Does the addition of chemotherapy (CT) to preoperative radiotherapy (preopRT) increase the pathological response in patients with resected rectal cancer: Report of the 22921 EORTC phase III trial.

Reviewer: Charles Wood, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2004

Presenter: J.-F. Bosset
Presenter's Affiliation: Besancon University Hospital, Besancon, France
Type of Session: Scientific


  • Preoperative radiation treatment is used frequently in cases of resectable rectal cancer due to the advantages of more precise tumor definition, decreased amount of irradiated normal tissue, pathological downstaging, increased resectability, and increased sphincter preservation.
  • This trial defines the role of 5-FU-based chemotherapy with regard to preoperative radiotherapy as it applies to pathological response and, ultimately, overall survival.

Materials and Methods

  • The study was a multicenter prospective randomized trial evaluating the addition of chemotherapy to preoperative radiation.
  • 1011 patients were enrolled between 4/93 and 4/03.
  • Patients were less than 80 years of age, had a WHO performance status of 0 or 1, were stage T3/T4NXM0 (per 1987 IUCC guidelines) via clinical staging or EUS, judged resectable, and randomized into four arms.
  • Arm 1 received preopRT alone.  Arm 2 received preopRT and 2 cycles of preop CT.  Arm 3 received preopRT and 4 cycles of postop CT.  Arm 4 received preopCTRT as well as postop CT.
  • The arms were then divided into groups 1 and 2.  Group 1 was defined as receiving no preop CT (arms 1 and 3).  Group 2 was defined as receiving preopCT (arms 2 and 4).
  • PreopRT was 45 Gy delivered over 5 weeks.
  • Preop and postop CT dosing was identical (5-FU 350mg/m2/d; LV 20mg/m2/d; days 1 through 5).  Preop CT was given during the 1st and 5th weeks of radiotherapy.
  • Surgery was undertaken between 3 and 10 weeks following radiation.  The surgical approach (LAR vs. APR) was decided upon at the time of patient entry.



  • 505 patients were randomized to group 1 (arms 1 and 3), and 506 pts. were included in group 2 (arms 2 and 4).  The groups were well-balanced with respect to age, gender, preoperative staging, and tumor distance from anal verge.  There was a slight increase in conservative surgery (LAR) in group 2.
  • The median time to surgery following preoperative treatment was 5.4 mos. in both groups.
  • Tumor size following preoperative treatment was significantly larger in group 1 (30 mm versus 25 mm, p<0.0001).
  • Tumor bed sterilization (T0) following preoperative treatment was significantly increased in group 2 (14% versus 5.3%, p<0.0001).
  • Downstaging (T0-2) following preoperative treatment occurred significantly more often in group 2 (58.1% versus 42.9%, p<0.0001).
  • Nodal involvement, lymphatic invasion, perineural invasion, and venous invasion following preoperative treatment were significantly less in group 2 (LN: 20.9% versus 26.9%, p=0.031; LI: 11.4% vs. 17.4%, p=0.008; PNI: 7.6% versus 14.3%, p=0.001; VI: 9.1% versus 13.9%, p=0.021). 

Author's Conclusions

  • The addition of 5-FU-based chemotherapy to preoperative radiation in resectable colon cancer significantly increases the pathological response regarding tumor and nodal staging as well as lymphatic, perineural, and venous invasion.
  • The downstaging effect induces stage migration from pT3 and should be considered in future clinical trials.
  • Longer follow-up is required to assess the impact on local control and overall survival. 

Clinical/Scientific Implications

 Pathological evidence following surgical resection strongly supports the use of preoperative chemoradiation.  It is important to note that the median time to surgery was identical between the two groups, avoiding a bias regarding time required to display a pathological response.  It will be extremely interesting to observe the effect on local control and survival once the data matures.  In addition, local control will be of particular interest as the EORTC utilized radiation fields including only the tumor with margin, significantly smaller than the traditional fields employed in the United States.

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