Radiation Therapy in Operable and Locally Advanced Pancreatic Cancer

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It is well established that the development of distant metastatic disease represents the dominant pattern of tumor recurrence/progression among patients with operable and locally advanced pancreatic cancer. However, the contribution of localized or locoregional tumor burden to pancreatic cancer–associated morbidity and mortality may be underappreciated, and therefore balancing competing considerations of systemic versus local disease control becomes important in therapeutic decision-making. The role of local therapies, particularly radiation therapy, has remained somewhat controversial in this disease context. Several phase II and III trials have sought to address the relative importance and role of radiation in both the localized and locally advanced settings, including the sequencing of this modality relative to systemic therapy and its optimal means of administration. However, differences and limitations in study design have produced mixed results, particularly in terms of the contribution of radiation to overall survival benefit. An emerging paradigm that makes conceptual sense and remains the subject of active investigation is to start with a defined period of systemic treatment, thus limiting radiation to the subset of patients who do not manifest with metastatic disease during initial therapy and are therefore most likely to benefit from local control.

Correspondence: Andrew H. Ko, MD, Division of Hematology/Oncology, UCSF Comprehensive Cancer Center, 1600 Divisadero Street, Box 1705, San Francisco, CA 94115. E-mail: andrewko@medicine.ucsf.edu
  • 1.

    HattangadiJAHongTSYeapBY. Results and patterns of failure in patients treated with adjuvant combined chemoradiation therapy for resected pancreatic adenocarcinoma. Cancer2009;115:3640650.

    • Search Google Scholar
    • Export Citation
  • 2.

    NeoptolemosJPStockenDDFriessH. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med2004;350:12001210.

    • Search Google Scholar
    • Export Citation
  • 3.

    RegineWFWinterKAAbramsRA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA2008;299:10191026.

    • Search Google Scholar
    • Export Citation
  • 4.

    SpertiCPasqualiCPiccoliA. Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg1997;21:195200.

  • 5.

    Van den BroeckASergeantGEctorsN. Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma. Eur J Surg Oncol2009;35:600604.

    • Search Google Scholar
    • Export Citation
  • 6.

    Iacobuzio-DonahueCAFuBYachidaS. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol2009;27:18061813.

    • Search Google Scholar
    • Export Citation
  • 7.

    JemalASiegelRWardE. Cancer statistics, 2009. CA Cancer J Clin2009;59:225249.

  • 8.

    BirkmeyerJDSiewersAEFinlaysonEV. Hospital volume and surgical mortality in the United States. N Engl J Med2002;346:11281137.

  • 9.

    EppsteinerRWCsikeszNGMcPheeJT. Surgeon volume impacts hospital mortality for pancreatic resection. Ann Surg2009;249:635640.

  • 10.

    HermanJMSwartzMJHsuCC. 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 Oncol2008;26:35033510.

    • Search Google Scholar
    • Export Citation
  • 11.

    KalserMHEllenbergSS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg1985;120:899903.

    • Search Google Scholar
    • Export Citation
  • 12.

    KlinkenbijlJHJeekelJSahmoudT. 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 Surg1999;230:776782.

    • Search Google Scholar
    • Export Citation
  • 13.

    SmeenkHGvan EijckCHHopWC. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891. Ann Surg2007;246:734740.

    • Search Google Scholar
    • Export Citation
  • 14.

    WolffRAVaradhacharyGREvansDB. Adjuvant therapy for adenocarcinoma of the pancreas: analysis of reported trials and recommendations for future progress. Ann Surg Oncol2008;15:27732786.

    • Search Google Scholar
    • Export Citation
  • 15.

    OettleHPostSNeuhausP. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA2007;297:267277.

    • Search Google Scholar
    • Export Citation
  • 16.

    NeuhausPRiessHPostS. CONKO-001: final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer [abstract]. J Clin Oncol2008;26(Suppl 1):Abstract LBA 4504.

    • Search Google Scholar
    • Export Citation
  • 17.

    NeoptolemosJBüchlerMStockenDD. ESPAC-3(v2): a multicenter, international, open-label, randomized, controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma [abstract]. J Clin Oncol2009;27(Suppl 1):Abstract LBA 4505.

    • Search Google Scholar
    • Export Citation
  • 18.

    LaethemJLVMornexFAzriaD. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiation after curative resection for pancreatic cancer: updated results of a randomized EORTC/FFCD/GERCOR phase II study (40013-22012/9203) [abstract]. J Clin Oncol2009;27(Suppl1):Abstract 4527.

    • Search Google Scholar
    • Export Citation
  • 19.

    EvansDBVaradhacharyGRCraneCH. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol2008;26:34963502.

    • Search Google Scholar
    • Export Citation
  • 20.

    VaradhacharyGRWolffRACraneCH. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol2008;26:34873495.

    • Search Google Scholar
    • Export Citation
  • 21.

    KatzMHPistersPWEvansDB. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg2008;206:833846.

    • Search Google Scholar
    • Export Citation
  • 22.

    JaffeeEMHrubanRHBiedrzyckiB. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol2001;19:145156.

    • Search Google Scholar
    • Export Citation
  • 23.

    LaheruDYeoCBiedrzyckiB. A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreas [abstract]. J Clin Oncol2007;25(Suppl 1):Abstract 3010

    • Search Google Scholar
    • Export Citation
  • 24.

    PicozziVJAbramsRATraversoLW. ACOSOG Z05031: report on a multicenter, phase II trial for adjuvant therapy of resected pancreatic cancer using cisplatin, 5-FU, and alpha-interferon [asbtract]. J Clin Oncol2008;26(Suppl 1): Abtract A-4505.

    • Search Google Scholar
    • Export Citation
  • 25.

    FarrellJJElsalehHGarciaM. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology2009;136:187195.

    • Search Google Scholar
    • Export Citation
  • 26.

    KindlerHFribergGStadlerW. Bevacizumab (B) plus gemcitabine (G) in patient (pts) with advanced pancreatic cancer (PC): updated results of a multi-center phase II trial [abstract]. J Clin Oncol2004;22(Suppl 1):Abstract 4009.

    • Search Google Scholar
    • Export Citation
  • 27.

    LoehrerPPowellMCardenesH. A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201 [abstract]. J Clin Oncol2008;26(Suppl 1):Abstract 4506.

    • Search Google Scholar
    • Export Citation
  • 28.

    PoplinELevyDBerlinJ. Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion[FDR]) versus gemcitabine + oxaliplatin(GEMOX) in patients with advanced pancreatic cancer (E6201) [abstract]. J Clin Oncol2006;24(Suppl 1):Abstract LBA4004.

    • Search Google Scholar
    • Export Citation
  • 29.

    RichTHarrisJAbramsR. Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. Am J Clin Oncol2004;27:5156.

    • Search Google Scholar
    • Export Citation
  • 30.

    RichTMyersonRHarrisJ. 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) [abstract]. Presented at the 2006 Gastrointestinal Cancers Symposium; January 26–28 2006; San Francisco California. Abstract A-121.

    • Search Google Scholar
    • Export Citation
  • 31.

    CraneCHWinterKRegineWF. 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 Oncol2009;27:40964102.

    • Search Google Scholar
    • Export Citation
  • 32.

    ChauffertBMornexFBonnetainF. 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 Oncol2008;19:15921599.

    • Search Google Scholar
    • Export Citation
  • 33.

    CraneCVaradhacharyGJavleM. Multi-institutional phase II trial of induction cetuximab gemcitabine and oxaliplatin followed by radiotherapy with concurrent capecitabine and cetuximab for locally advanced pancreatic adenocarcinoma (LAPC) [abstract]. Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24 2010; Orlando Florida. Abstract 132.

    • Search Google Scholar
    • Export Citation
  • 34.

    HuguetFAndreTHammelP. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol2007;25:326331.

    • Search Google Scholar
    • Export Citation
  • 35.

    CraneCHEllisLMAbbruzzeseJL. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol2006;24:11451151.

    • Search Google Scholar
    • Export Citation
  • 36.

    KoAHQuiveyJMVenookAP. 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 Phys2007;68:809816.

    • Search Google Scholar
    • Export Citation
  • 37.

    Ben-JosefEGriffithKFrancisIR. Phase I radiation dose-escalation trial of intensity-modulated radiotherapy (IMRT) with concurrent fixed dose-rate gemcitabine (FDR-G) for unresectable pancreatic cancer [abstract]. J Clin Oncol2009;27(Suppl 1):Abstract 4602.

    • Search Google Scholar
    • Export Citation
  • 38.

    TammEPLoyerEMFariaS. Staging of pancreatic cancer with multidetector CT in the setting of preoperative chemoradiation therapy. Abdom Imaging2006;31:568574.

    • Search Google Scholar
    • Export Citation
  • 39.

    KoongACLeQTHoA. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys2004;58:10171021.

    • Search Google Scholar
    • Export Citation
  • 40.

    KoongACChristoffersonELeQT. 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 Phys2005;63:320323.

    • Search Google Scholar
    • Export Citation
  • 41.

    SchellenbergDGoodmanKLeeF. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys2008;72:678686.

    • Search Google Scholar
    • Export Citation
  • 42.

    ChangDTSchellenbergDShenJ. Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer2009;115:665672.

  • 43.

    HoyerMRoedHSengelovL. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol2005;76:4853.

    • Search Google Scholar
    • Export Citation
  • 44.

    MoertelCGChildsDSJrReitemeierRJ. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet1969;2:865867.

    • Search Google Scholar
    • Export Citation
  • 45.

    A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal Tumor Study Group. Ann Surg1979;189:205208.

    • Search Google Scholar
    • Export Citation
  • 46.

    MoertelCGFrytakSHahnRG. 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. Cancer1981;48:17051710.

    • Search Google Scholar
    • Export Citation
  • 47.

    KlaassenDJMacIntyreJMCattonGE. 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 Oncol1985;3:373378.

    • Search Google Scholar
    • Export Citation
  • 48.

    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 Inst1988;80:751755.

    • Search Google Scholar
    • Export Citation
  • 49.

    KindlerHLNiedzwieckiDHollisDR. A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): a preliminary analysis of Cancer and Leukemia Group B (CALGB) 80303 [abstract]. J Clin Oncol2007;26(Suppl 1):Abstract A108.

    • Search Google Scholar
    • Export Citation
  • 50.

    DuffyAKortmanskyJSchwartzGK. A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma. Ann Oncol2008;19:8691.

    • Search Google Scholar
    • Export Citation
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