, Volume 36, Issue 3, pp 289–299 | Cite as

Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

  • Nigel Fleeman
  • Ahmed Abdulla
  • Adrian Bagust
  • Sophie Beale
  • Marty Richardson
  • Angela Stainthorpe
  • Angela Boland
  • Eleanor Kotas
  • Joanne McEntee
  • Daniel Palmer
Review Article


The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute’s Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company’s evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company’s economic model. Using the discounted patient access scheme price for liposomal irinotecan + 5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin + 5-FU/LV. The ERG considered that the company’s base-case cost-effectiveness results for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV were underestimates and should be interpreted with extreme caution. Following implementation of a number of model amendments, the ERG’s modified exploratory ICER for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV was £106,898 per QALY gained. The AC accepted the majority of the ERG’s amendments to the model, and also highlighted that the total QALYs for oxaliplatin + 5-FU/LV were lower than for 5-FU/LV in the company’s model, which the AC considered to be clinically implausible. The AC therefore considered results from exploratory analyses, undertaken by the ERG, which included altering the QALY difference between liposomal irinotecan + 5-FU/LV and oxaliplatin + 5-FU/LV by ± 10%. These analyses resulted in ICERs for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV of between £201,019 per QALY gained to liposomal irinotecan + 5-FU/LV being dominated by oxaliplatin + 5-FU/LV. Therefore, despite uncertainty around the clinical-effectiveness evidence and cost-effectiveness results, the AC was confident that the ICER was in excess of £50,000 per QALY gained. The final guidance issued by NICE is that liposomal irinotecan + 5-FU/LV is not recommended within its marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.



The authors would like to thank Janette Greenhalgh who commented on an early draft of the paper.

Author Contributions

NF: Project lead, drafted the clinical results section and supervised the final report. AA: Critique of the company economic model and proposal of alternative interpretations of the economic evidence. AB: Checking, critiquing and validating the economic model/evidence. SB: Critical appraisal of the clinical and economic evidence, and editorial input. MR: Critical appraisal of the statistical evidence. AS: Summary and critical appraisal of the economic evidence. AB: Critical appraisal of the clinical and economic evidence, and editorial input. EK: Critical appraisal of the database searching. JM: Critical appraisal of the submission. DP: Clinical advice and critical appraisal of the clinical sections of the company’s submission. All authors read and commented on draft versions of this paper. This summary has not been externally reviewed by PharmacoEconomics.

Compliance with Ethical standards


This project was funded by the National Institute for Health Research Health Technology Assessment Programme (Project Number 15/121/02) [see the Health Technology Assessment programme website for further project information,]. This summary of the ERG report was compiled after the AC’s review. The views and opinions expressed are those of the authors and do not necessarily reflect those of the National Institute for Health and Care Excellence or the Department of Health.

Conflict of interests

Within the last 3 years, Daniel Palmer has received consultancy fees and funds for research from Baxalta, which is now part of Shire Pharmaceuticals. Nigel Fleeman, Ahmed Abdulla, Adrian Bagust, Sophie Beale, Marty Richardson, Angela Stainthorpe, Angela Boland, Eleanor Kotas and Joanne McEntee have no competing interests.


  1. 1.
    National Institute for Health and Clinical Excellence (NICE). Guide to the methods of technology appraisal 2013. Accessed 7 Feb 2017.
  2. 2.
    National Institute for Health and Care Excellence (NICE). Pegylated liposomal irinotecan for treating pancreatic cancer after gemcitabine Technology appraisal guidance [TA440]. Published date: 26 April 2017. Accessed 17 Aug 2017.
  3. 3.
    Cancer Research UK. Pancreatic cancer incidence statistics. Accessed 28 Mar 2017.
  4. 4.
    Cancer Research UK. Pancreatic cancer survival statistics. Accessed 28 Mar 2017.
  5. 5.
    Smyth EN, Bapat B, Ball DE, Andre T, Kaye JA. Metastatic pancreatic adenocarcinoma treatment patterns, health care resource use, and outcomes in France and the United Kingdom between 2009 and 2012: a retrospective study. Clin Ther. 2015;37(6):1301–16.CrossRefPubMedGoogle Scholar
  6. 6.
    National Institute for Health and Care Excellence (NICE). Single technology appraisal. Nanoliposomal irinotecan for treating pancreatic cancer after prior treatment with gemcitabine. Final scope. Accessed 21 Apr 2016.
  7. 7.
    Azmy A, Abdelwahab S, Yassen M. Oxaliplatin and bolus-modulated 5-fluorouracil as a second-line treatment for advanced pancreatic cancer: can bolus regimens replace FOLFOX when considered for second line? ISRN Oncol. 2013;2013:358538.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Bjerregaard J, Ladekarl M, Jensen H, Vestermark L, Farr K, Pfeiffer P. A randomized phase I/II study of everolimus, irinotecan, and cetuximab versus capecitabine and oxaliplatin in gemcitabine-resistant patients with pancreatic cancer. J Clin Oncol. 2014;32(3_suppl).
  9. 9.
    Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drug. 2012;30(3):1216–23.CrossRefGoogle Scholar
  10. 10.
    Chung VM, McDonough SL, Philip PA, Cardin DB, Wang-Gillam A, Hui L, et al. SWOG S1115: Randomized phase II trial of selumetinib (AZD6244; ARRY 142886) hydrogen sulfate (NSC-748727) and MK-2206 (NSC-749607) vs. mFOLFOX in pretreated patients (pts) with metastatic pancreatic cancer. J Clin Oncol. 2015;33(15_suppl).
  11. 11.
    Gill S, Ko Y-J, Cripps M, Beaudoin A, Dhesy-Thind S, Zulfiqar M, et al. PANCREOX: A randomized phase 3 study of 5FU/LV with or without oxaliplatin for second-line advanced pancreatic cancer (APC) in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2014;32(15_suppl).
  12. 12.
    Heinemann V, Vehling-Kaiser U, Waldschmidt D, Kettner E, Marten A, Winkelmann C, et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut. 2013;62(5):751–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Hurwitz HI, Uppal N, Wagner SA, Bendell JC, Beck JT, Wade SM 3rd, et al. Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J Clin Oncol. 2015;33(34):4039–47.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ioka T, Katayama K, Ishida N, Takada R, Yamai T, Fukutake N, et al. Randomized phase II study of best available fluoropyrimidine compared with continuation of gemcitabine (Gem) monotherapy in patients with Gem-refractory pancreatic cancer. J Clin Oncol. 2013;31(4_suppl).
  15. 15.
    Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32(23):2423–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dorken B, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011;47(11):1676–81.CrossRefPubMedGoogle Scholar
  17. 17.
    Shi SB, Ma TH, Tang XY, Li CH. Effect of second-line treatment with capecitabine and thalidomide in patients with advanced pancreatic cancer [in Chinese]. Zhonghua Zhong Liu Za Zhi. 2013;35(4):301–4.PubMedGoogle Scholar
  18. 18.
    Wang-Gillam A, Li C-P, Bodoky G, Dean A, Shan Y-S, Jameson G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2015;387(10018):545–57.CrossRefPubMedGoogle Scholar
  19. 19.
    Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, et al. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009;101(10):1658–63.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ko AH, Tempero MA, Shan YS, Su WC, Lin YL, Dito E, et al. A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer. Br J Cancer. 2013;109(4):920–5.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Sacco JJ, Botten J, Macbeth F, Bagust A, Clark P. The average body surface area of adult cancer patients in the UK: a multicentre retrospective study. PLoS One. 2010;5(1):e8933.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    British National Formulary. BNF online. 2016. Accessed 28 Mar 2017.
  23. 23.
    Department of Health. NHS reference costs 2014 to 2015. 2015. Accessed 11 May 2016.
  24. 24.
    Greenhalgh J, Beale S, Boland A, Bagust A, Dwan K, Richardson M, et al. Paclitaxel formulated as albumin-bound nanoparticles in combination with gemcitabine for previously untreated metastatic pancreatic cancer: a single technology appraisal. 2014. Accessed 21 Apr 2016.
  25. 25.
    Latimer N. NICE DSU Technical support document 14: Survival analysis for economic evaluations alongside clinical trials—extrapolation with patient-level data. Sheffield: NICE Decision Support Unit; 2011.Google Scholar
  26. 26.
    Department of Health. Drugs and pharmaceutical electronic market information (eMit). 2016. Accessed 5 Jun 2016.
  27. 27.
    Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003;13(3):176–81.CrossRefPubMedGoogle Scholar
  28. 28.
    National Institute for Health and Care Excellence (NICE). Paclitaxel as albumin-bound nanoparticles in combination with gemcitabine for previously untreated metastatic pancreatic cancer. Technology appraisal guidance [TA360]. Published date: 28 October 2015. Accessed 29 Mar 2017.
  29. 29.
    Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, et al. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016;27(4):673–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    van den Hout WB, Kramer GW, Noordijk EM, Leer JW. Cost-utility analysis of short- versus long-course palliative radiotherapy in patients with non-small-cell lung cancer. J Natl Cancer Inst. 2006;98(24):1786–94.CrossRefPubMedGoogle Scholar
  31. 31.
    Romanus D, Kindler HL, Archer L, Basch E, Niedzwiecki D, Weeks J, et al. Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial of the cancer and leukemia group B (CALGB 80303). J Pain Symptom Manag. 2012;43(2):205–17.CrossRefGoogle Scholar
  32. 32.
    National Institute for Health and Clinical Excellence (NICE). Appraising life-extending, end of life treatments. Supplementary advice to the Appraisal Committees. Revised in July 2009. Accessed 28 Mar 2017.

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Nigel Fleeman
    • 1
  • Ahmed Abdulla
    • 1
  • Adrian Bagust
    • 1
  • Sophie Beale
    • 1
  • Marty Richardson
    • 1
  • Angela Stainthorpe
    • 1
  • Angela Boland
    • 1
  • Eleanor Kotas
    • 1
  • Joanne McEntee
    • 2
  • Daniel Palmer
    • 3
  1. 1.Liverpool Reviews and Implementation GroupUniversity of LiverpoolLiverpoolUK
  2. 2.North West Medicines Information CentreLiverpoolUK
  3. 3.Molecular and Clinical Cancer MedicineUniversity of LiverpoolLiverpoolUK

Personalised recommendations