After surviving childhood cancer, patients who experience a subsequent neoplasm face a large increase in the risk of developing additional neoplasms, with more than one-quarter developing third or subsequent tumors, and particularly high rates found among those treated for nonmelanoma skin cancers, according to the authors of a large study published June 27 in the Journal of Clinical Oncology.

Over the last half-century, survival of childhood cancer has spiked sharply, from 30 percent of patients living longer than five years in 1960 to nearly 80 percent today. In 2005, it was estimated that approximately 328,000 survivors of childhood cancer were living in the U.S.

Despite this improved survival rate, aging survivors are not out of the woods. “Perhaps the most serious late complication for these survivors is the development of subsequent neoplasms (SNs), many of which are subsequent malignant neoplasms,” wrote Gregory T. Armstrong, MD, MSCE, from St. Jude Children’s Research Hospital in Memphis, Tenn., and co-authors. As the most common cause of treatment-related deaths in long-term survivors, “it is clear that the development of subsequent malignant neoplasms is a central issue for aging survivors,” Armstrong and colleagues offered.

The authors reviewed the rates of various cancers and tumors among a group of 14,358 childhood survivors of cancer who underwent initial treatment between 1970 and 1986 and were under 21 years of age at the time. Subjects were part of the Childhood Cancer Survivor Study (CCSS) and had been treated for initial diagnoses of leukemia, central nervous system malignancies, lymphomas, Wilms tumors, neuroblastomas, soft tissue sarcomas or bone tumors.

After a mean follow-up of 23 years, 9.6 percent of the nearly 15,000-patient cohort experienced SNs. Among these patients, more than one-quarter developed a second SN, and 39.6 percent of patients with a second SN developed third or later SNs.

Nonmelanoma skin cancer represented the most common SN, with a total of 1,104 episodes and occurring as the first SN in 485 of the 1,382 survivors who eventually developed SNs. Meanwhile, survivors of a primary Hodgkin’s lymphoma had the highest incidence of second SNs, reaching 50.3 percent of patients.

Among 176 patients with breast neoplasms as their first SNs, 37 developed a second breast SN. Other common SNs that “raise concern,” according to the authors, included meningiomas, cancers of the thyroid, soft-tissue carcinomas and central nervous system malignancies.

Patients diagnosed with SNs at older ages (30 years or above) faced significantly higher risks of developing second SNs. Exposure to radiation likewise paired with increased SNs, though the authors considered age to be a major confounder in this relationship.

“With increased follow-up time, survivors of childhood cancer are at increasing risk for multiple subsequent neoplasms,” the authors wrote. “Although previous studies have identified occurrences of multiple subsequent malignant neoplasms, the number of patients reported in any one study has been too small (range, two to 32) to allow detailed description and analysis.”

The authors emphasized the importance of further studies, particularly utilizing biospecimens from the same participants, to better identify genetic risk factors for SNs. In one example, Armstrong and colleagues noted that patients treated with radiation whose first SNs were nonmelanoma skin cancers encountered twice the risk of developing an invasive neoplasm compared with patients likewise exposed to radiation but who had an invasive malignant neoplasm as their first SN, rather than nonmelonma skin cancers.

“Considering the young age (median, 32 years) of the CCSS cohort, these survivors have yet to reach ages when sharp increases in the incidence of cancer in the general population occur. Therefore, it appears that the multiple tissue injuries accrued as a result of cancer therapy, along with the impact of genetic susceptibility of some survivors to multiple cancers, set the stage in the second decade of survival (median follow-up, 18 years) for a significant increase in the number of survivors with multiple cancers,” the authors added.

Armstrong and colleagues’ results highlighted the importance of annual dermatologic and other forms of screening, they said, particularly as more years increase patients’ risks of SNs.