Browsing by Author "Sauer, R."

Aim: The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy is recommended for patients with advanced disease (pT3/4 or pN+). In recent years, encouraging results of preoperative radiotherapy have been reported. This prospective randomized phase-III trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant radiochemotherapy to standard postoperative radiochemotherapy. We report on the design of the study and first results with regard to toxicity of radiochemotherapy and postoperative morbidity. Patients and Methods: Patients with Locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre- or postoperative radiochemotherapy: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumor and the pelvic Lymph nodes. 5-FU (1,000 mg/m(2)/d) was administered concomitantly in the first and fifth week of radiation as 120-h continuous infusion. Four additional cycles of 5-FU chemotherapy (500 mg/m(2)/d, iv bolus) were applied. Radiochemotherapy was identical in both arms except for a small-volume boost of 5.4 Gy in the postoperative setting. Time interval between radiochemotherapy and surgery was 4-6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. In addition, stratification according to surgeons involved has been provided for. Primary endpoints of the study are 5-year overall-survival. Local and distant control, secondary endpoints include rate of curative (RO) resections and sphincter saving procedures, toxicity of radiochemotherapy, surgical complications and quality of life. Results: As of 15th November 2000, 628 patients were randomized from 26 participating institutions: 310 patients were randomized to postoperative radiochemotherapy, 318 patients to preoperative radiochemotherapy. Acute toxicity (WHO) of radiochemotherapy was Low, with less than 15% of patients experiencing Grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative radiochemotherapy arm and 10% in the preoperative radiochemotherapy arm having Grade-3, and 1% in either arm having Grade-4 diarrhea. Erythema, nausea and Leukopenia were the next common toxicities, with Less than 3% of patients in either arm suffering Grade 3 or greater Leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postoperative radiochemotherapy) and 13% (preoperative radiochemotherapy) of patients, respectively, suffering from anastomotic Leakage, 4% (postoperative radiochemotherapy) and 3% (preoperative radiochemotherapy) from postoperative bleeding, and 6% (postoperative radiochemotherapy) and 5% (preoperative radiochemotherapy) from delayed wound healing. Conclusion: The patient accrual of our trial is satisfactory, neoadjuvant radiochemotherapy is well tolerated and bears, no higher risk for postoperative morbidity.

Single nucleotide polymorphisms (SNPs) may contribute to the malignant process and may show clinicopathological importance as prognostic markers. The multidrug resistance gene MDR1 encodes a membrane transporter which confers cytostatic drug resistance in tumors and protects normal tissues from xenobiotics. We analyzed the C3435T SNP in the MDR1 gene which is associated with altered cellular drug uptake in matched tumor and normal tissues of 45 patients suffering from colorectal carcinoma. We have developed a highly sensitive matrix-assisted laser desorption ionization time-of-flight mass spectrometty (MALDI-TOF-MS) method to survey the C3435T polymorphism in PCR-amplified fragments of the MDR1 gene. Thirteen patients were homozygous for C/C (29 %), 15 were heterozygous (33%) and 17 were homozygous for TIT (38%). None of the tumor samples showed an altered SNP compared to their matched normal tissue samples. As analyzed by the Kruskall-Wallis test, none of the clinicopathological parameters was significantly associated with homo- or heterozygosity. The combination of PCR, allele-specific primer extension reactions and MALDI-TOF-MS offers a promising alternative method for genotyping the MDR1 gene especially for heterozygous situations. The inherent advantages of MALDI-TOF-MS based genotyping include its high molecular resolution, high signal-to-noise-ratios and reproducibility, combined with an excellent sensitivity. As none of the tumor samples showed state compared to their matched normal tissue samples, the genotypic frequency of this polymorphism seems not to be altered during colorectal tumorigenesis.

BACKGROUND: Postoperative chemoradiotherapy is the recommended standard therapy for patients with locally advanced rectal cancer. In recent years, encouraging results with preoperative radiotherapy have been reported. We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer. METHODS: We randomly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day, five days per week, and fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of fluorouracil (500 mg per square meter per day) were given. Chemoradiotherapy was identical in the postoperative-treatment group, except for the delivery of a boost of 540 cGy. The primary end point was overall survival. RESULTS: Four hundred twenty-one patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80).The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group (P=0.006).Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14 percent and 24 percent, respectively (P=0.01). CONCLUSIONS: Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity but did not improve overall survival.