Is Robotic Surgery Superior in Rectal Cancer? Evaluating the Evidence from the REAL Trial

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Why Is This Important?

Ovarian cancer is diagnosed at an advanced stage in approximately 70% of cases, and survival rates remain low in this group. HIPEC (hyperthermic intraperitoneal chemotherapy) added to interval (post-neoadjuvant) cytoreductive surgery has become a topic of interest due to its potential to prolong survival in patients with high tumor burden. However, its effectiveness and toxicity profile have long been debated.

Until now, the most commonly used drug in HIPEC has been cisplatin, and large-scale data on paclitaxel were limited. This study, conducted across 27 centers in Spain and including 846 patients, is the first large-scale analysis directly comparing the two drugs.

Main Findings

Survival Outcomes

• In the matched group:
  • Overall survival: 58 months with cisplatin vs. 82 months with paclitaxel (HR = 0.74; p = 0.16 → not statistically significant)
  • Disease-free survival: 20 months with cisplatin vs. 21 months with paclitaxel (HR = 0.95; p = 0.70 → not statistically significant)
• Equivalence analysis: During the first 20 months for OS and the first 15 months for DFS, the groups were statistically equivalent.

Adverse Events and Complications

• Despite being administered at a higher dose (120 mg/m² for 60 minutes), paclitaxel did not differ significantly from cisplatin in terms of complication rates.
• Major complication rates were similar (p = 0.06).

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🔬 HIPEC: Application Details for Cisplatin and Paclitaxel

🧪 Cisplatin-Based HIPEC

• Dosage: 75–100 mg/m²
• Solvent: 4 liters of peritoneal perfusion fluid containing 1.5% dextrose
• Duration of application: 90 minutes
• Temperature: 42–43 °C
• Method: Open or closed technique
• Additional protection: Nephrotoxicity-reducing agents such as sodium thiosulfate may be added

Note: Cisplatin increases its cytotoxicity by forming cross-links with DNA in a hyperthermic environment. However, due to increased risk of kidney damage, patient selection is critically important.

🧪 Paclitaxel-Based HIPEC

• Dosage: 120 mg/m²
• Solvent: 4 liters of dextrose-based peritoneal fluid (usually 1.5%)
• Duration of application: 60 minutes
• Temperature: 42–43 °C
• Method: Open or closed HIPEC technique
• Additional measure: Kidney-protective measures not required (unlike with cisplatin)

Note: Paclitaxel halts mitosis by stabilizing microtubules. Its thermal synergy is less than cisplatin’s, but it offers the advantage of strong local effect and low toxicity.

📌 Comparative Table

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💡 Clinical Tips

• Paclitaxel is administered in a shorter time (60 min), potentially shortening surgical time.
• It has low systemic absorption and reduced toxicity risk.
• Cisplatin may have stronger antitumor activity but carries higher risk of side effects.

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Implications of the Findings

• Paclitaxel is equivalent to cisplatin in terms of survival outcomes.
• There is a 24-month increase in median overall survival, but it is not statistically significant.
• Equivalence margins were defined as ±10.

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📚 What Do Guidelines Say About HIPEC?

HIPEC (Hyperthermic Intraperitoneal Chemotherapy) is occasionally used in recurrent ovarian cancer—especially in platinum-sensitive recurrence cases—by some centers. However, international guidelines do not yet recommend this approach routinely.

🔹 Can Be Applied with Surgery After Neoadjuvant Therapy in Selected Patients

• Some centers perform HIPEC after neoadjuvant chemotherapy and cytoreductive surgery in platinum-sensitive recurrent patients with good performance status.
• However, it is clearly stated that HIPEC carries a higher risk of toxicity.
• Individualized risk-benefit assessment with the patient is strongly advised.
• Some patients may choose to decline this treatment due to high toxicity.

🔹 Not Recommended Without Neoadjuvant Therapy

Studies have reported that HIPEC does not show benefit in patients who undergo secondary cytoreductive surgery without receiving prior neoadjuvant therapy.

🔬 Key Randomized Data from the Literature

1. HIPEC and Median Overall Survival Benefit (n = 415, 2023)

• 415 women with platinum-sensitive recurrence were randomized to HIPEC or control before surgery following six cycles of platinum-based chemotherapy (with optional bevacizumab).
• Overall survival:
  HIPEC: 54 months – Control: 46 months (HR = 0.73; 95% CI: 0.56–0.96)
• Grade ≥3 toxicity rates:
  HIPEC: 49% – Control: 27%
• Most common side effects:
  • Anemia: 23% vs 14%
  • Hepatotoxicity: 11% vs 9%
  • Electrolyte imbalance: 14% vs 1%
  • Renal failure: 10% vs 1%

2. Use of HIPEC Without Neoadjuvant Therapy (n = 167)

In 167 patients with platinum-sensitive recurrence undergoing surgery without neoadjuvant therapy:

• PFS: Surgery + HIPEC: 25 months – Surgery only: 23 months
• No statistically significant difference.

📌 Summary of Guideline Recommendations

• HIPEC is not routinely recommended.
• It may be considered in selected platinum-sensitive recurrent patients who received neoadjuvant therapy, and only in experienced centers.
• Due to increased toxicity risk, informed consent and individualized decision-making are essential.
• It should not be presented as the only treatment option.

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What Does This Mean in Clinical Practice?

1. If renal failure, platinum allergy, or frailty is present, paclitaxel can be a safer alternative.
2. Complete tumor resection (CC-0) should be aimed for, and HIPEC should be performed in experienced centers.
3. Patient education and close monitoring of side effects are mandatory.
4. Prospective studies are needed to support broader use of paclitaxel in HIPEC.

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Limitations of This Study

• The retrospective design may result in missing data and selection bias.
• BRCA and HRD status were not evaluated.
• Other treatments that may affect long-term overall survival were not accounted for.

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Conclusion

Paclitaxel is a safe alternative in HIPEC with comparable efficacy and toxicity to cisplatin. It is a reasonable option in patients who cannot receive cisplatin.

Clinical Suggestion: In patients scheduled for interval cytoreductive surgery where cisplatin poses a risk, paclitaxel-based HIPEC is a rational and safe alternative.