Cancer as a Risk Factor for Long-Term Cognitive Deficit...

Cancer as a Risk Factor for Long-Term Cognitive Deficits and Dementia

ABSTRACT

Previous studies have shown that cancer survivors frequently experience short-term cognitive deficits, but it is unknown how long these deficits last or whether they worsen over time. Using a co-twin control design, the cognitive function of 702 cancer survivors aged 65 years and older was compared with that of their cancer-free twins. Dementia rates were also compared in 486 of the twin pairs discordant for cancer. Cancer survivors overall, as well as individuals who had survived cancer for 5 or more years before cognitive testing, were more likely than their co-twins to have cognitive dysfunction (odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.36 to 3.24; P<.001; and OR = 2.71, 95% CI = 1.47 to 5.01; P<.001, respectively). Cancer survivors were also twice as likely to be diagnosed with dementia as their co-twins, but this odds ratio did not reach statistical significance (OR = 2.0, 95% CI = 0.86 to 4.67; P = .10). These results suggest that cancer patients are at increased risk for long-term cognitive dysfunction compared with individuals who have never had cancer, even after controlling for the influence of genetic factors and rearing environment.


Lara H. Heflin, Beth E. Meyerowitz, Per Hall, Paul Lichtenstein, Boo Johansson, Nancy L. Pedersen, Margaret Gatz. Cancer as a Risk Factor for Long-Term Cognitive Deficits and Dementia. JNCI Journal of the National Cancer Institute 2005 97(11):854-85.

Correspondence to: Beth E. Meyerowitz, PhD, Department of Psychology, University of Southern California, Los Angeles, CA 90089–1061 (e-mail: meyerow@usc.edu).


FULL PAPER AND CORRESPONDENCE / EDITORIALS

Progress in the treatment of cancer has led to extended survival for many patients, making the understanding of long-term and late effects essential. Research has documented that patients exhibit cognitive deficits persisting up to 5 years post-treatment (1–12). Most studies have focused on short-term cognitive sequelae of treatments (1–14); however, evidence of neurologic changes in cancer survivors (15) suggests that some treatments may act as neurologic insults that decrease cognitive reserve or initiate pathologic processes of dementia (16). Subtle cognitive deficits have been identified in long-term survivors treated with chemotherapy, relative to those treated locally, suggesting that treatment-related deficits may indeed persist (17). It is possible that these cognitive deficits worsen and become most apparent in older age, when risk for cognitive dysfunction is increased.

The present study, approved by the University of Southern California and Karolinska Institutet internal review boards, investigated whether older cancer survivors exhibited long-term cognitive deficits and increased risk for dementia compared with co-twins without a cancer history. The twin design allowed the effects of cancer and its treatments to be considered while controlling for genetic and early environmental influences. Such control is important because estimates of heritability of cognitive functioning in older adults range from 32% to 79% (18–20), and dementia heritability is estimated at 43% to 60% (21,22).

Participants were twin pairs from the Swedish Twin Registry, a population-based registry of all twins residing in Sweden, who completed a telephone cognitive screening at age 65 years and older (23). The validated cognitive screening assessed orientation, short-term memory, working memory, general knowledge, verbal recall, and verbal abstract reasoning (24,25). If a twin performed poorly or was unable to be interviewed, an informant completed the Blessed Dementia Rating scale (26). Using cognitive screening scores and informant reports, an algorithm was used to assign cognitive functioning scores: 0 = cognitively intact, 1 = minor errors, 2 = poor performance, and 3 = cognitive dysfunction sufficient to interfere with managing everyday life demands.

Linkage between the Swedish Twin Registry and the Swedish Cancer Registry yielded 702 twin pairs in which one twin had been diagnosed with malignant cancer, excluding brain cancer due to its direct effect on cognition. The average age of participants was 74.9 years (standard deviation = 6.3 years). Analysis of variance showed no statistically significant age differences between long-term (≥5 years post-diagnosis of most recent cancer at the time of the cognitive screening), short-term (1–5 years post-diagnosis), and immediate (<1 year post-diagnosis) cancer survivors at the time of cognitive screening (P = .98). The mean time between cancer diagnosis and cognitive screening was 14.06 years for long-term survivors, 2.98 years for short-term survivors, and 0.53 years for immediate survivors. Table 1 shows time from diagnosis by cancer site.


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Table 1. Number of patients and time span (in years) between cancer diagnosis and cognitive functioning assessment for the 14 most common cancers in the sample and for all sites combined*
http://jnci.oxfordjournals.org/cgi/content-nw/full/97/11/854/TBL1
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Individuals obtaining a cognitive score of 3 upon screening, and their co-twins, received complete dementia work-ups. A neurologist and psychologist diagnosed dementia using Diagnostic and Statistical Manual-IV criteria (27) and classified non-demented individuals as intact or having questionable dementia. After ascertaining that cancer was diagnosed before dementia onset and excluding pairs containing individuals with questionable dementia, a total of 486 twin pairs discordant for cancer were available for the dementia analysis.

The prevalence of cognitive dysfunction by age of twins with and without cancer diagnoses is shown (Fig. 1). Overall, 14.5% of cancer-surviving twins had cognitive dysfunction (i.e., scoring 3), compared with 8.7% of their cancer-free twins. Two-sided McNemar's chi-square analyses and odds ratios (ORs) were used to determine whether cancer was a statistically significant risk factor for cognitive difficulties and dementia. Cancer history was statistically significantly associated with cognitive dysfunction overall and in long-term cancer survivors compared with their cancer-free co-twins (OR = 2.10, 95% confidence interval [CI] = 1.36 to 3.24; P<.001; and OR = 2.71, 95% CI = 1.47 to 5.01; P<.001, respectively, Table 2). A statistically significant difference between long-term cancer survivors and their co-twins was maintained when individuals with poor performance were grouped with those found to have more serious dysfunction (OR = 1.95, 95% CI = 1.33 to 2.85; P<.001). Short-term survivors did not have increased risk, however. These findings are consistent with the conceptualization that cancer or its treatments decrease cognitive reserve, making survivors more susceptible over time to reaching the threshold for measurable cognitive deficits.



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Fig. 1. Percentage of cancer-surviving and cancer-free twins classified by cognitive screening as having cognitive dysfunction. Patients and co-twins are grouped in 5-year age bands to illustrate the comparative increase in rate of cognitive dysfunction by age in cancer survivors relative to co-twins. The percentage of cancer survivors in each age band classified as having cognitive dysfunction (solid bars) and the percentage of cancer-free co-twins in each age band classified as having cognitive dysfunction (open bars) are shown.
http://jnci.oxfordjournals.org/cgi/content-nw/full/97/11/854/FIG1
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Table 2. Association of cognitive functioning scale scores with cancer diagnosis in twin pairs discordant for cancer, collapsed across cancer sites, stratified by time since cancer diagnosis*
http://jnci.oxfordjournals.org/cgi/content-nw/full/97/11/854/TBL2
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Cancer was not statistically significantly associated with dementia diagnosis (OR = 2.0, 95% CI = 0.86 to 4.67). Nevertheless, the point estimate suggests that the risk was twofold, which may represent a clinically meaningful difference. Power analysis using Dupont's method (28) indicated that the power to reject the null hypothesis was only .05.

Two limitations of this study should be noted. First, we did not have access to information on cancer treatments, preventing comparison of cognitive functioning among cancer survivors who received different treatments. Thus, the cognitive risk reported here may represent an overestimate for some cancer survivors and an underestimate for others. Second, because both cancer and cognitive decline could be influenced by many of the same factors, it is possible that other risk factors—such as alcohol consumption, sedentary lifestyle, or low socioeconomic status—influenced the development of both cancer and cognitive dysfunction. Twins do tend to be more similar than do unrelated individuals on many of these background factors, however (29).

This study has several strengths. We studied a large population-based cohort, including patients whose cancers had been diagnosed many years before cognitive assessment, unlike most studies that were smaller and assessed patients only up to 5 years post-treatment. Because an entire cohort of twins was contacted for participation in the cognitive screening, this study avoids many of the selection biases inherent in studies of hospital patients. Our outcome measures included a complete clinical dementia work-up. Furthermore, the twin design provided a control group that matched for at least 50% of genetic factors and for early environmental influences associated with growing up in the same family.

The nearly exclusive focus of prior studies on short-term cognitive function has left cancer patients and their medical teams uncertain whether cognitive deficits would persist or eventually abate. Our data suggest that cancer and its treatments may lower survivors' cognitive reserve and thus increase their long-term risk of cognitive dysfunction and dementia, a serious clinical concern for physicians treating cancer survivors. Further research should identify mechanisms that mediate the relationship between cancer and cognitive dysfunction and explore whether specific treatments are associated with long-term cognitive effects. This knowledge will help health care providers and patients make informed decisions about treatments.


NOTES

This study was funded by National Institutes of Health Grant No. R01 AG 08724 (MG), a Zenith Award from the Alzheimer's Association (ZEN-02–3895; MG), and a Multidisciplinary Research Training Grant in Gerontology (T32 AG 00037) to LHH.


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Manuscript received November 21, 2004; revised March 23, 2005; accepted March 28, 2005.


CORRESPONDENCE ABOUT THIS ARTICLE


William B. Grant. Re: Cancer as a Risk Factor for Long-Term Cognitive Deficits and Dementia. J Natl Cancer Inst 2005 97: 1549.

The recent report linking cancer as a risk factor for cognitive dysfunction at a statistically significant level and dementia at a non–statistically significant level (1) is interesting and highlights the possible risk of unwanted side effects from cancer treatment. However, the link between cancer and cognitive dysfunction is likely due to shared risk factors as well. The study overlooked the role of dietary and lifestyle factors (e.g., exercise, smoking) in modifying the risks of both cancer and dementia among the elderly.

Although genetics plays an important role in the etiology of cognitive dysfunction and dementia (1), so do diet and lifestyle (2–5). Furthermore, Japanese Americans and African Americans living in the United States have a two and four times greater risk, respectively, of Alzheimer disease than when living in their ancestral homelands, which is statistically correlated with national consumer dietary supply factors in linear regression analyses with r2 values ranging from 0.69 to 0.93 (2). Total energy and fat intake are directly associated with risk of Alzheimer disease, whereas fish and cereals/grains intake are inversely associated (2).

Cancer risk is also strongly linked to dietary and lifestyle factors [including smoking (6,7)]. Intake of animal products that are high in both fat and protein is associated with risk for many common cancers, such as breast and colon cancer (6). The mechanisms may include production of insulin-like growth factor I (IGF-I) (6) and endogenous sex hormones. A recent review highlighted the Western high-fat and refined-sugar diet and physical inactivity as important risk factors for cancer (7). Thus, cancer and dementia share several dietary and lifestyle risk factors.

In conclusion, recent findings indicate that contributions to cognitive dysfunction and dementia from both diet and lifestyle may occur prior to the development of cancer and its treatment. Further studies are required to determine the relative contributions from each.

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Lara H. Heflin, Beth E. Meyerowitz, Per Hall, Paul Lichtenstein, Boo Johansson, Nancy L. Pedersen, and Margaret Gatz. RESPONSE: Re: Cancer as a Risk Factor for Long-Term Cognitive Deficits and Dementia. J Natl Cancer Inst 2005 97: 1550.

Grant points out that cancer and dementia share several dietary and lifestyle risk factors. Although the analyses reported in our recent article (1) did not control for possible shared risk factors such as high-fat diets because we used a co-twin control design and twins tend to be similar in their eating and other habits, there was considerable control for diet and other lifestyle factors built into the design itself. Further, there is reason to believe that diet alone cannot account for the association between cancer and cognitive dysfunction. The most convincing studies in this respect are those that randomly assigned patients to receive different cancer treatments and found poorer cognitive performance among those randomized to some treatments than that found with other treatments; for example, to high-dose versus standard-dose chemotherapy (2) or to chemotherapy versus radiation (3). It seems unlikely that dietary and lifestyle covariates could be fully responsible for the adverse cognitive effects that were observed in these studies. It also seems improbable that the experience of "chemobrain" that patients report following their cancer treatment (4) is an effect of diet rather than a side effect of chemotherapy. In short, it seems likely that a major explanation for cognitive sequelae of cancer is cancer treatment.

We agree that there is provocative overlap in some of the potentially protective dietary factors that have been recommended in relation to cancer and to dementia, e.g., low fat (except for omega-3 fatty acids) and high intake of dark-skinned fruits and vegetables (5). We also note that in a recent survival analysis, Roe et al. (6) report that people with Alzheimer disease have a slower rate of subsequently developing cancer than a nondemented group; this finding raises more unresolved questions. Clearly, research is needed to understand the multiple mechanisms that are likely to play a role in the link between cancer and its treatments and later cognitive dysfunction, as we have noted previously (1).

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(1) Heflin LH, Meyerowitz BE, Hall P, Lichtenstein P, Johansson B, Pedersen NL, et al. Cancer as a risk factor for long-term cognitive deficits and dementia. J Natl Cancer Inst 2005;97:854–6.[Abstract/Free Full Text]

(2) van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998;90:210–8.[Abstract/Free Full Text]

(3) Kaasa S, Olsnes BT, Mastekaasa A. Neuropsychological evaluation of patients with inoperable non-small cell lung cancer treated with combination chemotherapy or radiotherapy. Acta Oncol 1988;27:241–6.[Medline]

(4) Huff C. Chemobrain: the hunt for answers. Monitor Psychol 2005;36:28.

(5) Alzheimer's Association. Adopt a brain-healthy diet. Available at: http://www.alz.org/maintainyourbrain/healthydiet.asp.

(6) Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC. Alzheimer disease and cancer. Neurology 2005;64:895–8.[Abstract/Free Full Text]




Editorial about this Article

Cancer as a Risk Factor for Dementia: A House Built on Shifting Sand
Jeffrey S. Wefel and Christina A. Meyers
J Natl Cancer Inst 2005 97: 788-789.

As advances in therapy have improved the survival rates of patients diagnosed with cancer, various survivorship issues have received attention, including the incidence of cognitive dysfunction and its relative impact on patient quality of life. For example, patients with breast and prostate cancer have 5-year relative survival rates of approximately 86% and 98%, respectively (1). However, recent studies have demonstrated that cognitive dysfunction may be present before treatment, may worsen acutely secondary to treatment-related neurotoxicity, and may continue after cessation of therapy (2–5). Concerns that exposure to cancer and cancer treatments may augment a patient's chance of developing future neurologic diseases, including dementia, have also received recent attention. These concerns are amplified in an aging population that has an increased risk for both cancer and dementia. Studies identifying links between cancers, cancer therapies, and cognitive dysfunction are necessary. It must also be determined if the neurotoxicities associated with these diseases and agents are persistent and if the mere history of cancer and exposure to these therapies create a diathesis for late emerging neurologic diseases such as dementia.

Diminished "cognitive reserve" has been hypothesized as a mechanism that increases the likelihood that patients with cancer may be later diagnosed with other neurologic diseases (6). Cognitive reserve is a theory that has been posited to help explain why individuals with a similar degree of brain pathology manifest different clinical sequelae (7). This theory has been conceptualized along two primary dimensions that consider either threshold differences (e.g., synapse counts) or cognitive processing differences (e.g., intelligence) between individuals. Reserve is purported to moderate the appearance of the clinical symptoms of a disease. Thus, patients with a history of cancer and exposure to antineoplastic therapies may experience a reduction in their cognitive reserve that leaves them vulnerable to later developing cognitive dysfunction from other neurologic illnesses that might have otherwise remained dormant.

In this issue of the Journal, Heflin et al. (6) report the results of a retrospective study of Swedish twin pairs discordant for a history of cancer. They report no statistically significant differences in the rate of clinician-determined dementia in twins with a history of non–central nervous system cancer, relative to their cancer-free co-twin controls. Using a telephone mental status screening interview or informant report as the basis for determining cognitive dysfunction, they reported that twins with a history of cancer had an increased risk of being classified as cognitively impaired compared with the unaffected twin. Subgroup analyses further demonstrated that this was true only for long-term survivors, those who had survived an average of 14 years since their cancer diagnosis. The authors hypothesized that this differential rate of cognitive dysfunction was due to reductions in cognitive reserve. However, a number of cautionary notes are warranted before accepting these conclusions.

Unfortunately, the use of mental status screening measures, including telephone screening instruments and informant reports, is of dubious value and should be abandoned in studies in which the expected cognitive sequelae are less severe than that of frank dementia (8,9). The HARMONY study, from which data for the Heflin et al. study were in part derived, demonstrated the poor diagnostic accuracy associated with the telephone mental status screen. Of the 1557 subjects in the HARMONY study who screened positive for cognitive dysfunction, only 46.4% received a clinician consensus diagnosis of dementia (10). This represents a very high false-positive error rate, which is acceptable for the purpose of screening case patients to undergo more rigorous diagnostic workup. However, the diagnostic error associated with this screening tool should preclude its use in analyses that attempt to determine if cancer history is associated with changes in cognitive function and dementia.

In the Heflin et al. study, all case patients suspected of having cognitive dysfunction underwent comprehensive neurologic and neuropsychological evaluations that resulted in a consensus clinical opinion regarding the presence or absence of dementia. Analysis of the clinician consensus diagnosis of dementia status did not show a statistically significant association between cancer history and dementia. A recent investigation by Roe et al. (11) using a prospective longitudinal design that included comprehensive neuropsychological assessment of cognitive function and histopathologic determination of dementia subtype also failed to find increased risk of developing dementia in patients with a history of cancer compared with cancer-free participants. In fact, they reported a statistically nonsignificant trend suggesting that the risk of developing dementia of the Alzheimer's type was actually marginally less in patients with a prior history of cancer than in cancer-free participants (11).

Although growing evidence supports the view that a subgroup of patients with non–central nervous system cancer experience cognitive dysfunction, not all patients are at equal risk, and data on the persistence of these deficits are scant. The challenge to date has been to convincingly demonstrate the existence of this subgroup of cancer patients through methodologically sound longitudinal trials. Altered cognitive function is best established by longitudinal neuropsychological assessments that allow the clinician to ascertain if there have been changes from a baseline state in association with the onset of a new condition or subsequent to a therapeutic intervention. Although Heflin et al. did not have the benefit of a longitudinal trial with complete medical and treatment histories, using the extensive neuropsychological and medical data collected in conjunction with the HARMONY study may have helped to clarify their conclusions. Issues that could have been clarified include: 1) whether differences in cognitive function between twins are evident on neuropsychological testing, 2) whether these group differences are due to a history of cancer or whether twins with a history of cancer have differential rates of other comorbid medical or psychiatric illness, 3) what controls were in place to diminish subjects' recall error when establishing that cancer predated the onset of dementia, and (4) what controls were in place to diminish expectancy effects on the part of the screening interviewer and the clinician evaluators (i.e., were they blind to the medical history and screening result of each subject they assessed)?

The suggestion by Heflin et al. that diminished cognitive reserve is the causal mechanism underlying the development of subsequent neurologic diseases is premature. Alternatively, cancer patients may demonstrate poor cognitive function due to: persistent neurotoxicity of their treatment; treatment toxicities affecting other organs systems, such as cardiotoxicity or endothelial damage, that contribute indirectly to cognitive dysfunction; secondary cancers, such as acute leukemias (12,13) that produce cognitive dysfunction; or new unrelated neurologic illnesses.

Thus, after a thorough diagnostic workup, Heflin et al. did not demonstrate a preponderance of dementia in co-twins with a history of cancer. Methodologic limitations, including their use of a poor measure of cognitive function, cross-sectional design, and failure to adequately rule out competing causes of suspected cognitive dysfunction, diminish confidence in their interpretation that cancer survivors demonstrated an increased risk of cognitive dysfunction than cancer-free co-twins. Support for their theory that diminished cognitive reserve was the mechanism through which long-term cognitive dysfunction comes to manifest itself was also lacking. There is evidence that cancer patients may experience acute and possibly persistent cognitive dysfunction (2,3,9). The conclusion by Heflin et al. that cancer patients are at risk for developing new late-onset cognitive dysfunction and dementia, however, was not supported and could potentially alarm patients and providers.

Longitudinal, multidisciplinary investigations are needed that can determine which agents and treatment regimens are most neurotoxic, the course of the cognitive and behavioral dysfunction, the cognitive and behavioral domains most affected, the mechanisms for these effects, the host risk factors that mediate the expression of this neurotoxicity, and the risk of developing late-emerging nononcologic neurologic diseases. Thereafter, intervention strategies can rationally be employed. Solid experimental design is the foundation from which meaningful conclusions can be drawn so that investigators can ensure that they do not find themselves with a house built on shifting sand.

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