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Origins and Evolution

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.

Ongoing Challenges

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?

Future Advances in Pediatric Oncology

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.

A Pediatric Oncologist’s View

To that end, I admit that I am not a psychiatrist, psychologist, or social worker. Instead, I work as a pediatric hematologist/oncologist and translational scientist with the strong conviction that a complete, quantitative analysis of cancer and the host in which it arises will provide the path to eradicating cancer. And yes, maybe the above scenario will be all that is needed. Thus, at least on the surface, there would appear to be an inherent conflict between the analytical assessment of cancer and the often-considered less analytical, “scientifically softer” world of psychosocial assessment of patient needs and outcomes. But maybe that conflicting point of view misses the essence of the issue.

In the Plague, Albert Camus strikes at the heart of such issues and apparent conflicting sides (Camus 1947). In the last third of the novel, a magistrate’s child is dying a horrific death from the plague with the key characters at his bedside: Paneloux, a priest; Castel, an experimental investigator trying a new treatment; and Jean Tarrou, a chronicler and companion of Rieux, the protagonist and physician.

When the child dies, Tarrou reflects, “Must we start all over again?” Castel aptly responds, “Perhaps. After all, he did fight it for a long time.”

Rieux abruptly walks away, brushing by Paneloux, who queries, “Come now doctor.”

Rieux turns to the priest and says, “Ah, now that one, at least, was innocent, as you very well know!”

He walks away, but the priest persists: “Why did you speak to me with such anger just now? I, too, found that unbearable to watch.”

In response, Rieux says, “That’s true. Forgive me. But tiredness is a form of madness. And there are times in this town when I can only feel outrage and revolt.”

The debate deepens with Paneloux responding, “I understand. It is outrageous because it is beyond us. But perhaps we should love what we cannot understand.”

Rieux counters, “No, Father, I have a different notion of love; and to the day I die I shall refuse to love this creation in which children are tortured.”

Paneloux retreats a bit and states, “Ah, doctor, I have just understood what is meant by God’s grace.”

Rieux, who will have none of this, retorts, “Which I don’t have, I know. But I don’t want to discuss this with you. We are working together for something that unites us at a higher level than prayer or blasphemy, and that’s all that counts.”

The priest concedes, “Yes, yes, you too are working for the salvation of mankind.”

A bit sardonically, Rieux moves back to reality with, “Salvation is too big a word for me. I don’t go that far. What interests me is man’s health, his health first of all.”

Sensing defeat, the priest says, “Yet, I have not managed to convince you!”

Rieux concedes, “What does it matter? What I hate is death and evil, as you know. And whether you accept this or not, we are together in enduring them and fighting against them. You see, even God himself cannot separate us now.”

Biology and Psychology

And so this complex mix of biology and psychology represents an inseparable weave. What happens in one part inexorably links to and impacts the other. But how does one articulate the right questions to study and the methodological approaches to use? Being at a loss for answers, such considerations in part led me to conceive of using the approach of narrative to help define some of the key questions better than I might otherwise do. To provide immediacy, I concluded that documentary film would provide the substrate to engage patients and their families during all stages of their treatment and in various physical settings, such as while in clinic, the hospital, at school, home, and in transit. Their stories would highlight the complexity of decision-making on their part as well as on that of caretakers, the nuances of research and clinical trials, the difficult issue of patient/caretaker boundaries, access to care and health-care disparities, the hope and fears of survivorship, and the brutal reality of accepting the end-of-life transition. Two incredible documentary filmmakers, Steven Bognar and Julia Reichert, agreed to actualize such a documentary with the film, “A Lion in the House” (http://www.lioninthehouse.com) (Reichert et al. 2011). While not providing definitive answers, I believe the film does accurately phrase key questions and provides a path for thinking together about defining credible answers. So while the quantitative analysis of host and cancer genomes, transcriptomes, epigenomes, proteomes, metabolomes, and kinomes is pursued, the response of patients and families to such catastrophe adds other profoundly complex venues for analysis and support. Most of these challenges are discussed in this book. However, bearing witness to them here is not intended to be redundant, but rather to highlight the continuum of challenges that require preventive and therapeutic intervention while demanding continued investigation.

The first issue that is strikingly evident is that pediatric patients with cancer have profound differences in neurocognitive and psychological capabilities. Pediatric patients also come with immediate and extended families who must grapple with the nuances of the impact of a child’s age on the response to diagnosis, treatment, pain, separation, altered body image, and uncertainty. Such considerations are clearly going to be extremely different for a newborn vs. a 2-year-old vs. an 8-year-old or a teenager. Rigorous tools to study neurocognitive and psychological adaption are still lacking for many of these ages.

The timing of evaluations and interventions also constitutes a continuously changing target. Critical events and responses present at diagnosis (disease description, treatment options, research trial considerations, guilt, fear, hope), during the initiation and continuation of treatment (dealing with adverse effects, including body image, neurocognitive changes, psychological adaption to isolation, pain, fear of dying, separation), and with new challenges that accompany end of treatment and survivorship (fear of recurrence, achieving normalcy and peer acceptance, dealing with resulting treatment and disease-related limitations, questions of fertility, issues of insurability, school, employment). As noted in Koocher and O’Malley’s insightful analogy in “Damocles Syndrome” (Koocher and O’Malley 1981), the realized fear of recurrence and its intense redefining of all the issues previously experienced represent a further challenge for patients, families, caretakers, and investigators.

Access to Quality Care for All

In a speech to the Medical Committee for Human Rights in 1966, Dr. Martin Luther King Jr. stated, “Of all the forms of inequality, injustice in health care is the most shocking and inhumane.” Many people have concluded that the catastrophic nature of a diagnosis of cancer in a child should automatically result in equality of care. Unfortunately, there also exists the reality that unequal treatment and supportive care remain problems. Consider the difference of a young teenage patient from a less fortunate socioeconomic environment taking a bus or taxi by himself for an appointment to receive chemotherapy compared to a child being taken to clinic by his parents in the family car. Consider a single mother balancing the time spent keeping a job while caring for other children and challenged to spend time with her dying, hospitalized child, compared to parents spending that time with their hospitalized child while extended family care for other children and adjustments are made for missed work. There is also the issue of access to new treatments on clinical trials depending upon one’s socioeconomic status. A large percentage of children with cancer have Medicaid or similar insurance plans, which often preclude access to certain treatments or clinical trials if they require travel to another state. The issue becomes even more poignant for patients and their families who live in resource poor countries, where abandonment of treatment, often based on economic considerations, remains a significant impediment to cure. These realities are extraordinarily challenging from a health-care delivery perspective, including psychosocial support, but they also raise important investigative questions in terms of how they impact patient and family adjustment and well-being.

Integrating Care and Discovery

We are left with what might be considered an overwhelming set of problems that involve the total care of patients and their families, including the integration of physical and psychological interventions. There is an essential need to define the methodological approaches to study key psychosocial questions and turn such studies into solutions. William Osler aptly stated in Aequanimitas (Osler 1910) that “Every patient you see is a lesson in much more than the malady from which he suffers.” The challenges of caring for the physical and psychosocial needs of all patients, including children with cancer, are enormous, and, yet, they are magnified by our lack of knowledge concerning the mechanisms that underlie the biology of cancer as well as the human response to disease. The development of new and more effective treatment regimens should include the study and assessment of such psychological, sociological, and quality-of-life responses to therapy. The complexity of such questions should not be a deterrent, but a challenge to be solved. If we had all receded from these challenges in the past, we would still be debating the paradox illustrated by Castel, Paneloux, and Rieux. Such debate should only serve to focus the questions and the potential solutions as achieved through compassionate care and rigorous investigation.