- Email: [email protected]
Chemotherapy liver injury
Chemotherapy liver injury Christopher D. Anderson, MD,a and Ravi S. Chari, MD,b St. Louis, MO, and Nashville, TN
From the Department of Surgery, Washington University School of Medicine, St. Louis, MO,a and Centennial Medical Center,b Nashville, TN
ADVANCES IN CHEMOTHERAPY AND THE INCREASED USE OF PRE-OPERATIVE CHEMOTHERAPY have combined to bring a welcome improvement in the outcome of liver metastatic colorectal carcinoma. However, accompanying this has been a greater awareness of chemotherapy-associated hepatotoxicity. Thus, a clinical paradox has emerged wherein patients who present with initially unresectable liver metastatic colorectal carcinoma may be ‘‘downsized’’ to resectability, but the chemotherapy regimens may, in turn, increase the potential risks of or even preclude major liver resection. Many reports associate this chemotherapy-induced hepatotoxicity to increased operative morbidity and mortality.1-4 In this issue, Hubert et al attempt to address the clinical relevance of this problem by reviewing a large cohort of patients who underwent hepatic resection for liver metastatic colorectal carcinoma. Their results are corroborated by prior studies by suggesting that preresection chemotherapy, especially within the preceding 6 months, is associated sinusoidal injury of the liver. However, they fail to demonstrate an increase in operative morbidity or mortality related to preresection chemotherapy. It should be pointed out that this group employed an aggressive pre-operative planning protocol designed to optimize the remnant liver volume in chemotherapy-exposed patients. The recent increase in articles discussing this topic illustrates the difficulty that liver surgeons have in balancing aggressive resection strategies with aggressive chemotherapy strategies. Regimenspecific patterns of hepatic injury are described in the recent literature, and they generally fall within the spectrum of nonalcoholic fatty liver disease or hepatic sinusoidal injury.1-3 An association is Accepted for publication September 25, 2009. Reprint requests: Ravi S. Chari, MD, Department of Surgery, Centennial Medical Center, 2300 Patterson Street, Nashville, TN 37203. E-mail: [email protected]. Surgery 2010;147:195-6. 0039-6060/$ - see front matter Ó 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2009.09.030
found between oxaliplatin and hepatic sinusoidal injury, especially in patients with specific risk factors including female sex, >6 cycles of oxaliplatin-based chemotherapy, transaminitis, and decreased idocyaninine green retention rate.4 Several agents have been reported to contribute to the development of steatosis, but the progression to steatohepatitis seems to be strongly associated with both irinotecan and oxaliplatin.5,6 The molecular mechanism believed to be responsible for chemotherapy-associated hepatotoxicity is increased hepatic oxidative stress resulting from chemotherapy-generated reactive oxygen species. This mechanism is similar to many proposed models for the progression of simple steatosis to steatohepatisis. Thus, it is not surprising that in a recent publication in Surgery, Brouquet et al7 suggested that obesity (BMI >27) is 1 of the most important risk factors for the development of chemotherapyrelated liver injury. Given the epidemic of obesity, the baseline prevalence of steatosis and steatohepatisis in patients with colorectal liver metastases is likely to continue to increase. These hepatic alterations are themselves associated with increased operative risk from liver resection and likely cofactor with chemotherapy to increase the hepatic injury. Thus, it seems likely that the incidence of chemotherapy-related hepatotoxicity will continue to increase. The morbidity and mortality risks after liver resection in patients with chemotherapy-associated liver injury have been reviewed recently by Chun et al.1 It is generally accepted that major hepatectomy in patients with moderate hepatic steatosis (>30%) results in increased blood loss, longer stays in the intensive care unit, and increased postoperative morbidity.2 Similarly, liver resections in patients with steatohepatitis have been reported to have increased peri-operative mortality.5 Hepatic sinusoidal injury has been shown to increase peri-operative morbidity but not mortality.2 In this study by Hubert et al, the authors showed no increased mortality or morbidity in patients who received chemotherapy; however, they performed a more aggressive pre-operative optimization regimen in the SURGERY 195
196 Anderson and Chari
chemotherapy group, which likely improved the outcome in the most at-risk patients. This article serves to illustrate the point that careful pre-operative planning should be carried out before performing major liver resections in patients after chemotherapy. Although data supporting a specific target remnant liver volume in patients with chemotherapy-associated liver injury are lacking, the liberal use of contralateral portal vein embolization to ensure predicted remnant liver volumes between 30% and 40% seems to be a reasonable approach. Liver hypertrophy does not seem to be inhibited significantly by the concurrent administration of chemotherapy.8 Perhaps most importantly the lack of liver hypertrophy or hypertrophy of less than 5% serves as a strong indication that the liver lacks regenerative capacity and is associated with increased postoperative morbidity.2,9 Failure of hypertrophy of the remnant liver should serve as a strong relative contraindication to major liver resection.9 The timing of liver resection after chemotherapy is another important consideration. Current recommendations suggest waiting 5 weeks between chemotherapy and resection,10 and this interval has also been suggested as a reasonable approach after the administration of biologic agents.11 Finally, the 2-stage hepatectomy should be in the arsenal of liver surgeons considering major liver resections in patients with multiple liver tumors and chemotherapy-associated liver injury. In conclusion, aggressive chemotherapy for liver metastatic colorectal carcinoma remains a ‘‘double-edged sword.’’ On the one hand, it has served to improve overall outcomes for patients with colorectal carcinoma. But on the other hand, it can cause hepatotoxicity increasing morbidity and mortality after liver resection. An aggressive preoperative optimization and planning strategy coordinated by both the liver surgeon and the medical oncologist is necessary to maximize the
Surgery February 2010
therapeutic benefit of neoadjuvant chemotherapy for liver metastatic colorectal carcinoma.
REFERENCES 1. Chun YS, Laurent A, Maru D, Vauthey JN. Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol 2009;10:278-86. 2. Khan AZ, Morris-Stiff G, Makuuchi M. Patterns of chemotherapy-induced hepatic injury and their implications for patients undergoing liver resection for colorectal liver metastases. J Hepatobiliary Pancreat Surg 2009;16:137-44. 3. Kandutsch S, Klinger M, Hacker S, Wrba F, Gruenberger B, Gruenberger T. Patterns of hepatotoxicity after chemotherapy for colorectal cancer liver metastases. Eur J Surg Oncol 2008;34:1231-6. 4. Nakano H, Oussoultzoglou E, Rosso E, Casnedi S, ChenardNeu MP, 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. 5. 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. 6. 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. 7. Brouquet A, Benoist S, Julie C, Brezault C, Le Charpentier M, Dousset B, 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. 8. Covey AM, Brown KT, Jarnagin WR, Brody LA, Schwartz L, Tuorto S, et al. Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg 2008;247: 451-5. 9. Belghiti J. Arguments for a selective approach of preoperative portal vein embolization before major hepatic resection. J Hepatobiliary Pancreat Surg 2004;11:21-4. 10. Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases. Lancet 2008;371:963-5. 11. 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.
From the Department of Surgery, Washington University School of Medicine, St. Louis, MO,a and Centennial Medical Center,b Nashville, TN
ADVANCES IN CHEMOTHERAPY AND THE INCREASED USE OF PRE-OPERATIVE CHEMOTHERAPY have combined to bring a welcome improvement in the outcome of liver metastatic colorectal carcinoma. However, accompanying this has been a greater awareness of chemotherapy-associated hepatotoxicity. Thus, a clinical paradox has emerged wherein patients who present with initially unresectable liver metastatic colorectal carcinoma may be ‘‘downsized’’ to resectability, but the chemotherapy regimens may, in turn, increase the potential risks of or even preclude major liver resection. Many reports associate this chemotherapy-induced hepatotoxicity to increased operative morbidity and mortality.1-4 In this issue, Hubert et al attempt to address the clinical relevance of this problem by reviewing a large cohort of patients who underwent hepatic resection for liver metastatic colorectal carcinoma. Their results are corroborated by prior studies by suggesting that preresection chemotherapy, especially within the preceding 6 months, is associated sinusoidal injury of the liver. However, they fail to demonstrate an increase in operative morbidity or mortality related to preresection chemotherapy. It should be pointed out that this group employed an aggressive pre-operative planning protocol designed to optimize the remnant liver volume in chemotherapy-exposed patients. The recent increase in articles discussing this topic illustrates the difficulty that liver surgeons have in balancing aggressive resection strategies with aggressive chemotherapy strategies. Regimenspecific patterns of hepatic injury are described in the recent literature, and they generally fall within the spectrum of nonalcoholic fatty liver disease or hepatic sinusoidal injury.1-3 An association is Accepted for publication September 25, 2009. Reprint requests: Ravi S. Chari, MD, Department of Surgery, Centennial Medical Center, 2300 Patterson Street, Nashville, TN 37203. E-mail: [email protected]. Surgery 2010;147:195-6. 0039-6060/$ - see front matter Ó 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2009.09.030
found between oxaliplatin and hepatic sinusoidal injury, especially in patients with specific risk factors including female sex, >6 cycles of oxaliplatin-based chemotherapy, transaminitis, and decreased idocyaninine green retention rate.4 Several agents have been reported to contribute to the development of steatosis, but the progression to steatohepatitis seems to be strongly associated with both irinotecan and oxaliplatin.5,6 The molecular mechanism believed to be responsible for chemotherapy-associated hepatotoxicity is increased hepatic oxidative stress resulting from chemotherapy-generated reactive oxygen species. This mechanism is similar to many proposed models for the progression of simple steatosis to steatohepatisis. Thus, it is not surprising that in a recent publication in Surgery, Brouquet et al7 suggested that obesity (BMI >27) is 1 of the most important risk factors for the development of chemotherapyrelated liver injury. Given the epidemic of obesity, the baseline prevalence of steatosis and steatohepatisis in patients with colorectal liver metastases is likely to continue to increase. These hepatic alterations are themselves associated with increased operative risk from liver resection and likely cofactor with chemotherapy to increase the hepatic injury. Thus, it seems likely that the incidence of chemotherapy-related hepatotoxicity will continue to increase. The morbidity and mortality risks after liver resection in patients with chemotherapy-associated liver injury have been reviewed recently by Chun et al.1 It is generally accepted that major hepatectomy in patients with moderate hepatic steatosis (>30%) results in increased blood loss, longer stays in the intensive care unit, and increased postoperative morbidity.2 Similarly, liver resections in patients with steatohepatitis have been reported to have increased peri-operative mortality.5 Hepatic sinusoidal injury has been shown to increase peri-operative morbidity but not mortality.2 In this study by Hubert et al, the authors showed no increased mortality or morbidity in patients who received chemotherapy; however, they performed a more aggressive pre-operative optimization regimen in the SURGERY 195
196 Anderson and Chari
chemotherapy group, which likely improved the outcome in the most at-risk patients. This article serves to illustrate the point that careful pre-operative planning should be carried out before performing major liver resections in patients after chemotherapy. Although data supporting a specific target remnant liver volume in patients with chemotherapy-associated liver injury are lacking, the liberal use of contralateral portal vein embolization to ensure predicted remnant liver volumes between 30% and 40% seems to be a reasonable approach. Liver hypertrophy does not seem to be inhibited significantly by the concurrent administration of chemotherapy.8 Perhaps most importantly the lack of liver hypertrophy or hypertrophy of less than 5% serves as a strong indication that the liver lacks regenerative capacity and is associated with increased postoperative morbidity.2,9 Failure of hypertrophy of the remnant liver should serve as a strong relative contraindication to major liver resection.9 The timing of liver resection after chemotherapy is another important consideration. Current recommendations suggest waiting 5 weeks between chemotherapy and resection,10 and this interval has also been suggested as a reasonable approach after the administration of biologic agents.11 Finally, the 2-stage hepatectomy should be in the arsenal of liver surgeons considering major liver resections in patients with multiple liver tumors and chemotherapy-associated liver injury. In conclusion, aggressive chemotherapy for liver metastatic colorectal carcinoma remains a ‘‘double-edged sword.’’ On the one hand, it has served to improve overall outcomes for patients with colorectal carcinoma. But on the other hand, it can cause hepatotoxicity increasing morbidity and mortality after liver resection. An aggressive preoperative optimization and planning strategy coordinated by both the liver surgeon and the medical oncologist is necessary to maximize the
Surgery February 2010
therapeutic benefit of neoadjuvant chemotherapy for liver metastatic colorectal carcinoma.
REFERENCES 1. Chun YS, Laurent A, Maru D, Vauthey JN. Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol 2009;10:278-86. 2. Khan AZ, Morris-Stiff G, Makuuchi M. Patterns of chemotherapy-induced hepatic injury and their implications for patients undergoing liver resection for colorectal liver metastases. J Hepatobiliary Pancreat Surg 2009;16:137-44. 3. Kandutsch S, Klinger M, Hacker S, Wrba F, Gruenberger B, Gruenberger T. Patterns of hepatotoxicity after chemotherapy for colorectal cancer liver metastases. Eur J Surg Oncol 2008;34:1231-6. 4. Nakano H, Oussoultzoglou E, Rosso E, Casnedi S, ChenardNeu MP, 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. 5. 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. 6. 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. 7. Brouquet A, Benoist S, Julie C, Brezault C, Le Charpentier M, Dousset B, 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. 8. Covey AM, Brown KT, Jarnagin WR, Brody LA, Schwartz L, Tuorto S, et al. Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg 2008;247: 451-5. 9. Belghiti J. Arguments for a selective approach of preoperative portal vein embolization before major hepatic resection. J Hepatobiliary Pancreat Surg 2004;11:21-4. 10. Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases. Lancet 2008;371:963-5. 11. 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.