Alkylating Agents

Mechanisms, toxicity profiles, and key clinical pearls

AUC = area under the curve  ·  BEP = bleomycin, etoposide, cisplatin  ·  CNS = central nervous system  ·  CYP = cytochrome P450  ·  GFR = glomerular filtration rate  ·  HSCT = hematopoietic stem cell transplantation  ·  MGMT = O6-methylguanine-DNA methyltransferase  ·  SOS = sinusoidal obstruction syndrome  ·  TMZ = temozolomide

Platinum Compounds: Key Differences
Feature Cisplatin Carboplatin Oxaliplatin
Dose-limiting toxicity Nephrotoxicity, ototoxicity Thrombocytopenia Cumulative neuropathy
Dosing method Body surface area (mg/m²) Calvert formula (target AUC × [GFR + 25]) Body surface area (mg/m²)
Cross-resistance Complete with carboplatin Complete with cisplatin Partial only
Key indication Testicular (BEP), chemoradiation Ovarian, lung (when cisplatin not tolerated) Colorectal (FOLFOX)
Cyclophosphamide & Ifosfamide: Activation and Toxicity
Prodrug Activation
Hepatic CYP2B6 Pathway
  • Cyclophosphamide/ifosfamide → hepatic CYP2B6 → 4-hydroxycyclophosphamide
  • Spontaneous decomposition → phosphoramide mustard (active) + acrolein (toxic)
  • Acrolein excreted in urine → urothelial injury → hemorrhagic cystitis
  • Prevention: mesna binds acrolein in bladder; forced hydration for standard-dose cyclophosphamide
Ifosfamide-Specific
Encephalopathy & Fanconi Syndrome
  • Side-chain oxidation → chloroacetaldehyde → CNS toxicity
  • Onset 12–48 h after infusion: confusion, ataxia, seizures
  • Treatment: methylene blue 50 mg IV every 4–8 h
  • Renal tubular toxicity → Fanconi syndrome (phosphate, bicarbonate, glucose wasting)
  • Mesna mandatory at all ifosfamide doses
CNS-Penetrating Alkylating Agents
Nitrosoureas
Carmustine & Lomustine
  • High lipophilicity → blood-brain barrier penetration
  • Indications: glioblastoma, CNS lymphoma
  • Nadir delayed: 4–6 weeks (not 10–14 days)
  • Cycle interval: every 6 weeks minimum
  • Carmustine cumulative risk: pulmonary fibrosis above 1,200 mg/m²
Oral Agent
Temozolomide
  • 100% oral bioavailability; CNS penetration ~30% of plasma
  • Methylates O6-guanine → mismatch repair-mediated apoptosis
  • MGMT methylated → responds; MGMT unmethylated → poor response
  • Stupp protocol: TMZ + radiation → adjuvant TMZ ×6
  • Prophylaxis: trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia
Transplant Conditioning
Busulfan
  • Myeloablative conditioning before HSCT
  • IV preferred (oral bioavailability 40–100%)
  • Therapeutic drug monitoring: target AUC 900–1,350 μmol·min/day
  • Serious risk: hepatic SOS (hepatomegaly, jaundice, ascites)
  • Treatment for severe SOS: defibrotide
Nitrosourea Scheduling Rule: 6-Week Minimum Interval
Lomustine and carmustine produce myelosuppression with a nadir at 4 to 6 weeks, not the 10 to 14 days typical of other cytotoxics. Applying a standard 3- or 4-week cycle interval results in administering the next dose before the nadir of the first, generating overlapping and potentially fatal cumulative myelosuppression. Always verify the 6-week cycle interval before prescribing any nitrosourea.