Generic Name

Oxaliplatin

Mechanism

• Oxaliplatin is a third‑generation platinum‑based alkylating agent.
• Once inside the cell, it undergoes hydrolysis to release the active chloro­platinum(II) dichloro­amine complex.
• The complex forms DNA cross‑links primarily at the N7 position of guanine, creating both intrastrand and interstrand cross‑links.
• These lesions stall replication forks and trigger apoptosis in rapidly dividing tumor cells, particularly colorectal carcinoma cells that are deficient in mismatch repair.
• Oxaliplatin’s unique diaminocyclohexane ligand gives it a distinct spectrum of activity and a different toxicity profile compared to cisplatin and carboplatin.

Pharmacokinetics

• Absorption: Administered IV; 100 % bioavailability.
• Distribution: Highly protein‑bound (~90 %), with a volume of distribution of ~0.4 L/kg.
• Metabolism: Non‑enzymatic hydrolysis to an active platinum species; no significant CYP involvement.
• Elimination: Primarily renal; ~85 % excreted unchanged in urine within 48 h.
• Half‑life: 9–10 h (initial) with a longer terminal phase of 60–70 h due to slow dissociation from plasma proteins.
• Renal impairment: Dose adjustment required; in creatinine clearance <30 mL/min, consider a 20–30 % dose reduction.

Indications

• Metastatic colorectal cancer (mCRC): First‑line therapy in combination with 5‑fluorouracil (5‑FU) and leucovorin (FOLFOX regimen).
• Adjuvant therapy for stage III colon cancer post‑resection, in combination with 5‑FU/leucovorin.
• Colorectal cancer in combination with capecitabine (CAPOX regimen).
• Other indications (off‑label): Some use in gastric, pancreatic, and small‑cell lung cancers when combined with 5‑FU.

Contraindications

• Hypersensitivity to oxaliplatin or any component.
• Pre‑existing peripheral neuropathy (grade ≥2).
• Severe renal impairment (CrCl <30 mL/min) without dose adjustment.
• Pregnancy: Category C; avoid if possible.
• Pediatric use not approved; data limited.
• Warnings:
• Acute peripheral neuropathy (transient cold‑induced).
• Ocular toxicity (dry eyes, conjunctivitis).
• Potential for interstitial lung disease (rare).
• Hemorrhagic cystitis uncommon but reported.

Dosing

• Infuse over 2 hours to reduce infusion‑related reactions.
• Use a dedicated infusion pump; avoid rapid bolus.

Adverse Effects

Common (≥10 %):
• *Peripheral neuropathy* (acute cold‑induced, chronic).
• *Myelosuppression* (neutropenia, anemia, thrombocytopenia).
• *Gastrointestinal*: nausea, vomiting, diarrhea, mucositis.
• *Fluid retention* (edema, ascites).
• *Dermatologic*: rash, alopecia.

Serious (≤1 %):
• *Severe neuropathy* (grade 3–4, irreversible).
• *Cardiotoxicity* (QT prolongation, arrhythmias).
• *Interstitial lung disease* (pneumonitis).
• *Severe allergic reactions* (anaphylaxis).
• *Renal toxicity* (rare, often reversible).

Monitoring

• Baseline & every cycle: CBC with differential, CMP (renal panel), electrolytes.
• Neuropathy assessment: Visual Analog Scale (VAS) or FACT‑GOG‑NTX questionnaire; document baseline sensory function.
• Renal function: Serum creatinine, CrCl; adjust dose as needed.
• Infusion reactions: Vital signs during first infusion; monitor for rash, pruritus, hypotension.
• Tumor response: Imaging (CT/MRI) every 2–3 cycles per RECIST criteria.
• Adjuvant use: Follow-up colonoscopy and surveillance labs per NCCN guidelines.

Clinical Pearls

• Ice‑Bag Protocol: Applying ice packs to extremities before and during infusion markedly reduces acute cold‑induced neuropathy without affecting systemic efficacy.
• Premedication Strategy: A short course of oral antihistamine (diphenhydramine 25 mg) plus a low‑dose steroid (dexamethasone 4 mg IV) before the first infusion can lower the risk of hypersensitivity reactions.
• Renal Dosing Simplification: In patients with CrCl 30–59 mL/min, a 30 % dose reduction is sufficient; no need for a 60 % cut if CrCl >30 mL/min.
• Combination Synergy: Oxaliplatin plus 5‑FU/leucovorin synergistically increases DNA cross‑linking, permitting lower doses of each agent while maintaining efficacy.
• Long‑Term Neuropathy Management: Early dose interruption at grade 2 neuropathy and dose re‑initiation at reduced level (70 mg/m²) can prevent progression to irreversible damage.
• Infusion Duration Matters: Administering over 2 hours rather than 1 hour reduces infusion‑related toxicity by ~25 %.
• Ocular Care: Patients should use preservative‑free artificial tears during and after treatment; refer to ophthalmology if vision changes occur.

Key Takeaway: Oxaliplatin remains a cornerstone of colorectal cancer therapy. Its distinct pharmacodynamics and manageable toxicity profile, when paired with proper premedication, infusion technique, and vigilant monitoring, allow clinicians to maximize therapeutic benefit while minimizing adverse effects.