Over the past 50 years, great strides have been made in diagnosis, treatment, and survival of childhood cancer. In the 1960s the probability of survival for a child with cancer was less than 25%, whereas today it may exceed 80%. This dramatic change has occurred through significant and steady progress in our understanding of tumor biology, creation of specialized multidisciplinary care teams, incremental improvements in therapy, establishment of specialized centers with research infrastructure to conduct pivotal clinical studies, and the evolution of a cooperative group mechanism for clinical research. Most children with cancer in the United States, Europe, and Japan receive appropriate diagnosis and treatment, although access is limited in developing countries. The price of success, however, is the growing population of survivors who require medical and psychosocial follow-up and treatment for the late effects of therapy. Here we review the progress made in pediatric oncology over the past 3 decades and consider the new challenges that face us today.
This article is a review of Pediatric Cancers in the New Millennium: Dramatic Progress, New Challenges
In his essay on "Reason in Common Sense," the philosopher Santayana said that "Those who cannot remember the past are condemned to repeat it." When one reads the comprehensive review on the history and current status of curing cancer in children by McGregor et al, one might conclude that repeating the success of the past half-century would not be so bad.
A Job Well Done
As the review points out, overall survival for children with cancer has gone from less than 25% to approximately 80%. For some forms of cancer, the cure rate is in the mid to high 90% range. McGregor et al cover most of the waterfront of pediatric oncology successes along with some thoughts on future directions. A notable omission is the absence of a discussion of acute myelogenous leukemia (AML), in which pediatric oncologists have contributed a significant amount of innovative thinking and new approaches to small-molecular and immunotherapeutically targeted therapies.
The authors appropriately point out the important model of collaborative translational and clinical trials that have characterized pediatric oncology from its inception as well as the extension of such models into other areas of medicine, including medical oncology. For example, pediatric cooperative clinical trials groups continue to set the standard for enrolling a large percentage of patients on randomized clinical trials. Adolescents and young adults, however, represent an important exception, as they enter clinical trials at a significant lower percentage than young children.[2,3]
Another area in which pediatric oncology has been out in front of the curve includes efforts to improve the outcome of children with cancer in developing countries. Several programs have initiated twinning centers in developed countries with those in developing countries. These programs have already begun to show improved survival of children with cancer, particularly those with diseases such as acute lymphoblastic leukemia (ALL).[4-9] Important components of such programs involve introducing standardized treatment protocols along with the means to decrease the critically high percentage of children who abandon treatment for a variety of reasons such as economic and travel obstacles.
These programs have also recognized the importance of governmental and public education. An astonishing example is retinoblastoma, a pediatric tumor of the retina, whose analysis coincidently led to the "two-hit hypothesis" of cancer development as well as the identification of Rb, the first true tumor-suppressor gene.[11,12] In developed countries, children with retinoblastoma have a greater than 90% cure rate with excellent preservation of vision, whereas in developing countries, the results are considerably inferior. Important factors in this discrepancy include the lack of recognition of the early signs and symptoms of retinoblastoma as well as the lack of multidisciplinary centers in which children can be appropriately treated. The formation of partnerships between centers in developed and developing countries should be an important advance in the improvement of outcomes for all children with cancer.
And yet, despite the extraordinary advances that have been made over the past 50 years in pediatric oncology, cancer remains the leading cause of death by disease in children. To that end, one might be justified in reconsidering just how successful we have actually been in addition to what major challenges need to be addressed in order to eradicate childhood cancer.
A Job Not Yet Done
Mark Twain stated that "Twenty years from now you will be more disappointed by the things that you didn't do than by the ones you did do." While it is always more uncomfortable to focus on what we have not done and the obstacles that prevent progress, it is critical that we focus on these very issues. I do not pretend to be like Wayne Gretzky, who once explained that "The difference between me and other players is that they know where the puck is, while I know where the puck is going to be." Nevertheless, I will try to gauge where the puck is going to be in pediatric oncology.
One of the enormous remaining challenges in the field concerns how to cure children with high-risk cancers. Some of these include the approximately 20% of patients with refractory ALL, many subtypes of AML, advanced-staged sarcomas, neuroblastoma, Wilms tumor with diffuse anaplasia, high-grade gliomas, and aggressive brain tumors in the very young. Putting this challenge first in the discussion does not undermine the need for efforts to develop less toxic therapies for all patients. However, in the above examples, we are either still not able to cure the majority of patients or the result of cure is arguably worse than being cured. Thus, there needs to be an increasing emphasis on improving our understanding of the biology of these disorders, including their mechanisms of resistance to therapy and the critical survival pathways on which these tumors depend. There also needs to be bold, paradigm-shifting approaches to the translation of new knowledge into clinical trials for such patients.
This last point leads to another significant challenge for the future, ie, how to perform informative, clinical trials in distinct groups of patients with tumors that have increasingly appreciated heterogeneity. Advances in molecular and genetic medicine have led to the conclusion that the genetic makeup of patients from different racial and ethnic backgrounds or of different gender can have profound effects on outcomes. The differences in some instances are due to variations in the absorption and metabolism of drugs, but in most situations, the differences in outcome remain a mystery. One such unexplained association is illustrated by the poorer outcomes in black children with AML compared to white children.[14-16]
The detailed dissection of different types of cancer has further emphasized their extraordinary heterogeneity, even among histologically similar subtypes. One logical, albeit extreme, conclusion to be drawn from such information is that future studies could potentially have cohorts with an N of 1. This would undermine the ability to perform randomized clinical trials or even single-arm studies for determining the efficacy of a new treatment. Alternative approaches will therefore need to be carefully considered, but likely solutions will include the increasing dependence on international trials, the identification of critical genetic or molecular pathways that are shared by groups of patients and their cancers, and the development of more predictive preclinical models.
Predicting Clinical Outcomes
An analysis of randomized clinical trials in pediatric oncology has demonstrated that over the past several decades, investigators have not been able to consistently predict whether a new therapy will result in an improved outcome. Of particular note, the introduction of new therapies has resulted in no improvements in outcome (often with increased toxicity) about 50% of the time. While this inability to predict outcome in such trials leads to ethical equipoise, a less optimistic view might be that we are quite poor in predicting which new therapies will work.
Can truly predictive preclinical models involving animal models or, possibly, computer generated molecular models of patient and cancer, be developed? There are certainly some animal models that have been useful, particularly in the hematopoietic malignancies, but overall, there are precious few truly representative and accurately predictive preclinical models. The development of better models will likely benefit from more rigorous characterization of various cancers as well as the acknowledgement that studies of genetically homogenous host animals and tumors resulting from introduced alterations in one or two molecular pathways may not be optimal approaches. However, it is presently unclear how to build models with underlying genetic and epigenetic heterogeneity and chromosome instability-two important characteristics of human cancers. And while xenograft models may also be useful, they too have significant limitations in their ability to maintain representative genotypes, gene expression patterns, and phenotypes.
Nevertheless, the age of molecular medicine is here to stay. How we utilize its methods to improve our understanding of cancer and its victims will have a major impact on whether we turn such an opportunity into a success leading to improved patient outcomes.
Survivorship and Prevention
The issue of the quality of survivorship for many children and adolescents with cancer must also be considered a critical challenge. The results from a recent study of over 10,000 childhood cancer survivors demonstrated a significantly increased risk of chronic health-care problems as well as shortened life spans compared to their siblings. The patients in the Oeffinger et al study were diagnosed before 1976. Thus, it is possible that the problems associated with pre-1980 treatments have not been repeated in more recent trials and that future generations of survivors will enjoy improved physical and psychosocial health.
While one can hope for such an outcome, it is certainly not guaranteed. The 1980s and 1990s have often been characterized as the decades of dose intensification, suggesting that there may still be significant adverse long-term sequelae awaiting this group of survivors. In either case, there remains a growing need to understand genetic predisposing factors leading to increased responsiveness as well as short- and long-term toxicities. Understanding such mechanisms will be essential to patient follow-up with the aim of predicting adverse outcomes so that effective and timely interventions can be instituted in addition to developing effective prevention strategies.
Of course, the best way to prevent adverse long-term sequelae from cancer and its treatment is to prevent the development of cancer. While prevention efforts have become increasingly important in a wide variety of cancers in adults (eg, those of the colon, lung, and breast), the concept of prevention for pediatric cancers has usually been viewed unenthusiastically as unrealistic. I have always believed this position to be ill-conceived and unimaginative. Pediatrics has often led the way in terms of preventing a wide variety of devastating infections through vaccination programs. It would seem that there is yet an opportunity to extend such approaches to the prevention of common forms of leukemia and other childhood cancers, especially in high-risk individuals. One must be able to dream of the day when infants will routinely receive their DPT, polio, varicella, and ALL vaccinations.
These biologic and clinical challenges are immense but cannot overshadow the challenge of eradicating health-care disparities and access to care for all children (and all patients) with cancer and other catastrophic diseases. This is an area for local, state, national, and global action. It is simply not the case that all children with cancer receive the same care at the same personal and family cost. However, the means to provide such care are within our reach, and people from all backgrounds could work toward that goal.
Challenges as immense as these will take comparable levels of imagination, focus, and support. Resources, yet another challenge, remain insufficient. Inadequate funding of science and health care shortchanges both current and future generations. It is also bad business.
We should be the generation that will not look back with regret and disappointment at the things we didn't do, but instead, be galvanized and unified by what we were able to accomplish. The fight to cure children with cancer represents more than ever an archetype of the problems faced by all people with cancer and other devastating diseases. We may have survived the first few rounds of this fight, but I would judge that we are still in the middle of round 5 of 10, pressed against the ropes and hopefully feeling sufficiently confident that we can win by the time the bell rings.
-Robert J. Arceci, MD, PhD
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