A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis
- The Second Affiliated Hospital of Zhejiang University School of Medicine, China
- Vanderbilt University Medical Center, United States
Figures
Figure 1
Viable tumor residues (VTR) after treatment of cTACE verus TILA-TACE.
Patients’ demographic parameters were described in Table 1. The relative therapeutic improvement by TILA-TACE was 81.1%. Relative therapeutic improvement by bicarbonate is defined as [(μ1-μ2)/μ1] × (100%), where μ1 is the mean of viable tumor residues after treatment (cTACE) and μ2 the mean residual after treatment (TILA-TACE), and the maximal therapeutic improvement is 100%. Differences in VTR between two groups were statistically significant (p<0.0001), as assessed using the general linear model after adjustment for viable tumor volume before treatment
-
Figure 1—source data 1
Calculation of viable volume residues of each patient in the nonrandomized study after the first round treatment.
- https://cdn.elifesciences.org/articles/15691/elife-15691-fig1-data1-v3.xlsx
Figure 2
Tumor objective response to cTACE or TILA-TACE categorized according to EASL criteria.
Rate of tumor response to treatment and representative MRI images of tumor before and after treatment (A) in the cTACE group (n=27) and (B) in the TILA-TACE group (n=30). (C) The difference in tumor responses between two groups was statistically significant (p<0.0001), as assessed by the proportional odds model after adjustment for viable tumor volume before treatment. CR, complete necrosis; PR, viable tumor volume less than 50% of the viable tumor volume before treatment; SD, viable tumor volume larger than 50% of the viable tumor volume before treatment; PD, viable tumor volume larger than 100% after treatment.
-
Figure 2—source data 1
The criteria and classification of response to treatment in the nonrandomized study after the first round treatment.
- https://cdn.elifesciences.org/articles/15691/elife-15691-fig2-data1-v3.xlsx
Figure 3
Viable tumor residues after treatment with cTACE or TILA-TACE in the randomized controlled study.
The relative therapeutic improvement by TILA-TACE was 80.1%. Differences in VTR between two arms were statistically significant (p=0.0009), as assessed using the general linear model after adjustment for viable tumor volume before treatment.
-
Figure 3—source data 1
Calculation of viable volume residues of each patient in the randomized study after the first round treatment.
- https://cdn.elifesciences.org/articles/15691/elife-15691-fig3-data1-v3.xlsx
Figure 4
Tumor objective response to cTACE or TILA-TACE according to EASL criteria.
Twenty patients were randomly assigned to treatment of cTACE or TILA-TACE. (A) Tumor response rate to cTACE and representative MRI images of tumor before and after treatment. 10 patients were treated with cTACE. (B) Tumor response rate to TILA-TACE and representative MRI image of tumor before and after treatment. 10 patients were treated with TILA-TACE. (C) The pattern of tumor response to TILA-TACE and cTACE. The difference between 2 groups was statistically significant (p=0.003), as assessed using proportional odds model. CR, complete necrosis; PR, viable tumor volume less than 50% of the viable tumor volume before treatment; SD, viable tumor volume larger than 50% of the viable tumor volume before treatment; PD, viable tumor volume larger than 100% after treatment.
-
Figure 4—source data 1
The criteria and classification of response to treatment in the randomized study after the first round treatment.
- https://cdn.elifesciences.org/articles/15691/elife-15691-fig4-data1-v3.xlsx
Figure 5
Kaplan-meier analysis of cumulative survival of patients receiving TILA-TACE or cTACE treatment.
(A) Cumulative survival of patients described in Table 1. p=0.0052. (B) Survival of patients described in Table 2. Left panel, all patients; right panel, patients who initially assigned to cTACE but subsequently crossed over to TILA-TACE treatment were excluded. p>0.05. (C) Cumulative Survival of patients pooled from Table 1 and 2. p=0.0133.
-
Figure 5—source data 1
The survival status of each patient at the cut-off date in the nonrandomized and the randomized studies.
- https://cdn.elifesciences.org/articles/15691/elife-15691-fig5-data1-v3.xlsx
Tables
Table 1
Clinical and tumor characteristics of patients treated with cTACE and TILA-TACE in the nonrandomized study.
| Variables | Patients | |
|---|---|---|
| TILA-TACE | cTACE | |
| Patient number | 30 | 27 |
| Median age, years | 57 (Range 32–81) | 54 (Range 37–81) |
| Gender (M/F) | 27/3 (90.0%/10.0%) | 27/0 (100%/0%) |
| Aetiology | ||
| HBV | 24 (80.0%) | 25 (92.6%) |
| HCV | 0 (0%) | 0 (0%) |
| Non B-non C | 6 (20.0%) | 2 (7.4%) |
| Cirrhosis (radiology) | 30 (100%) | 27 (100%) |
| Bilirubin, μM | 16.9 ± 9.4 | 22.5 ± 11.6 |
| Albumin, g/L | 39.0 ± 6.9 | 37.4 ± 5.3 |
| AST, U/L | 74.9 ± 102.3 | 83.5 ± 54.1 |
| ALT, U/L | 54.1 ± 80.4 | 67.3 ± 43.5 |
| AFP, >400 ng/mL | 9 (30.0%) | 15 (55.6%) |
| Child-Pugh class, A/B | 27/3 (90.0%/10.0%) | 25/2 (92.6%/7.4%) |
| The size of largest tumor (cm) | 9.2 (range 5.0–13.6) | 10.3 (range 5.0–14.6) |
| Tumor >10 cm | 14 (46.7%) | 15 (55.6%) |
| Tumor 5~10 cm | 16 (53.3%) | 12 (44.4%) |
| Multifocal tumors in 1 lobe | 8 (26.7%) | 12 (44.4%) |
| Multifocal tumors in 2 lobes | 8 (26.7%) | 12 (44.4%) |
| BCLC stage | ||
| B | 19 (63.3%) | 18 (66.7%) |
| C | 11 (36.7%) | 9 (33.3%) |
| Macrovascular invasion | 5 (16.7%) | 4 (14.8%) |
| The right branch of portal vein | 4 (13.3%) | 2 (7.4%) |
| Hepatic vein | – | 1 (3.7%) |
| The right branch of portal + hepatic vein | 1 (3.3%) | 1 (3.7%) |
| Extra-hepatic metastasis | 8 (26.7%) | 8 (29.6%) |
| Lung | 1 (3.3%) | 6 (22.2%) |
| Lung + bone | 1 (3.3%) | 0 (0%) |
| Soft tissue | – | 0 (0%) |
| Lymph nodes | 5 (12.2%) | 0 (0%) |
| Bone | 1 (2.0%) | 1 (3.7%) |
| Bone+lymph node | – | 1 (3.7%) |
-
HBV, hepatitis B virius;
HCV, hepatitis C virius;
-
AST, Aspartate transaminase;
ALT, Alanine aminotransferase;
-
AFP, alpha-feto-protein.
Table 2
Geometric means of viable tumor residues after treatment of cTACE or TILA-TACE in the nonrandomized cohort of 57 patients.
| Geometric mean (95% CI) | |||
|---|---|---|---|
| cTACE (n=27) | TILA-TACE (n=30) | p value | |
| Crude VTR | 45.1% (30.3%–67.0%) | 7.1% (4.4%–11.5%) | <0.0001 |
| Multivariable adjusted VTR* | 45.6% (28.9%–72.0%) | 7.1% (4.6%–10.9%) | <0.0001 |
-
VTR: viable tumor residues;
cTACE: transarterial chemoembolization;
-
TILA-TACE: targeting-intratumoral-lactic-acidosis TACE;
*Adjusted for viable tumor volume prior to treatment and macrovascular invasion using the general linear regression. No appreciable alterations in results were found after adjustment for other covariates such as age, BCLC tumor stage, extra-hepatic metastasis, HBV DNA copy numbers, and tumor multifocality.
Table 3
| Variables | Patients | |
|---|---|---|
| TILA-TACE | cTACE | |
| Patient number | 10 | 10 |
| Median age, years | 58 (Range 40–86) | 53 (43–81) |
| Gender (M/F) | 9 /1 (90.0%/10.0%) | 7 /3 (70.0%/ 30.0%) |
| Aetiology | ||
| HBV | 9 (90.0%) | 8 (80.0%) |
| HCV | 0 (0%) | 0 (0%) |
| Non B-non C | 1 (10.0%) | 2 (20.0%) |
| Cirrhosis (radiology) | 10 (100%) | 10 (100%) |
| Bilirubin, μM | 17.2 ± 10.1 | 16.7 ± 7.6 |
| Albumin, g/L | 38.7 ± 3.1 | 38.1 ± 5.2 |
| AST, U/L | 64.8 ± 44.8 | 52.8 ± 19.2 |
| ALT, U/L | 60.6 ± 48.0 | 41.0 ± 29.9 |
| AFP, >400 ng/mL | 3 (30.0%) | 4 (40.0%) |
| Child-Pugh class, A/B | 10/0 (100%/0%) | 10/0 (100%/0%) |
| The size of largest tumor (cm) | 7.9 (range 5.0–13.5) | 7.5 (range 5.0–13.0) |
| Tumor >10 cm | 3 (30.0%) | 3 (30.0%) |
| Tumor 5~10 cm | 7 (70.0%) | 7 (70.0%) |
| Multifocal tumors in 1 lobe | 3 (30.0%) | 3 (30.0%) |
| Multifocal tumors in 2 lobes | 4 (40.0%) | 2 (20.0%) |
| BCLC stage | ||
| B | 7 (70.0%) | 8 (70.0%) |
| C | 3 (30.0%) | 2 (20.0%) |
| Macrovascular invasion | 2 (20.0%) | 1 (10.0%) |
| The right branch of portal vein | 1 (10.0%) | 1 (10.0%) |
| The left branch of portal vein | 1 (10.0%) | 0 (0%) |
| Extra-hepatic metastasis | 1 (10.0%) | 2 (20.0%) |
| Brain | 0 (0%) | 1 (10.0%) |
| Lymph nodes | 1 (10.0%) | 1 (10.0%) |
-
HBV, hepatitis B virius;
HCV, hepatitis C virius;
-
AST, Aspartate transaminase;
ALT, Alanine aminotransferase;
-
AFP, alpha-feto-protein.
Table 4
Geometric means of viable tumor residues after treatment of cTACE or TILA-TACE in the RCT.
| Geometric mean (95% CI) | |||
|---|---|---|---|
| cTACE (n=10) | TILA-TACE (n=10) | p value | |
| Crude VTR | 25.4% (10.1%–64.0%) | 4.6 (1.8%–11.4%) | 0.008 |
| Multivariable adjusted VTR* | 28.1% (13.9%–56.8%) | 4.1 (2.0%–8.4%) | 0.0009 |
-
VTR: viable tumor residues;
cTACE: transarterial chemoembolization;
-
TILA-TACE: targeting-intratumoral-lactic-acidosis TACE;
RCT: randomized clinical trial.
-
*Adjusted for viable tumor volume prior to treatment using the general linear regression. No appreciable alterations in results were found after adjusting for other covariates such as age, BCLC tumor stage, extra-hepatic metastasis, HBV DNA copy numbers, macrovascular invasion, and tumor multifocality individually.
Table 5
Adverse events of patients receiving TILA-TACE or cTACE.
| Adverse events* | TILA-TACE | cTACE† |
|---|---|---|
| Pain | 5 out of 30 | 3 out of 27 |
| Fever (≥38.5)‡ | 13 out of 30 | 9 out of 27 |
-
* The adverse events monitored also include acute hepatic decomposition, irreversible hepatic decompensation, respiratory failure or decompensation, biliary stricture or obstruction, liver abscess, gastrointestinal bleeding, arterial thrombosis, arterial-portal shunting. These events were not observed in the patients.
† Patients were retrospectively retrieved from our database.
-
‡ Mild fever occurred to all patients.
Table 6
Adverse events in patients in the RCT.
| Adverse events* | TILA-TACE | cTACE |
|---|---|---|
| Pain | 2 out of 10 | 1 out of 10 |
| Fever (≥38.5)† | 2 out of 10 | 3 out of 10 |
-
* The adverse events monitored also include acute hepatic decomposition, irreversible hepatic decompensation, respiratory failure or decompensation, biliary stricture or obstruction, liver abscess, gastrointestinal bleeding, arterial thrombosis, arterial-portal shunting. These events were not observed in the patients.
† Mild fever occurred to all patients.
Additional files
-
Supplementary file 1
Patient demographics, diagnosis, treatment, and follow-up in cTACE group in the nonrandomized study.
- https://cdn.elifesciences.org/articles/15691/elife-15691-supp1-v3.xlsx
-
Supplementary file 2
Patient demographics, diagnosis, treatment, and follow-up in TILA-TACE group in the nonrandomized study.
- https://cdn.elifesciences.org/articles/15691/elife-15691-supp2-v3.xlsx
-
Supplementary file 3
Patient demographics, diagnosis, treatment, and follow-up in RCT.
- https://cdn.elifesciences.org/articles/15691/elife-15691-supp3-v3.xlsx
-
Supplementary file 4
Sample size estimation for the randomized study.
- https://cdn.elifesciences.org/articles/15691/elife-15691-supp4-v3.xlsx
-
Supplementary file 5
Randomized controlled study of bicarbonate-enhanced and conventional transarterial chemoembolization in treatment of hepatocellular carcinoma (protocol number ZUSAHZUCI201401).
- https://cdn.elifesciences.org/articles/15691/elife-15691-supp5-v3.pdf
-
Reporting standard 1
CONSORT flor diagram.
- https://cdn.elifesciences.org/articles/15691/elife-15691-repstand1-v3.jpg
-
Reporting standard 2
CONSORT 2010 checklist.
- https://cdn.elifesciences.org/articles/15691/elife-15691-repstand2-v3.doc
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis
eLife 5:e15691.
https://doi.org/10.7554/eLife.15691
