Soon after effective therapies for some childhood malignancies were first identified, early leaders in our field had concerns about what would happen to surviving patients as they aged. In 1975, Giulio D’Angio, MD, one of the founders of modern pediatric radiation oncology, presciently called for the “development of ever more refined and precisely targeted methods of treatment, so that the increasing numbers of successfully treated children of today do not become the chronically ill adults of tomorrow.”1 Dr. D’Angio’s concerns were well founded.
Studies analyzing self-reported outcomes in adult survivors treated between 1970 and 1986 suggest that two-thirds have at least one chronic condition, and more than 25% have a serious, life-threatening, or debilitating condition.2 When adult survivors are directly evaluated for specific treatment-related outcomes, the estimate of cumulative prevalence of a serious chronic condition at 35 years after cancer diagnosis is a shockingly high 75%.3
Defining Safe Reductions in Therapy
Nearly all changes in the standards of care for pediatric cancer treatment are based upon results from cooperative group and consortium-sponsored clinical trials. Investigators from an alphabet soup of clinical trial consortia—POG, CCSG, NWTS, IRSG, COG, and others—focused on testing therapies aimed at increasing survival, although reducing long-term toxicity was a surprisingly early goal. In 1969, when the first national study testing Wilms tumor treatment strategies (NWTS1) began enrolling patients, the primary aim focused on reduction in therapy—determining which patients did not need radiotherapy to be cured.4 Over the ensuing 3 decades, we learned that we could safely eliminate radiation therapy for non-Hodgkin lymphoma,5 reduce or completely eliminate cranial radiation in treating leukemia,6,7 lower anthracycline exposure to avoid late congestive heart failure,8 and change the treatment of Hodgkin lymphoma to eliminate leukemogenic alkylating agents9 and to limit radiation use.10
Have these changes in childhood cancer treatment, so carefully studied in clinical trials and implemented as standard therapies, resulted in reduced likelihood of survivors becoming “the chronically ill adults of tomorrow”? Dr. Greg Armstrong, principal investigator of the Childhood Cancer Survivor Study (CCSS), and his colleagues utilized the CCSS to answer this question, looking for declines in late mortality—a potential indicator of burden of significant disease in aging survivors.11 As reported in The New England Journal of Medicine and reviewed in this issue of The ASCO Post, their results tell us that the changes we made have indeed had their impact. The many physicians, nurses, parents, patients, research coordinators, statisticians, and others who have contributed to these efforts, over many decades and in many clinical trials, deserve commendation and thanks.
A Closer Look at the CCSS
The CCSS is a retrospective cohort study of more than 35,000 childhood cancer survivors treated between 1970 and 1999. Participants were known to have survived at least 5 years. Their primary treatments were abstracted from medical records and their outcomes were established through longitudinal questionnaire-based self-report, as well as through examination of publicly available databases such as the National Death Index.
Dr. Armstrong and colleagues analyzed late mortality (beyond the 5-year survival point) over time in this cohort, studying 30 years of treatment changes and 15-year mortality outcomes. They confirmed that temporal changes in childhood cancer treatment indeed involved reduction in radiation exposure and in total dose of chemotherapies known to be associated with late sequelae. The percentage of patients exposed to radiation therapy decreased by nearly half from the 1970s (when 77% of survivors had received radiotherapy) to the 1990s (when only 41% received radiotherapy). Although more patients received chemotherapy in recent decades, the average cumulative dose per patient decreased over time.
Late mortality declined significantly over the 30 years studied. Among the 5-year survivors of childhood cancer whose original diagnosis was made in the 1970s, the cumulative mortality at 15 years after diagnosis was 10.7%; if the original diagnosis was made in the 1990s, this risk was 5.8%. Deaths from late effects, secondary malignancy and pulmonary and cardiac diseases, as well as the primary malignancy declined significantly. Although the decline in mortality could be attributed to better survivor care and screening, it is likely that the changes in therapy over time contributed to this reduction in mortality.
A Wealth of Outcomes
The CCSS is a National Cancer Institute–funded national resource for research in survivorship. Using the CCSS data, investigators from around the world have been able to analyze a wealth of outcomes in survivors of childhood cancer, including risk of chronic disease, health-behavior outcomes, cognitive outcomes, secondary and subsequent cancers, and late psychological health (to name a few). The cohort has provided important information used to inform treatment choice for newly diagnosed patients, direct the clinical care of survivors as they age, and design trials aimed at reducing late toxicity. Studies of biologic specimens collected from participants could lead to identification of genetic markers that may explain the variability of late outcomes and testable hypotheses about etiology and prevention.
The data and the specimens are available to be shared, providing a source of information and materials for new researchers in the field. Continued support for survivor research will be important going forward, as we enter a new era of therapeutic choices for cancer. (More information about the CCSS can be found at https://ccss.stjude.org.)
The Future of Survivorship Research
In combination with surgery and radiation therapy, cytotoxic chemotherapy remains the backbone of treatment for pediatric cancer, and improvements in survival outcomes over time are largely based upon refinement of their use in combination. Recent developments in cancer research have expanded our armamentarium to include antibody-based therapy, tyrosine kinase inhibitors, differentiation agents, cellular therapies, manipulation of the tumor microenvironment, and stimulation of immune surveillance, to name a few. As more biologically based therapies become available, removal of standard cytotoxic agents is a difficult undertaking, given the good outcomes we know we achieve today. However, tumor-specific target inhibition and immunotherapy will likely become a part of standard childhood cancer therapy in the future, at least for some patient groups. Some future therapies are predicted to require chronic oral therapy, a significant change from our current paradigm. No information is available yet to inform us how changes in therapy based upon a precision-medicine approach will impact upon adult survivor health, but we should learn from the early pediatric oncologists to be vigilant about studying the long-term outcomes of our patients. Survivorship research studies describing long-term outcomes of new agents will play an important role in defining the best 21st-century therapies. ■
Disclosure: Dr. Diller reported no potential conflicts of interest.
References
1. D’Angio GJ: Pediatric cancer in perspective: Cure is not enough. Cancer 35:866-870, 1975.
2. Oeffinger KC, Mertens AC, Sklar CA, et al: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355:1572-1582, 2006.
3. Hudson MM, Ness KK, Gurney JG, et al: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309:2371-2381, 2013.
4. D’Angio GJ, Evans AE, Breslow N, et al: The treatment of Wilms’ tumor: Results of the national Wilms’ tumor study. Cancer 38:633-646, 1976.
5. Link MP, Donaldson SS, Berard CW, et al: Results of treatment of childhood localized non-Hodgkin’s lymphoma with combination chemotherapy with or without radiotherapy. N Engl J Med 322:1169-1174, 1990.
6. Pui CH, Campana D, Pei D, et al: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360:2730-2741, 2009.
7. Moghrabi A, Levy DE, Asselin B, et al: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109:896-904, 2007.
8. Lipshultz SE, Cochran TR, Franco VI, et al: Treatment-related cardiotoxicity in survivors of childhood cancer. Nat Rev Clin Oncol 10:697-710, 2013.
9. Schellong G, Riepenhausen M, Creutzig U, et al: Low risk of secondary leukemias after chemotherapy without mechlorethamine in childhood Hodgkin’s disease. German-Austrian Pediatric Hodgkin’s Disease Group. J Clin Oncol 15:2247-2253, 1997.
10. Wolden SL, Chen L, Kelly KM, et al: Long-term results of CCG 5942: A randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin’s lymphoma—A report from the Children’s Oncology Group. J Clin Oncol 30:3174-3180, 2012.
11. Armstrong GT, Chen Y, Yasui Y, et al: Reduction in late mortality among 5-year survivors of childhood cancer. N Engl J Med. January 13, 2016 (early release online).
