Colon cancer - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main colon cancer page for regimens that include active anticancer treatment.
=Neoadjuvant therapy=
==No neoadjuvant therapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hu et al. 2024 (OPTICAL)	2016-01-06 to 2021-04-30	Phase 3 (C)	1a. mFOLFOX6 x 61b. CapeOx x 4	Might have lower DFS36 (primary endpoint)DFS36: 77.5% vs 82.1%(HR 1.35, 95% CI 0.97-1.85)
No systemic treatment before surgery.
====Subsequent treatment====
*Surgery
===References===
#OPTICAL: Hu H, Zhang J, Li Y, Wang X, Wang Z, Wang H, Kang L, Liu P, Lan P, Wu X, Zhen Y, Pei H, Huang Z, Zhang H, Chen W, Zeng Y, Lai J, Wei H, Huang X, Chen J, Chen J, Tao K, Xu Q, Peng X, Liang J, Cai G, Ding K, Ding Z, Hu M, Zhang W, Tang B, Hong C, Cao J, Huang Z, Cao W, Li F, Wang X, Wang C, Huang Y, Zhao Y, Cai Y, Ling J, Xie X, Wu Z, Shi L, Ling L, Liu H, Wang J, Huang M, Deng Y; OPTICAL study group. Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial. J Clin Oncol. 2024 Sep 1;42(25):2978-2988. Epub 2024 Apr 2. link to original article EuroPMC NCT02572141
=Adjuvant therapy, stage II=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moertel et al. 1995 (INT-0035) 	1984-1987 	Phase 3 (C)	5-FU & Levamisole 	Did not meet primary endpoint of OS
Laffer et al. 2008 (SAKK 40/87) 	1987-1993 	Phase 3 (C)	1. Portal venous 5-FU & Mitomycin2. 5-FU & Mitomycin	Did not meet primary endpoint of OS
Kemeny et al. 2022 (ECOG-ACRIN E1292)	1993-2000 	Phase 3 (C)	Peri-operative 5-FU 	Did not meet primary endpoint of OS
Schippinger et al. 2007 	1993-2003 	Phase 3 (C)	FULV 	Did not meet primary endpoint of OS
Hartung et al. 2005 	1997-2000 	Phase 3 (C)	Edrecolomab 	Did not meet primary endpoint of OS
Niedzwiecki et al. 2011 (CALGB 9581) 	1997-2002 	Phase 3 (C)	Edrecolomab 	Did not meet primary endpoint of OS
No systemic treatment after surgery for stage II colon cancer.
====Preceding treatment====
*Surgery
===References===
#INT-0035: Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA; North Central Cancer Treatment Group; SWOG; ECOG. Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer. J Clin Oncol. 1995 Dec;13(12):2936-43. link to original article EuroPMC
#Hartung G, Hofheinz RD, Dencausse Y, Sturm J, Kopp-Schneider A, Dietrich G, Fackler-Schwalbe I, Bornbusch D, Gonnermann M, Wojatschek C, Lindemann W, Eschenburg H, Jost K, Edler L, Hochhaus A, Queisser W. Adjuvant therapy with edrecolomab versus observation in stage II colon cancer: a multicenter randomized phase III study. Onkologie. 2005 Jun;28(6-7):347-50. Epub 2005 Jun 2. link to original article EuroPMC
#Schippinger W, Samonigg H, Schaberl-Moser R, Greil R, Thödtmann R, Tschmelitsch J, Jagoditsch M, Steger GG, Jakesz R, Herbst F, Hofbauer F, Rabl H, Wohlmuth P, Gnant M, Thaler J; ABCSG. A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer. Br J Cancer. 2007 Oct 22;97(8):1021-7. Epub 2007 Sep 25. link to original article link to PMC article EuroPMC
#SAKK 40/87: Laffer U, Metzger U, Aeberhard P, Lorenz M, Harder F, Maibach R, Zuber M, Herrmann R. Adjuvant perioperative portal vein or peripheral intravenous chemotherapy for potentially curative colorectal cancer: long-term results of a randomized controlled trial. Int J Colorectal Dis. 2008 Dec;23(12):1233-41. Epub 2008 Aug 8. link to original article EuroPMC
#CALGB 9581: Niedzwiecki D, Bertagnolli MM, Warren RS, Compton CC, Kemeny NE, Benson AB 3rd, Eckhardt SG, Alberts S, Porjosh GN, Kerr DJ, Fields A, Rougier P, Pipas JM, Schwartz JH, Atkins J, O'Rourke M, Perry MC, Goldberg RM, Mayer RJ, Colacchio TA. Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581. J Clin Oncol. 2011 Aug 10;29(23):3146-52. Epub 2011 Jul 11. link to original article link to PMC article EuroPMC NCT00002968
#ECOG-ACRIN E1292: Kemeny MM, Zhao F, Forastiere AA, Catalano P, Hamilton SR, Miedema BW, Dawson NA, Weiner LM, Smith BD, Mason BA, Graziano SL, Gilman PB, Venook AP, Pinto HA, Whitehead RP, O'Dwyer PJ, Benson AB. Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292). Ann Surg Oncol. 2023 Feb;30(2):1099-1109. Epub 2022 Oct 28. link to original article link to PMC article EuroPMC NCT00002525
#PanDRa-BD: jRCTs031190186
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Midgley et al. 2010 (VICTOR)	2002-2004 	Phase 3 (C)	Rofecoxib 	Did not meet primary endpoint of OS
No active antineoplastic treatment.
====Preceding treatment====
*Surgery
===References===
#VICTOR: Midgley RS, McConkey CC, Johnstone EC, Dunn JA, Smith JL, Grumett SA, Julier P, Iveson C, Yanagisawa Y, Warren B, Langman MJ, Kerr DJ. Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial. J Clin Oncol. 2010 Oct 20;28(30):4575-80. Epub 2010 Sep 13. link to original article EuroPMC NCT00031863
=Adjuvant therapy, stage III=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Panettiere et al. 1988 (SWOG S7510)	1975-1977 	Phase 3 (C)	1. 5-FU & Semustine2. 5-FU, Semustine, BCG 	Did not meet primary endpoint
Lessner et al. 1984 	1975-1979 	Phase 3 (C)	1. 5-FU & Semustine2. 5-FU, Semustine, BCG 3. BCG 	Did not meet primary endpoint of OS
Wolmark et al. 1988 (NSABP C-01) 	1977-1983 	Phase 3 (C)	1. MOF2. BCG 	Did not meet primary endpoint of OS1
Laffer et al. 1995 (SAKK 40/81) 	1981-1987 	Phase 3 (C)	Portal venous chemotherapy 	Seems to have shorter OS
Moertel et al. 1990 (SWOG S8591) 	1984-1987 	Phase 3 (C)	1. 5-FU & Levamisole 	Shorter OS
Moertel et al. 1990 (SWOG S8591) 	1984-1987 	Phase 3 (C)	2. Levamisole 	Not reported
Wolmark et al. 1990 (NSABP C-02) 	1984-1988 	Phase 3 (C)	Portal venous chemotherapy 	Might have shorter OS
Laurie et al. 1989 	Not reported 	Phase 3 (C)	1. 5-FU & Levamisole 	Seems to have shorter OS
Laurie et al. 1989 	Not reported 	Phase 3 (C)	2. Levamisole 	Not reported
Fielding et al. 1992 (AXIS-CRC) 	Not reported 	Phase 3 (C)	Portal venous chemotherapy 	Did not meet primary endpoint of OS
Riethmüller et al. 1994 	1985-1990 	Phase 3 (C)	Edrecolomab 	Seems to have shorter OS
Marsoni et al. 1995 (SITAC-01) 	Not reported 	Phase 3 (C)	FULV 	Seems to have shorter OS
Marsoni et al. 1995 (NCIC-CTG C-03)	Not reported 	Phase 3 (C)	FULV 	Seems to have shorter OS
Marsoni et al. 1995 (FFCD 8802) 	Not reported 	Phase 3 (C)	FULV 	Seems to have shorter OS
Vaillant et al. 2000 	1986-1991 	Phase 3 (C)	5-FU; IP 	Did not meet co-primary endpoints of DFS60/OS60
Rougier et al. 1998 	1987-1993 	Phase 3 (C)	Portal venous chemotherapy 	Did not meet primary endpoint of OS
Laffer et al. 2008 (SAKK 40/87) 	1987-1993 	Phase 3 (C)	1. Portal venous 5-FU & Mitomycin2. 5-FU & Mitomycin	Did not meet primary endpoint of OS
O'Connell et al. 1997 (CALGB 8896) 	1988-02 to 1989-08 	Phase 3 (C)	FULV 	Seems to have shorter OS
1Reported efficacy for NSABP C-01 is based on the 2004 update.
No systemic treatment after surgery. The AXIS trial is named "AXIS-CRC" here so as not to confuse it with the AXIS trial in renal cell carcinoma. Note that Marsoni et al. 1995 (IMPACT) is a pooled report of three RCTs.
====Preceding treatment====
*Surgery
===References===
#Lessner HE, Mayer RJ, Ellenberg SS, Holyoke ED; Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer--results of a prospectively randomized trial. N Engl J Med. 1984 Mar 22;310(12):737-43. link to original article EuroPMC
#NSABP C-01: Wolmark N, Fisher B, Rockette H, Redmond C, Wickerham DL, Fisher ER, Jones J, Glass A, Lerner H, Lawrence W, Prager D, Wexler M, Evans J, Cruz A, Dimitrov N, Jochimsen P; NSABP. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst. 1988 Mar 2;80(1):30-6. link to original article EuroPMC
##Update: Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N. Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst. 2004 Aug 4;96(15):1128-32. link to original article EuroPMC
##Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article EuroPMC
#SWOG S7510: Panettiere FJ, Goodman PJ, Costanzi JJ, Cruz AB Jr, Vaitkevicius VK, McCracken JD, Brownlee RW, Laufman L, Stephens RL, Bonnet J, Bottomley R, Rivkin S, Fletcher W, Oishi N, Chen TT. Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study. J Clin Oncol. 1988 Jun;6(6):947-54. link to original article EuroPMC
# Laurie JA, Moertel CG, Fleming TR, Wieand HS, Leigh JE, Rubin J, McCormack GW, Gerstner JB, Krook JE, Malliard J, Twito DI, Morton RF, Tschetter LK, Barlow JF; The North Central Cancer Treatment Group and the Mayo Clinic. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol. 1989 Oct;7(10):1447-56. link to original article EuroPMC
#Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352-8. link to original article EuroPMC
##Update: Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995 Mar 1;122(5):321-6. link to original article EuroPMC
# SWOG S8591: Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352-8. link to original article EuroPMC
## Update: Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Mailliard JA. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995 Mar 1;122(5):321-6. link to original article EuroPMC
#NSABP C-02: Wolmark N, Rockette H, Wickerham DL, Fisher B, Redmond C, Fisher ER, Potvin M, Davies RJ, Jones J, Robidoux A, Wexler M, Gordon P, Cruz AB, Horsley S, Nims TA, Thirlwell M, Phillips WA, Prager D, Stern HS, Lerner HJ, Frazier TG. Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project protocol C-02. J Clin Oncol. 1990 Sep;8(9):1466-75. link to original article EuroPMC
##Pooled update: Wilkinson NW, Yothers G, Lopa S, Costantino JP, Petrelli NJ, Wolmark N. Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05: a baseline from which to compare modern adjuvant trials. Ann Surg Oncol. 2010 Apr;17(4):959-66. link to original article link to PMC article EuroPMC
#AXIS: Fielding LP, Hittinger R, Grace RH, Fry JS. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet. 1992 Aug 29;340(8818):502-6. link to original article EuroPMC
#Riethmüller G, Schneider-Gädicke E, Schlimok G, Schmiegel W, Raab R, Höffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, Buggisch P, Witte J; German Cancer Aid 17-1A Study Group. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. Lancet. 1994 May 14;343(8907):1177-83. link to original article EuroPMC
#SAKK 40/81: Laffer U, Metzger U, Aeberhard P, Maibach R, Castiglione M, Goldhirsch A; Swiss Group for Clinical Cancer Research. Long-term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Lancet. 1995 Feb 11;345(8946):349-53. link to original article EuroPMC
#IMPACT: Marsoni S, Labianca R, Pancera G, Torri V, Zaniboni A, Erlichman C, Pater J, Shepherd L, Zee B, Seitz JF, Milan C, Pignon JP; International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet. 1995 Apr 15;345(8955):939-44. link to original article EuroPMC
##Update: Zaniboni A, Labianca R, Marsoni S, Torri V, Mosconi P, Grilli R, Apolone G, Cifani S, Tinazzi A; Gruppo Italiano Valutazione Interventi in Oncologia. GIVIO-SITAC 01: A randomized trial of adjuvant 5-fluorouracil and folinic acid administered to patients with colon carcinoma--long term results and evaluation of the indicators of health-related quality of life. Cancer. 1998 Jun 1;82(11):2135-44. link to original article EuroPMC
#CALGB 8896: O'Connell MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ, Wieand HS. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246-50. link to original article EuroPMC
##Pooled update: Erlichman C, O'Connell M, Kahn M, Marsoni S, Torri V, Tardio B, Zaniboni A, Pancera G, Martignoni G, Labianca R, Barni A, Seitz JF, Milan C, Bedenne L, Giovannini M, Letreut YP, Skillings J, Shepard L, Zee B, Petrioli R, Francini G; International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol. 1999 May;17(5):1356-63. link to original article EuroPMC
#Rougier P, Sahmoud T, Nitti D, Curran D, Doci R, De Waele B, Nakajima T, Rauschecker H, Labianca R, Pector JC, Marsoni S, Apolone G, Lasser P, Couvreur ML, Wils J; EORTC Gastrointestinal Tract Cancer Cooperative Group; Gruppo Interdisciplinare Valutazione Interventi in Oncologia; Japanese Foundation for Cancer Research. Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. Lancet. 1998 Jun 6;351(9117):1677-81. link to original article EuroPMC
#Vaillant JC, Nordlinger B, Deuffic S, Arnaud JP, Pelissier E, Favre JP, Jaeck D, Fourtanier G, Grandjean JP, Marre P, Letoublon C. Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: a multicenter phase III trial. Ann Surg. 2000 Apr;231(4):449-56. link to original article link to PMC article EuroPMC
#SAKK 40/87: Laffer U, Metzger U, Aeberhard P, Lorenz M, Harder F, Maibach R, Zuber M, Herrmann R. Adjuvant perioperative portal vein or peripheral intravenous chemotherapy for potentially curative colorectal cancer: long-term results of a randomized controlled trial. Int J Colorectal Dis. 2008 Dec;23(12):1233-41. Epub 2008 Aug 8. link to original article EuroPMC
#ADAGE: NCT02355379
#POLEM: NCT03827044
==Placebo==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Midgley et al. 2010 (VICTOR)	2002-2004 	Phase 3 (C)	Rofecoxib 	Did not meet primary endpoint of OSOS36: 86.9% vs 87.7%(HR 1.03, 95% CI 0.86-1.23)
Chia et al. 2025 (ASCOLT) 	2009-02-25 to 2021-06-30	Phase 3 (C)	Aspirin 	Did not meet primary endpoint of DFSDFS60: 74.8% vs 77%(HR 1.10, 95% CI 0.88-1.37)
No active antineoplastic treatment.
====Preceding treatment====
*Surgery
===References===
#VICTOR: Midgley RS, McConkey CC, Johnstone EC, Dunn JA, Smith JL, Grumett SA, Julier P, Iveson C, Yanagisawa Y, Warren B, Langman MJ, Kerr DJ. Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial. J Clin Oncol. 2010 Oct 20;28(30):4575-80. Epub 2010 Sep 13. link to original article EuroPMC NCT00031863
#ASCOLT: Chia JWK, Segelov E, Deng Y, Ho GF, Wang W, Han S, Sharma A, Ding K, Chen G, Jeffery MG, Tham CK, Ahn JB, Nott L, Zielinski R, Chao TY, van Hagen T, Wei PL, Day F, Mehta S, Yau T, Peng J, Hayes TM, Li Y, Gandhi M, Foo EMJ, Rahman N, Rothwell P, Ali R, Simes J, Toh HC. Aspirin after completion of standard adjuvant therapy for colorectal cancer (ASCOLT): an international, multicentre, phase 3, randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2025 Jan. Epub ahead of print. link to original article link to EuroPMC NCT00565708
Category:Colon cancer regimens
Category:Null regimens
Category:Disease-specific pages
Category:Colorectal cancers