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Supplementary data to:

Survival in patients with advanced-stage HCC and portal vein thrombosis: Comparison between conventional and drug-eluting beads TACE

Table of Contents

Supplementary Materials 2

Methods 2

Propensity Score Adjustment 2

Supplementary Tables 3

Supplementary References 7

Supplementary materials and methods

Methods

Propensity Score Adjustment

Different methods for propensity score matching were considered, namely, matching, subclassification, full matching and weighting. Weighting was chosen because it allowed us to use all individuals available in our relatively small sample. Under this approach the probability of receiving either treatment was obtained by modeling treatment received as a function of the observed covariates via a nonparametric boosted tree model [1]. In the analysis each patient was then weighted by the inverse probability of receiving the treatment they received; i.e., the cTACE group was weighted by one over their probability of receiving cTACE and the DEB-TACE group was weighted by one over their probability of receiving DEB-TACE. This weights both groups up to the combined sample, thus estimating the average treatment effect (ATE), which is the difference in outcomes if everyone in the sample were given cTACE versus if everyone were given DEB-TACE [1-4]. The variables included in the propensity score model were: location of PVT, diameter and multiplicity of the tumors, Child-Pugh class, Eastern Cooperative Oncology Group performance status (ECOG PS), extrahepatic metastasis, tumor burden (>50%) and tumor type (infiltrative vs. nodular). Age and sex were not included into propensity score analysis in order to limit the covariates to those utilized in the BCLC staging system as well as to strictly include the most relevant clinical parameters (Supplementary Table 1). The balance in the covariates was evaluated by the absolute standardized differences in means before and after weighting. A recommended threshold value for balance in the covariates is 0.2 [2]. The different cut-offs over all included covariates are summarized in the supplementary Table 1.

Supplementary Table 1. Cut-offs from the included covariates for the propensity score weighting according to the BCLC staging system

BCLC
Portal Venous Thrombosis / main vs. peripheral
Diameter / ≤ 3 cm vs. > 3 cm
Multiplicity / unifocal vs. multifocal
Child-Pugh Class / A – B vs. C
ECOG PS Score / 0 vs. 1-2 vs. ≥ 3
Extrahepatic Metastasis / no vs. yes
Tumor Burden / ≤ 50 % vs. > 50 %
Tumor Type / nodular vs. infiltrative

BCLC, Barcelona Clinic Liver Cancer; PVT, portal venous thrombosis; ECOG PS, Eastern Cooperative Oncology Group performance status

Supplementary Table 2. Balance between cTACE and DEB-TACE after propensity score weighting

SMD
ECOG PS score (0 vs. 1-2 or ≥ 3) / 0.026
ECOG PS score (1-2 vs. 0 or ≥ 3) / 0.034
Child-Pugh class (A or B vs. C) / 0.007
PVT (main vs. peripheral) / 0.034
Multiplicity / 0.031
Size of the dominant lesion
(≤ 3 cm vs. > 3 cm) / 0.091
Tumor burden / 0.022
Tumor type / 0.010
Extrahepatic Metastasis / 0.000
Covariates not included into the propensity score weighting
Cirrhosis / 0.013
Lobe / 0.226
Age / 0.16
Sex / 0.216
Lymph Node Metastasis / 0.461

The balance in the covariates was evaluated by the absolute standardized differences in means before and after weighting. A recommended threshold value for balance in the covariates is 0.2.

cTACE, conventional trans-arterial chemoembolization; DEB-TACE, drug-eluting beads TACE; BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status, PVT, portal venous thrombosis; SMD, absolute standardized difference in means

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Supplementary Table 3. Clinical and Laboratory Toxicities grade 3 or higher per procedure according to CTCAEv4.03

7 days Toxicity Report / 30 days Toxicity Report
BCLC C / BCLC D / BCLC C / BCLC D
cTACE / DEB-TACE / cTACE / DEB-TACE / cTACE / DEB-TACE / cTACE / DEB-TACE
Clinical Toxicity / N=162
No/ Yes / N=55
No/ Yes / N=23
No/ Yes / N=7
No/ Yes / N=58
No/ Yes / N=43
No/ Yes / N=8
No/ Yes / N=5
No/ Yes
PES / 140/22 / 41/14 / 21/2 / 5/2 / 24/34 / 11/32 / 0/8 / 3/2
Ascites/ Edema / 161/1 / 55/0 / 22/1 / 6/1 / 53/5 / 37/6 / 6/2 / 2/4
Rash / 161/1 / 54/1 / 23/0 / 7/0 / 58/0 / 43/0 / 8/0 / 5/0
Anemia / 162/0 / 53/2 / 23/0 / 7/0 / 57/1 / 43/0 / 8/0 / 5/0
Hyperglycemia / 161/1 / 55/0 / 23/0 / 7/0 / 58/0 / 43/0 / 8/0 / 5/0
Electrolyte Imbalance / 162/0 / 55/0 / 23/0 / 7/0 / 57/1 / 42/1 / 8/0 / 5/0
Diarrhea / 162/0 / 54/1 / 23/0 / 7/0 / 56/2 / 41/2 / 7/1 / 5/0
Esophagitis/ Gastritis / 162/0 / 55/0 / 23/0 / 7/0 / 56/2 / 43/0 / 8/0 / 5/0
Arrhytmia / 161/1 / 55/0 / 22/1 / 7/0 / 58/0 / 43/0 / 8/0 / 5/0
Shortness of Breath / 161/1 / 54/1 / 23/0 / 7/0 / 56/2 / 43/0 / 6/2 / 4/1
Respiratory Distress / 162/0 / 55/0 / 23/0 / 7/0 / 57/1 / 43/0 / 8/0 / 5/0
Pneumonitis / 161/1 / 55/0 / 23/0 / 7/0 / 58/0 / 43/0 / 8/0 / 5/0
Pneumonia / 161/1 / 55/0 / 23/0 / 7/0 / 58/0 / 42/1 / 8/0 / 5/0
Upper GI bleeding / 162/0 / 55/0 / 22/1 / 7/0 / 55/3 / 41/2 / 8/0 / 5/0
Biloma / 162/0 / 55/0 / 23/0 / 7/0 / 58/0 / 43/0 / 8/0 / 4/1
UTI / 160/2 / 55/0 / 23/0 / 7/0 / 58/0 / 43/0 / 8/0 / 5/0
Enterococcus / 162/0 / 55/0 / 23/0 / 7/0 / 58/0 / 42/1 / 8/0 / 5/0
Billiary Obstruction / 162/0 / 55/0 / 23/0 / 7/0 / 57/1 / 43/0 / 8/0 / 5/0
Acute Pancreatitis / 162/0 / 55/0 / 23/0 / 7/0 / 58/0 / 43/0 / 8/0 / 4/1
Cholecystitis / 161/1 / 55/0 / 23/0 / 7/0 / 58/0 / 43/0 / 8/0 / 5/0
SBP / 162/0 / 55/0 / 22/1 / 7/0 / 57/1 / 43/0 / 8/0 / 4/1
DIC / 162/0 / 55/0 / 23/0 / 7/0 / 57/1 / 43/0 / 7/1 / 5/0
Encepahlopathy / 159/3 / 53/2 / 22/1 / 7/0 / 50/8 / 43/0 / 8/0 / 5/0
Acute Renal Failure / 161/1 / 55/0 / 21/2 / 7/0 / 54/4 / 42/1 / 7/1 / 5/0
CIN / 162/0 / 54/1 / 23/0 / 7/0 / 58/0 / 43/0 / 8/0 / 5/0
Sepsis / 162/0 / 55/0 / 23/0 / 7/0 / 57/1 / 43/0 / 7/1 / 5/0
Death / 0 / 1 / 1 / 0 / 7 / 2 / 3 / 1
Laboratory Toxicity / N=22
No/ Yes / N=14
No/ Yes / N=6
No/ Yes / N=4
No/ Yes / N=80
No/ Yes / N=37
No/ Yes / N=11
No/ Yes / N=2
No/ Yes
Albumin / 22/0 / 14/0 / 4/2 / 4/0 / 78/2 / 37/0 / 10/1 / 2/0
Bilirubin / 17/5 / 12/2 / 2/4 / 2/2 / 68/12 / 35/2 / 6/5 / 1/1
ALP / 21/1 / 14/0 / 5/1 / 3/1 / 75/5 / 33/4 / 11/0 / 2/0
ALT / 14/8 / 10/4 / 5/1 / 3/1 / 76/4 / 37/0 / 11/0 / 2/0
AST / 15/7 / 8/6 / 2/4 / 1/3 / 71/9 / 35/2 / 10/1 / 2/0
Ammonia / 16/6 / 10/4 / 4/2 / 2/2 / 67/13 / 34/3 / 10/1 / 2/0

The toxicity report refers to all occurred adverse events within 7 or 8-30 days from per procedure from all available post-embolic report and laboratory data. Laboratory events refer to grade 3 or higher except of ammonia. Latter describes an increased level. Death refers to all procedures and is not limited to the availability of the post-procedural clinical reports.

CTCAEv4.03; common terminology criteria for adverse events version 4.03; cTACE, conventional trans-arterial chemoembolization; DEB-TACE, drug-eluting beads TACE; BCLC, Barcelona Clinic Liver Cancer; PES, post embolic syndrome (fatigue, nausea, vomiting, abdominal pain, fever without infection focus); GI, gastrointestinal; UTI, urinary tract infection; SBP, spontaneous bacterial peritonitis; DIC, disseminated intravascular coagulation; CIN, contrast-induced nephropathy; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; n/a, not applicable

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Supplementary references

1 McCaffrey DF, Ridgeway G, Morral AR (2004) Propensity score estimation with boosted regression for evaluating causal effects in observational studies. Psychol Methods 9:403-425

2 Stuart EA (2010) Matching methods for causal inference: A review and a look forward. Stat Sci 25:1-21

3 Lee BK, Lessler J, Stuart EA (2010) Improving propensity score weighting using machine learning. Stat Med 29:337-346

4 McDonald RJ, McDonald JS, Kallmes DF, Carter RE (2013) Behind the numbers: propensity score analysis-a primer for the diagnostic radiologist. Radiology 269:640-645