Platinum, polymorphisms, and personality: Impact on long-term neurotoxicity

Abstract

5036 Background: The reasons for the large inter-individual variation of chemotherapy-induced neuro- and ototoxicity (cNTX) are poorly understood. We aim to comprehensively assess the impact of age, cumulative dose of cisplatin (cdCis), polymorphic Glutathione S- transferase P1 (pGST-P1), and neuroticism on long-term cNTX in testicular cancer survivors (TCSs). Methods: A total of 635 TCSs had participated in a long-term follow-up survey (238 had received cisplatin-based chemotherapy [CisTCSs] and 397 were treated by surgery and/or radiotherapy [SurRadTCSs]). Self-reported neurotoxic symptoms (4 item-scores: 0: not at all; 1: a little; 2: quite a bit; 3: very much) and audiometrically assessed hearing impairment (6-categories according to population-based age-adjusted percentiles) were the primary outcome variables. Hearing results >75th percentile and self-reported item scores >2 were considered major symptoms. Lymphocyte-derived DNA was analyzed for pGSTP1 (functional A ⟶G polymorphism at bp 304). Neuroticism, i.e. the tendency to focus on negative events, was defined by scores > 5 of Eysenck’s shortened Personality Inventory (range 0- 6). Neurotoxicity and its associations with age, cdCis, neuroticism, and pGST-P1 were assessed by ordinal logistic regression analysis. Results: Major symptoms were significantly more prevalent in CisTCSs (18.1–34.0%) than in SurRadTCSs (9.6–20.6%). In SurRadTCSs age and neuroticism, but not pGST-P1 (data not shown), were significantly associated with self-reported symptoms. In CisTCSs cNTX was associated - in varying combinations - with age, cdCis, pGST-P1, and neuroticism. Age and neuroticism impacted significantly on tinnitus in SurRadTCSs. In CisTCSs however, only cdCis and pGST-P1 were associated with tinnitus and objective hearing impairment. Conclusions: Both age, cdCis, neuroticism and pGST-P1 explain inter-individual differences of long-term cNTX in TCSs. Disentangling of- and adjustment for these factors require large and homogeneous groups of cancer survivors. Age, neuroticism, cisplatin, and pGST-P1 in relation to neurotoxicity Self-reported symptoms and objective hearing impairment Cisplatin-treated TCSs (CisTCSs) (n=238; 67 TCS did not participate in audiometric examinations) Cisplatin-naïve TCSs (SurRadTCSs) (n=397; 24 TCS did not participate in audiometric examinations) Major symptoms Age (OR for decadal steps) Cisplatin (OR steps of 100 mg/m2) Neuroticism (present vs. absent) GSTP1 (GG vs. AA/AG as Reference) Major symptoms Age (OR for decadal steps) Neuroticism (present vs. absent) N (%) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) N (%) OR (95%CI) OR (95% CI) Paresthesias fingers 43 (18.1%) 1.2 (0.9–1.6) 1.0 (0.9–1.3) 2.3 (1.3–4.1) 1.9 (0.9–4.0) 46 (11.6%) 1.3 (1.1–1.7) 2.4 (1.5–3.9) Paresthesias toes 58 (24.4%) 1.8 (1.4–2.3) 1.3 (1.1–1.5) 3.0 (1.7–5.3) 2.1 (1.0–4.5) 58 (14.6%) 1.5 (1.3–1.8) 2.3 (1.4–3.8) Raynaud’s Phenomenon fingers 81 (34.0%) 1.2 (0.9–1.61) 1.1 (1.0–1.4) 2.3 (1.3–3.9) 1.0 (0.5–1.9) 55 (13.9%) 1.1 (09–1.3) 1.5 (1.0–2.5) Raynaud’s Phenomenon toes 70 (29.4%) 1.30 (1.0–1.7) 1.3 (1.1–1.6) 3.8 (2.2–6.8) 1.9 (0,9–3.9) 58 (14.6%) 1.4 (1.2–1.7) 2.3 (1.4–3.6) Tinnitus 54 (22.7%) 1.2 (0.9–1.5) 1.3 (1.1–1.5) 1.6 (0.9–2.8) 3.0 (1.3–6.9) 55 (13.9%) 1.5 (1.2–1.8) 2.0 (1.2–3.2) Hearing Impairment 58 (24.4%) 1.5 (1.2–2.0) 1.3 (1.1–1.5) 1.4 (0.8–2.4) 1.1 (0.6–2.2) 38 (9.6%) 1.7 (1.4–2.1) 1.5 (0.9–2.4) Audiometrically assessed hearing impairment 56 (23.5%) 1.2 (0.9–1.6) 1.6 (1.3–2.0) 1.3 (0.7–2.5) 4.2 (2.0–9.0) 82 of 375 (21.9%) 1.0 (0.8–1.1) 1.1 (0.7–1.7) OR: Odds ratio; 95% CI: 95% Confidence Interval, bold figures indicate a significant association (p<0.05) No significant financial relationships to disclose.