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Phase I/II Trial of Induction Chemotherapy Followed by Concurrent Chemoradiotherapy and Surgery for Locoregionally Advanced Pancreatic Cancer

  • Hepatobiliary and Pancreatic Tumors
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Abstract

Background

We used a novel combination of induction chemotherapy with gemcitabine (GEM) and cisplatin (CDDP), followed by concurrent chemoradiotherapy (CCRT) with the same agents in patients with locoregionally advanced pancreatic cancer. Surgery or additional chemotherapy followed on the basis of response.

Methods

Patients with borderline resectable or locally advanced pancreatic cancer received induction weekly with GEM (1000 mg/m2) or CDDP (30 g/m2). Patients without progression of disease then underwent surgery or CCRT, including four cohorts of escalating GEM/CDDP doses combined with full-dose radiotherapy. After CCRT, patients deemed resectable underwent surgery; patients with disease that remained unresectable and that did not progress received additional GEM/CDDP for 2 months.

Results

A mean 76% of intended GEM dose and 75% of CDDP dose was delivered during induction (n = 26). There were three incidences of grade 4 toxicity (fever or neutropenia). After induction, five patients progressed and one patient underwent resection. Eighteen patients received CCRT, and three patients underwent resection. After CCRT, disease of 10 patients progressed, and in 5 patients, it remained unresectable without progression, and the patient received additional GEM/CDDP. Dose-limiting toxicity was at dose level IV (thrombocytopenia). Median overall and disease-specific survival was 13 months.

Conclusion

GEM/CDDP induction chemotherapy followed by CCRT is well tolerated and rendered the disease of 4 of 26 patients resectable in this study. The recommended phase II dose for GEM and CDDP in combination with full-dose radiotherapy (5040 cGy) is 300 mg/m2 and 10 mg/m2 weekly for 5 weeks. Median survival in this group was 13 months. This neoadjuvant combined modality approach is both feasible and active; further studies are warranted.

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References

  1. Jemal A, Thomas A, Murray T, et al. Cancer Statistics. CA Cancer J Clin 2002;52:23–47.

    Article  PubMed  Google Scholar 

  2. Heinemann V, Quietzsch D, Gieseler F, et al. Randomized Phase III trial of gemcitabine pulse cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006;24:3946–52.

    Article  PubMed  CAS  Google Scholar 

  3. Bramhall SR, Allum WH, Jones AG, et al. Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of disease, in the west midlands: an epidemiological study. Br J Sur 1985;82:111–5.

    Article  Google Scholar 

  4. Parker S, Tong T, Bolden S, et al. Cancer statistics. CA Cancer J Clin 1997;47:5–27.

    Article  PubMed  CAS  Google Scholar 

  5. Trede M, Schwal G, Saeger H, et al. Survival after pancreaticoduodenectomy. Ann Surg 1990;211:447–58.

    Article  PubMed  CAS  Google Scholar 

  6. National Cancer Institute: Surveillance, Epidemiology, and End Results (SEER) *Stat 6.1 Database: Incidence—SEER 9 Regs Public Use, Bethesda, MD, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch. Nov 2004 Sub (1973–2002)

  7. National Comprehensive Cancer Network (NCCN). Pancreatic adenocarcinoma. Practice Guidelines in Oncology. v.1.2008. Fort Washington, PA. http://www.nccn.org/professionals/physician_gls/PDF/pancreatic.pdf

  8. Massuco P, Capussotti L, Magnino A, et al. Pancreatic resections after chemotherapy for locally advanced ductal adenocarcinoma: analysis of perioperative outcome and survival. Ann Surg Oncol 2006;13:1201–8.

    Article  Google Scholar 

  9. Talamonti M, Small W, Mulcahy M, et al. A Multi-institutional Phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol 2005;13:150–8.

    Article  Google Scholar 

  10. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 1997;15:928–37.

    PubMed  CAS  Google Scholar 

  11. Hoffman J, Lipsitz S, Pisansky T, et al. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group study. J Clin Oncol 1998;16:317–23.

    PubMed  CAS  Google Scholar 

  12. 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. Cancer 1981;48:1075–10.

    Article  Google Scholar 

  13. 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;80:751–5.

    Article  Google Scholar 

  14. Ammori JB, Colletti LM, Zalupski MM, et al. Surgical resection following radiation therapy with concurrent gemcitabine in patients with previously unresectable adenocarcinoma of the pancreas. J Gastrointest Surg 2003;7:766–72.

    Article  PubMed  Google Scholar 

  15. Chao C, Hoffman J, Ross E, et al. Pancreatic carcinoma deemed unresectable at exploration may be resected for cure: an institutional experience. Am Surg 2000;66:378–87.

    PubMed  CAS  Google Scholar 

  16. White RR, Hurwitz HI, Morse MA, et al. Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas. Ann Sur Oncol 2001;8:758–65.

    Article  CAS  Google Scholar 

  17. Kim HJ, Czischke K, Brennan MF, et al. Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer?. J Gastrointest Surg 2002;6:763–9.

    Article  PubMed  Google Scholar 

  18. Berlin JD, Catalano P, Thomas JP, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002;20:3270–5.

    Article  PubMed  CAS  Google Scholar 

  19. Moore MJ, Hamm J, Dancey J, et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:3296–302.

    Article  PubMed  CAS  Google Scholar 

  20. Rocha L, Green M, Roche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004;22:3776–83.

    Article  CAS  Google Scholar 

  21. Bramhall SR, Schultz J, Nemunaitis J, et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002;87:161–7.

    Article  PubMed  CAS  Google Scholar 

  22. Bramhal SR, Rosemurgy A, Brown PD, Marimastat Pancreatic Cancer Study Group. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001; 19:3477–55

    Google Scholar 

  23. Van Cutsem E, van de Velde H, Karase P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004;22:1430–8.

    Article  PubMed  CAS  Google Scholar 

  24. O’Reilly EM, Abou-Alfa GK, Letorneau R, et al. A randomized phase III trial of DX-8951f (exatecan mesylate) and gemcitabine vs gemcitabine alone in advanced pancreatic cancer. Proc Am Soc Clin Oncol 2004; 23:abstr 4006

  25. Richards DA, Kindler HL, Oettle H, et al. A randomized phase III study comparing gemcitabine + pemetrexed versus gemcitabine in patients with locally advanced and metastatic pancreas cancer. Proc Am Soc Clin Oncol 2004; 23:abstr 4007

  26. Louvet C, Labianca R, Hammel P, et al. GemOx (gemcitabine + oxaliplatin) versus Gem (gemcitabine) in non-resectable pancreatic adenocarcinoma: final results of the GERCOR/GISCAD Intergroup phase III. Proc Am Soc Clin Oncol 2004; 23:abstr 4008

  27. Burris HA, Moore MJ, Anderson 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;15:2403–13.

    PubMed  CAS  Google Scholar 

  28. Bergman A, Ruiz van Haperen V, Veerman G, et al. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 1996;2:521–30.

    PubMed  CAS  Google Scholar 

  29. Lawrence T, Chang E, Hahn T, et al. Radiosensitization of pancreatic cancer cells by 2′,-difluoro-2′deoxycytidine. Int J Radiat Oncol Biol Phys 1996;34:867–72.

    PubMed  CAS  Google Scholar 

  30. Pauwels B, Korst A, Lardon F, et al. Combined modality therapy of gemcitabine and radiation. Oncologist 2005;10:34–51.

    Article  PubMed  CAS  Google Scholar 

  31. Wilkowski R, Thoma M, Schauer R, et al. Effect of chemoradiotherapy with gemcitabine and cisplatin on locoregional control in patients with primary inoperable pancreatic cancer. World J Surg 2004;28:1011–8.

    Article  PubMed  Google Scholar 

  32. Haller DG. Chemotherapy for advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2003;56:16–23.

    PubMed  CAS  Google Scholar 

  33. Heinemann V. Gemcitabine based combination treatment of pancreatic cancer. Semin Oncol 2002;29:25–35.

    Article  PubMed  CAS  Google Scholar 

  34. Reni M, Cordio S, Milandri C, et al. Gemcitabine versus cisplatin epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol 2005;6:369–76.

    Article  PubMed  CAS  Google Scholar 

  35. Gastrointestinal Tumor Study Group. A multi-institutional comparative trial of radiation therapy alone and in combination with 5-FU for locally unresectable pancreatic cancer. Am Surg 1979;189:205–11

    Google Scholar 

  36. Cora L, Coffman L, Sher R, et al. Preoperative chemoradiation for adenocarcinoma of the pancreas and duodenum. Int J Radiat Oncol Biol Phys 1994;30:161–7.

    Google Scholar 

  37. Bajetta E, Di Bartolomeo M, Stani SC, et al. Chemotherapy as preoperative treatment in locally advanced unresectable pancreatic cancer patients: results of a feasibility study. J Radiat Oncol Biol Phys 1999;45:285–9.

    Article  CAS  Google Scholar 

  38. Jessup JM, Steele, Mayer RJ, et al. Neoadjuvant therapy for unresectable pancreatic adenocarcinoma. Arch Surg 1993; 128:559–64

  39. Kamthan AG, Morris J, Dalton J, et al. Combined modality therapy for stage II and stage III pancreatic carcinoma. J Clin Oncol 1997;15:2920–7.

    PubMed  CAS  Google Scholar 

  40. Poplin E, Corbett T, Flaherty L, et al. Difluorodeoxycytidine (dFDC)-gemcitabine: a phase I study. Invest New Drugs 1992;10:165–70.

    Article  PubMed  CAS  Google Scholar 

  41. Rothenberg M, Moore M, Cripps M, et al. A phase II trial of gemcitabine in patients with 5-FU refractory pancreas cancer. Ann Oncol 1996;7:347–53.

    PubMed  CAS  Google Scholar 

  42. McGinn C, Smith D, Ozark’s C, et al. A phase I study of gemcitabine in combination with radiation therapy in patients with localized, unresectable pancreatic cancer. Proc ASCO 1998;17:264a.

    Google Scholar 

  43. McGinn C, Zalupski M, Shureiqi I, et al. A phase I trial of radiation dose escalation with concurrent weekly full dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2001;19:4202–8.

    PubMed  CAS  Google Scholar 

  44. Eisbruch A, Shewach D, Bradford C, et al. Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study. J Clin Oncol 2001;19:792–9.

    PubMed  CAS  Google Scholar 

  45. Evans D, Rich T, Byrd D. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 1992;127:1335–9.

    PubMed  CAS  Google Scholar 

  46. Pisters PW, Abbruzzese JL, Janjan NA, et al. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol 1998;16:3843–50.

    PubMed  CAS  Google Scholar 

  47. Abou-Alfa GK, Letourneau R, Harker G, et al. O’Reilly EM. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 2006; 4:4441–7

    Google Scholar 

  48. Yeung R, Weese J, Hoffman J, et al. Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A phase II study. Cancer 1993;72:2124–33.

    Article  PubMed  CAS  Google Scholar 

  49. Weese JL, Nussbaum ML, Paul AR. Increased resectability of locally advanced pancreatic and periampullary carcinoma with neoadjuvant chemoradiotherapy. Int J Pancreatol 1990;7:177–85.

    PubMed  CAS  Google Scholar 

  50. White R, Lee C, Anscher M, et al. Preoperative chemoradiation for patients with locally advanced adenocarcinoma of the pancreas. Ann Surg Oncol 1999;6:38–45.

    Article  PubMed  Google Scholar 

  51. Delpero JR, Turrini O. Locally advanced pancreatic adenocarcinoma. Chemoradiotherapy, reevaluation and secondary resection. Cancer Radiother 2006;10:462–70.

    PubMed  Google Scholar 

  52. Adhoute X, Smith D, Vendrely V, et al. Subsequent resection of locally advanced pancreatic carcinoma after chemoradiotherapy. Gastroenterol Clin Biol 2006;30:224–30.

    Article  PubMed  Google Scholar 

  53. Sa Cunha A, Rault A, Laurent C, et al. Surgical resection after radiochemotherapy in patients with unresectable adenocarcinoma of the pancreas. Am Coll Surg 2005;201:359–65.

    Article  Google Scholar 

  54. Wanebo HJ, Glicksman AS, Vezeridis MP, et al. Preoperative chemotherapy, radiotherapy, and surgical resection of locally advanced pancreatic cancer. Arch Surg 2000;135:81–7.

    Article  PubMed  CAS  Google Scholar 

  55. Rau HG, Wichmann MW, Wilkowski R, et al. Surgical therapy of locally advanced and primary inoperable pancreatic carcinoma after neoadjuvant preoperative radio chemotherapy. Chirurg 2002;73:132–7.

    Article  PubMed  CAS  Google Scholar 

  56. Aristu J, Canon R, Pardo F, et al. Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer. Am J Clin Oncol 2003;26:30–6.

    Article  PubMed  Google Scholar 

  57. Crane CH, Abbruzzeze JL, Evans DB, et al. Is the therapeutic index better with Gemcitabine-based chemoradiation than with 5-FU-based chemoradiation in LAPC? Int J Radiat Oncol Biol Phys 2002;52:1293–302.

    Article  PubMed  CAS  Google Scholar 

  58. White RR, Tyler DS. Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin N Am 2004;13:675–84.

    Article  PubMed  Google Scholar 

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Author notes

  1. Bernadine Donahue

    Present address: Department of Radiation Oncology, Maimonides Cancer Center, 6300 8th Avenue, Brooklyn, NY, 11220, USA

Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, NYU Cancer Institute, New York University School of Medicine, 160 East 34th Street, 9th Floor, New York, NY, 10016, USA

    Jennifer L. Marti MD, Spiros P. Hiotis MD, PhD & Elliot Newman MD

  2. Division of Medical Oncology, Department of Medicine, NYU Cancer Institute, New York University School of Medicine, New York, NY, USA

    Howard S. Hochster MD & Theresa Ryan MD

  3. Department of Radiation Oncology, NYU Cancer Institute, New York University School of Medicine, New York, NY, USA

    Bernadine Donahue

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  1. Jennifer L. Marti MD
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  2. Howard S. Hochster MD
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Correspondence to Elliot Newman MD.

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Marti, J.L., Hochster, H.S., Hiotis, S.P. et al. Phase I/II Trial of Induction Chemotherapy Followed by Concurrent Chemoradiotherapy and Surgery for Locoregionally Advanced Pancreatic Cancer. Ann Surg Oncol 15, 3521–3531 (2008). https://doi.org/10.1245/s10434-008-0152-3

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