Abstract
Sorafenib and lenvatinib, as molecular‐targeted agents, constitute effective primary treatment options for advanced hepatocellular carcinoma (HCC). However, the choice of optimal primary treatment agent remains controversial. Here, we aimed to assess the respective outcomes between these agents as primary treatment in patients with advanced HCC through use of propensity score–matching analysis (PSMA). We enrolled 670 consecutive patients who were diagnosed with advanced HCC and received sorafenib (n = 524) or lenvatinib (n = 146) as the primary treatment among 18 participating institutions between May 2009 and October 2019. To reduce confounding, we used PSMA regarding seven variables related to advanced HCC prognosis, resulting in the selection of 292 patients (n = 146 for each agent). Following PSMA, no significant difference was observed in the outcome of overall survival time between patients treated with sorafenib or lenvatinib (median survival time 15.3 or 14.9 months, respectively; P = 0.2358). Patients treated with lenvatinib exhibited significantly greater therapeutic effects (response rate: 5% and 31%; disease control rate: 46% and 69% for sorafenib and lenvatinib, respectively; P < 0.0001), but showed significantly lower probability of transition to secondary treatment (sorafenib, 60%; lenvatinib, 45%; P < 0.0269) and higher any adverse events rate (sorafenib, 86%; lenvatinib, 95%; P = 0.0207). Conclusion: As a primary molecular‐targeted agent–based treatment for advanced HCC, our findings suggested that sorafenib is generally appropriate as it offers significantly lower frequency of adverse events and higher probability of transition to secondary treatment, in consideration of the enhanced postprogression survival mediated by sequential treatment. Alternatively, lenvatinib affords a significantly higher therapeutic effect and should be used when immediate tumor reduction is required.
Abbreviations
- AFP
alpha‐fetoprotein
- ALBI
albumin‐bilirubin
- BCLC
Barcelona Clinic Liver Cancer
- CI
confidence interval
- CR
complete response
- DCP
des‐gamma‐carboxy prothrombin
- HAIC
hepatic arterial infusion chemotherapy
- HBV
hepatitis B virus
- HCC
hepatocellular carcinoma
- HCV
hepatitis C virus
- HFSR
hand‐foot skin reaction
- HR
hazard ratio
- MST
median survival time
- MTA
molecular‐targeted agent
- OS
overall survival
- PD
progressive disease
- PFS
progression‐free survival
- PR
partial response
- PSMA
propensity score–matching analysis
- REFLECT
randomized, open‐label, phase 3 trial to compare the efficacy and safety of lenvatinib (e7080) versus sorafenib in first‐line treatment of subjects with unresectable hepatocellular carcinoma
- SD
stable disease
- SHARP
sorafenib hepatocellular carcinoma assessment randomized protocol
- TACE
transcatheter arterial chemoembolization
Significant progress has been made regarding treatments for hepatocellular carcinoma (HCC), particularly in hepatic resection, percutaneous radiofrequency ablation, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, radiation therapy, and liver transplantation.( 1 , 2 ) In addition, the treatment landscape for advanced HCC has also changed dramatically with the approval of molecular‐targeted agents (MTAs) such as sorafenib and lenvatinib.( 3 , 4 , 5 )
Sorafenib has been demonstrated to induce tumor cell apoptosis and targets multiple kinases, such as vascular endothelial growth factor (VEGF) receptors, platelet‐derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptors, BRAF, KIT, and other molecules.( 6 , 7 ) As an MTA‐based primary treatment for advanced HCC, sorafenib has been shown to provide survival benefit in patients with advanced HCC in the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP)( 3 ) and Asia‐Pacific studies,( 4 ) being subsequently approved to treat patients with advanced HCC in Japan in May 2009. Despite multiple clinical trials conducted to evaluate other MTAs, no drugs have been found to exhibit an efficacy superior to that of sorafenib against advanced HCC in primary treatment.( 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 )
Lenvatinib is an oral inhibitor of VEGF receptors, PDGF receptors, FGF receptors, c‐Raf, RET, KIT, and other molecules.( 16 , 17 ) In the REFLECT study (a multicenter randomized, open‐label, phase 3 trial to compare the efficacy and safety of lenvatinib [E7080] versus sorafenib in first‐line treatment of subjects with unresectable hepatocellular carcinoma) study, lenvatinib has been shown to be noninferior to sorafenib in terms of overall survival time in patients with advanced HCC as primary treatment.( 5 ) Administration of lenvatinib to patients with advanced HCC demonstrated antitumor activity and a tolerable safety profile in phase 2 and 3 studies,( 5 , 18 ) and was subsequently approved to treat patients with advanced HCC in Japan in March 2018.
As a result, the optimal choice of MTAs as primary treatment for advanced HCC remains controversial. Therefore, in this study we aimed to assess the real‐world treatment outcomes between sorafenib and lenvatinib in patients with advanced HCC. In addition, to reduce confounding, we applied propensity score–matching analysis (PSMA).
Experimental Procedures
Patients
Eligibility criteria for this study were similar to those of the SHARP( 3 ) and REFLECT studies.( 5 ) Since sorafenib’s approval in Japan, we have treated 784 patients with advanced HCC using MTAs (sorafenib, n = 550; regorafenib, n = 34; lenvatinib, n = 191; ramucirumab, n = 9) among 18 participating institutions of the Kurume Liver Cancer Study Group of Japan between May 2009 and October 2019. Until lenvatinib’s approval in Japan, 490 patients with advanced HCC were treated with sorafenib as the primary treatment option between May 2009 and February 2018. Following lenvatinib’s approval in Japan, 180 patients with advanced HCC were treated with MTAs (sorafenib, n = 34; lenvatinib, n = 146) as the primary treatment option between March 2018 and October 2019. Specifically, we prospectively enrolled 670 consecutive patients who were diagnosed with advanced HCC and received sorafenib (n = 524) or lenvatinib (n = 146) as the primary treatment option. HCC was either confirmed histologically or diagnosed using noninvasive criteria according to the European Association for the Study of Liver.( 19 ) The primary outcome of this study was overall survival time, which was defined as the time from initiation of sorafenib or lenvatinib treatment to the date of death or the patient’s last follow‐up. The study protocol was approved by the Ethics Committee of Kurume University (No. 10009, 18146) and the University Hospital Medical Information Network Center (No. UMIN000007427), and conformed to the guidelines of the 1975 Declaration of Helsinki. Patients were given comprehensive information regarding the details of the clinical study, and each provided written informed consent before participation.
Diagnosis
Intrahepatic lesions and vascular invasion were diagnosed using a combination of contrast‐enhanced computed tomography, magnetic resonance imaging, ultrasonography, and digital subtraction angiography. Additionally, alpha‐fetoprotein (AFP) and des‐gamma‐carboxy prothrombin (DCP) serum levels were measured up to 1 month before treatment. Intra‐abdominal metastases were detected through abdominal computed tomography, magnetic resonance imaging, and ultrasonography, which were performed to evaluate intrahepatic lesions. Pulmonary lesions were detected on chest radiography or computed tomography, which was routinely performed up to 1 month before treatment. Additional examinations, such as bone scintigraphy and brain computed tomography or magnetic resonance imaging, were indicated when symptoms attributable to extrahepatic metastasis appeared. These examinations were also conducted when AFP or DCP levels were elevated in a manner that could not be explained by the status of the intrahepatic lesions.( 19 ) Hepatic reserves were evaluated using both Child‐Pugh class (score) and albumin‐bilirubin (ALBI) grade.( 20 ) Tumor stage was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging classification.( 21 , 22 )
Treatment With MTAs
Performance status was used to determine the initial MTA dose, at the discretion of the chief physician. Discontinuation and dose reduction was allowed based on tolerance. Adverse events of MTAs were documented according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.( 23 , 24 , 25 ) Treatments were discontinued following development of adverse events of CTCAE grade 3 or above.
Assessment of Tumor Response
Imaging studies were performed 1 month following the initiation of MTA and every 4‐6 weeks thereafter to assess tumor response. The assessment was conducted according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST).( 26 ) Patients who died before their first radiographic assessment were classified as having progressive disease (PD). The time to radiologic progression was defined as the time from MTA initiation to disease progression. Data from patients who died without tumor progression were censored.
PSMA
To reduce confounding, we used PSMA to match patients treated with sorafenib (n = 524) to those treated with lenvatinib (n = 146).( 27 , 28 ) The following seven variables related to the prognosis of advanced HCC were taken into account at the start of follow‐up: age, sex, etiology, Child‐Pugh class, BCLC stage, AFP level, and DCP level. The propensity score of the patients treated with sorafenib and lenvatinib was 0.2100 ± 0.0996 and 0.2707 ± 0.1005, respectively (mean ± SD). We used these propensity scores to conduct one‐to‐one nearest‐neighbor matching within a caliper of 0.20, as this percentage of the SD of the logit of the propensity score has been shown to be generally suitable as a caliper of PSMA in previous studies.( 29 ) PSMA resulted in the selection of 292 patients (sorafenib, n = 146; lenvatinib, n = 146). Following PSMA, the propensity score of the patients treated with sorafenib and lenvatinib was 0.2704 ± 0.1004 and 0.2707 ± 0.1005, respectively (mean ± SD).
Statistical Analysis
Baseline patient characteristics were analyzed using descriptive statistical methods, whereas age, intrahepatic tumor size, AFP, and DCP were calculated using the Student t test, and sex, etiology, Child‐Pugh class, Child‐Pugh score, ALBI grade, BCLC stage, macrovascular invasion, extrahepatic metastasis, and intrahepatic tumor number were calculated using the chi‐square test. Survival curves were calculated using Kaplan‐Meier analysis with log‐rank test. A P value of less than 0.05 was considered statistically significant. JMP software (SAS Institute, Inc., Cary, NC) version 14 was used for all analyses.
Results
Patient Characteristics of Sorafenib and Lenvatinib Cohorts
Table 1 lists the characteristics of the 670 enrolled patients with advanced HCC receiving MTAs (sorafenib, n = 524; lenvatinib, n = 146). The median duration of the follow‐up period was 10.5 and 7.3 months, respectively. Age (P = 0.0391) was higher in the lenvatinib cohort, whereas Child‐Pugh class (P = 0.0021), score (P = 0.0402), and BCLC stage (P < 0.0001) were worse in the sorafenib cohort. Larger numbers of patients exhibited macrovascular invasion (P = 0.0065) and extrahepatic metastasis (P = 0.0001) in the sorafenib cohort. Sex, etiology, ALBI grade, intrahepatic tumor size and number, and AFP and DCP levels were equivalent between the sorafenib and lenvatinib cohorts.
Table 1.
Patient Characteristics of Sorafenib and Lenvatinib Cohorts
| Variable | Sorafenib (n = 524) | Lenvatinib (n = 146) | P Value |
|---|---|---|---|
| Age (years) | 70.9 ± 9.4 | 72.8 ± 9.6 | 0.0391 |
| 71.9 (33.4‐94.3) | 73.9 (44.7‐89.8) | ||
| Sex (male/female) | 414 (79%)/110 (21%) | 125 (86%)/21 (14%) | 0.0750 |
| Etiology (HBV/HCV/HBV + HCV/Both negative) | 94 (18%)/300 (57%)/5 (1%)/125 (24%) | 25 (17%)/77 (53%)/2 (1%)/42 (29%) | 0.6258 |
| Child‐Pugh class (A/B) | 415 (79%)/109 (21%) | 134 (92%)/12 (8%) | 0.0021 |
| Child‐Pugh score (5/6/7/8/9) | 256 (49%)/159 (30%)/72 (14%)/30 (6%)/7 (1%) | 81 (56%)/53 (36%)/6 (4%)/5 (3%)/1 (1%) | 0.0402 |
| ALBI grade (1/2/3) | 140 (27%)/368 (70%)/16 (3%) | 44 (30%)/98 (67%)/4 (3%) | 0.7070 |
| BCLC stage (B/C) | 169 (32%)/355 (68%) | 79 (54%)/67 (46%) | < 0.0001 |
| Macrovascular invasion (Yes/No) | 131 (25%)/393 (75%) | 21 (14%)/125 (86%) | 0.0065 |
| Extrahepatic metastasis (Yes/No) | 294 (56%)/230 (44%) | 56 (38%)/90 (62%) | 0.0001 |
| Intrahepatic tumor size (mm) | 38.0 ± 35.9 | 35.9 ± 29.0 | 0.5121 |
| 28.0 (0.0‐210.0) | 30.0 (0.0‐201.0) | ||
| Intrahepatic tumor number (0/1/2 or more) | 80 (15%)/39 (7%)/404 (77%) | 15 (10%)/8 (6%)/123 (84%) | 0.1852 |
| AFP (ng/mL) | 13,322 ± 77,879 | 3,281 ± 16,152 | 0.1222 |
| 141 (1‐987,600) | 79 (2‐146,260) | ||
| DCP (mAU/mL) | 16,928 ± 86,754 | 9,798 ± 48,112 | 0.3415 |
| 611 (2‐1,590,000) | 209 (12‐524,068) |
Results are expressed as the mean ± SD and the median (range) or n.
Survival Outcomes Between the Sorafenib and Lenvatinib Cohorts
Figure 1A shows the results of Kaplan‐Meier analysis with log‐rank test of radiologic progression‐free survival time in patients with advanced HCC receiving sorafenib (n = 524) and lenvatinib (n = 146). Median survival time (MST) was 3.7 (95% confidence interval [CI] = 3.2‐4.0) and 5.3 (95% CI = 4.6‐5.7) months, respectively (lenvatinib: P = 0.2656, hazard ratio [HR] = 0.881, 95% CI = 0.705‐1.101). The progression‐free survival time did not differ significantly between the sorafenib and lenvatinib cohorts.
Fig. 1.
(A,B) Survival outcomes of sorafenib (solid line; n = 524) and lenvatinib (dotted line; n = 146) cohorts. (A) Progression‐free survival. MST: 3.7 months (sorafenib) versus 5.3 months (lenvatinib); P = 0.2656; HR = 0.881 (95% CI = 0.705‐1.101). (B) Overall survival. MST: 11.7 months (sorafenib) versus 14.9 months (lenvatinib); P = 0.0010; HR = 0.557 (95% CI = 0.392‐0.793). (C,D) Survival outcomes of sorafenib (solid line; n = 146) and lenvatinib (dotted line; n = 146) cohorts following PSMA. (C) Progression‐free survival. MST: 4.5 months (sorafenib) versus 5.3 months (lenvatinib); P = 0.6795; HR = 1.059 (95% CI = 0.805‐1.393). (D) Overall survival. MST: 15.3 months (sorafenib) versus 14.9 months (lenvatinib); P = 0.2358; HR = 0.778 (95% CI = 0.514‐1.179).
Figure 1B shows the results of Kaplan‐Meier analysis with log‐rank test of overall survival time in patients with advanced HCC receiving sorafenib (n = 524) and lenvatinib (n = 146). MST was 11.7 (95% CI = 10.2‐13.2) and 14.9 (95% CI = 11.8‐) months, respectively (lenvatinib: P = 0.0010, HR = 0.557, 95% CI = 0.392‐0.793). The lenvatinib cohort exhibited significantly better outcome with regard to overall survival time than that of the sorafenib cohort.
Patient Characteristics Between Sorafenib and Lenvatinib Cohorts Following PSMA
Table 2 lists the characteristics of the 292 patients with advanced HCC receiving MTAs (sorafenib, n = 146; lenvatinib, n = 146) following PSMA. No significant differences were observed for any variables between the sorafenib and lenvatinib cohorts using PSMA.
Table 2.
Patient Characteristics of Sorafenib and Lenvatinib Cohorts Following PSMA
| Variable | Sorafenib (n = 146) | Lenvatinib (n = 146) | P Value |
|---|---|---|---|
| Age (years) | 72.8 ± 8.5 | 72.8 ± 9.6 | 0.9837 |
| 73.1 (48.3‐94.3) | 73.9 (44.7‐89.8) | ||
| Sex (male/female) | 121 (83%)/25 (17%) | 125 (86%)/21 (14%) | 0.5205 |
| Etiology (HBV/HCV/HBV + HCV/Both negative) | 24 (16%)/81 (56%)/2 (1%)/39 (27%) | 25 (17%)/77 (53%)/2 (1%)/42 (29%) | 0.9721 |
| Child‐Pugh class (A/B) | 137 (94%)/9 (6%) | 134 (92%)/12 (8%) | 0.4968 |
| Child‐Pugh score (5/6/7/8/9) | 84 (58%)/53 (36%)/8 (5%)/0 (0%)/1 (1%) | 81 (56%)/53 (36%)/6 (4%)/5 (3%)/1 (1%) | 0.2541 |
| ALBI grade (1/2/3) | 39 (27%)/105 (72%)/2 (1%) | 44 (30%)/98 (67%)/4 (3%) | 0.5299 |
| BCLC stage (B/C) | 81 (55%)/65 (45%) | 79 (54%)/67 (46%) | 0.8141 |
| Macrovascular invasion (yes/no) | 21 (14%)/125 (86%) | 21 (14%)/125 (86%) | 1.0000 |
| Extrahepatic metastasis (yes/no) | 55 (38%)/91 (62%) | 56 (38%)/90 (62%) | 0.9040 |
| Intrahepatic tumor size (mm) | 37.9 ± 32.0 | 35.9 ± 29.0 | 0.5834 |
| 27.5 (0.0‐190.0) | 30.0 (0.0‐201.0) | ||
| Intrahepatic tumor number (0/1/2 or more) | 15 (10%)/14 (10%)/117 (80%) | 15 (10%)/8 (6%)/123 (84%) | 0.4094 |
| AFP level (ng/mL) | 5,205 ± 21,675 | 3,281 ± 16,152 | 0.3905 |
| 46 (1‐186,300) | 79 (2‐146,260) | ||
| DCP level (mAU/mL) | 9,819 ± 34,200 | 9,798 ± 48,112 | 0.9966 |
| 381 (11‐335,810) | 209 (12‐524,068) |
Results are expressed as the mean ± SD and the median (range) or n.
Survival Outcomes Between Sorafenib and Lenvatinib Cohorts Following PSMA
Figure 1C shows the results of Kaplan‐Meier analysis with log‐rank test of radiologic progression‐free survival time in patients with advanced HCC receiving sorafenib (n = 146) and lenvatinib (n = 146) following PSMA. MST was 4.5 (95% CI = 3.8‐5.0) and 5.3 (95% CI = 4.6‐5.7) months, respectively (lenvatinib: P = 0.6795, HR = 1.059, 95% CI = 0.805‐1.393). The progression‐free survival time did not differ significantly between the sorafenib and lenvatinib cohorts following PSMA.
Figure 1D shows the results of Kaplan‐Meier analysis with log‐rank test of overall survival time in patients with advanced HCC receiving sorafenib (n = 146) and lenvatinib (n = 146) following PSMA. MST was 15.3 (95% CI = 12.3‐17.7) and 14.9 (95% CI = 11.8‐) months, respectively (lenvatinib: P = 0.2358, HR = 0.778, 95% CI = 0.514‐1.179). The overall survival time did not differ significantly between the sorafenib and lenvatinib cohorts following PSMA.
Therapeutic Effects Between Sorafenib and Lenvatinib Cohorts Following PSMA
Table 3 lists the results at the first radiologic assessment according to the mRECIST following PSMA. In the sorafenib cohort, the response rate was 5% and the disease control rate was 46%, whereas the respective values in the lenvatinib cohort were 31% and 69% (P < 0.0001). The lenvatinib cohort thus exhibited significantly higher therapeutic effects than those of the sorafenib cohort following PSMA.
Table 3.
Therapeutic Effects of Sorafenib and Lenvatinib Treatments Following PSMA
| Therapeutic Effect | Sorafenib (n = 146) | Lenvatinib (n = 146) |
|---|---|---|
| CR | 0 (0%) | 8 (5%) |
| PR | 7 (5%) | 38 (26%) |
| SD | 60 (41%) | 56 (38%) |
| PD | 66 (45%) | 33 (23%) |
| Not evaluable | 13 (9%) | 11 (8%) |
Survival Outcomes With Regard to Therapeutic Effects Following PSMA
Figure 2 shows the results of Kaplan‐Meier analysis with log‐rank test of overall survival time in patients with advanced HCC between those exhibiting complete response (CR) + partial response (PR) (n = 53), stable disease (SD) (n = 116), and PD (n = 99) following PSMA. MST was 30.2 (95% CI = 13.8‐46.6) months with CR + PR, 18.0 (95% CI = 14.4‐26.4) months with SD, and 11.8 (95% CI = 9.9‐14.9) months with PD (CR + PR vs. SD: P = 0.0920, HR = 0.585, 95% CI = 0.311‐1.099; CR + PR vs. PD: P = 0.0001, HR = 0.319, 95% CI = 0.172‐0.591; SD vs. PD: P = 0.0003, HR = 0.521, 95% CI = 0.365‐0.745). The CR + PR and SD cohorts exhibited significantly better outcome with respect to overall survival time than that of the PD cohort; moreover, the overall survival time did not differ significantly between CR + PR and SD cohorts following PSMA.
Fig. 2.
Survival outcomes of CR + PR (solid line; n = 53), SD (dotted line; n = 116), and PD (dash and dotted line; n = 99) cohorts following PSMA. MST: 30.2 months (CR + PR) versus 18.0 months (SD); P = 0.0920; HR = 0.585 (95% CI = 0.311‐1.099). MST: 30.2 months (CR + PR) versus 11.8 months (PD); P = 0.0001; HR = 0.319 (95% CI = 0.172‐0.591). MST: 18.0 months (SD) versus 11.8 months (PD); P = 0.0003, HR = 0.521 (95% CI = 0.365‐0.745).
Secondary Treatment in Sorafenib and Lenvatinib Cohorts Following PSMA
By October 2019, the end of the follow‐up period, 251 of the 292 patients had discontinued primary treatment with MTAs for advanced HCC following PSMA (sorafenib, n = 143; lenvatinib, n = 108). Table 4 lists the transition rate to secondary treatment following primary treatment with MTAs for advanced HCC following PSMA. In the sorafenib cohort, the transition rate to secondary treatment was 60%, whereas in the lenvatinib cohort the transition rate was 45% (P = 0.0269). The sorafenib cohort was found to have significantly higher transition rate to secondary treatment than that of the lenvatinib cohort following PSMA.
Table 4.
Secondary Treatment Following PSMA
| Secondary Treatment | Sorafenib (n = 143) | Lenvatinib (n = 108) |
|---|---|---|
| Yes (overlapped) | 86 (60%) | 49 (45%) |
| Other MTAs | 22 (15%) | 6 (6%) |
| TACE | 27 (19%) | 22 (20%) |
| HAIC | 22 (15%) | 14 (13%) |
| Radiation therapy | 15 (10%) | 7 (5%) |
| No | 57 (40%) | 59 (55%) |
Survival Outcomes Between Groups With and Without Secondary Treatment Following PSMA
Figure 3 shows the results of Kaplan‐Meier analysis with log‐rank test of overall survival time in patients with advanced HCC between those with (n = 135) and without (n = 157) secondary treatment consequent to primary treatment with MTAs following PSMA. MST was 18.0 (95% CI = 15.4‐24.1) and 12.9 (95% CI = 10.3‐16.9) months for patients with and without secondary treatment, respectively (with secondary treatment: P = 0.0004, HR = 0.542, 95% CI = 0.385‐0.763). Patients with HCC receiving secondary treatment consequent to primary treatment with MTAs exhibited significantly better outcome of overall survival time than that of patients without secondary treatment following PSMA.
Fig. 3.
Survival outcomes of patients with (dotted line; n = 135) and without (solid line; n = 157) secondary treatment following PSMA. MST: 18.0 months (with secondary treatment) versus 12.9 months (without secondary treatment); P = 0.0004; HR = 0.542 (95% CI = 0.385‐0.763).
Duration of Treatment Following PSMA
Figure 4 shows the results of Kaplan‐Meier analysis with log‐rank test of the duration of treatment in patients with advanced HCC receiving sorafenib (n = 146) and lenvatinib (n = 146) following PSMA. Median duration of treatment was 4.2 (95% CI = 3.3‐5.1) and 6.1 (95% CI = 5.6‐9.1) months, respectively (lenvatinib: P = 0.0202, HR = 0.708, 95% CI = 0.528‐0.949). The lenvatinib cohort was found to have a significantly longer treatment period than that of the sorafenib cohort following PSMA.
Fig. 4.
Duration of treatment of sorafenib (solid line; n = 146) and lenvatinib (dotted line; n = 146) following PSMA. Median duration of treatment: 4.2 months (sorafenib) versus 6.1 months (lenvatinib); P = 0.0202; HR = 0.708 (95% CI = 0.528‐0.949).
Adverse Events Between Sorafenib and Lenvatinib Cohorts Following PSMA
Table 5 lists the adverse events in sorafenib and lenvatinib cohorts following PSMA. Hand‐foot skin reaction was the most commonly observed adverse event in all 292 patients, occurring in 107 (37%) patients. Other frequent toxicities included fatigue (n = 86; 29%), diarrhea (n = 58; 20%), anorexia (n = 57; 20%), hypertension (n = 54; 18%), liver dysfunction (n = 44; 15%), hoarseness (n = 33; 11%), proteinuria (n = 18; 6%), and hypothyroidism (n = 14; 5%). In the sorafenib cohort, the most frequent adverse event was hand‐foot skin reaction (n = 64; 44%), whereas in the lenvatinib cohort the most frequent adverse event was fatigue (n = 69; 47%). Overall, the adverse events rates in the respective cohorts were 86% and 95% (P = 0.0207). Thus, the lenvatinib cohort was found to exhibit a significantly higher adverse‐event rate than that of the sorafenib cohort following PSMA.
Table 5.
Adverse Events of Sorafenib and Lenvatinib Treatments Following PSMA
| Adverse Event | Sorafenib (n = 146) | Lenvatinib (n = 146) | P Value |
|---|---|---|---|
| Yes (overlapped) | 126 (86%) | 138 (95%) | 0.0207 |
| HFSR | 64 (44%) | 43 (29%) | 0.0108 |
| Fatigue | 17 (12%) | 69 (47%) | < 0.0001 |
| Diarrhea | 23 (16%) | 35 (24%) | 0.0784 |
| Anorexia | 3 (2%) | 54 (37%) | < 0.0001 |
| Hypertension | 10 (7%) | 44 (30%) | < 0.0001 |
| Liver dysfunction | 22 (15%) | 20 (14%) | 0.7387 |
| Hoarseness | 3 (2%) | 30 (21%) | < 0.0001 |
| Proteinuria | 5 (3%) | 13 (9%) | 0.0516 |
| Hypothyroidism | 0 (0%) | 14 (10%) | < 0.0001 |
| No | 20 (14%) | 8 (5%) | 0.0171 |
Discussion
Currently, five drugs have shown clinical activity against advanced HCC in phase 3 clinical trials.( 30 ) Specifically, four drugs exhibited positive results from phase 3 trials using a superiority design (sorafenib in the primary treatment; regorafenib, ramucirumab, and cabozantinib in the secondary treatment), and one showed positive results with a noninferiority design (lenvatinib in the primary treatment).( 3 , 4 , 5 , 30 , 31 , 32 , 33 )
In the present study, we aimed to assess the real‐world treatment outcomes between sorafenib and lenvatinib as primary treatment in patients with advanced HCC using PSMA, to inform which of these MTAs should be used as primary treatment for advanced HCC. In our current study, the lenvatinib cohort exhibited a significantly better outcome with regard to overall survival time than the sorafenib cohort (Fig. 1B). However, following application of PSMA, no significant difference was observed in the outcome of overall survival time between the two cohorts (Fig. 1D). This was considered to result from the findings that sorafenib treatment tended to be disadvantageous with regard to both hepatic reserve factor and tumor factor compared with lenvatinib treatment (Table 1). Notably, this result was retained following PSMA, indicating that the results of the REFLECT study were reproducible.( 5 )
In the REFLECT study, lenvatinib was shown to be noninferior to sorafenib as a primary treatment in terms of overall survival time in patients with advanced HCC.( 5 ) Similarly, in our current study, lenvatinib as the primary treatment was not confirmed to be superior to sorafenib in terms of overall survival time in patients with advanced HCC, despite the high response rate (Table 3) and the long duration of treatment (Fig. 4) in the former. In particular, the CR + PR and SD cohorts exhibited significantly better outcome with regard to overall survival time than that of the PD cohort, whereas the overall survival time did not differ significantly between the CR + PR and SD cohorts (Fig. 2). Thus, no significant difference was observed as determined by best response to primary treatment with regard to the overall survival time from the initiation of MTAs. This result suggests that the clinical response might not reflect the overall survival time. A similar phenomenon has also been demonstrated in patients with metastatic renal cell carcinoma who received MTAs.( 34 )
Furthermore, the PD cohort exhibited the worst prognosis compared with that of CR + PR and SD cohorts (Fig. 2). Thus, primary lenvatinib and sorafenib treatments were considered to be sufficient to maintain SD, which confirms the general recognition of MTAs as being able to maintain SD.( 35 , 36 , 37 ) It is considered that the lack of correlation between primary treatment and the overall survival time may be due to the survival time associated with secondary treatment (i.e., postprogression survival time). Consistent with this, it has been reported that response rates and survival rates are not linked.( 38 ) This suggests that the transition to secondary treatment and extension of postprogression survival time are important for prolonging overall survival time with MTAs for advanced HCC.
In our current study, patients with HCC receiving secondary treatment consequent to primary treatment with MTAs exhibited significantly better outcome with regard to overall survival time than those without secondary treatment following primary treatment with MTAs (Fig. 3). In comparison, the lenvatinib cohort demonstrated a lower transition rate to secondary treatment (Table 4) and higher adverse‐event rate (Table 5). Therefore, in the lenvatinib cohort, it was likely that in many cases treatment was discontinued following receipt of only primary treatment. Subsequently, HCC progressed more readily, leading to the potential lack of difference in progression‐free survival time between the two groups. It has been reported that the postprogression survival time obtained by sequential treatment is more important than temporary antitumor effects for prolonging survival time.( 39 ) Thus, survival time is prolonged by consecutively increasing the treatment course, which suggests that sequential treatment exerts considerable influence on the prognosis of patients with advanced HCC receiving MTAs. For example, in the treatment of patients with unresectable colorectal cancer, the median overall survival time obtained from primary treatment has been steadily increasing.( 40 ) In the present study, it is considered that the lower transition rate to secondary treatment in the lenvatinib cohort is probably due to the high incidence of associated adverse events (Table 5). Thus, if the MTA could be administered with better liver function and without adverse events, it would be expected that the transition rate to sequential treatment would increase along with overall survival time.
It is important to consider primary treatment in terms of both sequential treatment considering postprogression survival and antitumor effect. Lenvatinib, as compared with placebo, was associated with significant improvements in progression‐free survival along with the response rate among patients with iodine‐131‐refractory thyroid cancer.( 41 , 42 ) Nevertheless, differences were identified that must be taken into consideration before choosing between sorafenib and lenvatinib for the treatment of thyroid cancer.( 43 ) In the SELECT study, lenvatinib afforded rapid shrinkage of neoplastic lesions, whereas sorafenib exhibited slower but still relevant activity.( 41 , 43 ) These findings indicated that lenvatinib would be appropriate to rapidly reduce the volume of a metastatic lesion in a short period of time, such as a vertebral lesion compromising the stability of the column and/or compressing the spinal cord. Applying this result to HCC, lenvatinib would be indicated following the need to rapidly reduce the volume of neoplastic lesions in a short period of time, such as with intrahepatic tumor at high risk of rupture or with macrovascular invasion.( 44 ) However, as the number of cases in the present study was small, further study is required to confirm this application.
Our current study has several limitations. First, the primary treatment, sorafenib or lenvatinib, was selected at the discretion of the chief physician and was not randomized. This resulted in a selection bias for patients treated with each agent. Therefore, to reduce confounding, we used PSMA to match patients treated with sorafenib to those treated with lenvatinib. Second, the follow‐up period in the lenvatinib cohort was relatively short compared with that of the sorafenib cohort, owing to approval not being obtained in Japan until March 2018 to treat patients with advanced HCC. Third, the size of the study cohort was relatively small. To confirm which MTA, sorafenib or lenvatinib, should be used as primary treatment for advanced HCC, prospective randomized studies with a larger number of subjects are required.
In conclusion, as a primary MTA‐based treatment for advanced HCC, our findings suggested that sorafenib is generally appropriate because it exhibits a significantly lower frequency of adverse events than lenvatinib in consideration of the enhanced postprogression survival associated with sequential treatment.
Acknowledgments
The authors thank the staff of the Kurume Liver Cancer Study Group of Japan and Asakura Medical Association Hospital, Chikugo City Hospital, Iwamoto Clinic, Kurume Central Hospital, Kurume General Hospital, Kurume University Hospital, Kurume University Medical Center, Kyushu Medical Center, Nagata Hospital, Ōmuta City Hospital, Saga Central Hospital, Saiseikai Ōmuta‐Hospital, Social Insurance Tagawa Hospital, St. Mary’s Hospital, Tobata Kyoritsu Hospital, Yame General Hospital, Yanagawa Hospital, and Yokokura Hospital for their valuable support. They also thank Editage (www.editage.jp) for the English language editing.
Potential conflict of interest: Nothing to report.
References
Author names in bold designate shared co‐first authorship.
- 1. Grandhi MS, Kim AK, Ronnekleiv‐Kelly SM, Kamel IR, Ghasebeh MA, Pawlik TM. Hepatocellular carcinoma: from diagnosis to treatment. Surg Oncol 2016;25:74‐85. [DOI] [PubMed] [Google Scholar]
- 2. Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol 2017;34:153‐159. [DOI] [PubMed] [Google Scholar]
- 3. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378‐390. [DOI] [PubMed] [Google Scholar]
- 4. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia‐Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double‐blind, placebo‐controlled trial. Lancet Oncol 2009;10:25‐34. [DOI] [PubMed] [Google Scholar]
- 5. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first‐line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non‐inferiority trial. Lancet 2018;391:1163‐1173. [DOI] [PubMed] [Google Scholar]
- 6. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099‐7109. [DOI] [PubMed] [Google Scholar]
- 7. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26:127‐132. [DOI] [PubMed] [Google Scholar]
- 8. Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013;31:4067‐4075. [DOI] [PubMed] [Google Scholar]
- 9. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as first‐line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK‐FL study. J Clin Oncol 2013;31:3517‐3524. [DOI] [PubMed] [Google Scholar]
- 10. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK‐PS study. J Clin Oncol 2013;31:3509‐3516. [DOI] [PubMed] [Google Scholar]
- 11. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015;33:172‐179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Kang YK, Yau T, Park JW, Lim HY, Lee TY, Obi S, et al. Randomized phase II study of axitinib versus placebo plus best supportive care in second‐line treatment of advanced hepatocellular carcinoma. Ann Oncol 2015;26:2457‐2463. [DOI] [PubMed] [Google Scholar]
- 13. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. Ramucirumab versus placebo as second‐line treatment in patients with advanced hepatocellular carcinoma following first‐line therapy with sorafenib (REACH): a randomised, double‐blind, multicentre, phase 3 trial. Lancet Oncol 2015;16:859‐870. [DOI] [PubMed] [Google Scholar]
- 14. Koeberle D, Dufour JF, Demeter G, Li Q, Ribi K, Samaras P, et al. Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann Oncol 2016;27:856‐861. [DOI] [PubMed] [Google Scholar]
- 15. Rimassa L, Assenat E, Peck‐Radosavljevic M, Pracht M, Zagonel V, Mathurin P, et al. Tivantinib for second‐line treatment of MET‐high, advanced hepatocellular carcinoma (METIV‐HCC): a final analysis of a phase 3, randomised, placebo‐controlled study. Lancet Oncol 2018;19:682‐693. [DOI] [PubMed] [Google Scholar]
- 16. Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008;122:664‐671. [DOI] [PubMed] [Google Scholar]
- 17. Stjepanovic N, Capdevila J. Multikinase inhibitors in the treatment of thyroid cancer: specific role of lenvatinib. Biologics 2014;8:129‐139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol 2017;52:512‐519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona‐2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421‐430. [DOI] [PubMed] [Google Scholar]
- 20. Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence‐based approach‐the ALBI grade. J Clin Oncol 2015;33:550‐558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:329‐338. [DOI] [PubMed] [Google Scholar]
- 22. Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 2010;30:61‐74. [DOI] [PubMed] [Google Scholar]
- 23. Liu YJ, Zhu GP, Guan XY. Comparison of the NCI‐CTCAE version 4.0 and version 3.0 in assessing chemoradiation‐induced oral mucositis for locally advanced nasopharyngeal carcinoma. Oral Oncol 2012;48:554‐559. [DOI] [PubMed] [Google Scholar]
- 24. Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, et al. Development of the National Cancer Institute's patient‐reported outcomes version of the common terminology criteria for adverse events (PRO‐CTCAE). J Natl Cancer Inst 2014;106 pii: dju244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Atkinson TM, Ryan SJ, Bennett AV, Stover AM, Saracino RM, Rogak LJ, et al. The association between clinician‐based common terminology criteria for adverse events (CTCAE) and patient‐reported outcomes (PRO): a systematic review. Support Care Cancer 2016;24:3669‐3676. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30:52‐60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. D'Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non‐randomized control group. Stat Med 1998;17:2265‐2281. [DOI] [PubMed] [Google Scholar]
- 28. Johnson SR, Tomlinson GA, Hawker GA, Granton JT, Feldman BM. Propensity score methods for bias reduction in observational studies of treatment effect. Rheum Dis Clin North Am 2018;44:203‐213. [DOI] [PubMed] [Google Scholar]
- 29. Austin PC. The performance of different propensity score methods for estimating marginal hazard ratios. Stat Med 2013;32:2837‐2849. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Llovet JM, Montal R, Villanueva A. Randomized trials and endpoints in advanced HCC: role of PFS as a surrogate of survival. J Hepatol 2019;70:1262‐1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet 2017;389:56‐66. [DOI] [PubMed] [Google Scholar]
- 32. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha‐fetoprotein concentrations (REACH‐2): a randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet Oncol 2019;20:282‐296. [DOI] [PubMed] [Google Scholar]
- 33. Abou‐Alfa GK, Meyer T, Cheng AL, El‐Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54‐63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Ueda K, Suekane S, Nishihara K, Ogasawara N, Kurose H, Hayashi S, et al. Duration of first‐line treatment with molecular targeted‐therapy is a prognostic factor in metastatic renal cell carcinoma. Anticancer Res 2015;35:3415‐3421. [PubMed] [Google Scholar]
- 35. Arizumi T, Ueshima K, Chishina H, Kono M, Takita M, Kitai S, et al. Duration of stable disease is associated with overall survival in patients with advanced hepatocellular carcinoma treated with sorafenib. Dig Dis 2014;32:705‐710. [DOI] [PubMed] [Google Scholar]
- 36. Ogasawara S, Chiba T, Ooka Y, Kanogawa N, Saito T, Motoyama T, et al. Sorafenib treatment in Child‐Pugh A and B patients with advanced hepatocellular carcinoma: safety, efficacy and prognostic factors. Invest New Drugs 2015;33:729‐739. [DOI] [PubMed] [Google Scholar]
- 37. Raoul JL, Adhoute X, Penaranda G, Perrier H, Castellani P, Oules V, et al. Sorafenib: experience and better management of side effects improve overall survival in hepatocellular carcinoma patients: a real‐life retrospective analysis. Liver Cancer 2019;8:457‐467. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Terashima T, Yamashita T, Toyama T, Arai K, Kawaguchi K, Kitamura K, et al. Surrogacy of time to progression for overall survival in advanced hepatocellular carcinoma treated with systemic therapy: a systematic review and meta‐analysis of randomized controlled trials. Liver Cancer 2019;8:130‐139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Terashima T, Yamashita T, Takata N, Nakagawa H, Toyama T, Arai K, et al. Post‐progression survival and progression‐free survival in patients with advanced hepatocellular carcinoma treated by sorafenib. Hepatol Res 2016;46:650‐656. [DOI] [PubMed] [Google Scholar]
- 40. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single‐agent therapy is used first line. J Clin Oncol 2005;23:9441‐9442. [DOI] [PubMed] [Google Scholar]
- 41. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine‐refractory thyroid cancer. N Engl J Med 2015;372:621‐630. [DOI] [PubMed] [Google Scholar]
- 42. Kiyota N, Schlumberger M, Muro K, Ando Y, Takahashi S, Kawai Y, et al. Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine‐refractory differentiated thyroid cancer. Cancer Sci 2015;106:1714‐1721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Valerio L, Pieruzzi L, Giani C, Agate L, Bottici V, Lorusso L, et al. Targeted therapy in thyroid cancer: state of the art. Clin Oncol (R Coll Radiol) 2017;29:316‐324. [DOI] [PubMed] [Google Scholar]
- 44. Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012;57:821‐829. [DOI] [PMC free article] [PubMed] [Google Scholar]