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Chapter 46: Comprehensive Pediatric Cancer Chemotherapy Notes

Chemotherapeutic Agents

• Two overarching classes
– Conventional cytotoxic drugs
* Cell–cycle–nonspecific: alkylators, platinums, most antitumor antibiotics (kill quiescent + cycling cells).
* Cell–cycle–specific: antimetabolites, tubulin poisons, topoisomerase inhibitors.
– Molecular-targeted agents (tyrosine-kinase inhibitors, mTOR inhibitors, antibodies, proteasome / HDAC / Hedgehog / Raf / FLT3 inhibitors, etc.).


• Table 46-1 summarises for each drug: mechanism, pediatric indications, route, elimination pathway, key enzymes/transporters, principal adverse effects.


• Selected mechanistic highlights
– Alkylators cross-link DNA (e.g.
* Mechlorethamine, melphalan, cyclophosphamide, ifosfamide).
– Antimetabolites mimic bases or folates (cytarabine, MTX, 6-MP, capecitabine …).
– Anthracyclines intercalate DNA and inhibit topo II (doxorubicin, daunorubicin).
– Tubulin interactive agents: vinca alkaloids (prevent polymerisation), taxanes (prevent depolymerisation).
– Topoisomerase-interactive: etoposide/teniposide (topo II), irinotecan/topotecan (topo I).
– Asparaginases deplete plasma asparagine → leukemic-cell starvation.
– Corticosteroids trigger receptor-mediated lympholysis.
– Retinoids & arsenic induce differentiation/apoptosis.
– TKIs block mutant or over-active kinases (ABL, Src, VEGFR, PDGFR, ALK, EGFR, BRAF).
– Biologics (rituximab, brentuximab vedotin, aldesleukin) exploit immune pathways.

Clinical Application of Chemotherapy

• Four roles

  1. Primary cytoreduction (curative for chemo-sensitive tumors: \text{ALL},\ \text{AML},\ \text{NHL},\ \text{HL},\ \text{GCT},\ \text{Wilms},\ \text{ERMS}).

  2. Adjuvant – eradicate occult micrometastases after surgery/radiation; has halved relapse rates in Wilms, Ewing, osteosarcoma, medulloblastoma.

  3. Neoadjuvant – shrink tumor pre-op (osteosarcoma, neuroblastoma, hepatoblastoma).

  4. Site-directed – drug into sanctuary sites (intrathecal for leukemia; arterial perfusion for extremity sarcoma/liver tumors/retinoblastoma).

Chemotherapy in Children

• Goal = deliver maximum tolerated dose (MTD) to maximise dose-intensity; narrow therapeutic index demands optimisation (Fig 46-1).
• Pediatric physiology differs → unique PK/PD & toxicity profile.
• Strategies to widen index
– Combination drugs with non-overlapping DLTs.
– “Rescue” (e.g.
leucovorin after MTX, stem-cell support after HDCT).
– Biologic modifiers to overcome resistance.
• Children often tolerate acute toxicity better (shorter neutropenia, mucositis) yet are more susceptible to certain late effects:
– Anthracycline cardiomyopathy, CNS cognitive sequelae, growth & fertility impairment.

Pharmacokinetic Changes During Childhood

Key PK parameters (Table 46-2)

T{1/2},\ AUC,\ F,\ Vd,\ C_{ss},\ Cl

Developmental alterations (Fig 46-2)

• Absorption
– Gastric pH neutral at birth → adult by ~2 yr.
– Low bile acids until \approx6\,\text{mo} → affects lipophilic drug micelles.
– Slow GI motility (< 8 mo).
– Enterocyte transporters mature post-natally (OATPs, PEPT1, ABCB1, etc.).
• Distribution
– Extracellular H$2$O =50\% body wt in preemies → 20\% in teens; ↑V$d$ for hydrophilic drugs in neonates.
– Body fat low at birth; diverges at puberty (♂↓, ♀↑).
– Protein binding low until 1–2 yr → ↑free fraction.
– BBB immature until ~3 yr.
• Metabolism
– CYP3A7 dominant fetus → falls after birth; CYP3A4/2D6/2C9 low then exceed adult levels between 2 wk–3 yr before normalising at puberty.
– Phase II glucuronidation only \sim30\% adult by 3 mo; adult by 6–12 mo.
• Excretion
– GFR \approx40\,\text{mL/min/1.73 m}^2 at term; adult by 6–12 mo.
– Tubular secretion/resorption mature 1–2 yr.
– Biliary excretion adult by 6 mo.

Drug Interactions

Combination Chemotherapy

• Selection criteria: single-agent activity, different MoA, non-cross-resistance, non-overlapping DLTs.
• Interactions can be synergistic, additive, antagonistic; influenced by sequence & schedule.

Coadministration of Non-anticancer Drugs

• CYP inducers (phenytoin, phenobarbital, rifampin, dexamethasone) ↓ AUC of CYP3A substrates.
• CYP inhibitors (azole antifungals, macrolides, aprepitant, valproate) ↑ toxicity risk (Fig 46-5).
• PPIs/antacids ↓ TKI absorption (dasatinib, nilotinib).
• NSAIDs, penicillins inhibit OAT1/3 → delayed MTX renal clearance.

Complementary & Alternative Medicine

• 31–84 % pediatric oncology pts use CAM; potential CYP / ABC modulation:
– Inducers: St John’s wort, melatonin, whey.
– Inhibitors: grapefruit juice, curcumin, goldenseal.
• Physicians must obtain CAM history; authoritative resources listed.

Pharmacogenetics & Genomics

Fundamental concepts

• SNP = base change ≥1 % population.
• HapMap & 1000 Genomes enable genome-wide SNP association.

Key pediatric examples (Table 46-4)

• Thiopurines:
– TPMT3A/3C/2 variants → low enzyme → neutropenia & >10\times TGN; dosage needs ↓ to 5!\text{–}!10\% (Figs 46-6,7). – PACSIN2 rs2413739 T lowers TPMT activity; ITPA rs41320251 ↑ toxicity when mercaptopurine dose TPMT-adjusted. • MTX pathway: SLC19A1 80A, DHFR 308A, TYMS 3/3, MTHFR 677T, SLCO1B1 rs4149056 influence EFS & toxicity; \text{AUC}_{48h}>0.9\,\mu M linked to mucositis. • Glucocorticoids: NR3C1 promoter SNPs, GSTM1/T1/P1 deletions relate to response, relapse, osteonecrosis (ACP1 rs12714403, TYMS/VDR/PAI-1 variants). • Asparaginase: ATF5 T1562C – worse EFS on E.coli enzyme; GRIA1 rs4958381 ↑ hypersensitivity. • Vincristine neuropathy: VDR intron 8 AA/AG, CYP3A5 expressers ↑ risk; PMP22 duplication catastrophic. • Anthracycline cardiotoxicity: CBR3 V244M GG ↑ risk even \le250\,\text{mg/m}^2 (Fig 46-9); SLC28A3 rs7853758 protective. • Cytarabine: SLC29A1 promoter haplotype ↑ hENT1; DCK –360G, CDA 79C/208A variants modify toxicity & outcome. • Platinum ototoxicity/neurotoxicity: ERCC2 751 G allele – poor response; GSTM3B protective hearing; TPMT rs12201199 & COMT rs9332377 predict loss; megalin rs2075252 risk.
• Irinotecan: UGT1A1*28 7/7 ↓ glucuronidation → toxicity at high-dose schedule.

Future

• Next-gen sequencing, tumor genome matching, integrated PK-PD-PG models → personalised dosing & targeted therapy.

New Drug Development

• Phases (Fig 46-12):
– I: 15–30 pts, define safety/MTD; pediatric starts ~80 % adult MTD; “rolling 6” design accelerates.
– II: < 100 pts, signal efficacy in given disease.
– III: randomised comparison; hundreds–thousands.
– IV: post-marketing surveillance.
• Preclinical models set target C{plasma} window; mouse LD${10}$ → start human at \approx0.1\times LD{10}. • Dose-escalation (3+3; modified Fibonacci) vs adaptive designs; MTD = dose with ≤1/6 DLT (Fig 46-13). • PK sampling in phase I defines C{max},\ T{1/2},\ AUC,\ Cl,\ Vd; guides later adaptive dosing.

Strategies to Improve Therapeutic Index (Table 46-6)

• BSA-based dosing remains pediatric standard; weight-based (<10 kg).
• Adjust for pathophysiology – CrCl-based carboplatin \text{Dose}(\text{mg})=\text{Target AUC}\times(\text{GFR}+25) (Calvert).
• Therapeutic drug monitoring (busulfan, MTX, 5-FU, etoposide, cisplatin).
• Feedback-controlled or Bayesian dosing (high-dose MTX).
• Chronotherapy: evening 6-MP, circadian-timed 5-FU, oxaliplatin, busulfan improve efficacy/toxicity.
• Biomodulation
– PK: CYP3A4 or ABCB1 inhibitors (ketoconazole, cyclosporin) ↑ oral bioavailability of etoposide/paclitaxel.
– PD: leucovorin (MTX/5-FU), amifostine (cisplatin), dexrazoxane (anthracycline), cefixime (irinotecan diarrhea).
• Schedule/sequence optimisation:
– MTX→5-FU synergistic; reverse antagonistic.
– Lestaurtinib after chemo antagonistic in MLL-r ALL; give chemo first.
– Fludarabine→cytarabine potentiates AML kill.

Conclusion & Perspectives

• Pediatric chemo now exploits integrated knowledge of
\text{PK}\,+\text{PD}\,+\text{PG}\,+\text{Development}.
• Genome sequencing + high-throughput screening → explosion of targeted agents; systems biology / modelling will guide truly individual therapy.
• Aim: maximise cure, minimise acute & late toxicity in children with cancer.