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Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients

Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients Clinical Studies British Journal of Cancer (2005) 92, 1862 – 1868 & 2005 Cancer Research UK All rights reserved 0007 – 0920/05 $30.00 www.bjcancer.com Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients ,1 4 1 2 1 1 3 2 TF Greten , F Papendorf , JS Bleck , T Kirchhoff , T Wohlberedt , S Kubicka , J Klempnauer , M Galanski and MP Manns Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule, Carl Neuberg Str 1, Hannover, 30625 Germany; 2 3 Department of Diagnostic Radiology, Medizinische Hochschule, Hannover, Germany; Department of Visceral and Transplantation Surgery, Medizinische Hochschule, Hannover, Germany; Cancer Center, Medizinische Hochschule, Hannover, Germany Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. However, treatment options are limited and often inefficient. The aim of this study was to determine current survival rates for patients diagnosed with HCC and to identify prognostic factors, which will help in choosing optimal therapies for individual patients. A retrospective analysis of medical records was performed on 389 patients who were identified through the central tumour registry at our institution from 1998 to 2003. Clinical parameters, treatments received and survival curves from time of diagnosis were analysed. Overall median survival was 11 months. Liver cirrhosis was diagnosed in 80.5% of all patients. A total of 170 patients received transarterial chemoembolisation (TACE) and/or percutaneous ethanol injections (PEI) with a median survival rate of 16 months for patients receiving TACE, 11 months for patients receiving PEI and 24 months for patients receiving TACE followed by PEI. Independent negative prognostic parameters for survival were the presence of portal vein thrombosis, advanced liver cirrhosis (Child–Pugh score B or C) and a score of 42. This study will help to estimate survival rates for patients with HCC according to their clinical status at diagnosis and the treatments received. British Journal of Cancer (2005) 92, 1862–1868. doi:10.1038/sj.bjc.6602590 www.bjcancer.com Published online 3 May 2005 & 2005 Cancer Research UK Keywords: chemoembolisation; liver transplantation; cancer; PEI Hepatocellular carcinoma (HCC) is the fifth most common cancer Japanese centre suggests that percutaneous tumour ablation worldwide, and the fourth most common cause of cancer-related methods can become as efficient as surgical procedures (Omata death (Parkin et al, 2001; Bosch et al, 2004). Although HCC occurs et al, 2004). more frequently in Southeast Asia and Africa, its incidence in In contrast to other cancers, the prognosis of patients with HCC Western countries has almost doubled in the past 20 years (El- is not solely related to tumour stage. Cirrhosis underlies the Serag, 2004) due to an increase of hepatitis C virus and alcohol- neoplasm in most cases and has major impact on the prognosis of induced liver cirrhosis (Morgan et al, 2004). patients with HCC. Accordingly, different prognostic systems Curative resection of HCC is possible (Hoofnagle, 2004), assessing liver function and tumour stage have been developed however the success of this approach is limited because of the such as the Okuda staging (Okuda et al, 1985), CLIP score (2000) high rate of tumour recurrence or the development of new and the BCLC (Llovet et al, 2004). Okuda staging is based on the tumours in the cirrhotic liver (Llovet et al, 2004). Liver size of the tumour, presence of ascites, serum albumin and transplantation has become a frequently used alternative, but it bilirubin levels. CLIP score is based on Child–Pugh stage, tumour is clearly not possible for all patients and a significant number of morphology, the presence of portal vein thrombosis and the AFP HCC reoccur in the transplanted liver (Schlitt et al, 1999). level, while the BCLC staging is similar to the Okuda staging Local ablative therapies are increasingly being used to treat system but includes the presence of vascular invasion if present. HCC, either as definitive therapy or as an intermediate step in Hepatocellular carcinoma is a major health problem around the patients awaiting liver transplantation. There is no standard world. However, the biology of the disease varies between different treatment for unresectable HCC, but transarterial chemoemboliza- areas. In Asia, HBV infection is the major risk factor for HCC, tion (TACE) has been shown to increase survival in a randomized whereas HCV infection and alcohol use are more frequently the controlled trial (Llovet et al, 2002). Percutaneous ethanol injection cause for liver cirrhosis and HCC in the Western world (Wang (PEI) has also proven to be relatively easy to perform and is et al, 2002). Additionally, the application of treatment options and inexpensive (Lencioni et al, 2004). Retrospective data from one the success with which they are applied varies as well, so that it is essential to study not only responses to therapy and overall survival in patients but also the prognostic risk factors (Stuart *Correspondence: Dr TF Greten, E-mail: [email protected] et al, 1996). Until today there is only limited data available Received 16 December 2004; revised 21 March 2005; accepted 21 describing the outcome related to baseline patient characteristics March 2005; published online 3 May 2005 among all patients with HCC in Western countries. Survival of HCC patients TF Greten et al Therefore, we have collected data from a large group of HCC Table 1 Patient characteristics at baseline patients, who were consecutively presented to our referral centre in Number of patients Germany between January 1998 and December 2003. We have retrospectively examined the clinical baseline characteristics of 389 Total number of patients 389 patients, as well as their respective forms of therapy and ultimate Male/female 309/80 outcomes. Using uni- and multivariate regression analysis, we have Age (mean/range) 64 (18 – 85) attempted to construct both a descriptive evaluation of the Child (A/B/C/no cirrhosis) 155/79/35/51 individual subgroups and their survival and to identify possible Hepatitis (B/C/B+C) 57/78/7 clinically evident prognostic factors at the time of presentation. AIH/haemachromatosis 4/17 Toxic/unknown 113/2 These data will help to find optimal treatment modalities for Nodes (1/41) 125/259 individual patients in the future and build a base for future clinical Liver lobe (right/left/both) 135/42/208 trials, when different therapy algorithms will be evaluated. Portal vein thrombosis (partial/complete/no) 65/17/294 OKUDA (1/2/3) 76/203/40 CLIP (0/1/2/3 – 6) 20/26/65/129 PATIENTS AND METHODS AFP (o400/X400) 196/137 Bilirubin (o17mmol/l/417mmol/l) 173/169 The central tumour registry at Medizinische Hochschule Hannover has collected data from all patients, who were presented with HCC at the Department of Gastroenterology, Hepatology and Endocri- nology since 1997. We have examined the medical records of all patients had metastatic disease at the time of diagnosis. Complete patients who were presented at our Department between January and partial portal vein thrombosis was found in 17 (4%) and 65 1998 and December 2004 to confirm the diagnosis and relevant (17%) of all patients. AFP levels were elevated above 400 ng/ml in clinical parameters. Hepatocellular carcinoma was diagnosed 137 (41%) patients and the elevated bilirubin levels were found in according to EASL guidelines (Bruix et al, 2001). The following 49% of the patients. parameters were examined: age, sex, clinical or pathological stage using the Okuda and CLIP score systems (Okuda et al, 1985; The Treatment Cancer of the Liver Italian Program, 2000). Presence or absence of cirrhosis was analysed and, if cirrhosis was present, the extent was A total of 37 patients underwent surgical therapy including liver classified according to the Child–Pugh classification (Child and transplantation in 12 cases. Patients, who were not eligible for Turcotte, 1964). Any risk factors for developing cirrhosis were primary surgery, were treated according the algorithm shown in registered including hepatitis B or C, haemochromatosis, alcohol Figure 1. If possible, all patients underwent primarily TACE abuse or autoimmune hepatitis. Alpha-fetoprotein levels were followed by PEI as previously suggested by Allgaier (Allgaier et al, analysed in all patients in the central clinical biochemistry 1998). If PEI was not possible after the first TACE, this treatment laboratory of our institution. In addition, any form of therapy was repeated if needed until the tumour progressed despite undergone by the patient was recorded. Survival was determined treatment. Overall, TACE was performed in 103 patients. A from the time of initial diagnosis. Actuarial survival was calculated mixture of lipiodol, cisplatin and doxorubicin was used in most using the methods of Kaplan and Meier (1958). Baseline cases and no TACE-related deaths occurred. Percutaneous ethanol parameters were analysed with the log-rank test to identify injection was performed in 121 patients, of which 52 patients potential prognostic factors. Multivariate analysis was then received both, PEI and TACE. Percutaneous ethanol injection was performed using the Cox proportional hazards regression (Cox repeated if new tumours appeared. Tables 3 and 4 show the and Oakes, 1984) including those parameters, which were number of PEIs performed for each group of patients. Finally, 147 significant according to the univariate test. patients were not eligible for either of the three treatment options Survival curves were compared using the Cox–Mantel log-rank (surgery, PEI and TACE) due to the extent of liver cirrhosis or test. Univariate and multiple regression analysis of covariance tumour and were treated with sandostatin, tamoxifen, pravasin, among patient characteristics were performed with the aid of SSP systemic chemotherapy or best supportive care (Table 2). Software. Survival RESULTS Average follow-up for all HCC patients in this study was 20.4 months. Overall median survival of all 389 patients was 11 months Patient characteristics from the date of diagnosis. The 1-year survival rate was 49%, after Three hundred and eighty-nine patients were seen at the 3 years 19% of all patients were still alive (Figure 2). Next, patients Department of Gastroenterology, Hepatology and Endocrinology were subdivided into different groups depending on their clinical between January 1998 and December 2003 with confirmed status at the time of initial presentation at our department. If liver diagnosis of HCC. Patient characteristics are summarised in cirrhosis was present, the Child score system was used to Table 1. The male to female ratio was 3.8 : 1 and liver cirrhosis was categorize patients into patients with Child A, Child B and Child present in 80.5% of the cases. Viral hepatitis and alcohol were the C cirrhosis, respectively. The 1- and 3-year survival rate differed most common cause for liver cirrhosis. The average age was 64 significantly between patients without cirrhosis or Child A years old (mean 18–85 years). In all, 52% of the patients had one cirrhosis and those with Child B or C cirrhosis (Figure 3), while liver lesion, 42% had two or three lesions and the remaining there was no significant difference in survival between patients patients had more than three lesions. We have used Okuda staging with Child A cirrhosis and no cirrhosis with a median survival of and CLIP score analysis to classify baseline parameters for those 17 and 16 months, respectively. Patients with Child B cirrhosis had HCC patients, for whom detailed staging information was a median survival rate of 6 months and patients with Child C available. Of 319 patients, 24% were classified as Okuda I, 64% cirrhosis had the poorest median survival of 4 months. as Okuda II, and 12% as Okuda III. Twenty (8%) patients had a Additionally, patient’s status at initial presentation in our CLIP score of zero. Twenty-six (11%) patients had a CLIP score of department was rated according to the CLIP score. As expected, one. Sixty-five (27%) patients had a CLIP score of two and 129 patients with a CLIP score of zero points had the best median (54%) patients had a CLIP score above two. A total of 33 (9%) survival of 36 months (Figure 4). Patients with a CLIP score of 1–2 & 2005 Cancer Research UK British Journal of Cancer (2005) 92(10), 1862 – 1868 Clinical Studies Clinical Studies Survival of HCC patients TF Greten et al Evaluation for Surgery primary resection Portal vein thrombosis  Evaluation for PEI without TACE  Liver, heart and kidney function  White blood count, platelets  performance status and past medical history Tumour mass < 50% liver Best supportive PEI care TACE Number and size of lesions Evaluation for PEI (< 5 and < 5 cm) Re-evaluation for 2nd TACE or best supportive care Figure 1 Treatment algorithm for patients with HCC. Table 2 Initial treatments received Table 3 Number of PEI, which was used to treat patients with PEI only Number of patients Number of PEIs Number of patients Surgery 25 (6.4%) 1 29 (42%) PEI 69 (17.7%) 2 20 (29%) TACE+PEI 52 (13.4%) 3 7 (10%) TACE 49 (12.6%) 43 13 (19%) Other 194 (49.9%) PEI¼ Percutaneous ethanol injections. PEI¼ Percutaneous ethanol injections; TACE¼ transarterial chemoembolisation. a b Twelve additional patients underwent liver transplantation. Including best supportive care and systemic treatment with sandostatin, tamoxifen, pravasin and Table 4 Number of PEI, which was used to treat patients with TACE two patients receiving RFA and two patients receiving TACE followed by surgery. followed by PEI had a median survival of 28 and 16 months and finally patients Number of PEIs Number of patients with a CLIP score 42 points had only a median survival of 8 1 17 (33%) months. 2 15 (29%) We also compared the group of patients with partial and 3 11 (21%) complete portal vein thrombosis, since it has been previously 43 9 (17%) suggested that thrombosis of the portal vein is an independent negative predictor of ultimate survival CLIP score (2000). Indeed, PEI¼ Percutaneous ethanol injections. British Journal of Cancer (2005) 92(10), 1862 – 1868 & 2005 Cancer Research UK + Survival of HCC patients TF Greten et al 01 23 4 56 Years Median survival (mo.) 11 (6−29) 1-year survival (%) 49 3-year survival rate (%) 19 Figure 2 Kaplan – Meier survival curve for all 389 patients. Median survival rate was 13 months, 1- and 3-year survival rate at 53 and 22 months. Median survival is presented as month (upper – lower interquartile range). CP B no cirrhosis CP C CP A 0 1 23 456 Years None A B C Median survival (mo.) 16 (8−36) 17 (7−34) 6 (4 −13) 4 (4 −10) 1-year survival (%) 55 61 29 17 3-year survival rate (%) 27 22 8 10 Figure 3 Kaplan –Meier survival curve for 355 patients depending on the presence and extent of liver cirrhosis according to Child–Pugh classification. Median survival is presented as month (upper – lower interquartile range). Table 5 Independent variables predictive of 5-year survival by multi- Finally, patient survival was analysed on the basis of the variate analysis treatments that the patients received. As shown in Figure 6, there was a significant segregation in survival curves. As expected, P Relative risk (95% CI) patients who underwent surgical therapy, had the best median survival rate of 52 months, followed by patients receiving TACE CLIP score 0.034 1.613 (1.036 – 2.511) and PEI (24 months), TACE (16 months) and PEI (11 months). Portal vein thrombosis o0.0001 2.443 (1.797 – 3.319) Patients, who were not eligible for surgery, TACE or PEI had a Child A vs Child B and C 0.012 1.965 (1.160 – 3.329) median survival rate of 6 months. Uni- and multivariate analysis of potential factors affecting patient survival was performed in order to identify those risk we were able to confirm this observation. Patients with portal vein factors, which predict survival of patients. This analysis is thrombosis had a significantly lower median survival of 6 months important to identify optimal therapies for patients with HCC. in contrast to patients without portal vein thrombosis, who had a Sex, age, tumour size, bilirubin, Child–Pugh score, Okuda stage, median survival rate of 16 months (Figure 5). CLIP stage, the presence of one or multiple tumours, the location & 2005 Cancer Research UK British Journal of Cancer (2005) 92(10), 1862 – 1868 Survival (%) Survival (%) Clinical Studies Clinical Studies Survival of HCC patients TF Greten et al Clip 0-2 Clip 3-6 0 12 3 45 6 Years 0 1 2 3-6 Median survival (mo.) 36 (22 − 48) 28 (10 − 52) 16 (6 − 29) 8 (4 − 13) 1-year survival (%) 84 64 59 32 3-year survival rate (%) 51 41 21 5 Figure 4 Kaplan –Meier survival curve for 240 patients depending on their initial CLIP score. Median survival is presented as month (upper – lower interquartile range). no PVT PVT 012 34 5 6 Years Median survival (mo.) 6 (4 − 11) 16 (7 − 34) 1-year survival (%) 22 58 3-year survival rate (%) 2 24 Figure 5 Kaplan – Meier survival curve for 341patients depending on the presence (þ ) or absence () of a portal vein thrombosis. Median survival is presented as month (upper – lower interquartile range). of the tumour in the liver were all evaluated. Only, CLIP score, Cancer of the Liver Italian Program, 2000; Villa et al, 2000; Rabe Child stage and the presence of portal vein thrombosis were et al, 2001; Herold et al, 2002), this study included a high number identified to be independent risk factors affecting patient survival of patients treated by TACE and PEI, which have become the most as shown in Table 5 by multivariate analysis. Additionally, frequently used treatments in the Western World. No patient was bilirubin, number and size of individual intrahepatic tumours excluded from our retrospective analysis in contrast to those were identified as independent risk factors by univariate analysis. studies, who investigated only the effect of surgery or local ablative therapy (Tanaka et al, 1998; Schlitt et al, 1999; O’Suilleabhain et al, 2003; Jaeck et al, 2004). Therefore, this data reflects the current situation, for unselected patients with HCC similar to a different DISCUSSION study published 9 years ago (Stuart et al, 1996). We have analysed 389 patients with HCC, who were treated at our As previously reported for other non-Asian centres (Stuart et al, department between 1998 and 2003. In contrast to a series of other 1996; Rabe et al, 2001; Erhardt et al, 2002), our patient population published studies (Chevret et al, 1999; Llovet et al, 1999; The differed significantly from Asian centres (Sithinamsuwan et al, British Journal of Cancer (2005) 92(10), 1862 – 1868 & 2005 Cancer Research UK Survival (%) Survival (%) Survival of HCC patients TF Greten et al TACE + PEI Surgery TACE PEI BSC 01 2 3 45 6 Years Surgery TACE PEI TACE +PEI Systemic therapy Median survival (mo.) 52 (40 − 64) 16 (8 − 41) 11 (6 − 29) 24 (17 − 34) 6 (4−12) 1-year survival (%) 90 54 49 92 25 3-year survival rate (%) 76 29 21 16 2 Figure 6 Kaplan – Meier survival curve for 288 patients depending on the therapy received. Median survival is presented as month (upper – lower interquartile range). 2000) with less HbsAg-positive patients in our study population. modalities chosen, similar results were reported by others (Stuart Moreover, the average age of our patients was 64 years old et al, 1996; Allgaier et al, 1998; Bruix and Llovet, 2002; Herold et al, indicating that currently HCC is more frequently diagnosed in 2002; O’Suilleabhain et al, 2003). older patients as described by others (Dohmen et al, 2004). Independent prognostic factors can help in assessing the In contrast to most retrospective reports, which focus on the individual prognosis for patients with HCC and are therefore epidemiology and risk factors contributing to development of HCC critical for the patients. In our analysis we were able to identify in Western countries (Kubicka et al, 2000; Rabe et al, 2001; Llovet CLIP score, the presence of portal vein thrombosis and extent of and Beaugrand, 2003; Caselitz et al, 2004), our analysis was liver cirrhosis as independent prognostic factors and demonstrate undertaken to analyse patient survival according to clinical stage the pivotal role of liver cirrhosis for the prognosis of patients with and possible treatment respectively and in order to identify HCC, which has previously also been described by a number of possible prognostic factors, which might prove to be helpful, when different groups (Bruix and Llovet, 2002). the best possible treatment has to be chosen for patients with HCC. In summary, our retrospective study provides important information for the treatment of patients with HCC, while it According to tumour stage, extent of liver cirrhosis and other clinical factors, different treatment options were chosen in this should be emphasised that firm definite conclusions should only study as indicated in Figure 1. Therefore different treatments were be drawn from prospectively randomized studies. Using a not directly comparable and survival differences might be due to significant number of patients we have calculated survival rates different stages of the disease. for all patients with HCC regardless of therapy using different The number of patients eligible for surgical resection was much criteria such as disease state and therapy options. These data will smaller than the number of patients receiving TACE and PEI. In form the basis for future randomised clinical trials evaluating new addition, the tumour stage and cirrhosis differed between these therapeutic options for the treatment of HCC. two groups leading to the observed differences in survival in contrast to studies published by others (Llovet et al, 2004). Similar to other reports, we saw a median survival of 24 months for the patients receiving TACE followed by PEI (Allgaier et al, 1998). A ACKNOWLEDGEMENTS significant number of patients, who were not eligible for a combined treatment of TACE and PEI due to their stage of We thank Silvia Polon and Monique Ho¨rning for help obtaining disease, were treated with TACE or PEI only. As expected these patient data and Dr Firouzeh Korangy for critical reading of the patients had lower survival rates. However, with minor differences manuscript. Tim F. Greten is supported by the Deutsche depending on the group of patients selected and treatment Forschungsgemeinschaft (KFO 119). 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Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients

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Springer Journals
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Copyright © 2005 by The Author(s)
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Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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10.1038/sj.bjc.6602590
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Clinical Studies British Journal of Cancer (2005) 92, 1862 – 1868 & 2005 Cancer Research UK All rights reserved 0007 – 0920/05 $30.00 www.bjcancer.com Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients ,1 4 1 2 1 1 3 2 TF Greten , F Papendorf , JS Bleck , T Kirchhoff , T Wohlberedt , S Kubicka , J Klempnauer , M Galanski and MP Manns Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule, Carl Neuberg Str 1, Hannover, 30625 Germany; 2 3 Department of Diagnostic Radiology, Medizinische Hochschule, Hannover, Germany; Department of Visceral and Transplantation Surgery, Medizinische Hochschule, Hannover, Germany; Cancer Center, Medizinische Hochschule, Hannover, Germany Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. However, treatment options are limited and often inefficient. The aim of this study was to determine current survival rates for patients diagnosed with HCC and to identify prognostic factors, which will help in choosing optimal therapies for individual patients. A retrospective analysis of medical records was performed on 389 patients who were identified through the central tumour registry at our institution from 1998 to 2003. Clinical parameters, treatments received and survival curves from time of diagnosis were analysed. Overall median survival was 11 months. Liver cirrhosis was diagnosed in 80.5% of all patients. A total of 170 patients received transarterial chemoembolisation (TACE) and/or percutaneous ethanol injections (PEI) with a median survival rate of 16 months for patients receiving TACE, 11 months for patients receiving PEI and 24 months for patients receiving TACE followed by PEI. Independent negative prognostic parameters for survival were the presence of portal vein thrombosis, advanced liver cirrhosis (Child–Pugh score B or C) and a score of 42. This study will help to estimate survival rates for patients with HCC according to their clinical status at diagnosis and the treatments received. British Journal of Cancer (2005) 92, 1862–1868. doi:10.1038/sj.bjc.6602590 www.bjcancer.com Published online 3 May 2005 & 2005 Cancer Research UK Keywords: chemoembolisation; liver transplantation; cancer; PEI Hepatocellular carcinoma (HCC) is the fifth most common cancer Japanese centre suggests that percutaneous tumour ablation worldwide, and the fourth most common cause of cancer-related methods can become as efficient as surgical procedures (Omata death (Parkin et al, 2001; Bosch et al, 2004). Although HCC occurs et al, 2004). more frequently in Southeast Asia and Africa, its incidence in In contrast to other cancers, the prognosis of patients with HCC Western countries has almost doubled in the past 20 years (El- is not solely related to tumour stage. Cirrhosis underlies the Serag, 2004) due to an increase of hepatitis C virus and alcohol- neoplasm in most cases and has major impact on the prognosis of induced liver cirrhosis (Morgan et al, 2004). patients with HCC. Accordingly, different prognostic systems Curative resection of HCC is possible (Hoofnagle, 2004), assessing liver function and tumour stage have been developed however the success of this approach is limited because of the such as the Okuda staging (Okuda et al, 1985), CLIP score (2000) high rate of tumour recurrence or the development of new and the BCLC (Llovet et al, 2004). Okuda staging is based on the tumours in the cirrhotic liver (Llovet et al, 2004). Liver size of the tumour, presence of ascites, serum albumin and transplantation has become a frequently used alternative, but it bilirubin levels. CLIP score is based on Child–Pugh stage, tumour is clearly not possible for all patients and a significant number of morphology, the presence of portal vein thrombosis and the AFP HCC reoccur in the transplanted liver (Schlitt et al, 1999). level, while the BCLC staging is similar to the Okuda staging Local ablative therapies are increasingly being used to treat system but includes the presence of vascular invasion if present. HCC, either as definitive therapy or as an intermediate step in Hepatocellular carcinoma is a major health problem around the patients awaiting liver transplantation. There is no standard world. However, the biology of the disease varies between different treatment for unresectable HCC, but transarterial chemoemboliza- areas. In Asia, HBV infection is the major risk factor for HCC, tion (TACE) has been shown to increase survival in a randomized whereas HCV infection and alcohol use are more frequently the controlled trial (Llovet et al, 2002). Percutaneous ethanol injection cause for liver cirrhosis and HCC in the Western world (Wang (PEI) has also proven to be relatively easy to perform and is et al, 2002). Additionally, the application of treatment options and inexpensive (Lencioni et al, 2004). Retrospective data from one the success with which they are applied varies as well, so that it is essential to study not only responses to therapy and overall survival in patients but also the prognostic risk factors (Stuart *Correspondence: Dr TF Greten, E-mail: [email protected] et al, 1996). Until today there is only limited data available Received 16 December 2004; revised 21 March 2005; accepted 21 describing the outcome related to baseline patient characteristics March 2005; published online 3 May 2005 among all patients with HCC in Western countries. Survival of HCC patients TF Greten et al Therefore, we have collected data from a large group of HCC Table 1 Patient characteristics at baseline patients, who were consecutively presented to our referral centre in Number of patients Germany between January 1998 and December 2003. We have retrospectively examined the clinical baseline characteristics of 389 Total number of patients 389 patients, as well as their respective forms of therapy and ultimate Male/female 309/80 outcomes. Using uni- and multivariate regression analysis, we have Age (mean/range) 64 (18 – 85) attempted to construct both a descriptive evaluation of the Child (A/B/C/no cirrhosis) 155/79/35/51 individual subgroups and their survival and to identify possible Hepatitis (B/C/B+C) 57/78/7 clinically evident prognostic factors at the time of presentation. AIH/haemachromatosis 4/17 Toxic/unknown 113/2 These data will help to find optimal treatment modalities for Nodes (1/41) 125/259 individual patients in the future and build a base for future clinical Liver lobe (right/left/both) 135/42/208 trials, when different therapy algorithms will be evaluated. Portal vein thrombosis (partial/complete/no) 65/17/294 OKUDA (1/2/3) 76/203/40 CLIP (0/1/2/3 – 6) 20/26/65/129 PATIENTS AND METHODS AFP (o400/X400) 196/137 Bilirubin (o17mmol/l/417mmol/l) 173/169 The central tumour registry at Medizinische Hochschule Hannover has collected data from all patients, who were presented with HCC at the Department of Gastroenterology, Hepatology and Endocri- nology since 1997. We have examined the medical records of all patients had metastatic disease at the time of diagnosis. Complete patients who were presented at our Department between January and partial portal vein thrombosis was found in 17 (4%) and 65 1998 and December 2004 to confirm the diagnosis and relevant (17%) of all patients. AFP levels were elevated above 400 ng/ml in clinical parameters. Hepatocellular carcinoma was diagnosed 137 (41%) patients and the elevated bilirubin levels were found in according to EASL guidelines (Bruix et al, 2001). The following 49% of the patients. parameters were examined: age, sex, clinical or pathological stage using the Okuda and CLIP score systems (Okuda et al, 1985; The Treatment Cancer of the Liver Italian Program, 2000). Presence or absence of cirrhosis was analysed and, if cirrhosis was present, the extent was A total of 37 patients underwent surgical therapy including liver classified according to the Child–Pugh classification (Child and transplantation in 12 cases. Patients, who were not eligible for Turcotte, 1964). Any risk factors for developing cirrhosis were primary surgery, were treated according the algorithm shown in registered including hepatitis B or C, haemochromatosis, alcohol Figure 1. If possible, all patients underwent primarily TACE abuse or autoimmune hepatitis. Alpha-fetoprotein levels were followed by PEI as previously suggested by Allgaier (Allgaier et al, analysed in all patients in the central clinical biochemistry 1998). If PEI was not possible after the first TACE, this treatment laboratory of our institution. In addition, any form of therapy was repeated if needed until the tumour progressed despite undergone by the patient was recorded. Survival was determined treatment. Overall, TACE was performed in 103 patients. A from the time of initial diagnosis. Actuarial survival was calculated mixture of lipiodol, cisplatin and doxorubicin was used in most using the methods of Kaplan and Meier (1958). Baseline cases and no TACE-related deaths occurred. Percutaneous ethanol parameters were analysed with the log-rank test to identify injection was performed in 121 patients, of which 52 patients potential prognostic factors. Multivariate analysis was then received both, PEI and TACE. Percutaneous ethanol injection was performed using the Cox proportional hazards regression (Cox repeated if new tumours appeared. Tables 3 and 4 show the and Oakes, 1984) including those parameters, which were number of PEIs performed for each group of patients. Finally, 147 significant according to the univariate test. patients were not eligible for either of the three treatment options Survival curves were compared using the Cox–Mantel log-rank (surgery, PEI and TACE) due to the extent of liver cirrhosis or test. Univariate and multiple regression analysis of covariance tumour and were treated with sandostatin, tamoxifen, pravasin, among patient characteristics were performed with the aid of SSP systemic chemotherapy or best supportive care (Table 2). Software. Survival RESULTS Average follow-up for all HCC patients in this study was 20.4 months. Overall median survival of all 389 patients was 11 months Patient characteristics from the date of diagnosis. The 1-year survival rate was 49%, after Three hundred and eighty-nine patients were seen at the 3 years 19% of all patients were still alive (Figure 2). Next, patients Department of Gastroenterology, Hepatology and Endocrinology were subdivided into different groups depending on their clinical between January 1998 and December 2003 with confirmed status at the time of initial presentation at our department. If liver diagnosis of HCC. Patient characteristics are summarised in cirrhosis was present, the Child score system was used to Table 1. The male to female ratio was 3.8 : 1 and liver cirrhosis was categorize patients into patients with Child A, Child B and Child present in 80.5% of the cases. Viral hepatitis and alcohol were the C cirrhosis, respectively. The 1- and 3-year survival rate differed most common cause for liver cirrhosis. The average age was 64 significantly between patients without cirrhosis or Child A years old (mean 18–85 years). In all, 52% of the patients had one cirrhosis and those with Child B or C cirrhosis (Figure 3), while liver lesion, 42% had two or three lesions and the remaining there was no significant difference in survival between patients patients had more than three lesions. We have used Okuda staging with Child A cirrhosis and no cirrhosis with a median survival of and CLIP score analysis to classify baseline parameters for those 17 and 16 months, respectively. Patients with Child B cirrhosis had HCC patients, for whom detailed staging information was a median survival rate of 6 months and patients with Child C available. Of 319 patients, 24% were classified as Okuda I, 64% cirrhosis had the poorest median survival of 4 months. as Okuda II, and 12% as Okuda III. Twenty (8%) patients had a Additionally, patient’s status at initial presentation in our CLIP score of zero. Twenty-six (11%) patients had a CLIP score of department was rated according to the CLIP score. As expected, one. Sixty-five (27%) patients had a CLIP score of two and 129 patients with a CLIP score of zero points had the best median (54%) patients had a CLIP score above two. A total of 33 (9%) survival of 36 months (Figure 4). Patients with a CLIP score of 1–2 & 2005 Cancer Research UK British Journal of Cancer (2005) 92(10), 1862 – 1868 Clinical Studies Clinical Studies Survival of HCC patients TF Greten et al Evaluation for Surgery primary resection Portal vein thrombosis  Evaluation for PEI without TACE  Liver, heart and kidney function  White blood count, platelets  performance status and past medical history Tumour mass < 50% liver Best supportive PEI care TACE Number and size of lesions Evaluation for PEI (< 5 and < 5 cm) Re-evaluation for 2nd TACE or best supportive care Figure 1 Treatment algorithm for patients with HCC. Table 2 Initial treatments received Table 3 Number of PEI, which was used to treat patients with PEI only Number of patients Number of PEIs Number of patients Surgery 25 (6.4%) 1 29 (42%) PEI 69 (17.7%) 2 20 (29%) TACE+PEI 52 (13.4%) 3 7 (10%) TACE 49 (12.6%) 43 13 (19%) Other 194 (49.9%) PEI¼ Percutaneous ethanol injections. PEI¼ Percutaneous ethanol injections; TACE¼ transarterial chemoembolisation. a b Twelve additional patients underwent liver transplantation. Including best supportive care and systemic treatment with sandostatin, tamoxifen, pravasin and Table 4 Number of PEI, which was used to treat patients with TACE two patients receiving RFA and two patients receiving TACE followed by surgery. followed by PEI had a median survival of 28 and 16 months and finally patients Number of PEIs Number of patients with a CLIP score 42 points had only a median survival of 8 1 17 (33%) months. 2 15 (29%) We also compared the group of patients with partial and 3 11 (21%) complete portal vein thrombosis, since it has been previously 43 9 (17%) suggested that thrombosis of the portal vein is an independent negative predictor of ultimate survival CLIP score (2000). Indeed, PEI¼ Percutaneous ethanol injections. British Journal of Cancer (2005) 92(10), 1862 – 1868 & 2005 Cancer Research UK + Survival of HCC patients TF Greten et al 01 23 4 56 Years Median survival (mo.) 11 (6−29) 1-year survival (%) 49 3-year survival rate (%) 19 Figure 2 Kaplan – Meier survival curve for all 389 patients. Median survival rate was 13 months, 1- and 3-year survival rate at 53 and 22 months. Median survival is presented as month (upper – lower interquartile range). CP B no cirrhosis CP C CP A 0 1 23 456 Years None A B C Median survival (mo.) 16 (8−36) 17 (7−34) 6 (4 −13) 4 (4 −10) 1-year survival (%) 55 61 29 17 3-year survival rate (%) 27 22 8 10 Figure 3 Kaplan –Meier survival curve for 355 patients depending on the presence and extent of liver cirrhosis according to Child–Pugh classification. Median survival is presented as month (upper – lower interquartile range). Table 5 Independent variables predictive of 5-year survival by multi- Finally, patient survival was analysed on the basis of the variate analysis treatments that the patients received. As shown in Figure 6, there was a significant segregation in survival curves. As expected, P Relative risk (95% CI) patients who underwent surgical therapy, had the best median survival rate of 52 months, followed by patients receiving TACE CLIP score 0.034 1.613 (1.036 – 2.511) and PEI (24 months), TACE (16 months) and PEI (11 months). Portal vein thrombosis o0.0001 2.443 (1.797 – 3.319) Patients, who were not eligible for surgery, TACE or PEI had a Child A vs Child B and C 0.012 1.965 (1.160 – 3.329) median survival rate of 6 months. Uni- and multivariate analysis of potential factors affecting patient survival was performed in order to identify those risk we were able to confirm this observation. Patients with portal vein factors, which predict survival of patients. This analysis is thrombosis had a significantly lower median survival of 6 months important to identify optimal therapies for patients with HCC. in contrast to patients without portal vein thrombosis, who had a Sex, age, tumour size, bilirubin, Child–Pugh score, Okuda stage, median survival rate of 16 months (Figure 5). CLIP stage, the presence of one or multiple tumours, the location & 2005 Cancer Research UK British Journal of Cancer (2005) 92(10), 1862 – 1868 Survival (%) Survival (%) Clinical Studies Clinical Studies Survival of HCC patients TF Greten et al Clip 0-2 Clip 3-6 0 12 3 45 6 Years 0 1 2 3-6 Median survival (mo.) 36 (22 − 48) 28 (10 − 52) 16 (6 − 29) 8 (4 − 13) 1-year survival (%) 84 64 59 32 3-year survival rate (%) 51 41 21 5 Figure 4 Kaplan –Meier survival curve for 240 patients depending on their initial CLIP score. Median survival is presented as month (upper – lower interquartile range). no PVT PVT 012 34 5 6 Years Median survival (mo.) 6 (4 − 11) 16 (7 − 34) 1-year survival (%) 22 58 3-year survival rate (%) 2 24 Figure 5 Kaplan – Meier survival curve for 341patients depending on the presence (þ ) or absence () of a portal vein thrombosis. Median survival is presented as month (upper – lower interquartile range). of the tumour in the liver were all evaluated. Only, CLIP score, Cancer of the Liver Italian Program, 2000; Villa et al, 2000; Rabe Child stage and the presence of portal vein thrombosis were et al, 2001; Herold et al, 2002), this study included a high number identified to be independent risk factors affecting patient survival of patients treated by TACE and PEI, which have become the most as shown in Table 5 by multivariate analysis. Additionally, frequently used treatments in the Western World. No patient was bilirubin, number and size of individual intrahepatic tumours excluded from our retrospective analysis in contrast to those were identified as independent risk factors by univariate analysis. studies, who investigated only the effect of surgery or local ablative therapy (Tanaka et al, 1998; Schlitt et al, 1999; O’Suilleabhain et al, 2003; Jaeck et al, 2004). Therefore, this data reflects the current situation, for unselected patients with HCC similar to a different DISCUSSION study published 9 years ago (Stuart et al, 1996). We have analysed 389 patients with HCC, who were treated at our As previously reported for other non-Asian centres (Stuart et al, department between 1998 and 2003. In contrast to a series of other 1996; Rabe et al, 2001; Erhardt et al, 2002), our patient population published studies (Chevret et al, 1999; Llovet et al, 1999; The differed significantly from Asian centres (Sithinamsuwan et al, British Journal of Cancer (2005) 92(10), 1862 – 1868 & 2005 Cancer Research UK Survival (%) Survival (%) Survival of HCC patients TF Greten et al TACE + PEI Surgery TACE PEI BSC 01 2 3 45 6 Years Surgery TACE PEI TACE +PEI Systemic therapy Median survival (mo.) 52 (40 − 64) 16 (8 − 41) 11 (6 − 29) 24 (17 − 34) 6 (4−12) 1-year survival (%) 90 54 49 92 25 3-year survival rate (%) 76 29 21 16 2 Figure 6 Kaplan – Meier survival curve for 288 patients depending on the therapy received. Median survival is presented as month (upper – lower interquartile range). 2000) with less HbsAg-positive patients in our study population. modalities chosen, similar results were reported by others (Stuart Moreover, the average age of our patients was 64 years old et al, 1996; Allgaier et al, 1998; Bruix and Llovet, 2002; Herold et al, indicating that currently HCC is more frequently diagnosed in 2002; O’Suilleabhain et al, 2003). older patients as described by others (Dohmen et al, 2004). Independent prognostic factors can help in assessing the In contrast to most retrospective reports, which focus on the individual prognosis for patients with HCC and are therefore epidemiology and risk factors contributing to development of HCC critical for the patients. In our analysis we were able to identify in Western countries (Kubicka et al, 2000; Rabe et al, 2001; Llovet CLIP score, the presence of portal vein thrombosis and extent of and Beaugrand, 2003; Caselitz et al, 2004), our analysis was liver cirrhosis as independent prognostic factors and demonstrate undertaken to analyse patient survival according to clinical stage the pivotal role of liver cirrhosis for the prognosis of patients with and possible treatment respectively and in order to identify HCC, which has previously also been described by a number of possible prognostic factors, which might prove to be helpful, when different groups (Bruix and Llovet, 2002). the best possible treatment has to be chosen for patients with HCC. In summary, our retrospective study provides important information for the treatment of patients with HCC, while it According to tumour stage, extent of liver cirrhosis and other clinical factors, different treatment options were chosen in this should be emphasised that firm definite conclusions should only study as indicated in Figure 1. Therefore different treatments were be drawn from prospectively randomized studies. Using a not directly comparable and survival differences might be due to significant number of patients we have calculated survival rates different stages of the disease. for all patients with HCC regardless of therapy using different The number of patients eligible for surgical resection was much criteria such as disease state and therapy options. These data will smaller than the number of patients receiving TACE and PEI. In form the basis for future randomised clinical trials evaluating new addition, the tumour stage and cirrhosis differed between these therapeutic options for the treatment of HCC. two groups leading to the observed differences in survival in contrast to studies published by others (Llovet et al, 2004). Similar to other reports, we saw a median survival of 24 months for the patients receiving TACE followed by PEI (Allgaier et al, 1998). A ACKNOWLEDGEMENTS significant number of patients, who were not eligible for a combined treatment of TACE and PEI due to their stage of We thank Silvia Polon and Monique Ho¨rning for help obtaining disease, were treated with TACE or PEI only. As expected these patient data and Dr Firouzeh Korangy for critical reading of the patients had lower survival rates. However, with minor differences manuscript. Tim F. Greten is supported by the Deutsche depending on the group of patients selected and treatment Forschungsgemeinschaft (KFO 119). 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British Journal of Cancer – Springer Journals

Published: May 3, 2005

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