International Journal of Radiation Oncology * Biology * Physics
Volume 82, Issue 2 , Pages 508-518 , 1 February 2012

Treatment of Locally Advanced Pancreatic Cancer: The Role of Radiation Therapy

  • Kimberly Johung, M.D., Ph.D.

      Affiliations

    • Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut
  • ,
  • Muhammad Wasif Saif, M.D., M.B.B.S.

      Affiliations

    • Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, and Pancreas Center, Presbyterian Hospital, New York, New York
  • ,
  • Bryan W. Chang, M.D.

      Affiliations

    • Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut
    • Corresponding Author InformationReprint requests to: Bryan W. Chang, M.D., Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040. Tel: (203) 737-2758; Fax (203) 785-4622

Received 7 March 2011 ,Revised 24 June 2011 ,Accepted 2 August 2011.

References 

  1. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300
  2. Katz MH, Pisters PW, Evans DB, et al. Borderline resectable pancreatic cancer: The importance of this emerging stage of disease. J Am Coll Surg. 2008;206:833–846discussion 846–838
  3. National Comprehensive Cancer Network. Practice guidelines in oncology: Pancreatic adenocarcinoma. 2011. Available at: www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed 10/31/2011.
  4. Moertel CG, Frytak S, Hahn RG, et al. 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. 1981;48:1705–1710
  5. Cohen SJ, Dobelbower R, Lipsitz S, et al. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys. 2005;62:1345–1350
  6. Sultana A, Tudur Smith C, Cunningham D, et al. Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy. Br J Cancer. 2007;96:1183–1190
  7. 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;27:1806–1813
  8. Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group. J Natl Cancer Inst. 1988;80:751–755
  9. Klaassen DJ, MacIntyre JM, Catton GE, et al. Treatment of locally unresectable cancer of the stomach and pancreas: A randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil–-an Eastern Cooperative Oncology Group study. J Clin Oncol. 1985;3:373–378
  10. Hazel JJ, Thirlwell MP, Huggins M, et al. Multi-drug chemotherapy with and without radiation for carcinoma of the stomach and pancreas: a prospective randomized trial. J Can Assoc Radiol. 1981;32:164–165
  11. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol. 1997;15:2403–2413
  12. Chauffert B, Mornex F, Bonnetain F, et al. 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. Ann Oncol. 2008;19:1592–1599
  13. Loehrer PJ, Powell ME, Cardenes HR, et al. A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201. J Clin Oncol. 2008;26:a4506
  14. Ioka T, Nakamura S, Nishiyama K. A randomized phase II study of gemcitabine 1000mg/msq and concurrent radiotherapy comparing gemcitabine alone for unresectable locally advanced pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2010;78:S102
  15. Ishii H, Okada S, Tokuuye K, et al. Protracted 5-fluorouracil infusion with concurrent radiotherapy as a treatment for locally advanced pancreatic carcinoma. Cancer. 1997;79:1516–1520
  16. André T, Balosso J, Louvet C, et al. Combined radiotherapy and chemotherapy (cisplatin and 5-fluorouracil) as palliative treatment for localized unresectable or adjuvant treatment for resected pancreatic adenocarcinoma: Results of a feasibility study. Int J Radiat Oncol Biol Phys. 2000;46:903–911
  17. Kornek GV, Schratter-Sehn A, Marczell A, et al. Treatment of unresectable, locally advanced pancreatic adenocarcinoma with combined radiochemotherapy with 5-fluorouracil, leucovorin and cisplatin. Br J Cancer. 2000;82:98–103
  18. Boz G, De Paoli A, Innocente R, et al. Radiotherapy and continuous infusion 5-fluorouracil in patients with nonresectable pancreatic carcinoma. Int J Radiat Oncol Biol Phys. 2001;51:736–740
  19. Shinchi H, Takao S, Noma H, et al. Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2002;53:146–150
  20. Rubin J, Gallagher JG, Schroeder G, et al. Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma. Cancer. 1996;78:1888–1891
  21. Moore MJ, Goldstein D, Hamm J, 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. J Clin Oncol. 2007;25:1960–1966
  22. Heinemann V, Labianca R, Hinke A, et al. Increased survival using platinum analog combined with gemcitabine compared to single-agent gemcitabine in advanced pancreatic cancer: Pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study. Ann Oncol. 2007;18:1652–1659
  23. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–1825
  24. Huguet F, André T, Hammel P, et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol. 2007;25:326–331
  25. Krishnan S, Rana V, Janjan NA, et al. Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer. 2007;110:47–55
  26. Schneider BJ, Ben-Josef E, McGinn CJ, et al. Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2005;63:1325–1330
  27. Mishra G, Butler J, Ho C, et al. 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. 2005;28:345–350
  28. Ko AH, Quivey JM, Venook AP, et al. A phase II study of fixed-dose rate gemcitabine plus low-dose cisplatin followed by consolidative chemoradiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2007;68:809–816
  29. Moureau-Zabotto L, Phélip JM, Afchain P, et al. Concomitant administration of weekly oxaliplatin, fluorouracil continuous infusion, and radiotherapy after 2 months of gemcitabine and oxaliplatin induction in patients with locally advanced pancreatic cancer: A Groupe Coordinateur Multidisciplinaire en Oncologie phase II study. J Clin Oncol. 2008;26:1080–1085
  30. Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;58:1017–1021
  31. Koong AC, Christofferson E, Le QT, et al. 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. 2005;63:320–323
  32. Hoyer M, Roed H, Sengelov L, et al. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol. 2005;76:48–53
  33. Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2008;72:678–686
  34. Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer. 2009;115:665–672
  35. Mahadevan A, Jain S, Goldstein M, et al. Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2010;78:735–742
  36. Willett CG, Del Castillo CF, Shih HA, et al. Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer. Ann Surg. 2005;241:295–299
  37. Mohiuddin M, Regine WF, Stevens J, et al. Combined intraoperative radiation and perioperative chemotherapy for unresectable cancers of the pancreas. J Clin Oncol. 1995;13:2764–2768
  38. Crane CH, Antolak JA, Rosen II, et al. Phase I study of concomitant gemcitabine and IMRT for patients with unresectable adenocarcinoma of the pancreatic head. Int J Gastrointest Cancer. 2001;30:123–132
  39. Ben-Josef E, Shields AF, Vaishampayan U, et al. Intensity-modulated radiotherapy (IMRT) and concurrent capecitabine for pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;59:454–459
  40. Marshall DT, O’Brien P, Hoffman B, et al. IMRT to reduce toxicity in chemoradiation for locally advanced pancreatic cancer: Preliminary results of a phase II trial. Int J Radiat Oncol Biol Phys. 2009;75:S267–S268
  41. Ben-Josef E, Griffith K, Francis IR, et al. Phase I radiation dose-escalation trial of intensity-modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G) for unresectable pancreatic cancer. J Clin Oncol. 2009;27:a4602
  42. Rich T, Harris J, Abrams R, et al. Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. Am J Clin Oncol. 2004;27:51–56
  43. Rich TA, Myerson RA, Harris J, et al. A randomized phase II trial of weekly gemcitabine (G), paclitaxel (P), and external irradiation followed by the farnesyl transferase inhibitor R115777 (NSC#702818) for locally advanced pancreatic cancer (RTOG 0020). American Society of Clinical Oncology. 2006;Gastrointestinal Cancers Symposium, Abstract 121
  44. Li CP, Chao Y, Chi KH, et al. Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: Gemcitabine versus 5-fluorouracil, a randomized controlled study. Int J Radiat Oncol Biol Phys. 2003;57:98–104
  45. McGinn CJ, Zalupski MM, Shureiqi I, et al. Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2001;19:4202–4208
  46. Crane CH, Wolff RA, Abbruzzese JL, et al. Combining gemcitabine with radiation in pancreatic cancer: understanding important variables influencing the therapeutic index. Semin Oncol. 2001;28:25–33
  47. Small W, 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;26:942–947
  48. Crane CH, Abbruzzese JL, Evans DB, et al. 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. 2002;52:1293–1302
  49. Blackstock AW, Tepper JE, Niedwiecki D, et al. 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. 2003;34:107–116
  50. Mattiucci GC, Morganti AG, Valentini V, et al. External beam radiotherapy plus 24-hour continuous infusion of gemcitabine in unresectable pancreatic carcinoma: long-term results of a phase II study. Int J Radiat Oncol Biol Phys. 2010;76:831–838
  51. Murphy JD, Adusumilli S, Griffith KA, et al. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2007;68:801–808
  52. Sudo K, Yamaguchi T, Ishihara T, et al. Phase II study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2011;80(1):119–125
  53. Ajani JA, Faust J, Ikeda K, et al. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol. 2005;23:6957–6965
  54. Crane CH, Winter K, Regine WF, et al. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411. J Clin Oncol. 2009;27:4096–4102
  55. Small W, Mulcahy MF, Rademaker A, et al. Phase II trial of full-dose gemcitabine and bevacizumab in combination with attenuated three-dimensional conformal radiotherapy in patients with localized pancreatic cancer. Int J Radiat Oncol Biol Phys. 2011;80:476–482
  56. Brunner TB, Geiger M, Grabenbauer GG, et al. Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer. J Clin Oncol. 2008;26:2699–2706
  57. Gupta AK, Cerniglia GJ, Mick R, et al. HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res. 2005;65:8256–8265
  58. Duffy A, Kortmansky J, Schwartz GK, et al. A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma. Ann Oncol. 2008;19:86–91
  59. Crane CH, Varadhachary GR, Yordy JS, et al. Phase II Trial of Cetuximab, Gemcitabine, and Oxaliplatin Followed by Chemoradiation With Cetuximab for Locally Advanced (T4) Pancreatic Adenocarcinoma: Correlation of Smad4(Dpc4) Immunostaining With Pattern of Disease Progression. J Clin Oncol. 2011;29(22):3037–3043
  60. Chang BW, Saif MW. Combining epidermal growth factor receptor inhibitors and radiation therapy in pancreatic cancer: small step or giant leap?. JOP. 2009;10:231–236

 Note—An online CME test for this article can be taken at http://astro.org/MOC.

 Conflict of interest: none.

PII: S0360-3016(11)03115-4

doi: 10.1016/j.ijrobp.2011.08.008

International Journal of Radiation Oncology * Biology * Physics
Volume 82, Issue 2 , Pages 508-518 , 1 February 2012