NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Cognitive impairment is a common complaint among cancer survivors and may be a consequence of the tumors themselves or direct effects of cancer-related treatment (eg, radiation therapy). This symptom may be especially prominent in survivors of primary central nervous system (CNS) cancers or those with brain metastases. In addition, survivors who never had brain involvement may also report difficulties in cognition.1 For some survivors, symptoms persist over the long term.2 When more severe, the presence of cognitive dysfunction can impact quality of life and function. Cognitive dysfunction is most commonly connected with chemotherapy (sometimes referred to as “chemobrain”), but evidence suggests that therapies other than chemotherapy, such as endocrine therapy and radiation, may be associated with cognitive impairments.3-9 A recent national cross-sectional study found that a history of cancer is independently associated with a 40% increase of the likelihood of self-reported memory problems.10
Cancer-related cognitive changes have primarily been studied in patients with CNS and breast cancers and lymphoma, and those who have undergone hematopoietic stem cell transplant (HSCT), with a wide incidence ranging from 19% to 78%.2,11-24 Deficits commonly occur in the domains of executive function, learning and memory, attention, and processing speed.2,23
Growing evidence supports the patient experience of cognitive dysfunction associated with cancer and its treatment. In one meta-analysis of 17 studies, women treated with chemotherapy for breast cancer 6 or more months previously (n=807) had lower functional abilities than those not treated with chemotherapy (n=291).14 These deficits were limited to verbal (eg, word-finding) and visuospatial (eg, copying complex images) abilities. However, when compared with their prechemotherapy baseline, no differences were noted among patients complaining of cognitive dysfunction. In another study, cognitive function was compared among 196 long-term survivors of breast cancer treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) who were, on average, 21 years out from diagnosis, and 1509 control patients with no history of cancer.25 The chemotherapy group did significantly worse on several neuropsychological tests (eg, immediate and delayed verbal memory, executive functioning, psychomotor speed). Finally, one study compared 101 patients who underwent an HSCT with 82 patients treated with a nonmyeloablative therapy; both groups showed mild cognitive impairments at baseline.26 Although no significant differences in cognitive dysfunction were identified at 2-year follow-up, patients who underwent HSCT had poorer performances in several areas, including attention and executive and psychomotor functions.
The correlation between patient reports of cognitive decline and results of neuropsychological testing has not been consistently demonstrated, possibly because of various definitions of cognitive dysfunction and differences in the statistical analyses across studies.23 However, a recent study of 189 breast cancer survivors found that memory and executive function complaints, present in approximately 20% of the cohort, showed a statistically significant association with results of domain-specific neuropsychological tests.27
The underlying mechanisms that might increase the risk for chemotherapy-induced cognitive changes are not known. Studies have reported elevated levels of cytokines or DNA damage as some of the possible mechanisms.28 Structural studies have supported the hypothesis that neurotoxicity resulting in damage to white matter of the brain may play an important role in cognitive deficits after chemotherapy treatment.2,5,13,29,30 In addition, fatigue and depression, common in cancer survivors, may negatively influence cognitive function, although several studies have found that cognitive dysfunction does not correlate with mood.25,31 Psychosomatic effects can also contribute, as evidenced by a recent study of patients to be treated with chemotherapy, which found that those who were informed of the possible cognitive side effects were more likely to report cognitive dysfunction and perform worse on neuropsychological testing than uninformed patients.32 A better understanding of the mechanisms that cause cancer-related cognitive impairment is essential for the development of treatments to improve cognitive function and quality of life in patients with cancer and survivors.1,33,34
In October 2006, the International Cognition and Cancer Taskforce (ICCTF) was formed, comprising a multidisciplinary group of health professionals and health advocates. The mission of ICCTF is to advance understanding of the impact of treatment-related cognitive and behavioral functioning in patients with non-CNS cancers.35 The group recently published recommendations regarding neuropsychological testing, defining cognitive impairment/changes, and future study design.34 ICCTF also has a Web site (www.icctf.com) to provide up-to-date information to both physicians and patients seeking assistance in the management of cognitive symptoms associated with cancer treatment.
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JimHSPhillipsKMChaitS. Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol2012;30:3578–3587.
JimHSSmallBHartmanS. Clinical predictors of cognitive function in adults treated with hematopoietic cell transplantation. Cancer2012;118:3407–3416.
MeadowsMEChangGJonesJA. Predictors of neuropsychological change in patients with chronic myelogenous leukemia and myelodysplastic syndrome. Arch Clin Neuropsychol2013;28:363–374.
ScherwathASchirmerLKruseM. Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study. Psychooncology2013;22:1509–1516.
ScocciantiSDettiBCipressiS. Changes in neurocognitive functioning and quality of life in adult patients with brain tumors treated with radiotherapy. J Neurooncol2012;108:291–308.
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SyrjalaKLArtherholtSBKurlandBF. Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years. J Clin Oncol2011;29:2397–2404.
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HarderHVan GoolARDuivenvoordenHJ. Case-referent comparison of cognitive functions in patients receiving haematopoietic stem-cell transplantation for haematological malignancies: two-year follow-up results. Eur J Cancer2007;43:2052–2059.
GanzPAKwanLCastellonSA. Cognitive complaints after breast cancer treatments: examining the relationship with neuropsychological test performance. J Natl Cancer Inst2013;105:791–801.
DeprezSBillietTSunaertSLeemansA. Diffusion tensor MRI of chemotherapy-induced cognitive impairment in non-CNS cancer patients: a review. Brain Imaging Behav2013;7:409–435.
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SchagenSBDasEVermeulenI. Information about chemotherapy-associated cognitive problems contributes to cognitive problems in cancer patients. Psychooncology2012;21:1132–1135.
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WefelJSVardyJAhlesTSchagenSB. International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol2011;12:703–708.
VardyJWefelJSAhlesT. Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. Ann Oncol2008;19:623–629.
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FergusonRJMcDonaldBCRocqueMA. Development of CBT for chemotherapy-related cognitive change: results of a waitlist control trial. Psychooncology2012;21:176–186.
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GehringKRoukemaJASitskoornMM. Review of recent studies on interventions for cognitive deficits in patients with cancer. Expert Rev Anticancer Ther2012;12:255–269.
Mar FanHGClemonsMXuW. A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Cancer2008;16:577–583.
ConklinHMKhanRBReddickWE. Acute neurocognitive response to methylphenidate among survivors of childhood cancer: a randomized, double-blind, cross-over trial. J Pediatr Psychol2007;32:1127–1139.
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