 County, Dazhou, Sichuan, China. 43 7 44 Department of Thoracic Surgery, The Third People's Hospital of Chengdu, Chengdu, 45 Sichuan, China. on September 26, 2021 by guest. Protected copyright. 46 47 8Department of Symptom Research, The University of Texas MD Anderson Cancer Center, 48 Houston, Texas, USA. 49 50 51 52 Correspondence to 53 Dr Qiuling Shi, Department of Symptom Research, The University of Texas MD Anderson 54 55 Cancer Center, 1515 Holcombe Blvd., Unit 1450 Houston, TX 77030, USA. Telephone: 56 713/745-3504, e-mail: [email protected]. 57 58 Dr Xiaojun Yang, Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, 59 1 60

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3 Sichuan Cancer Center, School of Medicine, University of Electronic Science and BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 5 Technology of China, No. 55, Section 4, South Renmin Road, Chengdu 610041, Sichuan, 6 China. Telephone: +86-028-85420366, e-mail: [email protected]. 7 8

9 # 10 These authors contributed equally to this work. 11 12 13 Word count 1863 words 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 2 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 5 ABSTRACT 6 7 8 Introduction Patient-reported outcome-based symptom monitoring and alerting have been 9 10 attractive for patient care after a tumour-removal surgery. However, the implementation 11 12 parameters of this patient-centred symptom management system in perioperative patients with 13 14 lung cancer are still lacking. We aim to develop a perioperative symptom scale (PSS) for 15 16 monitoring, to determine the optimal time points for symptom assessment, and to define the 17 alert thresholds for medical intervention. 18 For peer review only 19 20 Methods and analysis This study will prospectively recruit 300 patients undergoing lung 21 22 cancer surgery in 6 hospitals. The MD Anderson Symptom Inventory-lung cancer module 23 24 (MDASI-LC) is used to collect longitudinal symptom data preoperatively, daily 25 26 postoperatively during in-hospital stay, and weekly after discharge until 4 weeks or the start 27 28 of postoperative oncologic therapy. Symptoms that change significantly over time will be 29 30 generated as the PSS. We will determine the optimal time points for follow-up using the 31 32 generalised linear mixed-effects models. The MDASI-LC interference-measured functional 33 34 status will be used as the anchor for the alert thresholds. 35 36 Ethics and dissemination Ethics Committee of Sichuan Cancer Hospital approved this study 37 http://bmjopen.bmj.com/ 38 on October 16, 2017 (No. SCCHEC-02-2017-042). The manuscript is based on the latest 39 40 protocol of Version 3.0, September 15, 2019. The results of this study will be presented at 41 42 medical conferences and published in peer-reviewed journals. 43 44

45 Trials registration number NCT03341377. on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 3 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 ARTICLE SUMMARY 5 6 Strengths and limitations of this study 7 8 9 1. This is a multicentre, prospective, observational cohort study from the real-world clinical 10 11 setting in China. 12 13 2. It focuses on developing and validating utility parameters for future implementation of 14 15 patient-reported outcome-based perioperative symptom management in patients with lung 16 17 cancer. 18 For peer review only 19 20 3. It focuses on frequent perioperative longitudinal symptom data collection, including 21 22 preoperatively, daily postoperatively during in-hospital stay, and weekly after discharge until 23 24 4 weeks or the start of postoperative oncologic therapy. 25 26 4. The MD Anderson Symptom Inventory-lung cancer module is used to collect symptom 27 28 data. 29 30 31 5. The fact that five sub-centres joined the study midway may be a limitation. 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 4 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 INTRODUCTION 5 6 Lung cancer is the leading cause of death among all types of cancers,1 2 with surgery as one of 7 8 its main treatment methods. In 2015, approximately 147,000 lung cancer surgeries were 9 10 performed in tertiary hospitals in China.3 Thoracotomy or minimally invasive thoracoscopic 11 12 surgery can lead to severe and various postoperative symptoms, such as pain, fatigue, cough, 13 14 and shortness of breath.4-9 Adequate perioperative symptom control can accelerate 15 16 postoperative recovery, improve quality of life (QOL), and ensure timely return to intended 17 18 oncologic therapy,For and thus, peer potentially review benefit survival.10 only 11 Clinical trials have shown that 19 20 the use of patient-reported outcome (PRO)-based symptom monitoring in patients receiving 21 22 chemotherapy can not only improve QOL, but also significantly improve survival.12-14 23 24 However, very few studies have been conducted in the perioperative patients with lung 25 26 cancer.10 15 27 28 PRO-based symptom management is the key and ideal model for patient-centred care.15-19 29 30 However, there are still a few technical and methodological issues to be resolved before 31 32 implementing PRO tools in perioperative symptom management in patients with lung cancer. 33 34 First, a brief lung cancer surgery-specific measurement scale is lacking. Currently, four 35 36 commonly used lung cancer-specific PRO tools are available: the European Organisation for 37 http://bmjopen.bmj.com/ 38 Research and Treatment of Cancer Quality of Life Questionnaire–Lung Cancer Module 39 40 (EORTC QLQ-LC13), the Functional Assessment of Cancer Therapy–Lung (FACT-L), the 41 42 Lung Cancer Symptom Scale (LCSS), and the MD Anderson Symptom Inventory Lung 43 44 Cancer Module (MDASI-LC).16 20-24 These scales are primarily generated and validated in

45 on September 26, 2021 by guest. Protected copyright. 46 patients with lung cancer receiving chemotherapy and radiotherapy. It is still unknown 47 48 whether these items will be appropriate for patients undergoing lung cancer surgery. More 49 50 importantly, there are too many items on these instruments that hinder clinical application. 51 52 Second, the key symptom monitoring time points are undetermined. Usually, PRO data 53 54 collection for discharged patients who have undergone lung cancer surgery is limited to 55 56 follow-up clinic visits. The first follow-up clinic visit is approximately 4 weeks after 57 58 discharge. During these 4 weeks, the patient’s symptoms and functional status can change 59 5 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 18 4 rapidly, and these potential abnormalities are often ignored, leading to negative clinical 5 6 outcomes, for instance, postoperative complications, unplanned clinic visit or emergency 7 8 room visit. In addition, the absence of key PRO information influences the evaluation of 9 clinical outcomes.25 Third, evidence-based alert thresholds for perioperative intervention are 10 11 lacking. A definitive cutoff point of symptom score is the premise of patient symptom 12 13 monitoring and precision medical intervention. In this study, we aim to solve these 14 15 methodological issues, via developing and validating a perioperative symptom scale (PSS) for 16 17 symptom monitoring, determining the optimal time points for symptom assessment, and 18 For peer review only 19 defining the alert thresholds for medical intervention. 20 21 22 23 24 METHODS AND ANALYSIS 25 26 27 Study design 28 29 30 This is a real-world, ongoing, multicentre, prospective, observational cohort study. A flow 31 32 diagram of this study is shown in Figure 1. 33 34 35 36

37 Setting http://bmjopen.bmj.com/ 38 39 40 The study is being conducted in 6 hospitals in China, namely, Sichuan Cancer Hospital, The 41 Third People’s Hospital of Chengdu, The Seventh People’s Hospital of Chengdu, Jiangyou 42 43 People’s Hospital, Zigong First People’s Hospital, and Dazhu County People’s Hospital. This 44 45 study was initiated by Sichuan Cancer Hospital and started on November 2017. The other five on September 26, 2021 by guest. Protected copyright. 46 47 research centres joined the study in January 2019. This study is estimated to be completed 48 49 before March 31, 2020. 50 51 52 53 54 Study population 55 56 57 58 Eligible patients are required to be aged ≥18 years, have no cognitive impairment or be able 59 6 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 to understand the study requirements, be pathologically or clinically diagnosed as primary 5 6 lung cancer before surgery, and plan to undergo a surgical procedure. 7 8 9 10 11 Sample size calculation 12 13 This study primarily aims to establish a symptom scale that can be used to monitor 14 15 perioperative symptom burden in patients with lung cancer and that requires significant 16 17 changes over time during the perioperative period (from preoperatively to 4 weeks after 18 For peer review only 19 discharge). Our preliminary work showed that the overall standard deviation of the score of 20 21 the main symptom of lung cancer (0–10 score) was 2.2 in the first postoperative month. With 22 23 an average of 5 assessments, the rate of symptom score change over time was 0.1 points per 24 25 assessment according to the general linear regression model. In order to reject the null 26 27 hypothesis that the symptom scale does not change significantly over time, 239 patients with 28 29 effective symptom data are needed. The type I error rate is 5%, and the power is 80%. In 30 31 consideration of 20% attrition , the final sample size is approximately 300 (239/0.8) cases. 32 33 34 35 36 Outcome measures 37 http://bmjopen.bmj.com/ 38 39 Primary outcome in this study is perioperative symptom burden in patients with lung cancer, 40 41 as measured by the MDASI-LC. The symptom burden will be presented via a PSS, generated 42 43 from a subgroup of MDASI-LC symptom items that change significantly over the 44

45 perioperative period. The MDASI-LC is used to collect longitudinal symptom data on September 26, 2021 by guest. Protected copyright. 46 47 preoperatively (typically within 3 days before surgery), daily postoperatively (in-hospital stay 48 49 of ≤ 14 days), and weekly after discharge until 4 weeks (±3 days) or the start of postoperative 50 51 cancer therapy. The MDASI-LC is a lung cancer-specific PRO measurement, which has been 52 translated and validated in a Chinese setting. Secondary outcomes mainly include QOL 53 54 measured by a single-item QOL scale (UNISCALE)26 and functional status measured by 55 56 MDASI-LC interference items. The measurement time points of QOL are the same as that of 57 58 59 7 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 the MDASI-LC. We also measure patient’s perception of symptom and daily functioning 5 6 changes via a five-point Likert Scale weekly after discharge until 4 weeks (±3 days) or the 7 8 start of postoperative cancer therapy. 9 10 11 12 13 Withdrawal criteria 14 15 Participants will be withdrawn from this study if they meet the following criteria: (1) 16 17 cancellation of planned surgery, (2) >24 hours of postoperative endotracheal intubation in the 18 For peer review only 19 ICU, (3) postoperative length of hospital stay of >14 days, (4) severe complications 20 21 interfering with PRO data collection, (5) postoperative pathological diagnosis is not primary 22 23 lung cancer, (6) those who do not follow the study protocol (deliberately providing incorrect 24 25 PRO data), (7) those who ask to withdraw from the research, or (8) other conditions that 26 27 require withdrawal as assessed by the investigator. 28 29 30 31 32 Data collection, management, and monitoring 33 34 35 We use REDCap,27 28 a web-based software application for data storage and management 36

37 (http://125.71.214.100:888/redcap), to store and manage data. Electronic case report form http://bmjopen.bmj.com/ 38 39 (e-CRF) was designed on REDCap. It consists of 12 data collection instruments, namely, 40 41 demographic characteristics, preoperative characteristics, surgery information, anaesthesia 42 43 information, postoperative care, perioperative complications, pain management, MDASI-LC, 44

45 QOL, symptom and daily functioning changes, completion data, and follow-up information. on September 26, 2021 by guest. Protected copyright. 46 47 PRO data are collected using a paper questionnaire or an e-questionnaire and then recorded in 48 49 REDCap. Participants are instructed to fill out the scales independently. If they have 50 51 difficulties in completing the scales, investigators or other proxies will assist them by reading 52 each item aloud and recording their responses. All data are de-identified and entered into the 53 54 REDCap platform. Data are entered by a data entry clerk and checked regularly by a quality 55 56 controller. Data monitoring is carried out regularly by the Ethics Committee of Sichuan 57 58 59 8 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 Cancer Hospital. 5 6 7 8 9 Quality control 10 11 Investigators received standard operating procedure training before recruiting the patients. 12 13 The sub-centres receive regular online directions, telephone monitoring, and on-site 14 15 supervision conducted by the principal investigator or international expert from MD 16 17 Anderson Cancer Center. 18 For peer review only 19 20 21 22 23 Data analysis 24 25 For inclusion in the final analysis, the participants must complete the MDASI-LC assessments 26 27 preoperatively and at least two additional assessments postoperatively. The multiple 28 29 imputation method will be used to impute missing data. Continuous data will be expressed as 30 31 mean ± standard deviation or median and interquartile range. Categorical data will be 32 33 presented as number and percentage. We will use generalised linear mixed-effects models to 34 35 describe trajectories of symptom severity, symptom interference, and QOL during the entire 36

37 investigation period. Considering the time variable, days from surgery, as a continuous http://bmjopen.bmj.com/ 38 39 variable, symptoms that change significantly over time will be generated as the targets for 40 41 perioperative symptom monitoring. The PSS score will be obtained by averaging scores of all 42 43 targeted symptoms. Treating days from surgery as a categorical variable, we will estimate the 44

45 change of PSS from the previous assessment using a generalised linear mixed-effects model. on September 26, 2021 by guest. Protected copyright. 46 47 The optimal time points for monitoring will be determined as those with significant changes 48 49 in PSS. The alert thresholds will be generated as cutoff points for the PSS with the method

50 29 51 proposed by Serlin et al, using the 6 MDASI-LC interference items as the anchor. The 6 52 MDASI interference items have been validated as a reliable and sensitive measure for 53 54 functional status of patients undergoing cancer treatment19 30 and “functional recovery has 55 56 been considered as the most important target” for postoperative recovery by a large group of 57 58 59 9 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 31 4 international professionals. Differences are considered statistically significant if the 5 6 two-tailed p-values of <0.05. All data analyses will be performed using the SAS 9.4 (SAS 7 8 Institute Inc.). 9 10 11 12 13 Patient and public involvement statement 14 15 Patients and the general public were not involved in the design, recruitment, and 16 17 implementation of the study. We have no plans of informing the study participants regarding 18 For peer review only 19 the results of this study. However, the results will be disseminated to the applicants in the 20 21 form of a published article as requested. 22 23 24 25 26 ETHICS AND DISSEMINATION 27 28 29 This study was approved by the Ethics Committee of Sichuan Cancer Hospital on October 16, 30 31 2017 (No. SCCHEC-02-2017-042). Any amendments to the research protocol will be 32 33 submitted for ethical approval. All participants must provide informed consent. The results in 34 35 this study will be first reported at relevant medical conferences and then will eventually be 36

37 published in peer-reviewed journals. http://bmjopen.bmj.com/ 38 39 40 41 42 Acknowledgements We thank all the participants and their advisors involving in this study. 43 44

45 Contributors WD, YJ, JH, QL, XY, and QS contributed to the study design. WD, SX, RZ, XW, CW, on September 26, 2021 by guest. Protected copyright. 46 47 YZ, WF, XL, YM, HZ, and XC performed the study. WD, SX, RZ, XW, and CW drafted the initial 48 49 manuscript. QL, XY, and QS revised the draft. All authors have reviewed and approved the final 50 51 manuscript. 52 53 Funding This work was supported by Sichuan Science and Technology Program (grant number: 54 55 2011FZ0069 and 2019YFH0070), and National Natural Science Foundation of China (grant number: 56 57 81872506). 58 59 10 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 Competing interests None declared. 5 6 Patient consent for publication Not required. 7 8 9 Ethics approval Ethics Committee of Sichuan Cancer Hospital (No. SCCHEC-02-2017-042). 10 11 Provenance and peer review Not commissioned; externally peer reviewed. 12 13 14 15 16 REFERENCES 17 18 1. Siegel RL, MillerFor KD, Jemal peer A. Cancer statistics, review 2018. 2018;68:7-30. only 19 20 2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of 21 22 incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 23 24 2018;68:394-424. 25 26 3. Liao H, Mei JD, Liu CW, et al. [A survey on the current development of thoracic surgery in tertiary 27 28 hospitals of China]. Zhonghua Wai Ke Za Zhi 2018;56:888-91. 29 30 4. Lowery AE, Krebs P, Coups EJ, et al. Impact of symptom burden in post-surgical non-small cell 31 32 lung cancer survivors. Support Care Cancer 2014;22:173-80. 33 34 5. Oksholm T, Rustoen T, Cooper B, et al. Trajectories of Symptom Occurrence and Severity From 35 36 Before Through Five Months After Lung Cancer Surgery. J Pain Symptom Manage

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45 on September 26, 2021 by guest. Protected copyright. 46 non small-cell lung cancer. J Clin Oncol 2008;26:233-41. 47 8. Li WW, Lee TW, Lam SS, et al. Quality of life following lung cancer resection: video-assisted 48 49 thoracic surgery vs thoracotomy. Chest 2002;122:584-9. 50 51 9. Bendixen M, Jorgensen OD, Kronborg C, et al. Postoperative pain and quality of life after 52 53 lobectomy via video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage lung 54 55 cancer: a randomised controlled trial. Lancet Oncol 2016;17:836-44. 56 57 10. Cleeland CS, Wang XS, Shi Q, et al. Automated symptom alerts reduce postoperative symptom 58 59 11 60

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3 BMJ Open: first published as 10.1136/bmjopen-2019-030726 on 28 October 2019. Downloaded from 4 severity after cancer surgery: a randomized controlled clinical trial. J Clin Oncol 2011;29:994-1000. 5 6 11. Miralpeix E, Nick AM, Meyer LA, et al. A call for new standard of care in perioperative 7 8 gynecologic oncology practice: Impact of enhanced recovery after surgery (ERAS) programs. 9 Gynecol Oncol 2016;141:371-8. 10 11 12. Basch E, Deal AM, Kris MG, et al. Symptom Monitoring With Patient-Reported Outcomes During 12 13 Routine Cancer Treatment: A Randomized Controlled Trial. J Clin Oncol 2016;34:557-65. 14 15 13. Basch E, Deal AM, Dueck AC, et al. Overall Survival Results of a Trial Assessing 16 17 Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment. JAMA 18 For peer review only 19 2017;318:197-8. 20 21 14. Denis F, Basch E, Septans AL, et al. Two-Year Survival Comparing Web-Based Symptom 22 23 Monitoring vs Routine Surveillance Following Treatment for Lung Cancer. Jama 2019;321:306-7. 24 25 15. Khullar OV, Fernandez FG. Patient-Reported Outcomes in Thoracic Surgery. Thorac Surg Clin 26 27 2017;27:279-90. 28 29 16. Bouazza YB, Chiairi I, El Kharbouchi O, et al. Patient-reported outcome measures (PROMs) in the 30 31 management of lung cancer: A systematic review. Lung Cancer 2017;113:140-51. 32 33 17. Basch E. Patient-Reported Outcomes - Harnessing Patients' Voices to Improve Clinical Care. N 34 35 Engl J Med 2017;376:105-8. 36

37 18. Fagundes CP, Shi Q, Vaporciyan AA, et al. Symptom recovery after thoracic surgery: Measuring http://bmjopen.bmj.com/ 38 39 patient-reported outcomes with the MD Anderson Symptom Inventory. J Thorac Cardiovasc Surg 40 41 2015;150:613-9 e2. 42 43 19. Shi Q, Wang XS, Vaporciyan AA, et al. Patient-Reported Symptom Interference as a Measure of 44

45 Postsurgery Functional Recovery in Lung Cancer. J Pain Symptom Manage 2016;52:822-31. on September 26, 2021 by guest. Protected copyright. 46 47 20. Damm K, Roeske N, Jacob C. Health-related quality of life questionnaires in lung cancer trials: a 48 systematic literature review. Health Econ Rev 2013;3:15. 49 50 21. Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-LC13: a modular supplement to 51 52 the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. 53 54 EORTC Study Group on Quality of Life. Eur J Cancer 1994;30a:635-42. 55 56 22. Cella D. The Functional Assessment of Cancer Therapy-Lung and Lung Cancer Subscale assess 57 58 59 12 60

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37 http://bmjopen.bmj.com/ 38 30. Shi Q, Mendoza TR, Wang XS, et al. Using a symptom-specific instrument to measure 39 40 patient-reported daily functioning in patients with cancer. Eur J Cancer 2016;67:83-90. 41 42 43 31. Aahlin EK, von Meyenfeldt M, Dejong CH, et al. Functional recovery is considered the most 44

45 important target: a survey of dedicated professionals. Perioper Med (Lond) 2014;3:5. on September 26, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 13 60

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 Flow diagram of this study 41 on September 26, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml