Survival Predictability of BCLC & CLIP Staging Systems in Patients of Hepato-cellular Carcinoma.

Background: Hepatocellular Carcinoma (HCC) is the fifth mostcommon of malignant diseases. So far there is no consensus regarding which staging system is appropriate in predicting survival of the patients. The most widely used staging systems are CLIP and BCLC. The BCLC is endorsed by both EASL and AASLD.

Objective: The objective of the study was to estimate the frequency of 90 days survival of patient of Hepatocellular carcinoma presenting in different stages of BCLC and CLIP staging systems.

Materials and Methods: The study was conducted at Centre for Liver and Digestive Diseases (CLD) as a part of routine research by Research Clinic for Hepatocellular Carcinoma in Holy Family Hospital, and Rawalpindi. The study was conducted for six months and each patient was followed for outcome for 90 days. Proportion of patients of each gender (Males and Female) surviving at the end of 90 days was calculated for each staging group (BCLC and CLIP).

Results: The survival predictability was better in earlier stages of Hepatocellular carcinoma in both BCLC and CLIP scoring systems (BCLC stage 0, 100%; Early Stage 91.5% and CLIP class 0, 100%; CLIP class 1, 97.7%). The CLIP classification wasrevealed to be better in predicting outcome of patients having advance stages of the disease in terms of survival (CLIP class 2, 75.9% as compared to BCLC B, 61.9% and CLIP class 4 is 0 as compared to BCLC C 10%).

Conclusion :The CLIP classification was better predictor of survival of patients in terms of proportions than BCLC classification.

Keywords:AASLD (American Association of the Study of Liver Diseases), BCLC (Barcelona Clinic Liver Cancer) classification, CLIP (Cancer for Liver Italian Programme) classification, Hepatocellular carcinoma EASL (European Association for the Study of Liver Disease).

Received: May’2020                      Accepted: July’2020

INTRODUCTION

Hepatocellular Carcinoma (HCC) is the fifth most common malignant disease and the third leading cause of cancer related death in the world(1).It has maximum incidence rates about 85% in East Asia, sub-Saharan Africa, and Melanesia. The incidence rate is low in developed countries with the exception of Southern Europe where the occurrence in men (10.5 per 100,000)(2). Chronic Hepatitis B accounted for 44% and Chronic Hepatitis C is responsible for 21% cases worldwide(4).

-----------------------------------------------------------------------------
The survival predictability was better in earlier
stages of Hepatocellular carcinoma in both
BCLC (Barcelona Clinic Liver Cancer) classification.)
and CLIP scoring systems. The CLIP (Cancer
for Liver Italian Programme)classification
was found to be better in predicting outcome of
patients having advance stages of the disease in
terms of survival.

-----------------------------------------------------------------------------

In Pakistan its incidence is 8/100,000 per annum,(5) but the chronic liver disease is the common etiological factor for death and disease(6).Most HCC patients come with the advanced stage (advance un-opable tumour) and symptoms directly related to the tumor or hepatic decomposition and are candidates for Best Supportive Care (BSC)(7). Hepatitis C related Cirrhosis is the most common aetiology for HCC in Pakistan(8) In Pakistan its incidence is 8/100,000 per annum(3). In Pakistan, most HCC patients come with the advanced stage (advance unresectable tumour) and symptoms directly related to the tumor or hepatic decompensation with Hepatitis C related Cirrhosis as the most common aetiology(4). HCC is a unique tumor because survival and prognosis of the patients suffering from it not only depend upon tumor size and its extent but also upon the liver dysfunction and presence of cirrhosis. Patients known to have chronic hepatic parenchymal disease in whom a solid liver mass appears should be considered to have hepatocellular carcinoma until proven otherwise(5). The presence of co-morbidities can compromise liver functions and effect outcomes as well as treatment recommendations. Although more than 15 HCC staging classifications are available around the world. These classifications have been developed on different patient populations(6). All these staging systems are good in discriminating survival in HCC patients. However, there has been much discussion regarding which prognostic model is the appropriate(7). The most popular staging systems include Barcelona Clinic Liver Cancer System (BCLC), Cancer of Liver Italian Program (CLIP) score, Japan Integrated Staging System ( JIS), the American Joint Committee on Cancer-Tumor Node Metastasis (AJCC-TNM), Okuda, Chinese University Prognostic Index (CUPI), and Groupe d’Etude Traitment du Carcinome Hepatocellulaire (GETCH) prognostic classification(1). The BCLC system is endorsed by American Association of the Study of Liver Diseases (ASSLD) and the European Association for the Study of Liver Disease (EASL) as a standard staging system. This classification consists of variables that define tumor size, functional status of liver, and functional status of patient along with the variables that are related to treatment options obtained from studies with high level of evidence like cohort studies and randomized controlled trials. BCLC is widely validated in different clinical settings(8) @. However, its drawback includes use of subjective components, especially PST (Performance Status) and CTP (Child- Turcotte- Pugh) Score. Many studies were designed to assess the long-term prognostic and discriminatory ability of different staging systems. In Pakistan, commonly used system is BCLC. The CLIP is a new staging system which is emerging as having better discriminating ability and survival predictability. The rationale of my study is to asses these two commonly used Staging Systems in term of their discriminatory ability and survival predictability. So that a Staging System could be identified that matches our needs of predicting the survival in early and advanced stage of the disease as well as guiding management according to available resources.

MATERIALS AND METHODS

This cross-sectional observational study was part of the research led by Research Clinic for Hepatocellular Carcinoma, Centre for Liver and Digestive Diseases(CLD) in Holy Family Hospital, Rawalpindi. The study population was the out patients coming to the Research Clinic for treatment of Hepatocellular Carcinoma. The study was conducted for six months from 16th March 2016 to 15th September 2016.The required reference statistics were not available for sample size calculation, so a pilot study was conducted for the period of 90 days and reference statistics were calculated. The pilot study showed overall survival rate of 62%, BCLC stage 0 survival 60% (9.7% patients remained alive), and CLIP class 0 stage 55.5% (16.1% patients alive) at the end of 90 days. The sampling technique used was “Consecutive non-probability sampling.”a written informed consent was taken from all patients about their preparedness to participate in the study. Information was collected through person to person interviews with the patients and data was entered on the pre-tested questionnaire (see Annex. III), by a trained data collector and time of data entry was noted. The same patients were followed up by phone after 90 days and outcome (Alive/Dead) was assessed. Complete history along with clinical examination was recorded. The investigations like complete blood count, PT/APTT, INR, Serum creatinine, serum ALT, anti HCV RNA by serological tests, Hepatitis B surface antigen serology, Alpha fetoprotein levels, ultrasound abdomen and dynamic CT scan abdomen were carried out. The study data was analyzed by using SPSS Version 20. Descriptive statistics i.e. frequencies were calculated for variables like age, patient falling into each stage of BCLC, and CLIP classification systems. In addition, percentages, mean values, and standard deviations was calculated for all variables like number of patients present in each staging systems and their subclasses. Proportion of patients of each gender (males and female) surviving at the end of 90 days was calculated for each staging group.

RESULTS

The results of the study conducted during the period of six months are described in following section. The fate of each case was followed for 90 days and the outcome was recorded, accordingly. Total of 150 patients n= 85;56.7% were found to be survived and n=65;43.3% were discovered to be dead at the end of 90 days. The demographic and disease related characteristics of all patients registered in the study are given in Table:1

The patients presented in early stages of BCLC stage,Stage 0 and early stage had better 90 days survival as compared to advance and end stage BCLC stages as shown by their individual percentages Stage 0,100%; Early,91.5% versus Advance, 10%; End stage, 0. This is better explained in Table 2.

The early subclasses (Stage 0, early and intermediate) of BCLC staging systems are better predictor of survival as compared to advance subclasses (C and D). The patients presented in early stages had better 90 days survival as compared to patients with advance disease, this is depicted in Figure 1.

The survival of the patients was far better in early stages (0-3) of CLIP classification as compared to patients with advance stages (4,5). Both early and advance classes of CLIP staging system are better predictor of survival than BCLC staging systems shown in table 3, Figure 2.

DISCUSSION

In this study the survival of patients in terms of proportions was calculated at the end of ninety days for each case having different staging systems and their (BCLC & CLIP) subclasses. The maximum patients were presented in early sub classes of both staging systems. According to the results the survival predictability was better in earlier stages of Hepatocellular carcinoma in both BCLC and CLIP scoring systems ( BCLC stage 0, 100% ; Early Stage 91.5% and CLIP class 0, 100%; CLIP class 1, 97.7%) as mentioned in Table.11 and 12. CLIP classification was found to be better in estimating outcome of patients having advance stages of the disease in terms of survival (CLIP class 2, 75.9% as compared to BCLC B, 61.9% and CLIP class 4,5 is 0 as compared to BCLC C,10% ; BCLC D, 0). A study published in Cancer 2010 volume 116 provided comparative analysis of five staging models namely Barcelona Clinic Liver Cancer (BCLC) system, Cancer of the liver Italian program (CLIP), the Japan Integrated Score (JIS), Tokyo score and TNM staging systems. They comparison of survival distributions of different staging systems was done in terms of discriminatory ability. The patients were followed for mean duration of 14 months. They also found in this study that BCLC staging system may not be able to discriminate the outcome of patients at very early stage and far advance stages of the disease. On the other hand, the CLIP classification showed better predictive ability from very early to very advance cancer stage in terms of survival. In this study maximum patients were presented in early stages of the staging systems(9). This is similar to the results of this study. In an-other study published in 2008, the survival predictability of CLIP, French classification (GRETCH) and BCLC was compared. The ability to predict survival was studied in treated and untreated group. The CLIP was found to have highest predictability when studied in untreated group of patients. This is consistent with results of my study. However, prognostic capacity of stages deteriorated when applied to treated group. On contrary, the BCLC only achieved a slightly superior prognostic ability in treated patients as compared to CLIP score(1). The results of this study are also compared with another study from Department of Hepato gastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan. In this study the researchers conducted a comparative analysis about the the usefulness of different scoring systems to assess prognosis in HCC patients. Different classification systems like CLIP, CUPI, Okuda, BCLC classification were found useful to predict survival in patients with non-resectable HCC. When efficacy of different prognostic models was compared, Okuda and BCLC offered better results. The discriminative ability for deaths estimated by ROC curve was better for Okuda system. The patients included in their study were mainly at the advance liver disease whereas patients in my study were at the early stage of the disease. It appears that Okuda may be less accurate than CLIP and BCLC in the predicting survival in the early stages of disease(4). One more study published in the “Oncologist”, volume 15 reviewed all the studies conducted to validate different staging systems developed in different parts of the world. The review showed that the BCLC stage can be a candidate for standard classification, because of its endorsement by both EASL and AASLD. For all the statistics they reviewed, the CLIP classification was found to have better prognostic ability in maximum studies comparing different classification systems which is consistent with the results of my study(5).

Recommendations:

In the light of above discussion and limitations, I have made a few recommendations which are listed below that may help in future research on this topic.

• Further comparative and prospective studies are required to assess the discriminating ability of the two scoring models.

• The survival studies should be done for prolonged time in prospective manner for the diseases not having good prognosis. Hence, further work is required with follow up for a longer period necessary for better assessment of survival.

• Further studies covering the impact of treatment modalities and down staging on survival and discriminating ability of the two staging models should be performed.

• More studies should be conducted by including patients with intermediate and advanced stages of HCC.

• As to date no single prognostic model exists which is in agreement to all areas and all populations of the world, the derivation and validation of new models which best fit in to consensus should continue.

CONCLUSION

The survival in terms of proportions was calculated at the end of ninety days for each case having different staging systems (BCLC & CLIP) subclasses. The maximum number of patients presented in early sub-classes of both staging systems. According to the results, the survival predictability was better in earlier stages of Hepatocellular carcinoma in both BCLC and CLIP scoring systems. The CLIP classification was found to be better in predicting outcome of patients having advance stages of the disease in terms of survival. Thus, it is concluded that CLIP classification system is a better prognostic model in terms of survival proportions in advance stages of disease, provided that effect of treatment and down staging is not included in the measuring of proportion of patients survived.

1. Camma C, Di Marco V, Cabibbo G, Latteri F, Sandonato L, Parisi P, et al. Survival of patients with hepatocellular carcinoma in cirrhosis: a comparison of BCLC, CLIP and GRETCH staging systems. Alimentary pharmacology & therapeutics. 2008 Jul;28(1):62-75.

2. European Association for Study of L, European Organisation for R, Treatment of C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. European journal of cancer. 2012 Mar;48(5):599-641.

3. Ammanullah Abbasi Nb. Hepatocellular carcinoma: a clinicopathological study. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2010 August 2010;20(8):510- 3.

4. Abbas Z, Siddiqui AU, Luck NH, Hassan M, Mirza R, Naqvi A, et al. Prognostic factors of survival in patients with non-resectable hepatocellular carcinoma: hepatitis C versus miscellaneous etiology. JPMA The Journal of the Pakistan Medical Association. 2008 Nov;58(11):602-7.

5. Yang T, Zhang J, Lu JH, Yang LQ, Yang GS, Wu MC, et al. A new staging system for resectable hepatocellular carcinoma: comparison with six existing staging systems in a large Chinese cohort. Journal of cancer research and clinical oncology. 2011 May;137(5):739-50

6. Marrero JA, Kudo M, Bronowicki JP. The challenge of prognosis and staging for hepatocellular carcinoma. The oncologist. 2010;15 Suppl 4:23-33.

7. Michael.C.Kew. Hepatic Tumor and cysts. In: Mark Feldman LSF, Lawrence.J.brandt, editor. Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management 2. 8 ed. Philadelphia: Saunders Elsevier; 2007. p. 2007-28.

8. Cho YK. Comparison of seven staging systems in cirrhotic patients with hepatocellular carcinoma in a cohort of patients who underwent radiofrequency ablation with complete response. The American journal of gastroenterology. 2008 Jul;103(7):1835-6; author reply 6-7.

9. Hsu CY, Hsia CY, Huang YH, Su CW, Lin HC, Lee PC, et al. Selecting an optimal staging system for hepatocellular carcinoma: comparison of 5 currently used prognostic models. Cancer. 2010 Jun 15;116(12):3006-14.

10. Marrero JA, Kudo M, Bronowicki JP. The challenge of prognosis and staging for hepatocellular carcinoma. The oncologist. 2010;15 Suppl 4:23-33.

11. Michael.C.Kew. Hepatic Tumor and cysts. In: Mark Feldman LSF, Lawrence.J.brandt, editor. Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management 2. 8 ed. Philadelphia: Saunders Elsevier; 2007. p. 2007-28.

12. Tellapuri S, Sutphin PD, Beg MS, Singal AG, Kalva SP. Staging systems of hepatocellular carcinoma: A review. Indian J Gastroenterol. 2018 Nov;37(6):481-491.

13. Kinoshita A, Onoda H, Fushiya N, Koike K, Nishino H, Tajiri H. Staging systems for hepatocellular carcinoma: Current status and future perspectives. World J Hepatol. 2015 Mar 27;7(3):406- 24.

14. Maida M, Orlando E, Cammà C, Cabibbo G. Staging systems of hepatocellular carcinoma: a review of literature. World J Gastroenterol. 2014 Apr 21;20(15):4141-50.

15. Heimbach JK. Overview of the Updated AASLD Guidelines for the Management of HCC. Gastroenterol Hepatol (N Y). 2017 Dec;13(12):751-753.

16. Li XH, Wei L. The comparison among the guidelines for the diagnosis and treatment of hepatocellular carcinoma in China, AASLD and EASL. Zhonghua Gan Zang Bing Za Zhi. 2019 Mar 20;27(3):236-240.

17. Cho YK. Comparison of seven staging systems in cirrhotic patients with hepatocellular carcinoma in a cohort of patients who underwent radiofrequency ablation with complete response. The American journal of gastroenterology. 2008 Jul;103(7):1835-6; author reply 6-7.

18. Jaruvongvanich V, Sempokuya T, Wong L. Is there an optimal staging system or liver reserve model that can predict outcome in hepatocellular carcinoma? J Gastrointest Oncol. 2018 Aug;9(4):750-761.

19. Chen ZH, Hong YF, Lin J, Li X, Wu DH. Validation and ranking of seven staging systems of hepatocellular carcinoma. Oncol Lett. 2017 Jul;14(1):705-714.

20. Hsu CY, Hsia CY, Huang YH, Su CW, Lin HC, Lee PC, et al. Selecting an optimal staging system for hepatocellular carcinoma: comparison of 5 currently used prognostic models. Cancer. 2010 Jun 15;116(12):3006-14.