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