Association Between Pretreatment Emotional Distress and Survival Outcomes in Patients With Advanced Non-Small-Cell Lung Cancer: an individual patient data meta-analysis of 4632 patients in 7 trials

Association Between Pretreatment Emotional Distress and Survival Outcomes in Patients With Advanced Non-Small-Cell Lung Cancer: an individual patient data meta-analysis of 4632 patients in 7 trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Brief Communication Association Between Pretreatment Emotional Distress and Survival Outcomes in Patients With Advanced Non-Small-Cell Lung Cancer: an individual patient data meta-analysis of 4632 patients in 7 trials Jian-Guo Zhou, Xin Li, QiSha Li, Su-Han Jin, Xiaofei Chen, Juanyan Shen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5448848/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Emotional distress (ED) associated with worse survival outcomes in patients with melanoma and non-small-cell lung cancer treated with immune checkpoint inhibitors (ICIs). However, several preclinical studies suggest the association between stress and cancer treatment extends beyond ICIs alone. Here we used an individual patient data (IPD) meta-analysis of 4632 patients in 7 trials and a Kaplan-Meier analysis to verify broader connection between ED and survival outcomes in NSCLC patients. Kaplan-Meier analysis show that compared with patients without ED, patients with ED had worse survival outcomes, regardless of ICIs or chemotherapy (hazard ratio (HR) of overall survival (OS), 1.21, p=0.01; hazard ratio of progression-free survival (PFS), 1.19, p=0.01). IPD meta-analysis also supported results above (HR of OS, 1.18, 95% confidence interval (CI), 1.07-1.30; HR of PFS, 1.15, 95% CI, 1.03-1.28). Our research suggest that ED is only a prognostic biomarker in NSCLC, rather than a predictive biomarker for ICIs. Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer Biological sciences/Cancer/Tumour biomarkers Figures Figure 1 Figure 2 INTRODUCTION Emotional distress (ED) is a negative psychological state prevalent in cancer patients, commonly manifested as anxiety and depression 1 . Recent studies have great interest in the association between ED and survival outcomes of cancer patients, and demonstrated that ED associate with worse survival outcomes in patients with melanoma and non-small-cell lung cancer treated with immune checkpoint inhibitors (ICIs) 2,3 . Although several preclinical studies had demonstrated that stress can promote inflammation and immune evasion 4,5 , several preclinical studies indicated that stress can promote adrenaline, noradrenaline, and glucocorticoid secretion, which facilitate tumor proliferation and metastasis 6,7 . Those studies remind us the association between stress and cancer treatment extends beyond ICIs alone.To verify broader connection between ED and survival outcomes in NSCLC patients, we conducted an individual patient data (IPD) meta-analysis. Finally we identified 7 clinical trials which involve patients treated with atezolizumab, including 2 single-arm trials (BIRCH, FIR) and 5 randomized controlled trials (POPLAR, OAK, IMpower130, IMpower131, IMpower150) 8-14 . Among a total of 4632 participants, 2753 (59.43%) received first-line treatment; 3162 (68.26%) received ICIs; 1802 (38.90%) classified as ED and 2830 (61.10%) classified as non-ED. Kaplan-Meier analysis indicate that ED patients associate with worse survival outcomes, regardless of ICIs or chemotherapy (CT) (HR OS =1.21, p=0.01; HR PFS =1.19, p=0.01). Different from previous findings, which ED as a predictive biomarker for ICIs, our results show that ED is only a prognostic biomarker in NSCLC. Compared with non-ED, ED patients had worse OS in both ICIs ( ED vs non-ED, mOS, 13.34 m vs 16.07 m; p=0.01; HR, 1.21 [1.09-1.34]) and CT (ED vs non-ED, mOS, 12.02 m vs 13.93 m; p=0.01; HR, 1.19 [1.04-1.37]; Figure 1, A ). IPD meta-analysis indicate that the ED group exhibited worse OS outcome (HR=1.18 [1.07-1.30], p=0.01). Subgroup analysis confirmed this association in both ICIs (HR=1.18 [1.04-1.34], p=0.01) and CT groups (HR=1.18 [1.00-1.39], p=0.05; Figure 1, B ). We excluded clinical trials, which PFS not primary outcome, and investigated the association with ED and PFS in first-line clinical trials. Similarly, Kaplan-Meier analysis show ED patients had worse PFS regardless of ICIs (mPFS, 5.52 m vs 5.58 m; p=0.01; HR, 1.19 [1.06-1.33]) or CT (mPFS, 5.55 m vs 5.59 m; p=0.06; HR, 1.17 [0.99-1.37]; Figure 2, A ). IPD meta-analysis of PFS also supported results above (HR=1.15 [1.03-1.28], p=0.02; Figure 2, B ). The 7 trials included in the IPD meta-analysis had been validated as free from publication bias and the results of the IPD meta-analysis had been passed the heterogeneity and sensitivity analyses. DISCUSSION In this IPD meta-analysis encompassing 12 cohorts of 7 trials, we elucidate a significant association between ED and adverse survival outcomes among patients with NSCLC regardless of CT or ICIs. Preclinical studies provide complementary evidence for our findings that ED associate with prognosis of NSCLC. Yang et al. demonstrated that ED induces the expression of immunosuppressive transcription factor TSC22D3 in dendritic cells through glucocorticoids, impairing chemotherapy and immunotherapy in mouse models of lung cancer, colorectal cancer, and fibrosarcoma 15 . These findings remind us alleviate ED can be a potential potential strategy for cancer treatment. In comparison to the methodologies employed by the STRESS-LUNG study, which utilized the Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale to assess ED status, our approach with EORTC QLQ-C30 presents a more streamlined and clinically feasible alternative for evaluating ED. This simplification enhances the applicability of our findings in clinical practice, empowering clinicians to assess the psychological well-being of patients throughout their treatment journeys. This study has some limitations. In our research, once the patient has taken atezolizumab, they will be assigned to the ICIs group, regardless of whether they have previously received other treatments. While limitations of our study have been addressed through the integration of a multi-institutional clinical trials, further prospective studies and preclinical studies are imperative to validate the relationship between ED status and clinical outcomes not only in NSCLC but also in other cancer types. In conclusion, to our knowledge, this study is the first to propose correlation between ED and prognosis of NSCLC regardless of CT or ICIs. Therefore, we recommend the implementation of ED status assessment in clinical practice for NSCLC patients to improve their survival outcomes. METHODS Search strategy We searched Vivli data-sharing platform for studies which reported clinical trials of advanced NSCLC patients treated with atezolizumab, without language restrictions. Seven clinical trials were included: POPLAR (NCT01903993) 8 , IMpower131 (NCT02367794) 9 , OAK (NCT02008227) 10 , IMpower150 (NCT02366143) 11 , FIR (NCT01846416) 12 , BIRCH (NCT02031458) 13 , and IMpower130 (NCT02367781) 14 , all of them provided individual patient data. Cohort definition For each chosen randomized controlled trials, patients who received atezolizumab were assigned into the immune checkpoint inhibitors (ICI) cohort regardless of whether they had received platinum-based chemotherapy prior to that period, patients who did not receive atezolizumab were assigned to the chemotherapy (CT) cohort. For each single-arm trials, divided all individual patients into ICI cohorts. A total of 12 cohorts were obtained, of which 7 cohorts were ICI cohort and 5 cohorts were CT cohort. Method of assessing emotional distress status EORTC (European Organisation for Research and Treatment) QLQ-C30 version 3 was applied to evaluate Emotional distress (ED) status of patients. The QLQ-C30 includes 30 items, which can be summarised into five functional scales: Physical Functioning (PF), Role Functioning (RF), Social Functioning (SF), Emotional Functioning (EF), and Cognitive Functioning (CF); three symptom scales: Fatigue (FA), Pain (PA) and Nausea/Vomiting (NV); six single items: Appetite Loss (AP), Dyspnoea (DY), Insomnia (SL), Diarrhoea (DI), Constipation (CO), and Financial difficulties (FI) and a Global Health Status/Qol(QL). After evaluated by the questionnaire, the patient will receive a raw score, which can be transferred to a standard score (0 to 100) through the range reduction method with linear transformation. Patients with standard score > 71 were designated as the non-ED group and <= 71 as the ED group. 16,17 Kaplan-Meier analysis We integrated all individual patient data and first-line treatment patient data, grouped them into four groups according to ED status and treatment methods of patients separately: ED-ICI group; ED-CT group; NED-ICI group and NED-CT group. The median overall survival (mOS) and progression-free survival (mPFS) is obtained by using Kaplan-Mier analysis to estimate the survival function, plotting the survival curves and identifying the time at which the survival probability reaches 50% with OS and PFS as the primary endpoints respectively. Calculating and comparing mOS/mPFS, hazard ratios (HRs), 95%CI and p value between four groups (details see Statistical analysis ). Methodology for meta-analysis HR value and 95% CI were calculated for each cohort and then summed. We select the I 2 statistic as the statistical measure for heterogeneity testing. Meta analysis will choose the fixed effect model as final result when I 2 statistic 0.1, otherwise, choose the random effects model. Publication bias of cohorts were assessed by Egger linear regression, which consider as no publication bias if p value > 0.05. The stepwise elimination method was employed to assess stability of results. 18 Statistical analysis The Cox proportional hazards model was applied to estimate HRs and 95% CIs between ED group and non-ED group for each cohort, and the two-sided log-rank test was used to compare OS and PFS among the two groups, with the significance level alpha=0.05. Analysis was conducted in R version 4.4.1. The package we utilize as follows: the ‘Matefor’ package (version 4.6-0), the ‘survminer’ package (version 0.4.9). References Deshields, T.L. , et al. Addressing distress management challenges: Recommendations from the consensus panel of the American Psychosocial Oncology Society and the Association of Oncology Social Work. CA Cancer J Clin 71 , 407-436 (2021). Fraterman, I. , et al. Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma. Nature Medicine 29 , 3090-3099 (2023). Zeng, Y. , et al. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat Med 30 , 1680-1688 (2024). Antoni, M.H. & Dhabhar, F.S. The impact of psychosocial stress and stress management on immune responses in patients with cancer. Cancer 125 , 1417-1431 (2019). Colon-Echevarria, C.B., Lamboy-Caraballo, R., Aquino-Acevedo, A.N. & Armaiz-Pena, G.N. Neuroendocrine Regulation of Tumor-Associated Immune Cells. Front Oncol 9 , 1077 (2019). Eckerling, A., Ricon-Becker, I., Sorski, L., Sandbank, E. & Ben-Eliyahu, S. Stress and cancer: mechanisms, significance and future directions. Nature Reviews Cancer 21 , 767-785 (2021). Sandi, C. & Haller, J. Stress and the social brain: behavioural effects and neurobiological mechanisms. Nat Rev Neurosci 16 , 290-304 (2015). Fehlings, M. , et al. Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment. J Immunother Cancer 7 , 249 (2019). Jotte, R. , et al. Atezolizumab in Combination With Carboplatin and Nab-Paclitaxel in Advanced Squamous NSCLC (IMpower131): Results From a Randomized Phase III Trial. Journal of Thoracic Oncology 15 , 1351-1360 (2020). Rittmeyer, A. , et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389 , 255-265 (2017). Socinski, M.A. , et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 378 , 2288-2301 (2018). Spigel, D.R. , et al. FIR: Efficacy, Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1-Selected Patients With NSCLC. J Thorac Oncol 13 , 1733-1742 (2018). Wakelee, H. , et al. ORAL01.04: Phase II Trial of Atezolizumab for Patients with PD-L1–Selected Advanced NSCLC (BIRCH): Updated Efficacy and Exploratory Biomarker Results. Journal of Thoracic Oncology 11 , S251-S252 (2016). West, H. , et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20 , 924-937 (2019). Yang, H. , et al. Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity. Nat Med 25 , 1428-1441 (2019). Giesinger, J.M. , et al. Thresholds for clinical importance for four key domains of the EORTC QLQ-C30: physical functioning, emotional functioning, fatigue and pain. Health Qual Life Outcomes 14 , 87 (2016). Giesinger, J.M. , et al. Thresholds for clinical importance were established to improve interpretation of the EORTC QLQ-C30 in clinical practice and research. J Clin Epidemiol 118 , 1-8 (2020). Higgins, J.P.T., Green, S.P. & Cochrane, C. Cochrane handbook for systematic reviews of interventions , (The Cochrane Collaboration, U.K., 2021). Additional Declarations There is NO Competing Interest. Supplementary Files NMEDBC137304Ars.pdf Reporting Summary NMEDBC137304Aepc.pdf Editorial Policy Checklist Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5448848","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Brief Communication","associatedPublications":[],"authors":[{"id":384318932,"identity":"3d37c4d3-9310-4601-8d5f-95d433bbd62d","order_by":0,"name":"Jian-Guo Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYBACxmYYSwKIP0CYBsRrYZxBjBYEAGph5iFGC3M787OHX9tsGORnNx+TtvmzLbGBvXmbBEPNHTwOYzM3lm1LY2CccyxNOofndmIDz7EyCYZjz/D5xUxasu0wA7NEjpl0jgRQC5AhwdhwGI8W9m9gLWwgLRYGQC3ybwhp4TGT/AjUwgPSwpAAsoWHoJYyaYZzaTwSEmnJlj0Hbhu38aQVWyQcw63FsP/4NskfZTZy8jOSD9748ee2bD/74Y03PtTg0dIAiQ4euAgbiEjAqYGBQR7kuB94FIyCUTAKRsEoYAAAEelKnoOLyysAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-5021-3739","institution":"Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jian-Guo","middleName":"","lastName":"Zhou","suffix":""},{"id":384318933,"identity":"9b60221a-7932-4d50-ac4a-f45246819acd","order_by":1,"name":"Xin Li","email":"","orcid":"","institution":"Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Li","suffix":""},{"id":384318934,"identity":"43a9626c-7a49-4cdc-8638-3b45f7440f02","order_by":2,"name":"QiSha Li","email":"","orcid":"","institution":"Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University","correspondingAuthor":false,"prefix":"","firstName":"QiSha","middleName":"","lastName":"Li","suffix":""},{"id":384318935,"identity":"4874c89d-f376-4546-bc6e-7106ee5ad709","order_by":3,"name":"Su-Han Jin","email":"","orcid":"","institution":"Department of Orthodontics, Affiliated Stomatological Hospital of Zunyi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Su-Han","middleName":"","lastName":"Jin","suffix":""},{"id":384318936,"identity":"5b5d5aeb-0d20-48c6-8e5b-e3b3ab96e237","order_by":4,"name":"Xiaofei Chen","email":"","orcid":"","institution":"Oncology Biometrics, AstraZeneca, Gaithersburg, MD, United States","correspondingAuthor":false,"prefix":"","firstName":"Xiaofei","middleName":"","lastName":"Chen","suffix":""},{"id":384318937,"identity":"5dbd8828-b412-4638-97b0-92648db23fdf","order_by":5,"name":"Juanyan Shen","email":"","orcid":"","institution":"Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Juanyan","middleName":"","lastName":"Shen","suffix":""},{"id":384318938,"identity":"033c9b47-f8a8-4652-ac79-cb7df5e12437","order_by":6,"name":"Hu Ma","email":"","orcid":"","institution":"Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hu","middleName":"","lastName":"Ma","suffix":""}],"badges":[],"createdAt":"2024-11-13 17:35:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5448848/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5448848/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70586624,"identity":"dbd0e53b-ac73-4ab4-9941-4ada7fdd06cd","added_by":"auto","created_at":"2024-12-04 16:00:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":89309,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnalyses results of overall survival\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eA, overall survival for two different treatments in the subgroups of ED status. Survival curves were compared using two-sided log-rank test. Results show that patients treated with ICIs exhibit a significantly improved OS in both ED and non-ED group, and compared with patients with non-ED, those with ED have worse outcomes in both treated with ICIs and chemotherapy. B, forest plots illustrate the findings of IPD meta-analysis and subgroup analysis by treatment . Data is presented as the HR with error bars showing 95% CI. A total of 12 cohorts consistently showed a trend indicating that ED patients experience worse outcomes, aligning with the results from the IPD meta-analysis and subgroup analysis. These analysis of OS remind the association between ED and worse OS outcome.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5448848/v1/f261e35b038a5576cfb50c38.png"},{"id":70586625,"identity":"f39f30a8-2c9a-4029-83c7-edff823567d6","added_by":"auto","created_at":"2024-12-04 16:00:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":79914,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnalyses results of progression-free survival\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eA, survival curves of progression-free survival for two different treatment methods in the subgroups of ED status. Similar to results of analysis of OS, ED patients had worse PFS regardless of ICIs or chemotherapy, and patients treated with ICIs exhibited a significantly improved PFS in both ED and non-ED group. B, results of IPD meta-analysis and subgroup analysis for PFS were shown as forest plot. Data is presented as the HR with error bars showing 95% CI. A total of 8 cohorts show that ED patients have a worse PFS, and results of IPD meta-analysis and subgroup analysis support this finding. Analysis results of comprehensive OS and PFS illustrate that patients with ED have a worse survival outcome compared with patients with non-ED.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5448848/v1/1c726e4fad05a19f13d881dd.png"},{"id":73873768,"identity":"9a943ad7-c326-41fb-b42e-15ba6b8f6e9b","added_by":"auto","created_at":"2025-01-15 12:38:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":535449,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5448848/v1/d9677bb1-3f5a-4627-8976-3225ae567601.pdf"},{"id":70586626,"identity":"8cdb7708-9468-4929-8609-9737c9deab61","added_by":"auto","created_at":"2024-12-04 16:00:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1358350,"visible":true,"origin":"","legend":"Reporting Summary","description":"","filename":"NMEDBC137304Ars.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5448848/v1/0f93005a61dc133cfe9de821.pdf"},{"id":70586627,"identity":"44ee42a1-185f-4a19-89ca-62424580262f","added_by":"auto","created_at":"2024-12-04 16:00:40","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1424432,"visible":true,"origin":"","legend":"Editorial Policy Checklist","description":"","filename":"NMEDBC137304Aepc.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5448848/v1/6cd1efb9fe12f3b3fe0d3035.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Association Between Pretreatment Emotional Distress and Survival Outcomes in Patients With Advanced Non-Small-Cell Lung Cancer: an individual patient data meta-analysis of 4632 patients in 7 trials","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eEmotional distress (ED) is a negative psychological state prevalent in cancer patients, commonly manifested as anxiety and depression\u003csup\u003e1\u003c/sup\u003e. Recent studies have great interest in the association between ED and survival outcomes of cancer patients, and demonstrated that ED associate with worse survival outcomes in patients with melanoma and non-small-cell lung cancer treated with immune checkpoint inhibitors (ICIs)\u003csup\u003e2,3\u003c/sup\u003e. Although several preclinical studies had demonstrated that stress can promote inflammation and immune evasion\u003csup\u003e4,5\u003c/sup\u003e, several preclinical studies indicated that stress can promote adrenaline, noradrenaline, and glucocorticoid secretion, which facilitate tumor proliferation and metastasis\u003csup\u003e6,7\u003c/sup\u003e. Those studies remind us the association between stress and cancer treatment extends beyond ICIs alone.To verify broader connection between ED and survival outcomes in NSCLC patients, we conducted an individual patient data (IPD) meta-analysis.\u003c/p\u003e\n\u003cp\u003eFinally we identified 7 clinical trials which involve patients treated with atezolizumab, including 2 single-arm trials (BIRCH, FIR) and 5 randomized controlled trials (POPLAR, OAK, IMpower130, IMpower131, IMpower150)\u003csup\u003e8-14\u003c/sup\u003e. Among a total of 4632 participants, 2753 (59.43%) received first-line treatment; 3162 (68.26%) received ICIs; 1802 (38.90%) classified as ED and 2830 (61.10%) classified as non-ED.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKaplan-Meier analysis indicate that ED patients associate with worse survival outcomes, regardless of ICIs or chemotherapy (CT) (HR\u003csub\u003eOS\u003c/sub\u003e=1.21, p=0.01; HR\u003csub\u003ePFS\u003c/sub\u003e=1.19, p=0.01). Different from previous findings, which ED as a predictive biomarker for ICIs, our results show that ED is only a prognostic biomarker in NSCLC. Compared with non-ED, ED patients had worse OS in both ICIs ( ED vs non-ED, mOS, 13.34 m vs 16.07 m; p=0.01; HR, 1.21 [1.09-1.34]) and CT (ED vs non-ED, mOS, 12.02 m vs 13.93 m; p=0.01; HR, 1.19 [1.04-1.37]; \u003cstrong\u003eFigure 1, A\u003c/strong\u003e). IPD meta-analysis indicate that the ED group exhibited worse OS outcome (HR=1.18 [1.07-1.30], p=0.01). Subgroup analysis confirmed this association in both ICIs (HR=1.18 [1.04-1.34], p=0.01) and CT groups (HR=1.18 [1.00-1.39], p=0.05; \u003cstrong\u003eFigure 1, B\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe excluded clinical trials, which PFS not primary outcome, and investigated the association with ED and PFS in first-line clinical trials. Similarly, Kaplan-Meier analysis show ED patients had worse PFS regardless of ICIs (mPFS, 5.52 m vs 5.58 m; p=0.01; HR, 1.19 [1.06-1.33]) or CT (mPFS, 5.55 m vs 5.59 m; p=0.06; HR, 1.17 [0.99-1.37]; \u003cstrong\u003eFigure 2, A\u003c/strong\u003e). IPD meta-analysis of PFS also supported results above (HR=1.15 [1.03-1.28], p=0.02; \u003cstrong\u003eFigure 2, B\u003c/strong\u003e). The 7 trials included in the IPD meta-analysis had been validated as free from publication bias and the results of the IPD meta-analysis had been passed the heterogeneity and sensitivity analyses.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this IPD meta-analysis encompassing 12 cohorts of 7 trials, we elucidate a significant association between ED and adverse survival outcomes among patients with NSCLC regardless of CT or ICIs. Preclinical studies provide complementary evidence for our findings that ED associate with prognosis of NSCLC. Yang et al. demonstrated that ED induces the expression of immunosuppressive transcription factor TSC22D3 in dendritic cells through glucocorticoids, impairing chemotherapy and immunotherapy in mouse models of lung cancer, colorectal cancer, and fibrosarcoma\u003csup\u003e15\u003c/sup\u003e. These findings remind us alleviate ED can be a potential potential strategy for cancer treatment.\u003c/p\u003e\n\u003cp\u003eIn comparison to the methodologies employed by the STRESS-LUNG study, which utilized the Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale to assess ED status, our approach with EORTC QLQ-C30 presents a more streamlined and clinically feasible alternative for evaluating ED. This simplification enhances the applicability of our findings in clinical practice, empowering clinicians to assess the psychological well-being of patients throughout their treatment journeys.\u003c/p\u003e\n\u003cp\u003eThis study has some limitations. In our research, once the patient has taken atezolizumab, they will be assigned to the ICIs group, regardless of whether they have previously received other treatments. While limitations of our study have been addressed through the integration of a multi-institutional clinical trials, further prospective studies and preclinical studies are imperative to validate the relationship between ED status and clinical outcomes not only in NSCLC but also in other cancer types.\u003c/p\u003e\n\u003cp\u003eIn conclusion, to our knowledge, this study is the first to propose correlation between ED and prognosis of NSCLC regardless of CT or ICIs. Therefore, we recommend the implementation of ED status assessment in clinical practice for NSCLC patients to improve their survival outcomes.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cem\u003eSearch strategy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe searched Vivli data-sharing platform for studies which reported clinical trials of advanced NSCLC patients treated with atezolizumab, without language restrictions. Seven clinical trials were included: POPLAR (NCT01903993)\u003csup\u003e8\u003c/sup\u003e, IMpower131 (NCT02367794)\u003csup\u003e9\u003c/sup\u003e, OAK (NCT02008227)\u003csup\u003e10\u003c/sup\u003e, IMpower150 (NCT02366143)\u003csup\u003e11\u003c/sup\u003e, FIR (NCT01846416)\u003csup\u003e12\u003c/sup\u003e, BIRCH (NCT02031458)\u003csup\u003e13\u003c/sup\u003e, and IMpower130 (NCT02367781)\u003csup\u003e14\u003c/sup\u003e, all of them provided individual patient data.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCohort definition\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor each chosen randomized controlled trials, patients who received atezolizumab were assigned into the immune checkpoint inhibitors (ICI) cohort regardless of whether they had received platinum-based chemotherapy prior to that period, patients who did not receive atezolizumab were assigned to the chemotherapy (CT) cohort. For each single-arm trials, divided all individual patients into ICI cohorts. A total of 12 cohorts were obtained, of which 7 cohorts were ICI cohort and 5 cohorts were CT cohort.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethod of assessing emotional distress status\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEORTC (European Organisation for Research and Treatment) QLQ-C30 version 3 was applied to evaluate Emotional distress (ED) status of patients. The QLQ-C30 includes 30 items, which can be summarised into five functional scales: Physical Functioning (PF), Role Functioning (RF), Social Functioning (SF), Emotional Functioning (EF), and Cognitive Functioning (CF); three symptom scales: Fatigue (FA), Pain (PA) and Nausea/Vomiting (NV); six single items: Appetite Loss (AP), Dyspnoea (DY), Insomnia (SL), Diarrhoea (DI), Constipation (CO), and Financial difficulties (FI) and a Global Health Status/Qol(QL). After evaluated by the questionnaire, the patient will receive a raw score, which can be transferred to a standard score (0 to 100) through the range reduction method with linear transformation. Patients with standard score \u0026gt; 71 were designated as the non-ED group and \u0026lt;= 71 as the ED group.\u003csup\u003e16,17\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eKaplan-Meier analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe integrated all individual patient data and first-line treatment patient data, grouped them into four groups according to ED status and treatment methods of patients separately: ED-ICI group; ED-CT group; NED-ICI group and NED-CT group. The median overall survival (mOS) and progression-free survival (mPFS) is obtained by using Kaplan-Mier analysis to estimate the survival function, plotting the survival curves and identifying the time at which the survival probability reaches 50% with OS and PFS as the primary endpoints respectively. Calculating and comparing mOS/mPFS, hazard ratios (HRs), 95%CI and p value between four groups (details see \u003cem\u003eStatistical analysis\u003c/em\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethodology for meta-analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eHR value and 95% CI were calculated for each cohort and then summed. We select the I\u003csup\u003e2\u003c/sup\u003e statistic as the statistical measure for heterogeneity testing. Meta analysis will choose the fixed effect model as final result when I\u003csup\u003e2\u003c/sup\u003e statistic \u0026lt;= 40% and p value of heterogeneity testing \u0026gt; 0.1, otherwise, choose the random effects model. Publication bias of cohorts were assessed by Egger linear regression, which consider as no publication bias if p value \u0026gt; 0.05. The stepwise elimination method was employed to assess stability of results.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe Cox proportional hazards model was applied to estimate HRs and 95% CIs between ED group and non-ED group for each cohort, and the two-sided log-rank test was used to compare OS and PFS among the two groups, with the significance level alpha=0.05. Analysis was conducted in R version 4.4.1. The package we utilize as follows: the \u0026lsquo;Matefor\u0026rsquo; package (version 4.6-0), the \u0026lsquo;survminer\u0026rsquo; package (version 0.4.9).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDeshields, T.L.\u003cem\u003e, et al.\u003c/em\u003e Addressing distress management challenges: Recommendations from the consensus panel of the American Psychosocial Oncology Society and the Association of Oncology Social Work. \u003cem\u003eCA Cancer J Clin\u003c/em\u003e \u003cstrong\u003e71\u003c/strong\u003e, 407-436 (2021).\u003c/li\u003e\n\u003cli\u003eFraterman, I.\u003cem\u003e, et al.\u003c/em\u003e Association between pretreatment emotional distress and neoadjuvant immune checkpoint blockade response in melanoma. \u003cem\u003eNature Medicine\u003c/em\u003e \u003cstrong\u003e29\u003c/strong\u003e, 3090-3099 (2023).\u003c/li\u003e\n\u003cli\u003eZeng, Y.\u003cem\u003e, et al.\u003c/em\u003e Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. \u003cem\u003eNat Med\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, 1680-1688 (2024).\u003c/li\u003e\n\u003cli\u003eAntoni, M.H. \u0026amp; Dhabhar, F.S. 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However, several preclinical studies suggest the association between stress and cancer treatment extends beyond ICIs alone. Here we used an individual patient data (IPD) meta-analysis of 4632 patients in 7 trials and a Kaplan-Meier analysis to verify broader connection between ED and survival outcomes in NSCLC patients. Kaplan-Meier analysis show that compared with patients without ED, patients with ED had worse survival outcomes, regardless of ICIs or chemotherapy (hazard ratio (HR) of overall survival (OS), 1.21, p=0.01; hazard ratio of progression-free survival (PFS), 1.19, p=0.01). IPD meta-analysis also supported results above (HR of OS, 1.18, 95% confidence interval (CI), 1.07-1.30; HR of PFS, 1.15, 95% CI, 1.03-1.28). Our research suggest that ED is only a prognostic biomarker in NSCLC, rather than a predictive biomarker for ICIs.","manuscriptTitle":"Association Between Pretreatment Emotional Distress and Survival Outcomes in Patients With Advanced Non-Small-Cell Lung Cancer: an individual patient data meta-analysis of 4632 patients in 7 trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-04 16:00:35","doi":"10.21203/rs.3.rs-5448848/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1ef1bc77-548a-4d30-8466-b9a9a284fb44","owner":[],"postedDate":"December 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":40945646,"name":"Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer"},{"id":40945647,"name":"Biological sciences/Cancer/Tumour biomarkers"}],"tags":[],"updatedAt":"2025-04-02T16:36:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-04 16:00:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5448848","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5448848","identity":"rs-5448848","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}