- Email: [email protected]
M2024 Surgical Resection for Pancreatic Cancer: An Estimation of the Number Needed to Treat
with increased overall survival (64±22 vs. 18±5 months). Early lesions (PanIns) were also positive for CTSE while no staining was observed in normal ductal cells. Similar patterns were also observed in the transgenic K-Ras model. In contrast, HPDE, BxPC3, MPanc96, Panc1 and MiaPaca2 cells did not express CTSE protein and MOH and HPAC expressed only low levels. In order to study the functional relevance of our findings we generated MiaPaca2 cells, which express relatively high levels of CTSE. In contrast to the parental cells, CTSE expressing cells grew in clusters and readily formed cell adhesions. Proliferation of those cells was significantly decreased compared to control cells (0.4±0.1 vs. 0.6±0.1 after 72hrs). Migration was also significantly inhibited by CTSE expression (6±2 vs. 55±9 cells/5fields after 30hrs). CTSE expression was associated with increased expression of Ecadherin and decreased expression of vimentin, suggesting a mesenchymal to epithelial transition. Conclusions: CTSE is highly expressed in PanIn lesions and pancreatic adenocarcinomas but is lost in cancer cell lines. Positive staining for CTSE correlates with increased overall survival. CTSE expression correlated with decreased growth and migration and lead to changes suggesting mesenchymal to epithelial transition. Loss of CTSE may be important to support the aggressiveness of pancreatic cancer.
M2026
We have reported that fiber-modified conditionally replicative adenoviruses show augmented oncolytic effect for pancreatic cancer. Among them, switching adenovirus (Ad) fiber-knob region from type 5 to type 3 (5/3 modification) increased tumor transduction and showed highest anti-tumor effect after intratumoral as well as systemic vector administration (Ramirez et al, Am J Surg, in press). However, one big obstacle for clinical translation is absence of convenient animal model for toxicological study. Cotton rats and Syrian hamsters have been used for the toxicological study of replicative adenovirus without fiber modification, but rodent models are not usable for 5/3 vectors because 5/3 vectors do not infect rodent cells efficiently. Recently, there was a report about human adenovirus replication in pigs (Jogler et al, J Virol 2006). In this project, we tested the fiber-modified human adenovirus replication in pig cells in order to determine the applicability for preclinical toxicological test of fibermodified CRAds. We first evaluated the infectivity of human adenovirus vectors with unmodified, RGD-modified, and 5/3 modified fibers in human (Hs766T pancreatic cancer), mouse (Hepa1-6 hepatoma, Pan02 pancreatic cancer), hamster (HP1 and HapT1 pancreatic cancer), and pig (PK15 kidney) cells, respectively. 5/3 modification showed significant increase of infectivity in human cells and modest increase in PK-15 pig cells compared to fiber unmodified virus, while infectivity was 2 order lower in rodent cells. In binding assay, 5/3 virus showed increased binding to PK15 as well as human cells, while the rodent cells showed little binding, indicating absence of receptor for this virus. In concurrent with this, the flowcytometory with Ad5/3 fiber protein revealed that Ad5/3 fiber binds to human and pig cells but not to rodent cells. In the context of cytocidal effect, 5/3 vector efficiently killed PK15 and human cell (A549) but had no effect on rodent cells. When the virus replication was evaluated with the vector equipped with luciferase reporter for replication monitoring (Ono et al, Can Res 2005), both fiber-unmodified and 5/3 modified vector showed replication in PK15 although only fiber-unmodified replicated in rodent cells. This indicate that pig cell (PK15) is usable for toxicological assay for 5/3 modified oncolytic adenovirus. Such model is useful for preclinical evaluation of fiber modified oncolytic adenoviruses that we are developing for GI cancers.
M2024 Surgical Resection for Pancreatic Cancer: An Estimation of the Number Needed to Treat Sarah A. Rodriguez, Douglas O. Faigel BACKGROUND: Surgical resection is the only curative option for pancreatic cancer. Although most patients present with surgically unresectable disease, advances in surgical techniques such as portal vein reconstruction have made more patients eligible for resection and potential cure. However, many eligible patients still do not undergo surgery. AIM: To calculate the number needed to treat with surgical resection to gain one 5 year survival among all patients with pancreatic cancer, using incidence and mortality data from the SEER database. METHODS: The SEER 9 database was used. The study was limited to 1986-2000 to offset the potential survival benefit of chemotherapy, which became more widely used after 1985. Incidence of cancer, incidence of cancer directed surgery, and mortality data were obtained for 1986 and 2000. The change in rates of surgery and change in mortality were calculated and used to approximate the number needed to treat to gain one survival at 3 and 5 years. Data for 1999 was used for 5 year survival calculation. The assumption was made that all increases in survival were due to increases in surgery. RESULTS: The incidence of cancer in 1986 was 16.4 per 100,000 population and decreased slightly to 15.9/100,000 in 2000. The incidence of cancer-directed surgery increased steadily over the study period from 1.6/ 100,000 to 3/100,000. The surgery rate for 1986 is calculated by dividing the incidence of surgery in 1986 by the incidence of cancer in 1986, resulting in a surgery rate of 9.8%. The surgery rate for 2000 is 18.9%, a difference of +9.1%. 3 year survival for 1986 for all patients with pancreatic cancer was 3.9%, vs. 6.5% in 2000, an increase of 4.2%. The number needed to treat (NNT) with surgical resection to gain one 3 year survival is the change in surgical rate divided by the change in survival rate. This calculates to an NNT of 3.5. In other words, about 4 patients would need to undergo surgical resection to gain one 3 year survival. The same calculation was made for 5 year survival using data from 1999. The NNT to gain one 5 year survival is 3.95, or about 4 patients. When data was limited to patients with only local or regional stage disease, the NNT calculation is similar at 4.1. CONCLUSIONS: We have calculated the number of pancreatic cancer patients who need to undergo resection to gain one long term survival at about 4. Although this is the minimal possible NNT because it does not account for changes in survival due to improvements in chemotherapy, it suggests that a small increase in surgery rate may finally result in a clinically meaningful increase in survival. This NNT will be used for cost-effective analyses.
M2027 Inoperable Pancreatic Cancer Patients Receiving Contemporary Chemotherapeutic Regimens Who Have Prolonged Survival Exhibit An Increased Risk of Metal Stent Occlusion and Cholangitis James L. Buxbaum, Karen C. Bagatelos, Elmer Y. Chang, Henry K. Niho, James W. Ostroff Background: Biliary obstruction occurs in 90% of patients with inoperable pancreatic cancer. In the pre-gemcitabine era, the median survival for these patients was 4-5 months. Endoscopically placed metal stents, which are patent for a median of 6-9 months, have been the favored decompressive strategy. In the past decade chemotherapeutic options for advanced pancreatic cancer have improved with a median survival of greater than 7 months in recent trials. Thus, it is unknown whether metal stents will continue to be the optimal method of decompression or alternatively will become an unremovable nidus of infection and obstruction in those treated with chemotherapy. Methods: We reviewed all ERCP's performed for biliary obstruction in patients with pancreatic adenocarcinoma between November 1999 and December 2005 at UCSF Medical Center. Patients receiving chemotherapy, primarily as part of clinical trials, were included. Those who underwent potentially curative or palliative biliary diversion procedures were excluded. Results: Among the 202 patients with pancreatic cancer who underwent endoscopic biliary decompression, 56 received chemotherapy and did not undergo surgery. The median survival of this population was 12 months (mean 11.7). Twenty-six patients had locally advanced cancer and thirty had widespread metastases. Gemcitabine was administered to 88% of patients and 75% were treated with multi-agent chemotherapy. Procedures to relieve biliary obstruction were performed a median of one month after the diagnosis of malignancy. Decompression was achieved by endoscopic stenting in 93% of patients. Among the total of 111 endoscopic procedures performed, there were 2 complications, one post sphincterotomy bleed and one episode of pancreatitis. Metal stents were used in most of these cases. Seventeen of the patients (30%) required hospitalization for cholangitis or biliary obstruction. Sixteen of these cases occurred in patients whose survival was greater than or equal to ten months. Thus 50% of the patients surviving greater than 10 months (16/32) compared to 4% (1/24) of those surviving less, were hospitalized for complications of stent occlusion. The average length of hospitalization was 7.4 days. Conclusion: This cohort of inoperable pancreatic cancer patients undergoing chemotherapy survived longer than the expected patent period of metal stents employed for biliary decompression. The incidence of cholangitis and obstruction requiring hospitalization does increase markedly among long term survivors. Periodic plastic stent exchanges may prove to be a safer alternative to early expandable metal stent placement.
M2025 Inhibiting Pancreatic Cancer Growth and Sensitizing the Tumor to Radiotherapy Through Downregulation of SP Proteins Shilpa Oberoi, Rajesambhaji Borade, Neal McCollum, Santhi D. Konduri, Jimmie F. Colon, Cheryl H. Baker, Maen Abdelrahim Sp1, Sp3 and Sp4 proteins play a critical role in the growth and metastasis of pancreatic cancer cells. Initial studies screened a panel of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase 2 (COX-2) and COX-1 inhibitors for their effects on Sp protein expression. Only tolfenamic acid and its derivatives degraded all three Sp proteins. The most active compound was tolfenamic acid which also inhibited growth of Panc-1, L3.6pl and Panc28 pancreatic cancer cells. Tolfenamic acid induced proteasome-dependent degradation of Sp1, Sp3 and Sp4, and this response was blocked by the proteasome inhibitors gliotoxin and lactacystin. Tolfenamic acid also inhibited Vascular Endothelial Growth Factor (VEGF) and the antiapoptotic survivin mRNA/protein expression in Panc-1 and L3.6pl cells, and this was linked to decreased binding to and activation of proximal GC-rich sites in the VEGF and survivin promoter. Orthotopic model for pancreatic tumor growth has been used to investigate tolfenamic acid-induced antiangiogenic and proapoptotic responses. Treatment with 12.5 and 25 mg/kg tolfenamic acid decreased tumor growth, size and weight compared to solvent (control) and also decreased liver metastasis. In addition, tolfenamic acid increased sensitivity of pancreatic cancer cells and tumor to radiation therapy and this was mediated by blocking radiation-induced survivin protein overexpression. Thus, tolfenamic acid acts as a novel anticancer agent and radiation sensitizer through targeted degradation of Sp proteins that are highly overexpressed in tumor.
M2028 Low Dose Gemcitabine Improves the Prognosis of Elderly Patients with Unresectable Advanced Pancreatic Cancer Kazuyuki Matsumoto, Tatsuya Toyokawa, Yasuhiro Miyake, Hisae Yasumara, Masahiro Takahara, Eisuke Kaji, Morihito Nakatsu, Masaharu Ando, Mamoru Hirohata Background: Pancreatic cancer is increasing in incidence and the fourth leading cause of cancer death in the United States. Up to 90% of patients present with locally advanced or metastatic disease. Recently, the effect of gemcitabine on advanced pancreatic cancer has been recognized. On the other hand, the effect of gemcitabine on advanced disease in elderly patients has been unclear. This study was constructed in order to assess the effect of low dose gemcitabine on the prognosis of elderly patients with unresectable advanced pancreatic cancer. Methods: Fifty-eight patients aged more than 65 years old (32 males and 26 females with a median age of 76 years old) were prospectively included into this analysis. Patients
A-453
AGA Abstracts
AGA Abstracts
New Model for Testing Safety of Oncolytic Fiber-Modified Conditionally Replicative Adenovirus Designed for Pancreatic Cancer Julia Davydova, Eric J. Brown, Selwyn M. Vickers, Masato Yamamoto
M2026
We have reported that fiber-modified conditionally replicative adenoviruses show augmented oncolytic effect for pancreatic cancer. Among them, switching adenovirus (Ad) fiber-knob region from type 5 to type 3 (5/3 modification) increased tumor transduction and showed highest anti-tumor effect after intratumoral as well as systemic vector administration (Ramirez et al, Am J Surg, in press). However, one big obstacle for clinical translation is absence of convenient animal model for toxicological study. Cotton rats and Syrian hamsters have been used for the toxicological study of replicative adenovirus without fiber modification, but rodent models are not usable for 5/3 vectors because 5/3 vectors do not infect rodent cells efficiently. Recently, there was a report about human adenovirus replication in pigs (Jogler et al, J Virol 2006). In this project, we tested the fiber-modified human adenovirus replication in pig cells in order to determine the applicability for preclinical toxicological test of fibermodified CRAds. We first evaluated the infectivity of human adenovirus vectors with unmodified, RGD-modified, and 5/3 modified fibers in human (Hs766T pancreatic cancer), mouse (Hepa1-6 hepatoma, Pan02 pancreatic cancer), hamster (HP1 and HapT1 pancreatic cancer), and pig (PK15 kidney) cells, respectively. 5/3 modification showed significant increase of infectivity in human cells and modest increase in PK-15 pig cells compared to fiber unmodified virus, while infectivity was 2 order lower in rodent cells. In binding assay, 5/3 virus showed increased binding to PK15 as well as human cells, while the rodent cells showed little binding, indicating absence of receptor for this virus. In concurrent with this, the flowcytometory with Ad5/3 fiber protein revealed that Ad5/3 fiber binds to human and pig cells but not to rodent cells. In the context of cytocidal effect, 5/3 vector efficiently killed PK15 and human cell (A549) but had no effect on rodent cells. When the virus replication was evaluated with the vector equipped with luciferase reporter for replication monitoring (Ono et al, Can Res 2005), both fiber-unmodified and 5/3 modified vector showed replication in PK15 although only fiber-unmodified replicated in rodent cells. This indicate that pig cell (PK15) is usable for toxicological assay for 5/3 modified oncolytic adenovirus. Such model is useful for preclinical evaluation of fiber modified oncolytic adenoviruses that we are developing for GI cancers.
M2024 Surgical Resection for Pancreatic Cancer: An Estimation of the Number Needed to Treat Sarah A. Rodriguez, Douglas O. Faigel BACKGROUND: Surgical resection is the only curative option for pancreatic cancer. Although most patients present with surgically unresectable disease, advances in surgical techniques such as portal vein reconstruction have made more patients eligible for resection and potential cure. However, many eligible patients still do not undergo surgery. AIM: To calculate the number needed to treat with surgical resection to gain one 5 year survival among all patients with pancreatic cancer, using incidence and mortality data from the SEER database. METHODS: The SEER 9 database was used. The study was limited to 1986-2000 to offset the potential survival benefit of chemotherapy, which became more widely used after 1985. Incidence of cancer, incidence of cancer directed surgery, and mortality data were obtained for 1986 and 2000. The change in rates of surgery and change in mortality were calculated and used to approximate the number needed to treat to gain one survival at 3 and 5 years. Data for 1999 was used for 5 year survival calculation. The assumption was made that all increases in survival were due to increases in surgery. RESULTS: The incidence of cancer in 1986 was 16.4 per 100,000 population and decreased slightly to 15.9/100,000 in 2000. The incidence of cancer-directed surgery increased steadily over the study period from 1.6/ 100,000 to 3/100,000. The surgery rate for 1986 is calculated by dividing the incidence of surgery in 1986 by the incidence of cancer in 1986, resulting in a surgery rate of 9.8%. The surgery rate for 2000 is 18.9%, a difference of +9.1%. 3 year survival for 1986 for all patients with pancreatic cancer was 3.9%, vs. 6.5% in 2000, an increase of 4.2%. The number needed to treat (NNT) with surgical resection to gain one 3 year survival is the change in surgical rate divided by the change in survival rate. This calculates to an NNT of 3.5. In other words, about 4 patients would need to undergo surgical resection to gain one 3 year survival. The same calculation was made for 5 year survival using data from 1999. The NNT to gain one 5 year survival is 3.95, or about 4 patients. When data was limited to patients with only local or regional stage disease, the NNT calculation is similar at 4.1. CONCLUSIONS: We have calculated the number of pancreatic cancer patients who need to undergo resection to gain one long term survival at about 4. Although this is the minimal possible NNT because it does not account for changes in survival due to improvements in chemotherapy, it suggests that a small increase in surgery rate may finally result in a clinically meaningful increase in survival. This NNT will be used for cost-effective analyses.
M2027 Inoperable Pancreatic Cancer Patients Receiving Contemporary Chemotherapeutic Regimens Who Have Prolonged Survival Exhibit An Increased Risk of Metal Stent Occlusion and Cholangitis James L. Buxbaum, Karen C. Bagatelos, Elmer Y. Chang, Henry K. Niho, James W. Ostroff Background: Biliary obstruction occurs in 90% of patients with inoperable pancreatic cancer. In the pre-gemcitabine era, the median survival for these patients was 4-5 months. Endoscopically placed metal stents, which are patent for a median of 6-9 months, have been the favored decompressive strategy. In the past decade chemotherapeutic options for advanced pancreatic cancer have improved with a median survival of greater than 7 months in recent trials. Thus, it is unknown whether metal stents will continue to be the optimal method of decompression or alternatively will become an unremovable nidus of infection and obstruction in those treated with chemotherapy. Methods: We reviewed all ERCP's performed for biliary obstruction in patients with pancreatic adenocarcinoma between November 1999 and December 2005 at UCSF Medical Center. Patients receiving chemotherapy, primarily as part of clinical trials, were included. Those who underwent potentially curative or palliative biliary diversion procedures were excluded. Results: Among the 202 patients with pancreatic cancer who underwent endoscopic biliary decompression, 56 received chemotherapy and did not undergo surgery. The median survival of this population was 12 months (mean 11.7). Twenty-six patients had locally advanced cancer and thirty had widespread metastases. Gemcitabine was administered to 88% of patients and 75% were treated with multi-agent chemotherapy. Procedures to relieve biliary obstruction were performed a median of one month after the diagnosis of malignancy. Decompression was achieved by endoscopic stenting in 93% of patients. Among the total of 111 endoscopic procedures performed, there were 2 complications, one post sphincterotomy bleed and one episode of pancreatitis. Metal stents were used in most of these cases. Seventeen of the patients (30%) required hospitalization for cholangitis or biliary obstruction. Sixteen of these cases occurred in patients whose survival was greater than or equal to ten months. Thus 50% of the patients surviving greater than 10 months (16/32) compared to 4% (1/24) of those surviving less, were hospitalized for complications of stent occlusion. The average length of hospitalization was 7.4 days. Conclusion: This cohort of inoperable pancreatic cancer patients undergoing chemotherapy survived longer than the expected patent period of metal stents employed for biliary decompression. The incidence of cholangitis and obstruction requiring hospitalization does increase markedly among long term survivors. Periodic plastic stent exchanges may prove to be a safer alternative to early expandable metal stent placement.
M2025 Inhibiting Pancreatic Cancer Growth and Sensitizing the Tumor to Radiotherapy Through Downregulation of SP Proteins Shilpa Oberoi, Rajesambhaji Borade, Neal McCollum, Santhi D. Konduri, Jimmie F. Colon, Cheryl H. Baker, Maen Abdelrahim Sp1, Sp3 and Sp4 proteins play a critical role in the growth and metastasis of pancreatic cancer cells. Initial studies screened a panel of nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase 2 (COX-2) and COX-1 inhibitors for their effects on Sp protein expression. Only tolfenamic acid and its derivatives degraded all three Sp proteins. The most active compound was tolfenamic acid which also inhibited growth of Panc-1, L3.6pl and Panc28 pancreatic cancer cells. Tolfenamic acid induced proteasome-dependent degradation of Sp1, Sp3 and Sp4, and this response was blocked by the proteasome inhibitors gliotoxin and lactacystin. Tolfenamic acid also inhibited Vascular Endothelial Growth Factor (VEGF) and the antiapoptotic survivin mRNA/protein expression in Panc-1 and L3.6pl cells, and this was linked to decreased binding to and activation of proximal GC-rich sites in the VEGF and survivin promoter. Orthotopic model for pancreatic tumor growth has been used to investigate tolfenamic acid-induced antiangiogenic and proapoptotic responses. Treatment with 12.5 and 25 mg/kg tolfenamic acid decreased tumor growth, size and weight compared to solvent (control) and also decreased liver metastasis. In addition, tolfenamic acid increased sensitivity of pancreatic cancer cells and tumor to radiation therapy and this was mediated by blocking radiation-induced survivin protein overexpression. Thus, tolfenamic acid acts as a novel anticancer agent and radiation sensitizer through targeted degradation of Sp proteins that are highly overexpressed in tumor.
M2028 Low Dose Gemcitabine Improves the Prognosis of Elderly Patients with Unresectable Advanced Pancreatic Cancer Kazuyuki Matsumoto, Tatsuya Toyokawa, Yasuhiro Miyake, Hisae Yasumara, Masahiro Takahara, Eisuke Kaji, Morihito Nakatsu, Masaharu Ando, Mamoru Hirohata Background: Pancreatic cancer is increasing in incidence and the fourth leading cause of cancer death in the United States. Up to 90% of patients present with locally advanced or metastatic disease. Recently, the effect of gemcitabine on advanced pancreatic cancer has been recognized. On the other hand, the effect of gemcitabine on advanced disease in elderly patients has been unclear. This study was constructed in order to assess the effect of low dose gemcitabine on the prognosis of elderly patients with unresectable advanced pancreatic cancer. Methods: Fifty-eight patients aged more than 65 years old (32 males and 26 females with a median age of 76 years old) were prospectively included into this analysis. Patients
A-453
AGA Abstracts
AGA Abstracts
New Model for Testing Safety of Oncolytic Fiber-Modified Conditionally Replicative Adenovirus Designed for Pancreatic Cancer Julia Davydova, Eric J. Brown, Selwyn M. Vickers, Masato Yamamoto