The Impact of Chemotherapy on Cognitive Function: A Comprehensive Review of Cancer-related Cognitive Impairment and Treatment Options

INTRODUCTION

Cancer-related cognitive Impairment (CRCI), also known as “chemo brain,” is a neurocognitive complication commonly associated with cancer treatments, particularly chemotherapy, and has drawn significant attention in both clinical and research settings due to its profound impact on the quality of life (QoL) of survivors. First identified in the mid-20th century, CRCI manifests through a range of symptoms, including memory lapses, reduced executive functioning, concentration difficulties, attention deficits, and slower cognitive processing speeds, persisting for months or years after treatment.^[1] Epidemiological data suggest that CRCI affects an estimated 17% to 75% of cancer survivors worldwide, with the increasing global prevalence of cancer further emphasizing the importance of this condition. In India, the National Cancer Registry Program reported rising cancer rates, with 94.1 cases per 100,000 males and 103.6 cases per 100,000 females in 2020, indicating an increasing burden of cancer and its associated complications, such as CRCI.^[2] The pathogenesis of CRCI is still incompletely understood but is believed to be multifactorial. It involves mechanisms such as neuroinflammation triggered by chemotherapy agents, oxidative stress, mitochondrial dysfunction, disruption of the blood-brain barrier, and interference with hippocampal neurogenesis. Genetic factors, including polymorphisms in the APOE gene, as well as modifiable risk factors like age, psychological distress, and comorbid conditions such as anemia and metabolic syndromes, further complicate the etiology of this condition.^[3] The diagnosis of CRCI relies heavily on subjective self-reports from patients, structured neuropsychological assessments, and advanced neuroimaging techniques, such as functional MRI and positron emission tomography, which can detect alterations in brain connectivity and metabolism. Research has also explored the use of biomarkers, such as elevated inflammatory cytokines and decreased levels of brain-derived neurotrophic factor, as diagnostic tools, although clinical validation is still in progress. Clinically, CRCI can vary greatly in terms of both severity and duration, with some individuals experiencing transient symptoms and others suffering from chronic and progressive cognitive decline. Many of these symptoms overlap with those of depression and anxiety, complicating differential diagnosis and treatment.^[4] Treatment strategies for CRCI are primarily symptomatic and multidisciplinary, focusing on cognitive rehabilitation programs, pharmacological agents such as methylphenidate, modafinil, and donepezil, and lifestyle interventions, including physical exercise and mindfulness-based stress reduction techniques. Additionally, the Food and Drug Administration has approved memantine, a drug primarily used for Alzheimer’s disease, for managing cognitive symptoms in some cancer patients. A phase II single-arm trial also evaluated memantine for preventing cognitive decline due to chemotherapy for early-stage breast cancer.^[5] Recent advances in neuroprotective strategies, such as the use of anti-inflammatory drugs and antioxidant supplementation, show promise in mitigating CRCI. However, further research and clinical trials are necessary to fully validate these treatments. Despite progress in understanding and managing CRCI, significant challenges remain, such as the lack of standardized diagnostic criteria and the heterogeneous nature of the disorder, which complicates both research and clinical management.^[6]

CASE STUDIES

Several human case studies and trials should be conducted. Longitudinal studies utilizing advanced neuroimaging, cognitive tests, and biomarker analyses to map changes in memory, attention, and executive functions over time could investigate the progression of neurocognitive impairments in patients undergoing chemotherapy. Comparative case-control studies can explore cognitive differences between chemotherapy-treated patients, non-treated patients, and healthy controls, identifying potential genetic or metabolic risk factors. One case study highlights significant cognitive impairments experienced by a breast cancer patient following adjuvant chemotherapy, including declines in processing speed, memory, and executive function. Notably, cognitive improvements were observed over time, with some domains approaching or reaching baseline levels after 12 years. This underscores the importance of acknowledging patients’ subjective reports of cognitive changes and recognizing the potential for recovery with time and appropriate interventions. The findings emphasize the need for baseline cognitive assessments to accurately evaluate post-treatment changes, enabling the development of personalized support strategies for cancer survivors. The case also underscores the variability in individual experiences of cognitive impairments, such as memory and processing speed declines, in breast cancer patients undergoing adjuvant chemotherapy. It highlights the importance of addressing patients’ subjective complaints and advocates for tailored interventions and support to foster long-term cognitive recovery.^[7]

Additionally, a descriptive phenomenological study exploring the lived experiences of chemotherapy patients emphasizes that the “chemo brain” significantly affects concentration and memory. However, this issue often goes unrecognized by healthcare professionals. The study calls for improved communication, education, and acknowledgment of these impairments to empower patients. It also advocates for the development of coping strategies and the integration of supportive interventions, such as cognitive-behavioral therapies, to enhance the QoL for those affected.^[8]

Another case studied a 66-year-old female breast cancer survivor with focus and memory impairments, or “chemo brain,” following chemotherapy that ended 11 months prior. She also experienced lower extremity neuropathy, joint pain, and mild depression (Beck score of 17). Although her MoCA score of 27 was in the lower-normal range, she struggled with cognitive issues. Living with her husband, who provided feedback on BrightGo use, she showed improvements in all cognitive measures except NAB Word Generation, where performance remained normal. Both the participant and caregiver reported improved psychological well-being, sustained at follow-up. Although depression worsened initially, it decreased by 35% at follow-up, surpassing the Minimal Clinically Important Difference. She progressed from an average game difficulty of 3.3/16 to 12.5/16 by the last session.^[9]

Interventional studies should test cognitive therapies, including computerized brain training, cognitive-behavioral therapy, and mindfulness practices. Lifestyle modification trials focusing on exercise, diet, and sleep optimization could assess their role in mitigating symptoms. The neuroprotective benefits of complementary therapies, such as acupuncture and yoga, should be explored in randomized trials. Chinese electroacupuncture can prevent “chemo brain”, mitigate associated symptoms, and enhance the QoL in older cancer patients undergoing or about to begin chemotherapy. Additionally, the safety of this intervention for these patients will be assessed. The findings from this study will help advocate for the use of electroacupuncture in chemotherapy patients and guide the development of future real-world research. Pharmacological trials using drugs like N-acetylcysteine, methylphenidate, donepezil, and omega-3 fatty acids could provide critical data on their effectiveness in treating chemo brain. Further studies involving pediatric, elderly, and comorbid populations could uncover tailored strategies for vulnerable groups. Real-world research is necessary to evaluate the practical implementation of findings, ensuring comprehensive care for cognitive health in cancer survivors. These studies would offer valuable insights into the pathophysiology, management, and therapeutic innovations for chemo brain.^[10]

DISCUSSION

The pathophysiology of CRCI is complex and multifactorial, involving neuroinflammation and mitochondrial dysfunction. Current diagnostic methods rely on subjective self-reports and neuroimaging, but there is a need for more reliable biomarkers. Treatment strategies remain largely symptomatic, and multidisciplinary approaches incorporating pharmacological and cognitive interventions are being explored. New therapeutic approaches, including anti-inflammatory drugs and antioxidants, hold potential, but require further validation through clinical trials. Case studies illustrate the significant variability in CRCI experiences among cancer survivors and emphasize the importance of personalized care and baseline cognitive assessments. The integration of coping strategies, such as cognitive-behavioral therapy and mindfulness, can significantly improve the QoL of affected individuals.

CONCLUSION

CRCI remains a significant challenge for cancer survivors, affecting their cognitive function and QoL. While there is progress in understanding its pathophysiology and management, substantial gaps remain in diagnosis and treatment. Future research should focus on refining diagnostic tools, testing new pharmacological and non-pharmacological interventions, and developing personalized treatment strategies for CRCI to improve the long-term well-being of cancer survivors.