Lessons Learned and to Be Learned: Reducing Risk of Subsequent Malignancies in Childhood Cancer Survivors


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“Despite recent treatment improvements and decreased radiation exposures, vigilant health care, adherence to screening guidelines, and patient education about risks continue to be relevant.”
— Lisa Diller, MD

I recently saw a patient in our survivorship clinic. She was treated at age 15 years for Hodgkin lymphoma and is now in her early 50s. During the prior 2 decades, she had developed both bilateral breast cancer and thyroid cancer, as well as multiple basal cell carcinomas, all occurring within her mantle radiation field. 

This clinical scenario is now all too familiar. Treatments utilized for childhood cancer in the 1970s and 1980s were successful in terms of long-term cure but are now well known to be associated with subsequent cancers. The question now is: as we modified therapy in response to this concern, reducing the dose and volume of radiation and (in some cases) adding more aggressive chemotherapy, did we reduce the frequency of these second cancers? A recent report by Turcotte and colleagues from the Childhood Cancer Survivor Study,1 reviewed in this issue of The ASCO Post, suggests that reduction of radiation exposure does, in fact, reduce secondary cancer risk (as might have been expected), but the risk of subsequent malignancy remains elevated.

Hypothesis Confirmed

The Childhood Cancer Survivor Study is a large retrospective cohort study that enrolled patients who were 5-year survivors of childhood cancer diagnosed between 1970 and 1999. Treatment data were abstracted from medical records and included detailed reviews of chemotherapy, surgery, and radiation treatment. Participants completed baseline and follow-up questionnaires regarding their health, and, if a subsequent neoplasm was reported to have occurred at least 5 years from diagnosis, medical records, death certificates, or pathology reports were obtained to confirm this event. Turcotte and colleagues hypothesized that, over the decades, changes in treatment would result in reduction of the risk of subsequent tumors, both benign and malignant, and that this reduction would be related to reductions in the use of radiation therapy or radiation dose. 

In large part, this hypothesis was confirmed. The 15-year cumulative incidence of malignancy occurring in 5-year survivors decreased from 2.1% for survivors treated in the 1970s to 1.7% for the 1980s and 1.3% for the 1990s, and radiation dose reductions were associated with reductions in risk. 

Clinical Implications

What does this mean for the clinical oncology practitioner in choosing treatment regimens and in caring for survivors? For pediatric oncologists, minimizing radiation dose and treatment volume is now a standard of care; if radiation can be avoided or radiation exposure to normal tissues minimized, using lower doses or conformal techniques for example, this is almost always preferred. Current treatment trials are designed to minimize the number of patients exposed to radiation at all, examining response-based use of radiation after multiagent chemotherapy and (more recently) targeted antibody therapy, and focusing on long-term overall survival rather than event-free survival, accepting a higher risk of salvageable relapse. 

Of course, choosing the appropriate treatment regimen is based not only on subsequent malignancy risk, but on multiple factors including control of the primary cancer and other late-effect risks, such as heart disease, growth impairment, and infertility. Substitution of radiation with intensive chemotherapy does not eliminate late-effects risks. For example, the elimination of prophylactic central nervous system (CNS) radiation for children with leukemia is now standard, based on multiple cooperative group and consortium-based clinical trials showing that intrathecal chemotherapy can prevent CNS recurrence. Although the benefit of avoiding cranial radiation cannot be understated, both in terms of reduction of subsequent cancer risk and avoidance of radiation-associated cognitive impairment, intensification of intrathecal chemotherapy is not without its complications, both acute and long-term.

Similarly, as more patients survive with decreased exposure to radiation, fewer subsequent malignancies will be detected. However, as the authors acknowledge, risks remain elevated, and for certain subsequent malignancies, latency between exposure and new cancers may be long (beyond the 15 years analyzed in this temporal trend analysis). Despite recent treatment improvements and decreased radiation exposures, vigilant health care, adherence to screening guidelines, and patient education about risks continue to be relevant. 

Case Continuation

Back to my patient: She had been treated with mantle field radiation and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy. Her complaint now is shortness of breath. An exam and echocardiogram revealed critical aortic valve stenosis, likely resulting from radiation exposure.  The risk of late-onset radiation-associated heart disease, like second cancer risk, will hopefully decline in future years due to changes in the technique and overall use of radiation.  We await further work and follow-up from the Childhood Cancer Survivor Study to show improvement in cardiac and other late-onset radiation-associated toxicities. 

Disclosure: Dr. Diller has served on the Childhood Cancer Survivor Study (CCSS) Steering Committee and is the principal investigator for the CCSS study at the Dana-Farber Cancer Institute. 

Reference

1. Turcotte LM, Liu Q, Yasui Y, et al: Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970-2015. JAMA 317:814-824, 2017.



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