Predicting Prognosis in Hepatocellular Carcinoma: Comparison of Staging Systems in Pakistani Cohort

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1 ORIGINAL ARTICLE Predicting Prognosis in Hepatocellular Carcinoma: Comparison of Staging Systems in Pakistani Cohort Shahid Sarwar 1, Anwaar A. Khan 1 and Shandana Tarique 2 ABSTRACT Objective: To determine the clinical, biochemical and radiological prognostic indicators and to compare the performance of six staging systems in patients of hepatocellular carcinoma (HCC). Study Design: Descriptive study. Place and Duration of Study: Department of Gastroenterology, Doctors Hospital, Lahore, from October 2007 to December Methodology: Patients with HCC were included. Baseline clinical, hematological and radiological variables were noted. Patients were followed for 5 years or till death. Survival predictors were identified using Cox proportional hazard analysis and 6 prognostic staging systems were evaluated by determining homogeneity, discriminatory ability and monotonicity. Results: Of the 228 patients included, male to female ratio was 2.6/1 (165/63) and mean age was 56.5 ± 10.4 years. Majority of patients 189 (82.9%) were anti-hcv positive. Solitary HCC lesion was seen in 121 (53.1%) patients, 16 (7%) had 2 lesions while 73 (32%) had 3 or more lesions. Only 36 (15.8%) patients had palliative therapy for HCC. Survival rate was 45.2%, 25%, 12.3%, 7%, 2.2% and 1% for 6 months, 1, 2, 3, 4 and 5 years respectively. Male gender, portal vein thrombosis, serum albumin < 3.5 g/dl, tumor size 6 cm and alpha fetoprotein (AFP) 147 U/ml were bad prognostic indicators. OKUDA, GRETCH and early stages of CLIP had better homogeneity while CLIP showed superior discriminatory ability and monotonicity for predicting survival. Conclusion: Male gender, presence of portal vein thrombosis, low serum albumin, large tumor size and high AFP level are poor prognostic indicators in patients of HCC. CLIP has better performance in predicting mortality. Key Words: Hepatocellular carcinoma. Mortality. Predictors. Staging system. INTRODUCTION Hepatocellular Carcinoma (HCC) is the fifth leading cancer all over the world and is the third most common cause of cancer deaths. 1 Due to increasing prevalence of hepatitis B and C, HCC is likely to continue as major health threat in developing countries like Pakistan. Most cancers of human body can be staged based on size of tumor, invasion of lymphatic system and distant metastasis using Tumor, Nodes and Metastasis (TNM) staging system. Liver cancer is unique because of preexisting liver disease along with its possible complications, tendency for early vascular and local invasion and presence of diverse therapeutic options. 2 Application of TNM staging fails to give the desired prognostic information. 3 Child Turcotte Pugh (CTP) and Model for End Stage Liver Disease (MELD), as prognostic scores for liver cirrhosis, were mostly inefficient in predicting prognosis of liver cancer. This led to introduction of multiple staging classifications for HCC. 1 Department of Gastroenterology, Doctors Hospital, Lahore. 2 Department of Medicine, Gujranwala Medical College, Gujranwala. Correspondence: Dr. Shahid Sarwar, 153-D, Muslim Road, Jinnah Colony, Samanabad, Lahore. drnawalshahid@yahoo.com Received: July 03, 2014; Accepted: August 07, Attempts were made at developing staging system with focus on functional status of liver, local extent of tumor and functional status of patients. Initially it was Okuda, which was based on bilirubin, albumin and presence or absence of ascites along with size of tumor. 4 It was followed by multiple new staging systems including Cancer of Liver Italian Program (CLIP), 5 Japan Integrated System (JIS), 6 Barcelona Clinic Liver Cancer (BCLC) 7 and Grouped' Etude et de Traitement du Carcinome He patocellulaire (GRETCH). 8 Multiple studies have compared these staging systems in terms of predicting patient prognosis and results are diverse. Marrero in a large cohort of HCC patients identified BCLC as most efficient scoring system for prognosis, 8 while another large size study by Winkel concluded that CLIP is the most suitable staging system for HCC. 9 Presently BCLC is used for treatment decisions for HCC patients although it is criticized for being too algorithmic and for inadequate performance in non-surgical patients. In other words search for best performing prognostic score is still on. Differences in performance of staging scores are mainly due to different ethnic origin of patients, differences in underlying liver disease and availability of treatment options. Pakistani patients with HCC are mostly inflicted by underlying chronic hepatitis C as opposed to alcoholic cirrhosis in the western world or hepatitis B in majority of Asian population. 10 As HCC is being 648 Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (9):

2 Predicting prognosis in hepatocellular carcinoma diagnosed at advanced stage in these patients and curative treatment options i.e. liver transplantation and radiofrequency ablation are still not available to majority of HCC patients in our region, we can better evaluate these staging scores over natural course of illness in patients with HCC. It is imperative to evaluate these staging scores in our patients of HCC to better plan therapeutic interventions for them, once curative treatment options are widely available. This study was planned to determine clinical, biochemical and radiological prognostic indicators for HCC and to compare the ability of six staging systems for hepatocellular carcinoma to predict survival. Staging scores compared were CLIP, JIS, GRETCH, OKUDA, Tokyo and TNMJ. METHODOLOGY This descriptive study was carried out at the Doctors Hospital, Lahore, from October 2007 till December Diagnosis of HCC was based on American Association for Study of Liver Disease (AASLD) criteria 2005 at start of study but once AASLD guidelines of 2010 got published, new diagnostic criteria were used with its application retrospectively as well. 14 Patients suspected to have space occupying lesion larger than 1 cm diameter on ultrasound of liver underwent biphasic CT abdomen for confirmation of HCC. Early arterial enhancement of lesion and late venous washout were considered diagnostic for presence of HCC. Those with non-enhancing lesion or atypical pattern of enhancement underwent contrast enhanced MRI to look for typical features of HCC. In case of equivocal results on both CT and MRI, ultrasound guided biopsy of lesion was carried out. If histopathology report was nonconclusive, patients were excluded from study with advice to follow-up after 3 months. Sample size needed to draw conclusions was 214 with 90% confidence level, 5% margin of error and 50% expected 1 year mortality of HCC as calculated on Epitools online calculator. Informed consent was taken from patients before inclusion in study. Variables noted at time of diagnosis of HCC were duration of liver disease, etiology of underlying liver dysfunction if present, features of de-compensation i.e. variceal bleeding, ascites, hepatic encephalopathy, symptoms leading to diagnosis of HCC and signs of chronic liver disease on physical examination. Laboratory parameters noted were complete blood count, liver function tests, renal function tests, coagulation profile and alpha fetoprotein. All patients had abdominal ultrasound to look for liver size and texture, splenomegaly, portal vein diameter and ascites. Size of space occupying lesion, number of lesions, their invasion of portal or hepatic venous system and presence of lymph nodes were also determined on abdominal ultrasound. Features of tumor on CT scan, MRI with contrast enhancement pattern and histo-pathology findings on biopsy of lesion were also recorded. Patients were offered treatment for HCC depending on stage of illness as per AASLD guidelines, 11 were followed on 3 monthly intervals either as outpatients or via telephonic contact. Patients who completed 5 years follow-up or died during follow-up were included in final analysis. Survival of patients was calculated from time of diagnosis of HCC till death. Data were analyzed using SPSS version 20. Numerical variables were described as mean ± standard deviation or median value. Categorical variables were given as percentage. For continuous variables, patients were divided in two groups using median values. Chi-square (χ 2 ) and student t-test were used to compare patients with and without therapeutic intervention. As survival time of study patients was not normally distributed with skewness of 2.03 and kurtosis of 4.02, non-parametric test of Mann-Whitney U was used for uni-variate analysis by comparing median survival time and Interquartile Range (IQR) of survival of different variables. Variables other than staging scores with p-value less than 0.05 were analyzed by Cox proportional hazard regression analysis for performance as independent predictor of survival in multi-variate analysis. Prognostic performance of each scoring system was evaluated in three domains, homogeneity i.e. patients of one stage should have similar prognosis, discriminatory ability which means that patients with different stages should have different survival and monotonicity denoting patients of earlier stage of disease should have better prognosis as compared to those with advanced stage. Homogeneity was evaluated by first determining survival curves of each category of staging system using Kaplan Meier analysis. Discriminatory ability of each score was determined by calculating accuracy of 1, 3 and 5 years survival prediction of each score. This was determined by calculating area under receiver operating characteristic curve (AUC) for each staging system which is equivalent to concordance statistics, C-statistics. Monotonicity of staging score was determined by linear trend χ 2 test using Cox Regression model. RESULTS A total of 228 patients who either completed 5 years follow-up or died earlier during follow-up were included. The mean age was ± years with male to female ratio of 2.6/1 (165/63). Majority of patients 189 (82.9%) were anti-hcv positive, HBsAg was detected in 21 (9.2%), 2 patients had both hepatitis B and C, 1 patient was alcoholic and 15 (6.6%) were hepatitis B and C negative. Liver disease was de-compensated prior to diagnosis of HCC in 52 (22.8%) patients. Eighty one Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (9):

3 Shahid Sarwar, Anwaar A. Khan and Shandana Tarique (35.6%) had Child Turcotte Pugh (CTP) class A, 90 (39.4%) class B whereas class C was noted in 57 (25%). Diagnosis of HCC was made on routine follow-up of cirrhosis with minor symptoms in 60 (26.2%) patients, 35 (15.4%) presented with weakness and weight loss, 31(13.6%) had abdominal pain, 26 (11.4%) had upper gastrointestinal bleeding, 47 (20.6%) had worsening of ascites, 14 (6.1%) developed acute on chronic hepatitis and in 15 (7%) encephalopathy lead to the diagnosis of HCC. Majority of patients, 121 (53.1%) had solitary lesion, 16 (7.1%) had 2 lesions, 73 (32.1%) had 3 or more lesions whereas 18 (7.7%) patients had infiltrative type of HCC. Involvement of > 50% hepatic mass was noted in 125 (54.8%), portal vein thrombosis was identified in 79 (34.6%) whereas 33 (14.5%) had abdominal lymphadenopathy along with HCC. Thirty six (15.8%) patients underwent trans-arterial chemo-embolization (TACE), 2 (0.8%) received radio frequency ablation, 1 had tumor resection, 3 (1.3%) had liver transplantations and 4 (1.8%) patients opted for Sorafenib for treatment. Supportive therapy was opted in remaining 182 (79.9%) patients mostly due to advanced stage of HCC or non-affordability of patients. Patients with therapeutic intervention had lesser portal vein thrombosis, 10.8% vs. 41.2% (p-value < 0.001), lower mean CTP score 6.76 vs (p < 0.001), better performance score as assessed by Kornofsky's score, 80 vs (p < 0.001), smaller median tumor size 3.5 vs. 7 (p < 0.001) and better median survival time on follow-up 16 vs. 4 months (p < 0.001) as compared with patients with supportive treatment only. Patients were followed on 3 monthly intervals for 1st year and then 6 monthly for 5 years or till death. Survival of study patients with HCC was 45.2%, 25%, 12.3%, 7%, 2.2% and 1% at 6 months, 1, 2, 3, 4, and 5 years respectively (Table I). Variables with significant predictive power for mortality in uni-variate analysis were male gender (p = 0.008), serum bilirubin 1.3 mg/dl (p = 0.01), alkaline phosphatase 207 U/L (p = 0.006), serum albumin less than 3 gm/dl (p = 0.03), serum alpha fetoprotein (AFP) of 147 U/L or more (p < 0.001), size of tumor 6 cm or more (p < 0.001), presence of portal vein thrombosis (p = 0.001) and cumulative size of tumor more than 50% of liver volume (p < 0.001). Result of multi-variate analysis using Cox proportional hazard analysis of these variables is shown in Table II. Male gender, portal vein thrombosis, serum albumin < 3 gm/dl, size of SOL 6 cm, AFP 147 U/ml and cumulative size of tumor mass > 50% of liver size were independent prognostic indicators for mortality. Six commonly used prognostic scores, OKUDA, CLIP, TNMJ, JIS, Tokyo and GRETCH were evaluated for performance in predicting survival of patient. Homogeneity of scores was determined by Kaplan Meier curve for each scoring system as shown in Figure 1. OKUDA and GRETCH and early stages of CLIP had better homogeneity. Discriminatory ability of each score was determined by calculating Area Under Curve (AUC) for 6 months, 1 year, 2 years and 3 years survival as Table I: Univariate analysis for prediction of survival. Variables No. of patients Median survival p-value* n = 228 (IQR) Age < 55 years 76 6 (12) years (9) Gender Male / Female 143 / 57 4 (8) / 8 (14) Serum albumin 3 gm/dl 97 5 (6) 0.03 < 3 gm/dl (13) Total Bilirubin < 1.3 mg/dl 89 7 (13) mg/dl (7) Serum ALT (U/L) < (7) (12) Serum ALP (IU/L) < (11) (7) Serum creatinine (mg/dl) < (11) (10) Platelet (x 10 9 /L) < (8) (12) Alpha fetoprotein (U/L) < (15) < (6) Size of SOL < 6 cm (16) < cm (6) Portal vein thrombosis Yes 74 4 (6) No (13) Tumor size > 50% of liver mass Yes / No 117 / 82 4 (6) / 9 (19) < Ascites Yes / No 133 / 67 4 (8) / 7 (12) *p-value as determined by Mann Whitney U-test; IQR = Inter quartile range Table II: Multivariate analysis of variables for predicting survival. Variables Hazard ratio 95% Confidence p-value interval Male gender Alkaline phosphatase 207 IU/L Total Bilirubin 1.3 mg/dl Portal vein thrombosis Alpha fetoprotein 147 U/L Size of SOL 6 cm Serum albumin < 3 g/dl Size of SOL > 50% of liver Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (9):

4 Predicting prognosis in hepatocellular carcinoma Figure 1: Kaplan Meier curves for staging systems of HCC. Table III: Area under ROC curve for prognostic scores. Prognostic score Six month One year Two years Three years survival survival survival survival OKUDA CLIP TNMJ JIS GATECH Tokyo Table IV: Monotonicity of prognostic scores. Prognostic score Hazard ratio 95% CI Mean value Significance OKUDA CLIP TNMJ JIS GRETCH Tokyo given in Table III. AUC was comparable among different prognostic scores except CLIP which had better discriminatory ability as shown by better AUC (0.72 for 6 months, 0.75 for 1 year, 0.79 for 2 years and 0.84 for 3 years. Monotonicity of scores, shown in Table IV as determined by cox proportional hazard analysis also identified CLIP as best of 6 models with hazard ratio of 1.34 (p=0.002). DISCUSSION With limited therapeutic options and liver transplantation facility still in evolution, hepatocellular carcinoma continues to be a dreadful illness in Pakistan. Patients being diagnosed with HCC in this study are relatively younger with mean age of 56 years as compared with patients in western studies, 12 though Marrerio reported it to be 57 years. 8 Hepatitis C was responsible for liver disease in 82% of these patients. Kinoshita et al. 12 and Marrero et al. 8 also identified hepatitis C to be responsible for liver disease in 56% and 62% of HCC patients respectively. In a study by Butt, 67.9% patients of HCC were HCV positive. 13 Despite well established guidelines for screening of cirrhosis patients for HCC, only 26.2% of these patients were diagnosed to have HCC while being screened with ultrasound abdomen while rest were diagnosed on presenting with complications of HCC. Majority of patients had advanced HCC with 55% of patients having tumor involving more than 50% liver mass, very similar to what was noted in study by Pal. 14 Due to advanced stage of HCC at diagnosis and limited availability of therapeutic options at affordable cost, only 20% of these patients had therapeutic intervention that too palliative in nature. In contrast, 51.3% of HCC Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (9):

5 Shahid Sarwar, Anwaar A. Khan and Shandana Tarique patients in a study had curative intervention. 12 Similarly in another study 49% of patients with HCC had either transplantation or radiofrequency ablation. 8 Overall survival in these patients was low with 1, 3 and 5 years at 26%, 13.1% and 7.7% respectively. On the contrary, other reports have shown better prognosis especially in patients who received definitive treatment. Survival rate was 54.9%, 34.7% and 14.8% for 1, 3 and 5 years for those on palliative care whereas it was 95.9%, 71.3% and 41.4% for 1, 3 and 5 years respectively in patients with definitive therapy for HCC. 12 In a study by Grieco survival rate was 92%, 46% and 24% for 1, 3 and 5 years. 15 Inasmuch as 80% of these patients had no treatment for HCC, survival in our patients was poor. Chang reported 32% 1-year survival with median survival time of 6.8 months for patients without treatment for HCC. 16 Male gender, presence of portal vein thrombosis, serum albumin < 3 g/dl, size of tumor more than 6 cm and serum alpha fetoprotein more than 147 IU/ml were identified as independent predictors of adverse prognosis in patients with HCC. Tumor size, portal vein thrombosis and MELD score were markers of poor prognosis in Marrero study. 8 Grieco et al. concluded that low serum albumin, high serum bilirubin, tumor size 2-5 cm and number of tumors were poor survival indicators. 15 Prognostic markers identified in this study are tumor related except for serum albumin which is an indicator of underlying liver disease. Evaluation of commonly used prognostic staging systems in this study produced mixed results. OKUDA, GRETECH scores and early stages of CLIP have shown good homogeneity with significant difference in survival among different stages. CLIP has better discriminatory ability and monotonicity with significantly better area under curve and Hazard Ratio (HR). Kinoshita identified CLIP among 6 staging systems to have highest prognostic power with HR of 2.24 (p < 0.001) and linear trend χ 2 = Siddique also concluded that CLIP is the most reliable prognostic indicator for HCC patients. 17 Chen noted that CLIP along with JIS had better discriminatory ability than other prognosis scores, 18 but as in this study Grieco found CLIP not an efficient score in advanced stage of HCC. 15 Barcelona-Clinic Liver Cancer (BCLC) was not evaluated in this study. Presently it is the recommended prognostic score by European Association for Study of Liver Diseases (EASL). 19 However, it still needs validation in many parts of the world before becoming standard prognostic score. At present we do not have an ideal staging system for patients with HCC. It is probably due to different diagnostic criteria being used in studies, heterogeneous population and diversity in underlying liver disease with mix of compensated as well as decompensated liver disease. 20 In Camma words none of the staging system is a winner due to complex nature of liver cancer 21 which is precisely what can be concluded from the present results. Due to this lack of good prognostic score system for HCC, new prognostic score systems are being suggested i.e. Advanced Liver Cancer Prognostic Score (ALCPS), Glasgow Prognostic Score (GPS), Neutrophil to lymphocyte ratio and Prognostic Nutritional Index (PNI). 22 Further studies are needed in this region to identify the scoring system most suited to our patients. Identification of prognostic staging system with excellent survival prediction for patients of HCC is imperative to develop guidelines for therapeutic interventions like liver transplantation and radiofrequency ablation in our population once these treatment options are easily accessible. CONCLUSION Male gender, presence of portal vein thrombosis, low serum albumin, large tumor size and high AFP level are poor prognostic indicators in patients of HCC. CLIP has better performance in predicting mortality. REFERENCES 1. Bosch FX. Global epidemiology of hepatocellular carcinoma. In: Okuda K, Tabor E, editors. Liver cancer. New York: Churchill Livingston, 1997: Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, VanCutsem E, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit Lancet Oncol 2009; 10: Lei HJ, Chau GY, Lui WY, Tsay SH, King KL, Loong CC, et al. Prognostic value and clinical relevance of the 6th edition 2002 American Joint Committee on Cancer staging system in patients with resectable hepatocellular carcinoma. J Am Coll Surg 2006; 203: Okuda K, Ohtsuki T, Obata H, Tamimatsu M, Okazaki N, Nasegawa H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients. Cancer 1985; 56: The Cancer of the Liver Italian Program (CLIP) Investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients. Hepatology 1998; 28: Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol 2003; 38: Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram HS, Su GL, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005; 41: Winkel MD, Nagel D, Sappl J, Winkel PD, Lamerz R, Zech CJ, 652 Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (9):

6 Predicting prognosis in hepatocellular carcinoma et al. Prognosis of patients with hepatocellular carcinoma. validation and ranking of established staging-systems in a large Western HCC-Cohort. Plos One 2012; 7:e Khokhar N. Spectrum of chronic liver disease in a tertiary care hospital. J Pak Med Assoc 2002; 52: Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. AASLD practice guidelines. Hepatology 2011; 53: Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Tanaka K, et al. The Glasgow prognostic score, an inflammation based prognostic score, predicts survival in patients with hepatocellular carcinoma. BMC Cancer 2013; 13: Butt AS, Hamid S, Wadalawala AA, Ghurfan M, Javed AA, Farooq O, et al. Hepatocellular carcinoma in native South Asian Pakistani population; trends, clinic-pathological characteristics and differences in viral marker negative and viral hepatocellular carcinoma. BMC Res Notes 2013; 6: Pal S, Ramachanran J, Kurien RT, Eapen A, Ramakrishna B, Keshara SN, et al. Hepatocellular carcinoma continues to be diagnosed in the advanced stage: profile of hepatocellular carcinoma in a tertiary care hospital in South India. Trop Doct 2013; 43: Grieco A, Pompili M, Caminiti G, Miele L, Covino M, Alfei B, et al. Prognostic factors for survival in patients with earlyintermediate hepatocellular carcinoma undergoing nonsurgical therapy: comparison of OKUDA, CLIP and BCLC staging systems in a single Italian center. GUT 2005; 54: Chang HC, Lin YM, Yen AM, Chen SL, Wu WY, Chiu SY, et al. Predictors of long-term survival in hepatocellular carcinoma: a longitudinal follow-up of 108 patients with small tumor. Anticancer Res 2013; 33: Siddique I, El-Naga HA, Memon A, Thalib L, Hasan F, Al-Naqib B. CLIP score as prognostic indicator for hepatocellular carcinoma: experience with patients in the middle east. Eur J Gastroenterol Hepatol 2004; 16: Chen TW, Chu CM, Yu JC, Chen CJ, Chan DC, Liu YC, et al. Comparison of clinical staging systems in predicting surivival of hepatocellular carcinoma patients receiving major or minor hepatectomy. Eur J Surg Oncol 2007; 33: EASL-EORTC Clinical practice guidelines in management of hepatocellular carcinoma. European Association for the study of liver, European Organization for research and treatment of cancer. J Hepatol 2012; 56: Kim WR. The CLIP score: is it time to be clipped away? Liver Int 2009; 29: Camma C, Cabibbo G. Prognostic scores for hepatocellular carcinoma: none is the winner. Liver Int 2009; 29: Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Fushiya N, et al. Comparison of the prognostic value of inflammation based prognostic scores in patients with hepatocellular carcinoma. Br J Cancer 2012; 107: Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (9):