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BJS Open
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Oxford University Press UK

10.1093/bjsopen/zrae049
zrae049
Invited Commentary
AcademicSubjects/MED00910
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Hyperthermic intraperitoneal chemotherapy in colorectal cancer
Rau Beate Department of Surgery, Charité—Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Gül-Klein Safak Department of Surgery, Charité—Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Correspondence to: Beate Rau, General Surgery, Charité Universitätsmedizin, Augustenburger Platz 1, Berlin 13353, Germany (e-mail: beate.rau@charite.de)
6 2024
09 5 2024
09 5 2024
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10 4 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.
2024
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pmcCytoreductive surgery (CRS) in peritoneal metastasis of colorectal cancer (pmCRC) achieves, with 41 months median overall survival, extraordinarily good results compared with palliative systemic treatment. However, the question arises of whether the additional installation of hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent disease recurrence and increase overall survival. We have learned from several RCTs that additional HIPEC after CRS achieves a significantly better survival outcome. Unfortunately, these trials use different drug regimens, durations and dosages.

In the current issue of BJS Open, Fisher et al. aimed to evaluate the efficacy of HIPEC for pmCRC in a large data set of patients by analysing HIPEC protocols given to 2760 pmCRC patients from 39 centres1.

The aim of this retrospective analysis was to reconfirm the impact of HIPEC after CRS for pmCRC by evaluating drug regimens and drug dosages. The authors conclude that oxaliplatin-based HIPEC provided better outcomes compared with mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality rate difference favours the oxaliplatin-HIPEC group. A trend for dose–response between low- and high-dose HIPEC was reported.

The ‘standard’ is based on the results of randomized trials: we know that CRS + MMC (mitomycin)-based HIPEC is better than no CRS/HIPEC2 and that neoadjuvant oxaliplatin-based systemic therapy followed by CRS + mono-oxaliplatin-based HIPEC is not superior to CRS alone without HIPEC in patients (PRODIGE 7)3. These two randomized trials have several limitations, which have already been discussed in the literature4.

The PRODIGE 7 study raised controversy regarding the study design and inclusion criteria, calling into question the credibility of the study. There are several limitations of PRODIGE 7, such as the inclusion of patients with a peritoneal cancer index of less than 25, switching patients from the non-HIPEC to the HIPEC group, variation of the interval from the last day of preoperative systemic chemotherapy to surgery and the variety of given chemotherapy regimen.

In a retrospective clinical trial comparing HIPEC with oxaliplatin and mitomycin C for peritoneal metastases from CRC, Spiliotis et al. observed a significant improvement in overall survival in the mitomycin group (54 months versus 26 months for oxaliplatin)5. Based on years of clinical experience, our trial design includes the use of HIPEC with cisplatin in the experimental arm.

Is it the drug, the limitations of the study design or the fact that HIPEC has no additional impact on survival? Based on several positive randomized trials in other organs, HIPEC has been shown to have an impact on survival in peritoneal disease.

HIPEC with oxaliplatin did not show superiority—however, in other RCTs other drugs were effective: in ovarian cancer, high-dose cisplatin-HIPEC achieved significantly better outcomes in three randomized trials6–8 whereas carboplatin9 and paclitaxel10 did not.

Furthermore, in the GASTRIPEC trial, we were able to show that although there was no improvement in overall survival, there was an improvement in progression-free and metastasis-free survival in the group of patients who received HIPEC: the HIPEC group had a significantly improved rate of progression-free survival at 7.1 months compared with the control group, in which the average progression-free survival was only 3.5 months. Metastasis-free survival was also improved in the HIPEC group at 10.2 months compared with 9.2 months in the control group. In addition, the study authors found that the use of HIPEC did not result in any increase in morbidity rate11.

So different dosages, durations and combinations were used with unclear consequences on the cytoreductive efficacy. The impact of molecular biological factors (anti-epidermal growth factor receptor-antibodies, BRAFV600E-, HER2- and KRASG12C) and the results of promising targeted treatments concur with HIPEC efficiency. Furthermore, the optimal chemo-combination with respect to temperature, dosing of either 5-FU (5-Fluorouracil), oxaliplatin or maybe also irinotecan needs to be further investigated before a larger HIPEC trial in CRC can be launched again.

From an ongoing debate whether additional HIPEC adds value to the patient’s outcome, this retrospective, multi-institutional cohort study reports a detailed analysis for this topic. However, the conclusions of this analysis underlie several limitations. In this analysis, detailed information about response to preoperative treatment, lack of homogeneity and pathological information is missing.

Usage of HIPEC after CRS should be limited to clinical trials with clearly defined regimens and molecularly defined pmCRC in highly specialized centres. However, this retrospective analysis could show that an oxaliplatin in combination with irinotecan regimen showed the best results and is promising for further trials.

With respect to limited peritoneal metastases, the European Society of Medical Oncology guidelines state ‘complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal ChT (HIPEC) may provide prolonged survival when carried out in experienced high-volume centres’12. In addition, the NCCN guidelines for Colon Cancer (version 1.2024) recommend CRS and HIPEC ‘in selected patients diagnosed with metastatic spread to the peritoneum’ as a curative approach. However, the role of HIPEC in the setting of CRS is still controversial and further trials are crucial to determine if additional HIPEC after CRS is important.

Funding

The authors have no funding to declare.

Disclosure

The authors declare no conflict of interest.
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References

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