A Phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 31, 2008

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Presenter: N. Wolmark
Presenter's Affiliation: NSABP
Type of Session: Scientific

Background

  • Prior studies have demonstrated that postoperative adjuvant chemotherapy for patients with high-risk colon cancer improves patient outcome. The standard of care in the United States for adjuvant chemotherapy for colon cancer has been 5-FU and Leucovorin (FULV). Recently, the MOSAIC trial (Multicenter International Study of Oxaliplatin/5-Fluorouracil,Leucovorin in the Adjuvant Treatment of Colon Cancer) by Andre et. al. reported significantly increased 3-year disease-free survival (DFS) with addition of oxaliplatin to bolus and continuous-infusion fluorouracil (FU) combined with leucovorin, compared to FULV alone. This led to the approval by the FDA of FULV + Oxaliplatin for postoperative adjuvant therapy in patients with stage III colon cancer.
  • A similar trial was undertaken by the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-07, between February 2000 and November 2002. This trial is a phase III randomized study to compare FULV vs. FULV and oxaliplatin (FLOX) in Stage II and III colon cancer. Previously, it was reported at ASCO 2005 by Wolmark, et. al. that the FLOX regimen significantly prolonged 3-year disease-free survival when compared to FULV. In this secondary analysis, the authors report the data for overall survival for NSABP C-07 with a 67 month (5.5 year) median follow up time.

Materials and Methods

  • Between February 2000 and November 2002, 2,409 patients eligible for this trial were randomized to receive either the FULV or FLOX regimens. Patients eligible were those with stage II (T3-4,N0, M0) or stage III (T1-4, N1-2, M0) colon cancer who had undergone potentially curative surgical resection, without evidence of residual disease.
  • The FULV chemotherapy was given as described below: 5FU: 500 mg/m2 IV bolus weekly x 6 weeks, and LV: 500 mg/m2 IV bolus weekly x 6, each cycle x 3. The FLOX group received the same FULV regimen with the addition of oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each cycle x 3.
  • The primary endpoint was disease-free survival (DFS). The secondary endpoint was overall survival (OS). The analysis for this study examining overall survival was started 5 years after the completion of accrual in November 2002.
  • A Cox model was used to calculate hazard ratios and p-values were derived by a log-rank test stratifying for nodal status. 
 

Results

  • 2,409 patients were randomized in this study: 1,209 patients in the FULV arm vs. 1,200 patients in the FULV and oxaliplatin arm.   
  • 29% of patients were node-negative, and therefore Stage II colon carcinoma. 
  • The median follow up for this study was 67 months for the patients who were still alive. 
  • The patient characteristics and toxicity data for the study were not elaborated on by the authors, since this has been presented previously at ASCO 2005. 
  • The expected number of deaths was 700; however the actual number which occurred was only 560. Since thie number of deaths was lower than expected, the power to detect a difference in OS was reduced from 0.89 to 0.81.  
  • The hazard ratio for FLOX vs. FULV for DFS at 67 month follow up was 0.81 (95% CI 0.7-0.93); p=0.02. At the 3-year update presented at ASCO 2005, the difference in DFS between FLOX and FULV was 4.6%; at 5 years, the authors now report it to be 5.2%. This corresponds to a 19% risk reduction. 
  • The hazard ratio for FLOX vs. FULV for OS at 67 months was 0.85 (95% CI 0.72-1.01; p=0.06), which corresponds to a 15% reduction in risk of death with the addition on Oxaliplatin. In addition, there were 42 fewer deaths seen in the FLOX group compared to the FULV group (259 vs. 301 deaths, respectively). 
  • The authors also report that a 2% improvement in survival was seen at 5 years, which further  increased to 4.2% at 6 years. 
  • When patients were stratified by nodal status, it was found that node-negative patients (Stage II) did not benefit from the addition of Oxaliplatin. 
  • A shorter median time-to-recurrence was seen in the FLOX group compared to the 5FU group: 17.2 and 27.2 months respectively (p=0.02, HR-1.24). 
 

Author's Conclusions

  • A trend towards improved survival was seen for patients with Stage II or III colon cancer with the addition of oxaliplatin to FULV. 
  • The benefit of Oxaliplatin is independent of the schedule of FULV administration.
  • There were fewer deaths than had been anticipated in this trial.
  • The results of this trial were similar to those reported in the MOSAIC trial, and thus validate those findings.
  • Longer follow up (>5 years) is needed to see an overall survival benefit.

Clinical/Scientific Implications

  • This randomized Phase III clinical trial has significant implications for changing the current standard of care for adjuvant chemotherapy following surgical resection for patients with high-risk colon cancer. 
  • Although FULV is the commonly used regimen in the adjuvant setting for colon cancer, this study (similarly to the MOSAIC trial) shows a significant benefit in DFS with the addition of oxaliplatin. Additionally, although the authors did not report a significant difference in OS at 5 years, there is a strong trend towards an improvement in OS. This may eventually be significant with longer follow up.  There was a reduced number of deaths and an increased time to recurrence in the FLOX group. Given this data, it is reasonable to conclude that the addition of Oxaliplatin does confer a benefit and should be considered in Stage III colon cancer patients. 
  • The toxicity data has not been reported by the authors in this session; however, Oxaliplatin does have significant toxicities including neurotoxicity, and should be used carefully in selected patients.
  • The treatment of Stage II patients is controversial, as it is unclear whether the addition of Oxaliplatin in Stage II colon cancer patients is beneficial. Further studies examining the impact of Oxaliplatin on Stage II patients are necessary. In addition, future studies may involve developing genetic profiling tools, such as Oncotype DX in breast cancer, to identify patients who may benefit from Oxaliplatin. 
  • In the future, it will be beneficial to see data from this trial at a longer follow up period to assess the impact of the addition of Oxaliplatin on overall survival. This could change the standard of care for this disease, and hopefully improve outcomes. 

Patient Summary