Complications, continence and quality of life after an intensive preoperative radio-chemotherapy regimen for locally advanced rectal cancer: analysis of a phase I–II study

S: POSTER PRESENTATIONS P99 Complications, continence and quality of life after an intensive preoperative radio-chemotherapy regimen for locally advanced rectal cancer: analysis of a phase I-II study S. Pucciarelli, ~* E. Urso, ~ S. Serpentini, ~ E Toppan, I G.L. De Salvo, 2 G. Fabris, 3 M.L. Friso, 4 C. Asclaele, 5 A. Bruttocao, 6 M. Lise. 1 1. Clinica Chirurgica I[, University of Padova, Padova, Italy," 2. Centro Oncologico Regionale, Padova, Italy; 3. Divisione Chirurgica IL Padova, Italy; 4. Divisione di Radioterapia, Padova, Italy; 5. Divisione di Oncologia, Padova, Italy, 6. Chirurgia Geriatrica, Padova, Italy. Purpose: To make a prospective investigation of toxicity, functional and oncological outcome, and quality of life (QoL) in pts with locally advanced rectal cancer given intensive preoperative radio-chemotherapy (RTCT). Methods: From May 2000 to April 2002, 44 TNM stage II-III mid-low rectal cancer pts (mean age: 58 yrs, range: 35-74; M/F: 25/19) enrolled in a multicentric prospective phase I-II study were given RTCT (50.4 Gy/28E 5FU: 200-225mg/m2/day CI and weekly Oxaliplatin, 25-60 rag/m2) followed, 4 to 6 weeks later, by surgery. In 22 pts in a single surgical unit, anorectal function and QoL were investigated using the fecal incontinence scoring system (FISS) and EORTC QLQ-CR38 questionnaire, administered before RT (tO), preoperatively (tl), and one year after surgery (t2). Statistical analysis: KaplanMeier curves for overall (OS) and disease-free survival (DFS); repeated measures analysis o f variance for differences in scores over time. Results: Acute grade 3+ toxicity was observed in 8 pts; both sphincter-saving procedure and radical resection were performed in 39 cases. There were no operative deaths; major postoperative complications (anastomotic leak, n=5; hemoperitoneum, n = 1) occurred in 6 pts, of whom 4 required re-operation. Late complications requiring re-admission occurred in 13 patients, of whom 6 required surgery. Twelve (27%) pts had a pathological complete response (pCR). At a median follow-up of 20 months, 4 pts had recurrence and 3 died. A not significant worsening in FISS was observed: median score of 25, 25, and 62, for time tO, t l , and t2, respectively. Out of the parameters investigated using QLQ-CR38, only "future perspective" showed significant improvement over time (mean score: 33, 43 and 54). Actuarial OS and DFS at 30 months were 93 and 88%, respectively. Conclusion: Following this new aggressive RTCT preoperative regimen used by us, pCR, short-term oncological results, QoL and intestinal function observed appear to be promising, although drug toxicity and late post-surgical complications are not negligible P100 mTOR signaling is a possible new biochemical target for pancreatic cancer therapy D. Ito,* K. Fujimoto, R. Doi, E. Toyoda, T. Mori, K. Kami, Y. Shimada, M. Imamura. Surgery and Surgical Basic Science, Kyoto University, Kyoto, Kyoto, Japan. Introduction: The mammalian target of rapamycin (mTOR) plays a central role in the cell proliferation through the regulation of cell cycle. Dysregulation of mTOR signaling occurs in diverse hmnan tumors, and can confer higher susceptibility to inhibitors ofmTOR. In this study, we investigated whether the mTOR signaling is activated in 6 pancreatic cancer cell lines and tissue specimens of pancreatic ductal adenocarcinoma (PDA), and examined antiproliferative effects of the mTOR inhibitor, CCI-779. Methods: First, we examined the expression pattern of PTEN, phospho-Akt (AKT), p-mTOR (mTOR) and p-p70S6K (p70S6K) in 6 human pancreatic cancer cell lines and 20 tissue specimens of PDA by western blot and immunohistochemistry. Next, we examined the cytotoxicity of the mTOR inhibitor, CCI-779 (0200 nM) in the 6 cell lines in vitro as single agent and in combination with standard chemotherapeutic drug, gemcitabine (10 nM). Finally, the antitumor effects of CCI-779 were examined using in AsPC-1 and Suit-2 xenograft models. Results: As shown in the table below, on a panel of 6 pancreatic cancer cell lines, PTEN expression was detected in 4 cell lines except for KMP-3 and KMP-4 cells. Interestingly, Akt was strongly phosphorylated even in the 4 cell lines which showed the positive expression of PTEN. mTOR and p70S6K were activated in all of the 6 cell lines examined. In the tissue specimens of PDA, p-Akt expression was detected in 60% of the specimens, p-mTOR was detected 55%, and p-p70S6K was detected in 45%. With respect to the growth inhibitory effects of CCI-779, AsPC-1 and KMP-3 cells were highly sensitive to the treatment, and BxPC-3 and Suit-2 cells were slightly resistant. Intriguingly, CCI-779 had additive effects with gemcitabine in the 2 cell lines resistant to the treatment with CCI-779 alone such as BxPC-3 and Suit-2. Furthermore, CCI-779 induced antitumor activity in both of AsPC-1 (sensitive in vitro) and Suit-2 (resistant in vitro) xenografts. Conclusions: These results suggest that roTOR may be a good target for pancreatic cancer therapy and the roTOR inhibitor, CCI-779 is an important new agent to investigate in the treatment of pancreatic cancer. Expression of roTOR signaling and effect of CCI-779 on the growth of human pancreatic cancer eel)