Innovations in Cancer Treatment of Children

Although some children with specific subtypes of cancer have benefitted from targeted therapies or immunotherapies, the vast majority of children diagnosed with cancer today are still treated with standard chemotherapy and sometimes surgery and/or radiation therapy. As more children survive pediatric cancer, primary care pediatricians and pediatricians across subspecialties increasingly interact with childhood cancer survivors, children living with cancer, and their families (Fig 1). Pediatric cancer affects almost every facet of child and adolescent health. This State-of-the-Art article aims to provide pediatricians with an update on the state of pediatric cancer care. We highlight the following domains: reducing toxicity, cancer biology, novel therapies, detection and monitoring, and access to care, because these domains both represent areas of need for children with cancer and core topics in general pediatric medicine, such as long-term health, medical research and advancement, and health disparities.

Thanks to cooperative national clinical trial efforts over decades, some pediatric patients diagnosed with cancer, such as newly diagnosed standard risk B-cell lymphoblastic leukemia, now have excellent outcomes (>90% event-free and overall survival).¹¹  Despite these excellent outcomes, current treatment regimens result in significant risk of both short-term (during therapy) and long-term (after therapy completion) side effects, and many pediatric cancer survivors are diagnosed with 1 or more chronic health issues.^12–14  In the setting of overall excellent outcomes, a logical next-step is to determine how to better mitigate or treat toxicities while maintaining excellent overall survival. Table 1 highlights examples of only some of the toxicities encountered during cancer directed therapy to highlight the range of approaches to reduce or avoid those long-term effects. These approaches include future lifestyle modifications, protective medications, utilizing different chemotherapy regimens, and broadly reducing exposure to agents by optimizing risk stratification (what patients can still have excellent outcomes with less chemotherapy or radiation exposure).

One approach to toxicity reduction is decreasing cumulative doses of chemotherapy. Again, using leukemia as an example, chemotherapy is assigned by risk group. Patients with standard risk leukemia are exposed to less cumulative anthracyclines as compared with patients with high-risk leukemia.^15,16  Further, historically boys received an additional year of maintenance chemotherapy for the treatment of B-cell lymphoblastic leukemia on some cooperative treatment protocols. Current practice has eliminated this extra year of therapy for boys as with modern upfront intensive treatment regimens, the risks of this practice outweigh the benefits.¹⁷  Reduction or elimination of radiation therapy is another example of therapy modifications that can reduce late effects such as secondary malignancies. Recent data have demonstrated that radiation therapy can be eliminated for patients with Hodgkin lymphoma that demonstrate adequate response to chemotherapy.¹⁸ 

New chemotherapy formulations aimed at maintaining antitumor activity while reducing damage to normal tissue are emerging. Liposomal formulations of chemotherapy, such as doxorubicin, are in various stages of preclinical testing and clinical trials. In addition to less toxic formulations of traditional chemotherapy, immunotherapies have emerged as treatments with reduced—or different—toxicity profiles as compared with DNA damage directed chemotherapies. To date, immunotherapies have been most successful in the treatment of pediatric leukemias and lymphomas, and the long-term toxicity profiles of these treatments continue to be examined.^19–21 

Large sequencing efforts in pediatric oncology over the past decade have greatly enhanced understanding of germline alterations in children with cancer.^22–24  This is important not only for cancer predisposition and tumor biology but also for the way in which a child’s genetic make-up may alter how they metabolize drugs. Such pharmacogenomic analyses may reveal the need to dose reduce certain medications or prompt the use of certain drugs in patients demonstrating genetic factors that may make a medicine more efficacious. As ∼20% of children with cancer will be admitted to the hospital for the treatment of an adverse drug reaction,²⁵  this is an emerging area of importance given the steady rise in patient access to tumors and germline sequencing. Further, early prediction of patients whose tumors may not respond to a drug could help physicians consider alternatives earlier. One example of this is response to platinum agents being reduced by mutations in genes of the ERCC family of DNA excision repair proteins.²⁵ 

Until new treatment options emerge, some side effects are currently unavoidable, such as the likelihood of some treatments affecting fertility. Patients experiencing life-threatening oncologic medical emergencies often do not have time to undergo fertility preservation before initiation of gonadotoxic treatments. Cumulative exposure to cyclophosphamide and equivalent drugs greatly reduces a child’s future ability to have children.^26,27  Postpubertal females and males have the option for pretreatment oocyte or sperm cryopreservation.²⁸  Recent advances in fertility preservation have emerged and provide a way to enhance chances of future fertility while still successfully treating a child’s cancer. For example, prepubertal females at some specialized centers now have access to research protocols attempting ovarian cryopreservation for fertility preservation.^29,30  Infertility can have a major impact on an adult’s quality of life. Continued advances in fertility preservation—and affordable, reliable access to fertility counseling and preservation services—have the potential to significantly improve the long-term well-being of children and adolescents with cancer.³¹ 

Pediatric oncology patients routinely follow-up in survivorship clinics annually after completion of initial therapy and undergo active disease surveillance for a number of years. Predicted side effects from therapy are monitored over time. Efforts to optimize communication with primary care pediatricians and include pediatricians as an active member of the postcancer care team is a priority. Patients and families often move or re-establish care and, therefore, efforts have focused on establishing survivorship portals that can “move” with the patient.³²  A wealth of educational information and care guidelines are also provided, www.survivorshipguidelines.org.³³  Accurate and up to date communication regarding the overall health monitoring of survivors is also needed to ensure the successful transition to adult medicine care. Awareness and monitoring are key components to successful management of long-term toxicities for childhood cancer survivors (Fig 2).

An unfortunate reality of pediatric cancer is that some children still do not survive. Children diagnosed with brain tumors such as diffuse intrinsic pontine glioma (DIPG) and bone tumors such as osteosarcoma and metastatic Ewing sarcoma have not seen meaningful improvements in outcomes in decades. For these cancers, researchers strive to continue to better understand the biology of these tumors (heterogeneity, metastatic potential, immune evasion, treatment resistance, and stemness—a cancer cell’s ability to undergo “self-renewal and differentiation”³⁴ ) and corresponding interventions that may “move the needle” toward improving survival. As these cancer types are less common than pediatric leukemias, some of the challenges in understanding these tumors derives from the fact that they are relatively rare, thereby making tumor subpopulations more challenging to study.

For cancers with >50% survival at diagnosis such as bone sarcomas, a logical question to ask is: what biologic features make some primary tumors more aggressive than others? Pediatric sequencing efforts have clearly demonstrated the genetic profiles across the spectrum of pediatric cancers. Tumor subsets exist and there is a clear need to understand which tumor subsets are associated with inferior clinical outcomes. Aggressive tumor subtypes can then be studied to determine specific vulnerabilities, and ultimately provide clues to new treatments to test in patients with aggressive tumor subtypes. Neuroblastoma is an example of a solid tumor where ALK mutations and N-Myc amplification have been found to drive cancer progression and be associated with worse outcomes.^35,36  ALK inhibitors (eg, crizotinib, lorlatinib, etc) are being studied in the treatment of ALK mutated high risk neuroblastoma, an example of biologic understanding driving treatment change.³⁷  Dedicated efforts for defining risk groups for bone sarcomas are underway.

Before any compound being tested in clinical trials, preclinical testing is needed. Although cell lines are often useful for dissecting the effects of a compound on signaling pathways, cell lines often poorly mimic the complexity of the in vivo tumor microenvironment. With current preclinical models of many pediatric cancers, it is still challenging to predict clinical effectiveness of an agent.³⁸  We strive to use patient derived xenografts and immunocompetent models of cancer and to represent tumor subsets in preclinical studies. Advances in the generation of humanized mice (mice transplanted with human immune cells) allows investigators to now better understand the complex relationships between the tumor and the body’s immune system. Given the rise in immunotherapeutic approaches to cancer treatment in the past decade, immunocompetent modeling is a key emerging component in studying the efficacy of specific immunotherapies.³⁹ 

For rare tumors, every sample is valuable. National and international efforts to enhance biospecimen banking of difficult to treat cancers is a priority. The field continues to rely on the generosity and willingness of pediatric patients and their families to participate in research studies to advance our understanding of these cancers.⁴⁰  Optimizing sample storage conditions and annotation through data harmonization is an ongoing priority. For cancers such as DIPG, biopsy samples were historically not obtained and diagnosis was made based on clinical or MRI findings alone. Recent advances in neurosurgical stereotactic biopsy approaches now provide an opportunity for biopsy material from suspected DIPGs to be safely obtained.⁴¹  Such diagnostic biopsy material allows for a richer understanding of DIPG biology and researchers hope such samples will start to provide clues for new therapeutic approaches.

In addition to obtaining material at the time of original diagnostic biopsies, biopsy material at the time of relapse is also invaluable. Tumors change over time and after exposure to cytotoxic chemotherapy. Individual tumor subpopulations can develop resistance, ultimately resulting in disease relapse.^42,43  Historically, pediatric cancers were not always biopsied at the time of relapse to spare children from additional procedures. Given the need to better understand relapsed disease to improve outcomes and the ability to participate in clinical trials, for example, the National Cancer Institute-Children’s Oncology Group Pediatric MATCH trial (“matching” tumor alterations to possible targeted therapy), there has been a shift in practice and today, pediatric patients are more likely to be offered rebiopsy at the time of suspected disease progression.⁴⁴  The MATCH trial has demonstrated the feasibility of identifying personalized therapeutic options for pediatric patients with difficult to treat cancer.⁴⁵ 

New treatment approaches are needed to continue to improve upon long-term morbidity and mortality for pediatric patients with cancer. Examples of targeted agents (antibodies, cellular therapies, kinase inhibitors, antibody-drug conjugates, etc) used in the treatment of pediatric cancer are listed in Table 2.

The goal of precision oncology is to identify drugs predicted to work against tumors with specific mutations, etc. As noted above, The MATCH trial has demonstrated the feasibility of identifying personalized therapeutic options for pediatric patients with difficult to treat cancer.⁴⁵  Examples of recent precision oncology success stories in pediatric oncology include the utilization of NTRK inhibitors for rare NTRK pediatric solid tumors, such as infantile fibrosarcoma and RAF/MEK inhibitors for the treatment of low-grade gliomas in children.^46–48 

Hundreds of immunotherapies for the treatment of cancer now exist. Broadly, these therapies include engineered cells, such as CD19 CAR-T cells for the treatment of pediatric B-cell lymphoblastic leukemia, checkpoint inhibitors aimed at “reawakening” the body’s own immune system, cytokine manipulation, and agents aimed at remodeling the tumor microenvironment. Although challenges exist in the utilization of CAR-T cells for the treatment of solid tumors, exciting progress has been made in demonstrating the feasibility of CAR-T cell utilization for the treatment of currently incurable pediatric cancers such as DIPG (diffuse intrinsic pontine glioma).⁴⁹  Given the rapid rise in immunotherapies being developed in adults, there is significant future potential in immunomanipulation for the treatment of pediatric cancers. Currently, few children with cancer are treated with immunotherapies. In addition, we are only beginning to understand the long-term side effects of immunomanipulation on the health of children and adolescents. As these data emerge, continued communication with general pediatricians is essential to ensure that these effects are recognized and effectively addressed.

Tumors are known to be heterogeneous and develop treatment resistance, including resistance to targeted agents. Tumors rarely demonstrate long-term responses to single agents. Combination approaches to “attack” tumors using different methods is one way to circumvent the resistance. Combining DNA damaging agents with immunotherapies and utilizing antibody-drug conjugates are 2 examples of emerging multimodality therapies that have the potential to continue to change the landscape of pediatric cancer treatment. Immunotherapy timing (the delivery order of agents and/or severity of immunosuppression when agents are given) is especially critical when adding immunotherapies to existing treatment regimens. Preclinical data specifically addressing immunotherapy timing is an emerging topic of great interest.^50,51 

Disease monitoring is conducted both on-therapy and after completion of initial therapy for the treatment of cancer in children. Child exposure to radiation, such as that delivered by chest radiographs and CT scans, should always be avoided or minimized when possible. New technologies are emerging that likely will revolutionize the way tumor responses and relapses are monitored.

When tumor cells die, fragments of DNA from the tumor cells are released into the bloodstream of the patient. This circulating tumor DNA (ctDNA) can be detected in blood from patients with cancer⁵²  and provides many future opportunities: (1) more frequent monitoring of disease relapse at a level that a scan may not be able to detect, (2) reduce exposure to radiation, and (3) detect emerging resistant subpopulations of tumor cells while on therapy. One large question that ctDNA may be able to help address is whether earlier detection and treatment of relapses will improve outcomes. As ctDNA monitoring (“liquid biopsies”) is increasingly included on prospective clinical trials, we will come to more fully understand the potential of this technology. A recent example of the power of ctDNA was demonstrated in intermediate risk, fusion negative rhabdomyosarcoma, where investigators demonstrate that the presence of ctDNA in a patient’s serum at diagnosis is associated with a worse outcome (statistically significant inferior event-free and overall survival).⁵³ 

In addition to tumor sequencing, germline sequencing of pediatric patients with cancer has also increased and can complement and enhance knowledge derived from tumor-only sequencing.^54,55  As discussed above, there may be potential pharmacogenomic benefits of this information. Additionally, should a patient have a germline pathogenic variant in a cancer predisposition gene discovered, cancer screening recommendations may be suggested for the patient.^56,57  We know that some children develop secondary malignancies after their primary cancer therapy. We still do not fully understand which pathogenic germline findings may increase the likelihood of children developing a treatment-related secondary malignancy. Family members of children with cancer may be referred for genetic counseling and testing depending on the germline result found in the child. Many variants of unknown significance are detected during germline testing, and as more data emerge, screening and risk recommendation are updated over time. It is especially important to remember this for survivors who may not have had access to germline testing when initially diagnosed or treated, as they may desire testing. If testing did occur, a re-examination of the interpretation of the findings may be warranted given variant reclassifications over time. Many children’s hospitals nationally now have cancer predisposition programs where referrals for genetic counseling and testing are accepted both for patients with cancer and their family members.⁵⁸ 

Pediatricians are well aware that inequities in access to care exist. Pediatric oncology is not spared from this reality.

In the United States, Black children diagnosed with cancer continue to have inferior overall survival compared with white children. One example of many is that lower survival rates are observed among Black children with acute myeloid leukemia when compared with non-Hispanic white children.⁵⁹  The reasons for this are understudied and multifactorial, though minority populations remain underrepresented in cancer research.⁵⁹  Rates of relapse among minority children and those living in poverty also remain higher across disease groups,⁵⁹  highlighting the need for social determinants of health to be incorporated into treatment plans. Globally, overall survival for children with cancer varies based on the income status of the country in which they reside. Issues with access to cancer drugs, clinical trials, expert opinions for rare tumors, supportive care measures, and advanced testing such as tumor sequencing all contribute to the noted disparities.^59,60 

When considering clinical trials, an emerging approach in oncology is the integrated use of real-world data (RWD) or real world evidence. Although randomized control trials are the gold standard in pediatric oncology, for rare tumors and understanding subpopulations of patients, this is not always feasible. Examples of RWD include electronic medical record data, billing data, social media platforms, patient or family surveys, and information from tumor registries. For example, use of real world evidence helped lay the groundwork for the accelerated US Food and Drug Administration approval of blinatumomab for the treatment of relapsed or refractory B cell acute lymphoblastic leukemia in adults.⁶¹  Incorporation of RWD may help bridge some gaps in disparities in clinical trial access and more timely access to emerging drugs in pediatric oncology.

For survivors, access to specialty services, such as physical and occupational therapy, ongoing oncofertility and reproductive health resources, neuropsychologic testing, and behavioral health services are inconsistent. For example, survivors and their parents often experience post-traumatic stress disorder and anxiety, and lack of access to behavioral health resources can have a significant, lifelong negative impact on long-term health for cancer survivors.⁶²  Partnerships between pediatric oncologists and general pediatricians are key in advocating for both the needs of individual patients and for the health of children more broadly. A dedicated effort must be made to improve survival, mitigate toxicities, and promote lifelong health in all children with cancer.

A simplified statement of goals in pediatric oncology is to finally “break” the survival plateau for some solid tumors and to minimize toxicity for all children and adolescents diagnosed with cancer. Here, we highlighted several ways in which innovations in drug delivery, monitoring, novel therapeutics, and access to care continue to help move the field of pediatric oncology forward. Children with cancer need excellent longitudinal care both during and after completion of cancer directed therapy. Continuing to strengthen the partnership and communication between the patient’s pediatric oncology team and primary care pediatrician is essential in this mission.

ctDNA

circulating tumor DNA

DIPG

diffuse intrinsic pontine glioma

RWD

real world data