Cognitive Impairment in Long-Term Survivors of Testicular Cancer More Than 20 Years after Treatment

Johannes Stelwagen, Andrea T Meuleman, Sjoukje Lubberts, Gerrie Steursma, Lara M Kruyt, Jan W Donkerbroek, Coby Meijer, Annemiek M E Walenkamp, Joop D Lefrandt, Sandra E Rakers, Rients B Huitema, Marianne A A de Jong, Erwin M Wiegman, Alfons C M van den Bergh, Igle J de Jong, Joost A Agelink van Rentergem, Sanne B Schagen, Janine Nuver, Jourik A Gietema, Johannes Stelwagen, Andrea T Meuleman, Sjoukje Lubberts, Gerrie Steursma, Lara M Kruyt, Jan W Donkerbroek, Coby Meijer, Annemiek M E Walenkamp, Joop D Lefrandt, Sandra E Rakers, Rients B Huitema, Marianne A A de Jong, Erwin M Wiegman, Alfons C M van den Bergh, Igle J de Jong, Joost A Agelink van Rentergem, Sanne B Schagen, Janine Nuver, Jourik A Gietema

Abstract

Background: Impaired cognition can be a late effect after treatment in long-term testicular cancer (TC) survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very long-term TC survivors after CT or RT and compared the results with stage I TC survivors and controls.

Methods: In this cross-sectional multicenter cohort study, we enrolled TC survivors (treated with orchiectomy followed by CT or RT or orchiectomy only)-with a follow-up duration ≥ 20 years-and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, Category Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular aging parameters, including carotid pulse wave velocity (c-PWV) and advanced glycation end products (AGEs).

Results: We included 184 TC survivors (66 CT patients, 53 RT patients, and 65 orchiectomy-only patients) and 70 healthy controls. The median follow-up was 26 years (range: 20-42). TC survivors had a lower combined score of the cognitive tests (mean cumulative Z-score -0.85; 95% CI -1.39 to -0.33) compared to controls (mean 0.67; 95% CI -0.21 to 1.57, p < 0.01). In univariate analysis, the presence of hypogonadism (β -1.50, p < 0.01), high c-PWV (β -0.35, p = 0.09), and high AGEs (β -1.27, p = 0.02) were associated with lower cognitive scores, while only AGEs (β -1.17, p = 0.03) remained a significant predictor in multivariate analysis (Model R2 0.31, p < 0.01).

Conclusions: Long-term TC survivors performed worse on cognitive tests compared to controls. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment.

Trial registration: NCT02572934.

Keywords: cancer survivors; late toxicity; neurocognitive impairment; testicular cancer.

Conflict of interest statement

J.A.G. has received grants from Abbvie, Roche and Siemens, paid to the institution, outside the submitted work. All remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Consort diagram. The institutional database of testicular cancer patients treated at the University Medical Center of Groningen (UMCG) was used to identify testicular cancer survivors (TCS) treated with chemotherapy (CT). Patients were randomly selected and screened for inclusion. Eligible CT patients were approached if they were still alive and met the inclusion criteria:

Figure 2

Median Z-scores and 95% confidence…

Figure 2

Median Z-scores and 95% confidence intervals—calculated from normative means derived from the Advanced…

Figure 2
Median Z-scores and 95% confidence intervals—calculated from normative means derived from the Advanced Neuropsychological Diagnostics Infrastructure (ANDI)—for testicular cancer survivors (red) and healthy controls (blue). Abbreviations: AVLT, auditory verbal learning test; AVLT DR, auditory verbal learning test delayed recall; LFT, letter fluency test; CFT, category fluency test; TMT, trail making test. TC survivors scored worse than controls on the AVLT (mean Z-score −0.41 (95% CI: −0.54 to −0.28) vs. −0.04 (95% CI: −0.24 to 0.16), p < 0.01), the LF (mean Z-score −0.27 (95% CI: −0.40 to −0.14) vs. −0.02 (95% CI: −0.25 to 0.21), p = 0.04), and on both categories of the CFT (animals: mean Z-score −0.31 (95% CI: −0.43 to −0.19) vs. 0.03 (95% CI: −0.19 to 0.25), p < 0.01, profession: mean Z-score −0.33 (95% CI: −0.46 to −0.19) vs. 0.15 (95% CI: −0.14 to 0.43), p < 0.01).

Figure 3

Sum of Z-scores on cognitive…

Figure 3

Sum of Z-scores on cognitive tests per study group. Each dot represents the…

Figure 3
Sum of Z-scores on cognitive tests per study group. Each dot represents the sum of Z-scores on all cognitive tests for one individual. Bars represent median and 95% confidence intervals. Median sum of Z-scores was worse for TC survivors (mean −0.85; 95% CI −1.39 to −0.33) compared to the controls (mean 0.67; 95% CI −0.21 to 1.57, p < 0.01). No statistically significant differences were found between different treatment modalities for TC. Abbreviations: NS, not significant; TCS, testicular cancer survivors; CT, chemotherapy group; RT, radiotherapy group.
Figure 2
Figure 2
Median Z-scores and 95% confidence intervals—calculated from normative means derived from the Advanced Neuropsychological Diagnostics Infrastructure (ANDI)—for testicular cancer survivors (red) and healthy controls (blue). Abbreviations: AVLT, auditory verbal learning test; AVLT DR, auditory verbal learning test delayed recall; LFT, letter fluency test; CFT, category fluency test; TMT, trail making test. TC survivors scored worse than controls on the AVLT (mean Z-score −0.41 (95% CI: −0.54 to −0.28) vs. −0.04 (95% CI: −0.24 to 0.16), p < 0.01), the LF (mean Z-score −0.27 (95% CI: −0.40 to −0.14) vs. −0.02 (95% CI: −0.25 to 0.21), p = 0.04), and on both categories of the CFT (animals: mean Z-score −0.31 (95% CI: −0.43 to −0.19) vs. 0.03 (95% CI: −0.19 to 0.25), p < 0.01, profession: mean Z-score −0.33 (95% CI: −0.46 to −0.19) vs. 0.15 (95% CI: −0.14 to 0.43), p < 0.01).
Figure 3
Figure 3
Sum of Z-scores on cognitive tests per study group. Each dot represents the sum of Z-scores on all cognitive tests for one individual. Bars represent median and 95% confidence intervals. Median sum of Z-scores was worse for TC survivors (mean −0.85; 95% CI −1.39 to −0.33) compared to the controls (mean 0.67; 95% CI −0.21 to 1.57, p < 0.01). No statistically significant differences were found between different treatment modalities for TC. Abbreviations: NS, not significant; TCS, testicular cancer survivors; CT, chemotherapy group; RT, radiotherapy group.

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