Presenter: J.P. Gerard Presenter's Affiliation: Center Antoine Lacassagne, Nice, France Type of Session: Scientific
Multiple studies have demonstrated the safety and efficacy of preoperative radiation therapy for the treatment of advanced rectal cancer.
Data in patients given preoperative radiation therapy alone show unacceptably high rates of local failure (25-45%).
Many studies have demonstrated improved outcomes with concurrent chemotherapy and radiation therapy in the preoperative setting
In properly selected groups of patients, a combination of chemotherapy and radiation therapy (CRT) before surgical resection is considered the standard of care.
This study was designed in 1992, before there was a large body of data supporting the use of CRT preoperatively.
Materials and Methods
A multi-institutional phase III prospective study randomized 762 patients with T3 or T4 rectal cancers to either preoperative radiation therapy or preoperative radiation therapy with 5-fluorouracil.
Radiation was the same in both arms and was given in 25 fractions to 45Gy in 5 weeks.
5-fluorouracil was given as a 350 mg/m2 IV bolus with 20mg/m2 of folinic acid for 5 days during weeks 1 and 5 of radiation.
Patients were eligible if a digital rectal examination could be performed, they had T3 or T4 tumors, were younger than 80 and had ECOG performance status 0 or 1.
Overall survival was the primary endpoint.
Pathologic complete response, disease free survival, local control and toxicities were secondary endpoints.
Surgery was performed at 3-10 weeks post treatment, and total mesorectal excision was suggested but not required.
Following surgery, all patients were scheduled to receive 4 more cycles of chemotherapy.
Median follow-up is 69 months.
Groups were well balanced among a variety of demographic and disease factors including: gender, age, T stage, N stage and distance from the anal verge.
The CRT arm had improved 5 year local failure rates compared to the radiation alone arm (8% vs 16.5%).
Five year disease free survival and overall survival rates were not significantly different between the arms (DFS: CRT 56% vs RT 59%, OS: CRT 66% vs. RT 67%)
Pathologic complete response rates were significantly higher in the CRT arm compared to the radiation alone arm (12% vs. 3.7%).
There was no difference in rate of negative margins or rate of sphincter sparing operation performed between the two arms.
When examining various subgroups, the addition of chemotherapy always remained significantly related to improved local control.
CRT was significantly related to increased grade 3 or 4 toxicity compared to radiation alone (14.6% vs. 2.7%).
For T3/T4 rectal cancers treated preoperatively, CRT produces increased toxicity compared to radiation alone.
CRT increases the rate of disease sterilization as measured by pathologic complete response rate.
CRT increases the likelihood of local control compared to radiation alone.
There is not an improvement in either overall survival, disease free survival, or sphincter preservation seen with CRT compared to radiation alone.
This study was a well executed large randomized trial. The results of this trial add to the body of data demonstrating the efficacy and safety of preoperative concurrent chemoradiotherapy. The improvement in local control seen in the CRT arm argues that 5-FU works as a sensitizer for radiation. This leads to the idea that continuous infusion 5-FU is probably superior to bolus 5-FU when given at the same time as radiation therapy. Near constant levels of 5-FU, as is seen with continuous infusion pumps, have a better chance of providing radiosensitization than discontinuous, bolus administrations. Because this trial employed bolus 5-FU and low doses of bolus 5-FU compared to other trials, this may explain why a difference between the arms in rates of sphincter sparing surgery was not seen and why there was no difference in DFS and OS. Future research in this field will add new and different chemotherapeutic agents and targeted therapies in attempts to improve outcomes.