Platinum-based chemotherapy — in particular cisplatin and carboplatin — are a lifeline for children with certain cancers. These treatments, for instance, transformed the prognosis of hepatoblastoma, a rare cancer of the liver that is the most commonly diagnosed in childhood, from a five-year survival rate of 20% to more than 80% for localized tumors.
However, these medications work by damaging the DNA of cancer cells, and they are also known to cause mutations in the DNA of healthy cells, potentially raising the risk of new cancers later in life. The mutations have been documented in adults, but the picture is less clear when it comes to children. A new study published Thursday in Science sought a clearer understanding of the long-term impact of platinum agents in children treated for hepatoblastoma.
The study looked at children who had received platinum therapy followed by surgery to remove the tumor. The researchers sampled tissues from the liver — both healthy and cancerous — and the patient’s blood, analyzing them through a sophisticated DNA sequencing technique called NanoSeq.
They then compared the sequencing results to those from children who had been treated with different drugs, or had not been treated prior to surgery, as well as to fetal liver tissue. They found that being exposed to platinum agents led to hundreds of mutations in genes (on average 2,200 per liver sample), a burden of mutation usually found in adult livers. In other words, platinum aged the liver cells of treated children, making them look more like adult liver cells.
Mutation load also increased proportionally to platinum exposure: children who received only cisplatin had a smaller number of mutations than those who received both cisplatin and carboplatin. These mutations could increase the likelihood of liver pathologies, or the emergence of secondary tumors, the authors said.
“We found lots of cancer genes but also genes associated with long-term changes in liver metabolism,” said Foad Rouhani, one of the authors of the paper and a professor at King’s College in London. However, he stressed that “by no means does that mean that these cells will definitely become cancerous in time. All we talk about is there was evidence for potential for these cells to eventually cause problems further down the line.”
Liver cells showed many more mutations than blood cells, even though chemotherapy is a systemic treatment. “The platinum is doing something differently to liver cells than other cells. Either it’s been metabolized differently or the liver cells are repairing differently, we don’t really know yet,” said Rouhani. This could mean that the liver was more susceptible to the effects of platinum, or it could be the other way around: The extent of the mutations may explain why that liver got sick in the first place.
In a perspective article, Sanjeev Vasudevan and Donald Williams Parsons, both professors at Baylor College of Medicine in Houston, wrote that the findings “provide strong evidence for conducting survivorship studies of children that have undergone treatment for liver cancer beyond their third decade of life.”
For the study authors, its primary contribution lies in establishing that the damage occurs, so clinicians can monitor these patients more closely during their lifetimes, said Rouhani, and identify issues at an earlier stage.
But there could be a prospective impact on treatment. “If we understand the mechanism, can we then eventually be able to design next-generation chemotherapies which are highly effective at treating the cancer but actually leave the background tissue largely untouched?” said Rouhani.