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

Abstract

Purpose 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. Patients and Methods Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks × 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks × 26, experimental group). Results 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. Conclusion 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.

Clinicopathological significance of prolactin receptor expression in colorectal carcinoma and corresponding metastases

“…[4][5][6] The introduction of new drugs, the so-called biologicals, which selectively target pathways implicated in tumor growth and development, such as epidermal growth factor receptor or vascular endothelial growth factor antagonists, has further improved outcome of affected patients. [7][8][9] The role of human prolactin and its receptor, the prolactin receptor, in cancer has been analyzed for almost two decades. Prolactin receptor is expressed in various extrapituitary cells, including breast, liver, pancreas, and gastrointestinal tissues.…”

Risk of Serious Neutropenic Events in Cancer Patients Treated with Bevacizumab: A Meta-analysis

“…After evaluating each remaining study, 22 RCTs were selected for the meta-analysis (Hurwitz et al, 2005;Sandler et al, 2006;Escudier et al, 2007;Herbst et al, 2007;Karrison et al, 2007;Miller et al, 2007;Allegra et al, 2009;Baar et al, 2009;Moehler et al, 2009;Reck et al, 2009;Robert et al, 2009;Van Cutsem et al, 2009;Brufsky et al, 2010;Burger et al, 2010;Kang et al, 2010;Kelly et al, 2010;Kindler et al, 2010;Miles et al, 2010;Okines et al, 2010;Rini et al, 2010;Tebbutt et al, 2010;Zalcman et al, 2010). The selection process is summarized in Figure 1.…”

A phase 1 clinical trial of sequential pralatrexate followed by a 48‐hour infusion of 5‐fluorouracil given every other week in adult patients with solid tumors

“…An every-other-week schedule of leucovorin-modulated 5-FU has been widely tested, and is reported to be well tolerated. [21][22][23] FOLFOX-6 involves oxaliplatin given with leucovorin at a dose of 400 mg/m 2 and bolus 5-FU at a dose of 400 mg/m 2 , followed by a 46-hour infusion of 5-FU at a dose of 2600 mg/m 2 . 21 Modified FOLFOX-7 uses oxaliplatin with leucovorin at a dose of 400 mg/m 2 followed by a 46-hour infusion of 5-FU at a dose of 3000 mg/m 2 .…”

“…[21][22][23] FOLFOX-6 involves oxaliplatin given with leucovorin at a dose of 400 mg/m 2 and bolus 5-FU at a dose of 400 mg/m 2 , followed by a 46-hour infusion of 5-FU at a dose of 2600 mg/m 2 . 21 Modified FOLFOX-7 uses oxaliplatin with leucovorin at a dose of 400 mg/m 2 followed by a 46-hour infusion of 5-FU at a dose of 3000 mg/m 2 . 22 The results of a phase 1 trial of sequential irinotecan given with leucovorin at a dose of 500 mg/m 2 and 5-FU given as a 48-hour infusion recommended a 5-FU dose of 3125 mg/m 2 .…”