Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial

Abstract

Background: National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation.

Methods: Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided.

Results: Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3-4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm.

Conclusions: Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity.

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Figures

Figure 1.

CONSORT diagram: National Surgical Adjuvant Breast and Bowel Project protocol R-04. *All patients were assigned radiation therapy. †Includes pre- and post-amendment patients. ‡Post-amendment patients. FU = 5-fluorouracil; CAPE = capecitabine; OX = oxaliplatin.

Figure 2.

Three-year event rate for patients treated with either continuous infusion 5-FU or capecitabine with or without oxaliplatin for (A) local-regional recurrence for all patients and (B) local-regional recurrence rates for only those patients achieving an R0 resection in National Surgical Adjuvant Breast and Bowel Project R-04. Note: No significant fluoropyrimidine by oxaliplatin interaction. L/R = local-regional.

Figure 3.

Kaplan-Meier plots of local-regional recurrence for patients treated with (A) either continuous infusion 5-FU or capecitabine (B) with or without oxaliplatin in National Surgical Adjuvant Breast and Bowel Project R-04. L/R = local-regional.

Figure 4.

Five-year event rates for (A) disease-free survival and (B) overall survival for patients treated with either continuous infusion 5-FU or capecitabine with or without oxaliplatin in National Surgical Adjuvant Breast and Bowel Project R-04. Note: No significant fluoropyrimidine-by-oxaliplatin interaction.

Figure 5.

Kaplan-Meier plots of overall survival for patients treated with (A) either continuous infusion 5-FU or capecitabine (B) with or without oxaliplatin in National Surgical Adjuvant Breast and Bowel Project R-04.