Childhood Cancer and Functional Impacts Across the Care Continuum (2021) / Chapter Skim
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3 Treatment Modalities for Childhood Cancers
3 Treatment Modalities for Childhood Cancers
Pages 47-126
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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)
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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.
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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)
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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]
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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)
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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)
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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.
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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)
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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.
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Consolidation for solid tumors sometimes includes a high-dose chemotherapy with stem cell rescue (also referred to as an autologous transplant; see below)
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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)
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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)
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. Annex Table 3-4 includes a summary of selected immunologic agents, their mechanisms of action, and agent-specific side effects.
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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.
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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.
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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.
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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.
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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.
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. 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.
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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)
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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.
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. 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.
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. The result is likely to be the development of an increasing number of early clinical trials for children with solid tumors.
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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.
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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 least 50 percent of children diagnosed with cancer participate At in clinical trials.
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3-4 Negative psychological and social outcomes can be as important as medical late effects, and should be considered in a comprehen sive 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 im proved treatments through successive implementation of treat ment changes.
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3-8 strong rationale exists for the inclusion of adolescents aged 12 A 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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2017. Enrolling adolescents in disease/target-appropriate adult oncology clinical trials of investigational agents.
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2017. Childhood cancer survivorship and long-term outcomes.
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2017. Harnessing the immunotherapy revolution for the treatment of childhood cancers.
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2008. Progress in childhood cancer: 50 years of research collaboration, a report from the Children's Oncology Group.
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2018. Models of care for survivors of childhood cancer from across the globe: Advancing survivorship care in the next decade.
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2014. Radiation therapy digital data submission process for National Clinical Trials Network. International Journal of Radiation Oncology, Biology, Physics 90(2)
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80 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Acute and Long-Term Sequelae of Cancer Surgery Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 81 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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82 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 83 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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84 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 85 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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86 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 87 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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88 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 89 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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90 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 91 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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92 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 93 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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94 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 95 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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96 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 97 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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98 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-1 Continued Surgery Location Surgery Location (general) (specific)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 99 Acute Sequelae Long-Term or Late Effects Common Uncommon Common Uncommon (>20 percent) (<20 percent)
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External Brain • Fatigue • Ear pain or beam • Skin changes inflammation • Hair loss • Dry eye (if one or both eyes are treated) • Headache • Nausea or vomiting Eye • Dry eye • Conjunctivitis Head and neck • Fatigue • Change in taste • Skin changes • Difficulty swallowing • Hair loss • Dry mouth • Mouth sores • Sore throat Spine • Esophagitis Chest • Fatigue • Chest pain or • Skin changes discomfort • Cough • Difficulty swallowing • Shortness of breath
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 101 Long-Term or Late Effects* • Eye problems, including cataracts or loss of vision • Hearing problems • Neurocognitive and psychosocial impairments • Endocrine abnormalities, which can include growth hormone deficiency, precocious puberty, infertility, ovarian failure, hyperprolactinemia, testosterone deficiency, and thyroid problems • Central adrenal insufficiency (rare)
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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.
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 103 Long-Term or Late Effects* • Kidney problems • Liver problems • Lung problems • Nonfunctioning spleen • Ovarian failure • Problems during pregnancy • Effects on spinal growth (scoliosis, kyphosis, or decreased vertebral body growth)
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structure, causing breakage of the DNA strands when the cell tries to divide, ultimately leading to cell death Resting phase of cell cycle Melphalan (IV, PO) Thiotepa (IV)
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Late Effects Cancer Types Alopecia (A) Water retention Secondary Leukemia with sodium malignant Nausea and vomiting Lymphoma dysregulation neoplasms (N&V)
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106 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-3 Continued Example Agents (mode of Class Mechanism of Action Types administration) Alkylating "Classical" Busulfan (PO)
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Late Effects Cancer Types M, I, FN, N&V, GI, A Pulmonary SMN, F Preparatory toxicity (lung regimen for SCT Hepatic toxicity Chronic injury, chronic (HD; sinusoidal pulmonary interstitial fibrosis obstruction dysfunction and alveolar syndrome [SOS]
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108 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-3 Continued Example Agents (mode of Class Mechanism of Action Types administration) Antimetab- Mimic molecules Folic acid Methotrexate (IV, IT, olites needed by cells to antagonists PO, IM, SC)
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Late Effects Cancer Types GI, M (mild) Rash Leukoencepha- Leukemia/NHL lopathy Liver dysfunction Acute renal Osteosarcoma toxicity (HD)
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110 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-3 Continued Example Agents (mode of Class Mechanism of Action Types administration) Antimetab- Adenosine Fludarabine (IV)
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Late Effects Cancer Types M, I, FN, N&V, GI Opportunistic SMN Leukemia infections Fever, systemic Histiocytosis inflammatory Hepatic toxicity Preparatory response syndrome Neurotoxicity regimen for SCT Myalgia (pain, weakness, (fludarabine) paresthesias, Edema impaired mentation)
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112 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-3 Continued Example Agents (mode of Class Mechanism of Action Types administration) Plant Taxanes Paclitaxel (IV)
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Late Effects Cancer Types M, I, N&V, GI, A FN Sensory Recurrent solid and motor tumors Allergic reaction Cardiac toxicity neuropathy (docetaxel) Neurotoxicity Fluid retention, (paclitaxel)
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114 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-3 Continued Example Agents (mode of Class Mechanism of Action Types administration) Antitumor Act in different ways Anthracy- Doxorubicin (IV)
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Late Effects Cancer Types M, I, FN, N&V, GI, A Radiation recall SMN Leukemia (AML, ALL) Weakness/fatigue Late chronic cardiac toxicity Hodgkin Acute cardiac lymphoma/NHL toxicity Most extracranial Arrhythmia solid tumors AT/RT M, I, FN, N&V, GI, A Liver dysfunction Wilms tumor (enzyme Weakness/fatigue RMS elevation, Radiation recall hyperbilirubi nemia, SOS)
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116 CHILDHOOD CANCER AND FUNCTIONAL IMPACTS ANNEX TABLE 3-3 Continued Example Agents (mode of Class Mechanism of Action Types administration) Miscella- Adreno- Mitotane neous cortical (continued)
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Late Effects Cancer Types N&V, M Orthostatic Chronic adrenal Adrenocortical hypotension insufficiency carcinoma Weakness/fatigue Hypertension Dizziness Rash Mood changes Hypothyroidism Anaphylaxis/allergic Bleeding Permanent Leukemia reaction pancreatic insufficiency Local skin reaction Clotting abnormalities Pancreatitis
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Approved, with Pediatric Labeling, and/or in Development Through Clinical Trials Example Agents (mode of Drug Class Mechanism of Action Class Effects administration) Molecularly Targeted Small Molecules Receptor Inhibit specific GI Imatinib (PO)
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PDGFR (ALL) Rare vascular KIT Chronic myelogenous related events leukemia FLT3 FLT3-altered acute Y CT M myeloid leukemia (AML)
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pathway inhibition Alopecia Fatigue Arthralgia Myalgia Cell death Prevent normal GI Venetoclax (PO) pathway programmed cell Tumor lysis inhibitors death in response to syndrome damage Differentiating Induce multiple GI Arsenic trioxide agents cellular effects that (IV)
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MEK Plexiform neurofibroma Y P Cardiac and eye toxicity JAK Juvenile myelomonocytic Y P Opportunistic leukemia infection CT Graft-versus-host disease SMO Basal cell carcinoma Y CT Growth plate fusion Adult medulloblastoma BCL-2 Leukemias Y CT M (prolonged) PML-RARα Acute promyelocytic Y SC Differentiation leukemia syndrome RAR Neuroblastoma Y SC Dry skin Bone toxicity continued
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other bispecific them together; Abs typically a cancer cell Hepatic toxicity and an immune cell Targeted Genetically I, M, FN Tisagenlecleucel cellular engineered immune (IV)
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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 123 Agent-Specific Side Target Pediatric Uses FDA Status Effects EZH2 Epithelioid sarcoma Y P Secondary inhibitor malignant neoplasm Histone Leukemia Y CT Vascular events deacetylase Diffuse intrinsic pontine glioma CD20 Non-Hodgkin lymphoma Y P Reduced immune-globulins GD2 Neuroblastoma Y P Pain CD19- CD3 ALL Y P Cytokine release syndrome Neurotoxicity CD-19 Relapsed or refractory B Y P Cytokine release cell ALL syndrome Neurotoxicity CD30 Hodgkin lymphoma Y P Peripheral neuropathy ALCL CD33 AML Y P Hepatic toxicity Sinusoidal obstructive syndrome CD22 ALL Y CT Hepatic toxicity continued
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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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TREATMENT MODALITIES FOR CHILDHOOD CANCERS 125 Agent-Specific Side Target Pediatric Uses FDA Status Effects PD-1 Hodgkin lymphoma Y P N&V Tumors with mismatch Fatigue repair defect Y CT Flu-like symptoms CTLA-4 Melanoma Y P GI Hodgkin lymphoma CT Rash B7-H3 Neuroblastoma CT Headache Leptomeningeal Abdominal pain carcinomatosis Desmoplastic small round cell tumor Nor- Neuroblastoma CT M (may require stem epinephrine cell rescue) transporter
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