C

Cisplatin

Trade Names
Cis-diamminedichloroplatinum, CDDP, Platinol
 

Classification
Platinum analog

Category
Chemotherapy drug

Drug Manufacturer
Bristol-Myers Squibb

Mechanism of Action
 

• Covalently binds to DNA with preferential binding to the N-7 position of guanine and adenine.
• Reacts with two different sites on DNA to produce cross-links, either intrastrand (> 90%) or interstrand (< 5%). Formation of DNA adducts results in inhibition of DNA synthesis and function as well as inhibition of transcription.
• Binding to nuclear and cytoplasmic proteins may result in cytotoxic effects.

Mechanism of Resistance
 

• Decreased drug accumulation due to alterations in cellular transport.
• Increased inactivation by thiol-containing proteins such as glutathione and glutathione-related enzymes.
• Increased DNA repair enzyme activity (e.g., ERCC-1).
• Deficiency in mismatch repair (MMR) enzymes (e.g., hMHL1, hMSH2).

Absorption
Not absorbed orally. Systemic absorption is rapid and complete after intraperitoneal (IP) administration.

Distribution
Widely distributed to all tissues with highest concentrations in the liver and kidneys. Less than 10% remaining in the plasma 1 hour after infusion.

Metabolism
Plasma concentrations of cisplatin decay rapidly, with a half-life of approximately 20–30 minutes following bolus administration. Within the cytoplasm of the cell, low concentrations of chloride (4 mM) favor the aquation reaction whereby the chloride atom is replaced by a water molecule, resulting in a highly reactive species. Platinum clearance from plasma proceeds slowly after the first 2 hours due to covalent binding with serum proteins, such as albumin, transferrin, and γ-globulin. Approximately 10%–40% of a given dose of cisplatin is excreted in the urine in 24 hours, with 35%–50% being excreted in the urine after 5 days of administration. Approximately 15% of the drug is excreted unchanged.

Indications
 

1. Testicular cancer.
2. Ovarian cancer.
3. Bladder cancer.
4. Head and neck cancer.
5. Esophageal cancer.
6. Small cell and non–small cell lung cancer.
7. Non-Hodgkin's lymphoma.
8. Trophoblastic neoplasms.

Dosage Range
 

1. Ovarian cancer: 75 mg/m² IV on day 1 every 21 days as part of the cisplatin/paclitaxel regimen, and 100 mg/m² on day 1 every 21 days as part of the cisplatin/cyclophosphamide regimen.
2. Testicular cancer: 20 mg/m² IV on days 1–5 every 21 days as part of the PEB regimen.
3. Non–small lung cancer: 60–100 mg/m² IV on day 1 every 21 days as part of the cisplatin/etoposide or cisplatin/gemcitabine regimens.
4. Head and neck cancer: 20 mg/m²/day IV continuous infusion for 4 days.

Drug Preparation
 

• Available in 10- and 50-mg vials for IV use.
• Add sterile water to give a final concentration of 1 mg/mL.
• Further dilute solution with 100–1,000 mL (depending on the specific regimen and schedule) with 0.9% sodium chloride. Cisplatin should never be mixed with 5% dextrose alone as this will lead to precipitate formation. Drug stability is maintained in 0.9% sodium chloride.
• Reconstituted solution should be kept at room temperature to prevent formation of precipitate. Stable for 24 hours at room temperature. Do not refrigerate reconstituted solution.
• Use immediately if mannitol is added to the solution.
• Also available as a premixed solution (Platinol-AQ) at a concentration of 1 mg/mL.

Drug Interaction 1
Phenytoin―Cisplatin decreases pharmacologic effect of phenytoin. For this reason, phenytoin dose may need to be increased with concurrent use with cisplatin.

Drug Interaction 2
Amifostine, mesna―Cisplatin is directly inactivated by amifostine and mesna.

Drug Interaction 3
Aminoglycosides, amphotericin B, other nephrotoxic agents―Increased renal toxicity with concurrent use of cisplatin and aminoglycosides, amphotericin B, and/or other nephrotoxic agents.

Drug Interaction 4
Etoposide, methotrexate, ifosfamide, bleomycin―Cisplatin reduces the renal clearance of etoposide, methotrexate, ifosfamide, and bleomycin, resulting in the increased accumulation of each of these drugs.

Drug Interaction 5
Etoposide―Cisplatin may enhance the antitumor activity of etoposide.

Drug Interaction 6
Radiation therapy―Cisplatin acts as a radiosensitizing agent.

Drug Interaction 7
Paclitaxel―Cisplatin should be administered after paclitaxel when cisplatin and paclitaxel are used in combination. This sequence prevents delayed paclitaxel excretion and increased host toxicity.

Drug Interaction 8
Aminoglycosides, furosemide―Risk of ototoxicity is increased when cisplatin is combined with aminoglycosides and loop diuretics such as furosemide.

Special Considerations
 

1. Contraindicated in patients with known hypersensitivity to cisplatin or other platinum analogs.
2. Use with caution in patients with abnormal renal function. Dose of drug must be reduced in the setting of renal dysfunction. Creatinine clearance should be obtained at baseline and before each cycle of therapy. Carefully monitor renal function (BUN and creatinine) as well as serum electrolytes (Na, Mg, Ca, K) during treatment.
3. Fluid status of patient is critical. Patients must be hydrated before, during, and post drug administration. Usual approach is to give at least 1 liter before and 1 liter post drug treatment of 0.9% sodium chloride with 20 mEq of KCl. With higher doses of drug, more aggressive hydration should be considered with at least 2 liters of fluid administered before drug. In this setting, urine output should be greater than 100 cc/hr. Furosemide diuresis may be used after every 2 liters of fluid.
4. Use with caution in patients with hearing impairment or pre-existing peripheral neuropathy. Baseline audiology exam and periodic evaluation during therapy are recommended to monitor the effects of drug on hearing. Contraindicated in patients with pre-existing hearing deficit.
5. Cisplatin is a potent emetogenic agent. Give antiemetic premedication to prevent cisplatin-induced nausea and vomiting. Prophylaxis against delayed emesis (> 24 hours after the drug administration) is also recommended. A combination of a 5-HT3 antagonist (ondansetron or granisetron) and dexamethasone is standard therapy for prevention of nausea and vomiting.
6. Avoid aluminum needles when administering the drug because precipitate may form, resulting in decreased potency.
7. Cisplatin is inactivated in the presence of alkaline solutions containing sodium bicarbonate.

Toxicity 1
Nephrotoxicity. Dose-limiting toxicity in up to 35%–40% of patients. Effects on renal function are dose-related and usually observed at 10–20 days after therapy. Generally reversible. Electrolyte abnormalities, mainly hypomagnesemia, hypocalcemia, and hypokalemia, are common. Hyperuricemia rarely occurs.
 

Toxicity 2
Nausea and vomiting. Two forms are observed: acute (within the first 24 hours) and delayed (> 24 hours). Early form begins within 1 hour of starting cisplatin therapy and may last for 8–12 hours. The delayed form can last for 3–5 days.
 

Toxicity 3
Myelosuppression. Occurs in 25%–30% of patients, with WBCs, platelets, and RBCs equally affected. Leukopenia and thrombocytopenia are more pronounced at higher doses. Coombs-positive hemolytic anemia, independent from myelosuppression, also observed.
 

Toxicity 4
Neurotoxicity. Dose-limiting toxicity, usually in the form of peripheral sensory neuropathy. Paresthesias and numbness in a classic "stocking-glove" pattern. Tends to occur after several cycles of therapy and risk increases with cumulative doses. Loss of motor function, focal encephalopathy, and seizures also observed. Neurologic effects may be irreversible.
 

Toxicity 5
Ototoxicity with high-frequency hearing loss and tinnitus.
 

Toxicity 6
Hypersensitivity reactions consisting of facial edema, wheezing, bronchospasm, and hypotension. Occur within a few minutes of drug administration.
 

Toxicity 7
Ocular toxicity manifested as optic neuritis, papilledema, and cerebral blindness. Altered color perception may be observed in rare cases.
 

Toxicity 8
Transient elevation in LFTs, mainly SGOT and serum bilirubin.
 

Toxicity 9
Metallic taste of foods and loss of appetite.
 

Toxicity 10
Vascular events, including myocardial infarction, arteritis, cerebrovascular accidents, and thrombotic microangiopathy. Raynaud's phenomenon has been reported.
 

Toxicity 11
Azoospermia, impotence, and sterility.
 

Toxicity 12
Alopecia.
 

Toxicity 13
Inappropriate secretion of antidiuretic hormone (SIADH).