Advertisement
Research Article| Volume 9, ISSUE 1, P32-39, January 2018

Download started.

Ok

Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial

Published:August 12, 2017DOI:https://doi.org/10.1016/j.jgo.2017.07.010
Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial
Previous ArticleChallenges of conducting a prospective clinical trial for older patients: Lessons learned from NCCTG N0949 (alliance)
Next ArticleNeoadjuvant chemoradiation is associated with improved overall survival in older patients with esophageal cancer

      Abstract

      Objectives

      Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), compared with FOLFIRI alone, in patients with metastatic colorectal cancer previously treated with oxaliplatin-based therapy. This subset analysis of the VELOUR study investigates aflibercept plus FOLFIRI versus placebo plus FOLFIRI according to age.

      Methods

      Efficacy and safety were analyzed by treatment arm and age (≥ or <65 years).

      Results

      Overall, 443 patients were ≥65 years old (205 in aflibercept arm; 238 in placebo arm) and 783 were <65 years old (407 in aflibercept arm; 376 in placebo arm). Median OS was 12.6 versus 11.3 months (hazard ratio [HR]: 0.85; 95.34% CI 0.68–1.07) in patients ≥65 years old and 14.5 versus 12.5 months (HR: 0.80; 95.34% CI 0.67–0.95) in those patients <65 years old, for patients receiving FOLFIRI plus aflibercept or placebo, respectively. There was no interaction between treatment and age. Treatment-emergent adverse events (AEs) were comparable for patients <65 years and ≥65 years old. The incidence of grade 3/4 AEs was higher for patients ≥65 years old than for those <65 years old in both the aflibercept (89.3% versus 80.5%) and placebo (67.4% versus 59.4%) arms. Interaction tests for grade 3/4 antiangiogenic agent-related AEs suggested no heterogeneity between the older and younger patient populations (p > 0.1).

      Conclusion

      A limited but consistent benefit on both OS and PFS was associated with the addition of aflibercept to FOLFIRI compared with placebo in patients <65 and ≥65 years old, with a marked but manageable increase in the toxicity profile in older patients.

      Trial Registration

      clinicaltrials.gov NCT00561470

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Geriatric Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Register: Create an account
      Institutional Access: Sign in to ScienceDirect

      References

        • Ervik M.
        • Lam F.
        • Ferlay J.
        • Mery L.
        • Soerjomataram I.
        • Bray F.
        Cancer today.
        International Agency for Research on Cancer, Lyon, France2016 (Available from:)
        http://gco.iarc.fr/today
        Date accessed: September 5, 2016
        View in Article
        • Ferlay J.
        • Soerjomataram I.
        • Dikshit R.
        • Eser S.
        • Mathers C.
        • Rebelo M.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int J Cancer. 2015; 136: E359-86
        View in Article
        • Howlader N.
        • Noone A.M.
        • Krapcho M.
        • Miller A.P.
        • Bishop K.
        • Altekruse S.F.
        • et al.
        SEER cancer statistics review, 1975–2013, based on November 2015 SEER data submission, posted to the SEER web site, April 2016.
        National Cancer Institute Bethesda, MD2016 ([http://seer.cancer.gov/csr/1975_2013/])
        View in Article
        • Health and Social Care Information Centre
        National Bowel Cancer Audit Progess Report.
        in: Tripartite colorectal meeting, Birmingham July 2014. 2014 ([http://www.tripartite2014.org/content/uploads/2013/05/NBOCAP-2014-Progress-Report.pdf])
        View in Article
        • Sorbye H.
        • Pfeiffer P.
        • Cavalli-Bjorkman N.
        • Qvortrup C.
        • Holsen M.H.
        • Wentzel-Larsen T.
        • et al.
        Clinical trial enrollment, patient characteristics, and survival differences in prospectively registered metastatic colorectal cancer patients.
        Cancer. 2009; 115: 4679-4687
        View in Article
        • Papamichael D.
        • Audisio R.
        • Horiot J.C.
        • Glimelius B.
        • Sastre J.
        • Mitry E.
        • et al.
        Treatment of the elderly colorectal cancer patient: SIOG expert recommendations.
        Ann Oncol. 2009; 20: 5-16
        View in Article
        • Papamichael D.
        • Audisio R.A.
        • Glimelius B.
        • de Gramont A.
        • Glynne-Jones R.
        • Haller D.
        • et al.
        Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013.
        Ann Oncol. 2014; 26: 463-476
        View in Article
        • Van Cutsem E.
        • Cervantes A.
        • Adam R.
        • Sobrero A.
        • Van Krieken J.H.
        • Aderka D.
        • et al.
        ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.
        Ann Oncol. 2016; 27: 1386-1422
        View in Article
        • Van Cutsem E.
        • Nordlinger B.
        • Cervantes A.
        Advanced colorectal cancer: ESMO clinical practice guidelines for treatment.
        Ann Oncol. 2010; 21: v93-7
        View in Article
        • Aparicio T.
        • Desrame J.
        • Lecomte T.
        • Mitry E.
        • Belloc J.
        • Etienney I.
        • et al.
        Oxaliplatin- or irinotecan-based chemotherapy for metastatic colorectal cancer in the elderly.
        Br J Cancer. 2003; 89: 1439-1444
        View in Article
        • Beretta G.
        • Bollina R.
        • Cozzi C.
        Should we consider the weekly (w) chemotherapy (CT) with fluorouracil (F)+racemin folinic acid (f) a standard treatment for advanced/metastatic carcinoma of the digestive tract (DTC) in elderly patients (pts)?.
        Proc Am Soc Clin Oncol. 1997; 16 ([Abstract 920]): 259a
        View in Article
        • Folprecht G.
        • Cunningham D.
        • Ross P.
        • Glimelius B.
        • Di Costanzo F.
        • Wils J.
        • et al.
        Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials.
        Ann Oncol. 2004; 15: 1330-1338
        View in Article
        • Folprecht G.
        • Seymour M.
        • Saltz L.B.
        • Douillard J.Y.
        • Hecker H.
        • Stephens R.J.
        • et al.
        Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer. Combined analysis of 2,691 patients in randomized controlled trials.
        J Clin Oncol. 2008; 26: 1443-1451
        View in Article
        • Goldberg R.M.
        • Tabah-Fisch I.
        • Bleiberg H.
        • de Gramont A.
        • Tournigand C.
        • Andre T.
        • et al.
        Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer.
        J Clin Oncol. 2006; 24: 4085-4091
        View in Article
        • Aparicio T.
        • Jouve J.L.
        • Teillet L.
        • Gargot D.
        • Subtil F.
        • Le Brun-Ly V.
        • et al.
        Geriatric factors predict chemotherapy feasibility: ancillary results of FFCD 2001-02 phase III study in first-line chemotherapy for metastatic colorectal cancer in elderly patients.
        J Clin Oncol. 2013; 31: 1464-1470
        View in Article
        • Seymour M.T.
        • Thompson L.C.
        • Wasan H.S.
        • Middleton G.
        • Brewster A.E.
        • Shepherd S.F.
        • et al.
        Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial.
        Lancet. 2011; 377: 1749-1759
        View in Article
        • Hurria A.
        • Togawa K.
        • Mohile S.G.
        • Owusu C.
        • Klepin H.D.
        • Gross C.P.
        • et al.
        Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study.
        J Clin Oncol. 2011; 29: 3457-3465
        View in Article
        • Giantonio B.J.
        • Catalano P.J.
        • Meropol N.J.
        • O'Dwyer P.J.
        • Mitchell E.P.
        • Alberts S.R.
        • et al.
        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. 2007; 25: 1539-1544
        View in Article
        • Hurwitz H.
        • Fehrenbacher L.
        • Novotny W.
        • Cartwright T.
        • Hainsworth J.
        • Heim W.
        • et al.
        Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
        N Engl J Med. 2004; 350: 2335-2342
        View in Article
        • Saltz L.B.
        • Clarke S.
        • Diaz-Rubio E.
        • Scheithauer W.
        • Figer A.
        • Wong R.
        • et al.
        Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.
        J Clin Oncol. 2008; 26: 2013-2019
        View in Article
        • Cassidy J.
        • Saltz L.B.
        • Giantonio B.J.
        • Kabbinavar F.F.
        • Hurwitz H.I.
        • Rohr U.P.
        Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies.
        J Cancer Res Clin Oncol. 2010; 136: 737-743
        View in Article
        • Hurwitz H.I.
        • Tebbutt N.C.
        • Kabbinavar F.
        • Giantonio B.J.
        • Guan Z.Z.
        • Mitchell L.
        • et al.
        Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials.
        Oncologist. 2013; 18: 1004-1012
        View in Article
        • Van Cutsem E.
        • Tabernero J.
        • Lakomy R.
        • Prenen H.
        • Prausova J.
        • Macarulla T.
        • et al.
        Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.
        J Clin Oncol. 2012; 30: 3499-3506
        View in Article
        • Tabernero J.
        • Van Cutsem E.
        • Lakomy R.
        • Prausova J.
        • Ruff P.
        • van Hazel G.A.
        • et al.
        Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: Prespecified subgroup analyses from the VELOUR trial.
        Eur J Cancer. 2014; 50: 320-331
        View in Article
        • Van Cutsem E.
        • Joulain F.
        • Hoff P.M.
        • Mitchell E.
        • Ruff P.
        • Lakomy R.
        • et al.
        Aflibercept plus FOLFIRI vs. placebo plus FOLFIRI in second-line metastatic colorectal cancer: a post hoc analysis of survival from the phase III VELOUR study subsequent to exclusion of patients who had recurrence during or within 6 months of completing adjuvant oxaliplatin-based therapy.
        Target Oncol. 2016; 11: 383-400
        View in Article
        • Kaplan E.L.
        • Meier P.
        Nonparametric estimation from incomplete observations.
        J Am Stat Assoc. 1958; 53: 457-481
        View in Article
        • Ruff P.
        • Ferry D.R.
        • Lakomy R.
        • Prausova J.
        • Van Hazel G.A.
        • Hoff P.M.
        • et al.
        Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy.
        Eur J Cancer. 2015; 51: 18-26
        View in Article
        • Bordonaro R.
        • Sobrero A.
        • Frassineti L.
        • Ciuffreda L.
        • Aprile G.
        • Thomas A.L.
        • et al.
        Ziv-aflibercept in combination with FOLFIRI for second-line treatment of patients with metastatic colorectal cancer (mCRC): interim safety data from the global aflibercept safety and quality-of-life program (ASQoP amd AFEQT studies) in patients ≥65.
        J Clin Oncol. 2014; 32 ([Abstract 545])
        View in Article
        • Bordonaro R.
        • Frassineti L.
        • Ciuffreda L.
        • Aprile G.
        • Thomas A.
        • Vishwanath R.
        • et al.
        Ziv-aflibercept (Z) in combination with FOLFIRI for second-line treatment of patients with metastatic colorectal cancer (mCRC): interim safety data from the global aflibercept safety and quality-of-life program (ASQoP amd AFEQT studies) in patients aged 65 or older.
        J Clin Oncol. 2015; 33 ([Abstract 588])
        View in Article
        • Ruff P.
        • Ferry D.
        • Papamichael D.
        • Lakomy R.
        • Prausova J.
        • Van Hazel G.
        • et al.
        Observed benefit of aflibercept in mCRC patients ≥65 years old: results of a prespecified age-based analysis of the VELOUR study.
        Ann Oncol. 2013; 24 ([abstract O-0017]): iv18
        View in Article
      31. Zaltrap full prescribing information.
        http://products.sanofi.us/zaltrap/zaltrap.html
        View in Article
        • Thai H.T.
        • Veyrat-Follet C.
        • Mentre F.
        • Comets E.
        Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors.
        Cancer Chemother Pharmacol. 2013; 72: 167-180
        View in Article

      Article info

      Publication history

      Published online: August 12, 2017
      Accepted: July 26, 2017
      Received in revised form: April 27, 2017
      Received: January 27, 2017

      Identification

      DOI: https://doi.org/10.1016/j.jgo.2017.07.010

      Copyright

      © 2017 Elsevier Ltd. All rights reserved.

      ScienceDirect

      Access this article on ScienceDirect

      The content on this site is intended for healthcare professionals.


      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the Cookie Preference Center for this site.
      Copyright © 2023 Elsevier Inc. except certain content provided by third parties.


      RELX