Hyperthermic intraperitoneal chemotherapy in colorectal cancer: is COLOPEC just another brick in the wall?

Locally advanced colorectal cancer (CRC) is associated with a high risk to develop peritoneal metastases (PMs). If PM occurs, the prognosis of patients is poor and manifold clinical problems occur. Among those are the difficulties of diagnosis and follow-up, the meaning of primary and/or secondary resection in curative intent, clinical symptoms such as pain, and bowel problems (1). Therefore, the urgent concern is: How can we prevent PM in patients at risk and what are effective tools of our treatment repertoire to improve the outcome?

Systemic anticancer regimens have evolved into highly efficient treatment options for metastatic CRC, but targeted treatment options have failed in the adjuvant setting, so far. The neoadjuvant treatment for colon cancer using FOLFOX regimen in locally advanced tumors, which have a high risk of PM, is just about to be included in our treatment armamentarium but still is not standard of care for those patients. However, guidelines recommend no preoperative treatment in non-metastatic disease of colon cancer (2,3). So how should we approach patients with a pT4 pN0–2 cM0 situation? Curative oncological surgery combined with postoperative systemic treatment is standard of care for pT4 primaries. However, roughly 20–40% of these patients develop PM over time. To tackle this clinical problem a complete resection of the local peritoneum is done. In addition, hyperthermic intraperitoneal chemotherapy (HIPEC) may be applied with the aim to reduce the local recurrence rate and prolong disease-free and overall survival. The COLOPEC trial had been designed to answer the question whether the addition of HIPEC to the standard of care adjuvant chemotherapy improves PM-free survival at 18 months. The trial failed to meet its primary endpoint (4). With the long-term follow-up being published (5), again no difference in overall survival or PM-free survival could be detected. This is in line with the recently published randomized trials such as PRODIGE 7 and PROPHYLOCHIP-PRODIGE 15, both failing to prove an additional benefit of HIPEC in CRC treatment (6,7). A recent study investigated the use of HIPEC in a slightly different setting (8) and explored the prophylactic use of HIPEC in clinically T4-staged tumors. Using mitomycin after cytoreductive surgery, the 3-year local recurrence rate, the primary endpoint, has been significantly lower in HIPEC-treated patients than in patients with cytoreduction only. But neither disease-free survival nor overall survival had been impacted, so again, the question remains: is it worth the effort for cytoreductive surgery and HIPEC? Unfortunately, no data on the molecular makeup of the resected tumor has been disclosed which make it difficult to classify HIPEC in the therapeutic approach of CRC. Therefore, gold standard remains the adjuvant systemic chemotherapy.

So why should we continue with HIPEC in CRC? Firstly, HIPEC cannot be seen as a uniform treatment procedure. The anticancer efficacy of HIPEC depends on a variety of influencing factors: duration of application, temperature, cycles of treatment, drug, dosage, carrier, etc.

The COLOPEC trial used intraperitoneal oxaliplatin [460 mg/m², 30 minutes, concurrent 5-fluorouracil (5-FU)/leucovorin intravenously]. However, only 9% of randomized patients in the HIPEC arm got HIPEC simultaneously to the cytoreduction, and 91% of “HIPEC”-patients received the HIPEC 5–8 weeks postoperatively (4,5).

In PRODIGE 7, 400 mg/m², 20 minutes concurrent 5-FU/leucovorin was applied and either 460 mg/m² (“open technique”) or 360 mg/m² (“closed technique”) oxaliplatin was applied over 30 minutes (7).

In PROPHYLOCHIP-PRODIGE 15 400 mg/m², 20 minutes concurrent 5-FU/leucovorin was applied before starting HIPEC. Then, 460 mg/m² oxaliplatin (30 minutes 43 ℃) or 300–360 mg/m² oxaliplatin when combined with irinotecan (200 mg/m²) were applied (6).

Another regimen shown by Verwaal in patients with PM in metastatic CRC showed significant improvement (9). He used mitomycin C with 35 mg/m² and a duration of 90 minutes.

So different dosages, temperatures, and combinations were used with unclear consequences on the cytoreductive efficacy. As minimal residual disease, remaining single cells or cell clusters, are aimed to be treated with HIPEC, more effective substances and also targeted approaches such as anti-EGFR-antibodies, BRAFV600E, HER2, and KRASG12C targeting agent need to be explored. Furthermore, the optimal chemo-combination with respect to temperature, dosing of either 5-FU, oxaliplatin, or maybe also irinotecan needs to be further investigated before a larger HIPEC trial in CRC may be launched again. Those dose-finding experiments should also account for the molecular makeup of the treated CRC. As microsatellite stable (MSS) BRAFV600E and rat sarcoma (RAS) mutant CRC have a worse prognosis than RAS/BRAF wild-type tumors (10), trials should be stratified accordingly. As there is a strong association between locally advanced colon cancer (pT4) and microsatellite instability high-status, those tumors need to be excluded from further HIPEC trials as neoadjuvant immune-checkpoint inhibition should be standard of care for those patients (11).

With newer concepts, such as neoadjuvant treatment for locally advanced MSS CRC are currently tested, HIPEC trials in the non-metastatic setting should be included in perioperative concepts to better understand the meaning of HIPEC within locally advanced CRC.

What we learned is, that prophylactic HIPEC in this setting is not sufficient and should not delivered to patients with CRC at risk. However, this does not mean, that HIPEC is not effective at all. With respect to limited PMs, the European Society for Medical Oncology guidelines state that “complete cytoreductive surgery (CRS) and HIPEC may provide prolonged survival when carried out in experienced high-volume centers” (2). In addition, the National Comprehensive Cancer Network guidelines for Colon Cancer (version 2.2024) (3) recommend CRS and HIPEC “in selected patients diagnosed with metastatic spread to the peritoneum” as a curative approach. They also discuss the role of HIPEC in the setting of CRS as controversial.

In our view, usage of HIPEC in the adjuvant setting should be limited to clinical trials with clearly defined regimens and molecular defined CRC in highly specialized centers. In contrast, CRS is a well-defined procedure with potential curative intent in limited PM and should be applied to prolong patients’ survival.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-18/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-18/coif). S.S. reports consulting fees from AMGEN, AstraZeneca, Bayer, BMS, CV6, Daiichy.Sanyko, ESAI, Lilly, Merck-KGaA, MSD, Pierre-Fabre Medicament, Roche, Sanofi, Servier, Taiho, Takeda; personal fees from AMGEN, AstraZeneca, Bayer, BMS Daiichy-Sanyko, ESAI, Lilly, Merck-KGaA, MSD, Pierre-Fabre Medicament, Roche, Sanofi, Servier, Taiho, Takeda; support for attending meetings and/or travel from AstraZeneca Roche Amgen; and served as speaker role in AIO Working Group CRC within the DKG. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Tseng J, Bryan DS, Poli E, et al. Under-representation of peritoneal metastases in published clinical trials of metastatic colorectal cancer. Lancet Oncol 2017;18:711-2. [Crossref] [PubMed]
2. Cervantes A, Martinelli EESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo. Updated treatment recommendation for third-line treatment in advanced colorectal cancer from the ESMO Metastatic Colorectal Cancer Living Guideline. Ann Oncol 2024;35:241-3. [Crossref] [PubMed]
3. NCCN. NCCN Guidelines Colon Cancer Version 2.2024. 2024. Available online: https://www.nccn.org/login?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
4. Klaver CEL, Wisselink DD, Punt CJA, et al. Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. Lancet Gastroenterol Hepatol 2019;4:761-70. [Crossref] [PubMed]
5. Zwanenburg ES, El Klaver C, Wisselink DD, et al. Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial. J Clin Oncol 2024;42:140-5. [Crossref] [PubMed]
6. Goéré D, Glehen O, Quenet F, et al. Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): a randomised, phase 3 study. Lancet Oncol 2020;21:1147-54. [Crossref] [PubMed]
7. Quénet F, Elias D, Roca L, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:256-66. [Crossref] [PubMed]
8. Arjona-Sánchez A, Espinosa-Redondo E, Gutiérrez-Calvo A, et al. Efficacy and Safety of Intraoperative Hyperthermic Intraperitoneal Chemotherapy for Locally Advanced Colon Cancer: A Phase 3 Randomized Clinical Trial. JAMA Surg 2023;158:683-91. [Crossref] [PubMed]
9. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737-43. [Crossref] [PubMed]
10. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol 2015;16:1306-15. [Crossref] [PubMed]
11. Chalabi M, Verschoor YL, Van Den Berg J, et al. LBA7 Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Ann Oncol 2022;33:S1389. [Crossref]