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

A Arjona-Sánchez, P Barrios, E Boldo-Roda, B Camps, J Carrasco-Campos, V Concepción Martín, A García-Fadrique, A Gutiérrez-Calvo, R Morales, G Ortega-Pérez, E Pérez-Viejo, A Prada-Villaverde, J Torres-Melero, E Vicente, P Villarejo-Campos, J M Sánchez-Hidalgo, A Casado-Adam, Ruben García-Martin, Manuel Medina, T Caro, C Villar, Enrique Aranda, M T Cano-Osuna, C Díaz-López, E Torres-Tordera, F J Briceño-Delgado, S Rufián-Peña, A Arjona-Sánchez, P Barrios, E Boldo-Roda, B Camps, J Carrasco-Campos, V Concepción Martín, A García-Fadrique, A Gutiérrez-Calvo, R Morales, G Ortega-Pérez, E Pérez-Viejo, A Prada-Villaverde, J Torres-Melero, E Vicente, P Villarejo-Campos, J M Sánchez-Hidalgo, A Casado-Adam, Ruben García-Martin, Manuel Medina, T Caro, C Villar, Enrique Aranda, M T Cano-Osuna, C Díaz-López, E Torres-Tordera, F J Briceño-Delgado, S Rufián-Peña

Abstract

Background: Local relapse and peritoneal carcinomatosis (PC) for pT4 colon cancer is estimated in 15,6% and 36,7% for 12 months and 36 months from surgical resection respectively, achieving a 5 years overall survival of 6%. There are promising results using prophylactic HIPEC in this group of patients, and it is estimated that up to 26% of all T4 colon cancer could benefit from this treatment with a minimal morbidity. Adjuvant HIPEC is effective to avoid the possibility of peritoneal seeding after surgical resection. Taking into account these results and the cumulative experience in HIPEC use, we will lead a randomized controlled trial to determine the effectiveness and safety of adjuvant treatment with HIPEC vs. standard treatment in patients with colon cancer at high risk of peritoneal recurrence (pT4).

Methods/design: The aim of this study is to determine the effectiveness and safety of adjuvant HIPEC in preventing the development of PC in patients with colon cancer with a high risk of peritoneal recurrence (cT4). This study will be carried out in 15 Spanish HIPEC centres. Eligible for inclusion are patients who underwent curative resection for cT4NxM0 stage colon cancer. After resection of the primary tumour, 200 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously after the primary resection. Mitomycin C will be used as chemotherapeutic agent, for 60 min at 42-43 °C. Primary endpoint is loco-regional control (LC) in months and the rate of loco-regional control (%LC) at 12 months and 36 months after resection.

Discussion: We assumed that adjuvant HIPEC will reduce the expected absolute risk of peritoneal recurrence from 36% to 18% at 36 months for T4 colon-rectal carcinoma.

Trial registration: NCT02614534 ( clinicaltrial.gov ) Nov-2015.

Keywords: Chemoprophylaxis; Colon carcinoma; HIPEC; Peritoneal carcinomatosis.

Conflict of interest statement

Ethics approval and consent to participate

Our study has been approved by Hospital University Reina Sofia, Cordoba ethics committee at 29th june 2015. Ref. 2841. Since this approval, all the other local ethics committes approved the protocol in each center included in this trial. The informed consent must be signed by participant previous complete information from the investigators.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow-diagram HIPECT4 study

References

    1. Elferink MAG, de Jong KP, Klaase JM, Siemerink EJ, de Wilt JHW. Metachronous metastases from colorectal cancer: a population-based study in north-East Netherlands. Int J Color Dis. 2015;30:205–212. doi: 10.1007/s00384-014-2085-6.
    1. Franko J, Shi Q, Goldman CD, Pockaj BA, Nelson GD, Goldberg RM, et al. Treatment of colorectal peritoneal carcinomatosis with systemic chemotherapy: a pooled analysis of north central cancer treatment group phase III trials N9741 and N9841. J Clin Oncol. 2012;30:263–267. doi: 10.1200/JCO.2011.37.1039.
    1. Lemmens VE, Klaver YL, Verwaal VJ, Rutten HJ, Coebergh JWW, de Hingh IH. Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study. Int J Cancer. 2011;128:2717–2725. doi: 10.1002/ijc.25596.
    1. Shepherd NA, Baxter KJ, Love SB. The prognostic importance of peritoneal involvement in colonic cáncer: a prospective evaluation. Gastroenterology. 1997;112:1096–1102. doi: 10.1016/S0016-5085(97)70119-7.
    1. Snaebjornsson P, Coupe VMH, Jonasson L, Meijer GA, van Grieken NC, Jonasson JG. 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.
    1. Hompes D, Tiek J, Wolthuis A. HIPEC in T4a colon cancer: a defendable treatment to improve the oncologic outcome? Ann Oncol. 2012;23:3123–3129. doi: 10.1093/annonc/mds173.
    1. Verwaal VJ, van RS, de BE, van Sloothen GW, van TH, Boot H, 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;21:3737–3743. doi: 10.1200/JCO.2003.04.187.
    1. Arjona-Sanchez Peritoneal metastases of colorectal origin treated by cytoreduction and HIPEC: an overview. World J Gastrointest Oncol. 2014;6(10):407–412. doi: 10.4251/wjgo.v6.i10.407.
    1. Elias D, Honoré C, Dumont F, Ducreux M, Boige V, Malka D, Burtin P, Dromain C, Goéré D. Results of systematic secondlook surgery plus HIPEC in asymptomatic patients presenting a high risk of developing colorectal peritoneal carcinomatosis. Ann Surg. 2011;254:289–293. doi: 10.1097/SLA.0b013e31822638f6.
    1. Sloothaak DAM, Mirck B, Punt CJ a, Bemelman W a, van der Bilt JDW, D’Hoore A, et al. Intraperitoneal chemotherapy as adjuvant treatment to prevent peritoneal carcinomatosis of colorectal cancer origin: a systematic review. Br J Cancer 2014;111(6):1112–1121.
    1. Noura S, Ohue M, Shingai T. Effects of intraperitoneal chemotherapy with mitomycin c on the prevention of peritoneal recurrence in colorectal cáncer patients with positive peritoneal lavage cytology findings. Ann Surg Oncol. 2011;18:396–404. doi: 10.1245/s10434-010-1319-2.
    1. 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 Color Dis. 2014;29(9):1081–1089. doi: 10.1007/s00384-014-1929-4.
    1. Virzì S, Iusco D, Baratti D, Bonomi S, Grassi A, Kusamura S, Pilot DM. Study of adjuvant hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer at high risk for the development of peritoneal metastases. Tumori. 2013;99(5):589–595.
    1. Honore C, Goere D, Souadka A, Dumont F, Elias D. Definition of patients resenting a high risk of developing peritoneal carcinomatosis after curative surgery for colorectal cancer: a systematic review. Ann Surg Oncol. 2013;20(1):183–192. doi: 10.1245/s10434-012-2473-5.
    1. Klaver CEL, Musters GD, Bemelman WA, et al. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial. BMC Cancer. 2015;15:428. doi: 10.1186/s12885-015-1430-7.
    1. Hompes D, D’Hoore A, Wolthuis A, Fieuws S, Mirck B, Bruin S, et al. The use of Oxaliplatin or Mitomycin C in HIPEC treatment for peritoneal carcinomatosis from colorectal cancer: a comparative study. J Surg Oncol. 2014;109:527–532. doi: 10.1002/jso.23546.
    1. Turaga K, Levine E, Barone R, et al. Consensus guidelines from the American Society of Peritoneal Surface Malignancies on standardizing the Deliveryof Hyperthermic intraperitoneal chemotherapy (HIPEC)in colorectal cancer patients in the United States. Ann Surg Oncol. 2014;21:1501–1505. doi: 10.1245/s10434-013-3061-z.
    1. Arjona-Sánchez A, Muñoz Casares FC, Casado Adam A, et al. Outcome of patients with aggressive pseudomyxoma peritonei treated by cytoreductive surgery and intrapeitoneal chemotherapy. World J Surg. 2013;37(6):1263–1270. doi: 10.1007/s00268-013-2000-2.
    1. Prada-Villaverde A., Esquivel J., Lowy AM, et al. The American Society of Peritoneal Surface Malignancies Evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete Cytoreductive surgery. J Surg Oncol (2014) DOI 10.1002/jso.23728.
    1. Glehen O, Cotte E, Kusamura S, Deraco M, Baratti D, Passot G, et al. Hyperthermic intraperitoneal chemotherapy: nomenclature and modalities of perfusion. J Surg Oncol. 2008;98:242–246. doi: 10.1002/jso.21061.
    1. Kuhry E, Schwenk WF, Gaupset R, Romild U, Bonjer HJ Long-term results of laparoscopic colorectal cancer resection.Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003432. doi: 0.1002/14651858.CD003432.pub2.
    1. Arjona-Sanchez A, Cadenas Fabres A., Cabrera J, et al. “Assessment of RIFLE and AKIN criteria to define acute renal dysfunction for HIPEC procedures for ovarian and non ovarian peritoneal malignances”, Eur J Surg Oncol (2016)Feb, 10.1016/j.ejso.2015.12.016.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren