Complete pathological response after two-stage cytoreductive surgery with HIPEC for bulky pseudomyxoma peritonei

Background to the study

The optimal treatment for pseudomyxoma peritonei includes complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Overall survival rates reach 55% to 63% at 10 years and 50% to 59% at 15 years when complete cytoreduction is achieved.

However, some patients have such extensive disease (a Peritoneal Cancer Index above 30 or multiple implants on the digestive tract) that achieving complete cytoreduction (CC-R0/1) may require very extensive resections, with a high risk of morbidity, especially in patients whose nutritional status is compromised.

What does this strategy propose?

The study presents a proof of concept of two-stage cytoreductive surgery with HIPEC for patients with bulky pseudomyxoma peritonei, with the aim of achieving a CC-R0/1 resection through a complete pathological response after the first stage.

Study methodology

First surgical stage

This included resection of the whole peritoneal surface and/or of lesions at risk of causing obstruction, but carefully excluded all other resections of the digestive tract. The thickness of the residual tumour was defined with a limit of 5 mm, based on the tissue penetration of 3-5 mm during HIPEC.

HIPEC with oxaliplatin

In both stages, HIPEC with oxaliplatin 250 mg/m² was given in 0.5% glucose solution at 2 l/m². A less aggressive dose than usual (460 mg/m²) was chosen to reduce the risk of morbidity and ensure that both stages could be completed.

Second surgical stage

Performed after an interval of 3-4 months, it included a complete exploration, resection of macroscopic disease and resection or biopsy of the lesions described previously, even when they were not always macroscopically visible.

Main results

Main finding

No macroscopically visible residual disease was found at the second stage of cytoreductive surgery. All biopsies and specimens were free of residual disease on pathological examination and showed signs of fibrosis, suggesting a complete histological response to HIPEC.

Organ preservation

Only 1 patient required bowel resection during the first stage and 2 patients during the second stage. Preserving more organs helped to reduce morbidity.

Morbidity

• Only 1 Clavien-Dindo grade 3 event in each stage
• Mortality: 0%
• Median hospital stay: 16.5 days (first stage), 11.5 days (second stage)

Survival and follow-up

All patients are alive and free of recurrence after a median follow-up of 31.5 months (range 17-65 months).

Clinical implications

Redefining CC-R2

This study opens the door to a future refinement of the CC-R2 category and of the real need for the second stage when a complete pathological response is achieved. Traditionally:

• CC-R0: No macroscopic residual disease
• CC-R1: Maximum diameter of any residual nodule ≤2.5 mm
• CC-R2: Nodules between 2.5 mm and 2.5 cm
• CC-R3: Nodules larger than 2.5 cm

Advantages of the two-stage strategy

Choice of oxaliplatin

Oxaliplatin was chosen over other cytotoxic drugs on the basis of:

• Ex vivo studies that showed almost identical IC50 values for cisplatin and oxaliplatin in PMP subgroups
• The possibility of giving a higher intraperitoneal dose of oxaliplatin compared with cisplatin
• A good safety profile at a dose of 250 mg/m²

Future perspectives

This study proposes a change in the treatment of bulky pseudomyxoma peritonei. The results suggest that:

1. The two-stage strategy is feasible and safe in selected patients
2. A complete pathological response may remove the need for extensive resections in the second stage
3. Prospective studies are needed to confirm these preliminary results
4. Other de-escalation strategies may be developed on the basis of these findings

Conclusion

In this series of 8 patients with bulky low-grade pseudomyxoma peritonei, two-stage cytoreductive surgery with HIPEC achieved a complete pathological response with low morbidity while preserving organs. These are preliminary results that need to be confirmed in prospective studies.