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Lower radiation doses have decreased incidence of second malignancies in childhood cancer survivors
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Decreased exposure to radiation therapy has lowered incidence of subsequent malignancies in childhood cancer survivors diagnosed in the 1990s compared with those diagnosed in the 1970s, according to results of a longitudinal cohort study.
“We’ve known for several years that radiation therapy puts survivors at high risk for secondary cancers, and treatments have been modified to reduce radiation exposure,” Lucie M. Turcotte, MD, MPH, MS, assistant professor of pediatrics at University of Minnesota Medical School, said in a press release. “Still, no one has shown reducing the exposure has reduced subsequent cancer risk, [and] that’s what we’ve done in this paper.”
Researchers assessed changes in subsequent neoplasms among 23,603 cancer survivors (46% female) from the Childhood Cancer Survivor Study, the largest cohort of cancer survivors in North America. The survivors were aged younger than 21 years (mean age, 7.7 years) at first diagnosis of leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, central nervous system cancer, Wilms tumor, neuroblastoma, rhabdomyosarcoma or bone cancer between 1970 and 1999.
Patient follow-up began 5 years from diagnosis and ended at death or date of last patient-completed questionnaire. The mean follow-up ranged from 15.7 years for survivors diagnosed in the 1990s to 27.6 years for those diagnosed in the 1970s; the overall mean follow-up was 20.5 years, or 374,638 person-years at risk.
During follow-up, 1,639 survivors had 3,115 subsequent neoplasms, which included 1,026 subsequent malignancies, 233 benign meningiomas and 1,856 nonmelanoma skin cancers. The most commonly observed subsequent malignancies were breast and thyroid cancers.
The cumulative incidence of subsequent neoplasms 15 years from diagnosis was 2.9% (95% CI, 2.5-3.3) among survivors diagnosed in the 1970s; 2.4% (95% CI, 2.1-2.7) among survivors diagnosed in the 1980s; and 1.5% (95% CI, 1.3-1.8) among survivors diagnosed in the 1990s (1970s vs. 1980s, P = .02; 1970s vs. 1990s and 1980s vs. 1990s, P < .001 for both).
The cumulative burden of subsequent neoplasms per 100 survivors was 3.6 among survivors diagnosed in the 1970s compared with 2.8 among those diagnosed in the 1980s (P = .02) and 1.7 among those diagnosed in the 1990s (1980s vs. 1990s, P = .001; 1970s vs. 1990s, P < .001).
Survivors diagnosed in the 1990s had a significantly lower 15-year cumulative incidence for subsequent malignancies (1.3%; 95% CI, 1.1-1.5) compared with survivors diagnosed in the 1980s (1.7%; 95% CI, 1.5-2) and the 1970s (2.1%; 95% CI, 1.7-2.4; P < .001 for both).
With each 5-year increment, relative rates declined for subsequent malignancies (RR = 0.87; 95% CI, 0.82-0.93), meningiomas (RR = 0.85; 95% CI, 0.75-0.97) and nonmelanoma skin cancers (RR = 0.75; 95% CI, 0.67-0.84).
Between 1970 and 1999, researchers observed significant changes in therapies. The proportion of survivors treated with radiation therapy decreased from 77% in the 1970s to 54% in the 1980s and 33% in the 1990s.
Further, the median radiation treatment dose decreased from 30 Gy in the 1970s (interquartile range [IQR], 22-44) to 26 Gy in the 1990s (IQR, 18-52).
The researchers noted that the proportion of children treated with alkylating agents and anthracyclines increased over time; however, the median doses decreased. In addition, the number of children treated with epipodophyllotoxins and platinum agents increased over time, but the median cumulative dose of epipodophyllotoxins increased in the 1980s and decreased in the 1990s.
Survivors treated with radiation experienced a higher cumulative incidence of all types of subsequent neoplasms, regardless of the treatment decade.
Mediation analyses that modified adjustments from all treatment variables to specific components of treatment variables — such as maximum radiation dose and other treatments — showed that radiation therapy dose changes were the main cause of era-associated declines of subsequent neoplasm.
“The most ominous late effect of pediatric cancer treatment is a second malignancy. This study shows the efforts to reduce the late effects of treatment are paying off,” study researcher Gregory Armstrong, MD, MSCE, associate member of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital and a HemOnc Today Editorial Board member, said in a press release. “The risk for second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.” – by Melinda Stevens
Disclosures: Turcotte and Armstrong report no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Much effort over the last several decades has been placed on modifying therapy for children with cancer in ways to mitigate late effects, particularly second malignancies, which can be a considerable cause of morbidity and mortality. This study by Turcotte and colleagues is the first to analyze temporal trends in secondary malignancy incidence over time. Their report of over 23,000 childhood cancer survivors from the Childhood Cancer Survivors Study demonstrated a statistically significant reduction in the 15-year cumulative incidence of secondary neoplasms, including secondary malignancies, nonmelanoma skin cancers, and benign meningiomas among children treated in the 1990s compared with those treated in the 1970s or 1980s. The reduced incidence in secondary neoplasms was shown to be due primarily to changes in radiation dose and the decreasing utilization of radiation therapy over time. These results are encouraging, and they demonstrate success of a momentous effort to reduce long-term treatment-related morbidity for childhood cancer survivors. What was not available in this dataset, but is likely also a contributing factor to the reduced risk of second malignancies, is the modification of radiotherapy techniques over time toward the use of smaller field sizes resulting in reduced exposure to normal tissues — for example, the adoption of involved field radiotherapy for Hodkin and non-Hodgkin lymphoma results in reduced exposure to the breast or thyroid gland for many patients compared with the use of large mantle field radiation or total nodal irradiation in earlier years. As radiotherapy has continued to advance technologically since the 1990s in ways that further reduce the radiation exposure of normal tissues, including the widespread use of 3-dimentional treatment planning, highly conformal treatment delivery techniques and image guidance that have allowed for significantly reduced expansion margins and smaller radiation field sizes, we can expect to see declines to continue in the incidence of late secondary malignancies beyond what has been reported in this study. With the rapid rise in use of proton therapy, which significantly reduces the total integral dose delivered to a patient and is becoming standard practice for many childhood cancers, we hope that secondary malignancy risk can be even further minimized.
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