Colorectal 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 colorectal cancer page for regimens that include active anticancer treatment.


Adjuvant therapy

Observation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gray et al. 2000 (QUASAR part 2) 1994-05 to 2003-12 Phase 3 (C) FULV Inferior OS
Hasegawa et al. 2016 2004-2010 Phase 3 (C) Tegafur, Uracil, Leucovorin Inferior RFS

No systemic treatment after surgery.

Preceding treatment

References

  1. QUASAR part 2: Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ; Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007 Dec 15;370(9604):2020-9. link to original article PubMed NCT00005586
  2. Hasegawa K, Saiura A, Takayama T, Miyagawa S, Yamamoto J, Ijichi M, Teruya M, Yoshimi F, Kawasaki S, Koyama H, Oba M, Takahashi M, Mizunuma N, Matsuyama Y, Watanabe T, Makuuchi M, Kokudo N. Adjuvant oral uracil-tegafur with leucovorin for colorectal cancer liver metastases: A randomized controlled trial. PLoS One. 2016 Sep 2;11(9):e0162400. eCollection 2016. link to original article link to PMC article PubMed UMIN C000000013

Therapy for oligometastatic disease, including perioperative therapy and hyperthermic intra-peritoneal chemotherapy

Observation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Allen-Mersh et al. 1994 1988-1993 Phase 3 (C) Intrahepatic floxuridine Seems to have inferior OS
Kemeny et al. 1999 NR Phase 3 (C) Intrahepatic floxuridine Seems to have inferior OS
Portier et al. 2006 (FFCD 9002) 1991-2001 Phase 3 (C) FULV Might have inferior PFS1
Nordlinger et al. 2008 (EORTC 40983) 2000-2004 Phase 3 (C) FOLFOX4 Inferior PFS

1Reported efficacy for FFCD 9002 is based on the 2008 pooled update.
No treatment other than surgical resection of oligometastatic disease.

References

  1. Allen-Mersh TG, Earlam S, Fordy C, Abrams K, Houghton J. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet. 1994 Nov 5;344(8932):1255-60. link to original article PubMed
  2. Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, Bertino JR, Turnbull AD, Sullivan D, Stockman J, Blumgart LH, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999 Dec 30;341(27):2039-48. link to original article PubMed
  3. FFCD 9002: Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, Belghiti J, Piedbois P, Guimbaud R, Nordlinger B, Bugat R, Lazorthes F, Bedenne L. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006 Nov 1;24(31):4976-82. link to original article PubMed
    1. Pooled update: Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V, Elias D, O'Callaghan C, Langer B, Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008 Oct 20;26(30):4906-11. Epub 2008 Sep 15. link to original article PubMed
  4. EORTC 40983: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie; Australasian Gastro-Intestinal Trials Group; Fédération Francophone de Cancérologie Digestive. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. link to original article link to PMC article does not contain dosing details PubMed NCT00006479
    1. Update: Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie; Australasian Gastro-Intestinal Trials Group; Fédération Francophone de Cancérologie Digestive. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectalcancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. Epub 2013 Oct 11. link to original article PubMed

Metastatic disease, first-line

Best supportive care

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goldberg et al. 1995 1988-1992 Phase 3 (C) Octreotide Did not meet co-primary endpoints of PFS/OS
Smyth et al. 1995 (N-trial) 1989-1992 Phase 3 (C) TCNU Did not meet endpoint of OS50%

No active treatment.

References

  1. Goldberg RM, Moertel CG, Wieand HS, Krook JE, Schutt AJ, Veeder MH, Mailliard JA, Dalton RJ; North Central Cancer Treatment Group. A phase III evaluation of a somatostatin analogue (octreotide) in the treatment of patients with asymptomatic advanced colon carcinoma. Cancer. 1995 Sep 15;76(6):961-6. link to original article PubMed
  2. N-trial: Smyth JF, Hardcastle JD, Denton G, Alderson D, Grace RH, Mansi JL, Yosef HM, Nordle O, Lauri H, Wählby S. Two phase III trials of tauromustine (TCNU) in advanced colorectal cancer. Ann Oncol. 1995 Nov;6(9):948-9. link to original article PubMed

Maintenance after first-line therapy

Observation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Koeberle et al. 2015 (SAKK 41/06) 2007-2012 Phase 3 (C) Bevacizumab Inconclusive whether non-inferior TTP
Simkens et al. 2015 (CAIRO3) 2007-2012 Phase 3 (C) CAP-B Inferior PFS-2
Luo et al. 2016 2010-2013 Phase 3 (C) Capecitabine Inferior PFS
Aparicio et al. 2018 (PRODIGE 9) 2010-2013 Phase 3 (C) Bevacizumab Did not meet primary endpoint of TCD

No further treatment after first-line induction.

Preceding treatment

References

  1. SAKK 41/06: Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, Matter K, Winterhalder R, Borner M, Anchisi S, Moosmann P, Kollar A, Saletti P, Roth A, Frueh M, Kueng M, Popescu RA, Schacher S, Hess V, Herrmann R. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol. 2015 Apr;26(4):709-14. Epub 2015 Jan 20. link to original article PubMed NCT00544700
  2. CAIRO3: Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M; Dutch Colorectal Cancer Group. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet. 2015 May 9;385(9980):1843-52. Epub 2015 Apr 7. link to original article PubMed NCT00442637
    1. Update: Goey KKH, Elias SG, van Tinteren H, Laclé MM, Willems SM, Offerhaus GJA, de Leng WWJ, Strengman E, Ten Tije AJ, Creemers GM, van der Velden A, de Jongh FE, Erdkamp FLG, Tanis BC, Punt CJA, Koopman M. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017 Sep 1;28(9):2128-2134. link to original article PubMed
  3. Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016 Jun;27(6):1074-81. Epub 2016 Mar 2. link to original article PubMed NCT02027363
  4. PRODIGE 9: Aparicio T, Ghiringhelli F, Boige V, Le Malicot K, Taieb J, Bouché O, Phelip JM, François E, Borel C, Faroux R, Dahan L, Jacquot S, Genet D, Khemissa F, Suc E, Desseigne F, Texereau P, Lepage C, Bennouna J; PRODIGE 9 Investigators. Bevacizumab maintenance versus no maintenance during chemotherapy-free intervals in metastatic colorectal cancer: a randomized phase III trial (PRODIGE 9). J Clin Oncol. 2018 Mar 1;36(7):674-681. Epub 2018 Jan 18. link to original article PubMed NCT00952029

Advanced or metastatic disease, subsequent lines of therapy

Best supportive care

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 1998 (V301) 1995-NR Phase 3 (C) Irinotecan Inferior OS
Jonker et al. 2007 (NCIC-CTG CO.17) 2003-2005 Phase 3 (C) Cetuximab Inferior OS
Van Cutsem et al. 2007 (20020408) 2004-01 to 2005-06 Phase 3 (C) Panitumumab Inferior PFS
Kim et al. 2016 (20100007) 2011-2013 Phase 3 (C) Panitumumab Inferior OS
Chen et al. 2020 (NCIC-CTG CO.26) 2016-2017 Randomized Phase 2 (C) Durvalumab & Tremelimumab Might have inferior OS

No treatment except for supportive care.

References

  1. V301: Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, Johannesen TB, Starkhammar H, Topham CA, Awad L, Jacques C, Herait P. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998 Oct 31;352(9138):1413-8. link to original article PubMed
  2. 20020408: Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. link to original article PubMed NCT00113763
  3. NCIC-CTG CO.17: Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. link to original article PubMed NCT00079066
    1. Subgroup analysis: Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. link to original article PubMed
    2. Subgroup analysis: Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC-CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. link to original article PubMed
  4. 20100007: Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. link to original article link to PMC article PubMed NCT01412957
  5. NCIC-CTG CO.26: Chen EX, Jonker DJ, Loree JM, Kennecke HF, Berry SR, Couture F, Ahmad CE, Goffin JR, Kavan P, Harb M, Colwell B, Samimi S, Samson B, Abbas T, Aucoin N, Aubin F, Koski S, Wei AC, Magoski NM, Tu D, O'Callaghan CJ. Effect of Combined Immune Checkpoint Inhibition vs Best Supportive Care Alone in Patients With Advanced Colorectal Cancer: The Canadian Cancer Trials Group CO.26 Study. JAMA Oncol. 2020;6(6):831–838. link to article link to PMC article PubMed NCT02870920

Placebo

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rao et al. 2004 2000-03 to 2001-02 Phase 3 (C) Tipifarnib Did not meet primary endpoint of OS
Yoshino et al. 2012 2009-08-25 to 2010-04-12 Randomized Phase 2 (C) Trifluridine and tipiracil Inferior OS
Grothey et al. 2012 (CORRECT) 2010-04-30 to 2011-03-22 Phase 3 (C) Regorafenib Inferior OS
Li et al. 2015 (CONCUR) 2012-04-29 to 2013-02-06 Phase 3 (C) Regorafenib Inferior OS
Mayer et al. 2015 (RECOURSE) 2012-06-17 to 2013-10-08 Phase 3 (C) Trifluridine and tipiracil Inferior OS
Jonker et al. 2018 (NCIC-CTG CO.23) 2013-04-15 to 2014-05-23 Phase 3 (C) Napabucasin Did not meet primary endpoint of OS
Xu et al. 2017 (TERRA) 2013-2015 Phase 3 (C) Trifluridine and tipiracil Seems to have inferior OS
Hickish et al. 2017 (2014-PT026) 2014-05-20 to 2015-09-02 Phase 3 (C) MABp1 Inferior primary endpoint
Li et al. 2018 (FRESCO) 2014-2016 Phase 3 (C) Fruquintinib Inferior OS
Van Cutsem et al. 2018 (LUME-Colon 1) 2014-2016 Phase 3 (C) Nintedanib Inferior PFS
Chi et al. 2021 (ALTER0703) 2014-2016 Phase 3 (C) Anlotinib Did not meet primary endpoint of OS
Dasari et al. 2023 (FRESCO-2) 2020-08-12 to 2021-12-02 Phase 3 (C) Fruquintinib Inferior OS

No active antineoplastic treatment.

Prior treatment criteria

  • FRESCO: At least 2 lines of chemotherapy but no prior VEGFR inhibitor therapy, with progression
  • FRESCO-2: All current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil and/or regorafenib

References

  1. Rao S, Cunningham D, de Gramont A, Scheithauer W, Smakal M, Humblet Y, Kourteva G, Iveson T, Andre T, Dostalova J, Illes A, Belly R, Perez-Ruixo JJ, Park YC, Palmer PA. Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol. 2004 Oct 1;22(19):3950-7. link to original article PubMed
  2. Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, Tsuji A, Yamaguchi K, Muro K, Sugimoto N, Tsuji Y, Moriwaki T, Esaki T, Hamada C, Tanase T, Ohtsu A. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012 Oct;13(10):993-1001. Epub 2012 Aug 28. link to original article PubMed JapicCTI-090880
  3. CORRECT: Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. Epub 2012 Nov 22. link to original article PubMed NCT01103323
    1. Dataset: Project Data Sphere
  4. CONCUR: Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. Epub 2015 May 13. link to original article PubMed NCT01584830
  5. RECOURSE: Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. link to original article PubMed NCT01607957
    1. Subgroup analysis: Van Cutsem E, Mayer RJ, Laurent S, Winkler R, Grávalos C, Benavides M, Longo-Munoz F, Portales F, Ciardiello F, Siena S, Yamaguchi K, Muro K, Denda T, Tsuji Y, Makris L, Loehrer P, Lenz HJ, Ohtsu A; RECOURSE Study Group. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer. Eur J Cancer. 2018 Feb;90:63-72. Epub 2017 Dec 21. link to original article link to PMC article PubMed
  6. 2014-PT026: Hickish T, Andre T, Wyrwicz L, Saunders M, Sarosiek T, Kocsis J, Nemecek R, Rogowski W, Lesniewski-Kmak K, Petruzelka L, Apte RN, Mohanty P, Stecher M, Simard J, de Gramont A. MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2017 Feb;18(2):192-201. Epub 2017 Jan 14. link to original article PubMed NCT02138422
  7. TERRA: Xu J, Kim TW, Shen L, Sriuranpong V, Pan H, Xu R, Guo W, Han SW, Liu T, Park YS, Shi C, Bai Y, Bi F, Ahn JB, Qin S, Li Q, Wu C, Ma D, Lin D, Li J. Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: The TERRA study. J Clin Oncol. 2018 Feb 1;36(4):350-358. Epub 2017 Dec 7. link to original article PubMed NCT01955837
  8. NCIC-CTG CO.23: Jonker DJ, Nott L, Yoshino T, Gill S, Shapiro J, Ohtsu A, Zalcberg J, Vickers MM, Wei AC, Gao Y, Tebbutt NC, Markman B, Price T, Esaki T, Koski S, Hitron M, Li W, Li Y, Magoski NM, Li CJ, Simes J, Tu D, O'Callaghan CJ. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):263-270. Epub 2018 Feb 1. link to original article PubMed NCT01830621
  9. FRESCO: Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, Yang L, Deng Y, Chen ZD, Zhong H, Pan H, Guo W, Shu Y, Yuan Y, Zhou J, Xu N, Liu T, Ma D, Wu C, Cheng Y, Chen D, Li W, Sun S, Yu Z, Cao P, Chen H, Wang J, Wang S, Wang H, Fan S, Hua Y, Su W. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018 Jun 26;319(24):2486-2496. link to original article link to PMC article PubMed NCT02314819
  10. LUME-Colon 1: Van Cutsem E, Yoshino T, Lenz HJ, Lonardi S, Falcone A, Limón ML, Saunders M, Sobrero A, Park YS, Ferreiro R, Hong YS, Tomasek J, Taniguchi H, Ciardiello F, Stoehr J, Oum'Hamed Z, Vlassak S, Studeny M, Argiles G. Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study. Ann Oncol. 2018 Sep 1;29(9):1955-1963. link to original article link to PMC article PubMed NCT02149108
  11. ALTER0703: Chi Y, Shu Y, Ba Y, Bai Y, Qin B, Wang X, Xiong J, Xu N, Zhang H, Zhou J, Xu J, Cheng Y, Feng J, Hu C, Chen Y, Chen Z, Wang J, Dang C, Wang J, Wan Y, Tang Y, Wang D, Liu J, Wu M, Deng Y, Li X, Li Y, Dong J, Jiang D, Li G, Wu Q, Li J, Qi Y, Sun Y, Cai J. Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Trial (ALTER0703). Oncologist. 2021 Oct;26(10):e1693-e1703. Epub 2021 Jun 25. link to original article link to PMC article PubMed NCT02332499
  12. FRESCO-2: Dasari A, Lonardi S, Garcia-Carbonero R, Elez E, Yoshino T, Sobrero A, Yao J, García-Alfonso P, Kocsis J, Cubillo Gracian A, Sartore-Bianchi A, Satoh T, Randrian V, Tomasek J, Chong G, Paulson AS, Masuishi T, Jones J, Csőszi T, Cremolini C, Ghiringhelli F, Shergill A, Hochster HS, Krauss J, Bassam A, Ducreux M, Elme A, Faugeras L, Kasper S, Van Cutsem E, Arnold D, Nanda S, Yang Z, Schelman WR, Kania M, Tabernero J, Eng C; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023 Jul 1;402(10395):41-53. Epub 2023 Jun 15. link to original article PubMed NCT04322539
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