Ann Surg Oncol DOI 10.1245/s10434-014-3652-3
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Surgical Resection After Down-Staging of Locally Advanced Hepatocellular Carcinoma by Localized Concurrent Chemoradiotherapy Hyung Soon Lee, MD1, Gi Hong Choi, MD1, Jin Sub Choi, MD1, Kyung Sik Kim, MD1, Kwang-Hyub Han, MD2, Jinsil Seong, MD3, Sang Hoon Ahn, MD2, Do Young Kim, MD2, Jun Yong Park, MD2, Seung Up Kim, MD2, and Beom Kyung Kim, MD2 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea
1
ABSTRACT Background. This study evaluated the down-staging efficacy and impact on resectability of concurrent chemoradiotherapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) in locally advanced hepatocellular carcinoma, and identified prognostic factors of disease-free survival (DFS) and overall survival (OS) after curative resection. Methods. DFS and OS were investigated using clinicopathologic variables. Functional residual liver volume (FRLV) was assessed before CCRT and again before surgery in patients with major hepatectomy. Tumor marker response was defined as elevated tumor marker levels at diagnosis but levels below cutoff values before surgery (afetoprotein \ 20 ng/mL, protein induced by vitamin K absence or antagonist-II \ 40 mAU/mL). Results. Of 243 patients who received CCRT followed by HAIC between 2005 and 2011, 41 (16.9 %) underwent curative resection. Tumor down-staging was demonstrated in 32 (78 %) of the resected patients. FRLV significantly increased from 47.5 to 69.9 % before surgery in patients who underwent major hepatectomy. In addition, the OS of the curative resection group was significantly higher than the OS of the CCRT followed by HAIC alone group (49.6
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3652-3) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 13 November 2013 J. S. Choi, MD e-mail: [email protected]
vs. 9.8 % at 5-year survival; p \ 0.001). By multivariate analysis, the poor prognostic factors for DFS after curative resection were tumor marker non-response and the presence of a satellite nodule; however, tumor marker nonresponse was the only independent poor prognostic factor of OS. Conclusions. CCRT followed by HAIC increased resectability by down-staging tumors and increasing FRLV. Curative resection may provide good long-term survival in tumor marker responders who undergo CCRT followed by HAIC.
Resection and liver transplantation (LT) is the best curative treatment option in hepatocellular carcinoma (HCC).1 However, surgical treatment is possible in less than 20 % of patients because of the presence of an advanced lesion and associated poor liver function at the time of diagnosis.2 Thus, various non-surgical treatments for locally advanced HCC are performed with palliative intent, and HCC occasionally becomes resectable after palliative therapy.3–5 Recently, three-dimensional (3D) conformal radiotherapy has become recognized as an effective treatment for locally advanced HCC because it allows the irradiation dosage to be escalated without undue toxicity.6,7 Moreover, the combination of intra-arterial chemotherapy and localized 3D conformal radiotherapy reportedly improves treatment response rates. Our institution has attempted localized concurrent chemoradiotherapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) for locally advanced HCC with portal vein tumor thrombus (PVTT), and achieved promising results.8 Furthermore,
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CCRT followed by HAIC was found to cause unresectable HCC to become resectable in some cases. However, most locally advanced HCC cases require extensive hepatectomy due to extensive hepatic involvement despite tumor shrinkage after down-staging treatment.9 Therefore, the resectability of locally advanced HCC in such patients depends on sufficient residual liver volume after resection.10 This study evaluated the down-staging efficacy and impact of CCRT followed by HAIC on resectability in locally advanced HCC, and identified prognostic factors of disease-free survival (DFS) and overall survival (OS) after curative resection.
METHODS Patient Selection and Treatment Protocol We retrospectively reviewed patients who underwent CCRT followed by HAIC for locally advanced HCC between January 2005 and December 2011 at our institution. HCC was diagnosed based on pathologic confirmation or radiologic findings. Inclusion criteria for CCRT were age 18–75 years, an Eastern Cooperative Oncology Group performance status 0–1, life expectancy C3 months, Child– Pugh class A, and other adequate organ functions (serum creatinine\1.5 mg/dL, aminotransferase\5 times the upper limit of normal, absolute neutrophil count C1,500 cells/mL, platelet count C75,000/mL, and hemoglobin C10 g/dL). Patients with diffuse or multifocal bi-lobar tumors, extrahepatic metastasis or another concurrent malignancy, recent upper gastrointestinal bleeding, or any other underlying serious medical condition that could potentially interfere with participation in this study were excluded. This trial was approved by the Institutional Review Board of Yonsei University College of Medicine, Seoul, Republic of Korea. According to the standard localized CCRT protocol, computed tomography (CT)-based, 3D treatment planning was performed in all patients to determine target volumes, radiation ports, and dosages.11 The gross tumor volumes (GTV) were defined as the radiographically abnormal areas noted on the CT. A minimum of 5 mm around the GTV was included in the clinical target volume (CTV). For designing the planning target volume (PTV), the margins were individualized by observing the liver position as well as liver movement at the time of simulation. For determining the cranial-caudal margins, the distance of diaphragmatic excursion by respiration, which was observed fluoroscopically, was added to the cranial-caudal margins. The objective of the radiotherapy plan was to achieve delivery of the planned radiotherapy dose to the target volume as well as to protect non-tumor liver tissue.
A total of 45 gray (Gy) was prescribed in 25 fractions of 1.8 Gy over 5 weeks using a 6 megavolt (MV) or 10 MV linear accelerator. The protocol was intended to deliver 95 % of the prescribed dose encompassing the PTV around the CTV. Concurrent HAIC plus 5-fluorouracil (500 mg/ day for 5 h on 5 consecutive days) was delivered during the first and fifth weeks of radiotherapy through a percutaneous hepatic arterial catheter (Chemoport) implanted at the time of initial hepatic arterial angiography.8 One month after localized CCRT, HAIC with 5-fluorouracil (at 500 mg/m2 for 5 h on days 1–3) and cisplatin (at 60 mg/m2 for 2 h on day 2) were administered every 4 weeks for 3–12 cycles, according to tumor response. Repeated HAIC was stopped after three cycles in patients with progressive disease. The standard localized CCRT and HAIC protocols were strictly maintained during the study period.12 Radiologic response was evaluated by abdominal pelvic CT 1 month after completing localized CCRT and after every three HAIC sessions using the modified Response Evaluation Criteria in Solid Tumors.13 Radiologic responses were classified as complete response, partial response, stable disease, or progressive disease. Radiologic response was defined as the achievement of complete response or partial response. Serum a-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were evaluated at diagnosis and 1 month after completing CCRT and after every three HAIC sessions. Tumor marker response was defined using serum AFP and PIVKA-II cutoff values of 20 ng/mL and 40 mAU/mL, respectively (widely used clinical values).14,15 When a patient had an AFP of C20 ng/ mL and a PIVKA-II of C40 mAU/mL before CCRT, both tumor markers were decreased below cutoff levels before surgery. When a patient had one tumor marker above cutoff levels before CCRT, the elevated tumor marker was decreased to below its cutoff levels before surgery. Tumor resectability was assessed by liver surgeons before, during, and after completing CCRT. All CT scans were assessed by the liver surgeon and by radiologists. Curative resection was offered to patients at any HAIC cycle if it was considered based on radiologic findings that all gross lesions could be resected with a clear margin. Decisions of resection type were based on liver functional reserve and patient performance status. Major resection was defined as the resection of three or more anatomical segments as described by Couinaud.16 Clinical and pathologic tumor staging was performed according to the American Joint Committee on Cancer (AJCC) 7th TNM classification.17 Down-staging was defined as a decrease in pathologic T-stage after CCRT. Postoperative complications were analyzed using the Clavien–Dindo classification.18 When major resection was
Resection of HCC After Chemoradiotherapy
expected, functional residual liver volume (FRLV) was assessed by CT volumetry before CCRT and again before surgery. Contrast-enhanced CT scans of the liver were obtained at 5-mm intervals from the dome of the liver to the most inferior part of the organ. Liver volume was calculated using a commercial volumetry program (Voxel PlusÒ 2.0; Medisys Co., Seoul, Korea) after manually tracing the organ outline on CT images. Ten patients who received minor resection, central bisectionectomy, or LT were excluded from FRLV assessment. FRLV percentage was calculated as [remnant liver volume/(total liver volume - tumor volume) 9 100].19 Insufficient FRLV was defined as an FRLV of \40 %.20 Patients were followed up at 1 month after surgery and every 3 months. At each appointment, patients were screened for AFP and PIVKA-II, and a dynamic CT scan was performed. Statistical Analysis Data are presented as number of patients (%) or median (range). FRLV percentages were analyzed using the Wilcoxon signed-rank test. OS was defined as the time from CCRT commencement to death, and DFS was defined as the time from hepatectomy until the detection of recurrent disease or until the end of the observation period in the absence of recurrence. Survival rates were calculated by the Kaplan–Meier method, and differences between groups were assessed using the log-rank test. Prognostic factors were investigated using the following 18 clinicopathologic variables: (i) host factors based on data at diagnosis of HCC and response of CCRT, including age, gender, cirrhosis etiology, serum albumin, aspartate aminotransferase, and alanine aminotransferase, platelet count, indocyanine green retention rate at 15 min, serum AFP and PIVKA-II, radiologic response, and tumor marker response; and (ii) tumor factors based on pathologic data, including tumor size and number, cirrhosis, microvascular invasion, satellite nodules, and complete necrosis. Variables found to be significant prognostic factors of DFS or OS by univariate analysis were considered in the multivariate analysis, which was performed using the Cox proportional hazards model. Statistical analysis was performed using SPSS 18.0 (SPSS Inc., Chicago, IL, USA), and statistical significance was accepted for p \ 0.05.
RESULTS Patient Characteristics A total of 267 patients received CCRT followed by HAIC for locally advanced HCC. Twenty-four patients
were excluded from the analysis because of loss to followup (Fig. 1). Among the remaining 243 patients, 202 (83.1 %) patients received CCRT followed by HAIC therapy alone, and 41 (16.9 %) patients underwent curative resection after CCRT followed by HAIC. However, 22 (9.1 %) patients with CCRT followed by HAIC therapy alone did not complete the CCRT followed by HAIC due to upper gastrointestinal bleeding (n = 3), liver function deterioration (n = 12), or infection (n = 7). The patient characteristics at diagnosis of HCC are summarized in Table 1. Patients who underwent CCRT followed by HAIC alone had significantly higher total bilirubin levels, international normalized ratios, and AFP levels than patients who underwent resection after CCRT. In addition, the group that underwent CCRT followed by HAIC alone showed a significantly different initial T-stage compared with the group that underwent resection after CCRT. The locations of major vascular thrombus/invasion for T3b tumors were left PVTT in five patients, right PVTT in four patients, main PVTT in one patient, middle hepatic vein invasion in three patients, and right hepatic vein invasion in two patients (Table 2). Adjacent organ invasion for T4 tumors were adrenal in two cases, transverse colon in one case, inferior vena cava in three cases, and diaphragm in one case. Two patients with T4 tumors experienced spontaneously ruptured HCC. Median time between CCRT commencement and resection was 6 months (range 2–26), and the median cycles of HAIC numbered three (range 3–12). Thirty-two patients (78 %) achieved down-staging after CCRT followed by HAIC in pathologic analysis. Nine patients did not achieve downstaging in pathologic analysis. However, five patients (T1 = 3, T2 = 2) were radiologic responder, and four patients with T4 tumors showed disappearance of direct tumor invasion after CCRT followed by HAIC in radiologic findings. Therefore, these nine patients underwent curative resection. A tumor marker response was observed in 26 (63.4 %) patients. The median AFP levels at HCC diagnosis were 19.7 ng/mL (range 1.6–360,068), and the median PIVKA-II levels at HCC diagnosis were 2,000 mAU/mL (range 19–2,000). However, the median AFP levels before surgery were 6.5 ng/mL (range 1.7– 1,874), and the median PIVKA-II levels before surgery were 33 mAU/mL (range 10–5,695). Comparison of Prognoses for CCRT Followed by HAIC Alone and Curative Resection After CCRT Followed by HAIC Median survival of the curative resection group was 23 months (range 3–92), and the median survival of CCRT followed by HAIC alone patients was 10 months (range 0– 55). The OS of the curative resection group was
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N = 267 Follow up loss (N = 24) N = 243
T1 (N = 8)
T2 (N = 10)
50.0%
T3a (N = 28)
70.0%
T3b (N = 165)
21.4%
T4 (N = 32)
9.1%
28.1%
CCRT alone (N = 4)
Resection after CCRT (N = 4)
CCRT alone (N = 3)
Resection after CCRT (N = 7)
CCRT alone (N = 22)
Resection after CCRT (N = 6)
CCRT alone (N = 150)
Resection after CCRT (N = 15)
CCRT alone (N = 23)
Resection after CCRT (N = 9)
PD = 4
CR = 1 PR = 2 SD = 1
PD = 3
CR = 1 PR = 3 SD = 3
PR = 3a PD = 19
PD = 2 SD = 4
PR = 13b SD = 10 PD = 127
CR = 4 PR = 8 SD = 3
PR = 2b SD = 1 PD = 20
CR = 1 PR = 2 SD = 6
FIG. 1 Patient selection and radiologic response. a Three patients who showed partial response did not receive resection due to deterioration of liver function after CCRT. b Fifteen patients did not
receive resection due to the remnant thrombus in a major vessel. CCRT concurrent chemoradiotherapy, CR complete response, PR partial response, SD stable disease, PD progressive disease
significantly higher than the OS of the CCRT followed by HAIC alone group (p \ 0.001; Fig. 2).
Prognostic Factors for Disease-Free Survival and Overall Survival After Curative Resection
Complications After Curative Resection
According to univariate analysis, the poor prognostic factors of DFS were radiologic non-responder, tumor marker non-responder, and the presence of a satellite nodule. The poor prognostic factors of OS were radiologic non-responder and tumor marker non-responder (Supplementary Table 3). By multivariate analysis, the poor prognostic factors of DFS were tumor marker nonresponder and the presence of a satellite nodule. Furthermore, tumor marker non-responder was found to be the only independent poor prognostic factor of OS after curative resection (Table 3).
Nineteen patients experienced a complication, and five patients experienced a complication above type IIIa (Supplementary Table 1). A biliary complication developed in seven patients, and one of these patients died due to postoperative liver failure accompanied by bile leakage at the resected liver surface. Impact of CCRT Followed by HAIC on Functional Residual Liver Volume FRLV was assessed in patients who underwent major hepatectomy (Supplementary Table 2). Median FRLV was 47.5 % in the 31 patients who underwent major hepatectomy before CCRT followed by HAIC, and FRLV significantly increased to 69.9 % before surgery (p \ 0.001). In the 24 patients who underwent right liver resection, FRLV significantly increased from 39.8 to 66.1 % before surgery (p \ 0.001), and in the seven patients who underwent left liver resection, FRLV significantly increased from 64.4 to 93.7 % before surgery (p = 0.018). Furthermore, in the 12 patients with insufficient FRLV, FRLV also significantly increased from 34.7 to 60.0 % before surgery (p = 0.002).
DISCUSSION In our study, 78 % of patients who underwent curative resection after CCRT followed by HAIC achieved tumor down-staging, and curative resection after CCRT followed by HAIC resulted in significantly higher OS than CCRT followed by HAIC alone. Furthermore, FRLV was observed to increase significantly before surgery in patients who underwent major liver resection. Tumor marker non-responder and the presence of a satellite nodule were found to be poor prognostic factors of DFS after curative resection, but tumor marker nonresponder was the only independent predictor of OS.
Resection of HCC After Chemoradiotherapy TABLE 1 Patient characteristics at HCC diagnosis
TABLE 2 Down-staging profiles (n = 41)
Variables
Resection after CCRT (n = 41)
CCRT alone (n = 202)
p value
Age, years
57 (29–74)
58 (29–85)
0.155
Male gender
37 (90.2)
172 (85.1)
0.391
HBV
35 (85.4)
159 (78.7)
0.103
HCV
0 (0.0)
20 (9.9)
Non-B, non-C
6 (14.6)
23 (11.4)
3.9 (2.7–5.0)
3.9
Total bilirubin, mg/dL
0.6 (0.2–2.6)
0.9 (0.3–2.4)
INR
1.00 (0.87–1.58)
1.06 (0.83–1.66)
0.002
AFP, ng/mL
19.7 (1.6–360,068)
647 (0.3–120,000)
0.001
PIVKA-II, mAU/mL
2000 (19–2,000)
2000 (1.1–74,119)
ICG R15, %
9.7 (0.8–32.1)
Tumor size, cm Tumor number
Etiology of cirrhosis
Albumin, g/dL
Variables
Initial T-stage T1 T2 T3a T3b T4 (n = 4) (n = 7) (n = 6) (n = 15) (n = 9)
Reason for CCRT Insufficient FRLV (n = 17)
4
7
6
0
0
Major vessel invasion/ thrombus (n = 15)
0
0
0
15
0
Adjacent organ invasion (n = 7)
0
0
0
0
7
Spontaneously ruptured HCC (n = 2) Radiologic response
0
0
0
0
2
0.909
Complete response (n = 7)
1
1
0
4
1
12.1 (0.4–55.5)
0.107
Partial response (n = 17)
2
3
2
8
2
8.9 (3.5–18.3)
10.0 (3.0–22.0)
0.489
Stable disease (n = 17)
1
3
4
3
6
1 (1–5)
1 (1–8)
0.730
7
4
12
1
0.428 (2.6–5.0) \0.001
Initial T-stagea \0.001
Tumor marker response AFP \ 20 ng/mL 2 and/or PIVKAII \ 40 mAU/mL (n = 26)
T1
4 (9.8)
4 (2.0)
T2
7 (17.1)
3 (1.5)
T3a
6 (14.6)
22 (10.9)
T3b
15 (36.6)
150 (74.3)
T0 (n = 9)
1
2
0
5
1
T4
9 (22.0)
23 (11.4)
T1 (n = 14)
3
3
4
4
0
Pathologic T-stage
T2 (n = 11)
0
2
2
4
3
Right hepatectomy
18 (43.9)
T3a (n = 3)
0
0
0
2
1
Extended right hepatectomy
2 (4.9)
T3b (n = 0)
0
0
0
0
0
T4 (n = 4)
0
0
0
0
4
Right trisectionectomy
4 (9.8)
Left hepatectomy
3 (7.3)
1
5
6
15
5
Extended left hepatectomy
4 (9.8)
Italicized cells indicates that the tumor was down-staged after CCRT followed by HAIC
Central bisectionectomy
3 (7.3)
Segmentectomy
6 (14.6)
CCRT concurrent chemoradiotherapy, FRLV functional residual liver volume, HCC hepatocellular carcinoma, AFP a-fetoprotein, PIVKA-II protein induced by vitamin K absence or antagonist-II
Type of resection
Down-stage 32 (78.0 %)
Liver transplantation 1 (2.4) HBV hepatitis B virus, HCV hepatitis C virus, INR international normalized ratio, AFP a-fetoprotein, PIVKA-II protein induced by vitamin K absence or antagonist-II, ICG R-15 indocyanine green retention rate at 15 min a
According to the American Joint Committee on Cancer 7th TNM classification
The present study has several unique aspects compared with previous studies on surgery after the down-staging of unresectable HCC. First, we applied a single standardized treatment and patients were restricted to HCC alone.
Treatment and subject restriction are critical for accurate assessment of the treatment response because treatment response depends on the treatment and tumor type. Nevertheless, various down-staging treatments have been applied to heterogeneous tumors in previous studies. Meric et al.5 and Clavien et al.21 suggested that resection after down-staging with HAIC is a viable option for unresectable HCC and for liver metastasis from colorectal cancer. However, evaluation of the effect of down-staging with HAIC on HCC in their studies is difficult because of a lack of subject restriction. Lau et al.22 reported the results of
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100
P < 0.001
94.4%
Overall survival (%)
80
55.1%
60
49.6% 47.3%
40
Curative resection after CCRT followed by HAIC (n=41)
20 9.8%
CCRT followed by HAIC alone (n=202)
0 0
20
0.0% 60
40
80
100
Time after CCRT (Months) FIG. 2 Kaplan–Meier analysis of overall survival of the CCRT followed by HAIC alone group versus the curative resection after CCRT followed by HAIC group. CCRT concurrent chemoradiotherapy, HAIC hepatic arterial infusion chemotherapy TABLE 3 Multivariate analysis of prognostic factors for diseasefree survival and overall survival after curative resection Variable
Coefficient SE
p value Relative risk (95 % CI)
Disease-free survival Tumor marker non-responder
1.31
0.46 0.004
3.70 (1.51–9.09)
Presence of satellite 1.49 nodule
0.66 0.023
4.44 (1.22–16.12)
0.61 0.004
5.73 (1.72–19.10)
Overall survival Tumor marker non-responder
1.75
CI confidence interval, SE standard error
salvage surgery following down-staging in 49 patients with unresectable HCC, but various treatment strategies were adopted for down-staging, such as systemic chemotherapy, intra-arterial yttrium-90 microspheres, or sequential treatment. Thus, previous reports on the topic lack reproducibility, and few reports have been published on resection after down-staging treatment in advanced HCC. However, in the present study, we applied a single treatment for HCC alone and found that curative resection after down-staging in locally advanced HCC produced promising results. Second, the present study clearly demonstrates the reasons for unresectability before CCRT. HCC accompanied by major vessel thrombus/invasion, adjacent organ invasion, or
spontaneous tumor rupture are commonly accepted criteria for unresectability, although the resectability of huge HCCs is still a subject of debate.23 Although huge HCCs exhibit more aggressive biologic behaviors, they are occasionally resectable without down-staging therapy.23 Nevertheless, many authors have suggested that a huge HCC per se implies an unresectable tumor, although FRLV inadequacy was not clearly demonstrated before down-staging treatment.10 In the present study, FRLV insufficiency was demonstrated at diagnosis of HCC based on liver volumetry. Portal vein embolization (PVE) reportedly constitutes an effective means of preparation before extensive hepatectomy for a huge HCC with insufficient FRLV.19 However, the oncologic benefits of PVE remain controversial,24,25 and huge HCCs present a substantial risk of systemic dissemination or tumor rupture during tumor manipulation in the operating field.26,27 In this regard, CCRT followed by HAIC is believed to be a useful down-staging treatment for huge HCCs because it facilitates liver mobilization in the operation field because of size reduction. Furthermore, the biologic behaviors of huge HCCs are better evaluated by clinicians due to observations made during CCRT followed by HAIC. Our current study demonstrated a substantial increase in FRLV after CCRT followed by HAIC. This phenomenon is characterized by marked atrophy of the irradiated region, and the non-irradiated region appeared to show compensatory enlargement, which may be due to a hepatic regenerative response following parenchymal injury by CCRT.28,29 The hypertrophied non-irradiated region may provide functional compensation for the atrophied irradiated region. Of note, compensatory enlargement of the non-irradiated region may be as extensive as that seen following surgical resection and may be more profound than that seen after PVE.19,30,31 Substantial enlargement of the non-irradiated region after CCRT may result from true liver parenchymal atrophy rather than only a tumor volumetric change. However, the mechanism of compensatory enlargement of the non-irradiated region after CCRT still remains to be investigated. Thus, further investigation is necessary to determine factors that contribute to hypertrophy of the non-irradiated liver and to ultimately decide which patients may potentially benefit from CCRT followed by HAIC. The incidence of biliary complications after hepatectomy ranges from 4.1 to 12.8 %.32–35 In the present study, seven patients (17.0 %) experienced a biliary complication, which seems to be slightly higher than rates described in previous reports. Biliary complications in the present study may have been associated with impaired bile duct healing caused by fibrosis after radiotherapy.36 Furthermore, one patient died due to liver failure accompanied by bile leakage at the resected liver surface. Thus, careful
Resection of HCC After Chemoradiotherapy
dissection of liver parenchyma and precise repair of the remnant bile duct stump are required during hepatectomy in patients treated with CCRT followed by HAIC. Radiologic criteria are most commonly used for response evaluation after down-staging treatment. However, despite successful clinical correlations for other solid tumors, radiological response-based criteria have been criticized for not adequately reflecting treatment response and tumor viability in HCC.37–39 Thus, recent studies have highlighted the potential role of serial tumor marker monitoring for assessing treatment response, based on the assumption that tumor markers reflect tumor burden and activity.12,40 In accordance with previous studies, we found that tumor marker non-response was the only independent prognostic factor of OS after curative resection, which suggests that curative resection may be insufficient in patients with persistently elevated tumor markers after CCRT followed by HAIC. Thus, when a tumor showed radiologic response, but tumor markers remained elevated after CCRT, additional HAIC cycles or systemic therapy, such as sorafenib, should be considered. Improved OS after resection might be due to the selection of biologically less-aggressive tumors and better liver function or due to the treatment effect of surgical resection. To date, there is a lack of strong evidence of a good correlation between a radiologic complete response and pathologic complete necrosis. In the present study, six (85.7 %) of six radiologic complete responses showed pathologic complete necrosis; however, 17 (65.4 %) of 26 tumors with a tumor marker response still had viable tumors (Supplementary Fig. 1). Therefore, surgical resection is required after tumor down-staging, even in the tumors with a radiologic complete response and tumor marker response, to induce complete remission and to obtain pathological information. CONCLUSIONS CCRT followed by HAIC in patients with initially unresectable and locally advanced HCC allowed surgical resection in 16.9 % of patients after down-staging and/or increasing FRLV. Furthermore, curative resection after CCRT followed by HAIC resulted in good long-term outcomes and the possibility of a cure in a proportion of patients with locally advanced HCC. However, its role in improving DFS and OS in patients with locally advanced HCC needs to be further investigated in well-designed, prospective studies. ACKNOWLEDGMENT The authors are grateful to Dong-Su Jang (Medical Illustrator, Medical Research Support Section, Yonsei University College of Medicine, Seoul, South Korea) for his help with the figures.
CONFLICT OF INTEREST interest, financial or otherwise.
All authors have no conflict of
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H. S. Lee et al. 17. Edge SB CM, Compton CC. AJCC cancer staging manual. 7th ed. Chicago: Springer; 2009. 18. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien–Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250:187–96. 19. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg. 2003;237:208–17. 20. Azoulay D, Castaing D, Krissat J, et al. Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver. Ann Surg. 2000;232:665–72. 21. Clavien PA, Selzner N, Morse M, Selzner M, Paulson E. Downstaging of hepatocellular carcinoma and liver metastases from colorectal cancer by selective intra-arterial chemotherapy. Surgery. 2002;131:433–42. 22. Lau WY, Ho SK, Yu SC, Lai EC, Liew CT, Leung TW. Salvage surgery following downstaging of unresectable hepatocellular carcinoma. Ann Surg. 2004;240:299–305. 23. Choi GH, Han DH, Kim DH, et al. Outcome after curative resection for a huge (C10 cm) hepatocellular carcinoma and prognostic significance of gross tumor classification. Am J Surg. 2009;198:693–701. 24. Siriwardana RC, Lo CM, Chan SC, Fan ST. Role of portal vein embolization in hepatocellular carcinoma management and its effect on recurrence: a case–control study. World J Surg. 2012;36:1640–6. 25. Wakabayashi H, Ishimura K, Okano K, et al. Is preoperative portal vein embolization effective in improving prognosis after major hepatic resection in patients with advanced-stage hepatocellular carcinoma? Cancer. 2001;92:2384–90. 26. Liu CL, Fan ST, Cheung ST, Lo CM, Ng IO, Wong J. Anterior approach versus conventional approach right hepatic resection for large hepatocellular carcinoma: a prospective randomized controlled study. Ann Surg. 2006;244:194–203. 27. Koo J, Fung K, Siu KF, et al. Recovery of malignant tumor cells from the right atrium during hepatic resection for hepatocellular carcinoma. Cancer. 1983;52:1952–6. 28. Gaba RC, Lewandowski RJ, Kulik LM, et al. Radiation lobectomy: preliminary findings of hepatic volumetric response to lobar yttrium-90 radioembolization. Ann Surg Oncol. 2009;16:1587–96.
29. Imada H, Kato H, Yasuda S, et al. Compensatory enlargement of the liver after treatment of hepatocellular carcinoma with carbon ion radiotherapy: relation to prognosis and liver function. Radiother Oncol. 2010;96:236–42. 30. Chen MF, Hwang TL, Hung CF. Human liver regeneration after major hepatectomy: a study of liver volume by computed tomography. Ann Surg. 1991;213:227–9. 31. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg. 2008;247:49–57. 32. Boonstra EA, de Boer MT, Sieders E, Peeters PM, de Jong KP, Slooff MJ, et al. Risk factors for central bile duct injury complicating partial liver resection. Br J Surg. 2012;99:256–62. 33. Yoshioka R, Saiura A, Koga R, Seki M, Kishi Y, Yamamoto J. Predictive factors for bile leakage after hepatectomy: analysis of 505 consecutive patients. World J Surg. 2011;35:1898–903. 34. Zimmitti G, Roses RE, Andreou A, Shindoh J, Curley SA, Aloia TA, et al. Greater complexity of liver surgery is not associated with an increased incidence of liver-related complications except for bile leak: an experience with 2,628 consecutive resections. J Gastrointest Surg. 2013;17(1):57–64; discussion 64–5. 35. Sadamori H, Yagi T, Shinoura S, et al. Risk factors for major morbidity after liver resection for hepatocellular carcinoma. Br J Surg. 2013;100:122–9. 36. Guha C, Kavanagh BD. Hepatic radiation toxicity: avoidance and amelioration. Semin Radiat Oncol. 2011;21:256–63. 37. Lau WY, Leung TW, Lai BS, Liew CT, Ho SK, Yu SC, et al. Preoperative systemic chemoimmunotherapy and sequential resection for unresectable hepatocellular carcinoma. Ann Surg. 2001;233:236–41. 38. Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis. 2001;5:145–59. 39. Vora SR, Zheng H, Stadler ZK, Fuchs CS, Zhu AX. Serum alphafetoprotein response as a surrogate for clinical outcome in patients receiving systemic therapy for advanced hepatocellular carcinoma. Oncologist. 2009;14:717–25. 40. Chan SL, Mo FK, Johnson PJ, et al. New utility of an old marker: serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol. 2009;27:446– 52.
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Surgical Resection After Down-Staging of Locally Advanced Hepatocellular Carcinoma by Localized Concurrent Chemoradiotherapy Hyung Soon Lee, MD1, Gi Hong Choi, MD1, Jin Sub Choi, MD1, Kyung Sik Kim, MD1, Kwang-Hyub Han, MD2, Jinsil Seong, MD3, Sang Hoon Ahn, MD2, Do Young Kim, MD2, Jun Yong Park, MD2, Seung Up Kim, MD2, and Beom Kyung Kim, MD2 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea
1
ABSTRACT Background. This study evaluated the down-staging efficacy and impact on resectability of concurrent chemoradiotherapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) in locally advanced hepatocellular carcinoma, and identified prognostic factors of disease-free survival (DFS) and overall survival (OS) after curative resection. Methods. DFS and OS were investigated using clinicopathologic variables. Functional residual liver volume (FRLV) was assessed before CCRT and again before surgery in patients with major hepatectomy. Tumor marker response was defined as elevated tumor marker levels at diagnosis but levels below cutoff values before surgery (afetoprotein \ 20 ng/mL, protein induced by vitamin K absence or antagonist-II \ 40 mAU/mL). Results. Of 243 patients who received CCRT followed by HAIC between 2005 and 2011, 41 (16.9 %) underwent curative resection. Tumor down-staging was demonstrated in 32 (78 %) of the resected patients. FRLV significantly increased from 47.5 to 69.9 % before surgery in patients who underwent major hepatectomy. In addition, the OS of the curative resection group was significantly higher than the OS of the CCRT followed by HAIC alone group (49.6
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3652-3) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 13 November 2013 J. S. Choi, MD e-mail: [email protected]
vs. 9.8 % at 5-year survival; p \ 0.001). By multivariate analysis, the poor prognostic factors for DFS after curative resection were tumor marker non-response and the presence of a satellite nodule; however, tumor marker nonresponse was the only independent poor prognostic factor of OS. Conclusions. CCRT followed by HAIC increased resectability by down-staging tumors and increasing FRLV. Curative resection may provide good long-term survival in tumor marker responders who undergo CCRT followed by HAIC.
Resection and liver transplantation (LT) is the best curative treatment option in hepatocellular carcinoma (HCC).1 However, surgical treatment is possible in less than 20 % of patients because of the presence of an advanced lesion and associated poor liver function at the time of diagnosis.2 Thus, various non-surgical treatments for locally advanced HCC are performed with palliative intent, and HCC occasionally becomes resectable after palliative therapy.3–5 Recently, three-dimensional (3D) conformal radiotherapy has become recognized as an effective treatment for locally advanced HCC because it allows the irradiation dosage to be escalated without undue toxicity.6,7 Moreover, the combination of intra-arterial chemotherapy and localized 3D conformal radiotherapy reportedly improves treatment response rates. Our institution has attempted localized concurrent chemoradiotherapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) for locally advanced HCC with portal vein tumor thrombus (PVTT), and achieved promising results.8 Furthermore,
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CCRT followed by HAIC was found to cause unresectable HCC to become resectable in some cases. However, most locally advanced HCC cases require extensive hepatectomy due to extensive hepatic involvement despite tumor shrinkage after down-staging treatment.9 Therefore, the resectability of locally advanced HCC in such patients depends on sufficient residual liver volume after resection.10 This study evaluated the down-staging efficacy and impact of CCRT followed by HAIC on resectability in locally advanced HCC, and identified prognostic factors of disease-free survival (DFS) and overall survival (OS) after curative resection.
METHODS Patient Selection and Treatment Protocol We retrospectively reviewed patients who underwent CCRT followed by HAIC for locally advanced HCC between January 2005 and December 2011 at our institution. HCC was diagnosed based on pathologic confirmation or radiologic findings. Inclusion criteria for CCRT were age 18–75 years, an Eastern Cooperative Oncology Group performance status 0–1, life expectancy C3 months, Child– Pugh class A, and other adequate organ functions (serum creatinine\1.5 mg/dL, aminotransferase\5 times the upper limit of normal, absolute neutrophil count C1,500 cells/mL, platelet count C75,000/mL, and hemoglobin C10 g/dL). Patients with diffuse or multifocal bi-lobar tumors, extrahepatic metastasis or another concurrent malignancy, recent upper gastrointestinal bleeding, or any other underlying serious medical condition that could potentially interfere with participation in this study were excluded. This trial was approved by the Institutional Review Board of Yonsei University College of Medicine, Seoul, Republic of Korea. According to the standard localized CCRT protocol, computed tomography (CT)-based, 3D treatment planning was performed in all patients to determine target volumes, radiation ports, and dosages.11 The gross tumor volumes (GTV) were defined as the radiographically abnormal areas noted on the CT. A minimum of 5 mm around the GTV was included in the clinical target volume (CTV). For designing the planning target volume (PTV), the margins were individualized by observing the liver position as well as liver movement at the time of simulation. For determining the cranial-caudal margins, the distance of diaphragmatic excursion by respiration, which was observed fluoroscopically, was added to the cranial-caudal margins. The objective of the radiotherapy plan was to achieve delivery of the planned radiotherapy dose to the target volume as well as to protect non-tumor liver tissue.
A total of 45 gray (Gy) was prescribed in 25 fractions of 1.8 Gy over 5 weeks using a 6 megavolt (MV) or 10 MV linear accelerator. The protocol was intended to deliver 95 % of the prescribed dose encompassing the PTV around the CTV. Concurrent HAIC plus 5-fluorouracil (500 mg/ day for 5 h on 5 consecutive days) was delivered during the first and fifth weeks of radiotherapy through a percutaneous hepatic arterial catheter (Chemoport) implanted at the time of initial hepatic arterial angiography.8 One month after localized CCRT, HAIC with 5-fluorouracil (at 500 mg/m2 for 5 h on days 1–3) and cisplatin (at 60 mg/m2 for 2 h on day 2) were administered every 4 weeks for 3–12 cycles, according to tumor response. Repeated HAIC was stopped after three cycles in patients with progressive disease. The standard localized CCRT and HAIC protocols were strictly maintained during the study period.12 Radiologic response was evaluated by abdominal pelvic CT 1 month after completing localized CCRT and after every three HAIC sessions using the modified Response Evaluation Criteria in Solid Tumors.13 Radiologic responses were classified as complete response, partial response, stable disease, or progressive disease. Radiologic response was defined as the achievement of complete response or partial response. Serum a-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were evaluated at diagnosis and 1 month after completing CCRT and after every three HAIC sessions. Tumor marker response was defined using serum AFP and PIVKA-II cutoff values of 20 ng/mL and 40 mAU/mL, respectively (widely used clinical values).14,15 When a patient had an AFP of C20 ng/ mL and a PIVKA-II of C40 mAU/mL before CCRT, both tumor markers were decreased below cutoff levels before surgery. When a patient had one tumor marker above cutoff levels before CCRT, the elevated tumor marker was decreased to below its cutoff levels before surgery. Tumor resectability was assessed by liver surgeons before, during, and after completing CCRT. All CT scans were assessed by the liver surgeon and by radiologists. Curative resection was offered to patients at any HAIC cycle if it was considered based on radiologic findings that all gross lesions could be resected with a clear margin. Decisions of resection type were based on liver functional reserve and patient performance status. Major resection was defined as the resection of three or more anatomical segments as described by Couinaud.16 Clinical and pathologic tumor staging was performed according to the American Joint Committee on Cancer (AJCC) 7th TNM classification.17 Down-staging was defined as a decrease in pathologic T-stage after CCRT. Postoperative complications were analyzed using the Clavien–Dindo classification.18 When major resection was
Resection of HCC After Chemoradiotherapy
expected, functional residual liver volume (FRLV) was assessed by CT volumetry before CCRT and again before surgery. Contrast-enhanced CT scans of the liver were obtained at 5-mm intervals from the dome of the liver to the most inferior part of the organ. Liver volume was calculated using a commercial volumetry program (Voxel PlusÒ 2.0; Medisys Co., Seoul, Korea) after manually tracing the organ outline on CT images. Ten patients who received minor resection, central bisectionectomy, or LT were excluded from FRLV assessment. FRLV percentage was calculated as [remnant liver volume/(total liver volume - tumor volume) 9 100].19 Insufficient FRLV was defined as an FRLV of \40 %.20 Patients were followed up at 1 month after surgery and every 3 months. At each appointment, patients were screened for AFP and PIVKA-II, and a dynamic CT scan was performed. Statistical Analysis Data are presented as number of patients (%) or median (range). FRLV percentages were analyzed using the Wilcoxon signed-rank test. OS was defined as the time from CCRT commencement to death, and DFS was defined as the time from hepatectomy until the detection of recurrent disease or until the end of the observation period in the absence of recurrence. Survival rates were calculated by the Kaplan–Meier method, and differences between groups were assessed using the log-rank test. Prognostic factors were investigated using the following 18 clinicopathologic variables: (i) host factors based on data at diagnosis of HCC and response of CCRT, including age, gender, cirrhosis etiology, serum albumin, aspartate aminotransferase, and alanine aminotransferase, platelet count, indocyanine green retention rate at 15 min, serum AFP and PIVKA-II, radiologic response, and tumor marker response; and (ii) tumor factors based on pathologic data, including tumor size and number, cirrhosis, microvascular invasion, satellite nodules, and complete necrosis. Variables found to be significant prognostic factors of DFS or OS by univariate analysis were considered in the multivariate analysis, which was performed using the Cox proportional hazards model. Statistical analysis was performed using SPSS 18.0 (SPSS Inc., Chicago, IL, USA), and statistical significance was accepted for p \ 0.05.
RESULTS Patient Characteristics A total of 267 patients received CCRT followed by HAIC for locally advanced HCC. Twenty-four patients
were excluded from the analysis because of loss to followup (Fig. 1). Among the remaining 243 patients, 202 (83.1 %) patients received CCRT followed by HAIC therapy alone, and 41 (16.9 %) patients underwent curative resection after CCRT followed by HAIC. However, 22 (9.1 %) patients with CCRT followed by HAIC therapy alone did not complete the CCRT followed by HAIC due to upper gastrointestinal bleeding (n = 3), liver function deterioration (n = 12), or infection (n = 7). The patient characteristics at diagnosis of HCC are summarized in Table 1. Patients who underwent CCRT followed by HAIC alone had significantly higher total bilirubin levels, international normalized ratios, and AFP levels than patients who underwent resection after CCRT. In addition, the group that underwent CCRT followed by HAIC alone showed a significantly different initial T-stage compared with the group that underwent resection after CCRT. The locations of major vascular thrombus/invasion for T3b tumors were left PVTT in five patients, right PVTT in four patients, main PVTT in one patient, middle hepatic vein invasion in three patients, and right hepatic vein invasion in two patients (Table 2). Adjacent organ invasion for T4 tumors were adrenal in two cases, transverse colon in one case, inferior vena cava in three cases, and diaphragm in one case. Two patients with T4 tumors experienced spontaneously ruptured HCC. Median time between CCRT commencement and resection was 6 months (range 2–26), and the median cycles of HAIC numbered three (range 3–12). Thirty-two patients (78 %) achieved down-staging after CCRT followed by HAIC in pathologic analysis. Nine patients did not achieve downstaging in pathologic analysis. However, five patients (T1 = 3, T2 = 2) were radiologic responder, and four patients with T4 tumors showed disappearance of direct tumor invasion after CCRT followed by HAIC in radiologic findings. Therefore, these nine patients underwent curative resection. A tumor marker response was observed in 26 (63.4 %) patients. The median AFP levels at HCC diagnosis were 19.7 ng/mL (range 1.6–360,068), and the median PIVKA-II levels at HCC diagnosis were 2,000 mAU/mL (range 19–2,000). However, the median AFP levels before surgery were 6.5 ng/mL (range 1.7– 1,874), and the median PIVKA-II levels before surgery were 33 mAU/mL (range 10–5,695). Comparison of Prognoses for CCRT Followed by HAIC Alone and Curative Resection After CCRT Followed by HAIC Median survival of the curative resection group was 23 months (range 3–92), and the median survival of CCRT followed by HAIC alone patients was 10 months (range 0– 55). The OS of the curative resection group was
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N = 267 Follow up loss (N = 24) N = 243
T1 (N = 8)
T2 (N = 10)
50.0%
T3a (N = 28)
70.0%
T3b (N = 165)
21.4%
T4 (N = 32)
9.1%
28.1%
CCRT alone (N = 4)
Resection after CCRT (N = 4)
CCRT alone (N = 3)
Resection after CCRT (N = 7)
CCRT alone (N = 22)
Resection after CCRT (N = 6)
CCRT alone (N = 150)
Resection after CCRT (N = 15)
CCRT alone (N = 23)
Resection after CCRT (N = 9)
PD = 4
CR = 1 PR = 2 SD = 1
PD = 3
CR = 1 PR = 3 SD = 3
PR = 3a PD = 19
PD = 2 SD = 4
PR = 13b SD = 10 PD = 127
CR = 4 PR = 8 SD = 3
PR = 2b SD = 1 PD = 20
CR = 1 PR = 2 SD = 6
FIG. 1 Patient selection and radiologic response. a Three patients who showed partial response did not receive resection due to deterioration of liver function after CCRT. b Fifteen patients did not
receive resection due to the remnant thrombus in a major vessel. CCRT concurrent chemoradiotherapy, CR complete response, PR partial response, SD stable disease, PD progressive disease
significantly higher than the OS of the CCRT followed by HAIC alone group (p \ 0.001; Fig. 2).
Prognostic Factors for Disease-Free Survival and Overall Survival After Curative Resection
Complications After Curative Resection
According to univariate analysis, the poor prognostic factors of DFS were radiologic non-responder, tumor marker non-responder, and the presence of a satellite nodule. The poor prognostic factors of OS were radiologic non-responder and tumor marker non-responder (Supplementary Table 3). By multivariate analysis, the poor prognostic factors of DFS were tumor marker nonresponder and the presence of a satellite nodule. Furthermore, tumor marker non-responder was found to be the only independent poor prognostic factor of OS after curative resection (Table 3).
Nineteen patients experienced a complication, and five patients experienced a complication above type IIIa (Supplementary Table 1). A biliary complication developed in seven patients, and one of these patients died due to postoperative liver failure accompanied by bile leakage at the resected liver surface. Impact of CCRT Followed by HAIC on Functional Residual Liver Volume FRLV was assessed in patients who underwent major hepatectomy (Supplementary Table 2). Median FRLV was 47.5 % in the 31 patients who underwent major hepatectomy before CCRT followed by HAIC, and FRLV significantly increased to 69.9 % before surgery (p \ 0.001). In the 24 patients who underwent right liver resection, FRLV significantly increased from 39.8 to 66.1 % before surgery (p \ 0.001), and in the seven patients who underwent left liver resection, FRLV significantly increased from 64.4 to 93.7 % before surgery (p = 0.018). Furthermore, in the 12 patients with insufficient FRLV, FRLV also significantly increased from 34.7 to 60.0 % before surgery (p = 0.002).
DISCUSSION In our study, 78 % of patients who underwent curative resection after CCRT followed by HAIC achieved tumor down-staging, and curative resection after CCRT followed by HAIC resulted in significantly higher OS than CCRT followed by HAIC alone. Furthermore, FRLV was observed to increase significantly before surgery in patients who underwent major liver resection. Tumor marker non-responder and the presence of a satellite nodule were found to be poor prognostic factors of DFS after curative resection, but tumor marker nonresponder was the only independent predictor of OS.
Resection of HCC After Chemoradiotherapy TABLE 1 Patient characteristics at HCC diagnosis
TABLE 2 Down-staging profiles (n = 41)
Variables
Resection after CCRT (n = 41)
CCRT alone (n = 202)
p value
Age, years
57 (29–74)
58 (29–85)
0.155
Male gender
37 (90.2)
172 (85.1)
0.391
HBV
35 (85.4)
159 (78.7)
0.103
HCV
0 (0.0)
20 (9.9)
Non-B, non-C
6 (14.6)
23 (11.4)
3.9 (2.7–5.0)
3.9
Total bilirubin, mg/dL
0.6 (0.2–2.6)
0.9 (0.3–2.4)
INR
1.00 (0.87–1.58)
1.06 (0.83–1.66)
0.002
AFP, ng/mL
19.7 (1.6–360,068)
647 (0.3–120,000)
0.001
PIVKA-II, mAU/mL
2000 (19–2,000)
2000 (1.1–74,119)
ICG R15, %
9.7 (0.8–32.1)
Tumor size, cm Tumor number
Etiology of cirrhosis
Albumin, g/dL
Variables
Initial T-stage T1 T2 T3a T3b T4 (n = 4) (n = 7) (n = 6) (n = 15) (n = 9)
Reason for CCRT Insufficient FRLV (n = 17)
4
7
6
0
0
Major vessel invasion/ thrombus (n = 15)
0
0
0
15
0
Adjacent organ invasion (n = 7)
0
0
0
0
7
Spontaneously ruptured HCC (n = 2) Radiologic response
0
0
0
0
2
0.909
Complete response (n = 7)
1
1
0
4
1
12.1 (0.4–55.5)
0.107
Partial response (n = 17)
2
3
2
8
2
8.9 (3.5–18.3)
10.0 (3.0–22.0)
0.489
Stable disease (n = 17)
1
3
4
3
6
1 (1–5)
1 (1–8)
0.730
7
4
12
1
0.428 (2.6–5.0) \0.001
Initial T-stagea \0.001
Tumor marker response AFP \ 20 ng/mL 2 and/or PIVKAII \ 40 mAU/mL (n = 26)
T1
4 (9.8)
4 (2.0)
T2
7 (17.1)
3 (1.5)
T3a
6 (14.6)
22 (10.9)
T3b
15 (36.6)
150 (74.3)
T0 (n = 9)
1
2
0
5
1
T4
9 (22.0)
23 (11.4)
T1 (n = 14)
3
3
4
4
0
Pathologic T-stage
T2 (n = 11)
0
2
2
4
3
Right hepatectomy
18 (43.9)
T3a (n = 3)
0
0
0
2
1
Extended right hepatectomy
2 (4.9)
T3b (n = 0)
0
0
0
0
0
T4 (n = 4)
0
0
0
0
4
Right trisectionectomy
4 (9.8)
Left hepatectomy
3 (7.3)
1
5
6
15
5
Extended left hepatectomy
4 (9.8)
Italicized cells indicates that the tumor was down-staged after CCRT followed by HAIC
Central bisectionectomy
3 (7.3)
Segmentectomy
6 (14.6)
CCRT concurrent chemoradiotherapy, FRLV functional residual liver volume, HCC hepatocellular carcinoma, AFP a-fetoprotein, PIVKA-II protein induced by vitamin K absence or antagonist-II
Type of resection
Down-stage 32 (78.0 %)
Liver transplantation 1 (2.4) HBV hepatitis B virus, HCV hepatitis C virus, INR international normalized ratio, AFP a-fetoprotein, PIVKA-II protein induced by vitamin K absence or antagonist-II, ICG R-15 indocyanine green retention rate at 15 min a
According to the American Joint Committee on Cancer 7th TNM classification
The present study has several unique aspects compared with previous studies on surgery after the down-staging of unresectable HCC. First, we applied a single standardized treatment and patients were restricted to HCC alone.
Treatment and subject restriction are critical for accurate assessment of the treatment response because treatment response depends on the treatment and tumor type. Nevertheless, various down-staging treatments have been applied to heterogeneous tumors in previous studies. Meric et al.5 and Clavien et al.21 suggested that resection after down-staging with HAIC is a viable option for unresectable HCC and for liver metastasis from colorectal cancer. However, evaluation of the effect of down-staging with HAIC on HCC in their studies is difficult because of a lack of subject restriction. Lau et al.22 reported the results of
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100
P < 0.001
94.4%
Overall survival (%)
80
55.1%
60
49.6% 47.3%
40
Curative resection after CCRT followed by HAIC (n=41)
20 9.8%
CCRT followed by HAIC alone (n=202)
0 0
20
0.0% 60
40
80
100
Time after CCRT (Months) FIG. 2 Kaplan–Meier analysis of overall survival of the CCRT followed by HAIC alone group versus the curative resection after CCRT followed by HAIC group. CCRT concurrent chemoradiotherapy, HAIC hepatic arterial infusion chemotherapy TABLE 3 Multivariate analysis of prognostic factors for diseasefree survival and overall survival after curative resection Variable
Coefficient SE
p value Relative risk (95 % CI)
Disease-free survival Tumor marker non-responder
1.31
0.46 0.004
3.70 (1.51–9.09)
Presence of satellite 1.49 nodule
0.66 0.023
4.44 (1.22–16.12)
0.61 0.004
5.73 (1.72–19.10)
Overall survival Tumor marker non-responder
1.75
CI confidence interval, SE standard error
salvage surgery following down-staging in 49 patients with unresectable HCC, but various treatment strategies were adopted for down-staging, such as systemic chemotherapy, intra-arterial yttrium-90 microspheres, or sequential treatment. Thus, previous reports on the topic lack reproducibility, and few reports have been published on resection after down-staging treatment in advanced HCC. However, in the present study, we applied a single treatment for HCC alone and found that curative resection after down-staging in locally advanced HCC produced promising results. Second, the present study clearly demonstrates the reasons for unresectability before CCRT. HCC accompanied by major vessel thrombus/invasion, adjacent organ invasion, or
spontaneous tumor rupture are commonly accepted criteria for unresectability, although the resectability of huge HCCs is still a subject of debate.23 Although huge HCCs exhibit more aggressive biologic behaviors, they are occasionally resectable without down-staging therapy.23 Nevertheless, many authors have suggested that a huge HCC per se implies an unresectable tumor, although FRLV inadequacy was not clearly demonstrated before down-staging treatment.10 In the present study, FRLV insufficiency was demonstrated at diagnosis of HCC based on liver volumetry. Portal vein embolization (PVE) reportedly constitutes an effective means of preparation before extensive hepatectomy for a huge HCC with insufficient FRLV.19 However, the oncologic benefits of PVE remain controversial,24,25 and huge HCCs present a substantial risk of systemic dissemination or tumor rupture during tumor manipulation in the operating field.26,27 In this regard, CCRT followed by HAIC is believed to be a useful down-staging treatment for huge HCCs because it facilitates liver mobilization in the operation field because of size reduction. Furthermore, the biologic behaviors of huge HCCs are better evaluated by clinicians due to observations made during CCRT followed by HAIC. Our current study demonstrated a substantial increase in FRLV after CCRT followed by HAIC. This phenomenon is characterized by marked atrophy of the irradiated region, and the non-irradiated region appeared to show compensatory enlargement, which may be due to a hepatic regenerative response following parenchymal injury by CCRT.28,29 The hypertrophied non-irradiated region may provide functional compensation for the atrophied irradiated region. Of note, compensatory enlargement of the non-irradiated region may be as extensive as that seen following surgical resection and may be more profound than that seen after PVE.19,30,31 Substantial enlargement of the non-irradiated region after CCRT may result from true liver parenchymal atrophy rather than only a tumor volumetric change. However, the mechanism of compensatory enlargement of the non-irradiated region after CCRT still remains to be investigated. Thus, further investigation is necessary to determine factors that contribute to hypertrophy of the non-irradiated liver and to ultimately decide which patients may potentially benefit from CCRT followed by HAIC. The incidence of biliary complications after hepatectomy ranges from 4.1 to 12.8 %.32–35 In the present study, seven patients (17.0 %) experienced a biliary complication, which seems to be slightly higher than rates described in previous reports. Biliary complications in the present study may have been associated with impaired bile duct healing caused by fibrosis after radiotherapy.36 Furthermore, one patient died due to liver failure accompanied by bile leakage at the resected liver surface. Thus, careful
Resection of HCC After Chemoradiotherapy
dissection of liver parenchyma and precise repair of the remnant bile duct stump are required during hepatectomy in patients treated with CCRT followed by HAIC. Radiologic criteria are most commonly used for response evaluation after down-staging treatment. However, despite successful clinical correlations for other solid tumors, radiological response-based criteria have been criticized for not adequately reflecting treatment response and tumor viability in HCC.37–39 Thus, recent studies have highlighted the potential role of serial tumor marker monitoring for assessing treatment response, based on the assumption that tumor markers reflect tumor burden and activity.12,40 In accordance with previous studies, we found that tumor marker non-response was the only independent prognostic factor of OS after curative resection, which suggests that curative resection may be insufficient in patients with persistently elevated tumor markers after CCRT followed by HAIC. Thus, when a tumor showed radiologic response, but tumor markers remained elevated after CCRT, additional HAIC cycles or systemic therapy, such as sorafenib, should be considered. Improved OS after resection might be due to the selection of biologically less-aggressive tumors and better liver function or due to the treatment effect of surgical resection. To date, there is a lack of strong evidence of a good correlation between a radiologic complete response and pathologic complete necrosis. In the present study, six (85.7 %) of six radiologic complete responses showed pathologic complete necrosis; however, 17 (65.4 %) of 26 tumors with a tumor marker response still had viable tumors (Supplementary Fig. 1). Therefore, surgical resection is required after tumor down-staging, even in the tumors with a radiologic complete response and tumor marker response, to induce complete remission and to obtain pathological information. CONCLUSIONS CCRT followed by HAIC in patients with initially unresectable and locally advanced HCC allowed surgical resection in 16.9 % of patients after down-staging and/or increasing FRLV. Furthermore, curative resection after CCRT followed by HAIC resulted in good long-term outcomes and the possibility of a cure in a proportion of patients with locally advanced HCC. However, its role in improving DFS and OS in patients with locally advanced HCC needs to be further investigated in well-designed, prospective studies. ACKNOWLEDGMENT The authors are grateful to Dong-Su Jang (Medical Illustrator, Medical Research Support Section, Yonsei University College of Medicine, Seoul, South Korea) for his help with the figures.
CONFLICT OF INTEREST interest, financial or otherwise.
All authors have no conflict of
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