Cisplatin – Uses, Dosing, Administration, Side Effects

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  • Non-classical, bifunctional alkylating agent
  • Cell cycle nonspecific
  • Cisplatin was first synthesised in 1844 by Peyrone
  • Biological activity first discovered in 1965 by Rosenberg in E.coli
  • Observed that current delivered between platinum electrodes inhibition of coli
  • Led to development of cisplatin in the 1970s, carboplatin in the1980s, oxaliplatin and satraplatin in the 1990’s

Difference between Cisplatin and Carboplatin?

  • Need for an esterase activity to release the carboxylato moiety of the carboplatin molecule.
  • Delayed time frame for the formation of the specific DNA adducts with Carboplatin.
  • Proportion of adducts same as cisplatin.

Difference between Cisplatin and Oxaliplatin?

  • The carrier ligand is different for both and that is responsible for the differences.
  • Differences in the rates of formation and repair of oxaliplatin-DNA damage.
  • The proportion of adducts with oxaliplatin are lesser than cisplatin.

What is the mechanism of resistance to Cisplatin?

  • Altered cellular accumulation of drug by Copper transporters
  • Cytosolic inactivation of drug – peptides with sulfhydryl groups covalently bind to platinums
  • Increased DNA repair BY Neucleotide Excision Repair (NER) pathway
  • Altered apoptotic process due to defects in Mismatch Repair (MMR)

Pharmacokinetics and Pharmacodynamics

  • Cisplatin is scientifically CDDP – cis– di chloro diammino platinum
  • > 90% is plasma protein binding (PPB) at 4 hours infusion
  • 25% of the drug is excreted during the first 24 hours
  • Excretion is renal > 90%, and bile < 10%
  • Extensive protein binding which causes accumulation in many tissues
  • The terminal half-life is 1 -5 days

Cancer Types where Cisplatin is used (Indications)

  • Germ cell tumors
  • Head and Neck SCC
  • Lung cancer
  • Ovarian Cancers
  • Lymphomas
  • GI Cancers
  • Pediatric tumors – Hepatoblastoma, Neuroblastoma, Medulloblastoma
  • Osteosarcoma
  • Bladder cancer

Availability and Dosing

  • Supplied as 10 and 50 mg vials
  • Clear, colorless, sterile aqueous solution
  • Dosing – as intravenous injection

40mg/m2 weekly (HNSCC)

20mg/m2 D1-5 Q 3w (GCT)

75mg/m2 Q 3-4 w (ovarian,NSCLC)

120mg/m2 (over3days) Q 3wkly (OS)

  • Intraperitoneal (IP) in ovarian cancer – 100-200 mg/m2

Intraperitoneal Cisplatin

  • Used in ovarian cancer after optimal cytoreductive surgery.
  • A single lumen catheter with a port –  IP access.
  • CDDP mixed in 1 L of NS and warmed to 37°C, infused through the port via gravity drip as rapidly as possible.
  • A 2nd litre of NS to help distribute the drug.
  • Complications – myelosuppression, emesis, neuropathy, abdominal discomfort, etc

Administration

  • Administered in normal saline
  • Rationale – the leaving group
    • In the Intracellular Fluid (ICF), Cl is lysed by H2O to form an aquo ligand which is a better leaving group- so CDDP gets activated in ICF
    • In saline solution, due to high Cl- content the CDDP is maintained in the same form without getting activated
  • Exclude Mg2+, Aluminum needles as they chemically neutralize the compound
  • Administered in 250 ml NS
  • Infusion duration – 1 to 4 hours
  • Potassium and magnesium are always to be added
  • Mannitol in doses > 40 mg/m2

Premedication

  • Aprepitant (ideal)
  • Dexamethasone
  • Palnosetron or Ondansetron
  • Dexamethasone for 2-3 days after administration ( delayed emesis)

Hydration

  • Both pre- and post infusion
  • Atleast 1 litre of NS
  • Essential because 50% reductions in renal clearance may occur in the absence of preinfusion and postinfusion hydration
  • Reductions in renal function are nonoliguric
  • The extent of damage may not be fully reflected by changes in serum creatinine

Toxicity

Nausea and vomiting

Cisplatin is highly emetogenic drug. Adequate antiemetic prophylaxis helps to prevent nausea and vomiting with the drug, in most of the cases.

Nephrotoxicity

It is 5% with and 25-45% without hydration, so hydration plays a major role in preventing it. Risk factors for it are female gender, older age, smoking, and hypoalbuminemia. It leads to Cation loss (Mg2+ Ca2+)  Recovery usually takes over 2–4 weeks, but rarely it could be protracted or may be irreversible.

Acute toxicity

It is seen in those who have not received adequate hydration. Azotemia and a rising serum creatinine due to early proximal tubular damage (within 1-3 hours) are an indicator of acute nephrotoxicity with cisplatin. Urinary beta-2 microglobulin is a sensitive laboratory indicator.

Chronic toxicity

It is uasually seen in those who have been cured or had a long term remission after CDDP. It is characterised by an irreversible decrease in GFR without changes in serum creatinine. Renal tubular damage is reflected by an increase in urinary excretion of enzymes and loss of Mg+ and potassium.

Methods to Minimise Nephrotoxicity

  • Vigorous intravenous hydration
  • Mannitol to enhance urine flow
  • Amifostine –  detoxifies reactive metabolites and ROS scavenger
  • N-acetyl cysteine

Amifostine use

  • A phase-III trial in ovarian cancer found that amifostine reduced the incidence of nephrotoxicity from 33 to 10 %
  • ASCO in 2002 stated that amifostine could be considered in repeated administrations of CDDP for ovarian/ NSCLC

Not recommended as –

  • Availability of newer regimens that use lower doses of cisplatin or substitute carboplatin for cisplatin
  • Significant toxicity (nausea, vomiting, hypotension)
  • Costs
  • Concerns about interference with the antitumor efficacy

Neurotoxicity

It is a Cumulative toxicity with cisplatin usually seen at doses > 200mg/m2. Incidence of cisplatin induced neurotoxicity is approximately 20-30%. The presence of other known risk factors for CIPN (e.g., alcohol consumption, diabetes, high serum creatinine levels, or age) do not influence the incidence and severity. Peripheral sensory neuropathy is more common than motor neuropathy. Some less common symptoms are visual disturbances, cortical blindness, seizures, papilledema, and retrobulbar neuritis. Although it is reversible in most patients, it can persist for years in around 20% of patients.

Neurotoxicity mechanism

  • Dorsal Root Ganglion (DRG) neuron apoptosis
  • Formation of platinum intra- strand adducts and inter-strand crosslinks and
  • Interaction with mitochondrial DNA leading to oxidative stress, causing increased activity of p53 and mitochondrial release of cytochrome-c pathway.

Ototoxicity

It is a cumulative toxicity of cisplatin, reaching 5% with doses above 100mg/m2. Higher frequencies are affected more commonly (4000 – 8000 Hz). Main mechanism is depletion of glutathione and antioxidant enzymes in the cochlea. At lower doses (50 mg/m2), the inner hair cells and at higher frequencies, outer hair ( 5-fold higher ) cells are lost. The factors that may increase the risk are concurrent use of ototoxic agents, previous cranial irradiation, preexisting renal dysfunction, older age, etc.

Other Side Effects

  • Myelosuppression – In most of the cases, it is trilineage myelosuppression. Seen in around 25-30% cases.
  • Arrythmias, acute ishaemic events, glucose intolerance, pancreatitis, hypersensitivity reactions, leukaemia.
  • Acute hypersensitivity reactions are rare and seen after the 6th cycle.

Dose modifications

  • Creatinine clearance 40-60 ml/min, reduce the dose to 50%
  • Contraindicated when CrCl <40 ml/min
  • Contraindicated in history of previous life threatening hypersensitivity reactions
  • Relatively contraindicated in documented hearing impairment
  • Pregnancy – category D and also to be avoided during lactation

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