Cisplatin (Platinol)

Mechanism of Action

Cisplatin is a platinum-containing compound that works similarly to alkylating agents:

How Cisplatin Works

1. Cellular Uptake: Enters cells through passive diffusion and active transport
2. Activation: Inside cell, chloride atoms are displaced by water molecules (aquation), creating reactive species
3. DNA Binding: Platinum atom forms covalent bonds with DNA, primarily at guanine bases
4. Cross-Linking: Creates both intrastrand (within same DNA strand, 90%) and interstrand (between strands, 10%) cross-links
5. DNA Damage: Cross-links distort DNA structure, preventing replication and transcription
6. Cell Death: Triggers apoptosis (programmed cell death) when damage cannot be repaired

Cell Cycle Activity

• Cell cycle non-specific: Can kill cells in any phase of cell cycle
• Most effective: Against rapidly dividing cells
• Affects normal cells too: Especially bone marrow, GI tract, hair follicles, kidneys

Approved Uses

Cisplatin is FDA-approved for several cancers and used off-label for many others:

FDA-Approved Indications

1. Testicular Cancer

• Curative regimen: BEP (bleomycin, etoposide, cisplatin) or EP (etoposide, cisplatin)
• Cure rates: >95% for good-risk disease, 80-90% for intermediate-risk, 50-70% for poor-risk
• Standard dose: 20 mg/m² daily × 5 days every 3 weeks
• One of oncology's greatest success stories: Transformed from fatal to curable

2. Ovarian Cancer

• First-line: Historically cisplatin + paclitaxel (now largely replaced by carboplatin)
• Dose: 75 mg/m² every 3 weeks
• Note: Carboplatin preferred due to similar efficacy with less toxicity

3. Bladder Cancer (Advanced)

• Metastatic disease: MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) or GC (gemcitabine, cisplatin)
• Neoadjuvant: Before cystectomy for muscle-invasive disease
• Dose: 70 mg/m² day 1 every 3-4 weeks (GC regimen)

Common Off-Label Uses

1. Non-Small Cell Lung Cancer (NSCLC)

• Combined with: Etoposide, gemcitabine, vinorelbine, or pemetrexed
• Dose: 75-100 mg/m² every 3-4 weeks
• Note: Carboplatin often substituted for better tolerability

2. Head and Neck Cancer

• Definitive chemoradiation: Cisplatin 100 mg/m² every 3 weeks × 3 doses concurrent with radiation
• Alternative: Weekly cisplatin 40 mg/m² during radiation (better tolerated)
• Induction: TPF (docetaxel, cisplatin, 5-FU) before chemoradiation or surgery
• Most common platinum for this indication (carboplatin less effective)

3. Esophageal and Gastric Cancer

• Neoadjuvant/perioperative: Combined with 5-FU or capecitabine
• Definitive chemoradiation: Cisplatin + 5-FU
• Palliative: Multiple combination options

4. Cervical Cancer

• Concurrent with radiation: Weekly cisplatin 40 mg/m² (standard radiosensitizer)
• Metastatic: Cisplatin + paclitaxel + bevacizumab

5. Pancreatic Cancer

• Borderline resectable: Neoadjuvant chemotherapy
• Locally advanced: Chemoradiation

6. Anal Cancer

• Definitive chemoradiation: 5-FU + mitomycin C, or 5-FU + cisplatin

7. Mesothelioma

• Combined with pemetrexed: Standard first-line

Dosing and Administration

Cisplatin dosing varies widely by indication, regimen, and patient factors.

Standard Dosing Regimens

High-Dose Every 3-4 Weeks

• Dose: 50-100 mg/m² IV every 3-4 weeks
• Uses: Testicular cancer, ovarian cancer, bladder cancer, NSCLC
• Maximum single dose: Generally capped at 150-200 mg total
• Requires: Aggressive hydration, overnight hospital stay often needed

Moderate-Dose Every 3 Weeks (with Radiation)

• Dose: 100 mg/m² IV every 3 weeks × 3 cycles
• Uses: Head/neck cancer, cervical cancer (concurrent with radiation)
• Administration: Given on days 1, 22, and 43 of radiation therapy

Weekly Low-Dose (with Radiation)

• Dose: 30-40 mg/m² IV weekly during radiation therapy
• Uses: Alternative to every-3-week dosing for head/neck, cervical, esophageal cancer
• Advantages: Better tolerated, fewer hospitalizations, similar efficacy
• Duration: 6-7 weeks typically

Daily × 5 Days

• Dose: 15-20 mg/m² IV daily for 5 consecutive days
• Uses: Testicular cancer (BEP or EP regimen)
• Repeated: Every 3 weeks for 3-4 cycles
• Total per cycle: 75-100 mg/m²

Dose Modifications

Renal Impairment (Most Important)

Cisplatin is nephrotoxic and renally excreted - dose must be adjusted for impaired kidney function:

Important: Measure creatinine clearance (not just serum creatinine) before EACH dose using Cockcroft-Gault equation or 24-hour urine collection.

Hearing Loss (Ototoxicity)

• Baseline audiogram abnormal: Consider alternative agent
• Develops during treatment: Reduce dose by 50% or discontinue
• Severe/symptomatic hearing loss: Discontinue permanently

Neuropathy

• Grade 2 (moderate): Reduce dose by 20-25%
• Grade 3-4 (severe): Discontinue cisplatin, consider carboplatin substitution

Myelosuppression

• ANC <1,500 or platelets <100,000: Delay treatment until recovery
• Severe or prolonged: Reduce subsequent doses by 20-25%

Administration Technique

Preparation

• Never use: Aluminum-containing needles or administration sets (aluminum inactivates cisplatin)
• Diluent: 0.9% sodium chloride (normal saline) or 0.9% NaCl + mannitol
• Concentration: Typically 0.5-1 mg/mL for infusion
• Stability: Stable for 20 hours at room temperature in saline
• Light sensitive: Protect from light during administration

Infusion

• Rate: Infuse over 2-6 hours (longer for higher doses)
• Do NOT give as IV push or rapid infusion: Increases nephrotoxicity
• Central line preferred: For high doses or frequent administration
• Peripheral line acceptable: For lower doses if adequate vein access
• Extravasation: Not a vesicant but can cause irritation

Cumulative Dose Limits

• No absolute maximum defined
• Ototoxicity and neuropathy: Cumulative and dose-related
• Generally: Monitor closely after cumulative dose >300-400 mg/m²
• In curable settings (testicular cancer): Give full doses despite cumulative toxicity
• In palliative settings: May switch to carboplatin at lower cumulative doses to preserve quality of life

Hydration Protocol

Aggressive IV hydration is MANDATORY to prevent nephrotoxicity. This is the most important intervention for reducing kidney damage.

Standard Hydration Regimen

Pre-Hydration (Before Cisplatin)

• Fluid: 0.9% sodium chloride (normal saline)
• Volume: 1-2 liters
• Timing: Infuse over 2-4 hours before cisplatin
• Goal: Ensure good urine output (>100 mL/hour) before starting cisplatin

During Cisplatin Infusion

• Cisplatin diluted in: 250-1000 mL normal saline (depending on dose)
• May add mannitol: 12.5-25 g to promote diuresis (optional, controversial benefit)

Post-Hydration (After Cisplatin)

• Fluid: 0.9% sodium chloride
• Volume: 1-2 liters
• Timing: Infuse over 2-4 hours after cisplatin completion
• May add: Potassium chloride and magnesium sulfate to replace losses

Total Hydration

• Total IV fluids: 2-4 liters (or more) over 8-12 hours
• Outpatient for low doses: Possible with abbreviated hydration
• Inpatient for high doses: Often requires overnight stay for adequate hydration and monitoring

Monitoring During Hydration

• Urine output: Monitor closely; goal >100-150 mL/hour
• Specific gravity: Maintain <1.010 (dilute urine)
• Electrolytes: Check before and after (especially magnesium, potassium, calcium)
• Weight: Daily weights if hospitalized
• Fluid overload: Monitor for signs (especially in patients with heart failure)

Special Considerations

Heart Failure or Renal Impairment

• Challenge: Need hydration but at risk for fluid overload
• Options:
  • Reduce hydration volume with closer monitoring
  • Add furosemide (Lasix) to promote diuresis while hydrating
  • Consider carboplatin instead (doesn't require extensive hydration)

Ambulatory Infusion

• For weekly low-dose: Abbreviated hydration (500-1000 mL total) may be acceptable
• Encourage oral hydration: 2-3 liters of fluids at home for 24-48 hours after

Antiemetic Prophylaxis

Cisplatin is one of the most emetogenic (nausea/vomiting-inducing) chemotherapy drugs. Aggressive antiemetic prophylaxis is mandatory.

Standard Antiemetic Regimen

Four-drug combination recommended for high-dose cisplatin (≥50 mg/m²):

1. NK1 Receptor Antagonist

• Aprepitant (Emend): 125 mg PO day 1, then 80 mg PO days 2-3
• Fosaprepitant (Emend IV): 150 mg IV day 1 only
• Rolapitant (Varubi): 180 mg PO day 1 only
• Purpose: Prevents delayed nausea (days 2-5)

2. 5-HT3 Receptor Antagonist

• Ondansetron (Zofran): 16-24 mg IV or PO day 1
• Granisetron (Kytril): 1-2 mg IV or PO day 1, or transdermal patch
• Palonosetron (Aloxi): 0.25 mg IV day 1 (preferred - longer half-life)
• Purpose: Prevents acute nausea (first 24 hours)

3. Dexamethasone (Steroid)

• Day 1: 12 mg IV or PO (dose reduced if using NK1 antagonist)
• Days 2-4: 8 mg PO daily (or twice daily)
• Purpose: Prevents both acute and delayed nausea

4. Olanzapine (Zyprexa)

• Dose: 10 mg PO daily days 1-4
• Purpose: Additional prevention of delayed nausea, also helps with anxiety and sleep
• Note: Causes sedation (can be beneficial at bedtime)

Breakthrough Nausea Treatment

Despite prophylaxis, some patients still experience nausea. Rescue medications:

• Metoclopramide (Reglan): 10-20 mg PO/IV every 6-8 hours PRN
• Prochlorperazine (Compazine): 10 mg PO/IV every 6-8 hours PRN
• Lorazepam (Ativan): 0.5-2 mg PO/IV every 6-8 hours PRN (for anticipatory nausea, anxiety)
• Additional 5-HT3 antagonist: Can give additional doses

Timeline of Nausea with Cisplatin

• Acute (0-24 hours): Begins 1-2 hours after infusion, peaks 4-6 hours
• Delayed (24-120 hours): Days 2-5 after cisplatin, often worse than acute phase
• Anticipatory: Can develop before subsequent treatments (conditioned response)

Side Effects

Cisplatin causes significant toxicities that require careful monitoring and management.

Dose-Limiting Toxicities

Nephrotoxicity (Kidney Damage) - MOST SERIOUS

• Incidence: 25-35% (with hydration), up to 100% (without hydration)
• Mechanism: Direct tubular damage, primarily in proximal tubules
• Onset: Usually during or within 2 weeks of treatment
• Presentation:
  • Elevated serum creatinine (often permanent baseline increase)
  • Decreased creatinine clearance
  • Electrolyte wasting (hypomagnesemia, hypokalemia, hypocalcemia)
  • Usually non-oliguric (urine output maintained)
• Prevention:
  • Hydration: Most important - 2-4 liters IV saline
  • Avoid other nephrotoxic drugs (NSAIDs, aminoglycosides, IV contrast)
  • Monitor renal function before each dose
• Management:
  • Dose reduction or switch to carboplatin if CrCl declining
  • Aggressive electrolyte replacement (especially magnesium)
  • May require permanent renal replacement therapy if severe
• Recovery: Partial recovery may occur over months, but some permanent damage common

Ototoxicity (Hearing Loss)

• Incidence: 30-100% depending on dose and definition
• Mechanism: Damage to outer hair cells in cochlea
• Characteristics:
  • High-frequency hearing loss (4000-8000 Hz) first - often asymptomatic initially
  • Can progress to speech frequencies (conversational hearing)
  • May be unilateral or bilateral
  • Can worsen after treatment stops ("coasting")
  • Irreversible and permanent
• Risk factors:
  • Cumulative dose (increases significantly >400 mg/m²)
  • Age extremes (children and elderly at higher risk)
  • Concurrent cranial radiation
  • Aminoglycoside antibiotics
  • Pre-existing hearing loss
• Monitoring: Baseline and periodic audiograms, especially in children and with cumulative doses
• Prevention:
  • No proven effective strategy
  • Avoid ototoxic drugs (aminoglycosides, loop diuretics)
  • Sodium thiosulfate being studied in children
• Impact: Can significantly affect quality of life; hearing aids may be needed

Nausea and Vomiting - HIGHEST EMETOGENIC POTENTIAL

• Incidence: >90% without prophylaxis
• Severity: Can be severe and prolonged
• Phases: Acute (0-24h) and delayed (24-120h) - delayed often worse
• Prevention: See antiemetic section - four-drug regimen mandatory
• Impact: Major quality of life issue; can lead to dehydration, malnutrition, treatment refusal

Common Side Effects (>30%)

Myelosuppression

• Severity: Moderate (less than many other chemotherapy agents)
• Nadir: Days 18-23 (low point)
• Recovery: By day 28-35
• Pattern:
  • Leukopenia and thrombocytopenia most common
  • Anemia (dose-related, cumulative)
• G-CSF: Usually not needed for cisplatin alone; may be needed with combination regimens

Electrolyte Abnormalities

• Hypomagnesemia (low magnesium):
  • Very common (50-90%), can be severe
  • Due to renal tubular wasting
  • Can persist long-term
  • May require IV or high-dose oral supplementation
  • Can cause secondary hypocalcemia and hypokalemia
• Hypokalemia (low potassium): Often secondary to magnesium loss
• Hypocalcemia (low calcium): Due to hypomagnesemia
• Hyponatremia (low sodium): From SIADH (syndrome of inappropriate ADH)

Peripheral Neuropathy

• Incidence: 30-90% (dose and cumulative dose dependent)
• Type: Sensory neuropathy (numbness, tingling in hands/feet)
• Onset: After cumulative dose >300-400 mg/m²
• Characteristics:
  • Stocking-glove distribution
  • Loss of proprioception (position sense)
  • Loss of vibration sense
  • Areflexia (loss of reflexes)
  • Rarely motor involvement
• Can worsen after stopping ("coasting")
• May improve slowly over months to years, but often permanent to some degree
• Prevention: No proven strategy; dose reduction or discontinuation if severe
• Treatment: Duloxetine 30-60 mg daily for neuropathic pain

Less Common but Serious Side Effects

Hypersensitivity Reactions (1-10%)

• Timing: Can occur with first dose or after multiple exposures (sensitization)
• Symptoms: Facial flushing, wheezing, tachycardia, hypotension, rash, urticaria
• Severe: Anaphylaxis possible (rare)
• Management: Stop infusion, epinephrine, antihistamines, steroids
• Rechallenge: Possible with desensitization protocol if no alternative

Cardiac Toxicity (Rare)

• Arrhythmias, ischemia, cardiomyopathy (rare but serious)
• More common with high cumulative doses
• Monitor ECG if cardiac risk factors

Neurotoxicity (Central)

• Seizures (rare)
• Encephalopathy (rare)
• Lhermitte's sign (electric shock sensations with neck flexion)

Ocular Toxicity

• Optic neuritis, papilledema (rare)
• Cortical blindness (very rare)
• Report vision changes immediately

Vascular Toxicity

• Raynaud's phenomenon
• Thrombotic microangiopathy (rare but serious)
• Arterial events (stroke, MI) - rare

Hepatotoxicity

• Mild, transient elevation in liver enzymes
• Usually not clinically significant

Other Side Effects

• Fatigue: Very common, can be severe and prolonged
• Alopecia (hair loss): Mild and uncommon with cisplatin alone
• Diarrhea: Uncommon
• Mucositis: Mild, more common with combination therapy
• Metallic taste: Common during and after infusion
• Hiccups: Uncommon but can be persistent

Long-Term and Late Effects

• Chronic kidney disease: Cumulative kidney damage may worsen over years
• Permanent hearing loss
• Persistent neuropathy
• Persistent hypomagnesemia: May require lifelong supplementation
• Secondary malignancies: Slight increased risk (like other chemotherapy)
• Infertility: Can affect both men and women; discuss fertility preservation before treatment

Monitoring Parameters

Before Each Dose

• Renal function:
  • Serum creatinine
  • Creatinine clearance (CrCl): Calculate using Cockcroft-Gault or measure with 24-hour urine
  • BUN
• Complete blood count (CBC) with differential: Check ANC, platelets, hemoglobin
• Electrolytes:
  • Magnesium (most important to monitor)
  • Potassium, calcium, sodium
  • Replace before dosing if low
• Liver function tests: AST, ALT, bilirubin, alkaline phosphatase
• Neuropathy assessment: Ask about numbness, tingling, functional limitations
• Hearing assessment: Ask about hearing changes, tinnitus

During Infusion

• Vital signs: Monitor for hypersensitivity reactions
• Urine output: Goal >100-150 mL/hour
• Urine specific gravity: Keep <1.010

After Treatment

• Electrolytes: Recheck 24-48 hours after infusion (especially magnesium)
• Hydration status: Ensure adequate oral intake

Periodic Monitoring

• Audiogram:
  • Baseline before starting
  • Periodically during treatment (especially children, high cumulative doses)
  • After completing treatment if symptoms develop
• Neurologic exam: For neuropathy (vibration, proprioception, reflexes)

Long-Term Surveillance

• Annual renal function: For survivors (can develop late chronic kidney disease)
• Hearing evaluation: If symptoms develop
• Cardiovascular risk assessment: Increased risk in survivors

Drug Interactions

Major Interactions (Avoid or Use with Caution)

Nephrotoxic Drugs - AVOID

Concurrent use significantly increases kidney damage risk:

• Aminoglycoside antibiotics: Gentamicin, tobramycin, amikacin
• NSAIDs: Ibuprofen, naproxen, ketorolac (even short-term use)
• IV contrast dye: Delay CT scans with contrast if possible; if necessary, hydrate aggressively
• Amphotericin B: Antifungal
• Calcineurin inhibitors: Cyclosporine, tacrolimus

Ototoxic Drugs - AVOID

Increase hearing loss risk:

• Aminoglycosides: Additive ototoxicity
• Loop diuretics: Furosemide (Lasix), bumetanide - use cautiously if needed for fluid management

Phenytoin (Dilantin)

• Cisplatin reduces phenytoin levels
• Monitor phenytoin levels closely
• May need dose adjustment

Bleomycin

• Cisplatin reduces bleomycin clearance
• Increases bleomycin pulmonary toxicity risk
• Common combination (BEP for testicular cancer) but requires careful monitoring

Taxanes (Paclitaxel, Docetaxel)

• Sequence matters: Give cisplatin BEFORE taxane to reduce toxicity
• Reverse sequence increases myelosuppression

Other Interactions

• Live vaccines: Avoid during treatment (immunosuppression)
• Anticoagulants: Monitor INR closely if on warfarin
• Other chemotherapy: Additive myelosuppression with most agents

Warnings and Precautions

Contraindications

• Pre-existing renal impairment: CrCl <30 mL/min (use carboplatin instead)
• Severe hearing loss
• Severe myelosuppression
• Hypersensitivity to platinum compounds
• Pregnancy (Category D)

Pregnancy and Breastfeeding

• Pregnancy Category D: Can cause fetal harm
• Contraception: Effective contraception required during and for 6 months after treatment (both men and women)
• Fertility:
  • Can cause permanent infertility in both sexes
  • Discuss sperm banking (men) or egg/embryo preservation (women) BEFORE starting
• Breastfeeding: Contraindicated - discontinue nursing

Special Populations

Elderly Patients

• Higher risk of nephrotoxicity, ototoxicity, neuropathy
• Often have reduced baseline renal function
• Calculate CrCl (don't rely on serum creatinine alone)
• Consider carboplatin as alternative
• More aggressive hydration may be challenging (heart failure, fluid overload risk)

Pediatric Patients

• Very high risk of ototoxicity - hearing loss can impair language development
• Baseline and frequent audiograms essential
• Consider sodium thiosulfate otoprotection (investigational)
• Growth and development monitoring

Renal Impairment

• Dose reduction required if CrCl 30-60 mL/min
• Contraindicated if CrCl <30 mL/min
• Use carboplatin instead for moderate to severe impairment

Hepatic Impairment

• No specific dose adjustment required (minimal hepatic metabolism)
• Monitor liver function

Handling and Disposal

• Hazardous drug: Healthcare workers must use appropriate PPE
• Caregivers: Wear gloves when handling patient's body fluids for 48 hours after treatment
• Disposal: Toilet can be used (flush twice), but separate if on septic system

Frequently Asked Questions