Vardy J, Dhillon HM, Pond GR, et al. Cognitive function and fatigue after diagnosis of colorectal cancer. Ann Oncol. 2014;25(12):2404-2412. Epub 2014 Sep 11.
Prospective, longitudinal study with community matched controls
Participants were divided into 3 groups. Group 1 had localized colorectal cancer (CRC), stages I through III (n=291). Group 2 had limited metastatic disease or locally recurrent CRC (n=72). Group 3 consisted of healthy controls (HC) from the community matched for age and gender (n=72). All participants had good performance status according to the Eastern Cooperative Oncology Group scale. Exclusionary criteria included prior malignancy; any comorbidities that could impair cognition; history of alcohol abuse or psychiatric disorders; abnormal hematological, renal, or liver function; or poor English fluency.
Primary endpoints were cognitive function assessed by Global Deficit Score (GDS) and fatigue assessed by the Functional Assessment of Cancer Therapy-Fatigue (FACT-F). The GDS was composed of several tests of cognition, including computer-based Cambridge Neuropsychological Tested Automated Battery and modified Six Elements Test. All participants were evaluated with the FACT-Cogitive to assess perceptions of their cognitive function. Quality of life and fatigue were assessed using the FACT-F and FACT-General subscales. Anxiety and depression were assessed through the 12-item General Health Questionnaire. Blood parameters were measured in group 1 and HC and included 10 cytokines, clotting factors, sex hormones, carcinoembryonic protein (CEA), and apolipoprotein-E genotype.
The primary outcome measure, GDS, showed significant differences in the early stage CRC (group 1) and metastatic CRC (group 2) vs HC (group 3). Group 3 had a cognitive impairment rate of 15% (11/72) vs 45% (126/281) of participants in group 2 (odds ratio [OR]:4.51, 95% confidence interval [CI]:2.28-8.93; P<.001) and 47% (31/66) of Group 3 (OR: 4.51, CI:2.20-10.97; P<.001). Women in group 1 had greater cognitive impairment than men in the same group (55/105 [52%] vs 71/176 [40%]; P<.050). Fatigue was reported by 52% (149/287) of group 1 and 26% (19/72) of group 3 (P<.001). Overall, women reported more fatigue than men (P=.005). Cognitive function was not associated with blood parameters measured, including cytokines, sex hormones, clotting factors, CEA, or apolipoprotein-E genotype.
Cognitive deficits associated with cancer treatment have been documented mostly in women with breast cancer.1 However, few studies that have assessed cognitive function before treatment. This, the first prospective study assessing pretreatment fatigue and cognition in CRC patients, suggests cognitive deficits may be part of the disease process itself.
Chemotherapy-related cognitive impairment, more commonly referred to as “chemo brain,” has been anecdotally reported since the advent of chemotherapy.
Today we have a much better appreciation of the involvement of cytokines in the promotion and progression of cancerous growths. Since many of these cytokines increase inflammation as well as decrease blood flow, it is not surprising that cancer is coming to a crossroads with our understanding of cognitive decline, which uses the same pathways.2,3 This idea that cancer can lead to systemic biological aberrations that may induce cognitive degeneration dates back more than 15 years.4
Chemotherapy-related cognitive impairment, more commonly referred to as “chemo brain,” has been anecdotally reported since the advent of chemotherapy. Recent research confirms cognitive deficits are not only real but can last decades for some.5 Direct neurotoxicity to the brain is one logical explanation. Another explanation gaining attention is the effect of proinflammatory cytokines, which result from chemotherapy. Such immune cytokines as interleukin (IL)-1 and IL-6 and tumor necrosis factor alpha have been implicated in the inflammatory effects of treatment. Interestingly, these are the same cytokines that are produced by cancerous processes. They are also the same family of cytokines that are implicated in causing cognitive degeneration.6 The presence of cognitive deficits before chemotherapy begins is now thought to play at least some role in what patients perceive as “chemo brain.” Since the cancer and the chemotherapy share this proinflammatory penchant,7 the degree to which the cancer itself and the chemotherapy each contribute to “chemo brain” is difficult to surmise.
Several small prospective studies have suggested that cognitive decline precedes chemotherapy and/or radiation. Fifty patients with leukemia or myelodysplastic syndrome showed that cognitive impairment was evident along with increases in inflammatory cytokines (especially IL-6) before the initiation of chemotherapy.8 In another trial of 30 small-cell lung cancer patients, cognitive deficits were present before chemotherapy and/or surgery as well as before prophylactic irradiation to the brain.9,10 Another study assessing various cognitive parameters in 84 women with nonmetastatic primary breast cancer found the majority had impairment before the initiation of chemotherapy.11
While the current study did not show significant elevations of cytokines in those with the greatest cognitive deficits, the authors noted that “median levels of most cytokines were significantly higher in cancer patients than healthy controls” and tended to increase with severity of disease. The lack of a direct association between cytokine levels and cognitive decline implies a more complex mechanism(s) than simple inflammation. In addition, confounders such as nutritional status, sleep disturbance, comedications, comorbidities, and blood flow may have influenced cognitive function testing.
It is important to emphasize that the presence of cognitive deficits before treatment does not negate the possible exacerbation of these deficits with treatment. It merely emphasizes that the underlying biology of inflammation and impaired cognitive function should be addressed at all points along the cancer care continuum.
- Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol. 2000;18(14):2695-2701.
- Huberman M, Sredni B, Stern L, Kott E, Shalit F. IL-2 and IL-6 secretion in dementia: correlation with type and severity of disease. J Neurol Sci. 1995;130(2):161-164.
- Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition—the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc. 2002;50(12):2041-2056.
- Raber J, Sorg O, Horn TF, et al. Inflammatory cytokines: putative regulators of neuronal and neuro-endocrine function. Brain Res Rev. 1998;26(2-3):320-326.
- Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Gundy C, Schagen SB. Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol. 2012;30(10):1080-1086.
- Bettcher BM, Kramer JH. Longitudinal inflammation, cognitive decline, and Alzheimer's disease: a mini-review. Clin Pharmacol Ther. 2014;96(4):464-469.
- Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? Cancer. 2003;97(11):2919-2925.
- Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer. 2005;104(4):788-793.
- Komaki R, Meyers CA, Shin DM, et al. Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys. 1995;33(1):179-182.
- Meyers CA, Byrne KS, Komaki R. Cognitive deficits in patients with small cell lung cancer before and after chemotherapy. Lung Cancer. 1995;12(3):231-235.
- Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA. “Chemobrain” in breast carcinoma? Cancer. 2004;101(3):466-475.