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Purpose Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Two randomized trials demonstrated an advantage for adjuvant radiotherapy (RT) compared with a wait-and-see policy. We conducted a randomized, controlled clinical trial to compare RP followed by immediate RT with RP alone for patients with pT3 prostate cancer and an undetectable prostate-specific antigen (PSA) level after RP. Methods After RP, 192 men were randomly assigned to a wait-and-see policy, and 193 men were assigned to immediate postoperative RT. Eligible patients had pT3 pN0 tumors. Patients who did not achieve an undetectable PSA after RP were excluded from treatment according to random assignment (n = 78; 20%). Of the remaining 307 patients, 34 patients on the RT arm did not receive RT and five patients on the wait-and-see arm received RT. Therefore, 114 patients underwent RT and 154 patients were treated with a wait-and-see policy. The primary end point was biochemical progression-free survival. Results Biochemical progression-free survival after 5 years in patients with undetectable PSA after RP was significantly improved in the RT group (72%; 95% CI, 65% to 81%; v 54%, 95% CI, 45% to 63%; hazard ratio = 0.53; 95% CI, 0.37 to 0.79; P = .0015). On univariate analysis, Gleason score more than 6 and less than 7, PSA before RP, tumor stage, and positive surgical margins were predictors of outcome. The rate of grade 3 to 4 late adverse effects was 0.3%. Conclusion Adjuvant RT for pT3 prostate cancer with postoperatively undetectable PSA significantly reduces the risk of biochemical progression. Further follow-up is needed to assess the effect on metastases-free and overall survival.

435 Background: The role of obesity and the incidence of high-risk clear cell renal cell carcinoma (ccRCC) are poorly understood. We examined the association of obesity with lymphatic spread and survival using data from an international Phase III clinical trial testing the efficacy of adjuvant treatment with cG250 antibody in subjects with non-metastatic (ccRCC) at high risk for recurrence. Methods: We reviewed the clinical and pathologic records of 864 patients across three continents and 14 countries that were enrolled in a prospective, double blind, placebo controlled study of adjuvant cG250 Ab treatment for high-risk ccRCC. Clinical features analyzed included age, gender, race, body mass index (BMI), and performance status. A single pathologist centrally reviewed the specimens for TNM stage and nuclear grade. BMI was stratified into normal (2), overweight (25.0–29.9 kg/m2), obese (30.0–34.9 kg/m2), and morbidly obese (≥35 kg/m2). We examined the association between BMI, disease severity, and survival using logistic and Cox regression analyses, respectively. Results: Mean BMI was 28.2 kg/m2. The vast majority of our cohort was overweight (43%) and an additional 29% were obese (or morbidly obese). The incidence of lymphatic spread decreased with rising BMI: normal was 11%; overweight was 8%; obese was 5%; and morbidly obese was 2%. Obesity was associated with improved disease-free and overall survival, log rank=0.01 and

4507^ Background: cG250 (Rencarex) is a chimeric monoclonal antibody that binds to the CAIX cell-surface antigen present on 95% of ccRCC. Its safety and activity in phase II studies provided the rationale to investigate its use as an adjuvant monotherapy in subjects with clinically localized high-risk ccRCC—50% of whom progress to metastatic disease. Methods: We performed an international, prospective, multicenter, phase III trial of the efficacy and safety of adjuvant cG250 vs placebo (randomized 1:1) by assessing disease-free (DFS) and overall survival (OS) in 864 RCC patients after nephrectomy. Inclusion criteria were: 1) T3/T4 N0/M0; 2) any T stage and N+/M0; or 3) T1b/T2 N0/M0 high-grade ccRCC. Treatment consisted of a 50 mg loading dose followed by 23-weekly infusions of 20 mg. DFS and CAIX antigen expression were quantified by an independent radiological review and a central pathologist. CAIX score was derived by multiplying the intensity of staining (1–3) by the fraction of positive of cells (0–1), yielding a range of 0.0–3.0. Results: Baseline demographics were well balanced across groups. Treatment demonstrated an excellent safety profile. There were 360 confirmed recurrences and 181 deaths during follow up. When compared with the placebo group, cG250-treated subjects did not enjoy a statistically significant DFS (HR=0.99, p=0.74) or OS advantage (HR=1.01, p=0.94). Median DFS and OS were over 6 years and never reached irrespective of treatment, respectively. However, on subset analysis, subjects with high CAIX expression (>2.0) who received cG250 experienced a statistically significant treatment effect with improved DFS (HR=0.55; p=0.01). Conclusions: While cG250 appears not to have clinical benefit in the adjuvant treatment for all high-risk patients, cG250-treated patients with a high CAIX score appeared to have a significantly improved DFS. The CAIX score may help in stratifying patients who may benefit from cG250 adjuvant therapy. Notwithstanding this benefit, the surprising median DFS of over 6 years and outstanding OS in high-risk patients represent a significant challenge to adjuvant ccRCC drug development. Clinical trial information: NCT00087022.

10569 Background: Recent studies suggest that increased epidermal growth factor receptor (EGFR) gene copy number assessed by in situ hybridization predicts response to cetuximab in patients (pts) with advanced colorectal cancer (mCRC). Additionally, preclinical data indicate that HER2, a member of the EGFR family, can modulate the efficacy of anti-EGFR monoclonal antibodies. Methods: We assessed EGFR and HER2 gene copies by fluorescent in situ hybridization (FISH) on paraffin-embedded samples from 70 pts with mCRC treated with cetuximab alone or with irinotecan. FISH was assessed either on primary tumors (55 pts) or on metastases (15 pts) according to two parameters: the absolute copy number of genes and chromosome (chr) centromeres, and their frequencies in 100 tumor cells. A sensitivity analysis was performed and fitted to outcome data in an attempt to define relevant cutoffs. EGFR protein expression by immunohistochemistry was deemed positive with =10% tumor cells being stained. Multiple paired samples originating from different tumor sources were analyzed whenever available (27 pts). Results: The overall response rate was 25%. Prevalent FISH patterns were disomy (8%) and balanced polysomy (90%) for EGFR gene and chr 7. EGFR amplification was seen in two pts (2%), of which only one responded. HER2 amplification was seen in two of 54 pts (3%), both experiencing stable disease. Average EGFR copies and frequency of tumor cells with >2 copies respectively ranged from 1.6 to 4.0 and from 10% to 90%, thus reflecting a substantial tumor heterogeneity. Despite assessing multiple centile cutoffs of gene copy numbers and their frequencies in tumor cells, we found no association between EGFR and HER2 copy numbers and objective response, time to progression, and overall survival. Analysis of paired samples did not improve the predictive value of EGFR copies by FISH. Excluding EGFR amplification, associated to a strong (3+) EGFR staining, we found no correlation between EGFR copy number and protein expression. Conclusions: Neither EGFR nor HER2 copies by FISH, nor EGFR expression, are predictors of outcome in mCRC pts treated with cetuximab. FISH might still play a role in screening EGFR and HER2 amplification, but cost-effectiveness is debatable. [Table: see text]