|Year : 2020 | Volume
| Issue : 3 | Page : 569-571
Impact of systemic therapies on cognition in patients with primary brain tumors
Debnarayan Dutta1, Rakesh Jalali2
1 Department of Radiation Oncology, Amrita Institute of Medical Science, Kochi, Kerala, India
2 Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
|Date of Submission||01-Aug-2020|
|Date of Decision||04-Aug-2020|
|Date of Acceptance||05-Aug-2020|
|Date of Web Publication||19-Sep-2020|
Apollo Proton Centre, 100 Feet Road, Taramani, Chennai - 600 041, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Dutta D, Jalali R. Impact of systemic therapies on cognition in patients with primary brain tumors. Cancer Res Stat Treat 2020;3:569-71
Chemotherapy-related cognitive impairment (CRCI) also known as “chemo brain,” is characterized by a decline in various neuropsychological functions after systemic therapies. It may also be caused by other anticancer treatments such as radiation therapy and surgery. It is well known that cognitive impairment may occur in patients with cancer even before administering anti-cancer treatment, such as systemic therapies, and therefore, may not be solely related to chemotherapeutic agents. Therefore, a more appropriate term for this condition would be “cancer-related cognitive dysfunction” (CRCI). In any case, CRCI is relatively less explored in general, and there is no consensus on its exact definition. Moreover, definitive diagnostic criteria and a well-defined prevention protocol have not been clearly established. However, in recent years, the advancements in cancer treatment have led to an improvement in survival rates. As a result, CRCI is gaining increased recognition as a serious survivorship issue.
“Chemo brain” or CRCI has been hitherto largely addressed in breast cancer, colon cancer, and lymphomas, mainly in relation to alkylating agents such as cyclophosphamide, antimetabolites such as methotrexate, and topoisomerase inhibitors such as taxanes., The exact mechanism of the causation of CRCI is still debated. A common hypothesis espouses that anticancer agents impair the self-renewal potential of neural progenitor cells and chromatin remodeling in the hippocampus. Carmustine (BCNU), cisplatin, and cytarabine impair the neural precursor cells, whereas carmustine, methotrexate, and cytarabine reduce the neural stem cell populations located in the subventricular zone and the dentate gyrus. In addition, there are preclinical animal model data demonstrating the shrinkage of the hippocampus after the use of various chemotherapeutic agents. Genetic predisposition and demographic (ethnic) variations may also play a role in the occurrence of CRCI. A National Health and Nutrition Examination Survey found difficulty in memory recall and confusion rates to be of the order of 14% in patients with a history of chemotherapy and 8% in those not receiving systemic therapy.
In patients with primary brain tumors per se, the role of chemotherapy in cognitive function impairments appears to be far more complex. The various confounding factors, including the site of the lesion, type of surgery, radiation therapy, its dose schedule, the type of radiation therapy, amount of residual disease, disease status after treatment, pretreatment cognitive function status, additional deficits after surgery, neuroendocrine status, recurrence/progression of the disease process, and many more may obscure the actual contribution of any modality including systemic therapies to cognitive functional impairment. Sparing of the hippocampus and the left temporal lobe has already been shown to preserve the cognitive function in patients with brain tumors.,,
The present work by Adak et al. published in this issue is a cross-sectional study on 100 consecutive patients with primary brain tumors treated with systemic therapy. The cognitive function of these patients was assessed using a Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire. Various treatment- and patient-related parameters were evaluated with FACT domain scores. The majority of the patients in the cohort were young (median age, 39 years), educated (42% university graduates), and with a diagnosis of high-grade gliomas (HGGs) (71%). A proportion of patients (12%) also received re-radiation. The most commonly used systemic therapy agent was temozolomide (TMZ), followed by the procarbazine, lomustine, and vincristine (PCV) regimen. The authors found that the mean scores calculated for the perceived cognitive impairment (CogPCI), the impact of perceived cognitive impairment on quality of life (QOL) (CogQOL), comments from others (CogOth), and perceived cognitive abilities (CogPCA) were lower in the chemotherapy cohort as compared to the expected scores in the normal population. No significant association was, however, observed between the various subscales of FACT-Cog and the factors such as older age (>60 years), gender, education, and the affected lobe (frontal, temporal, and parietal). The present study is unique and has evaluated the cognitive function domain scores in Indian patients with primary brain tumors treated with systemic therapy, and the investigators must be complimented for undertaking such a study. Data from the study will act as a suitable template to embark on an appropriately designed prospective study in a larger patient cohort, and the inclusion of confounding factors in the analysis will eliminate the present limitations. CRCI reporting is relatively sparse, even in patients treated in the west.,, High-dose methotrexate in primary CNS lymphoma has been shown to impact a few cognitive domains and may also be responsible for encephalomalacia. In craniospinal radiation, chemotherapy is added, and the radiation dose reduced to improve the cognitive function. In a prospective study on patients with low-grade gliomas (LGGs), the impact of PCV on cognitive function domains was evaluated. There were no decline in the Mini-Mental State Examination scores of the patients with LGG treated with PCV alone when compared to those treated with radiation therapy alone. In LGG, TMZ was not only successful in terms of extending the survival duration but also showed proven efficacy in maintaining or even improving the health-related QOL. PCV has not shown any detrimental impact on the health-related QOL domain scores in long-term follow-up. A prospective phase II study evaluated the cognitive function of patients with anaplastic astrocytomas and oligodendroglioma treated with PCV after radiation therapy. About 10% of the patients developed serious neurological function deterioration and dementia. The evaluation of cognitive function in a small cohort of patients with glioblastoma multiforme treated with concomitant TMZ and radiation therapy revealed that the cognitive function was preserved till progression. In the RTOG 0825 randomized study evaluating the role of bevacizumab (BVZ) in HGG, no survival benefit was observed. In the BVZ arm, however, in addition to worsening of hypertension, thromboembolic events, intestinal perforation, and neutropenia, the QOL and neurocognitive function also showed a decline.
The impact of chemotherapy on cognitive function in patients with primary brain tumors is complex. Several patient-related confounding factors such as the location and type of the tumor, type of surgery, radiation schedule, type of radiation therapy, and radiation dose to critical structures (hippocampus and left temporal lobe) influence the cognitive function scores. The timing of the assessment, assessment modules used, frequency of assessment, and the educational and economic status of the patients also influence the cognitive function scores. The impact of the cognitive function domain scores in routine clinical practice is different from that in a trial setting. In a relatively large Indian study, including patients with HGG treated with TMZ and other systemic therapies, where the QOL was assessed using the EORTC scales, most of the domains, including cognitive scores were similar compared to those observed in the patients from the west. In addition, it was seen that patients with lower pretreatment cognitive domain scores showed a further decline in the cognitive function domain scores after treatment, whereas patients with preserved cognitive function before treatment had relatively preserved functions after treatment as well. The FACT questionnaire requires less time, can be done by less trained personnel, and has relatively easy to evaluate domain scores. Nevertheless, it has some limitations related to scoring and issues with frequent repetition of the test.
Individuals with an adequate cognitive reserve may have the ability to overcome any detrimental effects of systemic therapy and other treatments by increasing the activity of some parts of the brain. This is called “cognitive compensation.” In this phenomenon, another part of the brain may take up the activity of the “diseased” brain region and blur the effect of chemotherapy on the declining cognitive function. Cognitive rehabilitation and strengthening may reinforce “cognitive compensation” and preserve cognitive function. Several pharmacologic interventions such as methylphenidate (CNS stimulant), donepezil (ACEesterase inhibitor), and memantine (NMDA inhibitor antagonist) have shown promising early outcome data in preserving cognitive function.
Molecular signatures may also influence the impact of treatment on cognitive function decline. Patients with glioma with IDH1 mutation have been shown to exhibit less cognitive impairment than their wild-type counterparts after treatment. The status of APOE ε4 allele (risk factor for Alzheimer's disease), catechol-O-methyl transferase, brain-derived neurotrophic factor, and dystrobrevin-binding protein 1 (DTNBP1) genes may influence cognitive function domain scores after systemic therapy. However, the clinical evidence is still insufficient and needs validation from prospective studies.
In summary, the role of chemotherapy-induced cognitive impairment in primary brain tumors is not well explored. Adak et al.'s study is an intriguing one and provides data in this relatively unexplored area of research. Studies such as these are suitable bases for carrying out further prospective longitudinal work on Indian patients with brain tumors treated with systemic therapy.
| References|| |
Jim HS, Phillips KM, Chait S, Faul LA, Popa MA, Lee YH, et al
. Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol 2012;30:3578-87.
Coomans MB, Van der Linden SD, Gehring K, Taphoorn MJ. Treatment of cognitive deficits in brain tumour patients: Current status and future directions. Curr Opin Oncol 2019;31:540-7.
Cascella M, Di Napoli R, Carbone D, Cuomo GF, Bimonte S, Muzio MR. Chemotherapy-related cognitive impairment: Mechanisms, clinical features and research perspectives. Recenti Prog Med 2018;109:523-30.
Seigers R, Fardell JE. Neurobiological basis of chemotherapy-induced cognitive impairment: A review of rodent research. Neurosci Biobehav Rev 2011;35:729-41.
Briones TL, Woods J. Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC Neurosci 2011;12:124.
Jean-Pierre P, Winters PC, Ahles TA, et al
. Prevalence of self-reported memory problems in adult cancer survivors: A national cross-sectional study. J Oncol Pract 2012;8:30-4. doi:10.1200/JOP.2011.000231.
Goda JS, Dutta D, Krishna U, et al
. Hippocampal radiotherapy dose-constraints for predicting long-term neurocognitive outcomes: Mature data from a prospective trial in young patients with brain tumors [published online ahead of print, 2020 Mar 30]. Neuro Oncol. 2020;noaa076. doi:10.1093/neuonc/noaa076.
Jalali R, Gupta T, Goda JS, Goswami S, Shah N, Dutta D, et al
. Efficacy of Stereotactic Conformal Radiotherapy vs Conventional Radiotherapy on Benign and Low-Grade Brain Tumors: A Randomized Clinical Trial. JAMA Oncol 2017;3:1368-76.
Adak S, Singh GK, Menon N, Dale O, Srinivas S, Das S, et al
. Cognitive score in patients with primary brain tumors undergoing systemic therapy-a cross-sectional study. Cancer Res Stat Treat 2020;3:455-60. [Full text]
Prabhu RS, Won M, Shaw EG, Hu C, Brachman DG, Buckner JC,et al
. Effect of the addition of chemotherapy to radiotherapy on cognitive function in patients with low-grade glioma: Secondary analysis of RTOG 98-02. J Clin Oncol 2014;32:535-41.
Hilverda K, Bosma I, Heimans JJ, Postma TJ, Peter Vandertop W, Slotman BJ, et al
. Cognitive functioning in glioblastoma patients during radiotherapy and temozolomide treatment: initial findings. J Neurooncol 2010;97:89-94. doi: 10.1007/s11060-009-9993-2.
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al
. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N
Engl J Med 2014;370:699-708.
Budrukkar A, Jalali R, Dutta D, Sarin R, Devlekar R, Parab S. Prospective Quality of Life assessment using EORTC QLQ 30 and brain cancer module (BN 20) in 257 consecutive adult patients with primary brain tumours in a typical Neuro-Oncology clinic in India. J Neurooncol 2010;95:413-9.
Taphoorn MJ, Stupp R, Coens C, Osoba D, Kortmann R, Bent MJ, et al
. Health-related quality of life in patients with glioblastoma: A randomised controlled trial. Lancet Oncol 2005;6:937-44.
Kesler SR, Noll K, Cahill DP, Rao G, Wefel JS. The effect of IDH1 mutation on the structural connectome in malignant astrocytoma. J Neurooncol 2017;131:565-74.
Correa DD, Satagopan J, Cheung K, Arora AK, Kryza-Lacombe M, Xu Y, et al
. COMT, BDNF, and DTNBP1 polymorphisms and cognitive functions in patients with brain tumors. Neuro Oncol 2016;18:1425-33.