Introduction and Rationale
Introduction and Rationale
Cancer is gradually emerging as leading cause of deaths in India with more than 2.5
million patients suffering from the disease.[1] This increase in incidence can either be attributed to increased lifespan and better
diagnostic techniques or it may reflect a realistic pattern due to exposure to risk
factors for cancer.
India is still grappling with overwhelmingly poor outcomes in cancer patients due
to a variety of reasons including late stages at presentation, delay in diagnosis
due to poor referral system, capricious public health-care system and infrastructure,
high abandonment rates, and lack of availability of newer drugs, whereas developed
world is now focusing on perspectives such as de-escalation of therapies, preservation
of fertility, cardiotoxicity, and cognitive issues that help cancer survivors getting
better quality of life (qol) and living a more productive life. Through this commentary,
we have focused on the aspect of cognition related to chemotherapy or cancer per se
and its relevance to India. Besides, we have also proposed the schema of studies that
need to be conducted and challenges ahead.
Cancer-induced cognitive dysfunction encompasses range of difficulties that tend to
include relatively subtle changes in memory, concentration, and executive function
that can show up in the weeks during and months after completion of cancer treatment
and persist thereafter in up to 75% of cancer patients.[2]
The etiology of cognitive deficits in cancer patients could be multifactorial (psychological
stress, occurrence of cancer itself, brain irradiation, intrathecal chemotherapy,
direct treatment for brain cancer or metastasis, and systemic chemotherapy). Its importance
lies in the significant distress in professional reintegration, interpersonal relationships,
and leisure activities. This might also affect future qol and might bring a feeling
of worthlessness.
Contemporary Evidence: Clinical
Contemporary Evidence: Clinical
Among the common tumors and in tumors in which relatively longer outcomes are expected,
cognitive deficit is found in 20%–40% patients as per various studies.[3] Cruzado et al. in a longitudinal study of FOLFOX 4 chemotherapy in colorectal patients found mild
and transient negative effect of chemotherapy on verbal memory. Surprisingly, in this
study, 37% of patients had cognitive impairment in the prechemotherapy evaluation
giving emphasis on the proposition that cancer per se might cause cognitive dysfunction.[4] Similarly, in a series of lung cancer patients, Simó et al. demonstrated cognitive impairment before and after chemotherapy. Before starting
the treatment, patients showed verbal memory deficits and widespread white matter
damage.[5] This underscores the fact that cancer patients have preexisting cognitive dysfunction
and could be hypothesized to be related to interactions between inherent metabolic
activity of cancer, systemic inflammation by cytokines, and brain function. Thus,
the baseline cognitive status (prechemotherapy) is essential so as to ascertain the
exact cognitive deficit.[6]
The occurrence of cognitive dysfunction has been replicated in variety of malignancies.
In a recent study, neuropsychological assessments were done to determine adjuvant
chemotherapy's association with cognitive dysfunction in men with nonseminomatous
germ cell tumors. The authors found significantly high risk of cognitive dysfunction
at 12 months of therapy in chemotherapy as compared to surveillance group in dose-dependent
manner.[7] Further, Jacola et al documented that attention deficits were more pronounced with higher intensity chemotherapy
in survivors of acute lymphoblastic lymphoma.[8] It can be inferred that dose/intensity and duration of treatment can affect cognition
as a direct correlate.
With these reinforcing data, it seems that cognition is a real problem and needs to
be addressed at least in cancers with good long-term outcomes.
Contemporary Evidence: Functional Magnetic Resonance Imaging and Electroencephalography
Contemporary Evidence: Functional Magnetic Resonance Imaging and Electroencephalography
Majority of the studies conducted till date have used standard neuropsychological
tests to assess cognitive deficits, pertaining to memory, attention, concentration,
learning, executive functions, and processing speed. However, magnitude of these deficits
both in terms of structural changes, leading to functional manifestations, has been
less addressed till now. Electroimaging (electroencephalography [EEG]) and neuroimaging
(functional magnetic resonance imaging [fMRI]) could serve to evaluate the cognitive
deficits and to follow up in these patients.
Several brain imaging-related studies have reported that there is a decrease in integrity
of white matter, which correlates with processing speed. Inagaki et al. studied regional brain volume difference in breast cancer patients exposed to chemotherapy
with those not exposed using MRI.[9] They reported reduced superior frontal gyri and parahippocampal gyrus volume, which
correlated with poor attention/concentration and impaired memory performance, respectively,
4 months after the completion of chemotherapy, though no change was observed 1-year
posttreatment. Recently, Jenkins et al. found reduction in the volume of subgenual, dorsal anterior cingulate and inferior
temporal gyrus in chemotherapy group.[10] Conflicting reports are available for fMRI studies in terms of hypoactivation and
hyperactivation in brain activities when breast cancer patients on chemotherapy were
compared to controls.[11]
Recently, Bruno et al. in 2012 studied resting state networks in patients of breast cancer as compared
to healthy controls using fMRI. They found that there is disrupted default mode network
in frontal, striatal, and temporal regions of the brain.[12]
Quantitative EEG can be used as a better tool not only for assessing connectivity
but also can decipher temporal dynamics. Only one pilot study has been done so far
by Moore et al. in 2014 using quantitative EEG on 16 electrode data. They studied that EEG power
measurement has the potential to provide a sensitive neurophysiologic correlate of
cancer treatment-related fatigue and cognitive dysfunction in seven pairs of case–control
breast cancer patients and found that EEG amplitude was increased in breast cancer
patients as compared to controls.[13] Further, source estimation was not done in these patients. Quantitative EEG (128
electrodes) will be an apt tool to address wide gap in the literature. It has been
shown that the application of more than 100 EEG channels is not only favorable but
also necessary to guarantee a reasonable accuracy in the calculations of cortical
source density or cortical mapping.[14] There are experimental evidence supporting that denser EEG systems can help recover
more information.[15] Brodbeck et al. showed that epileptic focus localization improved (sensitivity and specificity)
using 128 electrode arrays as compared to 32 channel arrays.[16]
Thus, using 128 channels, EEG improves localization, and as compared to MRI, it has
superlative temporal resolution as well.[17]
Mathan et al. further studied efficacy of EEG-based estimation of cognitive load among individuals
experiencing cancer-related cognitive deficits. However, the effect of chemotherapy
on cognition was not documented.[18] Pilot study results regarding the feasibility of electroencephalography biofeedback
to reduce subjective cognitive complaints for breast cancer survivors also demonstrated
significant improvements in perceived cognitive function (n = 23).[19] Thus, these modalities can be used for intervention, thereby improving prognosis
in these patients.
Indian Data and Its Implications
Indian Data and Its Implications
Unfortunately, if we dwell upon Indian statistics, there seems to be negligible research
in this area. Sequeira et al. in a case–control study of 60 patients comparing 30 patients with breast cancer
revealed a significant cognitive deficit in patients as compared to controls.[1] It is imperative to prioritize not only diagnosis and treatment but also improving
secondary outcomes such as cognition. This may be all the more important in young
patients, wherein cognitive deficit may ruin their qol both personally and professionally.
The impact of cancer and cancer treatment on health-care costs is not only due to
direct cost incurring due to treatment but also due to indirect costs pertaining to
loss of days from work both during and after treatment (due to iatrogenic causes).
Moreover, the intangible cost like suffering for both the patient and the caregiver
are difficult to measure.
Thus, onco-economics does cause a significant burden on nation and individual (especially
in country like India where there is a lack/limited health insurance). Addressing
them at the appropriate time may help them in decision-making process during chemotherapy
and significantly improve their qol.
What next?
The question arises as to what strategies must be undertaken to bridge the gap between
what is done and what needs to be done so as to improve both diagnosis and prognosis
of the patient during and after therapeutic interventions. First of all, awareness
about cognitive effects to both health providers and patients/caregivers so that appropriate
remedial measures may be taken to improve the outcome. Second, task force may be formed
to address the secondary outcomes of cancer survivors. Last but not least, funding/
grants to investigators to carry out research addressing secondary outcomes may work
hand in hand to complement conventional diagnosis and treatment.
Such strategies have the potential of improving cognitive deficits due to chemotherapy/cancer
and may secondarily provide more satisfaction and better onco-economics in cancer
survivors.
Keeping this in mind, we aim to initiate our research on cognition and cancer and
we welcome collaborators who share similar vision.
