Cancer related fatigue (CRF), also referred to as asthenia (1), is a common and frequently disabling symptom among patients diagnosed with advanced breast cancer (ABC). Cancer treatment related fatigue (CTRF) a specific manifestation of CRF, typically occurs at the initiation of anticancer treatment protocols and is characterized by its persistence after rest. CTRF is frequently associated with chemotherapy, immunotherapy or endocrine therapy (2) and can persist for months or even years following treatment completion (3, 4). While the terms fatigue, asthenia, weakness, exhaustion, malaise, and tiredness are frequently used interchangeably by both physicians and patients, it is important to note that only fatigue and asthenia are officially defined as medical conditions in the Medical Subject Heading (MeSH) Index (5). CRF often appears before treatment starts and may persist after the cessation of the treatment (5). At present, the reported prevalence of CRF in advanced cancer patients ranges from 50% to 71%. However, precise estimates are challenging due to variations in the populations studied and the associated methodological approaches (6). CRF often occurs in tandem with other troublesome symptoms such as pain, sleep disturbance and depression (5). As a result of the multifaceted nature of CRF symptoms, multiple definitions exist within the literature. It is commonly agreed among authors that CRF encompasses a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or its treatment that is not proportional to recent physical activity (PA) and interferes with usual functioning (7–9). Moreover, CRF assessment involves a subjective experience that requires the patient to express themselves directly through self-reporting (7).

Innovative therapies for ABC, such as the new generation of antibody-drug conjugates (ADCs), have significantly improved survival rates in terms of both progression-free survival and overall survival. Consequently, patients undergoing these treatments may experience extended periods of CTRF, necessitating dedicated long-term care plans, the focus of this paper (3). CTRF frequently remains unnoticed and untreated, in part because of its multifactorial origins. The clinical expression of CTRF varies depending on tumor stage and treatment (7, 8, 10, 11). Growing evidence indicates that a gradual decline in PA and subsequent deconditioning before the start of new anticancer treatments are likely to play a significant role in triggering chronic fatigue symptoms (7, 11, 12). These symptoms may be further exacerbated by concurrent factors such as disease progression and cancer-related adverse events and also by external causes such as impact on family or social life (11–13). Deconditioned states and CTRF have also been linked with psychological distress, which in turn undermines quality of life (QoL) and potentially reduces overall survival (9). In addition to improving fatigue, physical exercise has been shown to reduce side effects during and after treatment. The PREFERABLE-EFFET study demonstrated an improvement in fatigue and health-related quality of life (HRQOL) in metastatic breast cancer patients after 9 months of supervised exercise (14).

To address the high prevalence and severity of CTRF and the associated distress suffered by ABC patients, a group of French breast cancer experts came together to provide an overview of fatigue screening and management in ABC patients in Europe. This article aims to outline current guidelines for assessing and managing CTRF while presenting the Working Group’s opinions on priority actionable actions for evaluating and alleviating fatigue in ABC patients to enhance their QoL.

Despite significant progress in understanding CRF and its treatment-related counterpart, a specific diagnostic algorithm has not been definitively established (7). The most recent Clinical Practice Guidelines from the European Society for Medical Oncology (ESMO) advocate for the screening of CTRF through patient self-reporting, using a 10-point numerical rating scale (NRS) or a visual analog scale (VAS) to gauge fatigue (7). However, these methods have inherent limitations, primarily stemming from their incapacity to encompass the myriad of symptoms that often accompany or impact fatigue. Another challenge inherent in CTRF detection pertains to the comparison of fatigue assessments over time, regardless of the screening tool used (7). Although several instruments for measuring fatigue have been developed, their predominant use remains confined to clinical research (15). Diagnostic assessment in European guidelines, including French recommendations for cancer patient supportive care, emphasizes the importance of identifying contributing and comorbid conditions amenable to treatment strategies (7, 11). This necessitates a comprehensive evaluation encompassing the patient’s fatigue history, a thorough medical examination, an evaluation of the underlying malignant disease, a systemic review, a mental status examination, and a defined set of laboratory tests. All modifiable contributing factors should be managed and periodically reassessed through ongoing fatigue screening, which should be consistently integrated into the continuum of care (7, 11).

To address the symptoms and underlying factors of CTRF, a comprehensive approach involving both non-pharmacological interventions (such as adapted PA, nutritional management, and strategies targeting cognitive, behavioral, educational, motivational aspects) and pharmacological treatments (including optimization of anticancer drug doses and management of associated toxicities) might be considered (7, 11, 16). Accumulating evidence in the context of advanced cancer suggests that PA is an effective therapeutic modality for improving fatigue, physical and psychosocial functions, quality of life, body composition, and sleep quality (17). Regular PA is also associated with lower cancer incidence and mortality, as well as a lower rate of tumor recurrence (18). As evidenced by a prospective study involving 103 patients with metastatic or locally recurrent breast cancer (mean age: 53.8 years; mean follow-up: 60.43 months), engaging in one or more hours of moderate PA per day was associated with a 23% reduction in mortality compared to individuals who participated in less than one hour of daily exercise (19). Recommendations for aerobic PA include engaging in at least 150 minutes per week of moderate activities (e.g. 30 minutes of brisk walking a day; 3 times a week “aerobic” exercise; 30 minutes, 2 times a week strength exercises) or at least 75 minutes per week of vigorous activities (such as brisk or very brisk walking; 25 minutes, 2 times a week aerobic exercise; 25 minutes, 1 time a week strength exercises), or a combination thereof. The mechanisms underlying the antitumor effects of exercise remain incompletely understood. These effects might be associated with exercise’s direct impact on tumor cells, which could involve the inhibition of tumor cell proliferation, induction of apoptosis, upregulation of tumor suppressor genes, and the exertion of anti-inflammatory effects (8, 20). PA may also play a role in mitigating cytokine dysregulation induced by CRF/CTRF and reducing the levels of tumor necrosis factor (18). In addition, exercise has the capacity to enhance immune function, thereby contributing to its potential antitumor activity (8, 20). Accordingly, moderate-intensity physical exercise punctuated by rest intervals, along with aerobic and functional resistance training, is recommended for non-cachexic ABC patients with CRF or CTRF (7, 11, 16, 21). However, the presence of CRF/CTRF appears to function as a physiological deterrent to PA engagement among patients. Furthermore, a lack of social support, suboptimal guidance from healthcare professionals (HCPs), and limited access to fitness facilities equipped with knowledgeable staff for patient education represent substantial obstacles to patient involvement in PA (22, 23).

Psychosocial interventions, including psychosocial counseling, psychotherapy, and mind-body interventions, assist patients in assessing their CRF and adapting to their prevailing condition and treatment (7, 11). To empower patients, contemporary guidelines incorporate educational programs aimed at equipping them with the knowledge and skills necessary to understand the multifactorial nature of CTRF, its influencing factors, and its patterns during and post-cancer treatment (7, 11, 24). As illustrated in a meta-analysis of 14 studies involving 2,213 participants with various cancer types, educational strategies appear to exert a limited effect on fatigue intensity but have a moderate impact on reducing fatigue-related distress (24). This suggests that counseling programs should be implemented alongside other interventions (7, 25). It is noteworthy that patients often express a need for educational interventions and guidance from medical staff. A recent study involving 2,508 German cancer patients revealed that approximately 60% of respondents lacked information concerning fatigue, underscoring the need for further research to enhance the delivery of patient education and its seamless integration into routine care (26).

CRF is a well-recognized symptom of ABC, its intensity and impact on a patient’s daily life may frequently be exacerbated by cancer treatments. This specific manifestation of fatigue, known as CTRF coincides with treatment onset and may last over and beyond its course, in some cases for several years (5). Poorly understood and characterized by the inability of rest, or sleep, to provide relief, improvement of its management might be expected to improve the treatment experience for patients with ABC as a complement to the greater OS and PFS, they nowadays regularly benefit from. Despite existing general recommendations for managing CRF (3, 7, 11), everyday management of the specific manifestation of CTRF is today suboptimal, as our survey confirms. Conscious of the need to actively explore innovative ways to improve the management of CTRF, the Working Group aims to propose an expert opinion of actions that will assist the practical management of CTRF and enable patients to experience a more satisfactory treatment pathway.

The fatigue experienced in cancer is of two types, psychological and physical. In the survey, doctors were shown to overestimate the importance of psychological fatigue at the time of diagnosis and before treatment unlike patients, who consider that physical fatigue is already present at this point. This divergence is of potential importance as it is known that if a symptom is present before treatment begins, it will only worsen, often significantly, once therapy is initiated (30). However, CRF may diminish with the effectiveness of the treatment in a certain number of cases, despite the fatigue inherent in the anti-cancer treatment. The patients’ impression of fatigue differs at treatment initiation depending on their employment status. Those in employment at the time of treatment initiation complain of psychological fatigue whereas those not actively employed are more likely to complain of physical fatigue. Once treatment begins however, the opinions of both groups converged, with the physical effects of therapy causing fatigue mutually recognized. Therefore, it is crucial to establish a precise diagnosis to exclude any alternative causes of fatigue beyond the impact of treatment.

CRF has a significant impact on many different areas of life which emphasizes its multifactorial nature. When the perceptions of patients and medical doctors on the dimensions affected by fatigue are compared, discordance becomes apparent. Oncologists seem mainly focused on the patient’s “physical” well-being, and less on the “social” side. While more than half of patients feel that fatigue adversely affects family well-being, just over a third of oncologists are of this opinion. The effect on a patient’s intimate life is also underestimated by oncologists despite a third of patients stating that their intimate life is affected by fatigue. On the other hand, doctors overestimate the effect of fatigue on the patients’ hope to overcome their disease.

Addressing the issues of fatigue linked to treatment is crucial and requires open discussions within the medical field and with patients to optimize treatment outcomes. The survey shows that discussion of fatigue with oncologists is both possible and desired by patients underscoring a willingness to engage in conversations about fatigue. However, there were discrepancies in the answers that show this is an area where improvement is required. Firstly, the majority of oncologists stated that they assess fatigue levels at consultation but the low response rate from patients (n=8/132) on this item suggests that the patient themselves may not be aware, or do not know whether, their doctor is assessing their fatigue. This reinforces the need for better communication between doctor and patient regarding fatigue characterization. Moreover, the patients strongly felt that when it came to fatigue, they were not being listened to, and healthcare professionals exhibited a sense of “fatality” when the subject was raised (33%), an adverse event that had to be “lived with”. While oncologists are aware of these patient concerns, they feel that the dedicated structure needed to support patients is missing. Considering the recognized importance of their role and their proximity to the patient (27–29), surprisingly few patients had discussed their fatigue with their cancer nurse. This is suggestive of potential gaps in the actual implementation of care.

The improvement of CTRF management is also crucial to prevent the necessity to reduce the dose of anticancer treatment. Dose reduction is associated with poorer overall survival (31). Every oncologist surveyed reported that they had, at least at one point, needed to reduce therapeutic doses, suggesting that CTRF can be so severe that oncologists often feel they have no alternative options. There is clear evidence that CTRF can be ameliorated by APA which reduces insomnia and improves the quality and quantity of sleep (30). Additionally, it increases cardio-respiratory fitness, with an improvement in inflammatory variables. Adapted exercise is safe and well tolerated by patients undergoing cancer treatments or in the rehabilitation phase and offers patients a non-pharmacologic alternative which is appealing (7, 11, 16, 21). Consistent with current best practice guidelines, the majority of surveyed oncologists said they recommended APA to their patients, while only half the patients who responded had participated in APA programs. These results may highlight potential miscommunication between patient and physician or a broader inability to implement APA, indicating that adequate time and support mechanisms may not be in place. Oncologists in our survey mentioned the lack of sports facilities to offer and the lack of dedicated time in consultations to accompany patients further in their care, which coupled with a deficit of therapeutic options, creates an important unmet need in the management of CTRF. These findings are similar to those of a larger nationwide study carried out by AFSOS (Association Francophone Des Soins Oncologiques De Support) in 2013 which found that among 700 doctors and 1–500 patients, 98% of oncologists said they had offered advice but only 55% of patients had any recollection of supportive care being proposed (32). The AFSOS 2017 report suggests, once again, that communication about the available support services is not reaching patients and is offered late in the treatment process (33).

Even when offered, in practice there are considerable barriers to its effective implementation including the need for a solid network of sports centers and coaches to maintain the motivation required by patients to obtain positive effects. There is also a lack of evidence as to the best exercise routine to follow. While many systematic reviews with meta-analyses on exercise and CRF have been conducted, the direction of results and especially the magnitude of effect have varied substantially (19, 30, 31, 34). Thus, leaving physicians with the knowledge that APA should be offered but unsure as to the best program to recommend.

A major finding from this new survey was that more time should be committed to understanding CTRF. Oncologists were of the view that training would strengthen their knowledge base and allow them to offer more practical advice to their patients, citing a lack of clinical research and a need for effective treatments. For successful management, frequent reiteration is necessary. To implement this effectively and to avoid over burdening already busy personnel, certain tasks (announcement consultation, complete fatigue assessment, access to supportive care etc.) could be delegated to other HCPs particularly oncology nurses in order to create a seamless and effective pathway. Patients surveyed referred frequently, to having obtained help with their fatigue from sources other than their oncologist.

From recent systemic reviews and studies it would appear that interventions to combat CRF in cancer patients and survivors led by nurses show particular promise. This is especially the case if the focus is multidisciplinary including, exercise and psychological, and behavioral approaches (35). More research is needed in order to determine the most acceptable forms of intervention, but it appears that even relatively short periods of nurse-led exercise intervention, 4 to 6 weeks, can have positive effects (36). If such interventions also adopt a holistic approach to care they are particularly effective in improving health-related quality of life if (37). These findings are aligned with those of the survey in which 40% of the oncologists thought that expanding the role of the oncology nurse would be beneficial to outcomes.

Patients also obtain help from their GPs and patient associations. The latter provide valuable support by facilitating the sharing of experiences, offering supportive oncological care, and presenting complementary alternative practices. A collaborative approach between physicians and these associations could be constructive to ensure that patients receive well-informed guidance and holistic support in addressing CRF. Multidisciplinary commitment and communication are primordial to successful outcomes, which extends to possible external sources for management of APA.

Finally, the lack of oversight from the oncologist regarding the validity and way patients are treated outside the healthcare establishment is a notable concern. To address this, patient associations could play a crucial role by organizing informative sessions on recommended alternative practices, such as webinars, providing education to patients. Digital tools, particularly exercise apps, can also be used to enhance patients’ knowledge and provide them with personalized advice.

CTRF has a substantial impact on quality of life, particularly on well-being, for patients with ABC. However, CTRF is not an inevitability and its effects can be mitigated through careful management, including the differential diagnosis from CRF. Once diagnosed immediate adjustment of therapeutic doses, especially discontinuation of treatment, is not recommended. Dose reduction of anticancer therapies should be considered an exceptional measure and a last resort. APA should be offered to all patients, starting before the initiation of treatment and continuing throughout its course, as it offers physiological, physical, and psychological benefits to all patients. The management of CTRF requires a multidisciplinary approach that extends from the hospital into the wider healthcare community.

To provide a comprehensive and patient-centered care approach for CTRF, the Working Group has elaborated five key strategies to ensure the prompt identification and effective management of CTRF in ABC patients ( Table 2 ). These suggestions are intended to support oncologists in the diagnosis and assessment of fatigue during the treatment process and to elucidate the priorities for CTRF management, drawing upon the expertise of nutritionists, psychiatrists, pain management experts, and supportive care providers ( Figures 4 ). It is important to note that these should be customized to account for the capabilities of the medical facility and the specific attributes of individual patients, including comorbidities, concurrent medications, medication history, and unique patient preferences. Treatment decisions should always be made through a mutual agreement involving patients, HCPs and other caregivers.