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Association of Sodium Thiosulfate with Risk of Ototoxic Effects from Platinum-Based Chemotherapy a Systematic Review and Meta-Analysis

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Association of Sodium Thiosulfate with Risk of Ototoxic Effects from Platinum-Based Chemotherapy a Systematic Review and Meta-Analysis Original Investigation | Oncology Association of Sodium Thiosulfate With Risk of Ototoxic Effects From Platinum-Based Chemotherapy A Systematic Review and Meta-analysis Chih-Hao Chen, MD; Chii-Yuan Huang, MD, PhD; Heng-Yu Haley Lin, MD, MPH; Mao-Che Wang, MD, PhD; Chun-Yu Chang, MD; Yen-Fu Cheng, MD, PhD Abstract Key Points Question Is the use of sodium IMPORTANCE Platinum-induced ototoxic effects are a significant issue because platinum-based thiosulfate associated with decreased chemotherapy is one of the most commonly used therapeutic medications. Sodium thiosulfate (STS) risk of ototoxic effects among patients is considered a potential otoprotectant for the prevention of platinum-induced ototoxic effects that treated with platinum-induced functions by binding the platinum-based agent, but its administration raises concerns regarding the chemotherapy? substantial attenuation of the antineoplastic outcome associated with platinum. Findings In this meta-analysis of 4 OBJECTIVE To evaluate the association between concurrent STS and reduced risk of ototoxic clinical trials, including 3 randomized effects among patients undergoing platinum-based chemotherapy and to evaluate outcomes, clinical trials and 278 patients, sodium including event-free survival, overall survival, and adverse outcomes. thiosulfate (STS) was associated with a decreased risk of ototoxic effects when DATA SOURCES From inception through November 7, 2020, databases, including the Cochrane administered during the course of Library, PubMed, Embase, Web of Science, and Scopus, were searched. platinum-based chemotherapy. Meaning This finding suggests that the STUDY SELECTION Studies enrolling patients with cancer who were undergoing platinum-based prophylactic use of STS should be chemotherapy that compared ototoxic effects development between patients who received STS and considered when platinum-based patients who did not and provided adequate information for meta-analysis were regarded as eligible. chemotherapy is indicated and that This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses further large-scale trials are essential for (PRISMA) guidelines. solid application. DATA EXTRACTION AND SYNTHESIS The data were extracted by 2 reviewers independently. A random-effects model was used to explore objectives. + Supplemental content Author affiliations and article information are MAIN OUTCOMES AND MEASURES Relative risks (RRs) for ototoxic effects development and listed at the end of this article. hemopoietic event development comparing the experimental group and the control group were estimated. Secondary outcomes were hazard ratios (HRs) for event-free survival and overall survival. Sensitivity analysis and trial sequential analysis were conducted to further consolidate pooled results. RESULTS Among 4 eligible studies that were included, there were 3 randomized clinical trials and 1 controlled study. A total of 278 patients were allocated to the experimental group (ie, platinum- based chemotherapy plus STS; 158 patients, including 13 patients using contralatral ears of the control group as samples) or the control group (ie, chemotherapy; 133 patients, including 13 patients using contralateral ears of the experimental group as samples). Overall, patients who received STS had a statistically significantly decreased risk of ototoxic effects during the course of platinum-based chemotherapy (RR, 0.61; 95% CI, 0.49-0.77; P < .001; I2 = 5.0%) without a statistically significant increase in the risk of poor event-free survival (HR, 1.13; 95% CI, 0.70-1.82; P =.61;I2 = 0%) or overall survival (HR, 1.90; 95% CI, 0.90-4.03; P =.09;I2 = 0%). In the trial sequential analysis of event-free (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2021;4(8):e2118895. doi:10.1001/jamanetworkopen.2021.18895 (Reprinted) August 2, 2021 1/13 Downloaded From: https://jamanetwork.com/ on 09/27/2021 JAMA Network Open | Oncology Sodium Thiosulfate and Risk of Ototoxic Effects From Platinum-Based Chemotherapy Abstract (continued) survival (z = −0.52) and overall survival (z = −1.68), although the cumulative z curves did not surpass the traditional significance boundary (−1.96 to 1.96 for both) or sequential monitoring boundary (event-free survival: −8.0 to 8.0; overall survival boundary not renderable in the analysis because the information size was too small) of the adjusted CI, they did not reach the required information size. CONCLUSIONS AND RELEVANCE This meta-analysis found that concurrent STS delivery was associated with a decreased risk of platinum-induced ototoxic effects among patients treated with platinum-induced chemotherapy. These findings suggest that concurrent STS for protection against ototoxic effects should be considered for patients indicated for platinum-based chemotherapy. JAMA Network Open. 2021;4(8):e2118895. doi:10.1001/jamanetworkopen.2021.18895 Introduction Platinum-based chemotherapy is one of the most commonly used therapeutic agents in the treatment of solid tumors in pediatric and adult patients, including those with non–small cell lung carcinoma, ovarian cancer, hepatoblastoma, and head and neck cancer.1-4 However, the adverse outcomes associated with platinum, including nephrotoxic effects, myelosuppression, and ototoxic effects, limit its use and may be associated with long-term comorbidities in these patients.5 While medical intervention for prevention of nephrotoxic effects has been well illustrated, the prevention of platinum-induced ototoxic effects remains stagnant.6-8 Studies9,10 from 2005 and 2017 found that platinum can be sustained in the cochlea indefinitely, which is associated with long-term otologic complications, such as sensorineural hearing loss, tinnitus, and vestibulopathy. On the basis of the well-illustrated mechanism of platinum-induced ototoxic effects, studies identifying possible otoprotectants have been conducted in recent decades.8,11-13 Among otoprotective agents, the most studied14-16 has been amifostine, an aminothiol prodrug that is dephosphorylated to an active thiol that acts as a reactive oxygen scavenger. Although the association of amifostine with protection against nephrotoxic effects has been demonstrated, amifostine has failed to show an otoprotective association in previous studies.16-19 On the other hand, sodium thiosulfate (STS) has emerged as a promising otoprotectant. By protecting cells from apoptosis, STS has been found to be otoprotective in previous studies.20-22 However, concern that STS attenuates the antineoplastic outcome remains because 1 of the mechanisms of this medication is covalently binding to cisplatin;23,24 therefore, the transtympanic approach of STS has been attempted to avoid systemic influence on the antineoplastic outcome of platinum-based chemotherapy, although the results remain inconclusive.25,26 Additionally, under the circumstance that STS may potentially be associated with the antitumor efficacy of cisplatin, survival analysis is also needed to apply the medication safely in the clinic. Regarding these issues, this study aimed to systematically review the current literature on the association of STS with the prevention of platinum-induced toxic effects. To explore the association of STS with the development of ototoxic effects and oncologic-related survival and the association of concurrent factors with these outcomes, we identified controlled studies and performed a meta- analysis to evaluate the efficacy of STS among patients with cancer undergoing platinum-based chemotherapy. Methods This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.27 The patient data used in this systematic review and meta-analysis were deidentified. JAMA Network Open. 2021;4(8):e2118895. doi:10.1001/jamanetworkopen.2021.18895 (Reprinted) August 2, 2021 2/13 Downloaded From: https://jamanetwork.com/ on 09/27/2021 JAMA Network Open | Oncology Sodium Thiosulfate and Risk of Ototoxic Effects From Platinum-Based Chemotherapy Study Inclusion Included studies were selected according to the following criteria: the study compared STS with a control regarding the outcome of interest (ie, development of ototoxic effects), the study clearly defined ototoxic effects, and the study provided an account of adequate information to quantify the effect estimates for meta-analysis. Studies were required to meet all conditions. Search Strategy and Identification of Eligible Studies From inception through November 7, 2020, we searched databases, including the Cochrane Library, PubMed, Embase, Web of Science, and Scopus. We used a consolidation of Medical Subject Headings (MeSH) and text words to create 3 subsets of citations, 1 including studies of platinum-based treatment (ie, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, and satraplatin), the second including hearing complications (ie, hearing loss, hearing impairment, and ototoxicity), and the third including sodium thiosulfate treatment (ie, sodium thiosulfate). The detailed search strategy is displayed in eTable 1 in the Supplement. The identified records were screened by titles, abstracts, and keywords. Records with potential eligibility were then obtained for full-text review. After review of the full texts by 2 authors (C.H.C. and C.Y.C.), the effect estimates of interest were extracted by consensus. Criteria were that the primary data should
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