Clinical phase I/II trial to investigate neoadjuvant intensity-modulated short term radiation therapy (5 × 5 Gy) and intraoperative radiation therapy (15 Gy) in patients with primarily resectable pancreatic cancer - NEOPANC

Falk Roeder, Carmen Timke, Ladan Saleh-Ebrahimi, Lutz Schneider, Thilo Hackert, Werner Hartwig, Annette Kopp-Schneider, Frank W Hensley, Markus W Buechler, Juergen Debus, Peter E Huber, Jens Werner, Falk Roeder, Carmen Timke, Ladan Saleh-Ebrahimi, Lutz Schneider, Thilo Hackert, Werner Hartwig, Annette Kopp-Schneider, Frank W Hensley, Markus W Buechler, Juergen Debus, Peter E Huber, Jens Werner

Abstract

Background: The current standard treatment, at least in Europe, for patients with primarily resectable tumors, consists of surgery followed by adjuvant chemotherapy. But even in this prognostic favourable group, long term survival is disappointing because of high local and distant failure rates. Postoperative chemoradiation has shown improved local control and overalls survival compared to surgery alone but the value of additional radiation has been questioned in case of adjuvant chemotherapy. However, there remains a strong rationale for the addition of radiation therapy considering the high rates of microscopically incomplete resections after surgery. As postoperative administration of radiation therapy has some general disadvantages, neoadjuvant and intraoperative approaches theoretically offer benefits in terms of dose escalation, reduction of toxicity and patients comfort especially if hypofractionated regimens with highly conformal techniques like intensity-modulated radiation therapy are considered.

Methods/design: The NEOPANC trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant short course intensity-modulated radiation therapy (5 × 5 Gy) in combination with surgery and intraoperative radiation therapy (15 Gy), followed by adjuvant chemotherapy according to the german treatment guidelines, in patients with primarily resectable pancreatic cancer. The aim of accrual is 46 patients.

Discussion: The primary objectives of the NEOPANC trial are to evaluate the general feasibility of this approach and the local recurrence rate after one year. Secondary endpoints are progression-free survival, overall survival, acute and late toxicity, postoperative morbidity and mortality and quality of life.

Trial registration: NCT01372735.

Figures

Figure 1
Figure 1
Flow Chart of the NEOPANC Study. IMRT: intensity-modulated radiation therapy, IORT: Intraoperative Radiation Therapy, Gy: Gray, Fx: Fractions.

References

    1. Parkin DM, Bray FI, Devessa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001;37:4–66.
    1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics, 2005. CA Cancer J Clin. 2005;55:10–30. doi: 10.3322/canjclin.55.1.10.
    1. Sener SF, Fremgen A, Imperato JP, Sylvester J, Chmiel JS. Pancreatic cancer: a report of treatment and survival trends for 100313 patients diagnosed from 1985-1995 using the national cancer database. J Am Coll Surg. 1999;189:1–7. doi: 10.1016/S1072-7515(99)00075-7.
    1. Welsch T, Büchler MW, Schmidt J. Surgery for pancreatic cancer. Z Gastroenterol. 2008;46:1393–1403. doi: 10.1055/s-2008-1027790.
    1. Willett CG, Lewandrowski K, Warshaw AL, Efird J, Compton CC. Resection margins in carcinoma of the head of the pancreas. Ann Surg. 1993;217:144–148. doi: 10.1097/00000658-199302000-00008.
    1. Sperti C, Pasquali C, Piccoli A, Pedrazzoli S. Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg. 1997;21:195–200. doi: 10.1007/s002689900215.
    1. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120:899–903. doi: 10.1001/archsurg.1985.01390320023003.
    1. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297:267–277. doi: 10.1001/jama.297.3.267.
    1. Neoptolemos JP, Stocken DD, Tudur Smith C, Bassi C, Ghaneh P, Owen E, Moore M, Padbury R, Doi R, Smith D, Buechler MW. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and 3(v1) trials. Br J Cancer. 2009;100:246–250. doi: 10.1038/sj.bjc.6604838.
    1. Timke C, Debus J. Die Rolle der Strahlentherapie bei der Behandlung des Pankreaskarzinoms aus der Sicht des Radioonkologen. Radiologe. 2009;49:149–153. doi: 10.1007/s00117-008-1758-y.
    1. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Marus P, Tschemlitsch J, Hager E, Hess CF, Karstens JH, Liersch T, SChmidberger H, Raab R. for the German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–1740. doi: 10.1056/NEJMoa040694.
    1. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steuo WH, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van Krieken JH, Leer JW, van der Velde CJ. for the Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638–646. doi: 10.1056/NEJMoa010580.
    1. White RR, Tyler DS. Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin North Am. 2004;13:675–684. doi: 10.1016/j.soc.2004.06.001.
    1. Valentini V, Beets-Tan, Borras JM, Krivokapic Z, Leer JW, Pahlman L, Rödel C, Schmoll HJ, Scott N, Van de Velde C, Verfaillie C. Evidence and Research in Rectal Cancer. Radiotherapy and Oncology. 2008;87:449–474. doi: 10.1016/j.radonc.2008.05.022.
    1. Spitz FR, Abbruzzese JL, Lee JE, Pisters PWT, Fenoglio CJ, Cleary KR, Janjan NA, Goswitz MS, Rich TA, Evans DE. Preoperative and postoperative chemoradiation strategies in patients treated with pancreatico-duodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15:928–937.
    1. Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, Sauter PK, Coleman J, Hruban RH, Lillemoe KD. Resected adenocarcinoma of the pancreas - 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000;4:567–579. doi: 10.1016/S1091-255X(00)80105-5.
    1. Krempien R, Muenter MW, Harms W, Debus J. Neoadjuvant chemoradiation in patients with pancreatic adenocarcinoma. HPB Oxford. 2006;8:22–28.
    1. Stessin AM, Meyer JE, Sherr DL. Neoadjuvant radiation is associated with improved survival in patients with resectable pancreatic cancer: An analysis of data from the surveillance, epidemiology, and end results (SEER) registry. Int J Radiat Oncol Biol Phys. 2008;72:1128–1133. doi: 10.1016/j.ijrobp.2008.02.065.
    1. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish rectal cancer trial. N Engl J Med. 1997;336:980–987.
    1. Bujko K, Nowacki MP, Nasierowska-Guttmeijer A, Michalski W, Bebenek M, Kryj M. for the Polish Colorectal Study Group. Long-term results of a randomized trial comparing preoperative short-couse radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93:1215–1223. doi: 10.1002/bjs.5506.
    1. Frykholm GJ, Isacsson U, Nygard K, Montelius A, Jung B, Pahlman L, Glimelius B. Preoperative radiotherapy in rectal carcinoma - aspects of acute adverse effects and radiation technique. Int J Radiat Biol Oncol Phys. 1996;35:1039–1048. doi: 10.1016/0360-3016(96)00229-5.
    1. Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H, Schirmacher P, Büchler MW. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008;15:1651–1660. doi: 10.1245/s10434-008-9839-8.
    1. Verbeke CS. Resections margins and R1 rates in pancreatic cancer - are we there yet? Histopathology. 2008;52:787–796. doi: 10.1111/j.1365-2559.2007.02935.x.
    1. Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer. Br J Surg. 2006;93:1232–1237. doi: 10.1002/bjs.5397.
    1. Valentini V, Calvo F, Reni M, Krempien R, SEdlmayer F, Buchler MW, Buchler MW, Di Carlo V, Doglietto GB, Fastner G, Garcia-Sabrido JL, Mattiucci G, Morganti AG, Passoni P, Roeder F, d' Agostino GR. Intra-operative radiotherapy (IORT) in pancreatic cancer: Joint analysis of the ISIORT-Europe experience. Radiother Oncol. 2009;91:54–59. doi: 10.1016/j.radonc.2008.07.020.
    1. Halperin EC, Perez CA, Brady LW, editor. Perez and Brady's Principles and Practice of Radiation Oncology. 5. Lippincott Williams & Wilkins; 2008.
    1. Krempien R, Roeder F, Oertel S, Weitz J, Hensley FW, Timke C, Funk A, Lindel K, Harms W, Buchler MW, Debus J, Treiber M. Intraoperative electron-beam therapy for primary and recurrent retroperitoneal soft-tissue sarcoma. Int J Radiat Biol Oncol Phys. 2006;65:773–779. doi: 10.1016/j.ijrobp.2006.01.028.
    1. Kinsella TJ, Sindelar WF, Lack E, Glatstein E, Rosneberg SA. Preliminary results of a randomized study of adjuvant radiation therapy in respectable adult retroperitoneal soft tissue sarcoma. J Clin Oncol. 1988;6:18–25.
    1. Reni M, Pannucci MG, Ferreri AJ, Balzano G, Passoni P, Cattaneo GM, Cordio S, Scaglietti U, Zerbi A, Ceresoli GL, Fiorino C, Calandrino R, Staudacher C, Villa E, Di Carlo V. Effect on local control and survival of electron beam intraoperative irradiation for respectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2001;50:651–658. doi: 10.1016/S0360-3016(01)01470-5.
    1. Adler G, Seufferlein T, Bischoff SC, Brambs HJ, Feuerbach S, Grabenbauer C, Hahn S, Heinemann V, Hohenberger W, Langrehr JM, Lutz MP, Micke O, Neuhaus H, Neuhaus P, Oettle H, Schlag PM, Schmid R, Schmiegel W, Schlottmann K, Werner J, Wiedenmann B, Kopp I. S3-Leitlinie "exokrines Pankreaskarzinom" 2007. Z Gastroenterol. 2007;45:487–523. doi: 10.1055/s-2007-963224.
    1. Aaaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC. et al.The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–376. doi: 10.1093/jnci/85.5.365.
    1. Hjermstad MJ, Fossa SD, Bjordal K, Kaasa S. Test/Retest study of the European organization for research and treatment of cancer core quality-of-life questionnaire. J Clin Oncol. 1995;13:1249–1254.
    1. Fitzsimmons D, Johnson CD, Geoge S, Payne S, Sandberg AA, Bassi C, Beger HG, Birk D, Buchler MW, Dervenis C, Fernandez Cruz L, Friess H, Grahm AL, Jeekel J, Laugier R, Meyer D, Singer MW, Tihanyi T. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the OLQ-C30 in patients with pancreatic cancer. EORTC study group on quality of life. Eur J Cancer. 1999;35:939–941. doi: 10.1016/S0959-8049(99)00047-7.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera