The Evolution of Chemoradiation Strategies for Locally Advanced Pancreatic Cancer

  • A. William Blackstock
  • Stacy Wentworth
Part of the M. D. Anderson Solid Tumor Oncology Series book series (MDA)

In the United States, the incidence of pancreatic cancer has been on the rise since the 1930s and has seemed to level out since the 1970s. In 2008, it is projected that an estimated 37,680 new cases of pancreatic cancer will be diagnosed in the United States, resulting in approximately 34,290 deaths from the disease (1). Mortality rates closely follow incidence rates because of the poor prognosis of pancreatic cancer. In the United States, it is the fourth and the fifth most common cancer in men and women, respectively, and has the lowest 5-year survival rate of any cancer; generally <5% with little improvement in survival observed in the past 20 years (1, 2). Most patients who have pancreatic cancer succumb to metastatic disease, and current available treatments have had little impact on survival, indicating a lack of adequate systemic treatments. Surgery offers the only potential cure for pancreatic carcinoma, yet <20% of the patients present with tumors that are ultimately deemed resectable. Approximately two thirds of all pancreatic cancer patients have metastatic disease at the time of diagnosis, whereas the majority of the remaining patients have locally advanced unresectable disease. Cures for patients with locally advanced/unresectable pancreatic cancer are only anecdotal.


Pancreatic Cancer Clin Oncol Maximal Tolerate Dose External Beam Radiation Radiat Oncol Biol Phys 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Jemal A, Siegel R, Ward E, 2008, Cancer statistics. CA Cancer J Clin 58(2):71–96.CrossRefPubMedGoogle Scholar
  2. 2.
    Evans D, Abbrezzese J, Willett C. 2001, Cancer of the pancreas. Lippincott Williams & Wilkins, Philadelphia,.Google Scholar
  3. 3.
    American Joint Committee on Cancer Staging Manual. Exocrine pancreas, 6th ed. New York, Springer, 2002.Google Scholar
  4. 4.
    Minsky BD, Hilaris B, Fuks Z. 1988, The role of radiation therapy in the control of pain from pancreatic carcinoma. J Pain Symptom Manage 3(4): 199–205.CrossRefPubMedGoogle Scholar
  5. 5.
    Roldan GE, Gunderson LL, Nagorney DM, 1988, External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer 61(6):1110–1116.CrossRefPubMedGoogle Scholar
  6. 6.
    Shipley WU, Wood WC, Tepper JE, 1984, Intraoperative electron beam irradiation for patients with unresectable pancreatic carcinoma. Ann Surg 200(3):289–296.CrossRefPubMedGoogle Scholar
  7. 7.
    Wood WC, Shipley WU, Gunderson LL, 1982, Intraoperative irradiation for unresectable pancreatic carcinoma. Cancer 49(6):1272–1275.CrossRefPubMedGoogle Scholar
  8. 8.
    Tepper JE, Shipley WU, Warshaw AL, 1987, The role of misonidazole combined with intra-operative radiation therapy in the treatment of pancreatic carcinoma. J Clin Oncol 5(4):579–584.PubMedGoogle Scholar
  9. 9.
    Garton GR, Gunderson LL, Nagorney DM, 1993, High-dose preoperative external beam and intraoperative irradiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 27(5):1153–1157.PubMedGoogle Scholar
  10. 10.
    Sindelar WF, Kinsella TJ. 1999, Studies of intraoperative radiotherapy in carcinoma of the pancreas. Ann Oncol 10(Suppl 4):226–230.CrossRefPubMedGoogle Scholar
  11. 11.
    Tepper JE, Noyes D, Krall JM, 1991, Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 21 (5): 1145–1149.Google Scholar
  12. 12.
    Willett CG, Castillo CF, Del Shih HA, 2005, Long-term results of intraoperative electron beam irradiation(IOERT) for patients with unresectable pancreatic cancer. Ann Surg 241(2):295–299.CrossRefPubMedGoogle Scholar
  13. 13.
    Shipley WU, Nardi GL, Cohen AM, 1980, Iodine-125 implant and external beam irradiation in patients with localized pancreatic carcinoma: a comparative study to surgical resection. Cancer 45(4):709–714.CrossRefPubMedGoogle Scholar
  14. 14.
    Syed AM, Puthawala AA, Neblett DL. 1983, Interstitial iodine-125 implant in the management of unresectable pancreatic carcinoma. Cancer 52(5):808–813.CrossRefPubMedGoogle Scholar
  15. 15.
    Dobelbower RR, Jr., Merrick HW, 3rd., Ahuja RK, 1986, 125I interstitial implant, precision high-dose external beam therapy, and 5-FU for unresectable adenocarcinoma of pancreas and extrahepatic biliary tree. Cancer 58(10):2185–2195.CrossRefPubMedGoogle Scholar
  16. 16.
    Mohiuddin M, Cantor RJ, Biermann W, 1988, Combined modality treatment of localized unresectable adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 14: 79–84.PubMedGoogle Scholar
  17. 17.
    Peretz T, Nori D, Hilaris B, 1989, Treatment of primary unresectable carcinoma of the pancreas with I-125 implantation. Int J Radiat Oncol Biol Phys 17 (5): 931–935.PubMedGoogle Scholar
  18. 18.
    Smith FP, Schein PS, Macdonald JS, 1981, Fast neutron irradiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 7 (11): 1527–1531.PubMedGoogle Scholar
  19. 19.
    Al-Abdulla AS, Hussey DH, Olson MH, 1981, Experience with fast neutron therapy for unre-sectable carcinoma of the pancreas. Int J Radiat Oncol Biol Phys 7 (2): 165–172.PubMedGoogle Scholar
  20. 20.
    Cohen L, Woodruff KH, Hendrickson FR, 1985, Response of pancreatic cancer to local irradiation with high-energy neutrons. Cancer 56(6):1235–1241.CrossRefPubMedGoogle Scholar
  21. 21.
    Thomas FJ, Krall J, Hendrickson F, 1989, Evaluation of neutron irradiation of pancreatic cancer. Results of a randomized Radiation Therapy Oncology Group clinical trial. Am J Clin Oncol 12(4):283–289.CrossRefPubMedGoogle Scholar
  22. 22.
    Linstadt D, Quivey JM, Castro JR, 1988, Comparison of helium-ion radiation therapy and split-course megavoltage irradiation for unresectable adenocarcinoma of the pancreas. Final report of a Northern California Oncology Group randomized prospective clinical trial. Radiology 168(1):261–264.PubMedGoogle Scholar
  23. 23.
    Crane CH, Antolak JA, Rosen II, 2001, Phase I study of concomitant gemcitabine and IMRT for patients with unresectable adenocarcinoma of the pancreatic head. Int J Gastrointest Cancer 30(3):123–132.CrossRefPubMedGoogle Scholar
  24. 24.
    Milano MT, Chmura SJ, Garofalo MC, 2004, Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys 59 (2): 445–453.PubMedGoogle Scholar
  25. 25.
    Landry JC, Yang GY, Ting JY, 2002, 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. Med Dosim 27(2):121–129.CrossRefPubMedGoogle Scholar
  26. 26.
    Koong AC, Christofferson E, Le QT, 2005, Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 63 (2): 320–323.PubMedGoogle Scholar
  27. 27.
    Hoyer M, Roed H, Sengelov L, 2005, Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol 76 (1): 48–53.CrossRefPubMedGoogle Scholar
  28. 28.
    Moertel CG, Childs DS, Jr., Reitemeier RJ, 1969, Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2 (7626):865–867.CrossRefPubMedGoogle Scholar
  29. 29.
    Moertel CG, Frytak S, Hahn RG, 1981, Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 48(8):1705–1710.CrossRefPubMedGoogle Scholar
  30. 30.
    Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group. Cancer 1985, 56(11):2563–2568.CrossRefPubMedGoogle Scholar
  31. 31.
    Gastrointestinal Tumor Study Group: Treatment of locally unresectable carcinoma of the pancreas: A comparison of combined modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 1988, 80:751–755.CrossRefGoogle Scholar
  32. 32.
    Klassen DJ, MacIntyre JM, Catton GE, 1985, Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-flurouracil alone with radiation plus concurrent and maintenance 5-fluorouracil—An Eastern Cooperative Oncology Group Study. J Clin Oncol 3(3):373–378.Google Scholar
  33. 33.
    O’ Connell MJ, Martenson JA, Wieand HS, 1994, Improving adjuvant therapy for rectal cancer by combining protracted-infusion flurouracil with radiation therapy after curative surgery. N Engl J Med 331:502–507.CrossRefGoogle Scholar
  34. 34.
    Whittington R, Neuberg D, Tester WJ, 1995, Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial. J Clin Oncol 13:227–232.PubMedGoogle Scholar
  35. 35.
    Poen JC, Collins HL, Niederhuber JE, 1998, Chemo-radiotherapy for localized pancreatic cancer: increased dose intensity and reduced acute toxicity with concomitant radiotherapy and protracted venous infusion 5-fluorouracil. Int J Radiat Oncol Biol Phys 40 (1): 93–99.CrossRefPubMedGoogle Scholar
  36. 36.
    Ben-Josef E, Shields AF, Vaishampayan U, 2004, Intensity-modulated radiotherapy (IMRT) and concurrent capecitabine for pancreatic cancer. Int J Radiat Oncol Biol Phys 59: 454–459.PubMedGoogle Scholar
  37. 37.
    Saif MW, Eloubeidi MA, Russo S, 2005, Phase I study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: expression analysis of genes related to outcome. J Clin Oncol 23:8679–8687.CrossRefPubMedGoogle Scholar
  38. 38.
    Schneider BJ, Ben-Josef E, McGinn CJ, 2005, Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 63: 1325–1330.CrossRefPubMedGoogle Scholar
  39. 39.
    Burris HA, 3rd Moore MJ, Andersen J, 1997, Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413.PubMedGoogle Scholar
  40. 40.
    Fields MT, Eisbruch A, Normolle D, 2000, Radiosensitization produced in vivo by once- vs. twice-weekly 2'2'-difluoro-2'-deoxycytidine (gemcitabine). Int J Radiat Oncol Biol Phys. 47 (3):785–791.CrossRefPubMedGoogle Scholar
  41. 41.
    Lawrence TS, Chang EY, Hahn TM, 1996, Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine. Int J Radiat Oncol Biol Phys 34: 867–872.PubMedGoogle Scholar
  42. 42.
    Milas L, Fujii T, Hunter N, 1999, Enhancement of tumor radioresponse in vivo by gemcitabine. Cancer Res 59:107–114.PubMedGoogle Scholar
  43. 43.
    Poggi MM, Kroog GS, Russo A, 2002, Phase I study of weekly gemcitabine as a radiation sensitizer for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 54: 670–676.PubMedGoogle Scholar
  44. 44.
    Blackstock AW, Bernard SA, Richards F, 1999; Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol 17:2208–2212.PubMedGoogle Scholar
  45. 45.
    Pipas JM, Mitchell SE, Barth RJ, Jr., 2001, Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 50 (5): 1317–1322.PubMedGoogle Scholar
  46. 46.
    Blackstock AW, Tepper JE, Niedwiecki D, 2003, Cancer and leukemia group B (CALGB) 89805: phase II chemoradiation trial using gemcitabine in patients with locoregional adenocarcinoma of the pancreas. Int J Gastrointest Cancer 34:107–116.CrossRefPubMedGoogle Scholar
  47. 47.
    Mishra G, Butler J, Ho C, 2005, Phase II trial of induction gemcitabine/CPT-11 followed by a twice-weekly infusion of gemcitabine and concurrent external beam radiation for the treatment of locally advanced pancreatic cancer. Am J Clin Oncol 28:345–350.CrossRefPubMedGoogle Scholar
  48. 48.
    McGinn CJ, Zalupski MM, Shureiqi I,  2 001, Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 19:4202–428.PubMedGoogle Scholar
  49. 49.
    Crane CH, Janjan NA, Evans DB, 2001, Toxicity and efficacy of concurrent gemcitabine and radiotherapy for locally advanced pancreatic cancer. Int J Pancreatol 29 (1): 9–18.CrossRefPubMedGoogle Scholar
  50. 50.
    Wolff RA, Evans DB, Gravel DM, 2001, Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res 7 (8):2246–2253.PubMedGoogle Scholar
  51. 51.
    Ikeda M, Okada S, Tokuuye K, 2002, A phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with locally advanced pancreatic cancer. Br J Cancer 86 (10):1551–1554.CrossRefPubMedGoogle Scholar
  52. 52.
    Okusaka T, Ito Y, Ueno H, 2004, Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. Br J Cancer 91(4):673–677.PubMedGoogle Scholar
  53. 53.
    Epelbaum R, Rosenblatt E, Nasrallah S, 2002, Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J Surg Oncol 81 (3):138–143.CrossRefPubMedGoogle Scholar
  54. 54.
    Crane CH, Abbruzzese JL, Evans DB, 2002, Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer? Int J Radiat Oncol Biol Phys 52 (5): 1293–1302.CrossRefPubMedGoogle Scholar
  55. 55.
    Li CP, Chao Y, Chi KH, 2003, Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study. Int J Radiat Oncol Biol Phys 57 (1): 98–104.PubMedGoogle Scholar
  56. 56.
    Talamonti MS, Catalano PJ, Vaughn DJ, 2000, Eastern Cooperative Oncology Group Phase I trial of protracted venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer: a regimen with unexpected early toxicity. J Clin Oncol 18(19):3384–3389.PubMedGoogle Scholar
  57. 57.
    Willett CG, Czito BG, Bendell JC, 2005, Locally advanced pancreatic cancer. J Clin Oncol 23:4538–4544.CrossRefPubMedGoogle Scholar
  58. 58.
    Safran H, Dipetrillo T, Iannitti D, 2002, Gemcitabine, paclitaxel, and radiation for locally advanced pancreatic cancer: a Phase I trial. Int J Radiat Oncol Biol Phys 54 (1): 137–141.PubMedGoogle Scholar
  59. 59.
    Rich T, Harris J, Abrams R, 2004, Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. Am J Clin Oncol 27 (1):51–56.CrossRefPubMedGoogle Scholar
  60. 60.
    Ashamalla H, Zaki B, Mokhtar B, 2003, Hyperfractionated radiotherapy and paclitaxel for locally advanced/unresectable pancreatic cancer. I nt J Radiat Oncol Biol Phys 55 (3):679–687.CrossRefGoogle Scholar
  61. 61.
    Viret F, Ychou M, Goncalves A, 2003, Docetaxel and radiotherapy and pancreatic cancer. Pancreas 27(3):214–219.CrossRefPubMedGoogle Scholar
  62. 62.
    Crane CH, Ellis LM, Abbruzzese JL, 2006, Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol 24(7):1145–1115.CrossRefPubMedGoogle Scholar
  63. 63.
    Crane CH, Mason K, Janjan NA, 2003, Initial experience combining cyclooxygenase-2 inhibition with chemoradiation for locally advanced pancreatic cancer. American J Clin Oncol 26 (4):S81–S84.CrossRefGoogle Scholar
  64. 64.
    Ferrari V, Valcamonico F, Amoroso V, 2006, Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol 57(2):185–190.CrossRefPubMedGoogle Scholar
  65. 65.
    Rayes BF, El Zalupski MM, Shields 2005, A phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer. Invest New Drugs 23(6):583–590.CrossRefPubMedGoogle Scholar
  66. 66.
    Milella M, Gelibter A, Cosimo S, Di 2004, Pilot study of celecoxib and infusional 5-fluorou-racil as second-line treatment for advanced pancreatic carcinoma. Cancer 101(1):133–138.CrossRefPubMedGoogle Scholar
  67. 67.
    Xiong HQ, Abbruzzese JL. 2002, Epidermal growth factor receptor-targeted therapy for pan-creatic cancer. Semin Oncol 29(5 Suppl 14):31–37.CrossRefPubMedGoogle Scholar
  68. 68.
    Dong M, Nio Y, Guo KJ, 1998, Epidermal growth factor and its receptor as prognostic indicators in Chinese patients with pancreatic cancer. Anticancer Res 18(6B):4613–4619.PubMedGoogle Scholar
  69. 69.
    Xiong HQ, Rosenberg A, LoBuglio A, 2004, Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. J Clin Oncol 22(13):2610–2616.CrossRefPubMedGoogle Scholar
  70. 70.
    Safran H, Iannitti D, Ramanathan R. 2004, Herceptin and gemcitabine for metastic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 22:706–712.CrossRefPubMedGoogle Scholar
  71. 71. Moore MJ, Goldstein D, Hamm J et al. Erlotinib improves survival when added to gemcitabine in patients with advanced pancreatic cancer: A phase III trial of the national Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Paper presented at: 2005 Gastrointestinal Cancers Symposium: Current status and future directions for prevention and management; January 27-29; Holly wood, FL. Abstract 77. Available at:
  72. 72. Kortmanksy JS, O’Reilly EM, Minksy BD, 2005; A phase I trial of erlotinib, gemcitabine and radiation for patients with locally advanced, unresectable pancreatic cancer. J Clin Oncol 23 (Suppl):334s (abstract 4107).Google Scholar

Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • A. William Blackstock
    • 1
  • Stacy Wentworth
    • 1
  1. 1.Department of Radiation OncologyWake Forest UniversityWinston-SalemUSA

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