Published Ahead of Print on May 8, 2015 as 10.1634/theoncologist.2014-0470.
Hepatobiliary
Adjuvant Transarterial Chemoembolization Following Liver Resection for Intrahepatic Cholangiocarcinoma Based on Survival Risk Stratification JUN LI,a,* QING WANG,a,* ZHENGQING LEI,a,* DONG WU,a ANFENG SI,a KUI WANG,a XUYING WAN,b YIZHOU WANG,a ZHENLIN YAN,a YONG XIA,a WAN YEE LAU,a,c MENGCHAO WU,a FENG SHENa Departments of aHepatic Surgery and bChinese Traditional Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People’s Republic of China; cFaculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People’s Republic of China *Contributed equally. Disclosures of potential conflicts of interest may be found at the end of this article.
ABSTRACT Background. The effectiveness of adjuvant transarterial chemoembolization (TACE) for intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study was performed to identify ICC patients who would benefit from adjuvant TACE. Patients and Methods. The study included 553 patients who underwent hepatectomy for ICC between January 2008 and February 2011 at the Eastern Hepatobiliary Surgery Hospital and who were treated with or without TACE (122 with TACE and 431 without TACE). Survival risk stratification was performed using the established prognostic nomogram (ICC nomogram). The predictive performance was evaluated by concordance index and calibration. The tumor recurrence and overall survival (OS) rates were analyzed by the Kaplan-Meier method before and after propensity score matching (PSM).
Results. The predictive performance of the ICC nomogram was demonstratedbythewell-fittedcalibration curves andanoptimal c-index of 0.71 for OS prediction. In the whole cohort, the 5-year recurrence and OS rates between the TACE and non-TACE groups were significantly different (5-year recurrence: 72.9% vs. 78.1%; OS: 38.4% vs. 29.7%). After 1:1 PSM, the TACE and non-TACE groups (122 patients each) had similar 5-year recurrence and OS rates (5-year recurrence: 72.9% vs. 74.2%; OS: 38.4% vs. 36.0%). By survival risk stratification based on ICC nomogram, only the patients in the lowest tertile (nomogram scores $77) benefited from adjuvant TACE (TACE vs. non-TACE groups: 90.4% vs. 95.9% for 5-year recurrence; 21.3% vs. 6.2% for 5-year OS). Conclusion. Adjuvant TACE following liver resection might be suitable for ICC patients with high ICC nomogram scores ($77). The Oncologist 2015;20:1–8
Implications for Practice: The accurate predictive performance of the established prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) following liver resection was reconfirmed in an independent cohort with 553 patients. Based on the survival risk stratification using the nomogram, adjuvant transarterial chemoembolization following liver resection might be suitable only for ICC patients with high scores from the nomogram.
INTRODUCTION Intrahepatic cholangiocarcinoma (ICC) accounts for 10%–15% of primary hepatic malignancies, with occurrence second only to hepatocellular carcinoma (HCC) [1]. The incidence of ICC varies greatly among different regions, with more than 80% of ICC in Asia and sub-Saharan Africa and 55% in the People’s Republic of China [2, 3]. Recently, increasing incidence of ICC has been reported worldwide [4]. Liver resection is still the primary and the most effective treatment for ICC [4–8]; however, ICC is known to have
aggressive metastatic behavior, and the surgical prognosis is still poor [5]. The reported 5-year postsurgical survival rates ranged from 20% to 35% [6–8].There is still no well-established adjuvant protocol for ICC after R0 liver resection [4]. Previous studies showed transarterial chemoembolization (TACE) to be beneficial for patients with advanced and unresectable ICCs [9, 10]; however, to the best of our knowledge, only three studies reported the use of adjuvant TACE in ICC patients after curative resection. Shen et al. reported that postoperative TACE failed
Correspondence: Feng Shen, M.D., Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People’s Republic of China. Telephone: 086-21-81875005; E-Mail: [email protected] Received December 10, 2014; accepted for publication March 5, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2014-0470
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Key Words. Intrahepatic cholangiocarcinoma x Hepatectomy x Adjuvant transarterial chemoembolization x Prognosis
Published Ahead of Print on May 8, 2015 as 10.1634/theoncologist.2014-0470.
Adjuvant TACE for ICC After Hepatectomy
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PATIENTS AND METHODS Patients Prospectively collected data of 594 consecutive patients who underwent liver resection for ICC between January 2008 and February 2011 at the Eastern Hepatobiliary Surgery Hospital (EHBH) were reviewed. This study was approved by the institutional ethics committee of the EHBH. Informed consent was obtained from all patients before surgery for their data to be used for research and was censored September 30, 2014.
Preoperative Examination, Hepatectomy, and Adjuvant TACE Detailed history and complete physical examination were conducted for all patients who were admitted to the EHBH with a diagnosis of primary liver malignancy. They were routinely investigated with immunological indexes of hepatitis B and C, hepatitis B virus-DNA load, liver function test, and serum tumor markers including a-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). Imaging studies with chest computed tomography (CT), abdominal ultrasound, contrast-enhanced CT, and/or magnetic resonance imaging (MRI) of the abdomen were conducted. Positron emission tomography (PET) was performed for patients with clinical or radiological suspicion of intra- or extrahepatic metastases. A preoperative diagnosis of ICC was based mainly on radiological findings [18], with or without raised serum markers, and on other clinical findings. The status of perihepatic lymph node was evaluated with contrast-enhanced CT scan or PET.
Table 1. Clinicopathologic baseline of the TACE and non-TACE groups (n 5 553) Variable
TACE (n 5 122)
Age, years 54 (35–74) Sex Female 25 (20.5) Male 97 (79.5) AFP, mg/L 3.7 (0.9–1,210) CA19-9, U/L 31.8 (0.6–1,000) CEA, mg/L 2.2 (0.6–65.7) TBIL, mmol/L 12.5 (5.2–33.0) ALB, g/L 42.2 (34.6–49.0) ALT, U/L 28.3 (10.4–217.6) ALP, U/L 96 (46–305) Diameter, cm 5.5 (2.0–14.9) Number Single 97 (79.5) Multiple 25 (20.5) Cirrhosis No 93 (76.2) Yes 29 (23.8) Surgical 0.4 (0.1–2.4) margin, cm Blood transfusion No 107 (87.7) Yes 15 (12.3) Hepatectomy Minor 104 (85.2) Major 18 (14.8) Differentiation Well 0 (0) Moderate 112 (91.8) Poor 10 (8.2) Vascular invasion No 105 (86.1) Yes 17 (13.9) LN metastasis No 109 (89.3) Yes 13 (10.7) Local invasion No 116 (95.1) Yes 6 (4.9) Nomogram 38.3 (10.8–159.1) prediction score
Non-TACE (n 5 431)
p valuea
54 (36–76)
.437
160 (37.1) 271 (62.9) 3.6 (0.8–1,210) 42.7 (0.6–1,000) 2.9 (0.5–121.9) 12.1 (6.1–166.3) 42.0 (32.6–49.0) 26.2 (8.4–218.3) 104 (49–492) 6.0 (1.8–16.0)
.001
299 (69.8) 132 (30.2)
.028
338 (78.4) 93 (21.6) 0.4 (0.1–2.1)
.606
355 (82.4) 76 (17.6)
.160
345 (80.0) 86 (20.0)
.194
12 (2.8) 371 (86.1) 48 (11.1)
.103
375 (87.0) 56 (13.0)
.786
340 (78.9) 91 (21.1)
.009
.234 .007 .002 .867 .160 .756 .040 .229
.592
389 (90.3) .095 42 (9.7) 57.9 (11.5–205.6) ,.001
Data are expressed as median (2.5th to 97.5th percentiles) or number (percentage). a Based on Mann-Whitney U test or chi-square test whenever appropriate. Abbreviations: AFP, a-fetoprotein; ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; LN, lymph node; TACE, transarterial chemoembolization; TBIL, total bilirubin time.
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to delay tumor recurrence but prolonged overall survival (OS) of patients with early tumor recurrence [11].Two other reports suggested that TACE improved survival of patients with ICC .5 cm or at an advanced TNM stage (stage III [T3N0M0] or IV [T4N0M0 and AnyTN1M0]) [12, 13]. For patients with ICC at stage I (T1N0M0), this procedure not only failed to improve survival but might even promote tumor recurrence [13].These studies have been criticized because TACE was given to patients with varying degrees of predicted survival risk and because of relatively small sample sizes. For prediction of survival in patients with ICC, several staging systems, including the 7th edition of the American Joint Committee on Cancer TNM staging system, have been proposed, but a universally accepted prognostic model for patients with ICC is still lacking [14–17]. Recently, we reported on a prognostic nomogram (the ICC nomogram) that was specifically established for patients with ICC and that had good long-term survival prediction after partial hepatectomy [7]. Unlike other contemporary staging systems, this nomogram can provide a prognostic prediction at an individual level. In this study, tumor recurrence and long-term OS between the two groups of patients treated with or without adjuvant TACE after R0 liver resection for ICC were compared, and propensity score matching (PSM) was used to minimize confounding factors of clinicopathologic features. Furthermore, we tried to identify a subgroup of patients who would benefit from adjuvant TACE based on survival risk stratification using the ICC nomogram.
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addition to the patient’s decision to receive adjuvant TACE, they were also required to have a WHO performance status 0–1, ChildPugh class A or B, normal kidney function, white blood cell count $3.0 3109/L, and plateletcount $50 3109/L. Adjuvant TACE was carried out within 2 months of liver resection by injecting 3–5 mL iodized oil emulsion (Lipiodol; Guerbet Laboratories, Aulnaysous-Bois, France, http://www.guerbet.com) with 5-fluorouracil (500 mg), hydroxycamptothecin (10 mg), and epirubicin (20 mg).
Eligibility Patients were enrolled into this study if they (a) had a histopathological diagnosis of ICC, (b) had no history of other malignancies, (c) had not received any preoperative anticancer therapy, and (d) underwent an R0 resection. Patients who had incomplete clinical data; uncertain diagnosis among ICC, hilar, and extrahepatic cholangiocarcinoma; and perioperative mortality were excluded from this study.
Figure 1. Calibration plots for probable survival of patients at 3 and 5 years after hepatectomy. Abbreviation: OS, overall survival.
Patients were followed up once every 2 months in the first 2 years and then once every 3 months. Serum levels of CA19-9, CEA, and AFP; liver function tests; and an abdominal ultrasound were performed at each of the follow-up visits. A contrast-enhanced CT or MRI was performed once every 6 months or earlier if tumor recurrence was clinically suspected. ICC recurrence or metastasis was defined as new lesions with radiologic features of ICC on two imaging studies.Tumor recurrence was treated with re-resection, percutaneous ablation, radiotherapy, TACE, and supportive care, according to the patient’s general condition, liver function, and the morphology and location of the recurrence.
Statistical Analysis The indications of partial hepatectomy for ICC were (a) patients aged ,80 years with World Health Organization (WHO) performance status 0–1 before surgery, (b) solitary or multiple intrahepatic tumors that were evaluated to be technically resectable, (c) the estimated volume of future liver remnant was .30% in normal livers and .50% in cirrhotic livers, (d) liver function of Child-Pugh grade A and B7, and (e) no evidence of extrahepatic metastasis. Patients with suspicious metastasis to perihepatic lymph nodes on preoperative CTscan or PET were considered for operation, as long as these lymph nodes could be resected completely and safely, as judged preoperatively by experienced surgeons. An anatomical liver resection was the preferred operation if the tumor was within a segment, sector, or hemiliver. Nonanatomical resection was used for peripherally situated lesions. Dissection of perihepatic lymph nodes was carried out for patients with ICC diagnosed pre- or intraoperatively. The newly found intrahepatic nodules and direct invasion of adjacent structures identified intraoperatively were resected whenever possible. Hepaticojejunostomy was carried out in patients with tumor involving the primary and secondary bile ducts. Histopathological study of the resected specimens was independently carried out by three pathologists who came to a consensus by discussion if there was any controversy. After operation, all patients received similar routine treatment except for adjuvant TACE. A detailed discussion of the pros and cons of adjuvant TACE was held between the operating surgeons and the patients who had received an R0 resection. In
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OS and time to recurrence (TTR) were used as primary endpoints. OS was defined as the interval between the date of liver resection to the date of the patient’s death or the date of the last follow-up.TTR was calculated from the date of operation to the date when recurrence or metastasis was diagnosed. Variables were expressed as ratios or as median (range). Continuous variables were compared with the paired t test or Mann-Whitney U test, as appropriate. Categorical variables were compared with the chi-square test or Fisher’s exact test. Survival curves were depicted using the Kaplan-Meier method and compared using the log-rank test. All reported p values were two-sided, and p values of ,.05 were considered to indicate statistical significance. Analysis by the ICC nomogram followed what we reported previously [7] (supplemental online Table 1). Statistical performance of the nomogram was assessed by discrimination and calibration. Concordance index (c-index) was used to determine the discrimination ability. Calibration referred to the agreement between the predicted versus the observed Kaplan-Meier estimates of survival probability. Bootstraps with 500 resamples were used for these activities. After comparing the clinicopathologic data between the patients treated with or without adjuvant TACE (TACE group, n 5 122;non-TACE group, n 5 431), PSM was used [19] to perform rigorous adjustment for significant differences in baseline characteristicsbetweenthesetwogroupsofpatients.A1:1match was done using the nearest-neighbor matching method and pairs on the propensity-score logit within a range of 0.1 SD [20]. ©AlphaMed Press 2015
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Follow-Up
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Adjuvant TACE for ICC After Hepatectomy
Data analysis was performed using SPSS 19.0 for Windows (IBM Corp, Armonk, NY, http://www.ibm.com) and R software v. 2.10.1 (R Foundation for Statistical Computing, Vienna, Austria, http://www.r-project.org).
that of the TNM staging system (0.64; 95% CI: 0.61–0.67). The calibration plot for the probability of survival at 3 or 5 years after liver resection showed optimal agreement between the prediction of the nomogram and the actual observation (Fig. 1).
RESULTS
Prognosis of Patients Treated With or Without Adjuvant TACE in the Whole Cohort
Clinicopathologic Characteristics
Median OS in the TACE and non-TACE groups was 27.6 months (range: 4.4–76.2 months) and 20.4 months (range: 1.2–76.0 months), respectively.The 1-, 3-, and 5-year OS rates in the TACE group were 79.5%, 47.3%, and 38.4%, respectively, which were significantly higher than those of the non-TACE group (63.1%, 36.4%, and 29.7%, respectively; p 5 .007) (Fig. 2A). The median TTR in the TACE and non-TACE groups was 22.0 months (range: 2.5–73.5 months) and 14.3 months (range: 1.1–76.0 months), respectively.The 1-, 3-, and 5-year recurrence ratesintheTACEgroupwere35.2%,64.5%,and72.9%,respectively, which were significantly lower than those of the non-TACE group (45.6%, 69.5%, and 78.1%, respectively; p 5 .039) (Fig. 2B).
The clinicopathologic characteristics of the 553 patients who were enrolled in this study are shown in Table 1. The median age was 54 years, and 368 patients (66.5%) were male. Overall, 104 patients (18.8%) received major hepatectomy, and 91 patients (16.5%) received perioperative blood transfusion.The median size of the resected tumors was 5.7 cm, and 396 patients (71.6%) had a single tumor. Adjuvant TACE was carried out in 122 patients (22.1%).
Prognosis and Predictive Performance of the ICC Nomogram The median follow-up for all enrolled patients was 25.3 months (range: 2.2–76.2 months).The median OS was 23.0 months (range: 1.2–76.2 months), and the 1-, 3-, and 5-year OS rates were 66.7%, 38.8%, and 31.7%, respectively. The median TTR was 16.2 months (range: 1.1–76.0 months). The postoperative 1-, 3-, and 5-year tumorrecurrencerateswere43.3%,68.4%,and77.0%,respectively. The c-index of the ICC nomogram for OS prediction was 0.71 (95% confidence interval [CI]: 0.68–0.73), which was higher than
Prognosis of Patients Treated With or Without Adjuvant TACE in the Cohort After PSM Before PSM,patients whowere treated withorwithoutadjuvant TACE differed significantly by sex; preoperative serum levels of CA19-9, CEA and ALP; multinodularity; lymph node metastasis; and ICC nomogram scores (Table 1). Because the unbalanced variables, except for sex, had been incorporated into the ICC
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Figure 2. Comparison of overall survival and tumor recurrence rates between the TACE and non-TACE groups before and after propensity score matching (PSM). (A, B): Overall survival and tumor recurrence before PSM. (C, D): Overall survival and tumor recurrence after PSM. Abbreviation: TACE, transarterial chemoembolization.
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Table 2. Clinicopathologic baseline of the TACE and non-TACE groups after PSM (n 5 244) Variable
TACE (n 5 122)
54 (35–75) 27 (22.1) 95 (77.9) 4.0 (0.8–1,210) 28.1 (0.6–1,000) 2.8 (0.4–44.7) 12.7 (6.2–170.8) 42.2 (34.2–48.1) 29.9 (8.5–328.4) 103 (47–541) 5.0 (1.8–15.9)
p valuea .787 .755 .869 .877 .112 .684 .314 .094 .268 .385
94 (77.0) 28 (23.0)
.641
88 (72.1) 34 (27.9) 0.4 (0.1–2.7)
.465
108 (88.5) 14 (11.5)
.843
103 (84.4) 19 (15.6)
.858
5 (4.1) 104 (85.2) 13 (10.7)
.058
109 (89.3) 13 (10.7)
.436
104 (78.9) 18 (14.0)
.336
.335
117 (95.9) .758 5 (4.1) 38.4 (11.4–165.9) .754
Data are expressed as median (2.5th to 97.5th percentiles) or number (percentage). a Based on Mann-Whitney U test or chi-square test whenever appropriate. Abbreviations: AFP, a-fetoprotein; ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; LN, lymph node; PSM, propensity score matching; TACE, transarterial chemoembolization; TBIL, total bilirubin time.
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Figure 3. Comparison of overall survival (A) and tumor recurrence (B) rates in patients stratified into tertiles according to the intrahepatic cholangiocarcinoma nomogram.
nomogram, we performed PSM with only two factors (sex and nomogram scores) to reduce the variability between these two groups of patients. After 1:1 PSM, a cohort with 122 patients each in the TACE and non-TACE groups was obtained. The differences in the baseline clinicopathologic features between the two groups of patients became insignificant (Table 2). Median OSinthe TACE and non-TACEgroups was27.6months (range: 4.4–76.2) and 23.2 months (range: 1.2–76.0 months), respectively.There were no significant differences in the 1-, 3-, and 5-year OSrates betweenthetwo groups (79.5%, 47.3%,and 38.4% vs. 66.4%, 41.1%, and 36.0%; p 5 .223) (Fig. 2C). The median TTR was 22.0 months (range: 2.5–73.5 months) and 15.7 months (range: 1.1–76.0 months), respectively. The 1-, 3-, and 5-year tumor recurrence rates in the TACE group were similar to those of the non-TACE group (35.2%, 64.5%, and 72.9% vs. 42.0%, 64.1%, and 74.2%; p 5 .298) (Fig. 2D).
Effect of Adjuvant TACE Based on Survival Risk Stratification Patients with different survival risks were stratified using the TNM staging system. As shown in supplemental online Figure 1, the TNM system showed good prognostic stratification for patients between stage I (n 5 283) and II (n 5 127); however, patients in stages III (n 5 29) and IV (n 5 114) were not optimally stratified. Adjuvant TACE failed to improve survival and decrease tumor recurrence for patients at stages I (p 5 .366 for OS and p 5 .593 for recurrence) and II (p 5 .506 ©AlphaMed Press 2015
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Age, years 54 (35–74) Sex Female 25 (20.5) Male 97 (79.5) AFP, mg/L 3.7 (0.9–1,210) CA19-9, U/L 31.8 (0.6–1,000) CEA, mg/L 2.2 (0.6–65.7) TBIL, mmol/L 12.5 (5.2–33.0) ALB, g/L 42.2 (34.6–49.0) ALT, U/L 28.3 (10.4–217.6) ALP, U/L 96 (46–305) Diameter, cm 5.5 (2.0–14.9) Number Single 97 (79.5) Multiple 25 (20.5) Cirrhosis No 93 (76.2) Yes 29 (23.8) Surgical 0.4 (0.1–2.4) margin, cm Blood transfusion No 107 (87.7) Yes 15 (12.3) Hepatectomy Minor 104 (85.2) Major 18 (14.8) Differentiation Well 0 (0) Moderate 112 (91.8) Poor 10 (8.2) Vascular invasion No 105 (86.1) Yes 17 (13.9) LN metastasis No 109 (89.3) Yes 13 (10.7) Local invasion No 116 (95.1) Yes 6 (4.9) Nomogram 38.3 (10.8–159.1) prediction score
Non-TACE (n 5 122)
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Table 3. The clinicopathologic characteristics of subgroups stratified by the ICC nomogram Variable
Lowest tertile (n 5 185)
Middle tertile (n 5 184)
Top tertile (n 5 184)
p valuea
p valueb
p valuec
CEA, mg/L CA19-9, U/mL Vascular invasion, yes LN metastasis, yes Local invasion, yes Number of tumors, 1 nodule 2–3 nodules .3 nodules or PI Size of tumor, cm
4.6 (0.5–849.6) 256.7 (0.7–1,000) 46 (24.9) 84 (45.4) 40 (21.6)
2.5 (0.7–45.7) 40.7 (1.1–1,000) 27 (14.7) 20 (10.9) 8 (4.3)
2.1 (0.4–7.5) 19.5 (0.6–239.1) 0 (0.0) 0 (0.0) 0 (0.0)
,.001 ,.001 .014 ,.001 ,.001
,.001 ,.001 ,.001 ,.001 ,.001
.001 ,.001 ,.001 ,.001 .004
79 (42.7) 65 (35.1) 41 (22.2) 8.0 (3.0–18.0)
134 (72.8) 50 (27.2) 0 (0.0) 6.0 (2.0–14.8)
183 (99.5) 1 (0.5) 0 (0.0) 4.6 (1.2–7.4)
,.001
,.001
,.001
,.001
,.001
,.001
and p 5 .439, respectively) (supplemental online Fig. 2A–2D). Although adjuvant TACE seemed to improve prognoses in patients at stages III and IV, it did not produce significant differences in OS and tumor recurrence rates between the TACE and non-TACE groups (p 5 .081 and p 5 .153, respectively) (supplemental online Fig. 2E, 2F). Survival stratification was carried out by stratifying patients into tertiles based on scores as calculated by the ICC nomogram. After calculation, 184 patients were placed in the top tertile with a score of #34, and 185 patients were placed in the lowest tertile with a score of $77; the remaining 184 patients were stratified into the middle tertile. The 5-year OS and tumor recurrence rates were significantly different among the three tertiles (p , .001) (Fig. 3). The detailed clinicopathologic characteristics of the three tertiles based on the ICC nomogram are presented in Table 3, and the prognostic features in the lowest tertile were the most negative. There were no significant differences in the OS and tumor recurrence rates between the TACE and non-TACE groups in the top and middle tertiles (Fig. 4A–4D); however, for patients in the lowest tertile, the 1-, 3-, and 5-year OS rates of the TACE group (61.3%, 28.3%, and 21.3%) were significantly higher than those of the non-TACE group (33.8%, 7.0%, and 6.2%; p 5 .001) (Fig. 4E). The corresponding tumor recurrence rates were 45.2%, 85.7%, and 90.4% in the TACE group, respectively, and were significantly lower than those of the non-TACE group (69.3%, 92.5%, and 95.9%, p 5 .007) (Fig. 4F).
DISCUSSION Liver resection is still the first-line treatment for patients with ICC [4]. Unfortunately, long-term survival outcomes are worse than those of patients with HCC [5–8]. There is still no wellestablished adjuvant therapy for patients with ICC after liver resection [4]. Preliminary results from previously reported studies suggested that adjuvant TACE might benefit selected patients, but these studies failed to clarify how to select these patients [11–13]. In our study, we tried to identify this subgroup of patients through survival risk stratification.
Although several staging systems have been proposed for survival risk stratification of ICC patients following liver resection [14–17], the best system is still unknown. In the TNM staging system [17], tumor size is no longer a prognostic factor; rather, tumor classification is based on the number of lesions, vascular invasion, lymph node metastasis, invasion of adjacent structures, and type of macroscopic tumor. However, a recent meta-analysis pointed out that the failure to identify any impact of tumor size on OS could be explained by the limited number of patients with small tumors (,5 cm) included in previously studies [21]. Furthermore, more factors were probably involved that would affect the prognosis of ICC after liver resection, and the role of these additional risk variables, in addition to the TNM factors, should be further studied [22–24]. Recently, we reported a prognostic nomogram for ICC patients who underwent partial hepatectomy [7]. This nomogram incorporated important prognostic factors with their respective weights on survival impact and was significantly better than the conventional staging systems for survival prediction. In the present study, a new independent cohort of ICC patients was used. Our ICC nomogram still performed well in prognostic prediction, with a c-index of 0.71, which was similar to that in our original report [7] and still higher than that of the TNM staging system (c-index 0.64). TACE is commonly used in patients with intermediatestage hepatic malignant tumors, which are not amenable to surgical resection or local ablation [9, 10, 25, 26].The rationale for TACE is that the intra-arterial infusion of a cytotoxic agent followed by embolization of the tumor-feeding blood vessels will result in strong cytotoxic and ischemic effects [27, 28]. Although ICC is not overtly hypervascular on CTor MRI studies, tumor blushes on angiography are frequently identified [29]. To the best ofour knowledge, no reliable evidence supports the use of adjuvant TACE in ICC patients after R0 liver resection [4, 11–13]. Previously reported studies of small numbers of patients showed that adjuvant TACE improved OS in patients with ICC at advanced tumor stages (stages III and IV) [12, 13];
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Data are expressed as median (2.5th to 97.5th percentiles) or number (percentage); comparison was based on Mann-Whitney U test or chi-square test whenever appropriate. a Lowest tertile vs. middle tertile. b Lowest tertile vs. top tertile. c Middle tertile vs. top tertile. Abbreviations: CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; ICC, intrahepatic cholangiocarcinoma; LN, lymph node; PI, periductal invasion.
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however, our present study failed to support this result. As defined by the TNM staging system, tumors with local structural invasion of perihepatic structures are classified as stage III, and tumors with periductal invasion are classified as stage IVA if there is no lymph node and distant metastasis; tumors with lymph node metastasis and without distant metastasis are classified as stage IVB. Because local structural or periductal invasion can be completely resected together with the primary tumor or after careful lymph node dissection to remove all locally involved lymph nodes, some patients with ICC at stage III or IV can still obtain a fair prognosis by surgical resection. In the present study, 21.7% (31 of 143) of these patients did not develop tumor recurrence within 24 months after resection. Consequently, there is heterogeneity in patients with ICC with stages III and IV, as supported by a recent report from the Mayo Clinic [30]. To reduce this
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heterogeneity, we stratified our patients into three tertiles according to the scores derived from the ICC nomogram and showed that only patients with the highest scores achieved survival benefit from adjuvant TACE. Our study has limitations. This is a single-institution study, the decision to carry out adjuvant TACE is not random, and our study still had the potential for selection biases, although we used PSM in an attempt to decrease these biases. A welldesigned randomized controlled trial is required to confirm the results obtained in the present study.
CONCLUSION Based on the survival risk stratification using the ICC nomogram and the comparison of long-term outcomes between patients treated with or without adjuvant TACE before and after PSM, we demonstrated that adjuvant TACE following liver ©AlphaMed Press 2015
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Figure 4. Comparison of overall survival and tumor recurrence rates between the TACE and non-TACE groups with different survival risk stratified by the intrahepatic cholangiocarcinoma nomogram. Overall survival is shown for the top (A), middle (C), and lowest (E) tertiles. Tumor recurrence is shown for the top (B), middle (D), and lowest tertiles (F). Abbreviation: TACE, transarterial chemoembolization.
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resection for ICC benefited only the patients with high nomogram scores ($77).
ACKNOWLEDGMENTS This study was supported by the State Key Project on Infectious Diseases of China (2012ZX10002-016 to F.S.), the Natural Science Foundation of Shanghai (12ZR1439700 to J.L.), and the Medical Guiding Project of Shanghai (201346801 to J.L.).
AUTHOR CONTRIBUTIONS Conception/Design: Jun Li, Wan Yee Lau, Feng Shen
Provision of study material or patients: Zhengqing Lei, Kui Wang, Xuying Wan, Feng Shen Collection and/or assembly of data: Jun Li, Qing Wang, Anfeng Si, Kui Wang, Xuying Wan, Zhenlin Yan, Feng Shen Data analysis and interpretation: Jun Li, Qing Wang, Zhengqing Lei, Anfeng Si, Yizhou Wang, Yong Xia, Feng Shen Manuscript writing: Jun Li, Qing Wang, Zhengqing Lei, Dong Wu, Wan Yee Lau, Mengchao Wu, Feng Shen Final approval of manuscript: Jun Li, Qing Wang, Zhengqing Lei, Dong Wu, Anfeng Si, Kui Wang, Xuying Wan, Yizhou Wang, Zhenlin Yan, Yong Xia, Wan Yee Lau, Mengchao Wu, Feng Shen
DISCLOSURES The authors indicated no financial relationships.
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13. Li T, Qin LX, Zhou J et al. Staging, prognostic factors and adjuvant therapy of intrahepatic cholangiocarcinoma after curative resection. Liver Int 2014;34:953–960. 14. Okabayashi T,Yamamoto J, Kosuge T etal.A new staging system for mass-forming intrahepatic cholangiocarcinoma: Analysis of preoperative and postoperative variables. Cancer 2001;92:2374–2383. 15. Yamasaki S. Intrahepatic cholangiocarcinoma: Macroscopic type and stage classification. J Hepatobiliary Pancreat Surg 2003;10:288–291. 16. Nathan H, Aloia TA, Vauthey JN et al. A proposed staging system for intrahepatic cholangiocarcinoma. Ann Surg Oncol 2009;16:14– 22. 17. Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edition of the AJCC Cancer Staging Manual and the future of TNM. Ann Surg Oncol 2010;17:1471–1474. 18. Endo I, Gonen M, Yopp AC et al. Intrahepatic cholangiocarcinoma: Rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008;248:84–96. 19. Dehejia R,Wahba S. Propensity score matching methods for nonexperimental causal studies. Rev Econ Stat 2002;84:151–161. 20. D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17: 2265–2281. 21. Mavros MN, Economopoulos KP, Alexiou VG et al. Treatment and prognosis for patients with
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intrahepatic cholangiocarcinoma after curative surgery: Retrospective control study. World J Surg 2011;35:2083–2091.
Hepatobiliary
Adjuvant Transarterial Chemoembolization Following Liver Resection for Intrahepatic Cholangiocarcinoma Based on Survival Risk Stratification JUN LI,a,* QING WANG,a,* ZHENGQING LEI,a,* DONG WU,a ANFENG SI,a KUI WANG,a XUYING WAN,b YIZHOU WANG,a ZHENLIN YAN,a YONG XIA,a WAN YEE LAU,a,c MENGCHAO WU,a FENG SHENa Departments of aHepatic Surgery and bChinese Traditional Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People’s Republic of China; cFaculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People’s Republic of China *Contributed equally. Disclosures of potential conflicts of interest may be found at the end of this article.
ABSTRACT Background. The effectiveness of adjuvant transarterial chemoembolization (TACE) for intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study was performed to identify ICC patients who would benefit from adjuvant TACE. Patients and Methods. The study included 553 patients who underwent hepatectomy for ICC between January 2008 and February 2011 at the Eastern Hepatobiliary Surgery Hospital and who were treated with or without TACE (122 with TACE and 431 without TACE). Survival risk stratification was performed using the established prognostic nomogram (ICC nomogram). The predictive performance was evaluated by concordance index and calibration. The tumor recurrence and overall survival (OS) rates were analyzed by the Kaplan-Meier method before and after propensity score matching (PSM).
Results. The predictive performance of the ICC nomogram was demonstratedbythewell-fittedcalibration curves andanoptimal c-index of 0.71 for OS prediction. In the whole cohort, the 5-year recurrence and OS rates between the TACE and non-TACE groups were significantly different (5-year recurrence: 72.9% vs. 78.1%; OS: 38.4% vs. 29.7%). After 1:1 PSM, the TACE and non-TACE groups (122 patients each) had similar 5-year recurrence and OS rates (5-year recurrence: 72.9% vs. 74.2%; OS: 38.4% vs. 36.0%). By survival risk stratification based on ICC nomogram, only the patients in the lowest tertile (nomogram scores $77) benefited from adjuvant TACE (TACE vs. non-TACE groups: 90.4% vs. 95.9% for 5-year recurrence; 21.3% vs. 6.2% for 5-year OS). Conclusion. Adjuvant TACE following liver resection might be suitable for ICC patients with high ICC nomogram scores ($77). The Oncologist 2015;20:1–8
Implications for Practice: The accurate predictive performance of the established prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) following liver resection was reconfirmed in an independent cohort with 553 patients. Based on the survival risk stratification using the nomogram, adjuvant transarterial chemoembolization following liver resection might be suitable only for ICC patients with high scores from the nomogram.
INTRODUCTION Intrahepatic cholangiocarcinoma (ICC) accounts for 10%–15% of primary hepatic malignancies, with occurrence second only to hepatocellular carcinoma (HCC) [1]. The incidence of ICC varies greatly among different regions, with more than 80% of ICC in Asia and sub-Saharan Africa and 55% in the People’s Republic of China [2, 3]. Recently, increasing incidence of ICC has been reported worldwide [4]. Liver resection is still the primary and the most effective treatment for ICC [4–8]; however, ICC is known to have
aggressive metastatic behavior, and the surgical prognosis is still poor [5]. The reported 5-year postsurgical survival rates ranged from 20% to 35% [6–8].There is still no well-established adjuvant protocol for ICC after R0 liver resection [4]. Previous studies showed transarterial chemoembolization (TACE) to be beneficial for patients with advanced and unresectable ICCs [9, 10]; however, to the best of our knowledge, only three studies reported the use of adjuvant TACE in ICC patients after curative resection. Shen et al. reported that postoperative TACE failed
Correspondence: Feng Shen, M.D., Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People’s Republic of China. Telephone: 086-21-81875005; E-Mail: [email protected] Received December 10, 2014; accepted for publication March 5, 2015. ©AlphaMed Press 1083-7159/2015/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2014-0470
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Key Words. Intrahepatic cholangiocarcinoma x Hepatectomy x Adjuvant transarterial chemoembolization x Prognosis
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PATIENTS AND METHODS Patients Prospectively collected data of 594 consecutive patients who underwent liver resection for ICC between January 2008 and February 2011 at the Eastern Hepatobiliary Surgery Hospital (EHBH) were reviewed. This study was approved by the institutional ethics committee of the EHBH. Informed consent was obtained from all patients before surgery for their data to be used for research and was censored September 30, 2014.
Preoperative Examination, Hepatectomy, and Adjuvant TACE Detailed history and complete physical examination were conducted for all patients who were admitted to the EHBH with a diagnosis of primary liver malignancy. They were routinely investigated with immunological indexes of hepatitis B and C, hepatitis B virus-DNA load, liver function test, and serum tumor markers including a-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). Imaging studies with chest computed tomography (CT), abdominal ultrasound, contrast-enhanced CT, and/or magnetic resonance imaging (MRI) of the abdomen were conducted. Positron emission tomography (PET) was performed for patients with clinical or radiological suspicion of intra- or extrahepatic metastases. A preoperative diagnosis of ICC was based mainly on radiological findings [18], with or without raised serum markers, and on other clinical findings. The status of perihepatic lymph node was evaluated with contrast-enhanced CT scan or PET.
Table 1. Clinicopathologic baseline of the TACE and non-TACE groups (n 5 553) Variable
TACE (n 5 122)
Age, years 54 (35–74) Sex Female 25 (20.5) Male 97 (79.5) AFP, mg/L 3.7 (0.9–1,210) CA19-9, U/L 31.8 (0.6–1,000) CEA, mg/L 2.2 (0.6–65.7) TBIL, mmol/L 12.5 (5.2–33.0) ALB, g/L 42.2 (34.6–49.0) ALT, U/L 28.3 (10.4–217.6) ALP, U/L 96 (46–305) Diameter, cm 5.5 (2.0–14.9) Number Single 97 (79.5) Multiple 25 (20.5) Cirrhosis No 93 (76.2) Yes 29 (23.8) Surgical 0.4 (0.1–2.4) margin, cm Blood transfusion No 107 (87.7) Yes 15 (12.3) Hepatectomy Minor 104 (85.2) Major 18 (14.8) Differentiation Well 0 (0) Moderate 112 (91.8) Poor 10 (8.2) Vascular invasion No 105 (86.1) Yes 17 (13.9) LN metastasis No 109 (89.3) Yes 13 (10.7) Local invasion No 116 (95.1) Yes 6 (4.9) Nomogram 38.3 (10.8–159.1) prediction score
Non-TACE (n 5 431)
p valuea
54 (36–76)
.437
160 (37.1) 271 (62.9) 3.6 (0.8–1,210) 42.7 (0.6–1,000) 2.9 (0.5–121.9) 12.1 (6.1–166.3) 42.0 (32.6–49.0) 26.2 (8.4–218.3) 104 (49–492) 6.0 (1.8–16.0)
.001
299 (69.8) 132 (30.2)
.028
338 (78.4) 93 (21.6) 0.4 (0.1–2.1)
.606
355 (82.4) 76 (17.6)
.160
345 (80.0) 86 (20.0)
.194
12 (2.8) 371 (86.1) 48 (11.1)
.103
375 (87.0) 56 (13.0)
.786
340 (78.9) 91 (21.1)
.009
.234 .007 .002 .867 .160 .756 .040 .229
.592
389 (90.3) .095 42 (9.7) 57.9 (11.5–205.6) ,.001
Data are expressed as median (2.5th to 97.5th percentiles) or number (percentage). a Based on Mann-Whitney U test or chi-square test whenever appropriate. Abbreviations: AFP, a-fetoprotein; ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; LN, lymph node; TACE, transarterial chemoembolization; TBIL, total bilirubin time.
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to delay tumor recurrence but prolonged overall survival (OS) of patients with early tumor recurrence [11].Two other reports suggested that TACE improved survival of patients with ICC .5 cm or at an advanced TNM stage (stage III [T3N0M0] or IV [T4N0M0 and AnyTN1M0]) [12, 13]. For patients with ICC at stage I (T1N0M0), this procedure not only failed to improve survival but might even promote tumor recurrence [13].These studies have been criticized because TACE was given to patients with varying degrees of predicted survival risk and because of relatively small sample sizes. For prediction of survival in patients with ICC, several staging systems, including the 7th edition of the American Joint Committee on Cancer TNM staging system, have been proposed, but a universally accepted prognostic model for patients with ICC is still lacking [14–17]. Recently, we reported on a prognostic nomogram (the ICC nomogram) that was specifically established for patients with ICC and that had good long-term survival prediction after partial hepatectomy [7]. Unlike other contemporary staging systems, this nomogram can provide a prognostic prediction at an individual level. In this study, tumor recurrence and long-term OS between the two groups of patients treated with or without adjuvant TACE after R0 liver resection for ICC were compared, and propensity score matching (PSM) was used to minimize confounding factors of clinicopathologic features. Furthermore, we tried to identify a subgroup of patients who would benefit from adjuvant TACE based on survival risk stratification using the ICC nomogram.
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addition to the patient’s decision to receive adjuvant TACE, they were also required to have a WHO performance status 0–1, ChildPugh class A or B, normal kidney function, white blood cell count $3.0 3109/L, and plateletcount $50 3109/L. Adjuvant TACE was carried out within 2 months of liver resection by injecting 3–5 mL iodized oil emulsion (Lipiodol; Guerbet Laboratories, Aulnaysous-Bois, France, http://www.guerbet.com) with 5-fluorouracil (500 mg), hydroxycamptothecin (10 mg), and epirubicin (20 mg).
Eligibility Patients were enrolled into this study if they (a) had a histopathological diagnosis of ICC, (b) had no history of other malignancies, (c) had not received any preoperative anticancer therapy, and (d) underwent an R0 resection. Patients who had incomplete clinical data; uncertain diagnosis among ICC, hilar, and extrahepatic cholangiocarcinoma; and perioperative mortality were excluded from this study.
Figure 1. Calibration plots for probable survival of patients at 3 and 5 years after hepatectomy. Abbreviation: OS, overall survival.
Patients were followed up once every 2 months in the first 2 years and then once every 3 months. Serum levels of CA19-9, CEA, and AFP; liver function tests; and an abdominal ultrasound were performed at each of the follow-up visits. A contrast-enhanced CT or MRI was performed once every 6 months or earlier if tumor recurrence was clinically suspected. ICC recurrence or metastasis was defined as new lesions with radiologic features of ICC on two imaging studies.Tumor recurrence was treated with re-resection, percutaneous ablation, radiotherapy, TACE, and supportive care, according to the patient’s general condition, liver function, and the morphology and location of the recurrence.
Statistical Analysis The indications of partial hepatectomy for ICC were (a) patients aged ,80 years with World Health Organization (WHO) performance status 0–1 before surgery, (b) solitary or multiple intrahepatic tumors that were evaluated to be technically resectable, (c) the estimated volume of future liver remnant was .30% in normal livers and .50% in cirrhotic livers, (d) liver function of Child-Pugh grade A and B7, and (e) no evidence of extrahepatic metastasis. Patients with suspicious metastasis to perihepatic lymph nodes on preoperative CTscan or PET were considered for operation, as long as these lymph nodes could be resected completely and safely, as judged preoperatively by experienced surgeons. An anatomical liver resection was the preferred operation if the tumor was within a segment, sector, or hemiliver. Nonanatomical resection was used for peripherally situated lesions. Dissection of perihepatic lymph nodes was carried out for patients with ICC diagnosed pre- or intraoperatively. The newly found intrahepatic nodules and direct invasion of adjacent structures identified intraoperatively were resected whenever possible. Hepaticojejunostomy was carried out in patients with tumor involving the primary and secondary bile ducts. Histopathological study of the resected specimens was independently carried out by three pathologists who came to a consensus by discussion if there was any controversy. After operation, all patients received similar routine treatment except for adjuvant TACE. A detailed discussion of the pros and cons of adjuvant TACE was held between the operating surgeons and the patients who had received an R0 resection. In
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OS and time to recurrence (TTR) were used as primary endpoints. OS was defined as the interval between the date of liver resection to the date of the patient’s death or the date of the last follow-up.TTR was calculated from the date of operation to the date when recurrence or metastasis was diagnosed. Variables were expressed as ratios or as median (range). Continuous variables were compared with the paired t test or Mann-Whitney U test, as appropriate. Categorical variables were compared with the chi-square test or Fisher’s exact test. Survival curves were depicted using the Kaplan-Meier method and compared using the log-rank test. All reported p values were two-sided, and p values of ,.05 were considered to indicate statistical significance. Analysis by the ICC nomogram followed what we reported previously [7] (supplemental online Table 1). Statistical performance of the nomogram was assessed by discrimination and calibration. Concordance index (c-index) was used to determine the discrimination ability. Calibration referred to the agreement between the predicted versus the observed Kaplan-Meier estimates of survival probability. Bootstraps with 500 resamples were used for these activities. After comparing the clinicopathologic data between the patients treated with or without adjuvant TACE (TACE group, n 5 122;non-TACE group, n 5 431), PSM was used [19] to perform rigorous adjustment for significant differences in baseline characteristicsbetweenthesetwogroupsofpatients.A1:1match was done using the nearest-neighbor matching method and pairs on the propensity-score logit within a range of 0.1 SD [20]. ©AlphaMed Press 2015
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Follow-Up
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Adjuvant TACE for ICC After Hepatectomy
Data analysis was performed using SPSS 19.0 for Windows (IBM Corp, Armonk, NY, http://www.ibm.com) and R software v. 2.10.1 (R Foundation for Statistical Computing, Vienna, Austria, http://www.r-project.org).
that of the TNM staging system (0.64; 95% CI: 0.61–0.67). The calibration plot for the probability of survival at 3 or 5 years after liver resection showed optimal agreement between the prediction of the nomogram and the actual observation (Fig. 1).
RESULTS
Prognosis of Patients Treated With or Without Adjuvant TACE in the Whole Cohort
Clinicopathologic Characteristics
Median OS in the TACE and non-TACE groups was 27.6 months (range: 4.4–76.2 months) and 20.4 months (range: 1.2–76.0 months), respectively.The 1-, 3-, and 5-year OS rates in the TACE group were 79.5%, 47.3%, and 38.4%, respectively, which were significantly higher than those of the non-TACE group (63.1%, 36.4%, and 29.7%, respectively; p 5 .007) (Fig. 2A). The median TTR in the TACE and non-TACE groups was 22.0 months (range: 2.5–73.5 months) and 14.3 months (range: 1.1–76.0 months), respectively.The 1-, 3-, and 5-year recurrence ratesintheTACEgroupwere35.2%,64.5%,and72.9%,respectively, which were significantly lower than those of the non-TACE group (45.6%, 69.5%, and 78.1%, respectively; p 5 .039) (Fig. 2B).
The clinicopathologic characteristics of the 553 patients who were enrolled in this study are shown in Table 1. The median age was 54 years, and 368 patients (66.5%) were male. Overall, 104 patients (18.8%) received major hepatectomy, and 91 patients (16.5%) received perioperative blood transfusion.The median size of the resected tumors was 5.7 cm, and 396 patients (71.6%) had a single tumor. Adjuvant TACE was carried out in 122 patients (22.1%).
Prognosis and Predictive Performance of the ICC Nomogram The median follow-up for all enrolled patients was 25.3 months (range: 2.2–76.2 months).The median OS was 23.0 months (range: 1.2–76.2 months), and the 1-, 3-, and 5-year OS rates were 66.7%, 38.8%, and 31.7%, respectively. The median TTR was 16.2 months (range: 1.1–76.0 months). The postoperative 1-, 3-, and 5-year tumorrecurrencerateswere43.3%,68.4%,and77.0%,respectively. The c-index of the ICC nomogram for OS prediction was 0.71 (95% confidence interval [CI]: 0.68–0.73), which was higher than
Prognosis of Patients Treated With or Without Adjuvant TACE in the Cohort After PSM Before PSM,patients whowere treated withorwithoutadjuvant TACE differed significantly by sex; preoperative serum levels of CA19-9, CEA and ALP; multinodularity; lymph node metastasis; and ICC nomogram scores (Table 1). Because the unbalanced variables, except for sex, had been incorporated into the ICC
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Figure 2. Comparison of overall survival and tumor recurrence rates between the TACE and non-TACE groups before and after propensity score matching (PSM). (A, B): Overall survival and tumor recurrence before PSM. (C, D): Overall survival and tumor recurrence after PSM. Abbreviation: TACE, transarterial chemoembolization.
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Table 2. Clinicopathologic baseline of the TACE and non-TACE groups after PSM (n 5 244) Variable
TACE (n 5 122)
54 (35–75) 27 (22.1) 95 (77.9) 4.0 (0.8–1,210) 28.1 (0.6–1,000) 2.8 (0.4–44.7) 12.7 (6.2–170.8) 42.2 (34.2–48.1) 29.9 (8.5–328.4) 103 (47–541) 5.0 (1.8–15.9)
p valuea .787 .755 .869 .877 .112 .684 .314 .094 .268 .385
94 (77.0) 28 (23.0)
.641
88 (72.1) 34 (27.9) 0.4 (0.1–2.7)
.465
108 (88.5) 14 (11.5)
.843
103 (84.4) 19 (15.6)
.858
5 (4.1) 104 (85.2) 13 (10.7)
.058
109 (89.3) 13 (10.7)
.436
104 (78.9) 18 (14.0)
.336
.335
117 (95.9) .758 5 (4.1) 38.4 (11.4–165.9) .754
Data are expressed as median (2.5th to 97.5th percentiles) or number (percentage). a Based on Mann-Whitney U test or chi-square test whenever appropriate. Abbreviations: AFP, a-fetoprotein; ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; LN, lymph node; PSM, propensity score matching; TACE, transarterial chemoembolization; TBIL, total bilirubin time.
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Figure 3. Comparison of overall survival (A) and tumor recurrence (B) rates in patients stratified into tertiles according to the intrahepatic cholangiocarcinoma nomogram.
nomogram, we performed PSM with only two factors (sex and nomogram scores) to reduce the variability between these two groups of patients. After 1:1 PSM, a cohort with 122 patients each in the TACE and non-TACE groups was obtained. The differences in the baseline clinicopathologic features between the two groups of patients became insignificant (Table 2). Median OSinthe TACE and non-TACEgroups was27.6months (range: 4.4–76.2) and 23.2 months (range: 1.2–76.0 months), respectively.There were no significant differences in the 1-, 3-, and 5-year OSrates betweenthetwo groups (79.5%, 47.3%,and 38.4% vs. 66.4%, 41.1%, and 36.0%; p 5 .223) (Fig. 2C). The median TTR was 22.0 months (range: 2.5–73.5 months) and 15.7 months (range: 1.1–76.0 months), respectively. The 1-, 3-, and 5-year tumor recurrence rates in the TACE group were similar to those of the non-TACE group (35.2%, 64.5%, and 72.9% vs. 42.0%, 64.1%, and 74.2%; p 5 .298) (Fig. 2D).
Effect of Adjuvant TACE Based on Survival Risk Stratification Patients with different survival risks were stratified using the TNM staging system. As shown in supplemental online Figure 1, the TNM system showed good prognostic stratification for patients between stage I (n 5 283) and II (n 5 127); however, patients in stages III (n 5 29) and IV (n 5 114) were not optimally stratified. Adjuvant TACE failed to improve survival and decrease tumor recurrence for patients at stages I (p 5 .366 for OS and p 5 .593 for recurrence) and II (p 5 .506 ©AlphaMed Press 2015
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Age, years 54 (35–74) Sex Female 25 (20.5) Male 97 (79.5) AFP, mg/L 3.7 (0.9–1,210) CA19-9, U/L 31.8 (0.6–1,000) CEA, mg/L 2.2 (0.6–65.7) TBIL, mmol/L 12.5 (5.2–33.0) ALB, g/L 42.2 (34.6–49.0) ALT, U/L 28.3 (10.4–217.6) ALP, U/L 96 (46–305) Diameter, cm 5.5 (2.0–14.9) Number Single 97 (79.5) Multiple 25 (20.5) Cirrhosis No 93 (76.2) Yes 29 (23.8) Surgical 0.4 (0.1–2.4) margin, cm Blood transfusion No 107 (87.7) Yes 15 (12.3) Hepatectomy Minor 104 (85.2) Major 18 (14.8) Differentiation Well 0 (0) Moderate 112 (91.8) Poor 10 (8.2) Vascular invasion No 105 (86.1) Yes 17 (13.9) LN metastasis No 109 (89.3) Yes 13 (10.7) Local invasion No 116 (95.1) Yes 6 (4.9) Nomogram 38.3 (10.8–159.1) prediction score
Non-TACE (n 5 122)
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Table 3. The clinicopathologic characteristics of subgroups stratified by the ICC nomogram Variable
Lowest tertile (n 5 185)
Middle tertile (n 5 184)
Top tertile (n 5 184)
p valuea
p valueb
p valuec
CEA, mg/L CA19-9, U/mL Vascular invasion, yes LN metastasis, yes Local invasion, yes Number of tumors, 1 nodule 2–3 nodules .3 nodules or PI Size of tumor, cm
4.6 (0.5–849.6) 256.7 (0.7–1,000) 46 (24.9) 84 (45.4) 40 (21.6)
2.5 (0.7–45.7) 40.7 (1.1–1,000) 27 (14.7) 20 (10.9) 8 (4.3)
2.1 (0.4–7.5) 19.5 (0.6–239.1) 0 (0.0) 0 (0.0) 0 (0.0)
,.001 ,.001 .014 ,.001 ,.001
,.001 ,.001 ,.001 ,.001 ,.001
.001 ,.001 ,.001 ,.001 .004
79 (42.7) 65 (35.1) 41 (22.2) 8.0 (3.0–18.0)
134 (72.8) 50 (27.2) 0 (0.0) 6.0 (2.0–14.8)
183 (99.5) 1 (0.5) 0 (0.0) 4.6 (1.2–7.4)
,.001
,.001
,.001
,.001
,.001
,.001
and p 5 .439, respectively) (supplemental online Fig. 2A–2D). Although adjuvant TACE seemed to improve prognoses in patients at stages III and IV, it did not produce significant differences in OS and tumor recurrence rates between the TACE and non-TACE groups (p 5 .081 and p 5 .153, respectively) (supplemental online Fig. 2E, 2F). Survival stratification was carried out by stratifying patients into tertiles based on scores as calculated by the ICC nomogram. After calculation, 184 patients were placed in the top tertile with a score of #34, and 185 patients were placed in the lowest tertile with a score of $77; the remaining 184 patients were stratified into the middle tertile. The 5-year OS and tumor recurrence rates were significantly different among the three tertiles (p , .001) (Fig. 3). The detailed clinicopathologic characteristics of the three tertiles based on the ICC nomogram are presented in Table 3, and the prognostic features in the lowest tertile were the most negative. There were no significant differences in the OS and tumor recurrence rates between the TACE and non-TACE groups in the top and middle tertiles (Fig. 4A–4D); however, for patients in the lowest tertile, the 1-, 3-, and 5-year OS rates of the TACE group (61.3%, 28.3%, and 21.3%) were significantly higher than those of the non-TACE group (33.8%, 7.0%, and 6.2%; p 5 .001) (Fig. 4E). The corresponding tumor recurrence rates were 45.2%, 85.7%, and 90.4% in the TACE group, respectively, and were significantly lower than those of the non-TACE group (69.3%, 92.5%, and 95.9%, p 5 .007) (Fig. 4F).
DISCUSSION Liver resection is still the first-line treatment for patients with ICC [4]. Unfortunately, long-term survival outcomes are worse than those of patients with HCC [5–8]. There is still no wellestablished adjuvant therapy for patients with ICC after liver resection [4]. Preliminary results from previously reported studies suggested that adjuvant TACE might benefit selected patients, but these studies failed to clarify how to select these patients [11–13]. In our study, we tried to identify this subgroup of patients through survival risk stratification.
Although several staging systems have been proposed for survival risk stratification of ICC patients following liver resection [14–17], the best system is still unknown. In the TNM staging system [17], tumor size is no longer a prognostic factor; rather, tumor classification is based on the number of lesions, vascular invasion, lymph node metastasis, invasion of adjacent structures, and type of macroscopic tumor. However, a recent meta-analysis pointed out that the failure to identify any impact of tumor size on OS could be explained by the limited number of patients with small tumors (,5 cm) included in previously studies [21]. Furthermore, more factors were probably involved that would affect the prognosis of ICC after liver resection, and the role of these additional risk variables, in addition to the TNM factors, should be further studied [22–24]. Recently, we reported a prognostic nomogram for ICC patients who underwent partial hepatectomy [7]. This nomogram incorporated important prognostic factors with their respective weights on survival impact and was significantly better than the conventional staging systems for survival prediction. In the present study, a new independent cohort of ICC patients was used. Our ICC nomogram still performed well in prognostic prediction, with a c-index of 0.71, which was similar to that in our original report [7] and still higher than that of the TNM staging system (c-index 0.64). TACE is commonly used in patients with intermediatestage hepatic malignant tumors, which are not amenable to surgical resection or local ablation [9, 10, 25, 26].The rationale for TACE is that the intra-arterial infusion of a cytotoxic agent followed by embolization of the tumor-feeding blood vessels will result in strong cytotoxic and ischemic effects [27, 28]. Although ICC is not overtly hypervascular on CTor MRI studies, tumor blushes on angiography are frequently identified [29]. To the best ofour knowledge, no reliable evidence supports the use of adjuvant TACE in ICC patients after R0 liver resection [4, 11–13]. Previously reported studies of small numbers of patients showed that adjuvant TACE improved OS in patients with ICC at advanced tumor stages (stages III and IV) [12, 13];
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Data are expressed as median (2.5th to 97.5th percentiles) or number (percentage); comparison was based on Mann-Whitney U test or chi-square test whenever appropriate. a Lowest tertile vs. middle tertile. b Lowest tertile vs. top tertile. c Middle tertile vs. top tertile. Abbreviations: CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; ICC, intrahepatic cholangiocarcinoma; LN, lymph node; PI, periductal invasion.
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Li, Wang, Lei et al.
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however, our present study failed to support this result. As defined by the TNM staging system, tumors with local structural invasion of perihepatic structures are classified as stage III, and tumors with periductal invasion are classified as stage IVA if there is no lymph node and distant metastasis; tumors with lymph node metastasis and without distant metastasis are classified as stage IVB. Because local structural or periductal invasion can be completely resected together with the primary tumor or after careful lymph node dissection to remove all locally involved lymph nodes, some patients with ICC at stage III or IV can still obtain a fair prognosis by surgical resection. In the present study, 21.7% (31 of 143) of these patients did not develop tumor recurrence within 24 months after resection. Consequently, there is heterogeneity in patients with ICC with stages III and IV, as supported by a recent report from the Mayo Clinic [30]. To reduce this
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heterogeneity, we stratified our patients into three tertiles according to the scores derived from the ICC nomogram and showed that only patients with the highest scores achieved survival benefit from adjuvant TACE. Our study has limitations. This is a single-institution study, the decision to carry out adjuvant TACE is not random, and our study still had the potential for selection biases, although we used PSM in an attempt to decrease these biases. A welldesigned randomized controlled trial is required to confirm the results obtained in the present study.
CONCLUSION Based on the survival risk stratification using the ICC nomogram and the comparison of long-term outcomes between patients treated with or without adjuvant TACE before and after PSM, we demonstrated that adjuvant TACE following liver ©AlphaMed Press 2015
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Figure 4. Comparison of overall survival and tumor recurrence rates between the TACE and non-TACE groups with different survival risk stratified by the intrahepatic cholangiocarcinoma nomogram. Overall survival is shown for the top (A), middle (C), and lowest (E) tertiles. Tumor recurrence is shown for the top (B), middle (D), and lowest tertiles (F). Abbreviation: TACE, transarterial chemoembolization.
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resection for ICC benefited only the patients with high nomogram scores ($77).
ACKNOWLEDGMENTS This study was supported by the State Key Project on Infectious Diseases of China (2012ZX10002-016 to F.S.), the Natural Science Foundation of Shanghai (12ZR1439700 to J.L.), and the Medical Guiding Project of Shanghai (201346801 to J.L.).
AUTHOR CONTRIBUTIONS Conception/Design: Jun Li, Wan Yee Lau, Feng Shen
Provision of study material or patients: Zhengqing Lei, Kui Wang, Xuying Wan, Feng Shen Collection and/or assembly of data: Jun Li, Qing Wang, Anfeng Si, Kui Wang, Xuying Wan, Zhenlin Yan, Feng Shen Data analysis and interpretation: Jun Li, Qing Wang, Zhengqing Lei, Anfeng Si, Yizhou Wang, Yong Xia, Feng Shen Manuscript writing: Jun Li, Qing Wang, Zhengqing Lei, Dong Wu, Wan Yee Lau, Mengchao Wu, Feng Shen Final approval of manuscript: Jun Li, Qing Wang, Zhengqing Lei, Dong Wu, Anfeng Si, Kui Wang, Xuying Wan, Yizhou Wang, Zhenlin Yan, Yong Xia, Wan Yee Lau, Mengchao Wu, Feng Shen
DISCLOSURES The authors indicated no financial relationships.
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