Concomitant Chemoradiation Using Gemcitabine in Locally Advanced Hepatocellular Carcinoma

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Most of patients present with advanced disease that cannot be treated with curative or ablative intent. The aim of the study was to assess the therapeutic benefit of concurrent chemoradiotherapy (CCRT) in patients with advanced HCC and to identify factors that predict OS. Methods: Patients with radiologically or biopsy proven primary HCC from 2010 to 2013 were included in the study. Gemcitabine was given in a dose of 70 mg/m once weekly for three weeks during external beam radiotherapy 30 Gy/2 Gy/fraction/five fractions per week in the Clinical Oncology Department, Assiut, Egypt. Results: Forty-nine patients were eligible but forty patients were evaluable for assessment. The partial response rate (PR) was 35% (14 patients), 16 patients (40%) had stable disease (SD) and the progressive disease was 25%. Painful hepatomegaly was significantly relieved in 70% of patients. Transaminases rose as grade 3 toxicity in 15% of patients. Longer overall survival (OS) was significantly observed in patients with performance status 0, child-Pugh A, Barcelona Clinic Liver cancer Stage B, PR and α fetoprotein level decrement. Conclusion: Concurrent chemoradiotherapt provides an acceptable response and palliation of pain in advances HCC. Our findings showed that better survival for patients with good performance and liver functions.


Introduction
Hepatocellular carcinoma (HCC) accounting for 75% -85% of primary liver cancer [1].High risk patients should enter into a surveillance program to diagnose the disease in early stage and increase survival [2].
Primary liver cancer is the sixth most commonly occurring cancer in the world and the fourth cause of cancer mortality.The highest incidence of HCC is in Eastern and South-Eastern Asia.Egypt, Gambia and Guninea represent the highest incidence in Northern and western Africa [3].
In Egypt, liver cancer represents 23.8% of cancer incidence in both sexes.The proportions and age standardized incidence rate (ASR) of liver cancer were highest in Lower Egypt (29.6%), less in Middle, and least in Upper Egypt (8.2%) [4].
Risk factors for the incidence of HCC include chronic infection of hepatitis B, hepatitis C, alcoholic hepatitis, non-alcoholic fatty liver disease and liver cirrhosis from any cause [5].
Staging of patients with HCC is important both for the prognostication and deciding the treatment.In this tumor, the prognosis depends upon the tumor stage and the liver function impairment due to underlying cirrhosis liver [6].
Many staging systems have been used for staging of HCC taking in to account the tumor status (known by tumor size and number, presence of vascular invasion and extrahepatic spread), liver function (defined by the Child-Pugh's class which determines the levels of serum bilirubin, albumin, presence of ascites and portal hypertension) and general health status of the patient (graded by the Eastern Cooperative Oncology Group classification) [7].
Staging systems commonly used in HCC include the European systems {Barcelona Clinic Liver Cancer (BCLC) staging system [8]} and Asian systems {Okuda staging system [9]}.
HCC mostly remain within the liver, but multifocality and vascular invasion are common [10].For treatment selection, an acceptable balance between surviving the remaining liver function and tumor control is a challenge [11].
Surgical resection of HCC is indicated for limited cases of HCCs.Radiofrequency ablation is used for the treatment of HCCs of certain size and number [12].Transcatheter arterial chemoembolization (TACE)) using iodized poppy seed oil, Lipiodol and anticancer drugs are used for the treatment of unresectable HCC [13].
Currently, the Korean Liver Cancer Study Group and National Comprehensive Cancer Network guidelines recommend combined radiotherapy (RT) and chemotherapy for selected cases of HCC.Concurrent chemoradiotherapy can augment the therapeutic successes for locally advanced HCC [14].
The aim of the study was to evaluate the efficacy of concurrent gemcitabine and external beam radiotherapy in locally advanced hepatocellular carcinoma and to define prognostic factors for survival among patients.

Patients and Methods
This prospective single arm phase II study was conducted in Clinical Oncology department, Faculty of Medicine, Assiut University, Egypt to assess the efficacy and safety profile of concurrent gemcitabine and external beam radiotherapy for the treatment of unresectable hepatocelluar carcinoma (HCC).

Inclusion criteria
Patients were included if they had a pathological confirmation of HCC or had fulfilled the American Association for the Study of Liver Diseases (AASLD) [15] criteria of the appearance of nodules on single dynamic technique either computed tomography (CT) or magnetic resonance imaging (MRI) showing intense arterial uptake followed by "washout" of contrast in the venous-delayed phases.
Patients were included if they have stage B/C using Barcelona Clinic Liver cancer (BCLC) staging system [16].Patients were not candidate for transarterial embolization.
Exclusion criteria Patients were excluded if they had Easter cooperative oncology group (ECOG) performance status >2, extrhepatic metastases, a history of radiotherapy to the abdominal area or concurrent chemoradiotherapy was not the first treatment.
A baseline evaluation included medical history, clinical examination including signs of liver cirrhosis (ascites and encephalopathy), performance status scoring, laboratory studies including complete blood count, liver and renal function tests, scoring of liver functions by Child-Pugh scoring, serologic markers for hepatitis B or C viruses and α-fetoprotein level (reference range, 0 to 15 ng/mL).Imaging studies (dynamic CT abdomen or MRI of the liver) was required.Bone scan or brain magnetic resonance was done when indicated.The Child-Pugh score was calculated from obtained clinical and laboratory data.
Treatment plan Gemcitabine was given as IV infusion over 30 minutes in a dose of 70 mg/m 2 once weekly for three weeks started with day 1 of radiotherapy.
Gross tumor volume (GTV) defined radiological as abnormal area seen on CT scan and clinical target volume (CTV) defined as GTV plus 1 cm margin.We irradiated the planning tumor volume as CTV plus 0.5 -2.5 cm (determined under fluoroscopy) in the cranial-caudal dimensions to account for liver motion from respiration.A 2-dimensional radiotherapy using anteroposterior and posteroanterior fields was used.The radiation treatment was delivered with 60 Co up to 30 Gy. Radiation therapy was administered once daily, five fractions a week at 2 Gy/fraction.
Evaluation of response and toxicity Assessment of response was characterized according to the modified-Response Evaluation Criteria in Solid Tumors (m-RECIST) [17] defined as: Complete response, partial response, stable disease and progressive disease.
Evaluation of the disease and monitoring of toxicity was done monthly by physical/laboratory examination and contrast enhanced imaging CT/MRI scan every 3 -6 months for 2 years then annually.
In patients in whom the serum AFP level was elevated before treatment, assay was done one month after termination of treatment, every 3 months for 2 years, Toxic effects were assessed weekly during chemoradiation and after completion of chemoradiotherapy by using common toxicity criteria of the National Cancer Institute version 4.0 [18].

Statistical analysis
The outcome measurement of this treatment included response rate, progression-free survival and overall survival.
Progression-free survival (PFS) was calculated from the date of initiation of treatment to the documented date of progression or date of last follow-up.
Overall survival (OS) is defined as the time from the start of chemoradiation to the date of death or last follow-up.
Baseline characteristics of the patients were expressed as percentage and median.Survival analysis was estimated with the use of Kaplan-Meier method.Differences in survival among their prognostic variables were tested by using log-rank test.A P value < 0.05 was considered statistically significant.All statistical analysis was performed using SPSS 21.0 (SPSS, Inc.Chicago, IL).

Results
Between July 1, 2010 and June 30, 2013, 49 patients with HCC were included in the study; of these, 9 patients did not complete the treatment plan and the remaining 40 patients were included in the analyses.The baseline patient characteristics are listed in Table 1.
Seventy-five percent of the evaluable patients were men and 83% of the cohort had liver cirrhosis.Thirty (75%) patients had HCC associated with hepatitis C infection and Alpha-Fetoprotein was elevated in 85% of patients.Regarding staging of HCC patients in the current study, twenty patients (65%) had Child-Pugh stage B and sixteen (40%) patients had BCLC stage C.In addition, thirty patients (75%) had painful hepatomegaly.
Forty patients were evaluable for response assessment of concurrent chemoradiation.According to m-RECIST for evaluation of response, fourteen patients (35%) had a partial radiological tumor response, sixteen patients (40%) had stable disease and ten patients (25%) had progressive disease.Among patients who had painful hepatomegaly, the response rate to chemoradiation was significantly different (70% vs. 30%, P = 0.03).The median overall survival was 7 months (95% confidence interval [CI] 2.63 -11.36) and the progression-free survival was 4 months (95% CI, 2.51 -5.48).Treatment outcome is summarized in Table 2.
Prognostic factors for overall survival identified by univariate analysis were performance status 0, Alpha-fetoprotein decrement, BCLC stag B, Child-Pugh stag A and partial response were significantly associated with survival as reported in Table 3.
On performing multivariate analysis using all prognostic factors, ECOG   Twenty percent of patients had grade II diarrhea and rise in serum tranaminase level while fifteen percent of patients had grade III rise in serum transaminase level.Grading of toxicity of chemoradiation is shown in Table 5.
Partial responders of HCC patients treated by concurrent chemoradiation had significantly longer survival than patients showing stable disease and progressive disease (median OS 7 months for PR vs. 4 months for SD and 2 months for PD).
Kaplan-Meier curve of overall survival of patients according to the types of response is presented in Figure 1.
Median overall survival of 40 HCC patients treated by concurrent chemoradiation was 7 months.Kaplan-Meier curve of overall survival of patients with HCC included in the analysis is presented in Figure 2.

Discussion
Hepatocellular carcinoma is an important health issue, particularly in regions where viral hepatitis prevalence is high.In Egypt, Africa HCC represents 23.8% of cancer incidence [4].The current study investigates the clinical outcomes of concurrent external beam radiotherapy and weekly gemcitabine in patients with HCC.
In this study, the partial response (PR) rate to concurrent chemradiation (CCRT) was 35% was achieved.These results were comparable to the results of the study done by Masood AI et al. [19] who reported 36% as overall response rate.
Grade 3 toxicity of CCRT in the current study was seen in 15% of patients as raised liver enzymes.Toxicity of CCRT using systemic chemotherapy had acceptable toxicity in locally advanced HCC [19].The combination of radiotherapy (RT) and locoregional therapy such as transarterial chemoemblization (TACE) has become one of the effective therapies for HCC.Radiotherapy can be used as a complement to incomplete TACE and a treatment for liver thrombus [20].
A meta-analysis was done to evaluate the effect of TACE plus RT versus TACE alone on tumor response, survival, and adverse events.Patients receiving TACE plus RT showed significantly better complete response and 1-year survival compared with TACE alone and the survival benefit increased for 5-year survival [21].
Another study reported that patients with unresectable HCC treated with RT, either as CCRT or in combination with TACE, showed effective intrahepatic control and prolonged survival [22].
Update results of a study on patients with advanced HCC who had portal vein thrombosis revealed that survival was significantly longer in patients treated with hepatic arterial infusion of chemotherapy + RT than with sorafenib monotherapy [23].
Safe delivery of ablative doses of RT to focal liver tumors is limited by the tolerance of the liver and adjacent tissues.3-diminsional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) are techniques used to target tumors with higher doses while sparing normal surrounding tissues.Image-guided RT (IGRT) is currently used to assist in the delivery of 3DRT, IMRT and sterotactic RT along with respiratory motion compensation and tumor visualization [24].
In the present study radiotherapy was prescribed for delivering palliative and not curative treatment.Radiation dose was limited to 30 Gy to prevent radiotherapy-induces liver disease (RILD) if the whole liver included in the target volume because the mean liver dose associated with a 5% risk of RILD is 28 Gy at 2 Gy per fraction for primary liver cancer [25].
In the analyses of prognostic factors, the CCRT treatment in this study showed a significantly higher OS with performance status 0, BCLC stage B, Child-Pugh A, partial responders and AFP responders.
Other In patients with huge HCC (>10 cm) treated by multimodality including RT, the significant prognostic factors of survival were number of tumors, initial AFP level, percent AFP decrement, treatment response, and hepatic resection [27].
The correlation between AFP response and survival outcome in patients with HCC has been reported in other studies as a prognostic factor for survival [28] [29].
Regarding the role of radiotherapy in palliation of pain, the present study showed that a significant number of patients had a symptomatic relief of pain (painful hepatomegaly).These results are in agreement with the results of the study done by Hammad AY et al., who reported that RT was the best palliative therapy for HCC and provided a survival benefit for patients with stage IV disease.In their study, 18% of patients received RT to the liver as palliative treatment of pain [30].
This study has some of the limitations of a prospective study.First are the less restrictive inclusion criteria for acceptance of participants, lack of follow-up data about tumor progression was it inside or outside the radiation field and whether there was reactivation of viral hepatitis after liver irradiation.Second are the limitations in administration of advanced radiation technologies with the delivery of higher external beam radiation dose and combining it with novel target/immunotherapy agents.

Conclusion
Concurrent chemoradiotherapt provides an acceptable response with minimal toxicity in advances HCC.Our findings showed that better survival for patients with a good performance and liver functions.CCRT will be recommended for patients with advanced HCC for palliation of pain.
M.-A.-E.H. Mohamed DOI: 10.4236/jct.2018.9120841030 Journal of Cancer Therapy then 6 monthly.Patients with chronic intermittent hepatic pain were assessed according to pain scale of 0 to 10 (patient self assessment).Patients with underlying liver disease were closely observed, monitored and appropriately treated.

Table 1 .
Clinical characteristics of patients with locally advanced hepatocellular carcinoma.

Table 2 .
Treatment outcomes after concomitant gemcitabine and radiotherapy in patients with advanced hepatocellular carcinoma.

Table 3 .
Univariate analysis of prognostic factors for progression-free survival (PFS) after concomitant gemcitabine and radiotherapy in patients with hepatocellular carcinoma.

Table 4 .
Multivariate analysis of prognostic factors of progression-free survival of the study cohort of patients with hepatocellular carcinoma treated with chemoradiation.