Sorafenib as first-line treatment for patients with primary hepatocellular carcinoma: an outcome evaluation

Abstract

Objective

To evaluate the clinical outcomes following first-line treatment with sorafenib in patients with primary hepatocellular carcinoma (HCC).

Methods

This retrospective cohort study enrolled patients with primary HCC that had been treated with sorafenib. Their data were collected from the hospital medical records database at three time-points: after three cycles, after six cycles and at the end of the sorafenib treatment regimen. The starting dose was 800 mg/day sorafenib but this could be reduced to 600 mg/day or 400 mg/day if patients developed adverse events (AEs).

Results

A total of 98 patients participated in the study. Of these, nine (9.2%) had a partial response, 47 patients (48.0%) had stable disease and 42 patients (42.9%) had progressive disease. The overall disease control rate was 57.1% (56 of 98 patients). Median progression-free survival for the overall cohort was 4.7 months. The most common AEs were hand-foot skin reaction (49 of 98 patients; 50.0%), fatigue (41 of 98 patients; 41.8%), appetite loss (39 of 98 patients; 39.8%) and hepatotoxicity/transaminitis (24 of 98 patients; 24.5%). The majority of the AEs were toxicity grades 1 and 2.

Conclusion

Sorafenib as a first-line treatment for primary HCC patients provided survival benefits and the AEs were well tolerated by patients.

Introduction

Hepatocellular carcinoma (HCC) is a malignancy with a high mortality rate and an increasing annual incidence. ¹ According to GLOBOCAN 2020 global estimates, HCC is the sixth most common cancer and is the second leading causes of cancer death with over 905 677 new cases each year. ¹ In Vietnam, HCC is ranked the first among all cancers in both morbidity and mortality, with a standardized age incidence rate of 39/100 000 in males and 9.5/100 000 in females. ¹

Treatment of HCC depends on the stage of cancer and liver function. For patients with early stages of the disease, radical treatment with surgery or liver transplantation can result in a good outcome, with 5-year overall survival up to 50%. ² For unresectable HCC at an intermediate stage, local treatment with embolization can help to improve the median survival up to 2 years. Thus, it has become the first choice of non-surgical treatment for liver cancer patients. ³ When diagnosed at the advanced stage, the disease often has a poor prognosis with very few treatment options and systemic chemotherapy has been shown not to be beneficial for these patients. ⁴

As a consequence of the significant developments in the molecular biology of HCC, treatment efficacy has been improved with new drugs used as targeted therapy or immunotherapy.^5,6 Sorafenib, a multikinase inhibitor has demonstrated significant survival benefits for patients with HCC at advanced stage in phase III trials in the Asia-Pacific region (Asia-Pacific trial) ⁵ and in the US and Europe (SHARP trial). ⁷ For example, the SHARP trial showed that the group using sorafenib had a median overall survival (OS) of 10.7 months, higher than the median OS of the placebo group (7.9 months) and there was an acceptable level of toxicity, with most adverse effects being toxicity grades 1 and 2. ⁷

In Vietnam, sorafenib has been licensed by the Ministry of Health for HCC treatment since 2009 and since then some studies have demonstrated that HCC patients treated with sorafenib had an OS ranging from 5.2 to 10.7 months.^8–11 At the Hanoi Oncology Hospital, Hanoi, Vietnam, HCC treatment with sorafenib has been used since 2013, but so far, there has not been any study evaluating the effectiveness and toxicity of this regimen. Therefore, this current retrospective study aimed to: (i) evaluate the outcome of HCC patients having first-line treatment with sorafenib; (ii) describe the adverse events of sorafenib as a first-line treatment on HCC patients.

Patients and methods

Patient population

This retrospective cohort study included patients in the Department of On-demand GI Medical Oncology, Hanoi Oncology Hospital, Hanoi, Vietnam. The study was conducted between August 2021 and December 2021. Patient data were collected from the hospital medical records database. All patient details were de-identified. The inclusion criteria were as follows: (i) patients were diagnosed with HCC based on the Diagnosis and Treatment Guidelines for primary HCC of Vietnam Ministry of Health 2020; (ii) patients received sorafenib as a first-line treatment between 1 January 2017 and 30 June 2021; (iii) patients were not eligible for surgery or had disease progression after surgical or locoregional therapies; (iv) their liver function measured by the Child–Pugh score was at the level A or B ≤ 8; (v) patients did not have other serious acute or chronic diseases; (vi) patients had at least one target lesion measurable on computed tomography or magnetic resonance imaging scans according to the Response Evaluation Criteria in Solid Tumors (RECIST); (vii) their organ and bone marrow functions were within acceptable limits; (viii) patients had a complete medical record. Any of the included patients were subsequently excluded if they met any of the following criteria: (i) secondary liver cancer; (ii) lost to follow-up; (iii) their Eastern Cooperative Oncology Group (ECOG) performance status score was 3; (iv) they did not comply with the sorafenib regimen; (v) had previously received systemic therapy. The data for included patients were collected at three time-points: after three cycles, after six cycles and at the end of the sorafenib treatment regimen. The starting does of sorafenib was 800 mg/day. Specifically, NEXAVAR 200 mg tablets were taken orally twice a day, 2 tablets/time, at least 1 h before or 2 h after a meal. Adverse events (AEs) and their toxicity grades were closely monitored. If patients developed AEs, the dose was reduced to 600 mg/day and then 400 mg/day if the AEs still existed or worsened. The treatment was discontinued when patients no longer clinically benefited from the therapy or had unacceptable adverse events.

The protocol of this study was approved by the Human Research Ethics Committee of Hanoi Oncology Hospital, Hanoi, Vietnam (no. 885/QD-BVUB; 26 April 2021). According to this approval, since this study was retrospective and patient data were de-identified, it was exempted from getting IRB approval and informed consent from patients.

Data collection

Patient characteristics and disease status of the study participants included age, sex, hepatitis status, ECOG, tumour characteristics (tumour size, macroscopic vascular invasion, extrahepatic metastasis), disease stage (Barcelona Clinic Liver Cancer, failure after local intervention/recurrence, metastasis), Child–Pugh score and alpha-fetoprotein (AFP) level before treatment. AEs and their toxicity grades were evaluated after the first 2 weeks of treatment and every 4 weeks after that. The dose would be reduced to 600 mg/day or 400 mg/day if patients developed AEs. Treatment response was defined by the RECIST guideline version 1.1 and was assessed after 8 weeks from the day treatment started. ¹² Treatment was continued until the occurrence of disease progression, hepatic deterioration to Child–Pugh class C, unacceptable AEs or death. The reporting of this study conforms the STROBE guidelines. ¹³

Statistical analyses

All statistical analyses were performed using the SPSS® statistical package, version 16.0 (SPSS Inc., Chicago, IL, USA) for Windows®. Survival analysis includes estimating means of probability and calculating occurrence of events according to Kaplan–Meier. For quantitative variables, χ²-test was used for comparisons. In the case of an expected frequency <5, χ²-test with Fisher's correction was used. The differences when comparing rates and estimating odds ratio (OR) risks were statistically significant when the P-value was <0.05.

Results

This retrospective cohort study included data from 98 patients from the hospital database. As this was a retrospective study, all medical records were selected at the same time using the filtering function following the inclusion and exclusion criteria. The selection process is presented in Figure 1.

Figure 1.

Flow chart showing progress through enrolment, selection and analysis in a retrospective study that analysed clinical outcomes in patients with hepatocellular cancer (HCC) that received sorafenib as a first-line treatment. ECOG, Eastern Cooperative Oncology Group.

As shown in the Table 1, most patients were aged between 40 and 65 years old (75 of 98; 76.5%). Men were in the majority (88 of 98; 89.8%). Most patients were diagnosed at Barcelona Clinic Liver Cancer C (65 of 98; 66.3%) and 67 of 98 patients (68.4%) had hepatitis B infection. Child–Pugh A accounted for the highest rate with 79 of 98 patients (80.6%). The majority of patients (96 of 98; 98.0%) had a good overall health condition with ECOG performance status scores of 0–1. In terms of HCC characteristics, more than half of cases (51 of 98 patients; 52.0%) had liver tumours located in both liver lobes. Of the 98 patients, 60 (61.2%) had portal vein thrombosis, 17 (17.3%) had distant metastases and 83 (84.7%) had an AFP level ≥20 ng/ml before treatment. Regarding treatment, 33 of 98 (33.7%) patients had a history of local intervention before enrolment in the study, including surgery (four of 98; 4.1%), transarterial chemoembolization (27.6%) and radiofrequency ablation (2.0%).

Table 1.

Demographic and clinical characteristics of patients (n = 98) included in a retrospective study that analysed clinical outcomes in patients with hepatocellular cancer that received sorafenib as a first-line treatment.

Characteristic	Total cohortn = 98	Characteristic	Total cohortn = 98
Age, years		Hepatitis
<40	7 (7.1)	Hepatitis B	67 (68.4)
40–65	75 (76.5)	Hepatitis C	4 (4.1)
>65	16 (16.3)	Hepatitis B and C	0 (0.0)
Sex		None	27 (27.6)
Male	88 (89.8)	Tumour site in the liver
Female	10 (10.2)	Right lobe	32 (32.7)
ECOG		Left lobe	15 (15.3)
0	72 (73.5)	Both lobes	51 (52.0)
1	24 (24.5)	AFP before treatment, ng/ml
2	2 (2.0)	<20	15 (15.3)
Diagnosis		≥20	83 (84.7)
Stage C of BCLC	65 (66.3)	Tumour spread
Failure after local intervention	20 (20.4)	PVT	60 (61.2)
Recurrence, metastasis	13 (13.3)	Distant metastasis	17 (17.3)
Child–Pugh score		Both PVT and distant metastasis	21 (21.4)
A5	51 (52.0)	On-site treatment before
A6	28 (28.6)	Surgery	4 (4.1)
B7	15 (15.3)	TACE	27 (27.6)
B8	4 (4.1)	RFA	2 (2.0)

Data presented as n of patients (%).

ECOG, Eastern Cooperative Oncology Group; AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; PVT, Portal vein thrombosis; TACE, transarterial chemoembolization; RFA, radiofrequency ablation.

In terms of the dose of sorafenib administered, 52 of 98 (53.1%) patients were treated with the full dose of sorafenib (800 mg/day); and 31 of 98 (31.6%) received 600 mg/day and 15 of 98 (15.3%) received 400 mg/day. None of the patients had to discontinue the sorafenib regime.

Based on the RECIST guideline, the overall response rate was 9.2% (nine of 98 patients); of these patients, all had a partial response and none had a complete response (Table 2). Of the 98 patients, 47 patients (48.0%) had stable disease and 42 patients (42.9%) had progressive disease. An analysis demonstrated that the response level was not associated with primary tumour site, diagnostic characteristics or liver function as assessed by the Child–Pugh score. Figure 2 presents the median progression-free survival (PFS) for the overall cohort, which was 4.7 months (95% confidence interval, 0.5, 48). There were 21 patients with a PFS < 3 months and the longest PFS was 48 months.

Table 2.

Distribution of patients (n = 98) included in a retrospective study that analysed clinical outcomes in patients with hepatocellular cancer that received sorafenib as a first-line treatment stratified according to their response to treatment.

Characteristic	RECIST clinical response
	Partial responsen = 9	Stable diseasen = 47	Progressive diseasen = 42
Diagnosis
Stage C of BCLC	5	27	33
Failure after local intervention	2	13	5
Recurrence, metastasis	2	7	4
Tumour site in the liver
Right lobe	3	15	14
Left lobe	4	7	4
Both lobes	2	25	24
Child–Pugh score
A	9	40	30
B	0	7	12

Data presented as n of patients.

No significant between-group differences (P ≥ 0.05).

RECIST, Response Evaluation Criteria in Solid Tumors; BCLC, Barcelona Clinic Liver Cancer.

Figure 2.

Progression-free survival in patients with hepatocellular cancer that received sorafenib as a first-line treatment.

In terms of the AEs associated with sorafenib treatment, AEs occurred in 83 of 98 (84.7%) patients, but only 18 of 98 (18.4%) patients had to delay treatment due to AEs and none of the patients discontinued treatment due to AEs. Hand-foot skin reaction (HFSR) was the most common AE (49 of 98 patients; 50.0%), followed by fatigue (41 of 98 patients; 41.8%), appetite loss (39 of 98 patients; 39.8%) and hepatotoxicity/transaminitis (24 of 98 patients; 24.5%) (Figure 3). The majority of the AEs were toxicity grade 1–2 and only seven of 98 (7.1%) patients had toxicity grade 3–4 AEs. Of the patients with toxicity grades 3–4 AEs: three of 98 (3.1%) had fatigue at grade 3; two of 98 (2.0%) had HFSR at grade 3; one of 98 (1.0%) had transaminitis (elevated liver enzymes) at grade 3; and one of 98 (1.0%) had grade 3 hypertension.

Figure 3.

Adverse events with toxicity grades in patients with hepatocellular cancer that received sorafenib as a first-line treatment. HFSR, hand-foot skin reaction. The colour version of this figure is available at: http://imr.sagepub.com.

Discussion

This current retrospective cohort study demonstrated that none of the 98 patients experienced a complete treatment response and only nine (9.2%) patients had a partial response. Of the 98 patients, 47 (48.0%) patients had stable disease and 42 (42.9%) had progressive disease. The overall disease control rate was 57.1% (56 of 98 patients).

Complete responses are very rare among international studies on sorafenib monotherapy for advanced HCC.^14,15 The partial response rate of the current study was 9.2%, which was higher than that of the SHARP trial (2%), ⁷ the Asia-Pacific trial (3.3%) ⁵ and HTT Nguyen’s study (4.5%). ⁸ The stable disease rate was 48.0% in the current study, which was lower than the SHARP trial (71%), ⁷ the Asia-Pacific trial (54%) ⁵ and HTT Nguyen’s study (54.5%). ⁸ The disease progression rate in the current study (42.9%) was higher than the SHARP trial (27%), ⁷ the Asia-Pacific (30.7%) ⁵ and HTT Nguyen’s study (41%). ⁸ The overall disease control rate (57.1%) in the current study was similar to that of the study of HTT Nguyen in Vietnam (59%) ⁸ and higher than that of the SHARP trial conducted in the US and Europe (43%). ⁷

In the current study, the median PFS was 4.7 months and the longest PFS recorded was 48 months. For cancer patients in general, and in patients with liver cancer in particular, the PFS duration is an important factor to evaluate treatment effectiveness. Time-to-progression (TTP) or PFS varies across international studies. For example, in the SHARP trial conducted in 21 countries in Europe, North America, South America and Australia on 602 patients, the TTP was 5.5 months. ⁷ In the Asia-Pacific trial conducted in China, Taiwan and Korea on 226 patients, the TTP was 2.8 months. ⁵ More recently, the median PFS in a multicentre trial conducted in Japan on 312 patients was 3.6 months. ¹⁶ Since the definition of TTP is similar to that of PFS, except with regard to patients who died from other causes,^17,18 a review of international studies on TTP or PFS of HCC patients treated with sorafenib was considered to be valid in order to compare their findings with the PFS in the current study. This review of the literature found that the median PFS of the Vietnamese patients in the current study was similar to that reported from the trials undertaken Europe, North America, South America and Australia; ⁷ and higher than that of the Asia-Pacific trial conducted in China, Taiwan and Korea. ⁵ When compared with recent domestic studies, the median PFS in the current study was similar to that of HTT Nguyen’s study on 110 patients (median PFS of 4.57 months); ⁸ and lower than that of a previous study on 10 patients (median PFS of 7.2 months). ¹¹ However, studies evaluating the efficacy of sorafenib in Vietnam were mostly of a small size that involved a very small number of patients. The median PFS measured in the current study was lower than that observed in the SHARP trial, possibly because patients in SHARP trial had a higher proportion of Child–Pugh A (95%) patients and the proportion of patients with hepatitis B was low (19%); ⁷ while there was a lower proportion of patients with Child–Pugh A (80.6%) and the prevalence of hepatitis B prevalence was much higher (68.4%) in the current study. The median PFS in the current study was higher that of the Asia-Pacific trial possibly because the patients in the current study had a better overall health status with the majority of patients having an ECOG score of 0 (73.5%), whereas most of the patients (74.7%) in the Asia-Pacific trial had ECOG scores of 1 and 2. ⁵

Hepatocellular carcinoma is exceedingly heterogeneous. This feature plays an important role in disease progression, prognosis and drug resistance. HCC heterogeneity influences different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signalling pathways, changes in the DNA repair machinery and the development of a negative balance between apoptosis and survival of the cancer cells. ¹⁹ Sorafenib resistance could be either primary or acquired and is a major obstacle towards achieving a better outcome in advanced HCC patients. ²⁰ In addition, hepatitis B virus has been associated with sorafenib resistance by reducing ferroptosis via the SRSF2/PCLAF tv1 axis. ²¹ In the current study, the number of patients with hepatitis B were much higher than that of the SHARP trial (68.4% versus 19%, respectively) and that might be a reason that the lower PFS observed in the current study. ⁷

Regarding the adverse events associated with sorafenib treatment, the current study found a high rate of AEs (83 of 98; 84.7%). The most common AE observed in the current study was HFSR (50%), followed by fatigue (41.8%), appetite loss (39.8%), hepatotoxicity/transaminitis (24.5%) and diarrhoea (23.5%). High rates of AEs have also been reported in other studies worldwide. For example, in the GIDEON study, 83% of the patients had AEs, of which 64% were drug related; most of the AEs were toxicity grade 1 and 2, with only 9% being classified as serious. ²² The most common AEs in the GIDEON study were diarrhoea, HFSR and fatigue. ²² In the SHARP trial, 80% of patients had AEs of all grades; with 43.8% having diarrhoea, 26.3% having HFSR, 21.9% having fatigue, 17.5% having acne and 19% having hypertension. ⁷ Toxicity grades 3 and 4 AEs accounted for <10%. ⁷ In the Asia-Pacific trial, the most common AE was HFSR (45%), followed by diarrhoea (26%), fatigue (20%) and acne (20%). ⁵ The AEs associated with sorafenib treatment mostly affect the skin and gastrointestinal tract, with few AEs of the haematopoietic system. Even though AEs occurred in a high proportion of patients in the current study, they were mostly mild (toxicity grades 1 and 2), with few patients experiencing toxicity grade 3 and 4 AEs.

This current study had several limitations. First, it was an observational study that analysed retrospective data. Secondly, the number of patients was quite small. Therefore, the specific effects of sorafenib have not been completely evaluated, especially in patients with Child–Pugh B. Due to these limitations, these current findings cannot be generalized to the wider HCC population in Vietnam. Thirdly, it was not possible to consider information that was not in the medical records. For example, it would be useful to evaluate the effect of sorafenib on quality of life during and after taking this drug. Future studies should be undertaken in larger numbers of patients, especially those with Child–Pugh B, in order to fully evaluate the treatment outcomes of sorafenib as well as the quality of life of patients taking this drug.

In conclusion, this current retrospective study showed that sorafenib used as first-line treatment for primary HCC patients provided an overall disease control rate of 57.1% and a median PFS of 4.7 months. Although the overall AE rate was high, most AEs were mild (toxicity grades 1 and 2). These current findings were consistent with previous studies that analysed the efficiency and safety of sorafenib among HCC patients with advanced disease or those who had already failed local treatment. Sorafenib was shown to be beneficial in HCC patients in this current study and should continue to be used in clinical practice.