|Year : 2017 | Volume
| Issue : 3 | Page : 526-529
Advanced hepatocellular carcinoma: A regional cancer center experience of 48 cases
KN Lokesh, Tamojit Chaudhuri, KC Lakshmaiah, K Govind Babu, Lokanatha Dasappa, Linu Abraham Jacob, MC Suresh Babu, AH Rudresha, LK Rajeev
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Web Publication||24-May-2018|
Dr. Tamojit Chaudhuri
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
BACKGROUND: Hepatocellular carcinoma (HCC) is a major health burden and the seventh most common cause of cancer-related death in India. Patients with advanced unresectable HCC have a poor prognosis with a reported median survival of only 2–3 months with the best supportive care (BSC). Sorafenib is the only drug that has demonstrated a survival benefit over BSC in advanced HCC. Unfortunately, even though it has been used for a long time, there are very few published data regarding the experience of sorafenib therapy in advanced HCC from India. MATERIALS AND METHODS: Patients diagnosed with advanced HCC from January 2012 to July 2017 at our center were reviewed retrospectively. Patients' profile, time to progression, survival, and toxicity of sorafenib therapy were evaluated. RESULTS: Of the 48 advanced patients with HCC, 35 (72.9%) were male. The median age at diagnosis was 52 years. The most common presenting symptom was abdominal pain (77%, n = 37), followed by abdominal distension (37.5%, n = 18), loss of appetite and/or weight (33.3%, n = 16), and jaundice (16.7%, n = 8). Hepatitis B virus infection was documented in 37 patients (77%), whereas 4 patients had hepatitis C virus infection. Patients were treated with standard dose sorafenib (n = 30), BSC alone (n = 14), or transarterial chemoembolization followed by sorafenib (n = 4). Sorafenib therapy was well-tolerated in most cases. The median progression-free survival with upfront sorafenib was 4.3 months. The median overall survival (OS) of the patients who received upfront sorafenib was significantly better than those treated with BSC alone (5.9 vs 3.0 months; log-rank P= 0.00). CONCLUSION: Sorafenib therapy was well-tolerated and provided about 3 months longer median OS in our patients with advanced HCC than those treated with BSC alone.
Keywords: Barcelona Clinic Liver Cancer stage, hepatocellular carcinoma, sorafenib, transarterial chemoembolization
|How to cite this article:|
Lokesh K N, Chaudhuri T, Lakshmaiah K C, Babu K G, Dasappa L, Jacob LA, Suresh Babu M C, Rudresha A H, Rajeev L K. Advanced hepatocellular carcinoma: A regional cancer center experience of 48 cases. Indian J Cancer 2017;54:526-9
|How to cite this URL:|
Lokesh K N, Chaudhuri T, Lakshmaiah K C, Babu K G, Dasappa L, Jacob LA, Suresh Babu M C, Rudresha A H, Rajeev L K. Advanced hepatocellular carcinoma: A regional cancer center experience of 48 cases. Indian J Cancer [serial online] 2017 [cited 2021 Dec 7];54:526-9. Available from: https://www.indianjcancer.com/text.asp?2017/54/3/526/233153
| » Introduction|| |
Cancers of the liver are one of the most common types of cancer worldwide, and hepatocellular carcinoma (HCC) accounts for the majority (70%–90%) of them. HCC is a major health burden with a steadily increasing incidence globally. According to GLOBOCAN 2012 data, liver cancer is largely a problem of the less developed regions where 83% (50% in China alone) of the estimated 782,000 new cancer cases worldwide occurred in 2012. It is the fifth most common cancer in men (554,000 cases, 7.5% of the total) and the ninth in women (228,000 cases, 3.4%). HCC is the second most common cause of cancer-related death worldwide, which is estimated to be responsible for nearly 746,000 deaths in 2012 (9.1% of the total). It is more common in men than in women (male:female ratio of 2.4:1). The prognosis for liver cancer is very poor with an overall ratio of mortality to incidence of 0.95; and as such, the geographical patterns in incidence and mortality are similar.
In the areas that are endemic for hepatitis B and C, HCC is extremely common. Unfortunately, although India is an endemic zone for hepatitis B virus (HBV), there has been no comprehensively analyzed data for HCC in our country, and cancer registries probably do not reflect the accurate incidence. According to GLOBOCAN 2012 data, HCC is the seventh most common cause of cancer-related death in India. In our country, 70%–80% of all HCCs are related to HBV, approximately 15% are related to hepatitis C virus (HCV), and 5% to both HBV and HCV. Alcohol alone accounts for approximately 8% of all HCCs. In about 10%, no direct etiology is seen. Iron overload and aflatoxin may have a role to play in some geographical areas in India., The underreporting of HCC is possibly because of nonsurveillance of patients with chronic hepatitis B and carriers and patients with cirrhosis.
Most of the HCC cases in the Western countries are diagnosed in early stages because of better surveillance strategies. However, in India, the majority of the patients are detected in advanced stages, leading to high mortality rates. Patients with advanced unresectable HCC have a poor prognosis with a reported median survival of only 2–3 months with best supportive care (BSC). Sorafenib, an oral multikinase inhibitor, is the only drug that has demonstrated a survival benefit over BSC in advanced HCC. The aim of this retrospective study was to review the clinical data of the patients with advanced HCC treated at our Institute and to evaluate the outcomes of sorafenib therapy and BSC in this patient population.
| » Materials and Methods|| |
Patient selection, evaluation, and treatment
All consecutive cases diagnosed with advanced HCC between January 2012 and July 2017, at the Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India, were investigated retrospectively. All the patients underwent a detailed baseline evaluation including full medical history, physical examination, complete blood count, serum biochemical analysis including alpha fetoprotein (AFP), viral markers, electrocardiography, two-dimensional echocardiography, and contrast-enhanced computed tomography of the thorax, abdomen, and pelvis. The diagnosis of HCC was confirmed by microscopic examination and immunohistochemistry of the biopsy specimens. The immunohistochemical profile was performed using a panel of Hep Par-1, MOC-31, AFP, polyclonal carcinoembryonic antigen, glypican-3, arginase, CD10, and CD34.
Patients with Barcelona Clinic Liver Cancer (BCLC) stage B or stage C disease at baseline were treated with either upfront sorafenib 800 mg/day or transarterial chemoembolization (TACE) followed by sorafenib, and on progression treated with BSC.
Concomitant antiviral systemic therapy for HBV or HCV was allowed. Patients with BCLC stage D disease at presentation were offered BSC alone, which includes management of ascites, nutritional manipulation, treatment of comorbidities, and prevention of deterioration of hepatic functions. Sorafenib was discontinued if there were untoward adverse events, disease progression, or patient's refusal. The adverse events were classified based on the National Cancer Institute of Canada Common Terminology Criteria for Adverse Events, version 4.0.
The duration of progression-free survival (PFS) was defined as the time from the initiation of treatment until the documented disease progression, and overall survival (OS) was calculated from the date of diagnosis until death. The median OS was taken as the primary end-point for this retrospective analysis, and the secondary end-points were PFS and toxicity profile. All statistical analyses were performed using SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).
| » Results|| |
In all, 48 cases of advanced HCC, treated with upfront sorafenib (n = 30), TACE followed by sorafenib (n = 4), or BSC alone (n = 14), were retrospectively reviewed. The median age at diagnosis was 52 years, and majority were males (n = 35, 72.9%). Baseline demographic characteristics are summarized in [Table 1]. Sorafenib therapy was well-tolerated in most of the cases. The toxicity profile is summarized in [Table 2].
The median PFS with upfront sorafenib was 4.3 months (95% confidence interval [CI], 3.5–4.7 months). The median OS of the patients who received upfront sorafenib was 5.9 months (95% CI, 5.2–6.7 months), which was significantly better than those treated with BSC alone (3.0 months, 95% CI, 2.6–3.3 months; log-rank P = 0.00) [Figure 1]. Among the 30 patients who were treated with upfront sorafenib, BCLC B stage patients (n = 12) had a significantly better median OS (7.1 months, 95% CI, 5.7–8.6 months) than that of BCLC C stage patients (5.3 months, 95% CI, 4.7–6.1 months; log-rank P = 0.00) [Figure 2]. The patients, planned for TACE followed by sorafenib (n = 4), are all on sorafenib therapy at present (range: 1–4.8 months).
|Figure 1: Kaplan–Meier overall survival curve of advanced hepatocellular carcinoma patients (n = 48), treated with transarterial-chemoembolization + sorafenib, upfront sorafenib, and best supportive care alone|
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|Figure 2: Kaplan–Meier overall survival curve of advanced hepatocellular carcinoma patients treated with upfront sorafenib (n = 30). The Barcelona Clinic Liver Cancer stage B patients had a significantly better overall survival than stage C patients (log-rank P= 0.00)|
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| » Discussion|| |
Advanced HCC, defined by the presence of macroscopic portal vein invasion or lymph nodal or distant metastasis, accounts for one-third to half of all new HCCs diagnosed worldwide and is associated with extremely poor prognosis. Surgery and liver transplantation are considered contraindications as per current guidelines because of high recurrence rates., As such, they are deemed to be incurable. The recommended options for palliation of BCLC stage B and stage C disease are TACE and sorafenib. Presently, sorafenib is the only approved chemotherapeutic agent with a survival benefit over BSC, in advanced HCC. TACE-induced hypoxia can lead to release of angiogenic cytokines from tumor cells which can enhance tumor recurrence and metastases. Sorafenib exerts an antiangiogenic effect by blocking VEGF receptor-2 and-3 and platelet-derived growth factor receptor tyrosine kinase. Quite expectedly, the combination of TACE and sorafenib has shown to be an effective therapeutic strategy with an improved PFS and OS in advanced HCC.,
Till date, the clinical profile of patients with HCC has been published from various cancer centers in India, although very few of them reported the outcomes of sorafenib therapy in advanced HCC.,,,,, The median age of our patients was 52 years, which is similar to other reported studies from India.,, The male-to-female ratio was 2.7:1, although other studies from India have reported a higher male preponderance.,, Abdominal pain or discomfort was the dominant symptom in 77% of our patients followed by abdominal distension (37.5%) and loss of appetite and/or weight (33.3%). Anorexia (90%) and abdominal pain (80%) were the dominant symptoms in a study from eastern India, reported by Mukherjee et al. Kumar et al. too reported weakness and anorexia as the main presenting features, in their study including patients in north India. The prevalence of HBV positivity in patients with HCC in India ranges between 26% and 74%.,,, In this study, we noted that 77% of our patients with HCC are HBsAg-positive and 8.4% are positive for anti-HCV. Kumar et al. have also reported similar incidences of HBV infection (73%) and evidence of HCV infection (15%) in their patients. As observed in other Indian studies, serum AFP was raised to more than 400 ng/mL in 66.7% (n = 32) of our patients.,,,
Nandennavar et al. have reported a median OS of 3 months with sorafenib and 2 months with BSC in their study including patients in south India, which are similar to outcomes reported by Kostner et al. and Lee et al. Although in this study we found a much better outcome with sorafenib therapy. The median OS of our patients who received upfront sorafenib and BSC alone was 5.9 and 3 months, respectively. There were only 4% of patients with BCLC B stage and 68% of patients with BCLC C stage in a study by Nandennavar et al., whereas in our study 33.3% and 37.5% of patients had BCLC stage B and stage C disease, respectively. Clearly, a much higher proportion of patients with BCLC stage B disease in our study might be the main reason behind a better outcome with sorafenib therapy.
| » Conclusion|| |
In this study, we retrospectively investigated the demographic and clinical features of advanced HCC cases together with an analysis of outcomes with sorafenib therapy and BSC, in this patient population. This study showed that HBV infection is the commonest underlying etiological factor for HCC in south India, consistent with other published reports. Sorafenib was well-tolerated in our patients, with a median OS of 5.9 months. Clearly, larger prospective studies from other Indian centers are required to get a better picture of HCC and outcomes of sorafenib therapy in patients in India.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Venook AP, Papandreou C, Furuse J, de Guevara LL. The incidence and epidemiology of hepatocellular carcinoma: A global and regional perspective. Oncologist 2010;15 Suppl 4:5-13.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
Mallath MK, Taylor DG, Badwe RA, Rath GK, Shanta V, Pramesh CS, et al.
The growing burden of cancer in India: Epidemiology and social context. Lancet Oncol 2014;15:e205-12.
Kumar R, Saraswat MK, Sharma BC, Sakhuja P, Sarin SK. Characteristics of hepatocellular carcinoma in India: A retrospective analysis of 191 cases. QJM 2008;101:479-85.
Sarin SK, Thakur V, Guptan RC, Saigal S, Malhotra V, Thyagarajan SP, et al.
Profile of hepatocellular carcinoma in India: An insight into the possible etiologic associations. J Gastroenterol Hepatol 2001;16:666-73.
Durga R, Muralikrishna P. Viral markers in hepatocellular carcinoma. Indian J Gastroenterol 1994;13:A57.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.
Sorafenib in advanced hepatocellular carcinoma. N
Engl J Med 2008;359:378-90.
Wang JH, Changchien CS, Hu TH, Lee CM, Kee KM, Lin CY, et al.
The efficacy of treatment schedules according to Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma-Survival analysis of 3892 patients. Eur J Cancer 2008;44:1000-6.
Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An update. Hepatology 2011;53:1020-2.
European Association for The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908-43.
Raza A, Sood GK. Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J Gastroenterol 2014;20:4115-27.
Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A, et al.
Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): The role of angiogenesis and invasiveness. Am J Gastroenterol 2008;103:914-21.
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008;7:3129-40.
Zhang L, Hu P, Chen X, Bie P. Transarterial chemoembolization (TACE) plus sorafenib versus TACE for intermediate or advanced stage hepatocellular carcinoma: A meta-analysis. PLoS One 2014;9:e100305.
Varghese J, Kedarisetty C, Venkataraman J, Srinivasan V, Deepashree T, Uthappa M, et al.
Combination of TACE and Sorafenib Improves Outcomes in BCLC Stages B/C of Hepatocellular Carcinoma: A Single Centre Experience. Ann Hepatol 2017;16:247-54.
Mukherjee S, Dhar K, Datta S, Mukherjee AK. Hepatocellular carcinoma in Eastern India, a detail analytical report from a tertiary cancer hospital. Int J Sci Rep 2015;1:69-73.
Nagaich N, Sharma R, Katiyar P, Nagaich Y, Sharma I, Nijhawan S. Spectrum of hepatocellular carcinoma: Study from a tertiary cancer centre. J Cancer Prev Curr Res 2016;4:141.
Nandennavar MI, Karpurmath SV, Mandakalatur G, Prasad AE. Clinical profile of hepatocellular carcinoma and experience with sorafenib from a tertiary cancer centre in Southern India. Int J Res Med Sci 2017;5:379-83.
Kostner AH, Sorensen M, Olesen RK, Gronbaek H, Lassen U, Ladekarl M. Sorafenib in advanced hepatocellular carcinoma: A nationwide retrospective study of effi cacy and tolerability. Sci World J 2013; p. 6.
Lee SH, Song IH, Noh R, Kang HY, Kim SB, Ko SY. Clinical outcomes of patients with hepatocellular carcinoma treated with sorafenib: A retrospective study of routine clinical practice in multiinstitutions. BMC Cancer 2015;15:236.
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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