introduction
Breast cancer is one of the most common cancers in the world, with about 2.3 million new cases each year, seriously affecting global public health. Despite advances in early diagnosis and treatment, breast cancer remains one of the leading causes of cancer death in women. In 2020, approximately 700,000 people died from breast cancer worldwide, with advanced or metastatic breast cancer (MBC) being the leading cause of death. With advances in treatment, survival has been extended in patients with MBC, but quality of life (QOL) has not improved commensurate due to the side effects of long-term treatment and the disease itself. Fatigue is one of the most common and painful symptoms in MBC patients, with a significant negative impact on health-related quality of life (HRQOL). Other common symptoms include decreased physical health, anxiety and depression, neuropathy, and pain, among others, which not only affect the patient's daily life and psychological state, but can also lead to interruption or adjustment of treatment, which can negatively affect the patient's prognosis. In recent years, more and more studies have shown that appropriate physical exercise can reduce the side effects of cancer treatment and improve the quality of life of patients. Based on this, international guidelines recommend appropriate physical activity during and after cancer treatment. However, in the metastatic cancer setting, particularly in patients with MBC, there are few studies on exercise interventions, and there is insufficient evidence to support the specific effects of exercise on their quality of life and fatigue symptoms. Therefore, there is an urgent need for high-quality studies to fill this gap and provide scientifically effective interventions for patients with MBC. In order to solve this problem, on July 25, the study of Nature Medicine reported "Supervised, structured and individualized exercise in metastatic breast cancer: a randomized controlled trial", through a multinational randomized controlled trial (Randomized Controlled). Trial, RCT) – the PREFERABLE-EFFECT study that evaluated the effects of an exercise intervention in people with MBC. The study was conducted in five European countries and eight sites in Australia, enrolling a total of 357 patients with MBC who were required to have a life expectancy of at least six months and no unstable bone metastases. Participants were randomly assigned to either the usual care group (control group, n=179) or the 9-month supervised exercise program group (exercise group, n=178). The exercise group received a structured and individualized exercise intervention consisting of 1-hour multimodal training twice a week covering aerobic exercise, resistance training, and flexibility exercises. The main results of the study showed a significant reduction in physical fatigue in the exercise group after 6 months of intervention (-5.3, 95% CI, -10.0 to -0.6, Bonferroni–Holm-adjusted P-value=0.027; Cohen effect, 0.22), and a significant increase in HRQOL (4.8, 95% CI, 2.2-7.4, Bonferroni–Holm-adjusted P=0.0003; effect size, 0.33). In addition, the exercise group also showed significant improvements in physical health, role function, physical activity levels, and pain management. Although two serious adverse events (fractures) occurred during the intervention, neither was associated with bone metastases, suggesting that supervised exercise interventions are safe and feasible for patients with MBC. Overall, the study demonstrated that structured and individualized exercise interventions can significantly improve physical fatigue and HRQOL in MBC patients, and therefore recommended the inclusion of supervised aerobic and resistance exercise in the supportive care of MBC patients. This not only helps to alleviate the patient's symptoms and improve their quality of life, but also hopefully prolongs survival by enhancing physical function and mental state. It is hoped that the results of this study will provide strong support for future clinical practice and guideline updates.
In recent years, more and more studies have shown that appropriate physical exercise can reduce the side effects of cancer treatment and improve the quality of life of patients. Based on this, international guidelines recommend appropriate physical activity during and after cancer treatment. However, in the metastatic cancer setting, particularly in patients with MBC, there are few studies on exercise interventions, and there is insufficient evidence to support the specific effects of exercise on their quality of life and fatigue symptoms. Therefore, there is an urgent need for high-quality studies to fill this gap and provide scientifically effective interventions for patients with MBC.
To explore the specific effects of exercise interventions in people with MBC, this study evaluated the effects of structured and individualised exercise interventions on physical fatigue and HRQOL in people with MBC through a multi-country randomized controlled trial (RCT), the PREFERABLE-EFFECT study. The study was conducted in five European countries and eight sites in Australia, enrolling a total of 357 patients with MBC who were required to have a life expectancy of at least six months and no unstable bone metastases. Participants were randomly assigned to either the usual care group (control group, n=179) or the supervised exercise program group for 9 months (exercise group, n=178). The intervention exercise group received a structured and individualised exercise intervention consisting of 1-hour multimodal training twice a week covering aerobic exercise, resistance training, and flexibility exercises. The first 6 months of training were carried out under the supervision of professionals, and the last 3 months of training was changed from supervision to self-management. The control group received only usual care and general exercise advice, but no structured exercise training. Data collection and analysis were analysed for all participants at baseline, 3 months, 6 months, and 9 months to assess their physical fatigue (using the European Organisation for Research and Treatment of Cancer (EORTC)'s QLQ-FA12 scale) and HRQOL (using the EORTC's QLQ-C30 scale). Data analysis was performed using a mixed-effects model, adjusting for baseline values, treatment lines (initial treatment or follow-up treatment), and site impact.
研究中参与者的流动情况和分配结果（Credit: Nature Medicine）
Participant recruitment: A total of 357 patients were recruited. Randomization: These participants were randomly assigned to two groups: exercise intervention (n=178); Usual care group (control group, n=179). Follow-up and withdrawal: Follow-up in each group at each time point (3 months, 6 months, and 9 months) and the number and reason for withdrawal: At 3 months, 22 participants dropped out in the exercise group and 21 in the control group. At six months, 33 participants dropped out in the exercise group and 35 in the control group. At 9 months, 43 participants dropped out in the exercise group and 46 in the control group. Samples analyzed: Shows the final sample size included in the analysis, including which participants' data were used for the primary analysis, and the reasons for exclusion.
Key results
Of the 357 participants, 178 were assigned to the exercise group and 179 to the control group. The results showed a significant reduction in physical fatigue at 6 months in the exercise group (-5.3, 95% CI, -10.0 to -0.6, Bonferroni–Holm-adjusted P=0.027; Cohen effect size, 0.22) and a significant increase in HRQOL (4.8, 95% CI, 2.2-7.4, Bonferroni–Holm-adjusted P=0.0003; effect size, 0.33). Secondary OutcomesIn addition to the primary outcome, the exercise group also showed significant improvements in other areas. For example, at 3 and 9 months, HRQOL was still significantly higher in the exercise group than in the control group, at 3.9 (95% CI, 1.5-6.3, effect size 0.27) and 4.3 (95% CI, 1.4-7.3, effect size 0.30), respectively. In terms of physical health and pain management, the exercise group also showed sustained improvements, with a significant increase in physical fitness scores at nine months (BGD, 5.9, 95% CI, 2.2-9.6, effect size 0.33) and a significant reduction in pain scores (BGD, -6.5, 95% CI, -12.0 to -1.0, effect size 0.26). The physical activity level exercise group had a significant increase in self-reported duration of vigorous-intensity aerobic exercise and resistance exercise. Compared with control, the exercise group was associated with a 23-minute increase in weekly intensity aerobic activity at three months (95% CI, 14-33, effect size 0.73), a 24-minute increase at six months (95% CI, 15-33, effect size 0.77), and a 15-minute increase at nine months (95% CI, 5-24, effect size 0.48). Resistance exercise time increased by 30 minutes at three months (95% CI, 19-41, effect size 1.17), by 38 minutes at six months (95% CI, 27-49, effect size 1.49), and by 16 minutes at nine months (95% CI, 5-26, effect size 0.63). Physical activity levels also showed significant increases in objectively measured Very active physical activity levels in the exercise group. At six and nine months, the exercise group increased the time spent on vigorous physical activity by 7 minutes (95% CI, 2-12, effect 0.36) and 7 minutes (95% CI, 1-13, effect 0.36), respectively, while sedentary time was significantly reduced by 85 minutes (95% CI, -166 to -4, effect 0.32) at nine months. Safety: The safety of the exercise intervention was fully verified throughout the study. Although two serious adverse events (i.e., fractures) occurred in the exercise group, neither was associated with bone metastases. This suggests that structured and individualized exercise interventions are safe in patients with MBC.
运动对主要结局HRQOL（健康相关生活质量）和身体疲劳影响的调节因素（Credit: Nature Medicine）
Effect of clinical features: The study analysed the effects of different clinical features on the effect of exercise interventions, including factors such as patient age, severity of illness, and number of treatment lines (initial or subsequent treatment). The figure shows how these clinical features modulate the effects of exercise on HRQOL and physical fatigue. Effect of age: The study found that younger patients (< 50 years) benefited more from HRQOL (BGD, 8.4, 95% CI, 3.2-13.6), compared with patients aged ≥ 50 years (BGD, 3.3, 95% CI, 0.2-6.5). Effect of baseline level of pain: patients who reported significant pain at baseline (58%) had a more significant improvement in HRQOL (BGD, 6.0, 95% CI, 2.0-10.0), compared with less in patients without significant pain (BGD, 2.5, 95% CI, -0.8-5.7). Sensitivity analysis: The figure also shows the results of sensitivity analysis for physical fatigue and HRQOL at different clinical features and baseline levels. These results validate the significant positive effect of exercise interventions on primary outcomes and further support the need for exercise interventions in clinical practice. Overall Effect: Exercise interventions have shown a positive effect in different patient populations, both in terms of physical fatigue and HRQOL, but the effects are more pronounced in certain groups. These results highlight the potential advantages of individualized exercise interventions in cancer rehabilitation.
The results of the study show that structured and individualized exercise interventions have a significant positive effect on physical fatigue and HRQOL in MBC patients. Compared to the control group, the exercise group showed significant improvement at 6 months, and these improvements persisted at 9 months. These results support the need and feasibility of promoting exercise interventions in patients with MBC. Exercise interventions not only reduce fatigue, but also improve HRQOL and physical health, reduce pain, and enhance physical activity levels. Based on these findings, it is recommended that supervised aerobic and resistance exercise be included in the supportive care of patients with MBC. This not only helps to alleviate the patient's symptoms and improve their quality of life, but also hopefully prolongs survival by enhancing physical function and mental state.
In conclusion, the study validated the positive effects of structured and individualized exercise interventions on patients with MBC through a multi-national randomized controlled trial. These findings provide an important scientific basis for future clinical practice, suggesting that supervised aerobic and resistance exercise should be included in the routine care of MBC patients to improve their quality of life and physical health. It is hoped that the results of this study will provide strong support for future clinical practice and guideline updates, and encourage more research and practice to focus on the application of exercise intervention in cancer treatment to bring more well-being to cancer patients.
bibliography
Hiensch AE, Depenbusch J, Schmidt ME, Monninkhof EM, Pelaez M, Clauss D, Gunasekara N, Zimmer P, Belloso J, Trevaskis M, Rundqvist H, Wiskemann J, Müller J, Sweegers MG, Fremd C, Altena R, Gorecki M, Bijlsma R, van Leeuwen-Snoeks L, Ten Bokkel Huinink D, Sonke G, Lahuerta A, Mann GB, Francis PA, Richardson G, Malter W, van der Wall E, Aaronson NK, Senkus E, Urruticoechea A, Zopf EM, Bloch W, Stuiver MM, Wengstrom Y, Steindorf K, May AM. Supervised, structured and individualized exercise in metastatic breast cancer: a randomized controlled trial. Nat Med. 2024 Jul 25. doi: 10.1038/s41591-024-03143-y. Epub ahead of print. PMID: 39054374.https://www.nature.com/articles/s41591-024-03143-y
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