Cisplatin (cisplatin)

Dosage of cisplatin must be based on the clinical, renal, hematologic, and otic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. The clinician should consult published protocols for the dosage of cisplatin and other chemotherapeutic agents and the method and sequence of administration. At the usual dosage, courses of cisplatin therapy should not be given more frequently than once every 3-4 weeks. A repeat course of cisplatin should not be administered until the patient's renal, hematologic, and otic functions are within acceptable limits, and precautions must always be taken to treat an anaphylactoid reaction if it occurs. (See Cautions: Precautions and Contraindications.)

Inadvertent substitution of cisplatin for carboplatin can result in potentially fatal overdosage. Therefore, care should be taken to ensure that such mix-ups do not occur. In addition, care should be taken to avoid prescribing practices by clinicians that fail to differentiate between daily doses of cisplatin and a total cisplatin dosage used in one course of therapy. To minimize the risk of overdosage, the manufacturer recommends that an alerting mechanism be instituted to verify any prescription or order for cisplatin doses exceeding 100 mg/m2 per course. IV dosages exceeding 100 mg/m2 per course once every 3-4 weeks are rarely used. Other safeguard procedures to minimize the risk of accidental overdosage of cisplatin (e.g., overdosage resulting from inadvertent administration of the drug when carboplatin was intended) also should be considered.

Because cisplatin is considered an antineoplastic agent of high emetic risk, antiemetic therapy for the prevention of acute and delayed emesis is recommended. (See Emetogenic Effects in Cautions: GI Effects.)

While some evidence indicates that dose intensity (i.e., amount of platinum per unit time) is an important factor in achieving optimum results in patients with stage III or IV ovarian carcinoma, other evidence suggests that total platinum dose or duration of exposure is a more important factor in improving progression-free survival in responding patients. However, no improvement in response appears to occur with increased dose intensity or increased total dose once a certain threshold is reached. Although optimum duration of chemotherapy has not been clearly defined, there currently is no evidence of improved response and/or survival when the duration of drug administration exceeds 6 cycles. Despite the fact that platinum-containing combination chemotherapy regimens are associated with high response rates, no regimen has been found that is sufficiently active to prevent disease progression and/or recurrence in most women with stage III or IV ovarian carcinoma.

Other therapeutic techniques, such as interval debulking surgery, may improve survival in patients with advanced ovarian carcinoma. In a randomized study involving patients with residual lesions (greater than 1 cm) following primary surgery for advanced ovarian cancer (stages IIB through IV) who responded to cisplatin-based induction chemotherapy, those who received interval debulking surgery accompanied by subsequent chemotherapy had improved survival compared with those who received chemotherapy alone.

The usual dosage schedule for the M-VAC regimen is a monthly cycle consisting of IV cisplatin 70 mg/m2 (administered on day 2), IV methotrexate 30 mg/m2 (administered on days 1, 15, and 22), IV vinblastine 3 mg/m2 (administered on days 2, 15, and 22), and IV doxorubicin 30 mg/m2 (administered on day 2).

Higher doses of cisplatin are administered in the CMV regimen. The usual dosage schedule for the CMV regimen is a 21-day cycle consisting of IV cisplatin 100 mg/m2 (administered on day 2), IV methotrexate 30 mg/m2 (administered on days 1 and 8), and IV vinblastine 4 mg/m2 (administered on days 1 and 8).

Escalated doses in the M-VAC regimen with concomitant administration of hematopoietic therapy (GM-CSF or G-CSF) have been used in patients with advanced urothelial carcinoma. In a randomized, phase III trial, a higher rate of complete response but no difference in overall survival was observed in patients receiving high-dose M-VAC with G-CSF versus classic M-VAC alone (without G-CSF) for advanced bladder cancer.

Treatment with cisplatin-based regimens should be discontinued if objective response is not observed following 2 or 3 cycles of therapy. Although the optimal duration of therapy has not been fully determined, some experts recommend 4-6 cycles of therapy as tolerated for patients showing clinical response; additional cycles of therapy do not appear to improve outcome. Surgical resection, when indicated, generally is considered after 4 cycles of therapy; additional cycles of chemotherapy following surgery have not been shown to provide benefit.

Administration of cisplatin in divided doses may be necessary in patients with renal impairment receiving cisplatin-based regimens for the treatment of advanced bladder cancer.

Cisplatin therapy is contraindicated in patients with preexisting renal impairment. Because cisplatin-induced renal toxicity may become more prolonged and severe with repeated doses of the drug, the manufacturer states that cisplatin therapy should be resumed only when the patient has recovered normal renal function. (See Cautions: Precautions and Contraindications.)

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There are no severe contraindications for this drug.

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Cisplatin and/or its platinum-containing products appear to cross the placenta. Cisplatin may cause fetal harm when administered to a pregnant woman, but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus. Cisplatin has been shown to be teratogenic in mice and embryotoxic in mice and rats. Cisplatin should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant during the period in which they are receiving cisplatin therapy.

Cisplatin is distributed into milk. Because of the potential for serious adverse reactions to cisplatin in nursing infants, nursing should not be undertaken by women receiving the drug.

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