JCT  Vol.4 No.10 A , November 2013
Recent Developments and Current Issues in the Treatment of Pancreatic Cancer
Author(s) Helmut Oettle
ABSTRACT

Presently, many questions exist about what the optimal regimen comprises for all stages and treatment settings for pancreatic cancer. Since the CONKO-001 trial, adjuvant therapy following resection has become standard of care; however, outcomes are poor, with most patients experiencing disease recurrence, and new therapies have yet to be validated. Furthermore, the value of adjuvant radiotherapy has still not been clearly defined. Targeted treatment in combination with chemotherapy has been mostly disappointing so far in the adjuvant setting but immunotherapy holds potential for improving survival outcomes. Neoadjuvant treatment does not appear to provide much benefit in resectable patients but in the small subgroup of patients with borderline resectable/unresectable locally advanced disease it may increase the possibility of an R0 resection and, consequently, a substantial increase in survival duration. Use of capecitabine-based radiotherapy in patients with unresectable locally advanced disease appears to be more efficacious and better tolerated than gemcitabine-based chemoradiotherapy, with respect to survival outcomes. However, as with adjuvant treatment, the benefit of adding radiotherapy has not yet been definitively demonstrated. In patients with metastatic pancreatic cancer, targeting the stroma with nab-paclitaxel has shown promising results in a phase III trial setting when administered in combination with gemcitabine and, furthermore, this regimen is suitable for a broad range of patients due to its generally good tolerability profile. Because of its high toxicity, FOLFIRINOX is more suitable for younger patients with an excellent performance status who can withstand aggressive treatment and in patients with a worse performance status, gemcitabine monotherapy is considered to be a more appropriate treatment. Alternatively, gemcitabine in combination with erlotinib, the only targeted compound that has resulted in significant albeit small improvements in survival in patients with advanced disease, could be selected. However, the benefit-risk profile of this regimen is only favorable in a strictly defined, small patient subgroup who develop a treatment-related rash. Finally, with the elucidation of prognostic and predictive markers, treatment is expected to become ever more individualized, leading to improved efficacy outcomes and less unnecessary toxicity.


Cite this paper
H. Oettle, "Recent Developments and Current Issues in the Treatment of Pancreatic Cancer," Journal of Cancer Therapy, Vol. 4 No. 10, 2013, pp. 13-27. doi: 10.4236/jct.2013.410A003.
References
[1]   C. L. Wolfgang, J. M. Herman, D. A. Laheru, A. P. Klein, M. A. Erdek, et al., “Recent Progress in Pancreatic Cancer,” CA: A Cancer Journal for Clinicans, Vol. 63, No. 5, 2013, pp. 318-348. http://dx.doi.org/10.1002/caac.21190

[2]   L. Lombardi, T. Troiano, N. Silvestris, L. Nanni, T. P. Latiano, et al., “Combined Modality Treatments in Pancreatic Cancer,” Expert Opinion on Therapeutic Targets, Vol. 16, Suppl. 2, 2012, pp. S71-81. http://dx.doi.org/10.1517/14728222.2012.662959

[3]   R. A. Stathis and M. J. Moore, “Advanced Pancreatic Carcinoma: Current Treatment and Future Challenges,” Nature Reviews. Clinical Oncology, Vol. 7, No. 3, 2010, pp. 163-172. http://dx.doi.org/ 10.1038/nrclinonc.2009.236

[4]   M. Hidalgo, “Pancreatic Cancer,” The New England Journal of Medicine, Vol. 362, No. 17, 2010, pp. 1605-1617. http://dx.doi.org/10.1056/NEJMra0901557

[5]   A. Vincent, J. Herman, R. Schulick, R. H. Hruban and M. Goggins, “Pancreatic Cancer,” Lancet, Vol. 378, No. 9791, 2001, pp. 607-620. http://dx.doi.org/10.1016/S0140-6736(10)62307-0

[6]   M. M. Hassan, M. L. Bondy, R. A. Wolff, J. L. Abbruzzese, J. N. Vauthey, et al., “Risk Factors for Pancreatic Cancer: Case-Control Study,” The American Journal of Gastroenterology, Vol. 102, No. 12, 2007, pp. 2696-2707. http://dx.doi.org/10.1111/j.1572-0241.2007.01510.x

[7]   C. Shi, H. R. Hruban and A. P. Klein, “Familial Pancreatic Cancer,” Archives of Pathology & Laboratory Medicine, Vol. 133, No. 3, 2009, pp. 365-374.

[8]   A. Maitra and H. R. Hruban, “Pancreatic Cancer,” Annual Review of Pathology: Mechanisms of Disease, Vol. 3, 2008, pp. 157-188. http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806. 154305

[9]   S. Jones, X. Zhang, D. W. Parsons, J. C. Lin, R. J. Leary, et al., “Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses,” Science, Vol. 321, No. 5897, 2008, pp. 1801-1806. http://dx.doi.org/10.1126/science.1164368

[10]   G. Luo, J. Long, B. Zhang, C. Liu, J. Xu, et al., “Stroma and Pancreatic Ductal Adenocarcinoma: An Interaction Loop,” Biochimica et Biophysica Acta, Vol. 1826, No. 1, 2012, pp. 170-178.
http://dx.doi.org/10.1016/j.bbcan.2012.04.002

[11]   D. Mahadevan, D. D. Von Hoff, “Tumor-Stroma Interactions in Pancreatic Ductal Adenocarcinoma,” Molecular Cancer Therapeutics, Vol. 6, No. 4, 2007, pp. 1186-1197. http://dx.doi.org/10.1158/1535-7163.MCT-06-0686

[12]   M. V. Apte, S. Park, P. A. Phillips, N. Santucci, D. Goldstein, et al., “Desmoplastic Reaction in Pancreatic Cancer: Role of Pancreatic Stellate Cells,” Pancreas, Vol. 29, No. 3, 2004, pp. 179-187.
http://dx.doi.org/10.3389/fphys.2012.00344

[13]   A. Masamune and T. Shimosegawa, “Signal Transduction in Pancreatic Stellate Cells,” Journal of Gastroenterology, Vol. 44, No. 4, 2009, pp. 249-260. http://dx.doi.org/10.1007/s00535-009-0013-2

[14]   M. Erkan, C. Reiser-Erkan, C. W. Michalski, S. Deucker, D. Sauliunaite, et al., “Cancer-Stellate Cell Interactions Perpetuate the Hypoxia-fibrosis Cycle in Pancreatic Ductal Adenocarcinoma,” Neoplasia, Vol. 11, No. 5, 2009, pp. 497-508. http://dx.doi.org/10.1593/neo.81618

[15]   N. P. Desai, V. Trieu, L. Y. Hwang, R. Wu, P. Soon-Shiong, et al., “Improved Effectiveness of Nanoparticle Albumin-bound (nab) Paclitaxel versus Polysorbate-Based Docetaxel in Multiple Xenografts as a Function of HER2 and SPARC Status,” Anti-Cancer Drugs, Vol. 19, No. 9, 2008, pp. 899-909. http://dx.doi.org/10.1097/CAD.0b013e32830f9046

[16]   C. J. Lee, J. Dosch and D. M. Simeone, “Pancreatic Cancer Stem Cells,” Journal of Clinical Oncology, Vol. 26, No. 17, 2008, pp. 2806-2812. http://dx.doi.org/10.1200/JCO.2008.16.6702

[17]   P. C. Hermann, S. L. Huber, T. Herrler, A. Aicher, J. W. Ellwart, et al., “Distinct Populations of Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic Cancer,” Cell Stem Cell, Vol. 1, No. 3, 2007, pp. 313-323. http://dx.doi.org/10.1016/j.stem.2007.06.002

[18]   G. Bond-Smith, N. Banga, T. M. Hammond and C. J. Imber, “Pancreatic Adenocarcinoma,” BMJ, Vol. 344, 2012, Article ID: e2476. http://dx.doi.org/10.1136/bmj.e2476

[19]   C. G. Moertel, D. S. Childs Jr., R. J. Reitemeier, M. Y. Colby Jr., M. A. Holbrook, et al., “Combined 5-fluorouracil and Supervoltage Radiation Therapy of Locally Unresectable Gastrointestinal Cancer,” The Lancet, Vol. 2, No. 7626, 1969, pp. 865-867. http://dx.doi.org/10.1016/S0140-6736(69)92326-5

[20]   J. B. Haslam, P. J. Cavanaugh and S. L. Stroup, “Radiation Therapy in the Treatment of Irresectable Adenocarcinoma of the Pancreas,” Cancer, Vol. 32, No. 6, 1973, pp. 1341-1345.
http://dx.doi.org/10.1002/1097-0142(197312)32:6<1341::AID-CNCR2820320609>3.0.CO;2-A

[21]   M. H. Kaiser and S. S. Ellenberg, “Pancreatic Cancer. Adjuvant combined Radiation and Chemotherapy Following Curative Resection,” Archives of Surgery, Vol. 120, No. 8, 1985, pp. 899-903. http://dx.doi.org/10.1001/archsurg.1985.01390320023003

[22]   Gastrointestinal Tumor Study Group, “Further Evidence of Effective Adjuvant combined Radiation and Chemotherapy Following Curative Resection,” Cancer, Vol. 59, No. 12, 1987, pp. 2006-2010. http://dx.doi.org/10.1002/1097-0142(19870615)59:12<2006::AID-CNCR2820591206>3.0.CO;2-B

[23]   J. H. Klinkenbijl, J. Jeekel, T. Sahmoud, R. van Pel, M. L. Couvreur, et al., “Adjuvant Radiotherapy and 5-Fluorouracil after Curative Resection of Cancer of the Pancreas and Periampullary Region,” Annals of Surgery, Vol. 230, No. 6, 1999, pp. 776-782. http://dx.doi.org/10.1097/00000658-199912000-00006

[24]   H. G. Smeenk, C. H. J. van Eijck, W. C. Hop, J. Erdmann, K. C. K. Tran, et al., “Long-term Survival and Metastatic Pattern of Pancreatic and Periampullary Cancer after Adjuvant Chemoradiation or Observation: Long-term Results of EORTC trial 40891,” Annals of Surgery, Vol. 246, No. 5, 2007, pp. 734-740. http://dx.doi.org/10.1097/SLA.0b013e318156eef3

[25]   J. P. Neoptolemos, D. D. Stocken, H. Friess, C. Bassi, J. A. Dunn, et al., “A Randomized Trial of Chemoradiotherapy and Chemotherapy after Resection of Pancreatic Cancer,” The New England Journal of Medicine, Vol. 350, No. 12, 2004, pp. 1200-1210. http://dx.doi.org/10.1056/NEJMoa032295

[26]   H. Oettle, S. Post, P. Neuhaus, K. Gellert, J. Langrehr, et al., “Adjuvant Chemotherapy with Gemcitabine vs Observation in Patients Undergoing Curative-intent Resection of Pancreatic Cancer: A Randomized Controlled Trial.,” JAMA: The Journal of the American Medical Association, Vol. 297, No. 3, 2007, pp. 267-277. http://dx.doi.org/10.1001/jama.297.3.267

[27]   J. P. Neoptolemos, D. D. Stocken, C. Bassi, P. Ghaneh, D. Cunningham, et al., “Adjuvant Chemotherapy with Fluorouracil plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection,” JAMA: The Journal of the American Medical Association, Vol. 304, No. 10, 2010, pp. 1073-1081. http://dx.doi.org/10.1001/jama.2010.1275

[28]   H. A. Burris 3rd, M. J. Moore, J. Andersen, M. R. Green, M. L. Rothenberg, et al., “Improvements in Survival and Clinical Benefit with Gemcitabine as First-line Therapy for Patients with Advanced Pancreas Cancer: A Randomized Trial,” Journal of Clinical Oncology, Vol. 15, No. 6, 1997, pp. 2403-2413.

[29]   W. F. Regine, K. A. Winter, R. A. Abrams, H. Safran, J. P. Hoffman, et al., “Fluorouracil vs Gemcitabine Chemotherapy before and after Fluorouracil-based Chemoradiation following Resection of Pancreatic Adenocarcinoma: A Randomized Controlled Trial,” JAMA: The Journal of the American Medical Association, Vol. 299, No. 9, 2008, pp. 1019-26. http://dx.doi.org/10.1001/jama.299.9.1019

[30]   Fukutomi, K. Uesaka, N. Boku, H. Kanemoto, M. Konishi, et al., “JASPAC 01: Randomized Phase III Trial of Adjuvant Chemotherapy with Gemcitabine versus S-1 for Patients with Resected Pancreatic Cancer,” Journal of Clinical Oncology, Vol. 31, Suppl. 4003, 2013.

[31]   D. D. Stocken, M. W. Büchler, C. Dervenis, C. Bassi, H. Jeekel, et al., “Meta-Analysis of Randomised Adjuvant Therapy Trials for Pancreatic Cancer,” British Journal of Cancer, Vol. 92, No. 8, pp. 1372-1381. http://dx.doi.org/10.1038/sj.bjc.6602513

[32]   A. Vincent, J. Herman, R. Schulick, R. H. Hruban and M. Goggins, “Pancreatic Cancer,” The Lancet, Vol. 378, No. 9791, 2001, pp. 607-620. http://dx.doi.org/10.1016/S0140-6736(10)62307-0

[33]   M. J. Moore, D. Goldstein, J. Hamm, A. Figer, J. R. Hecht, et al., “Erlotinib plus Gemcitabine Compared with Gemcitabine alone in Patients with Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group,” Journal of Clinical Oncology, Vol. 25, No. 15, 2007, pp. 1960-1966.
http://dx.doi.org/10.1200/JCO.2006.07.9525

[34]   K. S. Gunturu, G. R. Rossi and M. W. Saif, “Immunotherapy Updates in Pancreatic Cancer: Are We There Yet?” Therapeutic Advances in Medical Oncology, Vol. 5, No. 1, 2013, pp. 81-89.
http://dx.doi.org/10.1177/1758834012462463

[35]   J. M. Hardacre, M. F. Mulcahy, et al., “Addition of Algenpantucel-L Immunotherapy to Standard of Care (SOC) Adjuvant Therapy for Pancreatic Cancer,” Journal of Clinical Oncology, Vol. 30, Suppl. 4049, 2012.

[36]   E. Lutz, C. J. Yeo, K. D. Lillemoe, B. Biedrzycki, B. Kobrin, 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,” Annals of Surgery, Vol. 253, No. 2, 2011, pp. 328-335. http://dx.doi.org/10.1097/SLA.0b013e3181fd271c

[37]   C. Belli, S. Cereda, S. Anand and M. Reni, “Neoadjuvant Therapy in Resectable Pancreatic Cancer: A Critical Review,” Cancer Treatment Reviews, Vol. 29, No. 5, 2013, pp. 518-524. http://dx.doi.org/ 10.1016/j.ctrv.2012.09.008

[38]   S. Heinrich, B. C. Pestalozzi, M. Schafer, A. Weber, P. Bauerfeind, et al., “Prospective Phase II Trial of Neoadjuvant Chemotherapy with Gemcitabine and Cisplatin for Resectable Adenocarcinoma of the Pancreatic Head,” Journal of Clinical Oncology, Vol. 26, No. 15, 2008, pp. 2526-2531.
http://dx.doi.org/10.1200/JCO.2007.15.5556

[39]   D. H. Palmer, D. D. Stocken, H. Hewitt, C. E. Markham, A. B. Hassan, et al., “A Randomized Phase 2 Trial of Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone versus Gemcitabine combined with Cisplatin,” Annals of Surgical Oncology, Vol. 14, No. 7, 2007, pp. 2088-2089. http://dx.doi.org/10.1245/s10434-007-9384-x

[40]   M. S. Talamonti, W. Small Jr., M. F. Mulcahy, J. D. Wayne, V. Attaluri, et al., “A Multi-Institutional Phase II Trial of Preoperative Full-dose Gemcitabine and Concurrent Radiation for Patients with Potentially Resectable Pancreatic Carcinoma,” Annals of Surgical Oncology, Vol. 13, No. 7, 2006, pp. 150-158. http://dx.doi.org/10.1245/ASO.2006.03.039

[41]   G. R. Varadhachary, R. A. Wolff, C. H. Crane, C. C. Sun, J. E. Lee, et al., “Preoperative Gemcitabine and Cisplatin Followed by Gemcitabine-Based Chemoradiation for Resectable Adenocarcinoma of the Pancreatic Head,” Journal of Clinical Oncology, Vol. 26, 2008, pp. 3487-3495. http://dx.doi.org/ 10.1200/JCO.2007.15.8642

[42]   S. Gillen, T. Schuster, C. Meyer Zum Büschenfelde, H. Friess and J. Kleeff, “Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-Analysis of Response and Resection Percentages,” PLoS Medicine, Vol. 7, No. 4, 2010. http://dx.doi.org/10.1371/journal.pmed.1000267

[43]   S. MacKenzie, H. Zeh, L. E. McCahill, T. D, Sielaff, N. Bahary, et al., “A Pilot Phase II Multicenter Study of Nab-paclitaxel (Nab-P) and Gemcitabine (G) as Preoperative Therapy for Potentially Resectable Pancreatic Cancer (PC),” Journal of Clinical Oncology, Vol. 31 Suppl. 4038, 2013.

[44]   D. Habermehl, K. Kessel, T. Welzel, H. Hof, A. Abdollahi, et al., “Neoadjuvant Chemoradiation with Gemcitabine for Locally Advanced Pancreatic Cancer,” Journal of Radiation Oncology, Vol. 7, No. 28, 2012, p. 28. http://dx.doi.org/10.1186/1748-717X-7-28

[45]   M. Nakamura, T. Kayashima, K. Fujiwara, Y. Nagayoshi and H. Kono, “Combination Therapy of Portal Vein Resection and Adjuvant Gemcitabine Improved Prognosis of Advanced Pancreatic Cancer,” Hepatogastroenterology, Vol. 60, No. 122, 2013, pp. 354-357. http://dx.doi.org/10.5754/hge12614

[46]   B. Chauffert, F. Mornex, F. Bonnetain, P. Rougier and C. Mariette, “Phase III Trial Comparing Intensive Induction Chemoradiotherapy (60 Gy, Infusional 5-FU and Intermittent Cisplatin) Followed by Maintenance Gemcitabine with Gemcitabine Alone for Locally Advanced Unresectable Pancreatic Cancer. Definitive Results of the 2000-01 FFCD/SFRO Study,” Annals of Oncology, Vol. 19, No. 9, 2008, pp. 1592-1599. http://dx.doi.org/10.1093/annonc/mdn281

[47]   P. J. Loehrer Sr, Y. Feng, H. Cardenes, L. Wagner, J. M. Brell, et al., “Gemcitabine Alone versus Gemcitabine plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial,” Journal of Clinical Oncology, Vol. 29, No. 31, 2011, pp. 4105-4112. http://dx.doi.org/10.1200/JCO.2011.34.8904

[48]   S. Mukherjee, C. Hurt, G. Griffiths, J. A. Bridgewater, T. Crosby, et al., “SCALOP: Results of a Randomized Phase II Study of Induction Chemotherapy Followed by Gemcitabine (G) or Capecitabine (Cap) based Chemoradiation (CRT) in Locally Advanced Pancreatic Cancer (LAN PC),” Journal of Clinical Oncology, Vol. 30, Suppl. 34, 2012.

[49]   P. Hammel, F. Huguet, J-L. Van Laethem, D. Goldstein, B. Glimelius, et al., “Comparison of Chemoradiotherapy (CRT) and Chemotherapy (CT) in Patients with a Locally Advanced Pancreatic Cancer (LAPC) Controlled after 4 Months of Gemcitabine with or without Erlotinib: Final Results of the International Phase III LAP 07 study,” Journal of Clinical Oncology, Vol. 31, Suppl. LBA4003, 2013.

[50]   J. M. Herman, A. T. Wild, H. Wang, P. T. Tran, K. J. Chang, et al., “Randomized Phase III Multi-Institutional Study of TNFerade Biologic with Fluorouracil and Radiotherapy for Locally Advanced Pancreatic Cancer,” Journal of Clinical Oncology, Vol. 31, 2013, pp. 886-894. http://dx.doi.org/ 10.1200/JCO.2012.44.7516

[51]   J. D. Berlin, P. Catalano, J. P. Thomas, J. W Kugler, D. G. Haller, et al., “Phase III Study of Gemcitabine in Combination with Fluorouracil versus Gemcitabine alone in Patients with Advanced Pancreatic Carcinoma: Eastern Cooperative Oncology Group Trial E2297,” Journal of Clinical Oncology, Vol. 20, No. 15, 2002, pp. 3270-3275. http://dx.doi.org/10.1200/JCO.2002.11.149

[52]   R. Herrmann, G. Bodoky, T. Ruhstaller, B. Glimelius, E. Bajetta E, et al., “Gemcitabine plus Capecitabine Compared with Gemcitabine alone in Advanced Pancreatic Cancer: A Randomized, Multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group,” Journal of Clinical Oncology, Vol. 25, No. 16, 2007, pp. 2212-2217. http://dx.doi.org/10.1200/JCO.2006.09.0886

[53]   C. Louvet, R. Labianca, P. Hammel, G. Lledo, M. G. Zampino, et al., “Gemcitabine in Combination with Oxaliplatin Compared with Gemcitabine alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD phase III Trial,” Journal of Clinical Oncology, Vol. 23, No. 15, 2005, pp. 3509-3516. http://dx.doi.org/10.1200/JCO.2005.06.023

[54]   V. Heinemann, D Quietzsch, F. Gieseler, M. Gonnermann, H. Schonekas, et al., “Randomized Phase III trial of Gemcitabine plus Cisplatin compared with Gemcitabine alone in Advanced Pancreatic Cancer,” Journal of Clinical Oncology, Vol. 24, No. 24, 2006, pp. 3946-3952. http://dx.doi.org/10.1200/ JCO.2005.06.023

[55]   C. M. Rocha Lima, M. R Gree, R Rotche, W. H. Miller, G. M. Jeffrey, et al., “Irinotecan plus Gemcitabine Results in no Survival Advantage Compared with Gemcitabine Monotherapy in Patients with Locally Advanced or Metastatic Pancreatic Cancer despite Increased Tumor Response Rate,” Journal of Clinical Oncology, Vol. 22, No. 18, 2004, pp. 3776-3783. http://dx.doi.org/10.1200/JCO.2004.12.082

[56]   H. Oettle, D. Richards, R. K. Ramanathan, J. L. van Laethem, M. Peeters, et al., “A Phase III Trial of Pemetrexed plus Gemcitabine versus Gemcitabine in Patients with Unresectable or Metastatic Pancreatic Cancer,” Annals of Oncology, Vol. 16, No. 10, 2005 pp. 1639-1645. http://dx.doi.org/ 10.1093/annonc/mdi309

[57]   A. Sultana, C. T. Smith, D. Cunningham, N. Starling, J. P. Neoptolemos, et al., “Meta-analyses of Chemotherapy for Locally Advanced and Metastatic Pancreatic Cancer”. Journal of Clinical Oncology, Vol. 25, No. 18, 2007, pp. 2607-1265. http://dx.doi.org/10.1200/JCO.2006.09.2551

[58]   V. Heinemann, S. Boeck, A. Hinke, R. Labianca, C. Louvet, et al., “Meta-Analysis of Randomized Trials: Evaluation of Benefit from Gemcitabine-based Combination Chemotherapy Applied in Advanced Pancreatic Cancer,” BMC Cancer, Vol. 8, 2008, p. 82. http://dx.doi.org/10.1186/1471-2407-8-82

[59]   E. van Cutsem, W. L. Vervenne, J. Bennouna, Y. Humblet Y, S. Gill, et al., “Phase III Trial of Bevacizumab in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic Cancer,” Journal of Clinical Oncology, Vol. 27, No. 13, 2009 pp. 2231-2237. http://dx.doi.org/ 10.1200/JCO.2008.20.0238

[60]   H. L. Kindler, D. Niedzwiecki, D. Hollis, S. Sutherland, D. Schrag, et al., “Gemcitabine plus Bevacizumab Compared with Gemcitabine plus Placebo in Patients with Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303),” Journal of Clinical Oncology, Vol. 28, No. 22, pp. 3617-3622. http://dx.doi.org/10.1200/JCO.2010.28.1386

[61]   P. A. Philip, J. Benedetti, C. L. Corless, R. Wong, E. M. O'Reill, et al., “Phase III Study Comparing Gemcitabine plus Cetuximab versus Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group-directed Intergroup Trial S0205,” Journal of Clinical Oncology, Vol. 28, No. 22, 2010, pp. 3605-3610. http://dx.doi.org/10.1200/JCO.2009.25.7550

[62]   J. P. Spano, C. Chodkiewicz, J. Maurel, R. Wong, H. Wasan, et al., “Efficacy of Gemcitabine Plus Axitinib Compared with Gemcitabine Alone in Patients with Advanced Pancreatic Cancer: An Open-label Randomised phase II Study,” Lancet, Vol. 371, No. 9630, pp. 2101-2108.
http://dx.doi.org/10.1016/S0140-6736(08)60661-3

[63]   A. Goncalves, M. Gilabert, E. Francois, L. Dahan, H. Perrier, et al., “BAYPAN Study: A Double-blind Phase III Randomized Trial Comparing Gemcitabine plus Sorafenib and Gemcitabine plus Placebo in Patients with Advanced Pancreatic Cancer,” Annals of Oncology, Vol. 23, No 11, pp. 2799-2805. http://dx.doi.org/10.1093/annonc/mds135

[64]   T. Conroy, F. Desseigne, M. Ychou, O. Bouché, R. Guimbaud, et al., “FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer,” The New England Journal of Medicine, Vol. 364, No. 19, pp. 1817-1825. http://dx.doi.org/10.1056/NEJMoa1011923

[65]   P. J. Hosein, J. Macintyre, C. Kawamura, J. C. Maldonado, V. Ernani, et al., “A Retrospective Study of Neoadjuvant FOLFIRINOX in Unresectable or Borderline-Resectable Locally Advanced Pancreatic Adenocarcinoma,” BMC Cancer, Vol. 12, No. 199, 2012. http://dx.doi.org/10.1186/1471-2407-12-199

[66]   T. Conroy, C. Gavoille, E. Samalin, M. Ychou, M. Ducreux, et al., “The Role of the FOLFIRINOX Regimen for Advanced Pancreatic Cancer,” Current Oncology Reports, Vol. 15, No. 2, 2013, pp. 182-189. http://dx.doi.org/10.1007/s11912-012-0290-4

[67]   A. Neesse, P. Michl, K. K. Frese, C. Feig, N. Cook, et al., “Stromal Biology and Therapy in Pancreatic Cancer,” Gut, Vol. 60, No. 6, 2011, pp. 861-868. http://dx.doi.org/10.1136/gut.2010.226092

[68]   J. R. Infante, H. Matsubayashi, N. Sato, J. Tonascia, A. P. Klein, et al., “Peritumoral Fibroblast SPARC Expression and Patient Outcome with Resectable Pancreatic Adenocarcinoma,” Journal of Clinical Oncology, Vol. 25, No. 3, 2007, pp. 319-325. http://dx.doi.org/10.1200/JCO.2006.07.8824

[69]   V. Trieu, J. Hwang and N. Desai, “Nanoparticle Albuminbound (nab) Technology may Enhance Antitumour Activity via Targeting of SPARC Protein,” Proceedings New Targets and Delivery System for Cancer Diagnosis and Treatment conference, Sidney Kramer Cancer Center, San Diego, 5-7 March 2007.

[70]   D. D. Von Hoff, R. K. Ramanathan, M. J. Borad, D. A. Laheru, L. S. Smith, et al., “Gemcitabine Plus Nab-Paclitaxel is an Active Regimen in Patients with Advanced Pancreatic Cancer: A Phase I/II Trial,” Journal of Clinical Oncology, Vol. 29, No. 34, 2011, pp. 4548-4554. http://dx.doi.org/10.1200/JCO. 2011.36.5742

[71]   D. D. von Hoff, T. J. Ervin, F. P. Arena, E. G. Chiorean, R. J. Infante, et al., “Randomized Phase III Study of Weekly Nab-Paclitaxel plus Gemcitabine versus Gemcitabine alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT),” Journal of Clinical Oncology, Vol. 30, Suppl. 34, 2012.

[72]   M. J. Moore, D. D. Von Hoff, T. J. Ervin, F. P. Arena, E. G. Chiorean, et al., “Prognostic Factors (PFs) of Survival in a Randomized Phase III Trial (MPACT) of Weekly Nab-paclitaxel (nab-P) plus Gemcitabine (G) versus G alone in Patients (pts) with Metastatic Pancreatic Cancer (MPC),” Journal of Clinical Oncology, Vol. 31, Suppl. 4059, 2013.

[73]   U. Pelzer, K. Kubica, J. Stieler, I. Schwaner, G. Heil, et al., “A Randomized Trial in Patients with Gemcitabine Refractory Pancreatic Cancer. Final Results of the CONKO 003 Study,” Journal of Clinical Oncology, Vol. 26, No. 15S, Suppl. 4508, 2008.

[74]   U. Pelzer, I. Schwaner, J. Stieler, M. Adler, J. Seraphin J., et al., “Best Supportive Care (BSC) versus Oxaliplatin, Folinic Acid and 5-Fluorouracil (OFF) Plus BSC in Patients for Second-line Advanced Pancreatic Cancer: A Phase III-study from the German CONKO-Study Group,” European Journal of Cancer, Vol. 47, No. 11, 2011, pp. 1676-1681. http://dx.doi.org/10.1016/j.ejca.2011.04.011

[75]   H. Q. Xiong, G. R. Varadhachary, J. C. Blais, K. R. Hess, J. L. Abbruzzese, et al., “Phase 2 Trial of Oxaliplatin plus Capecitabine (XELOX) as Second-line therapy for Patients with Advanced Pancreatic Cancer,” Cancer, Vol. 113, No. 8, 2008, pp. 2046-2052. http://dx.doi.org/10.1002/cncr.23810

[76]   N. Mizuno, K. Yamao, Y. Komatsu, M. Munakata, A. Ishiguro, et al., “Randomized Phase II Study of Best Available Fluoropyrimidine Compared with Continuation of Gemcitabine (Gem) Monotherapy in Patients with Gem-Refractory Pancreatic Cancer,” Journal of Clinical Oncology, Vol. 30, Suppl. 34, Abstr. 263, 2012.

[77]   T. Ioka, K. Katayama, N. Ishida, R. Takada, T. Yamai, et al., “Randomized Phase II Trial of S-1 versus S-1 Plus Irinotecan (IRIS) in Patients with Gemcitabine-Refractory Pancreatic Cancer,” Journal of Clinical Oncology, Vol. 30, Suppl. 34, Abstr. 287, 2012.

[78]   C. N. Oldenhuis, S. F. Oosting, J. A. Gietema and E. G. de Vries, “Prognostic versus Predictive Value of Biomarkers in Oncology,” European Journal of Cancer, Vol. 44, No. 7, 2008, pp. 946-953.
http://dx.doi.org/10.1016/j.ejca.2008.03.006

[79]   A. C. Berger, K. Winter, J. P. Hoffman, W. F. Regine, R. A. Abrams, 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,” International Journal of Radiation Oncology Biology Physics, Vol. 84, No. 3, 2012, pp. 291-297. http://dx.doi.org/10.1016/j.ijrobp.2012.04.035

[80]   E. G. Chiorean, D. D. Von Hoff, T. J. Ervin, F. P. Arena, J. R. Infante, et al., “CA19-9 Decrease at 8 Weeks as a Predictor of Overall Survival (OS) in a Randomized Phase III Trial (MPACT) of Weekly Nab-paclitaxel (nab-P) plus Gemcitabine (G) versus G alone in Patients with Metastatic Pancreatic Cancer (MPC),” Journal of Clinical Oncology, Vol. 31, Suppl. 4058, 2013.

[81]   C. Verslype, W. Verwvenne, J. Bennouna, Y. Humblet, J. Cosaert J, et al., “Rash as a Marker for the Efficacy of Gemcitabine plus Erlotinib-based Therapy in Pancreatic Cancer: Results from the AViTA Study,” Journal of Clinical Oncology, Vol. 27, Suppl. 4532, 2009.

[82]   J. Manzano, F. Rivera, M. Gala, M. Valladares, C. Pericay, et al., “A Phase II, Open Label Study to Evaluate the Relationship between Skin Rash and Survival in Patients with Unresectable and/or Metastatic Pancreatic Cancer Treated with Erlotinib combined with Gemcitabine.,” Journal of Clinical Oncology, Vol. 28, Abstr. 4094.

[83]   E. Aranda, J. L. Manzano, F. Rivera, M. Galán, M. Valladares-Ayerbes, et al., “Phase II Open-label Study of Erlotinib in Combination with Gemcitabine in Unresectable and/or Metastatic Adenocarcinoma of the Pancreas: Relationship between Skin Rash and Survival (Pantar Study),” Annals of Oncology, Vol. 23, No. 7, 2012, pp. 1919-1925. http://dx.doi.org/10.1093/annonc/mdr560

[84]   V. Heinemann, U. Vehling-Kaiser, D. Waldschmidt, E. Kettner, A. Marten, et al., “Gemcitabine Plus Erlotinib followed by Capecitabine versus Capecitabine plus Erlotinib followed by Gemcitabine in Advanced Pancreatic Cancer: Final Results of a Randomised Phase 3 Trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIOPK0104),” Gut, Vol. 62, No. 5, 2013, pp. 751-762.
http://dx.doi.org/10.1136/gutjnl-2012-302759

[85]   J. García-Manteiga, M. Molina-Arcas, F. J. Casado, A. Mazo and M. Pastor-Anglada, “Nucleoside Transporter Profiles in Human Pancreatic Cancer Cells: Role of hCNT1 in 2’,2’-Difluorodeoxycytidine-Induced Cytotoxicity,” Clinical Cancer Research, Vol. 9, No. 13, 2003, pp. 5000-5008.

[86]   J. P. Neoptolemos, W. Greenhalf, P. Ghaneh, D. H. Palmer, T. F. Cox, et al., “HENT1 Tumor Levels to Predict Survival of Pancreatic Ductal Adenocarcinoma Patients who Received Adjuvant Gemcitabine and Adjuvant 5FU on the ESPAC Trials,” Journal of Clinical Oncology, Vol. 31, Suppl. 4006, 2013.

[87]   J. J. Farrell, H. Elsaleh, M. Garcia, R. Lai, A. Ammar, et al., “Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients with Pancreatic Cancer,” Gastroenterology, Vol. 136, No. 1, 2009, pp. 187-195. http://dx.doi.org/10.1053/j.gastro.2008.09.067

 
 
Top