Usage
Cisplatin is primarily prescribed for the treatment of various types of cancer, including:
- Metastatic testicular cancer: In combination with other chemotherapeutic agents, after surgery and/or radiotherapy.
- Metastatic ovarian cancer: As a single agent or in combination (e.g., with cyclophosphamide), after surgery and/or radiotherapy.
- Advanced bladder cancer: As a single agent, when local treatments are no longer viable.
- Other cancers: Cisplatin may be used off-label for other malignancies like osteogenic sarcoma, neuroblastoma, head and neck cancers, melanoma, anal cancer, and recurrent brain tumors.
Pharmacological Classification: Antineoplastic agent (alkylating agent).
Mechanism of Action: Cisplatin binds to DNA, forming intrastrand and interstrand crosslinks, which disrupts DNA replication and transcription, ultimately leading to cell death.
Alternate Names
International Nonproprietary Name (INN): Cisplatin
Brand Names: Platinol-AQ, CISplatin
How It Works
Pharmacodynamics: Cisplatin exerts its cytotoxic effects by binding to DNA and forming crosslinks that prevent DNA replication and transcription. This ultimately leads to cell cycle arrest and apoptosis (programmed cell death).
Pharmacokinetics:
- Absorption: Administered intravenously, therefore 100% bioavailable at the administered dose.
- Distribution: Widely distributed throughout the body, with high concentrations found in the kidneys, liver, and intestines.
- Metabolism: Minimal metabolism occurs.
- Elimination: Primarily eliminated by the kidneys through glomerular filtration and tubular secretion, with some biliary excretion. The elimination half-life is prolonged in patients with renal impairment.
Mode of Action: Cisplatin enters the cell and undergoes aquation, where chloride ligands are replaced by water molecules. This activated form binds to purine bases on DNA, primarily guanine, forming intrastrand and interstrand crosslinks. These crosslinks distort the DNA helix, inhibiting DNA replication and RNA transcription.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Cisplatin’s primary mechanism is DNA crosslinking. No significant receptor binding, enzyme inhibition, or neurotransmitter modulation is associated with its anticancer effects.
Elimination Pathways: Cisplatin is primarily eliminated by the kidneys via glomerular filtration and tubular secretion. A small amount is excreted in the bile.
Dosage
Cisplatin dosing is individualized and depends on the type of cancer, patient’s condition, and other concurrent treatments. It is crucial to calculate the dosage based on body surface area (mg/m²).
Standard Dosage
Adults:
- Testicular Cancer: 20 mg/m²/day IV for 5 days, repeated every 3-4 weeks, usually in combination with other chemotherapy.
- Ovarian Cancer: 75-100 mg/m² IV every 3-4 weeks in combination with other agents like cyclophosphamide (600 mg/m² administered sequentially). As a single agent, 100 mg/m² IV every 4 weeks.
- Bladder Cancer: 50-70 mg/m² IV every 3-4 weeks as a single agent. Initial dose of 50 mg/m² every 4 weeks for heavily pre-treated patients.
Children:
- Osteogenic Sarcoma/Neuroblastoma: 90 mg/m² IV every 3 weeks OR 30 mg/m² IV weekly (off-label).
- Recurrent Brain Tumors: 60 mg/m² IV daily for 2 days, repeated every 3-4 weeks (off-label).
- General Pediatric Considerations: Cisplatin dosing in children should be carefully determined by an experienced pediatric oncologist. Renal function and hearing should be closely monitored.
Special Cases:
- Elderly Patients: Dose reduction may be required due to age-related decline in renal function. Closer monitoring of renal function and other side effects is essential. Lower doses and more frequent administration may be considered.
- Patients with Renal Impairment: Cisplatin is contraindicated in patients with severe renal impairment. Dose adjustment is mandatory in patients with mild to moderate renal impairment, based on creatinine clearance.
- Patients with Hepatic Dysfunction: Caution is advised, and dose adjustments may be needed. Liver function tests should be monitored.
- Patients with Comorbid Conditions: Dosage modifications should be considered based on the specific comorbidity and its impact on drug clearance or toxicity.
Clinical Use Cases
Cisplatin administration is not typically indicated in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations outside of its oncological use. Its use is reserved for specific cancer treatment regimens.
Dosage Adjustments
Dosage adjustments are necessary for patients with renal impairment, hepatic dysfunction, and other comorbid conditions. Genetic polymorphisms affecting drug metabolism may also influence dosing.
Side Effects
Common Side Effects:
- Nausea and vomiting (can be severe)
- Fatigue
- Loss of appetite
- Hair loss
- Changes in taste
- Diarrhea
- Anemia
- Thrombocytopenia (low platelet count)
- Neutropenia (low neutrophil count)
- Renal impairment
Rare but Serious Side Effects:
- Anaphylaxis (severe allergic reaction)
- Ototoxicity (hearing loss, tinnitus)
- Peripheral neuropathy (numbness, tingling, pain in hands and feet)
- Severe myelosuppression (bone marrow suppression)
- Acute renal failure
- Seizures
- Electrolyte imbalances (hypomagnesemia, hypocalcemia, hypokalemia)
Long-Term Effects:
- Permanent hearing loss
- Chronic kidney disease
- Peripheral neuropathy
- Secondary malignancies (e.g., leukemia)
Adverse Drug Reactions (ADR):
Clinically significant ADRs include anaphylaxis, severe myelosuppression, acute renal failure, and ototoxicity.
Contraindications
- Pre-existing renal impairment
- Myelosuppression
- Hearing impairment
- History of allergic reactions to cisplatin or other platinum-containing compounds
- Pregnancy and breastfeeding
Drug Interactions
Cisplatin has numerous drug interactions. Some clinically significant ones include:
- Aminoglycosides: Increased risk of nephrotoxicity.
- Anticonvulsants (e.g., phenytoin): Reduced anticonvulsant levels.
- Loop Diuretics (e.g., furosemide): Increased risk of ototoxicity and nephrotoxicity.
- Nephrotoxic drugs (e.g., amphotericin B): Increased nephrotoxicity.
- Aluminum-containing IV sets or needles: Inactivation of cisplatin.
It’s vital to review a comprehensive drug interaction list before administering cisplatin.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Pregnancy Category D (cisplatin can cause fetal harm).
- Fetal Risks: Teratogenic effects, miscarriage, low birth weight, premature birth, and neonatal complications (e.g., respiratory distress, cytopenias, hearing loss).
- Breastfeeding: Cisplatin is contraindicated during breastfeeding as it is excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: DNA crosslinking agent that disrupts DNA replication and transcription, leading to cell death.
- Side Effects: Nausea, vomiting, fatigue, myelosuppression, nephrotoxicity, ototoxicity, neuropathy.
- Contraindications: Renal impairment, myelosuppression, hearing impairment, hypersensitivity to platinum compounds.
- Drug Interactions: Numerous interactions, including aminoglycosides, anticonvulsants, loop diuretics.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Dose varies depending on cancer type and patient condition, typically 20-100 mg/m² IV.
- Monitoring Parameters: Renal function (creatinine, BUN, creatinine clearance), complete blood count (CBC), hearing tests, electrolytes (magnesium, calcium, potassium).
Popular Combinations
Cisplatin is frequently used in combination regimens:
- Testicular Cancer: Bleomycin, etoposide, ifosfamide.
- Ovarian Cancer: Cyclophosphamide, paclitaxel, carboplatin.
- Bladder Cancer: Gemcitabine, methotrexate, vinblastine.
Precautions
- Pre-screening for renal function, hearing, and hematological status is essential.
- Adequate hydration before, during, and after administration is crucial to reduce nephrotoxicity.
- Monitor renal function, complete blood count, and hearing during treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Cisplatin?
A: Cisplatin dosing is individualized based on the type of cancer, patient’s condition, and other concurrent treatments. Dosage is calculated in mg/m², and guidelines vary depending on the cancer. It is administered intravenously.
Q2: How is Cisplatin administered?
A: Cisplatin is always administered as a slow intravenous infusion. Rapid intravenous injection should be avoided.
Q3: What are the major side effects of Cisplatin?
A: Nephrotoxicity, myelosuppression, ototoxicity, nausea, and vomiting are major side effects. Peripheral neuropathy and anaphylaxis are also possible.
Q4: What precautions should be taken before administering Cisplatin?
A: Patients should be well-hydrated before, during, and after administration. Baseline renal function, complete blood count, and hearing tests are essential.
Q5: Can Cisplatin be given to pregnant or breastfeeding women?
A: No, Cisplatin is contraindicated in pregnancy and breastfeeding due to the risk of fetal harm and excretion in breast milk.
Q6: What are the signs of Cisplatin-induced nephrotoxicity?
A: Decreased urine output, elevated creatinine and BUN, electrolyte imbalances, and fluid retention are signs of nephrotoxicity.
Q7: How is Cisplatin-induced nephrotoxicity managed?
A: Hydration, monitoring of renal function, and dose adjustment are important. In some cases, discontinuation of cisplatin may be necessary.
Q8: What are the key drug interactions with Cisplatin?
A: Aminoglycosides, loop diuretics, nephrotoxic agents, and anticonvulsants can interact with Cisplatin.
Q9: What should be monitored during Cisplatin treatment?
A: Renal function (creatinine, BUN, electrolytes), complete blood count (CBC), hearing function, and signs of allergic reactions or peripheral neuropathy should be closely monitored during treatment.
Q10: What is the mechanism of action of Cisplatin?
A: Cisplatin crosslinks DNA, leading to inhibition of DNA replication and transcription, and ultimately, cell death.
