Adjuvant hyperthermic intraperitoneal chemotherapy in patient with locally advanced colon cancer
Editorial Commentary

Adjuvant hyperthermic intraperitoneal chemotherapy in patient with locally advanced colon cancer

Alvaro Arjona-Sanchez

Unit of Surgical Oncology, University Hospital Reina Sofia, Cordoba, Spain

Correspondence to: Correspondence to: Alvaro Arjona-Sanchez, PhD. Consultant Surgery in Unit of Surgical Oncology, Hospital University Reina Sofia, Menendez Pidal Av., 14004 Cordoba, Spain. Email: alvaroarjona@hotmail.com.

Provenance and Peer Review: This article was commissioned by the editorial office, Digestive Medicine Research. The article did not undergo external peer review.

Comment on: 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.


Received: 31 March 2020; Accepted: 17 April 2020; Published: 30 June 2020.

doi: 10.21037/dmr-20-35


For colon cancer, one of the risk factors identified to develop peritoneal carcinomatosis is the trans-serosal invasion of the tumour (pT4a-b). This feature represents a significant risk factor for survival by itself, in this way, the prognosis of pT4 becomes similar to patients with N2 and M1 stages with a 5 years overall survival of 20% (1). Local relapse and peritoneal recurrence for T4 patients is estimated in 15.6% and 36.7% for 12 and 36 months respectively from surgical resection (2).

When an oncologic surgeon has to deal with a locally advanced colon carcinoma, he always thinks that there should be an additional treatment for his patient to avoid a future loco-regional relapse. Most of the times, an oncologic resection in a locally advanced colon carcinoma means an aggressive surgery that includes multi-visceral resections and a hard postoperative course. After this great effort made for the patient and doctors, the likelihood of a local relapse might rise up to 36% (2).

One of these additional treatments is the administration of intraperitoneal chemotherapy in hyperthermic conditions (HIPEC), although we thought that it will be useful for this type of patients, we must be cautious and wait for the evidence to use it as a prophylactic treatment. In that sense, recently has been published the COLOPEC study (3), which has failed to demonstrate an improvement in the survival with the use of 30 minutes of HIPEC with oxaliplatin as adjuvant treatment in locally advanced colon cancer.

This study was based on the excellent results from previous studies performed. They delivered HIPEC after primary resection with oxaliplatin or mitomycin C. A significant reduction in peritoneal relapse and an improvement of survival were demonstrated (4,5). The main problem was that these studies had multiple bias to use them as an evidence to use HIPEC as standard prophylactic treatment. COLOPEC has been the first randomized controlled trial that has analysed the use of adjuvant HIPEC in the treatment of locally advanced and perforated colon cancer. Briefly, the experimental arm has been treated by primary resection and HIPEC (primary clinically T4) or delayed additional HIPEC after emergent surgery or confirmed pathological T4 (up to 8 weeks after surgery) by laparoscopic or open approach. A bidirectional HIPEC protocol was used: fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) were delivered intravenously followed by HIPEC using oxaliplatin (460 mg/m2) in a single dose for 30 min at a temperature of 42–43 °C.

Some troubles were found on this trial that the authors added in the discussion. The regimen of HIPEC used in this trial as prophylactic therapy had not demonstrated efficacy when it was used as adjuvant therapy in peritoneal carcinomatosis from colon cancer in the French multicentre trial PRODIGE 7 (6) where the authors considered the possibility that the time of HIPEC is too short to see the effect of the intraperitoneal oxaliplatin, or the drug was not effective for intraperitoneal delivery. This trial meant the change in the peritoneal carcinomatosis from colon management performing the cytoreductive surgery without HIPEC or using mitomycin C. Another question is the administration of HIPEC in a second stage could increase the morbidity and length of stay of these patients, as well as the potential delay of the usual adjuvant systemic treatment. The last trouble is that the endpoint was evaluated at 18 months after treatment, maybe this time of follow-up was too short to demonstrate a reduction in the rate of peritoneal relapse or survival benefits.

A Spanish clinical trial is on going, called HIPECT4 (7). This trial is still in a recruitment phase. This trial includes patients diagnosed of locally advanced colon carcinoma by radiological tests. The patient defined as cT4a/b N 0-2 M0 colon cancer are included on it. For the experimental arm the patient is treated by complete cytoreduction associating resection of target organs and HIPEC with mitomycin C 30 mg/m2 during 60 min. Open or laparoscopic approach are allowed. The primary endpoint is the rate of loco-regional relapse or peritoneal carcinomatosis with a follow-up of 36 months. This trial avoids a second stage surgery, its follow-up is longer and the drug used is mitomycin C instead of oxaliplatin (Table 1).

PROMEDANE study (8) is other randomized study where in its experimental arm the patients will receive oxaliplatin 460 mg/m2 and before the beginning of HIPEC an intravenous infusion of 400 mg/m2 of 5-FU and 20 mg/m2 of leucovorin will be administered, the primary endpoint is the incidence of peritoneal recurrence at 36 months. This study is not yet recruiting.

Table 1
Table 1 Active randomized controlled trial in prophylactic HIPEC for colon carcinoma
Full table

The third one comes from the Zhejiang University (9) where in the experimental arm the patients will receive HIPEC with mitomycin C (30 mg/m2 of body surface area), closed technique, as preferred. Duration: 60 minutes. Mean Intra-abdominal Temperature: 43 °C. This study is yet recruiting.

In spite of the belief of the benefits that the HIPEC could offer on these patients to avoid the metachronous peritoneal carcinomatosis or peritoneal relapse, we have to wait until the evidence says that the HIPEC gives a substantial benefits for these patients as a prophylactic treatment before considering its systematic use.


Acknowledgments

Funding: None.


Footnote

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/dmr-20-35). The author has no conflicts of interest to declare.

Ethical Statement: The author is 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. Snaebjornsson P, Coupe VM, Jonasson L, et al. pT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis. Shepherd's local peritoneal involvement revisited. Int J Cancer 2014;135:467-78. [Crossref] [PubMed]
  2. Hompes D, Tiek J, Wolthuis A, et al. HIPEC in T4a colon cancer: a defendable treatment to improve oncologic outcome? Ann Oncol 2012;23:3123-9. [Crossref] [PubMed]
  3. 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]
  4. Sloothaak DA, Mirck B, Punt CJ, et al. Intraperitoneal chemotherapy as adjuvant treatment to prevent peritoneal carcinomatosis of colorectal cancer origin: a systematic review. Br J Cancer 2014;111:1112-21. [Crossref] [PubMed]
  5. Sloothaak DA, Gardenbroek TJ, Crezee J, et al. Feasibility of adjuvant laparoscopic hyperthermic intraperitoneal chemotherapy in a short stay setting in patients with colorectal cancer at high risk of peritoneal carcinomatosis. Eur J Surg Oncol 2014;40:1453-8. [Crossref] [PubMed]
  6. 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. Proc Am Soc Clin Oncol 2018;36:LBA3503. [Crossref]
  7. 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]
  8. Sammartino P; Societa Italiana di Chirurgia Oncologica (SICO). PROMENADE Trial (Proactive Management of Endoperitoneal Spread in Colonic Cancer). 2015. Available online: https://clinicaltrials.gov/ct2/show/NCT02974556
  9. Trial Evaluating Surgery With Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Treating Patients With a High Risk of Developing Colorectal Peritoneal Carcinomatosis. Available online: https://clinicaltrials.gov/ct2/show/NCT02179489
doi: 10.21037/dmr-20-35
Cite this article as: Arjona-Sanchez A. Adjuvant hyperthermic intraperitoneal chemotherapy in patient with locally advanced colon cancer. Dig Med Res 2020;3:19.