HI-CT CON-CT RT-only HC

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
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* A HI-CT
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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
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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