The American Cancer Society and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program state that cancer is the second leading cause of death in children under the age of 14, after accidents. Pediatric cancers make up less than 1% of all newly diagnosed cancers annually. It is projected that there will be just over 11,000 new childhood cancer diagnoses, and that 1,190 children under the age of 15 will die from cancer in 2019. 1 This rotation at MD Anderson Cancer Center served as a broad look at many areas of Pediatric Oncology - Leukemia/Lymphoma Clinic, Non-Neural Solid Tumor Clinic, Neural Solid Tumor Clinic, Stem Cell Transplant Unit, Pediatric Radiology, and Adolescent/Young Adult Survivorship Clinic.
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Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, composing about 25% of all childhood cancers. Acute leukemia is the uncontrolled proliferation, spread, and accumulation of blasts (immature cells) and decreased production of typical blood cells by bone marrow. The clinical picture of ALL is non-specific and can include fatigue, pallor, anorexia, fever, infection, joint pain, and petechiae/purpura. Definitive diagnosis is made via bone marrow aspiration and biopsy, typically from the iliac crest under anesthesia. Bone marrow is examined for morphology, cytochemistry, immunophenotyping (helpful in identifying antigens for therapy and deciphering B cell or T cell line), and cytogenetics. Work up should include a complete blood count (CBC), chemistry (CMP), coagulation studies, chest X-ray, and lumbar puncture. Age and leukocyte count at diagnosis are major prognostic indicators. 2 According to lecture in clinic, standard-risk acute lymphoblastic leukemia (ALL) is defined as age at diagnosis between 2 and 10 years old, with white blood cell count less than 50,000 at diagnosis, and negative cytogenetic markers (such as the Philadelphia chromosome, which is also associated with chronic myeloblastic leukemia in adults). Patients who do not satisfy the criteria are considered high-risk. It should be noted that standard-risk acute lymphoblastic leukemia can be reclassified as high-risk if the patient is Minimal Residual Disease (MRD) positive upon repeat bone marrow aspiration after chemotherapy induction (Day 29 of treatment). In the last half century, cure rates have risen from roughly 10% to 90%, attributable to noticeably improved diagnostics and management of acute lymphoblastic leukemia. Treatment is administered in three phases – induction, consolidation, and maintenance, and the goal of treatment is remission. Induction usually consists of a steroid, vincristine, asparaginase, with or without anthracycline.3 Vincristine carries the side effects of peripheral neuropathy and alopecia. Anthracyclines like doxorubicin are cardiotoxic. Patients have stated that steroids are especially difficult to tolerate with indigestion, weight gain, and “puffiness”. While patients are undergoing chemotherapy, they also take Bactrim (sulfamethoxazole/trimethoprim) or pentamidine for Pneumocystis carinii pneumonia (PCP). Over 95% of patients achieve remission (less than 5% blasts) after induction. 3 Management of relapse accounts for multiple factors and is very challenging. Treatment is dependent upon site of relapse – marrow or extramedullary relapse. Marrow relapse can be treated with re-induction chemotherapy, bone marrow transplant, or Chimeric Antigen Receptor therapy. Chimeric Antigen Receptor T-Cells (CAR-T Therapy), also called Axicabtagene Ciloleucel, is a relatively new therapy used to treat refractory or relapsed acute lymphoblastic leukemia in the bone marrow. The patient’s own T-cells are harvested using apheresis and sent for modification in a lab, specifically to look for CD19 markers to target tumor cells. The modified T cells are then reinfused to the patient and sequelae monitored. Cytokine Release Syndrome (CRS) is a serious side effect of the treatment, as cytokines are inflammatory mediators and released by T cells. Signs and symptoms of CRS include fever, shortness of breath, arrhythmias, nausea/vomiting, liver damage, and kidney damage. CAR Related Encephalopathy Syndrome, related to CRS, is a neurological condition with symptoms such as delirium, confusion, agitation, and seizures. Tumor Lysis Syndrome (TLS) can occur, usually early after CAR T-cell transplant, in which lysed tumor cells spill their contents - notably potassium, phosphate, and uric acid - into the bloodstream, resulting in electrolyte imbalances and systemic issues. Prevention of Tumor Lysis Syndrome is of utmost importance - patients must be frequently monitored, hydrated, and if necessary, allopurinol may be used. Tumor Lysis Syndrome is not limited to CAR T-cell therapy and can occur after other cytotoxic regimens. At MD Anderson, the Stem Cell Transplant Team manages CAR-T Therapy.
Brain tumors are the second most common malignancy of childhood after leukemia/lymphoma and the most common cause for mortality and morbidity. Of this category, astrocytomas (“low-grade gliomas, brainstem gliomas, and non-brainstem high grade gliomas”) are the most common. The most common subset of astrocytomas are low-grade gliomas (World Health Organization grades I and II). In contrast to adult low-grade gliomas, pediatric low-grade gliomas rarely progress to become high-grade gliomas (World Health Organization grades III and IV). The most common low-grade glioma is the pilocytic astrocytoma (grade I). Pilocytic astrocytomas typically have a cystic component and remain localized. Presenting signs and symptoms will depend on where the tumor is located - cerebellar tumors may present with increased intracranial pressure (ICP) or hydrocephalus if obstructing the ventricular system. Supratentorial tumors may cause headaches or visual changes. Low-grade gliomas of the optic pathway are associated with Neurofibromatosis Type I. Fifteen to twenty percent of patients with neurofibromatosis type 1 develop low-grade gliomas. History and physical, with a focus on neurological exam, is the first part of accurate diagnosis. MRI of the brain and spine, lumbar puncture, bone marrow aspiration/biopsy, and tumor biopsy (if possible) are part of the extensive workup. Treatment depends on multiple factors - tumor location (50% of all childhood brain tumors are infratentorial), size, clinical presentation, and comorbidities. Complete surgical resection, if possible, is ideal. For sub-total resections or unresectable tumors, chemotherapy is necessary - vincristine and carboplatin are typically first-line therapy. Carboplatin can cause hearing loss and is nephrotoxic. Radiation therapy must be used judiciously and is usually reserved for tumors that do not respond to chemotherapy. Radiation to the growing brain comes with known adverse neurodevelopmental, psychological, and endocrine effects. Notably, radiation should not be used in patients with neurofibromatosis type I due to risk of secondary tumors and vasculopathy. As with all treatment, it is important to consider risks and benefits to the patient. 4
Osteosarcoma is the most common bone malignancy in children and young adults. These tumors begin in bones, most commonly the distal femur, and produce osteoid tumor tissue. Though it typically manifests in the long bones, it can occur in the hip, spine, ribs, and jaw. Patients who present with osteosarcoma typically complain of pain that is worse at night, with joint swelling, warmth, and limited range of motion. Osteosarcomas can also be a source of pathological fracture, though these fractures are seen with progressed disease. Thus, history and physical are of utmost importance in diagnosis. Workup includes chest X-Ray, MRIs, bone scans, a chest CT (the most common site of metastasis is the lung), complete blood count, chemistry, coagulation, PET scan, and an echocardiogram. Classically, osteosarcomas are associated with a “sunburst” pattern and Codman’s triangle on X-ray. Osteosarcoma is treated with neoadjuvant chemotherapy, surgical resection, and adjuvant chemotherapy. Osteosarcoma is treated with MAP chemotherapy – methotrexate, doxorubicin (anthracycline class of drug), and cisplatin (platinum-based alkylating agent). Methotrexate has the potential side effect of mucositis and myelosuppression. Doxorubicin is cardiotoxic and so echocardiograms must be ordered to monitor for changes in cardiac function – the clinician must also ask about cardiac symptoms such as dyspnea on exertion, orthopnea, chest pain, swelling of the lower extremities. Cisplatin is known to cause hearing loss and be nephrotoxic – baseline audiology and follow up should be obtained as well as monitoring of creatinine and GFR. Surgery options can include limb salvage (internal hardware, grafts), amputation, and rotationplasty for distal femur lesions. 5 Rotationplasty is an above-the-knee amputation with the lower leg rotated 180 degrees and neurovascularly re-attached so that the ankle becomes a functional knee joint. After extensive physical therapy and psychiatric counseling, the foot is fitted for a prosthesis. It is an ideal option for patients who wish to remain active. A 9-year-old patient, 3 years status post rotationplasty, was seen in clinic and stated that she is now a cheerleader for her elementary school.
Wilms’ tumor, also referred to as nephroblastoma, is the most common renal malignancy in children. This tumor is most often seen in children between one and five years old, with peak incidence at around 3 years old. The tumors are classified and staged based on histology – favorable or anaplastic (unfavorable) – and metastasis. Patients are generally well-appearing and an abdominal mass is found incidentally. Patients may also present with hematuria or hypertension. Because the tumor impinges on the abdominal space, patients may present with pain, anorexia, or vomiting. Workup for diagnosis of Wilms’ tumor include a complete blood ocunt, renal students, liver function tests, chemistry, and urinalysis. Imaging includes abdominal ultrasound and chest/abdomen CT. Surgery is the foundation of treatment and assists in identifying histology. Surgeons must be aware of risk of abdominal seeding of tumor and hemorrhaging the “pseudocapsule” of Wilms’ tumor. After partial or total nephrectomy, all patients receive chemotherapy. Stage I and II tumors receive vincristine and dactinomycin. Stage III and IV tumors receive this regimen with the addition of doxorubicin. Radiation is only necessary for Stage III and IV tumors or if there was tumor seeding during surgery. Wilms’ tumors can occur bilaterally – a Stage V classification. The mainstay would also be surgery with the goal of preserving some kidney tissue. 6
Largely due to clinical trials and advancements in biotechnology, the five-year survival rate for pediatric cancers is now above 80%.1 There are over 50 currently enrolling pediatric cancer trials at MD Anderson. In the MD Anderson clinics, providers and clinical researchers informed eligible patients and their families about clinical trials that are currently recruiting. MD Anderson is part of the Children’s Oncology Group (COG), a collective of pediatric cancer experts from hospitals, universities, and cancer centers worldwide that manage trials and develop protocols for the treatment of pediatric cancers. Patients are treated according to these Children’s Oncology Group protocols, ever-evolving standards-of-care in pediatric oncology. Advances in oncogenomic testing have also assisted in targeted therapy or “precision oncology”. MD Anderson predominantly uses Oncomine as a third-party company to send in tumor material for additional genetic/biomarker testing that is not necessarily included in the baseline general pathology for a tumor.
Survivorship brings its own challenges. As was evidenced by time spent in the MD Adolescent/Young Adult Survivorship Clinic, the long-term psychosocial needs of pediatric cancer patients need to be addressed and integrated into care beginning at diagnosis and carrying forward into their life beyond treatment. In a 2012 study by Kwak, et. al, post-traumatic stress symptoms were measured in young adults and adolescents with cancer at 6 and 12 months after diagnosis. Thirty-nine percent of subjects reported moderate to severe levels of post-traumatic stress symptoms at 6 months, and 44% of subjects reported this severity post-traumatic stress symptoms at 12 months. There was no statistically significant change between 6 and 12 months, thereby implying that post-traumatic stress symptoms can begin as early as 6 months and can persist even a year after diagnosis. Currently undergoing treatment, having surgical treatment, and unemployment/not attending school were factors associated with post-traumatic stress symptoms. 7 A study by Frederick, et. al published in Pediatric Blood and Cancer surveyed sixteen young childhood cancer survivors (ages 22-36) about what they perceived to be their needs as they transitioned into adult care. The study found that these survivors wished for their health education to come from their pediatric oncology provider and for the provider-patient relationship to be close with open communication about care and information during the transition to adult medical care. Additionally, the subjects wished for continued family support with acknowledgement of their patient autonomy. 8 The Adolescent/Young Adult Survivorship Clinic served patients from ages 9 to 39 and addressed topics unique to this phase of life, such as fertility options, vocational assistance, and peer support groups/resources. Physician Assistants working in Pediatric Oncology can play a vital role in forging strong patient relationships and in providing the education to patients and their support networks as they go through diagnosis, treatment, and their transition to survivorship.
As is evident, the Pediatric Oncology Physician Assistant can serve in many areas and is an integral part of medical management for this specialized population.
1. Key Statistics for Childhood Cancer. 2019; https://www.cancer.org/cancer/cancer-in-children/key-statistics.html. Accessed October 10, 2019.
2. Bhojwani D, Yang JJ, Pui C-H. Biology of Childhood Acute Lymphoblastic Leukemia. Pediatric Clinics of North America. 2015;62(1):47-60.
3. Kato M, Manabe A. Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatrics International. 2018;60(1):4-12.
4. Wells EM, Packer RJ. Pediatric brain tumors. Continuum (Minneapolis, Minn). 2015;21(2 Neuro-oncology):373-396.
5. Isakoff MS, Bielack SS, Meltzer P, Gorlick R. Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. Journal of Clinical Oncology. 2015;33(27):3029-3035.
6. Varan A. Wilms’ Tumor in Children: An Overview. Nephron Clinical Practice. 2008;108(2):c83-c90.
7. Kwak M, Zebrack BJ, Meeske KA, et al. Prevalence and predictors of post-traumatic stress symptoms in adolescent and young adult cancer survivors: a 1-year follow-up study. Psycho-Oncology. 2013;22(8):1798-1806.
8. Frederick NN, Bober SL, Berwick L, Tower M, Kenney LB. Preparing childhood cancer survivors for transition to adult care: The young adult perspective. Pediatric Blood & Cancer. 2017;64(10):e26544.
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