Preoperative therapy for lower rectal cancer and modifications in distance from anal sphincter.

PURPOSE: To assess the frequency and magnitude of changes in lower rectal cancer resulting from preoperative therapy and its impact on sphincter-saving surgery. Preoperative therapy can increase the rate of preserving surgery by shrinking the tumor and enhancing its distance from the anal sphincter. However, reliable data concerning these modifications are not yet available in published reports. METHODS AND MATERIALS: A total of 98 cases of locally advanced cancer of the lower rectum (90 Stage uT3-T4N0-N+ and 8 uT2N+M0) that had undergone preoperative therapy were studied by endorectal ultrasonography. The maximal size of the tumor and its distance from the anal sphincter were measured in millimeters before and after preoperative therapy. Surgery was performed 6-8 weeks after therapy, and the histopathologic margins were compared with the endorectal ultrasound data. RESULTS: Of the 90 cases, 82.5% showed tumor downsizing, varying from one-third to two-thirds or more of the original tumor mass. The distance between the tumor and the anal sphincter increased in 60.2% of cases. The median increase was 0.73 cm (range, 0.2-2.5). Downsizing was not always associated with an increase in distance. Preserving surgery was performed in 60.6% of cases. It was possible in nearly 30% of patients in whom the cancer had reached the anal sphincter before the preoperative therapy. The distal margin was tumor free in these cases. CONCLUSION: The results of our study have shown that in very low rectal cancer, preoperative therapy causes tumor downsizing in >80% of cases and in more than one-half enhances the distance between the tumor and anal sphincter. These modifications affect the primary surgical options, facilitating or making sphincter-saving surgery possible.

Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

PURPOSE: To evaluate expression of a panel of molecular markers, including p53, p21, MLH1, MSH2, MIB-1, thymidylate synthase, epidermal growth factor receptor (EGFR), and tissue vascular endothelial growth factor (VEGF), before and after treatment in patients treated with neoadjuvant chemoradiotherapy for locally advanced rectal cancer, to correlate the constitutive profile and dynamics of expression with pathologic response and outcome. METHODS AND MATERIALS: Expression of biomarkers was evaluated by immunohistochemistry in tumor samples from 91 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy (50 Gy) plus concurrent 5-fluorouracil by continuous intravenous infusion. RESULTS: A pathologic complete remission was observed in 14 patients (15.4%). Patients with MLH1-positive tumors had a higher pathologic complete response rate (24.3% vs. 9.4%; p = 0.055). Low expression of constitutive p21, absence of EGFR expression after chemoradiotherapy, and high Dworak's tumor regression grade (TRG) were significantly associated with improved disease-free survival and overall survival. A high MIB-1 value after chemoradiotherapy was significantly associated with worse overall survival. Multivariate analysis confirmed the prognostic value of constitutive p21 expression as well as EGFR expression and MIB-1 value after chemoradiotherapy among patients not achieving TRG 3-4. CONCLUSIONS: In our study, we observed the independent prognostic value of EGFR expression after chemoradiotherapy on disease-free survival. Moreover, our study suggests that a constitutive high p21 expression and a high MIB-1 value after neoadjuvant chemoradiotherapy treatment could predict worse outcome in locally advanced rectal cancer.

Prognostic value of Dworak grade of regression (GR) in patients with rectal carcinoma treated with preoperative radiochemotherapy.

BACKGROUND AND AIM: Preoperative radiochemotherapy improves local control in locally advanced rectal cancer; however, its role in prolonging survival is still controversial. In order to better define the subset in patients who might benefit from this multimodal treatment, we have evaluated the correlation between grade of regression (GR) to preoperative treatment and disease-free survival (DFS). METHODS: We reviewed retrospectively the surgical specimens of 106 patients with locally advanced T3/T4 N0/ M0 rectal cancer. All patients were treated preoperatively with radiotherapy and 5-fluorouracil-based regimen chemotherapy. We evaluated ypTNM stage, and tumor regression was graded using the Dworak system that varies from GR 0 (absence of regression) to GR 4 (complete regression). RESULTS: GR was as follows: GR 4, 16 patients (15%); GR 3, 25 patients (23.6%), GR 2, 30 patients (28.4%), GR 1, 32 patients (30.2%) and GR 0, 3 patients (2.8%). A significant correlation was found between GR and DFS. Three-year DFS was 100, 85, 82, 66 and 33% in GR 4, 3, 2, 1 and 0, respectively (p=0.01). DFS was significantly lower in patients with advanced stages at diagnosis and in patients without down-staging. Moreover, in postoperative stage II and III cases, GR 3 correlated with a better DFS than GR 2-0 (p=0.2 and p=0.4, respectively). CONCLUSIONS: The GR was a significant prognostic factor in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy. The pathological stage and down-staging also have prognostic value. The use of a standardized system to evaluate GR in rectal cancer can allow for comparisons between different institutions and can identify patients at worse prognosis to be treated with adjuvant therapy.

Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer.

PURPOSE: In advanced rectal cancer, chemoradiation can induce downstaging until complete disappearance of the tumor or its persistence in minimal form. The complete sterilized and the minimal residual disease often are considered similar. We evaluated the specific incidence of these two conditions and analyzed their impact in terms of local recurrence, distant metastasis, and survival. METHODS: We studied 139 uT3/T4 N0/N+ rectal cancers, treated with preoperative chemoradiation and curative surgery after six to eight weeks. We evaluated ypTNM stage and tumoral regression, according to the five degrees proposed by Dworak, with special attention to 4 and 3 (sterilized and minimal residual disease). RESULTS: Tumor downstaging occurred in 65 patients (46.7 percent), including 25 sterilized lesions (17.9 percent) and 24 minimal residual disease (17.2 percent). In median follow-up of 30 months, none of the patients with sterilized disease developed local or distant recurrence. Among patients with minimal residual disease, none developed local recurrence, whereas two (8.3 percent) developed distant metastasis, and one died from disease. In patients with gross residual disease (Grade 2, 1, 0) the percentage of local recurrence was 8.8 percent, distant recurrence 26.6 percent, and 13.3 percent died from disease. The difference between three groups is statistically significant as regards local and distant recurrence. CONCLUSIONS: After preoperative therapy, the sterilized disease shows an excellent prognosis. The minimal residual disease has an important numeric incidence. Its outcome is different, with a not-negligible risk of distant recurrence. The minimal residual disease has a much better prognosis in comparison with the gross residual disease.