What is the recommended dose and administration protocol for Cisplatin (Platinol) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC)?

Cisplatin HIPEC: Clinical Pearls and Dosing Protocol

Recommended Dose

For cisplatin HIPEC in ovarian cancer, use 75-100 mg/m² as the standard dose, with 100 mg/m² being the most widely validated regimen in prospective trials, though 70 mg/m² represents the safest dose with acceptable renal toxicity. 1, 2

Dose Selection Algorithm

• 100 mg/m²: Most common dose in NCCN-reviewed trials, supported by phase I data showing acceptable safety profile in recurrent disease 2, 3
• 70 mg/m²: Recommended dose from multicenter phase I trial specifically for neoadjuvant setting, based on dose-limiting toxicities at 80 mg/m² 4
• 75 mg/m²: Alternative validated dose used in multiple prospective trials 2

The critical distinction: 70 mg/m² should be used after neoadjuvant chemotherapy and interval debulking surgery, while 100 mg/m² has been validated primarily in recurrent platinum-sensitive disease. 4, 3

Technical Parameters

Temperature and Duration

• Temperature: Maintain 41-43°C throughout perfusion 1, 5
• Duration: 90 minutes for cisplatin protocols (minimum 60 minutes acceptable) 2, 5
• Perfusion volume: Typically 2-6 liters depending on body surface area and peritoneal cavity size 6

Critical Dosing Reality

Only approximately 79% of the calculated cisplatin dose is actually utilized during HIPEC, with roughly 20% remaining in the perfusate at procedure completion. 6 This loss is predictable: Actual dose (mg) = 30.079 + 0.667 × Total dose (mg) - 0.010 × Volume retained (ml). 6

Mandatory Nephroprotection

Sodium thiosulfate nephroprotection is required for cisplatin HIPEC to prevent dose-limiting renal toxicity. 5

Hydration Protocol

• Pre-treatment: 1-2 liters IV fluid infused 8-12 hours before HIPEC 7
• Post-treatment: Aggressive hydration continued to maintain urine output >100 mL/hour 7

Renal Toxicity Profile

At 80 mg/m² without adequate nephroprotection, expect: 4

• Creatinine clearance <30 mL/min in 18% of patients (3/17)
• Creatinine clearance 30-60 mL/min in additional 12% (2/17)
• Dose-limiting renal failure in 12% (2/17)

At 70 mg/m², renal impairment (CrCl 30-60 mL/min) occurs in approximately 20% but is typically reversible. 4

Patient Selection Criteria

Mandatory Requirements

HIPEC should only be performed in ovarian cancer patients who meet ALL of the following: 1

1. After neoadjuvant chemotherapy (minimum 3 cycles carboplatin AUC 5-6 + paclitaxel 175 mg/m²) 1
2. At interval debulking surgery (NOT primary debulking) 1
3. Complete cytoreduction achieved (CC-0 or CC-1, no residual disease >2.5 mm) 1
4. Normal baseline renal function (creatinine clearance >60 mL/min) 4
5. No excessive intraoperative bleeding 2

Absolute Contraindications

• Primary debulking surgery setting (no survival benefit demonstrated) 1
• Incomplete cytoreduction (residual disease >2.5 mm negates benefit) 1
• Extra-abdominal metastases 2
• Pre-existing renal dysfunction 4

Pharmacokinetic Advantage

Cisplatin HIPEC achieves a peritoneal-to-plasma AUC ratio of approximately 19.5:1 at 100 mg/m², providing high local drug exposure with limited systemic toxicity. 3 This favorable ratio is maintained across all dose levels (60-100 mg/m²), with cisplatin-DNA adduct formation confirmed in tumor samples. 3

Importantly, mild hyperthermia (40-43°C) does not significantly enhance cisplatin uptake into small peritoneal tumors compared to normothermic perfusion, suggesting the benefit derives primarily from high local drug concentration rather than temperature effects. 8

Integration with Systemic Chemotherapy

Sequencing Protocol

Standard regimen: 1

1. Neoadjuvant: Carboplatin AUC 5-6 + paclitaxel 175 mg/m² × 3 cycles
2. Interval debulking surgery + cisplatin HIPEC
3. Adjuvant: Carboplatin + paclitaxel × 3 additional cycles (total 6 cycles)

HIPEC does not compromise the ability to deliver standard postoperative platinum-based chemotherapy. 3 All patients in phase I trials successfully received planned adjuvant therapy. 3

Bevacizumab Maintenance

Following completion of 6 cycles of chemotherapy, bevacizumab 15 mg/kg every 3 weeks for 22 cycles can be added as maintenance therapy. 2, 4 In the phase I dose-finding trial, 20/30 patients (67%) started maintenance bevacizumab after HIPEC. 4

Perioperative Morbidity Expectations

Operative Metrics

• Median operative time: 300-600 minutes (5-10 hours) for combined cytoreduction + HIPEC 1, 2
• Median blood loss: Significant transfusion requirement common (mean 2-4 units) 2
• Hospital stay: 8-24 days median 1, 2

Complication Rates

Major/severe complications (Dindo grade ≥IIIb) occur in 9-40% of patients within 30 days. 1, 2 Common grade 3-4 toxicities include: 3

• Fatigue
• Postoperative pain
• Surgical site infection
• Renal dysfunction (see above)
• Peritonitis (rare, <5%)
• Hemorrhage requiring intervention (rare, <5%)

Critical Pitfalls to Avoid

1. Never use HIPEC at primary debulking surgery - randomized data show no benefit in this setting 1

2. Never proceed with HIPEC if complete cytoreduction cannot be achieved - suboptimal debulking (CC-2 or CC-3) eliminates any potential benefit 1

3. Never use 80 mg/m² or higher without robust nephroprotection protocols - unacceptable renal toxicity rates 4

4. Never substitute carboplatin for cisplatin in HIPEC - cisplatin is the only guideline-endorsed agent with survival benefit data 1

5. Never omit sodium thiosulfate nephroprotection - this is a consensus recommendation to prevent renal failure 5

6. Never use HIPEC in patients with extra-abdominal disease - these patients were excluded from all positive trials 2