Late eﬀects of cancer treatment on cogni+on and brain func+on in breast cancer survivors M.M. Stouten-‐Kemperman1,2, M.B. De Ruiter1,2, W. Boogerd3, L. Reneman2, S.B. Schagen1 Introduc+on Adjuvant chemotherapy (CT) for breast cancer (BC) is associated with cogniDve problems and brain funcDon alteraDons (Wefel & Schagen, 2012). In our previous mulDmodality study (de Ruiter et al., 2011, 2012), we assessed BC survivors who received high-‐dose CT (HI-‐CT) or radiotherapy (RT-‐only) 10 years earlier. In the current study, we examined neurotoxicity proﬁles of diﬀerent treatment strategies by extending our measurements to BC survivors who received convenDonal-‐
dose CT (CON-‐CT) ≥10 years earlier and healthy controls (HC). The BC survivors treated with CT were randomized to HI-‐CT or CON-‐CT. We aim at inves+ga+ng the late eﬀects of cancer treatment and its possible underlying mechanisms by comparing CT groups, and by comparing CT to RT-‐only and RT-‐only to HCs on neuropsychological and fMRI measurements. Methods Study popula+on: Study populaDon characterisDcs are summarized in Table 1. Measures: •  Comprehensive neuropsychological tesDng on average 2 months post-‐treatment (M1) and >10 years post treatment (M2). Calculate relaDve decline (# tests improved-‐# tests declined) •  3T MRI (FLAIR, T1, diﬀusion tensor imaging (DTI), fMRI, MR spectroscopy). •  An fMRI-‐adapted Tower of London (TOL, Figure 1A) and Paired-‐Associate paradigm (PA, Figure 1B) to measure execuDve funcDoning and memory (Figure 1). Results 0.84
0.82
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0.78
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0.72
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0.66
* A HI-CT
CON-CT
14
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* 10
RT-only
HC
* 8
6
4
B 2
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CON-CT
RT-only
HC
Count the number of steps
Neuropsychological assessment (Table 1) The percentage of parDcipants showing cogniDve impairment was 26.3% (Hi-‐CT), 12.5% (CON-‐CT), 0% (RT-‐only) and 3.7% (HC). Comparing M1 and M2, we found that relaDve cogniDve decline was present in 10.5% of the HI-‐CT paDents, 8.3% of the CON-‐CT and 6.7% of the RT-‐only paDents, whereas no cogniDve decline was found in the HC group. Sixty percent of the HI-‐CT (n=3) and 66.7% of the CON-‐CT paDents (n=2) who demonstrated late cogniDve impairment on M2 were also idenDﬁed as cogniDvely impaired on M1. Task performance
TOL (Figure 2A/2B, p<.05) •  HI-‐CT worse performance compared to RT-‐only. •  HI-‐CT and CON-‐CT faster reacDon Dmes than RT-‐only. Goal Start ß 2 A 0.3
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Figure 2 % Correct and reacDon Dmes (seconds) of (A,B) TOL and % correct of (C) retrieval per group. *p<.05
Paired associates (only retrieval in Figure 2C, p<.05) •  HI-‐CT group marginally worse performance (hits-‐false alarms) on retrieval compared to CON-‐CT and RT-‐only.
fMRI TOL & Paired associates (Figure 3A/B, considered sta@s@cally signiﬁcant at p<.001) •  HypoacDvaDon was found for HI-‐CT compared to CON-‐CT. •  HypoacDvaDon was found for both CT-‐groups vs. RT-‐only. •  HyperacDvaDon was found for RT-‐only compared to HC. A A) Tower of London paradigm and B) Paired Associates paradigm Table 1.
CharacterisDcs and cogniDve measures of the study populaDon.
N Age IQ (NART) Time since CT Cognitive impairment, n patients impaired M1 B Figure 3 Main task eﬀect and group diﬀerences for A) TOL and B) PA Encoding > low-‐level baseline (at p<.005 to show extent acDvaDon). Conclusion B Figure 1 Mean (SD) 0.4
0.35
3 à Cognitive impairment, n of patients impaired
M2 Cognitive impairment, n of patients declined
from M1-M2 Cognitive impairment, n of patients impaired
M2 who were also impaired on M1 Cognitive impairment, n of patients impaired
M2 according to ICCTF criteria HI-CT CON-CT RT-only HC 17 24 15 27 56.3 (5.5) 59.8 (6.3) 58.2 (5.8) 60.3 (4.8) 101.1 (17.9) 100.6 (13.1) 100.7 (17.3) 108.6 (14.1) 9.5 (0.8) 13.4 (0.7) NA NA 5 (26.3%) 4 (16.7%) 0 1 (3.7%) 5 (26.3%) 3 (12.5%) 0 1 (3.7%) 2 (10.5%) 2 (8.3%) 1 (6.7%) 0 3 (60%) 2 (66.7%) 0 0 10 (52.6%) 10 (41.7%) 8 (53.3%) 7 (25.9%) Our ﬁndings suggest diﬀerent neurotoxicity proﬁles for CT and RT-‐only, with HI-‐CT being more neurotoxic than CON-‐CT. We found a CT associaDon with late cogniDve impairment and the presence of late sustained cogniDve decline. fMRI measures show a possible mechanism of gradual hypoacDvaDon aGer CT combined with worse performance, depending on intensity type of CT. However, RT-‐only survivors are able to perform at a similar level as HC while showing hyperacDvaDon. This gives rise to the idea that paDents who received CT may be unable to compensate for their worse performance as a result of impaired brain funcDoning due to the late eﬀects of CT, whereas RT-‐only paDents need to devote greater corDcal resources for good performance, thereby performing less eﬃcient. Wefel, J. S., and Schagen, S. B. (2012),’Chemotherapy-‐related cogniDve dysfuncDon’ Current Neurology and Neuroscience Reports; de Ruiter et al. (2012), ‘Late eﬀects of high-‐dose adjuvant chemotherapy on white and gray mamer in breast cancer survivors: converging results from mulDmodal magneDc resonance imaging’, Human Brain Mapping. [email protected] 1 Division of Psychosocial Research and Epidemiology, The Netherlands Cancer InsDtute, Amsterdam, the Netherlands 2 Department of Radiology, Academic Medical Center, University of Amsterdam, the Netherlands 3 Department of Neuro-‐Oncology, Netherlands Cancer InsDtute, Amsterdam, the Netherlands