Journal of the National Cancer Institute Advance Access originally published online on September 9, 2008
JNCI Journal of the National Cancer Institute 2008 100(18):1271-1273; doi:10.1093/jnci/djn306
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Published by Oxford University Press 2008.
EDITORIALS |
Progress in the Curative Treatment of Childhood Hematologic Malignancies
Affiliations of authors: Hematologic Diseases Section, Pediatric Oncology Branch (ASW), Center for Cancer Research (LJH), National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences and Children's Oncology Group, COG Chair's Office, Bethesda, MD (GHR)
Correspondence to: Alan S. Wayne, MD, Hematologic Diseases Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 1W-3750, MSC 1104, 9000 Rockville Pike, Bethesda, MD 20892-1104 (e-mail: waynea{at}mail.nih.gov).
Hematologic malignancies account for approximately 40% of childhood cancer (1). Progress in the curative treatment of this group of cancers is one of the great medical success stories of the 20th century. There have been improvements in outcome for all major subtypes of pediatric leukemias and lymphomas, the most dramatic of which has been in acute lymphoblastic leukemia (ALL), the commonest childhood malignancy. At the time that the National Cancer Act of 1971 (Public Law 92-218) made the "conquest of cancer a national crusade" (President Richard M. Nixon, December 23, 1971) fewer than 10% of children with ALL survived for 10 years after diagnosis. Survival rates for children diagnosed with ALL have increased steadily over ensuing eras and now exceed 80% (2,3). Improvements in survival for childhood hematologic malignancies have been achieved as the result of serial clinical trials conducted by pediatric oncology cooperative groups and large single clinical research centers. Essential to these therapeutic advances has been the development of effective agents, along with combination chemotherapy and treatment phase–specific and central nervous system–directed regimens. The definition of clinical, pathological, and biologic risk groups has facilitated the critically important evolution of risk-based treatment stratification. This risk-based treatment approach occurred largely in the absence of new therapeutic agents over the past decade and represents the application of individualized cancer therapy before the introduction of molecularly targeted agents. Intensified regimens, including the judicious use of stem cell transplantation, have led to better outcomes for higher risk groups and for those who relapse. Equally essential has been the incorporation of aggressive multisystem supportive care, such as transfusion therapy and anti-infectious prophylaxis and treatment. As a consequence, hematologic malignancies, and pediatric oncology clinical trials in general, have become models for the successes of comprehensive cancer care.
Despite this dramatic and steady progress, the limitations of historic approaches to the treatment of pediatric hematologic malignancies have become clearer in recent years. As cure rates have risen, the rate of continued progress has plateaued. Treatment intensification seems unlikely to improve cure rates much further, and the risks of morbidity and mortality will continue to mount with this approach. Notably, despite the relative explosion in biologic discovery, few molecularly targeted agents have yet been integrated into standard therapy for pediatric hematologic malignancies (4,5). The incorporation of molecularly targeted agents into standard treatment will be essential, albeit challenging, if continued progress is to be made. Although the majority of children with hematologic malignancies are cured, leukemia remains the most frequent cause of death from cancer in children and adolescents (6). The outlook is particularly poor for certain subgroups, including infants and those with specific high-risk biologic characteristics such as Philadelphia chromosome–positive ALL. Although survival rates for ALL, non-Hodgkin lymphoma, and Hodgkin lymphoma now approach or exceed 90%, cure rates for children with acute nonlymphoblastic leukemia have only recently surpassed 50%. Importantly, long-term survival is not the sole measure of success of cancer therapy, and quality of life after treatment must be considered. Current therapies are associated with a wide array of acute and late toxic effects, the consequences of which are becoming increasingly apparent. For example, late effects of treatment affect more than two-thirds of long-term survivors of childhood hematologic malignancies, and 20%–30% of all survivors have severe, life-threatening, or fatal health conditions (7). Furthermore, the incidence of such toxic effects appears to continue to increase over time. Finally, current therapies are complex and expensive, which creates great challenges for patients, families, and medical care systems.
Five- and 10-year survival outcomes are generally employed in the assessment of cancer clinical trials. Consequently, the final evaluation of the success of a new treatment often lags well behind its implementation. New approaches that allow assessment of results earlier in the performance of clinical trials are essential if therapeutic progress is to keep pace with scientific developments. To that end, in this issue of the Journal, Pulte et al. (8) report results of their application of period analysis to estimate recent survival trends for children with pediatric hematologic malignancies. They assessed the 5- and 10-year survival of pediatric patients reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results database over three 5-year intervals from 1990 to 2004 and modeled expected survival for 2005–2009. Their projections suggest continuing improvements in survival outcomes for children with ALL, acute nonlymphoblastic leukemia, and non-Hodgkin lymphoma. This is potentially good news for future patients, their families, and society as a whole. However, the plateauing of survival improvements in ALL, non-Hodgkin lymphoma, and Hodgkin lymphoma reported by Pulte et al. indicates that we may be approaching the maximum achievable benefit from current treatment regimens. Also of concern are the authors’ 25-year survival projections, which reflect the occurrence of late deaths.
The projection methodology employed by Pulte et al. is based on the assumption that linear trends in survival from early periods continue into the future. Like any modeling technique, such projections may prove to be incorrect. Will past trends predict what is to come, particularly as novel molecularly targeted individualized approaches are incorporated into treatment?
Time is of the essence for children who have or will develop cancer. They cannot "afford" the historically prolonged process of designing, implementing, conducting, and evaluating new clinical trials. Pulte et al. (8) provide a prediction of the anticipated survival rates of recent clinical trials for pediatric patients with hematologic malignancies. If their projections prove to be valid, this approach may facilitate earlier evaluation of molecularly targeted agents and more rapid advances in therapy. Although the distance between 90% and 100% on a survival curve is short, history suggests that the time to close that final gap is long. If the National Cancer Act represents a promise to future generations of children with hematologic malignancies, we still "have miles to go before [we] sleep" (9) if we are to keep such promises. It seems clear that intensifying therapy further will result in little additional long-term survival benefit. By contrast, recent data offer proof of principle that the addition of molecularly targeted therapy to standard therapy can dramatically improve event-free survival in children with Philadelphia chromosome–positive ALL compared with both historic controls and contemporaneous patients treated with matched sibling donor allogeneic stem cell transplantation (10). We argue that there is no time to sleep; rather the pediatric oncology community should work tirelessly to define and validate the targets that can be exploited therapeutically in other subgroups of hematologic malignancies of childhood.
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J Natl Cancer Inst 2008 100: 1301-1309.
J Natl Cancer Inst 2008 100: 1269.
J Natl Cancer Inst 2008 100: 1269.
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