When cisplatin was first used to treat cancer in the late 70s, it made a big impact.

“It was the most extraordinary breakthrough treatment,” says Dr Penelope Brock, paediatric consultant at Great Ormond Street Hospital. “It started as a treatment for testicular cancer, but it wasn’t long before we started using it to treat children’s cancers as well.”

Unfortunately, as well as killing cancer cells, the chemotherapy also killed cells in the inner ear. This left over 60% of children with hearing loss after treatment.

The unexpected side effect has been a focus of Brock’s research since it was first discovered. And now, almost 40 years later, a solution may have arrived.

New research, funded by Cancer Research UK and published in the New England Journal of Medicine, shows a drug called sodium thiosulphate can protect against hearing loss after cisplatin treatment.

“With sodium thiosulphate, we have a real opportunity to make children’s cancer treatment safer. The results have been a long time coming, and I’m so glad they’re finally here.”

Measuring the problem

When Brock and her colleagues first noticed the side effect in the early 80s, it came as a complete surprise.

It’s a legal requirement for drugs to be rigorously tested in animals before they’re trialled in people, but sometimes side effects don’t show up. “We’d measured heart rate and blood pressure and lots of different things, but there had been no indication that the drug affected hearing,” says Brock.

To get a clearer picture of what was happening, Brock started to measure the side effect in children. Working with hearing specialist Dr Susan Bellman at Great Ormond Street, she created a simple way to monitor children’s hearing.

“We could compare children being treated in different hospital and countries with different courses of cisplatin and find out what was more or less toxic to their ears,” explains Brock. “The challenge was for years we couldn’t do anything about it.”

Through this work, Brock and her colleagues noticed a worrying trend. Some doctors were changing or reducing cisplatin treatment to try and reduce the side effects. This risked the treatment not working so well.

“I was really quite alarmed. We were very keen to find something that could protect children from losing their hearing without stopping cisplatin from doing its job,” says Brock.

A potential solution presented itself almost 15 years later, in a phone call from an American neurosurgeon. Dr Ed Neuwelt based in Portland, had been working on a molecule that might prevent cisplatin toxicity, called sodium thiosulphate. When he discovered Brock’s hearing score system, he got in touch and invited her to visit.

Neuwelt had tested the drug extensively in animals, developing special hearing tests to assess if the drug was working. And they’d started using sodium thiosulphate in adults with brain tumours.

The next step was to test if it could protect children from hearing loss.

Putting sodium thiosulphate to the test

Brock and her colleagues set up a clinical trial to test sodium thiosulphate alongside cisplatin in children with a rare type of liver cancer called hepatoblastoma.

“We chose localised hepatoblastoma for a number of reasons,” says Brock. “First, we now treat this cancer with just cisplatin and surgery, so we didn’t have to worry about side effects from other drugs. We also have a way to monitor how successful treatment is, using a marker in the blood called the alpha-foetoprotein, as well as watching the tumour shrink on imaging.”

Finally, children are usually diagnosed with hepatoblastoma at a very young age, around 13 months on average, which makes hearing loss particularly devastating.

“At that age, a child hasn’t learnt language, so it’s incredibly difficult for them to compensate when they lose their hearing.”

The Cancer Research UK-funded trial launched in 2007, with the first patient starting treatment at Great Ormond Street Hospital in December.

Over the next decade, 109 children in 12 countries were treated and monitored on the trial.

The results are in

To test sodium thiosulphate, Brock and her team split patients into two groups. The first group had standard treatment for hepatoblastoma: cisplatin and surgery. The other group had the same course of cisplatin and surgery, but were given sodium thiosulphate six hours after each cisplatin treatment.

For sodium thiosulphate to work it needed to protect children from hearing loss after cisplatin treatment without stopping cisplatin from killing the cancer cells.

And the results suggest it does just that.

Sodium thiosulphate reduced the number of children with hearing loss after cisplatin treatment. Almost 2 in 3 children who didn’t take sodium thiosulphate had some form of hearing loss after treatment. This dropped to 1 in 3 children who took the drug.

Importantly, sodium thiosulphate didn’t stop cisplatin from working. Scientists monitored survival for three years after treatment and figures were similar in the two groups.

“We were so pleased with the results, it was exactly what we were hoping for,” says Brock.

A bump in the road

While Brock’s trial was running, another group of researchers were also testing if sodium thiosulphate could protect against hearing loss in a range of children’s cancers. They published their findings in 2017.

“They showed that sodium thiosulphate can protect the hearing, similar to our results,” says Brock.

But the researchers published an additional analysis of the results, which was not in the original design of study. It suggested that sodium thiosulphate might stop cisplatin working as well as it would on its own.

“It’s made some doctors nervous and could stop them using the drug. But when you actually look at how they did their additional analysis, they’ve compared apples and oranges – the study just wasn’t set up to answer that question.”

What happens now?

Sodium thiosulphate, or Pedmark, is being reviewed for a licence for use in hepatoblastoma in the US and Europe. If that’s granted, further review would be needed to judge cost-effectiveness of the treatment before it could be made routinely available on the NHS.

And if sodium thiosulphate was granted a licence in the future for other tumours, the potential impact of the drug could be huge. Cisplatin is used to treat lots of children’s cancers, either as the initial drug of choice or if other treatments have failed. And although Brock and her colleagues only tested sodium thiosulphate in liver cancer, they think it could be useful in many more.

“This work has been almost 40 years in the making. It’s amazing to reach a point where we have something that could help protect children’s hearing and make cancer treatment safer.”

Katie

Reference

Brock, P, R., et al. Sodium Thiosulfate Protection of Cisplatin-Induced Ototoxicity. New England Journal of Medicinedoi/full/10.1056/NEJMoa1801109.