Database analysis of patients with hepatocellular carcinoma and treatment flow in early and advanced stages

Abstract Despite recent developments in treatment modalities and diagnosis, the prognosis of advanced hepatocellular carcinoma (HCC) remains unsatisfactory. To gain insight into treatment decisions for HCC patients, their characteristics and treatment flow in the early and advanced stages were examined. HCC patients' characteristics and treatment flow were retrospectively analyzed using the Japanese medical claims database. The 8999 patients' mean age at HCC diagnosis was 71.1 years, with no difference between early (Stage I/II) and advanced (Stage III/IV) stages. The mean observation period was 26.2 months, shorter in advanced than in early stages. HCV hepatitis was reported in 52.0% of HCC patients, with concomitant hypertension in 53.4%, type 2 diabetes in 45.8%, cirrhosis in 39.3%, and hyperlipidemia in 15.5%. The rates of HCV hepatitis, hypertension, and hyperlipidemia decreased with stage progression. Analysis of treatment flow showed that, at all disease stages, transcatheter arterial chemoembolization (TACE) was the most common first to fourth‐line treatment. Epirubicin was the most frequently (44.1%) used chemotherapeutic agent for first‐line TACE, followed by miriplatin (23.6%) and cisplatin (12.3%). With stage progression, cisplatin use increased. Sorafenib was used concomitantly for first‐line TACE in 3.2% of patients, and its use increased significantly in advanced stages. Clear differences in baseline characteristics and treatment flow between early and advanced stages were identified. Continuous analysis of the database with longer follow‐up may provide useful information about treatment selection and prediction of outcome such as survival.


| INTRODUC TI ON
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide; its primary risk factors include chronic infection by hepatitis B virus (HBV) or hepatitis C virus (HCV). Treatment options for HCC include resection, local ablation, hepatic arterial infusion chemotherapy (HAIC), transcatheter arterial chemoembolization (TACE), and liver transplantation. 1,2 Advances in treatment modalities and diagnosis have considerably improved the overall survival rate for HCC patients. 3,4 As the surveillance rate for HCC patients has increased in Japan, the disease stage at diagnosis has decreased, and the survival rate has concomitantly improved. 5 However, despite the developments in treatment modalities and diagnosis, the prognosis of advanced HCC patients remains unsatisfactory. Patients often experience recurrence, with limited treatment options for advanced stages of the disease.
Choice of treatment flow may differ with HCC stage. 6,7 According to the Barcelona Clinic Liver Cancer (BCLC) staging system, curative therapies such as liver transplantation, liver resection, and radiofrequency ablation (RFA) are recommended in early-stage HCC.
TACE is widely used when curative therapies cannot be performed, and it is recommended for intermediate-stage HCC and as a palliative treatment in advanced-stage HCC. 6,7 TACE can be an option in early-stage HCC for reasons such as poor residual liver function, comorbidities for surgery, and difficult RFA treatment location. 6,7 Sorafenib is recommended in advanced-stage HCC. 6 Because a large claim database analysis can reflect real-world medical circumstances, evidence has been accumulated through database research. Japan has a nation-wide health coverage system in which all citizens can receive health insurance and treatment. The national database that registers medical claims by all health care insurance has been developed and became available for research.
In a recent analysis in Japanese claims database, patients with liver disease related to HBV/HCV infection showed a higher incidence of HCC when aged ≥ 60 years. 8 In 4713 patients with liver cirrhosis or HBV/HCV infection, the HCC surveillance rate during follow-up was higher for patients with HBV/HCV infection than for those with nonviral cirrhosis. 9 In this study, the baseline characteristics and treatment flow of HCC patients were analyzed using the Japanese claims database.
The common therapies for HCC patients in early and advanced stages were identified, and the impact of tumor stage progression on the choice of treatment was examined.

| Study design and data source
This epidemiological study was conducted in accordance with the Guidelines for Good Pharmacoepidemiology Practices, 10 with particular attention to the differences in the characteristics of HCC patients and in treatment flow between early and advanced stages of the disease.
The Japanese medical claims database provided by Medical Data Vision Co., Ltd (MDV; Tokyo, Japan) was used for this study; it contains hospitalization summary, laboratory result, disease history, and medical claims data. The database source population was derived from 314 hospitals in Japan using the Diagnosis Procedure Combination system; the number of patients was approximately 20 million on March 31, 2017. 11 The database contains: an anonymized patient identifier; sex; age; medical service date; disease history; drug treatment; laboratory value standard set; and hospitalization data, comprising the outcome, cancer stage, Child-Pugh score, and other data related to patients' conditions. Age and sex distributions of HCC patients in this database are approximately similar to those in the National Database of Health Insurance Claim Information and Specified Medical Checkups, Japan. 12 In this study, the HCC patient data collected from 1 April 2008 to 31 January 2017 were analyzed.

| Disease definitions
According to the International Statistical Classification of Diseases: 10th Revision (ICD-10), HCC was identified with a definitive diagnosis of C220 meaning liver cell carcinoma. A history of ordering αfetoprotein (AFP) and desγ-carboxy prothrombin (DCP), diagnostic markers for HCC, was the second criterion for confirming HCC.

| Treatment definitions
Criteria for identifying treatment onset in the Japanese medical claims database were defined according to the treatment category codes used for treatment reimbursement in Japan. RFA was identified with codes starting with "K697," HAIC with those starting with "K611," percutaneous ethanol injection (PEI) with those starting with "J017," hepatectomy with those starting with "K695," and transcatheter arterial embolization (TAE) with those starting with "K615/ K6151/K6152/K6153." When there was a prescription history of anticancer drugs on the day of TAE, treatment was defined as TACE.
In the MDV database, the anatomical therapeutic chemical classification (ATC) code, defined by the European Pharmaceutical Market Research Association, was provided to classify the drugs.
The anticancer drugs used as chemotherapeutic agents for TACE were identified using ATC codes starting with "L01," but tablet-type drugs were excluded. Sorafenib (ATC code "L01H0") was a standard drug for HCC.

| Study design and population
The study aimed to understand the baseline characteristics of

| Analysis of patient characteristics and treatment flow
Body mass index (BMI), cancer stage, Child-Pugh score, and serum laboratory values were extracted from the data between the admission date for the initial hospitalization with definitive diagnosis and the HCC treatment initiation date. Comorbidity and the Charlson comorbidity index (CCI) were calculated from the data before the discharge date for the initial hospitalization with a definitive diagnosis. The definition of the observation period began on the earliest admission date with a definitive diagnosis of primary HCC and ended on the last prescription date.
Treatment flow for patients was visualized using a Sankey diagram. 13 The rates of initial treatments were determined from prescription orders, focusing on treatments including TACE, TAE, RFA, hepatectomy, PEI, HAIC, and sorafenib chemotherapy.
Statistical analysis was performed using R 3.4.1. Student's t test, Wilcoxon's rank-sum test for continuous variables, and Fisher's exact test for categorical variables were used to assess differences between early and advanced stages.  Serum laboratory values and Child Pugh scores were analyzed in a limited number of patients (Table 2)  Because TACE was the most common first-line treatment, chemotherapeutic agents used for first-line TACE were analyzed (Table 4).
Concomitant use of sorafenib for first TACE was reported in 3.2% of patients, and it was significantly higher in advanced stages than in early stages ( Table 4).
The second-line treatment chosen after the first TACE treatment was also analyzed (

Detailed information on the baseline characteristics of 8999
Japanese HCC patients was presented by disease stage. The results suggest that HCC is a common disease in elderly persons in Japan.
The observation period decreased with tumor stage progression, suggesting that HCC patients in advanced stages had a worse prognosis. Many patients had HCV hepatitis and concomitant hypertension, type 2 diabetes, cirrhosis, and hyperlipidemia. Interestingly, the rate of HCV hepatitis decreased in HCC patients with stage progression. In Japan, a long-term HCC surveillance program contributed to a significant increase in overall survival. 5 Therefore, HCC patients with HCV-hepatitis may have more opportunities for HCC surveillance and start treatment at earlier stages than HCC patients with HBV-hepatitis and nonviral hepatitis.
In this study, detailed information on treatment flow for the first-line and subsequent treatments for HCC patients was also presented. TACE was the most common first to fourth-line treatment

TA B L E 3 First-line treatments for HCC patients
in both early and advanced stages. The TACE treatment rationale is that the intraarterial infusion of cytotoxic agents followed by tumor-feeding blood vessel embolization induces strong cytotoxic and ischemic effects in tumors. Database analyses in other countries also reported that TACE was the most frequently selected first-line treatment. 14,15 The Sankey diagram in this study showed the complicated pattern of treatment flow for HCC patients. The ratio of treatment success, indicated by the ratio of no treatment in the later lines, was higher in early stages than advanced stages.  21 In a meta-analysis of randomized studies, time to disease progression was significantly prolonged in the TACE-sorafenib group compared with the TACE-alone group. 22 In conclusion, HCC patients' baseline characteristics and treatment flow differed between early and advanced stages. Continuous analysis of the database with longer follow-up may provide useful information about treatment selection and prediction of outcome such as survival.

CO N FLI C T O F I NTE R E S T
All authors are employees of Eisai Co., Ltd., Tokyo, Japan.

DATA AVA I L A B I L I T Y
The claims database used for this study can only be obtained by purchasing from a vendor (Medical Data Vision Co., Ltd; [URL] http:// www.mdv.co.jp/).

E TH I C S S TATEM ENT
This study analyzed anonymized medical claims data, and there was no active enrollment or active follow-up of study subjects, and no data were collected directly from individuals. Therefore, it was not necessary to receive ethics committee approval for this study.