New drug halves hearing loss in children following cancer treatment

Giving the drug sodium thiosulphate after chemotherapy reduces hearing loss in children treated for liver cancer, according to findings published in the New England Journal of Medicine today (Wednesday).

Results from the Cancer Research UK funded SIOPEL-6 clinical trial show that giving sodium thiosulphate (STS), after a type of chemotherapy called cisplatin, reduces hearing loss by nearly 50% in children treated for hepatoblastoma*, a childhood liver cancer.

This is a major step forward in minimising the number of children left with debilitating and long term side effects after being treated for cancer. Dr Penelope Brock, trial lead and paediatric consultant at Great Ormond Street Hospital, said: “We’re lucky to have such an effective treatment for this type of liver cancer. But like many cancer treatments, there can also be long term side effects. For children treated with cisplatin alone, a huge proportion are left with permanent hearing loss, which can be utterly debilitating. Even mild hearing loss can severely impact a child’s future development. Key consonants are heard at high frequencies like ‘s,’ ‘h,’ and ‘f’, and their loss can be particularly difficult for children who haven’t yet developed speech.

“This treatment combination could help ensure that parents aren’t faced with an upsetting scenario where successful cancer treatment comes at the cost of their child’s hearing.”

109 children took part in the trial, which was led by researchers at Great Ormond Street Hospital, and had either cisplatin alone or cisplatin followed by STS 6 hours later. While 63% of children given cisplatin alone suffered a degree of hearing loss, this was only the case for one third (33%) of children also given STS, meaning their risk of this side effect was reduced by 48%.**

Importantly, there was no difference in overall survival or incidence of cancer returning, meaning the treatment was just as effective if children were given STS.

Professor Pam Kearns, Cancer Research UK’s expert on children’s cancers at the University of Birmingham, said: “No child should have to suffer a disability as a result of their cancer treatment. Hearing is precious and we’re delighted to see that we can safeguard the future development of more children, without compromising the chance of curing their cancer.”

Cisplatin*** is a very effective treatment for many cancers including hepatoblastoma, for which survival has improved dramatically. However, around two thirds of children treated with this drug are left with some hearing loss. This is because while cisplatin is rapidly removed from the body following treatment, it is retained in and damages the cochlea, the portion of the inner ear responsible for hearing.

Preclinical and clinical research, by a team led by Dr Ed Neuwelt at Oregon Health and Science University, had previously shown that STS could prevent hearing loss caused by cisplatin. Scientists then determined how to delay when STS was given to patients to avoid any interference with cisplatin’s effect on their tumour.

In light of these latest results, STS could become part of a new standard of care for treating hepatoblastoma, and researchers are also looking at whether it could work for other children’s cancers where cisplatin is used as part of treatment. The next step is to get marketing authorisation from the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). It has already received a breakthrough therapy designation by the FDA and will be filed under a Paediatric Use Marketing Application in the EU.

Ollie Simpkin, 12, from Islington, was diagnosed with hepatoblastoma when he was five-months-old.  Ollie’s mum Philly Simpkin, said: “After eight rounds of chemotherapy and surgery at GOSH, the great news is that Ollie is now cancer free. While Cisplatin was very effective in shrinking Ollie’s tumour, it is a very strong drug which can lead to serious side effects including hearing loss. We are very thankful that this was kept to a minimum for Ollie but he has still lost the top end of his hearing. This means he struggles to hear in big crowds and has to sit at the front of the class. He really wants to learn to play the drums, but we can’t risk the damage getting any worse.

“When Ollie was going through treatment, STS hadn’t been developed yet, but it’s fantastic that this new treatment could prevent other children from experiencing similar damage that can have such a big impact on their life.” The SIOPEL-6 trial recruited patients from 52 centres in 12 countries. In the UK, the trial coordination was funded by Cancer Research UK. The STS drug was provided free of charge by Fennec Pharmaceuticals.****

“International trials like this are crucial to help us improve treatments for children,” added Professor Kearns. “The UK is a major contributor to clinical trials research across Europe and this is something we hope will continue. Researchers and patients need certainty on clinical trials both during and beyond the Brexit transition period.”

*Hepatoblastoma is a very rare type of primary liver cancer that usually affects young children. It is most often diagnosed in children under two. In the UK, there are around 15  cases of hepatoblastoma diagnosed in children (aged 0-14 years) each year. Doctors usually treat it with both surgery and chemotherapy.

**Hearing loss occurred in 63.0% of children given cisplatin alone, and in 32.7% of children given cisplatin plus STS. The relative risk of any hearing loss with cisplatin plus STS treatment was 0.52 translating to a 48% risk reduction relative to cisplatin alone.

3-year overall survival was 92.3% for the group given cisplatin and 98.2% for the group given cisplatin plus STS. 3-year event-free survival for the cisplatin alone and cisplatin plus STS groups were 78.8% and 81.2% respectively.

***Cisplatin is used in the treatment of children with neuroblastoma, osteosarcoma, medulloblastoma, malignant germ cell tumours and hepatoblastoma and hepatocellular carcinoma as well as in a number of other diseases at relapse.

For more information about cisplatin please visit the Cancer Research UK website:
****PEDMARKTM(a unique formulation of sodium thiosulfate (STS) developed by Fennec Pharmaceuticals) is a water-soluble thiol compound and acts as a chemical reducing agent.  Delayed administration (6 h) of high dose PEDMARKTM (16–20 g/m²) protects against platinum-induced ototoxicity in animal models and in patients.

NHIR improving the health and wealth of the nation through research. Established by the Department of Health and Social Care, the NIHR:

• funds high quality research to improve health
• trains and supports health researchers
• provides world-class research facilities
• works with the life sciences industry and charities to benefit all
• involves patients and the public at every step

• Cancer Research UK is the world’s leading cancer charity dedicated to saving lives through research.
• Cancer Research UK’s pioneering work into the prevention, diagnosis and treatment of cancer has helped save millions of lives.
• Cancer Research UK receives no funding from the UK government for its life-saving research. Every step it makes towards beating cancer relies on vital donations from the public.
• Cancer Research UK has been at the heart of the progress that has already seen survival in the UK double in the last 40 years.
• Today, two in four people survive their cancer for at least 10 years. Cancer Research UK’s ambition is to accelerate progress so that by 2034, three in four people will survive their cancer for at least 10 years.
• Cancer Research UK supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses.
• Together with its partners and supporters, Cancer Research UK's vision is to bring forward the day when all cancers are cured.
• For further information about Cancer Research UK's work or to find out how to support the charity, please call 0300 123 1022 or visit www.cancerresearchuk.org. Follow us on Twitter and Facebook.

Great Ormond Street Hospital is one of the world’s leading children’s hospitals with the broadest range of dedicated, children’s healthcare specialists under one roof in the UK. The hospital’s pioneering research and treatment gives hope to children from across the UK with the rarest, most complex and often life-threatening conditions. Our patients and families are central to everything we do – from the moment they come through the door and for as long as they need us.

The UCL Great Ormond Street Institute of Child Health (ICH) is part of the Faculty of Population Health Sciences within the School of Life and Medical Sciences at University College London. Together with its clinical partner Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH), it forms the largest concentration of children's health research in Europe. For more information visit www.ucl.ac.uk/ich

Cisplatin and other platinum compounds are essential chemotherapeutic components for many paediatric malignancies. Unfortunately, platinum-based therapies cause ototoxicity in many patients, and are particularly harmful to the survivors of paediatric cancer.

In the U.S. and Europe there is estimated that over 10,000 children are diagnosed with local cancers that may receive platinum-based chemotherapy. Localized cancers that receive platinum agents may have overall survival rates of greater than 80% further emphasizing the quality of life after treatment. The incidence of hearing loss in these children depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids. There is currently no established preventive agent for this hearing loss and only expensive, technically difficult and sub-optimal cochlear (inner ear) implants have been shown to provide some benefit. Infants and young children at critical stages of development lack speech language development and literacy, and older children and adolescents lack social-emotional development and educational achievement.

STS has been studied by cooperative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, The COG Protocol ACCL0431 and SIOPEL 6. Both studies are closed to recruitment. The COG ACCL0431 protocol enrolled one of five childhood cancers typically treated with intensive cisplatin therapy for localized and disseminated disease, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, and medulloblastoma. SIOPEL 6 enrolled only hepatoblastoma patients with localized tumors. COG ACCL0431 final results were published in the Lancet Oncology.