Stereotactic body radiation therapy with concurrent full-dose gemcitabine for locally advanced pancreatic cancer: a pilot trial demonstrating safety

Marie K Gurka, Sean P Collins, Rebecca Slack, Gary Tse, Aline Charabaty, Lisa Ley, Liam Berzcel, Siyuan Lei, Simeng Suy, Nadim Haddad, Reena Jha, Colin D Johnson, Patrick Jackson, John L Marshall, Michael J Pishvaian, Marie K Gurka, Sean P Collins, Rebecca Slack, Gary Tse, Aline Charabaty, Lisa Ley, Liam Berzcel, Siyuan Lei, Simeng Suy, Nadim Haddad, Reena Jha, Colin D Johnson, Patrick Jackson, John L Marshall, Michael J Pishvaian

Abstract

Background: Concurrent chemoradiation is a standard option for locally advanced pancreatic cancer (LAPC). Concurrent conventional radiation with full-dose gemcitabine has significant toxicity. Stereotactic body radiation therapy (SBRT) may provide the opportunity to administer radiation in a shorter time frame with similar efficacy and reduced toxicity. This Pilot study assessed the safety of concurrent full-dose gemcitabine with SBRT for LAPC.

Methods: Patients received gemcitabine, 1000 mg/m2 for 6 cycles. During week 4 of cycle 1, patients received SBRT (25 Gy delivered in five consecutive daily fractions of 5 Gy prescribed to the 75-83% isodose line). Acute and late toxicities were assessed using NIH CTCAE v3. Tumor response was assessed by RECIST. Patients underwent an esophagogastroduodenoscopy at baseline, 2, and 6 months to assess the duodenal mucosa. Quality of life (QoL) data was collected before and after treatment using the QLQ-C30 and QLQ-PAN26 questionnaires.

Results: Between September 2009 and February 2011, 11 patients enrolled with one withdrawal during radiation therapy. Patients had grade 1 to 2 gastrointestinal toxicity from the start of SBRT to 2 weeks after treatment. There were no grade 3 or greater radiation-related toxicities or delays for cycle 2 of gemcitabine. On endoscopy, there were no grade 2 or higher mucosal toxicities. Two patients had a partial response. The median progression free and overall survival were 6.8 and 12.2 months, respectively. Global QoL did not change between baseline and immediately after radiation treatment.

Conclusions: SBRT with concurrent full dose gemcitabine is safe when administered to patients with LAPC. There is no delay in administration of radiation or chemotherapy, and radiation is completed with minimal toxicity.

Figures

Figure 1
Figure 1
Schema: treatment algorithm and tumor assessment.
Figure 2
Figure 2
CyberKnife treatment planning for patient #2: A. Axial computed tomography images demonstrating the gross tumor volume (yellow), adjacent vascular volume (red), duodenum (green), stomach (orange), spinal cord (pink) and kidneys (blue). B. Isodose lines shown as follows: Blue 81% (prescription), white 70% and purple 50%.
Figure 3
Figure 3
Kaplan-Meier plot of (A) progression-free survival (PFS) and (B) overall survival (OS).
Figure 4
Figure 4
Quality of life. Number of patients who had improvement, no change, or worsening between baseline and immediately after SBRT and from baseline to one month after SBRT. Numbes may not add to 10 due to incomplete questionnaires.

References

    1. Moertel CG, Frytak S, Hahn RG, O'Connell MJ, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Childs DS, Holbrook MA. 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. doi: 10.1002/1097-0142(19811015)48:8<1705::AID-CNCR2820480803>;2-4.
    1. Moertel CG, Childs DS Jr, Reitemeier RJ, Colby MY Jr, Holbrook MA. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet. 1969;2:865–867.
    1. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst. 1988;80:751–755.
    1. Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, Benson AB 3rd. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011;29:4105–4112. doi: 10.1200/JCO.2011.34.8904.
    1. Chauffert B, Mornex F, Bonnetain F, Rougier P, Mariette C, Bouche O, Bosset JF, Aparicio T, Mineur L, Azzedine A. 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. doi: 10.1093/annonc/mdn281.
    1. Klaassen DJ, MacIntyre JM, Catton GE, Engstrom PF, Moertel CG. 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.
    1. Yovino S, Poppe M, Jabbour S, David V, Garofalo M, Pandya N, Alexander R, Hanna N, Regine WF. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys. 2011;79:158–162. doi: 10.1016/j.ijrobp.2009.10.043.
    1. Milano MT, Chmura SJ, Garofalo MC, Rash C, Roeske JC, Connell PP, Kwon OH, Jani AB, Heimann R. Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies: toxicity and clinical outcome. Int J Radiat Oncol Biol Phys. 2004;59:445–453. doi: 10.1016/j.ijrobp.2003.11.003.
    1. Feng M, Balter JM, Normolle D, Adusumilli S, Cao Y, Chenevert TL, Ben-Josef E. Characterization of pancreatic tumor motion using cine MRI: surrogates for tumor position should be used with caution. Int J Radiat Oncol Biol Phys. 2009;74:884–891. doi: 10.1016/j.ijrobp.2009.02.003.
    1. Horst E, Micke O, Moustakis C, Schuck A, Schafer U, Willich NA. Conformal therapy for pancreatic cancer: variation of organ position due to gastrointestinal distention–implications for treatment planning. Radiology. 2002;222:681–686. doi: 10.1148/radiol.2223010639.
    1. Murphy JD, Chang DT, Abelson J, Daly ME, Yeung HN, Nelson LM, Koong AC. Cost-effectiveness of modern radiotherapy techniques in locally advanced pancreatic cancer. Cancer. 2012;118:1119–1129. doi: 10.1002/cncr.26365.
    1. Koong AC, Christofferson E, Le QT, Goodman KA, Ho A, Kuo T, Ford JM, Fisher GA, Greco R, Norton J, Yang GP. 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. doi: 10.1016/j.ijrobp.2005.07.002.
    1. Schellenberg D, Goodman KA, Lee F, Chang S, Kuo T, Ford JM, Fisher GA, Quon A, Desser TS, Norton J. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2008;72:678–686. doi: 10.1016/j.ijrobp.2008.01.051.
    1. Murphy JD, Christman-Skieller C, Kim J, Dieterich S, Chang DT, Koong AC. A dosimetric model of duodenal toxicity after stereotactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys. 2010;78:1420–1426. doi: 10.1016/j.ijrobp.2009.09.075.
    1. Murphy JD, Adusumilli S, Griffith KA, Ray ME, Zalupski MM, Lawrence TS, Ben-Josef E. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2007;68:801–808. doi: 10.1016/j.ijrobp.2006.12.053.
    1. Rich T, Harris J, Abrams R, Erickson B, Doherty M, Paradelo J, Small W Jr, Safran H, Wanebo HJ. 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. doi: 10.1097/.
    1. Mahadevan A, Jain S, Goldstein M, Miksad R, Pleskow D, Sawhney M, Brennan D, Callery M, Vollmer C. Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2010;78:735–742. doi: 10.1016/j.ijrobp.2009.08.046.
    1. Mahadevan A, Miksad R, Goldstein M, Sullivan R, Bullock A, Buchbinder E, Pleskow D, Sawhney M, Kent T, Vollmer C, Callery M. Induction gemcitabine and stereotactic body radiotherapy for locally advanced nonmetastatic pancreas cancer. Int J Radiat Oncol Biol Phys. 2011;81:e615–622. doi: 10.1016/j.ijrobp.2011.04.045.
    1. Didolkar MS, Coleman CW, Brenner MJ, Chu KU, Olexa N, Stanwyck E, Yu A, Neerchal N, Rabinowitz S. Image-guided stereotactic radiosurgery for locally advanced pancreatic adenocarcinoma results of first 85 patients. J Gastrointest Surg. 2010;14:1547–1559. doi: 10.1007/s11605-010-1323-7.
    1. Polistina F, Costantin G, Casamassima F, Francescon P, Guglielmi R, Panizzoni G, Febbraro A, Ambrosino G. Unresectable locally advanced pancreatic cancer: a multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration. Ann Surg Oncol. 2010;17:2092–2101. doi: 10.1245/s10434-010-1019-y.
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
    1. Kilby W, Dooley JR, Kuduvalli G, Sayeh S, Maurer CR Jr. The CyberKnife robotic radiosurgery system in 2010. Technol Cancer Res Treat. 2010;9:433–452.
    1. Pishvaian AC, Collins B, Gagnon G, Ahlawat S, Haddad NG. EUS-guided fiducial placement for CyberKnife radiotherapy of mediastinal and abdominal malignancies. Gastrointest Endosc. 2006;64:412–417. doi: 10.1016/j.gie.2006.01.048.
    1. Spalding AC, Jee KW, Vineberg K, Jablonowski M, Fraass BA, Pan CC, Lawrence TS, Haken RK, Ben-Josef E. Potential for dose-escalation and reduction of risk in pancreatic cancer using IMRT optimization with lexicographic ordering and gEUD-based cost functions. Med Phys. 2007;34:521–529. doi: 10.1118/1.2426403.
    1. Sun W, Leong CN, Zhang Z, Lu JJ. Proposing the lymphatic target volume for elective radiation therapy for pancreatic cancer: a pooled analysis of clinical evidence. Radiat Oncol. 2010;5:28. doi: 10.1186/1748-717X-5-28.
    1. Gaedcke J, Gunawan B, Grade M, Szoke R, Liersch T, Becker H, Ghadimi BM. The mesopancreas is the primary site for R1 resection in pancreatic head cancer: relevance for clinical trials. Langenbecks Arch Surg. 2010;395:451–458. doi: 10.1007/s00423-009-0494-8.
    1. Arvold ND, Niemierko A, Mamon HJ, Fernandez-del Castillo C, Hong TS. Pancreatic cancer tumor size on CT scan versus pathologic specimen: implications for radiation treatment planning. Int J Radiat Oncol Biol Phys. 2011;80:1383–1390. doi: 10.1016/j.ijrobp.2010.04.058.
    1. Collins BT, Erickson K, Reichner CA, Collins SP, Gagnon GJ, Dieterich S, McRae DA, Zhang Y, Yousefi S, Levy E. Radical stereotactic radiosurgery with real-time tumor motion tracking in the treatment of small peripheral lung tumors. Radiat Oncol. 2007;2:39. doi: 10.1186/1748-717X-2-39.
    1. Wachter S, Gerstner N, Goldner G, Potzi R, Wambersie A, Potter R. Endoscopic scoring of late rectal mucosal damage after conformal radiotherapy for prostatic carcinoma. Radiother Oncol. 2000;54:11–19. doi: 10.1016/S0167-8140(99)00173-5.
    1. Fitzsimmons D, Johnson CD, George S, Payne S, Sandberg AA, Bassi C, Beger HG, Birk D, Buchler MW, Dervenis C. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-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.
    1. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481. doi: 10.1080/01621459.1958.10501452.
    1. Nakamura JL, Verhey LJ, Smith V, Petti PL, Lamborn KR, Larson DA, Wara WM, McDermott MW, Sneed PK. Dose conformity of gamma knife radiosurgery and risk factors for complications. Int J Radiat Oncol Biol Phys. 2001;51:1313–1319. doi: 10.1016/S0360-3016(01)01757-6.
    1. Ceha HM, Van Tienhoven G, Gouma DJ, Veenhof CH, Schneider CJ, Rauws EA, Phoa SS, Gonzalez Gonzalez D. Feasibility and efficacy of high dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma. Cancer. 2000;89:2222–2229. doi: 10.1002/1097-0142(20001201)89:11<2222::AID-CNCR10>;2-V.
    1. Fowler JF. Biological factors influencing optimum fractionation in radiation therapy. Acta Oncol. 2001;40:712–717. doi: 10.1080/02841860152619124.
    1. Furukawa H, Iwata R, Moriyama N. Growth rate of pancreatic adenocarcinoma: initial clinical experience. Pancreas. 2001;22:366–369. doi: 10.1097/00006676-200105000-00005.
    1. Roldan GE, Gunderson LL, Nagorney DM, Martin JK, Ilstrup DM, Holbrook MA, Kvols LK, McIlrath DC. External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer. 1988;61:1110–1116. doi: 10.1002/1097-0142(19880315)61:6<1110::AID-CNCR2820610610>;2-6.
    1. Gunderson LL, Martin JK, Kvols LK, Nagorney DM, Fieck JM, Wieand HS, Martinez A, O'Connell MJ, Earle JD, McIlrath DC. Intraoperative and external beam irradiation +/− 5-FU for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 1987;13:319–329. doi: 10.1016/0360-3016(87)90005-8.
    1. Mohiuddin M, Regine WF, Stevens J, Rosato F, Barbot D, Biermann W, Cantor R. Combined intraoperative radiation and perioperative chemotherapy for unresectable cancers of the pancreas. J Clin Oncol. 1995;13:2764–2768.
    1. Garton GR, Gunderson LL, Nagorney DM, Donohue JH, Martin JK, McIlrath DC, Cha SS. High-dose preoperative external beam and intraoperative irradiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 1993;27:1153–1157. doi: 10.1016/0360-3016(93)90537-6.
    1. Shipley WU, Nardi GL, Cohen AM, Ling CC. Iodine-125 implant and external beam irradiation in patients with localized pancreatic carcinoma: a comparative study to surgical resection. Cancer. 1980;45:709–714. doi: 10.1002/1097-0142(19800215)45:4<709::AID-CNCR2820450416>;2-5.
    1. Shipley WU, Tepper JE, Warshaw AL, Orlow EL. Intraoperative radiation therapy for patients with pancreatic carcinoma. World J Surg. 1984;8:929–934. doi: 10.1007/BF01656034.
    1. Mohiuddin M, Cantor RJ, Biermann W, Weiss SM, Barbot D, Rosato FE. Combined modality treatment of localized unresectable adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys. 1988;14:79–84. doi: 10.1016/0360-3016(88)90054-5.
    1. Lawrence TS, Chang EY, Hahn TM, Hertel LW, Shewach DS. Radiosensitization of pancreatic cancer cells by 2',2'-difluoro-2'-deoxycytidine. Int J Radiat Oncol Biol Phys. 1996;34:867–872. doi: 10.1016/0360-3016(95)02134-5.
    1. McGinn CJ, Zalupski MM, Shureiqi I, Robertson JM, Eckhauser FE, Smith DC, Brown D, Hejna G, Strawderman M, Normolle D, Lawrence TS. 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.
    1. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–1825. doi: 10.1056/NEJMoa1011923.

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