Abstract
Background
In recent years, the emerging new drugs in the Chinese market diversified the choice of systemic treatment, especially second-line (2L), for unresectable or advanced hepatic carcinoma (HC) patients, and their inclusion into the National Reimbursement Drug List (NRDL) further changed the clinical practice. The objective of this study was to describe the 2L treatment pattern among Chinese unresectable or advanced HC patients in a real-world setting.
Methods
All adult unresectable or advanced HC patients receiving 2L treatment were retrospectively identified from Tianjin Healthcare and Medical Big Data Platform, a regional electronic health record database in Tianjin, China. Patients were observed between 2018 and 2021. A descriptive analysis was conducted for study outcomes for the overall cohort and by subgroups before and after NRDL 2020 version implementation.
Results
A total of 123 patients were eligible for study inclusion. Targeted therapy (n=93, 75.6%) was the most commonly used 2L treatment category and regorafenib monotherapy (n=71, 57.7%) was the most common treatment type. Among patients receiving regorafenib as 2L treatment, sorafenib was the most commonly used first-line treatment. The percentage of patients using 2L treatments recommended by 2020 China Society of Clinical Oncology (CSCO) guideline changed from 87.2% to 59.2% after NRDL 2020 version implementation. The average daily doses of targeted therapies were generally lower than the labeling doses, while those of immune therapies were close to labeling doses. There was a trend towards increased treatment duration and reduced direct medical cost after NRDL 2020 version implementation.
Conclusions
Targeted therapy, especially regorafenib, was the most common 2L treatment for unresectable or advanced HC in China. Future study is necessary to evaluate their effectiveness and safety as 2L treatment for unresectable or advanced HC patients in China.
Keywords: Hepatic carcinoma (HC), second-line treatment (2L treatment), treatment pattern, regional electronic health record
Highlight box.
Key findings
• Targeted therapy (n=93, 75.6%) was the most commonly used second-line (2L) treatment category and regorafenib monotherapy (n=71, 57.7%) was the most common treatment type for unresectable or advanced hepatic carcinoma (HC).
What is known and what is new?
• In recent years, the emerging new drugs in the Chinese market diversified the choice of systemic treatment, especially 2L, for unresectable or advanced HC patients, and their inclusion into the National Reimbursement Drug List (NRDL) further changed the clinical practice.
• This study firstly described the 2L treatment pattern among Chinese patients with unresectable or advanced HC in a real-world setting.
What is the implication, and what should change now?
• NRDL implementation altered the treatment pattern and direct medical cost of 2L treatment for unresectable or advanced HC in China.
Introduction
Hepatic carcinoma (HC) was the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world in 2020 (1). According to the Global Cancer Statistics 2020 report, the number of new HC cases and deaths worldwide was 905,677 and 830,180, respectively (2). In China, the incidence of HC is as high as 27.6 per 100,000 population, ranking fifth among the countries with the highest incidence of primary liver cancer (3). The 5-year relative survival rate of liver cancer patients was 14.1% [2010–2014] in China, compared with 22.0% [2015–2021] in the United States (4,5).
Treatment options for HC are stage-dependent, with systemic therapy being recommended as first-line (1L) and second-line (2L) treatment of advanced HC patients with limited benefit from regional therapy by international (6) and China clinical guidelines (7). Systemic treatment, in contrast to regional treatment, refers to any treatment that targets at the entire body and usually includes tyrosine kinase inhibitors (TKIs) and immunotherapies for HC (8). For more than a decade, sorafenib has been the only systemic drug proven to be clinically effective for treating advanced HC (9,10).
Starting from the end of 2017, the approval of various novel drugs for systemic treatment by the National Medical Products Administration (NMPA) and the further inclusion of these drugs into the National Reimbursement Drug List (NRDL) dramatically changed the treatment landscape for unresectable or advanced HC in China, especially for 2L treatment (11). Some notable examples of 2L treatment include TKIs like regorafenib (adopted for NRDL in 2018 and renewed in 2020 with price reduction) and programmed death-1 inhibitors, such as camrelizumab (adopted for NRDL in 2020). These changes greatly impact HC treatment patterns in the real world.
Previous studies have assessed the real-world treatment patterns in advanced hepatocellular carcinoma (HCC) patients in United States (12), France (13), and Canada (14). However, most real-world studies investigating HC in China were related to the effectiveness and safety of treatment strategies (15-17).
Given the recent change in the novel HC-related drugs and their inclusion into the NRDL, it is paramount to evaluate the clinical practice among Chinese unresectable or advanced HC 2L patients in the real-world setting after 2018. This study aimed to describe the 2L treatment pattern, direct medical cost, and demographic and clinical characteristics among unresectable or advanced HC patients in the real world in China. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-1015/rc).
Methods
Study design
This was a retrospective cohort study. All patients were identified from the Tianjin Healthcare and Medical Big Data Platform, a regional electronic health record (EHR) database covering about 15 million residents in Tianjin, China. Patient-level data was extracted from tertiary and secondary hospitals and linked by unique patient numbers. Thus, the patient journey within Tianjin can be better tracked and observed.
Index date was defined as the date of initiating 2L therapy. Patients who met any of the following conditions, which occurred first, were considered as the end of observation: (I) death; (II) last visit; (III) being treated against other primary cancer after HC treatment; (IV) participating in clinical trials with free sample drugs during the 2L treatment; (V) clinician-anchored disease progression during 2L treatment; and (VI) reaching 31 December 2021.
The study was approved by ethics committees of Peking University Cancer Hospital & Institute (approval No. 2022YW69) and Tianjin University (approval No. TJUE-2022-219), and individual consent for this retrospective observational study was waived. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Study population
The study population comprised adult patients who were first diagnosed with unresectable or advanced HC and started the 1L treatment between 01 January 2018 and 30 September 2021, switched to the 2L treatment between 01 January 2019 and 30 September 2021, and had at least one HC-related visit record after the initiation of 2L treatment. The HC-related terms were used as key words to identify the patients rather than HCC, since a significant number of HCC diagnoses were recorded as HC in the database, while HCC accounts for majority of the HC diagnoses. The start time point of 01 January 2019 was selected based on the inclusion of regorafenib in the NRDL as the first 2L treatment against HCC in October 2018, allowing to capture the information of patients receiving new TKI agents from the beginning of 2019. To avoid selection bias, all patients in the database that met the eligibility criteria were included in the study.
Patients were considered having unresectable or advanced HC if they met any of the following criteria: (I) documented unresectable or advanced HC; (II) having a Barcelona Clinic Liver Cancer staging of advanced (C) or terminal (D); or China Liver Cancer staging of IIb, IIIa, IIIb, or IV, or any condition that met the above staging criteria; and (III) having any documented use of anticancer targeted or immune therapy in the database between 01 January 2018 and 30 September 2021.
Study measures
Study measures included demographic (i.e., age, sex, and medical insurance status) and clinical characteristics (i.e., etiology, site of extrahepatic metastasis), 1L and 2L treatment by category and type, the consistency of 2L treatment with the recommendation by 2020 China Society of Clinical Oncology (CSCO) HC guideline, ratio of average daily dose over labelling dose of each 2L treatment agent, duration of treatment (DoT), treatment flow between 1L and 2L treatment, and direct medical cost. We also presented some measures before and after 01 March 2021, which was the implementation date of the NRDL 2020 version.
Data collection and curation
The Tianjin Healthcare and Medical Big Data Platform is a province-level database covering electronic medical records from 43 tertiary and 39 secondary hospitals in Tianjin City, a municipality in North China. Patient-level data was automatically transmitted from hospitals and public health facilities of Tianjin on a regular basis and underwent routine data curation process, e.g., patient linkage by unique patient numbers, data de-identification, by the Tianjin Healthcare and Medical Big Data Platform. A significant manual effort was further invested in the data curation process for this study. To compile a comprehensive list of anticancer drugs, the drug records of patients potentially diagnosed with HC between 01 January 2018 and 30 September 2021 were meticulously reviewed. Given that a single drug may have numerous names in real-world data, a codebook was developed to map these names, resulting in a unified drug name for every single anticancer drug in the Core Drug List (Table S1). In addition, unstructured physician notes of all included patients were manually reviewed to identify 1L and 2L treatment and other key study variables.
Determination of line of therapy (LoT)
The patients’ LoT information was identified from prescription records of systemic drugs from the Core Drug List (Table S1) in the database. When the start dates of two drugs were within 21 days, these drugs might represent a LoT unless opposed by physician notes; otherwise, the second drug might represent a new LoT following the rules shown in Figure 1.
Figure 1.
Definition of line of therapy change. Same class of drugs are defined as follows: Class 1: cisplatin, carboplatin; Class 2: fluorouracil, capecitabine; Class 3: camrelizumab, tislelizumab, toripalimab, sintilimab, pembrolizumab; Class 4: atezolizumab, durvalumab. For platinum and fluorouracil, if the administration route cannot be confirmed as systemic administration, it will be considered locoregional administration and will not be included in any LoT. All LoT and LoT changes were verified by physician’s note if available. cPD, clinical progression of disease; LoT, line of therapy.
Statistical analyses
Descriptive summary was provided for all continuous and categorical variables. The flow between 1L and 2L treatment was summarized by Sankey diagrams. Continuous variables were summarized as mean, standard deviation (SD), median, interquartile range (IQR), minimum and maximum. Categorical variables were summarized as frequency and percentage. Subgroup analysis was performed based on the timing of certain study variables before and after 01 March 2021, which was the implementation date of the NRDL 2020 version. Missing data was not imputed.
Data analysis was conducted onsite at the Tianjin Healthcare Big Data Center using de-identified patient-level data. All data were analyzed with the SAS software 9.4 (SAS Inc., Cary, NC, USA) and the Sankey diagram was drawn using the R version 3.6.1.
Results
Patient characteristics
A total of 123 patients were eligible for study inclusion. The selection of patients followed the process outlined in Figure 2. The patient characteristics, etiology, and extrahepatic metastasis of these patients are shown in Table 1. Among 123 patients, 102 patients (82.9%) were male and the age at 2L treatment initiation ranged from 37.0 to 84.0 years (median age 62.0). Most patients (n=99, 81.1%) had basic medical insurance. Among 101 patients with available etiology data, 80 (79.2%) had hepatitis B. Among 37 patients with extrahepatic metastasis records, 17 (45.9%) had lung metastasis. The median duration of observation time was 3.8 months, ranging from 0.1 to 26.2 months.
Figure 2.
Patient flow chart. †, 21-day was used as the cutoff length of time to empirically identify patients with 2L treatment when at least two types of anticancer drugs were initiated. HC, hepatic carcinoma; 2L, second-line; NRDL, National Reimbursement Drug List.
Table 1. Characteristics, etiology and extrahepatic metastasis of Chinese unresectable or advanced hepatic carcinoma patients receiving second-line treatment.
| Variable | Overall (N=123) |
|---|---|
| Age (years) | |
| Mean (SD) | 61.5 (8.9) |
| Median (IQR) | 62.0 (11.0) |
| <65, n (%) | 78 (63.4) |
| ≥65, n (%) | 45 (36.6) |
| Sex, n (%) | |
| Female | 21 (17.1) |
| Male | 102 (82.9) |
| Medical insurance type (n=122), n (%) | |
| UEBMI | 54 (44.3) |
| URBMI | 10 (8.2) |
| Unspecified basic medical insurance | 30 (24.6) |
| Self-paid | 23 (18.9) |
| Off-site basic medical insurance | 5 (4.1) |
| Hepatic carcinoma etiology† (n=101), n (%) | |
| Hepatitis B | 80 (79.2) |
| Hepatitis C | 7 (6.9) |
| Non-alcoholic fatty liver disease | 2 (2.0) |
| Others | 12 (11.9) |
| Extrahepatic metastasis site‡ (n=37), n (%) | |
| Lung | 17 (45.9) |
| Regional lymph nodes | 13 (35.1) |
| Bone | 12 (32.4) |
| Adrenal glands | 1 (2.7) |
| Other or unspecific sites | 5 (13.5) |
| 1L treatment patterns, n (%) | |
| Chemotherapy alone | 6 (4.9) |
| Targeted therapy alone | 115 (93.5) |
| Sorafenib | 91 (74.0) |
| Others | 24 (19.5) |
| Targeted therapy plus immune therapy | 2 (1.6) |
†, of the 123 included patients, a total of 101 patients reported their etiology. The “Others” category includes those with more than one etiology. ‡, of the 123 included patients, a total of 37 patients had extrahepatic metastasis. A patient may have more than one extrahepatic metastasis site. IQR, interquartile range; 1L, first-line; SD, standard deviation; UEBMI, Urban Employee Basic Medical Insurance; URBMI, Urban Residents Basic Medical Insurance.
HC 2L treatment patterns by category and type
Among the 2L treatment categories, targeted therapy was the most commonly used category, accounting for 75.6% (n=93) of patients, followed by targeted plus immune therapy (15.4%, n=19), immune therapy (7.3%, n=9), and chemotherapy plus targeted or immune therapy (1.6%, n=2). Regorafenib monotherapy (n=71, 57.7%) was the most commonly used 2L treatment type. Before the implementation of the NRDL 2020 version, 85.1% (40/47) used targeted therapy as 2L treatment, which decreased to 69.7% (53/76) after the implementation of the NRDL 2020 version. Regorafenib remained the most commonly used 2L treatment before and after the implementation of the NRDL 2020 version, although the percentage reduced from 78.7% (37/47) to 44.7% (34/76). Table 2 presents the frequency and percentage of 2L treatment by category and type, both overall and before and after the implementation of the NRDL 2020 version.
Table 2. Second-line treatment patterns for Chinese unresectable or advanced hepatic carcinoma patients.
| Variable | Overall (N=123) | Before 01 March 2021† (N=47) | After 01 March 2021† (N=76) |
|---|---|---|---|
| Category of 2L treatment, n (%) | |||
| Targeted therapy alone | 93 (75.6) | 40 (85.1) | 53 (69.7) |
| Targeted therapy plus immune therapy | 19 (15.4) | 5 (10.6) | 14 (18.4) |
| Immune therapy alone | 9 (7.3) | 2 (4.3) | 7 (9.2) |
| Chemotherapy plus immune or targeted therapy | 2 (1.6) | – | 2 (2.6) |
| Type of 2L treatment, n (%) | |||
| Regorafenib | 71 (57.7) | 37 (78.7) | 34 (44.7) |
| Lenvatinib | 15 (12.2) | 1 (2.1) | 14 (18.4) |
| Camrelizumab | 7 (5.7) | – | 7 (9.2) |
| Camrelizumab + lenvatinib | 7 (5.7) | 1 (2.1) | 6 (7.9) |
| Camrelizumab + regorafenib | 4 (3.3) | – | 4 (5.3) |
| Sorafenib | 3 (2.4) | – | 3 (3.9) |
| Apatinib + camrelizumab | 2 (1.6) | 2 (4.3) | – |
| Camrelizumab + sorafenib | 2 (1.6) | – | 2 (2.6) |
| Sintilimab | 2 (1.6) | 2 (4.3) | – |
| Atezolizumab + bevacizumab + sorafenib | 1 (0.8) | – | 1 (1.3) |
| Bevacizumab | 1 (0.8) | 1 (2.1) | – |
| Camrelizumab + fluorouracil + oxaliplatin | 1 (0.8) | – | 1 (1.3) |
| Lenvatinib + regorafenib | 1 (0.8) | – | 1 (1.3) |
| Lenvatinib + tislelizumab | 1 (0.8) | – | 1 (1.3) |
| Lenvatinib + toripalimab | 1 (0.8) | 1 (2.1) | – |
| Lobaplatin + sorafenib | 1 (0.8) | – | 1 (1.3) |
| Regorafenib + sintilimab | 1 (0.8) | 1 (2.1) | – |
| Regorafenib + sorafenib | 1 (0.8) | – | 1 (1.3) |
| Regorafenib + thalidomide | 1 (0.8) | 1 (2.1) | – |
†, 01 March 2021 is the start date of the implementation of NRDL 2020 version. HC, hepatic carcinoma; 2L, second-line.
Regarding the consistency with the 2020 CSCO guideline, 87.2% (41/47) of patients used 2L treatments recommended by the 2020 CSCO guideline before the implementation of the NRDL 2020 version, which changed to 59.2% (45/76) after the implementation of the NRDL 2020 version.
Dose of each 2L drug
Table 3 presents the dose of each 2L drug. In general, the median average daily doses of targeted therapies were lower than labeling doses (with the ratio between 33.3% and 75.0%), while those of immune therapies were close to the labeling doses (with the ratio between 100.0% and 133.3%).
Table 3. Dose of each second-line drug for Chinese unresectable or advanced hepatic carcinoma patients.
| Drug name | N | Label recommended dose† (mg/day) | Median dose (mg/day) | Ratio to label recommendation |
|---|---|---|---|---|
| Regorafenib | 77 | 160 | 120.0 | 75.0% |
| Lenvatinib | 25 | 12 | 8.0 | 66.7% |
| Camrelizumab | 21 | 180 | 200.0 | 111.1% |
| Sorafenib | 8 | 800 | 400.0 | 50.0% |
| Sintilimab | 3 | 200 | 200.0 | 100.0% |
| Bevacizumab | 2 | 900 | 400.0 | 44.4% |
| Apatinib | 1 | 750 | 250.0 | 33.3% |
| Atezolizumab | 1 | 1,200 | 1,200.0 | 100.0% |
| Fluorouracil | 1 | 1,700 | 1,750.0 | 102.9% |
| Lobaplatin | 1 | 85 | 30.0 | 35.3% |
| Oxaliplatin | 1 | 144.5 | 100.0 | 69.2% |
| Tislelizumab | 1 | 200 | 200.0 | 100.0% |
| Toripalimab | 1 | 180 | 240.0 | 133.3% |
†, for all label recommended dose calculated by weight and body surface area, assume weight as 60 kg and body surface area as 1.7 m2.
Duration of treatment by 2L treatment category and type
Table 4 presents the DoT by 2L treatment category and type. The mean (SD) DoT of 2L treatment increased from 2.0 (1.8) to 2.9 (2.3) months after NRDL 2020 version implementation. By treatment category, the mean (SD) DoT was 3.3 (3.6) months for targeted therapy, 2.0 (1.8) months for targeted plus immune therapy, 4.2 (3.3) months for immune therapy, and 1.5 (1.4) months for chemotherapy plus targeted or immune therapy.
Table 4. Duration of treatment (month) by different second-line treatments for Chinese unresectable or advanced hepatic carcinoma patients.
| Variable | Overall | Before 01 March 2021† | After 01 March 2021† | |||||
|---|---|---|---|---|---|---|---|---|
| N | Mean (SD) | N | Mean (SD) | N | Mean (SD) | |||
| Overall | 123 | 3.1 (3.3) | 33 | 2.0 (1.8) | 76 | 2.9 (2.3) | ||
| Category of 2L treatment | ||||||||
| Targeted therapy alone | 93 | 3.3 (3.6) | 28 | 1.9 (1.9) | 53 | 3.1 (2.5) | ||
| Targeted therapy plus immune therapy | 19 | 2.0 (1.8) | 4 | 2.3 (1.8) | 14 | 1.9 (1.9) | ||
| Immune therapy alone | 9 | 4.2 (3.3) | 1 | 2.2 (0.0) | 7 | 3.4 (1.5) | ||
| Chemotherapy plus immune or targeted therapy | 2 | 1.5 (1.4) | 0 | – | 2 | 1.5 (1.4) | ||
| Type of 2L treatment | ||||||||
| Regorafenib | 71 | 3.7 (3.9) | 25 | 2.0 (1.9) | 34 | 3.5 (2.7) | ||
| Lenvatinib | 15 | 2.5 (1.9) | 1 | 1.2 (0.0) | 14 | 2.6 (2.0) | ||
| Camrelizumab | 7 | 3.4 (1.5) | 0 | – | 7 | 3.4 (1.5) | ||
| Camrelizumab + lenvatinib | 7 | 2.9 (2.4) | 0 | – | 6 | 2.8 (2.6) | ||
| Camrelizumab + regorafenib | 4 | 1.3 (0.4) | 0 | – | 4 | 1.3 (0.4) | ||
| Sorafenib | 3 | 1.0 (0.1) | 0 | – | 3 | 1.0 (0.1) | ||
| Apatinib + camrelizumab | 2 | 1.1 (1.4) | 2 | 1.1 (1.4) | 0 | – | ||
| Camrelizumab + sorafenib | 2 | 1.4 (1.6) | 0 | – | 2 | 1.4 (1.6) | ||
| Sintilimab | 2 | 7.2 (7.1) | 1 | 2.2 (0.0) | 0 | – | ||
| Atezolizumab + bevacizumab + sorafenib | 1 | 1.0 (0.0) | 0 | – | 1 | 1.0 (0.0) | ||
| Bevacizumab | 1 | 0.1 (0.0) | 1 | 0.1 (0.0) | 0 | – | ||
| Camrelizumab + fluorouracil + oxaliplatin | 1 | 2.5 (0.0) | 0 | – | 1 | 2.5 (0.0) | ||
| Lenvatinib + regorafenib | 1 | 4.2 (0.0) | 0 | – | 1 | 4.2 (0.0) | ||
| Lenvatinib + tislelizumab | 1 | 0.3 (0.0) | 0 | – | 1 | 0.3 (0.0) | ||
| Lenvatinib + toripalimab | 1 | 2.4 (0.0) | 1 | 2.4 (0.0) | 0 | – | ||
| Lobaplatin + sorafenib | 1 | 0.5 (0.0) | 0 | – | 1 | 0.5 (0.0) | ||
| Regorafenib + sintilimab | 1 | 4.5 (0.0) | 1 | 4.5 (0.0) | 0 | – | ||
| Regorafenib + sorafenib | 1 | 0.3 (0.0) | 0 | – | 1 | 0.3 (0.0) | ||
| Regorafenib + thalidomide | 1 | 1.8 (0.0) | 1 | 1.8 (0.0) | 0 | – | ||
†, 01 March 2021 is the start date of the implementation of NRDL 2020 version. The 2L treatment periods of 14 patients spanned over 01 March 2021, thus these patients were not included in either before or after 01 March 2021 subgroup. DoT, duration of treatment; 2L, second-line; NRDL, National Reimbursement Drug List; SD, standard deviation.
Treatment flow between 1L and 2L treatment
Figure 3 presents the treatment flow between 1L and 2L treatment by treatment type. Before receiving 2L treatment, most patients (n=91, 74%) used sorafenib as 1L treatment. Among patients using regorafenib as 2L treatment (n=71), the type of 1L treatment included sorafenib (n=65, 91.5%), lenvatinib (n=2, 2.8%), apatinib (n=2, 2.8%) and lobaplatin (n=2, 2.8%). Of the 91 patients using sorafenib as 1L treatment, 65 (71.4%) patients used regorafenib as 2L treatment, followed by lenvatinib (n=10, 11.0%), camrelizumab (n=6, 6.6%), and others (n=10, 11.0%).
Figure 3.
Sankey diagram of treatment flow for Chinese unresectable or advanced hepatic carcinoma patients by treatment type.
Direct medical cost of HC patients receiving 2L treatment
The mean total cost related to 2L treatment was 18,954 Chinese Yuan (CNY) per month and 72,088 CNY per year, constituted by drug cost (11,876 CNY per month and 42,176 CNY per year), testing cost (2,855 CNY per month and 10,362 CNY per year), other hospitalization cost (4,155 CNY per month and 19,257 CNY per year) and other outpatient cost (68 CNY per month and 294 CNY per year). After the implementation of the NRDL 2020 version, the mean total cost per month reduced from 26,942 to 16,804 CNY, primarily driven by reduced drug cost (18,869 vs. 10,072 CNY) and testing cost (4,051 vs. 2,547 CNY). The mean total cost per year reduced from 65,687 to 57,551 CNY, primarily driven by reduced drug cost (44,446 vs. 34,319 CNY). Assuming 60% of the drug cost could be reimbursed and 100% non-drug cost could be reimbursed, the estimated mean out-of-pocket cost per month was 14,948 and 6,847 CNY before and after NRDL 2020 version implementation, and the estimated mean out-of-pocket cost per year was 35,343 and 23,343 CNY before and after NRDL 2020 version implementation. Figure 4 shows the direct medical cost for HC patients receiving 2L treatments.
Figure 4.
Hepatic carcinoma-related average direct medical cost for eligible patients by different cost categories. The observation periods of 20 patients spanned over 01 March 2021, thus these patients were not included in either before or after 01 March 2021 subgroup. The costs within each bar may not sum up to the total cost of each bar in red due to rounding issue. CNY, Chinese Yuan.
Discussion
To our best knowledge, this is the first cohort study in China specifically focusing on real-world treatment patterns among unresectable or advanced HC patients receiving 2L treatment based on a regional EHR database. This study fills the knowledge gap of the various 2L treatments that Chinese unresectable or advanced HC patients received and sheds light on future unresectable or advanced HC treatment guidance in China. While the study primarily focused on the Chinese market, the insights gained can be extrapolated to understand broader trends and inform clinical practices worldwide.
Overall, the notable variety of different 2L treatment types (a total of 19 treatment types from 5 treatment categories) reflects the heterogeneity and complexity of the HC 2L treatment in real-world clinical practice. Among these different treatment categories, targeted therapy was most commonly used. Targeted therapy exhibits unique advantages in terms of better tolerability due to a narrower but more precise drug target (vs. chemotherapy) (18,19) and oral administration route (vs. chemotherapy and immune therapy). Specifically, the study observed that a notable proportion of patients used 2L treatment traditionally recommended as 1L treatment, e.g., 15 (12.2%) patients using lenvatinib as 2L treatment. In general, 1L treatments are usually the treatments with optimal efficacy, safety, and economic profile. Thus, it may still be preferred by clinicians and patients even if patients already fail another 1L treatment.
Regorafenib, an oral TKI approved for patients with unresectable HCC following sorafenib, was the most commonly used 2L treatment drug in our study. It was the first drug exhibiting survival benefits over placebo in HCC 2L patients (20,21). The apparent survival benefits of HCC patients from regorafenib treatment are shown by RESORCE, a Phase 3 trial, and REFINE, a real-world study (22,23). Based on our results, 91% of patients used sorafenib as 1L treatment among those who used regorafenib as 2L treatment, adding evidence that regorafenib is an important option for treating HCC patients who have progressed on sorafenib therapy (24). However, it was observed that in real-world clinical settings, approximately 10% of patients used regorafenib as 2L treatment following other 1L treatments, including apatinib, lenvatinib, and lobaplatin. Similar use of regorafenib was also observed in the REFINE study (23). Future study is needed to evaluate the effectiveness and safety of regorafenib in various settings.
Our study showed a decrease in the percentage of patients using 2L treatments recommended by the 2020 CSCO guideline after the implementation of the NRDL 2020 version. This reduction can be attributed primarily to the fact that lenvatinib was not recommended as 2L treatment in the 2020 CSCO guideline. In addition, multiple systemic treatments were approved by NMPA in 2020 and 2021. The increased innovative choices of HC treatment diversified the HC 2L treatment, resulting in the decreased percentage of using 2L treatments recommended by 2020 CSCO guideline.
In our study, the median average daily doses of targeted therapies were generally lower than labeling doses, while those of immune therapies were typically close to labeling doses. For instance, the median average daily dose of regorafenib (120 mg) in the study was lower than that of the labeling dose (160 mg). Likewise, 30% of HCC patients started regorafenib on 120 or 80 mg in a multicenter retrospective study in Korean (25), and a retrospective chart review in Kuwait found that only 20.9% reached the recommended 160 mg dose (26). Most clinical trials primarily involve non-Asian patients, who differ notably from Asian patients in efficacy and tolerability. Understanding these dosing patterns of targeted therapies can help clinicians in China and other countries to optimize treatment regimens for Asian patients for better outcomes. Additionally, patients in these trials tend to be healthier than real-world patients, resulting in reduced real-world dosing due to poorer tolerability, especially for TKI. Unlike targeted therapy, the immune therapy dose studied by clinical trials is usually the effective dose, and a higher dose does not bring additional risk (27,28).
The DoTs reported in our study are similar with those reported in other countries. For instance, the mean DoT of regorafenib was 3.7 months in our study, which is close to the 3.6 months in the RESORCE trial (22) and a systematic review of 809 intermediate or advanced HCC patients (29). Importantly, a longer mean DoT was observed in patients treated after the implementation of the NRDL 2020 version compared with those treated before, especially for the targeted therapy. Since unresectable or advanced HC is an incurable disease, patients generally continue treatment as long as it is tolerable and affordable, and their response to treatment is at least stable. Thus, a longer DoT might indicate superior effectiveness, safety, and economic profile of the treatment, which might suggest the implementation of NRDL 2020 version improved these aspects to some extent. The observed trend towards increased DoT after the implementation of the NRDL 2020 version suggests that similar reimbursement policies could be beneficial in other countries, potentially improving patient outcomes. To be noted, since patients whose DoT crossed the implementation time of the NRDL 2020 version were not counted in either subgroup of before or after NRDL 2020 version implementation, the DoTs among both subgroups were underestimated, thus were not directly comparable with those reported by other literatures.
There was a trend towards reduced direct medical cost and estimated out-of-pocket cost after NRDL 2020 version implementation. The trend reflected that the NRDL played an important role in reducing the disease burden from both payer and patient perspectives. Globally, the economic burden of HC is also significant, and strategies to reduce costs while maintaining effective treatment are crucial. The findings from China provide valuable insights into how reimbursement policies can alleviate financial strain on patients and healthcare systems. With consideration of disease burden relative to economic level, the direct medical cost per year accounted for 68.4% and 50.6% of Tianjin gross domestic product (GDP) per capita (30), and the average out-of-pocket cost per year accounted for 81.9% and 49.2% of Tianjin disposable income per capita before and after the NRDL 2020 version implementation (31). Although the trend of decreased economic disease burden was observed after the NRDL 2020 version implementation, the economic disease burden was still significant for HC patients relative to the economic level.
Our study has several limitations. First, the database did not include patients treated outside Tianjin, which undermines the generalizability of the treatment patterns to broader population in China. Second, due to the nature of regional EHR, certain data points exerted a relatively high missing rate, e.g., HC etiology, direct medical cost. For treatment-related records, however, the data completeness is adequate to answer the treatment patterns, average daily dose and DoT.
Conclusions
The study results show that targeted therapy, especially regorafenib, was the most common 2L treatment against HC in China. Among patients receiving regorafenib as 2L treatment, sorafenib was the most commonly used 1L treatment, while nearly 10% were treated by other drugs. In real-world practice, the doses of targeted therapies were generally lower than label recommendations. There was a trend toward longer DoT and lower direct medical cost after the implementation of the NRDL 2020 version. Due to increased innovative choices for HC treatment since NRDL 2020 version implementation, the percentage of patients using 2L treatment recommended by 2020 CSCO guideline changed. The integration of novel therapies, dose adjustments, and economic considerations are reflective of broader global practices. By understanding and applying these insights, clinicians worldwide can enhance treatment strategies, improve patient outcomes, and reduce the economic burden of HC. Future studies are necessary to evaluate the effectiveness and safety of different 2L treatments for unresectable or advanced HC patients in China and other countries, as continuous evaluation and adaptation of treatment protocols are necessary to address the evolving landscape of HC therapy.
Supplementary
The article’s supplementary files as
Acknowledgments
An abstract and poster relevant to this study have been previously published in the ISPOR 2024 conference (https://www.valueinhealthjournal.com/article/S1098-3015(24)01014-3/abstract?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1098301524010143%3Fshowall%3Dtrue).
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by ethics committees of Peking University Cancer Hospital & Institute (approval No. 2022YW69) and Tianjin University (approval No. TJUE-2022-219) and individual consent for this retrospective observational study was waived.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-1015/rc
Funding: This work was supported by Bayer Healthcare Company Ltd.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-1015/coif). All authors report that this study was supported by Bayer Healthcare Company Ltd. R.H. is a current employee of Bayer Healthcare Company Ltd. H.W. and K.C. are current employees of IQVIA Ltd. The authors have no other conflicts of interest to declare.
Data Sharing Statement
Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-1015/dss
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