The Prognostic Value of the Epidermal Growth Factor Receptor in Locally Advanced Rectal Cancer (LARC) Patients Treated with Preoperative Chemo-radiation

Reviewer: Chika Madu, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 17, 2005

Presenter: J. Kim
Presenter's Affiliation: Radiation Oncology, Chungnam National University, College of Medicine, Daejon, South Korea
Type of Session: Scientific

Background

More recently, the use of targeted agents against epidermal growth factor receptors (EGFR) has become more and more integrated into the treatment of colon cancers. The hypothesis being that inhibition of such receptors may translate into improved treatment responses. The purpose of this study was to evaluate the prognostic value of EGFR expression in pre-treatment biopsy specimens from patients with locally advanced rectal cancer. The end-points were overall survival (OS), disease free survival (DFS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and recurrence pattern.

Materials and Methods

Ninety two (92) patients with LARC (cT3/T4 or N+) without distant metastasis were enrolled between 1993 to1999,
All patients were treated with pre-operative concurrent chemo-radiation
Chemotherapy was 2 concurrent cycles of 5-FU and leucovorin
Radiation was given to the pelvis to 45Gy, followed by a boost to 50.4Gy at 180cGy daily fractions
All patients then underwent surgery at 6 weeks after chemo-radiation
EGFR expression was assessed in the pre-treatment biopsy by immunohistochemistry (IHC)
Expression of EGFR was determined by the intensity and extent of staining on IHC
A grade of 0-7 based on immunoreactive score (IRS) was assigned to all specimens, low (IRS 0-5), high (IRS 6-7)
Correlations were then made between EGFR expression and clinicopathologic characteristics such as age, gender, tumor mobility, clinical TNM staging, and pathologic staging.
Kaplan-Meier, logistic regression, and log-rank test were used to calculate survival outcomes, recurrence prediction, and prognostic value of EGFR expression respectively.

Results

Median Follow up was 70 months (5-139 months)
Median age was 58 years, there were 56 males, 36 females
The local failure rate was 11%, while the distant failure rate was 35%
EGFR expression was positive in 71% of the patients, with high grade expression in 9 patients.
There was no correlation between EGFR expression and gender, age, tumor mobility, clinical TNM stage, or pathologic TNM stage
Significant prognostic factors for OS were tumor mobility, clinical TNM stage, pathologic TNM stage, and grade of EGFR expression in univariate analysis
Tumor mobility, pathologic TNM stage, gender and grade of EGFR expression were all independent prognostic factors for DFS and DMFS, all with statistical significance
In multivariate analysis, the hazard ratio for DFS and DMFS in low vs. high EGFR expression were 0.34 (95% CI; 0.145-0.788, p=0.012) and 0.27 (95% CI; 0.114-0.64, p=0.003) respectively
Low-grade EGFR expression was also found to be a predictive factor for decreased distant metastasis with a hazard ratio of 0.08 (95% CI; 0.012-0.533, p=0.009)

Author's Conclusions

High EGFR expression in pre-treatment biopsy specimens is a predictor for adverse DFS and DMFS in patients with LARC
The use of molecular targeted therapy against EGFR in this group of patients may help determine whether there will be an improvement if DFS and DMFS particularly in patients with high EGFR expression

Clinical/Scientific Implications

These results concur with colon cancer findings that EGFR over-expression is associated with a poorer prognosis
Treatment guidelines for rectal cancer can sometimes be extrapolated from findings from colon cancer studies
However, the presence or expression of a target may not guarantee a response with inhibition of that target.
There continues to be a need for further investigation into what the optimal therapeutic agents should be for LARC
Current on-going clinical trials include evaluation of targeting agents as well as cytotoxic agents such as 5-FU, oxaliplatin, irinotecan, and capecitabine in LARC