Cytotoxic chemotherapy prolongs survival of patients with advanced and metastatic tumors. This is, however, a double-edged sword with many adverse effects. Since the liver has a rich blood supply and plays an active role in the metabolism of medications, it is not surprising that there can be hepatic injury related to chemotherapy. In addition, radioembolization may affect the parenchyma of normal and cirrhotic livers. We review chemotherapy-associated liver injury in patients with colorectal liver metastases, including downsizing chemotherapy and neoadjuvant chemotherapy. We discuss the mechanism of the hepatic injury, secondary to reactive oxygen species, and the spectrum of hepatic injury including, steatosis, steatohepatitis, hepatic sinusoidal injury and highlight the pharmacogenomics of such liver insults. Methods for reducing and treating the hepatotoxicity are discussed for specific agents including tamxifen and the newly introduced targeted antibodies. 1. Introduction Over the last few decades many novel cytotoxic chemotherapeutic agents have been developed which prolong survival of patients with advanced and metastatic tumors., More recently, specifically targeted antibodies and other biological agents have been introduced in various combinations with chemotherapy to further increase life expectancy. For some tumors, for example, colorectal cancer (CRC), preoperative treatment may “downsize” liver metastases to make them compatible with complete resection with a curative intent. External radiation therapy has been an integral part of the armamentarium against primary or metastatic liver tumors. Currently, radiation may be directly targeted at liver tumors with the radioembolization technique. This increased availability of beneficial treatment modalities does not come without a price. Administration of chemotherapy has always been complicated with many adverse effects. In this review we will focus on the effects of chemotherapy and radiotherapy on the liver. The liver may be affected by various pathological manifestations, some culminating in severe liver injury and even liver failure. Chemotherapy-induced liver injury may also bear on the morbidity and mortality after hepatic resection. Radioembolization, although relatively safe, may affect the parenchyma of normal and cirrhotic livers. 2. Chemotherapy-Associated Liver Injury in Patients with Colorectal Liver Metastases In the absence of any treatment, the prognosis of patients with liver metastases from CRC is dismal [1]. In those patients with resectable disease, liver surgery with
References
[1]
J. S. Wagner, M. A. Adson, and J. A. Van Heerden, “The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment,” Annals of Surgery, vol. 199, no. 5, pp. 502–508, 1984.
[2]
J. Figueras, J. Torras, C. Valls et al., “Surgical resection of colorectal liver metastases in patients with expanded indications: a single-center experience with 501 patients,” Diseases of the Colon and Rectum, vol. 50, no. 4, pp. 478–488, 2007.
[3]
M. L. Chen, C. H. Fang, L. S. Liang, L. H. Dai, and X. K. Wang, “A meta-analysis of chemotherapy regimen Fluorouracil/Leucovorin/Oxaliplatin Compared with Fluorouracil/Leucovorin in treating advanced colorectal cancer,” Surgical Oncology, vol. 19, no. 1, pp. 38–45, 2010.
[4]
L. B. Saltz, S. Clarke, E. Diaz-Rubio, et al., “Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study,” Journal of Clinical Oncology, vol. 26, no. 12, pp. 2013–2019, 2008.
[5]
P.-A. Clavien, H. Petrowsky, M. L. DeOliveira, and R. Graf, “Strategies for safer liver surgery and partial liver transplantation,” The New England Journal of Medicine, vol. 356, no. 15, pp. 1545–1559, 2007.
[6]
R. Adam, A. Laurent, D. Azoulay et al., “Two-stage hepatectomy: a planned strategy to treat irresectable liver tumors,” Annals of Surgery, vol. 232, no. 6, pp. 777–785, 2000.
[7]
K. Lehmann, A. Rickenbacher, A. Weber, et al., “Chemotherapy before liver resection of clorectal metastases: friend or foe?” Annals of Surgery, vol. 254, no. 5, pp. 1–11, 2011.
[8]
D. Zorzi, A. Laurent, T. M. Pawlik, G. Y. Lauwers, J.-N. Vauthey, and E. K. Abdalla, “Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases,” British Journal of Surgery, vol. 94, no. 3, pp. 274–286, 2007.
[9]
G. Morris-Stiff, Y.-M. Tan, and J. N. Vauthey, “Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases,” European Journal of Surgical Oncology, vol. 34, no. 6, pp. 609–614, 2008.
[10]
Y. Fong and D. J. Bentrem, “CASH (chemotherapy-associated steatohepatitis) costs,” Annals of Surgery, vol. 243, no. 1, pp. 8–9, 2006.
[11]
S. M. Robinson, C. H. Wilson, A. D. Burt, et al., “Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis,” Annals of Surgical Oncology, vol. 19, no. 13, pp. 4287–4299, 2012.
[12]
S.-C. Lim, J. E. Choi, H. S. Kang, and H. Si, “Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma,” International Journal of Cancer, vol. 126, no. 7, pp. 1582–1595, 2010.
[13]
Z. Li, H. Lin, S. Yang, and A. M. Diehl, “Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system,” Gastroenterology, vol. 123, no. 4, pp. 1304–1310, 2002.
[14]
M. A. E. Anna Diehl, “Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines,” American Journal of Physiology, vol. 282, no. 1, pp. G1–G5, 2002.
[15]
R. Vetel？inen, A. K. van Vliet, and T. M. van Gulik, “Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy,” Annals of Surgery, vol. 245, no. 1, pp. 44–50, 2007.
[16]
R. Vetel？inen, A. Van Vliet, D. J. Gouma, and T. M. Van Gulik, “Steatosis as a risk factor in liver surgery,” Annals of Surgery, vol. 245, no. 1, pp. 20–30, 2007.
[17]
J. Belghiti, K. Hiramatsu, S. Benoist, P. P. Massault, A. Sauvanet, and O. Farges, “Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection,” Journal of the American College of Surgeons, vol. 191, no. 1, pp. 38–46, 2000.
[18]
A. J. Bilchik, G. Poston, S. A. Curley et al., “Neoadjuvant chemotherapy for metastatic colon cancer: a cautionary note,” Journal of Clinical Oncology, vol. 23, no. 36, pp. 9073–9078, 2005.
[19]
G. Garcea and G. J. Maddern, “Liver failure after major hepatic resection,” Journal of Hepato-Biliary-Pancreatic Surgery, vol. 16, no. 2, pp. 145–155, 2009.
[20]
D. A. Kooby, Y. Fong, A. Suriawinata et al., “Impact of steatosis on perioperative outcome following hepatic resection,” Journal of Gastrointestinal Surgery, vol. 7, no. 8, pp. 1034–1044, 2003.
[21]
L. McCormack, H. Petrowsky, W. Jochum, K. Furrer, and P.-A. Clavien, “Hepatic steatosis is a risk factor for postoperative complications after major hepatectomy: a matched case-control study,” Annals of Surgery, vol. 245, no. 6, pp. 923–930, 2007.
[22]
C. G. Moertel, T. R. Fleming, J. S. Macdonald, D. G. Haller, and J. A. Laurie, “Hepatic toxicity associated with fluorouracil plus levamisole adjuvant therapy,” Journal of Clinical Oncology, vol. 11, no. 12, pp. 2386–2390, 1993.
[23]
P. D. Peppercorn, R. H. Reznek, P. Wilson, M. L. Slevin, and R. K. Gupta, “Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer,” British Journal of Cancer, vol. 77, no. 11, pp. 2008–2011, 1998.
[24]
P. Sorensen, A. L. Edal, E. L. Madsen, et al., “Reversible hepatic steatosis in patients treated with interferon alfa-2a and 5-fluorouracil,” Cancer, vol. 75, no. 10, pp. 2592–2596, 1995.
[25]
T. M. Pawlik, K. Olino, A. L. Gleisner, M. Torbenson, R. Schulick, and M. A. Choti, “Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome,” Journal of Gastrointestinal Surgery, vol. 11, no. 7, pp. 860–868, 2007.
[26]
J.-N. Vauthey, T. M. Pawlik, D. Ribero et al., “Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases,” Journal of Clinical Oncology, vol. 24, no. 13, pp. 2065–2072, 2006.
[27]
U. V. Gentilucci, D. Santini, B. Vincenzi, E. Fiori, A. Picardi, and G. Tonini, “Chemotherapy-induced steatohepatitis in colorectal cancer patients,” Journal of Clinical Oncology, vol. 24, no. 34, p. 5467, 2006.
[28]
A. Sahajpal, C. M. Vollmer Jr., E. Dixon et al., “Chemotherapy for colorectal cancer prior to liver resection for colorectal cancer hepatic metastases does not adversely affect peri-operative outcomes,” Journal of Surgical Oncology, vol. 95, no. 1, pp. 22–27, 2007.
[29]
F. G. Fernandez, J. Ritter, J. W. Goodwin, D. C. Linehan, W. G. Hawkins, and S. M. Strasberg, “Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases,” Journal of the American College of Surgeons, vol. 200, no. 6, pp. 845–853, 2005.
[30]
L. D. DeLeve, H. M. Shulman, and G. B. McDonald, “Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease),” Seminars in Liver Disease, vol. 22, no. 1, pp. 27–41, 2002.
[31]
C. Julie, M. Lutz, D. Aust, et al., “Pathological analysis of hepatic injury after oxaliplatin-based neoadjuvant chemotherapy of colorectal cancer liver metastases: results of the EORTC Intergroup phase III study 40983,” Journal of Clinical Oncology, vol. 25, abstract 241, 2007.
[32]
H. Nakano, E. Oussoultzoglou, E. Rosso et al., “Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy,” Annals of Surgery, vol. 247, no. 1, pp. 118–124, 2008.
[33]
A. Laurent, C. Nicco, C. Chéreau et al., “Controlling tumor growth by modulating endogenous production of reactive oxygen species,” Cancer Research, vol. 65, no. 3, pp. 948–956, 2005.
[34]
J. Alexandre, C. Nicco, C. Chéreau et al., “Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir,” Journal of the National Cancer Institute, vol. 98, no. 4, pp. 236–244, 2006.
[35]
H. H. Zeng, J. F. Lu, and K. Wang, “The effect of cisplatin and transplatin on the conformation and association of F-actin,” Cell Biology International, vol. 19, no. 6, pp. 491–497, 1995.
[36]
M. Karoui, C. Penna, M. Amin-Hashem et al., “Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases,” Annals of Surgery, vol. 243, no. 1, pp. 1–7, 2006.
[37]
T. Aloia, M. Sebagh, M. Plasse et al., “Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases,” Journal of Clinical Oncology, vol. 24, no. 31, pp. 4983–4990, 2006.
[38]
D. A. Kooby, J. Stockman, L. Ben-Porat et al., “Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases,” Annals of Surgery, vol. 237, no. 6, pp. 860–870, 2003.
[39]
J. M. Van Der Bol, R. H. Mathijssen, J. Verweij, et al., “CYP3A phenotype-based individualized dosing of irinotecan to reduce interindividual variability in pharmacokinetics and toxicity: result from a randomized trial,” Journal of Clinical Oncology, vol. 26, abstract 2506, 2008.
[40]
L. Iyer, S. Das, L. Janisch et al., “UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity,” Pharmacogenomics Journal, vol. 2, no. 1, pp. 43–47, 2002.
[41]
D. M. Kweekel, H. Gelderblom, and H.-J. Guchelaar, “Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy,” Cancer Treatment Reviews, vol. 31, no. 2, pp. 90–105, 2005.
[42]
Y. Kodama, C. S. Ng, T. T. Wu et al., “Comparison of CT methods for determining the fat content of the liver,” American Journal of Roentgenology, vol. 188, no. 5, pp. 1307–1312, 2007.
[43]
C. S. Cho, S. Curran, L. H. Schwartz et al., “Preoperative radiographic assessment of hepatic steatosis with histologic correlation,” Journal of the American College of Surgeons, vol. 206, no. 3, pp. 480–488, 2008.
[44]
S. Kopetz and J.-N. Vauthey, “Perioperative chemotherapy for resectable hepatic metastases,” The Lancet, vol. 371, no. 9617, pp. 963–965, 2008.
[45]
F. K. S. Welsh, H. S. Tilney, P. P. Tekkis, T. G. John, and M. Rees, “Safe liver resection following chemotherapy for colorectal metastases is a matter of timing,” British Journal of Cancer, vol. 96, no. 7, pp. 1037–1042, 2007.
[46]
D. Ribero, E. K. Abdalla, D. C. Madoff, M. Donadon, E. M. Loyer, and J.-N. Vauthey, “Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome,” British Journal of Surgery, vol. 94, no. 11, pp. 1386–1394, 2007.
[47]
G. Morris-Stiff, Y.-M. Tan, and J. N. Vauthey, “Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases,” European Journal of Surgical Oncology, vol. 34, no. 6, pp. 609–614, 2008.
[48]
L. Rubbia-Brandt, G. Y. Lauwers, H. Wang 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, vol. 56, no. 4, pp. 430–439, 2010.
[49]
A. E. M. van der Pool, H. A. Marsman, J. Verheij et al., “Effect of bevacizumab added preoperatively to oxaliplatin on liver injury and complications after resection of colorectal liver metastases,” Journal of Surgical Oncology, vol. 106, no. 7, pp. 892–897, 2012.
[50]
D. S. Pratt, T. A. Knox, and J. Erban, “Tamoxifen-induced steatohepatitis,” Annals of Internal Medicine, vol. 123, no. 3, p. 236, 1995.
[51]
A. Grieco, A. Forgione, L. Miele et al., “Fatty liver and drugs,” European Review for Medical and Pharmacological Sciences, vol. 9, no. 5, pp. 261–263, 2005.
[52]
S. Bruno, P. Maisonneuve, P. Castellana et al., “Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial,” British Medical Journal, vol. 330, no. 7497, pp. 932–935, 2005.
[53]
T. Saphner, S. Triest-Robertson, H. Li, and P. Holzman, “The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer,” Cancer, vol. 115, no. 14, pp. 3189–3195, 2009.
[54]
M. H. Ahmed and C. D. Byrne, “Non-alcoholic steatoheptatitis,” in Metabolic Syndrome, C. D. Byrne and S. Wild, Eds., pp. 279–303, John Wiley & Sons, London, UK, 2005.
[55]
M. H. Ahmed and K. A. Osman, “Tamoxifen induced-non-alcoholic steatohepatitis (NASH): has the time come for the oncologist to be diabetologist,” Breast Cancer Research and Treatment, vol. 97, no. 2, pp. 223–224, 2006.
[56]
D. Pessayre, B. Fromenty, and A. Mansouri, “Mitochondrial injury in steatohepatitis,” European Journal of Gastroenterology and Hepatology, vol. 16, no. 11, pp. 1095–1105, 2004.
[57]
T. Ohnishi, Y. Ogawa, T. Saibara et al., “CYP17 polymorphism and tamoxifen-induced hepatic steatosis,” Hepatology Research, vol. 33, no. 2, pp. 178–180, 2005.
[58]
N. Günel, U. Co？kun, F. B. Toruner et al., “Serum leptin levels are associated with tamoxifen-induced hepatic steatosis,” Current Medical Research and Opinion, vol. 19, no. 1, pp. 47–50, 2003.
[59]
A. Inno, M. Basso, F. M. Vecchio, et al., “Anastrozole-related acute hepatitis with autoimmune features: a case report,” BMC Gastroenterology, vol. 31, no. 11, p. 32, 2011.
[60]
L. de la Cruz, J. Romero-Vazquez, M. Jiménez-Sáenz, J. R. A. Padron, and J. M. Herrerias-Gutierrez, “Severe acute hepatitis in a patient treated with anastrozole,” The Lancet, vol. 369, no. 9555, pp. 23–24, 2007.
[61]
N. U. Lin, L. A. Carey, M. C. Liu et al., “Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer,” Journal of Clinical Oncology, vol. 26, no. 12, pp. 1993–1999, 2008.
[62]
S. Peroukides, T. Makatsoris, A. Koutras et al., “Lapatinib-induced hepatitis: a case report,” World Journal of Gastroenterology, vol. 17, no. 18, pp. 2349–2352, 2011.
[63]
C. F. Spraggs, L. R. Budde, L. P. Briley et al., “HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer,” Journal of Clinical Oncology, vol. 29, no. 6, pp. 667–673, 2011.
[64]
J. S. Weber, K. C. K？hler, and A. Hauschild, “Management of immune-related adverse events and kinetics of response with ipilimumab,” Journal of Clinical Oncology, vol. 30, no. 21, pp. 2691–2997, 2012.
[65]
C. Robert, L. Thomas, I. Bondarenko et al., “Ipilimumab plus dacarbazine for previously untreated metastatic melanoma,” The New England Journal of Medicine, vol. 364, no. 26, pp. 2517–2526, 2011.
[66]
J. D. Wolchok, B. Neyns, G. Linette et al., “Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study,” The Lancet Oncology, vol. 11, no. 2, pp. 155–164, 2010.
[67]
C. Guha and B. D. Kavanagh, “Hepatic radiation toxicity: avoidance and amelioration,” Seminars in Radiation Oncology, vol. 21, no. 4, pp. 256–263, 2011.
[68]
G. B. Reed Jr. and A. J. Cox Jr., “The human liver after radiation injury. A form of veno-occlusive disease,” American Journal of Pathology, vol. 48, no. 4, pp. 597–611, 1966.
[69]
S.-X. Liang, X.-D. Zhu, Z.-Y. Xu et al., “Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: the risk factors and hepatic radiation tolerance,” International Journal of Radiation Oncology Biology Physics, vol. 65, no. 2, pp. 426–434, 2006.
[70]
Z.-Y. Xu, S.-X. Liang, J. Zhu et al., “Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma,” International Journal of Radiation Oncology Biology Physics, vol. 65, no. 1, pp. 189–195, 2006.
[71]
J. C.-H. Cheng, J.-K. Wu, C.-M. Huang et al., “Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication,” International Journal of Radiation Oncology Biology Physics, vol. 54, no. 1, pp. 156–162, 2002.
[72]
T. S. Lawrence, “Hepatic toxicity resulting from cancer treatment,” International Journal of Radiation Oncology Biology Physics, vol. 31, no. 5, pp. 1237–1248, 1995.
[73]
B. Sangro, M. I？arrairaegui, and J. I. Bilbao, “Radioembolization for hepatocellular carcinoma,” Journal of Hepatology, vol. 56, no. 2, pp. 464–473, 2012.
[74]
M. Iarrairaegui, K. G. Thurston, J. I. Bilbao et al., “Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis,” Journal of Vascular and Interventional Radiology, vol. 21, no. 8, pp. 1205–1212, 2010.
[75]
A. O. Chan, M.-F. Yuen, C.-K. Hui, W.-K. Tso, and C.-L. Lai, “A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma,” Cancer, vol. 94, no. 6, pp. 1747–1752, 2002.
[76]
R. C. Gaba, A. Riaz, R. J. Lewandowski et al., “Safety of yttrium-90 microsphere radioembolization in patients with biliary obstruction,” Journal of Vascular and Interventional Radiology, vol. 21, no. 8, pp. 1213–1218, 2010.
[77]
J. I. Bilbao, A. De Martino, E. De Luis et al., “Biocompatibility, inflammatory response, and recannalization characteristics of nonradioactive resin microspheres: histological findings,” CardioVascular and Interventional Radiology, vol. 32, no. 4, pp. 727–736, 2009.
[78]
J. Furuse, H. Ishii, M. Nagase, M. Kawashima, T. Ogino, and M. Yoshino, “Adverse hepatic events caused by radiotherapy for advanced hepatocellular carcinoma,” Journal of Gastroenterology and Hepatology, vol. 20, no. 10, pp. 1512–1518, 2005.
[79]
W.-Y. Lau, A. S. Kennedy, Y. H. Kim et al., “Patient selection and activity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres,” International Journal of Radiation Oncology Biology Physics, vol. 82, no. 1, pp. 401–407, 2012.
[80]
B. Sangro, B. Gil-Alzugaray, J. Rodriguez et al., “Liver disease induced by radioembolization of liver tumors: description and possible risk factors,” Cancer, vol. 112, no. 7, pp. 1538–1546, 2008.
[81]
R. Salem, R. J. Lewandowski, M. F. Mulcahy et al., “Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes,” Gastroenterology, vol. 138, no. 1, pp. 52–64, 2010.
[82]
B. Sangro, L. Carpanese, R. Cianni et al., “Survival after Yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation,” Hepatology, vol. 54, no. 3, pp. 868–878, 2011.
