An important issue to consider is that not all individuals will display similar cognitive impairments even if undergoing the same regimen. Every individual is unique and his or her response to drugs and the type of cancer they have will alter the treatment received. It should also be noted that chemotherapy drugs are administrated as part of a complete regimen, with other medications included in order to reduce side effects; how these medications interact and effect cognition makes the results of clinical testing almost impossible to interpret. In terms of neurocognitive testing itself, there are many studies that examine the domains and the types of tests used5,11,27–29,31–33,44,45
for those in the post-chemotherapy phase. In the more than 50 studies that have been conducted to examine the long-term effects of chemotherapy, only a handful have included visual-spatial tasks; these types of tasks are paradigms that can be used to translate between clinical and pre-clinical models. Those tests that have been used have included the Block Design test, which is a subtest of Wechsler’s Adult Intelligence Scale-III that uses colored blocks to represent a design (), and the Rey-Osterrieth Complex Figure Test (RCFT), a memory test that is used to assess visuospatial construction or Visual Reproduction a subtest of the Wechsler’s Memory Scale—Revised (WMS-R) ().46–50
The results of these studies do not agree on whether chemotherapy impacts long-term visual-spatial memory, but the tasks used vary significantly and are, it should be noted again, not translatable to pre-clinical models ().
Chemotherapy and visual spatial impairments in humans.
The Morris water maze (MWM)51
is the most commonly used and recognized spatial learning and memory test used for the pre-clinical assessment of drug use and various confounding factors such as genetics, age, and gender, assessing these both in terms of acute and long-term learning and memory effects (). This rodent based test has been use for the understanding of the mechanism of neuro-physiological/neuro-anatomical changes and can be used to assess learning and memory in a way that is translatable to humans. The drugs that are part of the CMF regimen have been studied extensively in animals in terms of their acute and long-term cognitive effects using the MWM task. Examination at 7 days and 1 month after a single intravenous injection of methotrexate induced impairments in a MWM probe trial and delayed memory performance and novel object recognition.13,14
In mice injected intraperitoneally (i.p.) weekly with methotrexate, impairments were apparent in initial hidden spatial memory in a MWM.52
There have also been studies in pre-clinical models that have not shown there to be long-term cognitive impairments in animals that perform the MWM after repeated treatments with CMF.53,54
Of all these experiments, time between exposure and testing, number of injections, and type of test varied significantly. More consistency between studies is needed to definitively determine whether this paradigm mimics the cognitive effects seen in humans.
Figure 2 A representation of the Morris Water Maze (MWM) and Memory Island (MI) program translation between rodent and human tasks. (A) Diagram of the MWM pool and a representative path that a rodent takes to reach the platform. After chemotherapy treatment, rodents (more ...)
Additional medications are administered for women with estrogen positive cancers, including taxol (tamoxifen), which is an estrogen receptor modulator (SERM). Compared to women on chemotherapy alone, those women who received chemotherapy and tamoxifen scored lower in visual memory and verbal working memory ().47,49,55
A follow-up study of women who continued to take taxomifen for at least 5 years after chemotherapy treatment as a prevention measure also found that they faired negatively when compared to non-tamoxifen users, with more complaints of memory problems and reduced scores on narrative writing task.56
In rodent models, repeated administration of tamoxifen or combinations of methotrexate and 5-FU injections both produced deficits in acquisition and retention in an operant learning paradigm.57
Although the tests are not comparable, they indicate that secondary treatments are a potential confounding factor to consider when assessing post-chemotherapy neurocognitive side effects. Evidence supports that secondary drugs such as raloxifene, letrozole or exemestane (SERM/aromatase inhibitors) may be better alternatives to the more commonly used tamoxifen, as they appear to have fewer or no confounding side-effects on overall cognitive health.55,58–62
Although these drugs are newer to the market, they tend to be more expensive and as only a few studies are available, both doctors and patients have to consider options and weigh risks.
Today’s technology is advancing and so are the available methods of assessing learning and memory impairments. Using human versions of visual-spatial memory tasks such as the “Memory Island” (MI) program is a useful way of helping to transition from pre-clinical models to a clinical setting (). MI is a virtual reality program designed to mimic the MWM four-quadrant coordinate system. In MI, individuals find both visible (marked) and hidden targets on a virtual island designed by Dr. Jacob Raber (Oregon Health Science University) and Dean Inman (Oregon Research Institute) ().63
Performance measures are the same as in MWM, wherein distance, latency, velocity, and distance from the target can be assessed. MI examines motor coordination, working memory, picture recognition, visual-spatial memory, and verbal/non-verbal ability.63–66
MI can also be an appropriate measure of visual-spatial learning and memory suitable for use in multiple (non-English speaking) cultures, as it is considered a non-verbal test.66
MI adequately assesses depth perception, visual-spatial attention, figure-ground discrimination, spatial perception, and orientation.63–66
Furthermore, these types of paradigms can be utilized as quantitative and qualitative measures in research projects or for clinical screening following traumatic brain injury, as well as in the assessment of Alzheimer’s disease or other neurodegenerative conditions. Additionally, there are other tests that result in data that are easily translatable to clinical settings; these include Novel Image/Novel Location tasks, which examine spatial picture location recognition and are used to model novel object recognition in pre-clinical models.63,65,66
There have also been significant advances in touch screen technology to translate rhesus monkey working memory tasks into clinical assessments.67,68
Determining the long-term cognitive deficits that result from chemotherapy remains an urgent need and one that can be fulfilled through the use of translational paradigms.
In breast cancer survivors who were a minimum of 1 year post-chemotherapy (mixed regimens), a study found reduced performance in MI performance measures in terms of both immediate and delayed spatial memory when compared to health controls ().66
The breast cancer survivors were able to learn the tasks to a similar degree as the controls, but took longer to find the targets once the visible cues were gone (hidden trials).66
After 15 minutes in the delayed memory trial, only 50% of the breast cancer survivors were able to find the target compared to the 82% of healthy controls that were able to do so ().66
The results are similar to those found in the rodent model of long-term chemotherapy exposure.14,15
The study also found that particular coping strategies were associated with MI performance. Those that use emotional coping displayed reductions in learning and immediate MI performance when compared to those who use more problem-focused coping.66
Those that used problem-focused coping also performed better in delayed spatial memory performance, had higher general intelligence scores, and showed an increased ability to perform psychomotor speed tasks. Understanding the link between coping and cognition can help in the development of behavioral therapies to help patients resume normal functioning. Although this was only a pilot study and did not account for pre-chemotherapy differences, it does help to validate the use of MWM in pre-clinical testing for the assessment of the cognitive effects of chemotherapy drugs. Future longitudinal studies will include more subjects to assess different chemotherapy regimen effects as well as genetic, age-related, and other potential confounders.