1. Cancer Biology
  2. Medicine

A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis

  1. Ming Chao
  2. Hao Wu
  3. Kai Jin
  4. Bin Li
  5. Jianjun Wu
  6. Guangqiang Zhang
  7. Gong Yang
  8. Xun Hu  Is a corresponding author
  1. The Second Affiliated Hospital of Zhejiang University School of Medicine, China
  2. Vanderbilt University Medical Center, United States
https://doi.org/10.7554/eLife.15691
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Cite this article
  1. Ming Chao
  2. Hao Wu
  3. Kai Jin
  4. Bin Li
  5. Jianjun Wu
  6. Guangqiang Zhang
  7. Gong Yang
  8. Xun Hu
(2016)
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
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5 figures, 6 tables and 7 additional files

Figures

Figure 1
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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] × …

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
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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 …

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
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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 …

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
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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 …

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
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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 …

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.
VariablesPatients
TILA-TACEcTACE
Patient number3027
Median age, years57 (Range 32–81)54 (Range 37–81)
Gender (M/F)27/3 (90.0%/10.0%)27/0 (100%/0%)
Aetiology
 HBV24 (80.0%)25 (92.6%)
 HCV0 (0%)0 (0%)
 Non B-non C6 (20.0%)2 (7.4%)
Cirrhosis (radiology)30 (100%)27 (100%)
Bilirubin, μM16.9 ± 9.422.5 ± 11.6
Albumin, g/L39.0 ± 6.937.4 ± 5.3
AST, U/L74.9 ± 102.383.5 ± 54.1
ALT, U/L54.1 ± 80.467.3 ± 43.5
AFP, >400 ng/mL9 (30.0%)15 (55.6%)
Child-Pugh class, A/B27/3 (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 cm14 (46.7%)15 (55.6%)
 Tumor 5~10 cm16 (53.3%)12 (44.4%)
Multifocal tumors in 1 lobe8 (26.7%)12 (44.4%)
Multifocal tumors in 2 lobes8 (26.7%)12 (44.4%)
BCLC stage
 B19 (63.3%)18 (66.7%)
 C11 (36.7%)9 (33.3%)
Macrovascular invasion5 (16.7%)4 (14.8%)
 The right branch of portal vein4 (13.3%)2 (7.4%)
 Hepatic vein–1 (3.7%)
 The right branch of portal + hepatic vein1 (3.3%)1 (3.7%)
Extra-hepatic metastasis8 (26.7%)8 (29.6%)
 Lung1 (3.3%)6 (22.2%)
 Lung + bone1 (3.3%)0 (0%)
 Soft tissue–0 (0%)
 Lymph nodes5 (12.2%)0 (0%)
 Bone1 (2.0%)1 (3.7%)
 Bone+lymph node–1 (3.7%)

  1. HBV, hepatitis B virius;

    HCV, hepatitis C virius;

  2. AST, Aspartate transaminase;

    ALT, Alanine aminotransferase;

  3. 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 VTR45.1% (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

  1. VTR: viable tumor residues;

    cTACE: transarterial chemoembolization;

  2. 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
VariablesPatients
TILA-TACEcTACE
Patient number1010
Median age, years58 (Range 40–86)53 (43–81)
Gender (M/F)9 /1 (90.0%/10.0%)7 /3 (70.0%/ 30.0%)
Aetiology
 HBV9 (90.0%)8 (80.0%)
 HCV0 (0%)0 (0%)
 Non B-non C1 (10.0%)2 (20.0%)
Cirrhosis (radiology)10 (100%)10 (100%)
Bilirubin, μM17.2 ± 10.116.7 ± 7.6
Albumin, g/L38.7 ± 3.138.1 ± 5.2
AST, U/L64.8 ± 44.852.8 ± 19.2
ALT, U/L60.6 ± 48.041.0 ± 29.9
AFP, >400 ng/mL3 (30.0%)4 (40.0%)
Child-Pugh class, A/B10/0 (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 cm3 (30.0%)3 (30.0%)
 Tumor 5~10 cm7 (70.0%)7 (70.0%)
Multifocal tumors in 1 lobe3 (30.0%)3 (30.0%)
Multifocal tumors in 2 lobes4 (40.0%)2 (20.0%)
BCLC stage
 B7 (70.0%)8 (70.0%)
 C3 (30.0%)2 (20.0%)
Macrovascular invasion2 (20.0%)1 (10.0%)
 The right branch of portal vein1 (10.0%)1 (10.0%)
 The left branch of portal vein1 (10.0%)0 (0%)
Extra-hepatic metastasis1 (10.0%)2 (20.0%)
 Brain0 (0%)1 (10.0%)
 Lymph nodes1 (10.0%)1 (10.0%)

  1. HBV, hepatitis B virius;

    HCV, hepatitis C virius;

  2. AST, Aspartate transaminase;

    ALT, Alanine aminotransferase;

  3. 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 VTR25.4% (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

  1. VTR: viable tumor residues;

    cTACE: transarterial chemoembolization;

  2. TILA-TACE: targeting-intratumoral-lactic-acidosis TACE;

    RCT: randomized clinical trial.

  3. *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-TACEcTACE†
Pain5 out of 303 out of 27
Fever (≥38.5)‡13 out of 309 out of 27

  1. * 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.

  2. ‡ Mild fever occurred to all patients.

Table 6
Adverse events in patients in the RCT.
Adverse events*TILA-TACEcTACE
Pain2 out of 101 out of 10
Fever (≥38.5)†2 out of 103 out of 10

  1. * 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

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