Sodium thiosulfate for protection from cisplatin-induced hearing loss

P. R. Brock, R. Maibach, M. Childs, K. Rajput, D. Roebuck, M. J. Sullivan, V. Laithier, M. Ronghe, P. Dall'Igna, E. Hiyama, B. Brichard, J. Skeen, M. E. Mateos, M. Capra, A. A. Rangaswami, M. Ansari, C. Rechnitzer, G. J. Veal, A. Covezzoli, L. BrugièresG. Perilongo, P. Czauderna, B. Morland, Edward Neuwelt

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Abstract

BACKGROUND Cisplatin chemotherapy and surgery are effective treatments for children with standardrisk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (=3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P = 0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132; EudraCT number, 2007-002402-21.).

Original languageEnglish (US)
Pages (from-to)2376-2385
Number of pages10
JournalNew England Journal of Medicine
Volume378
Issue number25
DOIs
StatePublished - Jun 21 2018

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Hearing Loss
Cisplatin
Hepatoblastoma
Disease-Free Survival
Confidence Intervals
sodium thiosulfate
Hearing
Incidence
Pure-Tone Audiometry
Drug Therapy
Poisons
Body Surface Area
alpha-Fetoproteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Brock, P. R., Maibach, R., Childs, M., Rajput, K., Roebuck, D., Sullivan, M. J., ... Neuwelt, E. (2018). Sodium thiosulfate for protection from cisplatin-induced hearing loss. New England Journal of Medicine, 378(25), 2376-2385. https://doi.org/10.1056/NEJMoa1801109

Sodium thiosulfate for protection from cisplatin-induced hearing loss. / Brock, P. R.; Maibach, R.; Childs, M.; Rajput, K.; Roebuck, D.; Sullivan, M. J.; Laithier, V.; Ronghe, M.; Dall'Igna, P.; Hiyama, E.; Brichard, B.; Skeen, J.; Mateos, M. E.; Capra, M.; Rangaswami, A. A.; Ansari, M.; Rechnitzer, C.; Veal, G. J.; Covezzoli, A.; Brugières, L.; Perilongo, G.; Czauderna, P.; Morland, B.; Neuwelt, Edward.

In: New England Journal of Medicine, Vol. 378, No. 25, 21.06.2018, p. 2376-2385.

Research output: Contribution to journalArticle

Brock, PR, Maibach, R, Childs, M, Rajput, K, Roebuck, D, Sullivan, MJ, Laithier, V, Ronghe, M, Dall'Igna, P, Hiyama, E, Brichard, B, Skeen, J, Mateos, ME, Capra, M, Rangaswami, AA, Ansari, M, Rechnitzer, C, Veal, GJ, Covezzoli, A, Brugières, L, Perilongo, G, Czauderna, P, Morland, B & Neuwelt, E 2018, 'Sodium thiosulfate for protection from cisplatin-induced hearing loss', New England Journal of Medicine, vol. 378, no. 25, pp. 2376-2385. https://doi.org/10.1056/NEJMoa1801109
Brock PR, Maibach R, Childs M, Rajput K, Roebuck D, Sullivan MJ et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. New England Journal of Medicine. 2018 Jun 21;378(25):2376-2385. https://doi.org/10.1056/NEJMoa1801109
Brock, P. R. ; Maibach, R. ; Childs, M. ; Rajput, K. ; Roebuck, D. ; Sullivan, M. J. ; Laithier, V. ; Ronghe, M. ; Dall'Igna, P. ; Hiyama, E. ; Brichard, B. ; Skeen, J. ; Mateos, M. E. ; Capra, M. ; Rangaswami, A. A. ; Ansari, M. ; Rechnitzer, C. ; Veal, G. J. ; Covezzoli, A. ; Brugières, L. ; Perilongo, G. ; Czauderna, P. ; Morland, B. ; Neuwelt, Edward. / Sodium thiosulfate for protection from cisplatin-induced hearing loss. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 25. pp. 2376-2385.
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abstract = "BACKGROUND Cisplatin chemotherapy and surgery are effective treatments for children with standardrisk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (=3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33{\%}) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63{\%}) in the cisplatin-alone group, indicating a 48{\%} lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95{\%} confidence interval [CI], 0.33 to 0.81; P = 0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82{\%} (95{\%} CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79{\%} (95{\%} CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98{\%} (95{\%} CI, 88 to 100) and 92{\%} (95{\%} CI, 81 to 97), respectively. CONCLUSIONS The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132; EudraCT number, 2007-002402-21.).",
author = "Brock, {P. R.} and R. Maibach and M. Childs and K. Rajput and D. Roebuck and Sullivan, {M. J.} and V. Laithier and M. Ronghe and P. Dall'Igna and E. Hiyama and B. Brichard and J. Skeen and Mateos, {M. E.} and M. Capra and Rangaswami, {A. A.} and M. Ansari and C. Rechnitzer and Veal, {G. J.} and A. Covezzoli and L. Brugi{\`e}res and G. Perilongo and P. Czauderna and B. Morland and Edward Neuwelt",
year = "2018",
month = "6",
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doi = "10.1056/NEJMoa1801109",
language = "English (US)",
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pages = "2376--2385",
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TY - JOUR

T1 - Sodium thiosulfate for protection from cisplatin-induced hearing loss

AU - Brock, P. R.

AU - Maibach, R.

AU - Childs, M.

AU - Rajput, K.

AU - Roebuck, D.

AU - Sullivan, M. J.

AU - Laithier, V.

AU - Ronghe, M.

AU - Dall'Igna, P.

AU - Hiyama, E.

AU - Brichard, B.

AU - Skeen, J.

AU - Mateos, M. E.

AU - Capra, M.

AU - Rangaswami, A. A.

AU - Ansari, M.

AU - Rechnitzer, C.

AU - Veal, G. J.

AU - Covezzoli, A.

AU - Brugières, L.

AU - Perilongo, G.

AU - Czauderna, P.

AU - Morland, B.

AU - Neuwelt, Edward

PY - 2018/6/21

Y1 - 2018/6/21

N2 - BACKGROUND Cisplatin chemotherapy and surgery are effective treatments for children with standardrisk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (=3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P = 0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132; EudraCT number, 2007-002402-21.).

AB - BACKGROUND Cisplatin chemotherapy and surgery are effective treatments for children with standardrisk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (=3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P = 0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132; EudraCT number, 2007-002402-21.).

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