Platinum-based chemotherapy, particularly using cisplatin and carboplatin, has been crucial in treating children with specific cancers. These therapies have significantly improved the outlook for hepatoblastoma, a rare liver cancer common in children, increasing the five-year survival rate for localized tumors from 20% to over 80%.
Despite their effectiveness, these drugs work by damaging the DNA in cancer cells, and they can also cause mutations in healthy cells’ DNA, potentially increasing the risk of subsequent cancers later in life. While such mutations have been observed in adults, the situation is less clear in children. A recent study published Thursday in Science aimed to clarify the long-term effects of platinum treatments on children with hepatoblastoma.
The investigation focused on children who had undergone platinum chemotherapy followed by surgery to excise the tumor. Researchers collected samples from both healthy and cancerous liver tissues and the patients’ blood, using a sophisticated DNA sequencing method known as NanoSeq for analysis.
They compared the sequencing outcomes with those from children treated with other drugs or untreated before surgery, as well as to fetal liver tissue. The study revealed that exposure to platinum agents resulted in hundreds of mutations in the genes — averaging 2,200 per liver sample — a mutation load usually seen in adult livers. Essentially, platinum treatment aged the liver cells of the children, making them resemble adult liver cells.
The mutation load increased in proportion to platinum exposure, with children receiving only cisplatin showing fewer mutations than those treated with both cisplatin and carboplatin. According to the authors, these mutations could heighten the risk of liver diseases or the development of secondary tumors.
“We found lots of cancer genes but also genes associated with long-term changes in liver metabolism,” said Foad Rouhani, a professor at King’s College in London and one of the paper’s authors. However, he clarified that this does not definitively mean these cells will turn cancerous over time. Instead, there is potential for these cells to cause issues later on.
Liver cells exhibited significantly more mutations than blood cells, even though chemotherapy affects the entire body. “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 indicates the liver might be more vulnerable to platinum’s effects, or alternatively, the level of mutations might explain the liver’s initial illness.
In a perspective article, Sanjeev Vasudevan and Donald Williams Parsons, professors at Baylor College of Medicine in Houston, emphasized that the findings strongly support the need for survivorship studies of children treated for liver cancer into their thirties.
The primary contribution of the study, according to the authors, is confirming that such damage occurs, allowing clinicians to monitor these patients more closely throughout their lives and identify potential issues earlier, Rouhani said.
Furthermore, understanding these mechanisms might eventually enable the development of next-generation chemotherapies that are effective against cancer while sparing the surrounding healthy tissue, Rouhani suggested.
