Annals of Surgery

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Annals of Surgery Journal Club
Interactive resource for surgery residents and surgeons to discuss and critically evaluate articles published in Annals of Surgery selected by a monthly guest expert who will review an article each month, offer questions and respond to reader's comments.
Tuesday, January 8, 2013
January Journal Club
Moderator: Dr. Michael D'Angelica
Article: Adjuvant Chemotherapy With FOLFOX for Primary Colorectal Cancer Is Associated With Increased Somatic Gene Mutations and Inferior Survival in Patients Undergoing Hepatectomy for Metachronous Liver Metastases. Andreou, Andreas; Kopetz, Scott; Maru, Dipen M.; Chen, Su S.; Zimmitti, Giuseppe; Brouquet, Antoine; Shindoh, Junichi; Curley, Steven A.; Garrett, Christopher; Overman, Michael J.; Aloia, Thomas A.; Vauthey, Jean-Nicolas. Annals of Surgery. 256(4):642-650, October 2012.

Andreou and colleagues hypothesized that in patients with metachronous (disease-free interval > 1 year) liver metastases selected for hepatic resection, outcomes and underlying tumor biology would differ based on their previous exposure to FOLFOX or 5FU.  The authors retrospectively analyzed a group of patients with resectable metachronous liver metastases that underwent complete resection.  A total of 341 patients were analyzed after excluding patients with synchronous metastases, patients treated with radiofrequency ablation and those treated with adjuvant chemotherapy other than 5FU or FOLFOX.  Most of the patients (169) had received adjuvant 5FU and a similar number of patients (77 and 95 respectively) received either FOLFOX or no chemotherapy at the time of their primary colorectal resection.  The patients were gleaned from a prospectively maintained database including the years 1993 to 2010.  Of note, FOLFOX patients were only present from 2005 forward limiting their follow up and making this group of patients a distintinctly more ‘modern’ group of patients.  Patients who did not receive adjuvant chemotherapy were older, more frequently lymph node negative, had larger metastases and more frequently had a major pathologic response to pre-hepatectomy neoadjuvant chemotherapy.  As compared to patients who received adjuvant 5FU at the time of their primary colorectal resection, FOLFOX patients were younger, more frequently lymph node positive (79 vs 68%) and had smaller liver metastases.  The median follow-up was 53 months. The major finding of this study was that patients exposed to adjuvant chemotherapy had distinctly worse outcomes with FOLFOX patients faring the worst.  Three-year disease-free survival rates for the FOLFOX, 5FU and no chemotherapy groups were 14, 38 and 45% respectively (p <0.001 (no difference between 5FU and no chemotherapy)).  Three-year overall survival rates for the FOLFOX, 5FU and no chemotherapy groups were 58, 70 and 84% (p=0.002 overall, p=0.03 for 5FU vs no chemotherapy and p=0.04 for FOLFOX vs 5FU).  Furthermore, the FOLFOX patients had higher rates of somatic gene mutations compared to the 5FU and no chemotherapy groups.  Mutations in the KRAS gene essentially accounted for all of this difference. 

1.  Since this is a retrospective study that cannot definitively establish a causal relationship, what are the potential sources of bias that may have affected the reported associations?

2.  What statistical issues could question whether the findings are accurate?

3.  What are the potential clinical implications of these findings?

4.  What further studies would strengthen the association between FOLFOX and a higher rate of KRAS mutations?

Please feel free to comment on any or all of the questions above. We look forward to hearing from you, the Annals readers.

Dr. jon jones Jr. said:
Very interesting article and it begs the question which came first the aggresive potential or the effect of FOLFOX on liver metastasis for colorectal ca. Somatic gene (KRAS) mutation analysis prior to the therapy in both groups would help to answer the question. Another question is concerning the effect of the respective therapies if you do the OS evaluation as an intent to treat from time of colon surgery given the decreased OS and DFS after liver resection for FOLFOX vs 5FU or no treatment, the DFS was not different in the data provided between these groups. It follows but was not stated that the OS from time of CRC treatment would therefore be worse in the the FOLFOX group.
About the Author

Ronald B. Hirschl, M.D
Ronald B. Hirschl, M.D, is the Head of Pediatric Surgery at C.S. Mott Children’s Hospital at the University of Michigan. He is also a Director of the American Board of Surgery and Chair of the Pediatric Surgery Board. He is funded by the NIH to study long-term artificial lung support in Pediatric patients with chronic lung failure. Dr. Hirschl obtained his Masters of Science from the University of Michigan in Clinical Research Design and Statistical Analysis. He has been involved in a number of studies and trials on the topic of appendicitis.