TABLE 2.

Clinical Studies on the Otoprotective Effect of STS (with a control group)

Author, Year	Design	Patient Characteristics	No.: STS Group	No.: Comparison Group	Platinum Treatment	STS Specification	Audiometry	FU Time	Hearing Function Outcomes		P	Adverse Events	Survival
									With STS	Without STS
Studies in adults
Zuur et al,60 2007	RCT: phase 3	HNSCC Median age: 55 years	78: CIS + STS + radiotherapy (70 Gy)	80: CIS only + radiotherapy (70 Gy)	CIS + STS CIS IA; 4× 150 mg/m2 CIS only CIS IV; 3× 100 mg/m2	STS IV 9 g/m2 for 30 minutes + 12 g/m2 for 2 hours Concurrent with CIS	PTA 0.25-16 kHz	Median: 8 weeks post-Tx	HTL shifts >10 dB over time Mean HTL shift up to 4 kHz: 5.3 dB, and up to 12.5 kHz: 20.4 dB	HTL shifts >10 dB over time Mean HTL shift up to 4 kHz: 8.9 dB, and up to 12.5 kHz: 19.0 dB	<.001 (≤4 kHz)	NA	NA
Ishikawa et al,53 2015	Prospective cohort study	HNSCC Age: 45-82 years	7: CIS + STS + radiotherapy (60-70 Gy)	11: CIS only + radiotherapy (60-70 Gy)	CIS + STS CIS IA; 2-5× 100-180 mg/m2 CIS only CIS IV; 1-3× 66-85 mg/m2	STS IV 14 g/m2 for 4 hours Concurrent with CIS	PTA 0.125-12 kHz	1-3 weeks post-Tx	From baseline HTL shifts of 20 dB at 10 and 12 kHz	From baseline HTL shifts of 15-25 dB at 8 and 10 kHz	.028 .039 .016 .027	NA	NA
Studies in mixed cohorts of children and adults
Neuwelt et al,62 1998	Cohort study STS group: prospective Comparison group: retrospective	Brain tumors Age: 2-68 years	15: CARBO + STS 16 or 20 mg/m2 4: CARBO + STS 4 or 8 mg/m2	19: CARBO only	BBBD + CARBO IA over 10-min 400 mg/m2 per month 4-12 courses	STS IV over 15 minutes 4-20 mg/m2 2 hours after CARBO	PTA 0.25-8 kHz	Each month during Tx	HL in 33% with STS 16 or 20 mg/m2a Average loss after first cycle: 3.7 ± 2.0 dB at 8 kHz	HL in 79% Average loss after first cycle: 20.8 ± 5.9 dB at 8 kHz	<.05	Mild nausea, vomiting HN, ↑ blood pressure	NA
Doolittle et al,61 2001	Cohort study STS group: prospective Comparison group: retrospective	Brain tumors Age: 4-67 years	24: CARBO + STS after 2 hours 17: CARBO + STS after 4 hours	19: CARBO only	BBBD + CARBO IA over 10-min 400 mg/m2 per month 1-7 courses	STS IV over 15 minutes 16 or 20 mg/m2 2 or 4 hours after CARBO	PTA 0.25-8 kHz	Each month during Tx	STS2h: HL in 52% HTL shift at 8 and 4 kHz: 41.7 dB and 35.4 dB, respectively STS4h: HL in 29% HTL shift at 8 and 4 kHz: 34.1 dB and 28.6 dB, resp.	HL in 84% HTL shift at 8 and 4 kHz: 64.4 dB and 51.6 dB, respectively	.001 (at 8 kHz) .0075 (at 4 kHz)	NA	NA
Studies in children and adolescents
Freyer et al,41 2017	RCT: multicenter, open-label, phase 3	Any tumor Age: 1-18 years	49: CIS + STS	55: CIS only	CIS IV 6× CIS + STS: 393 mg/m2 (290-420) CIS only: 387 mg/m2 (305-466)	STS IV over 15 minutes 16 g/m2 6 hours after CIS	PTA 0.5-8 kHz	4 weeks post-Tx EFS + OS: median 3.5 years	HL in 29%	HL in 56%	.00022	Nephrotoxicity HP, HK	EFS + OS in both groups: P = .36 and .07, respectively EFS + OS in LD (N = 77): P = .73 and .88, respectively OS in DD (N = 47): P = .009
Brock et al,40 2018	RCT	SR HBL Age: 0-8 years	57: CIS + STS	52: CIS only	CIS IV 6× 80 mg/m2	STS IV over 15 minutes 20 mg/m2 6 hours after CIS	PTA 1-8 kHz	During Tx EFS + OS: median 3.0 years	HL in 33%	HL in 63%	.002	Neutropenia, HM, HP, HK	3-yr EFS in CIS + STS group: 82%, 95% CI 69%-90%; in CIS alone group 79%, 95% CI 65%-88% 3-yr OS CIS + STS: 98%, 95% CI 88%-100%; CIS alone 92%, 95% CI 81%-97%

Abbreviations: BBBD, blood-brain barrier disruption; CARBO, carboplatin; CIS, cisplatin; DD, disseminated disease; EFS, event-free survival; FU, follow-up; HBL, hepatoblastoma; HK, hypokalemia; HL, hearing loss; HM, hypermagnesemia; HN, hypernatremia; HNSCC, head and neck squamous cell carcinoma; HP, hypophosphatemia; HTL, hearing threshold level; IA, intra-arterial; IV, intravenous; LD, localized disease; NA, not assessed; OS, overall survival; RCT, randomized controlled trial; SR, standard risk; STS, sodium thiosulfate; Tx, treatment.

^a Most patients who received 4 or 8 mg/m² developed hearing loss.