9

Overall Conclusions¹

This chapter presents seven overall conclusions derived by the committee from evidence presented throughout the report. The first section provides narrative summaries of evidence supporting these overall conclusions. Chapters 2 through 8 of the report each end with a set of chapter-specific findings and conclusions based on the evidence presented in that chapter. The second section of this chapter includes a selection of those chapter-specific findings and conclusions that support each of the committee’s overall conclusions.

OVERALL CONCLUSIONS

Functional Impacts of Cancer and Its Treatment

Cancers occurring under the age of 18 years represent a highly heterogeneous group of malignancies with unique biologic and genetic features, as well as age-, sex- and race-specific incidence rates. The past four decades have seen a modest yet continuous increase in the incidence of cancers occurring under the age of 15 years both in the United States and internationally. Since the late 1960s, the survival rate in children diagnosed with cancer has steadily improved, with a corresponding decline in the cancer-specific death rate. Nevertheless, there remains a group of primary and recurrent cancers for which modern intensive, multimodal therapy is not curative.

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¹ This chapter does not include references. Citations to support the text and conclusions herein are provided in previous chapters of the report.

Although more than 85 percent of children diagnosed with cancer will now survive for more than 5 years after diagnosis, survival rates vary greatly depending on the cancer type and stage. The prognosis is particularly good for standard acute lymphoblastic leukemia; lymphomas; low-grade gliomas; and a subset of low-stage, chemo-sensitive solid tumors. Although progress has been made in the treatment of acute myeloid leukemia and neuroblastoma, survival remains unacceptably low. New therapies are urgently needed for diffuse midline glioma and several advanced sarcomas of bone and soft tissue, for which there has been minimal, if any, impact on long-term disease-free survival.

Although the improvements in survival are encouraging, they have come at the cost of survivors experiencing acute, chronic, and late adverse effects of the disease and its treatment. Treatment of childhood cancers generally includes the individual or combined use of surgery, radiation, chemotherapy, and other therapies. Because cancers often present with symptoms and signs resulting from the anatomic or physiologic impact of the cancer itself, one of the primary goals of initial cancer treatment is to reduce this impact and subsequently alleviate the severity of these impairments, which may affect function. While improvements are often seen with cancer treatment and rehabilitation interventions, full functional recovery may not be achieved. Long-term functional deficits come from a combination of the permanent destructive effects of the cancer itself and the detrimental effects of its treatment, and long-term follow-up of survivors of childhood cancer has yielded greater recognition and understanding of these chronic and late effects. Age at treatment contributes in a unique way to the risk and severity of long-term adverse effects experienced by survivors of childhood cancer.

Chronic health problems related to the toxicity of cancer treatment are common among survivors, increase in prevalence with time since diagnosis, and encompass a spectrum of biomedical and psychosocial disorders and associated functional limitations. Data on historical cohorts of survivors of childhood cancer show that the occurrence and severity of multiple chronic health conditions are substantially greater relative to individuals without a history of cancer. As a result, survivors are predisposed to greater hospital-related morbidity and premature mortality compared with age- and sex-matched controls. In addition, cancer treatment can result in cognitive deficits and have negative psychosocial impacts on children and their families that create negative outcomes with respect to functioning and overall well-being.

For these reasons, the committee drew the following overall conclusion:

1. During recent decades, the incidence of childhood cancers has increased at a modest rate, and the survival rates for many cancer types have improved. The result has been a growing number of

1. survivors of childhood cancer who, starting from the time of diagnosis, are adversely affected by cumulative physical, cognitive, and psychosocial functional deficits, whose severity may increase over time, as a result of the cancer and its treatment.
   • Despite improved overall survival, certain specific cancers, including certain hematologic malignancies with adverse genetic features, some central nervous system (CNS) and solid tumors with metastatic disease, or tumors that recur after primary therapy, have distinctively poor prognoses.
   • The functional, social, and psychosocial impacts of all childhood cancers on both the affected children and their families are significant, beginning at the time of diagnosis, continuing through treatment, and often lasting into survivorship.
   • The interruption of normal childhood during critical developmental stages by the diagnosis and treatment of a childhood cancer can be particularly debilitating and result in long-term adverse effects.
   • Although many survivors of childhood cancer experience persistent adverse physical, cognitive, and psychosocial effects from the cancer and its treatment, CNS tumors and some leukemias place survivors at especially high risk for cognitive deficits, and solid tumors are often associated with physical impairments and medical complications.

Adverse Effects of Treatment

Despite the success of multimodal therapy, the acute toxicities of radiation, chemotherapy, and stem cell transplantation remain high. The multimodal treatment of many cancers—utilizing combinations of surgical intervention, chemotherapy, and radiation therapy, as well as immunotherapies, including chimeric antigen receptor (CAR) T cell therapy, hematopoietic stem cell transplantation, and targeted therapies—is likely to expose children with cancer diagnoses to multiple treatment-related complications and late effects. As a result, a large proportion of survivors of childhood cancer are at significantly increased risk of experiencing serious, potentially disabling, and life-threatening acute, chronic, and late adverse effects of cancer and its treatment. It is likely that overall functional impairment and disability result from not only one but often multiple exposures to different treatments that can have a variety of adverse physical, functional, cognitive, and psychosocial effects. For this reason, it is important for survivors of childhood cancer to receive lifelong surveillance and appropriate interventions for treatment-related physical, cognitive, psychological, and emotional toxicities and late effects.

Medical side effects of therapy are common and can impact every organ system. Cognitive dysfunction also is commonly observed in survivors of childhood cancer, particularly those with a history of CNS cancer or CNS-directed therapies, including radiation and chemotherapy. In addition, anxiety, depression, and posttraumatic stress occur in a significant subset of survivors, and all survivors are at risk for experiencing the effects of cancer and its treatment on psychosocial and emotional functioning. Psychological late effects also may develop well after the completion of treatment.

As noted, the age of the child at treatment is a critical factor, and other factors can be important as well. For example, the risk of secondary malignant neoplasms (SMN) is associated with exposure to various treatments, including radiotherapy and certain chemotherapy classes, but that risk can be modified by age at exposure and genetic predisposition. In addition, many of the long-term and late effects of radiation therapy, which often are permanent, depend not only on the age of the child at treatment but also on the location and volume treated and the dose of radiation administered. For example, irradiation to the brain of a young child significantly increases the risk of neurocognitive injury and the subsequent risk of disability. Also, the completeness of surgical removal of solid tumors is a critical factor in determining the length of chemotherapy and the need for and dose of radiation therapy, which in turn affect the number and severity of side effects and thus the risk of disability.

Although most targeted and immunotherapies are relatively early in their clinical development for pediatric cancer, they offer promise for decreasing the adverse effects of treatment. Immunotherapy as maintenance therapy has been a major breakthrough in the treatment of neuroblastoma, for example. However, supportive longitudinal data are just beginning to emerge, and in general, the survival benefits and long-term consequences of newer therapies remain unknown.

For these reasons, the committee drew the following overall conclusion:

2. Treatment of childhood cancers generally includes individual or combined use of different modalities (e.g., surgery, radiation, chemotherapy), each of which can precipitate a range of acute, chronic, and late-occurring impairments.
   • Adverse physical, functional, cognitive, and psychosocial effects can occur regardless of treatment modality.
   • Acute effects of treatment can elicit impairment both during the treatment course and during a period of recovery following its completion.
   • The adverse effects of pediatric cancer therapy may also continue well past the end of treatment and can be cumulative and become more severe over time.

• It is important for survivors of childhood cancer to receive lifelong surveillance and appropriate interventions for treatment-related physical, cognitive, psychological, and emotional long-term and late effects.
• The severity of adverse effects can vary depending on cancer type; tumor location; presence of metastases; type of surgery received; treatment modality employed; duration of treatment; and such patient characteristics as age, genetics, and underlying preexisting conditions.
• Increasing understanding of the biology and pathogenesis of cancers is resulting in a growing number of targeted treatments that hold promise for less serious acute and long-term adverse effects.

Occurrence and Persistence of Functional Impairments

Adult survivors of pediatric cancer have a real and increasing risk of experiencing disabling conditions due to chronic and late effects and SMN resulting from the cancer and its treatment. Despite advances in treatment protocols and treatment modifications, physical complications, including neurologic, sensory (e.g., hearing), and musculoskeletal deficits, and late effects continue to occur and lead to functional impairment and restrictions on participation in school, organized sports, and work.

Cognitive sequelae, particularly among survivors of CNS tumors or other cancers involving CNS-directed treatment, may already be present at the time of diagnosis or begin at initiation of treatment, or later, but often persist and may progress in severity over time. Some may not be evident until a later developmental stage poses its functional demands. As a result, repeated screening and risk-based assessment of cognitive function over time is essential to characterize cognitive sequelae accurately in survivors of childhood cancer. Evaluation of IQ alone may underestimate the full neurocognitive sequelae experienced by survivors of childhood cancer. Survivors of cancers and treatments affecting the CNS most commonly experience deficits of attention, working memory, processing speed, executive functioning, and memory that have significant negative impacts on adaptive, educational, and vocational outcomes into adulthood, resulting in persistent functional impairment and reduced independence.

Certain subgroups of survivors (e.g., those heavily pretreated, undergoing bone marrow transplantation, having certain CNS tumor diagnoses) are most likely to experience the psychosocial and emotional functioning effects of cancer and its treatment, and may do so to a greater degree. Adolescent and young adult (AYA) survivors are at higher risk of anxiety, depression, and distress compared with same-age cohorts who have not experienced cancer. Although a slight majority of AYA survivors are able to realize educational

and vocational achievements similar to those of their peers, it may take them longer to do so or require academic or job modifications or support.

Although functional deficits resulting from cancer and its treatment can demonstrate improvement with intervention, long-term functional impairments are expected and may impact performance in the educational, vocational, social, self-care, and avocational arenas. For young survivors, an ongoing focus on shorter-term and intermediate effects of cancer treatment may promote the use of rehabilitative interventions that could have large positive effects on their overall quality of life. Yet, while rehabilitation strategies can improve a child’s level of independence and interaction with skills and activities, persistent measurable deficits will remain for the majority of neurologic and musculoskeletal late effects. These deficits almost uniformly cause impairments in mobility and independence in completion of activities of daily living, and many also cause impairments in communication and cognition skills. As demands for independence increase over time, moreover, deficits in adaptive functioning are likely to become more profound and noticeable across the survivor’s lifetime.

For these reasons, the committee drew the following overall conclusions:

3. Functional deficits resulting from cancer and its treatment can improve over time, but many may persist or worsen, or even have onset at a later time, resulting in long-term functional impairments whose effects include restrictions on participation in the educational, vocational, and avocational arenas.
   • Cognitive sequelae, especially among children treated for CNS tumors and those who receive certain types of chemotherapy, may begin at the time of diagnosis or initiation of treatment, but often persist and may progress in severity over time. Specific cognitive deficits (e.g., a decrease in processing speed related to radiation treatment) may begin well after treatment has concluded or may become evident at a later developmental stage associated with differing functional demands.
   • Long-term psychosocial effects are especially common among the following subgroups of children: those who undergo pretreatment prior to hematopoietic stem cell transplantation, those with CNS tumors, and those who experience significant physical late effects.
4. Many survivors of childhood cancer do not achieve an age-equivalent degree of independence in one or more of several domains, which may include mobility; endurance; activities of daily living; and cognitive, social, or communicative skills.

• Although rehabilitation services may improve the level of independence with respect to functional activities among survivors of childhood cancers, survivors may never achieve the full level of educational and vocational participation expected for their age or developmental stage.

Transition from Adolescence to Adulthood

The transition from adolescence to adulthood at age 18 poses particular challenges for children and adolescents diagnosed with cancer in at least two realms: (1) review of continued eligibility for those receiving U.S. Social Security Administration (SSA) disability benefits, and (2) continuity of cancer care and follow-up.

With respect to the first realm, when children turn 18, SSA reviews their eligibility to continue receiving disability benefits using its disability determination process for adults. This review process, called the age-18 redetermination, includes evaluation under nonmedical eligibility rules. SSA’s disability determination process for adults differs from that for children. The process for children consists of three steps, and at Step 3 involves a determination as to whether the child’s qualifying impairment(s) meets or medically equals SSA’s Listing of Impairments (listings) for children, or functionally equals criteria in the listings. In making this determination, SSA considers the child’s functioning compared with that of same-age children who do not have impairments. In contrast, the adjudication process for adults is based on medical–vocational evaluations and consists of five steps. As with children, Step 3 of the process involves a determination as to whether the adult’s qualifying impairment(s) meets or medically equals criteria in SSA’s listings for adults. Although some of the listings contain functional criteria, SSA does not expressly consider whether the severity of an adult applicant’s impairment(s) “functionally equals” the listing as it does for children. Adult applicants whose impairments do not meet or medically equal criteria in the listings move to Steps 4 and 5 of the disability determination process. At these steps, SSA evaluates applicants’ residual functional capacity (RFC) and determines whether their physical or mental RFC allows them to perform past relevant work (Step 4) or, in conjunction with such vocational factors as age, education, and work experience, including transferable skills, to perform other work in the national economy (Step 5). Adolescents who are being reconsidered for SSA disability benefits when turning age 18 must navigate the transition between the child determination process that incorporates functional equivalence to peers and the adult process that focuses on medical–vocational evaluations.

In addition to the differing disability determination processes for children and adults, there are differences in the structure of the child and adult

listings for cancer—notably with respect to the level of specificity. The child cancer listings currently contain a category of “malignant solid tumors,” which appears to encompass any malignant solid tumors that are not otherwise specifically called out in the listings. In contrast, the adult cancer listings do not include a “malignant solid tumor” category, instead calling out many of those solid tumors individually (e.g., soft-tissue sarcoma; skeletal system sarcoma; carcinoma of the kidneys, adrenal glands, or ureters).

The second realm—continuity of cancer care and follow-up—encompasses both individuals who are first diagnosed with cancer during adolescence and survivors of cancers diagnosed earlier in childhood. The National Cancer Institute defines the AYA population as patients diagnosed with a first cancer at ages 15–39. As a group, AYAs experience poorer outcomes compared with younger children and older adults. Many reasons for this discrepancy have been identified, including delays in diagnosis, suboptimal access and accrual to clinical trials, differences between pediatric and adult treatment protocols (i.e., whether treatment is administered by pediatric or adult medical oncology providers), differences in psychosocial supports, variable compliance with prescribed treatments, and dose delays and modifications.

Regardless of age at diagnosis, it is clear that childhood cancer and its treatment often precipitate chronic and late effects that adversely impact health and functioning in adult survivors. Diagnosis of medical conditions resulting from cancer treatment in childhood may require blood tests, echo-cardiograms, electrocardiograms, or other measures. SMN, which are rare in the first 5 years after cancer diagnosis, can cause significant morbidity and mortality in long-term survivors. Strategies for determining which survivors are at high risk and implementing surveillance for SMN have been established to improve morbidity and mortality through earlier identification of SMN, although few such strategies are implemented in survivors 18 years of age or younger. It is notable that the cognitive effects of cancer treatment not only often persist but also may progress in severity over time. As a result, survivors of childhood cancer require regular, ongoing, lifelong surveillance for physical, cognitive, psychological, and emotional treatment-related toxicities and late effects, some of which may not yet be recognized. However, complexities in the transition from pediatric to adult cancer care and follow-up may lead to disengagement in care, which in turn can result in more severe adverse outcomes in adult survivors of childhood cancer. While shifting from family to individual health insurance may contribute to the complexity of transitioning from pediatric to adult cancer care and follow-up, attrition at the point of transfer cannot be explained solely by issues of access, and special support is required to keep survivors engaged in the health care system into and through adulthood.

For these reasons, the committee drew the following overall conclusion:

5. The transition from adolescence to adulthood is particularly challenging for adolescents diagnosed with cancer, as well as for survivors of childhood cancer.
   • The change in SSA’s disability determination process during the transition from adolescence to adulthood introduces challenges for determining disability and sustaining benefits across the 18-year-old threshold.
   • Complexities in the transition from pediatric to adult cancer care and follow-up may lead to disengagement in care, which can result in more severe adverse outcomes in adult survivors of childhood cancers.
   • Attrition at the point of transfer from pediatric to adult cancer care cannot be explained solely by issues of access. Special support is necessary to keep survivors of childhood cancers engaged in the health care system into and through adulthood.

Participation in Clinical Trials

Clinical trials that aim to improve survival and limit toxicity are essential to advance care and outcomes for patients with childhood cancer, and participation in such trials is considered the standard of care in pediatric oncology. Ideally, all children diagnosed with cancer should have the opportunity to enroll in a trial, which will ensure that they are receiving the most up-to-date treatments while also enabling the generation of new knowledge about how best to treat patients with particular types of cancer. With increased trial availability and continued study, for example, a decrease in side effects is anticipated from such advances as precision radiation therapy, including proton therapy. Likewise, targeted and immunotherapies offer promise for addressing cancers with unmet clinical need, but further studies are required to understand how novel targeted and immunotherapies can be incorporated into the treatment of both newly diagnosed patients and relapsed and refractory patients. Continuing research on tumor biology and genomics may reveal additional therapeutic targets and treatment options. Trials to test investigational therapies for children with high-grade CNS and metastatic or relapsed non-CNS malignant solid tumors are especially needed. Studies to understand late effects of novel therapies and intervention studies to mitigate late effects and SMN in hematologic malignancies are imperative because although cure rates are high in many cases, the burden of toxicities and late effects is significant.

For these reasons, the committee drew the following overall conclusion:

6. Clinical trials advance the standard of care for patients with childhood cancers and are critical to improving survival while also

1. reducing toxicity, late effects, and subsequent neoplasms. Because of the small numbers of pediatric patients with cancer, trials would not generate meaningful results without a high rate of trial participation, which is generally considered the standard of care for childhood cancers.
   • Regulatory agencies have implemented changes to enable early access to novel therapeutic agents and to facilitate the participation of adolescents and young adults and pediatric patients with cancer in clinical trials.
   • It is important to increase the participation of adolescents and young adults in clinical trials, as their participation rate is typically much lower compared with younger children.
   • Increased engagement of patients, especially those from underrepresented groups, and their advocates in the development of clinical trials is important to enable representation of the patient and family perspective, including quality of life, tolerability of side effects, and goals of treatment, in the trial design.

Availability of Pediatric Cancer Care Services and Providers

High-quality pediatric cancer care requires management by a multidisciplinary team of clinicians with expertise in pediatric cancer care. The approaches to pediatric and adult cancer care frequently differ. Relative to oncologists who treat adults, pediatric oncologists often utilize different criteria for cancer staging and risk stratification (e.g., for Hodgkin lymphoma) and different treatment protocols. Surgical removal of pediatric solid tumors is complex and should be done by pediatric surgical subspecialists at specialized centers. Certain types of procedures (e.g., treatment of pelvic bone tumors with surgical resection and cytoreductive surgery and hyperthermic intraperitoneal chemotherapy; treatment of neuroblastomas with vascular involvement using radiofrequency ablation and cryoablation) are available only at highly specialized centers (HSCs)—centers in which an interventional radiologist or surgeon has received specialized training beyond the standard training for that specialty. Similarly, precision radiotherapy techniques, including proton beam radiation, are increasingly available and used to mitigate late effects in patients with childhood cancer. Pediatric oncologic care therefore often requires treatment at an HSC. Accordingly, patients from less densely populated and rural areas may have to travel some distance to reach a treatment center that can provide the specialized pediatric cancer care they require. Specialized treatment centers are available in every state, but HSCs are rare. In states without an HSC, out-of-state consultation would be expected for treatments available only in HSCs.

For these reasons, the committee drew the following overall conclusion:

7. The availability of and access to pediatric cancer treatments, clinical trials, follow-up care, and rehabilitation and psychological services can be limited by geography and other factors, such as the availability of experts in pediatric cancer and survivorship care, as well as specialized technology.
   • High-quality care for pediatric cancers relies on effective coordination among a highly specialized team across a broad range of disciplines.

SELECTED FINDINGS AND CONCLUSIONS IN SUPPORT OF THE COMMITTEE’S OVERALL CONCLUSIONS

Box 9-1 shows the links between the overall conclusions presented above and some of the most relevant chapter-specific findings and conclusions that support them.²

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² Not all of the committee’s chapter-specific findings and conclusions are included in Box 9-1. Those that are included are numbered according to the chapter in which they appear.

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