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The Impact of Modern Chemotherapy and Chemotherapy-Associated Liver Injuries (CALI) on Liver Function: Value of 99mTc-Labelled-Mebrofenin SPECT-Hepatobiliary Scintigraphy

  • Hepatobiliary Tumors
  • Published:
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Abstract

Background

Chemotherapy is increasingly used before hepatic resection, with controversial impact regarding liver function. This study aimed to assess the capacity of 99mTc-labelled-mebrofenin SPECT-hepatobiliary scintigraphy (HBS) to predict liver dysfunction due to chemotherapy and/or chemotherapeutic-associated liver injuries (CALI), such as sinusoidal obstruction syndrome (SOS) and nonalcoholic steatohepatitis (NASH) activity score (NAS).

Methods

From 2011 to 2015, all consecutive noncirrhotic patients scheduled for a major hepatectomy (≥ 3 segments) gave informed consent for preoperative SPECT-HBS allowing measurements of segmental liver function. As primary endpoint, HBS results were compared between patients with versus without (1) preoperative chemotherapy (≤ 3 months); and (2) CALI, mainly steatosis, NAS (Kleiner), or SOS (Rubbia-Brandt). Secondary endpoints were (1) other factors impairing function; and (2) impact of chemotherapy, and/or CALI on hepatocyte isolation outcome via liver tissues.

Results

Among 115 patients, 55 (47.8%) received chemotherapy. Sixteen developed SOS and 35 NAS, with worse postoperative outcome. Overall, chemotherapy had no impact on liver function, except above 12 cycles. In patients with CALI, a steatosis ≥ 30% significantly compromised function, as well as NAS, especially grades 2–5. Conversely, SOS had no impact, although subjected to very low patients number with severe SOS. Other factors impairing function were diabetes, overweight/obesity, or fibrosis. Similarly, chemotherapy in 73 of 164 patients had no effect on hepatocytes isolation outcome; regarding CALI, steatosis ≥ 30% and NAS impaired the yield and/or viability of hepatocytes, but not SOS.

Conclusions

In this first large, prospective study, HBS appeared to be a valuable tool to select heavily treated patients at risk of liver dysfunction through steatosis or NAS.

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References

  1. Sturesson C, Nilsson J, Eriksson S, Spelt L, Andersson R. Limiting factors for liver regeneration after a major hepatic resection for colorectal cancer metastases. HPB. 2013;15:646–52.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sturesson C, Keussen I, Tranberg KG. Prolonged chemotherapy impairs liver regeneration after portal vein occlusion: an audit of 26 patients. Eur J Surg Oncol. 2010;36:358–64.

    Article  CAS  PubMed  Google Scholar 

  3. Goere D, Farges O, Leporrier J, Sauvanet A, Vilgrain V, Belghiti J. Chemotherapy does not impair hypertrophy of the left liver after right portal vein obstruction. J Gastrointest Surg. 2006;10:365–70.

    Article  PubMed  Google Scholar 

  4. Rickenbacher A, DeOliveira ML, Tian Y, Jang JH, Riener M, Graf R, et al. Arguments against toxic effects of chemotherapy on liver injury and regeneration in an experimental model of partial hepatectomy. Liver Int. 2011;31:313–21.

    Article  CAS  PubMed  Google Scholar 

  5. De Graaf W, Bennink RJ, Vetelainen R, van Gulik TM. Nuclear imaging techniques for the assessment of hepatic function in liver surgery and transplantation. J Nucl Med. 2010;51:742–52.

    Article  PubMed  Google Scholar 

  6. Truant S, Oberlin O, Sergent G, Lebuffe G, Gambiez L, Ernst O, et al. Remnant liver volume to body weight ratio ≥ 0.5%: a new cut-off to estimate postoperative risks after extended resection in noncirrhotic liver. J Am Coll Surg. 2007;204:22–33.

  7. Kishi Y, Abdalla EK, Chun YS, Zorzi D, Madoff DC, Wallace MJ, et al. Three hundred and one consecutive extended right hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg. 2009;250:540–8.

    Article  PubMed  Google Scholar 

  8. Krishnamurthy S, Krishnamurthy GT. Technetium-99 m-iminodiacetic acid organic anions: review of biokinetics and clinical application in hepatology. Hepatology. 1989;9:139–53.

    Article  CAS  PubMed  Google Scholar 

  9. Choti M a, Sitzmann J V, Tiburi MF, Sumetchotimetha W, Rangsin R, Schulick RD, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235:759–66.

  10. Welsh FK, Tilney HS, Tekkis PP, John TG, Rees M. Safe liver resection following chemotherapy for colorectal metastases is a matter of timing. Br J Cancer. 2007;96:1037–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Takamoto T, Hashimoto T, Sano K, Maruyama Y, Inoue K, Ogata S, et al. Recovery of liver function after the cessation of preoperative chemotherapy for colorectal liver metastasis. Ann Surg Oncol. 2010;17:2747–55.

    Article  PubMed  Google Scholar 

  12. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–13.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Balzan S, Belghiti J, Farges O, Ogata S, Sauvanet A, Delefosse D, et al. The “50–50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy. Ann Surg. 2005;242:824–8.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mullen JT, Ribero D, Reddy SK, Donadon M, Zorzi D, Gautam S, et al. Hepatic insufficiency and mortality in 1,059 noncirrhotic patients undergoing major hepatectomy. J Am Coll Surg. 2007;204:854–62.

    Article  PubMed  Google Scholar 

  15. Skrzypczyk C, Truant S, Duhamel A, Langlois C, Boleslawski E, Koriche D, et al. Relevance of the ISGLS definition of posthepatectomy liver failure in early prediction of poor outcome after liver resection: study on 680 hepatectomies. Ann Surg. 2014;13:865–70.

    Article  Google Scholar 

  16. Ekman M, Fjalling M, Holmberg S, Person H. IODIDA clearance rate: a method for measuring hepatocyte uptake function. Transpl Proc. 1992;24:387–8.

    CAS  Google Scholar 

  17. Boleslawski E, Decanter G, Truant S, Bouras AF, Sulaberidze L, Oberlin O, et al. Right hepatectomy with extra-hepatic vascular division prior to transection: intention-to-treat analysis of a standardized policy. HPB. 2012;14:688–99.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15:460–6.

    Article  CAS  PubMed  Google Scholar 

  19. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    Article  PubMed  Google Scholar 

  20. Truant S, Bouras AF, Petrovai G, Buob D, Ernst O, Boleslawski E, et al. Volumetric gain of the liver after major hepatectomy in obese patients: a case-matched study in 84 patients. Ann Surg. 2013;258:696–704.

    Article  PubMed  Google Scholar 

  21. Vondran FW, Katenz E, Schwartlander R, Morgul MH, Raschzok N, Gong X, et al. Isolation of primary human hepatocytes after partial hepatectomy: criteria for identification of the most promising liver specimen. Artif Organs. 2008;32:205–13.

    Article  PubMed  Google Scholar 

  22. Seglen PO. Preparation of isolated rat liver cells. Methods Cell Biol. 1976;13:29–83.

    Article  CAS  PubMed  Google Scholar 

  23. Sharanek A, Burban A, Burbank M, Le Guevel R, Li R, Guillouzo A, et al. Rho-kinase/myosin light chain kinase pathway plays a key role in the impairment of bile canaliculi dynamics induced by cholestatic drugs. Sci Rep. 2016;6:24709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vauthey JN, Pawlik TM, Ribero D, Wu TT, Zorzi D, Hoff PM, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006;24:2065–72. https://doi.org/10.1200/JCO.2005.05.3074.

    Article  CAS  PubMed  Google Scholar 

  25. Pawlik TM, Olino K, Gleisner AL, Torbenson M, Schulick R, Choti MA. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg. 2007;11:860–8.

    Article  PubMed  Google Scholar 

  26. Scoggins CR, Campbell ML, Landry CS, Slomiany BA, Woodall CE, McMasters KM, et al. Preoperative chemotherapy does not increase morbidity or mortality of hepatic resection for colorectal cancer metastases. Ann Surg Oncol. 2009;16:35–41.

    Article  PubMed  Google Scholar 

  27. Karoui M, Penna C, Amin-Hashem M, Mitry E, Benoist S, Franc B, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243:1–7.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kishi Y, Zorzi D, Contreras CM, Maru DM, Kopetz S, Ribero D, et al. Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol. 2010;17:2870–6.

    Article  PubMed  Google Scholar 

  29. Brouquet A, Benoist S, Julie C, Penna C, Beauchet A, Rougier P, et al. Risk factors for chemotherapy-associated liver injuries: A multivariate analysis of a group of 146 patients with colorectal metastases. Surgery. 2009;145:362–71.

    Article  PubMed  Google Scholar 

  30. Vigano L, De Rosa G, Toso C, Andres A, Ferrero A, Roth A, et al. Reversibility of chemotherapy-related liver injury. J Hepatol. 2017;67:84–91.

    Article  CAS  PubMed  Google Scholar 

  31. Millet G, Truant S, Leteurtre E, Hebbar M, Zerbib P, Huet G, et al. Volumetric analysis of remnant liver regeneration after major hepatectomy in bevacizumab-treated patients: a case-matched study in 82 patients. Ann Surg. 2012;256:752–5.

    Article  Google Scholar 

  32. Pessaux P, Panaro F, Casnedi S, Zeca I, Marzano E, Bachellier P, et al. Targeted molecular therapies (cetuximab and bevacizumab) do not induce additional hepatotoxicity: Preliminary results of a case–control study. Eur J Surg Oncol. 2010;36:575–82.

    Article  CAS  PubMed  Google Scholar 

  33. Russolillo N, Langella S, Perotti S, Lo Tesoriere R, Forchino F, Ferrero A. Preoperative assessment of chemotherapeutic associated liver injury based on indocyanine green retention test. Int J Surg. 2016;31:80–5.

    Article  PubMed  Google Scholar 

  34. Wakiya T, Kudo D, Toyoki Y, Ishido K, Kimura N, Narumi S, et al. Evaluation of the usefulness of the indocyanine green clearance test for chemotherapy-associated liver injury in patients with colorectal cancer liver metastasis. Ann Surg Oncol. 2014;21:167–72. https://doi.org/10.1245/s10434-013-3203-3.

    Article  PubMed  Google Scholar 

  35. Narita M, Oussoultzoglou E, Chenard M-P, Fuchshuber P, Rather M, Rosso E, et al. Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization. Ann Surg Oncol. 2012;19:2230–7. https://doi.org/10.1245/s10434-011-2112-6.

    Article  PubMed  Google Scholar 

  36. Nakano H, Oussoultzoglou E, Rosso E, Casnedi S, Chenard-Neu M-PP, Dufour P, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg. 2008;247:118–24.

  37. Aloia T, Sebagh M, Plasse M, Karam V, Levi F, Giacchetti S, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol. 2006;24:4983–90.

    Article  CAS  PubMed  Google Scholar 

  38. Soubrane O, Brouquet A, Zalinski S, Terris B, Brezault C, Mallet V, et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome. Ann Surg. 2010;251:454–60.

    Article  PubMed  Google Scholar 

  39. Simpson AL, Leal JN, Pugalenthi A, Allen PJ, Dematteo RP, Fong Y, et al. Chemotherapy-induced splenic volume increase is independently associated with major complications after hepatic resection for metastatic colorectal cancer. J Am Coll Surg. 2015;220:271–80.

    Article  PubMed  Google Scholar 

  40. Schiffer E, Frossard JL, Rubbia-Brandt L, Mentha G, Pastor CM. Hepatic regeneration is decreased in a rat model of sinusoidal obstruction syndrome. J Surg Oncol. 2009;99:439–46.

    Article  PubMed  Google Scholar 

  41. Slade JH, Alattar ML, Fogelman DR, Overman MJ, Agarwal A, Maru DM, et al. Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic sinusoidal injury. Clin Colorectal Cancer. 2009;8:225–30.

    Article  CAS  PubMed  Google Scholar 

  42. Parikh AA, Gentner B, Wu TT, Curley SA, Ellis LM, Vauthey JN. Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg. 2003;7:1082–8.

    Article  PubMed  Google Scholar 

  43. Zeiss J, Merrick HW, Savolaine ER, Woldenberg LS, Kim K, Schlembach PJ. Fatty liver change as a result of hepatic artery infusion chemotherapy. Am J Clin Oncol. 1990;13:156–60.

    Article  CAS  PubMed  Google Scholar 

  44. Peppercorn PD, Reznek RH, Wilson P, Slevin ML, Gupta RK. Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer. Br J Cancer. 1998;77:2008–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rubbia-Brandt L, Lauwers GY, Wang H, Majno PE, Tanabe K, Zhu AX, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology. 2010;56:430–9.

    Article  PubMed  Google Scholar 

  46. Behrns KE, Tsiotos GG, DeSouza NF, Krishna MK, Ludwig J, Nagorney DM. Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg. 1998;2:292–8.

    Article  CAS  PubMed  Google Scholar 

  47. Kooby DA, Fong Y, Suriawinata A, Gonen M, Allen PJ, Klimstra DS, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg. 2003;7:1034–44.

    Article  PubMed  Google Scholar 

  48. Baumgaertner I, Ratziu V, Vaillant J-C, Hannoun L, Poynard T, André T. [Hepatotoxicity of metastatic colorectal cancer chemotherapy: systematic review]. Bull Cancer. 2010;97:559–69.

    Article  CAS  PubMed  Google Scholar 

  49. Salgado Júnior W, Donadelli CA de M, Dos Santos JS, Nonino CB. Influence of Roux-en-Y gastric bypass on the hepatocellular function and bile flow of obese patients assessed by scintigraphy with DISIDA. Obes Surg. 2016;26:2718–23.

  50. Şen H, Tan YZ, Binnetoğlu E, Aşik M, Güneş F, Erbağ G, et al. Evaluation of liver perfusion in diabetic patients using 99mTc-sestamibi. Wien Klin Wochenschr. 2015;127:19–23.

    Article  PubMed  CAS  Google Scholar 

  51. Rijzewijk LJ, van der Meer RW, Lubberink M, Lamb HJ, Romijn JA, de Roos A, et al. Liver fat content in type 2 diabetes: relationship with hepatic perfusion and substrate metabolism. Diabetes. 2010;59:2747–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kawahara T, Toso C, Douglas DN, Nourbakhsh M, Lewis JT, Tyrrell DL, et al. Factors affecting hepatocyte isolation, engraftment, and replication in an in vivo model. Liver Transpl. 2010;16:974–82.

    Article  Google Scholar 

  53. Le Roux F, Herpe Y-E, Bruyer A-S, Duverlie G, Regimbeau J-M. Les résultats de la culture d’hépatocytes primaires humains peuvent-ils être prédictifs des suites opératoires après hépatectomie (Abstract). J Chir (Communication Orale). 2014:A5–35.

  54. Hewes JC, Riddy D, Morris RW, Woodrooffe AJ, Davidson BR, Fuller B. A prospective study of isolated human hepatocyte function following liver resection for colorectal liver metastases: the effects of prior exposure to chemotherapy. J Hepatol. 2006;45:263–70.

    Article  CAS  PubMed  Google Scholar 

  55. Zhao J, van Mierlo KMC, Gómez-Ramírez J, Kim H, Pilgrim CHC, Pessaux P, et al. Systematic review of the influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases. Br J Surg. 2017;104:990–1002.

    Article  CAS  PubMed  Google Scholar 

  56. Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. J Am Med Assoc. 1999;282:1659–64.

    Article  CAS  Google Scholar 

  57. Yang SQ, Mandal AK, Huang J, Diehl AM. Disrupted signaling and inhibited regeneration in obese mice with fatty livers: Implications for nonalcoholic fatty liver disease pathophysiology. Hepatology. 2001;34:694–706.

    Article  CAS  PubMed  Google Scholar 

  58. Teramoto K, Bowers JL, Kruskal JB, Clouse ME. Hepatic microcirculatory changes after reperfusion in fatty and normal liver transplantation in the rat. Transplantation. 1993;56:1076–82.

    Article  CAS  PubMed  Google Scholar 

  59. Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449–57.

    Article  PubMed  Google Scholar 

  60. Allard MA, Sebagh M, Baillie G, Lemoine A, Dartigues P, Faitot F, et al. Comparison of complete pathologic response and hepatic injuries between hepatic arterial infusion and systemic administration of oxaliplatin in patients with colorectal liver metastases. Ann Surg Oncol. 2015;22:1925–32. https://doi.org/10.1245/s10434-014-4272-7.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Digestive Surgery and Transplantation, Univ. Lille, CHRU Lille, Lille, France

    Stéphanie Truant MD, PhD, Maxence Fulbert MD, Sabrina Dardenne MD, Mehdi El Amrani MD, PhD & François-René Pruvot MD, PhD

  2. CANTHER laboratory Cancer Heterogeneity, Plasticity and Resistance to Therapies UMR-S1277 INSERM, Team Mucins, Cancer and Drug Resistance, 59000, Lille, France

    Stéphanie Truant MD, PhD & Mehdi El Amrani MD, PhD

  3. Department of Nuclear Medicine, Univ. Lille, Lille, France

    Clio Baillet MD & Damien Huglo MD, PhD

  4. Department of Pathology, Univ. Lille, Lille, France

    Viviane Gnemmi MD, PhD & Emmanuelle Leteurtre MD, PhD

  5. Department of Medical Oncology, Univ. Lille, Lille, France

    Anthony Turpin MD, PhD

  6. Hepatology Unit, Univ. Lille, Lille, France

    Sébastien Dharancy MD, PhD & Laurent Dubuquoy PhD

  7. LIRIC-Lille Inflammation Research International Center-U995, Univ. Lille, Inserm, CHU Lille, Lille, France

    Sébastien Dharancy MD, PhD & Laurent Dubuquoy PhD

  8. Biopredic Laboratory, Rennes, France

    Christophe Chesné PhD

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  1. Stéphanie Truant MD, PhD
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  2. Clio Baillet MD
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Truant, S., Baillet, C., Gnemmi, V. et al. The Impact of Modern Chemotherapy and Chemotherapy-Associated Liver Injuries (CALI) on Liver Function: Value of 99mTc-Labelled-Mebrofenin SPECT-Hepatobiliary Scintigraphy. Ann Surg Oncol 28, 1959–1969 (2021). https://doi.org/10.1245/s10434-020-08988-4

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