Skip to main content

The Landmark Series: Locally Advanced Pancreatic Cancer and Ablative Therapy Options

Abstract

Locally advanced pancreatic cancer (LAPC) is a challenging disease to treat. There is consensus that systemic chemotherapy should be the first line of therapy for most patients. However, there is no consensus on how to manage those patients who do not have sufficient response to become candidates for resection but also do not have distant progression after weeks or months of systemic therapy. Radiation therapy is the most commonly used and best-studied local ablative therapy. One recent randomized controlled trial (LAP-07) failed to demonstrate an overall survival benefit for conventional chemoradiation therapy after induction chemotherapy versus chemotherapy alone. This study had several limitations, and ongoing studies are re-evaluating the role of chemoradiation after more effective chemotherapy regimens as well as more advanced radiation techniques. In parallel, there has been increasing interest in other thermal and non-thermal methods of ablation. In particular, irreversible electroporation has gained traction for treatment of LAPC, with at least one ongoing randomized controlled trial designed to address its role compared with systemic chemotherapy alone. Multiple preclinical and clinical studies are investigating combinations of local ablation and immunotherapy with the goal of generating immune responses that will meaningfully improve outcomes.

This is a preview of subscription content, access via your institution.

Fig. 1.
Fig. 2.
Fig. 3.

References

  1. 1.

    Ferrone CR, Marchegiani G, Hong TS, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;261(1):12–7.

    PubMed  Google Scholar 

  2. 2.

    Hackert T, Sachsenmaier M, Hinz U, et al. Locally advanced pancreatic cancer: neoadjuvant therapy with folfirinox results in resectability in 60% of the patients. Ann Surg. 2016;264(3):457–63.

    PubMed  Google Scholar 

  3. 3.

    Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol. 2016;17(6):801–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Tempero MA. NCCN guidelines updates: pancreatic cancer. J Natl Compr Cancer Netw. 2019;17(5.5):603–5.

    CAS  Google Scholar 

  5. 5.

    Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistic review, 1975–2017. 2019; Available from: http://seer.cancer.gov/csr/1975_2017/.

  6. 6.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

    PubMed  Google Scholar 

  7. 7.

    Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.

    Google Scholar 

  8. 8.

    Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.

    CAS  PubMed  Google Scholar 

  9. 9.

    Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27(11):1806–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    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 Inst. 1988. 80 (10): p. 751-5.

  11. 11.

    Loehrer PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2011;29(31):4105–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    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(3):373–8.

    CAS  PubMed  Google Scholar 

  13. 13.

    Chauffert B, Mornex F, Bonnetain F, et al. 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(9):1592–9.

    CAS  PubMed  Google Scholar 

  14. 14.

    Hammel P, Huguet F, van Laethem JL, et al. 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. 2016;315(17):1844–53.

    CAS  PubMed  Google Scholar 

  15. 15.

    Abrams RA, Winter KA, Regine WF, et al. Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704—a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys. 2012;82(2):809–16.

    CAS  PubMed  Google Scholar 

  16. 16.

    Reyngold M, Parikh P, Crane CH. Ablative radiation therapy for locally advanced pancreatic cancer: techniques and results. Radiat Oncol. 2019;14(1):95.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Dohopolski MJ, Glaser SM, Vargo JA, Balasubramani GK, Beriwal S. Stereotactic body radiotherapy for locally-advanced unresectable pancreatic cancer-patterns of care and overall survival. J Gastrointest Oncol. 2017;8(5):766–77.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    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(5):1420–6.

    PubMed  Google Scholar 

  19. 19.

    Herman JM, Chang DT, Goodman KA, et al. Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer. 2015;121(7):1128–37.

    CAS  PubMed  Google Scholar 

  20. 20.

    Comito T, Cozzi L, Clerici E, et al. Can stereotactic body radiation therapy be a viable and efficient therapeutic option for unresectable locally advanced pancreatic adenocarcinoma? Results of a phase 2 study. Technol Cancer Res Treat. 2017;16(3):295–301.

    PubMed  Google Scholar 

  21. 21.

    Tozzi A, Comito T, Alongi F, et al. SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono-institutional experience. Radiat Oncol. 2013;8:148.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Krempien R, Roeder F. Intraoperative radiation therapy (IORT) in pancreatic cancer. Radiat Oncol. 2017;12(1):8.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Roldan GE, Gunderson LL, Nagorney DM, et al. External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer. 1988;61(6):1110–6.

    CAS  PubMed  Google Scholar 

  24. 24.

    Mohiuddin M, Regine WF, Stevens J, et al. Combined intraoperative radiation and perioperative chemotherapy for unresectable cancers of the pancreas. J Clin Oncol. 1995;13(11):2764–8.

    CAS  PubMed  Google Scholar 

  25. 25.

    Schuricht AL, Spitz F, Barbot D, Rosato F. Intraoperative radiotherapy in the combined-modality management of pancreatic cancer. Am Surg. 1998;64(11):1043–9.

    CAS  PubMed  Google Scholar 

  26. 26.

    Harrison JM, Wo JY, Ferrone CR, et al. Intraoperative radiation therapy (IORT) for borderline resectable and locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) in the era of modern neoadjuvant treatment: short-term and long-term outcomes. Ann Surg Oncol. 2020;27(5):1400–6.

    PubMed  Google Scholar 

  27. 27.

    Tepper JE, Noyes D, Krall JM, et al. Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505 Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1991;21(5):1145–9.

    CAS  PubMed  Google Scholar 

  28. 28.

    Paiella S, Salvia R, Ramera M, et al. Local ablative strategies for ductal pancreatic cancer (radiofrequency ablation, irreversible electroporation): a review. Gastroenterol Res Pract. 2016;2016:4508376.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Saccomandi P, Lapergola A, Longo F, Schena E, Quero G. Thermal ablation of pancreatic cancer: a systematic literature review of clinical practice and pre-clinical studies. Int J Hyperthermia. 2018;35(1):398–418.

    PubMed  Google Scholar 

  30. 30.

    Cantore M, Girelli R, Mambrini A, et al. Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma. Br J Surg. 2012;99(8):1083–8.

    CAS  PubMed  Google Scholar 

  31. 31.

    Frigerio I, Girelli R, Giardino A, Regi P, Salvia R, Bassi C. Short term chemotherapy followed by radiofrequency ablation in stage III pancreatic cancer: results from a single center. J Hepatobiliary Pancreat Sci. 2013;20(6):574–7.

    PubMed  Google Scholar 

  32. 32.

    Girelli R, Frigerio I, Giardino A, et al. Results of 100 pancreatic radiofrequency ablations in the context of a multimodal strategy for stage III ductal adenocarcinoma. Langenbecks Arch Surg. 2013;398(1):63–9.

    PubMed  Google Scholar 

  33. 33.

    Ning Z, Xie J, Chen Q, et al. HIFU is safe, effective, and feasible in pancreatic cancer patients: a monocentric retrospective study among 523 patients. Onco Targets Ther. 2019;12:1021–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Davalos RV, Mir IL, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng. 2005;33(2):223–31.

    CAS  PubMed  Google Scholar 

  35. 35.

    Bower M, Sherwood L, Li Y, Martin R. Irreversible electroporation of the pancreas: definitive local therapy without systemic effects. J Surg Oncol. 2011;104(1):22–8.

    PubMed  Google Scholar 

  36. 36.

    Moris D, Machairas N, Tsilimigras DI, et al. Systematic review of surgical and percutaneous irreversible electroporation in the treatment of locally advanced pancreatic cancer. Ann Surg Oncol. 2019;26(6):1657–68.

    PubMed  Google Scholar 

  37. 37.

    Lee EW, Loh CT, Kee ST. Imaging guided percutaneous irreversible electroporation: ultrasound and immunohistological correlation. Technol Cancer Res Treat. 2007;6(4):287–94.

    PubMed  Google Scholar 

  38. 38.

    Martin RC, Durham AN, Besselink MG, et al. Irreversible electroporation in locally advanced pancreatic cancer: a call for standardization of energy delivery. J Surg Oncol. 2016;114(7):865–71.

    PubMed  Google Scholar 

  39. 39.

    Martin RC II. Irreversible electroporation of locally advanced pancreatic neck/body adenocarcinoma. J Gastrointest Oncol. 2015;6(3):329–35.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Martin RC. Irreversible electroporation of locally advanced pancreatic head adenocarcinoma. J Gastrointest Surg. 2013;17(10):1850–6.

    PubMed  Google Scholar 

  41. 41.

    Dunki-Jacobs EM, Philips P, Martin RC II. Evaluation of resistance as a measure of successful tumor ablation during irreversible electroporation of the pancreas. J Am Coll Surg. 2014;218(2):179–87.

    PubMed  Google Scholar 

  42. 42.

    Varadhachary GR, Tamm EP, Abbruzzese JL, et al. Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol. 2006;13(8):1035–46.

    PubMed  Google Scholar 

  43. 43.

    Kwon D, McFarland K, Velanovich V, Martin RC II. Borderline and locally advanced pancreatic adenocarcinoma margin accentuation with intraoperative irreversible electroporation. Surgery. 2014;156(4):910–20.

    PubMed  Google Scholar 

  44. 44.

    Martin RC, McFarland K, Ellis S, Velanovich V. Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. J Am Coll Surg. 2012;215(3):361–9.

    PubMed  Google Scholar 

  45. 45.

    Martin RC, McFarland K, Ellis S, Velanovich V. Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survival. Ann Surg Oncol. 2013;20(Suppl 3):S443–9.

    PubMed  Google Scholar 

  46. 46.

    Martin RC, Kwon D, Chalikonda S, et al., Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg. 2015. 262(3): p. 486-94; discussion 492-4.

  47. 47.

    Holland MM, Bhutiani N, Kruse EJ, et al., A prospective, multi-institution assessment of irreversible electroporation for treatment of locally advanced pancreatic adenocarcinoma: initial outcomes from the AHPBA pancreatic registry. HPB (Oxford), 2019.

  48. 48.

    Narayanan G, Hosein PJ, Beulaygue IC, et al. Percutaneous image-guided irreversible electroporation for the treatment of unresectable, locally advanced pancreatic adenocarcinoma. J Vasc Interv Radiol. 2017;28(3):342–8.

    PubMed  Google Scholar 

  49. 49.

    He C, Wang J, Sun S, et al. Irreversible electroporation versus radiotherapy after induction chemotherapy on survival in patients with locally advanced pancreatic cancer: a propensity score analysis. BMC Cancer. 2019;19(1):394.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Bhutiani N, Li Y, Zheng Q, et al. Electrochemotherapy with irreversible electroporation and FOLFIRINOX improves survival in murine models of pancreatic adenocarcinoma. Ann Surg Oncol. 2020;27(11):4348–59.

    PubMed  Google Scholar 

  51. 51.

    Woest MR, Wilson KD, Kruse EJ, Weiss MJ, Christein JD, White RR, Martin RCG. Optimizing patient selection for irreversible electroporation of locally advanced pancreatic cancer: analyses of survival (submitted).

  52. 52.

    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    O'Reilly EM, Oh DY, Dhani N, et al., Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 2019.

  55. 55.

    Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–7.

    CAS  PubMed  Google Scholar 

  56. 56.

    Azad A, YinLim S, D’Costa Z, et al. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med. 2017;9(2):167–80.

    CAS  PubMed  Google Scholar 

  57. 57.

    Yasmin-Karim S, Bruck PT, Moreau M, et al. Radiation and local anti-CD40 generate an effective in situ vaccine in preclinical models of pancreatic cancer. Front Immunol. 2018;9:2030.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Rech AJ, Dada H, Kotzin JJ, et al. Radiotherapy and CD40 activation separately augment immunity to checkpoint blockade in cancer. Cancer Res. 2018;78(15):4282–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Zhao J, Wen X, Tian L, et al. Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer. Nat Commun. 2019;10(1):899.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Garcia PA, Kos B, Rossmeisl JH Jr, Pavliha D, Miklavcic D, Davalos RV. Predictive therapeutic planning for irreversible electroporation treatment of spontaneous malignant glioma. Med Phys. 2017;44(9):4968–80.

    CAS  PubMed  Google Scholar 

  61. 61.

    He C, Wang J, Sun S, Zhang Y, Li S. Immunomodulatory effect after irreversible electroporation in patients with locally advanced pancreatic cancer. J Oncol. 2019;2019:9346017.

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Scheffer HJ, Stam AGM, Geboers B, et al. Irreversible electroporation of locally advanced pancreatic cancer transiently alleviates immune suppression and creates a window for antitumor T cell activation. Oncoimmunology. 2019;8(11):1652532.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Narayanan JSS, Ray P, Hayashi T, et al. Irreversible electroporation combined with checkpoint blockade and TLR7 stimulation induces antitumor immunity in a murine pancreatic cancer model. Cancer Immunol Res. 2019;7(10):1714–26.

    CAS  PubMed  Google Scholar 

  64. 64.

    Partridge BR, O’Brien TJ, Lorenzo MF, et al. High-frequency irreversible electroporation for treatment of primary liver cancer: a proof-of-principle study in canine hepatocellular carcinoma. J Vasc Interv Radiol. 2020;31(3):482–91.

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Ringel-Scaia VM, Beitel-White N, Lorenzo MF, et al. High-frequency irreversible electroporation is an effective tumor ablation strategy that induces immunologic cell death and promotes systemic anti-tumor immunity. EBioMedicine. 2019;44:112–25.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Gajiwala S, Torgeson A, Garrido-Laguna I, Kinsey C, Lloyd S. Combination immunotherapy and radiation therapy strategies for pancreatic cancer-targeting multiple steps in the cancer immunity cycle. J Gastrointest Oncol. 2018;9(6):1014–26.

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    O’Neill C, Hayat T, Hamm J, et al. A phase 1b trial of concurrent immunotherapy and irreversible electroporation in the treatment of locally advanced pancreatic adenocarcinoma. Surgery. 2020;168(4):610–6.

    PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Rebekah R. White MD.

Ethics declarations

Disclosures

RRW has received financial support for research from AngioDynamics, and RCGM is a paid consultant of AngioDynamics. JM receives compensation for consulting from Boston Consulting Group.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

White, R.R., Murphy, J.D. & Martin, R.C.G. The Landmark Series: Locally Advanced Pancreatic Cancer and Ablative Therapy Options. Ann Surg Oncol 28, 4173–4180 (2021). https://doi.org/10.1245/s10434-021-09662-z

Download citation