Ann Surg Oncol DOI 10.1245/s10434-015-5064-4
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Percutaneous Treatment of Localized Infiltrative Hepatocellular Carcinoma Developing on Cirrhosis Jean-Charles Nault1,2,3, Gise`le Nkontchou1, Pierre Nahon1,2,3, Ve´ronique Grando1, Vale´rie Bourcier1, Sandrine Barge1, Marianne Ziol2,3,4, Nicolas Sellier3,5, Nathalie Ganne-Carrie1,2,3, and Olivier Seror2,3,5 1
Liver Unit, Hoˆpital Jean Verdier, Hoˆpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hoˆpitaux de Paris, Bondy, France; 2Unite´ Mixte de Recherche 1162, Ge´nomique Fonctionnelle des Tumeurs Solides, Institut National de la Sante´ et de la Recherche Me´dicale, Paris, France; 3Unite´ de Formation et de Recherche Sante´ Me´decine et Biologie Humaine, Universite´ Paris 13, Communaute´ d’Universite´s et Etablissements Sorbonne Paris Cite´, Paris, France; 4 Department of Pathology, Hoˆpital Jean Verdier, Hoˆpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hoˆpitaux de Paris, Bondy, France; 5Radiology Department, Hoˆpital Jean Verdier, Hoˆpitaux Universitaires Paris-SeineSaint-Denis, Assistance-Publique Hoˆpitaux de Paris, Bondy, France
ABSTRACT Background. Infiltrating hepatocellular carcinoma (HCC) is characterized by a difficult diagnosis, dismal prognosis, and limited therapeutic options. We describe long-term results of percutaneous treatment of infiltrative HCC, i.e., multibipolar radiofrequency ablation (mbpRFA) and percutaneous intra-arterial ethanol injection (PIAEI). Methods. All cirrhotic patients with localized (up to two segments) infiltrating HCC treated by mbpRFA or PIAEI between 2002 and 2012 were included. Survival was analyzed using the Kaplan–Meier method, log-rank test, and Cox univariate followed by multivariate analyses. Results. Fifty-one patients were considered eligible for mbpRFA (n = 20) or PIAEI (n = 31). Cirrhosis etiologies were alcohol (67 %), hepatitis C (33 %), hepatitis B (16 %), and/or NASH (16 %). HCC were multinodular in 31 % of cases, with a median main tumor size of 60 mm (range 30–200) and macrovascular invasion in 59 % of cases. The median serum level of alphafetoprotein was 125 ng/ml (range 2–215,000). Treatment-related adverse events occurred in 58 %, mainly postablation syndrome (31 %), and one death (2 %). Median overall survival was 18.3 months, with 63, 35, 20, and 12 % survival at 1, 2, 3, and 4 years, respectively. Baseline serum bilirubin [normal [hazard ratio (HR) 2.98; 95 % confidence interval (CI)
Society of Surgical Oncology 2016 First Received: 11 June 2015 J.-C. Nault e-mail: [email protected]
1.38–6.50; P = 0.0057] and tumor burden [70 mm (HR 1.02; 95 % CI 1.003–1.04; P = 0.0221) were associated with poorer overall survival. The radiological response using mRECIST criteria and an alphafetoprotein decrease 1 month post-procedure was associated with increased overall survival (P = 0.0002 and P = 0.024, respectively). Discussion. Despite its overall poor prognosis, localized infiltrating HCC can be safely treated using percutaneous approaches, with potential survival benefits for these difficult-to-treat patients.
Infiltrating hepatocellular carcinoma (iHCC) is a rare subtype of HCC characterized by an ill-defined mass with poorly demarcated boundaries.1,2 Occasionally, tumor portal thrombosis is the sole overt sign of malignancy.3,4 iHCC is roughly identified in less than 5–10 % of all HCC and has a dismal prognosis.5,6 In patients without liver failure, palliative approaches include transarterial procedures, such as chemoembolization (TACE) and Y90 radioembolization (Y90RE), or systemic therapy, such as sorafenib.1,3,7 Percutaneous treatments, including radiofrequency ablation (RFA), are considered curative approaches to HCC treatment.8,9 Classical monopolar RFA is useful for treating small HCC \3 cm.10,11 However, multibipolar RFA (mbpRFA) could be used to treat larger tumors ranging from 5 to 10 cm, with long-term efficacy and a satisfactory safety profile.12 This treatment also was proposed to treat iHCC of diameter\10 cm and outside at-risk location to obtain a complete tumor necrosis without liver
J. Nault et al.
failure. However, currently published series report only small sample populations and include mainly mass-forming large HCC.12 Percutaneous intra-arterial ethanol injection (PIAEI) consists of percutaneously injecting pure ethanol into the feeding arteries of the tumor to induce tumor necrosis without damage to the surrounding liver.13 It can treat a large volume of HCC harboring a feeding artery at ultrasonography and not treatable with multibipolar RFA due to the large size of the tumors or an at-risk location. We previously reported the efficacy of this procedure in a small number of HCC consisting of both infiltrating and mass-forming tumors with manageable adverse events.13 However, potential use of percutaneous treatment for localized iHCC remains to be elucidated.
Radiological assessment was performed at 1 month and additional sessions of percutaneous treatment were proposed, if feasible, for patients with an incomplete response after the first session of treatment to achieve the best response. Follow-up After completion of percutaneous treatment, clinical examination, AFP, and CT scan or MRI was performed every 3 months during the first 2 years of follow-up and then every 6 months. In case of tumor recurrence, additional treatments were discussed at a multidisciplinary meeting.10 Patients were followed up until death or the last recorded visit before July 2014.
MATERIALS AND METHODS Adverse Events Inclusion Criteria Adverse events were recorded and classified using the SIR classification and Dindo-Clavien classifications.14,15 Deaths occurring during the month following treatment were systematically considered as treatment-related.
All consecutive cirrhotic patients with localized iHCC treated using a percutaneous approach at a single institute between 2002 and 2012 were retrospectively included in this study. In our study, localized iHCC was defined as nonnodular and nonencapsulated lesion with a margin poorly demarcated involving less than three segments at imaging using CT scan or MRI. Cirrhosis was histologically proven in all patients. HCC was diagnosed using either noninvasive criteria (61 % of cases, defined by EASL guidelines) or histology (39 % of cases) using percutaneous biopsy.10 Clinical, biological, and radiological data were assessed before percutaneous treatment.
The AFP response was defined by a decrease of at least 50 % in the AFP level after treatment. Only patients with a serum AFP level [20 ng/ml at baseline were analyzed for the AFP response. In other situations (decrease of \50 %, stable level or increase in the AFP level), it was classified as an AFP nonresponse.16,17
Percutaneous Treatment
Radiological Response Using mRECIST Criteria
The methods of the two types of percutaneous treatment, mbpRFA and PIAEI, have been extensively described.12,13 In a multidisciplinary meeting, percutaneous treatment was proposed if a given patients was considered unresectable due to comorbidity, presence of portal hypertension, or insufficient remaining liver volume. MbpRFA was proposed in patients with HCC \100 mm, with sufficient remaining nontumor liver tissue and situated outside a high-risk location (i.e., located near a major vessel or bile duct). PIAEI was proposed to patients with HCC displaying a visible feeding artery upon ultrasonography AND with a HCC [100 mm OR not treatable by mbpRFA due to a high-risk location or insufficient remaining nontumor tissue. When feasible, concomitant percutaneous treatment was proposed to destroy the largest possible tumor volume. Only localized iHCC involving no more two segments and with a visible target at imaging were considered as candidate to percutaneous treatments. Diffuse or bilobar iHCC were considered a contraindication to such treatments.
One month after the last treatment session, the radiological response was assessed using modified Recist (mRECIST) criteria.18 The radiological response was recorded as progressive disease (PD), stable disease (SD), partial response (PR), or complete response (CR). We classified patients as responders (including CR and PR) or nonresponders (including SD and PD) as previously described.19
Definition of the AFP Response
Endpoints and Statistical Analysis Continuous variables were reported using the median (minimum–maximum) and compared using the nonparametric Kruskal–Wallis test. Categoric variables were reported using numbers (percentages) and compared using the Fisher exact test or the Chi squared test. Overall survival (OS) was defined as time between date of treatment and death or last clinical follow-up. Time to progression (TTP) was defined by time between the date of treatment
Percutaneous Treatments of Infiltrating HCC TABLE 1 Description of the patients in the whole cohort and according to the type of treatment
Age (years)
All patients (n = 51)
Intra-arterial localization (n = 31, 61 %)
Multibipolar radiofrequency ablation (n = 20, 39 %)
P value
65 (48–81)
65 (49–81)
68 (48–79)
0.2925
Gender (male)
46 (90 %)
28 (90 %)
18 (90 %)
1.0000
Alcohol
34 (67 %)
21 (68 %)
13 (65 %)
1.0000
Hepatitis C
17 (33 %)
10 (32 %)
7 (35 %)
1.0000
Hepatitis B
8 (16 %)
5 (16 %)
3 (15 %)
1.0000
NASH
8 (16 %)
6 (19 %)
2 (10 %)
0.4564
Hemochromatosis Cirrhosis
1 (2 %) 51 (100 %)
0 (0 %) 31 (100 %)
1 (5 %) 20 (100 %)
0.3922 1.0000
Child Pugh A
46 (90 %)
28 (90 %)
18 (90 %)
1.0000
Child Pugh B
5 (10 %)
3 (10 %)
2 (10 %)
24 (52 %)
17 (57 %)
7 (44 %)
0.5379
Platelets (10 /mm )
120 (24–309)
100 (24–309)
145 (54–231)
0.0951
Albumin (g/dl)
39 (24–49)
39 (28–47)
41 (24–49)
0.0809
Prothrombin time (%)
81 (43–100)
80 (43–100)
83 (56–100)
0.3539
Total bilirubin (lmol/l)
12 (4–65)
13 (5–65)
12 (4–25)
0.2884
Ascites
4 (8 %)
3 (10 %)
1 (5 %)
1.0000
AFP (ng/ml)
125 (2–215,000)
170 (2–215,000)
100 (3–12,700)
0.1749
Portal hypertension 3
3
Size of the main nodule (mm)
60 (25–200)
70 (35–200)
54 (25–100)
0.0809
Sum of the size of all nodules (mm)
70 (40–250)
70 (40–250)
68 (40–115)
0.4562
No. of nodules
1 (1–4)
1 (1–4)
1 (1–3)
0.4797
Uninodular
35 (69 %)
23 (74 %)
12 (60 %)
0.3596
Multinodular Macrovascular invasion
16 (31 %) 30 (59 %)
8 (26 %) 23 (74 %)
8 (40 %) 7 (35 %)
0.0086
Segmental tumor portal thrombosis
28 (55 %)
21 (68 %)
7 (35 %)
0.08732
Total tumor portal thrombosis
1 (2 %)
1 (3 %)
0 (0 %)
Sus-hepatic vein tumor thrombosis
1 (2 %)
1 (3 %)
0 (0 %)
BCLC A
12 (24 %)
6 (19 %)
6 (30 %)
BCLC B
9 (18 %)
2 (6 %)
7 (35 %)
BCLC C
30 (59 %)
23 (75 %)
7 (35 %)
Radiological responder (CR ? PR)
40 (82 %)
24 (80 %)
16 (88 %)
Radiological nonresponder (SD ? PD)
9 (18 %)
6 (20 %)
3 (12 %)
0.0092
1.000
* Numbers (percentage); $median (minimum, maximum) Fisher exact test and v2 test for category variable and Kruskal–Wallis test for continuous variable Stable disease (SD), progressive disease (PD), partial response (PR), and complete response (CR) were assessed 1 month after the treatment using mRECIST criteria
and tumor progression or last clinical follow-up. Progression-free survival (PFS) was defined as time between date of treatment and death whatever the cause, tumor progression or last clinical follow-up. Survival curves were performed using the Kaplan–Meier method and the logrank test. The association between baseline features and survival was performed using univariate Cox analysis with multivariate Cox analysis. To bypass time-dependent bias, we performed the landmark method (at 1, 3, and 6 months) and Mantel Byar analysis.16,20
RESULTS Patient Characteristics Fifty-one patients with localized iHCC that developed on cirrhosis were included in this study (Table 1) [median age 65 years, male 90 %]. Etiologies of underlying liver disease included excessive alcohol consumption (67 %), HCV infection (33 %), HBV (16 %), and/or NASH (16 %). Sixteen patients (31 %) had more than one cause
J. Nault et al.
A 51 patients with limited infiltrative HCC
30 treated using intra-arterial ethanol injection
21 treated using multibipolar RFA
Concomittant treatment:
Concomittant treatment:
Intratumor ethanol (n=4),MWA(n=1), RFA (n=2)
Percutaneous alcoolisation of the tumor thrombus (n=1)
1 session of treatment (n=23)
2 session of treatment (n=5)
3 session of treatment (n=2)
4 session of treatment (n=1)
4 intra-arterial ethanol injection and 1 RFA
4 intra-arterial ethanol injection and 1 RFA
1 intra-arterial ethanol injection and 2 RFA
1 session of treatment (n=17)
2 session of treatment (n=3) 3 intra-arterial ethanol injection
Follow-up Tumor progression (n=40)
Additionnal treatment: sorafenib (n=14), RFA (n=14), intraarterial embolisation (n=10), intraarterial alcoolisation (n=1), MWA (n=2), IRE (n=1), Ytrium90 (=1)
Death (n=40) HCC related (n=31)
Treatment related (n=1)
Liver related, except HCC (n=1)
B
Non Liver related, (n=3)
Unknown (n=4)
C Arterial phase before treatment
Arterial phase 1 month after treatment
Portal phase before treatment
Portal phase 1 month after treatment
T1 with injection arterial phase before treatment
T1 without injection 1 month after treatment
T1 with injection portal phase before treatment
T1 with injection 1 month after treatment
Percutaneous Treatments of Infiltrating HCC
of cirrhosis. The median serum AFP level was 125 ng/ml (minimum–maximum: 2–215,000). HCC appeared as single infiltrative tumor in 69 % of patients. Median size of the main tumor was 60 mm (min–max: 25–200). Thirty patients (59 %) had radiological tumor macrovascular invasion, including 28 segmental involvements. HCC were classified as Barcelona clinical liver classification (BCLC) stage A in 24 % of cases (12 cases with among them 9 HCC [50 mm), BCLC stage B in 18 % of cases, and BCLC stage C in 59 % of cases. Twenty-nine patients were treatment-naive, whereas 22 had previously undergone HCC treatment. Twenty patients (39 %) were treated using mbpRFA and 31 (61 %) using PIAEI (Fig. 1). Patients treated by PIAEI had more advanced HCC (BCLC C 75 %) compared with those treated by mbpRFA (BCLC C 35 %, P = 0.0092), mainly because of more frequent macrovascular invasion in patients treated with PIAEI (Table 1).
A
Overall Survival 100
Percent survival
of IHCC (a). A 58-year-old man with alcoholic-related cirrhosis was treated by PIAIEI for a histologically proven IHCC of 75 mm of segment IV. CT scan with injection at the arterial phase and at the portal phase before and 3 months after treatment (b). A 54-year-old man with HCV-related cirrhosis was treated by mbpRFA for an IHCC of 55 mm of segment V. CT scan with injection at the arterial phase and at the portal phase before and 3 months after treatment (b). MWA microwave ablation; RFA radiofrequency ablation; IRE irreversible electroporation; Yttrium90 radioembolization with Yttrium 90
80 60 40 20 0
0
20
40
60
Time (months) Patients at risk
51
32
12
2
B
Progression free Survival
100
Percent survival
b FIG. 1 Flow chart of the study. Flow chart of percutaneous treatment
80 60 40 20 0 0
20
40
60
5
2
Time Patients at risk
50
20
Treatment Characteristics
•
PIAEI
In 7 patients treated by PIAEI (Fig. 1B), an additional concomitant treatment by intratumor alcoholization (n = 4), microwave ablation (n = 1), and mbpRFA (n = 2) was performed to destroy the largest possible tumor volume during a given session (Fig. 1). A median of 20 cc of ethanol (min–max: 7–38) was injected into a median of 2 feeding arteries (min–max: 1–4). •
mbpRFA
C
Time to progression 100
Percent survival
One session of treatment was performed in 40 patients and at least 2 sessions in 10 patients (Fig. 1).
80 60 40 20 0 0
20
40
60
2
2
Time Patients at risk
50
8
A median number of five electrodes (min–max: 2–12) were used to deliver a median value of 280 kJ (min–max: 80–570) during a median time of treatment of 35 min (min–max: 20–105) (Fig. 1c).
FIG. 2 Long-term survival. Overall survival (a), progression-free survival (b), and time to progression (c) of the whole cohort were described using the Kaplan–Meier method. The numbers at risk are reported under the x-axis
Safety
C to F). Moreover, 18 patients have postablation syndrome (35 %). Using the Dindo-Clavien classification, adverse events were classified as stage I in 4 cases, stage II in 11 cases, stage IIIa in 2 cases, and stage IIIb in 1 case. One
Using the SIR classification, 19 patients (37 %) experienced one adverse event (2 classified as A or B and 17 as
J. Nault et al. TABLE 2 Univariate and multivariate Cox analysis for overall survival HR
CR 95 %
P value
Age (years)
0.9986
0.9616–1.037
0.941
Gender (male)
1.089
0.4228–2.803
0.86
Presence of ascites
1.335
0.4029–4.422
0.637
Child Pugh (A vs. B)
1.09383
0.4251–2.814
0.8524
Portal hypertension
1.098
0.5669–2.126
0.782
HR
CR 95 %
P value
BCLC classification (A vs. B/C)
1.792
0.7997–4.016
0.1565
No. of HCCa
1.583
0.9629–2.604
0.0702
Sum of the size of the nodulesa
1.018
1.007–1.028
0.00088
1.0223
1.0032–1.042
0.0221
Size of the largest nodulea
1.016
1.003–1.028
0.0141
0.9975
0.9777–1.018
0.8079
Tumor portal thrombosis
1.337
0.69–2.589
0.39
Hepatitis B virus Hepatitis C virus
1.007 0.5843
0.4205–2.41 0.2907–1.174
0.988 0.131 1.8547
0.8782–3.917
0.1054
2.9872
1.3751–6.489
0.0057
Alcohol
2.302
1.102–4.805
0.0264
AFP (ng/ml)a
1
1; 1
0.822
GGTa
0.9892
0.9447–1.036
0.642
Creatinine (ymol/l)a
1.003
0.9903–1.015
0.67
Alkaline phosphatase (UI/L)a
0.5794
0.2143–1.567
0.282
Albumin (g/dl)a
1.003
0.9424–1.067
0.931
Total bilirubin [normal
2.746
1.299–5.806
0.0082
3
0.917
Platelets \150,000/mm
1.036
0.534–2.01
Prothrombin timea
0.9914
0.968–1.015
0.479
Previous treatment
1.191
0.6336–2.238
0.587
Treatment by multibipolar RFA
0.7841
0.417–1.474
0.45
AFP alpha-fetoprotein, GGT gamma-glutamyl transferase, RFA radiofrequency ablation, BCLC Barcelona Liver Cancer Classification, HCC hepatocellular carcinoma a
These variables were analyzed as continuous value in univariate analysis
treatment-related death (2 %, Dindo-Clavien V) occurred due to liver failure after mbpRFA. Among the three cases classified Dindo-Clavien IIIa and IIIb, one case of liver abscess required percutaneous drainage, one colonic perforation required long-term antibiotic treatment, and one case of biliary stenosis required stenting procedures. The type of treatment was not significantly associated with the occurrence of complications (P = 0.5659). Treatment of HCC with a sum of the size of the tumor [70 mm was associated with an increased rate of adverse Dindo-Clavien II to V events [odds ratio (OR) 4.84; 95 % CI 1.05–31.31; P = 0.02]. Long-Term Results: Overall Survival and Time to Progression After a mean follow-up of 18 months, 40 (78 %) patients experienced tumor progression and 40 patients died (78 %, Fig. 1). Among the 51 patients in our study, 4 (8 %) were lost to follow-up. Median OS was 18.3 months, and actuarial rates of survival at 1, 2, 3, and 4 years were 63, 35, 20, and 12 %, respectively (Fig. 2a).
Median PFS was 7.46 months, and actuarial rates of progression free-survival at 1, 2, 3, and 4 years were 35, 9, 4, and 2 %, respectively (Fig. 2b). The median TTP was 8 months and actuarial rates of tumor progression at 1, 2, 3, and 4 years were 62, 88, 91, and 91 %, respectively (Fig. 2c). Univariate and Multivariate Analyses of Survival For univariate analysis, size of the main tumor, sum of the size of all tumors, high alcohol intake, and higher total bilirubin levels were significantly associated with OS (Table 2). For multivariate analysis, the sum of the size of all tumors (HR 1.0223; 95 % CI 1.0032–1.042; P = 0.0221) and higher total bilirubin level ([1.2 mg/dl, [20 lmol) (HR 2.9872; 95 % CI 1.3751–6.489; P = 0.0057) remained independently associated with poorer OS (Table 2). When combining these two features, we were able to stratify the population according to prognosis (Figs. 3a–c). Patients with a sum of the size of all tumors \70 mm and with a normal bilirubin level had the longest OS (median OS 29.9 months) compared with
Percutaneous Treatments of Infiltrating HCC
A Overall Survival
Percent survival
100
Normal bilirubin level
80
High bilirubin level
P=0.0022 60 40 20 0 0
20
40
60
Time (months)
Patients at risk Normal bilirubin level
38
17
5
2
High bilirubin level
12
4
1
1
B
Overall Survival
Percent survival
Sum of the size < 70 mm Sum of the size ≥ 70 mm
P=0.0139
Time (months)
Patients at risk Sum of the size < 70 mm
23
14
4
1
Sum of the size ≥ 70 mm
27
7
2
2
Overall Survival
C
Percent survival
FIG. 3 Overall survival according to subgroup analysis. Overall survival in patients dichotomized according to the total bilirubin level (normal value \20 lmol/\1.2 mg/dl vs. high value [20 lmol/[1.2 mg/ dl) (a), dichotomized according to the median sum of the size of all nodules (\70 mm vs. C70 mm) (b), and according the combination of total bilirubin level and the sum of the size of all nodules (normal total bilirubin level AND sum of size of all nodules \70 mm vs. high total bilirubin level OR sum of size of all nodules C70 mm vs. high total bilirubin level AND sum of size of all nodules C70 mm) (c). Survival was assessed using the Kaplan– Meier method and the log-rank test. The numbers at risk are reported under the x-axis
Normal bilirubin and sum of size < 70 mm High bilirubin OR sum of size ≥ 70 mm
P
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Percutaneous Treatment of Localized Infiltrative Hepatocellular Carcinoma Developing on Cirrhosis Jean-Charles Nault1,2,3, Gise`le Nkontchou1, Pierre Nahon1,2,3, Ve´ronique Grando1, Vale´rie Bourcier1, Sandrine Barge1, Marianne Ziol2,3,4, Nicolas Sellier3,5, Nathalie Ganne-Carrie1,2,3, and Olivier Seror2,3,5 1
Liver Unit, Hoˆpital Jean Verdier, Hoˆpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hoˆpitaux de Paris, Bondy, France; 2Unite´ Mixte de Recherche 1162, Ge´nomique Fonctionnelle des Tumeurs Solides, Institut National de la Sante´ et de la Recherche Me´dicale, Paris, France; 3Unite´ de Formation et de Recherche Sante´ Me´decine et Biologie Humaine, Universite´ Paris 13, Communaute´ d’Universite´s et Etablissements Sorbonne Paris Cite´, Paris, France; 4 Department of Pathology, Hoˆpital Jean Verdier, Hoˆpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hoˆpitaux de Paris, Bondy, France; 5Radiology Department, Hoˆpital Jean Verdier, Hoˆpitaux Universitaires Paris-SeineSaint-Denis, Assistance-Publique Hoˆpitaux de Paris, Bondy, France
ABSTRACT Background. Infiltrating hepatocellular carcinoma (HCC) is characterized by a difficult diagnosis, dismal prognosis, and limited therapeutic options. We describe long-term results of percutaneous treatment of infiltrative HCC, i.e., multibipolar radiofrequency ablation (mbpRFA) and percutaneous intra-arterial ethanol injection (PIAEI). Methods. All cirrhotic patients with localized (up to two segments) infiltrating HCC treated by mbpRFA or PIAEI between 2002 and 2012 were included. Survival was analyzed using the Kaplan–Meier method, log-rank test, and Cox univariate followed by multivariate analyses. Results. Fifty-one patients were considered eligible for mbpRFA (n = 20) or PIAEI (n = 31). Cirrhosis etiologies were alcohol (67 %), hepatitis C (33 %), hepatitis B (16 %), and/or NASH (16 %). HCC were multinodular in 31 % of cases, with a median main tumor size of 60 mm (range 30–200) and macrovascular invasion in 59 % of cases. The median serum level of alphafetoprotein was 125 ng/ml (range 2–215,000). Treatment-related adverse events occurred in 58 %, mainly postablation syndrome (31 %), and one death (2 %). Median overall survival was 18.3 months, with 63, 35, 20, and 12 % survival at 1, 2, 3, and 4 years, respectively. Baseline serum bilirubin [normal [hazard ratio (HR) 2.98; 95 % confidence interval (CI)
Society of Surgical Oncology 2016 First Received: 11 June 2015 J.-C. Nault e-mail: [email protected]
1.38–6.50; P = 0.0057] and tumor burden [70 mm (HR 1.02; 95 % CI 1.003–1.04; P = 0.0221) were associated with poorer overall survival. The radiological response using mRECIST criteria and an alphafetoprotein decrease 1 month post-procedure was associated with increased overall survival (P = 0.0002 and P = 0.024, respectively). Discussion. Despite its overall poor prognosis, localized infiltrating HCC can be safely treated using percutaneous approaches, with potential survival benefits for these difficult-to-treat patients.
Infiltrating hepatocellular carcinoma (iHCC) is a rare subtype of HCC characterized by an ill-defined mass with poorly demarcated boundaries.1,2 Occasionally, tumor portal thrombosis is the sole overt sign of malignancy.3,4 iHCC is roughly identified in less than 5–10 % of all HCC and has a dismal prognosis.5,6 In patients without liver failure, palliative approaches include transarterial procedures, such as chemoembolization (TACE) and Y90 radioembolization (Y90RE), or systemic therapy, such as sorafenib.1,3,7 Percutaneous treatments, including radiofrequency ablation (RFA), are considered curative approaches to HCC treatment.8,9 Classical monopolar RFA is useful for treating small HCC \3 cm.10,11 However, multibipolar RFA (mbpRFA) could be used to treat larger tumors ranging from 5 to 10 cm, with long-term efficacy and a satisfactory safety profile.12 This treatment also was proposed to treat iHCC of diameter\10 cm and outside at-risk location to obtain a complete tumor necrosis without liver
J. Nault et al.
failure. However, currently published series report only small sample populations and include mainly mass-forming large HCC.12 Percutaneous intra-arterial ethanol injection (PIAEI) consists of percutaneously injecting pure ethanol into the feeding arteries of the tumor to induce tumor necrosis without damage to the surrounding liver.13 It can treat a large volume of HCC harboring a feeding artery at ultrasonography and not treatable with multibipolar RFA due to the large size of the tumors or an at-risk location. We previously reported the efficacy of this procedure in a small number of HCC consisting of both infiltrating and mass-forming tumors with manageable adverse events.13 However, potential use of percutaneous treatment for localized iHCC remains to be elucidated.
Radiological assessment was performed at 1 month and additional sessions of percutaneous treatment were proposed, if feasible, for patients with an incomplete response after the first session of treatment to achieve the best response. Follow-up After completion of percutaneous treatment, clinical examination, AFP, and CT scan or MRI was performed every 3 months during the first 2 years of follow-up and then every 6 months. In case of tumor recurrence, additional treatments were discussed at a multidisciplinary meeting.10 Patients were followed up until death or the last recorded visit before July 2014.
MATERIALS AND METHODS Adverse Events Inclusion Criteria Adverse events were recorded and classified using the SIR classification and Dindo-Clavien classifications.14,15 Deaths occurring during the month following treatment were systematically considered as treatment-related.
All consecutive cirrhotic patients with localized iHCC treated using a percutaneous approach at a single institute between 2002 and 2012 were retrospectively included in this study. In our study, localized iHCC was defined as nonnodular and nonencapsulated lesion with a margin poorly demarcated involving less than three segments at imaging using CT scan or MRI. Cirrhosis was histologically proven in all patients. HCC was diagnosed using either noninvasive criteria (61 % of cases, defined by EASL guidelines) or histology (39 % of cases) using percutaneous biopsy.10 Clinical, biological, and radiological data were assessed before percutaneous treatment.
The AFP response was defined by a decrease of at least 50 % in the AFP level after treatment. Only patients with a serum AFP level [20 ng/ml at baseline were analyzed for the AFP response. In other situations (decrease of \50 %, stable level or increase in the AFP level), it was classified as an AFP nonresponse.16,17
Percutaneous Treatment
Radiological Response Using mRECIST Criteria
The methods of the two types of percutaneous treatment, mbpRFA and PIAEI, have been extensively described.12,13 In a multidisciplinary meeting, percutaneous treatment was proposed if a given patients was considered unresectable due to comorbidity, presence of portal hypertension, or insufficient remaining liver volume. MbpRFA was proposed in patients with HCC \100 mm, with sufficient remaining nontumor liver tissue and situated outside a high-risk location (i.e., located near a major vessel or bile duct). PIAEI was proposed to patients with HCC displaying a visible feeding artery upon ultrasonography AND with a HCC [100 mm OR not treatable by mbpRFA due to a high-risk location or insufficient remaining nontumor tissue. When feasible, concomitant percutaneous treatment was proposed to destroy the largest possible tumor volume. Only localized iHCC involving no more two segments and with a visible target at imaging were considered as candidate to percutaneous treatments. Diffuse or bilobar iHCC were considered a contraindication to such treatments.
One month after the last treatment session, the radiological response was assessed using modified Recist (mRECIST) criteria.18 The radiological response was recorded as progressive disease (PD), stable disease (SD), partial response (PR), or complete response (CR). We classified patients as responders (including CR and PR) or nonresponders (including SD and PD) as previously described.19
Definition of the AFP Response
Endpoints and Statistical Analysis Continuous variables were reported using the median (minimum–maximum) and compared using the nonparametric Kruskal–Wallis test. Categoric variables were reported using numbers (percentages) and compared using the Fisher exact test or the Chi squared test. Overall survival (OS) was defined as time between date of treatment and death or last clinical follow-up. Time to progression (TTP) was defined by time between the date of treatment
Percutaneous Treatments of Infiltrating HCC TABLE 1 Description of the patients in the whole cohort and according to the type of treatment
Age (years)
All patients (n = 51)
Intra-arterial localization (n = 31, 61 %)
Multibipolar radiofrequency ablation (n = 20, 39 %)
P value
65 (48–81)
65 (49–81)
68 (48–79)
0.2925
Gender (male)
46 (90 %)
28 (90 %)
18 (90 %)
1.0000
Alcohol
34 (67 %)
21 (68 %)
13 (65 %)
1.0000
Hepatitis C
17 (33 %)
10 (32 %)
7 (35 %)
1.0000
Hepatitis B
8 (16 %)
5 (16 %)
3 (15 %)
1.0000
NASH
8 (16 %)
6 (19 %)
2 (10 %)
0.4564
Hemochromatosis Cirrhosis
1 (2 %) 51 (100 %)
0 (0 %) 31 (100 %)
1 (5 %) 20 (100 %)
0.3922 1.0000
Child Pugh A
46 (90 %)
28 (90 %)
18 (90 %)
1.0000
Child Pugh B
5 (10 %)
3 (10 %)
2 (10 %)
24 (52 %)
17 (57 %)
7 (44 %)
0.5379
Platelets (10 /mm )
120 (24–309)
100 (24–309)
145 (54–231)
0.0951
Albumin (g/dl)
39 (24–49)
39 (28–47)
41 (24–49)
0.0809
Prothrombin time (%)
81 (43–100)
80 (43–100)
83 (56–100)
0.3539
Total bilirubin (lmol/l)
12 (4–65)
13 (5–65)
12 (4–25)
0.2884
Ascites
4 (8 %)
3 (10 %)
1 (5 %)
1.0000
AFP (ng/ml)
125 (2–215,000)
170 (2–215,000)
100 (3–12,700)
0.1749
Portal hypertension 3
3
Size of the main nodule (mm)
60 (25–200)
70 (35–200)
54 (25–100)
0.0809
Sum of the size of all nodules (mm)
70 (40–250)
70 (40–250)
68 (40–115)
0.4562
No. of nodules
1 (1–4)
1 (1–4)
1 (1–3)
0.4797
Uninodular
35 (69 %)
23 (74 %)
12 (60 %)
0.3596
Multinodular Macrovascular invasion
16 (31 %) 30 (59 %)
8 (26 %) 23 (74 %)
8 (40 %) 7 (35 %)
0.0086
Segmental tumor portal thrombosis
28 (55 %)
21 (68 %)
7 (35 %)
0.08732
Total tumor portal thrombosis
1 (2 %)
1 (3 %)
0 (0 %)
Sus-hepatic vein tumor thrombosis
1 (2 %)
1 (3 %)
0 (0 %)
BCLC A
12 (24 %)
6 (19 %)
6 (30 %)
BCLC B
9 (18 %)
2 (6 %)
7 (35 %)
BCLC C
30 (59 %)
23 (75 %)
7 (35 %)
Radiological responder (CR ? PR)
40 (82 %)
24 (80 %)
16 (88 %)
Radiological nonresponder (SD ? PD)
9 (18 %)
6 (20 %)
3 (12 %)
0.0092
1.000
* Numbers (percentage); $median (minimum, maximum) Fisher exact test and v2 test for category variable and Kruskal–Wallis test for continuous variable Stable disease (SD), progressive disease (PD), partial response (PR), and complete response (CR) were assessed 1 month after the treatment using mRECIST criteria
and tumor progression or last clinical follow-up. Progression-free survival (PFS) was defined as time between date of treatment and death whatever the cause, tumor progression or last clinical follow-up. Survival curves were performed using the Kaplan–Meier method and the logrank test. The association between baseline features and survival was performed using univariate Cox analysis with multivariate Cox analysis. To bypass time-dependent bias, we performed the landmark method (at 1, 3, and 6 months) and Mantel Byar analysis.16,20
RESULTS Patient Characteristics Fifty-one patients with localized iHCC that developed on cirrhosis were included in this study (Table 1) [median age 65 years, male 90 %]. Etiologies of underlying liver disease included excessive alcohol consumption (67 %), HCV infection (33 %), HBV (16 %), and/or NASH (16 %). Sixteen patients (31 %) had more than one cause
J. Nault et al.
A 51 patients with limited infiltrative HCC
30 treated using intra-arterial ethanol injection
21 treated using multibipolar RFA
Concomittant treatment:
Concomittant treatment:
Intratumor ethanol (n=4),MWA(n=1), RFA (n=2)
Percutaneous alcoolisation of the tumor thrombus (n=1)
1 session of treatment (n=23)
2 session of treatment (n=5)
3 session of treatment (n=2)
4 session of treatment (n=1)
4 intra-arterial ethanol injection and 1 RFA
4 intra-arterial ethanol injection and 1 RFA
1 intra-arterial ethanol injection and 2 RFA
1 session of treatment (n=17)
2 session of treatment (n=3) 3 intra-arterial ethanol injection
Follow-up Tumor progression (n=40)
Additionnal treatment: sorafenib (n=14), RFA (n=14), intraarterial embolisation (n=10), intraarterial alcoolisation (n=1), MWA (n=2), IRE (n=1), Ytrium90 (=1)
Death (n=40) HCC related (n=31)
Treatment related (n=1)
Liver related, except HCC (n=1)
B
Non Liver related, (n=3)
Unknown (n=4)
C Arterial phase before treatment
Arterial phase 1 month after treatment
Portal phase before treatment
Portal phase 1 month after treatment
T1 with injection arterial phase before treatment
T1 without injection 1 month after treatment
T1 with injection portal phase before treatment
T1 with injection 1 month after treatment
Percutaneous Treatments of Infiltrating HCC
of cirrhosis. The median serum AFP level was 125 ng/ml (minimum–maximum: 2–215,000). HCC appeared as single infiltrative tumor in 69 % of patients. Median size of the main tumor was 60 mm (min–max: 25–200). Thirty patients (59 %) had radiological tumor macrovascular invasion, including 28 segmental involvements. HCC were classified as Barcelona clinical liver classification (BCLC) stage A in 24 % of cases (12 cases with among them 9 HCC [50 mm), BCLC stage B in 18 % of cases, and BCLC stage C in 59 % of cases. Twenty-nine patients were treatment-naive, whereas 22 had previously undergone HCC treatment. Twenty patients (39 %) were treated using mbpRFA and 31 (61 %) using PIAEI (Fig. 1). Patients treated by PIAEI had more advanced HCC (BCLC C 75 %) compared with those treated by mbpRFA (BCLC C 35 %, P = 0.0092), mainly because of more frequent macrovascular invasion in patients treated with PIAEI (Table 1).
A
Overall Survival 100
Percent survival
of IHCC (a). A 58-year-old man with alcoholic-related cirrhosis was treated by PIAIEI for a histologically proven IHCC of 75 mm of segment IV. CT scan with injection at the arterial phase and at the portal phase before and 3 months after treatment (b). A 54-year-old man with HCV-related cirrhosis was treated by mbpRFA for an IHCC of 55 mm of segment V. CT scan with injection at the arterial phase and at the portal phase before and 3 months after treatment (b). MWA microwave ablation; RFA radiofrequency ablation; IRE irreversible electroporation; Yttrium90 radioembolization with Yttrium 90
80 60 40 20 0
0
20
40
60
Time (months) Patients at risk
51
32
12
2
B
Progression free Survival
100
Percent survival
b FIG. 1 Flow chart of the study. Flow chart of percutaneous treatment
80 60 40 20 0 0
20
40
60
5
2
Time Patients at risk
50
20
Treatment Characteristics
•
PIAEI
In 7 patients treated by PIAEI (Fig. 1B), an additional concomitant treatment by intratumor alcoholization (n = 4), microwave ablation (n = 1), and mbpRFA (n = 2) was performed to destroy the largest possible tumor volume during a given session (Fig. 1). A median of 20 cc of ethanol (min–max: 7–38) was injected into a median of 2 feeding arteries (min–max: 1–4). •
mbpRFA
C
Time to progression 100
Percent survival
One session of treatment was performed in 40 patients and at least 2 sessions in 10 patients (Fig. 1).
80 60 40 20 0 0
20
40
60
2
2
Time Patients at risk
50
8
A median number of five electrodes (min–max: 2–12) were used to deliver a median value of 280 kJ (min–max: 80–570) during a median time of treatment of 35 min (min–max: 20–105) (Fig. 1c).
FIG. 2 Long-term survival. Overall survival (a), progression-free survival (b), and time to progression (c) of the whole cohort were described using the Kaplan–Meier method. The numbers at risk are reported under the x-axis
Safety
C to F). Moreover, 18 patients have postablation syndrome (35 %). Using the Dindo-Clavien classification, adverse events were classified as stage I in 4 cases, stage II in 11 cases, stage IIIa in 2 cases, and stage IIIb in 1 case. One
Using the SIR classification, 19 patients (37 %) experienced one adverse event (2 classified as A or B and 17 as
J. Nault et al. TABLE 2 Univariate and multivariate Cox analysis for overall survival HR
CR 95 %
P value
Age (years)
0.9986
0.9616–1.037
0.941
Gender (male)
1.089
0.4228–2.803
0.86
Presence of ascites
1.335
0.4029–4.422
0.637
Child Pugh (A vs. B)
1.09383
0.4251–2.814
0.8524
Portal hypertension
1.098
0.5669–2.126
0.782
HR
CR 95 %
P value
BCLC classification (A vs. B/C)
1.792
0.7997–4.016
0.1565
No. of HCCa
1.583
0.9629–2.604
0.0702
Sum of the size of the nodulesa
1.018
1.007–1.028
0.00088
1.0223
1.0032–1.042
0.0221
Size of the largest nodulea
1.016
1.003–1.028
0.0141
0.9975
0.9777–1.018
0.8079
Tumor portal thrombosis
1.337
0.69–2.589
0.39
Hepatitis B virus Hepatitis C virus
1.007 0.5843
0.4205–2.41 0.2907–1.174
0.988 0.131 1.8547
0.8782–3.917
0.1054
2.9872
1.3751–6.489
0.0057
Alcohol
2.302
1.102–4.805
0.0264
AFP (ng/ml)a
1
1; 1
0.822
GGTa
0.9892
0.9447–1.036
0.642
Creatinine (ymol/l)a
1.003
0.9903–1.015
0.67
Alkaline phosphatase (UI/L)a
0.5794
0.2143–1.567
0.282
Albumin (g/dl)a
1.003
0.9424–1.067
0.931
Total bilirubin [normal
2.746
1.299–5.806
0.0082
3
0.917
Platelets \150,000/mm
1.036
0.534–2.01
Prothrombin timea
0.9914
0.968–1.015
0.479
Previous treatment
1.191
0.6336–2.238
0.587
Treatment by multibipolar RFA
0.7841
0.417–1.474
0.45
AFP alpha-fetoprotein, GGT gamma-glutamyl transferase, RFA radiofrequency ablation, BCLC Barcelona Liver Cancer Classification, HCC hepatocellular carcinoma a
These variables were analyzed as continuous value in univariate analysis
treatment-related death (2 %, Dindo-Clavien V) occurred due to liver failure after mbpRFA. Among the three cases classified Dindo-Clavien IIIa and IIIb, one case of liver abscess required percutaneous drainage, one colonic perforation required long-term antibiotic treatment, and one case of biliary stenosis required stenting procedures. The type of treatment was not significantly associated with the occurrence of complications (P = 0.5659). Treatment of HCC with a sum of the size of the tumor [70 mm was associated with an increased rate of adverse Dindo-Clavien II to V events [odds ratio (OR) 4.84; 95 % CI 1.05–31.31; P = 0.02]. Long-Term Results: Overall Survival and Time to Progression After a mean follow-up of 18 months, 40 (78 %) patients experienced tumor progression and 40 patients died (78 %, Fig. 1). Among the 51 patients in our study, 4 (8 %) were lost to follow-up. Median OS was 18.3 months, and actuarial rates of survival at 1, 2, 3, and 4 years were 63, 35, 20, and 12 %, respectively (Fig. 2a).
Median PFS was 7.46 months, and actuarial rates of progression free-survival at 1, 2, 3, and 4 years were 35, 9, 4, and 2 %, respectively (Fig. 2b). The median TTP was 8 months and actuarial rates of tumor progression at 1, 2, 3, and 4 years were 62, 88, 91, and 91 %, respectively (Fig. 2c). Univariate and Multivariate Analyses of Survival For univariate analysis, size of the main tumor, sum of the size of all tumors, high alcohol intake, and higher total bilirubin levels were significantly associated with OS (Table 2). For multivariate analysis, the sum of the size of all tumors (HR 1.0223; 95 % CI 1.0032–1.042; P = 0.0221) and higher total bilirubin level ([1.2 mg/dl, [20 lmol) (HR 2.9872; 95 % CI 1.3751–6.489; P = 0.0057) remained independently associated with poorer OS (Table 2). When combining these two features, we were able to stratify the population according to prognosis (Figs. 3a–c). Patients with a sum of the size of all tumors \70 mm and with a normal bilirubin level had the longest OS (median OS 29.9 months) compared with
Percutaneous Treatments of Infiltrating HCC
A Overall Survival
Percent survival
100
Normal bilirubin level
80
High bilirubin level
P=0.0022 60 40 20 0 0
20
40
60
Time (months)
Patients at risk Normal bilirubin level
38
17
5
2
High bilirubin level
12
4
1
1
B
Overall Survival
Percent survival
Sum of the size < 70 mm Sum of the size ≥ 70 mm
P=0.0139
Time (months)
Patients at risk Sum of the size < 70 mm
23
14
4
1
Sum of the size ≥ 70 mm
27
7
2
2
Overall Survival
C
Percent survival
FIG. 3 Overall survival according to subgroup analysis. Overall survival in patients dichotomized according to the total bilirubin level (normal value \20 lmol/\1.2 mg/dl vs. high value [20 lmol/[1.2 mg/ dl) (a), dichotomized according to the median sum of the size of all nodules (\70 mm vs. C70 mm) (b), and according the combination of total bilirubin level and the sum of the size of all nodules (normal total bilirubin level AND sum of size of all nodules \70 mm vs. high total bilirubin level OR sum of size of all nodules C70 mm vs. high total bilirubin level AND sum of size of all nodules C70 mm) (c). Survival was assessed using the Kaplan– Meier method and the log-rank test. The numbers at risk are reported under the x-axis
Normal bilirubin and sum of size < 70 mm High bilirubin OR sum of size ≥ 70 mm
P
