Sisplatin

Clincal Effects:

CISPLATIN
  • USES: Cisplatin is a widely used anticancer agent. Most commonly, cisplatin is used to treat cancers of the testes, ovary, bladder, head and neck, esophagus, stomach, and lung. PHARMACOLOGY: Cisplatin binds to DNA bases, forming inter- and intra-strand crosslinks, which causes conformational changes, leading to DNA strand breaks and inhibiting DNA synthesis. TOXICOLOGY: An extension of therapeutic effects with inhibition of DNA synthesis affecting rapidly dividing cells first (eg, bone marrow, GI tract). EPIDEMIOLOGY: Inadvertent iatrogenic overdose has occurred, but is rare. OVERDOSE: Immediate effects (hours to days) include: severe nausea and vomiting and, less often, diarrhea. Early signs (within days) of toxicity are most commonly renal insufficiency and electrolyte abnormalities (hyponatremia, hypokalemia, hypomagnesemia, hypocalcemia). Ototoxicity (tinnitus, high-frequency deafness), peripheral neuropathy (mostly sensorineural), and bone marrow suppression are common, whereas retinopathy, seizures, hepatotoxicity, pancreatitis, respiratory failure, and overt encephalopathy are less often observed. ADVERSE EFFECTS: Adverse effects are expected with therapeutic doses. Nausea, vomiting, renal insufficiency (28% to 36%), electrolyte abnormalities, and neurotoxicity (peripheral neuropathy, mostly sensorineural) are the most often reported events. Nephrotoxicity is generally the dose-limiting effect. Hypersensitivity reactions may be observed in patients treated with more than 5 cycles of cisplatin therapy.

Range of Toxicity:

CISPLATIN
  • TOXICITY: Expect toxicity with therapeutic doses. Mild toxicity occurs with doses of 180 mg/m(2) or less, moderate toxicity may occur with doses of 180 to 300 mg/m(2), and severe toxicity has been reported with doses greater than 300 mg/m(2). Doses of 400 mg/m(2) are usually fatal. ADULT: Deaths have been reported with a total cisplatin dose of 640 mg over 4 days and 750 mg over 1 day. PEDIATRIC: A 3-year-old child died after receiving 400 mg/m(2). THERAPEUTIC DOSE: ADULT: 50 to 100 mg/m(2) IV as a single dose every 3 to 4 weeks. In earlier years, high-dose regimens involved using up to 200 mg/m(2) of cisplatin. PEDIATRIC: Cisplatin monotherapy, 80 mg/m(2), has been administered as a continuous 24-hr IV infusion every 14 days for 4 cycles in clinical trials.

Treatment:

CISPLATIN
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Aggressive IV fluid resuscitation with normal saline 3 to 6 L per day. Target urine output 1 to 3 mL/kg/hr. Avoid nephrotoxic drugs. Administer amifostine as soon as possible to prevent/limit nephrotoxicity (dose 910 mg/m(2) once daily as an intravenous infusion over 15 minutes). Treat nausea and vomiting with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, promethazine or prochlorperazine), corticosteroids (eg, dexamethasone), benzodiazepines (eg, lorazepam), 5-HT3 serotonin antagonists (eg, ondansetron, dolasetron, or granisetron), and/or antipsychotics (eg, haloperidol); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. Patients with severe neutropenia should be placed in protective isolation; administer granulocyte colony stimulating factor (filgrastim or sargramostim). Platelet and red cell transfusions may be necessary. MANAGEMENT OF SEVERE TOXICITY: Aggressive IV fluid resuscitation with normal saline 3 to 6 L per day. Target urine output 1 to 3 mL/kg/hr. Avoid nephrotoxic drugs. Administer amifostine as soon as possible to prevent/limit nephrotoxicity (dose 910 mg/m(2) once daily as an intravenous infusion over 15 minutes). Consider administration of sodium thiosulfate, ideally within 1 to 2 hours of overdose. In case of large overdoses, consider early plasmapheresis. Patients with severe neutropenia should be placed in protective isolation; administer granulocyte colony stimulating factor (filgrastim or sargramostim). Platelet and red cell transfusions may be necessary. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Administer high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, promethazine or prochlorperazine), corticosteroids (eg, dexamethasone), benzodiazepines (eg, lorazepam), 5-HT3 serotonin antagonists (eg, ondansetron, dolasetron, or granisetron), and/or antipsychotics (eg, haloperidol); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics.
  • Decontamination: PREHOSPITAL: Not helpful since overdose most often occurs by the intravenous route. HOSPITAL: Activated charcoal and/or gastric lavage are not helpful since overdose most often occurs by the intravenous route.
  • Airway management: Consider orotracheal intubation in patients with significant encephalopathy (ie, agitation, delirium), seizures, or respiratory failure.
  • Antidote: Amifostine reduces cisplatin-induced nephrotoxicity and neutropenia when administered prior to cisplatin therapy; there are no studies on its use after cisplatin overdose. However, if amifostine is being utilized as a remedy for cisplatin overdose, it should be administered as soon as possible after an overdose (dose 910 mg/m(2) once daily as an intravenous infusion over 15 minutes, optimal duration of therapy after overdose is not known). Sodium thiosulfate has been prophylactically administered in patients treated with cisplatin to prevent neurotoxicity and nephrotoxicity, and has been used in several cases of overdose. While there are no controlled studies of its use in overdose, sodium thiosulfate has limited toxic effects and it should be considered after significant overdose. It should ideally be administered within 1 to 2 hours of overdose, with a loading dose of 4 g sodium thiosulfate/m(2) intravenously over 15 minutes. This can be followed by an infusion of 12 g/m(2) over 6 hours or 2.7 g/m(2) per day in 3 divided doses. The optimal duration of therapy is not known. It is not known if administration of thiosulfate and amifostine is more beneficial than administration of amifostine alone.
  • Myelosuppression: Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
  • Neutropenia: Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
  • Febrile neutropenia: If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
  • Toxic nephropathy: Aggressive IV fluid resuscitation with normal saline 3 to 6 L per day. Target urine output 1 to 3 mL/kg/hr. Avoid nephrotoxic drugs. For prevention of cisplatin-induced nephrotoxicity, administer amifostine. The recommended dose is 910 mg/m(2) administered once daily as an intravenous infusion, over a 15-minute period.
  • Extravasation injury: If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Elevate the affected area. Apply ice packs for 15 to 20 minutes at least 4 times daily. Do not apply excessive cold to avoid tissue injury. Cold can cause local vasoconstriction and reduces fluid absorption. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy. DIMETHYL SULFOXIDE (DMSO): Treat site with topical DMSO (for a minimum of 7 days and maximum of 14 days); however, if blistering develops, discontinue DMSO and review site. SODIUM THIOSULFATE (SODIUM HYPOSULFITE): There are no clinical reports of the use of sodium thiosulfate following cisplatin extravasation. Its use for cisplatin extravasation is based on the ability of sodium thiosulfate to inactivate cisplatin. For extravasation of large amounts (greater than 20 mL) of highly concentrated (greater than 0.5 mg/mL solution) prepare a 0.17 moles/L solution by mixing 4 mL sodium thiosulfate 10% weight/volume with 6 mL sterile water for injection. Inject into extravasation site. Another source recommended the following dosing: inject 3 to 10 mL subQ into extravasation site.
  • Monitoring of patient: Monitor vital signs and mental status. Cisplatin plasma levels are not clinically useful or readily available. Closely monitor renal function, hepatic enzymes, and electrolytes. Monitor daily CBC with differential to detect bone marrow depression. Nadirs in circulating platelets and leukocytes typically occur between days 18 to 23 (range 7.5 to 45), with the majority of patients recovering by day 39 (range 13 to 62). Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract. Nerve conduction studies may be useful to evaluate neuropathy and audiometry to evaluate hearing loss.
  • Intrathecal injection: No clinical reports are available. The following information is derived from experience with other antineoplastic drugs. Keep patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free 0.9% saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hr). FFP (25 mL FFP/liter NS) or albumin 5% have also been used for perfusion; may be useful because of high protein binding of cisplatin. Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
  • Enhanced elimination procedure: Cisplatin is highly protein bound and can be removed by plasmapheresis. There is limited experience in the use of plasmapheresis after overdose, but it should be performed as soon as possible after significant overdose. The optimal volume, timing and duration of plasmapheresis is not known; monitor cisplatin concentrations, if possible, to guide therapy.
  • Patient disposition: HOME CRITERIA: There is no data to support home management. Patients with cisplatin overdose need to be admitted. OBSERVATION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), daily monitoring of CBC with differential until bone marrow suppression is resolved, and monitoring of serum electrolytes, renal function, and hepatic enzymes. CONSULT CRITERIA: Consult an oncologist, medical toxicologist, and/or a poison center for assistance in managing patients with cisplatin overdose. TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.