Article

Initial safety report of NSABP C-08: A randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer.

Department of Biostatistics, University of Pittsburgh, PA, USA.
Journal of Clinical Oncology (Impact Factor: 17.88). 05/2009; 27(20):3385-90. DOI: 10.1200/JCO.2009.21.9220
Source: PubMed

ABSTRACT The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer. We present safety information in advance of the planned analysis of efficacy.
Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks x 26, experimental group).
Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms (15.2% and 15.0%, respectively). Six-month mortality rates were 0.96% and 0.90% for the control and experimental groups, respectively. Grade 3+ toxicities that occurred more often in the experimental arm versus control arm included hypertension (12% v 1.8%, respectively), wound complications (abdominal incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, respectively). Grade 2+ neuropathy was increased in the experimental arm versus the control arm (grade 2, 33% v 29%, respectively; grade 3, 16% v 14%, respectively; and grade 4, < 1% each). In the experimental arm versus control arm, significantly less thrombocytopenia (1.4% v 3.4%, respectively) and fewer allergic reactions (3.1% v 4.7%, respectively) were observed. Advanced age was associated with a significantly greater rate of grade 4 and 5 toxicities regardless of treatment.
Bevacizumab with modified FOLFOX6 is well tolerated in the surgical adjuvant setting in these patients. No significant increase in GI perforation, hemorrhage, arterial or venous thrombotic events, or death with the addition of bevacizumab to modified FOLFOX6 has been observed. Follow-up for potential delayed adverse effects and efficacy is ongoing.

Full-text

Available from: Louis Fehrenbacher, Jun 10, 2015
1 Follower
 · 
111 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Two of the great successes in the many decades-long 'war on cancer' are the emergence of adjuvant chemotherapy regimens with lifesaving potential and the subsequent wave of 'targeted' therapies addressing the unique vulnerabilities of particular tumor types. The first intersection of adjuvant treatment and targeted treatment resulted in a spectacularly positive outcome as the addition of the anti-HER2 humanized monoclonal antibody trastuzumab to the standard adjuvant chemotherapy essentially halved the relapse rate among women with HER2+ tumors. Subsequent studies of adjuvant trastuzumab have confirmed its dramatic efficacy in a variety of chemotherapeutic contexts and have been instructive in elucidating some of the challenges ahead for newer targeted agents. The recent negative experience with bevacizumab in the adjuvant colon cancer setting suggests pitfalls and limitations of the current approach to developing adjuvant regimens. A change in thinking may be required to gain the substantial benefits implied by the trastuzumab experience in the broader context of targeted treatments. The case for a revitalized industry/academia/government partnership to address these challenges is compelling, with the potential for enormous patient and societal benefit. In order to bring potentially lifesaving benefits of this new generation of cancer drugs to patients more rapidly, changes to our 'war strategy' appear necessary.
    Current topics in microbiology and immunology 08/2011; DOI:10.1007/82_2011_166 · 3.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Adjuvant oxaliplatin plus capecitabine or leucovorin/5-fluorouracil (LV/5-FU) (XELOX/FOLFOX) is the standard of care for stage III colon cancer (CC); however, there is disagreement regarding oxaliplatin benefit in patients aged >70. In most analyses, the impact of medical comorbidity (MC) has not been assessed. Efficacy and safety of adjuvant XELOX/FOLFOX versus LV/5-FU were compared with respect to age and MC using pooled data from four randomized, controlled trials, selected for access to patient-level MC data and including commonly endorsed and utilized regimens.
    Annals of Oncology 01/2015; 26(4). DOI:10.1093/annonc/mdv003 · 6.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. Thirty patients were assigned to tivozanib 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8), fatigue (n = 8), and neutropenia (n = 6). MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical Colorectal Cancer 12/2014; 14(1). DOI:10.1016/j.clcc.2014.12.001 · 2.91 Impact Factor