1. Limitations in liver resection: Is preoperative chemotherapy limiting the extent of liver resection? Jürgen Klempnauer Department of General, Visceral and Transplantation Surgery Medizinische Hochschule Hannover, Germany

2. Typical chemotherapeutic agents a hepatobiliary surgeon is confronted with Adjuvant colon / rectal cancer treatment after resection of primary site *: 5-FU + leucovorin Capecitabine FOLFOX * NCCN + American Cancer Society: Colon and Rectal Cancer Treatment Guidelines – Version IV, February 2005 Most patients that have been exposed to chemotherapy prior to liver resection had adjuvant chemotherapy after resection of a colorectal primary tumor.

3. Hepatotoxicity of Chemotherapy Toxic liver injury can reproduce virtually any known pattern of injury: - necrosis - steatosis - fibrosis - cholestasis - vascular injury * King and Perry (2001); Oncologist 6:162-176 All chemotherapeutic agents have the potential to cause liver injury *.

4. Hepatotoxicity: Common toxicity criteria of the National Cancer Institute, version 2.0

5. Preoperative assessment of liver function to tailor the appropriate extent of resection Requirements of tumor free resection margins. Any underlying hepatic functional impairment that tends to limit the safe extent of resection.

6. Tests of liver function to assess hepatic reserve * Clearance / tolerance tests aminopyrine breath test indocyanine (ICG) retention (clearance) bromosulphalein (BSP) retention galactose tolerance bile acid tolerance beta-hydroxy butyrate/acetoacetate Functional imaging and blood flow: uptake/clearance reticuloendothelium sulfur colloid biliary excretion rose bengal hepatic diacetic acid (HIDA) receptor targeting neogalactosyl albumin (NGA) galactosyl serum albumin (GSA) * Schneider (2004). Surg Clin N Am 84:355-73 No single test appears to account for the variability of clinical resection results. No existing test has proven better than the Child-Pugh-Classification for assessing hepatic reserve.

7. Child-Pugh Score Clinical or biochemical measurement Points scored 12 3 Encephalopathy grade None1-2 3-4 AscitesAbsentMild Moderate to severe Bilirubin<35 µmol/l36-60 µmol/l >60 µmol/l Albumin>35 g/l28-35 g/l <28 g/l [INR][<1-7][1.7-2.3] [>2.3] Child-Pugh A Score 10

8. Integration of anatomical and functional imaging modalities may improve properative assessment of hepatic reserve in the future.

10. Chemotherapy and Liver Regeneration Schrem et al. (2004); Pharmacol Rev. 56(2):291-330 Interference with cell cycle progression by chemotherapy. Decreasing ability for liver regeneration and restoration of liver function. Hepatic resections trigger functional and parenchymal liver regeneration. Hepatocytes switch from the quiescent state into cell cycle progression followed by cell division and liver regrowth after resection.

11. Possible limitations of liver resection by preoperative chemotherapy Chemotherapy can lead to toxic liver injury. Negative impact on hepatic reserve. Chemotherapy compromises postoperative liver regeneration. Wait at least 4 – 6 weeks after chemotherapy before any planned liver resection ! „Wash-out phase of toxic agents“

12. Extended Hepatectomy Recommended minimal functional remnant liver volumes: ≥ 25 % in normal livers ≥ 40 % in livers with - moderate to severe steatosis, - cholestasis, - fibrosis or cirrhosis, - following chemotherapy. Tucker and Heaton (2005). Curr Opin Critical Care 11:150-155 Shoup et al. (2003). J Gastrointestinal Surg 7:325-330 Vauthey et al. (2000). Surgery 127: 512-519

13. Small for Size Liver Syndrome (SFSS) Insufficient functional liver mass after liver transplantation or extended hepatectomy. Postoperative liver dysfunction with: - prolonged cholestasis - coagulopathy - portal hypertension - ascites Predisposes to: Sepsis, GI bleeding, intestinal perforation, encephalopathy, mortality

14. Small for Size Liver Syndrome (SFSS)

15. Preoperative Portal Vein Embolization (PVE) Aim: Induction of hypertrophy of the anticipated liver remnant to increase functional hepatic reserve. Indications: < 25 % expected remnant volume in normal liver function or < 40 % expected remnant volume in compromised liver function. Contraindications: Significant hypertrophy cannot be expected in liver cirrhosis. PVE may result in hepatic failure in moderate to severe liver dysfunction. Abdalla et al. (2001) Br J Surg 88(2): 165-75 Broelsch et al. (2004) Surg Clin N Am 84: 495-511

16. Meta-analysis of PVE * Complications in less than 5 % of cases. No specific substance emerged as superior (cyanoacrylate, thrombin, coils or absolute alcohol). Increase in remnant liver volume averages 12 % of the total liver volume. Morbidity after consecutive resection less than 15 %. Mortality after consecutive resection: 6-7 % with cirrhosis 0-6,5 % without cirrhosis. Conclusion: PVE does not increase the risks associated with major liver resection. * Abdalla et al. (2001) Br J Surg 88(2): 165-75

17. anticipated small remnant volume, no extrahepatic spread 4 -6 weeks after chemotherapy + expected remnant < 40 % of liver volume Non-HCC, no transplant option Child-Pugh Class A bilirubin < 1,9 mg/dl no portal hypertension Child-Pugh Class B or C preoperative PVE (+TACE?) 4-6 weeks repeat volumetry expected remnant > 40 % of liver volume resection PEI, local ablation, clinical studies, palliative treatment, TLC CT oder MRI-volumetry of prospective remnant after virtual resection

18. Neoadjuvant chemotherapy for primarily unresectable colorectal metastases No. patients chemotherapy resection rate survival after resection Adam et al. (2004) * 1104 5-FU + leucovorin 12,5 % 33 % 5y. + oxaliplatin / 23 % 10y irinotecan Pozzo et al. (2004) ** 40 5-FU + folinic acid 32,5 % > 19 months + irinotecan Neoadjuvant chemotherapy may render patients with primarily unresectable colorectal metastases potentially curative resectable. * Adam et al. (2004) Ann Surg 240(4):644-57 ** Pozzo et al. (2004) Ann Oncol 15(6):933-9

19. Neoadjuvant chemotherapy for primarily unresectable HCC No. patients chemotherapy resection rate survival after resection Lau et al. (2004) * 49 doxorubicin 57 % 98 % 1y + cisliplatin 64 % 3y + 5-FU 57 % 5y + interferon-alpha or single doxorubicin Neoadjuvant chemotherapy may render patients with primarily unresectable HCC potentially curative resectable. * Lau et al. (2004) Ann Surg 240(2):299-305

20. Conclusions Respect toxic wash-out phase of 4 – 6 weeks prior to liver resection. Expect potential toxic liver injury. Consider negative impact of chemotherapy on liver regeneration. The Child-Pugh Score remains the most widely accepted clinical assessment tool for preoperative liver function. Consider portal vein embolization (PVE) in expected liver remnants < 40 % of total liver volume. Neoadjuvant chemotherapy may render previously unresectable colorectal liver metastases and HCC resectable by downstaging with encouraging results. The decision to resect and the choice of the extent of a hepatic resection are largely based on surgical judgement and experience.