Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial

Charlotte E. L. Klaver, Daniel D. Wisselink, Cornelis J. A. Punt, Petur Snaebjornsson, Johannes Crezee, Arend G. J. Aalbers, Alexandra Brandt, Andre J. A. Bremers, Jacobus W. A. Burger, Hans F. J. Fabry, Floris Ferenschild, Sebastiaan Festen, Wilhelmina M. U. van Grevenstein, Patrick H. J. Hemmer, Ignace H. J. T. de Hingh, Niels F. M. Kok, Gijsbert D. Musters, Lotte Schoonderwoerd, Jurriaan B. Tuynman, Anthony W. H. van de Ven & 69 others Henderik L. van Westreenen, Marinus J. Wiezer, David D. E. Zimmerman, Annette A. van Zweeden, Marcel G. W. Dijkgraaf, Pieter J. Tanis, Caroline S. Andeweg, Vivian P. Bastiaenen, Willem A. Bemelman, Jarmila D. W. van der Bilt, Johanne Bloemen, Frank C. den Boer, Djamila Boerma, Daan ten Bokkel Huinink, Walter J. A. Brokelman, Huib A. Cense, Esther C. J. Consten, Geert-Jan Creemers, Rogier M. P. H. Crolla, Jan-Willem T. Dekker, Jennifer Demelinne, Marc J. van Det, Karin K. van Diepen, Marjolein Diepeveen, Eino B. van Duyn, Esther D. van den Ende, Pauline Evers, Anna A. W. van Geloven, Erwin van der Harst, Jeroen Heemskerk, Joost T. Heikens, Daniel A. Hess, Bas Inberg, Jan Jansen, Frank W. H. Kloppenberg, Thomas J. M. Kootstra, R. T. J. Kortekaas, Maartje Los, Eva V. E. Madsen, H. C. J. van der Mijle, Linda Mol, Peter A. Neijenhuis, Simon W. Nienhuijs, Loes van den Nieuwenhof, Koen C. M. J. Peeters, Sebastiaan W. Polle, Jolien Pon, Pieter Poortman, Sandra A. Radema, Bert van Ramshorst, Philip R. de Reuver, Koen P. Rovers, Roderick F. Schmitz, Nina Sluiter, Dirkje W. Sommeijer, D. J. A. Sonneveld, T. C. van Sprundel, Sanne C. Veltkamp, Maarten Vermaas, Victor J. Verwaal, Emma Wassenaar, Johannes A. Wegdam, Johannes H. W. de Wilt, Marinke Westerterp, Fennie Wit, Arjen J. Witkamp, Karlijn van Woensdregt, Edwin S. van der Zaag, Mandy Zournas

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. Methods: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0–2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5–8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. Findings: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3–88·5] for the experimental group vs 76·2% [68·0–84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis. Interpretation: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. Funding: Organization for Health Research and Development and the Dutch Cancer Society.
Original languageEnglish
Pages (from-to)761-770
JournalThe Lancet Gastroenterology and Hepatology
Volume4
Issue number10
DOIs
Publication statusPublished - 1 Oct 2019

Cite this

Klaver, Charlotte E. L. ; Wisselink, Daniel D. ; Punt, Cornelis J. A. ; Snaebjornsson, Petur ; Crezee, Johannes ; Aalbers, Arend G. J. ; Brandt, Alexandra ; Bremers, Andre J. A. ; Burger, Jacobus W. A. ; Fabry, Hans F. J. ; Ferenschild, Floris ; Festen, Sebastiaan ; van Grevenstein, Wilhelmina M. U. ; Hemmer, Patrick H. J. ; de Hingh, Ignace H. J. T. ; Kok, Niels F. M. ; Musters, Gijsbert D. ; Schoonderwoerd, Lotte ; Tuynman, Jurriaan B. ; van de Ven, Anthony W. H. ; van Westreenen, Henderik L. ; Wiezer, Marinus J. ; Zimmerman, David D. E. ; van Zweeden, Annette A. ; Dijkgraaf, Marcel G. W. ; Tanis, Pieter J. ; Andeweg, Caroline S. ; Bastiaenen, Vivian P. ; Bemelman, Willem A. ; van der Bilt, Jarmila D. W. ; Bloemen, Johanne ; den Boer, Frank C. ; Boerma, Djamila ; ten Bokkel Huinink, Daan ; Brokelman, Walter J. A. ; Cense, Huib A. ; Consten, Esther C. J. ; Creemers, Geert-Jan ; Crolla, Rogier M. P. H. ; Dekker, Jan-Willem T. ; Demelinne, Jennifer ; van Det, Marc J. ; van Diepen, Karin K. ; Diepeveen, Marjolein ; van Duyn, Eino B. ; van den Ende, Esther D. ; Evers, Pauline ; van Geloven, Anna A. W. ; van der Harst, Erwin ; Heemskerk, Jeroen ; Heikens, Joost T. ; Hess, Daniel A. ; Inberg, Bas ; Jansen, Jan ; Kloppenberg, Frank W. H. ; Kootstra, Thomas J. M. ; Kortekaas, R. T. J. ; Los, Maartje ; Madsen, Eva V. E. ; van der Mijle, H. C. J. ; Mol, Linda ; Neijenhuis, Peter A. ; Nienhuijs, Simon W. ; van den Nieuwenhof, Loes ; Peeters, Koen C. M. J. ; Polle, Sebastiaan W. ; Pon, Jolien ; Poortman, Pieter ; Radema, Sandra A. ; van Ramshorst, Bert ; de Reuver, Philip R. ; Rovers, Koen P. ; Schmitz, Roderick F. ; Sluiter, Nina ; Sommeijer, Dirkje W. ; Sonneveld, D. J. A. ; van Sprundel, T. C. ; Veltkamp, Sanne C. ; Vermaas, Maarten ; Verwaal, Victor J. ; Wassenaar, Emma ; Wegdam, Johannes A. ; de Wilt, Johannes H. W. ; Westerterp, Marinke ; Wit, Fennie ; Witkamp, Arjen J. ; van Woensdregt, Karlijn ; van der Zaag, Edwin S. ; Zournas, Mandy. / Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. In: The Lancet Gastroenterology and Hepatology. 2019 ; Vol. 4, No. 10. pp. 761-770.
@article{1429696260bc41e18d7c2678419f1374,
title = "Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial",
abstract = "Background: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. Methods: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0–2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5–8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. Findings: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19{\%}) of 100 patients were diagnosed with peritoneal metastases: nine (47{\%}) during surgical exploration preceding intentional adjuvant HIPEC, eight (42{\%}) during routine follow-up, and two (11{\%}) during diagnostic laparoscopy at 18-months. In the control group, 23 (23{\%}) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30{\%}) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9{\%} [95{\%} CI 73·3–88·5] for the experimental group vs 76·2{\%} [68·0–84·4] for the control group, log-rank one-sided p=0·28). 12 (14{\%}) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1{\%}) encapsulating peritoneal sclerosis. Interpretation: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. Funding: Organization for Health Research and Development and the Dutch Cancer Society.",
author = "Klaver, {Charlotte E. L.} and Wisselink, {Daniel D.} and Punt, {Cornelis J. A.} and Petur Snaebjornsson and Johannes Crezee and Aalbers, {Arend G. J.} and Alexandra Brandt and Bremers, {Andre J. A.} and Burger, {Jacobus W. A.} and Fabry, {Hans F. J.} and Floris Ferenschild and Sebastiaan Festen and {van Grevenstein}, {Wilhelmina M. U.} and Hemmer, {Patrick H. J.} and {de Hingh}, {Ignace H. J. T.} and Kok, {Niels F. M.} and Musters, {Gijsbert D.} and Lotte Schoonderwoerd and Tuynman, {Jurriaan B.} and {van de Ven}, {Anthony W. H.} and {van Westreenen}, {Henderik L.} and Wiezer, {Marinus J.} and Zimmerman, {David D. E.} and {van Zweeden}, {Annette A.} and Dijkgraaf, {Marcel G. W.} and Tanis, {Pieter J.} and Andeweg, {Caroline S.} and Bastiaenen, {Vivian P.} and Bemelman, {Willem A.} and {van der Bilt}, {Jarmila D. W.} and Johanne Bloemen and {den Boer}, {Frank C.} and Djamila Boerma and {ten Bokkel Huinink}, Daan and Brokelman, {Walter J. A.} and Cense, {Huib A.} and Consten, {Esther C. J.} and Geert-Jan Creemers and Crolla, {Rogier M. P. H.} and Dekker, {Jan-Willem T.} and Jennifer Demelinne and {van Det}, {Marc J.} and {van Diepen}, {Karin K.} and Marjolein Diepeveen and {van Duyn}, {Eino B.} and {van den Ende}, {Esther D.} and Pauline Evers and {van Geloven}, {Anna A. W.} and {van der Harst}, Erwin and Jeroen Heemskerk and Heikens, {Joost T.} and Hess, {Daniel A.} and Bas Inberg and Jan Jansen and Kloppenberg, {Frank W. H.} and Kootstra, {Thomas J. M.} and Kortekaas, {R. T. J.} and Maartje Los and Madsen, {Eva V. E.} and {van der Mijle}, {H. C. J.} and Linda Mol and Neijenhuis, {Peter A.} and Nienhuijs, {Simon W.} and {van den Nieuwenhof}, Loes and Peeters, {Koen C. M. J.} and Polle, {Sebastiaan W.} and Jolien Pon and Pieter Poortman and Radema, {Sandra A.} and {van Ramshorst}, Bert and {de Reuver}, {Philip R.} and Rovers, {Koen P.} and Schmitz, {Roderick F.} and Nina Sluiter and Sommeijer, {Dirkje W.} and Sonneveld, {D. J. A.} and {van Sprundel}, {T. C.} and Veltkamp, {Sanne C.} and Maarten Vermaas and Verwaal, {Victor J.} and Emma Wassenaar and Wegdam, {Johannes A.} and {de Wilt}, {Johannes H. W.} and Marinke Westerterp and Fennie Wit and Witkamp, {Arjen J.} and {van Woensdregt}, Karlijn and {van der Zaag}, {Edwin S.} and Mandy Zournas",
year = "2019",
month = "10",
day = "1",
doi = "10.1016/S2468-1253(19)30239-0",
language = "English",
volume = "4",
pages = "761--770",
journal = "The Lancet Gastroenterology and Hepatology",
issn = "2468-1253",
publisher = "Elsevier Ltd",
number = "10",

}

Klaver, CEL, Wisselink, DD, Punt, CJA, Snaebjornsson, P, Crezee, J, Aalbers, AGJ, Brandt, A, Bremers, AJA, Burger, JWA, Fabry, HFJ, Ferenschild, F, Festen, S, van Grevenstein, WMU, Hemmer, PHJ, de Hingh, IHJT, Kok, NFM, Musters, GD, Schoonderwoerd, L, Tuynman, JB, van de Ven, AWH, van Westreenen, HL, Wiezer, MJ, Zimmerman, DDE, van Zweeden, AA, Dijkgraaf, MGW, Tanis, PJ, Andeweg, CS, Bastiaenen, VP, Bemelman, WA, van der Bilt, JDW, Bloemen, J, den Boer, FC, Boerma, D, ten Bokkel Huinink, D, Brokelman, WJA, Cense, HA, Consten, ECJ, Creemers, G-J, Crolla, RMPH, Dekker, J-WT, Demelinne, J, van Det, MJ, van Diepen, KK, Diepeveen, M, van Duyn, EB, van den Ende, ED, Evers, P, van Geloven, AAW, van der Harst, E, Heemskerk, J, Heikens, JT, Hess, DA, Inberg, B, Jansen, J, Kloppenberg, FWH, Kootstra, TJM, Kortekaas, RTJ, Los, M, Madsen, EVE, van der Mijle, HCJ, Mol, L, Neijenhuis, PA, Nienhuijs, SW, van den Nieuwenhof, L, Peeters, KCMJ, Polle, SW, Pon, J, Poortman, P, Radema, SA, van Ramshorst, B, de Reuver, PR, Rovers, KP, Schmitz, RF, Sluiter, N, Sommeijer, DW, Sonneveld, DJA, van Sprundel, TC, Veltkamp, SC, Vermaas, M, Verwaal, VJ, Wassenaar, E, Wegdam, JA, de Wilt, JHW, Westerterp, M, Wit, F, Witkamp, AJ, van Woensdregt, K, van der Zaag, ES & Zournas, M 2019, 'Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial' The Lancet Gastroenterology and Hepatology, vol. 4, no. 10, pp. 761-770. https://doi.org/10.1016/S2468-1253(19)30239-0

Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial. / Klaver, Charlotte E. L.; Wisselink, Daniel D.; Punt, Cornelis J. A.; Snaebjornsson, Petur; Crezee, Johannes; Aalbers, Arend G. J.; Brandt, Alexandra; Bremers, Andre J. A.; Burger, Jacobus W. A.; Fabry, Hans F. J.; Ferenschild, Floris; Festen, Sebastiaan; van Grevenstein, Wilhelmina M. U.; Hemmer, Patrick H. J.; de Hingh, Ignace H. J. T.; Kok, Niels F. M.; Musters, Gijsbert D.; Schoonderwoerd, Lotte; Tuynman, Jurriaan B.; van de Ven, Anthony W. H.; van Westreenen, Henderik L.; Wiezer, Marinus J.; Zimmerman, David D. E.; van Zweeden, Annette A.; Dijkgraaf, Marcel G. W.; Tanis, Pieter J.; Andeweg, Caroline S.; Bastiaenen, Vivian P.; Bemelman, Willem A.; van der Bilt, Jarmila D. W.; Bloemen, Johanne; den Boer, Frank C.; Boerma, Djamila; ten Bokkel Huinink, Daan; Brokelman, Walter J. A.; Cense, Huib A.; Consten, Esther C. J.; Creemers, Geert-Jan; Crolla, Rogier M. P. H.; Dekker, Jan-Willem T.; Demelinne, Jennifer; van Det, Marc J.; van Diepen, Karin K.; Diepeveen, Marjolein; van Duyn, Eino B.; van den Ende, Esther D.; Evers, Pauline; van Geloven, Anna A. W.; van der Harst, Erwin; Heemskerk, Jeroen; Heikens, Joost T.; Hess, Daniel A.; Inberg, Bas; Jansen, Jan; Kloppenberg, Frank W. H.; Kootstra, Thomas J. M.; Kortekaas, R. T. J.; Los, Maartje; Madsen, Eva V. E.; van der Mijle, H. C. J.; Mol, Linda; Neijenhuis, Peter A.; Nienhuijs, Simon W.; van den Nieuwenhof, Loes; Peeters, Koen C. M. J.; Polle, Sebastiaan W.; Pon, Jolien; Poortman, Pieter; Radema, Sandra A.; van Ramshorst, Bert; de Reuver, Philip R.; Rovers, Koen P.; Schmitz, Roderick F.; Sluiter, Nina; Sommeijer, Dirkje W.; Sonneveld, D. J. A.; van Sprundel, T. C.; Veltkamp, Sanne C.; Vermaas, Maarten; Verwaal, Victor J.; Wassenaar, Emma; Wegdam, Johannes A.; de Wilt, Johannes H. W.; Westerterp, Marinke; Wit, Fennie; Witkamp, Arjen J.; van Woensdregt, Karlijn; van der Zaag, Edwin S.; Zournas, Mandy.

In: The Lancet Gastroenterology and Hepatology, Vol. 4, No. 10, 01.10.2019, p. 761-770.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial

AU - Klaver, Charlotte E. L.

AU - Wisselink, Daniel D.

AU - Punt, Cornelis J. A.

AU - Snaebjornsson, Petur

AU - Crezee, Johannes

AU - Aalbers, Arend G. J.

AU - Brandt, Alexandra

AU - Bremers, Andre J. A.

AU - Burger, Jacobus W. A.

AU - Fabry, Hans F. J.

AU - Ferenschild, Floris

AU - Festen, Sebastiaan

AU - van Grevenstein, Wilhelmina M. U.

AU - Hemmer, Patrick H. J.

AU - de Hingh, Ignace H. J. T.

AU - Kok, Niels F. M.

AU - Musters, Gijsbert D.

AU - Schoonderwoerd, Lotte

AU - Tuynman, Jurriaan B.

AU - van de Ven, Anthony W. H.

AU - van Westreenen, Henderik L.

AU - Wiezer, Marinus J.

AU - Zimmerman, David D. E.

AU - van Zweeden, Annette A.

AU - Dijkgraaf, Marcel G. W.

AU - Tanis, Pieter J.

AU - Andeweg, Caroline S.

AU - Bastiaenen, Vivian P.

AU - Bemelman, Willem A.

AU - van der Bilt, Jarmila D. W.

AU - Bloemen, Johanne

AU - den Boer, Frank C.

AU - Boerma, Djamila

AU - ten Bokkel Huinink, Daan

AU - Brokelman, Walter J. A.

AU - Cense, Huib A.

AU - Consten, Esther C. J.

AU - Creemers, Geert-Jan

AU - Crolla, Rogier M. P. H.

AU - Dekker, Jan-Willem T.

AU - Demelinne, Jennifer

AU - van Det, Marc J.

AU - van Diepen, Karin K.

AU - Diepeveen, Marjolein

AU - van Duyn, Eino B.

AU - van den Ende, Esther D.

AU - Evers, Pauline

AU - van Geloven, Anna A. W.

AU - van der Harst, Erwin

AU - Heemskerk, Jeroen

AU - Heikens, Joost T.

AU - Hess, Daniel A.

AU - Inberg, Bas

AU - Jansen, Jan

AU - Kloppenberg, Frank W. H.

AU - Kootstra, Thomas J. M.

AU - Kortekaas, R. T. J.

AU - Los, Maartje

AU - Madsen, Eva V. E.

AU - van der Mijle, H. C. J.

AU - Mol, Linda

AU - Neijenhuis, Peter A.

AU - Nienhuijs, Simon W.

AU - van den Nieuwenhof, Loes

AU - Peeters, Koen C. M. J.

AU - Polle, Sebastiaan W.

AU - Pon, Jolien

AU - Poortman, Pieter

AU - Radema, Sandra A.

AU - van Ramshorst, Bert

AU - de Reuver, Philip R.

AU - Rovers, Koen P.

AU - Schmitz, Roderick F.

AU - Sluiter, Nina

AU - Sommeijer, Dirkje W.

AU - Sonneveld, D. J. A.

AU - van Sprundel, T. C.

AU - Veltkamp, Sanne C.

AU - Vermaas, Maarten

AU - Verwaal, Victor J.

AU - Wassenaar, Emma

AU - Wegdam, Johannes A.

AU - de Wilt, Johannes H. W.

AU - Westerterp, Marinke

AU - Wit, Fennie

AU - Witkamp, Arjen J.

AU - van Woensdregt, Karlijn

AU - van der Zaag, Edwin S.

AU - Zournas, Mandy

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Background: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. Methods: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0–2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5–8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. Findings: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3–88·5] for the experimental group vs 76·2% [68·0–84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis. Interpretation: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. Funding: Organization for Health Research and Development and the Dutch Cancer Society.

AB - Background: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer. Methods: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0–2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m2) for 30 min at 42°C, delivered simultaneously or within 5–8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086. Findings: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3–88·5] for the experimental group vs 76·2% [68·0–84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis. Interpretation: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial. Funding: Organization for Health Research and Development and the Dutch Cancer Society.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85071901171&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31371228

U2 - 10.1016/S2468-1253(19)30239-0

DO - 10.1016/S2468-1253(19)30239-0

M3 - Article

VL - 4

SP - 761

EP - 770

JO - The Lancet Gastroenterology and Hepatology

JF - The Lancet Gastroenterology and Hepatology

SN - 2468-1253

IS - 10

ER -