Effect of exercise for patients with advanced lung cancer and cancer-related fatigue: A systematic review and meta-analysis

Highlights

• •Exercise significantly reduces cancer-related fatigue (CRF) in patients with advanced lung cancer, with particular benefit in those aged ≤60 years, using traditional Chinese exercises, and in short-term interventions.
• •Beyond improving CRF, exercise enhances quality of life and reduces dyspnea in this population.
• •Minimal adverse effects were reported, supporting the safety of exercise for advanced lung cancer patients.
• •Individualized, short-term exercise offers a promising non-pharmacological option for managing CRF in patients with advanced lung cancer.
• •Given the current evidence base, further rigorous studies are needed to strengthen findings in this field.

Abstract

Background

Cancer-related fatigue (CRF) is a significant burden for patients with advanced lung cancer. While exercise is recommended for managing CRF during pre- and active treatment phases, evidence supporting its efficacy in advanced stage remains limited. This systematic review and meta-analysis aimed to quantify the effects of exercise on CRF and its common complications in patients with advanced lung cancer.

Methods

A systematic search of 4 databases (PubMed, Embase, Cochrane, and Web of Science) was conducted up to July 10, 2024 to identify relevant randomized controlled trials (RCTs). Studies were selected based on predefined eligibility criteria, including adult patients with advanced lung cancer reporting fatigue as an outcome. Study selection followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, and the risk of bias was assessed using the Cochrane Risk of Bias tool (RoB 2.0). The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Random- or fixed-effects models were used for meta-analyses based on heterogeneity levels.

Results

Eight RCTs involving 749 patients were included. Meta-analysis revealed that exercise significantly improved CRF in patients with advanced lung cancer (standardized mean difference (SMD) = –0.33; 95% confidence interval (95%CI): –0.54 to –0.12); p = 0.00; I² = 0.00%). Subgroup analysis showed greater efficacy in patients aged ≤60 years (p = 0.028), those engaging in traditional Chinese exercise (p = 0.003), and interventions lasting fewer than 12 weeks (p = 0.017). Exercise also significantly improved quality of life (SMD = 0.29; 95%CI: 0.02–0.55; p = 0.04; I² = 0.00%) and reduced dyspnea (SMD = –0.43; 95%CI: –0.71 to –0.16; p = 0.00; I² = 0.00%). No significant effects were observed on sleep quality, anxiety, or depression. The risk of bias across studies was moderate, and the quality of evidence, as evaluated by GRADE, was rated as low due to study limitations. Adverse events were minimal, with only one mild, exercise-related event reported.

Conclusion

Exercise significantly alleviates CRF in patients with advanced lung cancer, improves certain complications, and enhances quality of life. The intervention's effectiveness varies by age, type of exercise, and duration. Further high-quality studies are needed to validate these findings.

Graphical abstract

1. Introduction

Lung cancer is the second most prevalent malignancy worldwide.¹ Advancements in anti-tumor therapies have extended the treatment cycle and survival period of patients with lung cancer.² Cancer-related fatigue (CRF) is a common and frequent symptom burden associated with cancer and its treatment, occurring in 39%–90% of patients undergoing anti-cancer treatment.³ Studies indicate that patients with lung cancer endure a heavier burden of fatigue compared to other cancer types, with 81.5% of advanced lung cancer cases experiencing varying degrees of fatigue.⁴ The National Comprehensive Cancer Network (NCCN) guidelines define CRF as a distressing, persistent, and subjective sense of physical, emotional, and/or cognitive fatigue or exhaustion that is disproportionate to recent activity and interferes with normal functioning.⁵

The pathogenesis of CRF remains unclear and may involve skeletal muscle metabolism, inflammatory response, and nervous or central nervous system dysfunction.⁶ Additionally, CRF rarely exists alone and is often accompanied by insomnia, emotional disorders, dyspnea, and other symptoms. Current guidelines lack specific drug recommendations, and potential therapeutic agents, such as psychotropic drugs and corticosteroids, have limited efficacy and may pose potential toxicity with long-term use.⁷ As a result, in recent years, doctors and patients worldwide have increasingly turned to complementary medicine. Previous studies have demonstrated that non-drug therapies, particularly exercise, can alleviate CRF and various concomitant symptoms in patients with cancer, improve quality of life and survival rate, and are more effective than drug therapies.^8,9

While some systematic reviews have explored the effects of exercise on CRF in patients with lung cancer, most have concentrated on early- and mid-stage disease, with relatively few addressing advanced-stage cases.^10,11 Studies have demonstrated that exercise is safe for patients with advanced lung cancer^12,13 and that the occurrence of CRF in this population is closely associated with various factors, including treatment modalities and individual conditions of patients.¹⁴ The etiology of CRF in advanced-stage lung cancer differs from earlier stages due to the additional impact of tumor burden, radiotherapy, and chemotherapy,⁵ which significantly reduce cardiopulmonary function and exercise capacity. These complexities make it challenging to fully determine the precise impact of exercise interventions in this group. While recent studies have begun to explore the effects of different exercise modalities (e.g., aerobic vs. resistance training) on CRF across various types of cancer, including lung cancer,¹⁵ the optimal intervention is still unclear. Therefore, this study aims to evaluate the effectiveness and safety of exercise interventions in patients with advanced lung cancer and CRF through meta-analysis, providing medical evidence for the clinical practice and application of exercise.

2. Methods

This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines¹⁶ and has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD: 42024528936).

2.1. Literature search

Following the Population, Intervention, Comparison, Outcome, and Study Design (PICOS) principles outlined in PRISMA Guideline,¹⁶ all included studies met these criteria: (a) Participant type: Age 18 or older; and only patients with advanced lung cancer, including those clinically diagnosed with stage IIIb-IV non-small cell lung cancer (NSCLC) and extensive-stage small cell lung cancer (SCLC). Studies were included if patients with advanced lung cancer comprised more than 50% of the total patient population.¹⁷ (b) Intervention type: Exercise only, including combinations of aerobic exercise, endurance exercise, resistance training, and traditional Chinese exercise, with no restrictions on the exercise type, frequency, session length, or overall duration. Studies not exclusively focusing on exercise were excluded, including those combining other interventions like medication, nutritional support, and breathing training. Control group included general supportive care, health education, low frequency exercise, or no intervention. (c) Outcome type: Fatigue must be an outcome indicator, and CRF should be evaluated using a validated scale, such as Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy–Fatigue (FACT-F). (d) Study type: Randomized controlled trials (RCTs), including single-blind, open-label, 2-arm or 3-arm studies are allowed.

Electronic searches were conducted through July 10, 2024 across PubMed, Embase, Cochrane, and Web of Science databases without restrictions on language or publication period. The search strategy involved a combination of free words and Mesh terms, and the search terms mainly included “Lung Neoplasms”, “cancer related fatigue”, “exercise”, and “RCT”. Detailed search strategies for each database are available in the Supplementary materials.

After removing duplicate articles, 2 reviewers (YH and SG) independently assessed the search results using Endnote21 (Clarivate, London, UK). Following the screening criteria, irrelevant studies were excluded based on the titles and abstracts, while the remaining studies were retrieved and thoroughly reviewed. When disagreements arose, the 2 reviewers (YH and SG) discussed the issues until a consensus was achieved. If a consensus was still not achieved, the matter was discussed and resolved with the third senior author (YX).

2.2. Data extraction

All data were extracted independently by 2 reviewers (YH and SG) and recorded in a pre-prepared Excel table (Microsoft, Redmond, WA, USA). Extracted information included the first author, study type, study year, study population, sample size, ages of participants, type and stage of lung cancer, intervention type, duration, exercise session length, frequency, and number of follow-up visits. CRF and associated complications were evaluated using validated scales and scores before and after intervention. Statistical variables were extracted, including mean, standard deviation (SD), standard error (SE), and 95% confidence interval (95%CI).

2.3. Statistical analysis

Meta-analysis was conducted using Stata 16 (Stata Corp., College Station, TX, USA). Outcome indicators, evaluated via scale scores as continuous data, included the mean and SD for all experiments. For experiments lacking SD, conversion used the number of sample size (n), SE, applying the formula SD = SE × $\sqrt{n}$. Due to differences in the rating scales, standardized mean difference (SMD) was calculated to standardize the results, facilitating comparison across all studies. If the scales in different studies had varying directions (e.g., some scales were positively correlated with outcome measures while others were negatively correlated), the mean of the measures from negatively correlated scales was multiplied by –1 to ensure consistency.¹⁸

The I² statistic was used to evaluate heterogeneity. An I² value less than 50% indicated low heterogeneity, while a value of 50% or more indicated medium to high heterogeneity. If moderate or high heterogeneity was determined in the study, a random effects model was employed; otherwise, a fixed effects model was used. To investigate the impact of various factors on the effectiveness of exercise interventions, studies were grouped for subgroup analysis based on characteristics, such as patient demographics, exercise type, frequency, and duration.

2.4. Risk of bias, quality of evidence, and sensitivity analysis

Two examiners independently assessed the methodological quality of the studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0)¹⁹ was used to evaluate random sequence generation, allocation concealment, investigator and subject blinding, outcome blinding, data integrity, selective reporting, and other biases. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system,²⁰ evaluating factors such as risk of bias, inconsistencies, indirectness, imprecision, publication bias. Based on these evaluations, evidence quality was classified as high, medium, low, or very low. GRADE pro software was used to evaluate the evidence and summarize the findings. Any disagreements were resolved through discussion among reviewers, including senior authors when necessary.

To ensure the robustness of the meta-analysis results, a sensitivity analysis was conducted to exclude highly heterogeneous studies. This analysis assessed the impact of individual studies on the overall results using a one-by-one exclusion method, aiming to identify sources of high heterogeneity and to verify the reliability of the results.

3. Results

3.1. Study selection

The search strategies were conducted in PubMed, Embase, Cochrane, and Web of Science, retrieving a total of 842 references. After excluding duplicates and retracted studies, 621 articles remained. After title screening, 415 articles were excluded; and 106 articles were excluded after abstract screening, leaving 100 articles. After full text review, 92 literatures were excluded for reasons including lack of full text (n = 46), no results (n = 24), unclear advanced lung cancer stage (n = 13), no RCT (n = 5), and lack of fatigue as an outcome (n = 4). Additionally, 4 articles were excluded because fewer than 50% of participants were patients with advanced lung cancer. Ultimately, 8 articles were included in the final review: 6 for data analysis and 2 for systematic review only. Fig. 1 provides a flowchart summarizing the study screening process, in accordance with the PRISMA 2020 guidelines.¹⁶

Fig. 1.

Flowchart for the identification of studies included. RCT = randomized controlled trial.

3.2. Study characteristics

The studies were published between 2012 and 2023. A total of 749 participants were included, 1 multicenter study,²¹ 2 open-label studies,^22,23 and 2 three-arm studies.^21,24 Sample sizes ranged from 24 to 226 patients, totaling 687 patients diagnosed with advanced lung cancer. In 4 cases, the average participant age was over 60.22, 23, 24, 25 The intervention methods included 3 categories: (a) aerobic exercises, such as walking or cycling; (b) traditional Chinese exercises, such as Tai Chi and Qigong; (c) mixed exercises, combining aerobic exercise and strength training. Exercise sessions lasted from 90 min to 480 min, with intervention durations spanning 8–24 weeks. A total of 2 studies were conducted exclusively under the supervision of professional coaches or physical therapists,^23,26 5 studies included both professional supervision and self-practice,^{21,24,25,27,28} and 1 study was conducted under monitoring via a pedometer.²² Exercise intensity ranged from low to high. Three studies explicitly mentioned exercise goals.^22,23,25 Motivational strategies included sending scheduled messages, making phone calls, and encouraging patients to keep exercise diaries. Six studies tailored the exercise plans based on participants’ baseline status or recovery conditions,21, 22, 23, 24, 25^,27 and 3 studies regularly adjusted the exercise plans.^22,23,25 Exercise adherence ranged from 61.5% to 89.0%. Control groups received interventions ranging from low frequency exercise to health education, health care, group talk, or no intervention. CRF assessment scales varied across studies, including BFI, FACT-F, European Organisation for Research and Treatment of Cancer (EORTC)–Fatigue, and the Multi-dimensional Fatigue Symptom List–Short Form (MFSI-SF). More details related to the interventions, including specific exercise protocols, are summarized in Table 1.

Table 1.

General information of included studies.

Study	Stage & type	Design	Age	Duration	Supervision	Exercise intervention							Control	Fatigue scale
						Method	Type	Intensity	Goal	Motivation	Personalization	Adherence
Bade et al. (2021)22	III/IV NSCLC	Open-label RCT	>60	12 W	•FitBit accelerometer	n = 20 15-min teaching session → Increase step count by 400 steps/day based on baseline	Walk	Moderate to high	10,000 steps/day	Personalized text message twice daily	•Baseline activity •Adjust weekly	85%	n = 20 •Usual care •Exercise advice	EORTC
Cheung et al. (2021)24	IIIB/IV NSCLC	3 arm- Assessor blind RCT	>60	12 W (24, 48 W FU)	•Professionals •Heart-rate monitor	AE group: n = 10 •AE session: 1 h, twice weekly & SE (1set) session weekly •Self-practice: AE ≥ 1.5 h/W (after intervention: AE ≥ 2.5 h/W & SE (2sets)/2 days) TC group: n = 9 •1 h session, twice weekly •Self-practice: ≥0.5 h, 3 times weekly (after intervention: ≥2.5 h/W)	AE group: Walk, cycle & SE TC group: 24-form Yang style	Moderate	NR	Exercise log	Baseline fitness level	AE group: 75% TC group: 89%	n = 11 •Usual care •PA guidelines	BFI
Cheville et al. (2013)25	IV LC	RCT	>60	8 W	•Physical therapist •Omron pedometers	n = 33 1.5-h instructional session → Self-practice: REST: 10 repetitions twice weekly & walk 1 mile/20 min	SE (resistance bands) & walk	3.5 METs	Increase 15 repetitions of REST & steps by 10%	•Phone call at 1,3,5,7 W •Study calendar	Adjust every 2 W	76.9%	n = 33 No intervention	FACT-F
Dhillon et al. (2017)23	III/IV LC	Open-label RCT	>60	8 W (16, 24 W FU)	•Exercise provider •Accelerometer	n = 56 1-h session (45 min PA & 15 min behavioral change) 8 times weekly	AE & behavior change	Moderate to high	3 MET h/W	PA diary & workbook	Baseline fitness level & interest	PA: 69% Behavioral change: 75%	n = 55 Exercise & nutrition materials	FACT-F
Hwang et al. (2012)26	III/IV NSCLC	RCT	≤60	8 W	•Physical therapist	n = 13 0.5-h session (10 min warm-up & 5 min cool-down), 3 times weekly	Walk/ cycle	Moderate & high	NR	NR	Adjust every 1–2 W	71.2%	n = 11 •Usual care •Phone call every 2–3 W •Exercise instructions	EORTC
Molassiotis et al. (2021)28	I-IV LC	Single blind RCT	≤60	6 W (12 W FU)	•Professional coach •Instructional DVD	n = 78 1–2 W: 1.5 h, twice weekly (supervised practice) →3–6 W: ≥0.5 h, 5 times weekly (self-practice) →6–12 W:unsupervised practice	Qigong	Low	NR	•Exercise log •Weekly phone call	NR	61.5%	n = 72 •Usual care •Group talk	FACT-F
Takemura et al. (2023)21	IIIB/IV NSCLC	3 arm- assessor blind-multicenter RCT	≤60	16 W (48 W FU)	AE group: •Certified specialists •Materials & videos TC group: •TC master •Instructional DVD	AE group: n = 75 •1-h supervised session (AE+SE), twice monthly •Self-practice: AE ≥ 2.5 h/W & SE (2–3 sets)/2 days TC group: n = 76 •1-h group class, twice weekly •Self-practice daily	AE group: Cycle, walk & SE (resistance bands) TC group: 16-form Yang style	AE group: Moderate TC group: Low	NR	•WhatsApp messages weekly •Exercise diary	Personal capacity	•Mean session attendance: AE group: 8.50 (1.76) TC group: 27.30 (2.94)	n = 75 •Usual care •PA information •Exercise diary	BFI
Zhang et al. (2016)27	I-IV LC	RCT	≤60	6 W (12 W FU)	•Experienced instructors •Instructional DVD	n = 47 Teaching session (10-min warm-up) → Self-practice: 1 h/2 days, (10th–21st day of chemotherapy cycle)	8-form simplified Yang style	Low	NR	NR	Fit recovery status	NR	n = 44 Body circles & stretches, 1 h/2 days (10–21st day of chemotherapy cycle)	MFSI-SF

Abbreviations: AE = aerobic exercise; BFI = Brief Fatigue Inventory; EORTC = European Organization for the Research and Treatment of Cancer Quality of Life Core Questionnaire; FACT-F = 13-item Functional Assessment of Cancer Therapy-Fatigue; FU = follow up; LC = lung cancer; MET = metabolic equivalent task; MFSI-SF = Multidimensional Fatigue Symptom Inventory Short Form; NR = not reported; NSCLC = non-small cell lung cancer; PA = physical activity; RCT = randomized controlled trial; REST = rapid, easy, strength training; SE = strength exercise; TC = Tai Chi; W = weeks.

3.3. Risk of bias in studies and sensitivity analysis

All 8 studies performed random sequence generation21, 22, 23, 24, 25, 26, 27, 28 (using sealed envelopes or computer random number generation software). One study did not mention allocation hiding,²² 6 studies explicitly described the process,^21,24, 25, 26, 27, 28 and 1 study did not implement it based on research characteristics.²³ Two studies were open-label,^22,23 while 3 employed single-blinding or assessor-blinding.^21,24,28 Five studies showed a high risk of implementation bias because participant blinding was not feasible due to specificity.^{22,23,25,26,28} The remaining 3 studies, either 3-arm^21,24 or involving low-frequency exercise,²⁷ were assessed as low risk. Outcome assessment blinding was clearly reported in 4 studies,^22,23,26,27 while it was unclear in the remaining 4. Two studies reported only inter-group comparative data,^21,23 omitting complete intra-group data. Reporting bias was unclear in all studies except for those conducted by Dhillon et al.²³ and Takemura et al.²¹ All studies exhibited a low risk for other biases. The bias risk map is detailed in the Supplementary materials.

One study²³ characterized by a high risk of bias and low quality was excluded in a one-by-one sensitivity analysis, revealing no significant effect on the overall results (Supplementary materials).

3.4. Primary outcome

3.4.1. Fatigue

All studies used CRF as an outcome indicator, with data reported in 6 studies.^22,24, 25, 26, 27, 28 The studies available for analysis used different scales to evaluate changes in CRF, including EORTC,^22,26 FACT-F,^25,28 BFI,²⁴ and MFSI.²⁷ Except for the FACT-F scale, higher scores indicated greater levels of fatigue. The summary analysis, as shown in Fig. 2, indicated that at the intervention endpoint, exercise significantly improved CRF in patients with advanced lung cancer compared to the control group (SMD = –0.33; 95%CI: –0.54 to –0.12; p = 0.00; I² = 0.00%).

Fig. 2.

Forest plot of the improvement in cancer-related fatigue. 95%CI = 95% confidence interval; SMD = standardized mean difference.

3.4.2. Subgroup analysis

To explore the potential differences caused by various clinical factors, a subgroup analysis was conducted, as shown in Fig. 3. It was found that an exercise duration of fewer than 12 weeks (p = 0.017; I² = 19.60%), traditional Chinese exercise (p = 0.003; I² = 0.00%), and patients aged 60 years or younger (p = 0.028; I² = 16%) significantly impacted CRF in patients with advanced lung cancer.

Fig. 3.

Forest plot of the subgroup analysis of cancer-related fatigue. Mixed: combining aerobic exercise and strength training. 95%CI = 95% confidence interval; AE = aerobic exercise; SMD = standardized mean difference; TCE = traditional Chinese exercise.

3.5. Secondary outcomes

3.5.1. Quality of life – functional status

Three studies reported quality of life–functional status assessment,^24,25,28 2 using the EORTC scale^24,28 and one using the Functional Assessment of Cancer Therapy–General (FACT-G) scale.²⁵ Higher scores represented better functional status and quality of life. The results indicated that exercise significantly improved the quality of life in patients with advanced lung cancer compared to the control group (SMD = 0.29; 95%CI: 0.02–0.55; p = 0.04; I² = 0.00%), as shown in Fig. 4.

Fig. 4.

Forest plot of the improvement in quality of life-function. 95%CI = 95% confidence interval; SMD = standardized mean difference.

3.5.2. Dyspnea

Three studies reported outcomes for dyspnea,^22,26,28 assessed using the EORTC–Specific Symptom Scale, where higher scores indicated more severe symptoms. The results demonstrated that, compared to conventional care, exercise significantly reduced dyspnea in patients with advanced lung cancer (SMD = –0.43; 95%CI: –0.71 to –0.16; p = 0.00; I² = 0.00%), as shown in Fig. 5.

Fig. 5.

Forest plot of the improvement in dyspnea. 95%CI = 95% confidence interval; SMD = standardized mean difference.

3.5.3. Insomnia

Two studies reported outcomes for sleep quality^24,25: one used the Pittsburgh Sleep Quality Index (PSQI) scale,²⁴ where higher scores indicated poorer sleep quality, and the other used the Pain and Sleep Quality–Sleep Scale,²⁵ where higher scores indicated better sleep quality. The results demonstrated that exercise did not significantly improve sleep quality in patients with advanced lung cancer compared to controls (SMD = –0.15; 95%CI: –1.03 to 0.73; p = 0.74; I² = 71.04%), as shown in Fig. 6.

Fig. 6.

Forest plot of the change in insomnia, anxiety, and depression. 95%CI = 95% confidence interval; SMD = standardized mean difference.

3.5.4. Anxiety

Two studies reported outcomes for anxiety,^24,28 one using the Hospital Anxiety and Depression Scale–Anxiety subscale²⁴ and the other using the Depression Anxiety Stress Scales–Anxiety subscale.²⁸ In both scales, higher scores indicated more severe anxiety. The results demonstrated that exercise did not significantly improve anxiety in patients with advanced lung cancer compared to the control group (SMD = –0.48; 95%CI: –1.17 to 0.21; p = 0.18; I² = 67.49%), as shown in Fig. 6.

3.5.5. Depression

Two studies reported outcomes for depression,^22,24 one using the Hospital Anxiety and Depression Scale–Depression subscale²⁴ and the Patient Health Questionnaire-9 (PHQ-9) scale,²² both indicating that the higher scores reflect more severe depression. The results demonstrated that exercise did not significantly improve depressive symptoms in patients with advanced lung cancer compared to controls (SMD = 0.15; 95%CI: –0.61 to 0.91; p = 0.71; I² = 63.35%), as shown in Fig. 6.

3.6. Adverse events

Adverse events were observed in 7^21–26,28 of the 8 studies, as summarized in the Supplementary materials. Only 1 study reported 4 mild adverse events²³ (back or muscle soreness) associated with the exercise intervention, all of which resolved without treatment.

3.7. Certainty of evidence

The overall quality of the evidence was rated as low. The downgrading reasons included: (a) Serious risk of bias: Several studies lacked researcher and participant blinding, potentially leading to biased outcome evaluations. Additionally, some studies failed to directly report CRF outcomes, with instances of selective reporting and incomplete outcome data. (b) Serious indirectness: Some studies included patients with other types and stages of cancer and were not fully representative of the target population of patients with advanced lung cancer. In addition, CRF was only used as a secondary outcome indicator in most studies, limiting the direct applicability of the results. See Supplementary materials for GRADE grading tables.

4. Discussion

The incidence of fatigue is highest in advanced-stage patients, particularly among those with lung cancer, who experience more severe and challenging-to-manage CRF symptoms.²⁹ Complementary therapies, including exercise, massage, and psychological interventions are recommended in guidelines⁵ for both active and post-treatment CRF patients due to their proven efficacy and minimal side effects.^30,31 Previous studies on exercise for patients with lung cancer primarily focused on early and middle stages, lacking evidence on the effectiveness and safety of exercise for patients with advanced lung cancer. Some studies suggest that exercise can effectively improve CRF in advanced-stage patients^32,33 while others indicate that it has minimal impact in patients with lung cancer.³⁴ These earlier systematic reviews did not specify tumor types and stages, and thus failed to elucidate the role of exercise in patients with advanced lung cancer. Therefore, this review analyzed the latest RCTs from the past 11 years (2012–2023), summarizing the characteristics of these studies and specifically focusing on advanced lung cancer. Since CRF rarely occurs as an isolated symptom,⁵ this study also focused on the intervention effects of exercise on common complications of CRF in patients with advanced lung cancer, providing valuable insights for clinical symptom management. Furthermore, by including only RCTs, the study ensured high research quality and allowed for comprehensive subgroup analysis of clinical factors, resulting in more robust conclusions. To our knowledge, this is the first meta-analysis to investigate the effects of exercise on CRF in patients with advanced lung cancer, providing novel insights and reinforcing the evidence base for current guideline recommendations.

In our study, exercise significantly improved CRF in patients with advanced lung cancer. Although an MCID specifically for CRF in lung cancer has not yet been established, research has proposed MCID values for other cancer types or multiple cancer populations.³⁵ Notably, 5 out of 6 studies exceeded the MCID for scales such as EORTC,^22,26 FACT-F,^25,28 and MFSI,²⁷ indicating that exercise interventions may offer meaningful improvements in CRF for this population. Exercise could be a valuable non-pharmacological approach, helping to improve daily functioning, treatment tolerance, and overall quality of life for patients with advanced lung cancer. Further research is needed to establish a consistent MCID for CRF in lung cancer patients, which would enhance the precision of clinical assessments and interventions. Subgroup analysis revealed that short-term exercise (t < 12 weeks) had significant effects. This may be because as tumors progress in patients with advanced lung cancer, their physical function gradually declines. Over time, the burden of severe fatigue and other symptoms prevents them from meeting the high exercise standards required by many studies.³⁶ Additionally, cancer treatments such as radiotherapy and chemotherapy can cause cardiotoxicity, damage the cardiopulmonary system, and impair exercise capacity.³⁷ The effectiveness of CRF treatment is closely related to cancer progression, and non-drug therapies are often insufficient to reverse the condition in terminal patients.³¹ The effect of exercise on CRF was significant in patients aged 60 years or younger, suggesting that the effect of intervention on fatigue was closely related to baseline condition.²⁹ Furthermore, the effect of traditional Chinese sports intervention was notable.^38,39 Growing evidence suggests that physical and mental exercises, such as tai chi and Qigong, have a positive impact on patients with lung cancer. However, the long-term effects of traditional Chinese exercise on CRF remain unclear,⁴⁰ necessitating further clinical trials to confirm their effectiveness. This study also concluded that exercise could improve dyspnea, functional status, and quality of life in patients with advanced lung cancer, corroborating findings from previous systematic reviews.^4,33,41,42 Given that patients with lung cancer often experience more severe anxiety and depression compared to other cancer patients,⁴³ and their mental health tends to deteriorate as the disease progresses, exercise may not effectively mitigate anxiety and depression in patients with advanced lung cancer.

Research indicates that patients with advanced lung cancer often suffer from severe cardiopulmonary limitations and muscle atrophy. Exercise can potentially slow tumor progression by modulating the immune microenvironment, promoting tumor cell apoptosis, and regulating the tumor extracellular matrix.⁴⁴ Exercise may also alleviate treatment side effects and improve patient tolerability.⁴⁵ Additionally, exercise can enhance cardiorespiratory fitness, promote muscle recovery,⁴⁶ and generally improve overall patient status and quality of life. Clinical studies have observed that while most participants attempted an exercise program, fewer than half completed the intervention, and those who completed the program exhibited positive results.⁴⁷ Therefore, it is essential to approach the clinical prescription of exercise rehabilitation programs with caution.³⁷ It is necessary to carefully consider the patient's current tolerance and expected outcomes⁴⁸ as well as strategies to enhance patient compliance and reduce dropout rates. Only 1 of the included studies reported a minor adverse event related to the exercise intervention, specifically lower back muscle soreness, which was resolved without treatment. Compared to drug therapy, exercise is highly safe, free of significant side effects, and relatively low-cost, making it a suitable option for patients with advanced lung cancer and a potential clinical treatment approach.

In summary, patients with advanced lung cancer and CRF may benefit from starting exercise interventions as early as possible under appropriate conditions. In clinical practice, exercise plans for patients with advanced lung cancer and CRF should be individualized by medical staff and physical therapists, considering the patient's age, gender, exercise tolerance, and need for supervision. Plans should be adjusted moderately to achieve optimal improvement in CRF.⁴⁸

There are several limitations in the included studies, which may affect the conclusions of this research. Firstly, the total number of included studies is small, and the sample size of some studies is limited. Due to the characteristics of these studies, double blinding was not achieved, resulting in a high risk of bias of all studies. Moreover, most studies only used CRF as a secondary outcome indicator, which lowered the quality of the research evidence. This limitation challenges the interpretation and generalization of the results. Secondly, only 2 studies included insomnia, anxiety, and depression as outcome indicators, with one having a small sample size; this likely lead to statistical insignificance and high heterogeneity among these secondary outcome indicators and potentially misrepresented the true effects of exercise on patients with advanced lung cancer. Future RCTs should provide detailed demographic data and exercise programs, conduct clinical registration, prioritize CRF as the primary outcome indicator, observe patient compliance, and include comprehensive reports on the feasibility and safety of exercise.

5. Conclusion

The results of this study show that exercise can significantly improve CRF in patients with advanced lung cancer. It is safe, feasible, and the effectiveness of the intervention is closely related to various factors. Exercise can also alleviate common complications associated with CRF and enhance patients’ quality of life. In clinical practice, when using exercise to manage CRF in patients with advanced lung cancer, doctors should tailor exercise prescriptions based on the patient. Further large, multicenter, high-quality RCTs are needed to evaluate optimal intervention strategies and effects of exercise on CRF in patients with advanced lung cancer.

Authors’ contributions

All authors were involved in the selection and conceptualization of the topic. YH drafted the manuscript, and conducted the article screening and data collection with SG and YX; JD, JS performed the data analysis, and ZB ensured methodological rigor; ZL reviewed and edited the manuscript. All authors have read and approved the final version of the manuscript, and agree with the order of presentation of the authors.

Competing interests

The authors declare that they have no competing interests.