24 Follow-Up and Salvage Therapy for Recurrent Hepatocellular Carcinoma 385 use of radiofrequency (Chapter 17)ormicrowave(Chapter 18) ablation for recur- rent HCC has not been well studied. Therefore, we will focus on transplantation, repeat resection, and TACE as salvage therapy for liver recurrence. Poon et al. [1] evaluated their experience with 105 patients who developed intra- hepatic recurrence. These patients were treated with repeat resection (n = 11), TACE (n = 71), percutaneous ethanol injection (n = 6), systemic chemotherapy (n = 8), or palliative treatment (n = 9). The overall 1-, 3-, and 5-year survival rates from the time of recurrence were 65, 35, and 20%, respectively. The 1-, 3-, and 5-year survival rates for the 11 patients who underwent repeat resection after recurrence were 81, 69, and 69%, respectively. Five of these patients were alive and disease free for a range of 9–56 months after repeat resection, three were alive with recurrence, and four had died of recurrent disease. Of the 71 patients who under- went TACE for treatment for liver recurrence, the 1-, 3-, and 5-year survival rates were 72, 38, and 21%, respectively. The survival of these patients was significantly worse than those who underwent repeat resection. The 1-, 3-, and 5-year survival rates for the six patients who underwent percutaneous ethanol ablation were 67, 22, and 0%, respectively. Eight patients underwent systemic chemotherapy with a 1- year survival rate of 38%, but no patient survived 3 years. The nine patients who underwent palliative care only had a median survival rate of 2.7 months and there were no 1-year survivors. On multivariate analysis, Child’s Classification at the time of recurrence, serum albumin level at the time of recurrence, interval between ini- tial hepatectomy and recurrence, the number of recurrent tumors, the presence of extrahepatic recurrence, and type of treatment for recurrence were all statistically significant factors predicting survival. The authors concluded that aggressive mul- timodality treatment can result in prolonged survival for patients with intraheptic recurrence after curative resection for HCC. However, the optimal guidelines for patient management in this situation remain to be clarified. Shah et al. [4] reviewed their experience with 193 consecutive patients who underwent hepatic resection with curative intent for HCC. A total of 98 patients (51%) experienced recurrent cancer; initial tumor recurrence was confined to the liver in 86 patients (88%). Of the 98 patients who experienced tumor recurrence, 53 patients (54%) underwent additional therapy, including ablation (n = 31), repeat resection (n = 11), TACE (n = 8), and liver transplantation (n = 3). The patients who did not undergo any therapy either had a large tumor burden of recurrent mul- tifocal disease, extrahepatic disease, or refused further therapy. The overall survival rate for patients who underwent additional therapy was 45 months vs. 9 months for those that did not undergo further therapy. On multivariate analysis, vascular inva- sion, time to recurrence less than 12 months, and lack of additional therapy were all independent prognostic factors predictive of poor survival after hepatic recur- rence of HCC. The authors proposed the algorithm for treatment of recurrence after hepatic resection for HCC, as seen in Fig. 24.1. Poon et al. [2] reviewed the world literature regarding management of recurrent hepatocellular carcinoma after resection. Multiple series have documented 5-year survival rates between 37 and 87% for repeat resection after hepatic recurrence of HCC. In multiple studies, repeat resection was shown to result in improved survival 386 K.M. McMasters and J N. Vauthey Fig. 24.1 Proposed algorithm for treatment of recurrence after resection for HCC. TACE, transarterial chemoembolization. Reproduced from Surgery 2007 with permission from Elsevier/Mosby/Saunders [4] compared to nonsurgical therapy (Table 24.1)[1, 5–17]. In some studies, it has been shown that the overall survival rates of patients with recurrence managed by repeat resection, calculated from the time of first hepatic resection, were similar to those without recurrence. This certainly suggests that repeat resection is a valuable treatment modality for patients with hepatic recurrence. There are no prospective randomized trials to compare treatment modalities for patients with hepatic recur- rence; however, the data strongly suggest that repeat hepatic resection is an effective treatment for such patients. Poon et al. [2] also reviewed the results of TACE for recurrent hepatocellular car- cinoma after resection. Several series have reported 3-year survival rates of between 24 and 48% and 5-year survival rates between 0 and 27% for patients treated with TACE after recurrence. However, there is no level I evidence to suggest that TACE is superior to other therapies for patients with recurrent HCC in the liver (Table 24.2) [1, 11, 18–24]. Another study of the use of bland particle embolization after intra- hepatic recurrence of HCC demonstrated a median survival after embolization of 46 months, with actuarial survival rates at 1 year, 2 years, and 5 years after recurrence of 86, 74, and 47%, respectively [25]. Belghiti et al. [26] initially evaluated the feasibility and postoperative course of liver resection prior to liver transplantation for HCC in 18 patients, showing equivalent disease-free and overall survival for primary and secondary liver trans- plantation. They also reported similar overall incidence of complications in both groups. Vennarecci et al. [27] reviewed their experience with salvage liver transplan- tation in nine patients who experienced recurrent HCC in the liver after resection. 24 Follow-Up and Salvage Therapy for Recurrent Hepatocellular Carcinoma 387 Table 24.1 Repeat hepatic resection for recurrent hepatocellular carcinoma [4–17] Survival after recurrence Author (year [ref]) No. of patients Re-resection rate a (%) Surgical death rate b (%) 1 year (%) 3 years (%) 5 years (%) Re-resection compared with nonsurgical treatments c Nakajima (1993 [5]) 14 25 0 100 87 87 Better survival Matsuda (1993 [6]) 16 44 0 93 21 – Better survival Zhou (1993 [7]) 65 35 0 87 54 42 Better survival Kakazu (1993 [8]) 24 17 0 – 82 82 – Suenaga (1994 [9]) 18 24 0 88 37 37 Better survival Shimada (1994 [10]) 21 – 0 90 78 58 – Lee (1995 [11]) 25 31 0 72 45 – Better survival Nagasue (1996 [12]) 50 30 8 – – 50 Better survival Hu (1996 [13]) 59 48 0 69 44 – Better survival Shuto (1996 14]) 31 19 0 96 71 52 Better survival Shimada (1998 [15]) 41 – 0 100 68 45 – Arii (1998 [16]) 22 – 0 95 50 – – Farges (1998 [17]) 15 17 0 86 75 60 Better survival Poon (1999 [1]) 11 10 0 81 69 69 Better survival a Percentage of patient with intrahepatic recurrence undergoing re-resection b 30-day death rate c Nonsurgical treatments included transarterial chemoembolization, percutaneous ethanol injection, systemic or oral chemotherapy, and symptomatic treatment With permission from [2] 388 K.M. McMasters and J N. Vauthey Table 24.2 Transarterial chemoembolization for recurrent hepatocellular carcinoma Survival after recurrence Author (year [ref]) No. of patients TACE rate a (%) 1 year (%) 3 years (%) 5 years (%) Sasaki (1987 [18]) 30 70 84 25 – Nagao (1990 [19]) 17 41 88 35 – Nakao (1991 [20]) 66 81 88 42 27 Takayasu (1992 [21]) 50 42 64 24 5 Ouchi (1993 [22]) 12 63 75 75 27 Park (1993 [23]) 87 – 75 – – Okazaki (1993 [24]) 68 – 87 34 0 Lee (1995 [11]) 12 – 75 48 – Poon (1999 [1]) 71 68 72 38 21 TACE, transarterial chemoembolization a Percentage of patients with intrahepatic recurrence treated with TACE With permission from [2] They found that the post transplant 1-, 3-, and 5-year survival rates for salvage liver transplantation were 89, 89, and 89%, respectively, similar to those who underwent primary liver transplantation (78, 63, and 63%, respectively). The 1-, 3-, 5-year disease-free survival rates for salvage liver transplantation were 100, 100 and 100%, respectively vs. 89, 74, and 74% for those that underwent primary liver transplan- tation for HCC. They also found that the operative mortality rates, perioperative bleeding complications, operative times, intensive care unit stays, hospital stay, and overall incidence of postoperative complications were similar among patients who underwent salvage liver transplantation after prior resection vs. those who under- went primary liver transplantation for HCC. Facciuto et al. [28] also reported on a small series of five patients who underwent salvage liver transplantation for recur- rence after resection. At a median of 18 months after salvage transplant, all five patients were alive, four were free of disease, and one had developed recurrent HCC. Although there are limited data on the use of transplantation as salvage ther- apy after resection for HCC, the available evidence suggests that this is a potentially curative strategy with results that may be comparable to primary liver transplanta- tion for selected patients. Del Gaudio et al. [29] compared the results of 10 patients who underwent salvage liver transplantation after prior resection for HCC to 80 patients who underwent primary liver transplantation. Only 26% of resected patients were candidates for transplantation. The 5-year overall rates were 62% vs. 73% and disease-free survival rates were 48% vs. 71% comparing patients who under- went salvage transplantation vs. primary liver transplantation, respectively. While these results were not statistically different, the small number of patients in the salvage transplantation group may indicate the possibility of a type II statistical error. Whether resection followed by salvage transplantation is truly comparable to primary liver transplantation remains an open question. However, the shortage of available donor organs and the strict selection criteria for transplantation candidates 24 Follow-Up and Salvage Therapy for Recurrent Hepatocellular Carcinoma 389 limit this approach for most patients with recurrent HCC. Furthermore, the majority of patients who recur after liver resection were not transplantation candidates at the time of their initial therapy. A few studies have evaluated the role of resection for extrahepatic recurrence of HCC. Lo et al. [30] reviewed their experience with surgical resection of solitary lesions in the lung or abdomen in 12 patients, with a mean survival of 20 months; six patients survived disease free for more than 1 year. Another study from the same group [31] reported long-term survival ranging from 33 to 168 months after resection of solitary lung metastases from HCC in six patients. Other studies have documented prolonged survival after surgical resection of isolated recurrences in the adrenal gland, peritoneal cavity, or other extrahepatic sites [32, 33]. Conclusions There are no prospective randomized trials to compare the results of various ther- apies for patients with intrahepatic recurrence after potentially curative resection or ablation for HCC. However, the available evidence suggests that liver transplan- tation should be considered in those patients who are eligible. Retrospective data support the use of repeat resection in patients with intrahepatic recurrence. For patients who are not candidates for transplantation or repeat resection because of the size and distribution of recurrent tumors, the presence of concomitant extra- hepatic disease, age, overall medical condition, or poor liver function, ablative therapy should be considered when feasible. Radiofrequency, microwave, or percu- taneous ethanol ablation can be considered in patients with relatively small tumors amenable to such therapy. TACE and drug-eluting bead chemoembolization, intra- arterial radiotherapy, and systemic therapy should be considered as salvage therapy for those that cannot undergo resection or ablation; however, the data in support of such treatments are somewhat limited. Selected patients with resectable extrahep- atic metastases from HCC may benefit from surgical extirpation. Further studies are necessary to define the role of salvage therapy in the treatment of recurrent HCC. References 1. Poon RT, Fan ST, Lo CM, Liu CL, Wong J (1999) Intrahepatic recurrence after curative resec- tion of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg 229:216–222 2. Poon RT, Fan S-T, and Wong J (2000) Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg 232:10–24 3. NCCN (2009) Clinical Practice Guidelines in Oncology TM . Hepatobiliary Cancers 2. www.NCCN.org. Accessed June 2, 2010 4. Shah SA, Cleary SP, Wei AC et al (2007) Recurrence after liver resection for hepatocellular carcinoma: risk factors, treatment, and outcomes. Surgery 141:330–339 5. Nakajima Y, Ohmura T, Kimura J et al (1993) Role of surgical treatment for recurrent hepatocellular carcinoma after hepatic resection. World J Surg 17:792–795 390 K.M. McMasters and J N. Vauthey 6. Matsuda Y, Ito T, Oguchi Y et al (1993) Rationale of surgical management for recurrent hepatocellular carcinoma. Ann Surg 217:28–34 7. Zhou XD, Yu YQ, Tang ZY et al (1993) Surgical treatment of recurrent hepatocellular carcinoma. Hepatogastroenterology 40:333–336 8. Kakazu T, Makuuchi M, Kawasaki S et al (1993) Repeat hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterology 40:337–341 9. Suenaga M, Sugiura H, Kokuba Y et a l (1994) Repeated hepatic resection for recurrent hepatocellular carcinoma in eighteen cases. Surgery 115:452–457 10. Shimada M, Matsumata T, Taketomi A et al (1994) Repeat hepatectomy for recurrent hepatocellular carcinoma. Surgery 115:703–706 11. Lee PH, Lin WJ, Tsang YM et al (1995) Clinical management of recurrent hepatocellular carcinoma. Ann Surg 222:670–676 12. Nagasue N, Kohno T, Hayashi M et al (1996) Repeat hepatectomy for recurrent hepatocellular carcinoma. Br J Surg 83:127–131 13. Hu RH, Lee PH, Yu SC et al (1996) Surgical resection for recurrent hepatocellular carcinoma: prognosis and analysis of risk factors. Surgery 120:23–29 14. Shuto T, Kinoshita H, Hirohashi K et al (1996) Indication for, and effectiveness of, a second hepatic resection for recurrent hepatocellular carcinoma. Hepatogastroenterology 43:932–937 15. Shimada M, Takenaka K, Taguchi K et al (1998) Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma. Ann Surg 227:80–85 16. Arii S, Monden K, Niwano M et al (1998) Results of surgical treatment for recurrent hepato- cellular carcinoma: comparison of outcome among patients with multicentric carcinogenesis, intrahepatic metastasis and extraheptic recurrence. J Hepatobiliary Pancreat Surg 5:86–92 17. Farges O, Regimbeau JM, Belghiti J (1998) Aggressive management of recurrence following surgical resection of hepatocellular carcinoma. Hepatogastroenterology 45:1275–1280 18. Sasaki Y, Imaoka S, Fujita M et al (1987) Regional therapy in the management of intraheptic recurrence after surgery for hepatoma. Ann Surg 206:40–47 19. Nagao T, Inoue S, Yoshimi F et al (1990) Postoperative recurrence of hepatocellular carcinoma. Ann Surg 211:28–33 20. Nakao N, Kamino K, Miura K et al (1991) Recurrent hepatocellular carcinoma after par- tial hepatectomy: value of treatment with transcatheter arterial chemoembolization. AJR Am J Roentgenol 156:1177–1179 21. Takayasu K, Wakao F, Moriyama N et al (1992) Postresection recurrence of hepatocellu- lar carcinoma treated by arterial embolization: analysis of prognostic factors. Hepatology 16:906–911 22. Ouchi K, Matsubara S, Fukuhara K et al (1993) Recurrence of hepatocellular carcinoma in the liver remnant after hepatic resection. Am J Surg 166:270–273 23. Park JH, Han JK, Chung JW et al (1993) Postoperative recurrence of hepatocellular car- cinoma: results of transcatheter arterial chemoembolization. Cardiovasc Intervent Radiol 16:21–24 24. Okazaki M, Yamasaki S, Ono H et al (1993) Chemoembolotherapy for recurrent hepatocellu- lar carcinoma in the residual liver after hepatectomy. Hepatogastroenterology 40:320–323 25. Covey AM, Maluccio MA, Schubert J et al (2006) Particle embolization of recurrent hepatocellular carcinoma after hepatectomy. Cancer 106:2181–2189 26. Belghiti J, Cortes A, Abdalla EK, et al (2005) Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 241:671–672 27. Vennarecci G, Ettorre GM, Antonini M et al (2007) First-line liver resection and salvage liver transplantation are increasing therapeutic strategies for patients with hepatocellular carcinoma and child a cirrhosis. Transplant Proc 39:1857–1860 28. Facciuto ME, Koneru B, Rocca JP et al. (2008) Surgical treatment of hepatocellular carcinoma beyond Milan criteria. Results of liver resection, salvage transplantation, and primary liver transplantation. Ann Surg Oncol 15:1383–1391 24 Follow-Up and Salvage Therapy for Recurrent Hepatocellular Carcinoma 391 29. Del Gaudio M, Ercolani G, Ravaioli M et al (2008) Liver transplantation for recurrent hepa- tocellular carcinoma on cirrhosis after liver resection: University of Bologna experience. Am J Transplant 8:1177–1185 30. Lo CM, Lai EC, Fan ST, Choi TK, Wong J (1994) Resection for extrahepatic recurrence of hepatocellular carcinoma. Br J Surg 81:1019–1021 31. Lam CM, Lo CM, Yuen WK, Liu CL, Fan ST (1998) Prolonged survival in selected patients following surgical resection for pulmonary metastasis from hepatocellular carcinoma. Br J Surg 85:1198–1200 32. Park JS, Yoon DS, Kim KS et al (2007) What is the best treatment modality for adrenal metastasis from hepatocellular carcinoma? J Surg Oncol 96:32–36 33. Uka K, Aikata H, Takaki S et al (2007) Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol 13:414–420 Index A Note: The letters ‘f’ and ‘t’ following locators refer to figures and tables respectively. AASLD, see American Association for the Study of Liver Diseases (AASLD) AASLD guidelines for ultrasound surveillance, 63 AATD, see α 1 Antitrypsin deficiency (AATD) Abdalla, E. K., 109–129, 176, 176 Abe, T., 282 Ablative procedures cryoablation, 84 microwave, 84 radiofrequency, 84 Abou-Alfa, G. K., 355–364, 376 Acetic acid injection, 268 Acidic fibroblast growth factor (aFGF), 26 Advanced HCC, 70, 93, 95, 119, 219, 358, 360–361, 369, 376t, 379 AFGF, see Acidic fibroblast growth factor (aFGF) Aflatoxin (AF), 6, 24, 57, 100, 105 See also Aflatoxin B1 (AFB1) Aflatoxin B1 (AFB1), 23, 105, 288 AFP, see Alpha-fetoprotein (AFP) AFP-L3, 61, 384 AF, see Aflatoxin (AF) AJCC/UICC staging system, see American Joint Committee on Cancer/ International Union Against Cancer (AJCC/UICC) staging system Alagille syndrome, 28 Albany, C., 355–365 Albumin, 45–46 Alcohol consumption and HCC, 4–5 Aloia, T. A., 219–232 Alpha-fetoprotein (AFP), 37, 42, 46, 58–64, 82, 101, 102t, 111, 127–128, 130, 222, 230, 241, 307, 331, 346, 375f, 384 American Association for the Study of Liver Diseases (AASLD), 55, 63, 82, 91 American Joint Committee on Cancer (AJCC), 69, 73–76, 74t, 175, 222, 256 American Joint Committee on Cancer/ International Union Against Cancer (AJCC/UICC) staging system, 69, 74–78, 74t Anatomic segmentectomy, 191 Andrews, J., 322 Angiogenesis, 25–27 angiopoietins, role in, 26 FGF, pro-angiogenic activity, 26 neovasculature in tumour, role in cancer growth, 25 ‘vascular mimicry,’ 26 VEGF, role in tumour development, 26 Angiopoietin-2 (Ang-2), 364 Angiopoietins, 26, 364 Antero-lateral liver segments, see Laparoscopic liver segments Ante situm technique, 252, 254 α 1 Antitrypsin deficiency (AATD), 12, 28, 287 Apoptosis, 7, 10, 21–23, 47, 155–157, 343, 357, 371 Aquamantys TM , 213 Argon beam coagulator, 125 Asia-Pacific trial, 357–358 Aspergillus, 105 Atrophy (shrinkage) of hepatic segments, 153–154 Atypical resection (laproscopic)/ segmentectomy, 187, 190–194, 192f, 199f Avritscher, R., 153–178 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4, C Springer Science+Business Media, LLC 2011 393 394 Index B Backflow bleeding control, technique, 146–147 Ball valve thrombus syndrome, 246 Balmer, M. L., 21–30 Barcelona Clinic Liver Cancer (BCLC) staging system, 71, 73–74, 73t, 82, 221 patients with multifocal disease, treatment recommendations, 72 Basic fibroblast growth factor (bFGF), 26, 29t BCLC staging system, see Barcelona clinic liver cancer (BCLC) staging system Belghiti, J., 123, 128, 386 Belli, G., 194, 196, 200–202 Benign vs. malignant hepatic tumors, 46–48 CD 34, 46–47 glypican 3, 47 example, in grade III arising in cirrhotic lines, 48f expression in hepatocytic nodules, 47t HSP70, 47 Bevacizumab, 162, 346, 355, 358, 360, 363–364, 371, 372t, 373–374, 375f, 376t BFGF, see Basic fibroblast growth factor (bFGF) Bile duct stenosis, 283 Bi-lobar disease, 208 BioGlu (Cryolife), 214 Biology of HCC biological features of liver cancer, 23–24 angiogenesis, 25–27 HCC in non-cirrhotic liver, 27–28 liver stem cells, 24–25 metastasis, 29–30 telomere shortening, 27 cancer cell survival, criteria alterations in cell physiology, cause of malignant growth, 21 antiproliferative signals, 22 cancer metastasis, 23 growth signals, 22 induction of blood vessel formation by tumours, 23 long and winding road to cancer, 22f resistance to apoptosis, 22–23 telomere maintenance, 23 Bismuth, H., 128 Blanchard, R. J., 321 Bland transarterial embolization, 168 Bortezomib, 345, 372t Brivanib, 345, 364 Bruix, J., 112, 292 Bryant, R., 201, 210 Budd–Chiari syndrome, 246 Buell, J. F., 186, 194, 201, 209–218 N-Butyl cyanoacrylate (NBCA), 171 N-Butyl-2-cyanoacrylate (NBCA), 170 C Cadaveric liver allografts/transplants, 220 Camp,E.R.,261–271 Cancer of the Liver Italian Program (CLIP) score, 69–70 , 70t, 329 Japanese/Canadian validation study, 72 limitations, 73 vs. Okuda system, 73 Cancer stem cell (CSC), 25 “Capillarization” of sinusoids, 46 Carbon dioxide pneumoperitoneum, 188 Carcinogenic pathways, 370–371 Cardiac arrhythmia, 188 Carpanese, L. P. G., 331 Carr,B.I.,329 Carter, S., 297–315 Caudate lobectomies, 160, 198 CD 34, 46–47 CE-IOUS, see Contrast-Enhanced Intraoperative Ultrasonography (CE-IOUS) Cetuximab, 355, 359, 371, 372t, 374, 376t Charring, 277, 278 Chemoembolization, 291 See also Transarterial chemoembolization (TACE) Chemotherapeutic beads, 209 Chemotherapeutic drugs, 337, 338t, 339 Chemotherapy, 38, 40, 84, 93, 117f, 118–120, 121f, 161–162, 223–225, 228–229, 243, 287–288, 289f–290f, 290, 293–295, 299–301, 303, 314, 321, 337–348, 369, 374, 377, 385 See also High-dose chemotherapy; Systemic chemotherapy Chen, H. Y., 186, 194, 201 Chen, M. S., 266 Chen, T. M., 355 Cherqui, D., 185–202 Child–Pugh A disease, 91, 192, 295, 314, 330, 360–362 Child–Pugh B disease, 192–193, 202, 309, 361 Child–Pugh C disease, 241, 294, 294t, 314 Child–Pugh (CP) classification, 113–114, 113t Child–Turcotte–Pugh (CTP) score, 221 Chinese University Prognostic Index (CUPI), 69, 73–74, 73t Choi, H., 266, 268, 304 . the shortage of available donor organs and the strict selection criteria for transplantation candidates 24 Follow-Up and Salvage Therapy for Recurrent Hepatocellular Carcinoma 389 limit this. tumors amenable to such therapy. TACE and drug-eluting bead chemoembolization, intra- arterial radiotherapy, and systemic therapy should be considered as salvage therapy for those that cannot undergo. the liver after resection. 24 Follow-Up and Salvage Therapy for Recurrent Hepatocellular Carcinoma 387 Table 24.1 Repeat hepatic resection for recurrent hepatocellular carcinoma [4–17] Survival