GSTM1 null and GSTT1 null: predictors of cisplatin-caused acute ototoxicity measured by DPOAEs.

Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (n = 45) or bilateral (n = 23) involvement. The clinicopathological characteristics, hearing test results, germline GSTT1, GSTM1, and GSTP1 polymorphisms, and common laboratory parameters were included in the new analysis. Univariate and multivariate statistical tests were applied. According to multivariate logistic regression, the only independent predictor of unilateral ototoxicity (vs. non-affected) was a GSTM1 null genotype (OR = 4.52; 95%CI = 1.3-16.3), while for bilateral damage, the GSTT1 null genotype (OR = 4.76; 1.4-16) was a predictor. The higher starting serum urea level was characteristic of bilateral ototoxicity; however, the only independent marker of bilateral (vs. unilateral) ototoxicity was the presence of GSTT1 null genotype (OR = 2.44; 1.23-4.85). Different processes, involving the GSTM1 and GSTT1 genotypes, respectively, govern the development of acute unilateral and bilateral ototoxicities. Further research is needed to clarify these processes. Based on the above findings, patients whom are at risk may be selected for otoprotective therapies. KEY MESSAGES: The acute ototoxicity was determined by DPOAE in 118 testicular cancer patients. GSTM1 null was the only marker of unilateral ototoxicity (vs. non-affected). The only marker of bilateral hearing loss (vs. non-affected) was the GSTT1 null. GSTT1 null was also the marker of bilateral vs. unilateral ototoxicity. A high-risk group may be selected for new, individualized otoprotective treatment.

Abiraterone acetate + prednisolone treatment beyond prostate specific antigen and radiographic progression in metastatic castration-resistant prostate cancer patients.

OBJECTIVES: To investigate the overall survival (OS) of chemotherapy refractory patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate + prednisolone (AA + P) beyond prostate specific antigen (PSA) and radiographic progression (PRP) until clinical progression in comparison to patients treated until PRP. METHODS: At our institute the AA + P treatment started in 2011 in an early-access protocol trial. In October 2012 AA became generally available. From April 2011 to November 2014, 116 patients received AA + P. The clinical trial patients (T; n = 56) were treated beyond PRP until clinical progression. In the nonclinical trial group (NT; n = 57) the treatment was covered until PRP. Three patients are still under treatment. The 2 groups were statistically homogeneous, except AA + P treatment duration. The primary objective was the OS and the secondary the PSA progression-free and radiographic progression-free survivals. RESULTS: The median OS was significantly longer (P<0.0001) in the T group compared to the NT group: 21.9 (95% CI: 16.9-25) vs. 12.5 (9.3-14.1) months, respectively. In univariate analysis there were 11 parameters, which significantly affected OS, but in multivariate Cox analysis only alkaline phosphatase (AP) level at the start of treatment, systemic therapy after AA + P and cohort type (T or NT) proved to independently influence the OS. The progression-free survival curves of T and NT groups did not differ significantly. CONCLUSIONS: In our retrospective analysis low levels of AP at the start of treatment, systemic therapy applied after AA + P and treatment beyond PRP proved to be independent factors of longer OS in metastatic castration-resistant prostate cancer.

Early ototoxic changes in patients with germ cell tumor after first cycle of cisplatin-based therapy.

OBJECTIVE: To prospectively examine early hearing damage detectable with distortion product otoacoustic emission (DPOAE) after the first cycle of cisplatin treatment of patients with testicular tumor. STUDY DESIGN: Both ears of 137 consecutive patients were examined at 0.75 to 8 kHz before (B) and after (A) the first cycle of cisplatin (dose: 100 mg/m2 / 5 days). METHODS: The mean amplitudes (B vs. A) were compared with paired t test at each frequency. Ototoxic changes were considered when an individual amplitude difference (B-A) > 14 dB at 0.75 Hz or > 7 db at 1 to 8 kHz occurred. RESULTS: The mean amplitudes were statistically significantly lower after first cycle at 0.75, 6, and 8 kHz. The majority of patients (96%) presented positive differences (B-A) in one or both ears; in 85 (62%) cases, the positive difference reached the level of ototoxicity out of which 34 (40%) and 19 (22%) of patients suffered ototoxicity in one or both ears, respectively. The difference between right and left ears in distribution of ototoxic cases was nonsignificant. Forty-five (33%) and four (3%) patients showed ototoxicity at two or more frequencies in one or both ears, respectively. An increased proportion of ototoxic cases can be seen at 0.75 to 1 kHz and 6 to 8 kHz. CONCLUSION: After the first cycle of cisplatin treatment, early ototoxicity occurs in close to two-thirds of patients, as identified by measuring DPOAE. Therefore, further research for biomarkers is required, which can predict patients at risk in order to avoid an irreversible hearing loss by personalized, preventive therapies. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1909-1915, 2017.