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Two-stage surgery with HIPEC in pseudomyxoma peritonei

Complete pathological response after two-stage cytoreductive surgery with HIPEC for voluminous pseudomyxoma peritonei: proof of concept

02/06/2020 · Dr. François Quenet · International Journal of Hyperthermia

Two-stage surgery with HIPEC in pseudomyxoma peritonei
Dr. François Quenet

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Dr. François Quenet

Quenet Torrent Institute

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Abstract

Introduction

Pseudomyxoma peritonei (PMP) is a rare disease characterized by the progressive accumulation of mucinous ascites and peritoneal implants. The optimal treatment for PMP includes the combination of complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). In patients with very voluminous disease, achieving complete cytoreduction sometimes requires extremely aggressive surgeries. The aim of this article is to provide proof of concept for a two-stage cytoreductive surgery strategy in this patient group.

Methods

A two-stage strategy with cytoreductive surgery and HIPEC with oxaliplatin was proposed for patients with voluminous PMP, with significant involvement of the serosal surfaces of the intestine or colon and deteriorated nutritional status. Residual disease at the end of the first surgical stage was less than 5 mm thick in several implants. Clinical, surgical, and histopathological variables were analyzed.

Results

All eight patients completed the two-stage strategy. There was no mortality. One Clavien-Dindo grade 3 event occurred at each stage. After a median follow-up of 29.5 months, all patients were alive and without recurrence. All patients showed complete pathological response in samples obtained from residual sites during the second surgery.

Conclusion

The two-stage surgical strategy is feasible in patients with voluminous PMP and is associated with low severe morbidity and greater visceral preservation.

1. Introduction

Pseudomyxoma peritonei (PMP) is a rare disease characterized by the progressive accumulation of mucinous ascites and peritoneal implants, usually originating from a perforated mucinous tumor of the appendix.1 This perforation is usually due to lumen obstruction by tumor growth, leading to peritoneal dissemination of mucin-producing epithelial cells. Other origins such as ovary, urachus, colon, and pancreas have also been described, although much less frequently.

The optimal treatment for PMP consists of the combination of complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).2,3 Long-term survival data show clear superiority over historical treatments (tumor reduction surgery), making phase III trials ethically unfeasible. Overall survival reaches 55–63% at 10 years and 50–59% at 15 years.3 In contrast, the absence of treatment leads to progressive accumulation of mucin, increased abdominal girth, nutritional deterioration, and eventually obstruction and death.

As in most peritoneal surface neoplasms, completeness of cytoreduction is a major prognostic factor. Non-definitive surgery (debulking) worsens the prognosis.4,6 Another important factor is histological grade: the current classification distinguishes acellular mucin, low-grade peritoneal mucinous carcinoma, high-grade, and high-grade with signet ring cells.5 The first two have much better prognosis.

However, in patients with very voluminous disease (PCI >30 or multiple implants on small intestine and colon) complete cytoreduction may be impossible. In these cases, the only alternative is usually tumor reduction surgery. Although inferior, it may provide some benefit.6 The problem is that extensive surgery is associated with high morbidity, especially in malnourished patients.7

This study presents proof of concept for a two-stage cytoreductive surgery strategy with HIPEC with organ preservation, to ultimately allow CCR0-1 thanks to the complete pathological response obtained after the first stage.

2. Patients and Methods

2.1 Patients

Between June 2014 and June 2018, 52 patients with PMP were treated at the Montpellier Cancer Institute. Eight patients with voluminous disease were selected for two-stage surgery with HIPEC.

Inclusion criteria:

  • Adults fit for surgery
  • PCI >20
  • Acellular mucin or low-grade mucinous neoplasm
  • Gelatinous implants easily detachable except for a base <5 mm
  • Multiple implants on small intestine or colon that would require ≥3 resections

Patients with easily resectable disease or high-grade infiltrative lesions were excluded.

2.2 Surgery

Contrast-enhanced CT and diffusion MRI were performed before each stage.

Each stage included HIPEC with oxaliplatin 250 mg/m².20,21

Objective: achieve CCR0/1 at the end of treatment.

  • First stage: extensive peritoneal resection and lesions at risk of obstruction, avoiding intestinal resections. Residual disease <5 mm thick was left.
  • Second stage: complete exploration, resection of all macroscopic lesions and biopsy or resection of previous residual areas.

3. Results

8 Patients completed strategy
0% Mortality
100% Complete pathological response
29.5 Months follow-up (median)

Patient characteristics:

  • 8 patients (7 women)
  • Mean age: 66.5 years
  • Mean PCI: 25
  • All ASA III

First stage results:

After the first stage, residual disease was <5 mm on intestinal serosal surface.

Second stage results:

  • No macroscopic disease was observed
  • All samples showed only fibrosis
  • Complete pathological response in all patients

Morbidity and follow-up:

  • Interval between surgeries: median 4 months
  • Morbidity: 1 grade 3 complication at each stage12
  • Mortality: 0
  • Mean follow-up: 31.5 months
  • All alive and without recurrence

4. Discussion

This is the first study demonstrating the feasibility of this two-stage strategy with HIPEC in voluminous PMP.

Although the standard is CCR + HIPEC, up to 29% of extensive PMPs remain unresectable even in expert centers.13,14

A threshold of 5 mm residual disease was chosen based on HIPEC tissue penetration (3–5 mm).8,16

The complete pathological response observed questions even the need for the second stage in the future.

Oxaliplatin was chosen for its high possible intraperitoneal dose and good efficacy, using a moderate dose to reduce morbidity.21,22

Morbidity was low thanks to intestinal preservation.23,24

This strategy is especially promising in:

  • Low-grade PMP
  • Frail or malnourished patients
  • Very voluminous disease

Conclusion

Two-stage cytoreductive surgery with HIPEC:

  • ✓ Is feasible and safe
  • ✓ Has low morbidity
  • ✓ Allows visceral preservation
  • ✓ Achieves complete pathological response
  • ✓ Could change the approach to voluminous PMP

Acknowledgments

The authors wish to thank Mrs. Hélène de Forges for proofreading and formatting the English of the manuscript.

Declaration of conflict of interest

The authors declare no potential conflict of interest.

Funding

This work was funded by SIRIC Montpellier Cancer (grant number: INCa_Inserm_DGOS_12553).

ORCID

References

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