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Sex-related differences in postoperative patient-reported outcomes among lung cancer patients: a multicenter cohort study

BMC Cancer volume 25, Article number: 800 (2025) Cite this article

Abstract

Background

Studies on sex-related differences in post-lung cancer surgery symptoms are limited. Understanding these differences may provide insights into patient recovery. Therefore, we investigated sex-related differences in these symptoms and their underlying associated factors.

Methods

We included patients aged ≥ 18 years undergoing surgery for lung cancer from a multicenter cohort study (CN-PRO-Lung 1) that focused on postoperative lung cancer symptoms trajectories. On a daily assessment schedule, we evaluated patients’ symptoms and their impact on functioning from the day before surgery until discharge using the MD Anderson Symptom Inventory–Lung Cancer module. We evaluated sex-related differences in symptom scores over time and identified influencing factors using linear mixed models.

Results

Of 372 eligible patients (196 men and 176 women;) symptoms were milder in men than in women for pain (estimate = 0.427, P = 0.021), fatigue (estimate = 1.071, P < 0.001), shortness of breath (estimate = 0.431, P = 0.021), lack of appetite (estimate = 0.728, P < 0.001), dry mouth (estimate = 0.438, P = 0.015), and constipation (estimate = 0.887, P < 0.001) during postoperative hospitalization (median: 7 days). Pain scores decreased over time in both sexes (estimate = -0.440 in men, P < 0.001; -0.510 in women, P < 0.001), while different factors were associated with increased pain in each group. In men, higher American Society of Anesthesiologists (ASA) classification (estimate = 0.430, P = 0.035), advanced pTNM stage (estimate = 0.550, P = 0.007), and having more than one chest drain (estimate = 0.690, P = 0.001) were associated with greater pain. In women, systematic lymph node dissection was associated with increased pain (estimate = 0.700, P = 0.033).

Conclusions

Women reported a higher symptom burden than men in the early postoperative period after lung cancer surgery. Key factors associated with worse postoperative pain include higher ASA classification, advanced pTNM stage, and more than one chest tube in men and systematic lymph node dissection in women.

Trial registration number

NCT03341377

Peer Review reports

Introduction

Lung cancer is a significant global health concern, characterized by alarmingly high incidence and mortality rates [1]. Surgical intervention is widely recognized as the primary treatment for early-stage lung cancer [2]. However, individuals who have undergone lung cancer surgery frequently experience various postoperative symptoms that can profoundly impact their recovery processes and overall quality of life [3,4,5].

The symptom burden experienced by these patients has been extensively researched to identify strategies that improve symptom management and clinical outcomes [6,7,8,9,10]. However, these studies primarily focused on profiling and managing these symptoms within the patient group as a whole, without adequately considering sex-related differences in symptomatology [11,12,13]. Although previous studies have reported differences in the types and severity of postoperative symptoms between men and women with lung cancer [14,15,16,17,18,19], the precise causes underlying sex-specific differences in symptoms remains unclear [20].

Additionally, severe postoperative symptom burden interferes with daily functions and may affect postoperative recovery [21,22,23], increase the chance of readmission [24, 25], and even delay other postoperative treatments [26]. The monitoring and intervention of symptom burden can improve the postoperative symptom management of patients [7, 9, 26]; however, relevant supporting evidence for sex-related differences in symptoms and studies on its influencing factors are lacking.

To address this critical knowledge gap, this study aimed to investigate the differences in postoperative PROs, including symptoms and interference with daily functioning, between men and women who have undergone lung cancer surgery. Additionally, it sought to identify potential factors related to postoperative pain in men and women independently, to support the development of sex-specific postoperative care strategies.

Methods

Study design and patients

This study selected patients from a cohort study (CN-PRO-Lung 1, ClinicalTrials.gov identifier NCT03341377; trials registration first posted on 14 November, 2017) [27, 28] conducted in six tertiary hospitals from November 2017 to January 2020 that focused on the postoperative symptoms of primary lung cancer. The study protocol was approved by the Ethics Committee of Sichuan Cancer Hospital (No. SCCHEC-02-2017-042), and all patients provided written informed consent [27].

The inclusion criteria of this study were as follows: (1) age ≥ 18 years, (2) undergoing surgical treatment for primary lung cancer, and (3) pathologically confirmed primary lung cancer. Patients who met any one of the following criteria were excluded: (1) history of other cancers, (2) second surgery for lung cancer recurrence or double primary cancer, (3) metastatic lung cancer, or (4) preoperative neoadjuvant therapy.

General data collection

General patient information was extracted through the hospital’s electronic medical record system, including demographic characteristics, preoperative characteristics, surgical data, postoperative pathological diagnosis [postoperative pathological staging was based on the 8th edition of the Tumor–Node–Metastasis (TNM) lung cancer classification], postoperative complications, and other clinical data. The above information was recorded on the REDCap platform of Sichuan Cancer Hospital by researchers trained in standard operating procedures to ensure the accuracy and traceability of data collection [29].

PRO measurement instruments and outcome measures

The MD Anderson Symptom Inventory–Lung Cancer module (MDASI-LC) was used to assess symptoms [4, 30]. Symptom severity and its impact on daily functioning were collected at baseline (3 days preoperatively) and subsequently daily postoperatively at the hospital for less than 14 days [27]. The patients independently completed the MDASI-LC. When assistance was needed, the investigator only read the questions aloud and recorded the patient’s exact response without interpretation. All assessments were self-reported; no proxy responses were applicable or permitted in this study.

Pain management strategy

Postoperative pain management followed the World Health Organization three-step analgesic ladder and was consistently applied across all patients. None of the patients received local pain management strategies such as paravertebral blocks or epidurals, nor was patient-controlled analgesia (PCA) standard practice in this cohort. The attending physician adjusted the analgesic regimen based on the patient’s reported pain intensity, response to treatment, and potential side effects. Oral analgesics included NSAIDs (e.g., loxoprofen, aspirin), compound preparations (e.g., sustained-release codeine tablets), and weak opioids (e.g., compound codeine oral solutions, tramadol). Intravenous options comprised NSAIDs (e.g., trometamol ketorolac, parecoxib) and strong opioids (e.g., butorphanol, buprenorphine, dezocine, morphine, sufentanil). This individualized approach ensured that each patient’s pain management needs were met while maintaining a consistent overall protocol.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Sichuan Cancer Hospital (Approval number: SCCHEC-02-2017-042). Informed consent was obtained from all participants included in the study.

Statistical analysis

We analyzed the longitudinal PRO data of the patients from the preoperative day until discharge or the 7th day after surgery., given that the median length of postoperative hospital stay was 7 days. Normally and non-normally distributed continuous variables are presented as mean ± standard deviation and median and interquartile range, respectively. Categorical variables are expressed as numbers (percentages). To assess differences, the t-test and Mann–Whitney U test were used for the normally and non-normally distributed continuous variables, respectively, and the chi-squared or Fisher’s exact test was used for the categorical variables. Additionally, we calculated the completion rate at each time point to describe data availability.

A linear mixed-effect (LME) model was used to assess sex-related differences in symptom scores over time. The dependent variable was the score for each item, and the independent variables were sex, time, and adjustments for sex, adjusted age, education level, Charlson Comorbidity Index (CCI) score, smoking history, surgical approach (video-assisted thoracoscopic surgery [VATS] or open surgery), type of resection (lobectomy or extended resection), pathological TNM (pTNM) stage, histological type, and lymphadenectomy. Models were assessed using the maximum likelihood estimation method to evaluate the random effects of intercept and time and the fixed effects of independent variables (such as sex). Different covariance structures (unstructured, simple, first-order autoregressive, and compound symmetric) were compared during model building using the Bayesian information criterion (BIC). The first-order autoregressive model with the lowest BIC was selected to fit the models.

A LME model was usedto identify the risk factors for pain in men and women independently since pain was the most common and significantly different symptom between sexes in this study. The potential risk factors included the postoperative time and all patient characteristic variables. A two-tailed P-value of < 0.05 was considered statistically significant, and statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Sample demographic characteristics

Overall, 372 patients who met the inclusion criteria were included. Table 1 presents the demographic and disease characteristics of the patients. This study included 196 men and 176 women with mean ages of 58.18 ± 10.16 and 53.73 ± 9.80 years, respectively. More women had no smoking history (men = 32.14% vs. women = 96.59%,P < 0.001), whereas more men than women had a CCI score of ≥ 1 (men = 78.57% vs. women = 60.80%, P < 0.001). The proportion of men who underwent VATS was lower than that of women (men = 71.43% vs. women = 91.48%, P < 0.001). More women than men had a pTNM stage of ≤ I (men = 51.02% vs. women = 81.25%, P < 0.001). Adenocarcinoma was the most common histology in both sexes, although it was more common in women than in men (men = 71.43% vs. women = 94.32%, P < 0.001). More women underwent non-systematic lymph node dissection than men (men = 54.59% vs. women = 64.77%, P = 0.046). The median postoperative hospital stay was 7 days for men and 6 days for women (P < 0.001). Although the highest level of education (P = 0.019) and access (P = 0.014) differed between the sexes, the number of chest tubes placed, complications, and other demographic and disease characteristics were not significantly different (Table 1).

Table 1 Baseline demographic and patient characteristics
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Top five symptoms

Regarding PRO data availability, the preoperative completion rate in both men and women was 100%, whereas the postoperative completion rate during hospitalization was 91.08–98.43% and 88.24–97.16%, respectively. The lowest compliance rate within the first 7 days postoperatively was 91.08% for men on the sixth day and 88.24% for women on the seventh day. At discharge, the compliance rates were 76.02% and 84.66% for men and women, respectively.

The top five symptoms, identified based on the highest mean scores during hospitalization, were pain, coughing, fatigue, disturb sleep, shortness of breath. (Table 2). The mean scores of the top 5 symptoms for male and female patients showed statistically significant differences on the third day post-surgery.(Table 2).

Table 2 Comparison top five symptoms between male and female patients
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Comparison of pros longitudinally between men and women patients

As shown in Fig. 1; Table 3, the following symptoms were less severe in men than in women: pain (estimate = 0.427, P = 0.021), fatigue (estimate = 1.071, P < 0.001), shortness of breath (estimate = 0.431, P = 0.021), lack of appetite (estimate = 0.728, P < 0.001), dry mouth (estimate = 0.438, P = 0.015), and constipation (estimate = 0.887, P < 0.001).

Fig. 1
figure 1

Comparison of postoperative in-hospital patient-reported outcomes between men and women

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Table 3 Comparison of patient-reported outcomes during postoperative hospitalization between men and women
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In-hospital pain severity and its influencing factors

The pain score in patients (both sexes) was the lowest preoperatively (men vs. women, 0.56 ± 1.24 vs. 0.59 ± 1.31) and the highest on the first day postoperatively (men vs. women, 5.58 ± 2.61, 5.47 ± 2.53). On the day of discharge, the average scores were similar between both sexes. In men, postoperative time (Time, POD) was closely associated with a significant decrease in pain scores (estimate = -0.440, P < 0.001) (Table 4). Additionally, the American Society of Anesthesiologists (ASA) classification had a significant associated with postoperative pain (estimate = 0.430, P = 0.035), indicating that pain was more pronounced in men with an ASA classification of 1 or higher. Men with a pTNM stage higher than I also showed a significant increase in pain (estimate = 0.550, P = 0.007). The placement of two chest tubes was significantly associated with greater postoperative pain (estimate = 0.690, P = 0.001). In women, postoperative time (Time, POD) was similarly associated with a significant decrease in pain scores (estimate = -0.510, P < 0.001). Additionally, systematic lymph node dissection was associated with postoperative pain in women (estimate = 0.700, P = 0.033).

Table 4 Factors associated with postoperative pain in men and women with lung cancer
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Discussion

This study revealed sex-based disparities in symptoms following lung cancer surgery, with men reporting lower postoperative scores for pain, fatigue, shortness of breath, lack of appetite, dry mouth, and constipation. These differences were statistically significant and aligned with previous findings [31,32,33,34,35,36]. To the best of our knowledge, no prior longitudinal study has explored the differences in postoperative symptoms between men and women with lung cancer from the patient’s perspective. Additionally, the observed differences in the factors associated with pain trajectories in men and women indicate the necessity for tailored perioperative care strategies.

Previous studies have indicated significant sex-specific differences in postoperative symptom presentation in the context of various surgical procedures, and symptoms such as pain, fatigue, postoperative nausea, and vomiting have been typically found to be more pronounced in women than in men [31,32,33,34]. In our study, we found that pain incidence in both sexes was the lowest before lung cancer surgery but peaked on POD1. Notably, women reported higher pain scores than did men. The influence of sex on pain perception has been the subject of extensive research. Studies have suggested that women may have a lower pain threshold than men [37], which could explain why they experience more frequent and intense postoperative pain compared to their men counterparts [33]. These sex-related disparities may be partially explained by underlying biological and psychosocial mechanisms. Biologically, hormonal differences—particularly the role of estrogen—have been associated with increased pain sensitivity and inflammatory responses, potentially intensifying postoperative symptoms in women [38]. Psychosocial factors, such as greater emotional expressiveness and different pain coping strategies, may also influence symptom perception and reporting [39]. Women may be more likely to report symptoms, while men may underreport due to sociocultural expectations around stoicism. Understanding these complex interactions is essential for designing sex-specific approaches to symptom monitoring and management [40]. Pain is not only a physical and psychological challenge for patients but also interacts with various factors that can considerably affect postoperative recovery [3, 41, 42]. Therefore, developing targeted and individualized pain management strategies is essential. By effectively mitigating postoperative pain, quicker patient recovery and reduced risk of complications can be achieved.

For men, ASA classification, pTNM stage, and the number of chest tubes were particularly prominent factors influencing postoperative pain. First, the significant impact of ASA classification in men suggests that a higher ASA classification (≥ 1) may be associated with more complex postoperative management needs, which aligns with previous findings linking poorer ASA classification to adverse outcomes. Therefore, ASA classification should be considered when assessing postoperative pain in men. Second, men with a pTNM stage higher than I exhibited significantly increased pain, indicating that tumor staging may be associated with postoperative pain, especially in patients with more advanced disease. This finding underscores the importance of individualized pain management strategies. Additionally, the placement of two chest tubes was significantly associated with greater postoperative pain in men, likely reflecting the association between more invasive surgical procedures and increased pain levels, suggesting that clinicians should consider the additional burden of pain in postoperative chest tube management. In contrast, postoperative pain in women was more significantly influenced by systematic lymph node dissection. This finding is consistent with studies indicating that systematic lymph node dissection has been associated with greater tissue damage and postoperative complications in women. Therefore, pain management interventions in women may need to focus specifically on the extent of lymph node dissection and the speed of postoperative recovery.

Furthermore, while many of the observed differences were statistically significant, it is important to assess whether these differences hold clinical relevance. Based on existing literature, a change of approximately 0.8–1.0 on a 0–10 scale is generally considered the minimal clinically important difference (MCID) for patient-reported symptom scores [30, 43]. Interpreting our findings through the lens of MCID helps to distinguish statistically significant changes that likely have genuine clinical relevance from those with limited practical implications. This approach enables clinicians to better prioritize symptoms that may meaningfully affect patient care and informs the development of more targeted and effective postoperative interventions.

This research highlights the importance of sex differences in postoperative pain management. Men and women exhibit significant differences in the risk factors for postoperative pain, which may reflect physiological, psychological, and sociocultural factors. These findings suggest that clinical practice should involve the development of more individualized pain management strategies based on the patient’s sex, disease characteristics, and surgical approach to improve postoperative recovery outcomes.

Limitations

This study has several limitations. First, as an observational study, even though we used mixed-effect models to adjust for potential confounding factors, residual confounding is inevitable. For instance, psychosocial factors and hormonal differences were not measured and may have influenced the results, potentially limiting our ability to fully explain the observed sex differences in postoperative symptoms. Second, this study focused only on PROs during the postoperative hospital stay and did not include long-term follow-up data after discharge. As such, our findings are limited to early postoperative outcomes, and do not capture the trajectory of symptom resolution or persistence after discharge. Future studies should incorporate longitudinal follow-up to better understand recovery patterns and long-term sex differences in PROs. Third, the lack of formal adjustment for multiple comparisons may increase the risk of Type I errors. However, most key findings remained statistically significant under a conservative Bonferroni-corrected threshold (P < 0.0023), supporting the robustness of our results. Fourth, since our study population was exclusively Chinese, cultural norms around pain reporting and gender roles may have influenced the results, limiting the generalizability of our findings to non-Chinese populations. Lastly, while we adjusted for surgical approach (VATS vs. open) as a covariate, we did not perform subgroup analyses due to the limited sample size in the open surgery group. Further stratification by sex and surgical approach would reduce statistical power and reliability. Future research should further explore long-term postoperative symptoms and functional outcomes to comprehensively understand the influence of sex differences on the recovery process after lung cancer surgery. Moreover, future studies should include diverse cultural settings and consider adjustments for previously unmeasured factors, such as psychosocial and hormonal influences, to enhance the robustness and generalizability of the results.

Conclusion

This study revealed that women’s symptom burden was more severe in the initial days following lung cancer surgery. For men, particular attention should be given to higher ASA classification, pTNM stage, and use of two chest tubes. Meanwhile, systematic lymph node dissection may be an important factor associated with higher pain levels in women, requiring close clinical attention. These findings highlight the importance of targeted postoperative interventions, particularly early in the recovery period, to address sex-specific symptom patterns and enhance overall quality of life for both men and women.

Data availability

The authors are willing to share data, analytic methods, and study materials related to this article with other researchers, provided that they will not be used for commercial or profit purposes. The corresponding author of this article can be contacted by e-mail regarding the research materials needed, with reasons for their use. The authors will be glad to provide relevant materials after approval and discussion.

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Acknowledgements

We express our gratitude to all patients who willingly participated in this study, dedicating their time and providing invaluable assistance with data collection.

Funding

This work was supported by the National Key R&D Plan for Intergovernmental Cooperation, the Ministry of Science and Technology of China (grant number 2022YFE0133100) and the Natural Science Foundation of Sichuan Province (grant number 2023NSFSC1047). The funders played no part in the data collection, management, or analysis, nor did they have a role in the manuscript’s preparation, the decision to submit the manuscript for publication, or in the choice of the journal to which the manuscript was submitted.

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Author notes

  1. Jia Liao and Xiaoqun Hu contributed equally to this work as co-first authors.

  2. Xiaoqin Liu and Qiuling Shi contributed equally to this work as corresponding authors.

Authors and Affiliations

  1. Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, No. 55, Section 4, South Renmin Road, Chengdu, 610041, China

    Jia Liao, Xiaoqun Hu, Xing Wei, Wei Dai, Yaqin Wang, Qin Qin, Na Xu, Yuanyuan Li, Qiang Li, Qiuling Shi & Xiaoqin Liu

  2. State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China

    Hongfan Yu & Qiuling Shi

  3. School of Public Health, Chongqing Medical University, Chongqing, China

    Xin Tian & Qiuling Shi

Authors
  1. Jia Liao
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  2. Xiaoqun Hu
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  13. Xiaoqin Liu
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Contributions

Conceptualization: Jia Liao, Wei Dai, Qiuling Shi and Xiaoqin Liu.Data curation: Jia Liao, Xiaoqun Hu, Xing Wei, Wei Dai, Hongfan Yu, Xin Tian, Yaqin Wang, Qin Qin, Na Xu and Yuanyuan Li.Formal analysis: Jia Liao, Xing Wei, Hongfan Yu, Xin Tian and Xiaoqin Liu.Funding acquisition: Xing Wei and Qiuling Shi.Investigation: Jia Liao, Xiaoqun Hu, Xing Wei, Wei Dai, Hongfan Yu, Xin Tian, Yaqin Wang, Qin Qin, Na Xu, Yuanyuan Li, Qiang Li, Qiuling Shi, and Xiaoqin Liu.Methodology: Hongfan Yu, Xin Tian and Qiuling Shi.Project administration: Qiang Li, Qiuling Shi, and Xiaoqin Liu.Resources: Jia Liao, Xiaoqun Hu, Xing Wei, Wei Dai, Hongfan Yu, Xin Tian, Yaqin Wang, Qin Qin, Na Xu, Yuanyuan Li, Qiang Li, Qiuling Shi, and Xiaoqin Liu.Software: Jia Liao, Xing Wei, Hongfan Yu, Xin Tian and Qiuling Shi.Supervision: Xing Wei, Wei Dai, Qiang Li, Qiuling Shi, and Xiaoqin Liu.Validation: Jia Liao, Xing Wei, Wei Dai, Hongfan Yu, Qiuling Shi, and Xiaoqin Liu.Visualization: Hongfan Yu.Writing - original draft and Writing - review & editing: Jia Liao, Xiaoqun Hu, Xing Wei, Wei Dai, Hongfan Yu, Xin Tian, Yaqin Wang, Qin Qin, Na Xu, Yuanyuan Li, Qiang Li, Qiuling Shi, and Xiaoqin Liu.

Corresponding authors

Correspondence to Qiuling Shi or Xiaoqin Liu.

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Liao, J., Hu, X., Wei, X. et al. Sex-related differences in postoperative patient-reported outcomes among lung cancer patients: a multicenter cohort study. BMC Cancer 25, 800 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14191-z

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14191-z

Keywords

BMC Cancer

ISSN: 1471-2407

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