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Personalised radioembolization improves outcomes in refractory intra-hepatic cholangiocarcinoma: a multicenter study

  • Hugo LevillainEmail author
  • Ivan Duran Derijckere
  • Lieveke Ameye
  • Thomas Guiot
  • Arthur Braat
  • Carsten Meyer
  • Bruno Vanderlinden
  • Nick Reynaert
  • Alain Hendlisz
  • Marnix Lam
  • Christophe M. Deroose
  • Hojjat Ahmadzadehfar
  • Patrick Flamen
Original Article
Part of the following topical collections:
  1. Oncology – Digestive tract

Abstract

Purpose

Reported outcomes of patients with intra-hepatic cholangiocarcinoma (IH-CCA) treated with radioembolization are highly variable, which indicates differences in included patients’ characteristics and/or procedure-related variables. This study aimed to identify patient- and treatment-related variables predictive for radioembolization outcome.

Methods

This retrospective multicenter study enrolled 58 patients with unresectable and chemorefractory IH-CCA treated with resin 90Y-microspheres. Clinicopathologic data were collected from patient records. Metabolic parameters of liver tumor(s) and presence of lymph node metastasis were measured on baseline 18F-FDG-PET/CT. 99mTc-MAA tumor to liver uptake ratio (TLRMAA) was computed for each lesion on the SPECT-CT. Activity prescription using body-surface-area (BSA) or more personalized partition-model was recorded. The study endpoint was overall survival (OS) starting from date of radioembolization. Statistical analysis was performed by the log-rank test and multivariate Cox’s proportional hazards model.

Results

Median OS (mOS) post-radioembolization of the entire cohort was 10.3 months. Variables associated with significant differences in terms of OS were serum albumin (hazard ratio (HR) = 2.78, 95%CI:1.29–5.98, p = 0.002), total bilirubin (HR = 2.17, 95%CI:1.14–4.12, p = 0.009), aspartate aminotransferase (HR = 2.96, 95%CI:1.50–5.84, p < 0.001), alanine aminotransferase (HR = 2.02, 95%CI:1.05–3.90, p = 0.01) and γ-GT (HR = 2.61, 95%CI:1.31–5.22, p < 0.001). The presence of lymph node metastasis as well as a TLRMAA < 1.9 were associated with shorter mOS: HR = 2.35, 95%CI:1.08–5.11, p = 0.008 and HR = 2.92, 95%CI:1.01–8.44, p = 0.009, respectively. Finally, mOS was significantly shorter in patients treated according to the BSA method compared to the partition-model: mOS of 5.5 vs 14.9 months (HR = 2.52, 95%CI:1.23–5.16, p < 0.001). Multivariate analysis indicated that the only variable that increased outcome prediction above the clinical variables was the activity prescription method with HR of 2.26 (95%CI:1.09–4.70, p = 0.03). The average mean radiation dose to tumors was significantly higher with the partition-model (86Gy) versus BSA (38Gy).

Conclusion

Radioembolization efficacy in patients with unresectable recurrent and/or chemorefractory IH-CCA strongly depends on the tumor radiation dose. Personalized activity prescription should be performed.

Keywords

Intra-hepatic cholangiocarcinoma Radioembolization SIRT Yttrium-90 Resin microspheres 

Notes

Acknowledgments

This academic work was supported and sponsored by the Jules Bordet Institute. Part of the results was presented at the 2019 SNMMI–annual congress of the Society of Nuclear Medicine and Molecular Imaging as an oral presentation during the GI – Colorectal, liver, esophageal session (OP- 216).

Funding

This work was not supported by a grant.

Compliance with ethical standards

Conflict of interest

PF, AH, HA and CD played an advisory role and received honoraria from Sirtex.

ML is a consultant for BTG, Sirtex, Quirem and Terumo. He receives research support from BTG, Quirem and Terumo. The department of Radiology and Nuclear Medicine of the UMC Utrecht receives royalties from Quirem.

BV played an advisory role and received honoraria from Dosisoft.

The first author and all other co-authors have no conflicts of interest to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Jules Bordet Institute Ethics Committee (CE2575) and Ethics Committees of all other participating centres. For this type of study formal consent is not required.

This article does not contain any studies with animals performed by any of the authors.

Supplementary material

259_2019_4427_MOESM1_ESM.xlsx (14 kb)
Supplementary material 1 18F-FDG-PET/CT and 99mTc-SPECT/CT patient based analysis (XLSX 14 kb)
259_2019_4427_MOESM2_ESM.pdf (332 kb)
Supplementary material 2 Correlation matrix of the 20 continuous variables (PDF 332 kb)
259_2019_4427_MOESM3_ESM.xlsx (16 kb)
Supplementary material 3 Comparison between patients treated with the BSA method and patients treated with the partition-model (XLSX 16 kb)

References

  1. 1.
    Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. Hpb. 2008;10:77–82. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1365182X1530023X. Accessed Apr 2008.
  2. 2.
    Cucchetti A, Cappelli A, Mosconi C, Zhong JH, Cescon M, Pinna AD, et al. Improving patient selection for selective internal radiation therapy of intra-hepatic cholangiocarcinoma: a meta-regression study. Liver Int. 2017;37:1056–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Park J, Kim MH, Kim KP, Park DH, Moon SH, Song TJ, et al. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study. Gut Liver. 2009;3:298–305.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Tan JCC, Coburn NG, Baxter NN, Kiss A, Law CHL. Surgical management of intrahepatic cholangiocarcinoma—a population-based study. Ann Surg Oncol. 2008;15:600–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Currie B, Soulen M. Decision making: intra-arterial therapies for cholangiocarcinoma—TACE and TARE. Semin Intervent Radiol. 2017;34:092–100.  https://doi.org/10.1055/s-0037-1602591.CrossRefGoogle Scholar
  6. 6.
    Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81.  https://doi.org/10.1056/NEJMoa0908721.
  7. 7.
    Rafi S, Piduru SM, El-Rayes B, Kauh JS, Kooby DA, Sarmiento JM, et al. Yttrium-90 radioembolization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety study. Cardiovasc Intervent Radiol. 2013;36:440–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Saxena A, Bester L, Chua TC, Chu FC, Morris DL. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol. 2010;17:484–91.  https://doi.org/10.1245/s10434-009-0777-x.CrossRefPubMedGoogle Scholar
  9. 9.
    Hoffmann RT, Paprottka PM, Schön A, Bamberg F, Haug A, Dürr EM, et al. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol. 2012;35:105–16.CrossRefPubMedGoogle Scholar
  10. 10.
    Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(Suppl 1):122S–50S. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2755245&tool=pmcentrez&rendertype=abstract. Accessed 1 Oct 2009.
  11. 11.
    Grosser OS, Ulrich G, Furth C, Pech M, Ricke J, Amthauer H, et al. Intrahepatic activity distribution in radioembolization with Yttrium-90–labeled resin microspheres using the body surface area method—a less than perfect model. J Vasc Interv Radiol. 2015;26(11):1615–21. Available from: https://www.sciencedirect.com/science/article/pii/S1051044315006995?via%3Dihub. Accessed 28 Aug 2015.
  12. 12.
    Ho S, Lau WY, Leung TWT, Chan M, Ngar YK, Johnson PJ, et al. Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours. Eur J Nucl Med. 1996;23:947–52.CrossRefPubMedGoogle Scholar
  13. 13.
    Dieudonne A., Garin E, Laffont S, Rolland Y, Lebtahi R, Leguludec D, et al. Clinical feasibility of fast 3-dimensional dosimetry of the liver for treatment planning of hepatocellular carcinoma with 90Y-Microspheres. J Nucl Med 2011;52:1930–1937.Google Scholar
  14. 14.
    Levillain H, Duran Derijckere I, Marin G, Guiot T, Vouche M, Reynaert N, et al. 90Y-PET/CT-based dosimetry after selective internal radiation therapy predicts outcome in patients with liver metastases from colorectal cancer. EJNMMI Res. 2018;8:60.  https://doi.org/10.1186/s13550-018-0419-z.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    van den Hoven AF, Rosenbaum CENM, Elias SG, de Jong HWAM, Koopman M, Verkooijen HM, et al. Insights into the dose-response relationship of radioembolization with resin 90Y-Microspheres: a prospective cohort study in patients with colorectal cancer liver metastases. J Nucl Med. 2016;57:1014–9.  https://doi.org/10.2967/jnumed.115.166942.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Willowson KP, Hayes AR, Chan DLH, Tapner M, Bernard EJ, Maher R, et al. Clinical and imaging-based prognostic factors in radioembolisation of liver metastases from colorectal cancer: a retrospective exploratory analysis. EJNMMI Res. 2017;7:46.  https://doi.org/10.1186/s13550-017-0292-1.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Yttrium S-S. Resin microspheres [package insert]. North Sydney. Australia: SirTex Medical; 2017. Available from: https://www.sirtex.com/media/155126/ssl-us-13.pdf.
  18. 18.
    Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017;18:1159–71.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Gibbs P, Gebski V, Van Buskirk M, Thurston K, Cade DN, Van Hazel GA, et al. Selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first-line treatment of non-resectable liver metastases from colorectal cancer: the SIRFLOX study. BMC Cancer. 2014;14:1–10.CrossRefGoogle Scholar
  20. 20.
    Dutton SJ, Kenealy N, Love SB, Wasan HS, Sharma RA. FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional selective internal radiation therapy (SIRT) as first-line treatment for patients with unresectable liver-on. BMC Cancer. 2014;14:497. Available from: http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/279/CN-01115279/frame.html. Accessed 31 Jan 2016.
  21. 21.
    Cremonesi M, Chiesa C, Strigari L, Ferrari M, Botta F, Guerriero F, et al. Radioembolization of hepatic lesions from a radiobiology and dosimetric perspective. Front Oncol. 2014;4:210.Google Scholar
  22. 22.
    Kao YH, Hock Tan AE, Burgmans MC, Irani FG, Khoo LS, Gong Lo RH, et al. Image-guided personalized predictive dosimetry by artery-specific SPECT/CT partition modeling for safe and effective 90Y Radioembolization. J Nucl Med 2012;53:559–566. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22343503. Accessed 17 Sep 2012.
  23. 23.
    Woff E, Hendlisz A, Garcia C, Deleporte A, Delaunoit T, Maréchal R, et al. Monitoring metabolic response using FDG PET-CT during targeted therapy for metastatic colorectal cancer. Eur J Nucl Med Mol Imaging. 2016;43:1792–801.  https://doi.org/10.1007/s00259-016-3365-x.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010;11:48–54.Google Scholar
  25. 25.
    Haug AR, Heinemann V, Bruns CJ, Hoffmann R, Jakobs T, Bartenstein P, et al. 18F-FDG PET independently predicts survival in patients with cholangiocellular carcinoma treated with 90Y microspheres. Eur J Nucl Med Mol Imaging. 2011;38:1037–45.CrossRefPubMedGoogle Scholar
  26. 26.
    Thelen A, Scholz A, Weichert W, Wiedenmann B, Neuhaus P, Gener R, et al. Tumor-associated angiogenesis and lymphangiogenesis correlate with progression of intrahepatic cholangiocarcinoma. Am J Gastroenterol. 2010;105:1123–32.CrossRefPubMedGoogle Scholar
  27. 27.
    Flamen P, Vanderlinden B, Delatte P, Ghanem G, Ameye L, Van Den Eynde M, et al. Multimodality imaging can predict the metabolic response of unresectable colorectal liver metastases to radioembolization therapy with Yttrium-90 labeled resin microspheres. Phys Med Biol. 2008;53:6591–603.CrossRefPubMedGoogle Scholar
  28. 28.
    Garin E, Lenoir L, Rolland Y, Edeline J, Mesbah H, Laffont S, et al. Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass Microspheres: preliminary results. J Nucl Med. 2012;53:255–63.  https://doi.org/10.2967/jnumed.111.094235.CrossRefPubMedGoogle Scholar
  29. 29.
    Manceau V, Palard X, Rolland Y, Pracht M, Le Sourd S, Laffont S, et al. A MAA-based dosimetric study in patients with intrahepatic cholangiocarcinoma treated with a combination of chemotherapy and 90Y-loaded glass microsphere selective internal radiation therapy. Eur J Nucl Med Mol Imaging. 2018;45(10):1731–41. Available from: https://link.springer.com/article/10.1007%2Fs00259-018-3990-7. Accessed 20 Mar 2018.

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Hugo Levillain
    • 1
    Email author
  • Ivan Duran Derijckere
    • 1
  • Lieveke Ameye
    • 2
  • Thomas Guiot
    • 3
  • Arthur Braat
    • 4
  • Carsten Meyer
    • 5
  • Bruno Vanderlinden
    • 3
  • Nick Reynaert
    • 3
  • Alain Hendlisz
    • 6
  • Marnix Lam
    • 4
  • Christophe M. Deroose
    • 7
  • Hojjat Ahmadzadehfar
    • 8
  • Patrick Flamen
    • 1
  1. 1.Nuclear Medicine Department, Jules Bordet InstituteUniversité Libre de BruxellesBrusselsBelgium
  2. 2.Data Center Department, Jules Bordet InstituteUniversité Libre de BruxellesBrusselsBelgium
  3. 3.Medical Physics Department, Jules Bordet InstituteUniversité Libre de BruxellesBrusselsBelgium
  4. 4.Radiology and Nuclear Medicine DepartmentUniversity Medical Center UtrechtUtrechtThe Netherlands
  5. 5.Radiology DepartmentUniversity Hospital BonnBonnGermany
  6. 6.Digestive Oncology Department, Jules Bordet InstituteUniversité Libre de BruxellesBrusselsBelgium
  7. 7.Department of Imaging and PathologyNuclear Medicine, University Hospitals Leuven and Nuclear Medicine and Molecular ImagingLeuvenBelgium
  8. 8.Nuclear Medicine DepartmentUniversity Hospital BonnBonnGermany

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