Abstract
Background
The sensitivity of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in hepatocellular carcinoma (HCC) is low; however, clinical evidence demonstrating its prognostic value in patients with HCC has recently been reported. This study aimed to assess the value of 18F-FDG-PET/CT as a tool for evaluating the response of HCC to lenvatinib treatment.
Methods
We evaluated 11 consecutive patients with HCC diagnosed by dynamic CT or magnetic resonance imaging combined with 18F-FDG-PET/CT from April 2018 to December 2019. The tumor-to-normal liver ratio (TLR) of the target tumor was measured before and during the course of lenvatinib treatment with 18F-FDG-PET/CT (pre and post analysis, respectively), with a TLR ≥2 classified as PET-positive HCC. At the time of each evaluation, we also used the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the modified RECIST (mRECIST), and the tumor marker alfa-fetoprotein (AFP).
Results
Of 11 patients, 3 (27%) and 8 (73%) had an objective response to lenvatinib treatment at the time of post-analysis by RECIST 1.1 and mRECIST, respectively. There were 3 (27%) and 7 (64%) patients with PET-positive HCC at the time of pre- and post-analysis, respectively. There was a significant correlation between the rates of change in AFP and TLR during lenvatinib treatment (r = 0.69, p = 0.019). Based on these results, we were able to perform liver resection on 4 patients with PET-positive HCC as conversion therapy. Three samples from these patients showed poorly differentiated tumors.
Conclusion
18F-FDG-PET/CT has potential as an evaluation tool for describing biological tumor behavior and reflecting disease progression, location, and treatment response. This modality may provide useful information for considering prognosis and subsequent therapy.
Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography, Hepatocellular carcinoma, Lenvatinib, Tyrosine kinase inhibitor
Introduction
Lenvatinib is the first approved molecular-targeted agent for first-line treatment of unresectable advanced hepatocellular carcinoma (HCC) worldwide [1]. It is an oral multikinase inhibitor that inhibits the proliferation of cancer cells and angiogenesis, leading to a decrease in tumor volume and intratumoral arterial feeding. The modified Response Evaluation Criteria in Solid Tumors (mRECIST), which depend on intratumoral arterial enhancement, are commonly used to evaluate the response of HCC to treatment [2]. However, the true viability of HCC during lenvatinib treatment remains unclear.
18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) reflects the glucose metabolism of cancer cells, but its sensitivity in HCC has been reported to be lower than in other solid tumors [3, 4]. Thus, the usefulness of 18F-FDG-PET/CT in HCC is limited. However, there is evidence that 18F-FDG-PET/CT-positive HCC is strongly associated with poor histological differentiation [5]. Recently, we reported the utility of 18F-FDG uptake in HCC as a useful predictor of an extremely rapid response to lenvatinib [6].
Several years ago, Harimoto et al. [7] reported that increased fibroblast growth factor receptor (FGFR) 2 expression correlated significantly with poor histological differentiation, a higher incidence of portal vein invasion, and a high AFP level. Lenvatinib, an inhibitor of vascular endothelial growth factor receptor 1–3, FGFR1–4, platelet-derived growth factor receptor-α, Ret, and Kit, was reported to be noninferior to sorafenib with respect to overall survival in patients with untreated advanced HCC [8, 9]. Therefore, potential FGFR inhibition by lenvatinib may have influenced this rapid treatment response.
Usually, treatment response is assessed with dynamic CT or MRI, which depend only on tumor blood flow, especially with mRECIST. However, a decrease in tumor blood flow does not always mean tumor necrosis, and the mechanism of action of lenvatinib is to decrease tumor blood flow by inhibiting angiogenesis. Therefore, this tool remains controversial for the evaluation of lenvatinib treatment response from a clinical standpoint.
Until now, no data regarding the change in accumulation of 18F-FDG during lenvatinib treatment have been reported. Therefore, in this study, we assessed the value of 18F-FDG-PET/CT as a tool for evaluating lenvatinib treatment response by comparing it with other tools, such as mRECIST, RECIST 1.1, and the tumor marker alfa-fetoprotein (AFP).
Patients and Methods
Study Population
From April 2018 to December 2019, 91 patients received systemic anticancer treatment with lenvatinib for unresectable HCC at the Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
The following inclusion criteria were used in this retrospective study: (1) dynamic CT or magnetic resonance imaging (MRI) performed prior to initiation of lenvatinib; (2) a tumor showing hyperenhancement in the arterial phase of dynamic CT or MRI; (3) 18F-FDG-PET/CT performed prior to the introduction of lenvatinib; (4) triple-phase dynamic CT or MRI and 18F-FDG-PET/CT performed to evaluate the treatment response to lenvatinib; (5) Child-Pugh class A liver function at the time of lenvatinib initiation; (6) Barcelona Clinic Liver Cancer (BLCL) stage A–C categorization; (7) patients with unresectable HCC who did not want to undergo local ablation or chemoembolization therapy for various reasons (i.e., tumor size, number, and location; extrahepatic metastasis; transcatheter arterial chemoembolization [TACE] failure/refractoriness [10]; and other complications); (8) no treatment history with lenvatinib; (9) treatment interval >28 days since previous tyrosine kinase inhibitor (sorafenib or regorafenib) therapy; and (10) observation period of 8 weeks or more. Ultimately, 11 patients were enrolled in the current study.
Diagnosis of HCC
The diagnosis of HCC was based predominantly on imaging analysis using dynamic CT or MRI. When a liver nodule showed hyperenhancement in the arterial phase of the dynamic study and washout in the portal or delayed phase, the nodule was diagnosed as HCC.
Imaging Analysis of HCC Using 18F-FDG-PET/CT
Within 1 month before the initiation of lenvatinib, 18F-FDG-PET/CT was performed using a dedicated whole-body PET scanner (Biograph mCT Flow40; Siemens Healthcare, Germany). With SYNAPSE VINCENT v4 software for semiquantitative analysis, the volume of interest was drawn along the outline of the tumor, and the maximum standardized uptake value (SUVmax) and mean SUV (SUVmean) in each intra- and extrahepatic target tumor were calculated. Of the lesions measured, that with the highest 18F-FDG uptake was selected and used to calculate the tumor-to-normal liver ratio (TLR). Next, to measure normal liver activity, 3 nonoverlapping spherical 1-cm3 volumes of interest were drawn in the liver (2 in the right lobe and 1 in the left) on the axial PET images, avoiding the HCC areas seen on dynamic CT. The TLR was calculated using the following equation: TLR = SUVmax of the tumor/SUVmean of the normal liver. Based on previous reports, we defined HCC with a TLR ≥2 as FDG-PET-positive HCC to indicate high malignant potential.
Lenvatinib Treatment and Assessment of Adverse Events
Lenvatinib (Lenvima®; Eisai, Tokyo, Japan) was given orally (8 mg/day to patients <60 kg, or 12 mg/day to patients >60 kg). Treatment was discontinued in the case of any unacceptable or serious adverse events (AEs) or significant clinical tumor progression. According to the guidelines for the administration of lenvatinib, the dose should be reduced or treatment interrupted if a patient develops grade >3 AEs or any unacceptable drug-related grade 2 AEs. AEs were assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0 [11]. If a drug-related AE occurred, a dose reduction or temporary interruption was implemented until the AE improved to grade 1 or 2, according to the guidelines provided by the manufacturer.
Treatment Response Evaluation
The treatment response was evaluated according to RECIST 1.1 [12] and mRECIST [2]. We assessed the best tumor response during 2–12 weeks using dynamic CT or MRI.
The treatment response was assessed independently by an expert hepatologist (Y. Kawamura) and an expert hepatobiliary surgeon (J. Shindoh) who were blinded to the clinical data. Discrepancies between these two examiners were resolved by consensus review including an additional reviewer (K. Ikeda).
Follow-Up Protocol
Physicians examined the patients every 1–2 weeks after the initiation of lenvatinib, and biochemical laboratory and urine tests were also performed. After the initiation of lenvatinib, the patients underwent dynamic CT or MRI to evaluate the best treatment response at 2–12 weeks. After the first evaluation of the treatment response, dynamic CT or MRI was performed every 1–3 months. Post-18F-FDG-PET/CT analysis was performed when tumor viability was indefinite even though CT, MRI, and a tumor marker were used. This time was defined as the time of post-analysis.
Method of Evaluation at the Time of Post-18F-FDG-PET/CT Analysis
Within 1 month of the post-18F-FDG-PET/CT analysis, dynamic CT or MRI was performed and tumor response was evaluated. According to RECIST 1.1 and mRECIST assessment, the target lesion was assessed by anatomic size and intratumoral arterial enhancement. In this study, “disease control” was defined as successful tumor control without progressive disease (PD) state at the time of post-analysis of lenvatinib treatment with or without additional sequential therapies. Changes in AFP and TLR values were calculated using the following mathematical formulae:
ΔTLR = [TLR value at the time of post-analysis] − [TLR value at the time of pre-analysis]
ΔAFP = [AFP value at the time of post-analysis] − [AFP value at the time of pre-analysis]
ΔTLR (%) = ΔTLR/[TLR value at the time of pre-analysis]
ΔAFP (%) = ΔAFP/[AFP value at the time of pre-analysis]
Statistical Analysis
Statistical analysis was performed with IBM SPSS software (v26.0; SPSS Inc., Chicago, IL, USA). Data are expressed as the median and range. Correlations were analyzed with the Spearman correlation test. p values <0.05 were considered to indicate statistical significance.
Results
Patient Demographics
We enrolled 11 patients using 18F-FDG-PET/CT for evaluating the treatment response to lenvatinib. Table 1 shows the baseline characteristics of the 11 patients. There were 8 men and 3 women; their median age was 67 years (range, 59–83). Two patients had BCLC stage A, 6 patients had BCLC stage B, and 3 patients had BCLC stage C disease. The median value of AFP before lenvatinib treatment was 20 µg/L (range, 0.8–6,687). The median values of SUVmax and TLR on 18F-FDG-PET/CT before lenvatinib treatment were 3.77 (range, 2.53–8.72) and 1.45 (range, 1.25–3.66), respectively.
Table 1.
Baseline characteristics of the patients with HCC treated with lenvatinib and evaluated by 18F-FDG-PET/CT
| Case No. | Age, years | Sex | Etiology | AFP, µg/L | BCLC stage | CPS | Pretreatment image analysis using 18F-FDG-PET/CT |
|
|---|---|---|---|---|---|---|---|---|
| SUVmax | TLR | |||||||
| 1 | 79 | M | Others | 153 | B | 5 | 3.86 | 1.40 |
| 2 | 67 | M | Alcohol | 2.0 | B | 6 | 2.53 | 1.29 |
| 3 | 67 | M | HBV | 6,687 | B | 5 | 3.45 | 1.49 |
| 4 | 80 | M | Others | 9.40 | B | 5 | 8.72 | 3.66 |
| 5 | 83 | M | HCV | 25.0 | C | 5 | 6.24 | 2.81 |
| 6 | 65 | F | HCV | 373.0 | A | 6 | 4.30 | 1.45 |
| 7 | 69 | F | HCV | 126 | A | 5 | 3.52 | 1.25 |
| 8 | 59 | M | HCV | 5.9 | C | 5 | 6.44 | 3.20 |
| 9 | 66 | M | HCV | 13 | C | 5 | 2.60 | 1.25 |
| 10 | 77 | F | Other | 20 | B | 5 | 3.13 | 1.25 |
| 11 | 59 | M | Alcohol | 0.8 | B | 6 | 3.77 | 1.71 |
HCC, hepatocellular carcinoma; 18F-FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography/computed tomography; AFP, alfa-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CPS, Child-Pugh score; SUVmax, maximum standardized uptake value; TLR, tumor-to-normal liver ratio; HBV, hepatitis B virus; HCV, hepatitis C virus.
Evaluation of the Initial Treatment Response at 2–12 Weeks by Dynamic CT
According to the RECIST 1.1 assessment conducted at 2–12 weeks, no patient had a complete response (CR), 6 patients had a partial response (PR), 5 patients had stable disease (SD), and no patient had PD. According to mRECIST assessment, 3 patients had a CR, 6 had a PR, and 2 had SD. No patient had PD (Table 2). Among the 11 patients, 6 and 9 patients had an objective response by RECIST 1.1 and mRECIST, respectively.
Table 2.
Correlation of 18FDG-PET/CT images and AFP tumor marker during lenvatinib treatment
| Case No. | Initial treatment response at 2–12 weeks using dynamic CT |
Evaluation at the time of post-analysis |
Changes in values |
Lenvatinib dose between analysis |
Additional treatment |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| RECIST1.1 | mRECIST | RECIST1.1 | mRECIST | disease control | TLR | ΔTLR | % | AFP, µg/L | ΔAFP, µg/L | % | interval, months | initial dose, mg | RDI, % | pre- to post-analysis | after post-analysis | |
| 1 | PR | CR | PD | PR | − | 5.37 | 3.96 | 282 | 3,214 | 3,061 | 2,001 | 10.6 | 12 | 45 | TACE | Death |
| 2 | PR | PR | SD | SD | + | 2.42 | 1.13 | 88 | 6.1 | 4.1 | 205 | 13.3 | 8 | 52 | None | None |
| 3 | SD | SD | SD | SD | + | 2.62 | 1.13 | 76 | 34,451 | 27,764 | 415 | 6.7 | 8 | 100 | TACE | RAM, operation |
| 4 | PR | CR | SD | CR | + | 4.67 | 1.01 | 28 | 12.1 | 2.7 | 29 | 6.5 | 12 | 72 | None | Operation |
| 5 | SD | PR | SD | PR | + | 3.71 | 0.90 | 32 | 16.0 | −9.0 | −36 | 2.0 | 8 | 100 | None | Operation |
| 6 | SD | SD | SD | PR | + | 2.22 | 0.78 | 54 | 17,275 | 16,902 | 4,531 | 17.3 | 12 | 24 | TACE | RAM |
| 7 | SD | PR | PD | PR | − | 1.45 | 0.20 | 16 | 286 | 160 | 127 | 17.5 | 8 | 51 | TACE | RAM |
| 8 | PR | CR | PR | CR | + | 3.10 | −0.10 | −3.2 | 12.6 | 6.7 | 114 | 7.3 | 8 | 100 | None | Operation |
| 9 | PR | PR | PR | PR | + | 1.09 | −0.16 | −13 | 6.0 | −7.0 | −54 | 5.4 | 12 | 84 | None | TACE |
| 10 | SD | PR | SD | SD | + | 0.82 | −0.43 | −35 | 32.5 | 12.5 | 63 | 11.4 | 8 | 27 | TACE | TACE |
| 11 | PR | PR | PR | PR | + | 0.79 | −0.91 | −54 | 0.6 | −0.2 | −25 | 13.3 | 12 | 43 | TACE | None |
18F-FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography/computed tomography; CT, computed tomography; mRECIST, modified Response Evaluation Criteria in Solid Tumors; RECIST, Response Evaluation Criteria in Solid Tumors; TLR, tumor-to-normal liver ratio; AFP, alfa-fetoprotein; RDI, relative dose intensity; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TACE, transcatheter arterial chemoembolization; RAM, ramucirumab.
Evaluation at the Time of Post-Analysis
According to the RECIST 1.1 assessment conducted at the time of post-analysis, no patient had a CR, 3 patients had a PR, 6 had SD, and 2 had PD. According to mRECIST assessment, 2 patients had a CR, 6 had a PR, and 3 had SD. No patient had PD (Table 2). Among the 4 patients with a ΔTLR <0, 3 patients had an objective response according to RECIST 1.1 and mRECIST, respectively. In contrast, among the 7 patients with a ΔTLR ≥0, no and 5 patients had an objective response by RECIST 1.1 and mRECIST, respectively (Fig. 1). Nine patients had good cancer control with lenvatinib and other additional therapies (mainly TACE, n = 6) at the time of post-analysis.
Fig. 1.
Relationship between evaluation with dynamic CT (RECIST 1.1 and mRECIST) and the tumor-to-normal liver standardized uptake value ratio (TLR) measured by 18F-FDG-PET/CT. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
Correlation of TLR and AFP between Pre- and Post-Analysis
The median change in TLR and AFP was 0.78 (range, −0.91 to 3.96) and 6.7 µg/L (range, −9.0 to 27,764), respectively. The median rate of change in TLR and AFP was 27.5% (range, −53.6 to 282) and 114% (range, −53.8 to 2,001), respectively. In 4 patients, TLR values were decreased. The median interval between pre- and post-18F-FDG-PET/CT analysis was 10.6 months (range, 2.0–17.5). There was a significant correlation between the rates of change in AFP and TLR (r = 0.69; p = 0.019) (Fig. 2). Example images for 2 patients are shown in Figures 3 and 4.
Fig. 2.
Correlation of tumor-to-normal liver ratio (TLR) and alfa-fetoprotein (AFP) between pre- and post-analysis.
Fig. 3.
Upregulation of FDG uptake during lenvatinib treatment: a case presentation. a Dynamic CT image at pre-treatment analysis. b Dynamic CT image at post-treatment analysis. c18F-FDG-PET/CT image at pre-treatment analysis. d18F-FDG-PET/CT image at post-treatment analysis. Baseline and follow-up imaging analysis during lenvatinib treatment of a 67-year-old male patient with HCC (case 2). These tumors were in stable disease with a decrease in arterial blood flow, and there was no significant increase in tumor size (a, b). However, there was higher tumor uptake in the second scan (d) than in the first scan (c), indicating no actual tumoral necrosis with lenvatinib treatment (13.3 months) and a poor prognosis. 18F-FDG-PET/CT during therapy with a molecular-targeted agent provided more information on HCC. 18F-FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography/computed tomography; HCC, hepatocellular carcinoma.
Fig. 4.
Downregulation of FDG uptake during lenvatinib treatment: a case presentation. a Dynamic CT image at pre-treatment analysis. b Dynamic CT image at post-treatment analysis. c18F-FDG-PET/CT image at pre-treatment analysis. d18F-FDG-PET/CT image at post-treatment analysis. Baseline and follow-up imaging analysis during lenvatinib treatment of a 59-year-old male patient with HCC (case 8). These tumors were in complete response with the disappearance of intratumoral arterial enhancement, and there was no significant increase in tumor size (a, b). The AFP tumor marker also did not change. There was lower tumor uptake in the second scan (d) than in the first scan (c), but it still remained. This indicated that the tumor survived, even though the patient had received lenvatinib treatment (7.3 months). Thus, we were able to perform liver resection as conversion therapy. The histological diagnosis was poorly differentiated HCC. 18F-FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography/computed tomography; HCC, hepatocellular carcinoma; AFP, alfa-fetoprotein.
Medical Treatment
Among the 11 patients, 3 experienced a change in tyrosine kinase inhibitor to ramucirumab, 4 patients underwent liver resection, and 2 patients received TACE as subsequent therapy. Two patients continued lenvatinib treatment, and 1 patient died a few days after post-analysis.
Histological Tumor Differentiation of Liver Resection Samples
Among the 11 patients, 4 (cases 3, 4, 5, and 8) underwent liver resection, and all 4 cases had a TLR >2 at the time of post-analysis (Table 3). One case had a moderately differentiated tumor, but all other cases had poorly differentiated tumors.
Table 3.
Relationships between histological tumor differentiation, AFP tumor marker, and imaging findings by 18FDG-PET/CT in patients with HCC who underwent surgical resection
| Case No. | At the time of post-analysis |
Pathological tumor differentiation | |
|---|---|---|---|
| TLR | AFP, ng/dL | ||
| 3 | 2.62 | 34,451 | Moderate |
| 4 | 4.67 | 12.1 | Poor |
| 5 | 3.71 | 16.0 | Poor |
| 8 | 3.10 | 12.6 | Poor |
AFP, alfa-fetoprotein; 18F-FDG-PET/CT, 18F-fluorodeoxy-glucose positron emission tomography/computed tomography; HCC, hepatocellular carcinoma; TLR, tumor-to-normal liver ratio.
Discussion
This study investigated the value of 18F-FDG-PET/CT as a tool for evaluating the response to lenvatinib treatment compared with mRECIST, RECIST 1.1, and AFP. Our results suggest that the rate of change in TLR is associated with the tumor marker AFP and pathological tumor differentiation. To the best of our knowledge, this is the first study focusing on treatment response using 18F-FDG-PET/CT in patients with HCC treated with lenvatinib.
RECIST is a general method for evaluating treatment response based on tumor shrinkage [13, 14]. However, the treatment response of HCC is poorly correlated with the clinical outcome by RECIST for many molecular-targeted agents and interventional therapies [15, 16]. In 2008, the American Association for the Study of Liver Diseases (AASLD) developed mRECIST, which depends on intratumoral arterial enhancement, and mRECIST has been the main tool for evaluating the treatment response of HCC. However, it may also be difficult to evaluate the tumor response by mRECIST during lenvatinib treatment because its mechanism of action is to decrease the number of intratumoral feeding arteries to inhibit angiogenesis and proliferation of HCC. In this study, among 11 patients, 6 and 9 had an objective response by RECIST 1.1 and mRECIST at 2–12 weeks, respectively, with similar outcomes at the time of post-analysis; 3 and 8 patients had an objective response by RECIST 1.1 and mRECIST, respectively (Table 2). In addition, among the 7 patients with a ΔTLR ≥0, responses were judged differently by RECIST 1.1 and mRECIST (Fig. 1). This may indicate that the evaluation of response by mRECIST during lenvatinib treatment was an overestimation and uncertain from a clinical standpoint.
Although the sensitivity of 18F-FDG-PET/CT in HCC is low, previous studies about its predictive value for poor prognosis have been published [3, 15, 17, 18]. On the other hand, the TLR has been reported as a useful predictor of an extremely rapid response to lenvatinib [6]. However, researchers have focused on the prognostic and predictive value, and there have been few studies investigating the treatment response. In our study, we evaluated treatment response using 18F-FDG-PET/CT before and after lenvatinib treatment. The results showed that patients with a decreased TLR primarily experienced objective responses by RECIST 1.1 and mRECIST (Fig. 1), and a significant correlation was observed between the rates of change in AFP and TLR during lenvatinib treatment (r = 0.69, p = 0.019) (Fig. 2). This means that the TLR may serve as a surrogate marker of lenvatinib treatment response. In addition to the reflection on total treatment response, imaging analysis using 18F-FDG-PET/CT demonstrates the localization of the tumor, unlike tumor markers. Therefore, we were able to perform liver resection in 4 cases using 18F-FDG-PET/CT as conversion therapy.
18F-FDG-PET/CT is also a good predictor of tumor differentiation and biological properties in HCC [5, 19, 20, 21, 22, 23]. High-histological-grade HCC has increased glucose transporter and hexokinase activity, which are positively correlated with FDG uptake [5, 24, 25]. In our study, 4 liver resection samples with a TLR >2 had greater malignant pathology regardless of the AFP value. Based on the results of our previous studies, 1 had a moderately differentiated tumor and 3 had poorly differentiated tumors (Table 3).
Among the 11 patients, 3 (27%) had PET-positive HCC at the time of pre-analysis, but 7 (64%) had PET-positive HCC at the time of post-analysis. Considering that the sensitivity of 18F-FDG-PET/CT for HCC diagnosis was reported to be about 50% or lower [20, 26], on the other hand, there were many cases presented as PET-positive HCC at the time of post-analysis and the number of patients with PET-positive HCC increased during lenvatinib treatment. This result means that the tumoral biological condition might convert aerobiosis to anaerobiosis for survival under the action of lenvatinib, inhibiting angiogenesis to decrease intratumoral arterial blood flow and proliferation of HCC. 18F-FDG-PET/CT has the potential to be an evaluation tool for describing biological tumor behavior and reflecting disease progression, location, and treatment response. This modality could provide useful information in considering prognosis and conversion therapy (Fig. 3, 4).
There are several limitations to this study. First, the sample size is small, resulting in statistical bias and inaccurate conclusions. Second, the diagnosis of HCC was based exclusively on imaging analysis. Third, patients underwent different therapies (mainly TACE, n = 6) before post-analysis, which may have influenced their outcomes. Fourth, although FDG-PET/CT analysis is an optional imaging tool, for various reasons, it is not as easy to perform as other types of imaging such as CT or MRI, and it has a relatively high cost, with a small number and uneven distribution of required instruments. Therefore, our findings should be interpreted with caution due to these limitations.
Conclusion
During lenvatinib treatment, response evaluation based on intratumoral blood flow was sometimes uncertain. Evaluation with 18F-FDG-PET/CT depends not on intratumoral blood flow but on actual biological tumor behavior. In addition to the reflection of treatment response as a tumor marker, 18F-FDG-PET/CT shows tumoral localization. Therefore, this modality may provide valuable information that could impact individual decision-making on the most appropriate subsequent therapy.
Statement of Ethics
Ethics approval and consent to participate: this retrospective non-intervention study was approved by the Institutional Review Board of Toranomon Hospital (protocol No. 1438-H/B). The study was performed in accordance with the Declaration of Helsinki. Because of the anonymous nature of the data and the opt-out disclosed on our institution's homepage (https://www.crc-toranomonhosp.jp/wp-content/uploads/2020/01/rinken_1438HB_2.pdf), the requirement for additional informed consent to participate in this study was deemed unnecessary according to the Japanese national regulation “Ethical Guidelines for Medical and Health Research Involving Human Subjects” (https://www.mhlw.go.jp/file/06-Seisakujouhou-10600000-Daijinkanboukouseikagakuka/0000080278.pdf).
Conflict of Interest Statement
Y. Kawamura, M. Kobayashi, J. Shindoh, and H. Kumada report receiving honoraria from Eisai. The other authors declare no conflicts of interest.
Funding Sources
This study was funded by the Okinaka Memorial Institute for Medical Research and the Japanese Ministry of Health, Labor and Welfare.
Author Contributions
D. Yamashige: study concept and design, acquisition of data, statistical analysis, and drafting of the manuscript. Y. Kawamura: study concept and design, acquisition of data, statistical analysis. M. Kobayashi: acquisition of data and statistical analysis. J. Shindoh: acquisition of data, statistical analysis, and critical revision of the manuscript. Y. Kobayashi: acquisition of data. S. Okubo: acquisition of data. A. Kajiwara: acquisition of data. K. Kasuya: acquisition of data. S. Iritani: acquisition of data. S. Fujiyama: acquisition of data. T. Hosaka: acquisition of data. S. Saitoh: acquisition of data. H. Sezaki: acquisition of data. N. Akuta: acquisition of data. F. Suzuki: acquisition of data. Y. Suzuki: acquisition of data. K. Ikeda: acquisition of data, statistical analysis, and study supervision. Y. Arase: acquisition of data. M. Hashimoto: acquisition of data. H. Kumada: acquisition of data.
Acknowledgments
This work was supported in part by grants from the Ministry of Health, Labor and Welfare in Japan and the Japan Agency for Medical Research and Development.
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