Study Identifies Chemotherapy Agent As Major Risk Factor In Secondary Childhood Cancer

BUFFALO, N.Y. -- Researchers from the University at Buffalo and Roswell Park Cancer Institute have identified a frequently used chemotherapy agent, doxorubicin, as a major risk factor for causing secondary cancers in children and adolescents who survive their initial disease.

While physicians have known for years that second cancers occur in some children who have been successfully treated for an initial malignancy, this is the first study to analyze the effects of the full range of chemotherapeutic agents and radiation therapy used today on the development of second cancers in a group of pediatric cancer patients, said Daniel M. Green, M.D., principal investigator.

"This study gives us the most accurate estimate yet of the incidence of secondary tumors in an unselected group of children following treatment of first tumors," added Green, professor of pediatrics at UB and Roswell Park.

"It allows us to inform parents more accurately about the nature of this complication."

The findings of the study of 1,406 children are reported in the current (November) issue of Medical and Pediatric Oncology and were presented in May at the annual meeting of the Society for Pediatric Research.

Green said the research could result in doxorubicin being removed from some multi-drug chemotherapy regimens if risks are found to outweigh the benefits.

In addition, it may shed light on characteristics of patients who are genetically predisposed to developing second cancers.

"These drugs are very powerful carcinogens," Green said, "but they don’t cause second cancers in everyone. Therefore, the people who do develop cancer must have special characteristics. The biological response of these patients to doxorubicin may be a marker for genetic susceptibility. "

The study tracked a cohort of 1,406 patients less than 20 years old who were treated at Roswell Park between Jan. 1, 1960 and December 31, 1989. The researchers' goal was to identify disease and treatment factors of modern cancer therapy that increase the risk of occurrence of a second malignancy.

Prior treatment with doxorubicin and splenectomy were the only variables found to increase risk at statistically significant levels, Green said.

Radiation therapy, shown in some other studies to increase risk of developing specific types of second cancers, was not a significant risk factor when all types of cancers in this cohort were considered together.

Twenty-five secondary tumors developed in the children in the study. This rate of occurrence represents a five-times greater risk of developing a malignancy than in the New York State population at large, Green said.

To arrive at their conclusions, researchers analyzed the records of 1,406 consecutive children or adolescents, 793 males and 613 females, who came to Roswell Park for treatment for first cancers during the defined study period. All patients were followed yearly. Forty-six percent were 9 years old or younger, 54 percent were between 10 and 20.

The treatment history showed 86 children received surgery only; 60, radiation only; 348, chemotherapy only; 50, surgery and radiation; 151, surgery and chemotherapy; 435, radiation and chemotherapy, and 272, surgery, radiation and chemotherapy. Four patients died before receiving any treatment.

Twenty-five children had developed secondary cancers as of November 1992. The only significant risk factors were splenectomy (surgical removal of the spleen) and treatment with doxorubicin.

The research, Green said, is both exciting and sad.

"Modern cancer therapy is allowing children to survive much longer than in the past. The average age of our study’s survivors is 27. But the treatment leaves some of them vulnerable to another cancer. And many of these secondary cancers are very difficult to treat."

The study was supported by grants from the Association for Research of Childhood Cancer and the National Cancer Institute.

Other members of the research team were Michael A. Zevon, Ph.D.; Peter A Reese; Geoffrey S. Lowrie; John F. Gaeta, M.D.; John I. Pearce; Arthur M. Michalek, Ph.D., and Elizabeth A. Stephens.