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1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29. Review/Other-Tx N/A To provide the expected numbers of new cancer cases and deaths in 2015 nationally and for each state, as well as a comprehensive overview of cancer incidence, mortality, and survival rates and trends using the most current population-based data. The article also estimates the total number of deaths averted nationally during the past 2 decades and by state in 2011 as a result of the continual decline in cancer death rates and present actual number of deaths reported in 2011 by age for the 10 leading causes of death and for the 5 leading causes of cancer death. Cancer death rates have been continuously declining for the past 2 decades. Overall, the risk of dying from cancer decreased by 22% between 1991 and 2011. Regionally, progress has been most rapid for residents of the Northeast, among whom death rates have declined by 25% to 30%, and slowest in the South, where rates declined by about 15%. Further reductions in cancer death rates can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those in the lowest socioeconomic bracket and other disadvantaged populations. 4
2. Cress RD, Yin D, Clarke L, Bold R, Holly EA. Survival among patients with adenocarcinoma of the pancreas: a population-based study (United States). Cancer Causes Control. 2006;17(4):403-409. Review/Other-Tx 10,612 patients To evaluate survival of patients diagnosed in California with adenocarcinoma of the pancreas by demographic and tumor-related factors. A total of 10,612 eligible patients were identified of whom 1674 (15.8%) underwent surgical resection. Patients of lower SES were less likely to undergo resection and somewhat less likely to survive. Median survival was 3.5 months for patients who were not resected and 13.3 months for those who underwent resection. Adjuvant therapy was associated with a decreased risk of death among patients who underwent resection. 4
3. Narimatsu H, Iwasaki H, Nakayama F, et al. Lewis and secretor gene dosages affect CA19-9 and DU-PAN-2 serum levels in normal individuals and colorectal cancer patients. Cancer Res. 1998;58(3):512-518. Review/Other-Dx 400 normal individuals; 168 patients with colorectal cancer To examine larger numbers of normal individuals and colorectal cancer patients to determine both of the Le and Se genotypes to determine to what extent the Le and Se gene dosages affect the CAI9-9 and DU-PAN-2 values. The 400 normal individuals were separated into nine groups by their Le and Se genotypes, as follows: group 1, Le/Le and se/se; group 2, Le/le and se/se; group 3, Le/Le and Se/se; group 4, Le/le and Se/se; group 5, Le/Le and Se/Se; group 6, Le/le and Se/Se; group 7, le/le and se/se; group 8, le/le and Se/se; and group 9, le/le and Se/Se. The group 1 individuals, having homozygous inactive Se alleles (se/se) and homozygous active Le alleles (Le/Le), exhibited the highest mean CA19-9 value. The CA19-9 value clearly ranged from a high in group 1 to a low in group 9. All of the Le-negative individuals who had the le/le genotype (groups 7, 8, and 9) had completely negative CA19-9 values, i.e., under 1.0 unit/ml, irrespective of the Se genotype. Group 7 individuals (le/le and se/se) showed a higher mean DU-PAN-2 value than did individuals in other groups. The Le-negative individuals in groups 8 and 9 also showed a higher mean DU-PAN-2 value than did the Le-positive individuals in groups 1-6. We recommend that the revised Le and Se genotype-dependent positive/negative cutoff values for CA19-9 and DU-PAN-2, determined in this study, be applied for more accurate cancer diagnoses. The Le and Se genotypes of 168 patients with colorectal cancer were also examined, and the CA19-9 and DU-PAN-2 values were measured before surgical resection. All 15 Le-negative patients (le/le) with colorectal cancer again showed undetectable CA19-9 values, i.e., under 1.0 unit/ml, but many of them exhibited highly positive DU-PAN-2 values. In contrast, many of the Le-positive patients (Le/Le or Le/le) had positive CA19-9 values, whereas very few of them exhibited positive DU-PAN-2 values. 4
4. Hartwig W, Strobel O, Hinz U, et al. CA19-9 in potentially resectable pancreatic cancer: perspective to adjust surgical and perioperative therapy. Ann Surg Oncol. 2013;20(7):2188-2196. Observational-Tx 1,543 patients with preoperative serum levels; control cohort of 706 patients with chronic pancreatitis To determine the prognostic role of perioperative serum tumor marker carbohydrate antigen 19-9 (CA19-9) in pancreatic adenocarcinoma, with a focus on implications for pre- and postoperative therapeutic consequences. The more that preoperative CA19-9 increased, the lower were tumor resectability and survival rates. Resectability and 5-year survival varied from 80 to 38 % and from 27 to 0 % for CA19-9 <37 versus >/=4,000 U/ml, respectively. The R0 resection rate was as low as 15 % in all patients with CA19-9 levels >/=1,000 U/ml. CA19-9 increased with the stage of the disease and was highest in AJCC stage IV. Patients with an early postoperative CA19-9 increase had a dismal prognosis. Hyperbilirubinemia did not markedly affect CA19-9 levels (correlation coefficient </=0.135). 2
5. Kinsella TJ, Seo Y, Willis J, et al. The impact of resection margin status and postoperative CA19-9 levels on survival and patterns of recurrence after postoperative high-dose radiotherapy with 5-FU-based concurrent chemotherapy for resectable pancreatic cancer. Am J Clin Oncol. 2008;31(5):446-453. Observational-Tx 75 patients To analyze the impact of surgical margins and other clinicopathological data on treatment outcomes on 75 patients treated from 1999 to 2006 by initial potentially curative surgery (+/- intraoperative radiotherapy), followed by high-dose 3-dimensional conformal radiation therapy and concomitant fluoropyrimidine-based chemoradiotherapy. With a median follow-up of 28 months, the median, 2-year and 5-year overall survival (OS) rates were 18.1 month, 41% and 23.6%, respectively. Disease-free survival (DFS) rates were of 11.4 months, 35% and 20%, respectively. Only 2 clinicopathological features, positive (< or =1 mm) surgical margins (P < 0.05) and a 2-fold (>70 U/mL) elevation of the postoperative serum CA19-9 (P < 0.001) impacted OS and disease-free survival. In patients with negative (>1 mm) surgical margins and a low (< or =70 U/mL) postoperative CA19-9, the projected 2- and 5-year OS were 80% and 65%, respectively, compared with 40% and 10% with positive surgical margins and a low CA19-9 and to 10% and 0% with positive or negative surgical margins and a high (>70 U/mL) CA19-9. Positive surgical margins (P < 0.001) and an elevated postoperative CA19-9 (P < 0.001) also predicted early development of distant metastases, whereas isolated loco-regional failure was less common and not affected by these or other clinicopathological features. 2
6. Kim J-E, Lee KT, Lee JK, Paik SW, Rhee JC, Choi KW. Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population. Journal of Gastroenterology and Hepatology. 2004;19(2):182-186. Observational-Dx 70,940 asymptomatic persons To determine the clinical usefulness of CA 19-9 as a screening tool for pancreatic cancer in asymptomatic subjects. The number of subjects with a level of CA 19-9 above the cutoff of 37 U/mL was 1063 (1.5%), including four cases diagnosed with pancreatic cancer. The prevalence of pancreatic cancer over the age of 30 years is 13.66 per 100 000 population in Korea. Therefore, the sensitivity is 100% and the specificity 98.5%. However, the positive predictive value of CA 19-9 for detecting pancreatic cancer is only 0.9% in the asymptomatic population. 3
7. Steinberg W. The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990;85(4):350-355. Review/Other-Dx N/A To review the clinical utility of the CA 19-9 tumor-associated antigen. Since Koprowski and coworkers discovered the CA 19-9 antigen 10 yr ago, it has become the most useful blood test in the diagnosis and management of patients with cancer of the pancreas. With an upper limit of normal of 37 U/ml, the assay's overall sensitivity is approximately 80% and its specificity is 90%. If higher cutoffs are used, the specificity rises so that, at levels greater than 1000 U/ml, the marker's specificity approaches 100%. Acute cholangitis and cirrhosis are two benign conditions that might raise this assay significantly. This tumor-associated marker is also helpful in predicting unresectability of pancreatic adenocarcinoma, as 96% of tumors that result in blood levels greater than 1000 U/ml have been found to be unresectable. After potentially curative surgery, the CA 19-9 can help prognosticate survival. Patients who normalize their CA 19-9 postoperatively live longer than those who do not. Furthermore, the assay, when used serially, predicts recurrence of disease prior to radiographic or clinical findings. The CA 19-9 is currently the "gold" standard marker for pancreatic cancer, against which other assays in this field will be judged. 4
8. Alexakis N, Gomatos IP, Sbarounis S, et al. High serum CA 19-9 but not tumor size should select patients for staging laparoscopy in radiological resectable pancreas head and peri-ampullary cancer. Eur J Surg Oncol. 2015;41(2):265-269. Observational-Dx 126 patients To validate current recommendations for the selective use of staging laparoscopy in patients with radiological resectable pancreas head and peri-ampullary tumors. Over a 6 year time period, 136 patients were evaluated, 126 patients were deemed radiological resectable and underwent laparotomy and 10 patients were characterized radiological unresectable. There were 111 patients with pancreas head resection and 15 without resection (8 due to extensive vascular involvement and 3 due to peritoneal/liver metastases). The sensitivity, specificity, PPV and NPV of pre-operative radiological imaging in determining unresectability due to liver/peritoneal metastases were 42%, 100%, 100% and 94.7% respectively. There was a significant difference in CA 19-9 values between metastatic and non-metastatic disease (p = 0.020). ROC curve analysis calculated the optimal CA 19-9 cutoff point for predicting metastasis at 215.37 U/ml with a sensitivity of 72.7%, a specificity of 58.3%, PPV of 15.1% and NPV of 95.5%. Tumor diameter was not a significant factor in predicting resectability. Laparoscopy would have been useful in only 5.3% of patients in the present series. 3
9. Brown EG, Canter RJ, Bold RJ. Preoperative CA 19-9 kinetics as a prognostic variable in radiographically resectable pancreatic adenocarcinoma. J Surg Oncol. 2015;111(3):293-298. Observational-Tx 72 patients To investigate the kinetics of CA 19-9 in the absence of therapy. Forty-seven out of 72 patients (65%) had resectable disease. Unresectable patients had higher absolute change in CA 19-9 than patients with resectable disease (97 U/ml vs. -34 U/ml) as well as higher rate of change (4 U/ml/day vs. -1 U/ml/day). Receiver operating characteristic curves identified predictive thresholds for absolute (>/=50 U/ml) and rate of CA 19-9 change (>/=1 U/ml/day) that accurately identified unresectable patients. Survival analysis revealed that a change in CA 19-9 <50 U/ml and a rate of change <1 U/ml/day predicted improved survival (P = 0.04, P = 0.02); however, for patients with resectable disease, CA 19-9 changes did not predict survival. 2
10. Konigsrainer I, Zieker D, Symons S, Horlacher K, Konigsrainer A, Beckert S. Do patient- and tumor-related factors predict the peritoneal spread of pancreatic adenocarcinoma? Surg Today. 2014;44(2):260-263. Observational-Tx 29 patients with PC; 29 patients without To compare the tumor- and patient-related variables in patients with and without intraoperatively confirmed PC who were operated on with the intention of curative resection Clinical jaundice and diarrhea were more frequently present in patients without PC. The CA 19-9 levels were significantly higher in patients with PC compared to those in patients without PC. No other differences were observed in the patient- or tumor-related factors between the two groups. 2
11. Winter JM, Yeo CJ, Brody JR. Diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. J Surg Oncol. 2013;107(1):15-22. Review/Other-Dx N/A To review diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. No results stated in abstract. 4
12. Bardeesy N, Cheng KH, Berger JH, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20(22):3130-3146. Observational-Dx unknown quantity of mice To understand the role of Smad4 in normal pancreas development and physiology as well as in the genesis and progression of PDAC, alone or together with other common PDAC genetic lesions. Selective SMAD4 deletion in the pancreatic epithelium had no discernable impact on pancreatic development or physiology. However, when combined with the activated KRAS(G12D) allele, SMAD4 deficiency enabled rapid progression of KRAS(G12D)-initiated neoplasms. While KRAS(G12D) alone elicited premalignant pancreatic intraepithelial neoplasia (PanIN) that progressed slowly to carcinoma, the combination of KRAS(G12D) and SMAD4 deficiency resulted in the rapid development of tumors resembling intraductal papillary mucinous neoplasia (IPMN), a precursor to PDAC in humans. SMAD4 deficiency also accelerated PDAC development of KRAS(G12D) INK4A/ARF heterozygous mice and altered the tumor phenotype; while tumors with intact SMAD4 frequently exhibited epithelial-to-mesenchymal transition (EMT), PDAC null for SMAD4 retained a differentiated histopathology with increased expression of epithelial markers. SMAD4 status in PDAC cell lines was associated with differential responses to transforming growth factor-beta (TGF-beta) in vitro with a subset of SMAD4 wild-type lines showing prominent TGF-beta-induced proliferation and migration. 4
13. Blackford A, Serrano OK, Wolfgang CL, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15(14):4674-4679. Observational-Dx 89 patients To determine if any genes with somatic changes correlate with patient outcome following surgical resection. When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95% confidence interval, 1.20-3.05; P = 0.006). Patients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (> or =4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival. 3
14. Oshima M, Okano K, Muraki S, et al. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg. 2013;258(2):336-346. Observational-Dx 106 patients To clarify the clinical implications of the status of the 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4). Abnormal immunolabeling of p53 was detected in 81.1% of PDACs and was significantly associated with tumor dedifferentiation (P = 0.022) and the presence of locoregional recurrence (P = 0.020). Loss of p16 and Smad4/Dpc4 immunolabeling was identified in 67.0% and 60.4%, respectively. Loss of p16 immunolabeling was associated with lymphatic invasion (P = 0.012) and postoperative widespread metastases (P < 0.001). A significant correlation was found between Smad4/Dpc4 immunolabeling and tumor size (P = 0.006), lymphatic invasion (P = 0.033), and lymph node metastasis (P = 0.006). Interestingly, all of the 6 patients demonstrating 5-year survival had intact SMAD4/DPC4. Kaplan-Meier survival analysis showed that lymph node metastasis (P = 0.001), lymphatic invasion (P = 0.008), the tumor (T) factor (T3 vs. T1/T2, P = 0.004), loss of p16 immunolabeling (P = 0.029), and loss of Smad4/Dpc4 immunolabeling (P < 0.001) were significantly associated with shorter overall survival. Multivariate analysis revealed that loss of Smad4/Dpc4 immunolabeling was an independent and significant poor prognostic factor for overall and disease-free survival. On analysis of combinations of the status of these 3 genes, increasing number of alterations reflected poorer survival. 3
15. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27(11):1806-1813. Observational-Tx 76 patients To present the clinical and pathologic features at autopsy of the first 76 patients with pancreatic cancer who participated in this program with particular reference to the histopathologic findings and genetic status in relation to patterns of failure. At autopsy, 30% of patients died with locally destructive pancreatic cancer, and 70% died with widespread metastatic disease. These divergent patterns of failure found at autopsy (locally destructive v metastatic) were unrelated to clinical stage at initial presentation, treatment history, or histopathologic features. However, Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy, a sensitive marker of DPC4 genetic status, was highly correlated with the presence of widespread metastasis but not with locally destructive tumors (P = .007). 2
16. Campbell F, Smith RA, Whelan P, et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology. 2009;55(3):277-283. Observational-Tx 163 patients To identify the proportion of pancreatoduodenectomy specimens in which 'equivocal' RMs are present (tumour involvement within 1 mm of, but not directly reaching, one or more resection margins) and whether the survival of these patients was similar to that of patients with 'unequivocal' RM involvement. Patients with histologically confirmed pancreatic ductal adenocarcinoma undergoing pancreatoduodenectomy between 1997 and 2007 (n = 163) were identified from a prospective database. One hundred and twenty-eight cases (79%) were classified as R1. Of these, 57 (45% of all R1 cases) were based on 'equivocal' margin involvement. There was no significant difference in overall survival between equivocal and unequivocal R1 resections (log rank, P = 0.102). All R1 resections had a poorer survival on univariate (log rank, P = 0.013), but not multivariate, analysis (Cox, P = 0.132). 2
17. Chang DK, Johns AL, Merrett ND, et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol. 2009;27(17):2855-2862. Observational-Tx 365 patients To identify a clinically relevant definition of margin-positive status (R1) that would better reflect outcome after pancreatectomy and to address the issue of estimating the risk of local recurrence and stratification of patients for entry into clinical trials. Microscopic involvement of a resection margin by tumor was associated with a poor prognosis. Stratifying the minimum clearance of resection margins by 0.5-mm increments demonstrated that although median survival was no different to clear margins based on these definitions, it was not until the resection margin was clear by more than 1.5 mm that optimal long-term survival was achieved. 2
18. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg. 2001;234(6):758-768. Experimental-Tx 541 patients To assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. Of 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. 1
19. Bhatti I, Peacock O, Awan AK, Semeraro D, Larvin M, Hall RI. Lymph node ratio versus number of affected lymph nodes as predictors of survival for resected pancreatic adenocarcinoma. World J Surg. 2010;34(4):768-775. Observational-Tx 84 patients To compare the prognostic significance of the lymph node ratio (LNR) with the absolute number of affected lymph nodes for resected pancreatic ductal adenocarcinoma. An LNR of > or =0.2 (median survival 8.1 vs. 35.7 months with LNR < 0.2; p < 0.001) and > or =0.3 (median survival 5.9 vs. 29.6 months with LNR < 0.3; p < 0.001), tumor size (p < 0.017), positive resection margin (p < 0.001), and nodal involvement (p < 0.001) were found to be significant prognostic markers following univariate analysis. Following multivariate analysis, only LNR at both levels [> or =0.2 (p = 0.05; HR 1.8) and LNR of > or =0.3 (p = 0.01; HR 2.7)] were independent predictors of a poor outcome. The number of lymph nodes examined had no effect on overall survival in either node-positive patients (p = 0.339) or node-negative patients (p = 0.473). 2
20. Pawlik TM, Gleisner AL, Cameron JL, et al. Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer. Surgery. 2007;141(5):610-618. Observational-Tx 905 pancreaticoduodenectomy patients To investigate the ratio of the number of lymph nodes harboring metastatic cancer to the total number of lymph nodes examined (lymph node ratio [LNR]) with regard to outcome after pancreaticoduodenectomy for ductal cancer of the pancreas. There were 187 (20.7%) of the 905 patients who had negative peripancreatic lymph nodes (N0), whereas 718 (79.3%) of the 905 patients had lymph node metastases (N1). The median number of lymph nodes evaluated in the N0 group was 15 versus 18 in the N1 group (P = .12). At median follow-up of 24 months, the median survival for all patients was 17.4 months, and the 5-year actuarial survival rate was 16.1%. Patients with lymph node metastases had a shorter median overall survival (16.5 months) compared with patients with negative lymph nodes (25.3 months; P = .001). Compared with the total number of lymph nodes examined or total number of lymph node metastases, LNR was the most compelling predictor of survival. As the LNR increased, median overall survival decreased (LNR = 0, 25.3 months; LNR > 0 to 0.2, 21.7 months; LNR > 0.2 to 0.4, 15.3 months; LNR > 0.4, 12.2 months; P = .001). After adjusting for other factors associated with survival, LNR remained an independent predictor of overall survival (P < .001). 2
21. Riediger H, Keck T, Wellner U, et al. The lymph node ratio is the strongest prognostic factor after resection of pancreatic cancer. J Gastrointest Surg. 2009;13(7):1337-1344. Observational-Tx 182 patients To evaluate potential prognostic factors in 182 patients after resection of pancreatic cancer including assessment of LN ratio. In all 204 resected patients, operative mortality was 3.9% (n = 8). In the 182 patients with follow-up, 70% had free resection margins, 62% had G1- or G2-classified tumors, and 70% positive LN. Median tumor size was 30 (7-80) mm. The median number of examined LN was 16 and median number of involved LN 1 (range 0-22). Median LN ratio was 0.1 (0-0.79). Cumulative 5-year survival (5-year SV) in all patients was 15%. In univariate analysis, a LN ratio > or = 0.2 (5-year SV 6% vs. 19% with LN ratio < 0.2; p = 0.003), LN ratio > or = 0.3 (5-year SV 0% vs. 18% with LN ratio < 0.3; p < 0.001), a positive resection margin (p < 0.01) and poor differentiation (G3/G4; p < 0.03) were associated with poorer survival. In multivariate analysis, a LN ratio > or = 0.2 (p < 0.02; relative risk RR 1.6), LN ratio > or = 0.3 (p < 0.001; RR 2.2), positive margins (p < 0.02; RR 1.7), and poor differentiation (p < 0.03; RR 1.5) were independent factors predicting a poorer outcome. The conventional nodal status or the number of examined nodes (in all patients and in the subgroups of node positive or negative patients) had no significant influence on survival. Patients with one metastatic LN had the same outcome as patients with negative nodes, but prognosis decreased significantly in patients with two or more LN involved. 2
22. Gleisner AL, Spolverato G, Ejaz A, Pawlik TM. Time-related changes in the prognostic significance of the total number of examined lymph nodes in node-negative pancreatic head cancer. J Surg Oncol. 2014;110(7):858-863. Observational-Tx 3,406 patients To assess time trends in the association between the total number of lymph nodes examined (TNLE) and survival in patients operated for adenocarcinoma of the head of pancreas. A total of 3,406 patients were included. Although TNLE was associated with survival, the effect was not uniform. Compared to patients with >12 TNLE, survival decreased with lower TNLE (4-12 TNLE: hazard ratio [HR] 1.27, 95% CI 1.10-1.46; <4 TNLE: HR 1.39, 95% CI 1.20-1.60) among patients diagnosed between 1988 and 2002. In contrast, for those diagnosed between 2003 and 2007, while there was decreased survival for those with <4 nodes (HR 1.44, 95% CI 1.22-1.71), no effect was seen for patients with TNLE 4-12 (HR 0.98, 95% CI 0.85-1.14). 2
23. Artinyan A, Soriano PA, Prendergast C, Low T, Ellenhorn JD, Kim J. The anatomic location of pancreatic cancer is a prognostic factor for survival. HPB (Oxford). 2008;10(5):371-376. Observational-Tx 33,752 patients To examine the relationship between tumor location and survival. Median survival for the entire cohort was five months and was significantly lower for BT compared to HD lesions (four vs. six months, p<0.001). Distant metastases (67% vs. 36%, p<0.001) were greater and cancer-directed surgery (16% vs. 30%, p<0.001) was lower for BT tumors. Of 6443 resected patients, HD patients (n=5118) were younger, had a greater number of harvested lymph nodes, were more likely to be lymph node-positive, and had a higher proportion of T3/T4 lesions. Significant univariate predictors of survival included age, T-stage, number of positive and harvested lymph nodes. On multivariate analysis, BT location was a significant prognostic factor for decreased survival (OR 1.11, 95% CI 1.00-1.23, p=0.05). 2
24. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120(8):899-903. Experimental-Tx 43 patients To assess the value of this combination regiment in prolonging survival time and disease-free survival time. Twenty-two patients randomized to no adjuvant treatment and 21 to combined therapy were analyzed. Neither life-threatening toxic reaction nor death due to toxic effect was encountered. The study was terminated prematurely because of an unacceptably low rate of accrual combined with the observation of increasingly large survival differences between the study arms. Median survival for the treatment group (20 months) was significantly longer than that observed for the control group (11 months). Four patients, three in the treated and one in the control group, have survived five years or longer following surgery. The extent of the tumor and initial performance status were significantly and independently related to survival. 1
25. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer. 1987;59(12):2006-2010. Experimental-Tx 30 patients To demonstrate that the results of the randomized trial could be replicated. The registered patients had median survival time of 18 months. Ten patients were alive at 18.9 to 42.4 months (median, 25.0). Two-year actuarial survival was 46% (95% confidence interval [CI], 0.28, 0.65) compared with 43% (95% CI, 0.25, 0.63) for 21 patients randomized to treatment and 18% (95% CI, 0.08, 0.36) for 22 patients randomized to control. 2
26. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230(6):776-782; discussion 782-774. Experimental-Tx 207 patients To investigate the survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery in patients with pancreatic head and periampullary cancers. Between 1987 and 1995, 218 patients were randomized (108 patients in the observation group, 110 patients in the treatment group). Eleven patients were ineligible (five in the observation group and six in the treatment group). Baseline characteristics were comparable between the two groups. One hundred fourteen patients (55%) had pancreatic cancer (54 in the observation group and 60 in the treatment group). In the treatment arm, 21 patients (20%) received no treatment because of postoperative complications or patient refusal. In the treatment group, only minor toxicity was observed. The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group (log-rank, p = 0.208). The 2-year survival estimates were 41% and 51 %, respectively. The results when stratifying for tumor location showed a 2-year survival rate of 26% in the observation group and 34% in the treatment group (log-rank, p = 0.099) in pancreatic head cancer; in periampullary cancer, the 2-year survival rate was 63% in the observation group and 67% in the treatment group (log-rank, p = 0.737). No reduction of locoregional recurrence rates was apparent in the groups. 1
27. Garofalo MC, Regine WF, Tan MT. On statistical reanalysis, the EORTC trial is a positive trial for adjuvant chemoradiation in pancreatic cancer. Ann Surg. 2006;244(2):332-333; author reply 333. Review/Other-Tx N/A No abstract available. N/A 4
28. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-1210. Experimental-Tx 289 patients To report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors. 1
29. Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001;358(9293):1576-1585. Experimental-Tx 353 patients To assess the roles of chemoradiotherapy and chemotherapy in a randomised study. 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0-62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without; hazard ratio 1.18 [95% CI 0.90-1.55], p=0.24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without; hazard ratio 0.66 [0.52-0.83], p=0.0005). 1
30. Choti MA. Adjuvant therapy for pancreatic cancer--the debate continues. N Engl J Med. 2004;350(12):1249-1251. Review/Other-Tx N/A No abstract available. N/A 4
31. Koshy MC, Landry JC, Cavanaugh SX, et al. A challenge to the therapeutic nihilism of ESPAC-1. Int J Radiat Oncol Biol Phys. 2005;61(4):965-966. Review/Other-Tx N/A No abstract available. N/A 4
32. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267-277. Experimental-Tx 368 patients To test the hypothesis that adjuvant chemotherapy with gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more. More than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (95% confidence interval, 6.1-7.8; P<.001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, 17-23.4; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank). 1
33. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473-1481. Experimental-Tx 354 patients To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). 1
34. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299(9):1019-1026. Experimental-Tx 451 patients To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma. A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%). 1
35. Berger AC, Winter K, Hoffman JP, et al. Five year results of US intergroup/RTOG 9704 with postoperative CA 19-9 </=90 U/mL and comparison to the CONKO-001 trial. Int J Radiat Oncol Biol Phys. 2012;84(3):e291-297. Observational-Tx 385 patients To examine cutoff points of 90 U/mL and 180 U/mL, provide a 5-year update of trial 9704, and compare patients with CA 19-9 <90 U/mL to those in the CONKO-001 trial. Both univariate (hazard ratio [HR] = 3.2; 95% confidence interval [CI], 2.3-4.3, P<.0001) and multivariate (HR = 3.1; 95% CI, 2.2-4.2, P<.0001) analyses demonstrated a statistically significant decrease in OS for CA 19-9 serum level of >/=90 U/mL. For patients in the gemcitabine (Gem) treatment arm with CA 19-9 <90 U/mL, median survival was 21 months. For patients with CA 19-9 >/=90 U/mL, this number dropped to 10 months. In patients with pancreatic head tumors in the Gem treatment arm with RT quality assurance per protocol and CA 19-9 of <90 U/mL, median survival and 5-year rate were 24 months and 34%. In comparison, the median survival and 5-year OS rate for patients in the Gem arm of the CONKO trial were 22 months and 21%. 2
36. Abrams RA, Winter KA, Regine WF, et al. Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704--a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys. 2012;82(2):809-816. Observational-Tx 416 patients To explore whether failure to adhere to specified RT guidelines influenced survival and/or toxicity. RT was scored for 416 patients: 216 PP and 200 <PP. For all pancreatic sites (head, body/tail) median survival (MS) for PP vs. <PP was 1.74 vs. 1.46 years (log-rank p = 0.0077). In multivariate analysis, PP vs. <PP score correlated more strongly with MS than assigned treatment arm (p = 0.014, p = NS, respectively); for patients with pancreatic head tumors, both PP score and gemcitabine treatment correlated with improved MS (p = 0.016, p = 0.043, respectively). For all tumor locations, PP score was associated with decreased risk of failure (p = 0.016) and, for gemcitabine patients, a trend toward reduced Grade 4/5 nonhematologic toxicity (p = 0.065). 2
37. Berger AC, Garcia M, Jr., Hoffman JP, et al. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol. 2008;26(36):5918-5922. Experimental-Tx 385 patients To evaluate the ability of postresectional CA 19-9 to predict survival. Three hundred eighty-five patients patients had assessable CA 19-9 levels. The majority had a CA 19-9 level lower than 180 or < or = 90 (n = 220 and 200, respectively), while 34% were Lewis Antigen negative and 33 (9%) and 53 (14%) patients had levels higher than 180 and higher than 90. When CA 19-9 was analyzed as a dichotomized variable, there was a significant survival difference favoring patients with CA 19-9 lower than 180 (hazard ratio [HR], 3.53; P < .0001). This corresponds to a 72% reduction in the risk of death for patients with a CA 19-9 lower than 180. This was also true for patients with CA 19-9 < or = 90 (HR, 3.4; P < .0001). Multivariate analyses confirmed that CA 19-9, when analyzed as both a continuous and a dichotomized variable, is a highly significant predictor of OS in patients with resected pancreatic cancer. 1
38. Regine WF, Winter KA, Abrams R, et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011;18(5):1319-1326. Experimental-Tx 451 patients To report the long term results of this trial. Four hundred fifty-one patients were eligible. Univariate analysis showed no difference in OS. Pancreatic head tumor patients (n = 388) had a median survival and 5-year OS of 20.5 months and 22% with gemcitabine versus 17.1 months and 18% with 5-FU. On multivariate analysis, patients on the gemcitabine arm with pancreatic head tumors experienced a trend toward improved OS (P = 0.08). First site of relapse local recurrence in 28% of patients versus distant relapse in 73%. 1
39. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304(10):1073-1081. Experimental-Tx 1,088 patients To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. 1
40. Valle JW, Palmer D, Jackson R, et al. Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. J Clin Oncol. 2014;32(6):504-512. Observational-Tx 985 patients To investigate the effect that the time between surgery and the start of chemotherapy, as well as the completion of planned chemotherapy, had on the long-term survival of patients in this trial. There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P < .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P < .001). 2
41. Sinn M, Liersch T, Gellert K, et al. CONKO-005: Adjuvant therapy in R0 resected pancreatic cancer patients with gemcitabine plus erlotinib versus gemcitabine for 24 weeks—A prospective randomized phase III study. J Clin Oncol. 2015;33(suppl; abstr 4007). Experimental-Tx 436 patients To evaluate an additional effect of the EGFR-tyrosinkinase-inhibitor erlotinib (Erlo 100 mg p.o. daily) in combination with Gem (1000 mg/m² i.v. day 1,8,15, q29) for 24 weeks in pts after R0 resection. Between April 2008 and July 2013, 219 pts were randomized to GemErlo and 217 to Gem. Pts characteristics are well balanced (GemErlo/Gem): age (median 63/65 years), tumor status (T3/T4 88/86%), nodal status (N pos 64/66%), grading (G3 33/34%). After a median follow up of 41 months (March 2015), 350 events (80%) occurred. Median treatment duration was 22 weeks in both groups. Grade 3/4 toxicities were (GemErlo%/Gem%): rash 7/0.4, diarrhea 5/1, nausea 2/2, fatigue 5/2, hypertension 3/1,GGT 9/9, neutropenia 27/28, thrombopenia 5/2. There was no difference in DFS (median: GemErlo 11.6 months, Gem 11.6 months; HR 0.89, 95%CI 0.72-1.10) or OS (median: GemErlo 24.6 months, Gem 26.5 months; HR 0.90, 95%CI 0.71-1.15). There was no correlation between the grade of rash and an improved DFS in the GemErlo group (median: rash grade 0-1 vs > = grade 2 12.2 vs 11.0 months; HR 0.91, 95%CI 0.66-1.25). OS curves show a late divergence in favour of GemErlo (estimated survival after 2/3/4/5-years: 54/36/31/28% vs 53/33/22/19%). 1
42. Hishinuma S, Ogata Y, Tomikawa M, Ozawa I, Hirabayashi K, Igarashi S. Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings. J Gastrointest Surg. 2006;10(4):511-518. Review/Other-Tx 27 autopsied patients To determine the sites of recurrence after curative resection of pancreatic cancer by histopathological examination of autopsied specimens. The pattern of recurrence was classified as follows: (1) local recurrence, (2) hepatic metastasis, (3) peritoneal dissemination, (4) para-aortic lymph node metastasis, and (5) distant metastasis not including hepatic metastasis, peritoneal dissemination, and para-aortic lymph node metastasis. Of the 27 autopsied patients, recurrence was confirmed for 22 of 24 patients, except for three who died of early postoperative complications. Eighteen (75%) of the 24 patients had local recurrence, 12 (50%) had hepatic metastasis, and 11 (46%) had both. For four patients, local recurrence confirmed by autopsy was undetectable by computed tomography, because the recurrent lesions had infiltrated without forming a tumor mass. Peritoneal dissemination, para-aortic lymph node metastasis, and distant metastasis were found for eight (33%), five (21%), and 18 (75%) of the cases, respectively. Twenty patients died of cancer, but local recurrence was judged to be the direct cause of death of only four. Local recurrence frequently occurs, but is rarely a direct cause of death, and most patients died of metastatic disease. 4
43. Herman JM, Swartz MJ, Hsu CC, et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol. 2008;26(21):3503-3510. Observational-Tx 616 patients To examine the efficacy of adjuvant chemoradiotherapy after pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PC) in patients undergoing resection at Johns Hopkins Hospital (JHH; Baltimore, MD). The median follow-up was 17.8 months (interquartile range, 9.7 to 33.5 months). Overall median survival was 17.9 months (95% CI, 16.3 to 19.5 months). Groups were similar with respect to tumor size, nodal status, and margin status, but the CRT group was younger (P < .001), and less likely to present with a severe comorbid disease (P = .001). Patients with carcinomas larger than 3 cm (P = .001), grade 3 and 4 (P < .001), margin-positive resection (P = .001), and complications after surgery (P = .017) had poor long-term survival. Patients receiving CRT experienced an improved median (21.2 v 14.4 months; P < .001), 2-year (43.9% v 31.9%), and 5-year (20.1% v 15.4%) survival compared with no CRT. After controlling for high-risk features, CRT was still associated with improved survival (relative risk = 0.74; 95% CI, 0.62 to 0.89). 2
44. Corsini MM, Miller RC, Haddock MG, et al. Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975-2005). J Clin Oncol. 2008;26(21):3511-3516. Observational-Tx 472 patients To determine prognostic factors and impact of adjuvant chemotherapy (CT) and radiotherapy (RT) on overall survival (OS) after resection of pancreatic adenocarcinoma. Six patients died within 30 days of surgery. For the 466 surviving patients, median follow-up was 32.4 months; median OS was 21.6 months. Median OS after adjuvant CT-RT was 25.2 versus 19.2 months after no adjuvant therapy (P = .001). Two-year OS was 50% versus 39%, and 5-year OS was 28% versus 17%. Adverse prognostic factors identified by univariate and multivariate analysis included positive lymph nodes (risk ratio [RR] = 1.3; P < .001), high histologic grade (RR = 1.2; P < .001), and no adjuvant therapy (RR = 1.3; P < .001). Tumor extension beyond the pancreas was an adverse prognostic factor by univariate analysis alone (P = .03). Patients receiving adjuvant therapy had more adverse prognostic factors than those not receiving adjuvant therapy (P = .001). 2
45. Hsu CC, Herman JM, Corsini MM, et al. Adjuvant chemoradiation for pancreatic adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study. Ann Surg Oncol. 2010;17(4):981-990. Observational-Tx 1,092 To examine efficacy of adjuvant CRT in resected pancreatic adenocarcinoma compared with surgery alone. Median survival was 18.8 months. Overall survival (OS) was longer among recipients of CRT versus surgery alone (median survival 21.1 vs. 15.5 months, P < .001; 2- and 5-year OS 44.7 vs. 34.6%; 22.3 vs. 16.1%, P < .001). Compared with surgery alone, adjuvant CRT improved survival in propensity score analysis for all patients by 33% (P < .001), with improved survival when stratified by age, margin, node, and T-stage (RR = 0.57-0.75, P < .05). Matched-pair analysis demonstrated OS was longer with CRT (21.9 vs. 14.3 months median survival; 2- and 5-year OS 45.5 vs. 31.4%; 25.4 vs. 12.2%, P < .001). 2
46. Colbert LE, Hall WA, Nickleach D, et al. Chemoradiation therapy sequencing for resected pancreatic adenocarcinoma in the National Cancer Data Base. Cancer. 2014;120(4):499-506. Observational-Tx 5,414 patients To use the large National Cancer Data Base (NCDB), which contains detailed patient-linked data on approximately 70% of newly diagnosed cancer cases in the United States, to provide a rationale for a randomized study to evaluate the role of neoadjuvant therapy in PAC in the future. A total of 5414 patients were identified. Of these, 277 received prRT and 5137 received poRT. Overall, 92.9% received chemotherapy and 7.1% received RT alone; 56% (2990 of 5307) of patients had stage III disease, according to American Joint Commission on Cancer (AJCC) staging manual, 5th edition. Median tumor size was 3 cm (range: 0-9.9 cm); 82% (199 of 244) of patients with prRT had negative surgical margins; 72% (3383 of 4699) of patients with poRT had negative margins. Forty-one percent (71 of 173) of patients with prRT were lymph node (LN)-positive; 65% (3159 of 4833) of patients with poRT were LN-positive. Median OS for patients with prRT was 18 months (95% CI = 18-19 months) and for patients with poRT, 19 months (95% CI = 17-22 months). 2
47. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127(11):1335-1339. Review/Other-Tx 28 patients To determine the morbidity and mortality of preoperative chemoradiation followed by pancreaticoduodenectomy in patients with adenocarcinoma of the pancreas and to document the radiologic and pathologic response to preoperative chemoradiation. Hospital admission because of gastrointestinal toxic effects was required in nine patients, yet no patient experienced a delay in operation. Restaging was performed 4 to 5 weeks after completion of chemoradiation, and five patients were found to have metastatic disease; the 23 patients without evidence of progressive disease underwent laparotomy. At laparotomy, three patients were found to have unsuspected metastatic disease, three patients had unresectable locally advanced disease, and 17 patients were able to undergo pancreaticoduodenectomy. One perioperative death resulted from myocardial infarction, and perioperative complications occurred in three patients. Histologic evidence of tumor cell injury was present in all resected specimens. 4
48. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3496-3502. Experimental-Tx 86 patients To assess the outcomes of patients who received preoperative gemcitabine-based chemoradiation and pancreaticoduodenectomy (PD) for stage I/II pancreatic adenocarcinoma. The study enrolled 86 patients. At the time of restaging, disease progression or a decline in performance status precluded 13 patients from surgery. Seventy-three (85%) of 86 patients were taken to surgery, extrapancreatic disease was found in nine, and 64 (74%) of 86 underwent a successful PD. Median overall survival (86 patients) was 22.7 months with a 27% 5-year survival. Median survival was 34 months for the 64 patients who underwent PD and 7 months for the 22 unresected patients (P < .001). The 5-year survival for those who did and did not undergo PD was 36% and 0%, respectively. 2
49. Golcher H, Brunner TB, Witzigmann H, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol. 2015;191(1):7-16. Experimental-Tx 66 patients To examine the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a randomized phase II trial. The trial was stopped after 73 patients; 66 patients were eligible for analysis. Twenty nine of 33 allocated patients received chemoradiotherapy. Radiotherapy was completed in all patients. Chemotherapy was changed in 3 patients due to toxicity. Tumor resection was performed in 23 vs. 19 patients (A vs. B). The R0 resection rate was 48% (A) and 52% (B, P = 0.81) and (y)pN0 was 30% (A) vs. 39% (B, P = 0.44), respectively. Postoperative complications were comparable in both groups. mOS was 14.4 vs. 17.4 months (A vs. B; intention-to-treat analysis; P = 0.96). After tumor resection, mOS was 18.9 vs. 25.0 months (A vs. B; P = 0.79). 1
50. Hong TS, Ryan DP, Borger DR, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89(4):830-838. Experimental-Tx 50 patients To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). 2
51. Kharofa J, Tsai S, Kelly T, et al. Neoadjuvant chemoradiation with IMRT in resectable and borderline resectable pancreatic cancer. Radiother Oncol. 2014;113(1):41-46. Observational-Tx 69 patients To evaluate the acute toxicity, clinical outcomes, and patterns of failure in resectable and BLR PDA patients treated with neoadjuvant chemoradiation utilizing an IMRT approach. Neoadjuvant chemoradiation was completed in 69 patients (39 BLR and 30 resectable). Induction chemotherapy was used in 32 (82%) of the 39 patients with BLR disease prior to chemoXRT. All resectable patients were treated with chemoXRT alone. Following neoadjuvant treatment, 48 (70%) of the 69 patients underwent successful pancreatic resection with 47 (98%) being margin negative (RO). In 30 of the BLR patients who had arterial abutment or SMV occlusion, 19 (63%) were surgically resected and all had RO resections. The cumulative incidence of local failure at 1 and 2 years was 2% (95% CI 0-6%) and 9% (95% CI 0.6-17%) respectively. The median overall survival for all patients, patients undergoing resection, and patients without resection were 20, 26 and 11 months respectively. Sixteen (23%) of the 69 patients are alive without disease with a median follow-up of 47 months (36-60). 2
52. Pisters PW, Abbruzzese JL, Janjan NA, et al. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol. 1998;16(12):3843-3850. Experimental-Tx 35 patients To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. 2
53. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3487-3495. Experimental-Tx 90 patients To report the results of a phase II trial of preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation (Gem-Cis- XRT) in stage I/II adenocarcinoma of the pancreatic head. The study enrolled 90 patients; 79 patients (88%) completed chemo-chemoradiation. Sixty-two (78%) of 79 patients were taken to surgery and 52 (66%) of 79 underwent PD. The median overall survival of all 90 patients was 17.4 months. Median survival for the 79 patients who completed chemo-chemoradiation was 18.7 months, with a median survival of 31 months for the 52 patients who underwent PD and 10.5 months for the 27 patients who did not undergo surgical resection of their primary tumor (P < .001). 1
54. Talamonti MS, Small W, Jr., Mulcahy MF, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol. 2006;13(2):150-158. Experimental-Tx 20 patients To evaluate the toxicity associated with this neoadjuvant regimen in a multi-institutional setting; to determine radiographic, tumor marker, and pathologic responses to treatment; to evaluate morbidity and mortality among patients who undergo resection after completion of therapy; and to estimate overall survival in patients treated with this approach. There were 10 men and 10 women, with a median age of 58 years (range, 50-80 years). Nineteen patients (95%) completed therapy without interruption, and one experienced grade 3 gastrointestinal toxicity. The mean weight loss after therapy was 4.0%. Of 20 patients taken to surgery, 17 (85%) underwent resections (16 pancreaticoduodenectomies and 1 distal pancreatectomy). The complication rate was 24%, with an average length of stay of 13.5 days. There were no operative deaths. Pathologic analysis revealed clear margins in 16 (94%) of 17 and uninvolved lymph nodes in 11 (65%) of 17 specimens. One specimen contained no residual tumor, and three specimens revealed only microscopic foci of residual disease. With a median follow-up of 18 months, 7 (41%) of the 17 patients with resected disease are alive with no recurrence, 3 (18%) are alive with distant metastases, and 7 (41%) have died. 1
55. Small W, Jr., Berlin J, Freedman GM, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2008;26(6):942-947. Experimental-Tx 39 patients To assess safety and efficacy of full-dose gemcitabine administered before and during concurrent three-dimensional conformal radiation (3D-CRT) in patients with nonmetastatic pancreatic cancer. Forty-one patients enrolled at six institutions between April 2002 and October 2003. Among the 39 treated patients, the most common toxicities were grade 3 neutropenia (12.8%), grade 3 nausea (10.3%), and grade 3 vomiting (10.3%). The response rate was 5.1% and disease control rate was 84.6%. Mean post-treatment CA 19-9 levels (228 +/- 347 U/mL) were significantly (P = .006) reduced compared with pretreatment levels (1,241 +/- 2,124 U/mL). Thirteen (81%) of 16 patients initially judged resectable, three (33%) of nine borderline-resectable patients, and one (7%) of 14 unresectable patients underwent resection after therapy. One-year survival rates were 73% for all patients, 94% for resectable patients, 76% for borderline-resectable patients, and 47% for unresectable patients. 1
56. Brunner TB, Baum U, Grabenbauer GG, Sauer R, Lambrecht U. Large topographic variability of upper abdominal lymphatics and the consequences for radiation treatment planning. Radiother Oncol. 2006;81(2):190-195. Review/Other-Tx 104 patients scans To quantify the substantial variability of the morphology and location of the upper abdominal vessels by the analysis of the vascular anatomy in CT scans. Vascular origin varied most for the inferior mesenteric artery (IMA) with substantial PTV size differences. Volumetric variability was analysed for PDAC (IMA versus renal hilum as caudal margin). Additional PTV for IMA was < 100 cc (median) but ranged up to 350 cc in CT (100-199 ml in 14/34 and > 200 ml in 3/34 patients). Data from treatment planning confirmed this observation. 4
57. van der Geld YG, van Triest B, Verbakel WF, et al. Evaluation of four-dimensional computed tomography-based intensity-modulated and respiratory-gated radiotherapy techniques for pancreatic carcinoma. Int J Radiat Oncol Biol Phys. 2008;72(4):1215-1220. Observational-Tx 10 patients To compare conformal radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and respiration-gated radiotherapy (RGRT) planning techniques for pancreatic cancer. Compared with the CRT plans, IMRT significantly reduced the mean volume of right kidney exposed to 20 Gy from 27.7% +/- 17.7% to 16.0% +/- 18.2% (standard deviation) (p < 0.01), but this was not achieved for the left kidney (11.1% +/- 14.2% to 5.7% +/- 6.5%; p = 0.1). The IMRT plans also reduced the mean gastric, hepatic, and small bowel doses (p < 0.01). No additional reductions in the dose to the kidneys or other organs at risk were seen when RGRT plans were combined with either CRT or IMRT, and the findings for RGRT in end-expiration and end-inspiration were similar. 2
58. Landry JC, Yang GY, Ting JY, et al. Treatment of pancreatic cancer tumors with intensity-modulated radiation therapy (IMRT) using the volume at risk approach (VARA): Employing dose-volume histogram (DVH) and normal tissue complication probability (NTCP) to evaluate small bowel toxicity. Medical Dosimetry. 2002;27(2):121-129. Experimental-Tx 10 patients To evaluate the influence of IMRT with inverse treatment planning on the dose-volume histograms (DVHs) of normal tissue compared to standard 3-dimensional conformal radiation treatment (3D-CRT) in patients with pancreatic cancer. The average dose delivered to one third of the small bowel was lower with the IMRT plan compared to 3D-CRT. The IMRT plan resulted in one third of the small bowel receiving 30.2 ± 12.9 Gy vs. 38.5 ± 14.2 Gy with 3D-CRT (p = 0.006). The median volume of small bowel that received greater than either 50 or 60 Gy was reduced with IMRT. The median volume of small bowel exceeding 50 Gy was 19.2 ± 11.2% (range 3% to 45%) compared to 31.4 ± 21.3 (range 7% to 70%) for 3D-CRT (p = 0.048). The median volume of small bowel that received greater than 60 Gy was 12.5 ± 4.8% for IMRT compared to 19.8 ± 18.6% for 3D-CRT (p = 0.034). The VaRA approach employing IMRT techniques resulted in a lower dose per volume of small bowel that exceeded 60 Gy. We used the Lyman-Kutcher models to compare the probability of small bowel injury employing IMRT compared to 3D-CRT. The BIOPLAN model predicted a small bowel complication probability of 9.3 ± 6% with IMRT compared to 24.4 ± 18.9% with 3D-CRT delivery of dose (p = 0.021). 2
59. Yovino S, Poppe M, Jabbour S, et al. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys. 2011;79(1):158-162. Observational-Tx 46 patients To evaluate acute toxicity outcomes at two university hospitals (the University of Maryland Medical Center and the University of Medicine and Dentistry of New Jersey) and compares these data with toxicity results from the recently reported US Intergroup adjuvant CRT trial (Radiation Therapy Oncology Group [RTOG] 97-04), where all patients were treated with conventional 3-D planning techniques. The overall incidence of Grade 3-4 acute GI toxicity was low in patients receiving IMRT-based CRT. When compared with patients who had three-dimensional treatment planning (RTOG 97-04), IMRT significantly reduced the incidence of Grade 3-4 nausea and vomiting (0% vs. 11%, p = 0.024) and diarrhea (3% vs. 18%, p = 0.017). There was no significant difference in the incidence of Grade 3-4 weight loss between the two groups of patients. 2
60. Bhasin DK, Rana SS, Jahagirdar S, Nagi B. Does the pancreas move with respiration? J Gastroenterol Hepatol. 2006;21(9):1424-1427. Observational-Tx 22 patients To assess the movement of pancreas with respiration using fluoroscopy, a simple and inexpensive method. Twenty-two patients (mean age 35.45 + or - 11.29 years, 17 men) with chronic pancreatitis were included in the study. Ten patients had pancreatic calcification and 12 had an indwelling pancreatic duct stent (two in the dorsal duct, 10 in the ventral duct). In all patients, the pancreas moved downward in the craniocaudal direction on deep inspiration. Pancreatic excursion from maximum inspiration to maximum expiration ranged from 0.1 to 3.4 cm. In addition, a medial movement of the head of pancreas was also noted in most of the patients. On univariate analysis, no association was found between the range of movement and the age or sex of the patient, duration or etiology of disease, presence or absence of calcification, severity of ductal changes of chronic pancreatitis and the length or diameter of the pancreatic stent placed. 2
61. Horst E, Micke O, Moustakis C, Schuck A, Schafer U, Willich NA. Conformal therapy for pancreatic cancer: variation of organ position due to gastrointestinal distention--implications for treatment planning. Radiology. 2002;222(3):681-686. Experimental-Tx 20 patients To quantify nonrespiratory organ motion in the pancreatic region and its effect on clinical target volume. Significant translations of the volume of interest were observed. The most mobile parts of the target organs were the pancreatic tail (P =.001) and the superior mesenteric artery (P =.01). Larger variations from the mean in the planning CT protocol in which negative contrast material was used usually resulted in a slightly larger clinical target volume expansion. 2
62. Whitfield G, Jain P, Green M, et al. Quantifying motion for pancreatic radiotherapy margin calculation. Radiother Oncol. 2012;103(3):360-366. Observational-Tx 13 patients, 109 CBCT scans To quantify 3-dimensional (3D) target motion in patients undergoing pancreatic RT, allowing subsequent calculation of treatment margins to incorporate the observed group motion. Using an off-line CBCT correction protocol, systematic (random) setup errors were 2.4 (3.2), 2.0 (1.7) and 3.2 (3.6)mm laterally (left-right), vertically (anterior-posterior) and longitudinally (cranio-caudal), respectively. Fiducial motion varied substantially. Random inter-fractional changes in mean fiducial position were 2.0, 1.6 and 2.6mm; 95% of intra-fractional peak-to-peak fiducial motion was up to 6.7, 10.1 and 20.6mm, respectively. Calculated clinical to planning target volume (CTV-PTV) margins were 1.4 cm laterally, 1.4 cm vertically and 3.0 cm longitudinally for 3D conformal RT, reduced to 0.9, 1.0 and 1.8 cm, respectively, if using 4D planning and online setup correction. 2
63. Huguet F, Goodman KA, Azria D, Racadot S, Abrams RA. Radiotherapy technical considerations in the management of locally advanced pancreatic cancer: American-French consensus recommendations. Int J Radiat Oncol Biol Phys. 2012;83(5):1355-1364. Review/Other-Tx N/A To propose consensus recommendations for use in the development of future trials testing new chemotherapy combinations with radiotherapy. Based on this analysis of the literature, we recommend either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to a total dose of 50 to 54 Gy at 1.8 to 2 Gy per fraction. We propose gross tumor volume identification to be followed by an expansion of 1.5 to 2 cm anteriorly, posteriorly, and laterally, and 2 to 3 cm craniocaudally to generate the planning target volume. The craniocaudal margins can be reduced with the use of respiratory gating. Organs at risk are liver, kidneys, spinal cord, stomach, and small bowel. Stereotactic body radiation therapy should not be used for pancreatic cancer outside of clinical trials. Radiotherapy quality assurance is mandatory in clinical trials. 4
64. Dholakia AS, Kumar R, Raman SP, et al. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys. 2013;87(5):1007-1015. Observational-Tx 202 patients To generate a map of local recurrences after pancreaticoduodenectomy (PD) for patients with resectable pancreatic ductal adenocarcinoma (PDA) and to model an adjuvant radiation therapy planning treatment volume (PTV) that encompasses a majority of local recurrences. Of the 202 patients in the study, 40 (20%), 34 (17%), and 128 (63%) received NA, CTA, and CRT adjuvant therapy, respectively. The rate of margin-positive resections was greater in CRT patients than in CTA patients (28% vs 9%, P=.023). Local recurrence occurred in 90 of the 202 patients overall (45%) and in 19 (48%), 22 (65%), and 49 (38%) in the NA, CTA, and CRT groups, respectively. Ninety percent of recurrences were within a 3.0-cm right-lateral, 2.0-cm left-lateral, 1.5-cm anterior, 1.0-cm posterior, 1.0-cm superior, and 2.0-cm inferior expansion of the combined CA and SMA contours. Three simulated radiation treatment plans using these expansions with adjustments to avoid nearby structures were created to demonstrate the use of this treatment volume. 2
65. Goodman KA, Regine WF, Dawson LA, et al. Radiation Therapy Oncology Group consensus panel guidelines for the delineation of the clinical target volume in the postoperative treatment of pancreatic head cancer. Int J Radiat Oncol Biol Phys. 2012;83(3):901-908. Review/Other-Tx N/A To develop contouring guidelines to be used in the Radiation Therapy Oncology Group protocol 0848, a Phase III randomized trial evaluating the benefit of adjuvant chemoradiation in patients with resected head of pancreas cancer. New contouring recommendations based on CT anatomy were established. Written guidelines for the delineation of the postoperative CTV and normal tissues, as well as a Web-based atlas, were developed. 4
66. Yovino S, Maidment BW, 3rd, Herman JM, et al. Analysis of local control in patients receiving IMRT for resected pancreatic cancers. Int J Radiat Oncol Biol Phys. 2012;83(3):916-920. Observational-Tx 71 patients To analyze patterns of first failure among patients treated with IMRT for resected pancreatic cancer. At median follow-up of 24 months, 49/71 patients (69%) had failed. The predominant failure pattern was distant metastases in 35/71 patients (49%). The most common site of metastases was the liver. Fourteen patients (19%) developed locoregional failure in the tumor bed alone in 5 patients, regional nodes in 4 patients, and concurrently with metastases in 5 patients. Median overall survival (OS) was 25 months. On univariate analysis, nodal status, margin status, postoperative CA 19-9 level, and weight loss during treatment were predictive for OS. On multivariate analysis, higher postoperative CA19-9 levels predicted for worse OS on a continuous basis (p < 0.01). A trend to worse OS was seen among patients with more weight loss during therapy (p = 0.06). Patients with positive nodes and positive margins also had significantly worse OS (HR for death 2.8, 95% CI 1.1-7.5; HR for death 2.6, 95% CI 1.1-6.2, respectively). Grade 3-4 nausea and vomiting was seen in 8% of patients. Late complication of small bowel obstruction occurred in 4 (6%) patients. 2
67. Hall WA, Colbert LE, Liu Y, et al. The influence of adjuvant radiotherapy dose on overall survival in patients with resected pancreatic adenocarcinoma. Cancer. 2013;119(12):2350-2357. Observational-Tx 1,385 patients To determine whether there is an association between overall survival (OS) and A-RT dose. A total of 1385 patients met the inclusion criteria. The median age of the patients was 64 years (range, 29 years-87 years). All patients underwent surgical resection and A-RT with or without chemotherapy. A total of 231 patients were diagnosed with stage I disease, 273 were diagnosed with stage II disease, 734 were diagnosed with stage III disease, and 126 were diagnosed with stage IVA disease (according to the fifth edition of the American Joint Committee on Cancer); 21 were found to have an unknown stage of disease. The median A-RT dose was 45 Gy (range, 1.63 Gy-69 Gy). The median OS was 21 months (95% confidence interval [95% CI], 19 months-23 months). On multivariate analysis, an A-RT dose < 40 Gy (hazards ratio [HR], 1.30 [95% CI, 1.03-1.66]; P = .031), an A-RT dose of 40 Gy to < 50 Gy (HR, 1.17 [95% CI, 1.00-1.37]; P = .05), and an A-RT dose >/= 55 Gy (HR, 1.44 [95% CI, 1.08-1.93]; P = .013) predicted worse OS compared with the reference category of 50 Gy to < 55 Gy. 2
68. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523(7559):177-182. Observational-Dx breast cancer patients (n = 32), pancreatic ductal adenocarcinoma patients (n = 190) and healthy donors (n = 100) To identify and isolate cancer specific exosomes in body fluids to enable the identification of DNA, RNA and proteins without contamination from non-cancer exosomes, and aid in the treatment and management of cancer. GPC1(+) crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. 1
69. RTOG 0848 Protocol Information. A Phase IIR and A Phase III Trial Evaluating Both Erlotinib (Ph IIR) And Chemoradiation (Ph III) As Adjuvant Treatment For Patients With Resected Head Of Pancreas Adenocarcinoma. 2014; Available at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0848. Accessed April 3, 2015. Review/Other-Tx Ongoing PhII-R: To determine whether the addition of erlotinib to gemcitabine adjuvant chemotherapy shows a signal for improved survival as compared to gemcitabine alone following R0 or R1 resection of head of pancreas adenocarcinoma (including adenocarcinoma of the head, neck, and uncinate process).  Ph III-To determine whether the use of concurrent fluoropyrimidine and radiotherapy following adjuvant gemcitabine based chemotherapy further enhances survival for such patients who are without evidence of progressive disease after 5 cycles of gemcitabine based chemotherapy.http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0848 This trial is still recruiting study subjects and results are not available yet. 4
70. Franke AJ, Rosati LM, Pawlik TM, Kumar R, Herman JM. The role of radiation therapy in pancreatic ductal adenocarcinoma in the neoadjuvant and adjuvant settings. Semin Oncol. 2015;42(1):144-162. Review/Other-Tx N/A To review the data supporting or refuting the role of radiation therapy in the neoadjuvant and adjuvant settings of PCA management, with a particular focus on determining which patients may be more likely to benefit from radiation therapy. Results not stated in abstract. 4
71. Kim EJ, Ben-Josef E, Herman JM, et al. A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer. Cancer. 2013;119(15):2692-2700. Experimental-Tx 68 patients To evaluate preoperative treatment with full-dose gemcitabine, oxaliplatin, and radiation therapy (RT) in patients with localized pancreatic cancer. Sixty-eight evaluable patients received treatment at 4 centers. By central radiology review, 23 patients had resectable disease, 39 patients had borderline resectable disease, and 6 patients had unresectable disease. Sixty-six patients (97%) completed cycle 1 with RT, and 61 patients (90%) completed cycle 2. Grade >/=3 adverse events during preoperative therapy included neutropenia (32%), thrombocytopenia (25%), and biliary obstruction/cholangitis (14%). Forty-three patients underwent resection (63%), and complete (R0) resection was achieved in 36 of those 43 patients (84%). The median overall survival was 18.2 months (95% confidence interval, 13-26.9 months) for all patients, 27.1 months (95% confidence interval, 21.2-47.1 months) for those who underwent resection, and 10.9 months (95% confidence interval, 6.1-12.6 months) for those who did not undergo resection. A decrease in CA 19-9 level after neoadjuvant therapy was associated with R0 resection (P = .02), which resulted in a median survival of 34.6 months (95% confidence interval, 20.3-47.1 months). Fourteen patients (21%) are alive and disease free at a median follow-up of 31.4 months (range, 24-47.6 months). 1
72. Le DT, Wang-Gillam A, Picozzi V, et al. Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes-Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer. J Clin Oncol. 2015:[E-pub ahead of print]. Experimental-Tx 90 patients To compare Cy/GVAX followed by CRS-207 with Cy/GVAX alone in patients with metastatic PDA. A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received >/= two regimens for metastatic disease. Mean number of doses (+/- standard deviation) administered in arms A and B were 5.5 +/- 4.5 and 3.7 +/- 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. 1
73. Lutz E, Yeo CJ, Lillemoe KD, et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg. 2011;253(2):328-335. Experimental-Tx 60 participants To test the safety and efficacy of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapy administered in patients with resected pancreatic adenocarcinoma. The median disease-free survival is 17.3 months (95% CI, 14.6-22.8) with median survival of 24.8 months (95% CI, 21.2-31.6). The administration of immunotherapy was well tolerated. In addition, the post-immunotherapy induction of mesothelin-specific CD8+ T cells in HLA-A1+ and HLA-A2+patients correlates with disease-free survival. 1
74. Laheru D, Jaffee EM. Immunotherapy for pancreatic cancer - science driving clinical progress. Nat Rev Cancer. 2005;5(6):459-467. Review/Other-Tx N/A To review new developments in immunotherapy for pancreatic cancer. No results stated in abstract. 4
75. Ng SSW, Tsao MS, Chow S, Hedley DW. Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res. 2000;60(19):5451-5455. Review/Other-Tx N/A To investigate the significance of PI3K-PKB/Akt cell survival pathway in mediating drug resistance and the effects of PI3K inhibitors on gemcitabine treatment in human pancreatic cancer cells. After exposure to 20 microM gemcitabine for 48 h and in the continuous presence of the drug, treatment with the P13K inhibitors wortmannin (50-200 nM) and LY294002 (15-120 microM) for 4 h substantially enhanced apoptosis in a concentration-dependent manner as compared with treatment with gemcitabine alone, as determined by the loss of mitochondrial membrane potential and the increase in propidium iodide uptake using flow cytometry. Furthermore, Western blotting showed that the reduction of phosphorylated PKB/Akt levels correlated with the enhancement of gemcitabine-induced apoptosis, suggesting that the PI3K-PKB/Akt pathway plays a significant role in mediating drug resistance in human pancreatic cancer cells. 4
76. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. Experimental-Tx 342 patients To further explore FOLFIRINOX as compared with single agent gemcitabine as first-line treatment in patients with metastatic pancreatic cancer. The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). 1
77. Moningi S, Dholakia AS, Raman SP, et al. The Role of Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Single-Institution Experience. Ann Surg Oncol. 2015;22(7):2352-2358. Observational-Tx 88 patients To review our institutional experience of SBRT in the treatment of locally advanced (LAPC) and borderline resectable (BRPC) PCA. A total of 88 patients were included in the analysis, 74 with LAPC and 14 with BRPC. The median age at diagnosis was 67.2 years, and median follow-up from date of diagnosis for LAPC and BRPC patients was 14.5 and 10.3 months, respectively. Median OS from date of diagnosis was 18.4 months (LAPC, 18.4 mo; BRPC, 14.4 mo) and median PFS was 9.8 months (95 % CI 8.0-12.3). Acute toxicity was minimal with only three patients (3.4 %) experiencing acute grade >/=3 toxicity. Late grade >/=2 gastrointestinal toxicity was seen in five patients (5.7 %). Of the 19 patients (21.6 %) who underwent surgery, 79 % were LAPC patients and 84 % had margin-negative resections. 2
78. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703. Experimental-Tx 861 patients To investigate the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. 1