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

Ann Surg. 2012 Oct;256(4):642-50. doi: 10.1097/SLA.0b013e31826b4dcc.


Objective: We hypothesized that metachronous colorectal liver metastases (CLM) have different biology after failure of oxaliplatin (FOLFOX) compared to 5-fluorouracil (5-FU) or no chemotherapy for adjuvant treatment of colorectal cancer (CRC).

Background: It is unclear whether patients treated with liver resection for metachronous CLM after adjuvant FOLFOX for CRC have worse outcomes than those who received 5-FU or no chemotherapy.

Methods: We identified 341 patients who underwent hepatectomy for metachronous CLM (disease-free interval ≥12 months, 1993-2010). Mass-spectroscopy genotyping for somatic gene mutations in CLM was performed in a subset of 129 patients.

Results: Adjuvant treatment for primary CRC was FOLFOX in 77 patients, 5-FU in 169 patients, and no chemotherapy in 95 patients. Node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P < 0.0001). Median metastasis size was smaller in the FOLFOX group (2.5 cm) than in the 5-FU (3.0 cm) or no-chemotherapy (3.5 cm) groups, (P = 0.008) although prehepatectomy chemotherapy utilization, metastases number, and carcinoembryonic antigen levels were similar. Disease-free survival (DFS) and overall survival (OS) rates after hepatectomy were worse in patients treated with adjuvant FOLFOX [DFS at 3 years: 14% vs 38% (5-FU) vs 45% (no-chemo), OS at 3 years: 58% vs 70% (5-FU) vs 84% (no-chemo)]. On multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P < 0.0001) and OS (P < 0.0001). Mutation analysis revealed ≥1 mutations in 57% of patients (27/47) after FOLFOX, 29% (12/41) after 5-FU, and 32% (13/41) after no chemotherapy (P = 0.011).

Conclusions: Adjuvant FOLFOX for primary CRC is associated with a high rate of somatic mutations in liver metastases and inferior outcomes after hepatectomy for metachronous CLM.

Publication types

  • Comparative Study
  • Evaluation Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics
  • Chemotherapy, Adjuvant
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / surgery
  • DNA Mutational Analysis
  • Female
  • Fluorouracil / therapeutic use
  • Follow-Up Studies
  • Hepatectomy*
  • Humans
  • Leucovorin / therapeutic use
  • Liver Neoplasms / genetics
  • Liver Neoplasms / mortality
  • Liver Neoplasms / secondary*
  • Liver Neoplasms / surgery
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Multivariate Analysis
  • Mutation
  • Organoplatinum Compounds / therapeutic use
  • Postoperative Complications
  • Retrospective Studies
  • Survival Analysis
  • Treatment Outcome


  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • Organoplatinum Compounds
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol