CHAPTER 21: Oncology

GENERAL PRINCIPLES

• Cancer cells are rapidly dividing, and therefore more susceptible to cytotoxic agents

• Combination therapy is useful for preventing the development of resistance and overcoming existing resistance by using agents with different mechanisms of action

  • ✓ Also permits more intensive overall therapy by using agents with nonoverlapping toxicities

• Dose-intensification effective as most malignancies have a steep dose-response curve

  • ✓ Two main approaches: Increase dose (per cycle or by increasing the total number of chemotherapy cycles) or decrease interval between treatment cycles

  • ✓ Increases supportive care requirements

• Adjuvant therapy: Administration of systemic chemotherapy in the absence of overt disease

  • ✓ Targeted at micrometastases (see Solid Tumor section)

• Toxicities: Myelosuppression, alopecia, nausea/vomiting are most common acute toxicities (see Principles of Supportive Care for management of specific toxicities)

  • ✓ Long-term many agents affect fertility and can cause secondary leukemia

  • ✓ See Table 21-1 for specific toxicities relevant to commonly used agents in pediatric oncology

GENERAL PRINCIPLES

• Delivery of ionizing radiation typically by external beam

• Biologic effect achieved by inducing direct and indirect DNA damage

• Different tumor types have different required doses for efficacy

  • ✓ Wide range (e.g., 21 Gy for neuroblastoma/lymphoma, up to 60+Gy for sarcomas)

• Normal tissues have different dose tolerance thresholds before toxicity is seen

• Effect (and toxicity) can be potentiated by concomitant chemotherapy (e.g., doxorubicin, dactinomycin)

• Radiation recall: Inflammation in previous radiation field after administration of certain chemotherapy (days to years after original treatment)

• Photons versus protons

  • ✓ Photons are standard, but deliver radiation to all structures in path (i.e., entry and exit doses)

    • ▪ Intensity-modulated RT (IMRT) is used to carve out treatment volume to minimize exposure to normal tissues

  • ✓ Protons are heavier and deposit radiation more precisely at target

    • ▪ Decreased exposure to normal tissues as they enter/exit target areas

INDICATIONS

• Local control: Can be used as sole or complementary way to control disease around primary site of tumor (e.g., in Ewing sarcoma, when margins are positive after resection)

• Metastatic disease: Targeting metastatic sites and bone lesions, or total lung radiation for persistent lung metastases (e.g., Ewing sarcoma and Wilms tumor)

• Cranial/craniospinal

  • ✓ Brain tumors with metastatic disease or potential

  • ✓ ALL with CNS involvement (particularly T-cell)

• Total body irradiation: Conditioning option for HSCT (particularly in ALL)

• Symptom management: In relapsed disease, can control cancer-related pain, particularly at bony sites

• Emergencies: Occasionally used to manage impending organ-function threats of tumors (e.g., spinal cord compression, ocular tumors, mediastinal masses)

TOXICITY

• Proportional to dose-intensity and radiation field (area exposed). Younger children are generally more susceptible to late effects (neurocognitive, growth, etc.)

  • ✓ Acute

  • ✓ Dermatitis

  • ✓ Mucosal damage

  • ✓ Cytopenias from marrow damage

  • ✓ Fatigue

• Chronic

  • ✓ CNS: Neurocognitive impairment, second tumors, endocrinopathies

  • ✓ Musculoskeletal: Growth impairment (especially if growth plate involved), arthritis, avascular necrosis

  • ✓ Cardiopulmonary: Cardiac dysfunction, pulmonary fibrosis

  • ✓ Second malignant neoplasms: Often sarcomas, particularly osteosarcoma; breast

• Typically employed for biopsy of suspected mass to obtain histological diagnosis and aid with staging a patient via exploration of peritoneal washings and lymph nodes sampling in certain settings (e.g., pelvic masses)

• Depending on the type of tumor, surgery occurs at different points in therapy (typically up front in brain tumors or germ cell tumors) or after several weeks of therapy as local control in other tumors (some sarcomas and neuroblastoma)

• The goal of surgery may be complete resection, removal of discrete metastatic lesions (e.g., lung metastases in osteosarcoma) or in a palliative setting, debulking the tumor to decrease pressure or symptoms from compression of local structures

TYPES AND INDICATIONS

• Allogeneic: Replacing recipient’s marrow with hematopoietic stem cells from another person (allograft)

  • ✓ Indications

    • ▪ Malignancies: ALL (mostly ≥CR2), AML, CML, JMML, MDS

    • ▪ Bone marrow failure: Aplastic anemia, Fanconi, severe congenital neutropenia, etc.

    • ▪ Hemoglobinopathies: β-thalassemia major, severe sickle cell disease

    • ▪ Primary immunodeficiencies: SCID, HLH, WAS, CGD, NEMO, etc.

    • ▪ Metabolic disorders: Mucopolysaccharidoses, leukodystrophies, osteopetrosis

• Autologous: Infusing patient’s previously stored stem cells after delivery of high-dose chemotherapy—better thought of as a rescue after high-dose chemotherapy

  • ✓ Indications: Treatment of certain tumors that are chemosensitive but at high risk for relapse

    • ▪ High-risk neuroblastoma and medulloblastoma

    • ▪ Relapsed lymphomas

PRINCIPLES OF ALLOGENEIC TRANSPLANTATION

• Approach depends on goal of transplant

  • ✓ Hematologic malignancy

    • ▪ Treat cancer with high-dose chemotherapy +/− radiation

    • ▪ Immunosuppress recipient to accept allogeneic graft

    • ▪ Make space in marrow

  • ✓ Defective hematopoietic cell(s)

    • ▪ Only need to immunosuppress and make space

• Conditioning regimen: Prepares the patient to receive the allograft

  • ✓ Myeloablative: High-dose chemotherapy +/− radiation to completely ablate marrow

  • ✓ Reduced-intensity: Less toxic regimen that is sometimes used for nonmalignant indications or heavily pretreated patients; still highly immunosuppressive

• Donors: Chosen based on best available HLA match, and other factors (gender, CMV status, etc.)

  • ✓ Matched siblings preferred

  • ✓ Alternative donors: Unrelated voluntary donors; umbilical cord blood; parent (mismatched related, haploidentical)

• Stem cell sources: Bone marrow, mobilized peripheral blood stem cells, umbilical cord blood

  • ✓ Chosen based on availability and type/purpose of transplant

  • ✓ Sources differ by engraftment kinetics, immune reconstitution, risk of GVHD, etc.

• Graft-versus-host disease (GVHD): Process by which donor T-cells recognize recipient antigens as foreign and induce tissue damage

  • ✓ Increased risk with decreased HLA matching

  • ✓ Allograft recipients receive prophylaxis with calcineurin inhibitor +/− steroids or methotrexate or mycophenolate

  • ✓ Acute: Skin (erythema→desquamation), liver (cholestasis), and/or GI tract (diarrhea)

  • ✓ Chronic form resembles autoimmune diseases like scleroderma

  • ✓ Treatment with immunosuppression (1st line=steroids)

• Immune function and opportunistic infections

  • ✓ Patients at very high risk for infection, even after engraftment

  • ✓ Viruses: CMV, adenovirus, HSV, VZV, EBV, HHV6

  • ✓ Fungus: Candida, Aspergillus, mucormycosis

  • ✓ Bacteria: GNR, Strep mitis, Staph species; bacteremia most common early post-transplant

  • ✓ Pneumocystis jirovecii pneumonia: Universal prophylaxis

• BMT-specific organ toxicities

  • ✓ Veno-occlusive disease (VOD): Disorder of vascular damage/thrombosis in small vessels of liver that occurs in first several weeks after transplant

    • ▪ Painful hepatomegaly, ascites, weight gain, direct hyperbilirubinemia, portal vein flow reversal, splenomegaly, refractory thrombocytopenia, kidney injury

  • ✓ Idiopathic pulmonary syndrome: Noninfectious noncardiac respiratory insufficiency occurring in first weeks after transplant

GENERAL PRINCIPLES

• Bone marrow suppression from cancer and its treatment decrease granulocytes and thus cancer patients lack a first line of defense against bacterial infection

• Patients with fever and neutropenia (ANC <500/mm³) deserve critical attention

• Definitions of fever and neutropenia vary by treating center but commonly:

  • ✓ Fever: A single temperature taken orally that is greater than 38.3–38.5°C or three temperatures greater than 38.0°C in a 24-hour period

  • ✓ Neutropenia: An absolute neutrophil count (ANC) less than 500 cells/mm³ or less than 1000 cells/mm³ and falling

CANCER AND THE IMMUNOCOMPROMISED HOST

• Cancer can increase infectious risk by inherent immunosuppression (leukemia) or by a mass creating obstruction of an organ (bladder, biliary tree, etc.) and subsequent development of infection

• Therapy disrupts normal barriers to infection including myelosuppression, disruption of the mucosal epithelium, local tissue breakdown, skin disruption, and the presence of foreign bodies such as a central venous catheter

• Many febrile, neutropenic patients have an occult infection but symptoms may be subtle or inapparent due to lack of inflammatory reaction

• When pathogens are documented, bacteria are the most common (85–90%)

• Infections with mold or fungi are most common in patients exposed to chronic broad-spectrum antibiotics or with prolonged neutropenia

• High-risk features: Inpatient at the time of diagnosis, uncontrolled cancer, comorbidities (hypotension, tachypnea, hypoxemia, mucositis), prolonged neutropenia (>5 days), higher fever, lower absolute neutrophil count (i.e., ANC <100/ μL)

APPROACH TO THE HISTORY AND PHYSICAL EXAM

• Key pieces of the history and physical exam:

  • ✓ Determine the date of the most recent chemotherapy to predict the expected direction of the WBC trend as most agents cause suppression 7–10 days after infusion

  • ✓ Note any recent blood transfusions (transfusion reaction can cause fever), and history of other infections (may guide antibiotic choices)

  • ✓ Critical to assess what type of indwelling catheter the child has (none, PIV, PICC, Broviac^®, Port-A-Cath^®), as these carry various risks of infection and antibiotic coverage may differ

• Perform a thorough physical examination focusing on:

  • ✓ The oropharynx (looking for mucositis, gingival involvement)

  • ✓ The central venous line sites (looking for signs of infection, such as erythema, tenderness, or discharge at the site of insertion)

  • ✓ Skin (looking for lesions that could indicate opportunistic fungus or molds)

  • ✓ Abdominal exam: A neutropenic patient is also at risk for neutropenic colitis (typhlitis), a fatal complication, so perform a thorough abdominal examination and consult with a surgeon if there is any concern. Hepatosplenomegaly should also be assessed

  • ✓ The perineum (looking for perianal abscesses)

  • ✓ Physical exam findings may be subtle or absent in profoundly neutropenic patients

DIAGNOSTICS

• At least one set of blood cultures from each lumen of the central venous catheter and, in some institutions, a culture from a peripheral site before initiation of antibiotics

• If the catheter site is inflamed or draining, send Gram stain and culture for bacteria and fungi

• If lesion is persistent or chronic, send acid-fast stain and culture

• CT scan (head/sinuses, chest, abdomen) for evaluation of fungal disease with WBC count recovery in patients who have prolonged febrile neutropenia or in patients on longstanding broad-spectrum IV antibiotics who develop a new fever

MANAGEMENT

• Empiric Antibiotic Therapy:

  • ✓ Since gram-positive or gram-negative organisms can cause infection, empiric therapy must be broad spectrum (including anti-pseudomonal coverage) and bactericidal. Antibiotic choice depends on the individual institutional resistance patterns and the combinations used are quite varied and are institution specific. Typical empiric combinations include:

    • ▪ Monotherapy with cefepime, ceftazidime, or imipenem/meropenem

    • ▪ Two drug therapy with a third- or fourth-generation cephalosporin or an anti-pseudomonal penicillin in addition to an aminoglycoside

    • ▪ Consider addition of vancomycin for gram-positive coverage if:

      • ▷ High institutional rate of gram-positive organisms leading to severe infection; suspected central line infection; receipt of intensive chemotherapy known to result in severe mucositis (SCT, AML); recent infection sensitive to vancomycin; colonization with vancomycin-sensitive organisms; patients presenting with hypotension

  • ✓ If there are signs of a specific infection on exam, add appropriate coverage (i.e., gram-positive coverage for skin infection or anaerobic coverage for perirectal or oral infection)

  • ✓ If no organism can be identified, broad coverage (usually with a third- or fourth-generation cephalosporin) should continue until the patient is afebrile with evidence of bone marrow recovery (e.g., ANC above 200–500 cells/mm³ on 2 consecutive days and rising)

• Empiric Antifungal Therapy: Should be started in patients who have persistent febrile neutropenia (>3–5 days) or a new fever while on broad-spectrum empiric antibacterial coverage. Risk is greatest in HSCT and hematologic malignancy patients; solid organ patients with expected duration of neutropenia <5 days are a low risk

• Remove central venous catheters: If there is evidence of a subcutaneous tunnel infection, periportal infection, fungemia, atypical mycobacteremia, or persistently positive bacterial blood cultures, despite IV antibiotics, or in a critically ill patient

• Fever with a true infection may not develop in patients receiving steroids as part of their therapy or for chronic symptom management. Empiric antibiotic coverage should be considered in afebrile patients taking steroids that are neutropenic and have signs or symptoms suggestive of infection

• Avoid rectal interventions (taking temperature or giving medicines) in a patient with neutropenia, except in an emergency

DEFINED AS WBC ON PRESENTATION >100,000/mm³

• Often seen in AML, ALL, and CML in decreasing order

• Sometimes asymptomatic, but symptoms arise from WBC sludging, stasis, and increased blood viscosity and can include:

  • ✓ CNS: Confusion, headache, focal neurologic symptoms, somnolence

  • ✓ Respiratory: Dyspnea, respiratory insufficiency, hypoxemia

  • ✓ Renal: From severe tumor burden and associated lysis

• Despite profound anemia, transfusions of packed red cells in patients with hyperleukocytosis have been associated with poor outcomes. (Transfusions must be discussed with oncology and intensive care teams)

• Interventions are made in any symptomatic patient, or if WBC>200,000/mm³ in AML or 300,000–400,000/mm³ in ALL

  • ✓ Early options include: Leukopheresis, low-dose cytoreductive chemotherapy (hydroxyurea or cytarabine). Careful attention to risk of tumor lysis syndrome (see below) is mandatory

  • ✓ Definitive therapy is initiation of cancer-directed treatment

A mass that compromises the integrity of the spinal cord, conus medullaris, or cauda equina.

EPIDEMIOLOGY

• Acute compression of the spinal cord develops in 3–5% of children with cancer. (This must be differentiated from back pain of other etiologies that develops in 5–10% of patients with cancer)

• Sarcomas (especially Ewing) account for about 50% of cases. Other commonly involved tumors include neuroblastoma, leukemia, and lymphoma

ETIOLOGY

• Tumor in the epidural or subarachnoid space

• Metastatic spread to the cord parenchyma or the vertebrae with secondary cord compression

• Extension of paravertebral tumor through the intervertebral foramina leading to epidural compression

• Subarachnoid spread down the spinal cord from a primary CNS tumor

PATHOPHYSIOLOGY

• Physical compression of the spinal cord, conus, or cauda equina leads to impaired blood flow, which results in venous hypertension and vasogenic cord edema, hemorrhage, ischemia, and eventually, infarction

CLINICAL MANIFESTATIONS

• Back pain with localized tenderness is presenting sign in 80% of patients

• Radicular pain

• Abnormalities of bowel or bladder dysfunction (i.e., incontinence, retention)

• Most have objective motor loss

• Patent/parent report of: Night-waking, weakness, pain, tingling, bowel or bladder dysfunction

DIAGNOSTICS

• Spine radiographs: May be helpful, but are abnormal in less than 50% of cases

• Radionuclide bone scanning: More sensitive than plain films, but are not appropriate with evolving neurological dysfunction

• MRI with and without gadolinium: Detects presence and extent of epidural involvement, intraparenchymal spread of tumor, and small lesions compressing nerve roots in the cauda equina

• Cerebrospinal fluid analysis: Important in the evaluation of subarachnoid disease and meningeal leukemia or carcinomatosis, but is not appropriate before the initial imaging

MANAGEMENT

• Perform detailed neurologic exam

• If patient has focal spinal tenderness or neurologic deficit, determine the nature of symptoms and if they are progressive

• If neurologic symptoms are evolving, discuss initiation of steroids (see below) with an oncologist and perform MRI with and without gadolinium

• If evidence of spinal cord compression by imaging, consider urgent chemotherapy, surgery, or local radiation only after careful discussion with all disciplines as initial management decisions can have a profound effect on future therapy and patient function. Escalation to an intensive care unit is recommended

• Empiric management with dexamethasone:

  • ✓ For progressive dysfunction with significant physical deficits, administer 1–2 mg/kg/day as loading dose followed by 1.5 mg/kg/day divided every 6 hours

  • ✓ For mild stable deficits, administer 0.25–1 mg/kg/dose every 6 hours

• Definitive therapy is initiation of appropriate cancer-directed treatment, so diagnostic biopsy should be pursued emergently, and often empiric chemotherapy is initiated to treat most likely histologies while awaiting a definitive pathologic diagnosis

Signs and symptoms that result from compression, obstruction, or thrombosis of the superior vena cava (SVC). Superior mediastinal syndrome (SMS) includes SVC syndrome (SVCS) with associated tracheal compression.

ETIOLOGY

• Malignant (90%): Most commonly seen with non-Hodgkin lymphoma, Hodgkin disease, T-cell ALL, and germ cell tumors

• Nonmalignant: Vascular thrombosis secondary to central venous line, thrombotic complications of cardiovascular surgery for congenital heart disease, infectious masses (i.e., tuberculosis, histoplasmosis, aspergillosis), bronchogenic cyst; hamartoma; ganglioneuroma

PATHOPHYSIOLOGY

• Tumor or infection in the nodes or thymus can compress the SVC, causing venous stasis

• The trachea and right main stem bronchus in infants and children are smaller than that in adults and minimal compression/swelling can result in obstructive symptoms. Compression, clotting, and edema decrease airflow and reduce venous return from the head, neck, and upper thorax, leading to the signs and symptoms of SVCS and SMS

CLINICAL MANIFESTATIONS

• 75% of children with mediastinal masses have respiratory symptoms that are aggravated when the patient is supine

• Signs: Edema and/or cyanosis of the face, neck, and upper extremities; plethoric appearance; conjunctival suffusion; cervical and thoracic venous distention; wheezing; stridor; pleural/pericardial effusion

• Symptoms: Cough, dyspnea, dysphagia, orthopnea, hoarseness, wheezing, stridor, chest pain, anxiety, headache, confusion secondary to carbon dioxide retention

DIAGNOSTICS

• Chest x-ray demonstrates mass

  • ✓ Laboratory evaluation:

  • ✓ CBC: Pancytopenia, leukocytosis, blasts on smear (leukemia, lymphoma), left shift (infection)

  • ✓ Chemistry panel: Potassium, calcium, phosphorus, creatinine, uric acid, LDH (can be elevated with leukemia, lymphoma)

  • ✓ α-fetoprotein, β-hCG: Elevated in germ cell tumors

  • ✓ Urine catecholamines: Elevated in neuroblastoma

  • ✓ ESR: Can be elevated with lymphoma

• Assess risk for general anesthesia/surgery:

  • ✓ If respiratory distress or orthopnea at presentation: High risk for anesthesia

  • ✓ If even minimal symptoms, full evaluation is necessary before sedation: CT scan, echocardiography, pulmonary function testing including a volume flow loop to assess reserve

• Sedation or general anesthesia in patients with a mediastinal mass may be contraindicated because they can decrease respiratory drive and result in respiratory failure, decreased venous return, and circulatory collapse

MANAGEMENT

• Clinical Decision-Making

  • ✓ General principle is to establish diagnosis/staging with the least invasive test possible, particularly if high risk for anesthesia

  • ✓ If CBC and other studies confirm diagnosis, begin tumor-specific treatment in consultation with oncology team

  • ✓ If no diagnosis is made after initial noninvasive studies, continue evaluation and assess risk of patient for anesthesia to safely obtain tumor tissue

    • ▪ If patient is at low risk for anesthesia, perform diagnostic procedures and then begin tumor-specific treatment

    • ▪ If patient is at high risk for anesthesia, perform necessary procedures unsedated or treat empirically with chemotherapy or radiation based on the most likely disease, although this is can complicate the eventual diagnostic procedure. Empiric therapy should only be done after consultation with an oncologist if possible

• General Management Issues

  • ✓ Control the airway, give oxygen, and avoid intubation if possible

  • ✓ Extreme care in handling the patient: Minimize stress, sedation, and avoid the supine position

  • ✓ If tissue diagnosis is not possible, empiric therapy may be necessary

  • ✓ Empiric use of steroids, RT, and chemotherapy can all affect masses and lymph nodes making subsequent tissue diagnosis and treatment more difficult, but these interventions are sometimes medically indicated

Metabolic abnormalities that result from dying tumor cells and the rapid release of intracellular metabolites into circulation that exceeds the excretory capacity of the kidneys. Tumor lysis syndrome (TLS) often occurs at presentation or within 12–72 hours after the start of chemotherapy. The classic triad involves hyperuricemia, hyperkalemia, and hyperphosphatemia

• Hyperuricemia: Results from the release of nucleic acids from malignant cell breakdown. Uric acid is soluble at physiologic pH, but precipitates in the acidic environment of the kidney and can lead to acute renal failure

• Hyperkalemia: Potassium is the principal intracellular cation and serum levels can also increase with acute renal failure. High serum potassium can cause fatal dysrhythmias

• Hyperphosphatemia: Lymphoblasts have four times the content of phosphate as normal lymphocytes; leads to hypocalcemia by decreasing production of calcitriol, decreasing absorption of calcium from the GI tract and from precipitation; if $Ca + 2 × PO 4 − 3$ product reaches 60, calcium phosphate crystals form and precipitate in the microvasculature, leading to acute renal failure

ETIOLOGY

• Most common: Burkitt lymphoma (BL), lymphoblastic lymphoma, ALL (T-cell)

• Predisposing factors: Tumors with high growth fraction and sensitivity to chemotherapy, bulky tumors, high pre-therapy uric acid or LDH, poor urine output, high WBC count

CLINICAL MANIFESTATIONS

• Usually have no signs or symptoms; most commonly occurs in the 24 hours after starting treatment

• May present with vomiting or diarrhea

• May present with evidence of hypocalcemia: Muscle weakness, spasms, tetany, seizures, renal failure

• Strategies for the prevention and management of TLS are outlined in Table 21-2

PRESENTATION

• Manifestations of a single or multiple cytopenias

  • ✓ Anemia: Headache, light-headedness, dyspnea on exertion, palpitations, fatigue, pallor, irritability

  • ✓ Thrombocytopenia: Mucosal bleeding, petechiae, purpura, easy bruising

  • ✓ Leukopenia/neutropenia: Fevers, mucosal ulceration, invasive bacterial infections

DIFFERENTIAL DIAGNOSIS

• Broad division between decreased bone marrow production and peripheral destruction (or combination)

  • ✓ Decreased production: Bone marrow failure (inherited or acquired), leukemia, lymphoma, metastatic solid tumor, infection (CMV, EBV, HHV6, parvovirus, etc.), hemophagocytosis (HLH)

  • ✓ Destruction/consumption: Evan’s syndrome, hypersplenism, combinations of causes of individual cytopenias

EVALUATION

• History: Fever pattern, bone pain, weight loss, night sweats

• Physical examination: Lymphadenopathy, hepatosplenomegaly

• CBC/differential/reticulocyte count with review of peripheral blood smear

  • ✓ Smear review critical for blasts and evidence of stressed marrow (nucleated RBCs or teardrop) that may suggest infiltrative process

• Electrolytes (with Mg, Ph), BUN/Cr, hepatic panel

• LDH and uric acid to evaluate for TLS

• PT/INR and PTT; fibrinogen if abnormal

• CXR for mediastinal mass or adenopathy

• Bone marrow examination (aspirate and biopsy) for definitive diagnosis

• Features suggestive of a malignancy include prominent constitutional symptoms, bone pain, adenopathy, hepatomegaly, mediastinal mass, or laboratory evidence of TLS

Accounts for approximately 30% of childhood cancer. Characterized by excessive proliferation of early hematopoietic cells (blasts) whose maturation has been arrested. Lymphoid leukemia (ALL) represents 80% of cases; myeloid leukemia (AML) 20%.

CLINICAL MANIFESTATIONS

• Bone marrow replacement: Cytopenias and their associated symptoms

• Uncontrolled proliferation: Bone pain, adenopathy, organomegaly, fever

• Unique presentations: Coagulopathy (APML), anterior mediastinal mass (T-cell ALL), chloromas (collections of myeloid blasts), leukemia cutis (cutaneous infiltrates—often bluish), testicular mass (ALL)

INITIAL MANAGEMENT

• Two priorities are to obtain a prompt diagnosis and address existing or potential oncologic emergencies

  • ✓ Diagnosis: Bone marrow aspirate/biopsy and LP with intrathecal chemotherapy (if confident in malignancy based on presentation/smear)

  • ✓ Emergencies: TLS, infection, hyperleukocytosis, cytopenias, anterior mediastinal mass, coagulopathy

• Once diagnosis is established, disease-specific therapy (see below) is implemented

ALL: ACUTE LYMPHOBLASTIC LEUKEMIA

• Divided into two groups based on immunophenotype of blasts: B-cell (80%) and T-cell (20%). T-cell ALL tends to affect older patients, have more extramedullary disease (CNS involvement, lymphadenopathy, mediastinal mass, hepatosplenomegaly), and be more difficult to treat

• Prognostic factors

  • ✓ Immunophenotype (T-cell worse than B-cell)

  • ✓ CNS status (involved is worse)

  • ✓ Initial total WBC (≥50,000/mm³ is worse)

  • ✓ Age (≥10 years is worse than age 1–9.99 years; infants ≤1 years have very poor prognosis)

  • ✓ Cytogenetics

    • ▪ Favorable: Hyperdiploid, t(12;21)

    • ▪ Unfavorable: Hypodiploid, Ph+—t(9;22), MLL rearranged, other molecular markers

  • ✓ Response to therapy

    • ▪ Failure to achieve remission by end of induction is very poor prognostic factor

    • ▪ Minimal residual disease (MRD) is very sensitive measure of remission status now used to identify patients who need augmented therapy

• Treatment

  • ✓ Conventional chemotherapy is capable of curing the majority (>80%) of childhood ALL, is typically delivered over a 2–3 year period, and is divided into phases each having a specific purpose. Exact treatment regimens are based on risk stratification, which is dictated by above prognostic factors

  • ✓ Induction: Establish a complete remission

    • ▪ Drugs: Steroid, asparaginase, vincristine +/− daunorubicin

    • ▪ Duration: 1 month

  • ✓ Consolidation: Increased CNS-targeted therapy and consolidation of systemic remission

    • ▪ Drugs: Incorporates different agents than induction; protocol-specific

    • ▪ Duration: 1–2 months

  • ✓ Interim maintenance: Continued CNS treatment; systemic treatment with less myelosuppression

  • ✓ Delayed intensification: Period of intensive treatment, essentially repeating induction and part of consolidation

    • ▪ Duration: 2 months

  • ✓ Maintenance: Prevent relapse and eradicate residual disease with continuous low-intensity chemotherapy

    • ▪Drugs: Mostly oral chemotherapy (6-MP and methotrexate) with monthly VCR and steroid pulses

    • ▪Duration: 1–2 years

  • ✓ CNS treatment: All patients receive CNS-targeted therapy with intrathecal chemotherapy

    • ▪ If CNS+ at diagnosis, CNS therapy more intensive +/− cranial radiation

    • ▪ T-cell patients more likely to be CNS+ and receive cranial radiation

  • ✓ Relapse

    • ▪ Relapsed ALL is the fourth most common childhood cancer, occurring in approximately 20% of all ALL patients. Treatment approach is dictated by risk, which is based on timing and site of relapsed disease:

    • ▪ Low risk: Late (>18 months) isolated extramedullary (CNS/testes)→conventional chemotherapy

    • ▪ Intermediate risk: Early (<18 months) extramedullary; late (>36 months) bone marrow or combined relapse →decision re: chemo versus HSCT at discretion of family/oncologist and based on donor availability

    • ▪ High risk: Early (<36 months) bone marrow/combined→HSCT with any available donor

    • ▪ T-cell: HSCT generally recommended regardless of timing or site

  • ✓ Special groups

    • ▪ Infants: ALL occurring in children <1 year is a biologically unique disease with frequent MLL rearrangements, and is very difficult to cure, with the majority of children dying of relapsed disease. The role of HSCT is controversial given that optimal conditioning involves total body irradiation to a very young child, and survival benefit has not been definitively established

    • ▪ Trisomy 21: Confers a much higher risk of ALL; generally similar treatment is utilized, although effort made to de-intensify and reduce methotrexate toxicity

AML: ACUTE MYELOID LEUKEMIA

• Generally divided into de novo AML (occurring in previously well child), secondary AML (occurring in child with history of exposure to certain chemotherapy agents, or in child with bone marrow failure syndrome or MDS), and acute promyelocytic leukemia (APML)

• Prognostic factors

  • ✓ Cytogenetics and molecular features

    • ▪ Low risk: t(8;21), inv16, CEPB, NPM

    • ▪ High risk: Monosomy 7, 5q-, FLT3 ITD

      • ▷ All therapy- or MDS-related AML is considered high risk

    • ▪ Intermediate risk: All others

  • ✓ Response to therapy

    • ▪ Failure to achieve remission after first induction cycle is poor prognostic factor

    • ▪ MRD is increasingly used to evaluate quality of remission and assign subsequent treatment courses

• Treatment

  • ✓ General approach: Cure rates vary from 20 to 80% based on risk

  • ✓ 3–4 intensive chemotherapy cycles +/− HSCT for consolidation

  • ✓ Decision regarding stem cell transplant in first remission (CR1)

    • ▪ Low risk: No

    • ▪ Intermediate risk: If end-induction remission status poor or MSD

    • ▪ High risk: Any available donor

  • ✓ Structure

    • ▪ Induction I and II: Cytarabine, daunorubicin, and etoposide

    • ▪ Intensification I and II: Cytarabine with either etoposide, mitoxantrone, or asparaginase

    • ▪ If HSCT used, typically after three cycles of chemotherapy

• Relapse

  • ✓ All children with relapsed AML are treated with intensive chemotherapy followed by HSCT if remission can be achieved; prognosis is very poor

• Special groups

  • ✓ APML: Unique form of AML that has a characteristic cytogenetic abnormality—t(15;17)—making it amenable to targeted therapy with the differentiating agent all-trans retinoic acid (ATRA)

    • ▪ Therapy with ATRA on top of induction and maintenance chemotherapy

  • ✓ Trisomy 21: Generally seen in ≤4 years old and associated with very good prognosis even with decreased intensity of therapy. Generally AMKL (acute megakaryocytic leukemia)

    • ▪ TMD: Transient myeloproliferative disorder seen in first weeks to months of life associated with increased peripheral blasts +/− organomegaly

    • ▪ Only requires therapy if respiratory compromise, but increases risk of acquiring AML later in life

PRESENTATION

• Features suggestive of a malignant etiology

  • ✓ Generalized or ≥2 nodal regions or any supraclavicular

  • ✓ Firm (rubbery), painless, enlarging, no overlying erythema/cellulitis

  • ✓ Constitutional symptoms, organomegaly, mediastinal mass

DIFFERENTIAL DIAGNOSIS

• Based on pattern (focal/diffuse), characteristics (size, pain, firmness, etc.), associated symptoms, and other physical exam findings

• Other masquerading etiologies

  • ✓ EBV, CMV, toxoplasmosis

  • ✓ Cat-scratch disease

  • ✓ Atypical mycobacterium

  • ✓ Kawasaki disease

EVALUATION

• History and physical

• CBC/differential, review of peripheral blood smear, electrolytes, LDH, uric acid, infection testing

• CXR

• CT of affected areas (if concern for lymphoma, include neck, chest, abdomen, pelvis)

• Biopsy if concern for malignancy or diagnostic uncertainty in ill child

  • ✓ Should be in consultation with oncologist

  • ✓ Excisional biopsy preferred as nodal architecture important in lymphoma diagnosis

• Staging of lymphomas

  • ✓ CT (as above)

  • ✓ PET/CT

  • ✓ Bone marrow aspirates and biopsies (bilateral)

  • ✓ LP (if NHL)

Generally divided into Hodgkin (40%) and non-Hodgkin (60%) lymphoma based on immunophenotype of malignant cells. Comprises about 10–15% of childhood cancers, and up to 25% in adolescent age group.

HODGKIN LYMPHOMA (HL)

• Malignant cell represents the minority of cellular composition of lymph node; remainder is mixed infiltrate of mature lymphocytes, eosinophils, and monocytes/macrophages. In classical HL, the malignant cell is termed the Reed–Sternberg cell and is giant, multi-nucleated with prominent nucleoli

• Presentation

  • ✓ Lymph node enlargement is often more indolent than in NHL

  • ✓ Cervical and supraclavicular nodes are most frequently involved and anterior mediastinal masses are common (60%) (See Oncologic Emergencies section)

  • ✓ Constitutional symptoms of fever, night sweats, and unintentional weight loss (B symptoms) occur in 20–30%

  • ✓ Oncologic emergencies in HL are uncommon. Anterior mediastinal masses usually do not enlarge quickly enough to case cardiopulmonary compromise and the malignant cell does not turnover rapidly enough to cause TLS

• Staging and risk stratification

  • ✓ Staging based on site(s) of nodal involvement (Ann Arbor system)

    • ▪ Stage I: 1 region

    • ▪ Stage II: ≥2 regions on same side of diaphragm

    • ▪ Stage III: ≥2 regions on both sides of diaphragm

    • ▪ Stage IV: Diffuse disease or bone marrow involvement

  • ✓ Risk stratification: Based on stage, presence of B symptoms, and bulk (specific measurements done by radiology in conjunction with oncologist)

    • ▪ Low risk: Stage I or II without B symptoms or bulk

    • ▪ High risk: Stage III or IV with B symptoms

    • ▪ Intermediate risk: All other stages

• Treatment

  • ✓ Multi-agent chemotherapy +/− radiation of involved lymph node areas

  • ✓ Since cure of HL is successful in >90% of children, current regimens focus on de-intensifying therapy (typically by removal of radiation) in children at lower risk of relapse to avoid late effects

  • ✓ For low and intermediate risk, if there is a good response to chemo, omission of XRT should be strongly considered

• Relapse

  • ✓ Most children with relapsed HL can be salvaged. Treatment involves initial chemotherapy followed by autologous HSCT +/− radiation

• Late effects

  • ✓ Long-term adverse effects of therapy occur with all childhood cancers, but survivors of HL are among those at highest risk

  • ✓ Second cancers: Breast, thyroid, skin, soft tissue sarcomas (XRT); AML (chemotherapy/radiation)

  • ✓ Cardiac: Anthracycline-exposure/radiation

  • ✓ Pulmonary: Bleomycin/radiation

  • ✓ Fertility: Alkylating agents (boys>girls; young>older)

NON-HODGKIN LYMPHOMA (NHL)

• Subtypes

  • ✓ Based on phenotype (B versus T) and differentiation (mature versus precursor) of lymphoma cells

    • ▪ Mature B-cell: Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL)

    • ▪ Mature T-cell: Anaplastic large cell lymphoma (ALCL)

    • ▪ Precursor: Lymphoblastic lymphoma (LL) (T>>B)

• Presentation

  • ✓ Can present with symptoms similar to HL with a generally more aggressive pattern, or in relatively unique ways based on subtype

  • ✓ Burkitt: Abdominal lymphadenopathy that can serve as lead-point for intussusception

  • ✓ Lymphoblastic lymphoma: Mediastinal mass, effusions, and bulky adenopathy

  • ✓ ALCL: Nonspecific presentations, with skin findings, waxing and waning fevers/adenopathy

• Staging

  • ✓ Staging is based on number of nodal areas and sites involved (St. Jude system)

    • ▪ Stage I: 1 region (not abdomen or mediastinum)

    • ▪ Stage II: ≥2 regions on same side of diaphragm; resectable abdominal tumor

    • ▪ Stage III: ≥2 regions on both sides of diaphragm; any chest, paraspinal, or unresectable abdominal tumor

    • ▪ Stage IV: CNS or bone marrow involvement

• Treatment

  • ✓ BL/DLBCL: Short, but intensive, therapy with multi-agent systemic and intrathecal chemotherapy

  • ✓ LL: Treated like ALL, with up-front intensive therapy followed by maintenance, over 2–3 years

  • ✓ ALCL: Intermediate intensity and length

• Relapse

  • ✓ Difficult to cure in general; treatment with intensive chemotherapy followed by autologous HCT +/− radiation

• Special groups

  • ✓ Immunocompromised hosts: Children with acquired or inherited immunodeficiencies are at increased risk of developing NHL (particular B-cell)

  • ✓ Recipients of solid organ transplants: Post-transplant lymphoproliferative disease (PTLD)

    • ▪ EBV driven

    • ▪ Management: Reduction in immunosuppression, EBV-targeted therapies (e.g., rituximab), and antineoplastic therapy if indicated based on histologic type

  • ✓ Primary mediastinal B-cell lymphoma (PMBCL): Biologically unique form of DLBCL that originates from thymic tissue, is locally invasive, and relatively resistant to conventional chemotherapy

HISTORY

• Duration, pain, vomiting/diarrhea, obstruction, B symptoms (fever, night sweats, weight loss), age, underlying genetic syndrome

PHYSICAL EXAM

• Location, size, mobility, consistency

EVALUATION

• Labs include CBC, LFTs, uric acid, LDH, urinalysis, tumor markers (AFP, bHCG, urine HVA/VMA)

• Diagnostic imaging (CT/MRI, PET, MIBG)

EPIDEMIOLOGY

• Represents about 6% of childhood cancer

• Most commonly diagnosed in children less than 5 years old

• Can be associated with other congenital anomalies

  • ✓ Cryptorchidism, hypospadias

  • ✓ WAGR (Wilms tumor, aniridia, genitourinary malformation, mental Retardation)—germline deletion at 11p

  • ✓ Denys–Drash—Pseudohermaphroditism, renal disease, Wilms tumor—WT1 mutation

  • ✓ Beckwith–Wiedemann—macroglossia, omphalocele, visceromegaly

  • ✓ Perlman syndrome

  • ✓ Simpson–Golabi–Behmel syndrome

ETIOLOGY/GENETICS

• WT1—Wilms tumor suppressor gene

  • ✓ Patients with bilateral disease may have constitutional WT1 mutations

• WT2—Genomic imprinting within the WT2 locus may account for BWS

  • ✓ Loss of heterozygosity at 16q and 1p are hypothesized to portend a worse outcome

• Deregulation of the Wnt pathway also plays a role in WT

CLINICAL MANIFESTATIONS

• Pain, hematuria, fever, and hypertension

• Varicoceles can be seen in males with spermatic vein compression

• Note any signs of syndromes associated with Wilms tumor including aniridia, facial abnormalities of Beckwith–Wiedemann syndrome, hemihypertrophy, or GU anomalies

DIAGNOSIS AND STAGING

• Laboratory evaluation: Complete blood count, urinalysis, electrolytes, BUN/creatinine, liver function

• Primary tumor imaging: CT/MRI, ultrasound to assess involvement of IVC

• Metastatic evaluation: CT chest. Bone scan and brain MRI can be considered if histology shows clear cell sarcoma or rhabdoid tumor of kidney

• Staging:

  • ✓ Stage I: Tumor confined to the kidney, completely resected

  • ✓ Stage II: Tumor extends beyond the kidney, but is completely resected

  • ✓ Stage III: Gross or microscopic residual tumor remains postoperatively

  • ✓ Stage IV: Hematogenous metastases or lymph node metastases outside the abdomen

  • ✓ Stage V: Bilateral tumors

PROGNOSIS

• Tumor size, young age, histology, absence of metastases and favorable features of the primary tumor (lack of capsular or vascular invasion) are predictive of more favorable outcome

TREATMENT

• Surgery

  • ✓ When feasible, an up-front nephrectomy is preferred for unilateral tumors. This allows for examination of histology as well as complete staging of lymph nodes

  • ✓ Unresectable, unilateral tumors may be biopsied, although special consideration should be made for the possibility of “up-staging,” should there be intra-operative spillage. In certain circumstances, treatment without biopsy is preferred

  • ✓ Nephron-sparing surgery is being investigated for patients with bilateral disease

• Chemotherapy

  • ✓ Stage I/II favorable histology: Vincristine/actinomycin for 6 months

  • ✓ Stage III: Vincristine/actinomycin/doxorubicin + radiation (see below)

  • ✓ Stage IV: As stage III + lung irradiation for lung metastases

  • ✓ Stage V: Special considerations based on extent of local stage

• Radiation therapy

  • ✓ Stage III: Flank radiation, extending across vertebral column to avoid scoliosis

  • ✓ Stage III + peritoneal spill/rupture: Whole abdomen irradiation

  • ✓ Stage IV: Stage III radiation + whole lung radiation

A malignant tumor derived from neural crest cells that can be found anywhere along the sympathetic chain, including the adrenal medulla. Variations in location and histologic differentiation result in a wide range of biologic and clinical characteristics.

EPIDEMIOLOGY

• Neuroblastoma (NBL) is the most common extracranial solid tumor in children

• Most commonly diagnosed in children less than 5 years old; median age is 17 months

ETIOLOGY/GENETICS

• MYCN amplification is associated with advanced disease and a worse outcome

• 1p and 11q loss of heterozygosity is independently associated with a worse outcome

• ALK (anaplastic lymphoma kinase)—Activating mutations in ALK have been shown to be a cause of hereditary neuroblastoma. Mutations and amplifications are also found in about 10% of sporadic cases

  • ✓ Associated syndromes

  • ✓ Hirschsprung disease

  • ✓ Central hypoventilation

  • ✓ Neurofibromatosis

CLINICAL MANIFESTATIONS

• Classic signs and symptoms include fever, weight loss, limp, periorbital ecchymosis/proptosis, bone pain, and pancytopenia

• Tumors can occur anywhere along the sympathetic chain

  • ✓ Abdomen/adrenal—Can be detected as an asymptomatic mass or with abdominal pain; more common in younger children

  • ✓ Thoracic/paraspinal—Can present as an asymptomatic mass or with spinal cord compression

  • ✓ Cervical—Can present with Horner’s syndrome (ptosis, myosis, anhidrosis); more common in infants

• Elevated catecholamines (HVA, VMA) can lead to hypertension or flushing

• Most common sites of metastases are regional nodes, bone, bone marrow, liver, and skin. Rarely, metastases can occur in lung and brain

• Infants can present with skin involvement (stage 4S) with bluish, non-tender subcutaneous nodules

• Paraneoplastic manifestations

• Opsoclonus myoclonus ataxia syndrome—Presumed secondary to anti-neural antibodies

• Secretory diarrhea—Associated with vasoactive intestinal peptide (VIP) secretion

DIAGNOSIS/STAGING/RISK STRATIFICATION

• Biopsy is preferred, whenever possible, for histologic confirmation, as well as to have tissue for molecular diagnostic studies

• Laboratory evaluation

• CBC with differential, electrolytes, BUN/creatinine, liver function tests, urinary HVA/VMA, LDH

• Bilateral bone marrow aspirates and biopsies

• Imaging

• CT/MRI of primary tumor including chest/abdomen/pelvis

• MIBG scan

• Staging (International Risk Group Neuroblastoma Staging System)

  • ✓ L1: Localized tumor not involving vital structures as defined by a list of image-defined risk factors and confined to one body compartment

  • ✓ L2: Locoregional tumor with presence of one or more image-defined risk factors

  • ✓ M: Metastatic disease (except stage MS)

  • ✓ MS: Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow

• Risk stratification (low, intermediate, or high): Complex algorithm based on age, stage, MYCN status, histology, and ploidy

PROGNOSIS

• Age/Stage: Age greater than 2 years and increased stage are the most important factors predictive of unfavorable disease outcome

• Pathology: Undifferentiated tumors with high mitotic rate have a poor prognosis

• Molecular genetics: MYCN amplification (unfavorable), hyperdiploid (favorable), chromosomal deletion of allelic loss (unfavorable)

TREATMENT (RISK-RELATED)

• Low risk: Surgery alone

• Intermediate risk

  • ✓ Surgery

  • ✓ Chemotherapy—Carboplatin, cyclophosphamide, etoposide, doxorubicin

  • ✓ Radiation—Can be considered in cases where tumor bulk precludes surgery and tumor does not respond to chemotherapy

• High risk

  • ✓ Chemotherapy: Topotecan, cyclophosphamide, vincristine, doxorubicin, cisplatin, etoposide

  • ✓ Surgery: Best possible resection of primary tumor

  • ✓ Autologous stem cell transplant

  • ✓ Radiation therapy—To primary tumor site and other sites not responding to induction chemotherapy

  • ✓ Immunotherapy: Ch14.18 monoclonal antibody combined with IL-2 or GM-CSF

  • ✓ Isotretinoin: 6-month course to promote maturation of any remaining malignant neuroblastoma cells

• Relapsed disease

  • ✓ No known cure

  • ✓ I¹³¹ MIBG can be used as a form of RT to palliate painful sites of disease

• Neonates with MS disease often require urgent treatment secondary to respiratory distress and abdominal competition

  • ✓ Chemotherapy

  • ✓ Radiation therapy—Reserved for cases where tumor does not respond rapidly enough to chemotherapy

Osteosarcoma (OS) is a malignant bone tumor arising from mesenchymal cells. It is unique in its production of immature bone (osteoid) by cell stroma.

Ewing sarcoma (ES) is part of a family of tumors comprising a histologic spectrum ranging from undifferentiated small round blue cells to differentiated cells resembling peripheral neuroectodermal tissue (PNETs).

EPIDEMIOLOGY

• Most common bone tumor in adolescence

  • ✓ Likely relationship between rapid bone growth and development of OS

• More common in boys than girls

• More common in blacks than whites

• Usually occurs in metaphyseal portions of long bones (distal femur, proximal tibia, proximal humerus)

ETIOLOGY/GENETICS

• Only known factor that increases risk for OS is ionizing radiation

ASSOCIATED CLINICAL SYNDROMES

• Rothmund–Thomson (autosomal recessive): Poikioderma, small stature, and skeletal dysplasia

  • ✓ Mutation in RECQL4 gene

• Hereditary retinoblastoma

  • ✓ Germline mutation in Rb gene

• Li–Fraumeni syndrome: Cancer predisposition

  • ✓ P53 mutation

CLINICAL MANIFESTATIONS

• Pain over involved site with or without associated soft tissue mass

• Can have erythema, warmth, or swelling that mimics infection

• Can result in pathologic fracture

DIAGNOSIS/STAGING

• Biopsy: Open biopsy should be performed by an experienced orthopedic surgeon (ideally should be the surgeon who will perform later definitive surgery). Incision and technique are extremely important and can affect the subsequent surgery as well as the patient’s prognosis if not performed properly

• Staging:

  • ✓ Imaging of primary tumor: MRI should include both the joint above and the joint below to examine for skip lesions

  • ✓ Metastatic evaluation: Chest CT, bone scan

PROGNOSIS

• Extent of disease at diagnosis (metastatic disease unfavorable)

• Location of primary tumor

  • ✓ Axial skeleton is unfavorable, due to difficulty in obtaining a full resection

• Tumor size (>15 cm is unfavorable)

• Young age (<10 years is unfavorable)

• Histologic response at the time of local control (<90% tumor necrosis is unfavorable)

TREATMENT

• Pre-surgical (neoadjuvant) chemotherapy: Cisplatin/doxorubicin/methotrexate

  • ✓ Allows evaluation of tumor responsiveness to chemotherapy in a uniform manner, eradication of micrometastases early instead of waiting until postoperative recovery and demonstrated improvement in outcome

SURGERY

• Removal of all gross and microscopic tumor is essential to prevent local recurrence. Surgical procedures include either amputation or limb-salvage procedures (allografts, vascularized grafts, endoprostheses, rotationplasty)

• The type of surgical procedure depends on tumor location, size, presence of metastatic disease, age, skeletal development, lifestyle preference, and desired activities

• Post-surgical (adjuvant) chemotherapy: Cisplatin/doxorubicin/Methotrexate

EPIDEMIOLOGY

• Second most common bone tumor in adolescence

• More common in boys than girls

• More common in whites than blacks

• Usually diaphyseal

ETIOLOGY/GENETICS

• T(11;22) is present in about 85% of tumors

  • ✓ Results in a chimeric EWS-FLI1 transcription product

  • ✓ Detection by RT-PCR and FISH

CLINICAL MANIFESTATIONS

• Constitutional symptoms—Fever, weight loss

• Pain over involved site with or without associated soft tissue mass

• Paraspinal tumors can present with spinal cord compression

• Can have erythema, warmth, or swelling that mimics infection

• Can result in pathologic fracture

DIAGNOSIS/STAGING

• Biopsy: Open biopsy should be performed by an experienced orthopedic surgeon (ideally should be the surgeon who will perform later definitive surgery). Incision and technique are extremely important and can affect the subsequent surgery as well as the patient’s prognosis if not performed properly

• Staging:

  • ✓ Imaging of primary tumor—For bony primaries, MRI should include both the joint above and the joint below to examine for skip lesions

  • ✓ Metastatic evaluation—Chest CT, bone scan +/− PET scan, bilateral bone marrow aspirates, and biopsies

PROGNOSIS

• Presence of metastatic disease is the most important adverse prognostic factor

• Primary site (pelvis is unfavorable)

• Larger tumor size is unfavorable

• Poor response to initial therapy is unfavorable

• Older age is unfavorable

TREATMENT

• Pre-surgical (neoadjuvant) chemotherapy: Vincristine, doxorubicin, cyclophosphamide alternating with etoposide/ifosfamide on a compressed, every 2 week, schedule

• Every patient is assumed to have micrometastatic disease at diagnosis and the primary treatment involves combination chemotherapy. Goal is to decrease primary tumor volume for both eventual local control and immediate control of micrometastatic disease

• Local control: Approach depends on the site and whether radiation would cause significant growth or functional difficulty. Each potential site of disease is associated with varied options for surgery and radiotherapy. Final decision balances the need for complete tumor eradication with the goal of maintaining function

• Post-surgical (adjuvant) chemotherapy

Tumor derived from primitive mesenchyme that may develop into muscle, fat, fibrous tissue, bone, or cartilage.

EPIDEMIOLOGY

• Two-thirds of cases diagnosed in children less than 6 years (largely embryonal histology)

• Small second peak in adolescence (largely alveolar histology)

• Relationship between age at diagnosis and site of primary tumor/histology

  • ✓ Head and neck tumors most common in children less than 8 years

  • ✓ Orbital tumors almost always embryonal

  • ✓ Extremity tumors more common in adolescents and usually alveolar

ETIOLOGY/GENETICS

• Vast majority of cases are sporadic

• Associated syndromes:

  • ✓ Neurofibromatosis Type I

  • ✓ Li-Fraumeni—p53 mutation, cancer predisposition

  • ✓ Costello syndrome (growth retardation, coarse facies, developmental delay)

  • ✓ Alveolar disease has characteristic translocation: t(2;13)

    • ▪ Fusion of PAX3 or PAX7 with FKHR (transcription factor)

  • ✓ Embryonal disease has loss of heterozygosity at 11p15

CLINICAL MANIFESTATIONS

• Disturbance in normal function due to mass effect

• Head/neck: Proptosis, ophthalmoplegia, visual disturbance, chronic sinus obstruction

• Genitourinary tract: Dysuria, hematuria, pain, urinary obstruction, constipation. Testicular disease often presents with painless unilateral enlargement

  • ✓ Extremity: Pain, tenderness, and erythema of the affected limb

  • ✓ Other less common sites: Biliary tract, perineal, intrathoracic, retroperitoneal

• Metastatic disease (present in <25% at diagnosis)

  • ✓ Lymph nodes, lung, bone/bone marrow are most common sites

DIAGNOSIS/STAGING

• Biopsy/surgical resection if feasible without excessive morbidity

• CBC with differential, comprehensive metabolic panel including renal function and liver function testing

• Group: Depends on extent of initial resection

• I: Complete resection, negative margins

• II: Microscopic residual disease

• III: Gross residual disease

• IV: Metastatic disease

• Stage: Depends on primary site, size of primary tumor, and involvement of nodes

  • ✓ I: Favorable site (orbit, superficial head and neck, biliary tree, paratestis, vagina)

  • ✓ II: Unfavorable site, <5cm, no nodal involvement

  • ✓ III: Unfavorable site and >5 cm OR <5 cm with nodal involvement

  • ✓ IV: Metastatic disease

• Staging evaluation:

  • ✓ Primary site imaging (CT/MRI)

  • ✓ Chest CT

  • ✓ Bone scan/PET scan

  • ✓ Bilateral bone marrow aspirates and biopsies

FAVORABLE PROGNOSTIC FACTORS

• Absence of metastatic disease

• Favorable site (orbit, superficial head and neck, biliary tree, paratestis, vagina)

• Low group/stage

• Embryonal histology

  • ✓ Age <10 years

TREATMENT

• Surgery: Always use unless impaired function or cosmetic result. Up-front aggressive surgery or wide excision should not be used in the female genital tract, orbit, bladder, or biliary tract

• Chemotherapy: Combination depends on risk group stratification (combination of group and stage)

  • ✓ Most common agents: Vincristine, actinomycin, cyclophosphamide

• Radiation therapy: Dose, fractionation, and therapy for certain tumor locations (orbit/cranial tumors) are variable and controversial. In general, RT is given for patients with large tumors, alveolar histology, and for those without surgical options for local control

Approach to the patient with a suspected brain tumor

• Patients with brain tumors may be asymptomatic, but commonly diagnosis is made after clinical symptoms such as new onset seizure, intractable headache, persistent nausea or vomiting (especially in the morning), or new onset focal neurologic symptoms (visual loss, ataxia, confusion, etc.) lead to imaging studies

• Tumor location will dictate presenting signs and symptoms. Initial care is directed at emergent management of increased intracranial pressure, spinal cord compression, respiratory or cardiovascular compromise, if present

• Involvement of neurosurgical, oncology, and critical care services is mandatory

EPIDEMIOLOGY

• Second most common group of all pediatric malignancies (about 20% of total)

• Age: Incidence peaks in first decade

  • ✓ Supratentorial tumors: Most common in patients younger than 1 year and older than 11 years

  • ✓ Infratentorial tumors: More common in patients 1–11 years of age

• Sex: Slightly higher in male predominance overall

• Risk factors and predisposing conditions:

  • ✓ Genetic disorders (<10% of cases): NF-1, NF-2, tuberous sclerosis, von Hippel–Lindau, Turcot syndrome, Gorlin syndrome, Li-Fraumeni syndrome, Cowden syndrome, retinoblastoma

  • ✓ Ionizing radiation immunosuppression: Higher risk of CNS lymphoma in patients with inherited or acquired T-cell dysfunction (CVID, Wiskott–Aldrich syndrome, ataxia/telangiectasia, AIDS, and solid organ transplant patients)

Clinical presentation of tumors based on location (Table 21-3)

• Supratentorial (cerebrum, basal ganglia, thalamus/hypothalamus, pituitary pineal, optic): Increased intracranial pressure (ICP), seizures, visual loss, hemiparesis, headache, emesis; new need for glasses; difficulty in school; behavioral difficulty, personality changes; failure to thrive; change in dominant hand; diencephalic syndrome (failure to thrive with increasing appetite and good mood); endocrinopathies such as diabetes insipidus, short stature; Parinaud’s syndrome (poor upward gaze, poor pupillary light reflex but normal to accommodation and convergence nystagmus)

• Infratentorial (cerebellum, brainstem): Ataxia, clumsiness, worsening handwriting, dysarthria; nystagmus; head tilt; cranial nerve palsy; increased ICP from ventricular compression (morning headache and vomiting); extreme vomiting if near area postrema

• Nonspecific signs and symptoms: Change in activity level, change in appetite with associated weight gain or loss, delayed or precocious puberty, macrocephaly in infants, vomiting, complaints consistent with spinal cord involvement such as back pain or bowel/bladder dysfunction (see Oncologic Emergencies section)

DIAGNOSTICS

• CT scan of brain with and without contrast (useful as a quick screen, especially in unstable patients) evaluates ventricular size, midline shift, and hemorrhage; inadequate for anatomic detail and often misses smaller tumors or those in the posterior fossa

• Brain MRI with gadolinium

• Spinal MRI to evaluate for drop metastases/leptomeningeal spread (sometimes seen in PNET, medulloblastoma, germ cell tumors, ependymoma, GBM

• Magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) being used more, but not uniformly

• Lumbar puncture (only after scan and evaluation for increased intracranial pressure) for glucose, protein, culture, cytology, and markers such as α-fetoprotein and B-HCG

• Bone marrow aspirate/biopsy for some PNETs

• Surgical biopsy for histological diagnosis is critical prior to treatment except in cases of diffusely infiltrating pontine gliomas, visual pathway gliomas (in kids with NF1), and tectal gliomas, which are diagnosed from neuroimaging findings and in cases of elevated B-HCG and AFP

MANAGEMENT

• Initial management of increased intracranial pressure, respiratory or cardiovascular stabilization if present, with involvement of neurosurgical and critical care services

• Tumor-directed therapy

  • ✓ Approach is based on biologic potential of tumor and method of spread (see table 12-3). In general, tumors with higher biologic potential require therapy directed at the entire neuroaxis (e.g., CSI/chemotherapy) and those with lower biologic potential or only local invasion may be treated with surgery or local XRT alone

  • ✓ An ideal approach includes an experienced, multidisciplinary team including a pediatric neurosurgeon, oncologist, radiation oncologist, neurocognitive specialist, endocrinologist, and neuro-ophthalmologist

• Observation: Some benign tumors like optic pathway/hypothalamic gliomas can remain stable for years and can be monitored with surveillance imaging, opting for treatment for visual decline or significant tumor progression

• Surgery: Balance preservation of function and maximization of tumor removal. For some tumors (JPA), surgery alone is adequate therapy. Diffuse tumors are not amenable to complete resection, but biopsy and identification of the tumor are often critical and may be achieved using CT- or MRI-guided stereotactic surgical techniques

• Chemotherapy: Used in combination and specific to tumor type

  • ✓ Presence of the blood–brain barrier is an obstacle to effective therapy, although this may be disrupted in the setting of active neoplasm

  • ✓ Active agents include alkylating agents (cyclophosphamide, ifosfamide, thiotepa, cisplatin, carboplatin, and temozolomide), antimetabolites (methotrexate), and plant alkaloids (vincristine, etoposide)

  • ✓ For aggressive or recurrent tumors, high-dose (marrow ablative) chemotherapy with stem cell rescue has been used

  • ✓ Use of chemotherapy has enabled a decrease in the doses of radiation, sparing late effects to the developing brain

• Radiation therapy

  • ✓ Aimed at tumor bed and/or craniospinal area for spread or prophylaxis

  • ✓ Proton beam therapy (versus traditional photon) is being used increasingly in children for its precise targeting and potential for fewer late effects

  • ✓ Age, comorbidities, and balance of early and late toxicity must be considered

  • ✓ Radiation is used most commonly in medulloblastoma, PNET, ependymoma, high-grade gliomas, diffuse brainstem glioma, and germ cell tumors

  • ✓ In some tumor types, radiation is reserved for residual tumor, if chemotherapy fails or progression occurs

• Newer modalities:

  • ✓ Antiangiogenic agents are part of many therapies now

  • ✓ Other promising agents under investigation include: Differentiating agents (cis-retinoic acid, histone-deacetylase inhibitors), tyrosine kinase inhibitors, molecular targets, and immunotherapy

INFECTIOUS PROPHYLAXIS

• Streptococcus mitis: Patients with a history of Strep mitis require prophylaxis when they become neutropenic, typically with clindamycin, vancomycin, or the narrowest antibiotic their strain of S. mitis was sensitive to

• Pneumocystis pneumonia: Patients receiving chemotherapy or other forms of immunosuppressive therapy are at risk for Pneumocystis jirovecii pneumonia

  • ✓ Most effective prophylactic agent is cotrimoxazole (sulfamethoxazole/trimethoprim), usually given twice a day × 2 days a week

  • ✓ Other agents available include dapsone, aerosolized pentamidine (IV for patients <5 years old), and atovaquone, but are inferior as there is increased potential for Pneumocystis breakthrough with these second-line agents

  • ✓ PCP prophylaxis is typically continued for 3–6 months after therapy or longer (12 months) in stem cell transplant patients

• Fungal prophylaxis:

  • ✓ Increased risk correlates to prolonged/profound neutropenia (AML, relapsed ALL, stem cell transplant) or to profound lymphopenia (transplant patients with GVHD, alemtuzumab exposure, etc.) in patients receiving the most intense chemotherapy

  • ✓ When neutropenic, patients are typically started on an antifungal agent like fluconazole or another at the discretion of the treating team

  • ✓ Studies are ongoing to determine the best fungal prophylaxis for this population

Any rapidly dividing cell, like gastrointestinal or oral mucosa, can suffer effects of chemotherapy and break down, become ulcerated or inflamed causing mucositis. Doxorubicin, daunorubicin, methotrexate, and cytarabine are most commonly associated with mucositis.

SIGNS AND SYMPTOMS

• Pain, drooling, dysphagia, abdominal pain, diarrhea, melena, or hematochezia

• Mucositis can interfere with adequate oral hydration and also create an entry point for infectious agents

  • ✓ Patients receiving high-dose cytarabine or HSCT are at particularly high risk for a mucositis-related infection, including Streptococcus mitis, which can cause life-threatening sepsis

TREATMENT

• Debridement with sponges dabbed in sterile saline

• Analgesia with “magic mouthwash” (2% viscous lidocaine, liquid Maalox^®, and liquid diphenhydramine) every 4 to 6 hours

• Oral mucositis can also be complicated or worsened by oral thrush so an antifungal agent (nystatin or fluconazole) may be indicated

• Treatment modalities for anal mucositis: Stool softeners, creams applied to the anal verge (nystatin cream, zinc oxide)

• Mucositis can cause significant discomfort and patients may require intravenous fluids, parenteral nutrition, or IV opioid therapy

GENERAL PRINCIPLES

• Nausea and vomiting can be caused by chemotherapy and radiation, or can occur postoperatively

• Consequences include dehydration, electrolyte imbalance, anorexia, weight loss, and increased susceptibility to infections

• Chemotherapy-induced nausea vomiting (CINV) is defined by when it occurs:

  • ✓ Acute: Occurs within the first 24 hours after receiving chemotherapy

  • ✓ Delayed: Occurs >24 hours after administration and can persist up to 1 week after therapy (common with platinum-based chemotherapy)

  • ✓ Breakthrough CINV: Defined as more than three episodes of emesis or retching within 24 hours and occurs despite proper prophylaxis

  • ✓ Anticipatory CINV: A preconditioned emetic response often related to anxiety surrounding treatments due to prior poor control of nausea/emesis. Can also be triggered by tastes, odor, or sights

EMETOGENICITY AND TREATMENT GUIDELINES

• Emetogenicity varies among commonly used chemotherapeutic agents (Table 21-4)

  • ✓ If multiple chemotherapy agents or radiation are given on a single day, the emetogenicity is generally classified based on the most highly emetogenic agent

  • ✓ If multiple days of chemotherapy are being given consecutively, the emetogenicity is generally classified by the most highly emetogenic agent given each day of therapy

• Prophylactic antiemetic regimens

  • ✓ Consider oral before IV antiemetics

  • ✓ Requires administration of 5HT3-antagonist (e.g., ondansetron, granisetron) antiemetics “around the clock” (i.e., scheduled) rather than symptomatically (or as needed) for patients actively receiving chemotherapy. This may include dexamethasone

  • ✓ Common regimens:

    • ▪ Low: No routine antiemetics recommended

    • ▪ Moderate: Promethazine, prochlorperazine + diphenhydramine

    • ▪ Moderate/High: 5HT3 antagonist* (e.g., ondansetron) +/− dexamethasone orally/IV q24h (maximum 8 mg q24h)

    • ▪ High: 5HT3 antagonist* + dexamethasone orally/IV q12h (maximum 8 mg q12h). May also include an NK-1 receptor antagonist (aprepitant)

  *Based on new recommendations due to QTc prolongation, no more than 16 mg/dose IV of ondansetron should be administered in a single dose. Patient may still have daily total of 24 mg.

• Breakthrough emesis:

  • ✓ Requires as needed rescues or adjunct medications, which can include dexamethasone, benzodiazepines (lorazepam), cannaboids, antihistamines, anticholinergics, phenothiazines, promotility agents (metoclopramide), or additional 5HT3 antagonist if daily maximum dose not reached

• Bone marrow transplant patients usually receive antiemetics until 24 hours after the last dose of chemotherapy or irradiation

• Antiemetic regimens are usually institution specific, so please consult the formulary at treating center for dosing guidelines

NUTRITIONAL SUPPORT

• Malnutrition is very prevalent in oncology patients

• Is often multifactorial: Decreased intake, poor absorption, increased caloric losses, and/or increased metabolic demand

• Malnutrition is associated with increased risk of infection, prolonged hospitalization, and poorer outcomes as compared to healthy weight patients

• When supplemental nutrition is required, the enteral route, by mouth, is preferred

• Patients with mucositis or severe nausea may require tube feedings via nasogastric or other routes

• Placing a gastrostomy tube for nutritional and medication delivery purposes may be beneficial in certain patients (where radiation or severe mucositis may impair eating/taking medications)

• Appetite stimulants can be considered in appropriate patients

• Total parenteral nutrition (TPN) is less favored, but often times necessary for weight maintenance

• Being overweight has also been associated with poor outcomes, so maintaining a healthy weight is critical

PAIN

Somatic or Visceral Pain

• Typically managed with opioid therapy, as anti-inflammatory medications like ibuprofen, which can affect platelet function, are contraindicated in patients with actual or expected thrombocytopenia

• Begin with oral regimens and proceed to IV as needed, following the WHO two-step opioid ladder, with some patients requiring a PCA (patient controlled analgesia device)

• Proper bowel regimens (stool softeners plus cathartic agents) are required for patients being started on opioid therapy to prevent significant constipation associated with opioid use (which is, of note, the only side effect of opioids to which patients do not become tolerant)

Neuropathic Pain

• Neuropathic pain is a common side effect of several chemotherapy and immunotherapy regimens

• GABA analogs like gabapentin and pregabalin are helpful for these symptoms, but require a slow titration to be effective

• Depending on the length of pain therapy, a slow taper off of the medication may be required

PSYCHOSOCIAL AND PSYCHIATRIC SUPPORT

• Patients with cancer are at increased risk of psychological distress, including anxiety, adjustment disorder, and depression. They are also more likely to experience sleep disturbances as a result of treatment factors, hospitalizations, medication side effects, and psychosocial stressors

• Appropriate attention should be made to addressing these symptoms and their management. Consultation with psychosocial support teams and child life staff is prudent and can be beneficial

TRANSFUSION

• There is wide variation in practice, so please consult the oncologic team at a given institution. Patients with clinical indications for blood products (bleeding, anemia, gallops, etc.) should be transfused at the discretion of the treating provider

Packed Red Cell Transfusions

• Typically indicated if the patient is symptomatic from anemia or the hemoglobin is <7–8g/dL

• Prior to procedures and radiation, some centers aim for hemoglobin closer to 9–10g/dL (mainly for anesthesia purposes)

• Ensure that all blood products are irradiated and leukoreduced; in addition, for a CMV-negative or pre/post bone marrow transplant patient, blood should also be CMV antibody negative

Platelets

• Transfusion of platelets is typically indicated when platelet counts are <10,000/mm³ or there is active bleeding

• In bone marrow transplant or neuro-oncology patients with residual tumor, or children who are very active, higher thresholds of 20,000/mm³ are typically followed

• Platelets should be >20,000–30,000/mm³ for lumbar puncture

• Prior to neurosurgical procedures or other procedures with significant risk bleeding, platelet goal should be over 50,000/mm³

• There is no accepted platelet requirement for bone marrow aspirate or biopsy

Special Situations

• Patients at risk for hyperviscosity syndrome (new diagnosis of leukemia with elevated WBC >100,000/mm³) should only be transfused in discussion with oncology given high risk of vascular sludging and sequelae (stroke, pulmonary failure, cardiac dysfunction)

• Patients on concurrent anticoagulation for history of thrombosis are typically maintained at platelet count >50,000/mm³

• Provision of fresh frozen plasma, cryoprecipitate, or vitamin K is sometimes required for correction of severe coagulopathy in specific cases (e.g., preoperative or in DIC associated with APML) but is not a standard practice in all patients

VACCINATION

• Aside from the yearly inactivated influenza vaccine, routine immunizations should be deferred in all patients undergoing cancer chemotherapy

• Revaccination should not begin until at least 6 months after therapy is complete, and longer (12 months) post-allogeneic bone marrow transplantation

VASCULAR ACCESS

• Patients undergoing treatment for chemotherapy typically require indwelling central lines

• Temporary lines such as IVs are not typically used for certain chemotherapy, given concerns for subcutaneous extravasation into skin or joints

• Peripherally inserted central catheters (PICC) can provide up to 2 weeks of continued access but are less favored than more permanent options such as subcutaneous ports (Port-a-cath^®) or tunneled central venous line (Broviac^®, Hickman^®)

• The choice of line depends on diagnosis and treatment protocol (based on type and rate of administration of chemotherapy and supportive care requirements), as well as planned future care (stem cell transplant, etc.)