Cancer in children has always been inexorably linked to feelings of unfathomable unfairness, urgent pleas for cures, and the psychological challenges for patients and their families. While the incidence of childhood cancer represents only about 2 % of all cancers, the impact of its treatment extends beyond the child and includes the family and the community. The worldwide incidence of childhood cancer has been estimated to be about 200,000 cases annually. Approximately 80 % of children are cured in developed countries, but that cure rate is inversed in resource-poor countries where often less than 20 % of children are cured. The incidence of cancer also appears to be slowly increasing (Rodriguez-Galindo et al. 2013; Spector et al. 2013; Pritchard-Jones et al. 2013).

The origins of the fight to cure children with cancer arose in the seemingly contradictory efforts of war and welfare with the adoption of nitrogen mustard for the treatment of adult patients with lymphoma. However, the true entry of children with cancer onto this stage had its beginning in the late 1940s with the publication of the Farber and Diamond study entitled “Temporary Remissions in Acute Leukemia in Children Produced by Folic Acid Antagonist, 4-amenopteroyl-Glutamic Acid (Aminopterin)” (Farber and Diamond 1948). Farber went on to establish the Children’s Cancer Research Foundation, later the Sidney Farber Cancer Institute (now Dana Farber Cancer Institute), with the conviction that basic scientists and physicians could work together to eradicate these dreaded diseases.

The promise of finding curative therapies for children and adults with cancer ignited much enthusiasm and hope that in turn led to several important initiatives. These included the engagement of the federal government, culminating, in large part through the efforts of Ms. Mary Lasker and the Citizen’s Committee for the Conquest of Cancer, in substantial financial support through the “War on Cancer” channeled through the National Cancer Act (National Cancer Institute 1971). Subsequent efforts led to the development of more integrated, comprehensive cancer centers, broad-based anti-cancer drug screening (something Farber anticipated early on), preclinical models, pediatric and medical oncology specialty training, as well as the beginnings of cooperative clinical trial groups.

In many ways, the work that focused on curing children with cancer pioneered many of the optimal approaches to understanding and optimizing the treatment of all patients with cancer. One of these lessons was the realization that there was strength in numbers and that progress would depend on trained pediatric specialists working together. The emergence of the Children’s Cancer Group followed by the Pediatric Oncology Group, the National Wilms Tumor Study Group, and the Intergroup Rhabdomyosarcoma Group all paved the course for their merger into the Children’s Oncology Group, well before the clinical trial groups focused on adults began to integrate their work.

Other key approaches took advantage of new scientific insights and the exploitation of older drugs, as many newer drugs lagged behind or were never approved for children. Pediatric investigators and caregivers pioneered the need for optimal supportive care and they established integrated, multidisciplinary care teams. Further, the development of carefully designed national and sometimes international cooperative group clinical trials, has clearly played a fundamental role in improving survival rates to what they are today.

The progress that has been made is clearly momentous, and, yet, there are several important realities that temporize enthusiasm and provide significant challenges. The first is the acknowledgement that cancer remains the leading cause of death by disease in children. Further, there remain several types of cancer with either extremely poor or universally fatal outcomes such as brainstem gliomas and metastatic sarcomas. The unfortunate underside of modern therapeutic approaches, including more intensive treatment regimens and expanded use of radiation therapy and bone marrow transplantation, have resulted in significant adverse, late effects in survivors (Meadows 2003). Oeffinger et al. reported that about 66 % of survivors of childhood cancer had at least one related adverse condition and about 25 % had one serious and potentially life-threatening condition (Oeffinger et al. 2006). Such reports have focused on the physical consequences of survivorship, and as noted throughout this textbook, psychosocial issues constitute an equally enormous challenge. The high survival rates are offset by significant rates of adverse late effects. Thus, if one considers what a true cure rate is, i.e., having a child cured of their cancer without the encumbrances of adverse effects, I believe a recalculation is indicated that results in a figure less than 20 % (80 % minus the 66 % noted above).

Another critical issue is that of the “adolescent gap” of clinical trial participation (Bleyer 2005). The adolescent and young adult populations have low rates of participation in clinical trials, and they have not had the same increases in survival as younger and older patients with cancer. Similarly, data demonstrates that approximately 85 % of children with cancer are in resource-poor countries, without access to clinical trials or often without access to basic treatments. There also remain areas within developed countries in which children have lower survival rates. Both groups of patients represent underserved populations and this must be addressed.

Finally, an issue that may not be commonly considered as problematic is that of our inability to predict whether a new treatment is more likely than not to improve responses and outcomes (Kumar et al. 2005). While this provides caretakers with equipoise when speaking to families about whether to enter a randomized clinical trial, it nevertheless remains a substantial limitation. Essentially, the question arises as to why we are not better at predicting whether a new drug will improve outcomes or not?

A possible solution to such predictive ambiguity may reside in the development of “omic” and refined drug sensitivity testing. The ability to integrate such information in terms of the contextual, biological complexity of a cancer and in a form that would significantly improve our ability to predict meaningful clinical responses from single and combination therapies in individual patients may be one of our greatest challenges. Further, there are also the legitimate concerns for patients and their immediate and extended family members concerning the genomic implications of these approaches, as not infrequently, they result in findings of potentially important inherited disease predisposition in otherwise healthy members of the family. In addition, methodologies to determine how best to define success with such personalized approaches to therapy, resulting in small numbers of patients treated, are in need of development, along with agreement from investigators, drug developers, legislators, and regulatory agencies.

Thus, while there are significant challenges to achieving success in this investigative area, such approaches have extraordinary potential to profoundly change current treatment paradigms. The future of effective in silico predictive testing of drugs prior to treating patients is likely to change the very core of how medicine, and pediatric oncology, is practiced in the future. A direct consequence of these advances is whether there will be equitable access to patients from different socioeconomic and geographic settings. This latter point will clearly be a key issue as to how effective such new technologies and approaches are utilized and judged.

Without invoking the quatrains of Nostradamus, one might envision a future in which you or your child would sense something is wrong, such as a lump in the neck, and go to your physician, in this scenario, an android-based integrative system. The visit would involve an android making automated decisions based on extensive neural networks that would lead to an integrated omic analysis and a diagnosis of a particular type of lymphoma and treatment plan. During this entire scenario, no human would ask you how you feel or what concerns or fears you have if this treatment does not work. While the challenges of the biology are daunting enough, addressing such psychosocial issues represent an equally challenging area, in which, however, many of us find ourselves quite inadequate.