Oxaliplatin – Uses, Dosing, Administration, Side Effects

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Pharmacokinetics and Pharmacodynamics

  • 1,2-diamminocyclohexaneoxalato-platinum
  • Levels decrease in a triphasic fashion
    Terminal t1/2 = 27.3 hr
  • 85% Plasma Protein Binding (PPB) at 2-5 hours
  • Renal elimination predominantly, >50% of the drug is excreted through kidneys
  • No dose adjustment with a creatinine clearance > 20 ml/min

Cancer Types where Oxaliplatin is used (Indications)

  • Metastatic colorectal
  • Early-stage colon cancer
  • Metastatic pancreatic cancer
  • Metastatic gastro-esophageal cancer
  • Recurrent germ cell tumor

Cisplatin vs Oxaliplatin

  • FDA approved for colorectal cancer. Not been extensively studied in other malignancies
  • Cisplatin is effective in upper GI malignancy where as oxaliplatin is more effective in colorectal cancer
  • This difference is due to 1,2-diaminocyclohexane carrier ligand, which inhibits replicative bypass of platinum DNA adducts

Availability and Dosing

  • Available as 50- and 100-mg vials
  • It is a white crystalline powder
  • Administer in a 5% dextrose IV
  • Dosing – 85 mg/m2 q2weeks; 130 mg/m2 q3weeks
  • Although infusion can be done in 2 to 6 hours, 2 hours is most commonly used

Administration

  • Reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of water for Injection or 5% Dextrose
  • Further diluted in 250-500 mL of 5% Dextrose
  • RECONSTITUTION MUST NEVER BE DONE WITH NS / CHLORIDE-CONTAINING SOLUTIONS.
  • Reconstitution in normal saline leads to rapid inactivation to reactive compounds mono- and dichloroplatinum,
  • Diaquoplatinum also reacts with tissues causing neurotoxicity

Toxicity

Dose-Limiting

  • Peripheral sensory neuropathy- seen in 65%
  • In all DACH containing compounds
    • Acute dysesthesias – may be ameliorated by prolonging the infusion to 6 hours
    • Persistent peripheral neuropathy
  • Grade 2 or worse neuropathy seen in 40–50% , grade 3 neuropathy in 10–20% of patients

Common

  • Nausea and vomiting
  • Diarrhea
  • Myelosuppression

Oxaliplatin-Induced Neurotoxicity

Acute Neurotoxicity

  • Common (90% of patients)
  • May appear at first treatment cycle
  • Onset during or within hours to days
  • Transient, short lived, < 2 weeks
  • Cold-triggered or cold-aggravated
  • Dysesthesias and paresthesias of distal extremities, perioral, oral, and pharyngolaryngeal areas
  • Associated symptoms of muscular hyperactivity including jaw tightness, cramps, and fasciculations
  • Depending on dosing schedule (infusion rate)

Chronic Neurotoxicity

  • 10% to 15% – cumulative dose of 750 to 850 mg/m2
  • Not schedule-dependent
  • Symmetric dysesthesias , paresthesias persist between cycles
  • Progressive functional impairment: loss of fine sensorimotor coordination, sensory ataxia
  • Spares motor neurons (like cisplatin)
  • Lasts > 2 weeks
  • Partially reversible in about 80% and completely in about 40% at 6–8 months

Neurotoxicity – Mechanism

  • Acute neurotoxicity
    • Altering the current of voltage-gated Na(+) channels in response to oxalate
    • Oxalate may also interact indirectly with the voltage-gated Na(+) channels through chelation Ca and Mg
  • Chronic neurotoxicity
    • Dose-dependent accumulation of platinums in the DRG neuronal atrophy and apoptosis

Prevention

  • A stop-and-go approach with intermittent oxaliplatin dosing
  • Dose modification
  • The concurrent use of neuromodulatory agents
    • Calcium and magnesium infusions have been tried on the basis that they may bind to oxalate
    • Glutathione
    • N-acetyl cysteine
    • Glutamine
    • Oxcarbamazapine, carbamazapine
    • Xaliproden, gabapentin, pregabalin

Treatment

  • Venlafaxine tried in the treatment of acute OXIN
    • A randomized trial in patients with acute OXIN receiving FOLFOX for adjuvant or palliative treatment of colon cancer demonstrated a reduction in acute OXIN from 31.3% in the placebo arm vs 5.3% in the venlafaxine arm (P = 0.03)
    • Also there was a reduction in the incidence of chronic OXIN that was grade >2 from 33% in the placebo  vs 0% in the venlafaxine arm
  • Amitriptyline – nonsignificant trend to improvement

Supportive care

  • Prolonging the infusion time
  • Avoid cold temperatures
  • If exposure to cold temperatures cannot be avoided, such as use of the refrigerator, wear gloves during the exposure
  • Use face masks in cold weather
  • Use cotton socks, pot holders, rubber gloves for dish washing
  • Assess the water temperature in the home
  • Use moisturizer

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