# Impact of induction therapy in locally advanced intrahepatic cholangiocarcinoma

Alix Dhote, Stylianos Tzedakis, Christian Hobeika, Ugo Marchese, Romain Coriat, Alexandra Nassar, Aurélie Beaufrère, Tatiana Codjia, Claire Goumard, Olivier Scatton, et al.

► To cite this version:

Alix Dhote, Stylianos Tzedakis, Christian Hobeika, Ugo Marchese, Romain Coriat, et al. Impact of induction therapy in locally advanced intrahepatic cholangiocarcinoma. EJSO - European Journal of Surgical Oncology, 2023, 10.1016/j.ejso.2023.05.014. hal-04172878

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Distributed under a Creative Commons Attribution 4.0 International License
1 **Impact of induction therapy in locally advanced intrahepatic cholangiocarcinoma**

2

3

4 Alix Dhote¹,⁹, Stylianos Tzedakis¹,¹⁰, Christian Hobeika²,¹⁰, Ugo Marchese¹,¹⁰,

5 Romain Coriat³,¹⁰, Alexandra Nassar¹,¹⁰, Aurélie Beaufrère⁴,¹⁰, Tatiana Codjia²,¹⁰,

6 Claire Goumard⁵,⁹, Olivier Scatton⁵,⁹, Anthony Dohan⁶,¹⁰, Maxime Ronot⁷,¹⁰,

7 Benoit Terris⁸,¹⁰, Mickael Lesurtel²,¹⁰, Safi Dokmak²,¹⁰, François Cauchy²,¹⁰,

8 David Fuks¹,¹⁰.

9

10 1. Service De Chirurgie Digestive, Hépatobiliaire Et Endocrinienne, Hôpital Cochin - Paris, France

11

12 2. Service De Chirurgie Digestive, Hépato-Bilio-Pancréatique Et Transplantation Hépatique, Hôpital Beaujon, Clichy, France

13

14 3. Service De Cancérologie, Hôpital Cochin - Paris, France

15 4. Service d'Anatomie et cytologie pathologique, APHP.Nord, FHU MOSAIC,

16 Hôpital Beaujon, Clichy, France

17 5. Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique, Hôpital Pitié-Salpêtrière - Paris, France

18

19 6. Service De Radiologie, Hôpital Cochin - Paris, France

20 7. Service De Radiologie, Hôpital Beaujon, APHP.Nord, Clichy, France

21 8. Service d'Anatomie et cytologie pathologique, Hôpital Cochin - Paris,

22 France

23 9. Université Paris-Sorbonne, Paris, France
24 10. Université Paris Cité, Paris, France

25

26

27 **Corresponding author:**

28 Alix Dhote, MD

29 Digestive, Hepato-Biliary and Endocrine Surgery Department, Hôpital Cochin

30 Université Paris Cité, Paris, France

31 E-mail: alixdhote@hotmail.fr

32

33 **Conflicts of interest:** The authors have no conflict of interest to declare. There
34 has been no previous communication with any society or meeting regarding
35 this article.

36

37 **Abbreviations:** ASA, American Society of Anesthesiologists; ICC, Intrahepatic
38 Cholangiocarcinoma; NAT, neoadjuvant treatment; US, Upfront Surgery

39

40
41 **ABSTRACT**

42 **Introduction.** After local or systemic treatment, a small number of patients with 43 primarily unresectable intrahepatic cholangiocarcinoma (ICC) may benefit 44 from secondary resection. This study aimed to analyze the oncological 45 outcome of patients who underwent radical surgery after preoperative 46 treatment.

47 **Methods.** From 2000 to 2021, all patients who underwent curative-intent liver 48 resection for ICC in three tertiary centers were selected. Patients were divided 49 into two groups: upfront surgery (US) and preoperative treatment (POT). 50 Oncologic data (preoperative treatment, histologic data, adjuvant 51 chemotherapy, overall survival, and recurrence-free survival) were compared 52 between the two groups.

53 **Results.** Among 198 included patients, 31 (15.7%) received POT including 54 chemotherapy (74.2%), radioembolization (12.9%), chemoembolization 55 (9.7%), or combined radiotherapy and chemotherapy (3.2%). Major resection 56 was performed in 156 (78.8%) patients, and 53 (26.8%) had vascular and/or 57 biliary reconstruction. Histological findings were similar between US and POT 58 group and were not affected by the type of POT.

59 After a median follow-up of 23 months, recurrence rate (58.1% POT vs. 55.1% 60 US, p=0.760) and type were similar between groups. Recurrence-free survival 61 at 1 and 3 years (41.9% and 22.6% vs. 46.7 and 21.6% in the POT and US, 62 respectively, p=0.989) and overall survival at 1 and 3 years (77.4% and 32.3% 63 vs. 69.5% and 34.7% in the POT and US respectively, p=0.323) were similar and 64 independent of the POT type.
**Conclusion.** After POT, downstaged patients who underwent curative-intent resection for initially unresectable ICC have similar long-term outcomes as those undergoing upfront surgery.

68
69 INTRODUCTION

70 Cholangiocarcinoma is the second most common primary liver tumor after
71 hepatocellular carcinoma¹, and intrahepatic cholangiocarcinomas (ICC)
72 represent 20% of them. Over past decades, the incidence of ICC has
73 increased², but only 30% of patients have access to a curative-intent surgery³.
74 Indeed, these tumors are poorly symptomatic and therefore diagnosed at an
75 advanced stage. The prognosis of ICC is dismal, with an overall 5-year survival
76 rate of 9%, while complete surgical resection (negative resection margins and
77 adequate lymphadenectomy) offers a 5-year survival of 35%⁴,⁵.

78 To date, no randomized study has assessed the role of local or systemic
79 induction treatment in locally advanced ICC and the only recommended
80 treatment includes chemotherapy with gemcitabine and platinum-based
81 chemotherapy⁶. Three retrospective studies have already reported the
82 experience of curative-intent resections after tumor downstaging by
83 chemotherapy⁷,⁸. However, among the different treatments used, transarterial
84 chemoembolization or radioembolization have also been reported to convert
85 initially unresectable into resectable tumors and impact long-term
86 survival⁹,¹⁰,⁸,¹¹,¹². Indeed, a phase 2 prospective study evaluating the
87 association of radioembolization and chemotherapy as an induction
88 treatment in locally advanced ICC showed promising results for downsizing to
89 resection¹³.

90 The present study aimed to analyze the results of surgical resection and
91 compare oncological outcomes between patients who underwent upfront
92 surgery (US) with curative-intent and patients undergoing surgery after a
93 preoperative treatment (POT) and to analyze histological outcomes
94 according to the POT received.

95

## 96 METHODS

97 **Study population**

98 From January 2000 to June 2021, all patients undergoing curative-intent
99 hepatic resection for ICC in three French tertiary centers were selected. Data
100 were collected from prospectively maintained databases. Patients
101 secondarily resectable after receiving a preoperative treatment (POT) i.e.
102 chemotherapy, radio-chemotherapy, chemoembolization, or
103 radioembolization followed by surgery were compared with those who had
104 upfront surgery (US) regarding histologic and long-term outcomes. Patients
105 with perihilar cholangiocarcinoma, hepato-cholangiocarcinoma, gallbladder
106 carcinoma or patients presenting extrahepatic lesions were excluded from
107 the analysis. This study was conducted in accordance with the Declaration of
108 Helsinki and all participants were informed and gave written consent for their
109 medical information to be used for scientific research.

110

111 **Preoperative management**

112 After a complete initial work-up with computed tomography (CT) scan
113 and a magnetic resonance imaging (MRI), a local multidisciplinary meeting
114 including medical oncologists, radiologists, and hepatobiliary surgeons
115 reviewed all cases. Moreover, patient files with non-resectable tumors were
116 reviewed conjointly by the surgical (ST, DF, OS, ML) and radiologic team (AD,
117 MR) to confirm initial non resectability. Resectability was defined as an
118 anticipated complete resection with adequate margins (glissonean, biliary
119 and vascular), and no suspect distant lymph node involvement, leaving a
120 sufficient functional future liver remnant (remnant liver volume to body weight
121 ratio ≥ 0.5%), with an arterial and venous vascularization and biliary drainage.

122 Preoperative biliary drainage (endoscopic retrograde biliary drainage or
123 percutaneous transhepatic drainage) was performed in case of obstructive
124 jaundice. A portal vein embolization was required if the remnant liver volume
125 to body weight ratio was less than 0.5%. Vascular resection was discussed
126 before surgery on imaging data and during surgery if a macroscopic
127 involvement was observed and a vascular reconstruction was possible.

128 Tumors associated with pedicle invasion without achievable reconstruction or
129 multifocal ICC with bilobar lesions were contraindications for surgery and a
130 palliative treatment based on platinum chemotherapy was initiated. For
131 locally advanced tumors an induction treatment was proposed with the aim
132 to induce tumor downsizing and subsequent surgery.

133 Patients treated with radioembolization received concomitant first-line
134 systemic platinum-based chemotherapy while patients treated with
135 chemoembolization underwent two cycles of selective chemoembolization
136 with Doxorubicin-Eluting microspheres. Response to treatment was assessed
137 according to Response Evaluation Criteria for Solid Tumors (RECIST) 1.1
138 criteria¹⁴.

139
140 **Operative procedures**

141 Liver resections were performed either by a right subcostal incision or
142 laparoscopy when a vascular reconstruction was not judged necessary.

143 Hepatectomy was conducted with the intention of having macroscopic
144 resection margins of at least 1 cm from the tumor. Ultrasonography was
145 performed intraoperatively to assess tumor resectability. Parenchymal
146 transection was performed with the assistance of an ultrasonic dissector and
147 hemostasis was performed using bipolar forceps. To minimize blood loss during
148 parenchymal transection, clamping of the hepatic pedicle was performed
149 when judged necessary. Hepatic pedicle lymphadenectomy was routinely
150 performed. When a macroscopic hepatic or portal vein involvement was
151 detected, venous resection and reconstruction was performed using direct
152 closure, peritoneum patch or autologous/heterologous graft interposition.

153

154 **Pathology and postoperative outcomes**

155 Clinicopathologic variables collected included: size and number of
156 lesions, tumor differentiation, morphological type (mass-forming, intra-ductal
157 growth, and periductal infiltrating), vascular emboli, and perineural invasion.

158 Tumor staging was assessed on the resected specimen by a pathologist,
159 reclassified according to American Joint Commission on Cancer (AJCC) TNM
160 classification (8th edition)¹⁵. R0 margin was defined as a margin of at least
161 1mm from the tumor, and R1 margin was defined as a margin of less than
162 1mm from the tumor on the pathological specimen.
163

In patients undergoing POT, tumor response was assessed and compared according to the therapy received (chemotherapy, chemoembolization or radioembolization).

164

165

166

Postoperative morbidity and mortality were assessed within 90 days of surgery. All post-operative complications were recorded and graded according to the Dindo-Clavien classification¹⁶. In addition, liver-related complications including post-hepatectomy insufficiency, bile leakage and hemorrhage were defined according to the International Study Group of Liver Surgery criteria¹⁷,¹⁸,¹⁹.

167

168

169

170

171

172

173

## Follow-up

174

175

176

177

Patients received adjuvant chemotherapy according to the recommendations of the period during which they were treated. Until February 2014, gemcitabine associated to oxaliplatin were administrated for 6 months to patients as part of the Prodige 12-accord 18-unicancer GI trial²⁰. Thereafter, no postoperative chemotherapy was administered until the results of the BILCAP study were launched in 2019²¹. Patients subsequently received capecitabine for 6 months.

178

179

180

181

182

183

184

185

186

Patients were followed-up with clinical evaluation, tumor markers (CA 19.9 level) and CT scan every 3-6 months for five years. If a recurrence was suspected, additional imaging techniques were performed with MRI and/or positron emission tomography-CT (PET-CT). A biopsy was performed if the diagnosis remained uncertain. The therapeutic strategy was discussed in multidisciplinary meetings. For disease recurrence involving only the liver, an
iterative hepatic resection or radiofrequency ablation (RFA) associated to
chemotherapy was proposed. Patients underwent palliative chemotherapy
for unresectable tumors and extra-hepatic recurrence (gemcitabine and/or
platinum-based chemotherapy).

The primary endpoints of the study were overall survival (OS) and
recurrence-free survival (RFS) defined respectively by the time between the
operation and death of the patient, and the time between the operation
and appearance of a local or distant recurrence on follow-up imaging.

## Statistical Analysis

Continuous variables are expressed as medians with 25-75 interquartile
range (IQR) or mean values with standard deviation (SD) and were
compared using the Mann-Whitney test as appropriate. Categorical
variables are summarized in frequency and percentage and were compared
using the Pearson's Chi-square test of Fisher's exact test as appropriate.

Overall survival (OS) and recurrence-free survival (RFS) were assessed with the
Kaplan-Meier Method. To compare survival between two groups, a Log Rank
Test was used. All reported p-values were two-sided and a p-value of less
than 0.05 was considered statistically significant. Multiplicity adjustments for
pairwise comparisons when three or more groups were compared were
made through a Holm correction. All statistical analyses were performed using
Graphpad PRISM (6.0 Version).

209
## 210 RESULTS

### 211 Study population

During the study period, 198 patients underwent curative-intent resection for ICC. Of these, 31 (15.7%) patients received a POT, and 167 (84.3%) underwent US. Causes of non resectability are detailed in Supplementary Table 1. Among patients who responded to treatment, 23 (74.2%) patients received chemotherapy alone, four (12.9%) patients received radioembolization associated with chemotherapy, three (9.7%) patients received chemoembolization and finally one (3.2%) patient received radiochemotherapy.

As detailed in **Table 1**, both patients' demographic data and tumor characteristics were similar between POT and US groups. At baseline, the presence of multiple tumors was observed more frequently in the POT than US group (29.0% vs. 7.2%, p = 0.001).

### 225 Intraoperative and postoperative data

Major hepatectomy was performed in 25 (80.6%) and 131 (78.4%) patients in the POT and US groups, respectively (p = 0.783). Type of surgical procedure and postoperative outcomes were similar in both groups, as illustrated in **Table 2**. Vascular resections were necessary in four (12.9%) patients of the POT group and 21 (12.6%) patients of the US group (p = 1.000). In the POT group, one patient underwent a portal resection, and three patients a lateral inferior vena cava resection. In the US group, vascular procedures consisted of portal resection in 20 patients (12.0%), lateral inferior
234

vena cava resection was performed in 8 patients, and hepatic artery reconstruction in three patients.

235

236

237

## Histological outcomes

238

R0 resection rate was 87.1%, and 80.2% in the POT and US group, respectively (p = 0.368). Most tumors were classified as T1-T2 (87.1% in the POT group and 77.2% in the US group). The rate of lymph node involvement was also similar (40.0% in the POT group vs. 32.4% in the US group). Tumoral vascular emboli were more often observed in the US group (54.5% vs. 32.3%, p = 0.023). Histological characteristics are shown in **Table 3**.

239

240

241

242

243

244

Histology result comparison between different POT showed no histological difference in terms of staging, lymph node invasion, and resection margin. Residual tumor rate ≤ 5.0% was found in 2 (50.0%) patients treated with radioembolization and 1 (4.3%) patient treated with systemic chemotherapy. **Table 4** details histological characteristics according to the type of preoperative treatment.

245

246

247

248

249

250

251

## Long-term outcomes

252

Postoperatively, 13 patients (41.9%) in the POT group and 45 patients (26.9%) in the US group underwent adjuvant chemotherapy (p = 0.092). After a median follow-up of 23 months, recurrence was observed in 18 (58.1%) patients of the POT and 92 (55.1%) patients of the US group (p = 0.760). **Table 5** describes the pattern of recurrence and its management. Overall survival (OS) at 1 and 3 years was 77.4% and 32.3% in the POT group and 69.5% and

253

254

255

256

257
258 34.7% in the US group (p = 0.323) as shown in **Figure 2**. Recurrence-free survival

259 (RFS) at 1 and 3 years was 41.9% and 22.6% in the POT group and 46.7% and

260 21.6% in the US group (p = 0.989) as shown in **Figure 3**. **Figure 4** and

261 Supplementary Figure 1 compare OS according to the preoperative

262 treatment and demonstrate similar OS at 1 and 3-years between the 3 POT

263 groups (p=0.424) as well as individual POT groups and Upfront surgery,

264 respectively.

265

266
267 DISCUSSION

268 This study aimed to investigate the efficacy of different induction
269 treatments to downsize initially unresectable ICC to surgery and to compare
270 long-term outcomes with upfront resectable patients. We observed that
271 secondarily resected ICC treated with POT had similar OS and RFS as patients
272 treated with US.

273 Over the past two decades, several studies have focused on the
274 control of locally advanced ICC, however the role of different induction
275 treatments to downsize unresectable ICC to resection has not been
276 thoroughly evaluated. Le Roy et al⁷ observed in a retrospective cohort of 74
277 patients that OS and RFS of patients operated after a preoperative
278 chemotherapy were similar to those of patients treated with upfront surgery.
279 Lunsford et al²² similarly showed in a prospective series of 12 patients, an OS of
280 83.3% at 5 years after liver transplantation in patients with initial locally
281 advanced ICC stabilized by neoadjuvant chemotherapy. These results
282 suggest that patients with locally advanced ICC downstaged with
283 neoadjuvant chemotherapy can undergo surgery, with long-term results
284 comparable to resectable patients. The present study also confirms the similar
285 longterm outcomes of induction chemotherapy compared with US.

286 Selective internal radiation therapy (SIRT) is a locoregional treatment
287 currently used in the treatment of intermediate and locally advanced
288 (Barcelona Clinic Liver Cancer stage B and C) hepatocellular carcinoma
289 (HCC)²³,²⁴. SIRT has also given promising results in bridging initially unresectable
290 intrahepatic cholangiocarcinoma to surgery²⁵,⁹,²⁶. In the present study, four
291 patients were treated by SIRT associated with a platinum-based
292 chemotherapy. Histological characteristics and OS were similar to patients
293 treated with preoperative chemotherapy alone. Several studies have
294 assessed the association of chemotherapy and SIRT as an induction
295 treatment for locally advanced ICC. Riby et al.⁸ showed that SIRT associated
296 with chemotherapy was associated with a significant benefit on OS, which
297 was similar to OS of resectable patients. Another prospective study confirmed
298 the benefit of the combination of SIRT and chemotherapy on unresectable
299 ICC, with a secondary resection rate of 22%¹³. In addition, a recent
300 multicenter randomised phase 2 trial showed that personalized dosimetry
301 induces a significant improvement in tumor response and OS compared with
302 standard dosimetry in unresectable unifocal or multifocal HCC²⁷ and a phase
303 3 study is currently being conducted to confirm these findings. In our study we
304 did not observe any significant difference in survival of SIRT treatment
305 compared with other preoperative treatments although statistical power is
306 limited due to the low number of patients in the different POT groups.

307 In contrast to rectal adenocarcinoma, where a decrease in the rate of
308 invaded nodes is observed after a neoadjuvant treatment²⁸, such a result was
309 not observed in our study. Le Roy et al.⁷ also observed a similar rate of lymph
310 node invasion between US and neoadjuvant chemotherapy groups (18.0%
311 and 21.0% respectively, p = 0.786). A negative impact of tumor necrosis on OS
312 and RFS has been suggested in several studies for hepatocellular
313 carcinoma²⁹,³⁰ and peri-hilar cholangiocarcinoma³¹. A retrospective study
314 showed that tumor necrosis was associated with a worse OS and RFS at 5
315 years among patients with an ICC³². A more recent retrospective study³³ on a
316 large cohort of 757 patients confirmed the association between tumor
317 necrosis and OS and RFS only on stage T1 ICC while no similar association was
318 observed in more advanced stages. These studies suggest that tumor necrosis
319 could be an important prognostic histologic outcome. In the present study
320 we investigated if tumor necrosis could be affected by the type of POT but
321 such an impact was not confirmed. Moreover, in terms of microscopic
322 surgical margins⁴, lymph node invasion³⁴, differentiation, or perineural
323 infiltration³², this study did not show any difference between US and POT
324 groups, nor in the subgroup analysis comparing the different types of POT.

325 This study has some limitations among which are its retrospective nature
326 and patient data assessment treated for over 20 years, and change of
327 adjuvant treatment protocols over time. However, locally advanced ICC are
328 rare tumors, with a limited conversion rate to surgery ranging from 18 and
329 53%¹³,⁷,¹¹, therefore obtaining a large number of patients or designing
330 prospective trials can be challenging. Over the past decades years, surgical
331 techniques have evolved and progressed, and the definition of locally
332 advanced ICC has also probably changed. Finally, although three French
333 tertiary centers specialized in ICC have participated, statistical power of
334 subgroup analysis is limited due to the limited sample size of each POT group.

335 In conclusion, this study suggests that patients with initially unresectable
336 ICC treated with POT present similar longterm outcomes with patients
337 undergoing upfront surgery for initially resectable ICC. Histological analysis of
338 surgical specimens according to the type of POT did not reveal any
difference in histological response, although further studies are needed to

confirm this observation.

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448
<figure><img src="image_2.png" /><figcaption>Fig 1 : Flowchart</figcaption></figure>
<table><caption>Table 1: Preoperative demographic data for patients who received upfront surgery or preoperative treatment</caption><thead><tr><th>Variables</th><th>Upfront surgery (n=167)</th><th>Preoperative Treatment (n=31)</th><th>p value</th></tr></thead><tbody><tr><td><strong>Clinical data</strong></td><td></td><td></td><td></td></tr><tr><td>Male gender, n</td><td>81 (48.5%)</td><td>17 (54.8%)</td><td>0.517</td></tr><tr><td>Age, years (mean)</td><td>64 (53-76)</td><td>61 (49-73)</td><td>0.176</td></tr><tr><td>BMI, kg/m<sup>2</sup> (mean)</td><td>26 (21-31)</td><td>26 (20-31)</td><td>0.475</td></tr><tr><td>ASA Score ≥ 3</td><td>24 (14.4%)</td><td>7 (22.6%)</td><td>0.281</td></tr><tr><td>Diabetes</td><td>30 (18.0%)</td><td>7 (22.6%)</td><td>0.616</td></tr><tr><td>Hypertension</td><td>85 (50.9%)</td><td>11 (35.5%)</td><td>0.115</td></tr><tr><td>Dyslipidemia</td><td>57 (34.1%)</td><td>5 (16.1%)</td><td>0.058</td></tr><tr><td>Cardiovascular disease</td><td>38 (22.8%)</td><td>4 (12.9%)</td><td>0.337</td></tr><tr><td>Respiratory disease</td><td>24 (14.4%)</td><td>4 (12.9%)</td><td>&gt; 0.999</td></tr><tr><td>Cirrhosis</td><td>19 (11.4%)</td><td>4 (12.9%)</td><td>0.764</td></tr><tr><td><strong>Tumor characteristics at baseline</strong></td><td></td><td></td><td></td></tr><tr><td>Tumor size, cm (median)</td><td>6.0 (4.0-8.5)</td><td>7.2 (4.5-10.0)</td><td>0.301</td></tr><tr><td>Tumor ≥ 5cm</td><td>98 (58.7%)</td><td>22 (71.0%)</td><td>0.233</td></tr><tr><td>Multiple tumors</td><td>12 (7.2%)</td><td>9 (29.0%)</td><td>0.001</td></tr><tr><td>Symptoms at diagnosis</td><td>83 (49.7%)</td><td>15 (48.4%)</td><td>0.893</td></tr><tr><td>Biliary drainage</td><td>16 (9.6%)</td><td>2 (6.5%)</td><td>0.744</td></tr><tr><td>Portal vein embolization</td><td>23 (13.8%)</td><td>7 (22.6%)</td><td>0.272</td></tr><tr><td><strong>Blood tests at baseline</strong></td><td></td><td></td><td></td></tr><tr><td>Prothrombin time (mean)</td><td>100 (89-111)</td><td>94 (83-105)</td><td>0.053</td></tr><tr><td>Bilirubin (mean)</td><td>16 (0-45)</td><td>9 (5-13)</td><td>0.027</td></tr></tbody></table>

Footnote: Continuous variables are expressed as medians (+/- 25-75 interquartile range) or mean (+/- standard deviation) and were compared using the Mann-Whitney test. Categorical variables are summarized in frequency and percentage and were compared using the Pearson's Chi-square test of Fisher's exact test. Abbreviations: BMI, Body Mass Index; ASA Score, American Society of Anesthesiologists
<table><caption>Table 2: Intraoperative data for patients who received upfront surgery or preoperative treatment</caption><thead><tr><th>Variables</th><th>Upfront surgery (n=167)</th><th>Preoperative Treatment (n=31)</th><th>p value</th></tr></thead><tbody><tr><td><strong>Intraoperative data</strong></td><td></td><td></td><td></td></tr><tr><td>Major liver resection</td><td>131 (78.4%)</td><td>25 (80.6%)</td><td>0.783</td></tr><tr><td>Number of resected segments, mean (SD)</td><td>4 (3-5)</td><td>4 (2-6)</td><td>0.541</td></tr><tr><td>Lymph node dissection</td><td>108 (64.7%)</td><td>20 (64.5%)</td><td>0.987</td></tr><tr><td>Vascular resection</td><td>21 (12.6%)</td><td>4 (12.9%)</td><td>&gt; 0.999</td></tr><tr><td>Biliary resection</td><td>33 (19.8%)</td><td>4 (12.9%)</td><td>0.459</td></tr><tr><td>Hepatic pedicle clamping</td><td>120 (71.9%)</td><td>22 (71.0%)</td><td>0.920</td></tr><tr><td>Estimated blood loss ≥ 500 mL</td><td>62 (37.1%)</td><td>11 (35.5%)</td><td>0.862</td></tr><tr><td>Duration of surgery, min (mean)</td><td>336 (220-452)</td><td>294 (196-391)</td><td>0.079</td></tr><tr><td>Laparoscopy</td><td>12 (7.2%)</td><td>3 (9.7%)</td><td>0.710</td></tr><tr><td><strong>Post-operative outcomes</strong></td><td></td><td></td><td></td></tr><tr><td>Duration of hospital stay, days, mean (SD)</td><td>17 (0-34)</td><td>15 (6-24)</td><td>0.193</td></tr><tr><td>Dindo-Clavien grade ≥ 3</td><td>60 (35.9%)</td><td>12 (38.7%)</td><td>0.767</td></tr><tr><td>Liver failure</td><td>27 (16.2%)</td><td>4 (12.9%)</td><td>0.646</td></tr><tr><td>Mortality at 90 days</td><td>14 (8.4%)</td><td>3 (9.7%)</td><td>0.734</td></tr></tbody></table>

Footnote: Continuous variables are expressed as medians (+/- 25-75 interquartile range) or mean (+/- standard deviation, SD) and were compared using the Mann-Whitney test. Categorical variables are summarized in frequency and percentage and were compared using the Pearson's Chi-square test of Fisher's exact test.
<table><caption>Table 3: Histological outcomes of patients who received upfront surgery or preoperative treatment</caption><thead><tr><th>Variables</th><th>Upfront surgery (n=167)</th><th>Preoperative Treatment (n=31)</th><th>p value</th></tr></thead><tbody><tr><td>Tumor characteristics</td><td></td><td></td><td></td></tr><tr><td>T1-T2</td><td>129 (77.2%)</td><td>27 (87.1%)</td><td>0.218</td></tr><tr><td>T3-T4</td><td>36 (21.6%)</td><td>3 (9.7%)</td><td>0.147</td></tr><tr><td>N+</td><td>35 (32.4%)</td><td>8 (40.0%)</td><td>0.509</td></tr><tr><td>Resection</td><td></td><td></td><td></td></tr><tr><td>R0</td><td>134 (80.2%)</td><td>27 (87.1%)</td><td>0.368</td></tr><tr><td>R1</td><td>26 (15.6%)</td><td>4 (12.9%)</td><td>&gt; 0.999</td></tr><tr><td>R2</td><td>7 (4.2%)</td><td>0</td><td>0.599</td></tr><tr><td>Histologic subtype</td><td></td><td></td><td></td></tr><tr><td>Massforming</td><td>152 (91.0%)</td><td>31 (100%)</td><td>0.134</td></tr><tr><td>Periductal</td><td>10 (6.0%)</td><td>1 (3.2%)</td><td>&gt; 0.999</td></tr><tr><td>Intraductal</td><td>2 (1.2%)</td><td>1 (3.2%)</td><td>0.402</td></tr><tr><td>Differentiation</td><td></td><td></td><td></td></tr><tr><td>Well</td><td>40 (24.0%)</td><td>10 (32.3%)</td><td>0.328</td></tr><tr><td>Moderate</td><td>101 (60.5%)</td><td>14 (45.2%)</td><td>0.112</td></tr><tr><td>Poor</td><td>16 (9.6%)</td><td>7 (22.6%)</td><td>0.061</td></tr><tr><td>Vascular emboli</td><td>91 (54.5%)</td><td>10 (32.3%)</td><td>0.023</td></tr><tr><td>Perineural invasion</td><td>71 (42.5%)</td><td>10 (32.3%)</td><td>0.286</td></tr><tr><td>Satellite nodules¶</td><td>50 (29.9%)</td><td>11 (35.5%)</td><td>0.414</td></tr><tr><td>Endobiliary extension</td><td>20 (12.0%)</td><td>4 (12.9%)</td><td>0.763</td></tr><tr><td>Non tumoral liver</td><td></td><td></td><td></td></tr><tr><td>Normal liver</td><td>61 (36.5%)</td><td>12 (38.7%)</td><td>0.817</td></tr><tr><td>NASH</td><td>21 (12.6%)</td><td>7 (22.6%)</td><td>0.161</td></tr><tr><td>Cirrhosis</td><td>22 (13.2%)</td><td>2 (6.5%)</td><td>0.382</td></tr><tr><td>Adjuvant chemotherapy</td><td>45 (26.9%)</td><td>13 (41.9%)</td><td>0.092</td></tr></tbody></table>

Footnote: Continuous variables are expressed as medians (+/- 25-75 interquartile range) or mean (+/- standard deviation) and were compared using the Mann-Whitney test. Categorical variables are summarized in frequency and percentage and were compared using the Pearson's Chi-square test of Fisher's exact test. ¶Satellite nodules correspond to multifocal microscopic nodules seen on microscopy.
<table><caption>Table 4: Response to induction treatment and Histological outcomes according to the preoperative treatment received</caption><thead><tr><th>Variables</th><th>Chemotherapy (n=23)*</th><th>Radioembolization (n=4)</th><th>Chemoembolization (n=3)</th><th>p value</th></tr></thead><tbody><tr><td>Response at CT-Scan</td><td></td><td></td><td></td><td></td></tr><tr><td>Partial response</td><td>12 (52.2%)</td><td>3 (75.0%)</td><td>1 (33.3%)</td><td>0.536</td></tr><tr><td>Stability</td><td>8 (34.8%)</td><td>1 (25.0%)</td><td>1 (33.3%)</td><td>-</td></tr><tr><td>Progression</td><td>2 (8.7%)</td><td>0</td><td>0</td><td>-</td></tr><tr><td>Tumor size, cm (median)</td><td>6.0 (3.5-9.0)</td><td>7.2 (2.6-12.3)</td><td>3.0 (1.0-7.5)</td><td>0.450</td></tr><tr><td>Tumor ≥ 5 cm</td><td>15 (65.2%)</td><td>2 (50.0%)</td><td>1 (33.3%)</td><td>0.518</td></tr><tr><td>Number of tumors (median)</td><td>1 (1.0-2.0)</td><td>1 (1.0-1.0)</td><td>1 (1.0-1.0)</td><td>0.248</td></tr><tr><td>N+</td><td>6 (37.5%)</td><td>0</td><td>2 (100%)</td><td>-</td></tr><tr><td>Resection</td><td></td><td></td><td></td><td></td></tr><tr><td>RO</td><td>21 (91.3%)</td><td>3 (75%)</td><td>2 (66.7%)</td><td>-</td></tr><tr><td>R1</td><td>2 (8.7%)</td><td>1 (25%)</td><td>1 (33.3%)</td><td>-</td></tr><tr><td>Differentiation</td><td></td><td></td><td></td><td></td></tr><tr><td>Well</td><td>7 (30.4%)</td><td>1 (25%)</td><td>2 (66.7%)</td><td>-</td></tr><tr><td>Moderate</td><td>11 (47.8%)</td><td>1 (25%)</td><td>1 (33.3%)</td><td>0.651</td></tr><tr><td>Poor</td><td>5 (21.7%)</td><td>2 (50%)</td><td>0</td><td>-</td></tr><tr><td>Tumor necrosis</td><td>8 (34.8%)</td><td>1 (25%)</td><td>1 (33.3%)</td><td>-</td></tr><tr><td>Vascular emboli</td><td>8 (34.8%)</td><td>1 (25%)</td><td>1 (33.3%)</td><td>-</td></tr><tr><td>Perineural invasion</td><td>9 (39.1%)</td><td>0</td><td>1 (33.3%)</td><td>-</td></tr><tr><td>Satellite nodules¶</td><td>10 (43.5%)</td><td>0</td><td>1 (33.3%)</td><td>0.248</td></tr><tr><td>Endobiliary extension</td><td>3 (13.0%)</td><td>0</td><td>0</td><td>-</td></tr></tbody></table>

<footnote>Footnote: Continuous variables are expressed as medians (+/- 25-75 interquartile range) or mean (+/- standard deviation) and were compared using the Anova test. Categorical variables are summarized in frequency and percentage and were compared using the Pearson's Chi-square test of Fisher's exact test. *One patient received a mixed radiochemotherapy treatment and was not included in this table. ¶Satellite nodules correspond to multifocal microscopic nodules seen on microscopy.</footnote>
<table><caption>Table 5: Long-term recurrence of patients who received upfront surgery or preoperative treatment</caption><thead><tr><th>Variables</th><th>Upfront surgery (n=167)</th><th>Preoperative Treatment (n=31)</th><th>p value</th></tr></thead><tbody><tr><td>Recurrence</td><td>92 (55.1%)</td><td>18 (58.1%)</td><td>0.760</td></tr><tr><td>Liver</td><td>57 (34.1%)</td><td>13 (41.9%)</td><td>0.404</td></tr><tr><td>Extra-hepatic</td><td>47 (28.1%)</td><td>9 (29.0%)</td><td>0.920</td></tr><tr><td>Lymph node</td><td>27 (16.2%)</td><td>3 (9.7%)</td><td>0.428</td></tr><tr><td>Carcinomatosis</td><td>17 (10.2%)</td><td>0</td><td>0.080</td></tr><tr><td>Treatment for recurrence</td><td></td><td></td><td></td></tr><tr><td>Surgery</td><td>12 (13.0%)</td><td>2 (11.1%)</td><td>-</td></tr><tr><td>Radiofrequency ablation</td><td>7 (7.6%)</td><td>4 (22.2%)</td><td>-</td></tr><tr><td>Palliative chemotherapy</td><td>56 (60.9%)</td><td>9 (50.0%)</td><td>-</td></tr><tr><td>Palliative radiotherapy</td><td>5 (5.4%)</td><td>1 (5.6%)</td><td>-</td></tr><tr><td>Radioembolization</td><td>2 (2.2%)</td><td>0</td><td>-</td></tr><tr><td>Palliative care</td><td>5 (5.4%)</td><td>1 (5.6%)</td><td>-</td></tr></tbody></table>

Footnote: Continuous variables are expressed as medians (+/- 25-75 interquartile range) or mean (+/- standard deviation) and were compared using the Mann-Whitney test. Categorical variables are summarized in frequency and percentage and were compared using the Pearson's Chi-square test of Fisher's exact test.
<figure><img src="image_3.png" /><figcaption>Fig 3: Recurrence free survival of patients who underwent upfront surgery compared to patients who received preoperative treatment</figcaption></figure>

<figure><img src="image_4.png" /></figure>
<figure><img src="image_5.png" /><figcaption>Fig 4: Overall survival of patients who received a preoperative treatment, compared according to POT</figcaption></figure>