Skip to main content

Advertisement

SpringerLink
Log in

Multicenter phase II study of second-line bevacizumab plus doublet combination chemotherapy in patients with metastatic colorectal cancer progressed after upfront bevacizumab plus doublet combination chemotherapy

  • PHASE II STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background To investigate the efficacy and safety of bevacizumab beyond first progression combined with doublet chemotherapy in patients with metastatic colorectal cancer. Methods This multicenter phase II study included 76 patients with metastatic colorectal cancer progressed after first-line bevacizumab plus doublet chemotherapy. Study treatment consisted of second-line continuation of bevacizumab plus crossover standard doublet chemotherapy, consisting of FOLFOX, CapeOX, or FOLFIRI. Bevacizumab was administered in doses of 5 mg/kg/2-week or 7.5 mg/kg/3-week according to the schedules of the combined regimen. Results Median progression-free survival (PFS) and overall survival (OS) was 6.5 months (95 % CI, 5.2–7.8) and 12.8 months (95 % CI, 8.8–16.9), respectively, with no significant differences according to combined doublet chemotherapy. The response rate (RR) was 17.1 % (95 % CI, 8.6–5.6) with no statistical significance between regimens (p = 0.053). The first-line RR and PFS did not affect the second-line efficacy outcomes; RR (14.0 % vs 21.2 %, p = 0.405), median PFS (5.6 vs 6.7 months, p = 0.335), and OS (15.4 vs 11.0 months, p = 0.383) were not different between previous responders and non-responders, and the median PFS (p = 0.186) and OS (p = 0.495) were not different either according to the length of first-line PFS; however, OS from the first-line chemotherapy was longer in patients with longer first-line PFS (26.4 vs 14.8 months, p = 0.010). Bevacizumab-related significant adverse events included proteinuria (1.3 %) and thromboembolism (1.3 %). Conclusions Bevacizumab beyond first progression could be considered a treatment strategy even in patients progressed after first-line bevacizumab plus doublet chemotherapy. Second-line efficacy outcomes did not differ according to the first-line responses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18(16):2938–2947

    PubMed  Google Scholar 

  2. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P (2000) Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 355(9209):1041–1047

    Article  PubMed  CAS  Google Scholar 

  3. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25(12):1539–1544. doi:10.1200/JCO.2006.09.6305

    Article  PubMed  CAS  Google Scholar 

  4. Grothey A, Sugrue MM, Purdie DM, Dong W, Sargent D, Hedrick E, Kozloff M (2008) Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 26(33):5326–5334. doi:10.1200/JCO.2008.16.3212

    Article  PubMed  CAS  Google Scholar 

  5. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, Schwartzberg L, Hedrick E (2008) Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 26(21):3523–3529. doi:10.1200/JCO.2007.15.4138

    Article  PubMed  CAS  Google Scholar 

  6. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. doi:10.1056/NEJMoa032691

    Article  PubMed  CAS  Google Scholar 

  7. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019. doi:10.1200/JCO.2007.14.9930

    Article  PubMed  CAS  Google Scholar 

  8. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22(2):229–237. doi:10.1200/JCO.2004.05.113

    Article  PubMed  CAS  Google Scholar 

  9. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29(15):2011–2019. doi:10.1200/JCO.2010.33.5091

    Article  PubMed  Google Scholar 

  10. Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, Dibartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, Bridgewater J, Cunningham D (2009) Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. doi:10.1093/annonc/mdp233

  11. Bekaii-Saab TS, Grothey A, Bendell JC, Kozloff M, Cohn AL, Mun Y, Fish S, Flick ED, Dalal D, Hurwitz H (2012) Effectiveness and safety of second-line (2L) irinotecan- and oxaliplatin-based regimens after first-line (1L) bevacizumab (BV)-containing treatment (tx) for metastatic colorectal cancer (mCRC): results from the ARIES observational cohort study. ASCO Meet Abstr 30(4_suppl):535

    Google Scholar 

  12. Kozloff M, Bekaii-Saab TS, Bendell JC, Cohn AL, Hurwitz H, Roach N, Tezcan H, Fish S, Flick ED, Mun Y, Dalal D, Grothey A (2011) Effectiveness of first- or second-line bevacizumab (BV) treatment (tx) in elderly patients (pts) with metastatic colorectal cancer (mCRC) in ARIES, an observational cohort study (OCS). ASCO Meet Abstr 29(15_suppl):3625

    Google Scholar 

  13. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Investig 105(8):R15–R24. doi:10.1172/JCI8829

    Article  PubMed  CAS  Google Scholar 

  14. Klement G, Huang P, Mayer B, Green SK, Man S, Bohlen P, Hicklin D, Kerbel RS (2002) Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. Clin Cancer Res: Off J Am Assoc Cancer Res 8(1):221–232

    CAS  Google Scholar 

  15. Kopetz S, Abbruzzese JL (2009) Hidden biases in an observational study of bevacizumab beyond progression. J Clin Oncol 27(10):1732–1733. doi:10.1200/JCO.2009.21.2084, author reply 1733

    Article  PubMed  Google Scholar 

  16. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, Gollins S, Siu LL, Laguerre S, Cunningham D (2008) Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol 19(10):1720–1726. doi:10.1093/annonc/mdn370

    Article  PubMed  CAS  Google Scholar 

  17. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J (2010) Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28(31):4706–4713. doi:10.1200/JCO.2009.27.6055

    Article  PubMed  CAS  Google Scholar 

  18. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kroning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd (2008) EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26(14):2311–2319. doi:10.1200/JCO.2007.13.1193

    Article  PubMed  CAS  Google Scholar 

  19. Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, Van Hazel G, Moiseyenko V, Ferry D, McKendrick J, Soussan-Lazard K, Boelle E, Allegra C (2011) Results from VELOUR, a phase 3 study of aflibercept (A) versus placebo (pbo) in combination with FOLFIRI for the treatment of patients (pt) with previously treated metastatic colorectal cancer (MCRC). Eur J Cancer 47(Supplement 2 (0)):5. doi:10.1016/s0959-8049(11)70105-8

    Article  Google Scholar 

  20. Horita Y, Yamada Y, Kato K, Hirashima Y, Akiyoshi K, Nagashima K, Nakajima T, Hamaguchi T, Shimada Y (2011) Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial. Int J Clin Oncol / Japan Soc Clin Oncol. doi:10.1007/s10147-011-0331-2

  21. Arnold D, Andre T, Bennouna J, Sastre J, Osterlund PJ, Greil R, Van Cutsem E, Von Moos R, Reyes-Rivera I, Bendahmane B, Kubicka S (2012) Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). ASCO Meet Abstr 30(18_suppl):CRA3503

    Google Scholar 

  22. 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 (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765. doi:10.1056/NEJMoa0804385

    Article  PubMed  CAS  Google Scholar 

  23. 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 (2007) 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 25(13):1658–1664. doi:10.1200/JCO.2006.08.1620

    Article  PubMed  Google Scholar 

  24. Mishima H, Oba K, Sakamoto J, Muro K, Yoshino T, Hyodo I, Maehara Y (2012) FOLFIRI plus bevacizumab 5 mg/kg versus 10 mg/kg as second-line therapy in patients with metastatic colorectal cancer who have failed first-line bevacizumab plus oxaliplatin-based therapy: a randomized phase III study (EAGLE Study). Jpn J Clin Oncol 42(2):134–138. doi:10.1093/jjco/hyr180

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065 and A062254). Bevacizumab was kindly provided by Roche Korea Co., Ltd.

Conflict of interest statement

We declare that we have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Yong Sang Hong, Kyu-pyo Kim, Jae-Lyun Lee & Tae Won Kim

  2. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Jeeyun Lee, Young Suk Park, Joon Oh Park & Se Hoon Park

  3. Center for Colorectal Cancer, National Cancer Center, Goyang, Korea

    Sun Young Kim & Ji Yeon Baek

  4. Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

    Jee Hyun Kim & Keun-Wook Lee

  5. Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Tae-You Kim

Authors
  1. Yong Sang Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeeyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyu-pyo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae-Lyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young Suk Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joon Oh Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Se Hoon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sun Young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ji Yeon Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jee Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Keun-Wook Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tae-You Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tae Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tae Won Kim.

Additional information

Yong Sang Hong and Jeeyun Lee equally contributed to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table

Treatment exposure. (DOC 45 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hong, Y.S., Lee, J., Kim, Kp. et al. Multicenter phase II study of second-line bevacizumab plus doublet combination chemotherapy in patients with metastatic colorectal cancer progressed after upfront bevacizumab plus doublet combination chemotherapy. Invest New Drugs 31, 183–191 (2013). https://doi.org/10.1007/s10637-012-9853-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-012-9853-3

Keywords

Search

Navigation