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Initial Safety Report of NSABP C-08, a Randomized Phase III Study of Modified 5-Flurouracil (5-FU/leucovorin (LCV) and oxalliplatin (OX) (mFOLFOX6) with or without Bevacizumab (bev) in the Adjuvant Treatment of Patients with Stage II/III Colon Cancer

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 4 de junio del 2008

Presenter: Allegra, C.J.
Presenter's Affiliation: University of Florida
Type of Session: Scientific

Background

• There is a rationale for combining antiangiogenic agents, such as bevacizumab, with cytotoxic chemotherapy, such as mFOLFOX6, in the treatment of solid tumors. The tumor vasculature is thought to be disorganized and leaky, resulting in high interstial pressure and difficulty in delivering therapeutic drugs to the tumor cells.  Vascular normalization, posited by Dr. Rakesh Jain, suggests that antiangiogenic drugs may be able to temporarily “normalize” the vasculature of tumors, decreasing interstitial pressure, and allowing cytotoxic chemotherapeutic agents greater access to the tumor. 
• Prior studies have shown the superiority of FOLFOX over 5-FU and leucovorin alone (Andre NEJM, 2004); however, recurrences are still a problem (PFS of 78% at 3 years in Stage II/III patients), and additional agents may help improve outcomes.
• Prior studies of patients with advanced/metastatic colon cancer have shown a survival benefit when bevacizumab (Bev) is combined with FOLFOX therapy, and this regimen is now FDA-approved for the second-line treatment of colon cancer.
• The present study examines the role of mFOLFOX6 combined with Bev in the treatment of stage II/III colon cancer.

Materials and Methods

• The present study, C-08, is a phase III randomized trial which randomized patients to either mFOLFOX6 or mFOLFOX6 plus Bev.
• Patients with Stage II or III colon cancer were included in the present study
• Patients were first stratified by the number of positive lymph nodes, and then randomized to treatment with either mFOLFOX6 (group A) versus mFOLFOX6 plus Bev (group B).
• Inclusion and exclusion criteria are as follows:
  • patients were randomized between 29-50 days after surgery
  • patients had an ECOG performance status of 0-1
  • patients had to have none of the following within 12 months of randomization:
    • cerebrovascular accident, transient ischemic attack, peripheral vascular disease, or myocardial infarction   
• Dosing of mFOLFOX6 was as follows:
  • Oxalliplatin (OX) 85 mg/ m²
  • Leucovorin (LCV) 400 mg/ m²
  • 5-FU was given as a bolus of 400 mg/ m²
  • 5-FU was then given as a continuous infusion at a dose of 2,400 mg/ m² over 46 hours 
•  Dosing for Bev was as follows:
  • 5 mg/kg every two weeks for 26 cycles
• The primary end point of this study was disease-free survival (DFS).

Results

• From September 2004 to October 2006, a total of 2,710 patients were randomized.
  • 1,356 patients were randomized to group A and 1,354 patients were randomized to group B 
• Demographics between the two groups were well balanced as follows:

·       Median follow up was 28.5 months for both arms, median age was ~58 yo for both arms and ~50% of patients were male for both arms.

·       Significantly more patients received 1000 mg of OX cumulatively in group B compared with group A.

·       The median cumulative OX dose delivered was 850 mg for group A and 880 mg for group B (p=0.002).

·       The median duration that patients in group B took Bev was 11.6 months.  The rate at which patients stopped Bev treatment appeared to correlate with when patients dropped out of chemotherapy.  After chemotherapy ended, Bev drop out continued but at a slower rate. 

·       Toxicity:

o      70% of patients in group A versus 77% of patients in group B had grade 3 or higher toxicity, which was significantly different.

o      There was no difference in venous thrombosis, neutropenia or fatigue between the two groups.

o      The frequency of neuropathy was similar between the two arms, but there was more grade 3 of higher neuropathy in group B, likely due to the higher OX dose.

o      There was no difference in the rates of cardiac, CNS, GI perforation or hemorrhage between the two groups. 

o      There was a decrease in thrombocytopenia and allergic reaction in group B.

o      There were higher rates of hypertension, pain, proteinuria, and wound complications in group B. 

§       23 (1.7%) of patients had serious wound complications, all were grade 3

§       22 required additional surgery

§       ½ stopped Bev

§       Median time to the event was 5 months

§       Pain was predominantly in the chest, joints and muscles

§       After the completion of chemotherapy, patients still had wound complications, hypertension, proteinuria, and pain, implying that these toxicities were due to the Bev.

o      In both arms, older patients tolerated the treatment worse, with patients older than 60 having more grade 3 and 4 toxicity.

Author's Conclusions

• Bev and mFOLFOX6 has acceptable toxicity and are safe in a selected population of patients.  However, adjuvant use of this agent can not yet be recommended as this regimen has not yet been shown to improve outcomes.
• The addition of Bev did not result in a decrease in the mFOLFOX6 dose.
• Hypertension, wound complications, and proteinuria increased with Bev but these are manageable side effects.
• Neuropathy was likely due to the increased dose of OX in the Bev arm.  The authors theorize that this may be due to physicians stopping Bev first when toxicities occurred, such that patients in group B got additional cycles of mFOLFOX6.

Clinical/Scientific Implications

• This is a very important study as it not only compared the efficacy of mFOLFOX6 + Bev versus mFOLFOX6, but it also evaluated the toxicity associated with combined treatment with mFOLFOX6 and Bev.  Bev is an antiangiogenic agent, and there is great concern about how it could affect vasculopathic patients, such as those with significant coronary artery disease, hence the exclusion of these patients from this study.  Even in patients with normal vessels, there is concern about damage to the kidney and the risk of gastric perforation due to the antiangiogenic effects of Bev, particularly when it is used with other agents.  There is also concern about the use of Bev resulting in hemorrhage as has been seen in some patients with lung cancer treated with Bev.  From the results of this study, it appears that Bev does not significantly increase the risk of these toxicities, aside from the renal toxicity.  However, long-term follow up is needed as some of these toxicities may present late or worsen over time.

• The authors make the appropriate statement that no conclusions can be made about the efficacy of this therapy as the follow up is short and up until now no improvement in overall survival has been seen.  Nonetheless, this study suggests that Bev is safe and we await long term results.