Locally advanced colorectal cancers (CRC) comprise of 10–20% of all CRC (1,2), and pose several management challenges to the surgeon. These tumours extend through the serosa of the bowel, and present with perforation, obstruction and/or invasion of adjacent organs or structures. They are classified as T4 lesions by the American Joint Committee on Cancer staging schema (3). In addition to their presentation, the locally advanced CRC are often associated with local recurrence and the development of peritoneal metastases (PM). These recurrences are difficult to treat and hence synonymous with poor prognoses and difficult to manage complications.
Hyperthermic intraperitoneal chemotherapy (HIPEC), in combination with cytoreductive surgery has increasingly been recognised as an effective treatment option in selected CRC patients with recurrent disease confined to the peritoneum (4-8). As a result, given the proof of concept of HIPEC as an effective treatment strategy for peritoneal disease, locally advanced CRC are currently being investigated in several adjuvant HIPEC trials (9-11) in an attempt to reduce the risk of PM and local recurrence. This review article sets out to examine the current literature regarding the use of HIPEC for locally advanced CRC.
The development of PM is associated with a poor prognosis, with median survival of about 6 months if untreated, and between 6–15 months if treated with palliative systemic therapy (12). This survival outcome is significantly worse compared to palliative treatment for non-peritoneal recurrences. In addition, the quality-of-life (QOL) of patients with PM is often considerably reduced because of ascites, and bowel, ureteric and biliary obstruction caused by the peritoneal disease. In selected patients with metastatic disease confined to the peritoneum, cytoreductive surgery (CRS) and HIPEC have been shown to confer survival benefit. A large number of phase II studies and one randomized controlled trial have been published on CRS-HIPEC for CRC, demonstrating an improved survival in comparison with systemic chemotherapy only (4-7). However, the effectiveness of CRS-HIPEC depends largely on the amount of disease, the extent of cytoreduction and type of chemotherapy (13-15). With complete cytoreduction and HIPEC, 5-year survival rates of 40–51% have been reported (14). Moreover, survival is appreciably lower if macroscopic disease remains. Additionally, CRS-HIPEC is associated with substantial morbidity (16,17).
It is clear that there are significant disadvantages in treating PM at a late stage, however it is recognized that early detection of peritoneal disease is difficult, even with current state-of-the-art imaging techniques. As a result, the majority of patients with PM present with extensive disease, and are often only offered palliative treatment. Therein lies the need for effective prophylactic treatment to prevent the development of PM in high-risk patients.
Patients at high-risk of developing PM
Important risk factors for metachronous PM typically include more than just T4 disease. Other prognostic features include the presence of tumour perforation, mucinous and signet ring cell histology, nodal stage, right-sidedness and positive resection margins (18). As can be appreciated in the following paragraphs, the definition of high-risk CRC varies in each study, but typically always includes T4 locally advanced tumours.
To date, there have been 2 prospective case-control studies done to evaluate the feasibility and utility of HIPEC in reducing PM in high-risk CRC patients (19,20). Both reported improved 5-year overall survival rates in the patients who received prophylactic HIPEC at the time of primary surgery. In the study by Sammartino et al. (19), high-risk cases were defined by T4, perforation and mucinous histology. Prophylactic HIPEC was with oxaliplatin. PM and local recurrence developed significantly less often in the patients who received prophylactic HIPEC compared to controls (4% vs. 28%) (P<0.03). Patients in the prophylactic HIPEC group also survived longer (median overall survival 59.5 vs. 52 months). Despite similar morbidity, Kaplan-Meier survival curves disclosed significantly longer disease-free and overall survival in the prophylactic HIPEC, than in the control group (P<0.05 and P<0.04).
In the paper by Baratti et al. (20), high-risk cases were defined as T4, synchronous krukenburg tumours and minimal peritoneal disease. Prophylactic HIPEC was with cisplatin and mitomycin-C, and correlated to lower PM cumulative incidence [hazard ratio (HR) 0.04, 95% CI, 0.01–0.31; P=0.002], and better overall survival (HR 0.25, 95% CI, 0.07–0.89; P=0.039) and progression-free survival (HR 0.31, 95% CI, 0.11–0.85; P=0.028). Reported morbidities from HIPEC were minimal in both papers, and there were no reported mortalities. Our institution is currently completing a feasibility study on prophylactic HIPEC for high risk colorectal cancers, and the preliminary results have also shown that prophylactic HIPEC is feasible with minimal morbidity, and does not delay time to adjuvant systemic therapy.
A French HIPEC group attempted to determine the utility of HIPEC in high-risk patients by performing a systemic re-look surgery and HIPEC with oxaliplatin, at 1 year post primary surgery for high-risk CRC patients (21). The 41 patients included in the study were all asymptomatic, with negative cross-sectional imaging and tumour markers, during their 1-year follow-up after primary surgery. In these 41 patients, the investigators found an astounding rate of occult PM of 56%. This study suitably illustrates the reality of PM in advanced CRC and the difficulty in detecting PM at an early stage, while highlighting the potential utility of prophylactic HIPEC.
A minimally invasive approach has also been described by Chouillard et al. as a safe and feasible tool to administer adjuvant HIPEC in patients whose primaries pose a high risk of peritoneal recurrence (22). In this study, 16 colorectal patients with either: (I) T4 or N2 and above primaries; (II) positive peritoneal cytology; (III) localised satellite nodules; (IV) perforated or obstructed primary tumor were enrolled. Staged laparoscopic HIPEC was performed at a mean interval of 5 weeks (range, 0–8 weeks) from the primary surgery. There was no conversion to open HIPEC and major morbidity occurred in 19% (n=4) of patients.
Randomised controlled trials
There are several randomised studies, designed to explore the utility of HIPEC for locally advanced CRC patients. Currently, only the Dutch COLOPEC trial has been completed and published (9), while the French PROPHYLOCHIP trial is completed but has only been presented and not yet published (10), and two other studies by the Italian and Chinese groups are still open for recruitment (23,24).
COLOPEC was the first published study, carried out in nine specialised HIPEC hospitals in the Netherlands. The study included 204 patients, with T4 or perforated colon cancers, who were randomly assigned (1:1) before curative resection of the primary tumour to adjuvant HIPEC followed by adjuvant systemic chemotherapy or to adjuvant systemic chemotherapy alone. Adjuvant HIPEC was with oxaliplatin, and was either performed simultaneously (9%) or within five to eight weeks (91%) after the primary tumour resection. All patients without evidence of recurrent disease at 18 months were subjected to a diagnostic laparoscopy, and the primary end points were PM-free survival at 18 months.
Within the HIPEC group, 19 (19%) patients were diagnosed with PM: 9 (47%) during surgical exploration preceding intentional adjuvant HIPEC, 8 (42%) during routine follow-up, and 2 (11%) during the 18-month diagnostic laparoscopy. In the non-HIPEC group, 23 (23%) patients were diagnosed with PM: 7 (30%) during laparoscopy at 18-months and the remaining 16 during regular follow-up, before 18 months. In the intention-to-treat analysis, there was no difference in PM-free survival at 18 months [80.9% (95% CI, 73.3–88.5%) for the HIPEC group vs. 76.2% (68.0–84.4%) for the non-HIPEC group, log-rank one-sided P=0.28]. The complication rate for the patients who received adjuvant HIPEC was 14%. The authors concluded that adjuvant HIPEC with oxaliplatin for patients with T4 or perforated colon cancer did not result in improved 18 months PM-free survival.
The main criticism of the COLOPEC study is the high proportion (91%) of patients who received adjuvant HIPEC at the delayed setting (5 to 8 weeks post primary tumour resection), during which adhesions may have limited the distribution and effectiveness of HIPEC. In addition, 9 (9%) of the 100 patients in the HIPEC group had PM detected before the HIPEC could be given.
The PROPHYLOCHIP trial also did not show any benefit of adjuvant HIPEC with oxaliplatin in patients with minimal resected PM, Krunkenburg tumours, or a perforated primary tumour compared with surveillance (3-year disease-free survival 51% vs. 44%, P=0.75) (10).
The results of these two trials question the effectiveness of the 30-min HIPEC protocol with oxaliplatin, and may be due to the limited exposure to the chemotherapy, resulting in an inadequate antitumor effect. In addition, the time at which the adjuvant HIPEC is delivered is also crucial, and ideally during the time of primary resection.
The PROMENADE, APEC and HIPECT4 trials investigating adjuvant HIPEC for locally advanced CRC are currently recruiting patients, with the latter using mitomycin-C, and will certainly shed more light on this matter.
Colorectal local recurrences
The role of CRS and HIPEC in the management of locally recurrent colorectal cancer is a matter of debate. While some consider local and peritoneal recurrences as a single entity, both representing indications for CRS & HIPEC (25); others frown upon the use of HIPEC in isolated local recurrences (26,27). Dumont et al. in an attempt to differentiate the two compared the clinico-pathological characteristic of patients with local vs. peritoneal recurrence following CRS & HIPEC and found the former to have a higher likelihood of organ involvement and lymph node metastases and an increased mortality (27). Limited data in this area precludes us from making any firm conclusions, suggesting the need for future prospective studies to differentiate the two during the selection of patients for CRS and HIPEC.
In light of PRODIGE-7
The most recent debate regarding HIPEC for CRC, surfaced after the much awaited PRODIGE-7 trial was presented in 2018 (13). This trial was designed to investigate the role of HIPEC in metachronous PM, but did not show a survival benefit of the addition of HIPEC to cytoreductive surgery. Despite the results, and bearing in mind that this trial has not been published to date, CRS and HIPEC are still used worldwide, largely because the results cannot be extrapolated to mitomycin-C as the chemotherapy drug, nor to the up-front application in the adjuvant setting.
The challenge of managing locally advanced CRC remain, but might be lessened by the use of HIPEC in the adjuvant setting. Despite the negative trials, HIPEC continues to hold promise of reducing these difficulties and is continuously being evaluated in several trials, and may prove more effective if used for locally advanced CRC with additional high-risk features.
Provenance and Peer Review: This article was commissioned by the Guest Editors (Nan Zun Teo, James Chi-Yong Ngu) for the series “Current Strategies in Colon Cancer Management” published in Journal of Gastrointestinal Oncology. The article was sent for external peer review organized by the Guest Editors and the editorial office.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jgo.2019.12.10). The series “Current Strategies in Colon Cancer Management” was commissioned by the editorial office without any funding or sponsorship. The authors have no other 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/.
- Gao P, Song YX, Wang ZN, et al. Is the prediction of prognosis not improved by the seventh edition of the TNM classification for colorectal cancer? Analysis of the surveillance, epidemiology, and end results (SEER) database. BMC Cancer 2013;13:123.
- Gezen C, Kement M, Altuntas Y, et al. Results after multivisceral resections of locally advanced colorectal cancers: an analysis on clinical and pathological T4 tumors. World J Surg Oncol 2012;10:39. [Crossref] [PubMed]
- Jessup JM, Goldberg RM, Aware EA, et al. Colon and Rectum. In: AJCC Cancer Staging Manual, 8th. Chicago: AJCC, 2017:251.
- Elias D, Gilly F, Boutitie F, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol 2010;28:63-8. [Crossref] [PubMed]
- 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. [Crossref] [PubMed]
- Huang CQ, Min Y, Wang SY, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival for peritoneal carcinomatosis from colorectal cancer: a systematic review and meta-analysis of current evidence. Oncotarget 2017;8:55657-83. [Crossref] [PubMed]
- Mirnezami R, Mehta AM, Chandrakumaran K, et al. Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy improves survival in patients with colorectal peritoneal metastases compared with systemic chemotherapy alone. Br J Cancer 2014;111:1500-8. [Crossref] [PubMed]
- Verwaal VJ, Boot H, Aleman BM. Recurrences after peritoneal carcinomatosis of colorectal origin treated by cytoreduction and hyperthermic intraperitoneal chemotherapy: Location, treatment, and outcome. Ann Surg Oncol 2004;11:375-9. [Crossref] [PubMed]
- Klaver CEL, Wisselink DD, Punt CJA, et al. COLOPEC collaborators group. 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]
- Cortes-Guiral D, Elias D, Cascales-Campos PA, et al. Second-look surgery plus hyperthermic intraperitoneal chemotherapy for patients with colorectal cancer at high risk of peritoneal carcinomatosis: Does it really save lives? World J Gastroenterol 2017;23:377-81. [Crossref] [PubMed]
- Arjona-Sánchez A, Barrios P, Boldo-Roda E, et al. HIPECT4: multicentre, randomized clinical trial to evaluate safety and efficacy of Hyperthermic intra-peritoneal chemotherapy (HIPEC) with Mitomycin C used during surgery for treatment of locally advanced colorectal carcinoma. BMC Cancer 2018;18:183. [Crossref] [PubMed]
- Köhne CH, van Cutsem E, Wils J, et al. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol 2005;23:4856. [Crossref] [PubMed]
- Quenet F, Elias D, Roca L, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7 J Clin Oncol 2018;36:LBA3503. (abstract). [Crossref]
- Sugarbaker PH, Jablonsky KA. Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg 1995;221:124-32. [Crossref] [PubMed]
- Narasimhan V, Warrier S, Michael M, et al. Oxaliplatin versus Mitomycin C following complete cytoreduction for colorectal peritoneal metastases: a comparative study. J Gastrointest Surg 2019. [Epub ahead of print]. [Crossref] [PubMed]
- Lee TC, Wima K, Sussman JJ, et al. Readmissions After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: a US HIPEC Collaborative Study. J Gastrointest Surg 2020;24:165-76. [Crossref] [PubMed]
- Somashekhar SP, Yethadka R, Kumar CR, et al. Toxicity profile of chemotherapy agents used in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies. Eur J Surg Oncol 2020;46:577-81. [PubMed]
- Segelman J, Granath F, Holm T, et al. Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer. Br J Surg 2012;99:699-705. [Crossref] [PubMed]
- Sammartino P, Sibio S, Biacchi D, et al. Long-term results after proactive management for locoregional control in patients with colonic cancer at high risk of peritoneal metastases. Int J Colorectal Dis 2014;29:1081-9. [Crossref] [PubMed]
- Baratti D, Kusamura S, Iusco D, et al. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the Time of Primary Curative Surgery in Patients with Colorectal Cancer at High Risk for Metachronous Peritoneal Metastases. Ann Surg Oncol 2017;24:167-75. [Crossref] [PubMed]
- Elias D, Honoré C, Dumont F, et al. Results of systematic second-look surgery plus HIPEC in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis. Ann Surg 2011;254:289-93. [Crossref] [PubMed]
- Chouillard E, Ata T, De Jonghe B, et al. Staged laparoscopic adjuvant intraperitoneal chemohyperthermia after complete resection for locally advanced colorectal or gastric cancer: a preliminary experience. Surg Endosc 2009;23:363-9. [Crossref] [PubMed]
- Proactive Management of Endoperitoneal Spread in Colonic Cancer (PROMENADE). Available online: https://clinicaltrials.gov/ct2/show/NCT02974556
- Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Versus no HIPEC in Locally Advanced Colorectal Cancer (APEC Study). Available online: https://clinicaltrials.gov/ct2/show/NCT02965248
- Sugarbaker PH. Update on the prevention of local recurrence and peritoneal metastases in patients with colorectal cancer. World J Gastroenterol 2014;20:9286-91. [PubMed]
- Dumont F, Kothodinis K, Goéré D, et al. Central retroperitoneal recurrences from colorectal cancer: are lymph node and locoregional recurrences the same disease?. Eur J Surg Oncol 2012;38:611-6. [Crossref] [PubMed]
- Dumont F, Joseph S, Lorimier G, et al. Intra-abdominal recurrence from colorectal carcinoma: Differences and similarities between local and peritoneal recurrence. Surg Oncol 2020;32:23-9. [Crossref] [PubMed]