Hepatocellular carcinoma (HCC), is aggressive tumor with higher morbidity and mortality compared to other cancers and is usually diagnosed in advance stage.(8) Most of the burden lies in developing countries.(9)
This study focuses on patient characteristics, tumor characteristics, risk factors and outcomes in HCC patients from India as data in view of clinical profile and outcomes are limited in India sceniora.
In present study mean age was 59.63 ± 10.88 years ranging from 29–80 years with male predominance ( male to female ratio: 6.4: 1) which was similar to Salem S et al study, 59.9 ± 11.0 years ranging from 28–85 years and male to female ratio 5.7:1.(9)
Alcohol addiction and HbsAg reactivity was seen in 40.68 % and 38.98 % patients respectively. HBV and HCV are the most important precursors for HCC development on a global scale, together accounting for over 80% of liver cancer cases worldwide.(10) HBV infection is the leading cause of chronic liver disease in India and is responsible for 35–60% of chronic liver disease and 60–80% of HCC.(7) Earlier studies from India suggest that the odds ratio of HbsAg positivity among HCC patients is one of the highest in the world.(11) About 15 million people are infected by HCV and the population prevalence of anti-HCV antibodies is about 1%.(12) Thus, there is a large pool of people who are at risk of developing chronic liver disease and, therefore, HCC. In the current study, no patient was HCV reactive.
Also, the younger age of HCC patients with HBV infection can be explained by 2 facts. First, the HBV carrier pool in India usually reaches a plateau by the age of 5 years. (13, 14) In the general population, it is estimated that about 75% of carriers would have acquired infection by horizontal spread during early childhood and about 25% by vertical transmission.(15) Second, HBV is a more potent oncogenic stimulus and can cause HCC without cirrhosis.(16)
In our study majority of the patient had AFP ≥ 400 (79.66 %) which was contradictory to Greten et al. study in which AFP ≥ 400 was observed in 41%.(17)
In a study by Salem S et al. (9) larger bulk of patients presented with multifocality (53.8 %) and cirrhotic liver (82.3 %), which was in comparison was contradictory to the present study, multifocality and cirrhosis were seen in 71.19 % and 25.42%, respectively. Cirrhosis is one of the cause that increases risk for HCC at various levels. Cirrhosis due to viral hepatitis are at higher risk of developing HCC than non-viral-induced cirrhosis. The portal vein thrombosis was observed in 30.51 % of patients in the present study which was similar to the study by Zhu Q et al. (36 %).(18)
The median tumor size 10 cm ranging from 6–22 cm while a study by Salem S et al. found the median tumor diameter was 6.0 cm (range 1.5–15.0 cm).(9)
In the present study documentation of diagnosis was dominantly achieved by biopsy/ FNAC then radiological and laboratory test/AFP (81.36% vs 18.64 %) which was similar to Salem S et al. study (63% vs 19%).(9) While it was mainly by radiological and laboratory tests in the Italian study.(19) However, there is a dramatic shift to radiological and laboratory tests for the diagnosis of HCC nowadays. Also an elevated AFP level in conjunction with imaging results showing the presence of growing liver mass has been shown to have a high positive predictive value for HCC in 2 retrospective analyses (20, 21) involving the small number of patients.
The majority of patients in the current study are in the advance stage (III/ IV), child pugh score B and C, CLIP score ≥ 3 which was similar to Salem S et al. (9) (TNM and Child Pugh Score) and Cabibbo et al.(19) study (Barcelona Clinic Liver Cancer (BCLC), Child Pugh Score, Cancer of the Liver Italian Program scores.), athought these study used different staging system.
6.2 Association Between Possible Risk Factors and Survival
In the current study, various possible risk factors such as age, gender, KPS, Alcohol addiction, Viral Status (HbsAg/ HCV), AFP levels, cirrhosis, portal vein thrombosis, multifocality, tumor size, tumor stage, child pugh score, CLIP score, bilirubin levels, prothrombin time and treatment modality were compared with survival period and it was observed that none of the factors were significantly associated with survival period (P < 0.05). Also, no of the variables showed significant associated with 6 months survival (P > 0.05) by univariate analysis using the chi-square test and fisher exact test. However age < 59 yrs, male gender, KPS ≤ 60, AFP ≥ 400, cirrhosis, multifocality, tumour size > 10 cm, advance stage (IIIB/IV), child pugh score B/C, CLIP score ≥ 4 and raised bilirubin level had poorer survival compared to other associated factors.
Also patients receiving TACE followed by sorafenib + Palliative care had better survival then patients for palliative care alone with median overall survival, 9 months and 4 months, respectively, p: 0.133. Ohki T et al. found that median overall survival time (861 vs. 467 days, P = 0.01) from the time of non-responsiveness to TACE were significantly longer with TACE followed by sorafenib within 14 days than TACE alone.(27)
Kaplan-Meier survival curve analysis was done using log-rank test for possible risk factors for survival period and hazards ratios with 95% confidence interval and it was observed that of all risk factors highest hazard was found with a multifocal lesion (2.0577) and results were significantly higher than unifocal lesion (95 % confidence interval: 0.9225 to 4.5900, p 0.0451) with median survival period of 7 vs 9.5 months. Similarly, it was observed in the present study that age < 59 years, KPS ≤ 60, male gender, alcoholic, HbsAg reactive, presence of portal vein thrombosis had 1.0933, 1.8792, 1.8267, 1.2647, 0.8182, and 1.2749 times more hazard as compared to age ≥ 59 years, KPS > 60, female gender, non-alcoholic, HbsAg non-reactive and absence of portal vein thrombosis with a median survival period of 7 vs 7.5 months, 6.5 vs 8 months, 7 vs 9.5 months, 7 vs 8 months, 7 vs 7.5 months, 6.5 vs 8 months respectively. However this difference was not found statistically significant. In current study we also observed that non cirrhotic patients had 0.7550 times more hazards than cirrhotic patients with a median survival of 7 vs 9 months (p = 0.5284).
A study in contradictory to present study, found that HCC risk increased with age: adjusted HR was 1.97 (95% CI, 0.99–3.87) for 40–49 years; adjusted HR was 3.00 (95% CI, 1.55–5.81) for 50–59 years; and adjusted HR was 4.02 (95% CI, 2.03–7.94) for more than 60 years vs less than 40 years. (28) Presence of cirrhosis increased risk of developing HCC in patients than without cirrhosis (adjusted HR = 3.69; 95% CI, 2.82–4.83). However, even among non-cirrhotic patients with high levels of alanine aminotransferase—regardless of race, the annual incidence of HCC was more than 0.2% for patients older than 40 years. (28)
The present results were also not consistent with the finding of a study by Greten et al.(17) They observed that the presence of portal vein thrombosis, advanced liver cirrhosis (Child–Pugh score B or C), and CLIP score of > 2 were Independent negative prognostic parameters for survival ( P < 0.05). Overall median survival was 11 months. (17)
A study by Rosellini et al.(29) concluded that absence of therapy, Child-Pugh's Class C, alfa-fetoprotein greater than 400 ng/ml, presence of symptoms, severe ascites, tumor involving both lobes and multifocality were variables associated with significantly decreased survival on univariate analysis. While Multiple regression analysis (Cox model) revealed that the mixed internal echo pattern of hepatocellular carcinoma and the presence of moderate or severe ascites were independent predictors of the high risk of death. The median survival from the time of diagnosis was 12 months.
Tumor size > 2 cm, multifocality, non-anatomic resection and vascular invasion were associated with worse prognosis (hazard ratio [HR] = 1.56, 1.34, 1.44, and 2.03, respectively P < 0.05) in study by Zhu Q et al. (18)
Paul et al. (30) observed that vascular invasion, Okuda staging, and therapy were independent factors associated with survival. Treated patients had better median survival compared to untreated ones (16 months vs. 7 months, p < 0.05) which was similar to the present study (9 months vs 4 months respectively) although results were not statistically significant ( p: 0.133). The above study also concluded that Serum AFP is not a very sensitive marker for diagnosis or surveillance.
Male gender, advanced Child-Pugh class, ascites, and distant metastases were associated with poor survival (P < 0.05). While, in multivariate analysis; the presence of ascites and Child-Pugh class were independent predictors of poor survival as concluded by Salem et al.(9)
Child-Pugh class, serum alpha-fetoprotein, tumor size, portal vein thrombosis, and TNM stage were found to be independent prognostic factors for survival among HCC patients in a study by Lee S et al.(8), with median overall survival of 10.8 months.
The poor outcome in present study could be related to the late presentation as most patients present with stage III or IV and poor liver functional reserve. Late presentation could be related to decreased awareness among patients and possibly primary health care physicians. This could be due to the fact that symptoms and signs of HCC could be attributed to the long-lasting underlying cirrhosis. Late presentation could also be related to the absence of adequate nationwide HCC screening programs. Other factors like pesticides may play a role in hepatocarcinogenesis (alfatoxins) and consequently HCCs in rural inhabitants. Also none of the patients was offered surgical resection due to the advanced stage of diseases in the present study.
In the present study, major constraints observed were retrospective study type, limited sample size, and no records focusing on assessment of molecular biology and tumor characteristic.
Also, no liver transplantation services were available at our center and also limited services with long waiting periods in India make availability difficult. Liver transplantation for hepatocellular carcinoma has the potential to eliminate both the tumor as well as the underlying cirrhosis and is the ideal treatment for HCC in cirrhotic liver as well as massive HCC in non-cirrhotic liver. Limitations in organ availability, necessitate the stringent selection of patients who would likely to derive the most benefit. Selection criteria have considered tumor size, number, volume as well as biological features. Cadaveric liver transplantation is limited by a shortage of donors and prolonged waiting periods. Additionally, the procedure is very expensive and, with no health insurance facilities available and severe economic constraints, it is virtually out of reach for the majority of the patients in India.(30) However, Living donor liver transplantation has expanded donor options and has the advantage of a lower waiting period and not impacting the non-HCC waiting list.
The inability to demonstrate a relationship between various possible risk factors (except multifocality) and OS on Kaplan-Meier survival curve analysis in the current study may be due to differences in study design, study population, definition, and criteria used in the study and underpowered sample size.