Skip to main content

Advertisement

Log in

Treatment of primary or recurrent non-resectable pancreatic cancer with proton beam irradiation combined with gemcitabine-based chemotherapy

  • Original Article
  • Published:
Strahlentherapie und Onkologie Aims and scope Submit manuscript

Abstract

Background

Pancreatic cancer accounts for around 4.6% of cancers deaths worldwide per year. Despite many advances in treatment regimes, the prognosis is still poor. Only 20% of tumors are primarily resectable. Recurrences—both with distant metastasis as well as locoregional—are frequent. For patients with primary nonresectable localized disease or localized recurrences, we offered chemoradiation to achieve local control over a long period of time. We here report our results on combined chemoradiation of pancreatic tumors and local recurrences using proton beam therapy.

Materials and methods

We report on 25 patients with localized nonresectable pancreatic cancer (15 patients) or local recurrent disease (10 patients). All patients were treated with combined proton radiochemotherapy. Overall survival, progression-free survival, local control, and treatment-related toxicity were analyzed using statistically methods.

Results

Median RT dose was 54.0 Gy (RBE) for proton irradiation. The toxicity of treatment was acceptable. Four CTCAE grade III and IV adverse events (bone marrow disfunction, gastrointestinal [GI] disorders, stent dislocation, myocardial infarction) were recorded during or directly after the end of radiotherapy; two of them were related to combined chemoradiation (bone marrow disfunction, GI disorders). Six weeks after radiotherapy, one additional grade IV toxicity was reported (ileus, caused by peritoneal carcinomatosis, not treatment related). The median progression-free survival was 5.9 months and median overall survival was 11.0 months. The pretherapy CA19‑9 level was a statistically significant prognostic factor for enhanced overall survival. Local control at 6 months and 12 months were determined to be 86% and 80%, respectively.

Conclusion

Combined proton chemoradiation leads to high local control rates. Unfortunately, PFS and OS are driven by distant metastasis and were not improved compared to historical data and reports. With this in mind, enhanced chemotherapeutical regimes, in combination with local irradiation, should be evaluated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Boimel PJ, Berman AT, Li J, Apisarnthanarax S, Both S, Lelionis K, Larson GL, Teitelbaum U, Lukens JN, Ben-Josef E, Metz JM, Plastaras JP (2017) Proton beam reirradiation for locally recurrent pancreatic adenocarcinoma. J Gastrointest Oncol 8(4):665–674

    Article  PubMed  PubMed Central  Google Scholar 

  2. Chauffert B, Mornex F, Bonnetain F, Rougier P, Mariette C, Bouché O, Bosset JF, Aparicio T, Mineur L, Azzedine A, Hammel P, Butel J, Stremsdoerfer N, Maingon P, Bedenne L (2008) 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 19(9):1592–1599

    Article  CAS  PubMed  Google Scholar 

  3. Comito T, Cozzi L, Zerbi A, Franzese C, Clerici E, Tozzi A, Iftode C, Navarria P, D’Agostino G, Fogliata A, Mancosu P, Tomatis S, Carnaghi C, Personeni N, Santoro A, Scorsetti M (2017) Clinical results of stereotactic body radiotherapy (SBRT) in the treatment of isolated local recurrence of pancreatic cancer after R0 surgery: A retrospective study. Eur J Surg Oncol 43(4):735–742

    Article  CAS  PubMed  Google Scholar 

  4. Dagoglu N, Callery M, Moser J, Tseng J, Kent T, Bullock A, Miksad R, Mancias JD, Mahadevan A (2016) Stereotactic body radiotherapy (SBRT) reirradiation for recurrent pancreas cancer. J Cancer 7(3):283–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fietkau R, Ghadimi M, Grützmann R, Wittel UA, Jacobasch L, Uhl W, Croner RS, Bechstein WO, Neumann UP, Waldschmidt D, Boeck SH, Moosmann N, Reinacher-Schick AC, Golcher H, Adler W, Semrau S, Kallies A, Hecht M, Tannapfel A, Oettle H (2022) Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: First results of the CONKO-007 trial. JCO Clin Cancer Inform 40(16_suppl):4008

    Google Scholar 

  6. Fietkau R, Grützmann R, Wittel UA, Croner RS, Jacobasch L, Neumann UP, Reinacher-Schick A, Imhoff D, Boeck S, Keilholz L, Oettle H, Hohenberger WM, Golcher H, Bechstein WO, Uhl W, Pirkl A, Adler W, Semrau S, Rutzner S, Ghadimi M, Lubgan D (2021) R0 resection following chemo (radio)therapy improves survival of primary inoperable pancreatic cancer patients. Interim results of the German randomized CONKO-007± trial. Strahlenther Onkol 197(1):8–18

    Article  CAS  PubMed  Google Scholar 

  7. Habermehl D, Brecht IC, Bergmann F, Welzel T, Rieken S, Werner J, Schirmacher P, Büchler MW, Debus J, Combs SE (2013) Chemoradiation in patients with isolated recurrent pancreatic cancer—therapeutical efficacy and probability of re-resection. Radiat Oncol 8:27

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hammel P, Huguet F, van Laethem J‑L, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C (2016) Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of Gemcitabine with or without Erlotinib: the LAP07 randomized clinical trial. JAMA 315(17):1844–1853

    Article  CAS  PubMed  Google Scholar 

  9. Hiroshima Y, Fukumitsu N, Saito T, Numajiri H, Murofushi KN, Ohnishi K, Nonaka T, Ishikawa H, Okumura T, Sakurai H (2019) Concurrent chemoradiotherapy using proton beams for unresectable locally advanced pancreatic cancer. Radiother Oncol 136:37–43

    Article  PubMed  Google Scholar 

  10. Huang J, Robertson JM, Margolis J, Balaraman S, Gustafson G, Khilanani P, Nadeau L, Jury R, McIntosh B (2011) Long-term results of full-dose gemcitabine with radiation therapy compared to 5‑fluorouracil with radiation therapy for locally advanced pancreas cancer. Radiother Oncol 99(2):114–119

    Article  CAS  PubMed  Google Scholar 

  11. Jethwa KR, Tryggestad EJ, Whitaker TJ, Giffey BT, Kazemba BD, Neben-Wittich MA, Merrell KW, Haddock MG, Hallemeier CL (2018) Initial experience with intensity modulated proton therapy for intact, clinically localized pancreas cancer: Clinical implementation, dosimetric analysis, acute treatment-related adverse events, and patient-reported outcomes. Adv Radiat Oncol 3(3):314–321

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kawashiro S, Yamada S, Isozaki Y, Nemoto K, Tsuji H, Kamada T (2018) Carbon-ion radiotherapy for locoregional recurrence after primary surgery for pancreatic cancer. Radiother Oncol 129(1):101–104

    Article  PubMed  Google Scholar 

  13. Kim TH, Lee WJ, Woo SM, Kim H, Oh ES, Lee JH, Han S‑S, Park S‑J, Suh Y‑G, Moon SH, Kim SS, Kim DY (2018) Effectiveness and safety of simultaneous integrated boost-proton beam therapy for localized pancreatic cancer. Technol Cancer Res Treat 17:1533033818783879

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kovač JD, Mayer P, Hackert T, Klauss M (2019) The time to and type of pancreatic cancer recurrence after surgical resection: is prediction possible? Acad Radiol 26(6):775–781

    Article  PubMed  Google Scholar 

  15. Liermann J, Ben-Josef E, Syed M, Debus J, Herfarth K, Naumann P (2022) Carbon ion radiotherapy as definitive treatment in locally recurrent pancreatic cancer. Strahlenther Onkol 198(4):378–387

    Article  PubMed  Google Scholar 

  16. Lukens JN, Mick R, Demas KL, Apisarnthanarax S, Metz JM, McCall D, O’Dwyer PJ, Teitelbaum U, Both S, Plastaras JP (2013) Acute toxicity of proton versus photon chemoradiation therapy for pancreatic adenocarcinoma: a cohort study. Int J Radiat Oncol Biol Phys 87(2):311

    Article  Google Scholar 

  17. Maemura K, Mataki Y, Kurahara H, Kawasaki Y, Iino S, Sakoda M, Ueno S, Arimura T, Higashi R, Yoshiura T, Shinchi H, Natsugoe S (2017) Comparison of proton beam radiotherapy and hyper-fractionated accelerated chemoradiotherapy for locally advanced pancreatic cancer. Pancreatology 17(5):833–838

    Article  PubMed  Google Scholar 

  18. McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS (2018) Pancreatic cancer: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 24(43):4846–4861

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mizumoto T, Terashima K, Matsuo Y, Nagano F, Demizu Y, Mima M, Sulaiman NS, Tokumaru S, Okimoto T, Toyama H, Fukumoto T (2019) Proton radiotherapy for isolated local recurrence of primary resected pancreatic ductal Adenocarcinoma. Ann Surg Oncol 26(8):2587–2594

    Article  PubMed  Google Scholar 

  20. Mohan R, Grosshans D (2017) Proton therapy—present and future. Adv Drug Deliv Rev 109:26–44

    Article  PubMed  Google Scholar 

  21. Nakamura A, Itasaka S, Takaori K, Kawaguchi Y, Shibuya K, Yoshimura M, Matsuo Y, Mizowaki T, Uemoto S, Hiraoka M (2014) Radiotherapy for patients with isolated local recurrence of primary resected pancreatic cancer. Prolonged disease-free interval associated with favorable prognosis. Strahlenther Onkol 190(5):485–490

    Article  PubMed  Google Scholar 

  22. Nichols RC, George TJ, Zaiden RA, Awad ZT, Asbun HJ, Huh S, Ho MW, Mendenhall NP, Morris CG, Hoppe BS (2013) Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity. Acta Oncol 52(3):498–505

    Article  CAS  PubMed  Google Scholar 

  23. Ogura Y, Terashima K, Nanno Y, Park S, Suga M, Takahashi D, Matsuo Y, Sulaiman NS, Tokumaru S, Okimoto T, Toyama H, Fukumoto T (2022) Factors associated with long-term survival in gemcitabine-concurrent proton radiotherapy for non-metastatic locally advanced pancreatic cancer: a single-center retrospective study. Radiat Oncol 17(1):32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. O’Reilly D, Fou L, Hasler E, Hawkins J, O’Connell S, Pelone F, Callaway M, Campbell F, Capel M, Charnley R, Corrie P, Elliot D, Goodburn L, Jewell A, Joharchi S, McGeeney L, Mukherjee S, Oppong K, Whelan P, Primrose J, Neoptolemos J (2018) Diagnosis and management of pancreatic cancer in adults: a summary of guidelines from the UK National Institute for Health and Care Excellence. Pancreatology 18(8):962–970

    Article  PubMed  Google Scholar 

  25. Rutenberg MS, Nichols RC (2020) Proton beam radiotherapy for pancreas cancer. J Gastrointest Oncol 11(1):166–175

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ryan JF, Groot VP, Rosati LM, Hacker-Prietz A, Narang AK, McNutt TR, Jackson JF, Le DT, Jaffee EM, Zheng L, Laheru DA, He J, Pawlik TM, Weiss MJ, Wolfgang CL, Herman JM (2018) Stereotactic body radiation therapy for isolated local recurrence after surgical resection of pancreatic ductal adenocarcinoma appears to be safe and effective. Ann Surg Oncol 25(1):280–289

    Article  PubMed  Google Scholar 

  27. Sachsman S, Nichols RC, Morris CG, Zaiden R, Johnson EA, Awad Z, Bose D, Ho MW, Huh SN, Li Z, Kelly P, Hoppe BS (2014) Proton therapy and concomitant capecitabine for non-metastatic unresectable pancreatic adenocarcinoma. Int J Part Ther 1(3):692–701

    Article  Google Scholar 

  28. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin 71(3):209–249

    Article  Google Scholar 

  29. Tamm EP, Balachandran A, Bhosale PR, Katz MH, Fleming JB, Lee JH, Varadhachary GR (2012) Imaging of pancreatic adenocarcinoma: update on staging/resectability. Radiol Clin North Am 50(3):407–428

    Article  PubMed  Google Scholar 

  30. Terashima K, Demizu Y, Hashimoto N, Jin D, Mima M, Fujii O, Niwa Y, Takatori K, Kitajima N, Sirakawa S, Yonson K, Hishikawa Y, Abe M, Sasaki R, Sugimura K, Murakami M (2012) A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis. Radiother Oncol 103(1):25–31

    Article  PubMed  Google Scholar 

  31. Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, Buijsen J, Busch OR, Creemers G‑JM, van Dam RM, Eskens FALM, Festen S, de Groot JWB, Groot Koerkamp B, de Hingh IH, Homs MYV, van Hooft JE, Kerver ED, Luelmo SAC, Neelis KJ, Nuyttens J, Paardekooper GMRM, Patijn GA, van der Sangen MJC, de Vos-Geelen J, Wilmink JW, Zwinderman AH, Punt CJ, van Eijck CH, van Tienhoven G (2020) Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the Dutch randomized phase III PREOPANC trial. J Clin Oncol 38(16):1763–1773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wild AT, Hiniker SM, Chang DT, Tran PT, Khashab MA, Limaye MR, Laheru DA, Le DT, Kumar R, Pai JS, Hargens B, Sharabi AB, Shin EJ, Zheng L, Pawlik TM, Wolfgang CL, Koong AC, Herman JM (2013) Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: experience from two institutions. J Gastrointest Oncol 4(4):343–351

    PubMed  PubMed Central  Google Scholar 

  33. Woodhouse KD, Elrakhawy M, Jain A, Ben-Josef E, Metz JM, Plastaras JP, Lukens JN (2016) Acute toxicity of proton versus photon adjuvant chemoradiation in the treatment of pancreatic cancer: a cohort study. Int J Radiat Oncol Biol Phys 96(2):E208–E209

    Article  Google Scholar 

  34. Rapp T, Rutenberg M, Morris C, Nichols R (2022) Dose-escalated proton therapy with elective nodal irradiation and concomitant chemotherapy for unresectable, borderline resectable or medically inoperable pancreatic cancer: a phase II trial. J Gastrointest Oncol 13:1395–1401

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S. Lautenschlaeger.

Ethics declarations

Conflict of interest

S. Lautenschlaeger, C. Dumke, L. Exeli, H. Hauswald, R. Engenhart-Cabillic and F. Eberle declare that they have no competing interests.

Additional information

Data Availability

The anonymized dataset is available upon request from the corresponding author.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lautenschlaeger, S., Dumke, C., Exeli, L. et al. Treatment of primary or recurrent non-resectable pancreatic cancer with proton beam irradiation combined with gemcitabine-based chemotherapy. Strahlenther Onkol 199, 982–991 (2023). https://doi.org/10.1007/s00066-023-02106-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00066-023-02106-5

Keywords

Navigation