ON_RC_2024_Peds_Handout_FINAL_(enduring_only).pdf

PEDIATRIC MALIGNANCIES AND SUPPORTIVE CARE Jennifer Young, PharmD, BCOP Clinical Pharmacy Specialist – Pediatric Hematology / Oncology Cincinnati Children’s Hospital Medical...

PEDIATRIC MALIGNANCIES AND SUPPORTIVE CARE Jennifer Young, PharmD, BCOP Clinical Pharmacy Specialist – Pediatric Hematology / Oncology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio LEARNING OBJECTIVES At the end of the presentation and after reviewing the accompanying reading materials, the participant should be able to: 1. Design an appropriate patient-specific treatment, supportive care, and monitoring plan taking into consideration efficacy and safety outcomes from clinical trials and current treatment guidelines for pediatric patients with cancer. 2. Assess the prognostic impact of relevant cancer-related molecular biology testing for a pediatric patient with cancer. 3. Discuss with a pediatric patient who has cancer and his or her caregiver the short- and long- term treatment goals, including post-therapy and survivorship. 4. Assess the regulatory, ethical, and patient rights issues related to conducting research, including informed consent and confidentiality. NOTE: This handout includes a discussion of the following pediatric disease-states: Acute Lymphoblastic Leukemia, Central Nervous System Tumors, Neuroblastoma, Non-Hodgkin Lymphoma (Burkitt), Wilms Tumor, Ewing Sarcoma, and Retinoblastoma. The following pediatric practice & supportive care topics will also be discussed: Febrile Neutropenia, Acute Chemotherapy-Induced Nausea and Vomiting, Pediatric Informed Consent, Compassionate Use and Pediatric Survivorship. ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 1  PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) Patient Case #1: SW is a 5-year-old female with intermittent fevers, vomiting, fatigue and inability to keep up in play with her brothers for the last week. On the morning of presentation, SW had one episode of blood-tinged emesis and coughed up a large clot which prompted her parents to bring SW to the emergency department. A CBC is obtained in the emergency department which reveals: Hb 5.4g/dL, PLT 21,000 cell/mm3, WBC 102,000 cells/m3 with 72% peripheral blasts. After a full evaluation and work-up, SW is diagnosed with precursor B-cell acute lymphoblastic leukemia. 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, calaspargase, and daunorubicin I. Risk Estimation1-5 NCI Risk Stratification of B-cell ALL6 Standard Risk High Risk Age 1–9.99 years Age < 1 year or ≥ 10 years AND OR Initial WBC < 50,000 cells/mm3 Initial WBC ≥ 50,000 cells/mm3 A. While still incorporating the NCI-risk stratification, pediatric research groups have further refined current strategies of risk-stratification to intensify therapy for those at high risk of relapse and avoid treatment-related toxicity in those with lower risk disease. B. Biological features refining clinical risk groups: 1. Immunophenotype a. Immunophenotypes: B-cell (85%) or T-cell (15%) b. T-cell ALL is a higher risk disease 2. Involvement of sanctuary sites – regions of the body where leukemia cells may be protected from effects of systemic chemotherapy; require site-specific treatment a. CNS Disease7,8 1) CNS 1 = absence of blasts in CSF, regardless of WBC count 2) CNS 2 = WBC in CSF < 5 cells/μl with CSF blasts on cytospin 3) CNS 3 = WBC in CSF ≥ 5 cells/μl with CSF blasts on cytospin or clinical symptoms (CNS 3 stratifies patients to high risk) b. Testicular Disease 1) Often stratifies patients to high-risk 3. Genetics9 ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 2  a. B-cell ALL: 1) Favorable: High hyperdiploidy (51-67 chromosomes), EVT6-RUNX1 fusion 2) Unfavorable: Hypodiploidy (< 44 chromosomes), KMT2A- rearrangement, BCR-ABL1 or BCR-ABL1-like, iAMP21, IKZF1 C. Steroid Pre-treatment 1. Definition = administration of more than 24 hours of systemic steroids within the 2 weeks prior to diagnosis 2. Steroid pre-treatment may cause the initial WBC to be falsely low, which limits the utility of the WBC in risk stratification. Since the presenting WBC is a component of initial risk stratification, steroid pre-treatment is criteria for up-stratification to high risk. D. Response to initial therapy 1. B-cell ALL a. Critical assessment point for B-cell patients is end of induction. Minimal residual disease (MRD) defined as < 0.01%. 2. T-cell ALL a. Critical assessment point for T-cell patients is end of consolidation rather than end of induction. Residual MRD > 0.1% at end of consolidation is classified as very high risk. General Features of Pediatric ALL Risk Groups10,11 Presence of ALL of the following: Age 1–9.99 years and initial WBC < 50,000 cells/mm3 No CNS-3 disease Low Risk No testicular involvement Presence of either double trisomies 4 and 10, or ETV6-RUNX1 Minimal residual disease (MRD) < 0.01% on day 8 and at the end of induction Age 1–9.99 years and initial WBC < 50,000 cells/mm3 with B-cell ALL not otherwise classified as Standard Risk low risk or high risk Presence of ANY of the following: Age < 1 year or ≥ 10 years Initial WBC > 50,000 cells/mm3 High Risk T-cell lineage ALL Steroid pre-treatment Presence of CNS-3 disease or testicular disease Patients may advance to high risk based on MRD > 0.01% at the end of induction Presence of ANY of the following: BCR-ABL Very High Risk KMT2A Hypodiploidy Patients may advance to very high risk if induction failure (>5% blasts at end of induction) Note: Risk stratification differs by research group/protocol ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 3 II. Treatment 12-16 A. Three phases of therapy are required (Induction, Consolidation/Post-Induction Intensive Chemotherapy, and Maintenance) Induction (4-6 week duration) Goal: Induce a complete morphologic remission 90-95% of patients will achieve first remission at end of induction17 Standard risk (3 drug induction): High risk (4 drug induction): Dexamethasone Dexamethasone (< 10 years) or prednisone (≥ Vincristine 1.5mg/m2 (max 2mg) weekly x 4 10 years) doses Vincristine 1.5mg/m2 (max 2mg) weekly x 4 Pegaspargase or calaspargase 2,500 units/m2 doses IM or IV x 1 dose Pegaspargase or calaspargase 2,500 units/m2 IM or IV x 1 dose Daunorubicin 25mg/m2 IV weekly x 2-4 doses Corticosteroid choice based on age for high risk patients14,18-23: Dexamethasone exhibits increased CNS penetration, more potent cytotoxicity against leukemia cells, prevention of CNS relapse, and improved EFS Dexamethasone also associated with increased bacterial / fungal infections and osteonecrosis in children ≥ 10 years of age Balance of risk vs benefit – patients < 10 years receive dexamethasone while patients ≥ 10 years receive prednisone Intrathecal (IT) therapy: IT agents: methotrexate, cytarabine, and/or hydrocortisone o Dosing is age-based, to approximate CSF volume Diagnostic LP with IT cytarabine given on or before day 1 of induction o Cytarabine drug of choice for diagnostic LP as it is active in both ALL and AML CNS-directed therapy is required for all patients to prevent CNS relapse, even in the absence of CNS disease at diagnosis End of Induction Disease Evaluation: Minimal Residual Disease (MRD) testing10 o Evaluated at the end of induction (day 29) o Remission defined as MRD ≤ 0.01% leukemic cells o MRD at end of induction (B-cell patients) is the strongest predictor of EFS and OS (more significant than WBC at diagnosis, age, genetic features, or early response to steroids)24-26 Consolidation / Interim Maintenance / Delayed Intensification Goal: Eliminate residual disease and eradicate or prevent CNS leukemia Total duration 6-9 months Consolidation (4-8 weeks): Combination chemotherapy incorporating vincristine and mercaptopurine (6-MP) Additional agents added in high risk groups (cyclophosphamide, cytarabine, pegaspargase or calaspargase) Note: T-cell ALL therapy is intensified with the addition of nelarabine during post-induction therapy. Residual MRD > 0.1% at end of consolidation is classified as very high risk for T-cell ALL. Interim Maintenance (8 weeks): Combination chemotherapy, often including IV methotrexate, vincristine, 6-MP and IT methotrexate Interim maintenance may be given once, or repeated after delayed intensification depending on the protocol ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 4  Methotrexate is key component of interim maintenance o Standard Risk ALL – escalating dose IV methotrexate (Capizzi methotrexate)27 o High / Very High Risk ALL – high dose methotrexate23 Delayed Intensification (8 weeks): Combination chemotherapy with cyclophosphamide, cytarabine, vincristine, pegaspargase or calaspargase, dexamethasone and 6-MP or thioguanine (6-TG) Addition of delayed intensification to ALL treatment regimen has significantly improved EFS Maintenance Goal: Ensure durable remission Total duration 2 years from the start of interim maintenance Standard backbone: Daily 6-mercaptopurine (6-MP) 75mg/m2/day PO Weekly methotrexate 20mg/m2 IV or PO Intermittent pulses of vincristine Intermittent pulses of corticosteroid PO Titration of oral chemotherapy: 6-MP and methotrexate doses are adjusted to maintain goal ANC 0.5 x 109/L to 1.5 x 109/L If excess myelosuppression (ANC < 0.5 x 109/L): o Hold both 6-MP and methotrexate until recovery, then restart at decreased dosing o For persistent neutropenia, consider checking thiopurine S-methyltransferase (TPMT) and nudix (nucleoside diphosphate linked moiety X)-type motif 15 (NUDT15) status if not already known If inadequate myelosuppression (ANC > 1.5 x 109/L): o If sustained for 6-8 weeks, increase 6-MP or methotrexate doses in alternating fashion by 25% with each adjustment o If both 6-MP and methotrexate are increased without a response in ANC, non-compliance should be considered o May consider sending 6-MP metabolites (6-TGN / 6-MMPN) Patient Case #1, Answer: Correct Answer: D. Dexamethasone, vincristine, calaspargase and daunorubicin SW is classified as high risk due to her presenting WBC of > 50,000 cells/mm3. High risk patients receive four drug induction with a corticosteroid, vincristine, calaspargase and daunorubicin. Dexamethasone is the preferred corticosteroid for patients younger than 10 years of age due to increased CNS penetration. Prednisone is the preferred corticosteroid for patients older than 10 years of age due to increased rates of osteonecrosis and fungal infections with dexamethasone. Calaspargase is used in place of pegaspargase in patients age of 21 years or younger. B. Additional treatment considerations: 1. Ph+ ALL patients will receive tyrosine kinase inhibitor (TKI) therapy (such as imatinib, dasatinib, or nilotinib) with more intensive combination chemotherapy a. Addition of TKI has improved EFS28 b. Encourage enrollment in a clinical trial ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 5  2. Calaspargase pegol-mknl (Asparlas®) a. Calaspargase pegol-mknl contains an asparaginase enzyme derived from Escherichia coli, as a conjugate of L-asparaginase and monomethoxypolyethlyene glycol with a succinimidyl carbonate linker. Calaspargase pegol-mknl differs from the previously available pegaspargase (Oncaspar®) product due to a more hydrolytically stable succinimidyl carbonate linker which results in a longer half-life and more prolonged duration of action b. Indications and dose: 1) For use as a component of multi-agent chemotherapy regimen for treatment of ALL in pediatric and young adult patients aged 1 month to 21 years 2) 2,500 units/m2 given IV no more frequently than every 21 days c. Toxicities: hypersensitivity reactions, pancreatitis, thrombosis, hemorrhage, hepatotoxicity, hyperglycemia d. Therapeutic drug monitoring: Serum asparaginase activity levels Patient Case #1, Continued – Question #2: SW tolerates induction therapy well with minimal residual disease on day 29 of < 0.01%. Her next phase of therapy is consolidation which includes mercaptopurine (6MP). The results of SW’s pharmacogenetic testing is below. TPMT *3A / *3A (poor metabolizer) NUDT15 *1A / *1A (normal metabolizer) Based on this information, what is the recommended starting dose for mercaptopurine (6MP) for SW? A. 6MP at standard dosing as no adjustment is required B. 6MP decreased to 50% dosing seven days per week C. 6MP decreased to 50% dosing three days per week D. 6MP decreased to 10% dosing three days per week III. Pharmacogenetic Considerations29 – TPMT and NUDT15 TPMT NUDT15 TPMT catabolizes 6-MP and thioguanine to inactive NUDT15 catalyzes the conversion of cytotoxic metabolites thioguanine triphosphate metabolites to the less toxic Inverse relationship between TPMT activity and thioguanine monophosphate active thioguanine nucleotide (TGN) metabolite Variants more common in those of Asian and accumulation in erythrocytes Hispanic descent Variants more common in those of Caucasian and African descent TPMT and NUDT15 results should be used in conjunction when both are available. Patients that are defined poor or intermediate metabolizers for either should be dosed per that enzyme’s recommendations. Patients that are intermediate metabolizers for both may require further dose reduction as compared to patients that are intermediate metabolizers for only one enzyme. Consider testing at diagnosis to have results available at time of thiopurine prescribing and administration. ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 6  Dosing Recommendations based on TPMT Genotype TPMT Genotype Activity Recommended Starting Dose Normal / High Activity Homozygous wild-type (90% of patients) Initiate normal starting dose “Normal metabolizer” Intermediate Activity Heterozygous (10% of patients) Initiate at 30-80% of full dose “Intermediate metabolizer” Low / Absent Activity Initiate at 10% of full dose and Homozygous deficient (0.3% of patients) administer 3 times per week “Poor metabolizer” Dosing Recommendations based on NUDT15 Genotype NUDT15 Genotype Activity Recommended Starting Dose Normal / High Activity Homozygous wild-type Initiate normal starting dose “Normal metabolizer” Intermediate Activity Heterozygous Initiate at 30-80% of full dose “Intermediate metabolizer” Low / Absent Activity 6-MP: 10 mg/m2/day Homozygous deficient “Poor metabolizer” 6-TG: 25% dosing IV. Relapsed ALL5,30 A. Approximately 15-20% of children with ALL will relapse B. Isolated BM relapse (50-60% of cases) C. Extramedullary relapse 1. Isolated – If < 5% leukemic cells in BM 2. Combined – If > 5% leukemic cells in BM 3. Most common sites of extramedullary relapse are CNS & testicles 4. Patients with t(1;19), large leukemic burden, T-lineage, and leukemic cells in the CSF at diagnosis are at increased risk of CNS relapse31 D. Prognostic factors5,30 1. Time to relapse a. Early: < 36 months after initial diagnosis for isolated or combined bone marrow relapse OR < 18 months from initial diagnosis for isolated extramedullary b. Late: ≥ 36 months after initial diagnosis for isolated or combined bone marrow relapse OR ≥ 18 months from initial diagnosis for isolated extramedullary relapse 2. Site of relapse a. Isolated extramedullary relapse and combined BM/extramedullary relapse both have better prognosis than isolated BM relapse ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 7  3. Immunophenotype a. T-cell accounts for ~15% of relapses E. Treatment of relapsed ALL 1. Re-induction therapy – may repeat original therapy if late BM relapse 2. Clinical trial or novel chemotherapy agent/regimen not already utilized 3. Targeted therapy a. Blinatumomab32 b. Tisagenlecleucel33 – FDA-indicated for relapsed (≥ second relapse) or refractory ALL in patients up to 25 years old 4. Cranial irradiation is utilized in CNS relapse 5. Allogeneic hematopoietic stem cell transplantation (HSCT)34 a. Allogeneic HSCT has been shown to improve survival in certain high-risk populations. No role for autologous transplant in pediatric ALL. F. ASTCT (American Society for Transplantation and Cellular Therapy) 2020 Recommendations for Role of Allogeneic HSCT in Pediatric ALL35,36: 1. Patients in first complete remission (CR1) a. Recommended if: primary induction failure with subsequent complete remission b. Consider if: T-ALL, hypodiploid ALL, persistent MRD positivity c. Ph+ ALL t(9;22): landscape is changing with use of intensive chemotherapy + TKIs; no clear advantage of early HSCT 2. Patients in second complete remission (CR2) a. Recommended if: Pre-B ALL with early BM relapse, T-ALL with BM relapse, or ALL with third or greater relapse b. Consider if: late BM relapse, persistent MRD positivity 3. Allogeneic HSCT is NOT recommended for patients who do not reach complete morphologic remission, as disease-free survival is 750 Given in 6-week cycles x 8 cycles Given in 6-week cycles x 8 cycles 3. Treatment for Children ≥3 years of age with High Risk50-52 a. Overall Strategy: Surgery + “Standard dose” RT + Chemotherapy -OR- High-dose Chemotherapy Plus Autologous Stem Cell Rescue 1) Treatment strategies vary, and enrollment in a clinical trial is advisable43 b. Surgery – Goal is gross total resection, if possible c. Radiation (Standard Dose) - Initiate after surgical resection d. Chemotherapy - Agents used to treat average risk disease are the same to treat high risk, but optimal regimen is still unknown ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 12 Treatment Regimen for Medulloblastoma – High Risk Children ≥ 3 Years Old During Radiation Therapy Vincristine 1.5 mg/m2 (max 2 mg) IV weekly x 6-8 weeks Starting 6-weeks After Completion of Radiation: Vincristine 1.5 mg/m2 IV weekly (max 2 mg) x 3 weeks Lomustine 100 mg/m2 PO on day 1 Prednisone Prednisone 40 mg/m2 PO x 14 days (VCP)51 Given as 6-week cycles x 8 cycles 1) High-dose chemotherapy plus autologous stem cell rescue53,54 a) Some studies have utilized high-dose chemotherapy (cisplatin, vincristine, high-dose cyclophosphamide) with autologous stem-cell rescue b) Tandem high-dose chemotherapy with thiotepa and autologous stem cell rescue followed by CSI has also been evaluated, with 5-year EFS = 72%54 4. Treatment of Children < 3 years of age a. Overall Strategy: Surgery + aggressive multi-agent adjuvant therapy ± autologous stem cell rescue. Therapeutic approaches attempt to delay or avoid the use of CSI due to adverse neurocognitive outcomes in this age group. b. Surgery - Gross total resection remains paramount, as local control with radiation is omitted. c. Chemotherapy 1) Various regimens: cyclophosphamide, etoposide, cisplatin and vincristine ± HDMTX ± intrathecal or intraventricular chemotherapy i. Relapsed Disease a. Prognosis is poor, with 5-year survival ~25% b. Local recurrence has more favorable outcomes than systemic recurrence c. In children < 3 years who did not receive initial RT, radiation is often used as salvage b. Prognosis41,53 a. 60%–80% survival is possible with aggressive surgery, radiation, and chemotherapy 1) Average-risk patients ≥ 3 years – EFS ~83% 2) High-risk patients ≥ 3 years – EFS ~70% 3) High-risk patients < 3 years – EFS ~57% ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 13  b. Patients with desmoplastic/nodular histology have superior prognosis c. Must consider adverse effects of aggressive treatment 1) Disease and treatment-related morbidity (physical, psychological, etc.) are often significant and often exceed that of other pediatric malignancies 2. Pediatric Diffuse High-Grade Glioma 1. Rare, biologically diverse group of tumors. In contrast to adult tumors, pediatric diffuse high- grade gliomas require molecular testing for diagnosis and optimal treatment. 2. Incidence 1.8 per 100,000 children and adolescents a. Aggressive tumors with poor prognosis, 5-year OS < 20% 3. Risk Factors: a. Inherited predispositions – Neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome, Lynch syndrome b. Prior exposure to cranial radiation 4. Treatment – may include surgery, radiation and chemotherapy a. Adjuvant therapy: Radiation therapy with concurrent temozolomide, adjuvant temozolomide and lomustine 1) For patients < 3 years of age – recommend chemotherapy only (without radiation due to significant long-term toxicities in younger age group) a) Cyclophosphamide + vincristine + cisplatin + etoposide b) Vincristine + carboplatin + temozolomide c) May consider targeted therapy b. Recurrent / progressive disease: targeted therapy 1) BRAF V600E mutated – dabrafenib + trametinib, or vemurafenib 2) TRK-fusion positive – Larotrectinib or entrectinib 3) Hypermutant tumor – nivolumab or pembrolizumab 3. Astrocytomas55-58 1. Slow growing, indolent brain tumors (WHO class I & II) that very rarely undergo malignant transformation a. This contrasts with adult low-grade gliomas which are more aggressive in nature 2. May be located anywhere in the CNS a. Cerebellum is most common location, followed by cerebrum, deep mid-line structures, optic pathway, and brain stem (discussed in the following section) b. Pilocytic astrocytoma is the most common pediatric low-grade glioma (LGG) 3. Treatment59 a. Surgery ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 14  1) Cornerstone of LGG treatment; gross total resection is achieved in 60–80% of surgeries, which is largely influenced by tumor location a) Cerebellar astrocytomas—often cured by surgical excision alone b) Supratentorial midline tumors—resection may not be possible 2) Management of incompletely resected tumors remains controversial a) Can use “watch and wait” approach if there are minimal symptoms, otherwise proceed to adjuvant therapies (below) b. Radiation 1) Indication is controversial due to known radiation toxicities; typically reserved for patients who progress after surgery or who are symptomatic 2) Avoid in children less than 5 years of age if possible due to adverse effects 3) Improves local control and decreases rate of recurrence, but no known impact on survival c. Chemotherapy60-63 1) Similar to radiation, chemotherapy is reserved for patients with progressive or symptomatic disease after surgical resection; often chemotherapy is used before resorting to cranial irradiation 2) Carboplatin + vincristine (CV) – most commonly used 1st line regimen a) Allergic reactions occur in 10–40% of children receiving frequent carboplatin (typically delayed, median 8th dose) i. Reactions vary: facial flushing, urticaria, agitation, abdominal pain, edema, and bronchospasm ii. Children with respiratory compromise should not be re- challenged. Some centers will cautiously re-challenge patients with grade 1-2 reactions or use desensitization protocols64 CV Regimen Induction Carboplatin 175 mg/m2 IV weekly x 4 weeks, then 2 weeks off, then weekly x 4 weeks Vincristine 1.5 mg/m2 (0.05 mg/kg if < 12 kg) IV weekly (max 2 mg) x 10 weeks (CV) Administered x 1 cycle Maintenance Carboplatin 175 mg/m2 IV weekly x 4 weeks Vincristine 1.5 mg/m2 (0.05 mg/kg if < 12 kg) IV weekly (max 2 mg) x 3 weeks (CV) Administered x 8 cycles 3) Multi-agent regimen TPCV (thioguanine, procarbazine, lomustine, and vincristine)60 TPCV Regimen ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 15  Thioguanine 30 mg/m2 PO every 6 hours 12 doses Days 0-2 Procarbazine 50 mg/m2 PO every 6 hours x 4 doses Days 2-3 Lomustine 110 mg/m2 PO x 1 Day 3 Vincristine 1.5 mg/m2 (0.05 mg/kg if < 12 kg) (max 2 mg) IV Day 14 & Day 28 (TPCV) Administered x 8 cycles a. Regimen may be selected by the clinician based on toxicity and patient factors – CV (hypersensitivity, peripheral neuropathy) or TPCV (infertility, secondary malignancy, peripheral neuropathy) b. Weekly vinblastine (6 mg/m2 with a maximum 10 mg/dose weekly for a total duration of 52 weeks) is an alternative for relapsed/refractory patients, or those with hypersensitivity to carboplatin65 B. Prognosis 1. Excellent long-term overall survival >85% 2. Low grade astrocytomas are often cured with surgical excision; overall 10-year survival rate of 69-100% with complete resection, 67-87% with incomplete resection, and 67- 94% with incomplete resection and RT 3. Recurrences of low-grade tumors are often manageable with surgery and/or local RT as recurrence is usually local Patient Case #2, Answer: Correct Answer: D: Risk of long-term neurocognitive toxicity RJ will not receive radiation therapy due to his age of < 3 years. He is considered high risk because of his age, despite having otherwise favorable risk factors ( 10 copies per diploid genome) is associated with advanced stage disease and a poor prognosis B. Chromosome 11q loss of heterozygosity 1. Present in 30-40% of patients 2. Predicts poor prognosis C. Chromosome 1p loss of heterozygosity or chromosome 17q gain are associated with a poor prognosis D. Tumor DNA content (ploidy) 1. Diploid (DNA index = 1) 2. Hyperdiploid (DNA index >1) = favorable prognostic indicator 3. Most useful as prognostic factor in locoregional disease E. Sporadic ALK oncogene mutations—gene involved in nervous system development ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 17 III. Treatment66,67 A. Modalities 1. Surgery68 a. Goals of surgery are to establish a diagnosis, excise tumor, determine degree of disease spread, and provide tissue for biologic testing b. Lymph node sampling is required c. Can be curative for localized disease d. Delayed primary (second look) surgery for high-risk patients is used to determine response and remove residual disease 2. Radiation a. Radiosensitive tumor, but often not curable with radiation alone due to presence of metastatic disease and limitations of radiation adverse effects b. May be used in oncologic emergencies (spinal cord compression or loss of vision) or as palliative treatment c. I-MIBG (metaiodobenzylguanidine) – Radio-conjugate therapeutic option for 131 patients with relapsed or refractory NB. 3. Chemotherapy a. Major treatment modality for patients with localized, unresectable disease or infants with disseminated disease b. Used in all but stage 1 or MS / 4S c. Older children with disseminated disease do not respond as well and are less likely to be cured with chemotherapy. d. Resistance to chemotherapy is a major barrier to improving survival in high-risk patients, leading to increasing regimen dose-intensity Neuroblastoma Disease Characteristics and Treatment Strategies by Risk Low Risk Intermediate Risk High Risk MS Localized tumor Localized tumor with Metastases to bone or Age < 18 months locoregional LN bone marrow Favorable histology involvement Liver, skin or bone MYCN amplification marrow metastases Hyperdiploidy No MYCN amplification Multimodal treatment Observation, likely to May be cured with Multimodal treatment (+immunotherapy) spontaneously regress surgery alone ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 18  B. Treatment of Low Risk Disease69 1. International Neuroblastoma Staging System (INSS) Stage 1 a. Surgery alone is highly effective initial therapy, with OS 99% b. Local recurrences can be managed with second surgery c. Metastatic recurrences salvageable with chemotherapy 2. INSS Stage 2 a. Surgery alone initial treatment of choice; 5-year OS 96% C. Treatment of Intermediate Risk Disease70 1. Heterogeneous group of patients a. Mainly very young patients with metastatic disease or patients of all ages with large, unresectable primary tumors b. Multimodal treatment, no standard chemotherapy regimen D. Treatment of High Risk Disease71 1. Low cure rate, aggressive therapy required 2. Induction – Induce maximum reduction in tumor bulk at primary and metastatic sites a. Cyclophosphamide / Doxorubicin / Vincristine + Cisplatin / Etoposide is a standard induction regimen example b. Dose-intensity is thought to overcome chemotherapy resistance c. Topotecan, an agent with activity in relapsed neuroblastoma, is now being incorporated in COG induction regimens Induction for High Risk Neuroblastoma72 Cycles 1, 2, 4, 6 Cyclophosphamide 2.1 gm/m2/day on days 1, 2 (with MESNA) Doxorubicin 25 mg/m2/day IV as continuous infusion Days 1-3 Vincristine 0.67 mg/m2/day IV as a bolus or continuous infusion Days 1-3 (CAV) (max of 2 mg over 72 hrs) Cycles 3 & 5 Cisplatin 50 mg/m2 IV Days 1-4 Etoposide 200 mg/m2 IV Days 1-3 (P-VP) 3. Local Control—Debulking of primary tumor a. Occurs after 4-6 cycles of induction chemotherapy – delayed surgery increases rates of complete resection b. Radiation therapy to eliminate local minimal residual disease after surgery ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 19  4. Consolidation—Eliminate resistant tumor clones a. Two consolidation modalities have been studied: 1) Intensive chemotherapy OR 2) Myeloablative chemotherapy with autologous stem cell rescue b. Based on growing body of supportive studies, tandem autologous stem cell transplant is the preferred strategy for consolidation in COG studies Patient Case #3, Answer: Correct Answer: C. Cyclophosphamide, doxorubicin, vincristine (CAV) alternating with cisplatin/etoposide (P- VP) plus local control with surgical resection and radiation therapy For the treatment of high-risk neuroblastoma, MB’s treatment should include Induction, Consolidation, and Maintenance phases. Induction will include chemotherapy such as CAV alternating with P-VP, plus local control with surgical resection and radiation therapy after hematopoietic stem cell transplant. Consolidation may include intensive chemotherapy or autologous transplantation. Based on the randomized clinical trial demonstrating improved overall survival, maintenance therapy should include anti-GD2 monoclonal antibody with GM-CSF, and isotretinoin. Patient Case #3, Continued – Question #2: MB has completed induction and consolidation therapy. He presents to clinic today to begin cycle 1 of maintenance immunotherapy with dinutuximab. Which of the following medication classes would be contraindicated concurrently with dinutuximab? A. Growth factors B. Corticosteroids C. Proton pump inhibitors D. NSAIDs 5. Maintenance therapy—Goal to eradicate any residual tumor, prevent relapse a. Isotretinoin 1) Induces cellular differentiation and decreases proliferation of neuroblastoma cells 2) Standard of care treatment for the last decade b. Immunotherapy73,74 1) Target: Glycolipid disialoganglioside (GD2), a surface glycolipid highly expressed by neuroblastomas (100%), gliomas, and some melanomas and sarcomas a) GD2 expression in healthy tissues is limited to melanocytes, neurons, and peripheral sensory nerve fibers – responsible for some of the classic adverse effects of GD2-targeted antibodies ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 20  2) Anti-GD2 antibody: Dinutuximab75 a) Indicated in combination with GM-CSF, IL-2 and isotretinoin for treatment of high-risk neuroblastoma patients with at least a partial response to upfront therapy i. Note: IL-2 removed from standard approach due to toxicity contribution without survival benefit76 b) Dose: 17.5 mg/m2/day IV infusion over 10 to 20 hours x 4 consecutive days for maximum of 5 cycles. Infusions should NOT last > 20 hours, even if the total dose has not been delivered. Dinutuximab Supportive Care75 Hydration Normal saline 10 mL/kg IV infusion one hour prior to dinutuximab Pre-medications as primary prophylaxis for hypersensitivity reactions Diphenhydramine (0.5 to 1 mg/kg; maximum dose 50 mg) or other antihistamine IV over 10 to 15 minutes starting 20 minutes prior to infusion and every 4 to 6 hours as tolerated during the infusion Acetaminophen (10 to 15 mg/kg; maximum dose 650 mg) 20 minutes prior to infusion and every 4 to 6 hours as needed for fever or pain Pain Opioid therapy – should be used prophylactically as continuous infusion with bolus PRN Consider adjunctive agents for neuropathic pain Miscellaneous Albumin repletion to maintain albumin ≥ 3.0gm/dL to decrease risk of capillary leak Patient Case #3, Answer: Correct Answer: B – Corticosteroids Corticosteroids are contraindicated during dinutuximab therapy. Dinutuximab is an immunotherapy treatment that harnesses the patient’s own immune system, including T-cells and natural killer cells, to induce destruction of GD2 expressing cells. Concurrent administration of corticosteroids would decrease the number and functionality of these effector cells, and thereby reduce the efficacy of dinutuximab. E. Treatment of Stage MS (also known as 4S)77 1. Criteria for MS classification: patient < 18 months, metastases limited to skin, liver and / or bone marrow (< 10% malignant cells in BM) 2. With favorable genetics (no MYCN amplification, no 11q aberration), most tumors spontaneously regress – observation is recommended a. If respiratory compromise or other signs of organ dysfunction become evident, moderately intensive chemotherapy is indicated b. RT should be reserved for life-threatening complications that progress despite chemotherapy ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 21  3. With unfavorable genetics (MYCN amplification or 11q aberration), patients should be treated as HR VI. Prognosis68,78 A. Positive prognostic factors 1. Younger age at diagnosis (< 18 months), locoregional disease, hyperdiploidy, favorable tumor histology, normal MYCN copy number, complete resection of primary tumor B. 5-year survival for infants is ~90% and ~55% for older children. It is important to note that newer treatment paradigms (especially immunotherapy) will likely improve these overall survival rates in the future C. Survival based on risk group 1. Low risk—95% 2. Intermediate risk—80-90% 3. High risk— < 50% ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 22  NON-HODGKIN LYMPHOMA I. Background/Overview79,80 A. Diverse collection of lymphomas B. In children, non-Hodgkin lymphoma (NHL) is distinct from that of adults 1. Adult lymphomas are more commonly low- or intermediate-grade 2. Pediatric NHL is typically high-grade a. Systemic disease with hematologic dissemination is similar to what is observed in leukemia (unlike Hodgkin lymphoma) C. If disease burden in the bone marrow is high, disease course and treatment is analogous to that of leukemia Classification of Non-Hodgkin Lymphomas Diffuse Large B-Cell Primary Mediastinal Anaplastic Large Cell Burkitt Lymphoma Lymphoma Large B-cell Lymphoma Lymphoma 40% childhood NHL 10% childhood NHL 2% childhood NHL 10% childhood NHL Treatment Short course and Treated with intensive Intensified Low-stage disease strategies intensive multi- therapies similar to chemotherapy, optimal treated with short agent Burkitt lymphoma first line therapy not course chemotherapy chemotherapy defined Advanced stage treated similar to Burkitt lymphoma / DLBCL Survival 5 year EFS > 80% 5 year EFS > 90% 5-year EFS > 80% 5 year EFS 60-70% II. Burkitt Lymphoma81 A. Genomics80 - Characteristic translocation of C-MYC oncogene with immunoglobulin production genes, most commonly t(8;14) B. Treatment Basics82-86 1. Very high risk for tumor lysis syndrome (see Acute Leukemias materials for more information on Tumor Lysis Syndrome) a. Rapidly growing tumor, cell doubling time 24-48 hours87 b. Reduction chemotherapy phase with low-dose cyclophosphamide, vincristine and prednisone is used for tumor de-bulking 1) Goal to decrease tumor burden by ~20%; mitigate risk of tumor lysis complications. Prophylactic rasburicase may be used prior to starting reduction therapy. ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 23  Patient Case #4: RG is a 6-year-old male presenting to the emergency department with intermittent vomiting and severe abdominal pain over the past month. A CT scan reveals an intraabdominal mass. RG is referred to a pediatric oncologist. Further work-up includes a biopsy of the mass which reveals small, non-cleaved cells. A PET scan identifies lymph nodes in the cervical region. RG is diagnosed with Burkitt lymphoma. CSF evaluation is positive for disease while bone marrow evaluation is negative for disease. What chemotherapy treatment is most appropriate for RG to receive at this time? 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. C. Early dose-intensity is critical – short term, multi-agent chemotherapy D. Radiation and / or surgery do not play a major role in management E. Toxicity remains a significant problem – renal failure, infections, and mucositis are the most common non-hematological toxicities F. CNS-directed therapy 1. Prophylaxis a. Combination of high-dose systemic therapy (methotrexate and cytarabine) and intrathecal therapy with methotrexate, hydrocortisone and cytarabine b. No current role for cranial radiation 2. Treatment of patients with CNS disease a. Require additional intensive chemotherapy cycles b. May benefit from higher doses of methotrexate c. CYVE courses add high-dose cytarabine ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 24 Summary of Treatment Regimens for Burkitt Lymphoma81,88,89 Group Characteristics Principles of Treatment Therapy (NOTE: Rituximab may be added in current protocols) Completely resected With only local control and no COPAD x 2 cycles (cyclophosphamide, stage I and systemic chemotherapy ≤ 20% of vincristine, prednisone, doxorubicin) Low Risk Group A abdominal stage II patients with localized disease will survive free of relapse90 No IT or HDMTX needed Multiple extra- Reduced-dose cyclophosphamide COP (cyclophosphamide, vincristine, Intermediate Risk abdominal sites and elimination of maintenance prednisone) COPADM x 2 cycles (cyclophosphamide, Group B Non-resected stage I is possible in selected patients vincristine, prednisone, doxorubicin, and II, III, IV (marrow based on FAB/LMB 96 study HDMTX) < 25% blasts, no CNS CYM x 2 cycles (cytarabine, HDMTX 3 g/m2) disease) > 25% blasts in Escalated dose of HDMTX and COP (cyclophosphamide, vincristine, marrow and / or CNS add high-dose cytarabine plus prednisone) disease etoposide COPADM x 2 cycles (cyclophosphamide, vincristine, prednisone, doxorubicin, High Risk Group C Includes maintenance HDMTX 8 g/m2) *higher dose MTX than Group B CYVE x 2 cycles (high-dose cytarabine, etoposide) Maintenance x 2-4 cycles Abbreviations: COP (cyclophosphamide, vincristine, prednisone) COPAD (cyclophosphamide, vincristine, prednisone, doxorubicin) COPADM (cyclophosphamide, vincristine, prednisone, doxorubicin, high-dose methotrexate) CYM (cytarabine, high-dose methotrexate) CYVE (high-dose cytarabine, etoposide) F. Treatment Response 1. Response at day 7 and after 2-3 courses of induction/consolidation chemotherapy are used for disease assessment based on LMB and BFM studies a. Response at day 7 after COP of < 20% tumor reduction is a poor prognostic factor b. Poor response or lack of CR after 2-3 cycles may result in intensification of therapy G. Rituximab91,92,93 1. Shown to be active in the management of adults with B-cell lymphoma and in some children with refractory or recurrent Burkitt lymphoma/B-ALL 2. BFM incorporated rituximab in a non-randomized window therapy, prior to the delivery of conventional chemotherapy and confirmed the activity of single agent rituximab in pediatric Burkitt lymphoma 3. Rituximab added to standard LBM backbone improved EFS (93.9% vs 82.3%) and OS (95.1% vs 87.3%)93 ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 25 Burkitt Lymphoma Group B Treatment Example86 Reduction (COP) Cyclophosphamide 300 mg/m2 IV x 1 Reduction of tumor bulk Vincristine 1 mg/m2 IV x 1 (max 2 mg) Permits management of Prednisone 60 mg/m2/day PO divided BID x 7 days metabolic complications Induction (COPADM) Cyclophosphamide 250 mg/m2/dose IV q12h x 6 doses Starts 1 week after COP Vincristine 2 mg/m2 IV x 1 (max 2 mg) begins (Day 8 of COP) Prednisone 60 mg/m2/day PO divided BID x 7 days, plus three day taper 2 courses Doxorubicin 60 mg/m2 IV after 1st dose of cyclophosphamide Methotrexate 3 gm/m2 IV over 3 hours with leucovorin rescue Consolidation (CYM) Cytarabine 100 mg/m2 IV as continuous infusion x 5 days 2 courses Methotrexate 3 gm/m2 IV over 3 hours with leucovorin rescue III. Relapse79,94,95 A. Relapses typically occur within 6 months to 1 year post-treatment B. Prognosis is dismal in light of the fact that aggressive initial therapy was already exhausted C. Multi-agent re-induction 1. ICE ± R96 (ifosfamide, carboplatin, etoposide ± rituximab) 2. DECAL (dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase) 3. DHAP (dexamethasone, high-dose cytarabine, cisplatin) 4. Novel targeted therapies (obinutuzumab, ibrutinib) +/- chemotherapy D. Autologous HSCT97-99 IV. Prognosis80,82,83,86 A. Advances in treatment strategies and molecular pathogenesis have increased event-free survival to >95% for low-risk (Group A) patients and >90% for higher-risk patients (Groups B & C). Patient Case #4, Answer: Correct Answer: C. A single reduction course followed by four cycles of multi-agent chemotherapy and maintenance therapy RG would be classified as group C or high risk due to the presence of CNS disease. Group C therapy includes an escalated dose of high-dose methotrexate and high-dose cytarabine plus etoposide when compared to Group B or intermediate risk therapy. Group C patients will also receive a maintenance phase of therapy which Group A and B patients do not. ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 26  WILMS TUMOR Patient Case #6: SC is a 3-year-old male who presents to his pediatrician with a mass noted by his parents during his nightly bath. The mass seems to be mobile, as it is not always in the same location in the abdomen. SC does not have pain when the parents palpate the mass. His parents also note mild hematuria the day prior to the office visit. On physical exam, SC is noted to be mildly hypertensive, and an ultrasound reveals an encapsulated mass arising from the left kidney. SC is diagnosed with unilateral Wilms tumor, stage I disease of favorable histology with loss of heterozygosity at chromosomes 1p and 16q. He is stratified as having standard-risk disease. Which of the following 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 I. Genomics100-103 A. Appears to result from functional loss of tumor suppressor genes, rather than activation of oncogenes B. WT1 tumor suppressor gene is required for normal renal and gonadal development 1. Deletion of WT1, isolated to chromosome 11p13 is present in 15-20% of patients C. Also associated with 1. Deletion of WT2, a chromosomal aberration at 11p15 2. Familial Wilms tumor loci (17q and 19q) 3. TP53 mutations D. NWTS-V study104 demonstrated that loss of heterozygosity (LOH) at both 16q and 1p in patients with favorable histology WT is an independent poor prognostic factor II. Prevention and Screening A. No established screening for general population B. Approximately 5% of Wilms tumors (WT) are associated with a pre-disposing genetic syndrome (>50 disorders have been implicated) 1. Genitourinary tract abnormalities (cryptorchidism, gonadal dysgenesis) 2. Congenital disorders (aniridia, hemihypertrophy) 3. Predisposing syndromes a. Beckwith-Wiedemann Syndrome (BWS) b. WAGR (Wilms, aniridia, genitourinary abnormalities, mental retardation) - > 50% risk of developing WT ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 27  c. Denys-Drash Syndrome - > 50% risk of developing WT d. National Cancer Institute recommends screening at least to the age of 7 in patients with genetic syndromes associated with increased risk III. Treatment105,106 A. Surgery107,108 1. May be performed up-front or after a few cycles of chemotherapy a. Rationale for up-front: unaltered histologic and biologic staging, including lymph node involvement (recommended by COG) b. Rationale for delayed: decreased risk of tumor rupture during surgery and lower post-operative staging (recommended by International Society of Pediatric Oncology - SIOP) 1) Tumor spillage results in required whole abdomen RT 2. Inspection of peritoneal surface, liver, and lymph nodes 3. Biopsy of any suspicious lesions + lymph node sample 4. Avoid capsular rupture & tumor spillage if surgery is delayed B. Radiation 1. Reserved for patients with stage III-IV disease, typically 1080 cGy to tumor bed 2. Whole abdomen RT is indicated when peritoneal seeding, spillage during surgery, or pre-operative rupture occurs 3. Patients with pulmonary metastases historically received whole lung irradiation a. Recent data suggest that chemotherapy and surgery may be sufficient, and that only patients with persistent or recurrent nodules need radiation109 4. If pulmonary or whole abdominal radiation is required to treat metastases, doses and timing of dactinomycin and doxorubicin should be adjusted per protocol to reduce the risk of radiation dermatitis/radiation recall C. Chemotherapy110-117 1. Chemotherapy is used for the majority of patients (excluding very low risk disease) a. Vincristine, dactinomycin, doxorubicin, and cyclophosphamide (added for higher risk patients) are the most active agents b. In relapse, ifosfamide, carboplatin, doxorubicin, and etoposide are utilized ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 28  D. Treatment by risk group according to NWTSG102,106,118,119 Very Low Risk Low Risk Standard Risk Higher Risk High Risk Patients with all of Favorable histology -LOH at Favorable histology Anaplastic histology the following: PLUS at least one of chromosomes 1p - Favorable the following: and 16q in patients -LOH at 1p/16q plus -Includes all histology -Age ≥ 2 years ³ 2 years of age with stage III/IV tumor patients with -Age < 2 years -Tumor weight ≥ otherwise favorable infiltration unfavorable-risk -Tumor < 550g 550g risk factors -Stage IV tumor histology tumors, -Stage II tumor -Patients with stage infiltration with a regardless of infiltration III tumor infiltration lack of rapid patient age / stage / with otherwise response of lung LOH favorable risk nodes to initial factors therapy Nephrectomy EE-4A regimen DD-4A regimen DD-4A x 2 cycles Treat per COG followed by (dactinomycin and (dactinomycin, with evaluation at AREN0321 observation vincristine) vincristine and week 6 doxorubicin) +/- -Patients with rapid -Patients receive No RT indicated local RT resolution of lung either DD-4A, nodules or no LOH Regimen I (Stage I/II tumor will receive a total 9 (cyclophosphamide, infiltration dose not cycles of DD-4A doxorubicin, receive RT, stage III -All other patients vincristine, tumors receive RT) escalated to etoposide) + RT, regimen M UH-1 (vincristine, (cyclophosphamide, dactinomycin, doxorubicin, doxorubicin with vincristine, addition of carboplatin, cyclophosphamide etoposide) + RT, and etoposide) for surgery alone or 11 cycles window chemotherapy ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 29 Wilms Tumor—EE-4A Regimen113 Dactinomycin 0.045mg/kg/dose IV (max dose 2.3mg) If > 30kg – 1.35mg/m2/dose IV (max dose 2.3mg) Given at weeks 0, 3, 6, 9, 12, 15, and 18 Total = 7 doses dactinomycin Vincristine Weeks 1-10 (given weekly x 10 doses): 0.05mg/kg/dose IV (max 2mg) - If > 30kg – 1.5mg/m2/dose IV (max 2mg) Begin day 7 after nephrectomy (week 1) if peristalsis has been established Weeks 12-18 (given weeks 12, 15, 18) 0.067mg/kg/dose IV (max 2mg) If > 30kg – 2 mg/m2/dose IV (max 2mg) Total = 3 doses vincristine Wilms Tumor—DD-4A Regimen113 Dactinomycin Weeks 1-25: Age < 1 year – Dactinomycin 0.023mg/kg/dose IV (max 2.3mg) Age ≥ 1 year – Dactinomycin 0.045mg/kg/dose IV (max 2.3mg) Given weeks 1, 7, 13, 19 and 25 Total = 5 doses dactinomycin Vincristine Weeks 1-12 (weekly x 10 doses): Age < 1 year – 0.025mg/kg/dose IV (max 2mg) Age 1 – 2.99 years – 0.05mg/kg/dose IV (max 2mg) Age ≥ 3 years – 1.5mg/m2/dose IV (max 2mg) Weeks 13-25 (every 3 weeks x 5 doses): Age < 1 year – 0.034mg/kg/dose IV (max 2mg) Age 1 – 2.99 years – 0.067mg/kg/dose IV (max 2mg) Age ≥ 3 years – 2mg/m2/dose IV (max 2mg) Total = 15 doses vincristine Doxorubicin Weeks 1-12 (given weeks 4 and 10): Age < 1 year – 1.5mg/kg/dose IV Age ≥ 1 year – 45mg/m2/dose IV Weeks 13-25 (given weeks 16 and 22): Age < 1 year – 1mg/kg/dose IV Age ≥ 1 year – 30mg/m2/dose IV Total = 4 doses doxorubicin ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 30  1. Bilateral Wilms Tumor a. Includes all patients with bilateral renal involvement (stage V disease), 10% of cases b. Treated according to COG AREN0534, which aims to improve renal-sparing surgery and decrease recurrence rates by administering doxorubicin in addition to vincristine and dactinomycin for 6-12 weeks, followed by nephron-sparing surgery, and lastly risk-stratified adjuvant chemotherapy IV. Prognosis102,103,106 A. Overall excellent prognosis 1. Localized disease OS = 90% 2. Metastatic disease OS = 75% B. Positive prognostic Factors 1. Favorable histology 2. Localized, unilateral disease C. Poor prognostic factors 1. Diffuse anaplasia histologic subtype 2. LOH at chromosomes 1p and 16q 3. Relapsed WT (including those with favorable histology) D. Late effects of WT remain problematic 1. At 25 years after diagnosis, 25% of WT survivors have a grade 3–4 chronic condition 2. Specific toxicities include doxorubicin-associated cardiac toxicity, pregnancy complications in women who received flank-irradiation, and secondary malignancies Patient Case #6, Answer: Correct Answer: C. Loss of heterozygosity at 1p and 16q This patient otherwise has favorable risk factors and would be classified as low risk, however the presence of loss of heterozygosity at both 1p and 16q define this patient as standard risk. Loss of heterozygosity at 1p and 16q is an independent poor prognostic factor. ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 31  EWING SARCOMA Patient Case #7: SM is a 12-year-old male who presents to his pediatrician with persistent pain of his right leg. His parents originally attributed it to playing sports, but it has continued over the past few months. The physician palpates a mass in the right leg and orders a MRI which confirms the mass. Tumor biopsy confirms small, round, blue cells, identified as Ewing sarcoma. Fortunately, SM’s work-up is negative for metastases. Based on this information, which of the following treatments is the most appropriate for SM? A. Vincristine, doxorubicin, cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) every 3 weeks B. Vincristine, doxorubicin, cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) every 2 weeks C. Vincristine, doxorubicin, cyclophosphamide (VDC) every 3 weeks followed by autologous stem cell transplant D. Vincristine, topotecan, cyclophosphamide every 2 weeks followed by autologous stem cell transplant I. Genomics120-122 A. t(11;22) is characteristic of the disease (85-95% of cases) and results in EWS-FLI1 gene fusion 1. t(11;22) diagnostic for Ewing Sarcoma (ES) 2. Tumors that lack this fusion usually have EWS gene joined to another related gene II. Treatment123-125 A. Treatment of Ewing Sarcoma (ES) includes a multidisciplinary team approach with goal to preserve as much function as possible while obtaining complete local control and treating/preventing metastatic disease with systemic therapy. 1. Surgery a. Surgery is a critical component of multi-modal therapy, and the preferred method of local control (if feasible) b. Historically radiation was preferred over surgery, but modern surgical techniques have increased limb-sparing surgeries and modern prosthetics have allowed for the resection of tumors involving essential bones c. Goal of surgery is complete resection with wide margins d. Tumor should be necrotic at the time of resection (due to neoadjuvant chemotherapy) 1) Persistence of > 10% viable tumor cells at resection is associated with poor prognosis e. During standard ES treatment, surgery is performed at week 13 2. Radiation a. ES is extremely radiosensitive, but use is limited by risk of radiation adverse effects such as secondary malignancy and local recurrence rates as high as 35% ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 32  b. Typically reserved for patients with unresectable tumors, incomplete resections, or those opposed to aggressive surgery c. Definitive radiotherapy involves 50-55 Gy to primary tumor with 2-cm margin, and should also include scars from surgery/biopsy 1) Radiation doses greater than 60 Gy have been associated with an excess in secondary sarcomas (20% incidence) d. There are no randomized trials of surgery vs. RT vs. surgery + RT; therefore, it is not known which modality of local control is superior. 3. Chemotherapy a. Neoadjuvant / adjuvant chemotherapy is standard of care for all patients, with or without measurable metastases 1) Subclinical metastases are assumed to be present in nearly all patients; adjuvant chemotherapy required Chemotherapy Evolution for Ewing Sarcoma IESS-I Indicated superiority of 4-drug VACD over 3-drug VAC Improved local control (96% vs 86%) and EFS (60% vs 24%) Demonstrated utility of doxorubicin à VACD became standard IESS-II High-dose intermittent VACD vs low-dose continuous VACD 5 year EFS improved with high dose intermittent VACD (77% vs 63%) INT-0091 Investigated ifosfamide + etoposide alternating with VACD 5 year EFS improved and overall survival (72% vs 61%) improved Marked decrease in local relapse led to improvement in outcome AEWS0031 Interval compression: VDC-IE every 2 weeks vs VDC-IE every 3 weeks Compression provided increased dose intensity with no increased toxicity Improved OS and EFS à VDC-IE every 2 weeks became standard *VACD = vincristine, dactinomycin, cyclophosphamide, doxorubicin; VAC = vincristine, dactinomycin, cyclophosphamide; VDC-IE = vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide Treatment of Localized Ewing Sarcoma: VDC-IE regimen126 Regimen Drug Dose Week of Administration Vincristine 1.5 mg/m2 IV (max 2 mg) on Day 1 1, 5, 9, 15, 19, 23, 27 VDC Doxorubicin 37.5 mg/m2 IV on Days 1 and 2 1, 5, 9, 15, 19 Cyclophosphamide 1.2 gm/m2 IV on Day 1 1, 5, 9, 15, 19, 23, 27 Alternating Every 2 Weeks with Ifosfamide 1.8 gm/m2 IV daily x 5 days with MESNA on Days 1-5 3, 7, 11, 17, 21, 25, 29 IE Etoposide 100 mg/m2 IV daily x 5 days on Days 1-5 3, 7, 11, 17, 21, 25, 29 2) Metastatic disease a) Currently no standard of care, but may include high-dose chemotherapy with autologous stem cell rescue ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 33 Patient Case #7, Answer: Correct Answer: B. Vincristine, doxorubicin, cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) every 2 weeks SM should be treated with interval-compressed therapy (every 14 days) based on the AEWS0031 protocol consisting of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide. SM will also require local control with surgery and/or radiation therapy. III. Prognosis125 A. The most important prognostic factor is extent of disease at diagnosis (presence or absence of metastases) 1. Localized disease at diagnosis – OS = 65-75% 2. Metastatic disease at diagnosis – 5-year OS < 30% a. Isolated pulmonary metastases have more favorable prognosis, 3-year OS up to 52% 3. Poor prognostic factors: a. Tumors of axial skeleton (reduced resectability) b. Large tumor size – primary tumor volume > 200mL or maximal diameter > 8cm c. Bone marrow involvement d. Poor histologic response to neoadjuvant chemotherapy e. Older age at diagnosis f. Fever at presentation g. Elevated LDH at presentation ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 34  RETINOBLASTOMA Patient Case #8: CH is a 2-year-old female who presents to the pediatrician with her mother, who states she is concerned about her daughter’s left eye. The mother says that when she takes flash photographs of the child, her left eye appears white, while her right eye appears red. CH is otherwise asymptomatic. The pediatrician notes no extra- ocular findings on exam and makes CH an appointment with an ophthalmologist for an eye exam under anesthesia. The pediatric oncologist completes CH’s diagnostic work-up and she is found to have unilateral retinoblastoma measuring 4 mm with vitreous seeding within 2 mm of the tumor (intraocular International Classification of Intraocular Retinoblastoma (ICIR) group C disease). Based on this information, which of the following is the most appropriate treatment for CH? A. Focal therapy only B. External beam radiation C. Vincristine, etoposide, and carboplatin x 2 cycles D. Focal therapy and vincristine, etoposide, and carboplatin x 6 cycles I. Genomics127,128 A. Familial tendency—Patients with germinal mutations have 45% chance of having a child with the disease; genetic counseling/testing is recommended B. Hereditary cases are associated with RB1 gene mutation at chromosome 13q14 1. First discovered tumor-suppressor gene 2. Autosomal dominant inheritance C. Two-Hit Hypothesis127 1. Two mutational events or “hits” produce malignancy a. Hereditary RB (40% of cases): a. Germ cell (RB1 gene mutation) + somatic cell mutation b. 85% develop bilateral disease; 15% develop unilateral disease b. Non-Hereditary / Sporadic RB (60% of cases): a. Somatic cell mutation + somatic cell mutation b. More than 99% develop unilateral disease; rarely bilateral II. Prevention and Screening129,130 A. At-risk children with a positive family history should undergo routine dilated funduscopic exams starting shortly after birth B. Frequency of exams is dependent on degree of risk and different algorithms have been proposed, but generally exams should occur monthly then gradually decrease in frequency, with screening lasting until at least 2-4 years of age ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 35 III. Treatment128,131-133 A. Treatment is individualized to preserve vision and maximize cure rates. Initial treatment strategies are defined by unilateral vs. bilateral involvement, disease extension (intraocular vs. extraocular), possibility of maintaining vision. B. Surgery 1. Enucleation (surgical removal of affected eye) is necessary in patients when preservation of vision is not possible, such as those with tumor invasion into the anterior chamber, those with secondary glaucoma, or tumors occupying >75% of the vitreous space. a. Now performed less frequently due to advancement of eye-sparing local and systemic treatments C. Focal therapy 1. Utilized for small tumors (< 3 - 6 mm) 2. Methods include: laser photocoagulation, cryotherapy 3. Thought to be synergistic with chemotherapy D. Radiation 1. Highly radiosensitive malignancy 2. Plaque RT/brachytherapy (focal radiation) a. Used for smaller tumors and for salvage b. Radioactive implant is placed on sclera at center of tumor c. Average treatment lasts 2-4 days 3. External beam radiation therapy (EBRT) a. Reserved for intraocular RB when conservative therapy has failed, for orbital disease, or for CNS/metastatic disease b. Associated with an increased risk of second cancers E. Periocular & Intraocular Chemotherapy 1. Provides high local drug concentration a. Chemotherapy distribution into the vitreous cavity is highly variable when given intravenously 2. Intravitreal or subtenon chemotherapy 3. Intra-arterial (IA) chemotherapy a. Local chemotherapy administration into ophthalmic artery via catheter placement in femoral or other artery b. Maximizes penetration to retina and vitreous space and increases rate of globe salvage, while mitigating systemic toxicities c. Most commonly used agents: melphalan, topotecan, carboplatin ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 36  d. Reported adverse effects include neutropenia, periocular edema, vasculopathy e. Overall, IA chemotherapy results in prevention of enucleation in 70-80% of eyes F. Systemic Chemotherapy 1. Indications a. Intraocular disease with high-risk features (optic nerve involvement, significant choroidal infiltration > 3 mm, or a combination of features such as involvement of uvea, anterior chambers, or optic nerve134) requires systemic chemotherapy. This may include ICIR (International Classification for Intraocular Retinoblastoma) Group B-C eyes and Group D-E eyes as a means to prevent enucleation. i. Patients who undergo enucleation and subsequent pathology reveals high-risk features also require systemic chemotherapy ii. Bilateral disease patients often receive systemic chemotherapy in an effort to preserve vision iii. ICIR Group A eyes do not require up-front systemic chemotherapy b. Extraocular disease requires systemic chemotherapy 2. Effective agents include: platinum compounds, etoposide, cyclophosphamide, doxorubicin, vincristine, and ifosfamide135-137 G. Treatment of Extraocular Disease 1. Orbital/locoregional disease138-140 a. Neoadjuvant chemotherapy, delayed enucleation, adjuvant chemotherapy and EBRT b. Regimens include vincristine, cisplatin, cyclophosphamide, doxorubicin, or etoposide split with 2-3 cycles before surgery and 4-6 cycles post-operatively c. Local control with EBRT (40-45 Gy) is a standard component of treatment d. Screening for metastatic disease is paramount, as 30-40% of patients with locoregional disease will present with distant metastases e. Cure can be achieved in up to 85% of patients 2. Metastatic, No CNS Involvement a. Very rare in developed countries b. Metastases may develop in the bone, bone marrow, and less commonly visceral organs c. Previously poor outcomes with standard-dose systemic chemotherapy, which has improved with the use of myeloablative regimens d. Induction chemotherapy such as vincristine, cisplatin, cyclophosphamide, etoposide e. Consolidation with high-dose chemotherapy with autologous stem cell rescue ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 37  i. Chemotherapy agents vary, inclusion of thiotepa is hypothesized as improving outcomes due to CNS penetration, but data are lacking f. Radiation therapy is sometimes used, not standardized 3. Metastatic, CNS Involvement a. Very rare in developed countries b. Platinum-based chemotherapy c. Prognosis is dismal IV. Prognosis17 A. Local control can be achieved in 70-80% of patients B. More than 90% of children survive retinoblastoma itself, but the incidence of a secondary malignancy is 3-6% 1. Frequently osteosarcoma within previous RT field C. Survival with useful vision decreases with higher intraocular staging 1. Visual acuity is dependent on tumor location, with greatest reduction in tumors involving the macula D. Metastatic disease is still associated with a poor prognosis ©2024 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved. 38 General Treatment Strategies for Retinoblastoma128,133,140,141 Treatment of Intraocular Disease Treatment of Extraocular Disease Orbital/ ICIR Group → A B C-D E Metastatic Locoregional Non-CNS CNS enucleation enucleation based on Focal based on yes yes Yes may be after start of intra- Therapy unavoidable chemotherapy intraocular ocular staging staging Intra-arterial only if consider as consider consider - - - Chemotherapy progression