Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery in colorectal carcinoma at high risk of peritoneal carcinomatosis: short-term and long-term outcomes from the CHECK study - protocol for a randomised, multicentre, phase 3 trial

Fabio Pacelli, Chiara Gerardi, Eliana Rulli, Carlo Abatini, Stefano Rotolo, Silvio Garattini, Gianluigi Melotti, Valter Torri, Fabio Galli, Erica Rulli, Andrea Di Giorgio, CHECK Investigators, Fabio Pacelli, Chiara Gerardi, Eliana Rulli, Carlo Abatini, Stefano Rotolo, Silvio Garattini, Gianluigi Melotti, Valter Torri, Fabio Galli, Erica Rulli, Andrea Di Giorgio, CHECK Investigators

Abstract

Introduction: Up to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts' involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking.

Methods and analysis: This is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method.

Ethics and dissemination: This trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings.

Trial registration number: NCT03914820.

Keywords: CHEMOTHERAPY; Colorectal surgery; Gastrointestinal tumours; SURGERY.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study protocol flow diagram. HIPEC, hyperthermic intraperitoneal chemotherapy; ECOG, Eastern Cooperative Oncology Group Performance Status; FOLFOX, oxaliplatin, 5-fluorouracil, leucovorin; XELOX, oxaliplatin, capecitabine

References

    1. AIRTUM . AIRTUM – I numeri del cancro in Italia 2017, 2017. Available:
    1. 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. 10.1002/bjs.8679
    1. Koppe MJ, Boerman OC, Oyen WJG, et al. . Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies. Ann Surg 2006;243:212–22. 10.1097/01.sla.0000197702.46394.16
    1. Grothey A, Sargent D, Goldberg RM, et al. . Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209–14. 10.1200/JCO.2004.11.037
    1. Sorich MJ, Wiese MD, Rowland A, et al. . Extended Ras mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol 2015;26:13–21. 10.1093/annonc/mdu378
    1. Tabernero J, Yoshino T, Cohn AL, et al. . Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (raise): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015;16:499–508. 10.1016/S1470-2045(15)70127-0
    1. 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. 10.1016/S1470-2045(15)00122-9
    1. Sugarbaker PH, Jablonski 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. 10.1097/00000658-199502000-00002
    1. Elias D, Blot F, El Otmany A, et al. . Curative treatment of peritoneal carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer 2001;92:71–6. 10.1002/1097-0142(20010701)92:1<71::AID-CNCR1293>;2-9
    1. Levine EA, Stewart JH, Shen P, et al. . Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1,000 patients. J Am Coll Surg 2014;218:573–85. 10.1016/j.jamcollsurg.2013.12.013
    1. Jacquet P, Averbach A, Stephens AD, et al. . Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies. Oncology 1998;55:130–8. 10.1159/000011847
    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 Colorectal Dis 2014;29:1081–9. 10.1007/s00384-014-1929-4
    1. 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. 10.1245/s10434-016-5488-5
    1. Graf W, Westlin JE, Påhlman L, et al. . Adjuvant intraperitoneal 5-fluorouracil and intravenous leucovorin after colorectal cancer surgery: a randomized phase II placebo-controlled study. Int J Colorectal Dis 1994;9:35–9. 10.1007/BF00304298
    1. Kelsen DP, Saltz L, Cohen AM, et al. . A phase I trial of immediate postoperative intraperitoneal floxuridine and leucovorin plus systemic 5-fluorouracil and levamisole after resection of high risk colon cancer. Cancer 1994;74:2224–33. 10.1002/1097-0142(19941015)74:8<2224::AID-CNCR2820740804>;2-A
    1. Palermo JA, Richards F, Lohman KK, et al. . Phase II trial of adjuvant radiation and intraperitoneal 5-fluorouracil for locally advanced colon cancer: results with 10-year follow-up. Int J Radiat Oncol Biol Phys 2000;47:725–33. 10.1016/S0360-3016(00)00474-0
    1. Scheithauer W, Kornek GV, Marczell A, et al. . Combined intravenous and intraperitoneal chemotherapy with fluorouracil + leucovorin vs fluorouracil + levamisole for adjuvant therapy of resected colon carcinoma. Br J Cancer 1998;77:1349–54. 10.1038/bjc.1998.225
    1. Tentes AAK, Spiliotis ID, Korakianitis OS, et al. . Adjuvant perioperative intraperitoneal chemotherapy in locally advanced colorectal carcinoma: preliminary results. ISRN Surg 2011;2011:1–6. 10.5402/2011/529876
    1. Vaillant JC, Nordlinger B, Deuffic S, et al. . Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: a multicenter phase III trial. Ann Surg 2000;231:449–56. 10.1097/00000658-200004000-00001
    1. Goere D, Glehen O, Quenet F, et al. . Results of a randomized phase 3 study evaluating the potential benefit of a second-look surgery plus HIPEC in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP- NTC01226394). Journal of Clinical Oncology 2018;36:3531. 10.1200/JCO.2018.36.15_suppl.3531
    1. 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. Journal of Clinical Oncology 2018;36:A3503. 10.1200/JCO.2018.36.18_suppl.LBA3503
    1. 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. 10.1016/S2468-1253(19)30239-0
    1. van Driel WJ, Koole SN, Sikorska K, et al. . Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med 2018;378:230–40. 10.1056/NEJMoa1708618
    1. 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. 10.1186/s12885-018-4096-0
    1. Cavaliere F, De Simone M, Virzì S, et al. . Prognostic factors and oncologic outcome in 146 patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: Italian multicenter study S.I.T.I.L.O. Eur J Surg Oncol 2011;37:148–54. 10.1016/j.ejso.2010.10.014
    1. Ceelen W, Van Nieuwenhove Y, Putte DV, et al. . Neoadjuvant chemotherapy with bevacizumab may improve outcome after cytoreduction and hyperthermic intraperitoneal chemoperfusion (HIPEC) for colorectal carcinomatosis. Ann Surg Oncol 2014;21:3023–8. 10.1245/s10434-014-3713-7
    1. Leung V, Huo YR, Liauw W, et al. . Oxaliplatin versus mitomycin C for HIPEC in colorectal cancer peritoneal carcinomatosis. Eur J Surg Oncol 2017;43:144–9. 10.1016/j.ejso.2016.09.015
    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;110:779–85. 10.1002/jso.23728
    1. Sánchez-García S, Villarejo-Campos P, Padilla-Valverde D, et al. . Intraperitoneal chemotherapy hyperthermia (HIPEC) for peritoneal carcinomatosis of ovarian cancer origin by fluid and CO2 recirculation using the closed abdomen technique (PRS-1.0 combat): a clinical pilot study. Int J Hyperthermia 2016;32:488–95. 10.3109/02656736.2016.1152515
    1. Cianci S, Vizzielli G, Fagotti A, et al. . A novel HIPEC technique using hybrid CO2 recirculation system: intra-abdominal diffusion test in a porcine model. Updates Surg 2018;70:529–33. 10.1007/s13304-018-0557-x
    1. Padilla-Valverde D, Sanchez-Garcia S, García-Santos E, et al. . Usefulness of thermographic analysis to control temperature homogeneity in the development and implementation of a closed recirculating CO2 chemohyperthermia model. Int J Hyperthermia 2017;33:220–6. 10.1080/02656736.2016.1237679
    1. Sánchez-García S, Padilla-Valverde D, Villarejo-Campos P, et al. . Hyperthermic chemotherapy intra-abdominal laparoscopic approach: development of a laparoscopic model using CO2 recirculation system and clinical translation in peritoneal carcinomatosis. Int J Hyperthermia 2017;33:684–9. 10.1080/02656736.2017.1302100
    1. Noncommunicable diseases S, Monitoring and Reporting . The impact of the COVID-19 pandemic on noncommunicable disease resources and services: results of a rapid assessment, 2020.
    1. Sharpless NE. COVID-19 and cancer. Science 2020;368:1290. 10.1126/science.abd3377
    1. Smrke A, Younger E, Wilson R, et al. . Telemedicine during the COVID-19 pandemic: impact on care for rare cancers. JCO Glob Oncol 2020;6:1046–51. 10.1200/GO.20.00220
    1. AIOM - Linee guida tumori del Colon 2021.
    1. Argilés G, Tabernero J, Labianca R, et al. . Localised colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:1291–305. 10.1016/j.annonc.2020.06.022
    1. Cianci S, Abatini C, Fagotti A, et al. . Hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies using new hybrid CO2 system: preliminary experience in referral center. Updates Surg 2019;71:555–60. 10.1007/s13304-018-0578-5
    1. Rotolo S, Di Giorgio A, Santullo F, et al. . Cytoreductive surgery and mitomycin C hyperthermic intraperitoneal chemotherapy with CO 2 recirculation (HIPEC-CO 2) for colorectal cancer peritoneal metastases: analysis of short-term outcomes. Updates in Surgery 2021;29:1–6.
    1. Clavien PA, Barkun J, de Oliveira ML, et al. . The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009;250:187–96. 10.1097/SLA.0b013e3181b13ca2
    1. Kaibara N, Hamazoe R, Iitsuka Y, et al. . Hyperthermic peritoneal perfusion combined with anticancer chemotherapy as prophylactic treatment of peritoneal recurrence of gastric cancer. Hepatogastroenterology 1989;36:75–8.
    1. Koga S, Hamazoe R, Maeta M, et al. . Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C. Cancer 1988;61:232–7. 10.1002/1097-0142(19880115)61:2<232::AID-CNCR2820610205>;2-U
    1. Yonemura Y, de Aretxabala X, Fujimura T, et al. . Intraoperative chemohyperthermic peritoneal perfusion as an adjuvant to gastric cancer: final results of a randomized controlled study. Hepatogastroenterology 2001;48:1776–82.
    1. Coccolini F, Celotti A, Ceresoli M, et al. . Hyperthermic intraperitoneal chemotherapy (HIPEC) and neoadjuvant chemotherapy as prophylaxis of peritoneal carcinosis from advanced gastric cancer-effects on overall and disease free survival. J Gastrointest Oncol 2016;7:523–9. 10.21037/jgo.2016.06.05
    1. Kim JY, Bae HS. A controlled clinical study of serosa-invasive gastric carcinoma patients who underwent surgery plus intraperitoneal hyperthermo-chemo-perfusion (IHCP). Gastric Cancer 2001;4:27–33. 10.1007/s101200100013
    1. Kunisaki C, Shimada H, Nomura M, et al. . Lack of efficacy of prophylactic continuous hyperthermic peritoneal perfusion on subsequent peritoneal recurrence and survival in patients with advanced gastric cancer. Surgery 2002;131:521–8. 10.1067/msy.2002.123769
    1. Kunisaki C, Shimada H, Nomura M, et al. . Therapeutic strategy for scirrhous type gastric cancer. Hepatogastroenterology 2005;52:314–8.
    1. Murata S, Kaida S, Kodama H, et al. . A propensity-matched analysis comparing hepatic recurrence after curative gastrectomy followed by adjuvant HIPEC to surgery alone for advanced gastric cancer. JCO 2016;34:4056. 10.1200/JCO.2016.34.15_suppl.4056
    1. Ceelen W. HIPEC with oxaliplatin for colorectal peritoneal metastasis: the end of the road? Eur J Surg Oncol 2019;45:400–2. 10.1016/j.ejso.2018.10.542
    1. Johnson B, Eng C. More questions regarding HIPEC in colorectal carcinomatosis. Lancet Gastroenterol Hepatol 2019;4:744–5. 10.1016/S2468-1253(19)30254-7
    1. Panteix G, Guillaumont M, Cherpin L, et al. . Study of the pharmacokinetics of mitomycin C in humans during intraperitoneal chemohyperthermia with special mention of the concentration in local tissues. Oncology 1993;50:366–70. 10.1159/000227211
    1. Song N, Pogue-Geile KL, Gavin PG, et al. . Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes: secondary analysis of NSABP C-07/NRG oncology randomized clinical trial. JAMA Oncol 2016;2:1162–9. 10.1001/jamaoncol.2016.2314
    1. 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. 10.1200/JCO.2003.04.187
    1. van Santvoort HC, Braam HJ, Spekreijse KR, et al. . Peritoneal carcinomatosis in T4 colorectal cancer: occurrence and risk factors. Ann Surg Oncol 2014;21:1686–91. 10.1245/s10434-013-3461-0
    1. Nerad E, Lahaye MJ, Maas M, et al. . Diagnostic accuracy of CT for local staging of colon cancer: a systematic review and meta-analysis. American Journal of Roentgenology 2016;207:984–95. 10.2214/AJR.15.15785
    1. Stewart CJR, Hillery S, Platell C, et al. . Assessment of serosal invasion and criteria for the classification of pathological (P) T4 staging in colorectal carcinoma: confusions, controversies and criticisms. Cancers 2011;3:164–81. 10.3390/cancers3010164
    1. Choo J-M, Baek S-J, Kwak J-M, et al. . Clinical characteristics and oncologic outcomes in patients with preoperative clinical T3 and T4 colon cancer who were staged as pathologic T3. Ann Surg Treat Res 2020;99:37–43. 10.4174/astr.2020.99.1.37

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner