Abstract
Background:
The use of the ethiodized oil- Lipiodol in conventional trans-arterial chemoembolization (cTACE) ensures radiopacity to visualize drug delivery in the process of providing selective drug targeting to hepatic cancers and arterial embolization. Lipiodol functions as a carrier of chemo drugs for targeted therapy, as an embolic agent, augmenting the drug effect by efflux into the portal veins as well as a predictor for the tumor response and survival.
Purpose:
To prospectively evaluate the role of 3D quantitative assessment of intra-procedural Lipiodol deposition in liver tumors on CBCT immediately after cTACE as a predictive biomarker for the outcome of cTACE.
Materials & Methods:
This was a post-hoc analysis of data from an IRB-approved prospective clinical trial. Thirty-two patients with hepatocellular carcinoma or liver metastases underwent contrast enhanced CBCT obtained immediately after cTACE, unenhanced MDCT at 24 hours after cTACE, and follow-up imaging 30-, 90- and 180-days post-procedure. Lipiodol deposition was quantified on CBCT after cTACE and was characterized by 4 ordinal levels: ≤25%, >25–50%, >50–75%, >75%. Tumor response was assessed on follow-up MRI. Lipiodol deposition on imaging, correlation between Lipiodol deposition and tumor response criteria, and correlation between Lipiodol coverage and median overall survival (MOS) were evaluated.
Results:
Image analysis demonstrated a high degree of agreement between the Lipiodol deposition on CBCT and the 24hr post-TACE CT, with a Bland-Altman plot of Lipiodol deposition on imaging demonstrated a bias of 2.75, with 95%-limits-of-agreement: −16.6 to 22.1%. An inverse relationship between Lipiodol deposition in responders versus non-responders for two-dimensional EASL reached statistical significance at 30 days (p=0.02) and 90 days (p=0.05). Comparing the Lipiodol deposition in Modified Response Evaluation Criteria in Solid Tumors (mRECIST) responders versus non-responders showed a statistically significant higher volumetric deposition in responders for European Association for the Study of the Liver (EASL)-30d, EASL-90d, and quantitative EASL-180d. The correlation between the relative Lipiodol deposition and the change in enhancing tumor volume showed a negative association post-cTACE (30-day: p<0.001; rho=−0.63). A Kaplan-Meier analysis for patients with high vs. low Lipiodol deposition showed a MOS of 46 vs. 33 months (p=0.05).
Conclusion:
3D quantification of Lipiodol deposition on intra-procedural CBCT is a predictive biomarker of outcome in patients with primary or metastatic liver cancer undergoing cTACE. There are spatial and volumetric agreements between 3D quantification of Lipiodol deposition on intra-procedural CBCT and 24h post-cTACE MDCT. The spatial and volumetric agreement between Lipiodol deposition on intra-procedural CBCT and 24hr post-cTACE MDCT could suggest that acquiring MDCT 24 hours after cTACE is redundant. Importantly, the demonstrated relationship between levels of tumor coverage with Lipiodol and degree and timeline of tumor response after cTACE underline the role of Lipiodol as an intra-procedural surrogate for tumor response, with potential implications for the prediction of survival.
Keywords: Lipiodol, TACE, imaging biomarker, liver cancer, tumor response, ceMRI
1. Introduction
Liver cancer, primary or metastatic, is the 4th-most common cause of cancer-related mortality in the world, with 8.2% of all cancer deaths, despite recent advances in treatment modalities [1]. Hepatocellular carcinoma (HCC) constitutes 75–85% of primary liver cancers, and for many patients, treatments are not curative in nature since liver lesions are diagnosed at advanced stages [2, 3]. Image-guided catheter-based locoregional therapies play a central role in the treatment of patients with unresectable HCC or liver-dominant metastatic disease [4].
Transarterial chemoembolization (TACE) is one of the most widely performed image-guided catheter-based locoregional therapies [5, 6]. The conventional-TACE (cTACE) has been established as the first-line therapy in patient with intermediate-stage HCC [7]. cTACE generally uses a water-in-oil emulsion of chemotherapeutic agents mixed with the ethiodized oil- Lipiodol. This solution is selectively injected into tumor-feeding branches of hepatic arteries, followed by bland embolic agents to cut off proximal blood supply [8].
In addition to its function as a micro-embolic agent and drug carrier, Lipiodol is ethiodized which allows for radiographic visualization of this injectable agent on both intra-procedural cone-beam computed tomography (CBCT) as well as on post-procedural multi-detector computed tomography (MDCT) [9]. As a vehicle for drug delivery, the volume and deposition pattern of Lipiodol may represent a quantifiable biomarker for deposition of chemotherapy [2]. Multiple studies have shown that Lipiodol and chemotherapeutic agent can be detected within tumors for several months after administration [10–13]. Therefore, immediate quantification of Lipiodol deposition can potentially be used to predict treatment efficacy and tumor response. Indeed, identifying non-responders early could result in improved patient outcomes [14]. A prior analysis of 36 patients evaluated the ability of Lipiodol deposition to predict short-term tumor response at one month [15]. However, the ability of intra-procedural Lipiodol deposition to predict response at intermediate-, and long-term follow-up is still unknown, and there is no data to suggest correlation with overall survival.
Many clinical practices continue to utilize dedicated non-contrast MDCT imaging 24 hours post-TACE to assess Lipiodol deposition to confirm the desired therapeutic outcome and evaluate for possible non-target deposits [16]. Despite many retrospective cohorts, the equivalence between assessing Lipiodol deposition on intra-procedural CBCT and 24-hour post-TACE CT has not yet been fully established or translated into clinical practice. The increase in utilization and improvement of intra-procedural CBCT imaging may allow for significant workflow optimization. The acquired cross-sectional imaging data can be used directly during the procedure without adding an additional dedicated CT exam the following day, while achieving similar predictive end points.
Therefore, our post-hoc analysis of prospective clinical trial data was aimed to study role of Lipiodol deposition on intra-procedural CBCT: i) as a surrogate for Lipiodol retention on 24h post-cTACE, ii) predict short-, intermediate-, and long-term tumor response on contrast enhanced MRI (CE-MRI) and finally, and iii) potential imaging biomarker to predict patient survival.
2. Materials & Methods
2.1. Patient Selection
This study was a post-hoc analysis from a prospective clinical trial, conducted in compliance with the Declaration of Helsinki on ethical principles for medical research involving human subjects, and approved by the institutional review board. Patients enrolled in this clinical trial were recruited by a multidisciplinary team, and included those with a diagnosis of HCC or other solid liver tumor (non-HCC, intrahepatic cholangiocarcinoma, or liver-predominant metastatic disease). Patients were at least 18 years of age, with Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and Child Pugh class A or B (for the HCC cohort). Exclusion criteria involved those with contraindications to specific chemotherapy agents used in the study (doxorubicin and mitomycin c), advanced cardiac or severe systemic disease, main portal vein thrombosis, known allergy to Lipiodol, poppy seed oil or iodinated contrast agents, or patients who are breast feeding or pregnant. The post-hoc study included thirty-two (HCC, n=18 and non-HCC, n=14) of thirty-nine total patients enrolled in the clinical trial with acceptable quality intra-procedural CBCT images and treated with cTACE between 2013 and 2015. Amongst the six patients enrolled with intrahepatic cholangiocarcinoma: one had right liver lobe disease, two had left liver lobe disease, and three had multifocal disease. Amongst the eight patients enrolled with liver-predominant metastatic disease, two had unifocal disease and six had multifocal disease. Four patients had a TACE procedure performed prior to this study for lesions not targeted in the current study. All treated target lesions were therapy-naive in this trial. A summary of patient baseline characteristics is provided in Table 1.
Table 1:
Baseline characteristics of the Patient Cohort
| Parameter | All Patients | Non-HCC | |
|---|---|---|---|
| Data format | Mean (SD) | Mean (SD) | Mean (SD) |
| Age (years) | 59.41 (10.28) | 59.61 (6.95) | 59.14 (13.74) |
| Sex (male/female) | 22/10 | 14/4 | 8/6 |
| Ethnicity | |||
| White | 18 | 8 | 10 |
| African American | 8 | 8 | 0 |
| Hispanic | 1 | 0 | 1 |
| Other | 5 | 2 | 3 |
| Tumor type | |||
| HCC | 18 | 18 | N/A |
| Neuroendocrine: GI | 4 | N/A | 4 |
| Neuroendocrine: pancreatic | 2 | N/A | 2 |
| Cholangiocarcinoma | 6 | N/A | 6 |
| Cutaneous melanoma | 1 | N/A | 1 |
| Uveal melanoma | 1 | N/A | 1 |
| Clinical history and treatment | |||
| HBV | 2 | 2 | 0 |
| HCV | 14 | 14 | 0 |
| Cirrhosis | 17 | 17 | 0 |
| TACE prior to enrollment (for non-target lesions) | 4 | 3 | 1 |
| Child-Pugh score (A/B/C) | 24/8/0 | 10/8/0 | 14/0/0 |
| ECOG performance status (0/1/2) | 18/12/2 | 11/6/1 | 7/6/1 |
| BCLC (A/B/C/D) | 7/4/7/0 | 7/4/7/0 | N/A |
| Treatment with sorafenib | 2 | 2 | N/A |
| Baseline imaging characteristics | |||
| Tumor diameter (cm) | 6.77 (4.28) | 3.96 (1.89) | 10.19 (3.96) |
| Enhancing tumor diameter (cm) | 4.71 (2.64) | 3.08 (1.53) | 6.69 (2.46) |
| Tumor area (cm2) | 30.44 (38.23) | 10.59 (11.01) | 54.53 (45.63) |
| Enhancing tumor area (cm2) | 13.36 (17.42) | 6.06 (5.67) | 22.22 (22.51) |
| Tumor volume (cm3) | 203.72 (465.83) | 45.72 (72.97) | 395.57 (649.36) |
| Enhancing tumor volume (cm3) | 110.26 (296.93) | 26.00 (35.56) | 212.58 (425.80) |
| Tumor enhancement (%) | 55.77 (28.31) | 59.02 (31.53) | 51.81 (27.78) |
| Tumor burden (%) | 8.61 (12.82) | 3.41 (5.60) | 14.93 (16.14) |
| Enhancing tumor burden (%) | 4.60 (7.91) | 1.95 (2.66) | 7.83 (10.72) |
| Liver volume (cm3) | 1919.15 (834.60) | 1906.83 (935.34) | 1935.26 (970.07) |
| SUV mean | 4.99 (4.75) | 3.21 (1.62) | 7.02 (6.32) |
| SUV: lesion/liver ratio | 2.29 (2.29) | 1.43 (0.71) | 3.29 (3.06) |
| SUV: lesion/blood ratio | 3.12 (3.36) | 1.80 (0.95) | 4.61 (4.46) |
BCLC, Barcelona Clinic Liver Cancer staging; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus.
2.2. Imaging and Follow-up Technique
Preprocedural imaging included multiphasic contrast-enhanced (CE) CT, multiphasic CE-MRI scan of the liver, and fluorodeoxyglucose (FDG)-PET/CT scans. A non-contrast CT scan of the abdomen was obtained 24 hours after undergoing cTACE to demonstrate Lipiodol deposition within the targeted portion of the liver. Patients included in the study had follow-up imaging and clinical evaluation performed at 30 days, 90 days, and 180 days after completion of cTACE. Follow-up imaging included multiphase CE-CT and CE-MRI of the liver, and PET-CT (only at the 90- and 180-days post-procedure timepoints). Follow-up clinical evaluation included physical examinations, laboratory tests, and tumor marker analysis.
2.3. cTACE Procedure
The cTACE procedure was performed according to standard institutional protocol by an interventional radiologist with 19 years of experience in hepatic interventions. Firstly, the arterial supply to the hepatic tumor is evaluated by hepatic arteriography and cone-beam CT with the intra-arterial injection of contrast medium. Lobar, selective, and super-selective cTACE was performed in this study, based on protocols used in the study by Savic et al. [17]. A cTACE was considered lobar if the catheters were placed in the right or left hepatic artery branches, or right or left hepatic artery if replaced (2nd order) [17]. A cTACE was considered selective if a coaxial catheter was placed in a sector or segmental artery branch (3rd/4th order) [17]. A cTACE was considered super-selective if the catheter was placed in smaller branches of the hepatic vasculature than the ones discussed above. Dual-phase CBCT was performed to confirm the number of feeder arteries by automated segmentation-based feeder identifier software-EmboGuide (Philips Healthcare, Best, The Netherlands). Once the appropriate vessel was selected, chemoembolization was performed (specific amounts titrated to each patient) using approximately 10 cc of Lipiodol (Lipiodol; Guerbet, Paris, France) and 10 cc of chemotherapy (with 50 mg Doxorubicin and 10 mg of Mitomycin-C (Pharmacia & Upjohn, Peapack, NJ)), mixed 1:1 for a total of 20 cc. Embolization of the proximal feeding arteries with 100–300-micron gelatin-coated tris-acryl microspheres (Merit Medical, South Jordan, UT) to achieve arterial stasis was performed. Further details on the cTACE technique are found in the Supplemental Materials.
2.4. Intra-procedural Cone-beam CT
Before and immediately after chemoembolization, all patients had CBCT imaging performed using a commercial angiographic system (Allura Xper FD20, Philips Healthcare, Best, The Netherlands) with the XperCT option, enabling CBCT acquisition and volumetric image reconstruction. Non-contrast and dual-phase post-contrast images were acquired before and after the procedure [18]. Details on CBCT acquisition are present in the Supplemental Materials.
2.5. Quantification of Lipiodol Deposition
Volumetric analysis was performed by a radiological reader who did not perform the cTACE procedure. A semi-automated quantification software (IntelliSpacePortal V8.0, Philips Healthcare, Haifa, Israel) was used to compute overall tumor volumes and Lipiodol deposition volume (in cm3), which has been extensively validated [19–26]. Intra-procedural CBCT images were selected and the tumor volume was segmented. A region of interest of non-tumor hepatic parenchyma was selected as the baseline (liver background noise ratio) for calculations to quantify the total volume of Lipiodol deposition and Lipiodol deposition relative to the entire tumor volume (Figure 1).
Figure 1:
A three panel CT scan image from one representative patient (HCC in the left hepatic lobe, lobar embolization with catheter positioned in the left hepatic artery) highlighting the Lipiodol segmentation and quantification process. In panel A) the red outline depicts a semi-automated segmentation of the tumor. Panel B) shows the overlay of the three-dimensional structure of the tumor as generated by the segmentation software on a cross-sectional imagine slice. Panel C) depicts the overlay of the quantified Lipiodol deposition heatmap (using a technique analogous to qEASL computation) over a cross-sectional imaging slice.
2.6. Tumor Response Assessment
World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), European Association for the Study of the Liver (EASL), and quantitative EASL (qEASL) guidelines were used for tumor response assessment for each target lesion according to one-dimensional longest enhancing dimension [22, 27–31]. Measurement of the volumetric enhancing qEASL parameter was performed using similar semi-automatic techniques for quantifying volumetric Lipiodol deposition. Tumor assessment criteria were analyzed on follow-up imaging at 30 days, 90 days, and 180 days post-TACE. Based on the guidelines, tumor response was divided into progressive disease (PD), stable disease (SD), partial response (PR), complete response (CR). Patients with CR and PR were considered to be responders, while patients with SD and PD were considered as non-responders.
2.7. Statistical Analysis
Data were analyzed using Prism version 7 (GraphPad, San Diego, California). Bland-Altman statistics were used to assess agreement between Lipiodol deposition on CBCT and 24-hour post-TACE CT. Spearman correlation was used to analyze correlation between Lipiodol deposition on CBCT and difference of volumetric enhancing tumor % on CE-MRI. Wilcoxon rank-sum test was used to evaluate differences in Lipiodol deposition between Responders and Non-responders (for each mRECIST, EASL, qEASL). Kaplan-Meier analysis was used to assess differences in survival between patients with high Lipiodol deposition (values greater than the median) and low Lipiodol deposition (values less than the median). A p-value ≤ 0.05 was considered statistically significant.
2.8. IRB Statement
The study was conducted after approval by the Institutional Review Board at the home institution. The data used in this study included 32 of 39 patients who underwent a clinical trial involving cTACE treatment between 2013 and 2015 (trial completed on April 15th, 2020). Written informed consent was obtained according to institutional guidelines and the protocols used in the study were approved by the Human Investigations Committee of the home institution.
3. Results
3.1. Agreement of CBCT and 24h post-TACE CT
Bland-Altman statistics demonstrated high agreement between percentage Lipiodol deposition in the tumor on CBCT and 24-hour post-TACE CT (Figure 2). This included a minimal mean bias of 2.8% towards Lipiodol deposition on CBCT images with a standard deviation of 8.9%. The upper ninety-five percent limit of agreement was 22.1%, while the lower ninety-five percent limit of agreement was −16.6%.
Figure 2:
Figure depicts a Bland-Altman analysis on the percentage of Lipiodol deposition on intra-procedural CBCT versus 24-hour post-TACE CT. The y-axis represents the percentage difference in amounts of Lipiodol (in the tumor) between the two imaging modalities on a particular patient whereas the x-axis represents the average percentage of Lipiodol deposition (in the tumor) between the two imaging modalities. A high agreement was demonstrated, with a mean bias of 2.7% and 95% limits of agreement (plotted in black dotted lines) between −16.6% and 22.1%.
3.2. Lipiodol Deposition in Responders Versus Non-responders
Results showed higher percentage of Lipiodol deposition in responders, on CBCT, compared with non-responders (Figure 3). The complete findings have been presented in Table 2. However, this inverse relationship of Lipiodol deposition (on post-procedural CBCT) and tumor response status with time was statistically significant only for two-dimensional EASL (at 30- and 90-days) and three-dimensional qEASL criteria (at 180-days). None of the tests involving the mRECIST criterion were statistically significant.
Figure 3:
Figure depicts a 3-panel scatter plot with error bar measurements, with two subsets of our patient cohort (divided into responders [in black] and non-responders [in gray]). The y-axis in all the panels is the percentage of Lipiodol deposition (in the tumor) on the CBCT scan. The x-axis represents the three post-procedure time points imaging was performed: 30, 90, and 180 days. The three panels depict different tumor response assessment criterion: Panel A) represents mRECIST, Panel B) represents EASL, and Panel C) represents qEASL
Table 2:
Tumor response assessment vs. follow-up time post-cTACE for Responders vs. Non-responders
| Time post-cTACE | 30-day | 90-day | 180-day |
|---|---|---|---|
| Tumor Response Assessment Responders vs. Non-Responders | Percentage (p-value) | Percentage (p-value) | Percentage (p-value) |
| mRECIST | 72% vs. 61% (0.49) | 82% vs. 61% (0.14) | 67% vs. 76% (0.52) |
| 2-D EASL | 83% vs. 54% (0.02) | 80% vs. 54% (0.05) | 76% vs. 68% (0.56) |
| 3-D qEASL | 87%vs61% (0.14) | 86% vs. 65% (0.08) | 86% vs. 62%% (0.05) |
Bolding indicates statistical significance
An inverse relationship between Lipiodol deposition in responders versus non-responders for two-dimensional EASL reached statistical significance at 30 days and 90 days. Specifically, the mean percentage Lipiodol deposition was 83% at 30 days for responders compared with 54% for non-responders (p=0.02) and 80% at 90 days for responders compared with 54% for non-responders (p=0.05).
Similar analysis for three-dimensional qEASL resulted in higher percentage Lipiodol deposition for responders versus non-responders at all time points, which reached statistical significance for the 180-day time point: 85% at 180 days for responders compared with 62% for non-responders (p=0.05).
3.3. Relationship between Lipiodol Deposition (on post-procedural CBCT) and Enhancing Tumor Volume with Time
A Spearman correlation analysis demonstrated an overall trend of decreased residual enhancing tumor volume, on ce-MRI (normalized to baseline imaging) for each of the three time points. This is represented in Figure 4 which highlights that an inverse correlation between the percentage of tumor covered by Lipiodol on post-procedural CBCT and the enhancing tumor volume on follow-up imaging. There was a reverse linear correlation with rho value of −0.63 at 30 days (N=24) with 95% confidence interval from −0.83 to −0.29 (p < 0.001), a reverse linear correlation with rho of −0.69 at 90 days (N=15) with 95% confidence interval from −0.89 to −0.26 (p = 0.006), and a reverse linear correlation with rho of −0.66 at 180 days (N=12) with 95% confidence interval from −0.90 to −0.12 (p = 0.02).
Figure 4:
Figure depicts a 3-panel scatter plot with a linear regression trend line. The y-axis in all the panels represents the difference in percentage of residual enhancing tumor volume (normalized to baseline imaging) on the follow-up ceMRI scans. The x-axis represents the percentage of Lipiodol deposition (in the tumor) on CBCT. The three panels depict different time points post-procedure that imaging was performed: Panel A) represents 30 days, Panel B) represents 90 days, and Panel C) represents 180 days. Spearman correlation analysis results and the associate p-values are present in the respective panels as well.
3.4. Survival Analysis
Kaplan-Meier survival curves demonstrating separation with greater survival in patients with high Lipiodol (defined as values greater than the median) deposition on intra-procedural CBCT compared with the low Lipiodol (defined as values lower than the median) deposition group (Figure 5). Median survival was 46 months for patients with high Lipiodol deposition versus 33 months for patients with low Lipiodol deposition. The Log-rank (Mantel-Cox) p-value was computed to be 0.05. However, since the original prospective study was designed for a 6-month time point, a note was made of a large number of censored patients in our longer-term survival data (N=13 in the high deposition group, N=10 in the low deposition group).
Figure 5:
Figure depicts a Kaplan-Meier survival analysis between patients with high Lipiodol deposition (above the median value, depicted in black) and low Lipiodol deposition (below the median value, depicted in gray). The y-axis represents the percentage of patients in a particular cohort who survived while the x-axis represents the time (number of months post-TACE).
4. Discussion
This post-hoc analysis of a prospective phase clinical trial showed three main findings. First, there was an agreement between the percentage of tumor containing Lipiodol on intra-procedural CBCT and 24-hour post-cTACE CT. Additionally, there was a trend of improved tumor response for increasing Lipiodol deposition at 30 days, 90 days, and 180 days post-TACE. Finally, while limited to a relatively smaller number of patients, our prospective study suggested significantly increased survival in patients with high Lipiodol deposition on intra-procedural CBCT compared to those with low Lipiodol deposition. All the imaging analysis were three-dimensional quantitative in nature.
By demonstrating agreement between Lipiodol deposition on intra-procedural CBCT and 24-hour post-cTACE CT, our results suggest that lipiodol deposition measurement on intraprocedural CBCT may be used as a surrogate for lipiodol deposition on 24-hour post-cTACE noncontract MDCT. Therefore, it is conceivable that using 24-hour post-TACE MDCT imaging may be redundant and unnecessary if adequate-quality intra-procedural CBCT images are acquired. This is in agreement with another study that found that CBCT was more accurate than fluoroscopy for quantifying Lipiodol deposition in four discrete categories [32]. A similar trend was found in a prior 11 patient study quantifying volumetric Lipiodol deposition between CBCT and multi-detector CT [33]. Another study computed the average Hounsfield units of Lipiodol deposition in CBCT and multi-detector CT [34], also finding high correlation between the two. Overall, our study adds to the growing body of evidence that CBCT may be equivalent to follow-up non-contrast CT for evaluation of Lipiodol deposition while establishing the role of Lipiodol as an intra-procedural imaging biomarker in a prospective standardized trial protocol.
Our data demonstrates that Lipiodol deposition on intra-procedural CBCT can be used to predict short- (30 days), intermediate- (90 days), and long-term (180 days) tumor response on follow-up contrast enhanced MRI. Interestingly, this trend seemed to be greatest for response assessment relying on two-dimensional enhancement (EASL) and three-dimensional enhancement (qEASL) compared to one-dimensional enhancement (mRECIST), suggesting that there may be greater predictive strength when more completely accounting for the entire enhancing tumor. Moreover, the predictive ability of Lipiodol deposition on CBCT seemed to be highest, in general, for follow-up imaging at 30 days and 90 days, which could intuitively suggest that many patients develop detectable tumor recurrence from the time period between 90 days to 180 days which may have resulted in more diverging data end points. Our prospectively collected data validates prior suggestions from a study which compared CBCT Lipiodol deposition and tumor response by mRECIST 4–6 weeks post-TACE and equally found a high degree of correlation between Lipiodol deposition and tumor response [32].
Higher Lipiodol deposition on CBCT was associated in an overall trend of decreased percentage residual tumor volume at 30 days, 90 days, and 180 days. For instance, the patient with the poorest treatment response within our cohort had less than 25% Lipiodol deposition on CBCT and demonstrated an 8-fold increase in enhancing tumor at 30 days and 90 days (the patient was lost to follow-up without 180-day imaging available). On the other hand, most patients with greater than 75% Lipiodol deposition had interval decrease in enhancing tumor on follow-up imaging. This data is in line with a prior investigation of CBCT Lipiodol deposition which also showed an analogous trend of short-term tumor response prediction at 30 days [15].
Furthermore, our long-term survival analysis showed significant survival benefits for patients with high Lipiodol deposition versus patients with low relative lesion coverage with Lipiodol, with a difference of approximately 13 months in MOS between the groups. Although this represents an intuitive finding due to better treatment efficacy, the small number of total patients and high level of censoring limit solid conclusions to be drawn from this data and larger cohorts should focus on the added value of Lipiodol deposition in the tumor as an intra-procedural predictor of patient survival.
This study has multiple limitations. The analyzed cohort of patients enrolled a small number of diverse patients, combining both HCC and metastatic liver disease, which limited a powerful subgroup analysis of these different patient populations. Some of these limitations were mitigated by a rigorous multi-modality imaging protocol at multiple study time points as well as a high level of procedural standardization applied to investigate Lipiodol as an imaging biomarker. A minor limitation, as previously mentioned in the Methods, is that a small subset (six patients) having a slightly different ratio of Lipiodol and chemotherapy that was administered to maintain flow rate. An additional limitation is the fact that a number of patients was censored within the long-term survival analysis, somewhat limiting the extrapolation of survival results.
In conclusion, findings of our prospective trial add to the growing body of knowledge on the use of intra-procedural Lipiodol as a marker for therapeutic efficacy. Particularly, the three-dimensional quantitative nature of the imaging and analysis along with the source of the data resulting from a prospective clinical trial add to the strengths of this study. The spatial and volumetric agreement between Lipiodol deposition on intra-procedural CBCT and 24hr post-cTACE MDCT could suggest that acquiring MDCT 24 hours after cTACE is redundant and can thus be omitted from clinical practice protocols. Importantly, the demonstrated relationship between levels of tumor coverage with Lipiodol and degree of tumor response at 30d, 90d, and 180d after cTACE underline the role of Lipiodol as an intra-procedural surrogate for tumor response, with potential implications for the prediction of survival.
Supplementary Material
Highlights.
Agreement in percentage of Lipiodol coverage of the tumor during cTACE on CBCT and 24h-post MDCT
Tumor coverage with Lipiodol is associated with sustained tumor response post-cTACE
Imaging biomarker- Lipiodol on intra-procedural CBCT, could predict focal disease progression.
Study suggests MDCT 24h after cTACE is redundant
Acknowledgments:
Geliang Gan and Yanhong Deng kindly provided statistical advice for this manuscript.
Funding:
This work was supported by Guerbet Pharmacueticals. This study has also received funding by NIH/NCI, Bethesda, MD, USA (R01 CA160771), and the Rolf W. Günther Foundation for Radiological Science, Aachen, Germany.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of Interest: Financial remuneration to authors and family members related to the subject of this article: T.S. and J.C. have a grant with Guerbet Pharmaceuticals for conduct of this study. M.L. is a Visage Imaging Research North America employee. Q.R. was a Philips Healthcare employee partly during the conduction of this study.
IRB: Our institutional review board approved this study and its associated protocol. Study is a Post-hoc analysis of data from an IRB-approved prospective clinical trial (NCT01877187).
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