PEDIATRIC ONCOLOGY — COMPLETE STUDY GUIDE ALL, AML, CNS TUMORS, NEUROBLASTOMA, WILMS TUMOR, RETINOBLASTOMA, OSTEOSARCOMA, EWING SARCOMA, RHABDOMYOSARCOMA, LYMPHOMAS, AND SUPPORTIVE CARE
SECTION 1: ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
CONCEPTUAL SUMMARY
Epidemiology: ALL is the most common pediatric malignancy, accounting for approximately 25–30% of all pediatric cancers. The most common translocation is TEL-AML1 t(12;21), seen most commonly in ages 2–5 and carrying the best prognosis. Other translocations include MLL rearrangement (infants, very poor prognosis), E2A-PBX1 (increased CNS relapse risk), and BCR-ABL/Philadelphia chromosome (older children, very poor prognosis, requires TKI).
Risk Stratification (NCI Criteria): Standard risk requires age 1–9.99 years AND WBC < 50,000 cells/mm³. High risk requires age < 1 or ≥ 10 years OR WBC ≥ 50,000 cells/mm³. MRD < 0.01% at end of induction (Day 29) = favorable response. MRD > 0.01% → upstaged to high risk. Favorable genetics (double trisomies 4 and 10 OR TEL-AML1) + negative MRD → Low Risk.
Induction Therapy: Standard risk (3-drug): dexamethasone + vincristine + pegaspargase. High risk (4-drug): above + daunorubicin. Dexamethasone is preferred for patients < 10 years (superior CNS penetration); prednisone preferred ≥ 10 years (less osteonecrosis and fungal infections). Calaspargase is used in place of pegaspargase in patients ≤ 21 years. Cyclophosphamide is NOT part of the induction backbone — it is introduced in consolidation/delayed intensification.
CNS Prophylaxis: Required for ALL patients regardless of CSF status. Intrathecal (IT) methotrexate ± cytarabine + hydrocortisone is standard. Triple IT therapy (methotrexate + cytarabine + hydrocortisone) is used for CNS treatment and prophylaxis. Cranial radiation is reserved for very high-risk or refractory cases only. Vincristine is ABSOLUTELY CONTRAINDICATED intrathecally — fatal neurotoxicity.
Maintenance Therapy: Daily oral 6-mercaptopurine (6-MP) + weekly methotrexate + intermittent vincristine and corticosteroids. Titrate to maintain ANC 0.5–1.5 × 10⁹/L. Hold BOTH 6-MP and methotrexate if ANC falls below threshold; restart at reduced doses.
Pharmacogenomics — 6-MP Dosing: TPMT or NUDT15 poor metabolizer → risk of fatal myelosuppression at normal doses. TPMT homozygous poor metabolizer → reduce to 10% dose, 3×/week. TPMT heterozygous (intermediate metabolizer) → reduce to 30–80% of full dose daily. TPMT variants are more common in Caucasian/African descent; NUDT15 variants are more common in Asian/Hispanic descent.
Down Syndrome and ALL: Classified as high risk; highly sensitive to methotrexate toxicity. HD-MTX dose capped at 500 mg/m² (vs. standard 5,000 mg/m²) to prevent severe mucositis and GI toxicity.
Relapsed/Refractory ALL: Relapsed ALL re-induction: dexamethasone + vincristine + pegaspargase + daunorubicin. T-cell ALL/lymphoblastic lymphoma relapse → nelarabine (FDA-approved; reduces CNS relapse risk). Blinatumomab for relapsed B-cell (CD19+) ALL — NOT for T-cell. Clofarabine (2nd-generation purine nucleoside analogue): used in refractory ALL; specifically designed to reduce neurotoxicity seen with fludarabine/cladribine.
Asparaginase: Local hypersensitivity to native E. coli asparaginase → switch to pegaspargase (less immunogenic). Premedication alone is insufficient — may mask systemic reaction with "silent inactivation." Discontinuation only after all formulations exhausted (including Erwinia asparaginase). Key toxicities: pancreatitis, hepatotoxicity, hyperglycemia, thrombosis, hypersensitivity.
Baseline Studies Before Anthracycline-Containing Induction: Echocardiogram (LVEF) + liver enzymes + direct bilirubin.
Secondary Malignancies (Late Effects): Cyclophosphamide (alkylating agent) + etoposide (topoisomerase II inhibitor) → secondary AML/MDS. Cranial radiation → secondary brain tumors, hypothyroidism. Latency for topoisomerase II inhibitor-related AML: 2–3 years; alkylator-related: 5–7 years.
PRACTICE QUESTIONS — ACUTE LYMPHOBLASTIC LEUKEMIA
Which is the most common malignancy overall in children?
A. Acute lymphoblastic leukemia (ALL)
B. Acute myeloid leukemia (AML)
C. Neuroblastoma
D. Wilms tumor
Explanation: ALL accounts for approximately 25–30% of all pediatric cancers, making it the most common overall pediatric malignancy. AML is less common and more aggressive. Neuroblastoma and Wilms tumor are solid tumors and fall behind leukemias in overall frequency.
[/expand]SW is a 5-year-old female diagnosed with precursor B-cell ALL. CBC reveals: Hgb 5.4 g/dL, PLT 21,000 cells/mm³, WBC 102,000 cells/mm³ with 72% peripheral blasts. What chemotherapy drugs should SW receive as part of her ALL induction therapy?
A. Dexamethasone, vincristine, and calaspargase
B. Prednisone, vincristine, calaspargase, and daunorubicin
C. Doxorubicin, vincristine, and pegaspargase
D. Dexamethasone, vincristine, pegaspargase, and daunorubicin
Explanation: SW is classified as high risk because her presenting WBC exceeds 50,000 cells/mm³. High-risk patients receive a four-drug induction with a corticosteroid, vincristine, pegaspargase, and daunorubicin. Dexamethasone is the preferred corticosteroid for patients younger than 10 years due to superior CNS penetration. Prednisone is preferred for patients ≥ 10 years due to increased rates of osteonecrosis and fungal infections with dexamethasone. Calaspargase is used in place of pegaspargase in patients aged ≤ 21 years — option A uses calaspargase but omits daunorubicin, which is required for high-risk disease. Option B incorrectly uses prednisone for a 5-year-old. Option C incorrectly uses doxorubicin instead of daunorubicin and omits a corticosteroid.
[/expand]RJ is a 3-year-old male diagnosed with B-cell ALL. CBC reveals: Hgb 5.4 g/dL, PLT 21,000 cells/mm³, WBC 20,000 cells/mm³ with 72.4% blasts. What chemotherapy drugs should RJ receive as part of his ALL induction?
A. Dexamethasone, vincristine, and pegaspargase
B. Prednisone, vincristine, pegaspargase, and daunorubicin
C. Doxorubicin, vincristine, and pegaspargase
D. Dexamethasone, vincristine, pegaspargase, and doxorubicin
Explanation: RJ is classified as standard risk — his age is within 1–9.99 years and his presenting WBC is < 50,000 cells/mm³. Standard-risk patients receive three-drug induction with a corticosteroid, vincristine, and pegaspargase. Dexamethasone is the preferred corticosteroid for patients younger than 10 years due to superior CNS penetration. Option B incorrectly uses prednisone and adds daunorubicin (only for high-risk). Options C and D incorrectly include doxorubicin, which is not the correct anthracycline (daunorubicin is standard) and is not needed for standard-risk disease.
[/expand]Z.P. is a 2-year-old girl with precursor B-cell ALL. WBC 28,000 cells/mm³, Hgb 6.5 g/dL, PLT 55,000 cells/mm³. Initial lumbar puncture is negative and DNA index is 1.22. She is receiving prednisone and intrathecal therapy. In addition to prednisone and intrathecal therapy, which of the following is the best therapy to initiate for Z.P.?
A. Cyclophosphamide, doxorubicin, and mercaptopurine
B. Vincristine, daunorubicin, and asparaginase
C. Cytarabine, daunorubicin, and asparaginase
D. Cytarabine, cyclophosphamide, and mercaptopurine
Explanation: Z.P. is standard risk (age 1–9.99 years, WBC < 50,000 cells/mm³) with a favorable DNA index (1.22 = hyperdiploidy). The induction backbone for ALL includes vincristine, asparaginase, and a corticosteroid (prednisone already given). Daunorubicin is the fourth agent used for high-risk patients and is included here given the question context. Option B correctly identifies the active agents for ALL induction. Options A, C, and D include cyclophosphamide, cytarabine, and mercaptopurine — all agents introduced in later phases (consolidation, maintenance, delayed intensification), NOT in induction.
[/expand]Which baseline studies are best performed before the initiation of ALL induction therapy in Z.P. (2-year-old with B-cell ALL receiving daunorubicin and asparaginase)?
A. Chest radiograph and CT of the chest
B. 24-hour urine collection and liver enzymes
C. Echocardiogram, direct bilirubin, and liver enzymes
D. Thyroid studies and echocardiography
Explanation: Echocardiogram is required before anthracycline (daunorubicin) therapy — anthracyclines cause dose-related cardiac toxicity, and Z.P.'s age (< 5 years) is a significant risk factor for late cardiac dysfunction. Direct bilirubin and liver enzymes establish baseline hepatic function because asparaginase (pegaspargase or calaspargase) causes hepatotoxicity as a primary acute toxicity. Chest radiograph (option A) is useful for detecting mediastinal mass in T-cell ALL but is not a baseline toxicity study. 24-hour urine collection (option B) is for agents causing renal toxicity (ifosfamide, cisplatin) — not standard for initial ALL induction. Thyroid studies (option D) are for follow-up of patients who received cranial or neck radiation, not as baseline studies before induction.
[/expand]At the end of induction, Z.P. has MRD < 0.01% in her bone marrow. Which of the following best describes how this will affect her risk classification?
A. Does not change her risk classification
B. Changes her to standard risk
C. Changes her to high risk D.
Changes her to very high risk
Explanation: Z.P. was initially classified as standard risk (age 1–9.99 years, WBC < 50,000 cells/mm³). MRD < 0.01% at end of induction (Day 29) represents a favorable response — this confirms she stays in her standard risk category and is NOT upstaged. If MRD were > 0.01%, she would advance to high risk. To qualify for the even lower "Low Risk" category, a patient must have standard risk criteria PLUS specific favorable genetics (double trisomies 4 and 10 or TEL-AML1) AND negative MRD. Z.P.'s favorable DNA index (hyperdiploidy) is suggestive but does not alone confirm the specific genetics required for low-risk reclassification.
[/expand]T.V. is a 6-year-old Caucasian boy in maintenance therapy for ALL with persistently low platelet, WBC, and RBC counts. He is neutropenic without lymphoblasts on his blood smear. Which genetic test is best to perform on T.V.?
A. Thymidylate synthase
B. Thiopurine S-methyltransferase (TPMT)
C. Glutathione S-transferase
D. Dihydrofolate reductase
Explanation: T.V. is in maintenance therapy receiving daily 6-mercaptopurine (6-MP). Persistent pancytopenia (myelosuppression) without evidence of relapse is a classic sign of 6-MP toxicity due to reduced TPMT enzyme activity. TPMT catabolizes 6-MP into inactive metabolites — patients with reduced or absent TPMT activity accumulate cytotoxic metabolites, causing life-threatening myelosuppression. TPMT variants are more common in Caucasian and African-descent patients. Thymidylate synthase, glutathione S-transferase, and dihydrofolate reductase are not standard genetic tests for monitoring myelosuppression during ALL maintenance therapy.
[/expand]T.V.'s genetic test confirms he is heterozygous for the TPMT polymorphism (intermediate metabolizer). Which of the following is the best recommendation for T.V.?
A. Continue the same mercaptopurine dose
B. Increase the mercaptopurine
C. Decrease the mercaptopurine
D. Discontinue the mercaptopurine
Explanation: T.V. is heterozygous for TPMT — an intermediate metabolizer with reduced enzyme activity. For intermediate metabolizers, the standard recommendation is to reduce the mercaptopurine dose to 30–80% of the full dose. T.V. is already experiencing persistent myelosuppression consistent with 6-MP toxicity. The appropriate action is to hold both 6-MP and methotrexate until count recovery, then restart at decreased dosing. Continuing the same dose (option A) would worsen myelosuppression. Increasing the dose (option B) is dangerous. Discontinuation (option D) is reserved for patients who have exhausted all dose reduction options — methotrexate is also a critical maintenance drug and cannot simply be omitted.
[/expand]SW's pharmacogenetic testing revealed TPMT *3A/*3A (poor metabolizer) and NUDT15 *1A/*1A (normal metabolizer). Her MRD at day 29 was < 0.01% and she is entering consolidation with mercaptopurine. What is the recommended starting dose for mercaptopurine (6-MP) for SW?
A. 6-MP 100% dosing, no adjustment required
B. 6-MP decreased to 50% dosing seven days per week
C. 6-MP decreased to 50% dosing three days per week
D. 6-MP decreased to 10% dosing three days per week
Answer: D. 6-MP decreased to 10% dosing three days per week
Explanation: SW's pharmacogenetic testing reveals she is homozygous deficient for TPMT (poor metabolizer) with normal NUDT15 activity. A TPMT poor metabolizer has low or absent TPMT enzyme activity — at normal doses, she is at risk for severe and potentially fatal myelosuppression due to accumulation of cytotoxic 6-MP metabolites. The recommended starting dose for TPMT homozygous poor metabolizers is 10% of the full dose administered only three times per week (not daily). This is the most important pharmacogenomic dose adjustment in pediatric ALL maintenance therapy.
[/expand]RJ is in maintenance therapy receiving weekly methotrexate and daily oral mercaptopurine. TPMT and NUDT15 genotyping are both homozygous wild type. At scheduled follow-up, his ANC is 200 cells/mm³. Which of the following recommendations is most appropriate for RJ at this time?
A. Resend TPMT genotyping
B. Hold both mercaptopurine and methotrexate
C. Omit dexamethasone from this cycle only
D. No change to therapy, check CBC at next visit
Explanation: RJ has an ANC of 200 cells/mm³, which falls below the target maintenance range of 0.5–1.5 × 10⁹/L (500–1,500 cells/mm³). Dosing of both mercaptopurine and methotrexate is titrated throughout maintenance to maintain ANC within this range. When myelosuppression occurs, BOTH agents are held until count recovery, then restarted at decreased doses. Resending TPMT genotyping (option A) is unnecessary since normal metabolizer status has been confirmed. Omitting only dexamethasone (option C) does not address the myelosuppression caused by oral chemotherapy. Continuing without change (option D) risks worsening myelosuppression and potential life-threatening infection.
[/expand]M.P. presents with redness, pain, and swelling at his injection site the morning after receiving his third dose of asparaginase. Which of the following is the best adjustment to M.P.'s therapy?
A. Continue asparaginase but decrease the dose
B. Change to pegaspargase
C. Continue asparaginase but premedicate M.P. next time
D. Give no additional asparaginase
Explanation: M.P. is receiving native E. coli L-asparaginase (given multiple times per week — 3 doses implies native form). The symptoms (redness, pain, swelling at injection site) represent a local hypersensitivity reaction. Local reactions to native asparaginase are a signal to switch to a less immunogenic formulation. Pegaspargase (pegylated asparaginase) is less immunogenic and is now the standard formulation. Premedication alone (option C) is insufficient — it can mask systemic reactions with "silent inactivation" where antibodies neutralize the drug while symptoms are suppressed. Decreasing the dose (option A) does not address immunogenicity. Discontinuing completely (option D) is only appropriate after all formulations (including Erwinia asparaginase) have been exhausted — asparaginase is a critical ALL drug and should not be stopped prematurely.
[/expand]C.D. is a 1-year-old girl with Down syndrome and ALL. She is due for high-dose methotrexate. Which of the following dose changes is best for C.D.?
A. No dosage modification is necessary
B. The dose should not be higher than 500 mg/m²
C. No dosage modification is needed as long as aggressive leucovorin rescue is administered
D. C.D. should not receive high-dose MTX
Explanation: Children with Down syndrome (Trisomy 21) are classified as high risk in ALL and are highly sensitive to methotrexate toxicity. The standard HD-MTX dose is 5,000 mg/m² for high-risk patients, but for Down syndrome patients, clinical protocols cap the methotrexate dose at 500 mg/m² to prevent severe, life-threatening mucositis and GI toxicity. Giving the full dose even with aggressive leucovorin rescue (option C) is generally avoided in Down syndrome patients due to the high risk of irreversible toxicity. Methotrexate is a critical component of ALL therapy and should not be omitted entirely (option D) — it is modified for safety. No modification (option A) would expose C.D. to 10 times the safe dose.
[/expand]Z.C. is a 7-year-old boy with relapsed ALL who has persistent disease despite front-line relapsed therapy. The decision is made to treat with clofarabine, cyclophosphamide, and etoposide. Which adverse event should be lessened by clofarabine compared to other nucleoside analogues?
A. Nephrotoxicity
B. Hepatotoxicity
C. Pulmonary toxicity
D. Neurotoxicity
Explanation: Clofarabine is a second-generation purine nucleoside analogue specifically developed to combine the beneficial mechanisms of earlier agents (like fludarabine and cladribine) while reducing severe neurotoxicity. Nelarabine, another nucleoside analogue used in T-cell ALL, carries dose-limiting neurologic toxicity with approximately 18% of patients experiencing grade 3 or higher neurotoxicity. High-dose cytarabine is also associated with neurocognitive defects. Clofarabine was designed to lessen this neurotoxicity risk while maintaining efficacy. Clofarabine is not known to reduce nephrotoxicity (option A) — it can actually cause capillary leak syndrome. Hepatotoxicity (option B) is a known toxicity of clofarabine, not one it reduces. Pulmonary toxicity (option C) is primarily associated with bleomycin and radiation, not nucleoside analogues.
[/expand]E.T. is a 4-year-old Caucasian girl with a normal WBC, decreased hemoglobin, and decreased platelets diagnosed with precursor B-cell ALL. Based on E.T.'s age and diagnosis, which of the following translocations is she most likely to have?
A. TEL-AML1
B. MLL gene rearrangement
C. E2A-PBX1 D. BCR-ABL
Explanation: E.T. is a 4-year-old standard-risk patient (age 1–9.99 years, normal WBC). TEL-AML1 — also known as ETV6-RUNX1 from the cryptic t(12;21) translocation — is the most common genetic lesion in pediatric ALL, most commonly seen in ages 2–5 and associated with favorable prognosis. It is one of the required biological markers for Low Risk classification. MLL gene rearrangement (option B) is an unfavorable marker associated with Very High Risk ALL and is most characteristic of infant leukemia (age < 1 year). E2A-PBX1 (option C) is associated with increased CNS relapse risk and is not the most common. BCR-ABL (option D) is the Philadelphia chromosome — an unfavorable marker associated with Very High Risk disease, more common in older children and adolescents.
[/expand]A 5-year-old girl is newly diagnosed with B-cell ALL and is starting induction therapy with vincristine, dexamethasone, pegaspargase, and daunorubicin. Which supportive care measure is MOST important to initiate during induction?
A. Prophylactic G-CSF
B. Pneumocystis jirovecii prophylaxis
C. Leucovorin rescue
D. Dexrazoxane
Explanation: PJP prophylaxis (TMP-SMX) is required during all steroid-containing regimens in pediatric ALL. Dexamethasone significantly increases the risk of opportunistic infections including Pneumocystis jirovecii pneumonia. TMP-SMX is the standard prophylactic agent. Prophylactic G-CSF (option A) is not a standard supportive measure for initial ALL induction — it is used in medulloblastoma protocols. Leucovorin rescue (option C) is required for high-dose methotrexate, which is given in consolidation and maintenance phases, not induction. Dexrazoxane (option D) is a cardioprotectant used with anthracyclines in some protocols but is not identified as a required routine supportive measure for ALL induction.
[/expand]During induction, a 5-year-old girl receiving vincristine, dexamethasone, pegaspargase, and daunorubicin develops abdominal pain, elevated amylase/lipase, and hyperglycemia. Which drug is most likely responsible?
A. Vincristine
B. Dexamethasone
C. Asparaginase
D. Daunorubicin
Explanation: The classic toxicity profile of asparaginase includes pancreatitis (elevated amylase/lipase + abdominal pain), hyperglycemia, hepatotoxicity, thrombosis, and hypersensitivity reactions. This clinical picture — abdominal pain with elevated pancreatic enzymes and hyperglycemia — is characteristic of asparaginase-induced pancreatitis. Vincristine (option A) causes peripheral neuropathy and has a 2 mg dose cap. Dexamethasone (option B) causes mood changes, infection risk, osteonecrosis, and hypertension — not pancreatitis or hyperamylasemia. Daunorubicin (option D) causes cardiotoxicity and myelosuppression.
[/expand]Which of the following is TRUE regarding CNS prophylaxis in ALL?
A. Systemic chemotherapy alone is sufficient for CNS disease prevention
B. Intrathecal methotrexate ± cytarabine and hydrocortisone are required
C. CNS prophylaxis is not needed unless blasts are seen in CSF
D. Cranial radiation is the standard first-line prophylaxis
Explanation: CNS prophylaxis is required for ALL patients regardless of CSF status — even if the lumbar puncture is negative for blasts. Intrathecal methotrexate ± cytarabine and hydrocortisone is the standard approach. Triple IT therapy (all three agents) is used for CNS treatment and prophylaxis in higher-risk patients. Systemic chemotherapy alone (option A) cannot adequately penetrate the CNS blood-brain barrier to prevent relapse. CNS prophylaxis is not conditional on CSF findings (option C) — it is given universally. Cranial radiation (option D) is reserved for very high-risk or refractory cases only — it is NOT first-line due to devastating long-term neurocognitive toxicity.
[/expand]A 6-year-old with ALL is receiving intrathecal chemotherapy for CNS prophylaxis. Which agent is absolutely contraindicated intrathecally?
A. Methotrexate
B. Cytarabine
C. Vincristine
D. Hydrocortisone
Explanation: Vincristine is ABSOLUTELY CONTRAINDICATED intrathecally — intrathecal vincristine causes fatal ascending paralysis and neurotoxicity. In every ALL protocol, vincristine is exclusively administered intravenously. The agents approved for intrathecal use in ALL are methotrexate, cytarabine, and hydrocortisone — all three make up the "triple IT therapy" for CNS treatment and prophylaxis. This is one of the most critical medication safety points in pediatric oncology — inadvertent intrathecal vincristine administration is a catastrophic, preventable medication error.
[/expand]KM is a 7-year-old male with relapsed high-risk B-cell ALL receiving re-induction with dexamethasone, vincristine, pegaspargase, and daunorubicin. On day 6, his ANC is 50 cells/mm³ and is anticipated to remain below 500 cells/mm³ throughout his 28-day induction cycle. Is KM a candidate for antibacterial prophylaxis with levofloxacin?
A. No, KM should not receive levofloxacin prophylaxis since it is not recommended in children younger than 10 years
B. Yes, KM should receive levofloxacin prophylaxis until his ANC recovers to greater than 500 cells/mm³
C. No, KM is not anticipated to experience prolonged neutropenia so is not a candidate for prophylaxis
D. Yes, KM should receive levofloxacin prophylaxis until his ANC recovers to greater than 1,000 cells/mm³
Explanation: Levofloxacin prophylaxis is recommended in pediatric patients with AML or relapsed ALL receiving chemotherapy with an anticipated ANC nadir < 500 cells/mm³ for at least 7 days. KM has relapsed ALL with a current ANC of 50 cells/mm³ anticipated to persist throughout his 28-day induction cycle — he clearly meets both criteria. Levofloxacin continues until ANC recovers to > 500 cells/mm³. There is no age restriction for levofloxacin prophylaxis in this context (option A is incorrect). Option D uses an incorrect ANC threshold of 1,000 cells/mm³ — the correct threshold is 500 cells/mm³.
[/expand]RS is a 4-year-old male with newly diagnosed ALL receiving induction therapy with dexamethasone, vincristine, and pegaspargase. On day 6, he develops a fever of 39.8°C with an ANC of 150 cells/mm³. Vital signs are otherwise stable and he is clinically well-appearing. He has no drug allergies. Which is the most appropriate choice of empiric antibiotic therapy for RS?
A. Piperacillin-tazobactam and vancomycin
B. Cefepime
C. Ciprofloxacin and vancomycin
D. Meropenem and gentamicin
Explanation: RS meets criteria for febrile neutropenia and requires immediate broad-spectrum antibiotics. For clinically stable patients with febrile neutropenia and no evidence of resistant organisms or clinical instability, monotherapy with an anti-pseudomonal beta-lactam such as cefepime, piperacillin-tazobactam, or meropenem is appropriate. Vancomycin is NOT routinely added unless the patient is clinically unstable or a resistant gram-positive organism is suspected — RS is well-appearing with stable vital signs. Double gram-negative coverage (option D) is not indicated. Ciprofloxacin + vancomycin (option C) is incorrect — oral/IV ciprofloxacin alone lacks adequate gram-negative breadth and adding vancomycin is not indicated here.
[/expand]JR is a 9-year-old male with Stage III relapsed T-cell lymphoblastic lymphoma presenting with bilateral cervical and inguinal lymphadenopathy. Which of the following agents is most appropriate for JR's disease?
A. Bortezomib
B. Pembrolizumab
C. Blinatumomab
D. Nelarabine
Explanation: Nelarabine received accelerated FDA approval for relapsed or refractory T-cell ALL and T-cell lymphoblastic lymphoma (T-LL) in pediatric populations. It is lineage-specific — appropriate for T-cell disease only. In addition to providing salvage activity, its inclusion in upfront T-ALL protocols has been shown to improve disease-free survival and significantly reduce CNS relapse risk. Blinatumomab (option C) is a targeted therapy for relapsed B-cell lineage (CD19+) ALL — it is NOT appropriate for T-cell disease. Bortezomib (option A) and pembrolizumab (option B) are not identified in standard relapse protocols for pediatric T-cell lymphoblastic lymphoma.
[/expand]A 19-year-old, 6 years off therapy for ALL, presents with secondary AML. His ALL therapy included MTX, cyclophosphamide, daunorubicin, mercaptopurine, etoposide, vincristine, and asparaginase. Which drugs most likely contributed to his secondary AML?
A. Daunorubicin and MTX
B. Cyclophosphamide and etoposide
C. Vincristine and cyclophosphamide
D. Asparaginase and MTX
Explanation: Cyclophosphamide is an alkylating agent — alkylating agents are explicitly associated with development of therapy-related secondary AML, with a latency of 5–7 years. Etoposide is a topoisomerase II inhibitor — also associated with secondary AML/MDS, with a shorter latency of 2–3 years. The combination of these two agents explains this patient's secondary AML presenting 6 years later. MTX (option A) is associated with neurocognitive defects and renal toxicity — not secondary AML. Vincristine (option C) causes neuropathy — not secondary malignancy. Asparaginase (option D) causes pancreatitis, thrombosis, and hepatotoxicity — not secondary AML.
[/expand]SECTION 2: ACUTE MYELOID LEUKEMIA (AML)
CONCEPTUAL SUMMARY
Subtypes and Cytogenetics: inv(16) → AML M4Eo (myelomonocytic with abnormal eosinophils) → favorable prognosis. t(8;21) → AML M2 → favorable prognosis. Favorable cytogenetics (inv(16), t(8;21)) → consolidation chemotherapy alone; no HSCT in CR1. High-risk cytogenetics (monosomy 7, complex karyotype, FLT3-ITD) → HSCT in CR1.
Presenting Features: AML M4/M5 (monocytic): chloroma (extramedullary myeloid sarcoma), gingival hyperplasia/bleeding, pallor. Mediastinal mass is NOT a feature of AML — it is characteristic of T-cell ALL/lymphoblastic lymphoma. AML diagnosis requires ≥ 20% bone marrow blasts (exception: inv(16) or t(8;21) regardless of blast %).
Induction: Standard — cytarabine + daunorubicin ("7+3") ± etoposide. Dexamethasone eye drops are required with high-dose cytarabine to prevent chemical conjunctivitis/keratitis (via tear excretion). Baseline echocardiogram required before anthracycline therapy.
Post-Induction: Consolidation: high-dose cytarabine (HiDAC) — backbone for all AML. CNS prophylaxis: required for all patients, especially M4/M5; intrathecal cytarabine is the drug of choice (active in both ALL and AML). Maintenance therapy: NOT standard in AML (unlike ALL). HSCT: only for high-risk cytogenetics or persistent/relapsed disease.
Refractory AML: Persistent MRD after 2 induction cycles → gemtuzumab ozogamicin (anti-CD33 antibody-drug conjugate). HSCT only after achieving MRD negativity. Heavily pretreated/relapsed refractory AML (investigational) → farnesyltransferase inhibitor (tipifarnib — targets RAS pathway).
Infectious Prophylaxis: Most common pathogen: gram-positive cocci (central line-related). Empiric febrile neutropenia: meropenem + vancomycin + caspofungin. Antifungal prophylaxis: voriconazole (preferred over amphotericin B).
Long-Term Complications (Chemo Only, No HSCT): Anthracyclines (daunorubicin): congestive heart failure, cardiac arrhythmias (highest risk if treated < 5 years). Etoposide + cyclophosphamide: secondary malignant neoplasm. Hypothyroidism, renal failure, hearing loss, avascular necrosis, ovarian failure: NOT expected without radiation or specific agents.
Cranial Radiation Late Effects: Hypothyroidism + secondary brain tumors (most specific). Congestive heart failure: associated with chest radiation + anthracyclines, NOT cranial radiation.
PRACTICE QUESTIONS — ACUTE MYELOID LEUKEMIA
A 9-year-old boy with newly diagnosed AML is started on cytarabine + daunorubicin ("7+3"). He is at high risk for tumor lysis syndrome (TLS).Which agent is most appropriate for TLS prophylaxis?
A. Allopurinol
B. Rasburicase
C. Febuxostat
D. Sodium bicarbonate
Explanation: High-risk TLS (particularly in ALL and AML with high tumor burden) requires rasburicase — a recombinant urate oxidase that DIRECTLY breaks down existing uric acid into allantoin, providing rapid reduction of elevated uric acid levels. Allopurinol (option A) prevents NEW uric acid production but does not lower already elevated levels — it is appropriate for lower-risk prophylaxis. Febuxostat (option C) is not widely used in pediatrics for TLS management. Sodium bicarbonate (option D) is no longer recommended because it increases calcium phosphate precipitation risk when phosphorus is elevated — a common finding in TLS.
[/expand]A.Y. is a 20-month-old girl with AML who has received two courses of induction therapy with cytarabine, etoposide, and daunorubicin. Her MRD is now 6%. She has tolerated therapy except for mild liver dysfunction. Which of the following is the best treatment for A.Y. at this time?
A. Gemtuzumab ozogamicin
B. Hematopoietic stem cell transplantation (HSCT)
C. Cytarabine, etoposide, and daunorubicin
D. Tipifarnib
Explanation: A.Y. has persistent MRD of 6% after two induction cycles — she has failed standard induction therapy. Gemtuzumab ozogamicin is an anti-CD33 antibody-drug conjugate indicated for persistent or refractory AML after induction failure — it targets leukemic blasts through a completely different mechanism. HSCT (option B) is only appropriate after achieving MRD negativity — transplanting with active disease would be ineffective. Repeating the same induction regimen (option C) is not appropriate after two failed cycles. Tipifarnib (option D) is a farnesyltransferase inhibitor used as an investigational agent for heavily pretreated relapsed/refractory AML, not as second-line after initial induction failure.
[/expand]Assuming A.Y. (20-month-old with AML) does not require HSCT, which long-term complications is she at greatest risk of developing once she reaches adulthood?
A. Congestive heart failure, second malignant neoplasm, and hypothyroidism
B. Renal failure, hearing loss, and cardiac arrhythmias
C. Second malignant neoplasm, congestive heart failure, and cardiac arrhythmias
D. Hearing loss, avascular necrosis, and ovarian failure
Explanation: A.Y. received daunorubicin (anthracycline) and etoposide. Anthracyclines cause dose-dependent cardiomyopathy — leading to congestive heart failure and cardiac arrhythmias. The highest risk is in patients treated at age < 5 years, making A.Y. (20 months) particularly vulnerable. Etoposide is a topoisomerase II inhibitor associated with therapy-related secondary malignant neoplasms. Hypothyroidism (option A) is primarily associated with cranial or neck radiation — A.Y. received chemotherapy only. Renal failure and hearing loss (option B) are associated with cisplatin and high-dose carboplatin — not agents A.Y. received. Avascular necrosis (option D) requires corticosteroids in patients ≥ 10 years; ovarian failure requires alkylating agents or gonadal radiation.
[/expand]G.H. is a 16-year-old boy receiving AML induction with cytarabine, daunorubicin, and etoposide. Which of the following drugs is best to administer while G.H. is receiving his induction therapy?
A. Dexamethasone eye drops with cytarabine
B. Dexrazoxane to be given before daunorubicin
C. A fluid bolus to be given before etoposide
D. Digoxin to be given before daunorubicin
Explanation: High-dose cytarabine causes chemical conjunctivitis and keratitis through tear excretion of the drug. Dexamethasone eye drops are the mandatory prophylactic intervention given with each dose of high-dose cytarabine to prevent this ocular toxicity. This is a classic and high-yield supportive care fact in pediatric AML. Dexrazoxane (option B) is a cardioprotectant studied with anthracyclines but is not a standard routine intervention in this setting. A fluid bolus before etoposide (option C) is not a standard requirement. Digoxin before daunorubicin (option D) has no clinical basis.
[/expand]A.P. is a 3-year-old boy diagnosed with AML with inv(16) cytogenetics. Which AML subtype is A.P. most likely to have and what is his prognosis?
A. AML M1 with a poor prognosis
B. AML M5 with a good prognosis
C. AML M2 with a very poor prognosis
D. AML M4Eo with a good prognosis
Explanation: The inv(16) translocation is the characteristic cytogenetic marker for AML M4Eo — Acute Myelomonocytic Leukemia with abnormal eosinophils. Inv(16) is classified as a favorable-risk cytogenetic marker in pediatric AML, associated with a good prognosis and excellent outcomes with intensive chemotherapy and consolidation — these patients generally achieve remission without requiring HSCT in first remission. AML M1 and M2 are not associated with inv(16). M5 is monocytic AML, associated with extramedullary disease but not specifically linked to the inv(16) translocation. M2 is associated with t(8;21) — also favorable but a different subtype.
[/expand]A.L. is a 2-year-old girl with AML M4 and inv(16). WBC 20,000 cells/mm³, Hgb 5 mg/dL, platelets 7,000 cells/mm³. Which combination of findings and symptoms did A.L. most likely have on presentation?
A. Mediastinal mass, gum bleeding, and pallor
B. Fever, splenomegaly, and hyperuricemia
C. Chloroma, gum bleeding, and pallor
D. Chloroma, fatigue, and bone marrow blasts less than 20%
Explanation: AML M4 (Acute Myelomonocytic Leukemia) is characterized by monocytic differentiation, which is associated with extramedullary disease. Chloroma (myeloid sarcoma) is an extramedullary collection of leukemic blasts classically associated with monocytic subtypes (M4, M5) and inv(16). Gingival hyperplasia and gum bleeding result from leukemic infiltration of the gingiva — a classic finding of monocytic AML. Pallor reflects severe anemia (Hgb 5 mg/dL). Mediastinal mass (option A) is the hallmark of T-cell ALL/lymphoblastic lymphoma — NOT AML. Option D is partially correct (chloroma) but inv(16) allows AML diagnosis even with < 20% blasts only by exception, not as the primary expected finding.
[/expand]Which is the best therapy for A.L. (AML M4 with inv(16)) after induction therapy?
A. HSCT and maintenance therapy
B. Consolidation therapy and radiation therapy
C. Maintenance therapy and radiation therapy
D. CNS prophylaxis and consolidation therapy
Explanation: After achieving remission with induction, post-induction therapy for AML includes consolidation (high-dose cytarabine) and CNS prophylaxis (intrathecal cytarabine — the drug of choice in both ALL and AML, given the dual activity). CNS prophylaxis is required for all AML patients, especially M4/M5 subtypes which have higher CNS tropism. Maintenance therapy (options A and C) is NOT standard in AML — unlike ALL. HSCT (option A) is reserved for high-risk cytogenetics or persistent/relapsed disease — A.L. has favorable inv(16) cytogenetics and should achieve good outcomes with chemotherapy alone without transplant in first remission. Radiation (options B and C) is not a standard component of post-induction therapy for pediatric AML.
[/expand]N.F. is a 7-year-old patient with newly diagnosed AML currently undergoing induction therapy who is expected to be immunosuppressed for the entire duration of induction. Which of the following antimicrobial regimens is best for N.F.?
A. Meropenem, vancomycin, and caspofungin
B. Voriconazole, oxacillin, and palivizumab
C. Voriconazole, vancomycin, and ciprofloxacin
D. Amphotericin B, metronidazole, and levofloxacin
Explanation: For empiric management of febrile neutropenia during AML induction, the recommended broad-spectrum approach covers gram-negative, gram-positive, AND fungal pathogens. Meropenem provides gram-negative coverage (including Pseudomonas). Vancomycin provides gram-positive coverage (particularly for central line-related infections with S. epidermidis and viridans streptococci — the most common pathogens in AML induction). Caspofungin provides antifungal coverage. For prophylaxis, voriconazole is preferred over amphotericin B. Option B is incorrect — palivizumab is for RSV prophylaxis in infants, not for neutropenic AML patients. Option C lacks antifungal coverage. Option D uses amphotericin B (less preferred than voriconazole) and metronidazole (for anaerobes, not indicated here).
[/expand]B.T. is a 17-year-old male who was treated for ALL at age 3 with conventional chemotherapy and cranial radiation for CNS prophylaxis. Which long-term complication is B.T. most likely to have because of his cranial radiation?
A. Hypothyroidism and secondary brain tumor
B. Hypothyroidism and congestive heart failure
C. Azoospermia and obesity
D. Secondary brain tumors and osteoporosis
Explanation: Cranial radiation causes two hallmark long-term complications: endocrinopathies (hypothyroidism) and secondary brain tumors. The radiation field for cranial prophylaxis covers the hypothalamic-pituitary axis, causing hypothyroidism and other endocrine disorders. Secondary brain tumors develop within the prior radiation field — the latency can be 5–20+ years. Congestive heart failure (option B) is associated with chest/mediastinal radiation and anthracyclines — NOT cranial radiation. Azoospermia (option C) requires radiation to the testes/pelvis or specific alkylating agents. Osteoporosis (option D) while present in cancer survivors is not the primary cranial radiation-specific complication.
[/expand]S.R. is a 6-year-old boy with relapsed refractory AML who has already completed four different treatment regimens. His parents still want him to receive curative chemotherapy and an investigational study is offered. Which class of chemotherapy agents is S.R. most likely to benefit from?
A. DNA topoisomerase I inhibitor
B. Nitrogen mustard alkylating agent
C. Farnesyltransferase inhibitor
D. Tyrosine kinase inhibitor
Explanation: In heavily pretreated relapsed/refractory AML where conventional mechanisms have been exhausted through four prior regimens, a farnesyltransferase inhibitor (tipifarnib) offers a completely novel mechanism of action by targeting the RAS signaling pathway — a biologically rational target given the frequency of RAS mutations in AML. An investigational context is appropriate here. DNA topoisomerase I inhibitors (option A), nitrogen mustard alkylating agents (option B), and tyrosine kinase inhibitors (option D) represent mechanisms that have likely already been employed or do not have established pediatric AML salvage evidence in this setting.
[/expand]SECTION 3: PEDIATRIC CNS TUMORS — MEDULLOBLASTOMA, ASTROCYTOMA, EPENDYMOMA, AND GLIOBLASTOMA
CONCEPTUAL SUMMARY
Most Common Pediatric Brain Tumor: Medulloblastoma is the most common MALIGNANT brain tumor of childhood (WHO Grade IV). Located in the posterior fossa, midline cerebellar vermis, invades the fourth ventricle. Symptoms: headaches, morning vomiting, ataxia, dizziness. The most common SOLID tumor in children overall is CNS tumors as a category.
Medulloblastoma Risk Stratification: Average risk: age ≥ 3 years, < 1.5 cm² residual tumor, no metastasis, non-anaplastic histology. High risk: age < 3 years (AUTOMATICALLY high risk regardless of other factors), ≥ 1.5 cm² residual tumor, metastatic disease (M1–M4), anaplastic OR large cell histology. ERBB2 (HER2) overexpression → significantly worse prognosis. Favorable molecular subgroup: WNT-activated (~95% OS).
Medulloblastoma Treatment (Age ≥ 3 years): Surgery (maximal resection) → craniospinal irradiation (CSI, initiated within 4 weeks of surgery) → adjuvant chemotherapy. Average risk: reduced-dose CSI (23.4 Gy) + boost to tumor bed. High risk: standard-dose CSI + chemotherapy. Adjuvant chemotherapy: cisplatin + cyclophosphamide + vincristine (or lomustine-based). During radiation: weekly vincristine as radiosensitizer.
Medulloblastoma Treatment (Age < 3 years): Radiation is OMITTED — devastating long-term neurocognitive toxicity in the developing brain. Surgery → aggressive multi-agent chemotherapy (cyclophosphamide, etoposide, cisplatin, vincristine ± HD-MTX). Goal: delay or avoid CSI while brain is developing. HD-MTX (5 g/m²) requires plasma concentration monitoring + leucovorin rescue.
Antiemetics in CNS Tumor Patients: Cisplatin is highly emetogenic → aprepitant + 5-HT3 antagonist (palonosetron preferred). Dexamethasone as antiemetic is AVOIDED in CNS tumor patients — may impair chemotherapy BBB penetration.
Neurocognitive Late Effects: Classic deficits — processing speed and working memory. Treatment: methylphenidate (improves attention, processing speed, working memory). Psychotherapy addresses mood/behavioral issues, NOT cognitive deficits. Amifostine is a cytoprotectant given BEFORE treatment — cannot reverse established deficits. Diazepam is a CNS depressant — would WORSEN cognitive deficits.
Low-Grade Glioma (WHO Grade I–II): Gross total resection → observation (potentially curative). Subtotal resection: chemotherapy required — cannot observe residual disease. Age < 10 years with residual/progressive disease: carboplatin + vincristine (delays radiation). Age ≥ 10 years: radiation OR chemotherapy. Carboplatin hypersensitivity occurs in 10–40% of children with frequent dosing → requires DESENSITIZATION (premedication alone is insufficient). Refractory to carboplatin-based regimen → temozolomide.
High-Grade Glioma/GBM (WHO Grade IV): Aggressive; poor prognosis (5-year OS < 20%). Treatment: surgery → radiation (mainstay; only treatment shown to prolong survival) → concurrent + adjuvant temozolomide. Dexamethasone: standard for tumor-related increased ICP (reduces vasogenic edema). Anticonvulsants: start ONLY if seizure activity is present; prefer NON-enzyme-inducing agents (levetiracetam) to avoid CYP3A4 interactions.
Ependymoma: Treatment sequence: surgery → radiation (primary adjuvant) → post-irradiation cisplatin-based combination chemotherapy. Age < 3 years: chemotherapy given PRE-irradiation to delay radiation. Extent of surgical resection = strongest prognostic factor.
Secondary CNS Malignancy (Late Effect): Cranial radiation + alkylating agents + topoisomerase II inhibitors → secondary high-grade glioma. Latency: 5–20+ years. Classic presentation: new onset headaches, vomiting, intractable seizures in a long-term cancer survivor.
PRACTICE QUESTIONS — PEDIATRIC CNS TUMORS
What is the most common solid tumor overall in children?
A. Brain/CNS tumors
B. Osteosarcoma
C. Neuroblastoma
D. Wilms tumor
Explanation: Among the major pediatric cancer categories — leukemias (~26%), CNS tumors (~18%), lymphomas (~14%) — because leukemias and lymphomas are hematologic malignancies (not solid tumors), CNS/brain tumors represent the most common category of SOLID tumors in children. Within this category, medulloblastoma is the most common malignant brain tumor. Neuroblastoma is the most common EXTRACRANIAL solid tumor. Wilms tumor is the most common kidney cancer in children. Osteosarcoma is the most common bone tumor.
[/expand]A 7-year-old boy presents with headaches, morning vomiting, and ataxia. Imaging reveals a posterior fossa mass arising from the midline cerebellar vermis invading the fourth ventricle — consistent with medulloblastoma. Which of the following is optimal therapy for this patient at this point in his clinical course?
A. Observation
B. Maximal surgical resection
C. Conformal radiotherapy
D. Adjuvant chemotherapy
Explanation: For any patient with a presumed diagnosis of medulloblastoma, surgery is the critical first step — complete or near-complete resection is of critical importance. All subsequent therapies (radiation and chemotherapy) are initiated after surgery. Radiation is most effective when initiated within 4 weeks post-surgery — delays are associated with worse prognosis. Observation (option A) is never appropriate for a WHO Grade IV tumor. Radiation (option C) and adjuvant chemotherapy (option D) follow surgery but are not appropriate as the FIRST intervention. The sequence is always: surgery → radiation (age ≥ 3) → chemotherapy.
[/expand]PJ is a 2-year-old boy with high-risk medulloblastoma. After surgical resection, he has < 1.5 cm² residual tumor and no evidence of metastatic disease. His parents ask why radiation is not a planned component of treatment. What is the most appropriate response to PJ's parents?
A. Radiation is reserved for anaplastic histology
B. Radiation is reserved for relapsed medulloblastoma
C. There is no benefit of radiation following complete surgical resection
D. The risk of long-term neurocognitive toxicity
Explanation: PJ will not receive radiation therapy solely because of his age (< 3 years). Despite having otherwise favorable risk features (< 1.5 cm² residual tumor, non-anaplastic histology, no metastases), he is automatically classified as HIGH RISK because patients under 3 years of age are not candidates for craniospinal irradiation. Radiation in the developing brain causes devastating long-term neurocognitive toxicity. Options A and B are incorrect — radiation is not reserved for anaplastic histology or relapse; it is a standard part of therapy for children ≥ 3 years regardless of histology. Option C is incorrect — radiation provides proven survival benefit but must be deferred in this age group for safety reasons.
[/expand]A 2-year-old girl with medulloblastoma has negative CSF cytology and less than 1.5 cm² residual tumor after surgery. Which of the following is the best radiation therapy option for her?
A. A.G. should not receive radiation therapy
B. 23.4-Gy craniospinal radiation with boost to the primary tumor bed
C. 23.4-Gy craniospinal radiation
D. Conformal boost to the residual tumor
Explanation: Children under 3 years of age with medulloblastoma are automatically classified as high risk and radiation is omitted — regardless of other favorable prognostic factors. The developing brain cannot tolerate craniospinal irradiation without devastating and irreversible neurocognitive consequences. The treatment strategy for these young patients involves aggressive multi-agent chemotherapy after surgery to delay or avoid CSI entirely. Options B and C describe 23.4 Gy craniospinal radiation — this reduced-dose regimen is the standard for average-risk patients aged ≥ 3 years, NOT for children under 3. Option D (conformal boost only) is also not appropriate as a standalone radiation strategy for this age group.
[/expand]T.S. is a 9-year-old boy with high-risk medulloblastoma who has just completed radiation therapy. Which chemotherapy regimen is best for T.S.?
A. Vincristine, cyclophosphamide, and fluorouracil
B. Cyclophosphamide, vinblastine, and carmustine
C. Cisplatin, carmustine, and vinblastine
D. Cisplatin, cyclophosphamide, and vincristine
Explanation: For high-risk medulloblastoma patients aged ≥ 3 years after completing radiation, the standard adjuvant chemotherapy regimen is cisplatin + vincristine + cyclophosphamide (based on COG Protocol A9961). This combination was studied as an alternative to lomustine-based therapy and has proven safety and efficacy. Fluorouracil (option A) is not a component of standard medulloblastoma regimens. Carmustine (options B and C) and vinblastine are not standard agents for medulloblastoma post-radiation chemotherapy — the standard nitrosourea when used is lomustine (CCNU), not carmustine.
[/expand]T.S.'s tumor tissue shows ERBB2 overexpression. Which of the following effects on T.S.'s prognosis is most likely?
A. None — ERBB2 has not been studied in medulloblastoma
B. None — results are equivocal
C. ERBB2-positive tumors have a significantly worse prognosis
D. ERBB2-positive tumors are more radiosensitive
Explanation: ERBB2 (HER2/neu) overexpression in medulloblastoma has been identified as an independent predictor of poor clinical outcome — ERBB2-positive tumors are associated with significantly lower overall survival rates. This molecular marker indicates aggressive disease biology. Favorable molecular subgroups in medulloblastoma include WNT-activated (~95% OS), while unfavorable groups include Group 3 with MYC amplification. ERBB2 positivity falls in the unfavorable category. Option A is incorrect — ERBB2 has been studied in medulloblastoma. Option B is incorrect — the results consistently point to worse prognosis. Option D is incorrect — ERBB2 positivity is not associated with increased radiosensitivity.
[/expand]T.S. has completed medulloblastoma therapy and is in remission. He now has worsening deficits in processing speed and working memory affecting his academic performance. Which is the best recommendation?
A. Psychotherapy
B. Methylphenidate
C. Amifostine
D. Diazepam
Answer: B. Methylphenidate
Explanation: Methylphenidate (a stimulant) is the standard pharmacological intervention for pediatric cancer survivors experiencing radiation-induced neurocognitive deficits — specifically improving attention, processing speed, and working memory. These deficits in processing speed and working memory are classic post-radiation sequelae from craniospinal irradiation. Psychotherapy (option A) addresses mood and behavioral issues but does NOT address the underlying biological deficit in processing speed or working memory. Amifostine (option C) is a cytoprotectant given BEFORE treatment — it cannot reverse established deficits once they have developed. Diazepam (option D) is a CNS depressant — it would WORSEN cognitive deficits, not improve them.
[/expand]AM is a 3-year-old male with medulloblastoma being admitted for chemotherapy with cisplatin, lomustine, and weekly vincristine. Which prophylactic antiemetic regimen would be most appropriate for AM?
A. Aprepitant, dexamethasone, and 5-HT3 antagonist
B. Fosaprepitant, dexamethasone, and 5-HT3 antagonist
C. Aprepitant and 5-HT3 antagonist
D. Dexamethasone and 5-HT3 antagonist
Explanation: Cisplatin is highly emetogenic and requires prophylaxis for highly emetogenic chemotherapy. However, AM is being treated for a CNS malignancy and dexamethasone as an antiemetic is AVOIDED in CNS tumor patients because dexamethasone may decrease chemotherapy penetration of the blood-brain barrier, reducing treatment efficacy. For patients receiving highly emetogenic chemotherapy who cannot receive dexamethasone, POGO guidelines recommend aprepitant + a 5-HT3 antagonist (palonosetron preferred). All options containing dexamethasone (A, B, D) are inappropriate in this CNS tumor context. Dexamethasone is still used for its intended purpose (ICP management) when clinically indicated — just NOT as an antiemetic in CNS tumor patients.
[/expand]W.E. is a 9-year-old boy with large cell anaplastic medulloblastoma. Imaging reveals disseminated disease and positive CSF cytology. He underwent maximal surgical resection. What is the best recommendation regarding timing of treatment for W.E.?
A. Do not administer chemotherapy; begin radiation therapy as soon as possible
B. Do not give radiation therapy; begin chemotherapy as soon as possible
C. Give chemotherapy as soon as possible; then begin radiation therapy
D. Begin radiation therapy as soon as possible; then begin chemotherapy
Explanation: W.E. is 9 years old (≥ 3 years), has disseminated disease (metastatic, M1-M4) and anaplastic histology — classified as high risk. For children ≥ 3 years, the standard sequence is surgery → radiation (as soon as possible, ideally within 4 weeks) → adjuvant chemotherapy. Delays in radiation are explicitly associated with worse prognosis. During radiation, weekly vincristine is given as a radiosensitizer. Post-radiation, intensive adjuvant chemotherapy (cisplatin, vincristine, cyclophosphamide) begins approximately 6 weeks after completing radiation. Omitting radiation (option B) is only for children < 3 years. Starting intensive chemotherapy first (option C) would delay the start of radiation, worsening prognosis.
[/expand]M.F. is a 2-year-old boy who underwent gross total resection of a large cell medulloblastoma in the right frontoparietal region. Which is the best treatment for M.F.?
A. No further therapy; observation only
B. Radiation therapy
C. Intrathecal methotrexate
D. Combination chemotherapy
Explanation: M.F. is 2 years old — automatically high risk and radiation is contraindicated due to devastating neurocognitive toxicity in the developing brain. After surgical resection, the standard treatment for children < 3 years is aggressive multi-agent combination chemotherapy (cyclophosphamide, etoposide, cisplatin, vincristine ± HD-MTX) to delay or avoid craniospinal irradiation. Observation (option A) is inappropriate for a WHO Grade IV highly invasive tumor. Radiation (option B) is contraindicated at this age. Intrathecal methotrexate alone (option C) is not an appropriate standalone therapy for medulloblastoma.
[/expand]M.F.'s pediatric oncologist asks about the use of high-dose methotrexate therapy for his medulloblastoma regimen. Which treatment and monitoring plan is best for M.F.?
- High-dose methotrexate therapy; monitor methotrexate plasma concentrations and administer leucovorin rescue
- Intrathecal and oral methotrexate; monitor methotrexate plasma concentrations and administer leucovorin rescue
- Methotrexate therapy with dosage individualized based on methotrexate clearance
- Combine systemic methotrexate and radiation therapy, with methotrexate monitoring
Explanation: High-dose methotrexate (HD-MTX at 5 g/m² IV) has shown excellent antitumor activity in infant medulloblastoma regimens. The mandatory companion interventions are leucovorin rescue and plasma MTX concentration monitoring to ensure drug clearance and guide leucovorin dosing duration. Intrathecal and oral methotrexate (option B) is not the administration route described — HD-MTX is given intravenously. Individualizing based on clearance (option C) is not the standard protocol described in these guidelines. Combining systemic methotrexate with radiation (option D) is contraindicated for M.F. because radiation must be avoided in children < 3 years.
[/expand]A.B. is a 10-year-old boy with a few weeks of intermittent headaches and seizures. Imaging reveals an enhancing mass that is clearly demarcated from surrounding normal brain. Which is the best treatment for A.B.?
A. Surgical resection
B. Radiation therapy
C. Combination chemotherapy
D. Combination chemoradiation therapy
Explanation: A.B.'s history of seizures with an enhancing, clearly demarcated mass is characteristic of a low-grade focal brain tumor — most likely a pilocytic astrocytoma. For pediatric low-grade gliomas, surgery is the cornerstone of treatment. The primary goal is gross total resection, which is achievable in 60–80% of cases and is potentially curative — observation after complete resection is a viable management strategy. Radiation (option B), chemotherapy (option C), and chemoradiation (option D) are all reserved for progressive or symptomatic disease after surgical resection, or for inoperable tumors. Radiation is also avoided or delayed in young children due to long-term adverse effects.
[/expand]Z.T. is a 3-year-old girl with low-grade glioma where only a subtotal resection was possible. Which is the best treatment for Z.T.?
A. Observation
B. Radiation therapy
C. Intrathecal methotrexate
D. Chemotherapy with carboplatin and vincristine
Explanation: For a 3-year-old (age < 10 years) with residual low-grade glioma after subtotal resection, carboplatin + vincristine is the standard chemotherapy regimen. This approach delays or avoids radiation in young children, preserving neurodevelopment. Observation (option A) is inappropriate when there is residual disease — observation is only for completely resected low-grade gliomas. Radiation (option B) is avoided in children under 10 years with residual progressive disease due to devastating neurodevelopmental consequences. Intrathecal methotrexate (option C) is used for CNS prophylaxis in leukemia — it has no role in the management of low-grade glioma.
[/expand]A.N. is a 4-year-old girl with recurrent pilocytic astrocytoma being treated with carboplatin and vincristine. After her second course, she has a hypersensitivity reaction presumably caused by carboplatin. Which is the best management for A.N.'s reaction?
- Desensitization of the patient is required to prevent any further hypersensitivity reactions to carboplatin
- Hypersensitivity to carboplatin does not occur and the clinician should seek alternative causes
- The combination of carboplatin with vincristine leads to greater incidence of hypersensitivity than carboplatin as a single agent
- Desensitization does not provide any advantage compared with premedication
Explanation: Carboplatin hypersensitivity occurs in 10–40% of children receiving frequent carboplatin — making option B clearly incorrect. A.N. has had 5–6 doses (two courses of weekly dosing) which places her in the window of risk. For pediatric patients who experience carboplatin hypersensitivity, desensitization protocols are the standard clinical strategy for rechallenge. Premedication alone (option D) is insufficient for platinum-based IgE-mediated hypersensitivity — desensitization with gradual re-exposure is required. The combination of carboplatin with vincristine (option C) does not specifically increase hypersensitivity incidence — this is a property of carboplatin frequency, not the combination.
[/expand]A.N.'s low-grade glioma is not responding to the carboplatin-based regimen. Which treatment option is best for A.N.?
A. Temozolomide
B. Cyclophosphamide
C. Topotecan
D. Carmustine
Explanation: Temozolomide is the standard salvage agent for progressive or refractory pediatric low-grade gliomas that fail carboplatin-based therapy. It is explicitly identified in treatment guidelines for pediatric brain tumors including gliomas, and is the standard concurrent + adjuvant agent for high-grade gliomas. Among the available options, it is the most appropriate for progressive CNS malignancy in this context. Cyclophosphamide (option B) is used in medulloblastoma and neuroblastoma — not as primary salvage for LGG. Topotecan (option C) has activity in relapsed neuroblastoma. Carmustine (option D) is a nitrosourea — not listed as a standard standalone salvage option for pediatric LGG in current guidelines.
[/expand]G.H. is a 12-year-old girl with WHO Grade 4 glioblastoma multiforme and symptoms consistent with increased intracranial pressure. Which statement regarding dexamethasone therapy is the best treatment option for G.H.?
- Dexamethasone should not be used because of the potential for interactions with her anticonvulsant
- Dexamethasone should be used to treat her increased intracranial pressure
- Dexamethasone should not be used to treat her increased intracranial pressure because no data are available
- Dexamethasone should be used as a single dose to treat her increased intracranial pressure
Explanation: Dexamethasone is the standard pharmacological intervention for tumor-related increased intracranial pressure and vasogenic edema associated with high-grade gliomas. Note the important distinction: dexamethasone is AVOIDED as an antiemetic in CNS tumor patients, but it IS indicated for treating symptomatic ICP. The benefits of controlling life-threatening ICP outweigh concerns. The anticonvulsant interaction (option A) — some enzyme-inducing anticonvulsants increase dexamethasone clearance via CYP3A4 — is managed through dose ADJUSTMENT, not avoidance. A single dose (option D) is insufficient — scheduled dosing is required to maintain reduction of ICP.
[/expand]G.H.'s glioblastoma was only subtotally resected. Which is the best treatment option for G.H.?
A. Observation
B. Temozolomide
C. Carmustine; then radiation therapy
D. Radiation therapy
Explanation: For high-grade glioma (GBM) after subtotal resection, radiation therapy is the mainstay of treatment and the only modality shown to prolong survival. The treatment sequence is surgery → radiation (concurrent with temozolomide) → adjuvant temozolomide. Radiation is the essential next step to address residual disease and provide local control. Observation (option A) is only for low-grade, slow-growing gliomas — completely inappropriate for WHO Grade IV GBM. Temozolomide alone (option B) is given concurrently with and after radiation, not as a standalone first step post-resection. Carmustine (option C) is not the standard first adjuvant choice — the standard regimen uses temozolomide (concurrent + adjuvant), not carmustine.
[/expand]P.M. is a 13-year-old boy with glioblastoma multiforme. His oncologist asks about anticonvulsant therapy. Which is the best recommendation regarding anticonvulsants for P.M.?
A. Start anticonvulsants prophylactically until P.M. can have surgical resection
B. Start anticonvulsants only if P.M. has seizure activity
C. Do not start anticonvulsants because of the potential for interaction with P.M.'s chemotherapy
D. Do not start anticonvulsants because P.M. is vomiting and will not be able to maintain a therapeutic concentration
Explanation: Anticonvulsants are started only if seizure activity is present — prophylactic anticonvulsants are NOT recommended for brain tumor patients without seizures. When anticonvulsants are needed, NON-enzyme-inducing agents (levetiracetam preferred) are chosen to avoid CYP3A4 interactions with chemotherapy and dexamethasone. Prophylactic use (option A) is not recommended. Option C is incorrect reasoning — the concern about drug interactions is managed by choosing the right anticonvulsant (levetiracetam), not by avoiding anticonvulsants entirely when clinically indicated. Option D is incorrect — vomiting does not contraindicate anticonvulsant use when seizures are present.
[/expand]T.M. is a 2-year-old boy with a supratentorial ependymoma presenting with numbness in his legs, morning headaches, and nausea/vomiting. Which is the best treatment option for T.M.?
A. Observation
B. Surgery
C. Radiation
D. Chemotherapy
Explanation: Surgery is the cornerstone of treatment for all pediatric CNS tumors including ependymoma — complete or near-complete resection is of critical importance, and extent of resection is the strongest prognostic factor for ependymoma. Radiation (option C) is avoided in children < 3 years due to devastating neurocognitive toxicity. Chemotherapy (option D) follows surgery in this age group to delay radiation — it is not the first intervention. Observation (option A) is not appropriate for a symptomatic malignant CNS tumor.
[/expand]What is the best recommendation regarding chemotherapy for T.M. (2-year-old with ependymoma)?
A. Cisplatin as a single agent
B. Combination chemotherapy pre-irradiation with a cisplatin-based regimen
C. Neoadjuvant chemotherapy before surgery with a cisplatin-based regimen
D. Combination chemotherapy post-irradiation with a cisplatin-based regimen
Explanation: For children < 3 years with ependymoma, the treatment strategy after surgery is combination chemotherapy given PRE-irradiation — specifically to delay or avoid craniospinal irradiation in the developing brain. Multi-agent cisplatin-based combination regimens (cisplatin, cyclophosphamide, etoposide, vincristine) are used. The sequence is surgery → combination chemotherapy → (radiation deferred until age > 3 if possible). Cisplatin monotherapy (option A) is insufficient — multi-agent therapy is required. Neoadjuvant chemotherapy before surgery (option C) is incorrect — surgical resection must be performed first. Post-irradiation chemotherapy (option D) is the sequence for patients ≥ 3 years where radiation is given first.
[/expand]M.V. is a 16-year-old female ALL survivor whose therapy included cyclophosphamide, etoposide, and extensive radiation. She now presents with headaches, nausea/vomiting, and intractable seizures. Which of the following best describes what has happened to M.V.?
A. Radiation-induced CNS damage
B. High-grade glioma as a secondary malignancy
C. Interaction between cyclophosphamide and etoposide
D. Chemotherapy-induced seizure disorder
Explanation: M.V. is a long-term cancer survivor whose prior therapy included cranial radiation, cyclophosphamide (alkylating agent), and etoposide (topoisomerase II inhibitor) — all established risk factors for secondary high-grade CNS malignancy. The latency for radiation-induced secondary brain tumors is 5–20+ years, and the classic presentation is new onset headaches, vomiting, and intractable seizures — all of which M.V. is experiencing. This represents the hallmark late presentation of a secondary high-grade glioma within the prior radiation field. Radiation-induced CNS damage (option A) causes neurocognitive deficits not acute ICP symptoms. Options C and D have no established mechanism for producing this presentation in a long-term survivor.
[/expand]SECTION 4: NEUROBLASTOMA, WILMS TUMOR, RETINOBLASTOMA, OSTEOSARCOMA, EWING SARCOMA, AND RHABDOMYOSARCOMA
CONCEPTUAL SUMMARY
Neuroblastoma: Most common extracranial solid tumor in children; arises from neural crest cells. Classic presentation: abdominal/adrenal mass, distended abdomen, weight loss, refusal to walk. Diagnostic markers: elevated urine VMA (vanillylmandelic acid) and HVA (homovanillic acid). High-risk features: MYCN amplification, unfavorable histology, diploidy, Stage 4, age > 18 months. Treatment (3 phases): Induction — CAV (cyclophosphamide + doxorubicin + vincristine) alternating with P-VP (cisplatin + etoposide) + surgical resection + radiation. Consolidation — tandem autologous SCT. Maintenance — dinutuximab (anti-GD2) + GM-CSF + isotretinoin. GM-CSF role: stimulates monocytes/macrophages/granulocytes → potentiates ADCC. Corticosteroids are CONTRAINDICATED concurrently with dinutuximab (suppress immune effector cells). Cisplatin ototoxicity: highest risk for age ≤ 4 years receiving cisplatin.
Wilms Tumor: Most common kidney cancer in children (typical age 2–3 years). Classic: painless, mobile abdominal mass noted during bathing, hematuria, hypertension. WAGR syndrome (Wilms, Aniridia, GU abnormalities, intellectual disability) → > 50% risk of Wilms. Aniridia is the key clinical marker for WAGR. LOH at chromosomes 1p and 16q in patients ≥ 2 years → upstaged to standard risk (independent poor prognostic factor). Treatment: Stage I–II (EE-4A): surgery + vincristine + actinomycin D. Stage III–IV (DD-4A): surgery + vincristine + actinomycin D + doxorubicin. Radiation indicated for Stage III and IV only. Vincristine dose: 1.5 mg/m² (max 2 mg).
Retinoblastoma: Most common intraocular malignancy of childhood. Classic: leukocoria (white pupillary reflex/"white eye" in flash photos). ~40% hereditary (RB1 germline mutation). RB1 mutation → significantly increased risk of secondary malignancies, especially osteosarcoma. Group A: focal therapy only. Groups B–C: focal therapy + vincristine + etoposide + carboplatin × ≥ 6 cycles (6 cycles significantly superior to 2 for globe salvage). External beam radiation: reserved as rescue therapy due to secondary cancer risk. Enucleation: for advanced Group E disease.
Osteosarcoma: Adolescents with localized bone pain. Standard regimen: high-dose methotrexate + doxorubicin + cisplatin (MAP) — perioperative (pre- and post-surgery). Echocardiogram required before and during therapy (doxorubicin cardiotoxicity). COG: echocardiogram every 2 years if cumulative doxorubicin ≥ 250 mg/m².
Ewing Sarcoma: Bone tumor; biopsy shows small, round, blue cells. Standard: VDC/IE — vincristine + doxorubicin + cyclophosphamide alternating with ifosfamide + etoposide every 2 weeks (interval compression per AEWS0031 protocol). Ifosfamide: hemorrhagic cystitis (via acrolein) → prevent with mesna + hydration. Ifosfamide: also causes encephalopathy. Ifosfamide: late renal toxicity.
Rhabdomyosarcoma: Most common soft-tissue sarcoma in children. Standard: VAC — vincristine + actinomycin D + cyclophosphamide. Cyclophosphamide → hemorrhagic cystitis → prevent with mesna + hydration. Vincristine dose capped at 2 mg.
Burkitt Lymphoma: Rapid growth (cell doubling time 24–48 hours) → very high TLS risk. t(8;14) C-MYC translocation. Reduction chemotherapy first (COP) → minimize TLS risk. Group A/B: reduction + 2–4 cycles chemo; no maintenance. Group C (high risk, CNS+ disease): reduction + 4 cycles escalated chemo + maintenance. Rasburicase for established/high-risk TLS.
T-cell Lymphoblastic Lymphoma: Treated with ALL-type regimens (~2 years). Relapse → nelarabine. Blinatumomab: B-cell only, NOT T-cell.
Hodgkin Lymphoma: Standard regimen: ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) ± radiation. Cumulative doxorubicin ≥ 250 mg/m² → echocardiogram every 2 years (COG). Bleomycin → pulmonary function monitoring.
PRACTICE QUESTIONS — SOLID TUMORS, LYMPHOMAS, AND SUPPORTIVE CARE
A 4-year-old girl presents with a unilateral abdominal mass and aniridia. Which pediatric tumor is most likely?
A. Ewing sarcoma
B. Neuroblastoma
C. Wilms tumor
D. Hepatoblastoma
Explanation: Aniridia (absence of the iris) is a key clinical marker for WAGR syndrome — Wilms tumor, Aniridia, Genitourinary abnormalities, and intellectual disability. Patients with WAGR syndrome have > 50% risk of developing Wilms tumor (nephroblastoma). Wilms tumor is the most common kidney cancer in children with typical presentation at ages 2–3 years as a palpable abdominal mass. Neuroblastoma (option B) also presents as an abdominal mass but is NOT associated with aniridia. Ewing sarcoma (option A) typically presents as a bone/soft tissue mass in the extremities. Hepatoblastoma (option D) is an abdominal mass but is associated with elevated AFP, not aniridia.
[/expand]Which is the most common extracranial solid tumor in children?
A. Osteosarcoma
B. Rhabdomyosarcoma
C. Ewing sarcoma
D. Neuroblastoma
Explanation: Neuroblastoma arises from neural crest cells and typically presents as an abdominal tumor involving the adrenal gland. It is the most common extracranial solid tumor in the pediatric population — particularly the most common solid tumor in infants. Wilms tumor is the most common RENAL tumor in children. Osteosarcoma and Ewing sarcoma are bone tumors. Rhabdomyosarcoma is the most common soft-tissue sarcoma. All of these are extracranial but none reaches the frequency of neuroblastoma.
[/expand]MB is a 2-year-old male with stage 4 neuroblastoma, MYCN amplification, unfavorable histology, and diploidy. What induction treatment is most appropriate for MB?
A. Local control with surgical resection and radiation therapy
B. Carboplatin, etoposide, cyclophosphamide, and doxorubicin plus local control
C. Cyclophosphamide, doxorubicin, vincristine (CAV) alternating with cisplatin/etoposide (P-VP) plus local control with surgical resection and radiation therapy
D. Tandem autologous stem cell transplant
Explanation: MB has high-risk neuroblastoma (stage 4, MYCN amplification, unfavorable histology, diploidy). The three-phase treatment for high-risk neuroblastoma is: Induction — CAV alternating with P-VP plus local control (surgical resection + radiation after HSCT); Consolidation — tandem autologous SCT; Maintenance — dinutuximab + GM-CSF + isotretinoin. Option A (local control only) is insufficient for high-risk disease. Option B uses an incorrect regimen. Option D (transplant) is the consolidation phase — it comes AFTER induction, not as initial therapy.
[/expand]MB has completed induction and consolidation therapy and begins maintenance immunotherapy with dinutuximab and GM-CSF. Which statement most accurately describes the role of GM-CSF in this regimen?
A. Shorten the duration of neutropenia
B. Potentiate antibody-dependent cell-mediated cytotoxicity
C. Decrease risk of dinutuximab-related infusion reactions
D. Adjunct for pain management
Explanation: GM-CSF stimulates the production of monocytes, macrophages, and granulocytes. These immune effector cells mediate antibody-dependent cell-mediated cytotoxicity (ADCC). The Fc fragment of the dinutuximab monoclonal antibody binds Fc receptors on these effector cells, which then engulf and destroy GD2-expressing tumor cells. GM-CSF is included specifically to maximize the ADCC mechanism. It does not shorten neutropenia in this context (option A), does not reduce infusion reactions (option C), and is not an analgesic (option D) — though dinutuximab itself causes significant pain requiring management.
[/expand]MB begins cycle 1 of maintenance immunotherapy with dinutuximab. Which medication class would be contraindicated concurrently with dinutuximab?
A. Growth factors
B. Corticosteroids
C. Proton pump inhibitors
D. NSAIDs
Explanation: Corticosteroids are CONTRAINDICATED during dinutuximab therapy. Dinutuximab harnesses the patient's immune system — including T-cells, natural killer cells, and macrophages — to destroy GD2-expressing neuroblastoma cells. Concurrent corticosteroids would suppress the number and functionality of these immune effector cells, significantly reducing dinutuximab efficacy. Growth factors (option A) — specifically GM-CSF — are actually USED concurrently to ENHANCE ADCC. PPIs (option C) and NSAIDs (option D) have no established contraindication with dinutuximab.
[/expand]A 3-year-old boy with an abdominal mass is diagnosed with neuroblastoma. Which laboratory marker is commonly elevated and aids in diagnosis?
A. AFP
B. β-hCG
C. Homovanillic acid (HVA) and vanillylmandelic acid (VMA) in urine
D. LDH
Explanation: Neuroblastoma arises from neural crest cells of the sympathetic nervous system and produces catecholamine metabolites — VMA (vanillylmandelic acid) and HVA (homovanillic acid) — that are elevated in urine and serve as standard diagnostic and monitoring markers. AFP (option A) is elevated in hepatoblastoma and germ cell tumors. β-hCG (option B) is elevated in germ cell tumors. LDH (option D) is a nonspecific tumor marker elevated in multiple malignancies but is not the specific diagnostic marker for neuroblastoma.
[/expand]SC is a 3-year-old male with stage I Wilms tumor of favorable histology with loss of heterozygosity (LOH) at chromosomes 1p and 16q. He is stratified as standard-risk disease. Which characteristic classifies SC as standard-risk disease?
A. Unilateral disease
B. Favorable histology
C. Loss of heterozygosity at chromosomes 1p and 16q
D. Age of 3 years old
Explanation: LOH at chromosomes 1p and 16q is an independent poor prognostic factor in patients with favorable histology Wilms tumor. A patient with favorable histology and stage I disease would normally be classified as LOW risk. However, the presence of LOH at 1p and 16q in a patient ≥ 2 years of age specifically UPSTAGES the patient to standard risk. Favorable histology (option B) and unilateral disease (option A) are positive prognostic features that alone would place this patient in a lower risk category. Age ≥ 2 years (option D) is a modifier used in conjunction with the LOH finding, but age alone does not determine risk.
[/expand]A 4-year-old girl presents with a painless abdominal mass. Imaging and biopsy confirm Wilms tumor (Stage III). Which is most consistent with standard therapy?
A. Surgery only
B. Surgery + chemotherapy (vincristine + actinomycin D ± doxorubicin)
C. Radiation alone
D. Chemotherapy only
Explanation: Stage III Wilms tumor requires the DD-4A regimen — surgery + vincristine + actinomycin D + doxorubicin. Additionally, radiation is indicated for stage III disease (though not listed in option B, the multimodal approach including surgery and chemotherapy aligns with standard of care). Surgery alone (option A) is only sufficient for low-risk stage I disease. Radiation alone (option C) is never appropriate without surgery and chemotherapy. Chemotherapy alone (option D) without surgery is not standard. Stage I–II uses the EE-4A regimen (vincristine + actinomycin D without doxorubicin); stages III–IV add doxorubicin.
[/expand]A 2-year-old girl presents with leukocoria (white pupillary reflex). Genetic testing confirms RB1 mutation. Which of the following is TRUE?
A. Retinoblastoma is usually benign and does not metastasize
B. RB1 mutation increases risk for secondary malignancies such as osteosarcoma
C. Systemic chemotherapy is always required at diagnosis
D. Radiation is the only effective therapy
Explanation: Hereditary retinoblastoma (~40% of cases) is associated with germline RB1 mutations, which significantly increase the risk of secondary malignancies — particularly osteosarcoma, often occurring within a prior radiation field. Retinoblastoma is a malignant tumor — it is NOT benign and CAN metastasize to bone, bone marrow, and CNS (option A is false). Systemic chemotherapy is NOT always required at diagnosis (option C) — Group A (very small tumors) is treated with focal therapy only, without systemic chemotherapy. Radiation is NOT the only effective therapy (option D) — in fact, radiation is reserved as a rescue option due to its association with secondary malignancies.
[/expand]CH is a 2-year-old female with unilateral retinoblastoma — ICIR group C disease (4 mm tumor with vitreous seeding within 2 mm of the tumor). Which is the most appropriate treatment for CH?
A. Focal therapy only
B. External beam radiation
C. Vincristine, etoposide, and carboplatin × 2 cycles
D. Focal therapy and vincristine, etoposide, and carboplatin × 6 cycles
Explanation: ICIR Group C disease requires both focal therapy (laser therapy or cryotherapy) AND systemic chemotherapy. The standard systemic regimen is vincristine + etoposide + carboplatin × ≥ 6 cycles. Six cycles are significantly superior to 2 cycles for globe salvage rates — option C is therefore incorrect despite the right regimen. Focal therapy alone (option A) is only appropriate for Group A (very small tumors). External beam radiation (option B) is reserved as rescue therapy for non-responders due to its association with secondary malignancies in RB1 mutation carriers. Intra-arterial chemotherapy is also an option for selected cases.
[/expand]A 12-year-old boy presents with persistent right leg pain. Biopsy confirms osteosarcoma. Which frontline regimen is correct?
A. VAC (vincristine, actinomycin D, cyclophosphamide)
B. High-dose methotrexate, doxorubicin, cisplatin
C. VDC/IE (vincristine, doxorubicin, cyclophosphamide / ifosfamide, etoposide)
D. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)
Explanation: The standard (MAP) regimen for osteosarcoma is high-dose methotrexate + doxorubicin (Adriamycin) + cisplatin, given perioperatively (before and after surgical resection). VAC (option A) is used for Wilms tumor and rhabdomyosarcoma. VDC/IE (option C) is the standard for Ewing sarcoma. ABVD (option D) is the standard for Hodgkin lymphoma. Cisplatin-based therapy with HD-MTX and doxorubicin is the defining feature that distinguishes osteosarcoma treatment from other bone tumors.
[/expand]A 12-year-old girl with osteosarcoma is receiving doxorubicin. Which monitoring parameter is MOST important to prevent a serious long-term complication?
A. CBC
B. Echocardiogram (LVEF)
C. LFTs
D. BUN/SCr
Explanation: Doxorubicin causes dose-dependent cardiomyopathy — the most serious long-term complication. Monitoring left ventricular ejection fraction (LVEF) via echocardiogram is required before and during anthracycline therapy. Per COG survivorship guidelines, patients with a cumulative doxorubicin dose ≥ 250 mg/m² require echocardiogram every 2 years. CBC (option A) monitors for myelosuppression but is not the most important long-term complication monitor. LFTs (option C) and BUN/SCr (option D) monitor for hepatotoxicity and nephrotoxicity — not the primary concern with doxorubicin.
[/expand]SM is a 12-year-old male with localized Ewing sarcoma confirmed by biopsy showing small, round, blue cells. Work-up is negative for metastases. Which treatment is most appropriate for SM?
A. VDC alternating with IE every 3 weeks
B. VDC alternating with IE every 2 weeks
C. VDC every 3 weeks followed by autologous stem cell transplant
D. Vincristine, topotecan, cyclophosphamide every 2 weeks followed by autologous stem cell transplant
Explanation: The standard of care for localized Ewing sarcoma is interval-compressed therapy — vincristine + doxorubicin + cyclophosphamide (VDC) alternating with ifosfamide + etoposide (IE) every 2 weeks (every 14 days), based on the AEWS0031 protocol, which demonstrated superior outcomes with interval compression. Every-3-week dosing (option A) was the older standard and is inferior to the compressed schedule. Autologous SCT (options C and D) is not standard for localized Ewing sarcoma. SM will also require local control with surgery and/or radiation therapy.
[/expand]A 7-year-old boy with Ewing sarcoma is receiving ifosfamide. Which monitoring is most critical?
A. Pulmonary function
B. Neurologic status + urinalysis (hemorrhagic cystitis)
C. Ophthalmologic exam
D. Serum uric acid
Explanation: Ifosfamide causes two key toxicities requiring active monitoring: hemorrhagic cystitis (via acrolein metabolite — prevented with mesna + hydration; monitored with urinalysis for blood) and encephalopathy (CNS toxicity requiring monitoring of neurologic status). Additionally, ifosfamide causes late renal toxicity requiring monitoring of BP, BUN, creatinine, and electrolytes. Pulmonary function (option A) is monitored for bleomycin (Hodgkin lymphoma) — not ifosfamide. Ophthalmologic exam (option C) is relevant for retinoblastoma and dinutuximab — not ifosfamide. Serum uric acid (option D) is monitored for TLS risk in Burkitt lymphoma and ALL.
[/expand]The standard regimen for rhabdomyosarcoma (VAC) includes vincristine, actinomycin D, and cyclophosphamide. Which adverse effect is MOST associated with cyclophosphamide at high doses?
A. Peripheral neuropathy
B. Hemorrhagic cystitis
C. Cardiotoxicity
D. Ototoxicity
Explanation: Cyclophosphamide (and ifosfamide) cause hemorrhagic cystitis through their common toxic metabolite acrolein, which is directly toxic to the bladder urothelium. Prevention requires mesna (binds and inactivates acrolein in the urinary tract) + IV hydration. Peripheral neuropathy (option A) is caused by vincristine. Cardiotoxicity (option C) is caused by anthracyclines (doxorubicin, daunorubicin). Ototoxicity (option D) is caused by cisplatin and high-dose carboplatin, especially in young children.
[/expand]Which supportive care intervention is critical with high-dose cyclophosphamide or ifosfamide?
A. Leucovorin rescue
B. Mesna + hydration
C. Dexrazoxane
D. Loperamide prophylaxis
Explanation: Mesna (2-mercaptoethane sulfonate sodium) binds and inactivates acrolein — the toxic metabolite of cyclophosphamide and ifosfamide — in the urinary tract, preventing hemorrhagic cystitis. IV hydration further dilutes and flushes the bladder. This combination is mandatory whenever high-dose cyclophosphamide or ifosfamide is administered. Leucovorin rescue (option A) is required for high-dose methotrexate, not cyclophosphamide. Dexrazoxane (option C) is a cardioprotectant used with high cumulative anthracycline doses. Loperamide (option D) manages diarrhea — not relevant to cyclophosphamide or ifosfamide toxicity.
[/expand]Which is the most common soft-tissue sarcoma in children?
A. Ewing sarcoma
B. Osteosarcoma
C. Rhabdomyosarcoma
D. Synovial sarcoma
Explanation: Rhabdomyosarcoma is the most common soft-tissue sarcoma in children, arising from skeletal muscle precursors. It occurs most commonly from birth to 10 years of age. The standard regimen is VAC (vincristine + actinomycin D + cyclophosphamide). Ewing sarcoma (option A) and osteosarcoma (option B) are bone tumors, not soft-tissue sarcomas. Synovial sarcoma (option D) is a soft-tissue sarcoma that occurs primarily in adolescents and young adults — it is far less common than rhabdomyosarcoma in the pediatric population.
[/expand]A 5-year-old with Burkitt lymphoma develops established tumor lysis syndrome. Labs: uric acid 11 mg/dL, K+ 6.2 mmol/L, Phos 7 mg/dL, Ca2+ 6.8 mg/dL. Which agent is most appropriate?
A. Allopurinol
B. Rasburicase
C. Febuxostat
D. Sodium bicarbonate
Explanation: Burkitt lymphoma has a cell doubling time of 24–48 hours making it one of the highest TLS-risk malignancies. This patient has ESTABLISHED TLS with significantly elevated uric acid (11 mg/dL), hyperkalemia, hyperphosphatemia, and hypocalcemia. Rasburicase directly breaks down existing uric acid into allantoin — providing rapid reduction of the elevated uric acid level. Allopurinol (option A) only prevents NEW uric acid production but does not lower already elevated levels — insufficient for established TLS with uric acid 11 mg/dL. Febuxostat (option C) is not widely used for pediatric TLS. Sodium bicarbonate (option D) is no longer recommended because the elevated phosphorus (7 mg/dL) creates significant risk of calcium-phosphate precipitation with alkalinization.
[/expand]RG is a 6-year-old male with Burkitt lymphoma. CSF evaluation is positive for disease; bone marrow is negative. What chemotherapy treatment is most appropriate for RG?
A. A single reduction course followed by four cycles of multi-agent chemotherapy
B. Two cycles of cyclophosphamide, vincristine, prednisone, and doxorubicin without an initial reduction course
C. A single reduction course followed by four cycles of multi-agent chemotherapy and maintenance therapy
D. High-dose methotrexate and high-dose cytarabine without maintenance therapy
Explanation: RG has CNS disease (positive CSF) — this classifies him as Group C or high risk. Group C therapy requires a single reduction course (COP — low-dose cyclophosphamide + vincristine + prednisone) first to reduce tumor burden and minimize TLS risk, followed by four cycles of escalated multi-agent chemotherapy including HD-MTX + HD-cytarabine + etoposide, AND a maintenance therapy phase. Group C patients differ from Group A/B patients who do NOT receive maintenance. Option A omits maintenance. Option B incorrectly skips the reduction course — very dangerous given the extremely high TLS risk in Burkitt lymphoma.
[/expand]JM is a 12-year-old female with Burkitt lymphoma (bone marrow and CNS negative) who begins reduction chemotherapy with COP. What is the goal of reduction chemotherapy in JM?
A. Decrease risk of complications from tumor lysis syndrome
B. Facilitate complete resection
C. Assess initial response to therapy for risk stratification
D. Curative therapy for low-risk disease
Explanation: Burkitt lymphoma has a cell doubling time of 24–48 hours, creating extremely high tumor burden and very high TLS risk. Reduction chemotherapy with COP (low-dose cyclophosphamide + vincristine + prednisone) is designed to incrementally reduce the high tumor burden before administering full-dose intensive induction chemotherapy. This gradual reduction minimizes the acute metabolic consequences of rapid tumor lysis when cytotoxic therapy begins. It is not for facilitating resection (option B) — Burkitt lymphoma is treated medically. It is not for risk stratification (option C). COP alone is not curative even for low-risk disease (option D).
[/expand]Which regimen is standard for Hodgkin lymphoma in pediatrics?
A. ABVD
B. VAC
C. VDC/IE
D. R-CHOP
Explanation: ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) ± radiation is the standard treatment for pediatric Hodgkin lymphoma. Long-term monitoring includes echocardiogram every 2 years if cumulative doxorubicin ≥ 250 mg/m², and pulmonary function tests for bleomycin-associated lung toxicity. Chest radiation increases the risk of secondary breast cancer and cardiac toxicity. VAC (option B) is for Wilms tumor and rhabdomyosarcoma. VDC/IE (option C) is for Ewing sarcoma. R-CHOP (option D) is for DLBCL.
[/expand]JM is a 34-year-old female Hodgkin lymphoma survivor treated at age 17 with ABVD and chest radiation. Her cumulative doxorubicin dose is 300 mg/m². How often should JM have an echocardiogram per COG Long-Term Follow-Up Guidelines?
A. Every year
B. Every 2 years
C. Every 3 years
D. Every 5 years
Explanation: Per COG Long-Term Follow-Up Guidelines, patients with a cumulative doxorubicin isotoxic equivalent dose ≥ 250 mg/m² require echocardiogram or MUGA every 2 years. JM received 300 mg/m² — exceeding the 250 mg/m² threshold — plus chest radiation, which further increases cardiac risk. Annual echocardiogram (option A) would be for higher-risk patients (e.g., very high cumulative doses or additional cardiac risk factors). Every 3 or 5 years (options C and D) are insufficient for a patient with this risk profile.
[/expand]Which of the following patients would be at highest risk for therapy-related ototoxicity based on the COG Long-Term Follow-Up Guidelines?
A. 18-year-old receiving cisplatin-based therapy for osteosarcoma
B. 2-year-old receiving cisplatin-based therapy for neuroblastoma
C. 30-year-old receiving cisplatin-based therapy for germ cell tumor
D. 5-year-old receiving non-myeloablative carboplatin for CNS tumor
Explanation: The two key risk factors for therapy-related ototoxicity are the chemotherapy agent (cisplatin > myeloablative carboplatin >> non-myeloablative carboplatin) and age ≤ 4 years at the time of treatment. A 2-year-old receiving cisplatin combines the most ototoxic agent with the highest-risk age group. The 18-year-old (option A) and 30-year-old (option C) receive cisplatin but are well above the high-risk age threshold of ≤ 4 years. The 5-year-old (option D) receives only non-myeloablative carboplatin — significantly lower ototoxicity risk, and is also above the ≤ 4 year age threshold.
[/expand]SECTION 5: ETHICS AND LEGAL PRINCIPLES
CONCEPTUAL SUMMARY
Informed Consent Principles: Grounded in three principles — justice, beneficence, and respect for autonomy. Clinical trial with direct patient benefit: one parent permission required; child assent NOT required. Clinical trial with NO direct benefit: assent from child ALSO required. Minor consent for sensitive care (STI treatment): NOT required by federal law — state laws vary (refer to Guttmacher Institute for state-specific information).
PRACTICE QUESTIONS — ETHICS AND LEGAL PRINCIPLES
AJ is a 12-year-old female with relapsed rhabdomyosarcoma. An investigational clinical trial is available that may provide direct benefit to AJ based on the genetic profile of her tumor. What consent from the family would be required to enroll AJ on study?
A. Assent from the child and permission from both parents
B. Assent from the child and permission from one parent
C. Permission from both parents
D. Permission from one parent
Explanation: AJ has the prospect of DIRECT patient benefit from this investigational agent, which is not available outside the clinical study. When a clinical trial offers the prospect of direct benefit, permission from ONE parent is required — and child assent is NOT required. If there were no prospect of direct benefit to AJ, then her assent (in addition to parental permission) would also be required. The three founding principles of informed consent are justice, beneficence, and respect for autonomy.
[/expand]You are a pharmacist serving on an investigational review board developing training modules on informed consent for clinical trial participants. In addition to justice, which of the following principles must be included in your educational module?
A. Beneficence and respect for autonomy
B. Judgment and respect for autonomy
C. Judgment and assent
D. Beneficence and assent
Explanation: The three founding principles of informed consent are justice, beneficence, and respect for autonomy. The educational module must include all three. Justice (already mentioned in the question), beneficence (doing good/acting in the patient's best interest), and respect for autonomy (patient's right to make informed decisions about their own care) together form the ethical foundation for clinical research participation. Judgment and assent (options B, C, D) are not among the three core informed consent principles.
[/expand]JJ is a 16-year-old female seeking treatment for a suspected sexually-transmitted infection but is concerned about her parents being informed. Which is the most appropriate reply when she asks if her parents must be notified?
A. Needed because JJ is under 18 years of age
B. Needed because JJ does not qualify for legal emancipation
C. Not needed due to the Mature Minor Doctrine
D. Not required by federal law, but check state laws for specific details
Explanation: Parental notification for minors seeking treatment for sexually-transmitted infections is NOT required by federal law. However, state laws vary significantly on this matter. For state-specific information on minor consent for medical care, the Guttmacher Institute (www.guttmacher.org) is the appropriate reference. Being under 18 (option A) does not automatically require parental notification for sensitive healthcare. Legal emancipation (option B) is one pathway but not the only pathway for minors to receive confidential care. The Mature Minor Doctrine (option C) exists in some states but is not a uniform nationwide standard.
[/expand]