The Effect of Control Group in the Study of the Cognitive Effects of Chemotherapy Barbara Collins Collins, The Ottawa Hospital, Canada ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Control Groups p Many breast cancer patients report cognitive disturbances during and after their chemotherapy Neuropsychological studies yield inconsistent results Cognitive effects, when found, are subtle Detection susceptible to methodological differences among studies Prospective versus retrospective study design Number and nature of cognitive tests used Manner in which impairment is defined ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Control Groups General consensus that, in most instances, prospective ti llongitudinal it di l study t d with ith pre- and d postt treatment testing is the preferred study design In prospective designs, subjects serve as their own controls However, repeat testing associated with practice effects Practice effects may actually be larger than treatment effects themselves Thus, still need to include a control group to account for practice ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Control Groups Options: Disease-specific control group Disease-nonspecific Disease nonspecific control group Healthy control group Hi t i l controls/Published Historical t l /P bli h d norms ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Disease-Specific Control Group Advantages Controls C t l +/ +/- for f effects ff t off disease di itself it lf and dh hostt factors that may predispose to disease and cognitive dysfunction y Controls for stress and distress associated with the diagnosis Disadvantages Patients not receiving treatment of interest (e.g., chemotherapy) h th ) may b be receiving i i alternate lt t ttreatments t t that affect cognition (e.g., anti-estrogen therapy in the case of BC)) Treatment prescribed according to disease characteristics, so treatment confounded with disease ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Healthy Control Group Advantages Availability May allow better matching on key demographic variables Disadvantages Fails to account for possible confounding factors, such as constitutional risk factors, psychological distress, and disease-related cognitive changes ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Published Norms Advantages Convenience, economy May have access to larger samples (with more reliable estimate ti t off PE) Disadvantages May be no published test-retest data Difficulty achieving good match on relevant demographic variables and testing intervals May be regional differences in test performance Testing conditions such as environment, examiner less consistent between groups Limited Li it d tto published bli h d measures ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Objective of Current Study To determine if results and conclusions drawn from a prospective, longitudinal y of cognitive g function in BC p patients study would differ according to control group used ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Methods: Participants 3 groups post-menopausal women between the ages of 50 and 65 28 BC patients who received adjuvant chemotherapy (Chemo Group) 28 BC patients who received hormonal therapy but no chemotherapy (Hormonal Group) 28 healthy volunteers (Healthy Group) Chemo and hormonal groups were selected from larger samples to most yp participants p on age g and education closelyy match the 28 healthy Previous history of cancer or chemotherapy, unstable psychiatric, neurological, or substance use disorders that might affect cognition were grounds for exclusion Group Chemo p Hormonal Healthy Age – Mean (SD) Range 59.07 (3.39) 52-66 58.64 (4.23) 59.32 (4.23) 0.81 51-65 51-66 Education – Mean (SD) Range 15.96 (2.69) 12-22 15.86 (2.86) 15.93 (2.54) 0.99 12-23 12-21 ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Methods: Assessment Schedule T1 (baseline) conducted prior to initiation of chemotherapy T2 conducted ~ 1 month following last chemotherapy treatment in chemo group H Hormonal l and dh healthy lth groups assessed d att equivalent intervals Average T1-T2 interval of 5-6 months ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Methods: Assessment Battery (Source for Norms) Executive Function Verbal Memory Trails B (Levine et al al., 2004) WCST (Tate et al., 1998) CVLT-II CVLT II (Total T1 T1-T5, T5 Delayed Recall) (Delis et al., 2000) Logical Memory II (WMS-III Manual) Language Boston Naming Test (Flanagan & Jackson, 1997) COWA (Levine et al., 2004) Processing Speed Digit-Symbol Coding (WAIS-III Manual) Symbol Search (WAIS-III (WAIS III Manual) Trails A (Levine et al., 2004) Visual Memory Family Pictures II (WMS-III Manual) Visuospatial Function Block Design (WAIS-III Manual) Working Memory Arithmetic (WAIS-III Manual) Digit Span (WAIS-III Manual) ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Methods: Analysis Reliable Change Index (RCI) plus practice effects model Calculated standardized change scores for each subject on each neuropsychological measure according to the following formula: [T2 score – (T1 + PE)] / Sdiff Where PE (practice effect) = mean difference between test and retest scores in the control group Sdiff (standard error of the difference) = √2(SE)2 ; SE = S1√1-r r = correlation between test-retest scores in control group RCI calculated 3 times using scores from hormonal group healthy group, group, group and published norms norms, respectively ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Methods: Analysis RCI of –2.0 or lower criterion for decline on a given measure RCIs of -2.0 or lower on ≥ 2 measures criterion for reliable cognitive decline for a given subject Reliable cognitive improvement = RCI score greater than or equal to +2.0 on ≥ 2 measures Chi Chi-square used d tto compare frequency f off reliable li bl cognitive decline and improvement across groups When using published norms norms, frequency of cognitive decline in chemo group was compared to the expected frequency of this occurrence in a normal sample (i.e., the bi binomial i l probability b bilit off obtaining bt i i ttwo or more standardized change scores of ≤ -2.0 by chance) ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Frequency of Decline by Control Group Group Basis for RCI Chemo Control Χ2 P Hormonal Group 29% 7% 4.38 0.04 Healthy Group 21% 0% 6.72 0.01 Norms 21% 4% 4.08 0.04 No difference in frequency of decline in chemo group across control conditions: Χ2 = 0.53, p = 0.77 ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Conclusions Significantly higher rate of cognitive decline in chemo group vs controls regardless of control method used Suggests gg that “chemo fog” g q quite robust p provided that measured adequately and that practice effects, base rates and relevant demographic factors accounted for At present, may be a challenge to find suitable published test-retest test retest norms for all tests so may require local controls Byy p pooling g control data from harmonised studies,, will establish an appropriate normative database which can be used for future studies ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE Thank You! Participants! The Ontario Chapter of the Canadian Breast Cancer Foundation and their pp supporters St d Coordinator Study C di t Joyce MacKenzie, M Ps ICCTF International Cognition and Cancer Task Force Conference March 15 15--17 th 2012 – PARIS - FRANCE