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NIHR Signal Sodium thiosulfate reduces hearing loss in children treated with chemotherapy

Published on 6 November 2018

doi: 10.3310/signal-000669

Treatment with sodium thiosulfate alongside cisplatin chemotherapy can reduce hearing loss in children with a liver tumour called hepatoblastoma. The risk of hearing loss was reduced by 48% in children who had the combination treatment compared with those who had cisplatin only.

This phase 3 trial involved 109 children with standard-risk hepatoblastoma and tested the addition of sodium thiosulfate six hours after cisplatin treatment. The additional drug caused few major side effects, and there was no difference in event-free or overall survival between treatment groups after three years.

Although small, the study adds to growing evidence that this well tolerated, cheap treatment might reduce cisplatin-induced hearing loss in a range of childhood cancers

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Why was this study needed?

Around 60% of children treated with cisplatin develop hearing loss, and there is currently no treatment to prevent it. Even mild hearing loss can significantly affect a child’s learning, development and quality of life, particularly in young children whose speech has not yet developed.

Preclinical and early-phase trials have indicated that sodium thiosulfate might protect against ear toxicity caused by cisplatin. It works by binding the platinum component of cisplatin to form a molecule that is not toxic to living cells and can be cleared from the body rapidly.

This trial was set up to investigate whether giving sodium thiosulfate six hours after cisplatin can protect against hearing loss without reducing the effectiveness of cancer treatment. Children with standard-risk hepatoblastoma were chosen as the patient group because they can be treated with cisplatin alone.

What did this study do?

SCIOPEL 6 was a phase 3 randomised controlled trial involving 109 children younger than 18 years with standard-risk hepatoblastoma contained within the liver. It tested cisplatin with sodium thiosulfate against cisplatin alone.

Cisplatin was given by continuous intravenous six-hour infusion every two weeks. Sodium thiosulfate was given six hours after the end of cisplatin infusion by 15-minute intravenous infusion. Four treatment courses were given before surgery, and two courses were given after surgery.

The primary endpoint was absolute hearing threshold, measured by pure-tone audiometry when children were at least 3.5 years old. Secondary endpoints included event-free and overall survival and adverse events.

This was a well-designed, multi-centred international study, so the results are reliable.

What did it find?

  • Sodium thiosulfate reduced the risk of any hearing loss by 48%. Hearing loss requiring hearing aids or cochlear implants occurred in 33% (18/55) of children in the sodium thiosulfate group compared with 63% (29/46) of children in the cisplatin-alone group (relative risk 0.52, 95% confidence interval [CI] 0.33 to 0.81).
  • The three-year overall survival rate was 98% (95% CI 88 to 100) in the cisplatin-sodium thiosulfate group and 92% (95% CI 81 to 97) in the cisplatin-only group.
  • Event-free survival rates at three years were 82% (95% CI 69 to 90) for the combination treatment and 79% (95% CI 65 to 88) in the cisplatin-only group.
  • A total of 68 serious adverse events were reported and 16 adverse reactions.
  • Eight serious adverse reactions were believed to be due to sodium thiosulfate. These included infections, low white cell count (neutropenia), anaemia, nausea and vomiting and tumour progression in two children.

What does current guidance say on this issue?

Sodium thiosulfate is not currently licensed for use alongside chemotherapy but is listed in the British National Formulary as an emergency treatment for cyanide poisoning.

No specific guidance on prevention of long-term side effects during cancer treatment in children is available, over and above recommendations on chemotherapy provision within the NICE 2005 guidance on improving outcomes in children and young people with cancer.

What are the implications?

This study suggests that sodium thiosulfate could offer a promising low-cost way to prevent hearing loss in children treated with cisplatin. Although this study was carried out in a small number of children with a rare type of cancer, the results agree with those from a US clinical trial which tested the drug in a wider range of cancers (although still in a small number of children).

These findings are likely to have broader relevance as cisplatin is widely used to treat other types of solid tumours in children. Further research is needed to address remaining concerns that sodium thiosulfate might reduce the effectiveness of tumour clearance by cisplatin.

Citation and Funding

Brock PR, Maibach R, Childs M, Rajput K, et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. N Engl J Med. 2018;378(25):2376-85.

SIOPEL 6 was an academic trial funded by Cancer Research UK in the UK and charity or NIH/government funded in other countries. Sodium thiosulfate was provided free by Fennec Pharmaceuticals, which had no role in the trial, data collection or authorship of the manuscript.

Bibliography

Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(1):63-74.

NICE. Improving outcomes in children and young people with cancer. CSG7. London: National Institute for Health and Care Excellence; 2005.

NIHR Horizon Scanning Centre. Sodium thiosulfate for prevention of hearing loss in children receiving cisplatin chemotherapy. 7091. Birmingham: National Institute for Health Research Horizon Scanning Centre; 2015.

The Royal Pharmaceutical Society. British National Formulary. London: The Royal Pharmaceutical Society; updated 2 October 2018.

Why was this study needed?

Around 60% of children treated with cisplatin develop hearing loss, and there is currently no treatment to prevent it. Even mild hearing loss can significantly affect a child’s learning, development and quality of life, particularly in young children whose speech has not yet developed.

Preclinical and early-phase trials have indicated that sodium thiosulfate might protect against ear toxicity caused by cisplatin. It works by binding the platinum component of cisplatin to form a molecule that is not toxic to living cells and can be cleared from the body rapidly.

This trial was set up to investigate whether giving sodium thiosulfate six hours after cisplatin can protect against hearing loss without reducing the effectiveness of cancer treatment. Children with standard-risk hepatoblastoma were chosen as the patient group because they can be treated with cisplatin alone.

What did this study do?

SCIOPEL 6 was a phase 3 randomised controlled trial involving 109 children younger than 18 years with standard-risk hepatoblastoma contained within the liver. It tested cisplatin with sodium thiosulfate against cisplatin alone.

Cisplatin was given by continuous intravenous six-hour infusion every two weeks. Sodium thiosulfate was given six hours after the end of cisplatin infusion by 15-minute intravenous infusion. Four treatment courses were given before surgery, and two courses were given after surgery.

The primary endpoint was absolute hearing threshold, measured by pure-tone audiometry when children were at least 3.5 years old. Secondary endpoints included event-free and overall survival and adverse events.

This was a well-designed, multi-centred international study, so the results are reliable.

What did it find?

  • Sodium thiosulfate reduced the risk of any hearing loss by 48%. Hearing loss requiring hearing aids or cochlear implants occurred in 33% (18/55) of children in the sodium thiosulfate group compared with 63% (29/46) of children in the cisplatin-alone group (relative risk 0.52, 95% confidence interval [CI] 0.33 to 0.81).
  • The three-year overall survival rate was 98% (95% CI 88 to 100) in the cisplatin-sodium thiosulfate group and 92% (95% CI 81 to 97) in the cisplatin-only group.
  • Event-free survival rates at three years were 82% (95% CI 69 to 90) for the combination treatment and 79% (95% CI 65 to 88) in the cisplatin-only group.
  • A total of 68 serious adverse events were reported and 16 adverse reactions.
  • Eight serious adverse reactions were believed to be due to sodium thiosulfate. These included infections, low white cell count (neutropenia), anaemia, nausea and vomiting and tumour progression in two children.

What does current guidance say on this issue?

Sodium thiosulfate is not currently licensed for use alongside chemotherapy but is listed in the British National Formulary as an emergency treatment for cyanide poisoning.

No specific guidance on prevention of long-term side effects during cancer treatment in children is available, over and above recommendations on chemotherapy provision within the NICE 2005 guidance on improving outcomes in children and young people with cancer.

What are the implications?

This study suggests that sodium thiosulfate could offer a promising low-cost way to prevent hearing loss in children treated with cisplatin. Although this study was carried out in a small number of children with a rare type of cancer, the results agree with those from a US clinical trial which tested the drug in a wider range of cancers (although still in a small number of children).

These findings are likely to have broader relevance as cisplatin is widely used to treat other types of solid tumours in children. Further research is needed to address remaining concerns that sodium thiosulfate might reduce the effectiveness of tumour clearance by cisplatin.

Citation and Funding

Brock PR, Maibach R, Childs M, Rajput K, et al. Sodium thiosulfate for protection from cisplatin-induced hearing loss. N Engl J Med. 2018;378(25):2376-85.

SIOPEL 6 was an academic trial funded by Cancer Research UK in the UK and charity or NIH/government funded in other countries. Sodium thiosulfate was provided free by Fennec Pharmaceuticals, which had no role in the trial, data collection or authorship of the manuscript.

Bibliography

Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(1):63-74.

NICE. Improving outcomes in children and young people with cancer. CSG7. London: National Institute for Health and Care Excellence; 2005.

NIHR Horizon Scanning Centre. Sodium thiosulfate for prevention of hearing loss in children receiving cisplatin chemotherapy. 7091. Birmingham: National Institute for Health Research Horizon Scanning Centre; 2015.

The Royal Pharmaceutical Society. British National Formulary. London: The Royal Pharmaceutical Society; updated 2 October 2018.

Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss

Published on 21 June 2018

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.,Brugieres, L.,Perilongo, G.,Czauderna, P.,Morland, B.,Neuwelt, E. A.

N Engl J Med Volume 378 Issue 25 , 2018

BACKGROUND: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk 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 .).

Expert commentary

Cisplatin is very effective in the treatment of several childhood cancers including hepatoblastoma, neuroblastoma and some brain tumours but can cause serious long-term hearing loss. This may cause significant psychosocial and educational difficulties in very young children who are still developing their speech.

This randomised controlled clinical trial showed that sodium thiosulfate reduced the risk of cisplatin-induced hearing loss in children with standard-risk hepatoblastoma and found no evidence of reduced three-year survival rates.

More research is needed urgently to confirm this very promising finding, especially in other tumours, since it is vital to be certain that sodium thiosulfate does not reduce cisplatin’s anti-tumour effectiveness.

Rod Skinner, Consultant in Paediatric and Adolescent Oncology / BMT, Honorary Professor of Childhood Cancer

Expert commentary

This study examined a new medicine to prevent hearing loss in children with cancer of the liver (hepatoblastoma).

All the children received cisplatin, a very effective drug but which can cause severe hearing loss, and were randomised to either get the sodium thiosulfate or not. Outcomes included the effect on hearing (less deafness with sodium thiosulfate), and also that the cancer was treated as well (which it was).

Hepatoblastoma is a rare cancer, so this will need testing in other cancers in children are treated with cisplatin as well. But this is a very exciting study, as drug toxicity can limit successful treatment of cancers.

Dr Dan Hawcutt, Senior Lecturer, Paediatric Clinical Pharmacology, University of Liverpool