Fatigue increased from pretreatment levels in nearly 35% of women at two years, with no link to changes in cardiac function, new research has found.
Fatigue remained heightened two years after starting breast cancer treatment in more than a third of women receiving chemotherapy, with depressive symptoms and perceived stress associated with fatigue independently of measures of cardiovascular function, US researchers have reported.
The researchers had expected that the changes in cardiac function associated with potentially cardiotoxic chemotherapy would contribute to longer-term fatigue. Instead, they found no association with fatigue and measures of cardiac function at two years.
The prospective cohort study included 381 women – 236 patients with stage I to III breast cancer and 145 noncancer comparators between 2017 and 2021 – who were followed for 24 months. They were receiving either chemotherapy containing doxorubicin, chemotherapy without doxorubicin, or aromatase inhibitors without chemotherapy.
Participants were recruited through 66 community hospitals in the US and assessed before treatment, at three months, and again at 24 months. The cohort had a mean age of 54 years, and 75.9% were White.
The study adjusted for cardiovascular risk factors including diabetes, hypertension, smoking, age, body mass index, haematocrit, use of potentially cardioprotective medications, and chemotherapy regimen.
At three months, women receiving chemotherapy had worsening fatigue, alongside declines in haematocrit, left ventricular ejection fraction, left ventricular circumferential strain, six-minute walk distance, and systolic blood pressure, compared with cancer-free controls and women receiving aromatase inhibitors without chemotherapy.
Perceived stress and depressive symptoms also increased in the chemotherapy groups. This was seen regardless of race, age, cancer stage, or receipt of cardioprotective medications.
Many of these physiological measures subsequently recovered by 24 months, however, and changes in six-minute walk distance, left ventricular ejection fraction, and left ventricular strain were not associated with fatigue at the two-year assessment.
Among those who received potentially cardiotoxic chemotherapy, 18.2% had clinically relevant fatigue two years after treatment began relative to aromatase inhibitors or controls, while 34.6% experienced a clinically significant increase in fatigue compared with their pretreatment level (an increase of at least five points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale).
These increases were not associated with changes in cardiac function or cardiovascular risk factors.
Depressive symptoms and perceived stress were found to be independently associated with fatigue and partly mediated the relationship between breast cancer treatment and longer-term fatigue. The association with depressive symptoms was approximately three times stronger than that with perceived stress.
At three months, worsening depressive symptoms were associated with greater fatigue (β −1.08, 95% CI −1.33 to −0.83), as was greater perceived stress (β −0.36, 95% CI −0.68 to −0.05). The associations remained significant at 24 months for both depressive symptoms (β −0.88, 95% CI −1.12 to −0.64) and perceived stress (β −0.32, 95% CI −0.62 to −0.01).
Compared with the comparator groups, both chemotherapy groups experienced increased fatigue at three months, with worsening depressive symptoms accounting for 14.5% and 19.1% of the respective total effects (indirect effects −1.16, 95% CI −2.44 to 0.13, and −1.91, 95% CI −3.33 to −0.49).
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By 24 months, fatigue had improved in both chemotherapy groups compared with three months, with improvements in depressive symptoms accounting for 21.4% and 25.0% of the respective effects (indirect effects 2.04, 95% CI 0.67–3.41, and 2.14, 95% CI 0.77–3.51).
The findings suggested that the persistence of fatigue after breast cancer treatment may not be explained by cardiac dysfunction alone, despite the known potential cardiotoxicity of some chemotherapy regimens, the authors noted.
“Importantly, this BC treatment–related fatigue was partially mediated by symptoms of depression and the presence of stress irrespective of cardiovascular function,” they wrote.
“Thus, post–BC treatment of fatigue may require strategies targeting depression and stress independent of cardiovascular function.
“Depressive symptoms are common (ranging from 12% to 25%) among participants with BC, are associated with poorer quality of life and may contribute to increased mortality.”
They said future studies should investigate other potential biological contributors to cancer-related fatigue, including immune, inflammatory, neuroendocrine, and neural processes.
They also noted that physical activity and psychosocial interventions have been associated with improvements in depressive symptoms and perceived stress, and suggested that screening for both factors could be considered when assessing persistent fatigue after breast cancer treatment.
