Skip to main content

Advertisement

Log in

The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer

Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy.

Methods

Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15.

Results

Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months.

Conclusions

The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.

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.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Kleeff J, Korc M, Apte M, et al. Pancreatic cancer. Nat Rev Dis Primers. 2016;2:16022.

    PubMed  Google Scholar 

  2. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74(11):2913–21.

    CAS  PubMed  Google Scholar 

  3. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473–81.

    CAS  PubMed  Google Scholar 

  4. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection. JAMA. 2010;304(10):1073–81.

    CAS  PubMed  Google Scholar 

  5. Uesaka K, Boku N, Fukutomi A, et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016;388(10041):248–57.

    CAS  PubMed  Google Scholar 

  6. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:2395–406.

    CAS  PubMed  Google Scholar 

  7. Neoptolemos JP, Palmer DH, Ghaneh P, et al. 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. 2017;389(10073):1011–24.

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  9. Tempero MA, Cardin DB, Goldstein D, et al. APACT: phase III randomized trial of adjuvant treatment with nab-paclitaxel (nab-P) plus gemcitabine (Gem) versus Gem alone in patients (pts) with resected pancreatic cancer (PC). J Clin Oncol. 2016;34(4 Suppl):TPS473.

    Google Scholar 

  10. Fathi A, Christians KK, George B, et al. Neoadjuvant therapy for localized pancreatic cancer: guiding principles. J Gastrointest Oncol. 2015;6(4):418–29.

    PubMed  PubMed Central  Google Scholar 

  11. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20.

    CAS  PubMed  Google Scholar 

  12. Hofheinz R-D, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012;13(6):579–88.

    CAS  PubMed  Google Scholar 

  13. Gillen S, Schuster T, Meyer zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLOS Med. 2010;7(4):e1000267.

    PubMed  PubMed Central  Google Scholar 

  14. Chang DK, Johns AL, Merrett ND, et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol. 2009;27(17):2855–62.

    PubMed  Google Scholar 

  15. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3496–502.

    CAS  PubMed  Google Scholar 

  16. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3487–95.

    CAS  PubMed  Google Scholar 

  17. Jang JY, Han Y, Lee H, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg. 2018;268(2):215–22.

    PubMed  Google Scholar 

  18. Van Tienhoven G, Versteijne E, Suker M, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial [abstract no. LBA4002]. J Clin Oncol. 2018. https://doi.org/10.1200/JCO.2018.36.18_suppl.LBA4002.

    Article  Google Scholar 

  19. Palmer D, Stocken D, Hewitt H, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol. 2007;14(7):2088–96.

    PubMed  Google Scholar 

  20. Heinrich S, Pestalozzi B, Schafer M, et al. Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and cisplatin for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(15):2526–31.

    CAS  PubMed  Google Scholar 

  21. O’Reilly E, Perelshteyn A, Jarnagin W, et al. A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma. Ann Surg. 2014;260(1):142–8.

    PubMed  Google Scholar 

  22. Lutfi W, Talamonti MS, Kantor O, et al. Perioperative chemotherapy is associated with a survival advantage in early stage adenocarcinoma of the pancreatic head. Surgery. 2016;160(3):714–24.

    PubMed  Google Scholar 

  23. Mokdad AA, Minter RM, Zhu H, et al. Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score matched analysis. J Clin Oncol. 2017;35(5):515–22.

    PubMed  Google Scholar 

  24. National Comprehensive Cancer Network. NCCN guidelines for patients: pancreatic cancer. 2017. https://www.nccn.org/patients/guidelines/pancreatic/files/assets/basic-html/page-1.html.

  25. Al-Hawary MM, Francis IR, Chari ST, et al. Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the Society of Abdominal Radiology and the American Pancreatic Association. Radiology. 2014;270(1):248–60.

    PubMed  Google Scholar 

  26. Ryan R, Gibbons D, Hyland JM, et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology. 2005;47(2):141–6.

    CAS  PubMed  Google Scholar 

  27. Chuong MD, Frakes JM, Figura N, et al. Histopathologic tumor response after induction chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer. J Gastrointest Oncol. 2015;7(2):221–7.

    Google Scholar 

  28. Vickers MM, Lee C, Tu D, et al. Significance of baseline and change in quality of life scores in predicting clinical outcomes in an international phase III trial of advanced pancreatic cancer: NCIC CTG PA.3. Pancreatology. 2016;16(6):1106–12.

    CAS  PubMed  Google Scholar 

  29. Tajima H, Ohta T, Kitagawa H, et al. Pilot study of neoadjuvant chemotherapy with gemcitabine and oral S-1 for resectable pancreatic cancer. Exp Ther Med. 2012;3(5):787–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Raut CP, Tseng JF, Sun CC, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007;246(1):52–60.

    PubMed  PubMed Central  Google Scholar 

  31. Hartwig W, Hackert T, Hinz U, et al. Pancreatic cancer surgery in the new millennium: better prediction of outcome. Ann Surg. 2011;254(2):311–9.

    PubMed  Google Scholar 

  32. Royal College of Pathologists of Australasia. Cancer of the exocrine pancreas, ampulla of Vater and distal common bile duct. Structured reporting protocol. 1st edition. Sydney: Royal College of Pathologists of Australasia; 2014.

    Google Scholar 

  33. Shinoto M, Yamada S, Yasuda S, et al. Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer. Cancer. 2013;119(1):45–51.

    PubMed  Google Scholar 

  34. Turrini O, Ychou M, Moureau-Zabotto L, et al. Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: new neoadjuvant regimen was safe and provided an interesting pathologic response. Eur J Surg Oncol. 2010;36(10):987–92.

    CAS  PubMed  Google Scholar 

  35. Alvarez-Gallego R, Cubillo A, Garralda E, et al. Pathological response to neoadjuvant gemcitabine plus nabpaclitaxel in pancreatic adenocarcinoma to improve survival. J Clin Oncol. 2016;34(15 Suppl):4109.

    Google Scholar 

  36. Ielpo B, Duran H, Diaz E, et al. Preoperative treatment with gemcitabine plus nab-paclitaxel is a safe and effective chemotherapy for pancreatic adenocarcinoma. Eur J Surg Oncol. 2016;42(9):1394–400.

    CAS  PubMed  Google Scholar 

  37. MacKenzie S, Zen H, McCahill LE, et al. A pilot phase II multicenter study of nab-paclitaxel (Nab-P) and gemcitabine (G) as preoperative therapy for potentially resectable pancreatic cancer (PC). J Clin Oncol. 2013;31(15Suppl):4038.

    Google Scholar 

  38. Sliesoriatis S, Desai NV, Trevino JG, et al. Final results for gemcitabine with nab-paclitaxel in neoadjuvant treatment of resectable pancreatic adenocarcinoma: GAIN-1 study. J Clin Oncol. 2014;32(15 Suppl):e15201.

    Google Scholar 

  39. Chandrasegaram MD, Goldstein D, Simes J, et al. Meta-analysis of radical resection rates and margin assessment in pancreatic cancer. Br J Surg. 2015;102(12):1459–72.

    CAS  PubMed  Google Scholar 

  40. Konstantinidis IT, Warshaw AL, Allen JN, et al. Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a ‘true’ R0 resection? Ann Surg. 2013;257(4):731–6.

    PubMed  Google Scholar 

  41. Mathur A, Ross SB, Luberice K, et al. Margin status impacts survival after pancreaticoduodenectomy but negative margins should not be pursued. Am Surg. 2014;80(4):353–60.

    PubMed  Google Scholar 

  42. Verbeke C, Lohr M, Karlsson JS, Del Chiaro M. Pathology reporting of pancreatic cancer following neoadjuvant therapy: challenges and uncertainties. Cancer Treat Rev. 2015;41(1):17–26.

    CAS  PubMed  Google Scholar 

  43. Sohal D, McDonough S, Ahmad SA, et al. SWOG S1505: Initial findings on eligibility and neoadjuvant chemotherapy experience with mfolfirinox versus gemcitabine/nab-paclitaxel for resectable pancreatic adenocarcinoma. J Clin Oncol. 2019;37(4 Suppl):414.

    Google Scholar 

  44. Mornex F, Girard N, Scoazec JY, et al. Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: the French SFRO-FFCD 97-04 phase II trial. Int J Radiat Oncol Biol Phys. 2006;65(5):1471–8.

    CAS  PubMed  Google Scholar 

  45. Scheithauer W, Ramanathan RK, Moore M, et al. Dose modification and efficacy of nab-paclitaxel plus gemcitabine vs. gemcitabine for patients with metastatic pancreatic cancer: phase III MPACT trial. J Gastrointest Oncol. 2016;7(3):469–78.

    PubMed  PubMed Central  Google Scholar 

  46. Serrano PE, Herman JM, Griffith KA, et al. Quality of life in a prospective multi-center phase II trial of neoadjuvant full dose gemcitabine, oxaliplatin and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;90(2):270–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Liao WC, Chien KL, Lin YL, et al. Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14(11):1095–103.

    PubMed  Google Scholar 

  48. 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 

  49. Tempero MA, Reni M, Riess H, et al. Randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma. J Clin Oncol. 2019;37(15 Suppl):4000.

    Google Scholar 

  50. Versteijne E, Vogel JA, Besselink MG, et al. Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg. 2018;105(8):946–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ettrich TJ, Berger AW, Muche R, et al. NEONAX: Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer: a phase II study of the AIO Pancreatic Cancer Group. J Clin Oncol. 2014;32(12 Suppl):tps4158.

    Google Scholar 

Download references

GAP Investigators

Trial Management Committee: A. Barbour (chair), D. Goldstein, J.S. Samra, M. Harris, Y.J. Chua, M. Burge, N. O’Rourke, S. Yip, V. Gebski, J. Simes, R. Hicks.

Independent Data Safety Monitoring Committee: A. Coates (chair), H. Gurney, V. Do, I. Marschner.

Clinical Trials Centre: J. Mitchell, M. Donoghoe, V. Gebski, J. Simes, S. Goldstone, S. Yip, J. Simes.

Participating Medical Oncologists: Y.J. Chua (The Canberra Hospital, Canberra, ACT, Australia), N. Pavlakis (Royal North Shore Hospital, Sydney, NSW, Australia), D. Goldstein (Prince of Wales Hospital, Sydney, NSW, Australia), M. Aghmesheh (Southern Medical Day Care Centre, Woolongong, NSW, Australia), M. Burge (Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia), W. Joubert (Icon Cancer Care Wesley, Brisbane, QLD, Australia), D. Grimes (Greenslopes Private Hospital, Brisbane, QLD, Australia), M. Harris (Monash Medical Centre, Melbourne, VIC, Australia).

Participating Surgeons: J.S. Samra, K.S. Haghighi, P. Truskett, S. Bagia, M. Jaber (Sydney, NSW, Australia); S. Gananadha (Canberra, ACT, Australia); N. O’Rourke, R. Bryant, L. Nathanson, D. Cavallucci, A. Barbour, J. Fawcett, T. O’Rourke (Brisbane, QLD, Australia); D. Croagh, R. Jones (Melbourne, VIC, Australia).

Funding

Specialized Therapeutics Australia provided funding support and supplied nab‐paclitaxel; gemcitabine was available on the Pharmaceutical Benefits Scheme (PBS). This study was partly funded by the GAP-T NHMRC Project Grant (APP1026563). Trial management and statistical support was undertaken by the NHMRC-CTC. The AGITG was the legal sponsor and the trial was registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12611000848909). The GAP study was conducted under the auspices of the AGITG, the legal sponsor, independently of the funders. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

AB and DG had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study Concept and Design: Barbour, Gebski, Kench, Goldstein. Acquisition, Analysis, or Interpretation of Data: All authors. Drafting of the Manuscript: Barbour, Goldstein, Donoghoe, Gebski, Chan. Critical Revision of the Manuscript for Important Intellectual Content: All authors. Statistical Analysis: Donoghoe, Gebski. Obtained Funding: Barbour, Goldstein, Kench. Administrative, Technical, or Material Support: Barbour, Goldstein, Mitchell, Chan. Study Supervision: Barbour, Goldstein, Mitchell, Chan, Chua, Samra, Burge, Harris, O’Rourke, Kench. Additional Contributions: John Simes from the CTC provided input into the study concept and design, critical revision of the manuscript, and statistical advice. Jonathon Fawcett from the Queensland Liver Transplant Service, Brisbane, QLD, Australia, provided independent assessment of pathology reports. Sherilyn Goldstone from the CTC assisted with manuscript preparation, and Chris Brown from the CTC is acknowledged for statistical work. Manju Chandrasegaram, AGITG Research Fellow and Hepatopancreatobiliary (HPB) and General Surgeon reviewed the surgical literature to inform this paper. These people were not specifically compensated for their work. Local investigators, surgeons, and data managers gathered the data, which were submitted to the CTC in Sydney, NSW, Australia, via an electronic data collection system.

Corresponding author

Correspondence to Andrew P. Barbour MBBS PhD FRACS FACS.

Ethics declarations

Disclosure

None of the authors has declared any potential conflicts of interest with respect to this study.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 58 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barbour, A.P., Samra, J.S., Haghighi, K.S. et al. The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer. Ann Surg Oncol 27, 2506–2515 (2020). https://doi.org/10.1245/s10434-020-08205-2

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-020-08205-2

Navigation