Advertisement

Aktuelle Entwicklungen zur neoadjuvanten und adjuvanten Therapie des Pankreaskarzinoms

  • Volker KunzmannEmail author
  • Thomas J. Ettrich
  • Ingo Hartlapp
  • Thomas Seufferlein
Onkologie
  • 11 Downloads

Zusammenfassung

Hintergrund

Trotz kurativ intendierter chirurgischer Resektion ist die Prognose des duktalen Pankreasadenokarzinoms (PDAC) aufgrund der aggressiven Tumorbiologie mit hohem Metastasierungspotenzial auch in lokalisierten Tumorstadien weiterhin sehr ungünstig (mediane Fünfjahresüberlebensrate ≤10 %).

Ziel

Die aktuellen systemischen Therapiekonzepte beim lokalisierten, nichtmetastasierten PDAC sollen dargestellt werden.

Material und Methoden

Diese Arbeit basiert auf einer selektiven Literaturrecherche in der Datenbank PubMed und aktueller Kongressabstracts zum Thema adjuvante und neoadjuvante Therapie des PDAC.

Ergebnisse

Seit Einführung und Weiterentwicklung einer effektiven adjuvanten Systemtherapie konnte die Prognose des resektablen PDAC konsekutiv verbessert werden, während adjuvante Radio(chemo)therapiekonzepte keinen klaren Zusatznutzen zeigen. Für selektierte Patientenkollektive (u. a. ECOG 0, Alter <70 Jahre) stellt aktuell die Kombinationstherapie nach dem modifizierten FOLFIRINOX-Schema den neuen Therapiestandard in der Adjuvanz dar. Alle anderen Patienten sollten weiterhin nach chirurgischer Resektion eine adjuvante Gemcitabin- oder 5‑Fluorouracil(5-FU)-basierte Systemtherapie über 6 Monate erhalten. Wegen des limitierten Zugangs zu einer effektiven postoperativen Systemtherapie (nur maximal 50 % aller resezierten Patienten erhalten eine adjuvante Systemtherapie) und des potenziellen Downsizing-Effekts mit Steigerung der R0-Resektabilitätsrate werden derzeit in Studien neoadjuvante Konzepte mit modernen Kombinationschemotherapien (FOLFIRINOX, Gemcitabin/nab-Paclitaxel) in verschiedenen lokalisierten Stadien des PDAC (resektabel, Borderline-resektabel, primär irresektabel) evaluiert. Diese stellen aber noch keinen allgemeinen Therapiestandard dar.

Schlussfolgerung

Eine effektive perioperative Systemtherapie stellt heutzutage einen integralen Bestandteil eines interdisziplinären Behandlungskonzepts lokalisierter PDAC dar.

Schlüsselwörter

Duktales Pankreasadenokarzinom Radio(chemo)therapie FOLFIRINOX-Schema Resektion Perioperative Therapie 

Recent developments in neoadjuvant and adjuvant treatment of pancreatic cancer

Abstract

Background

Despite the curative intent of surgical resection, pancreatic ductal adenocarcinoma (PDAC) even in localized stages has a very poor prognosis (5-year median overall survival ≤10%) due to the aggressive tumor biology with a high potential to develop metastatic disease.

Objective

This article presents the current concepts for systemic treatment in localized, non-metastatic PDAC.

Methods

This article is based on a selective literature search in the PubMed database and recent congress abstracts concerning adjuvant and neoadjuvant treatment of PDAC.

Results

With the introduction and further refinement of effective adjuvant systemic chemotherapy, the prognosis of resectable PDAC has been consecutively improved, whereas (chemo)radiotherapy concepts have not shown additional benefits. For selected patient subgroups (e. g. PS-ECOG 0, age <70 years) combination chemotherapy with the modified FOLFIRINOX regimen is considered the current standard treatment in the adjuvant setting. All other patients should receive adjuvant chemotherapy with gemcitabine or a 5-FU-based systemic treatment regimen over 6 months after surgical resection. Due to limited access to effective postoperative systemic treatment (only approximately 50% of resected patients receive an adjuvant chemotherapy) and the potential downsizing effect with an increase in the R0 resection rate, current clinical trials are evaluating neoadjuvant concepts with modern combination chemotherapy regimens (FOLFIRINOX, gemcitabine/nab-paclitaxel) in various localized stages of PDAC (resectable, borderline resectable, primarily nonresectable); however, this is not yet standard treatment outside clinical trials.

Conclusion

An effective perioperative systemic treatment is nowadays an essential part of the multidisciplinary treatment strategy for localized PDAC.

Keywords

Pancreatic ductal adenocarcinoma (Chemo)radiotherapy FOLFIRINOX Resection Perioperative therapy 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

V. Kunzmann: Forschungsunterstützung: Celgene; Vortragshonorare: BMS, Celgene, Merck, Servier; Advisory Boards: BMS, Celgene, Merck. T.J. Ettrich: Kongressunterstützung: Ipsen, Forschungsunterstützung: Servier; Vortragshonorare, Advisory Boards: Merck-Serono, Sanofi, Novartis, Bayer, BMS, Sanofi, Roche. T. Seufferlein: Forschungsunterstützung Sanofi-Genzyme, Celgene, Amgen; Vortragshonorare: Celgene, Servier, Merck, Roche, Falk Foundation, Shire, Novartis, Sanofi-Genzyme; Advisory Boards: BMS, Celgene, Halozyme, Lilly, Sanofi-Genzyme. I. Hartlapp: Advisory Boards: Roche

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Literatur

  1. 1.
    Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zulke C, Fahlke J, Arning MB et al (2013) Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310(14):1473–1481CrossRefGoogle Scholar
  2. 2.
    Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH et al (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148(1–2):349–361CrossRefGoogle Scholar
  3. 3.
    Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S, Doi R, Monden M, Hatori T, Tanaka M et al (2009) A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer 101(6):908–915CrossRefGoogle Scholar
  4. 4.
    Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C et al (2010) Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304(10):1073–1081CrossRefGoogle Scholar
  5. 5.
    Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O’Reilly DA, Cunningham D, Wadsley J et al (2017) Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 389(10073):1011–1024CrossRefGoogle Scholar
  6. 6.
    Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F et al (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350(12):1200–1210CrossRefGoogle Scholar
  7. 7.
    Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H et al (2016) Adjuvant chemotherapy of S‑1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 388(10041):248–257CrossRefGoogle Scholar
  8. 8.
    Conroy T, Hammel P, Hebbar M, Abdelghani BM, Wei AC, Raoul JL, Chone L, Francois E, Artru P, Biagi JJ et al (2018) FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 379(25):2395–2406CrossRefGoogle Scholar
  9. 9.
    Sinn M, Bahra M, Liersch T, Gellert K, Messmann H, Bechstein W, Waldschmidt D, Jacobasch L, Wilhelm M, Rau BM et al (2017) CONKO-005: Adjuvant chemotherapy with gemcitabine plus erlotinib versus gemcitabine alone in patients after R0 resection of pancreatic cancer: a multicenter randomized phase III trial. J Clin Oncol 35(29):3330–3337CrossRefGoogle Scholar
  10. 10.
    Sinn M, Liersch T, Gellert K, Riess H, Stübs P, Waldschmidt DT, Pelzer U, Stieler J, Striefler JK, Bahra M et al (2014) CONKO-006: A randomized double-blinded phase IIb-study of adjuvant therapy with gemcitabine + sorafenib/placebo for patients with R1-resection of pancreatic cancer. Ann Oncol 25(5):1–41.  https://doi.org/10.1093/annonc/mdu438.15 CrossRefGoogle Scholar
  11. 11.
    Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J (2010) Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. Plos Med 7(4):e1000267CrossRefGoogle Scholar
  12. 12.
    Assifi MM, Lu X, Eibl G, Reber HA, Li G, Hines OJ (2011) Neoadjuvant therapy in pancreatic adenocarcinoma: a meta-analysis of phase II trials. Surgery 150(3):466–473CrossRefGoogle Scholar
  13. 13.
    Andriulli A, Festa V, Botteri E, Valvano MR, Koch M, Bassi C, Maisonneuve P, Sebastiano PD (2012) Neoadjuvant/preoperative gemcitabine for patients with localized pancreatic cancer: a meta-analysis of prospective studies. Ann Surg Oncol 19(5):1644–1662CrossRefGoogle Scholar
  14. 14.
    Lee SM, Katz MH, Liu L, Sundar M, Wang H, Varadhachary GR, Wolff RA, Lee JE, Maitra A, Fleming JB et al (2016) Validation of a proposed tumor regression grading scheme for pancreatic ductal adenocarcinoma after neoadjuvant therapy as a prognostic indicator for survival. Am J Surg Pathol 40(12):1653–1660CrossRefGoogle Scholar
  15. 15.
    Alvarez R, Musteanu M, Garcia-Garcia E, Lopez-Casas PP, Megias D, Guerra C, Munoz M, Quijano Y, Cubillo A, Rodriguez-Pascual J et al (2013) Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer 109(4):926–933CrossRefGoogle Scholar
  16. 16.
    Marsh RW, Baker M, Catenacci DVT, Kozloff M, Polite BN, Posner MC, Roggin KK, Talamonti MS, Kindler HL (2016) Peri-operative modified FOLFIRINOX (mFOLFIRINOX) in resectable pancreatic cancer (PDAC): A pilot study. J Clin Oncol 34(4_suppl):312–312CrossRefGoogle Scholar
  17. 17.
    Mokdad AA, Minter RM, Zhu H, Augustine MM, Porembka MR, Wang SC, Yopp AC, Mansour JC, Choti MA, Polanco PM (2017) Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score matched analysis. J Clin Oncol 35(5):515–522CrossRefGoogle Scholar
  18. 18.
    Hewitt MJ, McPhail MJ, Possamai L, Dhar A, Vlavianos P, Monahan KJ (2012) EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis. Gastrointest Endosc 75(2):319–331CrossRefGoogle Scholar
  19. 19.
    Berger AW, Ettrich TJ, Schwerdel D, Reinacher-Schick A, Algül H, König A‑O, Gallmeier E, Wille K, Daum S, Geissler M et al (2018) A composite liquid biomarker for non-invasive diagnosis of resectable pancreatic ductal adenocarcinoma. Ann Oncol.  https://doi.org/10.1093/annonc/mdy303.044 CrossRefPubMedGoogle Scholar
  20. 20.
    Verma V, Li J, Lin C (2016) Neoadjuvant therapy for pancreatic cancer: systematic review of postoperative morbidity, mortality, and complications. Am J Clin Oncol 39(3):302–313CrossRefGoogle Scholar
  21. 21.
    Ettrich TJ, Berger AW, Perkhofer L, Daum S, Konig A, Dickhut A, Wittel U, Wille K, Geissler M, Algul H et al (2018) Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer—the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group. BMC Cancer 18(1):1298CrossRefGoogle Scholar
  22. 22.
    Suker M, Beumer BR, Sadot E, Marthey L, Faris JE, Mellon EA, El-Rayes BF, Wang-Gillam A, Lacy J, Hosein PJ et al (2016) FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 17(6):801–810CrossRefGoogle Scholar
  23. 23.
    Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouche O, Shannon J, Andre T et al (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):1844–1853CrossRefGoogle Scholar
  24. 24.
    Van Tienhoven G, Versteijne E, Suker M, Groothuis KBC, Busch OR, Bonsing BA, de Hingh IHJT, Festen S, Patijn GA, Vos-Geelen J et al (2018) Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): A randomized, controlled, multicenter phase III trial. J Clin Oncol 36(18_suppl):LBA4002CrossRefGoogle Scholar
  25. 25.
    Murphy JE, Wo JY, Ryan DP, Jiang W, Yeap BY, Drapek LC, Blaszkowsky LS, Kwak EL, Allen JN, Clark JW et al (2018) Total Neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol 4(7):963–969CrossRefGoogle Scholar
  26. 26.
    Katz MH, Shi Q, Ahmad SA, Herman JM, Marsh Rde W, Collisson E, Schwartz L, Frankel W, Martin R, Conway W et al (2016) Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancreatic cancer: alliance for clinical trials in oncology trial A021101. JAMA Surg 151(8):e161137CrossRefGoogle Scholar
  27. 27.
    Barenboim A, Lahat G, Geva R, Nachmany I, Nakache R, Goykhman Y, Brazowski E, Rosen G, Isakov O, Wolf I et al (2018) Neoadjuvant FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer: an intention to treat analysis. Eur J Surg Oncol 44(10):1619–1623CrossRefGoogle Scholar
  28. 28.
    Hammel P, Lacy J, Portales F, Sobrero AF, Cid RAP, Mozo JLM, Terrebonne E, Dowden SD, Li JS, Ong TJ et al (2018) Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC). J Clin Oncol 36(4_suppl):204CrossRefGoogle Scholar
  29. 29.
    Reni M, Balzano G, Zanon S, Zerbi A, Rimassa L, Castoldi R, Pinelli D, Mosconi S, Doglioni C, Chiaravalli M et al (2018) Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2–3 trial. Lancet Gastroenterol Hepatol 3(6):413–423CrossRefGoogle Scholar
  30. 30.
    Kunzmann V, Martens U, Alguel H, Siveke J et al (2018) Secondary resectability in locally advanced pancreatic cancer (LAPC) after nab-Paclitaxel/Gemcitabine- vs. FOLFIRINOX-based induction chemotherapy—minterim results of a randomized phase II AIO trial (NEOLAP). J Clin Oncol 36(4_suppl):348CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, ein Teil von Springer Nature 2019

Authors and Affiliations

  • Volker Kunzmann
    • 1
    Email author
  • Thomas J. Ettrich
    • 2
  • Ingo Hartlapp
    • 1
  • Thomas Seufferlein
    • 2
  1. 1.Medizinische Klinik und Poliklinik II & Comprehensive Cancer Center Mainfranken, Schwerpunkt Medizinische OnkologieUniversitätsklinikum WürzburgWürzburgDeutschland
  2. 2.Klinik für Innere Medizin IUniversitätsklinikum UlmUlmDeutschland

Personalised recommendations