Annals of Surgical Oncology

, Volume 26, Issue 12, pp 4100–4107 | Cite as

Dynamic Changes in Normal Liver Parenchymal Volume During Chemotherapy for Colorectal Cancer: Liver Atrophy as an Alternate Marker of Chemotherapy-Associated Liver Injury

  • Junichi ShindohEmail author
  • Yuta Kobayashi
  • Keiichi Kinowaki
  • Yoshihiro Mise
  • Wataru Gonoi
  • Shuntaro Yoshida
  • Keigo Tani
  • Shuichiro Matoba
  • Hiroya Kuroyanagi
  • Masaji Hashimoto
Hepatobiliary Tumors



The purpose of this study was to investigate the incidence, origin, and clinical significance of liver atrophy during chemotherapy for colorectal cancer.


This study included 103 patients who underwent chemotherapy before resection for colorectal liver metastases (training set) and 171 patients who underwent adjuvant or first-line chemotherapy without liver resection (validation set). A greater than 10% decrease (atrophy) or increase (hypertrophy) of the liver volume from the baseline was defined as a significant change.


In the training set, the numbers of patients who developed atrophy, no change of volume, and hypertrophy of the liver after chemotherapy were 15 (14.6%), 73 (70.9%), and 15 (14.6%), respectively. Liver atrophy was associated with impaired hepatic function, and the postoperative morbidity rate and refractory ascites/pleural effusion were higher in the patients with liver atrophy than those without (60.0% vs. 31.8%, P = 0.045 and 46.7% vs. 8.0%, P < 0.001, respectively). Histopathological examination revealed a strong association between sinusoidal injury and liver atrophy (P < 0.001). The cumulative incidence of liver atrophy increased with increasing duration of chemotherapy, whereas the incidence of liver atrophy was less frequent in patients who had received bevacizumab than those who had not in both the training set (odds ratio [OR], 0.13; P = 0.001) and the validation set (OR, 0.31; P = 0.007).


Liver atrophy is associated with impaired hepatic functional reserve and observed at an increasing frequency as the duration of chemotherapy increases with frequent histopathological evidence of sinusoidal injury in the liver. Bevacizumab may protect against the development of liver atrophy.



This study was supported by JSPS KAKENHI Grant No. 26861063 and a study grant from Okinaka Memorial Institute for Medical Disease 2018–2019.


Junichi Shindoh reports receiving honoraria from Chugai and Takeda. No other authors reported disclosures.

Supplementary material

10434_2019_7740_MOESM1_ESM.pptx (950 kb)
Supplemental Fig. 1 Study population. Supplemental Fig. 2: Correlation of 3D volumetry results between two independent examiners. Volumetric measurement results: examiner 1, 1198.7 ± 272.6 mL; examiner 2, 1199.9 ± 260.4 mL (r = 0.992, p < 0.0001). Supplemental Fig. 3: Various clinical manifestations with dynamic changes of the liver volume during/after chemotherapy for colorectal cancer. A Significant shrinkage of the liver (− 24.4%) with elevated serum transaminase and bilirubin levels. B Significant shrinkage of the liver (− 16.7%) associated with massive ascites. C Significant hypertrophy of the liver (+ 71.2%) with marked steatosis. Supplemental Fig. 4: Correlation between the degree of atrophy and changes in CT numbers. Supplemental Fig. 5: Correlation between the degree of atrophy and ICG retention rate at 15 min (PPTX 949 kb)


  1. 1.
    Brouquet A, Nordlinger B. Neoadjuvant therapy of colorectal liver metastases: lessons learned from clinical trials. J Surg Oncol. 2010;102:932–6.CrossRefGoogle Scholar
  2. 2.
    Shindoh J, Tzeng CW, Aloia TA, et al. Safety and efficacy of portal vein embolization before planned major or extended hepatectomy: an institutional experience of 358 patients. J Gastrointest Surg. 2014;18:45–51.CrossRefGoogle Scholar
  3. 3.
    Kishi Y, Zorzi D, Contreras CM, 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.CrossRefGoogle Scholar
  4. 4.
    Shindoh J, Tzeng CW, Aloia TA, et al. Optimal future liver remnant in patients treated with extensive preoperative chemotherapy for colorectal liver metastases. Ann Surg Oncol. 2013;20:2493–500.CrossRefGoogle Scholar
  5. 5.
    Vauthey JN, Pawlik TM, Ribero D, 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.CrossRefGoogle Scholar
  6. 6.
    Cauchy F, Aussilhou B, Dokmak S, et al. Reappraisal of the risks and benefits of major liver resection in patients with initially unresectable colorectal liver metastases. Ann Surg. 2012;256:746–52 (discussion 752–4).CrossRefGoogle Scholar
  7. 7.
    Lodewick TM, de Jong MC, van Dam RM, et al. Effects of postoperative morbidity on long-term outcome following surgery for colorectal liver metastases. World J Surg. 2015;39:478–86.CrossRefGoogle Scholar
  8. 8.
    Overman MJ, Maru DM, Charnsangavej C, et al. Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury. J Clin Oncol. 2010;28:2549–55.CrossRefGoogle Scholar
  9. 9.
    Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15:460–6.CrossRefGoogle Scholar
  10. 10.
    Shindoh J, Truty MJ, Aloia TA, et al. Kinetic growth rate after portal vein embolization predicts posthepatectomy outcomes: toward zero liver-related mortality in patients with colorectal liver metastases and small future liver remnant. J Am Coll Surg. 2013;216:201–9.CrossRefGoogle Scholar
  11. 11.
    Ribero D, Abdalla EK, Madoff DC, et al. Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome. Br J Surg. 2007;94:1386–94.CrossRefGoogle Scholar
  12. 12.
    Tani K, Shindoh J, Takamoto T, et al. Kinetic changes in liver parenchyma after preoperative chemotherapy for patients with colorectal liver metastases. J Gastrointest Surg. 2017;21:813–21.CrossRefGoogle Scholar
  13. 13.
    Omichi K, Yamashita S, Cloyd JM, et al. Portal vein embolization reduces postoperative hepatic insufficiency associated with postchemotherapy hepatic atrophy. J Gastrointest Surg. 2018;22:60–7.CrossRefGoogle Scholar
  14. 14.
    Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and adult standard liver volume for liver transplantation. Hepatology. 1995;21:1317–21.CrossRefGoogle Scholar
  15. 15.
    Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefGoogle Scholar
  16. 16.
    Overman MJ, Ferrarotto R, Raghav K, et al. The addition of bevacizumab to oxaliplatin-based chemotherapy: impact upon hepatic sinusoidal injury and thrombocytopenia. J Natl Cancer Inst. 2018;110:888–94.CrossRefGoogle Scholar
  17. 17.
    Klinger M, Eipeldauer S, Hacker S, et al. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol. 2009;35:515–20.CrossRefGoogle Scholar
  18. 18.
    Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. 2007;110:2761–7.CrossRefGoogle Scholar
  19. 19.
    Martins J, Alexandrino H, Oliveira R, et al. Sinusoidal dilation increases the risk of complications in hepatectomy for CRCLM—protective effect of bevacizumab and diabetes mellitus, serum gamma-glutamyltranspeptidase as predictive factor. Eur J Surg Oncol. 2016;42:713–21.CrossRefGoogle Scholar
  20. 20.
    Abdalla EK, Denys A, Chevalier P, et al. Total and segmental liver volume variations: implications for liver surgery. Surgery. 2004;135:404–10.CrossRefGoogle Scholar
  21. 21.
    Mise Y, Satou S, Shindoh J, et al. Three-dimensional volumetry in 107 normal livers reveals clinically relevant inter-segment variation in size. HPB (Oxford). 2014;16:439–47.CrossRefGoogle Scholar
  22. 22.
    Kobayashi Y, Kiya Y, Sugawara T, et al. Expanded Makuuchi’s criteria using estimated indocyanine green clearance rate of future liver remnant as a safety limit for maximum extent of liver resection. HPB (Oxford). 2019;21:990–7.CrossRefGoogle Scholar
  23. 23.
    Yokoyama Y, Nishio H, Ebata T, et al. Value of indocyanine green clearance of the future liver remnant in predicting outcome after resection for biliary cancer. Br J Surg. 2010;97:1260–8.CrossRefGoogle Scholar
  24. 24.
    Desmet VJ, Gerber M, Hoofnagle JH, et al. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19:1513–20.CrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Junichi Shindoh
    • 1
    • 2
    Email author
  • Yuta Kobayashi
    • 1
  • Keiichi Kinowaki
    • 3
  • Yoshihiro Mise
    • 4
  • Wataru Gonoi
    • 5
  • Shuntaro Yoshida
    • 6
  • Keigo Tani
    • 7
  • Shuichiro Matoba
    • 1
  • Hiroya Kuroyanagi
    • 1
  • Masaji Hashimoto
    • 1
  1. 1.Hepatobiliary-Pancreatic Surgery Division, Department of Gastroenterological SurgeryToranomon HospitalTokyoJapan
  2. 2.Okinaka Memorial Institute for Medical DiseaseTokyoJapan
  3. 3.Department of PathologyToranomon HospitalTokyoJapan
  4. 4.Department of Gastroenterological Surgery, Cancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
  5. 5.Department of Radiology, Graduate School of MedicineThe University of TokyoTokyoJapan
  6. 6.Department of Gastroenterology, Graduate School of MedicineThe University of TokyoTokyoJapan
  7. 7.Department of SurgeryTokyo Takanawa HospitalTokyoJapan

Personalised recommendations