Vitamin D Supplementation is a Promising Therapy for Pancreatic Ductal Adenocarcinoma in Conjunction with Current Chemoradiation Therapy.

BACKGROUND: The cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) are well known to play a dominant role in distant metastasis. Nevertheless, the effect on CAFs with current chemoradiation therapies remains uncertain. OBJECTIVE: This study aimed to reveal the role of CAFs under current chemoradiation therapy (CRT) and investigate the factors regulating CAFs. METHODS: α-SMA-positive cells in 86 resected PDAC specimens with/without preoperative CRT were evaluated by immunohistochemistry. Various factors, including the plasma levels of vitamin D, were investigated for association with the number of CAFs or distant metastasis-free survival (DMFS). Human pancreatic satellite cells (hPSCs) extracted from clinical specimens were used to validate the factors. RESULTS: All PDAC samples contained CAFs but the number varied widely. Multivariate analysis for DMFS indicated a larger number of CAFs was a significant risk factor. Univariate analysis for the number of CAFs identified two clinical factors: preoperative CRT and lower plasma levels of vitamin D. In subgroup analysis, the higher plasma level of vitamin D was a dominant factor for longer DMFS in PDAC patients after preoperative CRT. These results were validated by using extracted hPSCs. Irradiation activated stromal cells into CAFs facilitating malignant characteristics of PDAC and the change was inhibited by vitamin D supplementation in vitro. CONCLUSION: In conjunction with established current therapies, vitamin D supplementation may be an effective treatment for PDAC patients by inactivating CAFs.

Patients Treated with Preoperative Chemoradiation for Pancreatic Ductal Adenocarcinoma have Impaired Bone Density, a Predictor of Distant Metastasis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm that spreads to surrounding tissue or distant sites. This study investigated distant metastases in PDAC patients with or without preoperative chemoradiation therapy (CRT), focusing on vitamin D levels and bone density. METHODS: This study included 146 patients with PDAC who underwent surgery from 2007 to 2014. Bone density was evaluated using computed tomography, and the preoperative vitamin D level was calculated by enzyme-linked immunosorbent assay (ELISA) for patients with available plasma (48 cases). RESULTS: When the patients were divided into two groups according to the change in bone density, the group with decreased bone density had a shorter distant metastasis-free survival time (DMFS) after surgery than the other group (p < 0.05). Low vitamin D was a weak predictor of DMFS, but the difference was not significant (p = 0.08), perhaps because of the sample size. Multivariate analysis indicated three significant factors associated with distant metastasis: a decrease in bone density (hazard ratio [HR], 2.17; p = 0.04), normalization of the Dupan-2 value after surgery (hazard ratio [HR], 0.39; p = 0.02), and completion of adjuvant chemotherapy (HR, 0.29; p < 0.01). Univariate analysis showed that a low vitamin D concentration (<20 pg/ml) was a risk factor (p = 0.04) for bone density change. Multivariate analysis found that preoperative CRT was the only factor associated (±, OR, 5.8; p = 0.04) with bone density change, suggesting that preoperative CRT significantly decreases bone density in patients with insufficient vitamin D. CONCLUSION: Patients treated with preoperative CRT tend to have impaired bone density, which is a predictor of distant metastasis. Thus, vitamin D supplementation may decrease distant metastasis.

Interferon-based chemoradiation followed by gemcitabine for resected pancreatic adenocarcinoma: long-term follow-up.

To report long-term follow up of a phase II, single-arm trial of resectable pancreatic ductal adenocarcinoma (PDAC) treated with adjuvant interferon-based chemoradiation followed by gemcitabine to determine survival, recurrence, and complications. METHODS: From 2002 to 2005, 53 patients with PDAC underwent pancreaticoduodenectomy and received adjuvant interferon-based chemoradiation consisting of external-beam irradiation and simultaneous 3-drug chemotherapy of continuous daily 5-fluorouracil infusion, weekly intravenous bolus cisplatin, and subcutaneous interferon-α, followed by two months of weekly intravenous gemcitabine. RESULTS: Actual overall survival for the 5- and 10-year periods were 26% and 10%, respectively, with a median overall survival of 25 months (95% CI: 16.4-38.5). Adverse prognostic factors on multivariate analysis were positive tumor margin (p < 0.035), lymphovascular invasion (p < 0.015), and perineural invasion (p < 0.026). Median time to recurrence was 11 months. Positive tumor margin was associated with lymph node involvement (p < 0.005), portal vein resection (p < 0.038), and metastases (p < 0.018). Late complications were frequent and predominated by gastrointestinal and infectious complications. CONCLUSIONS: Adjuvant interferon-based chemoradiation for PDAC improves long-term survival compared to standard therapy. However, recurrence rates and long-term complications remain high, thus further studies are indicated to assess patient characteristics that indicate a favorable treatment profile.

Influence of Statins and Cholesterol on Mortality Among Patients With Pancreatic Cancer.

Background: Recent studies have suggested associations between statins and enhanced survival among patients with pancreatic ductal adenocarcinoma (PDAC). However, the relationship between statins, cholesterol, and survival remains unclear. Methods: We conducted a retrospective cohort study on 2142 PDAC patients in a regional integrated healthcare system from 2006 to 2014. Electronic pharmacy records were used to abstract information on the type, length, and dosage of statin exposures starting in the year prior to diagnosis. The cumulative and individual effects of simvastatin, lovastatin, atorvastatin, pravastatin, and rosuvastatin on mortality were assessed using Cox proportional hazards regression. Statins were evaluated as any use (pre- and postdiagnosis as a time-dependent variable) and baseline use (prediagnosis only). We also evaluated whether low-density lipoprotein (LDL) cholesterol, measured at various time windows prior to diagnosis, had an independent influence on survival. Additional analyses were performed to examine whether cholesterol mediated the relationship between statins and mortality. All models included age, race, stage, surgery, gemcitabine-based chemotherapy, and the Charlson comorbidity index as covariates. Results: Any (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.79 to 0.97) and baseline (HR = 0.88, 95% CI = 0.79 to 0.98) statin use were both associated with a decreased risk in mortality. When assessing individual statins, we found reduced mortality among simvastatin (HR = 0.87, 95% CI = 0.77 to 0.98) and atorvastatin (HR = 0.58, 95% CI = 0.46 to 0.72) users. Cholesterol was not associated with mortality and did not mediate any relationships between statins and survival. Conclusions: Statin use rather than cholesterol level was associated with lower mortality risk in patients with pancreatic cancer. Statins appear to improve survival through a lipid-independent mechanism.

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models.

Nab-paclitaxel has recently shown greater efficacy in pancreatic ductal adenocarcinoma (PDAC). Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis. We evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in preclinical PDAC models. In subcutaneous xenografts using AsPC-1 cells, average net tumor growth in different therapy groups was 248.3 mm3 in controls, 42.4 mm3 after nab-paclitaxel (p = 0.002), 93.3 mm3 after BMS-754807 (p = 0.01) and 1.9 mm3 after nab-paclitaxel plus BMS-754807 (p = 0.0002). In subcutaneous xenografts using Panc-1 cells, average net tumor growth in different therapy groups was: 294.3 mm3 in controls, 23.1 mm3 after nab-paclitaxel (p = 0.002), 118.2 mm3 after BMS-754807 (p = 0.02) and -87.4 mm3 (tumor regression) after nab-paclitaxel plus BMS-754807 (p = 0.0001). In peritoneal dissemination model using AsPC-1 cells, median animal survival was increased compared to controls (21 days) after therapy with nab-paclitaxel (40 days, a 90% increase, p = 0.002), BMS-754807 (27 days, a 29% increase, p = 0.01) and nab-paclitaxel plus BMS-754807 (47 days, a 124% increase, p = 0.005), respectively. Decrease in proliferation and increase in apoptosis by nab-paclitaxel and BMS-754807 therapy correlated with their in vivo antitumor activity. In vitro analysis revealed that the addition of IC25 dose of BMS-754807 decreased the nab-paclitaxel IC50 of PDAC cell lines. BMS-754807 therapy decreased phospho-IGF-1R/IR and phospho-AKT expression, and increased cleavage of caspase-3 and PARP-1. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective targeting option for pancreatic cancer therapy.

Treatment of Pancreatic Adenocarcinoma in Elderly Patients over 75 Years of Age: A Retrospective Series of 129 Patients.

PURPOSE: To better know the presentation and outcome of pancreatic adenocarcinoma in patients above 75 years of age. METHOD: Retrospective analysis of consecutive patients with a pancreatic adenocarcinoma seen in the Comprehensive Cancer Center of Marseille between January 2002 and January 2012 was used. RESULTS: During these 10 years, 129 patients older than 75 years of age were seen, 61 females and 68 males, median age 78. At diagnosis, the tumor was metastatic in 45%. First line treatments were: surgical resection in 22 cases, radio-chemotherapy in 20 cases (1 operated on later), systemic chemotherapy in 59 cases, and best supportive care alone in 28 cases. Resection was possible in 19 cases and was R0 in 17; post-operative mortality was 0%, and half received adjuvant chemotherapy. Median overall survival was 43 months with a 2-year overall survival of 64%. For locally advanced tumor, 16 received best supportive care and 33 a specific treatment (20 cases of radio-chemotherapy). Median overall survival was 9.1 months and 2-year overall, survival was 6.1%. Among the 58 metastatic patients, 79% received systemic chemotherapy (most by gemcitabine); tolerance was correct in half. Median overall survival was 4.7 months, with a 2-year overall survival of 5.3%. CONCLUSIONS: Surgery of pancreatic adenocarcinoma is feasible and safe in elderly patients with good outcomes. In advanced and metastatic patients, the outcome is poor despite a correct tolerance of systemic chemotherapy. Randomized trials specially designed for this population are urgently needed.

Metastasized pancreatic carcinoma with neoadjuvant FOLFIRINOX therapy and R0 resection.

Patients with metastasized carcinoma of the pancreas have a very poor prognosis, and long-term survival cannot be expected. This case report describes two patients with an initial diagnosis of metastatic pancreatic cancer, both with hepatic metastases and one with an additional peritoneal carcinomatosis. Initially, both patients were treated intravenously with the FOLFIRINOX chemotherapy regimen, consisting of 5-FU, folinic acid, irinotecan and oxaliplatin. Surprisingly, the FOLFIRINOX treatment resulted in complete resolution of the hepatic metastases in both patients, with no lesions detectable by computed tomography scan. Furthermore, treatment response included decreased diameter of the primary tumor in the tail of the pancreas and disappearance of the additional peritoneal carcinomatosis. Both patients were discussed by our multidisciplinary tumor board, which recommended surgical resections of the carcinoma. The R0 resection of the primary tumor was successful in both cases and, interestingly, the resected tissues showed no evidence of the hepatic metastases intraoperatively. In the first case, the patient received a postoperative 6-mo course of adjuvant chemotherapy with gemcitabine. In the second case, the patient continued to receive the FOLFIRINOX regimen for an additional 6 mo postoperatively. At 12 mo after the operation, a nonresectable retroperitoneal lymph node metastasis was detected in the first patient, whereas the second patient remained in complete remission at the time of this report (5 mo after the adjuvant therapy was discontinued). This case report is the first of its kind to describe two cases of hepatic metastatic pancreatic carcinoma that were resectable following treatment with FOLFIRINOX. Further studies are required to examine the role of FOLFIRINOX as a neoadjuvant treatment option in subgroups of patients with initially metastasized pancreatic carcinoma.

Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Pancreatic Adenocarcinoma.

INTRODUCTION: The SCAN pancreatic cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Five international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2014), the European Society of Medical Oncology (2012), Cancer Care Ontario (2013), the Japan Pancreas Society (2013) and the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, and the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (2005). Recommendations on the management of resected, borderline resectable, locally advanced and metastatic pancreatic adenocarcinoma were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore.

Hepatic arterial infusion chemotherapy reduced hepatic metastases from pancreatic cancer after pancreatectomy.

BACKGROUND/AIMS: This study aims to investigate the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) on liver metastases from pancreatic cancer after pancreatectomy. METHODOLOGY: We randomly assigned 106 patients with pancreatic cancer after pancreatectomy between 2005 and 2010 to receive 2 cycles of HAIC plus 4 cycles of systemic chemotherapy (Combined Therapy) or 6 cycles of systemic chemotherapy alone (Monotherapy). Both the HAIC and systemic chemotherapy regimen consisted of a 5-hour infusion of 5-fluorouracil 1000 mg/m2 on day 1 followed by gemcitabine 800 mg/m2 as an over 30-min infusion on day 1 and day 8. The treatment was started on an average of 21.2 days after surgery and repeated every 4 weeks. The disease-free survival, overall survival and liver metastases-free survival were compared. RESULTS: There was no significant difference in adverse effects between two groups. Significant differences were found in 3-year overall survival (Combined Therapy, 23.08 %; Monotherapy, 14.81%; P=0.0473) and liver metastases-free survival (Combined Therapy, 80.77%; Monotherapy, 55.56%; P=0.0014). CONCLUSIONS: HAIC effectively and safely prevents liver metastases and improves the prognosis of patients with pancreatic cancer after pancreatectomy.

Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.

BACKGROUND: Increasing evidence indicates an important role of transcription factor Yin Yang-1 (YY1) in human tumorigenesis. However, its function in cancer remains controversial and the relevance of YY1 to pancreatic ductal adenocarcinoma (PDAC) remains to be clarified. METHODS: In this study, we detected YY1 expression in clinical PDAC tissue samples and cell lines using quantitative RT-PCR, immunohistochemistry and western blotting. We also detected MUC4 and MMP10 mRNA levels in 108 PDAC samples using qRT-PCR and analyzed the correlations between YY1 and MUC4 or MMP10 expression. The role of YY1 in the proliferation, invasion and metastatic abilities of PDAC cells in vitro was studied by CCK-8 assay, cell migration and invasion assays. In vivo pancreatic tumor growth and metastasis was studied by a xenogenous subcutaneously implant model and a tail vein metastasis model. The potential mechanisms underlying YY1 mediated tumor progression in PDAC were explored by digital gene expression (DGE) sequencing, signal transduction pathways blockage experiments and luciferase assays. Statistical analysis was performed using the SPSS 15.0 software. RESULTS: We found that the expression of YY1 in PDACs was higher compared with their adjacent non-tumorous tissues and normal pancreas tissues. However, PDAC patients with high level overexpression of YY1 had better outcome than those with low level overexpression. YY1 expression levels were statistically negatively correlated with MMP10 expression levels, but not correlated with MUC4 expression levels. YY1 overexpression suppressed, whereas YY1 knockdown enhanced, the proliferation, invasion and metastatic properties of BXPC-3 cells, both in vitro and in vivo. YY1 suppresses invasion and metastasis of pancreatic cancer cells by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism. CONCLUSIONS: The present study suggested that YY1 plays a negative role, i.e. is a tumor suppressor, in PDAC, and may become a valuable diagnostic and prognostic marker of PDAC.

Safety and efficacy of adjuvant chemoradiation therapy with capecitabine after resection of pancreatic ductal adenocarcinoma: a retrospective review.

PURPOSE: To evaluate clinical outcomes and safety of adjuvant chemoradiation therapy (CRT) with capecitabine after resection of pancreatic adenocarcinoma at a single institution. PATIENTS AND METHODS: A retrospective analysis of patients undergoing adjuvant CRT with capecitabine after resection of pancreatic ductal adenocarcinoma between 2004 and 2007 yielded a total of 55 patients. Capecitabine was administered at 850 mg/m(2) twice daily every day per week radiotherapy (45 Gy in 25 fractions) over the 5 weeks. Sixteen percent of patients (N=9) went on to receive gemcitabine. RESULTS: Of 55 patients, 42 had curative (R0) resection and 13 had incomplete resection (R1). Median overall survival (OS) and progression free survival were 18.3 and 8.0 months for all patients, respectively. Patients receiving additional gemcitabine after adjuvant CRT with capecitabine showed better OS and progression free survival than those not receiving additional gemcitabine (P<0.05). In multivariate analysis, lymphovascular invasion (present vs. absent) and addition gemcitabine therapy (yes vs. no) were significant independent prognostic factors for OS (P<0.05). Local recurrence was observed in 10 patients, and distant recurrence in 26 patients, synchronously accounting for 6 recurrences. Ten patients (18.2%) had severe grade 3 toxicities. CONCLUSIONS: Capecitabine-based CRT after resection of pancreatic adenocarcinoma showed favorable outcomes and tolerable toxicity profiles.

Metastatic pancreatic cancer: is gemcitabine still the best standard treatment? (Review).

Pancreatic ductal adenocarcinoma is the fourth cause of death in the Western world. Surgery remains the only treatment offering an advantage in terms of overall survival (5-year survival range, 15-25%), but unfortunately only 10-20% of patients present resectable disease at the time of diagnosis. Hence chemotherapy, possibly combined with radiation therapy, remains the only treatment option aimed at palliation of symptoms and ensuring a better quality of life. Notwithstanding the efforts to find more effective therapies for the treatment of pancreatic cancer, significant results have not yet been achieved. Increasing interest has focused on integrated treatments, i.e. chemotherapy combined with targeted therapies, and a better selection of patients. This study examines the principal clinical trials that will help give clinicians an overview of the progress made in the systemic therapy for advanced pancreatic cancer patients in recent years.

Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.

PURPOSE: In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma. MATERIALS AND METHODS: PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %. RESULTS: The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth. CONCLUSION: The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDACs) are highly resistant to treatment due to changes in various signalling pathways. CK1 isoforms play important regulatory roles in these pathways. AIMS: We analysed the expression levels of CK1 delta and epsilon (CK1delta/in) in pancreatic tumour cells in order to validate the effects of CK1 inhibition by 3-[2,4,6-(trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261) on their proliferation and sensitivity to anti-CD95 and gemcitabine. METHODS: CK1delta/in expression levels were investigated by using western blotting and immunohistochemistry. Cell death was analysed by FACS analysis. Gene expression was assessed by real-time PCR and western blotting. The putative anti-tumoral effects of IC261 were tested in vivo in a subcutaneous mouse xenotransplantation model for pancreatic cancer. RESULTS: We found that CK1delta/in are highly expressed in pancreatic tumour cell lines and in higher graded PDACs. Inhibition of CK1delta/in by IC261 reduced pancreatic tumour cell growth in vitro and in vivo. Moreover, IC261 decreased the expression levels of several anti-apoptotic proteins and sensitised cells to CD95-mediated apoptosis. However, IC261 did not enhance gemcitabine-mediated cell death either in vitro or in vivo. CONCLUSIONS: Targeting CK1 isoforms by IC261 influences both pancreatic tumour cell growth and apoptosis sensitivity in vitro and the growth of induced tumours in vivo, thus providing a promising new strategy for the treatment of pancreatic tumours.

Expression of orotate phosphoribosyl transferase in human pancreatic cancer: implication for the efficacy of uracil and tegafur-based adjuvant chemotherapy.

The enzyme orotate phosphoribosyl transferase (OPRT) is involved in the metabolism of the anticancer drug 5-fluorouracil (5-FU), and is a key enzyme for conversion of 5-FU to its active form in tumor tissue. Little is known regarding the significance of OPRT in human pancreatic cancer. The present study was designed to assess the association between the activity of OPRT in the tumor, and the clinicopathological status and prognosis of human resectable pancreatic cancer, especially regarding its relevance to the efficacy of adjuvant chemotherapy with uracil and tegafur (UFT), cyclophosphamide (CPA) and/or gemcitabine (GEM). The present study included 99 resectable pancreatic cancers, which were all invasive ductal tubular carcinomas. OPRT was immunostained with a rabbit anti-human OPRT polyclonal antibody. OPRT was positively stained in 54 (54.5%) of 99 pancreatic cancers. The post-surgical survival rate of the OPRT (+) pancreatic cancers was significantly higher than that of the OPRT (-) ones. In the OPRT (+) group, the survival rate of the patients, who received adjuvant chemotherapy (ACT) with UFT, CPA or GEM, was significantly higher than that of the patients without ACT; however, in the OPRT (-) group, there was no difference in the survival between the ACT (+) and (-) groups. Multivariate analyses demonstrated that for all patients, primary tumor, status of nodal involvement (pN), residual tumor, level of dissection and CPA were significant variables for the prognosis: in OPRT (+) groups, primary tumor, nodal involvement, GEM and CPA were significant variables. In contrast, in the OPRT (-) group, pN was the only significant variable. The present study is the first report on the significance of OPRT in human pancreatic cancer, and the results indicate that the expression of OPRT may be useful to predict the response to adjuvant chemotherapy in human pancreatic cancer.

A multicenter randomized controlled trial to evaluate the effect of adjuvant cisplatin and 5-fluorouracil therapy after curative resection in cases of pancreatic cancer.

BACKGROUND: There have been few randomized controlled clinical trials until now to determine the effectiveness of adjuvant treatments for pancreatic cancer, and the results reported so far are inconsistent. METHODS: Patients with invasive ductal pancreatic cancer who underwent radical surgery with clear histological margins at 11 Japanese institutions were enrolled and randomly assigned to one of two groups: surgery-alone group (no further treatment after surgery) and the surgery + chemotherapy group [two courses of postoperative adjuvant systemic chemotherapy with cisplatin (80 mg/m(2), Day 1) and 5-fluorouracil (500 mg/m(2)/day, Days 1-5)]. Patients with a positive resectional margin or with resected distant metastases were excluded from the trial in order to minimize the influence of residual cancer. RESULTS: Between 1992 and 2000, 89 patients were randomized into the two arms of the trial (45 patients to the surgery + chemotherapy arm and 44 patients to the surgery-alone arm). Four patients in total were found to be ineligible (three in the surgery + chemotherapy group and one in the surgery-alone group). The baseline characteristics were comparable between the two groups. In the surgery + chemotherapy group, four patients did not receive the adjuvant treatment because of patient refusal. Toxicity was minor and acceptable among the eligible patients in the surgery + chemotherapy group. The estimated 5-year survival rates were 26.4% in the surgery + chemotherapy group and 14.9% in the surgery-alone group, and the median duration of survival was 12.5 months and 15.8 months, respectively. The recurrence rates at 5 years were 73.6 and 80.8%, respectively, in the surgery + chemotherapy and the surgery-alone groups. The differences in the survival and recurrence rates between the two groups were not statistically significant. CONCLUSIONS: Postoperative adjuvant chemotherapy using cisplatin and 5-fluorouracil was safe and well tolerated; however, no clear survival benefit could be demonstrated.

Prophylactic hepatic irradiation following curative resection of pancreatic cancer.

BACKGROUND/PURPOSE: It is unlikely that adjuvant chemoradiotherapy applied to the pancreatic bed alone significantly improves the survival of patients with resectable pancreatic cancer. The aim of the present study was to determine whether prophylactic hepatic irradiation (PHI) improved patient outcome after the curative resection of pancreatic cancer. METHODS: The study population was comprised of 34 patients (PHI group) who were administered PHI after curative resection of pancreatic cancer between September 1994 and December 2003. The whole liver was irradiated with a total dose of 19.8-22.0 Gy under continuous infusion of 5-fluorouracil. The cumulative rate of liver metastasis and the survival outcomes of the PHI group were compared with those of 31 patients without PHI (non-PHI group) who underwent curative resection of pancreatic cancer. RESULTS: The planned PHI was completed for 32 of the 34 patients. Two patients developed complications that might have been PHI-related. One developed liver abscesses which were successfully managed by percutaneous drainage. The other died of liver failure without recurrence 11 months after the operation. The cumulative incidence of liver metastasis was significantly lower for the PHI group than the non-PHI group (P=0.0455). Patients in the PHI group also survived significantly longer compared to those in the non-PHI group (P=0.0002). CONCLUSIONS: The present findings suggest that PHI is well tolerated and is a potentially effective treatment strategy after curative resection of pancreatic cancer, thereby providing the basis for a randomized controlled trial.

Effects of the antioxidative vitamins A, C and E on liver metastasis and intrametastatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters.

BACKGROUND/AIMS: Antioxidative vitamins are known to inhibit metastasis. Therefore we evaluated the impact of vitamins A (retinol), C (ascorbic acid) and E (alpha-tocopherol) on liver metastasis in a model of ductal pancreatic adenocarcinoma in hamster. METHODS: One hundred and twenty male Syrian hamsters were randomized into 8 groups (Gr.) (n = 15). Gr. 1-4 were given 0.5 ml normal saline subcutaneously (s.c.) weekly, whereas Gr. 5-8 received 10 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body weight s.c. for 3 months for tumor induction. In the 13th week Gr. 2 and 6 were administered retinol, Gr. 3 and 7 received ascorbic acid and Gr. 4 and 8 were given alpha-tocopherol orally. No treatment was performed in Gr. 1 and 5. After 24 weeks animals were sacrificed, pancreas and liver were histologically determined. Activities of glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD) and concentration of thiobarbituric-acid-reactive substances (TBARS) were analyzed in hepatic tissue. RESULTS: Retinol and alpha-tocopherol decreased the incidence of liver metastases (44.4 vs. 86.7%, p < 0.05). The number and size of liver metastases were significantly reduced by retinol. Activities of GSH-Px and SOD were increased and concentration of TBARS was decreased in NML and LiMe by all vitamins. CONCLUSION: Obviously, antioxidative vitamins prevent oxidative stress in hepatocytes. This may be one mechanism decreasing liver metastasis in pancreatic cancer in the present trial.

Emerging drugs in pancreatic cancer.

Improving survival in patients with pancreatic cancer remains a formidable challenge. For the few patients with localised stages of the disease, intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies remain non-validated and the survival benefit conferred by 5-fluorouracil-folinic acid adjuvant chemotherapy over radical surgery alone is still a matter of debate. Gemcitabine has recently emerged as the standard single agent in advanced stages of the disease and pharmacokinetic refinements such as the use of a fixed-dose infusion rate may further improve still rather modest result figures. At present, most efforts deal with the development of more effective doublet or triplet therapies, combining gemcitabine with either conventional cytotoxic drugs--the most promising being oxaliplatin--or more innovative, targeted therapeutic agents. Among these agents, matrix metalloprotease inhibitors and farnesyltransferase inhibitors have already undergone Phase III trials, alone or in combination with gemcitabine, with rather disappointing results. However, preclinical and Phase I and II studies of cyclooxygenase-2 or lipoxygenase inhibitors, various immunotherapeutic approaches and several tyrosine kinase inhibitors or monoclonal antibodies against growth factors or their receptors are encouraging and may provide some hope for patients with pancreatic cancer.