Tumor Response and Factors Affecting Survival of Using Sorafenib in Management of Advanced Hepatocellular Carcinoma

Purpose: Hepatocellular carcinoma (HCC) is a dismal tumor that is usually diagnosed at late stages. Sorafenib is the main line of treatment in advanced HCC cases while preserved hepatic functions. However, the drug has high costs and is associated with several side effects. We aimed to study the predictive factors for survival to limit patients with potential low response and exposure to side effects. Methods: This prospective cohort study included 64 patients with advanced HCC and who were treated using Sorafenib according to international guidelines. The modified Response evaluation criteria in solid tumors (RECIST) assessed treatment response and we did regression analysis for predictors of survival. Result: Our studied patients were predominantly males with mean age 59 years. They were Child A (48 patients) and Child B7 (16 patients). Lesions were large in size (mean 6.5 cm) and 50% had portal vein thrombosis. Stationary disease was recorded in 84.38% of patients with a mean duration of treatment 4.71 months and overall survival 11.25 ± 7.25 months. Hand and foot syndrome was the most common adverse event. Multivariate regression analysis showed that performance status (HR: 2.96, CI: (1.22-7.21), P-value 0.02) and tumor size ≥5cm (HR: 2.36, CI: (1.1-5.25) P-value 0.03) were the lone factors. Conclusion: We reported higher rates of stationary disease and good survival rates. The lone prognostic factors for survival were PS ≥2 and size of lesions ≥5 cm. Sorafenib is still a backbone treatment for advanced HCC patients till emergence of safer and more effective lines of treatment. Response and Factors Survival of Using Sorafenib in Management of Hepatocellular Carcinoma.


Introduction
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second leading cause of cancer related death worldwide [1]. The estimated incidence is 5-6% of all new cancers [2]. Due to complexity of HCC management, due to presence of multiple factors related to the malignancy and the underlying liver disease, proper management requires a multidisciplinary approach [3]. HCC is famous with its poor prognosis. This is mostly related to the aggressive biological behavior, rapid progression and the underlying chronic liver disease [4]. In clinical practice, more than 60% of HCC cases are diagnosed at late stages [5]. A restricted number of patients with early lesions have a chance for curative treatment such as liver transplantation and hepatic resection [6].
Also, portal vein thrombosis (PVT) is diagnosed in up to 40% of HCC patients when firstly presented [7].
Sorafenib, a multi kinase inhibitor, was the first drug to receive FDA approval for a beneficiary survival rate in patients with advanced HCC. Two major randomized controlled trials concluded an improved median overall survival by 2-3 months when compared to placebo [8,9]. Sorafenib became the standard of care treatment for advanced HCC with preserved hepatic functions. However, survival benefit proved to vary widely between individuals [10]. In addition, the drug is expensive and is associated with adverse events. For such results, it is better to determine HCC cases who may benefit from Sorafenib therapy and spare patients who are potentially resistant and got exposed to unnecessary toxicity [11]. As no validated biomarkers were proved to predict response to Sorafenib therapy, different parameters were studied for possible predicted values [12]. GIDEON study documented a strong predictive role to albumin and bilirubin [13]. ECOG performance status more than 0, older age than 72 years, presence of macrovascular invasion and presence of numerous focal lesions more than 7 lesions were predictive factors for poor prognosis in advanced HCC patients treated with Sorafenib [14]. Child Pugh score, BCLC stage and occurrence of significant side effects were similarly proposed as main prognostic factors [15]. With absence of clear and validated prognostic factors, we aim in our study to determine the different prognostic factors that are related to Sorafenib use in management of advanced HCC and impact of Sorafenib on overall survival of studied patients.

Patients and Methods
During the period September 2012 and June 2016, 1221 HCC patients were managed in our multidisciplinary clinic for HCC, Cairo University, Egypt. Among those patients, 64 cases received Sorafenib according to EASL guidelines and AASLD practice guidelines for management of HCC [16,17]  Concerning Sorafenib intake, we requested the patients to start with 200mg twice a day and we rose the dose to 400 mg twice a day (full dose) after two weeks. Thereafter, dose modifications were related to frequency and intensity of adverse events. Patients were scheduled for follow up two weeks after starting treatment then every month for first three months then fixed every three months.
Sorafenib was stopped whenever serious adverse events occurred, non-tolerability of the patients and/or marked clinical disease or radiological progressions were documented. During the follow up visits, patients were assessed for safety and efficacy of the drug.
Patients are questioned for potential side effects such as fatigue, diarrhea, skin manifestations that are compatible with hand and foot syndrome. Laboratory investigations include complete blood picture (CBC), liver biochemical profile (total bilirubin, serum albumin, INR and liver enzymes), renal profile and alpha fetoprotein (AFP). Imaging included triphasic CT abdomen or dynamic MRI liver. Assessment of efficacy was verified according to modified RECIST criteria (Response Evaluation Criteria in Solid Tumors [18].
Phone calls are performed for patients who missed their scheduled visits every six months. Overall survival was calculated as the total time between start of Sorafenib treatment and death.
Descriptive statistics were done, and categorical variables were presented as frequencies and percentages and numerical data as mean (SD) or median (IQR). Survival analysis was done and the median survival time of patients taking Sorafenib was determined.  (Figure 1).

Discussion
Since the introduction of Sorafenib in the management of advanced HCC, numerous studies tried to identify prognostic factors to avoid unnecessary side effects of the drug in potentially non-responding patients. None of the prognostic factors and systems proved to be optimal in prediction of survival in such patients [19]. to discontinuation within three months [23]. They also added that patients with poor prognosis and continued Sorafenib beyond progression had significantly prolonged survival. In agreement, Otsuka et al proved an advantage to continue Sorafenib even beyond progression disease and improvement of overall survival as compared to best supportive care [24]. Moreover, Cardoso et al concluded that increasing time of exposure of the drug and trying to reduce dose rather than to discontinue the drug if side effects occurred will improve survival of patients [15].
As we managed Child A-B7 patients with good performance status and we tried to prolong duration of treatment for more than 3 months, this also impacted our survival rates (mean OS 11.25 months). The two benchmark studies of Sorafenib (SHARP trial and Asia Pacific trial) reported an OS 6.5 and 10.7 months as compared to placebo (4.2 and 7.9 months) [8,9]. Selection of patients for Revising the literature, we found a great heterogeneity of factors and still no unique factor was agreed by different trials. Better survival rates correlated with history of previous hepatic resection (2) and aetiology of chronic liver disease if it was alcoholism [2] or chronic HCV [2,25,26]. Poor survival was predicted in relation to age [14,27], gender [2], performance status [14,27], macrovascular invasion [14,27], extrahepatic spread [2,27] and large lesions [14,27]. As for laboratory factors, AST, total bilirubin, AFP and CA19-9 correlated with survival [2,10,14,21,27]

Conclusion
In conclusion, to take home message, we managed advanced HCC patients with Sorafenib. We reported higher rates of stationary disease, prolonged duration of treatment (more than 3 months), high incidence of side effects and resultant good survival rates. The lone prognostic factors for survival were PS≥2 and size of lesions ≥5 cm. Sorafenib is still a backbone treatment for advanced HCC patients till emergence of safer and more effective lines of treatment of such drastic malignancy.

Funding
The authors have no relevant financial or non-financial interests to disclose.

Conflicts of Interest/Competing Interests
The authors have no conflicts of interest to declare that are relevant to the content of this article.

Consent to Participate
Include appropriate statements. Consent to participate written informed consent was obtained from the participants.

Consent for Publication
(N/A)

Availability of Data and Material:
The data that support the findings of this study are available on request from the corresponding author, [Shousha HI].