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BackgroundCisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy.MethodsA total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears.ResultsAlthough aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL.ConclusionsAspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.

Gemcitabine and cisplatin chemotherapy (GC regimen) represents a standard treatment for advanced urothelial carcinoma. We performed an open-label, single-arm, non-randomised, phase 2 trial evaluating the addition of sunitinib to standard GC chemotherapy (SGC regimen). Overall, 63 treatment-naïve participants were recruited and received up to six 21-d cycles of cisplatin 70 mg/m2 (intravenously [IV], day 1) and gemcitabine 1000 mg/m2 (IV, days 1 and 8) combined with sunitinib 37.5 mg (orally, days 2–15). Following review of toxicity after the first six patients, the sunitinib dose was reduced to 25 mg for all patients. Overall response rate was 64%, with response noted in 37 of 58 patients. At 6 mo, 30 of 58 assessable patients (52%; 90% confidence interval [CI], 40–63%) were progression free. Median overall survival was 12 mo (95% CI, 9–15) and was heavily influenced by Bajorin prognostic group. Grade 3–4 toxicities were predominantly haematologic and limited the deliverability of the triple SGC regimen. The trial did not meet its prespecified primary end point of >60% patients progression free at 6 mo. Cumulative myelosuppression led to treatment delays of gemcitabine and cisplatin and dose reduction and/or withdrawal of sunitinib in the majority of cases. The triple-drug combination was not well tolerated. Phase 3 evaluation of the triple SGC regimen in advanced transitional cell carcinoma is not recommended.Patient summaryThe addition of sunitinib to standard cisplatin and gemcitabine chemotherapy was poorly tolerated and did not improve outcomes in advanced urothelial carcinoma. Treatment delivery was limited by myelotoxicity.

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The 'Design, Setting and Participants' section of the abstract has been split to incorporate the interventions sections and now reads (lines 45-47): 'Design, Setting, and Participants: A retrospective analysis was conducted of a second-line phase II study in metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions. Intervention: The phase II trial assessed VEGF-targeted therapy ± Src inhibition.' The words 'to validate these findings' have been removed from the abstract conclusion (line 61) to keep the word count below 300. 2) The authors used definitions of radiological heterogeneity which were developed in patients with CRC liver mets and which were modified accordingly by the authors. Are the cutoffs used for 'homogeneous', 'low heterogeneous' and 'high heterogeneous' response arbitrary or is there evidence why these were chosen by the authors. Please briefly clarify to make it more understandable for our readers. The following has been added to the Patients and Methods section (lines 152-155): 'The cutoffs were determined using an optimal response model by van Kessel and colleagues. This involved modelling different cutoff values to identify which provided the highest discriminative capacity. Further details are provided in [6]. No further modelling was undertaken for the analysis presented in this paper.' 3) Please add the number of patients at risk at each time point with KM-curves. Please also use 12-mo intervals to make it easier to see yearly changes. 'Uni-and multivariate analyses were undertaken using Cox regression to calculate Hazard Ratios (HR). The univariate parameters were chosen on the basis of being known prognostic variables from previous studies (gender, Eastern Cooperative Oncology Group [ECOG] performance status, Memorial Sloan Kettering Cancer Center [MSKCC] risk group, nephrectomy status) or because they may be confounding factors to radiological heterogeneity (number of target lesions, sum of lesion diameters) [2, 7, 8]. All univariate parameters were included in the multivariate analysis.' Reviewer 1: We thank the reviewer for their kind comments. Reviewer 2: We thank the reviewer for their kind comments.