Childhood Cancer Research Challenges and Opportunities

An American Cancer Society Expert Roundtable Discussion

Children with many types of cancer are far more likely to survive the disease today than they were less than half a century ago. Take for example the 5-year survival rate for those with acute lymphocytic leukemia (ALL) – the most common cancer in children – it stands at about 90% today, up from 57% for children diagnosed from 1975 to 1979. Similar jumps in survival have occurred for numerous other childhood cancers.

But some childhood cancers have seen little or no survival progress, and cancer remains the leading cause of disease-related death in children and adolescents aged 0 to 19. And, many of the treatment improvements that have led to better survival in certain childhood cancers are often largely ineffective in other, more aggressive cancers.

There is also growing recognition and understanding of the harmful side effects that survivors of childhood cancer often face later in life as a result of toxic treatments like radiation and chemotherapy. Researchers, health professionals, and advocates are making increasing efforts to address these and other quality of life issues – not just physical, but emotional and financial as well – that young people with cancer and their families face.

For experts in the field, the topic of childhood cancer evokes both enthusiasm about great progress and frustration with barriers they have yet to overcome. In this Q&A, we invited a roundtable of top childhood cancer experts to share their perspectives on what has been accomplished, what more needs to be done, and the unique challenges children, adolescents, and young adults with cancer – and their loved ones – face during and after treatment.

The expert roundtable:

Kevin Shannon  in lab

Kevin Shannon, M.D.

Professor of pediatrics in the Department of Pediatrics at the University of California, San Francisco, School of Medicine. Shannon is a long-time pediatric cancer researcher and has made numerous breakthroughs in this area. He is also an American Cancer Society Research Professor.


Joanne WolfeJoanne Wolfe, M.D.

Director of pediatric palliative care at Boston Children’s Hospital and division chief of the Pediatric Palliative Care Service in the Department of Psychosocial Oncology and Palliative Care at Dana-Farber Cancer Institute. Wolfe has devoted her career to helping children with advanced cancer. She is a former American Cancer Society grantee and was honored in 2013 with the Society’s Pathfinder in Palliative Care Award for her pioneering work in this field.


Ching-Hon Pui

Ching-Hon Pui, M.D.

Chair of the Department of Oncology at St. Jude Children’s Research Hospital. Pui’s research involves the development of “total therapies” for children with leukemia. Pui is also an American Cancer Society FM Kirby Clinical Research Professor.


Archie Bleyer

Archie Bleyer, M.D.

Clinical research professor at Oregon Health & Sciences University. Bleyer conducts original clinical research in the area of adolescent and young adult (AYA) oncology. He is also a former American Cancer Society grantee.

Q. What progress have doctors and researchers made in treating children, adolescents, and young adults with cancer?

Ching-Hon Pui, M.D. 

Childhood cancer is arguably the most remarkable and rewarding story of cancer treatment in the last half century.

Five-year survival rates for many childhood cancer types have increased steadily. Similarly, cure rates for specific cancers have improved dramatically in recent decades, including for patients long considered at increased risk for a poor outcome because of their age or racial and ethnic background. St. Jude has demonstrated that with the right treatment and supportive care those survival gaps shrink and disappear.

While the causes of cancer in children, adolescents and young adults are still not fully known, genome-wide association studies (looking at sets of DNA in different people) and next-generation genome sequencing, for example, as conducted by the St. Jude - Washington University Pediatric Cancer Genome Project, have transformed our understanding of cancer biology and the genetic abnormalities responsible for cancers in younger patients. Work is really just beginning to evaluate if the genetic abnormalities driving cancer in adolescents and young adults have more in common with children or adults. In younger patients, evidence suggests that up to 10% inherit gene mutations that are a major contributor to their cancer. That susceptibility might leave individuals particularly vulnerable to developing cancer in specific environments. In fact, there is growing evidence that inherited genes help to explain some long-recognized racial and ethnic differences in the incidence of certain pediatric cancers as well as their risk of relapse.

Kevin Shannon, M.D. 

There have been major advances in understanding the molecular basis of childhood cancers in the last few years.

We now know a lot more about the inherited and acquired mutations that cause pediatric cancers. On the other hand, although we know more about the gene mutations in some of the most advanced and aggressive pediatric cancers such as acute myelocytic leukemia (AML)alveolar rhabdomyosarcoma (ARMS), and stage 4 neuroblastoma, this increased knowledge has not yet been translated into new treatments. There have been some notable exceptions such as combining a targeted drug with conventional chemotherapy in children and teens with Philadelphia chromosome-positive ALL.

Joanne Wolfe, M.D. 

Over the past 15 years or so, importantly, there has been an increasing awareness that we need to focus on the cancer experience and quality of life of children with cancer.

Over the past decade, for example, we have focused a lot on describing the childhood cancer experience. We have uncovered that there is a need for greater focus on communication and how we disclose diagnoses from the beginning to the end of the experience. We have been focusing on amplifying the child's voice and enabling them to report directly on their experience using technology, which kids are very proficient at, to help on a routine basis to report on their symptoms and quality of life.

What we have uncovered from the perspective of the child is a continued need to improve our approach to symptom management because they report high levels of distress. For example, over 50% of kids with advanced cancer report pain and that pain is highly distressing. Fatigue is another symptom that kids report with a high prevalence. We haven't really made very much progress in even thinking about the multidimensional aspects of the experience of fatigue or low energy in children with advanced cancer. But, we have found that simply the opportunity to consistently report on quality of life led to some improved quality of life outcomes, especially with regard to psychological well-being.

Archie Bleyer, M.D. 

When I started my career, some 45 years ago, about 90% of children with cancer were dead in just a few years and now the survival rate is greater than 80%.

It did take year after year of hard effort, but the progress in childhood cancer has been a great medical accomplishment. And, there have also been great advancements for adults – those over age 40 – with cancer. The problem is for those in between – the adolescent and young adult age group consisting of those aged 15 to 39. It is not that there hasn’t been progress, but in comparison to children and to older adults, this group lags behind. In the last 10 years, there has been improvement in survival for this age group, but in comparison to children, adolescents and young adults lag far behind – and they have actually flipped with children in terms of survival. Adolescents and young adults used to be better off than children in terms of 5-year survival rates for all cancers, but now the reverse is true.

Q. What are the unique issues that adolescents with cancer face? And, what more research is needed in this area specifically? 

Ching-Hon Pui, M.D.

Adolescents and young adults diagnosed with cancer have unique psychosocial and medical needs that are challenging to their developmental phase.

These include loss of emerging or newly gained independence, isolation from peers, concerns for future fertility, impact on academic and vocational goals, and threat to future health care and insurance access. The Society for Adolescent and Young Adult Oncology was formed to improve care and treatment of these patients through interdisciplinary research, education, communication and collaboration among health professionals worldwide. There is now a journal and annual meeting focused on this group of cancer patients. These efforts reflect the belief that patients between the ages of 15 and 39 are a distinct patient population within oncology.

Pediatric and adult oncology research and clinical agendas are now designed to focus on the unique biological, clinical, psychosocial, and survivorship issues of these age groups. Therefore, significant advances in adolescent and young adult cancer care will require a focused research approach.

I am particularly pleased that adolescent and young adult cancer patients are starting to receive some much needed and deserved research attention. For too long, patients in these older age groups were not routinely enrolled into clinical trials by the research community, which limited the ability to test new treatment options, but in recent years that has started to change. More and more adolescent patients are enrolled in cancer treatment protocols, so there is reason to hope that treatment outcomes should dramatically improve in the coming years.

Among patients with leukemia, older children and adolescents have historically had poorer treatment outcomes than younger children. The reasons for this have been poorly understood. Recent efforts have focused on the biological basis for these differences and have begun to identify important genetic differences between leukemia in adolescents and children. This will continue to be an important area of research across the spectrum of childhood cancers.

Joanne Wolfe, M.D.

Adolescents are going through enormous developmental and growth opportunities – from physical to psychological to social and sexual changes – and all that is disrupted when facing a diagnosis of cancer.

There is a lot to think about developmentally when it comes to an adolescent that is different from a younger child. They are in a period of aiming towards independence and the experience of an illness often keeps them very connected to their families, in ways that are of course beneficial, but also can limit their opportunities to explore life like healthy adolescents normally do. We have to be aware of that disruption as we are caring for adolescents with cancer and we need to figure out ways to smooth that over a little bit, fostering healthy development concurrent with cancer care.

I think we have to be more sophisticated about our interventions and strategically think about what is and is not going to work. For example, one of my mentees is working on an intervention aimed at enhancing resilience throughout the cancer diagnosis, especially targeting adolescents and young adults. The intervention is not only focused on the adolescent, but also on the family, because we know that empowering the entire family can lead to better psychological outcomes in all family members.

Archie Bleyer, M.D.

Not only are adolescents facing different challenges, but they also have different kinds of cancer.

Overall, they are facing an array of different obstacles. First off, being an adolescent is hard enough. For any healthy adolescent, that is the age of turmoil. Issues of race and ethnicity, drug use, sexual development, becoming educated, the challenge of finishing high school and getting accepted to college – it is the hardest time in life for almost everybody. And, then imagine adding a potentially fatal disease to that set of challenges. These adolescents are already challenged and you add the issue of cancer and the stigma it creates, as well as the potential loss of life, at a time when everything is compressed – you graduate, go on to college, etc., in such a few years’ time – cancer is something that completely puts all of that at risk. So, the psychosocial development of adolescents is so different and their challenges are unique and inordinate.

They also face financial challenges. Fortunately, now with the Affordable Care Act, all children up to age 26 can stay on their parents’ health insurance – so now they are much more hopeful of being able to get to the best care that they need. That has really helped with that challenge. Nonetheless, the challenges of finding a way to get education and become employed gets so much harder with cancer. Fortunately, we are making more progress in this group. Adolescents have had more progress in the past decade than young adults have in being placed on clinical trials. This has been a significant improvement – there has been a doubling or even tripling in the number of adolescents being put on clinical trials for cancers, which is the real hope for the future because their cancers are different and they need different strategies and clinical approaches. Unfortunately, for those older than age 18 and 19, there is no evidence that their placement on clinical trials has improved one bit since 2000. So, my concern is the gap may grow even greater in young adults.

Q. What are the biggest challenges in child, adolescent, and young adult cancer research, and what strategies are being used to overcome them?

Archie Bleyer, M.D.

New drug discovery is an obvious need for children, adolescents, and young adults.

Cancers in children, adolescents, and young adults are so different that each age group needs its own research effort. And, each cancer needs its own set of treatments – although we are learning that some cancers that seem different can be treated similarly.We need to find new drugs for these cancers – and do the clinical trials. That is where children have had the best outcome, because they have had the highest percentage of patients on clinical trials (more than half) – that is how we have learned which drugs to use to treat their cancers. Adolescents on the other hand have had much lower percentages participating on clinical trials (10%) – so we are missing learning about the drugs needed to treat their cancers.

The main problem is that the local healthcare delivery systems are not yet fully comfortable with clinical trials in the adolescent and young adult group. The health professionals aren’t bringing it up as a primary need for patients in that age group. In children, they do bring it up early – they say: “We have a clinical trial for you.” This doesn’t happen in adolescent and young adult oncology. It is not just health professionals though; there is also the difficulty of trying to get the patients to a clinical trial. A patient has to go to a major cancer center. This is highly organized in children (numerous foundations and organizations help with this). And for an adolescent, who is mired in their social network, settled in their high school, etc., it may be harder for them to leave emotionally and physically in order to go where the clinical trial is.

The lack of clinical trials for this age group is also partly due to financial limitations. For the pharmaceutical industry, what is their motivation to develop agents for patients for whom they make little to no profit? The percentage of adolescents and young adults with cancer, although higher compared with children, still represents a very small portion of the total cancer patient population. The drugs companies see this, but, we need to overcome it.

We need to take the lessons learned in pediatric oncology and apply them to adolescents and young adults. I like to say that the transition between pediatric and adult medicine has created an artificial barrier. Now, we are asking doctors to take care of this overlap group. We have to overcome this artificial idea of children versus adults. We need to rethink and develop a new discipline of young doctors who can take care of adolescents and young adults. And, we as a society have to overcome the idea of someone turning 18 and suddenly becoming an adult. This artificiality is also hurting medicine.

Joanne Wolfe, M.D.

While the number of children affected by cancer is relatively small, the experience has a ripple effect not only for the child, but also for the family.

Some of our research, for example, has uncovered high financial distress, significant financial losses as a result of the childhood cancer, families going from being at middle income levels to poor directly related to their child's cancer experience. That ripple effect is huge. Among children who do not survive, there are long-lasting effects among parents including high risk of anxiety, depression, sick leave and related economic consequences. Bereaved siblings also have a high period of vulnerability, especially in the year following the child’s death. Taken together, childhood cancer impacts on the immediate family and even the larger community to a very high degree.

As noted, there are many children who survive, but survivorship comes with consequences of the cancer experience and treatment. Some have long-lasting physical vulnerabilities like risk of heart disease or secondary cancers. Certainly childhood cancer brings with it opportunities for psychological growth, but some long-term survivors also live with learning disabilities and other neuropsychological long-term side effects such as post-traumatic stress disorder. These in turn impact on relationships, employment opportunities, and overall wellbeing. Due to this ripple effect, it is really important to recognize the need for funding to support research to improve not just cancer survivorship, but also the long-lasting effects that the cancer experience results in for the child, the family, and the larger community.

Ching-Hon Pui, M.D.

While great strides have been made in understanding and identifying the genetic basis of pediatric cancers, development of specific targeted therapies continues to lag.

Indeed, many recently identified specific genetic abnormalities are not targetable with current therapies. Much work is being done now to develop more targeted and novel therapies, and to determine the role of these genetic changes in tumor formation and treatment responsiveness. In addition, there is always a challenge to secure enough funding to conduct the comprehensive clinical and accompanying genomic studies in a large enough population to make discoveries in children with cancers, who make up only a small percent of all cancer patients. Because the pediatric cancer community is so well organized and interactive, the percentage of children with cancer being enrolled in clinical trials is much larger than adults, but cuts in NIH funding are limiting the science that can be done.

Kevin Shannon, M.D.

A major challenge is that many advanced solid tumors remain very difficult to treat despite intensive research.

Advanced solid tumors have remained problems in part because we have essentially maxed out what one would consider to be standard treatments such as chemotherapy and radiation. There have not been that many new chemotherapy drugs for childhood cancers in the last 15 or 20 years. And, there are going to be some tumors that aren’t going to respond to these standard treatments and for these we need entirely new treatment paradigms. We won’t stop using traditional approaches, but we need other approaches such as targeted therapies and immunotherapies.

Drug resistance in patients who relapse after an initial response to treatment is another major problem. Researchers are trying to address these issues by developing better preclinical models for testing drugs and drug combinations (both in tissue culture and in mice) and by investigating new treatment approaches. What we will see in the next decade is selecting tumors based on genetics. We will look at what mutations are present and apply the appropriate treatment. Initially, we will continue to use standard treatments, but over the longer haul we will be able to identify newer treatments that will allow us to back off on radiation and some of the more toxic chemo drugs that lead to late effects and second cancers. A lot will depend on improvements in precision (personalized) medicine and advanced tumor sequencing technologies, which will allow us to better understand what mutations are present and target therapy at them specifically.

Q. While there are more effective treatments available today than in the past for some pediatric cancers, many of the treatments that do exist involve toxicities that cause serious symptoms and/or subsequent late effects that interfere significantly with quality of life. What advances in treatment have been made to help address these symptoms and late effects that will help improve quality of life alongside survival?

Archie Bleyer, M.D.

The importance of adverse late effects is inversely proportional to the age of the patient when diagnosed.

The average age of diagnosis of cancer is 67. So, if the average survival is 10 years, then there is only a 10-year risk of late effects. But in children, they have to live with that late effect for their entire life and the same is true for adolescents and young adults. We have worked very hard on this problem, especially in pediatrics. First of all, we started curing these children in the 1960s and 1970s and now they are in their 40s and 50s and we have now started to learn from them because we have been able to follow them.

These late effects are every serious. First of all, there is the risk of developing another cancer. The treatments themselves have the potential to cause cancer. As we have learned that, we can replace or adjust therapies that cause cancer with less cancer-causing treatments. Hodgkin lymphoma and Ewing sarcoma, for example, have very high rates of second cancers. But we worked hard at finding out what causes it and either replaced the drug with a different agent or eliminated the drug because we found the group didn’t need it. And, in Hodgkin lymphoma, the second cancer rate has dropped dramatically in young patients who originally had that type of cancer. But, we have not achieved the same in older children.

Ching-Hon Pui, M.D.

The Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime (SJLIFE) study have identified specific anticancer therapies that adversely affect childhood cancer quality-of-life outcomes.

These research initiatives have been instrumental in characterizing the social, demographic, genetic, treatment, and behavioral factors contributing to excess risk of late morbidity and mortality and informing health screening and surveillance recommendations for long-term survivors. The field of pharmacogenetics represents one important advance in understanding drug toxicities, particularly individual patient variation in response to chemotherapy agents like mercaptopurine and thioguanine. St. Jude has already begun to incorporate this approach into clinical care.

Kevin Shannon, M.D.

I think the ongoing efforts using DNA sequencing and other techniques to identify patients who have a favorable prognosis will lead to less intensive treatment and fewer late side effects.

Also, replacing genotoxic (genetically damaging) drugs and radiation with more targeted treatments is another promising idea that is in early stages. Many pediatric oncology centers are also developing programs to follow patients long term to try to recognize and intervene early to reduce adverse late effects. 

Q. What more research needs to be done to reduce the likelihood and severity of late effects?

Archie Bleyer, M.D.

The late effects issues in adolescents and young adults have not been studied as much.

There has been a response, though. In the U.S., there are people working on the problem – new programs and centers are springing up all the time. Indeed, it is very impressive what is occurring across the country. What is lacking is organization. The centers and institutions that have discovered how to deal better with late effects issues are not sharing information and collaborating. There is a national late effects program for children, but we don’t have one for adolescents and young adults. That is going to happen, I just wish it would happen sooner than I expect it will.

Joanne Wolfe, M.D.

Research should be aimed at improving the cancer experience and long-term outcomes through the systematic development, evaluation and dissemination of interventions.

Many clinical trials are now aimed at modifying cancer-directed treatments to minimize long-term side effects and consequences. Then there are interventions focusing on the child as a person. These complex interventions might, throughout the course of childhood cancer treatment, enhance the resilience of the child and of the family and try to mitigate outcomes like financial distress or post-traumatic stress disorder. Throughout we need to continue to include the child's voice empowering them to be partners in figuring out the best ways to improve cancer outcomes.

Ching-Hon Pui, M.D.

We urgently need to develop therapies that will reduce the need for drugs and other treatments that are associated with long-term, adverse health outcomes.

There has been some progress on that front. In the field of childhood acute lymphoblastic and myeloid leukemia as well as non-Hodgkin lymphoma, improved use of chemotherapies allows us to eliminate the use of radiation and its attendant toxicities. Novel agents might one day make it possible to reduce the need for radiation therapy or carcinogenic agents for treatment of brain and solid tumors as well. To really address this problem, we need more effective, less-toxic targeted therapies. However, it will likely be decades before targeted therapies are developed for most childhood cancers, and therefore the use of curative combination chemotherapy will remain the mainstay of pediatric cancer treatment, and the challenge will be to use them more successfully and with less toxicity. To that end, our pharmacogenomics research is focused on identifying patients who are at high risk of specific toxicities of cancer chemotherapy, and develop strategies to mitigate these side effects and to improve quality of life without compromising the excellent cure rates for many childhood cancers.

Kevin Shannon, M.D.

Eliminating radiation and drugs that damage the DNA is perhaps the most important area of investigation to really address this problem by preventing it.

The key to late effects is like the key to infectious disease. The key to preventing infectious disease, like meningitis for example, is vaccination, which keeps it from occurring in the first place. In pediatric cancer, the key is developing drugs that don’t cause the late-effects issues to begin with. In a couple decades or more we will be changing the drugs and treatments we currently use. That will be a big frontier, but maybe a little further down the road.

Q. What are the most promising or exciting areas of pediatric cancer research? And, what new treatments might become available in the near future?

Archie Bleyer, M.D.

Perhaps one of the most exciting developments has been the ACA requirement that clinical trials have to be covered by health insurance.

This has eliminated the argument that the clinical trial will cost my family, my child, or spouse too much. So, support of clinical trials by the ACA as well as the ACA requiring insurance companies cover everyone regardless of preexisting conditions – that to me is as exciting as anything in the ability to improve research and getting at the basic issue of addressing how to treat different cancers in children, adolescents, and young adults.

Joanne Wolfe, M.D.

What is promising to me is that there is an increased focus on quality of life and the childhood cancer experience and the idea that we are becoming more sophisticated in how we are approaching this area of research.

For children and their families, treating the pain, symptoms and distress of cancer is as important as treating the disease. We are not presuming what is right or wrong, but we are testing interventions systematically and in a comprehensive way. We are now eliciting the voices of children and adolescents and through their direct feedback we can figure out ways to gradually and in a more nuanced manner provide a supportive environment for them during their cancer experience and beyond. For me, this is a critical area that needs to be continued and further developed so that we have a better understanding of how we can take care of these kids and their families. I would love to see a system where we are uniformly using similar tools across centers to track the childhood cancer experience so that we can then start building very comprehensive and effective interventions.

Kevin Shannon, M.D.

I think using molecular data to personalize care to increase effectiveness and reduce toxicity by giving more specific treatment is perhaps the most promising area.

Many targeted agents are in development or being tested in early clinical trials.