Background

Peritoneal metastasis in locally advanced colon cancer (T4 stage) is estimated around 25% at 3 years from surgical resection with a poor prognosis. There is controversy about the results using prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in this group of patients. We led a randomized controlled trial to determine the efficacy and safety of adjuvant HIPEC in patients with locally advanced colon cancer.

Methods

We did an open-label, randomized phase III study in 17 hospitals in Spain. Eligible patients were aged 18-75 years and had locally advanced primary colorectal cancer diagnosed preoperatively (cT4NxM0). Patients were randomly assigned (1:1) to surgery or surgery plus HIPEC (mitomycin C 30 mg/m2 during 60 minutes), both followed by systemic adjuvant chemotherapy. Randomisation was done via a web-based system, with stratification by treatment centre and gender. The primary outcome was 3 years loco-regional control rate, defined as the time from treatment to peritoneal disease recurrence or death form any cause, analysed by intention to treat (ITT). DFS and OS were secondary endpoints.

Results

Between November 2015 and January 2021 184 patients were recruited and randomized (89 experimental vs. 95 control). The median of follow-up was 36 (IQR 27-36) months. Demographic, tumour features, surgical management and final pathology reports were similar between both groups. The loco-regional control (LC) was improved in the experimental arm (35,3 ± 0.4 vs. 33.2 ± 0.8 months) with a 3 years LC rate of 97% vs. 87% (p = 0.025). No differences were observed in DFS and OS. The pT4 subgroup showed a clear benefit of LC in the HIPEC arm. No differences in morbidity were observed between groups.

Conclusions

The addition of hyperthermic intraperitoneal chemotherapy with mitomycin C to a complete surgical resection for locally advanced colon cancer improves the loco-regional control rate. This benefit becomes more evident in the subgroup of patients with pT4 colon cancer.

Clinical trial identification

NCT02614534.

Editorial acknowledgement

Legal entity responsible for the study

IMIBIC Maimonides Biomedical research Institute cordoba, Spain. Universitary Hospital Reina Sofia, Cordoba, Spain.

Funding

FIBICO (Biomedical Research Foundation, Cordoba) and Spanish Surgeon's Association (AEC).

Disclosure

All authors have declared no conflicts of interest.

Review

 

J Clin Med

. 2022 Jun 14;11(12):3406.

 doi: 10.3390/jcm11123406.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Summary of Key Clinical Trials

Kevin M Turner 1, Mackenzie C Morris 1, Davendra Sohal 2, Jeffrey J Sussman 3, Gregory C Wilson 3, Syed A Ahmad 3, Sameer H Patel 3

Affiliations expand

• PMID: 35743476
 
• PMCID: PMC9225119
 
• DOI: 10.3390/jcm11123406

Free PMC article

Abstract

The peritoneal cavity is a common site of metastatic spread from colorectal cancer (CRC). Patients with peritoneal metastases (PM) often have aggressive underlying tumor biology and poor survival. While only a minority of patients with CRC have potentially resectable disease, the high overall incidence of CRC makes management of PM a common clinical problem. In this population, cytoreductive surgery (CRS)-hyperthermic intraperitoneal chemotherapy (HIPEC) is the only effective therapy for appropriately selected patients. In this narrative review, we summarize the existing literature on CRS-HIPEC in colorectal PM. Recent prospective clinical trials have shown conflicting evidence regarding the benefit of HIPEC perfusion in addition to CRS. Current strategies to prevent PM in those at high-risk have been shown to be ineffective. Herein we will provide a framework for clinicians to understand and apply these data to treat this complex disease presentation.

Keywords: colorectal peritoneal carcinomatosis; cytoreductive surgery; hyperthermic intraperitoneal chemotherapy (HIPEC).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1 

Netherlands trial schema comparing CRS-HIPEC…

 

Figure 2 

PRODIGE 7 trial schem comparing…

 

Figure 3 

COLOPEC trial schema comparing adjuvant…

 

Figure 4 

PROPHYLOCHIP-PRODIGE 15 trial schema comparing…

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5. Conclusions

Colorectal PM is a clinical problem commonly encountered in practice, which requires evaluation and management at specialized centers by experienced clinicians. Attention to proper patient selection, in line with recommendations established in the Chicago consensus, is paramount to success [35]. The studies described in this review show that adjuvant HIPEC and delayed second-look surgery using 30 min of intraperitoneal oxaliplatin are ineffective strategies to reduce PM/recurrence and improve survival in patients with CRC PM. Although early data supported CRS-HIPEC, results from the recent PRODIGE 7 study question the added benefit of HIPEC for this treatment strategy. These studies confirm the benefit of CRS, which should be considered the standard of care. Although many methodological critiques of PRODIGE 7 exist, the onus now appears to be on HIPEC enthusiasts to develop future trials required to resolve criticisms of the study and demonstrate any potential survival benefit of HIPEC for CRC PM.

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Abbreviations

Colorectal cancer (CRC); peritoneal metastases (PM); cytoreductive surgery (CRS); hyperthermic intraperitoneal chemotherapy (HIPEC); completeness of cytoreduction (CCR); mitomycin C (MMC); randomized control trial (RCT); 5-fluorouracil (5-FU); overall survival (OS); peritoneal carcinomatosis index (PCI); circulating tumor DNA (ctDNA).

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Funding Statement

This research received no external funding.

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Author Contributions

Conceptualization, K.M.T. and S.H.P.; methodology, K.M.T. and S.H.P.; software, K.M.T.; resources, K.M.T. and M.C.M.; writing—original draft preparation, K.M.T., M.C.M. and S.H.P.; writing—review & editing, K.M.T., M.C.M., D.S., J.J.S., G.C.W., S.A.A. and S.H.P.; visualization, K.M.T.; supervision, S.A.A. and S.H.P.; project administration, K.M.T. and S.H.P. All authors have read and agreed to the published version of the manuscript.

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Informed Consent Statement

Patient consent was waived as a review of existing publicly available literature.

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Conflicts of Interest

The authors declare no conflict of interest.

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Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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