Skip to main content

Advertisement

SpringerLink
Log in

Surrogate End Points for Overall Survival in Metastatic, Locally Advanced, or Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis of 24 Randomized Controlled Trials

  • Pancreatic Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Overall survival (OS) has traditionally been the primary end point in studies evaluating the clinical benefit of first-line chemotherapy in metastatic, locally advanced, or unresectable pancreatic cancer (MLAUPC). Given the prolonged follow-up assessment required to obtain OS and its potential to be confounded by second-line treatments, this study sought to determine whether progression-free survival (PFS), response rate (RR), or disease control rate (DCR) can serve as a reliable surrogate for OS.

Methods

A systematic review and meta-analysis was performed including all phase 3 clinical trials for MLAUPC, with gemcitabine as the control arm of the trial. The hazard ratios (HRs) for OS and PFS and odds ratios (ORs) for RR and DCR were recorded. A weighted Pearson correlation coefficient was estimated for the association between OS and the other outcomes. The primary analysis used a random effects weighting model, whereas the secondary analyses used a fixed effects- or sample size-weighted approach.

Results

For the study, 24 randomized controlled trials were identified. The Pearson correlation coefficient between OS and PFS was 0.86 (95% confidence interval [CI] 0.67–0.94; p < 0.001). Sensitivity analysis of the studies with little to no crossover further showed a correlation coefficient of 0.91 (95% CI 0.76–0.97; p < 0.001). The correlation coefficient between OS and RR was 0.45 (95% CI 0.07–0.72; p = 0.02) and between OS and DCR was 0.74 (95% CI 0.38–0.90; p < 0.001).

Conclusions

First-line chemotherapy trials for MLAUPC show a robust correlation between OS and PFS, affirming its role as a surrogate of OS.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22:151–85.

    Article  PubMed  Google Scholar 

  2. He P, Lai TL, Su Z. Design of clinical trials with failure-time endpoints and interim analyses: an update after fifteen years. Contemp Clin Trials. 2015;45:103–112.

    Article  PubMed  Google Scholar 

  3. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol. 2003;21:1404–11.

    Article  PubMed  Google Scholar 

  4. Schilsky RL. End points in cancer clinical trials and the drug approval process. Clin Cancer Res. 2002;8:935–8.

    PubMed  Google Scholar 

  5. National Cancer Institute Dictionary of Cancer Terms. 2016. https://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed 2 Jan 2016.

  6. Foster NR, Qi Y, Shi Q, et al. Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials. Cancer. 2011;117:1262–71.

    Article  PubMed  Google Scholar 

  7. Giessen C, Laubender RP, Ankerst DP, et al. Progression-free survival as a surrogate endpoint for median overall survival in metastatic colorectal cancer: literature-based analysis from 50 randomized first-line trials. Clin Cancer Res. 2013;19:225–35.

    Article  CAS  PubMed  Google Scholar 

  8. Lara PN Jr, Moon J, Redman MW, et al. Disease control rate at 8 weeks predicts subsequent survival in platinum-treated extensive stage small-cell lung cancer: results from the Southwest Oncology Group (SWOG) database. Clin Lung Cancer. 2016;17:113–118; e111–112.

    Google Scholar 

  9. Flaherty KT, Hennig M, Lee SJ, et al. Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials. Lancet Oncol. 2014;15:297–304.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Burzykowski T, Buyse M, Piccart-Gebhart MJ, et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol. 2008;26:1987–92.

    Article  CAS  PubMed  Google Scholar 

  11. Delea TE, Khuu A, Heng DY, Haas T, Soulieres D. Association between treatment effects on disease progression end points and overall survival in clinical studies of patients with metastatic renal cell carcinoma. Br J Cancer. 2012;107:1059–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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;74:2913–21.

    Article  CAS  PubMed  Google Scholar 

  13. Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of the 6th edition AJCC Pancreatic Cancer Staging System: report from the National Cancer Database. Cancer. 2007;110:738–44.

    Article  PubMed  Google Scholar 

  14. Petrelli F, Coinu A, Borgonovo K, Cabiddu M, Barni S. Progression-free survival as surrogate endpoint in advanced pancreatic cancer: meta-analysis of 30 randomized first-line trials. Hepatobil Pancreatic Dis Int. 2015;14:124–31.

    Article  Google Scholar 

  15. Hamada T, Nakai Y, Isayama H, et al. Progression-free survival as a surrogate for overall survival in first-line chemotherapy for advanced pancreatic cancer. Eur J Cancer. 2016;65:11–20.

    Article  PubMed  Google Scholar 

  16. Rothstein H, Sutton AJ, Borenstein M. Publication bias in meta-analysis: prevention, assessment and adjustments. Wiley, Chichester, England; Hoboken, NJ, 2005.

    Book  Google Scholar 

  17. Eikelboom JW, Mehta SR, Pogue J, Yusuf S. Safety outcomes in meta-analyses of phase 2 vs phase 3 randomized trials: Intracranial hemorrhage in trials of bolus thrombolytic therapy. JAMA. 2001;285:444–50.

    Article  CAS  PubMed  Google Scholar 

  18. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  19. Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013;31:1640–8.

    Article  CAS  PubMed  Google Scholar 

  20. Fuchs CS, Azevedo S, Okusaka T, et al. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015;26:921–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gondos A, Arndt V, Holleczek B, Stegmaier C, Ziegler H, Brenner H. Cancer survival in Germany and the United States at the beginning of the 21st century: an up-to-date comparison by period analysis. Int J Cancer. 2007;121:395–400.

    Article  CAS  PubMed  Google Scholar 

  22. Brenner H. Long-term survival rates of cancer patients achieved by the end of the 20th century: a period analysis. Lancet. 2002;360:1131–5.

    Article  PubMed  Google Scholar 

  23. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Institute 2000;92:205–16.

    Article  CAS  Google Scholar 

  24. Lockhart AC, Rothenberg ML, Berlin JD. Treatment for pancreatic cancer: current therapy and continued progress. Gastroenterology. 2005;128:1642–54.

    Article  CAS  PubMed  Google Scholar 

  25. Rocha Lima CM, Green MR, Rotche 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  PubMed  Google Scholar 

  26. Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA, Marimastat Pancreatic Cancer Study G. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol. 2001;19:3447–55.

    Article  CAS  PubMed  Google Scholar 

  27. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Onco. 2005;23:3509–16.

    Article  CAS  Google Scholar 

  28. Giessen C, Laubender RP, Ankerst DP, et al. Surrogate endpoints in second-line treatment for mCRC: a systematic literature-based analysis from 23 randomised trials. Acta Oncol. 2015;54:187–93.

    Article  PubMed  Google Scholar 

  29. Lara PN Jr, Redman MW, Kelly K, et al. Disease control rate at 8 weeks predicts clinical benefit in advanced non-small-cell lung cancer: results from Southwest Oncology Group randomized trials. J Clin Oncol. 2008;26:463–7.

    Article  PubMed  Google Scholar 

  30. Chalmers TC, Levin H, Sacks HS, Reitman D, Berrier J, Nagalingam R. Meta-analysis of clinical trials as a scientific discipline: I. Control of bias and comparison with large co-operative trials. Stat Med. 1987;6:315–28.

    Article  CAS  PubMed  Google Scholar 

  31. Villar J, Carroli G, Belizan JM. Predictive ability of meta-analyses of randomised controlled trials. Lancet. 1995;345:772–6.

    Article  CAS  PubMed  Google Scholar 

  32. Cappelleri JC, Ioannidis JP, Schmid CH, et al. Large trials vs meta-analysis of smaller trials: how do their results compare? JAMA. 1996;276:1332–8.

    Article  CAS  PubMed  Google Scholar 

  33. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536–42.

    Article  CAS  PubMed  Google Scholar 

  35. Tang PA, Bentzen SM, Chen EX, Siu LL. Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol. 2007;25:4562–8.

    Article  PubMed  Google Scholar 

  36. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125:605–13.

    Article  CAS  PubMed  Google Scholar 

  37. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431–40.

    Article  CAS  PubMed  Google Scholar 

  38. Burzykowski T. Surrogate endpoints: wishful thinking or reality? Stat Methods Med Res. 2008;17:463–6.

    Article  PubMed  Google Scholar 

  39. Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol. 2006;24(27):4441–47.

    Article  CAS  PubMed  Google Scholar 

  40. Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB, 3rd. 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(15):3270–75.

    Article  CAS  PubMed  Google Scholar 

  41. Colucci G, Labianca R, Di Costanzo F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol. 2010;28(10):1645–51.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27(33):5513–18.

    Article  CAS  PubMed  Google Scholar 

  44. Dahan L, Bonnetain F, Ychou M, et al. Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301). Gut. 2010;59(11):1527–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goncalves A, Gilabert M, Francois E, et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012;23(11):2799–805.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007;25(16):2212–17.

    Article  CAS  PubMed  Google Scholar 

  48. Kindler HL, Richards DA, Garbo LE, et al. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol. 2012;23(11):2834–42.

    Article  CAS  PubMed  Google Scholar 

  49. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–66.

    Article  CAS  PubMed  Google Scholar 

  50. Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol. 2005;16(10):1639–45.

    Article  CAS  PubMed  Google Scholar 

  51. Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010;28(22):3605–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27(23):3778–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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(6):369–76.

    Article  CAS  PubMed  Google Scholar 

  54. Rougier P, Riess H, Manges R, et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013;49(12):2633–42.

    Article  CAS  PubMed  Google Scholar 

  55. O’Neil BH, Scott AJ, Ma WW, et al. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2016; 27(6):1180.

    Article  PubMed  Google Scholar 

  56. Stathopoulos GP, Syrigos K, Aravantinos G, et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer. 2006;95(5):587–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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.

    Article  Google Scholar 

Download references

Disclosure

There are no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Surgery, Stanford School of Medicine, Stanford, CA, USA

    Eleftherios A. Makris MD, PhD & George A. Poultsides MD

  2. Department of Biomedical Engineering, University of California Davis, Davis, CA, USA

    Regina MacBarb PhD

  3. Department of Public Health Sciences, University of California Davis, Davis, CA, USA

    Danielle J. Harvey PhD

Authors
  1. Eleftherios A. Makris MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Regina MacBarb PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Danielle J. Harvey PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George A. Poultsides MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George A. Poultsides MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Makris, E.A., MacBarb, R., Harvey, D.J. et al. Surrogate End Points for Overall Survival in Metastatic, Locally Advanced, or Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis of 24 Randomized Controlled Trials. Ann Surg Oncol 24, 2371–2378 (2017). https://doi.org/10.1245/s10434-017-5826-2

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-017-5826-2

Keywords

Search

Navigation