3

Treatment Modalities for Childhood Cancers

Many advances have been made in the treatment of pediatric cancers over the past century. Whereas childhood cancers were nearly uniformly fatal in the early 1900s, the 5-year overall survival rate for children with cancer has increased from approximately 60 percent in 1970 to greater than 85 percent currently (Chow et al., 2020). There have been two major contributors to these successes. First has been the establishment of pediatric cooperative groups (such as the Children’s Oncology Group [COG] [2020b]) and the enrollment of the majority of children (≥50 percent) diagnosed with cancer in clinical trials developed and coordinated by these groups—a proportion that stands in contrast to the fewer than 5 percent of adult oncology patients, and is all the more impressive given that all childhood cancers combined represent just 1 percent of all cancers (ACS, 2020a). This high rate of trial participation has allowed for uniform and prospective learning and the advancement of therapies in a consistent fashion over the years (Smith et al., 2014; Unger et al., 2016). Second has been the development and implementation of multimodal therapies to treat pediatric cancers. In addition, supportive care has advanced dramatically, improving the mortality and morbidity profiles of many standard therapies (Tonorezos et al., 2018; Unguru et al., 2019).

This chapter begins with a brief description of pediatric cooperative groups and the use of multimodal therapies. It then reviews in turn the standard treatment modalities for childhood cancers, including the toxicities associated with these therapies, and emerging treatments.

PEDIATRIC COOPERATIVE GROUPS

The COG is the primary cooperative group in the United States, with more than 200 member sites and disease committees addressing the majority of childhood tumors (O’Leary et al., 2008). Trials are conducted not only for patients with newly diagnosed disease but also for those with relapsed and refractory disease. Other consortia, including the Pediatric Early Phase Clinical Trials Network, the Pediatric Brain Tumor Consortium, the Pacific Pediatric Neuro-Oncology Consortium, New Approaches to Neuroblastoma Therapy, and Therapeutic Advances in Childhood Leukemia & Lymphoma, are developing and conducting clinical trials for children and young adults, with a focus on early-phase trials for refractory solid tumors or tumors for which no standard effective treatment options exist. In addition, some clinical trials of novel therapies—for example, novel immunotherapies—are conducted at single or limited academic institutions and not widely available. Promising new therapies identified by these groups are incorporated into clinical trials for children with newly diagnosed or relapsed cancers and thus have the potential to become standard therapies. While clinical trials for newly diagnosed patients are available at most of the COG’s participating sites, clinical trials for patients with recurrent disease and trials requiring specific equipment or expertise (such as metaiodobenzylguanidine or chimeric antigen receptor [CAR] T cell therapies or hematopoietic stem cell transplantation) are limited to fewer institutions and require travel and sometimes extended stays away from home. The pediatric oncology research community also collaborates with, and is part of, such international consortia as the International Society of Pediatric Oncology and such meetings as the International Symposium on Pediatric Neuro-Oncology. This collaboration is particularly helpful for understanding rare pediatric cancers, exchanging treatment approaches, and conducting selected international trials.

The high participation of children with cancer in clinical trials developed by cooperative groups whose membership includes leading disease experts has allowed for the development of improved treatments through successive implementation of treatment modifications. These advances have in turn resulted in decreasing mortality among children and adolescents diagnosed with cancer (Smith et al., 2014).

MULTIMODAL THERAPIES

For decades, the pillars of effective therapies for childhood cancer have been surgery; chemotherapy; radiation therapy; and, for specific tumors, hematopoietic stem cell transplantation. The combined use of these therapies has enabled substantial improvements in the long-term survival rates

for childhood hematologic malignancies and solid tumors over the past several decades.

At the same time, however, increased survival rates as a result of dose-intensified therapies have come at the cost of substantial acute and chronic toxicities, as well as late effects, that broadly impact the quality of life, function, and health of survivors of childhood cancer. This cost is increasingly being recognized as the number of survivors of childhood cancer increases (Bhakta et al., 2017; Robison and Hudson, 2014). In addition, despite significantly improved survival rates, a substantial fraction of children diagnosed with cancer still do not achieve long-term disease-free survival with standard up-front therapies (Galligan, 2017). Many of these patients become candidates for clinical trials with investigational therapies. For patients for whom no life-prolonging cancer therapy allowing acceptable quality of life exists, optimizing quality of life becomes an important goal of therapy.

In this context, efforts are under way to (1) follow all survivors of childhood cancer in specialized survivorship clinics to ensure optimal longitudinal care through adolescence and adulthood, (2) reduce treatment-related morbidities for patients with tumors with good prognostic features, and (3) develop less toxic but effective therapies. An objective of this work is to reduce and modify doses and schedules of radiation therapy or chemotherapy agents, as well as to incorporate novel treatment approaches into up-front therapy. Rapidly increasing knowledge of the molecular and genomic bases of cancers has resulted in the development of targeted therapies, also referred to as precision therapies, whereby new drugs specifically block the effects of tumor-specific changes, such as tumor mutations (Campbell et al., 2020). Some of these therapies have been highly successful and have been incorporated into standard treatments for children with newly diagnosed or relapsed cancers. Finally, the development of immunotherapies for pediatric cancers is expanding rapidly. Unique immunotherapies exist and are in development for a variety of pediatric tumors (Wedekind et al., 2018). While less advanced compared with new agents targeting genomic changes, some immunotherapies have proven to be effective for some children with solid tumors or hematologic malignancies. The following sections review in turn standard treatment modalities and emerging treatments.

STANDARD TREATMENT MODALITIES

In general terms, cancer treatments can be categorized as local or systemic. Local treatments include surgery and radiation therapy, which target a cancer specifically at its location in the body. As a result, the side effects or sequelae of local treatments stem from damage that occurs locally in the area targeted by the treatment. In contrast, systemic therapies, such as

most chemotherapies, circulate throughout and therefore affect cells in the entire body. High-quality pediatric cancer care typically is provided by a highly specialized team of clinicians across a broad range of disciplines in collaboration with primary care providers. In addition to physicians, team members may include nurse specialists, psychologists, neuropsychologists, nutritionists, rehabilitation specialists (e.g., physiatrists; physical, occupational, and speech therapists), social workers, child-life specialists, and others. Clinicians with expertise in pediatric cancer care typically practice at specialized centers (SCs). Although it may be necessary for patients from less densely populated and rural environments to travel some distance to reach such specialized pediatric care, SCs generally are available in every state. In addition, certain types of procedures are available only at highly specialized centers (HSCs), whose clinicians have received specialized training beyond the standard training for the respective specialty. An out-of-state consultation would be expected for treatments available only in HSCs.

Diagnosis

Accurate diagnosis is a critical first step for developing an appropriate cancer treatment plan. In addition to physical examination, a number of diagnostic tests are available, including blood tests, biopsy, bone marrow aspiration and biopsy, lumbar puncture, ultrasound, scans or radioisotope studies, and imaging (e.g., computed tomography [CT] scan, magnetic resonance imaging, positron emission tomography [PET], PET-CT scan). Whenever possible, it is important that testing be performed under the supervision of pediatric specialists at an SC (Cancer.Net Editorial Board, 2019). The specific tests conducted depend on a number of factors, such as the type of cancer suspected; the child’s signs and symptoms, age, and general health; and the results of any prior tests performed (Cancer.Net Editorial Board, 2019).

In most cases, a biopsy is the only way to know for certain whether cancer is present at a given location (Cancer.Net Editorial Board, 2019). Although generally not a treatment in itself, biopsy to remove tissue for analysis by a pathologist provides information critical to making a specific diagnosis and developing an appropriate treatment plan. There are many biopsy techniques, including aspiration biopsy (fine-needle aspiration), punch biopsy, ultrasound-guided needle biopsy, CT-guided needle biopsy, and surgical/open biopsy.

A closed (core needle) biopsy is now the most common biopsy technique employed. Closed biopsy is preferred in the lung, abdomen, pelvis, or spine or when a differential diagnosis is to be made among metastasis, local recurrence, or benign inflammatory tissue. Closed biopsies are performed

by interventional radiologists, necessitating good communication and an excellent working relationship between the interventional radiologist and the surgeon subsequently tasked with excising the tumor. It is less invasive and allows for faster recovery, but it also yields a smaller sample size, which can result in a poorer sample and increased chance of inaccurate or no diagnosis. This is especially the case when the clinician performing the biopsy or the pathologist reading the biopsy lacks specialized oncologic expertise. A nondiagnostic closed biopsy can be salvaged by an open, surgical biopsy.

Despite numerous advances in imaging and tissue sampling techniques, open biopsy, especially of bone and soft tissue, remains the gold standard for diagnosis. However, an open biopsy has a greater incidence of tumor spillage; hematoma; infection; and in the case of bone lesions, fracture. In addition, if an open biopsy is performed without knowledge of the correct surgical approach, subsequent definitive surgery and functional outcome may be compromised.

Data have shown that it is best if biopsies are performed at the treatment center rather than the referring institution. Mankin and colleagues (1982, 1996) published two series evaluating biopsies of primary malignant musculoskeletal sarcomas, finding that errors, complications, and changes in course based on incorrect histologic diagnosis or grade, which affect outcome (e.g., more complex resection, resulting in loss of function; tissue contamination and unnecessary amputation; local recurrence; or death), occurred 2–12 times more frequently (p <0.001) when the biopsy was performed in the referring institution rather than in the treatment center.

On an extremity, the biopsy should be performed in line with the planned resection. In the era of limb salvage, biopsy placement is critical. Bone and soft-tissue tumors can seed the incision or tract, so the biopsy or incision needs to be placed in an area where it can be excised (Espinosa et al., 2008). The needle path must be close to the incision that will be used for the definitive limb-sparing surgery to ensure that the entry point and the path of the biopsy can be resected. The path of the biopsy should lead directly to the site to be sampled and should not traverse an uninvolved compartment, joint, or neurovascular structure (Espinosa et al., 2008). While biopsies provide definitive diagnoses, they can, but should not, complicate the surgical procedure or outcome.

New techniques referred to as “liquid biopsies” may in the future offer means to monitor disease burden, recurrence, and response to therapy. Assays are in development with which to reproducibly evaluate blood samples for circulating tumor cells or cell-free DNA throughout the course of disease. Incorporation of these “liquid biopsies” during and after completion of treatment may ultimately impact diagnosis and therapy (Van Paemel et al., 2020).

Local Treatments

Surgery

Traditional surgery

Traditional surgery for a solid tumor, which involves the use of a scalpel to excise the diseased tissue, is performed under sterile conditions in a medical facility. The type of facility (e.g., doctor’s office, local hospital, specialty hospital) depends on the type of surgery, the location of the tumor, and the technique to be used. Surgical removal of pediatric solid tumors is complex and should be done by pediatric surgical subspecialists at SCs. Certain treatments (e.g., pelvic bone tumor surgical resection, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy [CRS-HIPEC], treatment of neuroblastomas with vascular involvement, radiofrequency ablation [RFA], cryoablation) are available only at HSCs.

The goal of surgery is to remove all or as much of a tumor as possible. Surgery may be combined with other types of treatment discussed below (e.g., radiation or chemotherapy) that may be used either before surgery to reduce the size of the tumor prior to its removal (the “neoadjuvant” setting) or after surgery to treat any cancer cells that remain (the “adjuvant” setting). In addition to traditional surgery, surgical techniques include cryosurgery and minimally invasive ablative surgery, such as CRS-HIPEC, RFA, and laser surgery.

Typically, acute effects of surgery and associated pain medications can include pain, nausea, vomiting, constipation, and headaches. Long-term effects depend on the type of operation, the tumor location and size, the child’s health, and other factors. Specific short- and long-term sequelae of different types of surgery are shown in Annex Table 3-1 at the end of the chapter.

Sentinel lymph node biopsy Sentinel lymph node biopsy (SLNB) refers to a surgical technique used to sample lymph nodes for the accurate staging of certain specific diagnoses, including soft-tissue sarcomas (STS) and melanoma. It entails lymphatic mapping to determine which lymph node(s) to remove, based on which is (are) most likely to harbor the metastatic disease. Therefore, SLNB is more accurate than random lymph node sampling. The technique is used primarily in the axilla, groin, and neck lymph node basins. First, hours or days before surgery, a nuclear tracer is injected into the site of the tumor (skin or soft tissue). Then, the surgeon may use a fluorescent or visible dye in the operating room in conjunction with the nuclear tracer. A small incision is made in the lymph node basin at the site of maximal uptake of the nuclear tracer, and the sentinel lymph node is identified and removed surgically. Only one to three lymph nodes need be removed, thus limiting the patient’s side effects compared with traditional lymph node excision surgery. SLNB should be performed at an SC.

Cryosurgery

Cryosurgery entails local application of intense cold to destroy tumors, usually accomplished with highly skilled use of a probe or pencil-like structure to destroy the tumor cells (NCI, 2020f). The extreme cold is commonly produced by the delivery of liquid nitrogen. Cryosurgery is used primarily as a less invasive alternative to traditional surgery and can be part of standard therapy for selected cases of retinoblastoma, intraocular and orbital tumors, hepatic tumors, and metastatic disease (Deschamps et al., 2014; Gombos, 2014; Robinson et al., 2004). In cryosurgery, the tumor is not actually removed, but the tissue is destroyed in place (Cranwell and Sinclair, 2017). The procedure is done at HSCs by interventional radiologists or surgeons.

Radiofrequency ablation

RFA, another means of destroying a tumor without actually doing “scalpel” surgery to remove it, utilizes heat to destroy cancer or other cells. It is most commonly performed in solid organs, such as the liver, lung, or bone, when a less invasive alternative to traditional surgery is preferable. It is performed at HSCs by interventional radiologists or surgeons (Yevich et al., 2019).

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

CRS-HIPEC entails the surgical removal of multiple intra-abdominal tumors, followed by intraoperative instillation of heated chemotherapy (Goodman et al., 2016). The goal of the heated chemotherapy is to kill any microscopic cells that may have been left behind at the time of the tumors’ surgical removal. This operation is used for rare cancers in children, adolescents, and young adults who have multiple intra-abdominal malignant tumors, usually dozens to hundreds, involving multiple different intra-abdominal organs (Hayes-Jordan et al., 2015). This procedure is performed at HSCs.

Radiation Therapy

Radiation therapy is used in the majority of pediatric cancers involving localized tumors. Most malignant brain tumors, head and neck cancers, and STS receive daily radiation during the course of treatment for a localized tumor. Radiation therapy is often used in conjunction with surgery and/or systemic treatments such as chemotherapy. It targets rapidly growing cells, such as cancer cells, killing them and/or preventing them from growing or reproducing (COG, 2020c; NCI, 2020d). Radiation therapy entails the delivery of ionizing radiation to a localized area, generally using external beam radiation administered by a linear accelerator. The key to modern radiation delivery is the ability to simulate the patient in order to design an optimal treatment plan. The simulator used for this purpose is a

machine that mimics a radiation therapy treatment unit. After simulation, physicists and physicians can formulate a treatment plan and calculate the precise dose delivery. Young children, typically less than 6 years of age, may require daily anesthesia to ensure the proper setup and precise delivery of the radiation. High-precision conformal radiotherapy techniques are increasingly being used to deliver the radiation dose more precisely to the targeted area, which decreases the amount of normal tissue that is irradiated.

External beam radiation therapy (EBRT)—the most common type of radiation therapy (COG, 2020c)—delivers radiation (usually photons) from a machine, typically a linear accelerator (NCI, 2020c). During EBRT, radiation beams are aimed at the tumor. Multiple “fields” or radiation beams are generally used to deliver the radiation precisely in accordance with the treatment plan so as to optimize delivery to the tumor while minimizing delivery to normal tissue near the tumor site.

Another form of EBRT involves proton beam radiation therapy produced from a cyclotron or synchrotron. The main advantage of proton beam therapy is physical rather than biologic since the dose deposited increases slowly with depth and reaches a short maximum near the end of the particle range. The beam has sharp edges with minimal scatter, and thus enables adequate delivery to the tumor area with reduced dose compared with conventional or advanced photon techniques (Baliga and Yock, 2019). As a result, proton beam therapy, along with other high-precision radiotherapy techniques, may be able to deliver radiation to a tumor while reducing damage to normal tissues. Recent studies have reported a decrease in long-term side effects in many pediatric diseases with use of this therapy, which increasingly is available and being used to mitigate late effects in survivors of childhood cancer (Baliga and Yock, 2019; Kuhlthau et al., 2012; Odei et al., 2017; Yock et al., 2016). Pediatric use of this therapy requires treatment at an HSC (Yu et al., 2014).

Protons may be preferred over photons for such brain tumors as medulloblastomas, germ cell tumors of the central nervous system (CNS), and ependymomas. For infiltrating tumors, such as many high-grade gliomas, the use of photons may be comparable as long as advanced techniques for planning and treatment are employed. Outside the CNS, some studies show improved results with protons for some patients with neuroblastoma, rhabdomyosarcoma, and other solid tumors (Baliga and Yock, 2019). Proton beam therapy also is being investigated in patients with Hodgkin lymphoma (NIH, 2020b) and has been incorporated into recent clinical trials under the COG and the National Clinical Trials Network (NIH, 2020a).

Typically, radiation is delivered on an outpatient basis, 5 days per week for 1 to 6 weeks, depending on the type of cancer. Giving the radiation in

small daily doses helps protect the normal tissue around the tumor from radiation injury. Radiation therapy to a child should be delivered in a cancer center experienced with treating children. The medical staff should include an anesthesiologist, oncologist, radiation oncologist, and surgeon, as well as others with pediatric expertise. The allied health staff should also include nurses, social workers, psychologists, rehabilitation specialists, and others with expertise in childhood cancers.

Damage to normal, healthy cells can occur when radiation passes through normal tissue to the target (tumor) site. The specific side effects of radiation depend on the total dose, location, and type of radiation therapy administered. Some cells can repair themselves, and thus some side effects are of short duration. Side effects that typically are temporary and can be controlled include

• fatigue (most common), with the patient often being able to continue all or some normal daily activities;
• skin damage or changes (also common), including redness and sensitivity (like that experienced with sunburn);
• hair loss in the area being treated;
• decreased blood counts;
• sore mouth and tooth decay (with radiation to head and neck); and
• gastrointestinal problems (with radiation to abdomen, pelvis, or brain [nausea]).

Chronic and late effects also may occur and often are permanent (Dhakal et al., 2016). Many of these effects depend on the age of the child at treatment, the location treated, and the dose of radiation administered. Irradiation to the brain of a young child may significantly increase the risk of neurocognitive injury and the subsequent risk of long-term, potentially progressive functional limitations resulting in disability (Duffner, 2004). Annex Table 3-2 summarizes the acute and long-term sequelae that may result from radiation therapy to specific parts of the body.

Systemic Treatments

Chemotherapy

Chemotherapy entails the use of chemical agents (cytotoxic drugs) to eliminate or slow the growth of cancer cells by interfering with cell division (COG, 2020a; NCI, 2020b). Cytotoxic drugs have the greatest effect on rapidly dividing cells such as cancer cells, but they do not distinguish between cancer cells and rapidly dividing normal cells, such as hair follicles or the lining of the intestinal tract. Many of the side effects of chemotherapy,

such as hair loss and diarrhea, are caused by the toxic effect of the drugs on normal cells in the body.

Chemotherapy is most commonly administered intravenously (into a vein), although certain drugs may be given orally (by mouth), intramuscularly (into the muscle), subcutaneously (under the skin), or intrathecally (into fluid around the spine) (COG, 2020a). Intravenous administration of chemotherapy typically is performed at an infusion center (either within a larger medical facility or in a stand-alone facility) over a period of time (hours).

The great majority of children being treated for cancer require a central venous access device (CVAD). A CVAD is required for safe delivery of chemotherapy while also providing a constant source of venous access through which to draw blood or deliver anesthetic medications without subjecting the child to repeated needle punctures whenever access to a vein is required. CVADs are temporary and are in place through the duration of therapy. Types of CVAD include a peripherally inserted central catheter line, tunneled “Broviac,” percutaneous central venous line, or subcutaneous port-a-cath. The care team chooses the type of line based on the age of the patient, the type of chemotherapy to be delivered, how long the line is anticipated to be needed, and other factors. For any CVAD, parents are responsible for checking and maintaining the line on a daily basis. Certain treatments are recommended to avoid occlusion or infection.

Primary chemotherapy refers to chemotherapy that is likely to be the only cancer treatment needed (e.g., for leukemia, some lymphomas, some widely metastatic solid tumors for which goals are palliative). Chemotherapy for leukemia and lymphoma can itself be divided into several stages, including induction (intended to eradicate the cancer); consolidation and delayed intensification (to deepen remission and address sanctuary sites such as the CNS); and maintenance therapy (extended low-dose outpatient treatment, often lasting years, to maintain remission; addressed in detail in Chapter 5).

As discussed above, for solid tumors, neoadjuvant chemotherapy (sometimes referred to as induction chemotherapy) may be given as a first step to shrink a tumor prior to the main treatment, which is often surgery or radiation. It may be used to test the adequacy of the treatment for shrinking the tumor, to reduce the morbidity associated with later surgery or radiation therapy, and to gain early control of microscopic metastases. Adjuvant chemotherapy (sometimes referred to as consolidation chemotherapy) is given after initial planned therapy to further control residual local or metastatic disease and help prevent recurrence. Consolidation for solid tumors sometimes includes a high-dose chemotherapy with stem cell rescue (also referred to as an autologous transplant; see below). Borrowing terminology from leukemia, solid tumor treatment may end with

a “maintenance” or “postconsolidation therapy,” which is commonly a prolonged, lower-intensity chemotherapy or more biological approach, including immunotherapy, designed to prevent recurrence from presumed minimal residual disease.

The treatment goals of chemotherapy are to eradicate the cancer, prevent recurrence, and achieve long-term disease control. As noted in Chapter 1, defining when cure from a pediatric cancer has been achieved in an individual patient is difficult, and the term “long-term survivor” may therefore be preferable (Haupt et al., 2007; Jankovic et al., 2018). At the same time, optimal treatment with chemotherapy involves achieving a delicate balance of the acute, chronic, and late effects of the therapy, as well as adequate provision of the rehabilitation and psychosocial support critical to achieve the most favorable outcome and performance for each patient.

Chemotherapy typically involves a combination of several drugs (combination chemotherapy) to eradicate tumor cells most effectively and prevent the development of chemotherapy resistance. Chemotherapy is frequently administered in cycles (one cycle = 21–28 days, although this may vary), which are repeated over variable durations ranging from a few months to several years, with the goal of eradicating tumors permanently. Chemotherapy protocols vary with respect to duration, frequency, and number of cycles, depending on the type and extent of the cancer, the types and dosages of the drugs and their expected toxicities, and the time needed for the patient to recover before the next round. The goal is to maximize the elimination of cancer cells while minimizing the negative effects on normal, healthy cells. Administering chemotherapy in cycles allows healthy cells time to recover before the next dose.

The types of normal cells most likely to be affected by chemotherapy include

• blood cells forming in the bone marrow,
• cells in the digestive tract,
• hair follicles, and
• cells in the reproductive system (NCI, 2020b).

Resulting acute side effects include

• decreased blood counts,
• fatigue,
• nausea and vomiting,
• diarrhea,
• mouth sores,
• hair loss, and
• infertility.

Decreased blood counts may include depletion of red blood cells, which carry oxygen, potentially resulting in anemia and fatigue; of white blood cells, potentially resulting in increased risk of infection and fever; and of platelets, which are needed for blood clotting, so that patients can experience bruising and bleeding. Patients may also experience changes in mood and emotions (e.g., depression, anxiety, anger, fear), and certain drugs may cause damage to organs (e.g., heart, lungs, kidneys). Potential long-term or late effects include infertility; secondary malignant neoplasms; cardiac and pulmonary dysfunction; hearing loss; neuropathies; and neurocognitive delays or deficits, including difficulties with learning and memory.

Cytotoxic chemotherapy drugs can be divided into five major classes based on their chemical structures and the ways in which they act on cancer cells. To increase efficacy, chemotherapy protocols often involve using a combination of drugs that act in different ways or interrupt cell division at different stages. Annex Table 3-3 summarizes the various classes of chemotherapy agents, their mechanisms of action, and their acute and long-term sequelae.

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation refers to the replacement of a person’s blood-forming cells after they have been destroyed by very high doses of radiation and/or chemotherapy that are used to treat certain types of cancer (NCI, 2020e). Although stem cell transplantation typically is used in the treatment of leukemia and lymphoma, it may also be used to treat some types of solid tumors. The stem cells used for transplantation can come from one of two sources. First, they may have been harvested previously from the person undergoing treatment (autologous transplant) to provide a rescue after high-dose chemoradiotherapy has destroyed normal blood-making cells. Autologous transplants are used most commonly to treat relapsed or refractory solid tumors or lymphomas (D’Souza et al., 2020). Second, stem cells from a compatible donor may be used (allogeneic transplant); sometimes, an identical twin serves as donor (syngeneic transplant). The stem cells may be harvested from the donor’s bone marrow or mobilized from peripheral blood, or may be retrieved from stored umbilical cord blood. Allogeneic transplant not only can provide a rescue with healthy marrow after high-dose chemoradiotherapy but also may create a graft-versus-malignancy effect by the transfer of a new immune system. Accordingly, allogeneic transplant is used most commonly to treat children with high-risk, relapsed, or refractory leukemias, as well as nonmalignant disorders.

Stem cell transplants are performed in hospitals that have a specialized transplant center certified by the Foundation for the Accreditation of

Cellular Therapy. Treatment can take several weeks to complete: 1–2 weeks of high-dose radiation or chemotherapy that ablates the existing bone marrow, followed by an intravenous infusion of the new blood-forming cells. The recovery phase for the immune system to become fully functional takes much longer, from a few months for an autologous transplant to 1–2 years for an allogeneic or syngeneic transplant.

Side effects depend on the doses of initial radiation and/or chemotherapy, the type of transplant (autologous, allogeneic, syngeneic), the type of cancer and how advanced it is, and the person’s overall health. The acute effects of the initial radiation and/or chemotherapy include increased risk of bleeding (decreased platelets) and infection (decreased white blood cells), as well as other effects described in the sections above on radiation and chemotherapy and in the associated annex tables. In addition, the sequelae of allogeneic transplants can include graft-versus-host disease, in which the transplanted white blood cells attack the cells in the recipient’s body. Typically manifesting with skin rash, liver toxicity, and diarrhea, graft-versus-host disease can be treated with steroids and other immunosuppressant drugs (NCI, 2020e).

Immunotherapy

Immunotherapy is a form of targeted therapy (Wedekind et al., 2018). In contrast to chemotherapies, which target the tumor cells directly, immunotherapies aim to eradicate tumors by activating the patient’s immune system. Broadly, immunotherapies can be divided into treatments that augment or stimulate natural immune responses and those that entail designing a synthetic immune therapy that results in new immune responses (Majzner et al., 2017). Annex Table 3-4 includes a summary of selected immunologic agents, their mechanisms of action, and agent-specific side effects.

The field of cancer immunotherapy has evolved and expanded greatly over the past decade, and is continuing to see rapid change. The following subsections describe some of the immunotherapies currently in use and undergoing continued evaluation in children with cancer.

Therapies augmenting natural immune response against tumors

Immune checkpoint inhibitors (ICIs) (e.g., anti-CTLA4 and anti-PD-1, PD-L1) block the interaction between T lymphocytes (T cells, which are important for immune reactions against tumors) and proteins made by the tumors. This checkpoint blockade can enable the T cells to slow the growth of tumors, to shrink them, and sometimes to eradicate them. Although several ICIs have been successful in the treatment of some adult cancers, such as melanoma, lung cancer, and bladder cancer, their use in children has been less successful, resulting in clinical responses in only small subsets of patients

(Davis et al., 2020; Wedekind et al., 2018). Notable exceptions are pediatric tumors with mutations in DNA mismatch repair genes (microsatellite instability high), which make the tumors susceptible to ICIs (Bouffet et al., 2016). In addition, ICIs show clinical benefit in children and adults with Hodgkin lymphoma. Aims of ongoing and future clinical research efforts include evaluating ICIs in combination with other agents and investigating strategies for making tumors more immunogenic.

Frequent side effects of ICIs include fatigue and anemia. In addition, ICIs can result in autoimmune-related toxicities, whereby the immune response targets the patient’s normal organs. These toxicities require early recognition and treatment and can be life-threatening. Examples include inflammation of the lungs (pneumonitis); brain (encephalitis); bowel (colitis), sometimes with severe diarrhea; and endocrine organs, such as the thyroid gland. The long-term side effects of ICIs are currently unknown, and fully characterizing them will require long-term evaluation of patients who received these therapies.

Therapies initiating new immune responses

Advances in genetic engineering have enabled the development of immune therapies that target surface markers (antigens) present on tumor cells but not, or to a much lesser degree, on normal cells. For example, significant advances have been made in the use of monoclonal antibodies such as CD20 in treating hematologic malignancies and of anti-GD2 (dinutuximab) in targeting high-risk neuroblastoma. Dinutuximab has become part of the standard therapy for high-risk neuroblastoma, along with chemotherapy, radiation therapy, and autologous stem cell transplant. Bispecific monoclonal antibodies (i.e., blinatumomab in acute lymphoblastic leukemia [ALL]) have been developed to simultaneously target CD19 expressed on leukemia cells and CD3 expressed on T cells so as to bring the tumor-fighting T cells to the tumor-causing B cells in children with ALL (PDQ Pediatric Editorial Board, 2020a).

In addition to monoclonal antibodies, CAR T cell therapy has dramatically changed outcomes for children with refractory acute ALL (PDQ Pediatric Editorial Board, 2020a). This therapy requires removing T cells from the patient by a process called apheresis, followed by genetically engineering them to give them the ability to target CD19. While the T cells are undergoing manipulation and expansion in culture, the patient typically receives a lymphodepleting chemotherapy aimed at reducing lymphocytes to “make space” for the CAR T cells. The CAR T cells are then reinfused into the patient and, if effective, will kill the leukemia cells.

One of the side effects of CAR T cell therapy is cytokine release syndrome (CRS), an inflammatory response that can result in high fevers; myalgias; fatigue; toxicity to the CNS, including somnolence, headaches, and seizures; and life-threatening cardiovascular collapse. Therapies that can

ameliorate CRS have been identified (Majzner et al., 2017), and patients undergoing CAR T cell therapies require close observation and treatment at institutions experienced with these ameliorating therapies.

Another side effect specifically of CD19 CAR T cell therapy is prolonged B lymphocyte aplasia (failure to repopulate), which may require that patients receive prolonged intravenous immunoglobulin (Ig) replacement following the therapy. CAR therapies for solid tumors, including neuroblastomas and osteosarcomas, have also undergone evaluation in clinical trials for children; however, their success with solid tumors has been limited compared with their use for hematologic malignancies. Emerging immunotherapies are discussed at the end of this chapter.

Targeted Therapies

Molecular targeted therapy refers to the use of drugs or other substances to target specific molecules involved in the growth, survival, and spread of certain types of cancer cells (NCI, 2020g). The advantage of molecular targeted therapy over traditional cytotoxic chemotherapy is the dramatic dependence of cancer cells, as opposed to normal cells, on the drug’s target, leading to improved selectivity and efficacy and often limiting the toxicity of therapy. The differential dependence on the target between cancer cells and normal cells is commonly related to a specific genetic or protein alteration present only in the cancer cells, which can be detected by modern diagnostic sequencing techniques. The terms “personalized medicine” and “precision oncology” refer to the concept of matching individual patients to drugs that target a genetic change present in their own tumors (Glade Bender et al., 2020).

For example, the 2001 approval of imatinib revolutionized the treatment of chronic myelogenous leukemia (CML) and a particularly aggressive form of childhood ALL, serving as the prototype for precision oncology and the successful integration of targeted agents into curative cancer therapy. Imatinib is a generally well-tolerated oral drug that specifically targets the chromosomal change formerly known as the Philadelphia (Ph) chromosome and now known as the BCR-ABL fusion kinase (novel growth-signaling protein), the genetic driver of both CML and so-called Ph+ childhood ALL (Hijiya and Suttorp, 2019; PDQ Pediatric Editorial Board, 2020a,b; Slayton et al., 2018). Both of these diseases previously required intensive chemotherapy and stem cell transplantation in most children. Another recent pediatric success story is the 2018 U.S. Food and Drug Administration’s (FDA’s) approval of the oral agent larotrectinib for a very small subset of solid tumors harboring a genetic alteration leading to overexpression of the NTRK protein. To date, the exquisite responsiveness of these rare NTRK-driven tumors to larotrectinib has allowed some children to avoid

disfiguring or debilitating surgeries, but for those patients with unresectable or metastatic disease, the durability of the response to and long-term effects of the therapy are as yet unknown (Laetsch et al., 2018).

There are a variety of other molecularly targeted therapies that work in different ways, but in general terms, most “interfere with the ability of cancer cells to grow, divide, repair and/or communicate with other cells” (Chemocare, 2020a). Some agents interfere with molecules (e.g., specific enzymes or proteins) involved in the proliferation of cancer cells. “Epigenetic” agents seek to alter the conformation of DNA to turn tumor suppressor genes or maturation programs back on. Still other drugs may limit blood vessel growth (antiangiogenics) and the delivery of oxygen and nutrients to tumors or help the immune system recognize and kill cancer cells (immunomodulatory therapy). Some more common side effects of molecularly targeted therapies include diarrhea, liver toxicity, and skin problems (e.g., rash, dry skin, nail changes). Antiangiogenic therapies characteristically cause high blood pressure and difficulties with blood clotting or bleeding and wound healing.

Specific molecules present on the surface of cancer cells (tumor antigens or receptors) also present an opportunity for targeted approaches to cancer therapy. Antibody techniques can be used as delivery systems for toxic substances or radioactivity directly to cancer cells, killing them but minimizing the effect on surrounding healthy cells. Although these targeted therapies are systemic and are delivered intravenously, they are designed to target cancer cells rather than all types of fast-growing cells. As a result, they cause less damage and may have fewer and often unique side effects compared with classic chemotherapy, although the long-term side effects of many targeted therapies are currently unknown. Longitudinal followup of children receiving these therapies will therefore be required to better understand their long-term effects.

Annex Table 3-4 summarizes selected targeted agents, their mechanisms of action, and agent-specific side effects.

Supportive Therapies and Care

As detailed above, multimodal cancer therapy can reliably be expected to cause a constellation of side effects, including low blood counts, immunosuppression, fatigue, nausea, vomiting, mouth sores, diarrhea, wound issues, and functional limitations. Those side effects may in turn result in additional hospitalizations, clinic visits, or home care needs to address sometimes life-threatening infection, anemia, thrombocytopenia, dehydration, malnutrition, pain, physical disability, anxiety, and depression. Supportive care for these common complications should be optimized not only to improve the quality of life of patients receiving anticancer

therapy but also to avoid treatment delays and interruptions that can adversely affect long-term outcomes, including the potential for cure. Parents/legal guardians and the patients themselves, to the extent feasible, are integral to the optimal delivery of supportive care. Teaching delivered by the multidisciplinary care team during each step of the treatment can ensure that supportive therapies are appropriately administered and that the patient is monitored and adverse events are expeditiously addressed. Parents and patients are part of the team ensuring optimal care not only for anticipated nausea and vomiting but also for emergent events, such as fever, that require immediate intervention. Palliative care, often inappropriately confounded with end-of-life care, is a holistic approach, often supplemented by dedicated specialized teams, focused on the prevention or early treatment of symptoms stemming from the cancer itself; adverse effects of therapy; and the psychological, social, and spiritual impacts of the disease on patients and their support systems. Described below are some of the more common aspects of supportive care as pertains to children with cancer.

Fertility preservation

Prior to the initiation of chemotherapy, it is important to address with both patient and family the risk of infertility associated with the chosen treatment regimen. The loss of childbearing potential poses a significant threat to the psychosocial well-being of survivors of pediatric cancer, as discussed further in Chapters 4 and 8. Discussions should focus on the appropriateness of fertility preservation strategies, since not all treatment protocols carry the same risk of infertility. The opportunity for fertility preservation may be limited by age, cost, access to expertise, and time afforded by the individual clinical situation. In some cases, patients will need to be referred to HSCs for fertility preservation procedures. Postpubertal children tend to have more options available, including sperm banking for males and egg stimulation and harvesting for females. Options for prepubertal children, while still largely considered investigational, are becoming increasingly prevalent, and consist of testicular biopsy and ovarian tissue retrieval for cryopreservation.

Infection

As previously mentioned, central lines, or CVADs, are used almost uniformly in pediatric oncology to facilitate the reliable delivery of chemotherapy and supportive care measures while diminishing pain and needle phobia for young patients. In the pediatric population, the relative benefits of central lines are believed to outweigh the risks, which include the need for sedation for line placement or removal, specialized catheter care to maintain line function, and increased risk of infection. The presence of a central line requires that all fevers be evaluated on an emergent basis to rule out the presence of a blood bacterial infection.

Overwhelming infection or sepsis in the setting of a low white blood cell count (neutropenia) is a major cause of treatment-related morbidity and mortality for children with cancer. The depth and duration of neutropenia are directly proportional to the risk of infection, which is why most patients undergoing hematopoietic stem cell transplantation or induction treatment for leukemia (dose-intensive multi-agent chemotherapy as initial treatment for leukemia) are required to remain hospitalized or live within a short distance of the hospital until their white blood cell count has recovered. Short- and long-acting growth stimulatory factors (filgrastim, sargramostim) are commonly used for primary prevention of neutropenia in patients undergoing cyclic myelosuppressive therapy for solid tumors and have been associated with a reduction in hospitalizations for neutropenic fever (Robinson et al., 2016).

All patients on active therapy or with central lines are required to undergo emergent evaluation of any new fever, including a physical exam, a blood culture, and blood counts, to determine whether they are neutropenic. On the basis of these findings, a decision is made as to whether antibiotics and/or hospitalization is required. While clinical practice varies, most pediatric oncology programs require delivery of at least 48 hours of broad-spectrum antibiotics as an inpatient or under other closely monitored circumstances for patients presenting with fever and neutropenia (Ahmed and Flynn, 2014). In cases in which patients appear ill or neutropenia is anticipated to be prolonged, it is not uncommon for hospitalization to be required for the duration of their neutropenia, until count recovery (Ahmed and Flynn, 2014). For so-called opportunistic infections resulting from global immunosuppression and T cell dysfunction, trimethoprim–sulfamethoxazole or an appropriate alternative is used for the prevention of pneumocystis jirovecii pneumonia (formerly known as PCP), and depending on the intensity and duration of therapy, the prophylactic use of antifungal and antiviral therapies may also be recommended.

Blood product transfusion

For patients receiving intensive chemotherapy for pediatric cancer, complete blood counts are monitored frequently for the presence of anemia and thrombocytopenia, which may indicate the need for platelet and blood transfusion. In accordance with the American Society for Clinical Oncology practice guidelines, red blood cell transfusion is generally considered if the hemoglobin level is below 7 to 8 g/dl (Valentine et al., 2018), and platelet transfusion is considered if the platelet count is below 10 × 10⁹/L or if the patient has clinically significant bleeding (Schiffer et al., 2018). While the need for red blood cell or platelet transfusion is dependent on diagnosis and treatment, it is estimated that it may be required for as many as two-thirds of children diagnosed with cancer during the course of their treatment (Lieberman et al., 2014).

Nausea and vomiting

Interventions to prevent and control acute chemotherapy-induced nausea and vomiting (CINV) have improved dramatically over the past two decades through the use of antiemetic drugs. Antiemetic drugs well studied in children include 5-HT3 antagonists (granisetron, ondansetron, palonosetron), steroids (dexamethasone), and aprepitant. Antiemetic therapy in pediatric patients has been reviewed and recommendations made as to whether to use three, two, one, or no antiemetic drugs based on whether the chemotherapeutic regimen is deemed to pose high, moderate, low, or minimal risk of CINV, respectively (Dupuis et al., 2017). Newer antiemetic agents, such as olanzapine, have been introduced in children but have yet to be adequately studied. Antiemetics, rescue drugs such as lorazepam and hydroxyzine, and prolonged hydration delivered in outpatient clinics or at home can all be used to reduce chemotherapy-related hospitalizations.

Nutrition

Prolonged or delayed nausea and vomiting in addition to mucositis (mouth sores) and changes in taste and smell can have a profound effect on children’s appetite and nutrition (ACS, 2020b). Good nutrition, in turn, has been associated with improved chemotherapy tolerance, improved survival outcomes, better quality of life, and decreased infection risk in children undergoing anticancer treatment. Pediatric patients require a balanced diet of protein, carbohydrates, fats, minerals, and vitamins, and should have access to nutritional guidance. Notably, the incidence of family food insecurity increases over the course of cancer therapy (Bona et al., 2016). Several nutritional interventions are available, including frequent high-protein, high-caloric meals and snacks; liquid nutritional supplements or protein powders; and if necessary, placement of a nasogastric or gastrostomy feeding tube to overcome behavioral or mechanical barriers. Use of the gut is always preferable to intravenous nutrition, which commonly necessitates hospitalization and home care and frequent monitoring of chemistries and nutrients, and increases risks for liver toxicity and infection (Bauer et al., 2011).

Pain

Mucositis is a common cause of acute treatment-related pain in children with cancer, particularly among those with leukemia or lymphoma and following stem cell transplantation. Initially managed with topical anesthetics, such as diphenhydramine or viscous lidocaine included in “magic mouthwash,” treatment of mucositis often requires escalation to an oral opioid and can be severe enough to warrant hospitalization for intravenous opioid or a patient-controlled analgesia (PCA) pump. For patients with solid tumors, acute tumor-related and postprocedural pain management can be quite challenging, frequently requiring prolonged hospitalization and supervision by a specialist, particularly for newer technologies such as

epidural PCA. Nonopioid interventions for acute pain control, including such complementary approaches as acupuncture and hypnosis, are increasingly coming into favor, and newer, comprehensive patient care guidelines for pediatric pain are in development.

Complex pain syndromes—including those due to peripheral neuropathy; phantom limb pain; and other chronic and neuropathic pain syndromes resulting from tumors, anticancer chemotherapy, or surgical intervention—can be physically and psychologically disabling and are best managed using a holistic approach. The best long-term functional outcomes can be achieved with a collaborative multidisciplinary model that combines pharmacologic intervention with intensive rehabilitation interventions and psychological support. The functional implications of pain are discussed in Chapter 4.

Psychosocial needs

Supportive care includes tending to the psychological, social, and spiritual needs of children and families. The recently released Psychosocial Standards of Care (Standards), the result of a comprehensive evidence-based consensus project, suggest that all children with cancer on active treatment (and their families) need ongoing assessment of their psychosocial needs and continual access to evidence-based psychosocial care and treatment (Wiener et al., 2015). In addition, the Standards specifically state that all youth with cancer and their families should be introduced to palliative care early in the diagnosis and should receive supportive care throughout the trajectory of illness, including attention to the psychological distress of both child and family (Weaver et al., 2015). While the evidence base for psychosocial interventions is less well developed than that for medical interventions, it is nonetheless critical to recognize that children with cancer face extreme distress, isolation, and potentially negative psychological and social outcomes that can impact their ability to function along typical developmental trajectories. These outcomes can be as important as medical late effects and should be considered in a comprehensive assessment of functioning for children undergoing treatment. Moreover, pediatric oncology teams have an ethical duty to care for the family as well as the child, because the well-being of the family impacts the child’s physical and mental health in cancer care (Jones et al., 2014). Additional information on psychosocial functional outcomes of cancer is provided in Chapters 4 and 8.

EMERGING TREATMENTS

While much of the standard therapy for pediatric childhood cancers still relies on surgery, radiation therapy, chemotherapy, and hematopoietic stem cell transplantation, new treatment modalities are increasingly becoming available (Campbell et al., 2020). They include precision therapies,

described above, which target oncogenic drivers of disease present in selected tumors, as well as some immunotherapies (see Annex Table 3-4). A brief review is provided here, as emerging therapies are advancing quickly and are associated with different adverse events and possibly functional outcomes compared with standard therapies currently in use.

Approaches to treating childhood cancers are evolving rapidly as a result of several factors. The increasing availability and decreasing cost of the technologies needed for comprehensive study of the genomics of pediatric cancers, tumor microenvironments, and immune cells are generating large datasets of new information. In addition, new bioinformatic and computational methods are being developed to allow for meaningful analysis of these datasets. The resulting increased understanding of tumor pathogenesis and progression will likely enable the identification of new approaches to treating childhood cancers.

Genomic Landscape of Childhood Tumors

The most significant advances have been realized in the increasing understanding of the genomic changes in childhood tumors (Gröbner et al., 2018). These advances have allowed for identification of specific genetic events, such as tumor mutations, fusions, and epigenetic events, that can be treated with new medical therapies specifically designed to target these aberrations. Studies have shown that approximately 50 percent of childhood tumors display genetic changes that can potentially be targeted with these therapies (Gröbner et al., 2018). The sequencing of not only the tumors but also the normal cells (germline) of patients with pediatric cancers has shown that approximately 7–10 percent of these patients have germline mutations that may predispose them to the development of cancers. It is important to follow these patients clinically since they may be at risk for developing additional cancers throughout their lifetime and may need appropriate genetic counseling.

As described in this chapter, the development of combination therapies has contributed substantially to the improved cure rates for and overall survival from childhood cancers. Some precision therapies have been highly successful as a single agent in targeting and eradicating tumors with mutations in oncogenic drivers (see Annex Table 3-4). Examples include the NTRK inhibitor larotrectinib for a variety of solid tumors with TRK fusions and ALK inhibitors for the treatment of anaplastic large-cell lymphomas with ALK mutations. However, the development of resistance to these targeted agents is an important problem. In addition, oncogenic drivers have been identified for only a small subset of pediatric solid tumors, and for tumors without an oncogenic driver, treatment with a single targeted agent is unlikely to result in substantial tumor shrinkage or disease stabilization.

Also, in some cases, an oncogenic driver may be known but not yet found to be targetable (e.g., EWS-FLI1 in Ewing sarcoma [Pushpam et al., 2020]).

Research is under way to determine how most effectively to combine new targeted therapies in clinical trials and incorporate these agents into up-front therapies. For example, the National Cancer Institute (NCI) and the COG are currently conducting NCI and COG MATCH trials. Patients with solid tumors and specific tumor mutations can be enrolled into 1 of more than 10 treatment arms, each targeting a specific mutation. This trial has been highly successful in providing single-agent targeted therapy to patients with solid tumors and specific genetic changes (Campbell et al., 2020). In the near future, NCI and the COG will expand on this work by developing Combination MATCH trials in which several targeted agents will be combined, and I MATCH trials in which an immunotherapy will be combined with targeted therapies.

Immunotherapies

Since the FDA approved CD19-directed CAR T cell therapy for CD19expressing ALLs, it has become apparent that up to 50 percent of children receiving this therapy will experience relapse with their leukemia, and that at the time of relapse, many leukemias will have lost the CD19 antigen (CD19-negative leukemia) (Bonifant and Tasian, 2020). As was the case with the initial development of cancer chemotherapy, where the administration of a combination of agents was required for cure, researchers are now developing CAR T cell therapies targeting other antigens present on leukemia cells, such as CD22, as well as simultaneously targeting several antigens in combination. Efforts to develop more effective immunotherapies for patients with solid tumors are ongoing (Weber et al., 2020). In addition, researchers are beginning to combine immunotherapy approaches with targeted therapies and chemotherapy. Many are beginning to consider immunotherapy as the fourth pillar of combination therapy, along with surgery, radiation, and chemotherapy. The Pediatric Cancer Immunotherapy Trials Network, sponsored by the NCI Cancer Therapy Evaluation Program, is a new consortium of academic sites with preclinical and clinical expertise in the conduct of multicenter trials of immunotherapies. The discovery of new pediatric tumor-specific targets and improvements in the design of antibody constructs and CAR T to enhance cell kill are likely to open new avenues for the use of immunotherapy in pediatric oncology.

Regulatory Approval of New Therapies for Children

While in the past, pediatric drug development lagged substantially behind the development of new drugs for adults, this situation has recently

changed (Campbell et al., 2020). For example, whereas enrollment of adolescents and young adults in clinical trials has been lower compared with both children under 12 and adults (Smith et al., 2014; Unger et al., 2016), FDA recently provided a strong rationale and support for the inclusion of adolescents aged 12 and older in early-phase clinical trials in adults (Chuk et al., 2017). In addition, through the RACE (Research to Accelerate Cures and Equity) for Children Act, FDA now requires pharmaceutical companies to evaluate novel agents primarily in development for adult cancers in children if their targets are present in and substantially relevant to pediatric tumors. A list of molecular targets considered potentially relevant to pediatric cancers has been developed by FDA, academia, and other parties (FDA, 2019). The result is likely to be the development of an increasing number of early clinical trials for children with solid tumors. Finally, FDA has developed novel approaches to drug approval. In addition to histology/disease-specific approvals, FDA recently approved two new agents on the basis of the presence of a molecular marker on tumors across different tumor types and across ages, children and adults: larotrectinib in TRK fusion and pembrolizumab for protein disulfide isomerase inhibition in microsatellite instability high pediatric and adult cancers (Campbell et al., 2020). These developments have begun to change the landscape of pediatric trials and will likely accelerate more successful development of new, more effective treatments for children with cancer.

Examples of New Treatments for Children

A recent example of a new and effective targeted therapy for children with the genetic tumor predisposition syndrome neurofibromatosis type 1 (NF1) is the MEK inhibitor selumetinib. Children with NF1 are prone to developing histologically benign but progressively growing and debilitating peripheral nerve sheath tumors called plexiform neurofibromas. In addition, children with NF1 have a high incidence of developing optic pathway tumors, which can result in multiple adverse events, including vision loss. Selumetinib blocks a signaling pathway that is hyperactive in these tumors. Clinical trials in children with NF1 and plexiform neurofibromas demonstrated for the first time consistent tumor shrinkage (Dombi et al., 2016), and more recently, clinical benefit in children with these tumors (Gross et al., 2020). In parallel, clinical trials targeting low-grade gliomas (LGGs) in NF1 also demonstrated tumor shrinkage (Fangusaro et al., 2019). A prospective COG coordinated trial comparing selumetinib with standard chemotherapy for children with newly diagnosed LGGs is now ongoing. FDA recently approved selumetinib for children with inoperable and symptomatic plexiform—neurofibroma—the first approved therapy for these tumors.

Advocacy and Patient Engagement in Clinical Trials

As new therapies, clinical trial designs, and outcome measures are developed for children and adults with tumors of unmet need, the importance of engaging patient advocates and representatives in clinical research and trial design is increasingly being recognized. The Cancer Moonshot Blue Ribbon Panel Report highlighted that “patients from underrepresented racial/ethnic minority groups and other underserved populations are not well represented in these past efforts, leading to lack of information on all types of cancers in all populations” and identified establishing effective patient engagement networks as a critical need (Blue Ribbon Panel, 2016, p. 11). Bringing “a nonscientific viewpoint to the research process” and communicating “a collective patient perspective” can influence clinical research and trial conduct positively in many ways (Perlmutter et al., 2013, 2015). Roles of patient advocates include participation in planning and implementing clinical trials, translating and disseminating research, communicating a sense of urgency, reviewing trial proposals, and ensuring a patient focus. Patient advocates and representatives thus are now an integral part of many consortia and academic institutions that engage in clinical research (Deverka et al., 2018; Perlmutter et al., 2015).

SUMMARY

The use of multimodal therapy has led to substantial improvement in the cure rates for pediatric hematologic malignancies and solid tumors over the past several decades. At the same time, however, the use of intensified therapies has resulted in substantial acute, chronic, and late effects that can significantly affect the quality of life, function, and health of survivors of childhood cancer. Efforts are under way to develop less toxic but effective therapies, including reductions and modifications of doses and schedules for radiation therapy and chemotherapy agents, and the incorporation of novel treatment approaches, such as different types of targeted therapies, into initial treatment strategies.

FINDINGS AND CONCLUSIONS

Findings

3-1 Treatment of childhood cancers generally includes the 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.

3-2 The improved overall survival of children with cancer has allowed for a greater understanding of the long-term and late toxicities of the various modalities of therapy.

3-3 There remains a group of primary and recurrent cancers for which standard intensive multimodal therapy is not curative.

3-4 Age at treatment contributes uniquely to the risk and severity of long-term adverse effects experienced by survivors of childhood cancer.

3-5 At least 50 percent of children diagnosed with cancer participate in clinical trials.

3-6 Rates of enrollment of adolescents and young adults in clinical trials are lower compared with rates for both children under 12 and adults.

3-7 Local cancer treatments such as surgery and radiation therapy target cancer at its location in the body. Resulting adverse effects are localized to the area targeted by the treatment.

3-8 Completeness of surgical removal of solid tumors is a critical factor in determining the length of chemotherapy required and both the need for and dose of radiation therapy.

3-9 Certain types of surgical procedures (e.g., pelvic bone tumor surgical resection, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, treatment of neuroblastomas with vascular involvement, radiofrequency ablation, cryoablation) are available only at highly specialized centers (HSCs).

3-10 Many of the long-term and late effects of radiation therapy, which often are permanent, depend on the child’s age at treatment, the location treated, and the dose of radiation administered. Irradiation to the brain of a young child can significantly increase the risk of neurocognitive injury and the subsequent risk of long-term, potentially progressive functional limitations resulting in disability.

3-11 High-precision radiotherapy, including proton beam radiation therapy, is increasingly available and used to mitigate late effects in survivors of childhood cancer. Pediatric oncologic care requires treatment at a HSC.

3-12 Systemic treatments such as most chemotherapies circulate throughout the body and therefore affect cells in the entire body. Resulting adverse effects typically are caused by toxic effects on normal cells and can occur throughout the body.

3-13 New treatment modalities offer promise for decreasing adverse effects, but supportive longitudinal data are early and evolving.

3-14 With a few notable exceptions, targeted and immunotherapies are at a relatively early stage in their clinical development for

pediatric cancer but offer promise for addressing cancers with unmet clinical need.

3-15 Cancer treatment can have negative psychosocial impacts on children with cancer and their families that lead to negative outcomes in functional and overall well-being.

3-16 Supportive care includes psychological, social, and familial care as well as medical care.

3-17 Palliative care is a holistic approach, often provided by dedicated specialized teams, focused on the prevention or early treatment of symptoms stemming from the cancer itself; adverse effects of therapy; and the psychological, social, and spiritual impact of the disease on patients and their support systems.

3-18 Palliative care is an important part of treatment that can be introduced early on to mitigate symptoms and suffering.

3-19 Pediatric cancer treatment typically is provided by a multidisciplinary pediatric care team in collaboration with primary care providers. In addition to physicians, team members may include nurse specialists, psychologists, neuropsychologists, nutritionists, rehabilitation specialists (e.g., physiatrists; physical, occupational, and speech therapists), social workers, child-life specialists, and others.

Conclusions

3-1 Quality pediatric cancer care requires management by a multidisciplinary team of cancer care providers with expertise in pediatrics.

3-2 It is important for surgical resection to be performed at specialized centers (SCs) because the completeness of surgical resection directly affects outcomes, the need for multimodal treatment, and the potential for disability.

3-3 Patients from less densely populated and rural environments may have to travel some distance to reach a treatment center that can provide specialized pediatric cancer care. SCs are available in every state, but HSCs are rare. An out-of-state consultation would be expected for treatments available only in HSCs.

3-4 Negative psychological and social outcomes can be as important as medical late effects, and should be considered in a comprehensive assessment of functioning for children undergoing treatment.

3-5 The high participation of children with cancer in clinical trials developed by cooperative groups whose membership includes leading disease experts has allowed for the development of improved treatments through successive implementation of treatment changes.

3-6 Clinical trials to improve survival and limit toxicity are urgently needed, and participation in such trials is considered the standard of care in pediatric oncology.

3-7 With increased availability and continued study, a decrease in side effects can be anticipated from advances in radiation therapy.

3-8 A strong rationale exists for the inclusion of adolescents aged 12 and older in early-phase clinical trials in adults.

3-9 Further studies are required to understand how novel targeted and immunotherapies can be incorporated into the treatment of newly diagnosed patients and how they can be used to address unmet clinical needs.

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ANNEX TABLE 3-1
Acute and Long-Term Sequelae of Cancer Surgery

NOTE: Tumor histology may vary per location.

* Pelvic resection: Enneking and Dunham (1978) classified pelvic lesion resections into three main types: Type I = resection confined to ilium; Type II = resection confined to the periacetabulum; Type III = resection confined to the pubis.

ANNEX TABLE 3-2
Acute and Long-Term Sequelae of Radiation Therapy

* Side effects depend on the radiation therapy dose, delivery technique, and volume; use of combined-modality therapy; and age of the patient at treatment. General late effects for any site include the long-term risk of secondary cancers.

SOURCES: COG, 2020c; Dhakal et al., 2016.

ANNEX TABLE 3-3
Acute and Long-Term Sequelae of Different Classes of Chemotherapy Agents

NOTE: BCNU = carmustine; CCNU = lomustine; DNA = deoxyribonucleic acid; DTIC = dacarbazine; IM = intramuscular; IT = intrathecal; IV = intravenous; PO = by mouth; SC = subcutaneous.

SOURCES: Chemocare, 2020b; NCI, 2020a,b; PDQ Pediatric Editorial Board, 2020a,b; Pizzo et al., 2016.

ANNEX TABLE 3-4
Targeted Therapy Agents: Selected Current (2020) U.S. Food and Drug Administration (FDA) Approved, with Pediatric Labeling, and/or in Development Through Clinical Trials

NOTE: ATRA = all-trans retinoic acid; CAR = chimeric antigen receptor; CT = clinical trial; GI = mouth sores (mucositis) and diarrhea; IV = intravenous; P = pediatric approval or labeling; PO = by mouth; SC = standard of care; Y = FDA-approved (for any indication).

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