- Email: [email protected]
2062 Increase in thymidine phosphorylase gene expression in tumor tissues is associated with response to preoperative chemoradiotherapy including S-1 or UFT in patients with rectal cancer
Abstracts
S349
2060 POSTER Acetylsalicylic acid as a neo-adjuvant agent during preoperative chemoradiation for rectal cancer A. Restivo1 , F. Cabras1 , F. Cocco1 , M. Scartozzi2 , L. Zorcolo1 . 1 Colorectal Surgery Unit, Department of Surgical Science, Cagliari, Italy; 2 Medical Oncology, Department of Medicine, Cagliari, Italy Background: Recently many studies have reported a positive prognostic effect with acetysalicilic acid (ASA) use in patients with established colorectal cancer, suggesting its possible adjuvant effect. The aim of this study was to investigate the anticancer effect of ASA use during preoperative chemoradiation for rectal cancer. Methods: 241 consecutive patients diagnosed with stage II-III rectal cancer and candidates for CRT were enrolled. Patients were assigned to two groups: group 1, patients taking ASA, and group 2, all remaining patients. Response to treatment and oncological outcomes were explored. Results: Acetysalicilic acid use was associated with a higher rate of tumor downstaging (67.6% vs. 43.6%, p = 0.01), GPR (46% vs. 19%, p < 0.001), and a slightly although not significant higher rate of CPR (22% vs. 13%, p = 0.196). ASA use was also associated with a better five years’ progression free (86.6% vs. 67.1%; HR = 0.32, 95% CI=0.12–0.84) and overall survival (90.6% vs. 73.2%; HR = 0.22, 95% CI=0.05–0.94). While chance of local relapse was similar (HR = 0.6, 95% CI=0.06−4.5), aspirin use was associated with a lower risk of developing metastasis (HR = 0.30, 95% CI=0.10– 0.86). Conclusion: Acetysalicilic acid might have anticancer activity against rectal cancer during preoperative chemoradiation for rectal cancer. This finding should be further investigated. No conflict of interest. 2061 POSTER High-risk clinical and pathologic features define prognostic subsets among stage III colon cancer patients A. Rosales Sotomayor1 , V. Rosas1 , A. Noguez Ramos1 , A. Gamboa 1 Dom´ınguez2 , F.D. Huitzil Melendez ´ , M. Mora-Pineda1 . 1 Instituto Nacional De Ciencias Medicas Y Nutricion Salvador Zubiran, Hematology and Oncology Department, Distrito Federal, Mexico; 2 Instituto Nacional De Ciencias Medicas Y Nutricion Salvador Zubiran, Pathology Department, Distrito Federal, Mexico Background: In stage II colon cancer pT4, obstruction/perforation, high grade, <12 lymph node examined, lymphatic, vascular and perineural invasion have been associated with worse prognosis. The effect of these high-risk features in stage III patients has not been explored. We hypothesize that a greater number of high-risk features is associated with poor prognosis. Material and Methods: We retrospectively reviewed the medical records of all patients with colon cancer and histological confirmation at our Institution from January 2004 to December 2012, 320 patients were identified. Relevant clinical and histological features were recorded at presentation. Overall survival (OS) was estimated using Kaplan–Meier method and survival distributions were compared using the Log-rank test. Table 1. Prognostic subsets among stage III colon cancer patients Variable
5-year survival
P
High-risk features 0 1−2 3 Nodal involvement N1c N1 N2
95% 71% 51%
0.022
for the cohort was 76%, median OS has not been reached. Multivariate analysis showed that the number of high-risk features was associated with a different survival rates in node-positive colon cancer patients (HR = 2.3; 95% CI 1.06–5.06; p = 0.034). Conclusions: In stage III disease, the survival vary according to the number of high-risk clinical and pathological features, these prognostic factors are easily available and inexpensive unlike genomic signatures which have been developed for the same purpose. No conflict of interest. 2062 POSTER Increase in thymidine phosphorylase gene expression in tumor tissues is associated with response to preoperative chemoradiotherapy including S-1 or UFT in patients with rectal cancer S. Sadahiro1 , T. Suzuki1 , A. Tanaka1 , K. Okada1 , G. Saito1 , A. Kamijo1 , H. Nagase2 . 1 Tokai University, Surgery, Isehara, Japan; 2 Taiho Pharmaceutical Co.-Ltd., Applied Pharmacology Lab., Tokushima, Japan Background: Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in locally advanced rectal cancer. Our previous study using pre-CRT biopsy specimens (pre-samples) suggested that low expression levels of thymidylate synthetase gene were associated with a better response to preoperative CRT with S-1 or UFT (ESMO 2014). Another our previous study using biopsy specimens obtained 7 days after starting CRT (post-samples) suggested that the histologic changes in H-Estained sections are strong predictors of the response to CRT (Int J Radiat Oncol Biol Phys 2013), suggesting that the expression levels of genes related to CRT sensitivity may change in post-samples. In this study, we examined the association of the response to CRT with the change in the expression levels of drug-related genes in post-samples. Materials and Methods: Data of 82 patients with locally advanced rectal cancer who received preoperative CRT with UFT or S-1 (± bevacizumab) for 5 weeks were analyzed. We assessed the pathological tumor response according to the tumor regression grade (TRG) and the Japanese classification of colorectal carcinoma (JCCC) criteria. A patient with TRG 1−2 or JCCC Grade 2−3 was defined as a responder. The mRNA expressions of pyrimidine-related enzymes, reduced folate-related enzymes and radiation-related enzymes (18 genes) in the pre- and postsamples were quantitatively evaluated using a RT-PCR assay. The patients were divided into low and high groups of post/pre-ratio of thymidine phosphorylase (TYMP) gene expression using the cutoff value determined by the receiver operating characteristic curve. Results: Pathological response was observed in 41 patients (50%) by TRG criteria, and in 59 patients (72%) by JCCC criteria. The post/pre ratios of the expression levels of 6 genes, including TYMP, were significantly higher in the responders than in the non-responders (p 0.05). The gene expression levels of TYMP, hypoxia-inducible factor 1 alpha subunit (HIF1A) and dihydropyrimidine dehydrogenase (DPYD) were significantly increased in the post-samples in the responders, but not in the non-responders. The response rates (60.8% by TRG criteria, 83.7% by JCCC criteria) in the high post/pre ratio of TYMP were significantly higher than those in low post/pre ratio of TYMP (p = 0.022 and p = 0.006, respectively). Conclusion: Detection of any increase in the gene expression levels of TYMP, HIF1A and DPYD in tumor tissues 7 days after starting CRT may be useful for predicting the efficacy of preoperative CRT with S-1 or UFT. The increase in TYMP expression levels in tumor tissues may induce the enhancement of 5-FU sensitivity, because TYMP is one of the main enzymes involved in the activation of 5-FU. Conflict of interest: Other Substantive Relationships: Mr. Hideki Nagase is an employee of Taiho Pharmaceutical Co. Ltd.
0.217 100% 80% 61%
Results: Of 320 patients, 63 had positive lymph nodes and were included (20%). Median age was 60 (28−89 y/o), 60% were male. The frequency of poor prognosis features were as follows: seven percent of patients had well-differentiated, 71% moderately-differentiated and 22% poorlydifferentiated tumors. Obstruction in 14% (N = 9), perforation in 3% (N = 2); lymphatic invasion in 40% (N = 25), vascular invasion 35% (N = 22), perineural invasion in 14% (N = 9), depth of penetration T4 in 76% (N = 48). Pathological N1c in 10% (N = 5), N1 involvement in 60% (N = 38) and N2 in 30% (N = 19); five-year survival rates per node involvement was 100% for N1c, 80% for N1 and 61% for N2. Number of high-risk features: none 40% (N = 25), one or two 36% (N = 23), three or more 24% (N = 15); five-year survival rates were 95%, 71% and 51% (p = 0.022), respectively. Thirty-six percent (N = 22) did not received adjuvant chemotherapy. Five-year survival
2063 POSTER Acute toxicity evaluation in preoperative radiochemotherapy with IMRT − simultaneous integrated boost in locally advanced rectal cancer (BISER study) F. Anderluh1 , J. But Hadzic1 , V. Velenik1 , I. Oblak1 , A. Secerov Ermenc1 , A. Jeromen1 , R. Hudej1 . 1 Institute of Oncology, Radiotherapy dept., Ljubljana, Slovenia Purpose: At the moment the standard treatment in operable locally and/or regionally advanced rectal cancer is preoperative radiochemotherapy with the total dose to the tumor of 50,4−54 Gy in daily fractions of 1,8−2 Gy. The purpose of our prospective phase II study was to evaluate feasibility and safety of preoperative capecitabine and accelerated synchronous integrated boost (SIB) intensity-modulated radiotherapy (IMRT) for locally advanced rectal cancer. Patients and Methods: Between January 2014 and March 2015, 51 patients (31 male, 20 female) with operable, stage II-III rectal adenocarcinoma
S349
2060 POSTER Acetylsalicylic acid as a neo-adjuvant agent during preoperative chemoradiation for rectal cancer A. Restivo1 , F. Cabras1 , F. Cocco1 , M. Scartozzi2 , L. Zorcolo1 . 1 Colorectal Surgery Unit, Department of Surgical Science, Cagliari, Italy; 2 Medical Oncology, Department of Medicine, Cagliari, Italy Background: Recently many studies have reported a positive prognostic effect with acetysalicilic acid (ASA) use in patients with established colorectal cancer, suggesting its possible adjuvant effect. The aim of this study was to investigate the anticancer effect of ASA use during preoperative chemoradiation for rectal cancer. Methods: 241 consecutive patients diagnosed with stage II-III rectal cancer and candidates for CRT were enrolled. Patients were assigned to two groups: group 1, patients taking ASA, and group 2, all remaining patients. Response to treatment and oncological outcomes were explored. Results: Acetysalicilic acid use was associated with a higher rate of tumor downstaging (67.6% vs. 43.6%, p = 0.01), GPR (46% vs. 19%, p < 0.001), and a slightly although not significant higher rate of CPR (22% vs. 13%, p = 0.196). ASA use was also associated with a better five years’ progression free (86.6% vs. 67.1%; HR = 0.32, 95% CI=0.12–0.84) and overall survival (90.6% vs. 73.2%; HR = 0.22, 95% CI=0.05–0.94). While chance of local relapse was similar (HR = 0.6, 95% CI=0.06−4.5), aspirin use was associated with a lower risk of developing metastasis (HR = 0.30, 95% CI=0.10– 0.86). Conclusion: Acetysalicilic acid might have anticancer activity against rectal cancer during preoperative chemoradiation for rectal cancer. This finding should be further investigated. No conflict of interest. 2061 POSTER High-risk clinical and pathologic features define prognostic subsets among stage III colon cancer patients A. Rosales Sotomayor1 , V. Rosas1 , A. Noguez Ramos1 , A. Gamboa 1 Dom´ınguez2 , F.D. Huitzil Melendez ´ , M. Mora-Pineda1 . 1 Instituto Nacional De Ciencias Medicas Y Nutricion Salvador Zubiran, Hematology and Oncology Department, Distrito Federal, Mexico; 2 Instituto Nacional De Ciencias Medicas Y Nutricion Salvador Zubiran, Pathology Department, Distrito Federal, Mexico Background: In stage II colon cancer pT4, obstruction/perforation, high grade, <12 lymph node examined, lymphatic, vascular and perineural invasion have been associated with worse prognosis. The effect of these high-risk features in stage III patients has not been explored. We hypothesize that a greater number of high-risk features is associated with poor prognosis. Material and Methods: We retrospectively reviewed the medical records of all patients with colon cancer and histological confirmation at our Institution from January 2004 to December 2012, 320 patients were identified. Relevant clinical and histological features were recorded at presentation. Overall survival (OS) was estimated using Kaplan–Meier method and survival distributions were compared using the Log-rank test. Table 1. Prognostic subsets among stage III colon cancer patients Variable
5-year survival
P
High-risk features 0 1−2 3 Nodal involvement N1c N1 N2
95% 71% 51%
0.022
for the cohort was 76%, median OS has not been reached. Multivariate analysis showed that the number of high-risk features was associated with a different survival rates in node-positive colon cancer patients (HR = 2.3; 95% CI 1.06–5.06; p = 0.034). Conclusions: In stage III disease, the survival vary according to the number of high-risk clinical and pathological features, these prognostic factors are easily available and inexpensive unlike genomic signatures which have been developed for the same purpose. No conflict of interest. 2062 POSTER Increase in thymidine phosphorylase gene expression in tumor tissues is associated with response to preoperative chemoradiotherapy including S-1 or UFT in patients with rectal cancer S. Sadahiro1 , T. Suzuki1 , A. Tanaka1 , K. Okada1 , G. Saito1 , A. Kamijo1 , H. Nagase2 . 1 Tokai University, Surgery, Isehara, Japan; 2 Taiho Pharmaceutical Co.-Ltd., Applied Pharmacology Lab., Tokushima, Japan Background: Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in locally advanced rectal cancer. Our previous study using pre-CRT biopsy specimens (pre-samples) suggested that low expression levels of thymidylate synthetase gene were associated with a better response to preoperative CRT with S-1 or UFT (ESMO 2014). Another our previous study using biopsy specimens obtained 7 days after starting CRT (post-samples) suggested that the histologic changes in H-Estained sections are strong predictors of the response to CRT (Int J Radiat Oncol Biol Phys 2013), suggesting that the expression levels of genes related to CRT sensitivity may change in post-samples. In this study, we examined the association of the response to CRT with the change in the expression levels of drug-related genes in post-samples. Materials and Methods: Data of 82 patients with locally advanced rectal cancer who received preoperative CRT with UFT or S-1 (± bevacizumab) for 5 weeks were analyzed. We assessed the pathological tumor response according to the tumor regression grade (TRG) and the Japanese classification of colorectal carcinoma (JCCC) criteria. A patient with TRG 1−2 or JCCC Grade 2−3 was defined as a responder. The mRNA expressions of pyrimidine-related enzymes, reduced folate-related enzymes and radiation-related enzymes (18 genes) in the pre- and postsamples were quantitatively evaluated using a RT-PCR assay. The patients were divided into low and high groups of post/pre-ratio of thymidine phosphorylase (TYMP) gene expression using the cutoff value determined by the receiver operating characteristic curve. Results: Pathological response was observed in 41 patients (50%) by TRG criteria, and in 59 patients (72%) by JCCC criteria. The post/pre ratios of the expression levels of 6 genes, including TYMP, were significantly higher in the responders than in the non-responders (p 0.05). The gene expression levels of TYMP, hypoxia-inducible factor 1 alpha subunit (HIF1A) and dihydropyrimidine dehydrogenase (DPYD) were significantly increased in the post-samples in the responders, but not in the non-responders. The response rates (60.8% by TRG criteria, 83.7% by JCCC criteria) in the high post/pre ratio of TYMP were significantly higher than those in low post/pre ratio of TYMP (p = 0.022 and p = 0.006, respectively). Conclusion: Detection of any increase in the gene expression levels of TYMP, HIF1A and DPYD in tumor tissues 7 days after starting CRT may be useful for predicting the efficacy of preoperative CRT with S-1 or UFT. The increase in TYMP expression levels in tumor tissues may induce the enhancement of 5-FU sensitivity, because TYMP is one of the main enzymes involved in the activation of 5-FU. Conflict of interest: Other Substantive Relationships: Mr. Hideki Nagase is an employee of Taiho Pharmaceutical Co. Ltd.
0.217 100% 80% 61%
Results: Of 320 patients, 63 had positive lymph nodes and were included (20%). Median age was 60 (28−89 y/o), 60% were male. The frequency of poor prognosis features were as follows: seven percent of patients had well-differentiated, 71% moderately-differentiated and 22% poorlydifferentiated tumors. Obstruction in 14% (N = 9), perforation in 3% (N = 2); lymphatic invasion in 40% (N = 25), vascular invasion 35% (N = 22), perineural invasion in 14% (N = 9), depth of penetration T4 in 76% (N = 48). Pathological N1c in 10% (N = 5), N1 involvement in 60% (N = 38) and N2 in 30% (N = 19); five-year survival rates per node involvement was 100% for N1c, 80% for N1 and 61% for N2. Number of high-risk features: none 40% (N = 25), one or two 36% (N = 23), three or more 24% (N = 15); five-year survival rates were 95%, 71% and 51% (p = 0.022), respectively. Thirty-six percent (N = 22) did not received adjuvant chemotherapy. Five-year survival
2063 POSTER Acute toxicity evaluation in preoperative radiochemotherapy with IMRT − simultaneous integrated boost in locally advanced rectal cancer (BISER study) F. Anderluh1 , J. But Hadzic1 , V. Velenik1 , I. Oblak1 , A. Secerov Ermenc1 , A. Jeromen1 , R. Hudej1 . 1 Institute of Oncology, Radiotherapy dept., Ljubljana, Slovenia Purpose: At the moment the standard treatment in operable locally and/or regionally advanced rectal cancer is preoperative radiochemotherapy with the total dose to the tumor of 50,4−54 Gy in daily fractions of 1,8−2 Gy. The purpose of our prospective phase II study was to evaluate feasibility and safety of preoperative capecitabine and accelerated synchronous integrated boost (SIB) intensity-modulated radiotherapy (IMRT) for locally advanced rectal cancer. Patients and Methods: Between January 2014 and March 2015, 51 patients (31 male, 20 female) with operable, stage II-III rectal adenocarcinoma