Adapting Pediatric Cancer Treatments to Spur Early Detection and Reduce Late Effects
Modifying pediatric cancer treatments to reduce occurrence of late effects and promoting early detection -- 5-year analysis of childhood cancers survivors.
CHICAGO—Modifying pediatric cancer treatments to reduce the occurrence of late effects and promoting early detection “is successfully translating into a significant reduction in observed late mortality,” an analysis of more than 34,000 5-year survivors of childhood cancers presented at the 2015 American Society of Clinical Oncology (ASCO) annual meeting has shown.
This improvement has been achieved over the past 3 decades, with all-cause mortality among 5-year survivors dropping from 12.4% to 6% at 15 years after diagnosis, said Gregory T. Armstrong MD, MSCE, a pediatric oncologist at St. Jude Children's Research Hospital in Memphis, TN.
“In just half a century, we have witnessed a remarkable improvement in the survival of childhood cancer. In the 1960s, less than 30% to 40% of children diagnosed with a malignancy achieved 5-year survival,” he said.
“Now, over 80% of children diagnosed with cancer will become 5-year survivors of their diease. As a result, as of 2013 it was estimated that there were over 420,000 survivors of childhood cancer in the United States and, by the year 2020 we would cross the threshold of over one-half million survivors. And, perhaps, even more remarkable, it can now be stated that 1 in every 750 persons in the United States is a survivor of childhood cancer.”
The study analyzed data from the Childhood Cancer Survivor Study, which evaluates long-term health outcomes in 5-year survivors of childhood cancer diagnosed between 1970 and 1999.
Thirty-one United States and Canadian hospitals currently participate in the study. The cohort, initiated in 1994, is an NIH-funded resource; any researcher interested in survivorship can request access to the data or banked biologic specimens.
“Previous work from the Childhood Cancer Survivor Study has identified that by 30 years from diagnosis, 18% of 5-year survivors will be deceased, and this is a time when these survivors are still in their 30s and 40s, relatively young, by anyone's standard,” he said.
These deaths are due to progression or recurrence of the primary cancer; external causes, such as accidents or suicide; and other health-related causes, primarily mortality due to late effects of cancer therapy. While the deaths from cancer progression or recurrence plateau over time, mortality from other health-related causes increases with each year survived since diagnosis.
The study evaluated 34,033 survivors alive at 5 years from a diagnosis of cancer at an age younger than 21 years to determine mortality due to nonrecurrence/non-external causes (NR/NE), which “includes deaths that reflect late effects of cancer therapy,” he said. Median follow-up was 21 years (range: 5-38 years).
Of the 3,958 deaths, 1,622 (41%) were attributable to NR/NE causes; these included subsequent neoplasms (751 patients), cardiac deaths (243 patients), and pulmonary deaths (136 patients).
During the same time period, cumulative incidence of deaths from other health-related causes decreased from 3.5% to 2.1%, with survivors diagnosed in more recent years having a statistically significant lower risk of dying from other health-related causes (including second cancer and heart or lung disease).
Changes in therapy by decade—1970s, 1980s, and 1990s—included reduced rates of cranial radiotherapy (RT) for acute lymphoblastic leukemia (ALL; 85%, 51%, 19%, respectively), reduced abdominal RT for Wilms tumor (78%, 53%, 43%, respectively) and reduced chest RT for Hodgkin lymphoma (HL; 87%, 79%, 61%, respectively). In addition, cumulative dose exposure of anthracycline has been reduced across these three diseases; for example, from 289 mg/m2 for ALL in the 1970s to 158 mg/m2 in the 1990s.
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Reductions in 15-year cumulative NR/NE mortality were observed across treatment eras for ALL (P<0.001), HL (P=0.02), and Wilms tumor (P<0.001).
Cardiac mortality decreased in ALL (P=0.03), Hodgkin lymphoma (P=0.06), and Wilms tumor (P=0.04), and subsequent neoplasm deaths decreased in Wilms tumor (P<0.001).
Year of diagnosis (adjusted for age, sex, diagnosis, and follow-up time) was significantly associated with a reduced risk of death from subsequent neoplasms (RR=0.84, CI: 0.78, 0.88), cardiac death (RR=0.77, CI: 0.68, 0.86) and pulmonary death (RR=0.77, CI: 0.66, 0.89).
“The now decades-long strategy of designing pediatric cancer treatment regimens with a focus on adult health and avoidance of late effects appears to have been successful. Taken along with the promotion of early detection of early late effects and improved treatment of late effects, this approach is now translated to extend the lifespan of many survivors of childhood cancer,” Dr. Armstrong said.
“Future directions include the need to assess the true impact of screening and early detection of late effects on mortality and the need to determine to what degree temporal changes in treatment have reduced the incidence of late effects, so that we not only extend the lifespan of survivors but their health span as well,” he concluded.
“For decades, we've strived to avoid the paradox in which children survive cancer, only to become sick or die years later because of the treatment they received,” said ASCO Expert Stephen Hunger, MD, in an ASCO press release.
“By carefully refining pediatric cancer treatment, we have improved long-term care and outcomes by leaps and bounds. Cure rates have increased with parallel decreases in death due to complications of cancer treatment. We hope that the positive trends we're seeing today will continue as our therapeutic approaches continue to improve over time.”
- Armstrong GT, Yasui Y, Chen Y, et al. Reduction in late mortality among 5-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS). J Clin Oncol. 2015;33:(suppl; abstr LBA2).