Single centre experience of liver resection for hepatocellular carcinoma in patients outside transplant criteria

EJSO 32 (2006) 568–572

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Single centre experience of liver resection for hepatocellular carcinoma in patients outside transplant criteria F. Chu, D.L. Morris* UNSW Department of Surgery, St George Hospital, Level 3 Pitney Building, Sydney, NSW 2217, Australia Accepted 8 February 2006 Available online 17 April 2006

Abstract Introduction: To report analysis of our results of liver resection for HCC outside the transplant criteria with preserved liver function. Methods: Between January 1990 and March 2005, 279 patients with HCC were seen at our institution and entered into a prospective database. There were 51 patients who did not fulfill the transplant criteria and underwent partial hepatectomy. Survival was determined by Kaplan– Meier analysis. Results: The median tumour size was 10.0 cm with a range of 3–20 cm. Twenty-nine patients had solitary tumours and 21 patients had two or more liver tumours, with four patients whose tumours were less than 5 cm in maximal diameter. Ten patients had bilobar disease. The 30-day mortality was 8%. The 1-, 3- and 5-year overall survival was 63, 40 and 33%, respectively, and the median survival was 16.6 months. Fifteen potential variables were analysed as potential predictors of adverse outcome. Multivariate analysis showed Child–Pugh classification, presence of cirrhosis, rupture on presentation and tumour histology to be independent prognostic factors on survival. Conclusion: Partial hepatectomy in patients with advanced HCC who are ineligible for transplantation can be performed safely and can achieve a 5-year survival of 33%. q 2006 Elsevier Ltd. All rights reserved. Keywords: Hepatocellular carcinoma; Resection; Survival; Transplantation; Mortality

Introduction Hepatocellular carcinoma (HCC) is a highly fatal solid organ tumour affecting more than a million persons annually world wide. Approximately, 80% of cases are found in Southeast Asian and sub-Sahara Africa. The age-adjusted incidence rates of HCC are climbing in the west, increasing from 1.3 per 100,000 during 1978–1980 to 4.1 per 100,000 during 1998–2000. This rising trend is mainly due to increased HCV infections, with an estimated 1.5% of the US population being infected by 2010. The incidence has increased significantly among younger persons (40–60 years old) during the period from 1991 to 1995 as compared with earlier periods.1 There is also evidence that both diabetes and obesity are risk factors for HCC.2 The best established curvative treatment of HCC is surgery, either liver resection or transplantation.3 For patients with decompensated liver disease and small

* Corresponding author. Tel.: C61 2 9350 2070; fax: C61 2 9350 3997. E-mail address: [email protected] (D.L. Morris).

0748-7983/$ - see front matter q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.02.005

HCCs, liver transplantation offers the best chance for long term survival. The Milan criteria4 and more recently, the University of California San Francisco (UCSF) criteria5 have shown 4-year survival rates of 75% for small HCCs. Resection is the only treatment option for patients whose HCC fall outside the Milan criteria and the slightly less restrictive UCSF criteria.3 Surgeons in the west are now treating increasing numbers of patients with HCC. In this paper, we critically analyse our results of liver resection for HCC outside the transplant criteria. Methods Between January 1990 and March 2005, 279 patients with HCC were seen at the St George Hospital Liver Unit and entered into a prospective database. Patients with potentially resectable HCC that fall outside transplant criteria due to tumour size or number were worked up for curative resection with analysis of their Child–Pugh score and serum alpha-fetoprotein (AFP) levels. Pre-operative imaging included lipiodol computerized tomography (CT) of the liver, lung CT and bone scans to assess anatomical

F. Chu, D.L. Morris / EJSO 32 (2006) 568–572

respectability and to exclude systemic disease. The diagnosis of HCC was made using a combination of preoperative imaging and AFP levels. We try to avoid a percutaneous biopsy for fear of tumour seeding. If both lipiodol CT and AFP levels are non-diagnostic, then a radiologically guided percutaneous biopsy was used to define the nature of the lesion. The criteria for hepatic resection included absence of extrahepatic disease and preserved liver function. In patients with cirrhosis, strict selection criteria were applied to avoid complications such as liver failure.3 The presence of tumour thrombus, invasion of the portal or hepatic veins is not absolute contraindication to surgery. Patients with bilobar HCC were considered for resection of largest lesion and ablation or limited resection of the lesion in the contralateral lobe. Those deemed potentially resectable were finally assessed at open surgery with intraoperative ultrasound and palpation. Patient with compromised liver function and fulfilled the Milan transplant criteria were referred to a Liver Transplant Unit. Potential curative treatments included partial hepatectomy, partial hepatectomy with ablative therapy (cryotherapy, radio-frequency ablation and alcohol) and ablative therapy only. Those patients deemed unresectable were given lipiodol I131, chemo-embolisation and palliative therapy. Those patients who underwent partial hepatectomy and did not fulfill the Milan or UCSF transplant criteria were selected for critical analysis. Data was extracted from a combination of prospective database, review of hospital and office notes and patient contact. Data was collected on patient demographics, hepatitis status, histopathology of tumour and uninvolved liver, hospital course and survival. All patients were followed up with liver function test, AFP levels and abdominal CT scan 6 months. When liver recurrence was suspected, then lipiodol CT was performed to assess possibility of further surgery or ablation. Hospital deaths were included in overall survival analysis but were excluded from disease-free survival analysis. Univariate analysis was performed on Kaplan– Meier curves using comparison by log-rank test. Multivariate analysis was performed using the Cox proportional hazards model to identify independent prognostic factors. All statistical analyses were performed using statistical software (SPSS 11.5 for Windows, SPSS Inc., Chicago, IL). Differences were considered significant at p!0.05.

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(HAC). One hundred and sixty-seven patients were treated by chemotherapy, palliative lipiodol I131 or supportive care. The overall median survival of the 279 patients with HCC was 10.1 months. Of the patients who underwent a surgical resection alone, the median survival was 36.3 months. The median survival for patients who underwent ablation, combination resection and ablation, hepatic arterial chemotherapy and supportive management were 21.0, 10.1, 8.7 and 4.9 months, respectively. There were 51 patients who did not fulfill the Milan or UCSF transplant criteria, these included 38 males and 13 females. The median age was 62.8 years, with 20 patients over 65 years of age. 19 out of 51 patients had histological evidence of cirrhosis and five patients were Childs B. The median tumour size was 10.0 cm with a range of 3– 20 cm. Thirty patients had solitary tumours and 21 patients had two or more liver tumours, with four patients whose tumours were less than 5 cm in maximal diameter. Ten patients had bilobar disease. Twenty-three patients had formal lobectomies, eight had extended hepatectomies, three had central resections and the rest had combination a segmental resections and ablative therapy (Table 1). The 30-day mortality was 8%. Of the four patients who died, one had a 20 cm HCC wrapping around the IVC who died of in ICU from DIC related to massive intraoperative blood loss requiring internal cardiac massage. One patient died from infected intraabdominal sepsis secondary to a bile leak. The third patient died with ICU 2 weeks after surgery from overwhelming sepsis and progressive liver failure. The final patient developed an acutely ischaemic limb and refused an amputation. The 1-, 3- and 5-year overall survival was 63, 40 and 33%, respectively, and the median survival was 16.6 months (Fig. 1). Fifteen variables were analysed as potential predictors of adverse outcome. On univariate analysis, age less than 65, absence of cirrhosis, Child–Pugh A classification, normalization of AFP post-operatively, intact tumour and well

Results Of the 279 patients with HCC treated at the St George Hospital Liver Unit, there were 230 men and 49 women. The median age at diagnosis was 65.4 years. One hundred and twelve patients underwent a surgical exploration; 40 underwent resection alone, 19 had a combination of resection and ablation, 24 had ablation alone, and 29 had insertion of hepatic artery catheters

Figure 1. Overall survival of patients not suitable for transplantation.

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Table 1 Influence of clinical and pathological parameters after resection of HCC No Cirrhosis No 32 Yes 19 Child–Pugh A 46 B 5 No. of lesions 1 30 O1 21 Satellitosis No 42 Yes 9 PV thrombus No 46 Yes 5 Rupture No 44 Yes 7 Microvascular invasion No 22 Yes 28 Histology Fibrolamellar 4 Well 19 Moderate 22 Poor 6

1-year (%)

3-year (%)

5-year (%)

p

74 45

49 26

43 17

0.037

68 20

45 0

37 0

0.005

72 50

48 29

35 29

0.278

78 33

44 22

35 22

0.175

68 20

42 20

34 20

0.217

66 43

48 0

40 0

0.007

66 63

47 37

47 24

0.319

100 78 55 17

75 50 38 0

50 50 28 0

0.0008

Table 2 Influence of clinical and pathological parameters after resection of HCC on tumour recurrence No

differentiated histology of tumour were shown to be associated with a favourable outcome (Table 1). In patients whose AFP have normalized post-operatively, the 5-year survival was 57%. Multivariate analysis showed Child– Pugh classification, presence of cirrhosis, rupture on presentation and tumour histology to be independent prognostic factors on survival. Twenty-seven patients developed tumour recurrences, with a 5-year recurrence free survival of 27% (Fig. 2). Liver only recurrence occurred in 12 patients, eight patients had multiple sites of recurrence, five had lung only and one had

Figure 2. Recurrence free survival of all resected patients with HCC.

Age !65 27 O65 20 Child–Pugh A 42 B 5 Normalisation of AFP No 13 Yes 22 PV thrombus No 43 Yes 4 MIcrovascular invasion No 20 Yes 27 Margin Not involved 28 Involved 19 Histology Fibrolamellar 4 Well 18 Moderate 20 Poor 5

1-year (%)

3-year (%)

5-year (%)

p

61 33

44 25

30 0

0.038

54 0

40 0

23 0

0.006

17 72

17 50

17 26

0.021

53 25

42 0

24 0

0.020

74 35

66 19

40 0

0.006

65 27

48 20

29 14

0.016

75 71 29 0

25 62 22 0

25 39 0 0

0.003

metastasis to his iliac crest. Of the 21 patients who remained disease free, their 5-year overall survival was 62%. On univariate analysis, Child–Pugh A classification, normalization of AFP post-operatively, absence of portal vein tumour or thrombus, absence of mircovascular invasion and well differentiated histology of tumour were shown to be associated with increased recurrence free survival (Table 2). However, on multivariate analysis, only Child–Pugh classification was shown to be significant. Discussion The premise of this paper is to analyse our survival data for patients undergoing liver resection that are not suitable for liver transplantation. The main reason for unsuitability is generally tumour characteristics that fall outside transplant criteria in patients with preserved liver function. There is no doubt that the best treatment for patients with small HCCs and compromized liver function is liver transplantation, either cadarvaric or living related.3 The current transplant criteria is solitary lesion less than 5 cm in diameter or three or fewer lesions all less than 3 cm in diameter without gross vascular invasion.4 A new slightly less restrictive criteria include patients with solitary HCC%6.5 cm, three or fewer lesions with the largest lesion %4.5 cm and a total lesion diameter %4.5 cm and a total tumour diameter %8 cm.5 However, even with this expanded indication, the majority of patients present with advanced disease, large or multiple tumours and fall outside of the transplant criteria.1 Even in those eligible for

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transplantation, there is still the problem of organ availability. Several centres have now reported 5-year survival rates of 65–75% in patients undergoing liver transplantation with the extended criteria. These results are encouraging but the number of cases reported per unit remains small. Yao et al. reported 5-year survival of 85% in 18 patients with pT3 tumours and Goodman et al. reported 5-year survival of 65% in nine patients with stage III disease.6–7 Others are reporting liver resection or radiofrequency ablation (RFA) of HCC as a bridge to transplantation. Adam et al. reported the results of 98 patients who underwent liver resection that where initially eligible for transplantation. The 5-year survival rate was 52%, with 20% of patients receiving a secondary liver transplant for recurrence.8 Others have used RFA as a bridge to liver transplantation because of long waiting periods. Lu et al. reported a 3-year survival rate of 74% in 52 patients undergoing liver transplantation.9 For tumours falling outside the current recommended transplant criteria, surgical resection remains the treatment of choice. The published mortality rate of liver resection for HCC vary from 1.7 to 7.4%.10–17 In the current study, the 30-day mortality rate was 8%, which is in keeping with surgical series from major surgical institutions. A nation wide survey from the United States looked at workload and its impact on hospital mortality rates. A high volume centre was classified as those hospitals performing 10 or more liver resections per year and low volume centres were those hospitals performing less than 10 liver resections per year. The mortality rate was 6.3% in high volume hospitals versus 15.5% in low volume hospitals, with a risk of in-hospital mortality odds ratio of 0.6.10 Our 5-year survival was 33%. Other units have also published similar results for transplant ineligible resected patients. An American paper reported 5-year survival rate of 31% and a median survival of 31 months for 180 patients not suitable for transplantation.12 A French paper reported on 328 liver resections for HCC over a 10 year period, with a 5-year survival of 37%.13 A multiinstitutional paper recently reported 5 year survival of 39% for large or mulitnodular HCC.16 Several units have now reported 5-year survival of around 50% in patients with resectable HCC. However, included in the analysis were up to 45% of patients with tumour diameter of less than 5 cm.12,17 Only 8% of our patients had tumour diameter of less than 5 cm. Only one third of our patients had histological evidence of cirrhosis. Other western centres have reported 50–70% of their HCC patients with cirrhosis. The presence of cirrhosis significantly influenced in-hospital mortality and overall survival. A French study of 328 liver resections for HCC found the in-hospital mortality rate for patients with normal livers was 1.7% compared to 7.4% for those with liver cirrhosis.9 The presence of cirrhosis also impacts on 5 years

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survival. Others have reported 5 year survival of 42% in patients with normal liver parenchyma compared to 37% in those with cirrhosis.18 The presence of microvascular invasion had been consistently found to be detrimental on survival. An American single centre study found the presence of microvascular invasion significantly decreased the 5-year survival from 48 to 23%. Microvascular invasion has also been linked to increasing likelihood of multifocal disease, larger and higher grade of tumours.19,20 In the latest International Union Against Cancer (UICC)/6th Edition American Union Joint Committee on Cancer (AJCC) staging for liver cancer, the presence of vascular invasion upgrades a tumour from T1 to T2. In a multicentre database with 591 patients, the presence of microscopic vascular invasion had a hazard ratio of 1.6 on multivariant analysis.21 Hepatic resection with removal of tumour thrombus in the main hepatic or intrahepatic portal vein are justified because of favourable survival over nonsurgical treatment. Several groups have reported 5-year survival of 42% in highly selected patients with portal vein thombus.22,23 Patients with bilobar HCC are generally considered as unsuitable for hepatic resection. There is now a trend towards aggressive ‘non-curative hepatic resection’, with reported 5-year survival rates of 20%. In a retrospective study from Hong Kong, patients with bilobar disease treated with resection and ablation of contralateral lobe tumour had significantly improved survival over non-resectional therapeutic approaches.24 In a nation wide survey from Japan, involving 12,118 liver resections for HCC, multivariant analysis showed age, liver disease, alpha-fetoprotein level, tumour diameter, number of tumours, intrahepatic extent of tumours, extrahepatic metastases, portal vein involvement, hepatic vein invasion, surgical curability, and uninvolved margin to be independent prognostic indicators of survival.25 The 5-year recurrence free survival in our series was 27%, with 57% of patients developing recurrences. The most common site was intrahepatic. Others have also reported tumour recurrence in roughly half their patients, with liver being the most common site (83%) and are able to achieve 5-year survival rates of 21% for 164 patients undergoing liver resection.26 The management of liver only recurrence should take a very aggressive approach, using various modalities including re-resection, local ablation, trans-arterial chemo-embolisation and lipiodol I131.27,28 Conclusion Partial hepatectomy in patients with HCC and preserved liver function can be performed safely and can achieve a 5-year survival of 33%.

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