Whilst significant advancements in clinical oncology that have improved long-term survival rates in cancer patients, the public health impact of cancer survivorship remains an area of unmet need.
One of the most debilitating consequences of cancer treatment is chemotherapy-induced cognitive impairment, often referred to as ‘chemobrain’ or ‘foggy brain syndrome’. This term describes the neurocognitive sequalae experienced by cancer patients during and following chemotherapy due to the substantial off-target effects of certain chemotherapy regimens on the central nervous system.
Globally, about 60% of cancer patients undergo chemotherapy. A modelling study published in the Lancet Oncology projects a 53% increase in the utilisation of first-line chemotherapy treatments by 2040, attributed to escalating cancer burden.
Breast cancer patients and survivors have a high incidence of chemobrain, with two-thirds presenting with clinically significant cognitive impairment following chemotherapy, reporting symptoms such as memory loss, difficulty concentrating and challenges in completing daily tasks. These cognitive impairments make it difficult for individuals to care for their families, return to work, study, or maintain a social life.
In breast cancer management, the utilisation of chemotherapy varies widely, ranging from 10-90% of cases depending on the stage and subtype of cancer. Typically, chemotherapy is employed in cases of advanced breast cancer, aggressive subtypes such as triple-negative breast cancer, or when the cancer has metastasised to lymph nodes or other organs.
Approximately 50% of individuals experience long-lasting clinically significant cognitive impairment that can persist for months and up to 20 years after the cessation of chemotherapy. Despite its prevalence and significant burden on breast cancer patients and survivors’ quality of life, the pathophysiology of chemobrain remains poorly understood, and there are no approved therapies for its prevention or treatment.
Clinical follow-up neuroimaging studies in breast cancer patients who have undergone chemotherapy have revealed functional and structural changes in brain regions crucial for learning and memory. These alterations include shifts in resting metabolism, hippocampal volume, and abnormalities in white matter microstructure.
Despite an increasing number of preclinical studies and clinical trials exploring the benefits of various lifestyle modifications, exercise interventions, cognitive rehabilitation through brain training/stimulation, and drug repurposing to ameliorate the condition, there are currently no recommended therapeutic treatment strategies to prevent chemobrain or improve cognitive outcomes in affected patients.
Moreover, the severity of chemobrain is likely underestimated due to lack of sensitivity and standardisation in neuropsychological assessments for cancer patients. There is a pressing need for novel approaches to comprehensively understand its pathophysiology and develop effective treatments for this primary comorbidity encountered by cancer patients and survivors.
An increasing body of preclinical animal model studies indicates that common first-line chemotherapies possess neurotoxic properties capable of inducing cognitive impairment.
Proposed mechanisms underlying chemotherapy-induced cognitive impairment are diverse and include neuroinflammation, increased oxidative stress, impaired myelination, neurodegeneration and anti-angiogenic effects, the latter leading to compromised microvascular blood flow.
Additionally, chemotherapy-induced disruptions to the blood-brain barrier may permit chemotherapeutic agents to enter the brain parenchyma and directly instigate cytotoxic effects. Intriguingly, the incidence of chemobrain is nearly doubled in individuals carrying the APOE4 gene, recognised for its association with neurovascular dysfunction and identified as the strongest genetic risk factor for Alzheimer’s disease, and thus may be a primary underlying causative mechanism of chemobrain.
Our research group is currently testing potential treatment solutions using novel neuroprotective compounds developed in our laboratory, utilising preclinical models of chemobrain. These compounds are ideal therapeutics for treating the multi-faceted nature of the syndrome due to their pleiotropic properties.
While previous efforts have predominately focused on treating chemobrain post-chemotherapy, our strategy aims to prevent its onset or mitigate its severity pre-emptively. By better understanding the underlying mechanisms of chemobrain, we hope to identify therapeutic candidates for clinical translation.
Key messages
- Chemotherapy can lead to clinically significant cognitive impairments known as ‘chemobrain’, affecting memory, concentration, and daily functioning
- Chemobrain is particularly prevalent in breast cancer patients, with about two-thirds experiencing symptoms following chemotherapy for up to 20 years after cessation of treatment
- Despite its prevalence, the pathophysiology of chemobrain is poorly understood, with no approved preventive or therapeutic strategies. Further research is needed.
Author competing interest – nil