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Introduction

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

A diminution in certain cognitive functions is reported in some patients during and after adjuvant cancer chemotherapy. The phenomenon has been observed not only in patients receiving chemotherapy for brain cancer, but also in patients receiving chemotherapy for cancers in peripheral locales, such as the breast. The cognitive diminution is said to affect an estimated one-third of such patients (1). It has become commonly known as ‘chemo-fog’ or ‘chemo-brain’ (1–4). However, several recent reports have challenged the methodology of studies purporting to document chemo-fog/brain and, therefore, its very existence. In the present report, we attempt to critically evaluate the state of the available published evidence regarding chemo-fog/chemo-brain. We do so by systematically addressing a sequence of questions that attempt to establish, first, whether cognitive impairment following chemotherapy has been adequately documented, and, second, if there is a causal relationship between such findings and the chemotherapy. There is a pressing need to address this issue, because some patients choose to discontinue chemotherapy when they learn of the purported negative consequences on cognitive function and others may unnecessarily be subject to such adverse effects if chemotherapy is not beneficial. If certain drugs are more responsible than others for cognitive impairment, then, in the short-term, clinical choices can be made on the basis of relative adverse effects on cognitive function and, in the long term, this potential adverse effect could be incorporated into drug-discovery screens, yielding future drugs producing less of the problem.

The questions are:

  • 1
    Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  • 2
    Is cognitive impairment associated with cancer itself, or other chronic illnesses, independent of chemotherapy?
  • 3
    Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce chemo-fog/chemo-brain?
  • 4
    Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than do others?
  • 5
    Is there a rational mechanism for the production of such effects?

As we found that not all of these questions can be adequately answered from the available literature, we propose clinical and preclinical study designs that might yield insight into the remaining questions.

Background

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

The terms chemo-fog and chemo-brain are loosely used to describe self-reported or observed cognitive impairment that is said to occur in a subgroup of patients who receive adjuvant cancer chemotherapy to eradicate the growth of possibly fatal occult metastases [estimates range widely, from 4% to 75% (5–12) and ongoing studies (4)] even years after completion of therapy. Another term, ‘chemotherapy-related cognitive impairment’ (13), goes further, suggesting some causal link. The domains of cognition most often said to be impacted include verbal and visual memory, attention, concentration, language, motor skills, multitasking and ability to organize information (2, 4, 14).

There are several published studies that report occurrence of chemo-fog/chemo-brain in cancer patients who have undergone adjuvant chemotherapy (5–12, 15–17). In one study (15) cognitive impairment (assessed by a battery of tests) was found to be a common occurrence in 50 consecutively admitted cancer patients. Another study (6) reported that 2 years (average) after therapy impairment of cognitive function (using a battery of neuropsychological tests) in breast cancer patients was greatest (32%) in patients randomly assigned to receive high-dose chemotherapy (n = 34), compared with those who received standard-dose therapy (17%; n = 36), or to controls (early stage disease) who did not receive chemotherapy (9%; n = 34). A third study (7) reported a significantly higher risk of late (about 2 years after treatment) cognitive impairment (concentration and memory) in breast carcinoma patients treated with six courses of chemotherapy (28%; n = 39) than patients who received the same surgical and radiation therapy, but not chemotherapy (12%; n = 34). The cognitive impairment was unaffected by anxiety, depression, fatigue, or self-reported complaints of cognitive dysfunction. Another study (12) reported a higher incidence of moderate or severe cognitive impairment in women receiving adjuvant chemotherapy for breast cancer (16%; n = 110) than healthy age-matched controls (selected by the patients) (4%; n = 100). The greater cognitive impairment in breast cancer patients following chemotherapy (compared with healthy controls) has been reported to be independent of patient age or menopausal status (9). Others (17) have reported persistent memory deficits (8-year follow-up) in children treated for acute lymphoblastic leukaemia with chemotherapy (n = 17) compared with those who received cranial irradiation or to healthy controls. However, the children attained normal school levels. The remaining studies, likewise conducted with varying degrees of methodological rigor, reported similar findings. Thus, the existence of chemo-fog/chemo-brain appears to be well established, including studies that used objective outcome measures for documentation of impairment of specific domains of cognitive functioning. However, the methodology used in some of these studies has been criticized (3, 18) and most did not permit an unequivocal establishment of a direct causal relationship with the chemotherapy.

The occurrence of some form of cognitive impairment following chemotherapy for brain cancer would seem logical, even expected. However, chemo-fog/chemo-brain has been associated with a variety of peripheral cancers, including leukaemia, prostate-, lymphoma-, testicular-, ovarian-, small cell lung- and breast-cancer (4, 19–21). Patient age is not a discriminating factor, as several studies have shown that children and elderly patients are susceptible (19, 21, 22). Chemo-fog/chemo-brain has been most studied and most often associated with breast cancer (4). The absence of sufficient information about its occurrence in men undergoing chemotherapy for breast cancer leaves open the question of a sex-specific phenomenon. There is a suggestion of a modest effect in young females, but not males, who had received central nervous system prophylactic chemotherapy for acute lymphocytic leukaemia (2–7 years prior) (none had received whole brain radiation therapy) (23), but the numbers are too small to be definitive. In terms of time-course, chemo-fog/chemo-brain occurs in the short-term and may continue for years after treatment (4, 10, 21) (Table 1), although some evidence suggests that it might be transient (recovery at 4 years post-treatment) (8).

Table 1.  Types of cognitive impairments after chemotherapy (CT) and time of measurement
StudyTime after CTA/CVM1VM2V/SIPSDomains measured
  1. +, cognitive impairment reported; A/C, attention/concentration; VM1, verbal memory; VM2, visual memory; V/S, visual/spatial functioning; IPS, information processing speed.

Wieneke and Dienst (5)6 months+++++Attention/concentration, verbal memory, visual memory, visual/spatial functioning, and speed of information processing
Van Dam et al. (6)2 years+ + +Attention, mental flexibility, speed of information processing, visual memory and motor function
Schagen et al. (7)2 years+++ +Memory, language, visual-motor, spatial, attention and concentration, and self-regulation and planning
Brezden et al. (9)During ++  Verbal function, memory, attention/concentration, motor functioning, visuospatial functioning, speed of information processing and mental flexibility
Ahles et al. (10)10 years +  +Verbal ability, Spatial ability, Verbal memory, working memory and psychomotor functioning

Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

This question can be answered in the affirmative. Test batteries include CLOX (a clock-drawing test), EXIT25 (a 25-item bedside measure), High Sensitivity Cognitive Screen, FACT (Functional Assessment of Cancer Therapy)-Cog, and CogState (a computer-based assessment battery) (4). The types of cognitive deficits measured with these batteries are attention, concentration, verbal memory, visual memory, visual/spatial and speed of information processing (4). Similar cognitive functions have been used by others (6) and are summarized in Table 2. It has been claimed that these do not include sensitive tests of executive function and that they require further examination of the ‘real-world’ impact of chemotherapy-induced cognitive decline (2).

Table 2.  Types of cognitive domains and their tests batteries
AttentionD2 test: consists of rows of letter randomly mixed together with a designated target letter. The subject is instructed to cross out all target letters.
Concentration/speedDigit Span of the Wechsler Adult Intelligence Scale (WAIS): involves forward and backward repetitions of series of digits.
Verbal learningRey Auditory Verbal Learning test: includes five learning trials of 15 word list, an interval of 20 min, a delayed recall, and a recognition trial consisting of the target words interspersed with 15 distracter words.
Visual memoryComplex Figure test: copy and recall. The subject is asked to copy a complex figure and, after a few minutes, the subject is asked to reproduce the figure without previous warning.
Visual conceptual and visuomotor trackingTrailmaking A and B: given in two parts, A and B. The subject must draw lines to connect consecutive numbered circles on one worksheet (part A) and then connect the same number of consecutively numbered and lettered circles on another worksheet by alternating between the two sequences (part B). The subject is urged to connect the circles as fast as possible.
Speed of information processingFepsy Visual Searching test: consists of finding a single grid pattern among 24 that matches the one in the centre of a computer screen. Overall, 24 different grids patterns have to be found. Fepsy Binary Choice test: the subject has to react differently to a red square presented on the left side of the computer screen than to a green square presented on the right side. The reaction time reflects motor speed and the decision-making process.

Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

Cancer

There seems to be sufficient objective evidence to conclude that cognitive impairment is observed in a subset of patients who receive chemotherapy for cancer. That is, if a population of patients who have undergone chemotherapy for cancer are administered a standardized battery of tests, a detectable impairment in certain cognitive domains is noted (5–12, 15–17, 24). What is less clear is the role of the chemotherapy (8). For example, it might be the biochemical aberrations of cancer itself, or the impact of a serious illness – and not the chemotherapy – that is the actual cause. Less information is available on this issue. Three studies will be highlighted:

The first (25) assessed 47 women (55–79 years of age), newly diagnosed with breast cancer, using test measures related to capacity to direct attention. The women were tested: (a) before surgery, (b) at 2 weeks post-surgery and (c) 3 months post-surgery. Cancer-free women of similar age (n = 48) were assessed following a routine screening mammogram and 3 months later. The breast cancer group scored significantly lower than the control group before treatment and showed only a gradual gain in capacity to direct attention over time. Thus, in older women newly diagnosed with breast cancer, reduced cognitive performance was observed before treatment and found to persist over an extended interval.

The second study (26) reviewed three prospective clinical research studies of a total of 84 female patients (mean age 50·4 years) undergoing adjuvant chemotherapy or hormonal therapy for breast cancer. This was the first report of a critical control, namely, cognitive status of the patients prior to receiving adjuvant chemotherapy. Cognitive impairment was assessed using five to 14 standard neuropsychological test batteries. The authors reported that approximately one-third (35%) of the patients exhibited impaired cognitive functioning on one or more of the tests, most often related to verbal memory (delayed recall) and verbal learning (long-term storage) (27). This study suggests that a significant component of chemo-fog/chemo-brain might be due to the cancer itself or the impact of knowing one has cancer and not necessarily to the chemotherapy. In previously published studies that assessed cognitive status following adjuvant chemotherapy (5–7, 9, 12), the frequency of cognitive dysfunction ranged from 17% to 75%. Thus, it has been suspected (26) that a large proportion of patients in earlier reports who were reported as having cognitive impairment after chemotherapy might have performed at the same level before chemotherapy and therefore the estimates of cognitive impairment, and attribution to the chemotherapy, were overestimated.

The third study (7) was a retrospective comparison of 39 women with operable breast carcinoma metastatic to the axillary lymph nodes who received adjuvant chemotherapy to a control group of 34 women with axillary lymph node-negative breast cancer who did not receive adjuvant therapy. The study group received six courses of chemotherapy cocktail (cyclophosphamide–methotrexate–fluorouracil; CMF) (many of the study group patients also received tamoxifen therapy for 3 years). Cognitive function was assessed a median of 1·9 (CMF patients) or 2·4 (controls) years after treatment using 14 standardized tests. Of the treated patients, 28% were found to have cognitive impairment (chemo-fog/chemo-brain) compared with 12% of the control patients. Thus, this study appears to demonstrate that adjuvant chemotherapy either has its own deleterious effect on cognitive function or it amplifies the effect of other factors.

Chronic illness

Patients who require chemotherapy have a chronic disease. Before singling out the chemotherapy, it is important to consider the role of the chronic illness. Cognitive impairment has been reported in patients with other, non-malignant chronic illnesses such as congestive heart failure (CHF) (28), type 2 diabetes mellitus (29), chronic obstructive pulmonary disorder (COPD) (30, 31) and depression (32).

The cognitive impairments identified in five studies examining patients with CHF (28) were similar to those described for chemo-fog/chemo-brain. A 2004 review of 10 studies of patients with type 2 diabetes (4538 patients, age 62–77 years, from the Netherlands, Japan, France, Canada and the USA) (29) reported a more rapid decline in cognitive function compared with the general population. A similar association of cognitive impairment (deficits in memory, speed of performance and cognition in routine mental operations) has also been reported for COPD patients compared with age-, education- and IQ-matched controls, even in the absence of hypoxaemia (30, 31).

Depression associated with serious illness might play a role in cognitive decline. A survey of 4392 depressed patients (males and females) aged 65 or older from a biracial community of Chicago assessed cognitive function using a 10-item version of the centre of epidemiological studies depression scale once or twice after baseline at 3-year intervals (32). The results revealed a positive correlation between the number of depressive symptoms and cognitive impairment.

Thus, patients receiving cancer chemotherapy already have pre-existing conditions that predispose them to cognitive impairment: chronic illness and cancer. Unless a prechemotherapy baseline is established, or comparison is made to untreated cancer patients with the same malignancy, the identification of chemo-fog/chemo-brain in patients receiving chemotherapy – no matter how well controlled the study – does not establish causality with the chemotherapy. It is in this regard that one study (26) is so enlightening. In this study, 84 women age 18 or older with breast carcinoma underwent thorough neuropsychological examination before starting systemic adjuvant chemotherapy. Thirty-six per cent of the women in the study displayed cognitive impairment before initiation of systemic therapy. The authors concluded that cognitive impairment pre-exists in breast cancer patients prior to systemic chemotherapy and, thus, previous studies might have overestimated the association of cognitive impairment with the chemotherapy.

Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

Perhaps it is not the chemotherapy that causes cognitive impairment, but rather the destruction of tumour cells and the consequent release of deleterious chemicals or an overactive response (e.g. anti-inflammatory, immunological, etc.) to the injury. To address this question, it would be helpful to know if other treatment modalities that destroy cells, such as radiation or surgery, also produce cognitive impairment.

Radiation therapy is an important part of treatment for many types of cancers and is used for cure or palliation alone or in addition to surgery and/or chemotherapy, in an estimated 60% or more of cancer patients (33). However, the treatment of cancer is often multi-modal and treatment with radiation alone is not often indicated. The combination of chemotherapy with radiation makes it difficult to separate the adverse effects.

In another study (34), cognitive function was evaluated in patients being treated for pituitary tumours. The study examined the effects of both radiotherapy and surgery on cognition. The study concluded that when compared with the normal population, there was evidence of declines in cognitive function in patients treated with surgery with or without radiotherapy. However, patients who received radiotherapy along with surgery performed worse than those who received surgery alone.

It is important to remember that not all patients undergoing cancer therapy of any type (surgery, radiation, or chemotherapy) experience or report declines in cognitive function (35).

Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

If the cause of chemo-fog/chemo-brain is chemotherapeutic drugs, the effect should be dose-related and it would seem reasonable to expect more reports associated with some drugs, or combinations of drugs, than others.

A dose-related effect was reported for use of high-dose adjuvant chemotherapy (mg/m2, i.v.) of FEC (4 cycles) = fluorouracil (500); epidoxorubicin (90–120); and cyclophosphamide (500) and CTC (1 cycle) = cyclophosphamide (6); thiotepa (480); and carboplatin (1·6) (Fig. 1) compared with standard-dose adjuvant chemotherapy of FEC (4 cycles) as adjuvant treatment of high-risk breast cancer that undergo high-dose chemotherpay with autologous bone marrow transplantation (6). More cognitive impairment was noted in patients given high-doses (32%) compared with standard-dose treatment (17%) and more cognitive impairment was noted in patients given standard-dose treatment than controls (9%; women diagnosed with stage I breast cancer not treated with chemotherapy).

image

Figure 1. Chemical structures of commonly used cancer chemotherapeutic agents. (1) 5-fluorouracil; (2) cyclophosphamide; (3) carboplatin; (4) thiotepa; (5) etoposide; (6) doxorubicin; (7) methotrexate.

Download figure to PowerPoint

A commonly used adjuvant chemotherapy for breast cancer is CMF, a combination of cyclophosphamide, methotrexate and 5-fluorouracil (36–38). The lack of sufficient comparative data (Table 3) makes assessment of the relative contribution of each agent impossible. One study (9) did not observe poorer cognitive function in patients who received CMF compared with CEF (a combination of cyclophosphamide, etoposide and fluorouracil). But this leaves open the question of whether it is one of the agents, or a combination of the agents, or if methotrexate and etoposide are implicated or exonerated.

Table 3.  Chemotherapeutic regimens
ReferencesTherapyCognitive impairment?
  1. A, doxorubicin; C, cyclophosphamide; E, epirubicin; F, 5-fluorouracil; M, methotrexate; T, docetaxal.

Wieneke and Dienst (5)CMF/CAFYes
Van Dam et al. (6)CTC (high dose) FECYes
Schagen et al. (7)CMFYes
Brezden et al. (9)CMF/CEFYes
Ahles et al. (10)CMF/CAF/otherYes

Is there a rational mechanism for the production of such effects?

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

An ability to reach the brain is often considered the first requirement for a drug to cause cognitive impairment. In order to do so, it must be lipid soluble or otherwise be able to cross the blood–brain barrier (which includes two layers of epithelial cells that are connected by tight junctions that restrict the types of compounds that can enter). Although a number of anticancer drugs are lipophilic (e.g. paclitaxel and vincristine), their brain levels following systemic administration are low, because of difficulty in crossing the blood–brain barrier or active transport out of the brain, as many of these drugs are substrates of the efflux pump P-glycoprotein (39). 5-Fluorouracil (but not methotrexate, cyclophosphamide, or vincristine) increases blood–brain barrier permeability (40), but only transiently (41). In fact, the relative inability of most agents commonly used in the treatment of breast cancer to reach the central nervous system in sufficient concentrations to treat brain metastases is a major problem (42). One study (43) administered chemotherapeutic agents intravenously to rats and measured the levels of the agents in induced-tumour (avian sarcoma virus-induced glioma) and surrounding brain tissue. They found that cyclophosphamide and fluorouracil and its metabolites penetrate normal brain, but to a lesser extent than does cyclophosphamide on its own. Methotrexate entry into tumour was variable, attaining only minimal concentrations in normal brain. Thus, some agents have been shown to be capable of crossing the blood–brain barrier, but access to the brain might not necessarily result in toxicity (44).

Even in the absence of definitive demonstration that current chemotherapeutic drugs get into the brain, mechanisms for a putative drug-induced chemo-fog/chemo-brain have been postulated. For example, cognitive impairment in breast cancer patients has been suggested to be a result of hormonal imbalances (particularly oestrogen), cytokine level imbalances, anaemia, or thrombosis (4) (although these might result from the cancer rather than the drugs). The argument for implicating alterations in oestrogen levels includes: oestrogen is thought to play a role in cognition by supporting cholinergic activity in the brain (3); adjuvant chemotherapy has been associated with premature menopause and menopausal symptoms in women with breast cancer (12, 45), an effect that might result in the problems with cognition similar to those seen in post-menopausal women (3, 46) and tamoxifen, an oestrogen antagonist used in breast cancer patients as part of adjuvant therapy, has been reported to cause ‘memory problems’ (3). The argument for implicating alterations in cytokine levels includes: cytokine levels are increased in cancer (47, 48) and during cancer treatment (49); cytokines can cross the blood–brain barrier (50); they are involved in various neuroimmmunoendocrine processes that affect brain function (50); increases in cytokine levels are suspected of producing ‘adverse cognitive effects’ (50) and cytokines are involved in neuronal remodelling (50) and may produce (transient) cognitive impairment through this mechanism. Cancer patients are prone to developing anaemia (and the consequent reduction of tissue oxygenation) as a result of the cancer itself (reduction in erythropoietin synthesis or secretion of ‘anaemia-inducing factor’), or radiation therapy or chemotherapy (47). Certain cancer patients are at higher risk of developing thrombosis (51) and breast cancer, along with surgery and chemotherapy, has been associated with susceptibility for thromboembolism (52).

Perhaps chemical substances released by intact or damaged cancer cells, or chemical mediators of the patient's immune response mechanisms, gain access to the brain and adversely affect cognitive functioning. For example, some authors (4) suggest that cytokines (immune-mediated inflammatory agents) released because of stress and/or the tumour itself might contribute to the cognitive impairment. It has also been suggested that microvascular clots might occur in certain malignancies, especially within the central nervous system, which can lead to selective decreased cerebral functioning because of impaired localized blood flow. Thus disease-related factors and patient-related factors (e.g. medical history, nutritional status, comorbid conditions, etc.) not only increase the risk of having cognitive impairment associated with a malignancy prechemotherapy, but also increase the risk of cognitive dysfunction with the administration of chemotherapy.

Of course, these postulated mechanisms presume that chemo-fog/chemo-brain is caused by chemotherapy. Definitive evidence to prove these mechanisms are related to cognitive dysfunction has not been established. Further studies are required to establish a cause-and-effect relationship.

Possible preventative/treatment measures

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

As the cause of cognitive dysfunction in cancer patients is not known, prevention is problematic. ‘Treatment’ primarily consists of supportive measures (to alleviate symptoms or enhance cognition) or is experimental, based on proposed theories of causality. Practical measures such as convenient arrangement of the home or work environment, memorization exercises, the use of mnemonic devices, notes, avoidance of distractions, etc. are recommended (4, 53). Experimental pharmacologic measures include methylphenidate, modafinil, oestrogen replacement, cytokine antagonists, anti-inflammatory agents, Alzheimer drugs, anti-anaemia drugs, and epoetin alpha (to increase red blood cell count and improve brain tissue oxygenation) (4, 54). However, we are unaware of a study that has documented improvement by a pharmacologic measure, i.e. had something like the following four-arm design: Arm 1 = cancer patients given chemotherapy; Arm 2 = cancer patients not given chemotherapy; Arm 3 = cancer patients given chemotherapy plus ‘treatment’ and Arm 4 = cancer patients not given chemotherapy, but given ‘treatment’. Without this type of study (which might not be ethically possible) positive results will remain circumstantial.

Animal models

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

It appears that the best, perhaps the only, way to currently address the question of putative cognitive effects of chemotherapeutic agents, independently of the other complications associated with such therapy, is to directly test them in animal models. Such models can assess the effects of the drugs independently of underlying chronic disease, physiological consequences of cancer or cancer treatment, or depression in the subjects. It is somewhat surprising, therefore, how few such studies have been conducted.

Two studies were reported in the summary of a workshop (4) (but were not found in a MedLine search as of March, 2006). In the first study, trouble retaining learned information (maze negotiation) was noted in inbred mice (not further described) 6 weeks after receiving a single high-dose of chemotherapy (not identified). In the second study, female rats were given five monthly cycles of chemotherapy (fluorouracil or cyclophosphamide) in doses sufficient to cause symptoms of toxicity. After recovery for 2 or 8 months, the rats were tested against control groups in the Stone 14-unit T-maze and the Morris water maze. At 2 months, the chemotherapy group was no worse than, in fact was better than, the control animals in maze performance and at 8 months, the groups were the same. Hence, there appeared to be no deleterious effect of chemotherapy treatment. A third study found that multiple intracerebroventricular injections of methotrexate to male rats, at doses sufficient to cause convulsions, produced learning and memory impairment (55). Clearly, additional studies need to be done.

Conclusions and perspective

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References

Chemo-fog/chemo-brain (cognitive dysfunction) represents a serious concern for cancer patients undergoing or contemplating chemotherapy. However, the causal relationship between this adverse outcome and the chemotherapy per se does not appear to have been unequivocally established. Thus, patients face a dilemma: undertake the treatment and possibly suffer the (unacceptable) adverse effects, or forego the treatment and possibly fare worse. Decisions are currently being made based on the assumption that the chemotherapy is at fault. The present review examines this issue and suggests that further information is sorely needed.

References

  1. Top of page
  2. Introduction
  3. Background
  4. Are there specific subjective or objective measures of the cognitive defect(s) that give rise to the terms chemo-fog and chemo-brain?
  5. Is cognitive impairment associated with cancer or other chronic illnesses, independent of chemotherapy?
  6. Is it just chemotherapy, or do other treatment modalities (such as radiation or surgery) also produce the phenomenon?
  7. Do certain chemotherapeutic agents produce chemo-fog/chemo-brain more than others?
  8. Is there a rational mechanism for the production of such effects?
  9. Possible preventative/treatment measures
  10. Animal models
  11. Conclusions and perspective
  12. References
  • 1
    Olin JJ (2001) Cognitive function after systemic therapy for breast cancer. Oncology, 15, 613618.
  • 2
    Anderson-Hanley C, Sherman ML, Riggs R, Agocha B, Compas B (2003) Neuropsychological effect of treatments for adults with cancer: A meta-analysis and review of the literature. Journal of the International Neuropsychological Society, 9, 967982.
  • 3
    Phillips KA, Bernhard J (2003) Adjuvant breast cancer treatment and cognitive function: current knowledge and research directions. Journal of the National Cancer Institute, 95, 190197.
  • 4
    Tannock IF, Tim AA, Ganz PA, van Dam FS (2004) Cognitive impairment associated with chemotherapy for cancer: report of a workshop. Journal of Clinical Oncology, 22, 22332239.
  • 5
    Wieneke MH, Dienst ER (1995) Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psychooncology, 4, 6166.
  • 6
    Van Dam FS, Schagen SB, Muller MJ, Boogerd W, Wall E, Fortuyn M, Rodenhuis S (1998) Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. Journal of the National Cancer Institute, 90, 210218.
  • 7
    Schagen S, van Dam F, Muller M, Boogerd W, Lindeboom J, Bruning P (1999) Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer, 85, 640650.
  • 8
    Schagen SB, Muller MJ, Boogerd W, Rosenbrand RM, Rhijn D, Rodenhuis S, van Dam FS (2002) Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients. Annals of Oncology, 13, 13871397.
  • 9
    Brezden C, Phillips K, Abdolell M, Bunston T, Tannock I (2000) Cognitive function in breast cancer patients receiving adjuvant chemotherapy. Journal of Clinical Oncology, 18, 26952701.
  • 10
    Ahles TA, Saykin AJ, Furstenberg CT et al. (2002) Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. Journal of Clinical Oncology, 20, 485493.
  • 11
    O'Shaughnessy JA (2002) Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. Clinical Breast Cancer, 3(Suppl. 3), S116S120.
  • 12
    Tchen N, Juffs HG, Downie FP et al. (2003) Cognitive changes, fatigue and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer: a prospective matched cohort study. Journal of Clinical Oncology, 21, 41754183.
  • 13
    Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA (2004) The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer, 100, 22922299.
  • 14
    Meyers C (2000) Neurocognitive dysfunction in cancer patients. Oncology, 14, 7581.
  • 15
    Silberfarb PM, Philibert D, Levine PM (1980) Psychosocial aspects of neoplastic disease: II. Affective and cognitive effects of chemotherapy in cancer patients. American Journal of Psychiatry, 137, 597601.
  • 16
    Schagen SB, Hamburger HL, Muller MJ et al. (2001) Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function. Journal of Neurooncology, 51, 159165.
  • 17
    Kingma A, van Dommelen RI, Mooyaart EL, Wilmink JT, Deelman BG, Kamps WA (2001) Slight cognitive impairment and magnetic resonance imaging abnormalities but normal school levels in children treated for acute lymphoblastic leukemia with chemotherapy only. Journal of Pediatrics, 139, 413420.
  • 18
    Kibiger G, Kirsh KL, Wall JR, Passik SD (2003) My mind is as clear as it used to be: a pilot study illustrating the difficulties of employing a single-item subjective screen to detect cognitive impairment in outpatients with cancer. Journal of Pain and Symptom Management, 26, 705715.
  • 19
    Appleton RE, Farrell K, Zaide J, Rogers P (1990) Decline in head growth and cognitive impairment in survivors of acute lymphoblastic leukemia. Archives of Disease in Childhood, 65, 530534.
  • 20
    Van Oosterhout AG, Ganzevles PG, Wilmink JT, De Geus BW, Van Vonderen RG, Twijnstra A (1996) Sequelae in long-term survivors of small cell lung cancer. International Journal of Radiation Oncology and Biological Physics, 34, 10371044.
  • 21
    Ahles TA (2004) Do systemic cancer treatments affect cognitive function? Lancet Oncology, 5, 270271.
  • 22
    Riva D, Giorgi C, Nichelli F et al. (2002) Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology, 59, 4853.
  • 23
    Brown RT, Madan-Swain A, Walco GA et al. (1998) Cognitive and academic late effects among children previously treated for acute lymphocytic leukemia receiving chemotherapy as CNS prophylaxis. Journal of Pediatric Psychiatry, 23, 333340.
  • 24
    Shilling V, Jenkins V, Fallowfield L, Howell T (2003) The effects of hormone therapy on cognition in breast cancer. Journal of Steroid Biochemistry and Molecular Biology, 86, 405412.
  • 25
    Cimprich B, Ronis DL (2001) Attention and symptom distress in women with and without breast cancer. Nursing Research, 50, 8694.
  • 26
    Wefel S, Lenzi R, Theriault R, Buzdar A, Cruickshank S, Meyers C (2004) ‘Chemobrain’ in breast carcinoma? A prologue. Cancer, 101, 466475.
  • 27
    Hannay HJ, Levin HS (1985) Selective reminding test: an examination of the equivalence of four forms. Journal of Clinical and Experimental Neuropsychology, 7, 251263.
  • 28
    Almeida OP, Flicker L (2001) The mind of a failing heart: a systematic review of the association between congestive heart failure and cognitive functioning. Internal Medicine Journal, 31, 290295.
  • 29
    Allena KV, Frier BM, Strachan MWJ (2004) The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations. European Journal of Pharmacology, 490, 169175.
  • 30
    Liesker JJ, Postma DS, Beukema RJ et al. (2004) Cognitive performance in patients with COPD. Respiratory Medicine, 98, 351356.
  • 31
    Antonelli Incalzi R, Marra C, Giordano A et al. (2003) Cognitive impairment in chronic obstructive pulmonary disease. A neuropsychological and SPECT study. Journal of Neurology, 250, 325332.
  • 32
    Wilson RS, Mendes de Leon CF, Bennett DA, Bienias JL, Evans DA (2004) Depressive symptoms and cognitive decline in a community population of older persons. Journal of Neurology and Neurosurgical Psychiatry, 75, 1212612129.
  • 33
    Holland J (2001) New treatment modalities in radiation therapy. Journal of Intravenous Nursing, 24, 95101.
  • 34
    Noad R, Narayanan KR, Howlett T, Lincoln NB, Page RC (2004) Evaluation of effects of radiotherapy for pituitary tumors on cognitive function and quality of life. Clinical Oncology Royal College Radiologists, 16, 233237.
  • 35
    Keime-Guibert F, Napolitano M, Delattre J (1998) Neurological complications of radiotherapy and chemotherapy. Journal of Neurology, 245, 695708.
  • 36
    Bonadonna G, Brusamolino E, Valagussa P (1976) Combination chemotherapy as an adjuvant treatment in operable breast cancer. New England Journal of Medicine, 294, 405410.
  • 37
    Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C (1995) Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years follow-up. New England Journal of Medicine, 332, 901906.
  • 38
    Harris J, Morrow M, Norton L. (1997) Cancer of the breast. In: DeVitaVT, HellmanS, RosenbergSA, eds. Cancer: principles & practice of oncology, vol. 2, 5th edn. Philadelphia: Lippincott-Raven Publishers, 15411616.
  • 39
    Kemper E, Boogerd W, Thuis I, Beijnen JH, van Tellingen O (2004) Modulation of the blood-brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours? Cancer Treatment Reviews, 30, 415423.
  • 40
    Neuwelt EA, Barnett P, Barranger J, McCormick C, Pagel M, Frenkel E (1983) Inability of dimethyl sulfoxide and 5-fluorouracil to open the blood-brain barrier. Neurosurgery, 12, 2934.
  • 41
    MacDonell LA, Potter PE, Leslie RA (1978) Localized changes in blood-brain barrier permeability following the administration of antineoplastic drugs. Cancer Research, 38, 29302934.
  • 42
    Fenner MH, Possinger K (2002) Chemotherapy for breast cancer brain metastases. Onkologie, 25, 474479.
  • 43
    Neuwelt EA, Barnett PA, Frenkel EP (1984) Chemotherapeutic agent permeability to normal brain and delivery to avian sarcoma virus-induced brain tumors in the rodent: observations on problems of drug delivery. Neurosurgery, 14, 154160.
  • 44
    Fliessbach K, Urbach H, Helmstaedter C et al. (2003) Cognitive performance and magnetic resonance imaging findings after high-dose systemic and intraventricular chemotherapy for primary central nervous system lymphoma. Archives of Neurology, 60, 563568.
  • 45
    Rock E, DeMichele A (2003) Nutritional approaches to late toxicities of adjuvant chemotherapy in breast cancer survivors. Journal of Nutrition, 133, 3785S3793S.
  • 46
    Birge SJ (2003) The use of estrogen in older women. Clinical Geriatric Medicine, 19, 617627.
  • 47
    Cunningham RS (2003) Anemia in the oncology patient: cognitive function and cancer. Cancer Nursing, 26, 39S41S.
  • 48
    Maier SF, Watkins LR (2003) Immune-to-central nervous system communication and its role in modulating pain and cognition: implications for cancer and cancer treatment. Brain, Behavior and Immunity, 17, S125S131.
  • 49
    Pusztai L, Mendoza TR, Reuben JM et al. (2004) Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine, 25, 94102.
  • 50
    Wilson CJ, Finch CE, Cohen HJ (2002) Cytokines and cognition – the case for a head-to-toe inflammatory paradigm. Journal of the Geriatric Society, 50, 20412056.
  • 51
    Sallah S, Wan JY, Nguyen NP (2002) Venous thrombosis in patients with solid tumors: determination of frequency and characteristics. Thrombosis Haemostasis, 87, 575579.
  • 52
    Caine GJ, Stonelake PS, Rea D, Lip GY (2003) Coagulopathic complications in breast cancer. Cancer, 98, 15781586.
  • 53
    Love S. (2006) Chemobrain/cognitive dysfunction. The website for women. http://www.susanlovemd.org/faq/chemobrain/chemobrain.html (accessed on 23 March 2006).
  • 54
    Foreman J. (2003) ‘‘Chemo Brain“ leaves patients at a loss. Health sense columns, http://www.myhealthsense.com/F030701_Chemo.html .
  • 55
    Madhyastha S, Somayaji SN, Rao MS, Nalini K, Bairy KL (2002) Hippocampal brain amines in methotrexate-induced learning and memory deficit. Canadian Journal of Physiology and Pharmacology, 80, 10761084.