Long-term outcomes of laparoscopic versus open liver resection for liver metastases from colorectal cancer: A comparative analysis of 168 consecutive cases at a single center Yasushi Hasegawa, MD, Hiroyuki Nitta, MD, Akira Sasaki, MD, Takeshi Takahara, MD, Hidenori Itabashi, MD, Hirokatsu Katagiri, MD, Koki Otsuka, MD, Satoshi Nishizuka, MD, PhD, and Go Wakabayashi, MD, PhD, FACS, Morioka City, Iwate, Japan
Background. Laparoscopic liver resection for liver metastases from colorectal cancer (CRLM) is performed in a relatively small number of institutions. Its operative results have been reported to be comparable with that of open laparotomy; however, information on its oncologic outcomes is scarce. This study aimed to compare the long-term outcomes of laparoscopic hepatectomy (LH) and open hepatectomy (OH) to treat CRLM at a single institution. Methods. We retrospectively reviewed data from 168 consecutive patients who underwent LH (n = 100) or OH (n = 68) for CRLM. The tumor characteristics, operative results, overall survival (OS) rate, recurrence-free survival (RFS) rate, and recurrence patterns were analyzed and compared. A previously published survival-predicting nomogram was applied to compare OS and RFS between the 2 patient groups. Results. The largest tumor diameter and the number of tumors were significantly larger in the OH group than in the LH group; however, no differences in other tumor factors were observed between the 2 groups. When matched by the nomogram, OS and RFS remained comparable between the 2 groups in every examined stratum, not only for low-risk patients but also for those with high risk. The recurrence patterns also were similar (liver: 30.2% vs 26.8%, P = .72; lung: 22.6% vs 34.1%, P = .22; peritoneum: 7.6% vs 4.9%, P = .45). Conclusion. The long-term outcomes of laparoscopic liver resection for CRLM were comparable with those of the open procedure in not only low-risk but also high-risk patients. (Surgery 2015;157:1065-72.) From the Department of Surgery, Iwate Medical University School of Medicine, Morioka City, Iwate, Japan
COLORECTAL CARCINOMA is one of the most common malignancies, and the liver is the most frequent site of metastasis. Liver metastasis occurs in approximately 50% of all patients with colorectal carcinoma. Hepatic resection is the only potential curative treatment for liver metastases from colorectal cancer (CRLM), resulting in a 5-year survival rate of 34–53%.1-4
Accepted for publication January 22, 2015. Reprint requests: Yasushi Hasegawa, MD, Department of Surgery, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka City, 020-8505 Iwate, Japan. E-mail: hasegawayas@ yahoo.co.jp. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2015.01.017
Laparoscopic hepatectomy (LH) has been established as a safe and feasible treatment option for liver tumors.5-11 Despite the clinical benefits of LH (eg, less blood loss, pain, and analgesic requirement; shorter hospital stay; and improved cosmetic results), its application remains limited because of the insufficient hepatic and laparoscopic operative experience among surgeons. Moreover, the procedure might not be accepted widely to treat CRLM, because reports on its long-term outcomes are few in umber.12-16 In a few previous case-matched series with superficially selected cases, investigators also reported the inferiority of laparoscopic liver resection. The present study aimed to compare the long-term outcomes of consecutive patients undergoing LH or open hepatectomy (OH) for the treatment of CRLM at a single institution. SURGERY 1065
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PATIENTS AND METHODS A prospective database of patients treated at our hospital was reviewed retrospectively for the purpose of this study. LH has been performed at our institution since May 1997, and the first LH for CRLM was performed in May 1998. From then until April 2013, 100 patients underwent LH for CRLM with a curative intent. During the same period, 68 patients underwent OH for CRLM with a curative intent. Thus, a total of 168 consecutive patients were included in this study. All patients were informed about the procedure, and consent was obtained before surgery. Patient and tumor characteristics, operative methods and results, overall survival (OS), recurrence-free survival (RFS), and recurrence patterns were analyzed and compared between LH and OH patients. Major hepatectomy was defined as the resection of 3 or more contiguous liver segments. Postoperative mortality was defined as any death within 90 days after liver resection. Postoperative morbidity was graded according to the Clavien-Dindo classification, and a major complication was defined as one of grade $ III severity.17 To compare the long-term survival of 2 patient groups with different tumor backgrounds, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) nomogram was used for OS and RFS. The JSHBPS preoperative scoring system was published in 2012.4 It classifies patients on the basis of 6 prognostic factors to predict patient survival: timing of liver metastases (metachronous: score 0, synchronous: score 3), primary lymph node (LN) status (absent: 0, present: 3), number of tumors (1: 0, 2–4: 4, $5: 9), largest tumor diameter (#5 cm: 0, >5 cm: 2), extrahepatic metastatic disease at hepatectomy (absent: 0, present: 4), and carbohydrate antigen (CA) 19-9 level (#100 U/ mL: 0, >100 U/mL: 4). Surgical technique. Laparoscopic liver resection was defined as pure laparoscopy, hand-assisted laparoscopy, or the hybrid technique.5 In pure laparoscopy, the operator stood to the right of the patient with the assistant and the scopist on the patient’s left. Four or five ports were placed, and a carbon dioxide pneumoperitoneum was maintained at 8 12 mm Hg. The liver parenchyma was transected by an ultrasonic dissector or clamp crush method.7,11 In the hybrid technique, the liver mobilization was performed through a laparoscope, followed by parenchymal transection being performed through a small laparotomy incision.10 In our institution, the length of the incision was 6–10 cm.
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Intraoperative ultrasonography was used routinely. with sonazoid-enhanced ultrasonography being conducted since 2008. The exclusion criteria for laparoscopic liver resection were a tumor size $10 cm, number of lesions to be resected $4, lesions spreading to other organs, and the need for bile ducts and/or vessels resection with reconstruction. Statistical analysis. Continuous data are expressed as median values with the corresponding ranges in parentheses. The Mann-Whitney U test was used to compare continuous data, whereas the v2 test was used for categorical data. Cumulative survival curves were plotted using the KaplanMeier method and statistically compared using the log-rank test. All survival-associated variables with a P value of < .05 in the univariate proportional hazards models were subsequently entered into a Cox multivariate regression model with backward elimination. All statistical analyses were performed using commercially available software (JMP version 900; SAS Institute, Cary, NC). RESULTS Patient characteristics. Between May 1998 and April 2013, 168 consecutive patients underwent hepatectomy for CRLM. Of these, 3 patients underwent 2-stage hepatectomy: 2 underwent LH, and 1 underwent OH. Thus, in total, 102 LH procedures (in 100 patients) and 69 OH procedures (in 68 patients) were performed during the study period. In the LH group, 61 (59.8%) procedures were of pure laparoscopy, whereas 41 (40.2%) were of the hybrid technique. Eight patients had extrahepatic metastatic disease at the time of their hepatectomy, 6 with lung metastases and 2 with lymph node metastases. Of these, 5 patients underwent radical resection of these metastases, whereas 3 did not. These 3 patients and another 1 who could not undergo second-stage hepatectomy were excluded from the RFS analysis. The median follow-up period of LH patients was 29.4 months (range, 1–128), and that of OH patients was 35.8 months (range, 2–185) (P = .27). At the time of analysis, 24 LH and 20 OH patients had been observed for 5 years. Patient characteristics are summarized in Table I. The largest tumor diameter was substantially larger in the OH group than in the LH group (35 vs 23 mm, P = .0002), and the median number of resected metastases was greater in the OH group (2 vs 1, P = .03); however, the LH group seemed to have more patients with primary LN metastases than the OH group (75.0% vs 61.8%, P = .07). No significant
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Table I. Patient characteristics Laparoscopic hepatectomy (n = 100) Age, y Male sex, n (%) Rectum primary, n (%) Synchronous liver metastases, n (%) Primary LN involvement, n (%) Number of liver metastases Largest tumor diameter, mm Extrahepatic metastases at hepatectomy, n (%) Serum CEA level at hepatectomy, ng/mL Serum CA19-9 level at hepatectomy, U/mL Pre-hepatectomy chemotherapy, n (%) with targeted therapy, n (%) Adjuvant chemotherapy, n (%) Preoperative score Follow-up period, mo
67 64 47 37 75 1 23 6 9.5 19.4 34 14 49 6 29.4
(24–91) (64.0) (47.0) (37.0) (75.0) (1–8) (7–95) (6.0) (0.5–712) (0–89,472) (34.0) (14.0) (51.0) (0–19) (1–128)
Open hepatectomy (n = 68) 65 43 33 31 42 2 35 2 11.7 18.5 29 13 36 7 35.8
(37–83) (63.2) (48.5) (45.6) (61.8) (1–12) (11–160) (3.0) (0.5–3,493) (0–3,573) (42.7) (19.1) (52.9) (0–21) (2–185)
P value .40 .92 .85 .27 .07 .03 .0002 .37 .31 .82 .26 .38 .81 .05 .27
CA19-9, Carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; LN, lymph node.
Table II. Operative methods Laparoscopic hepatectomy (n = 102)
Open hepatectomy (n = 69)
1 (1 6) 20 (19.6) 3 8 8 1 82 (80.4) 1 11 1 17 3 49
1 (1 7) 25 (36.2) 1 13 7 4 44 (63.8) 4 11 1 2 3 23
Number of hepatectomy during a surgery Major hepatectomy, n (%) Right trisectionectomy Right hemihepatectomy Left hemihepatectomy Central bisectionectomy Minor hepatectomy, n (%) Right anterior sectionectomy Right posterior sectionectomy Left medial sectionectomy Left lateral sectionectomy Segmentectomy Wedge resection only
differences in age, sex, site of primary tumor, timing of liver metastasis, extrahepatic metastatic disease, serum carcinoembryonic antigen level, and serum CA19-9 level at hepatectomy were observed between the 2 groups. Operative results. The proportion of LH was greater during the latter half of the study than during the first half (51.2% vs 67.9%, P = .03). The operative methods are summarized in Table II. The rate of major hepatectomy was greater in OH patients than in LH patients (36.2% vs 19.6%, P = .02). The number of hepatectomies during a surgery also tended to be higher in the OH group than in the LH group (P = .07). The operative results are summarized in Tables III and IV. LH was converted to open laparotomy
P value .07 .02
.02
in 1 patient because of little progress during surgery, and this patient was included in the LH group. The surgery time of LH patients was shorter (228 vs 277 min, P = .004), and their total blood loss was lower (127 vs 620 mL, P < .0001) than those of OH patients. In addition, the rate of major morbidity (Clavien-Dindo classification of $III) was lower (8.8% vs 24.6%, P = .005) and the hospitalization duration was less (9 vs 17 days, P < .0001) in patients with LH than in those who underwent OH. Gas embolism was not observed in patients with LH. There was 1 case of postoperative mortality in each group. The rate of pathologically positive surgical margins was comparable between the LH and OH groups (6.9% vs 8.7%, P = .66).
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Table III. Operative results Laparoscopic hepatectomy (n = 102) Surgery time, min Blood loss, mL Hospital stay, d Major morbidity, n (%) Mortality, n (%) Positive operative margin, n (%) Conversion to open laparotomy
228 127 9 9 1 7
Open hepatectomy (n = 69)
(70–591) (3–2,920) (4–256) (8.8) (0.98) (6.9) 1
277 620 16 17 1 6
(105–840) (15–2,788) (8–147) (24.6) (1.4) (8.7) —
P value .004 .0001 .0001 .005 1.00 .66
Table IV. Operative results of patients undergoing major hepatectomy Laparoscopic major hepatectomy (n = 20) Operative time, min Blood loss, mL Hospital stay, d Major morbidity, n (%) Mortality, n (%) Conversion to open laparotomy
292 283 12 5 1
(192–451) (30–1,200) (6–256) (25) (5.0) 1
The results of major hepatectomy are summarized in Table IV. The surgery time of patients with LH was comparable with that of patients with OH (292 vs 299 minutes, P = .91); however, their blood loss was less (283 vs 803 mL, P = .001), and hospitalization time tended to be less in patients with LH than in those undergoing OH (12 vs 19 days, P = .05). No greater differences were observed in the major morbidity and mortality rates between the 2 groups. Long-term outcomes. The 3- and 5-year OS rates of all patients were 62.9% and 53.0%, respectively, whereas the 3- and 5-year RFS rates were 37.3% and 34.4%, respectively. No differences in 5-year OS and RFS rates were observed between the LH and OH groups (OS: 56.8% vs 48.8%, P = .53; RFS: 39.7% vs 28.6%, P = .33). The high-risk factors for cancer recurrence are summarized in Table V. Univariate analysis revealed that the high-risk factors for cancer recurrence included synchronous liver metastasis, multiple liver metastases, CA19-9 levels of >100 U/mL, the receipt of prehepatectomy chemotherapy, the presence of major morbidity, and a positive surgical margin. In multivariate analyses, CA19-9 levels of >100 U/mL (hazard ratio: 2.21, 95% confidence interval: 1.26–3.77, P = .007) and a positive surgical margin (hazard ratio: 3.05, 95% confidence interval: 1.30–6.31, P = .01) were high-risk factors. We applied an available scoring system for all patients treated at our institution. OS and RFS were substantially different when patients were
Open major hepatectomy (n = 25) 299 803 19 8 1
(165–840) (143–2,788) (8–118) (32) (4.0)
P value .91 .001 .05 .61 .87
stratified according to their preoperative score (P < .0001 and P < .0001, respectively) (Fig 1, A and B). LH and OH patients were compared using this scoring system, and the survival curves for both procedures were similar at each score (Table VI, Figs 2 and 3). A summary of the recurrent lesions is provided in Table VII. A total of 94 recurrences were observed, 53 in the LH group and 41 in the OH group. The recurrence patterns were similar between the 2 groups. There were 16 (30.2%) liver metastases in the LH group and 11 (26.8%) in the OH group (P = .72). The corresponding numbers for lung metastases were 12 (22.6%) and 14 (34.1%) (P = .22), those for LN metastases were 2 (3.8%) and 4 (9.8%) (P = .24), and those for peritoneum dissemination were 4 (7.6%) and 2 (4.9%) (P = .60), respectively. Trocar site recurrence was not observed. DISCUSSION Despite the benefit of laparoscopic liver resection, LH for CRLM has not been accepted widely because the comparison of surgical technique and oncologic adequacy between LH and OH for CRLM remains controversial. Special concerns have been raised about the potential increase in positive margin rate or the failure to detect occult metastases when LH is performed. In this study, we performed an ‘‘intent-to-treat’’ analysis for all patients who underwent liver resection for CRLM, and the background characteristics differed between the 2 patient groups.
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Table V. Univariate and multivariate analyses of risk factors associated with RFS Univariate analyses n (%) Age >70 y Male sex Rectum primary Synchronous metastases Primary LN involvement Multiple liver metastases Tumor diameter >50 mm CEA >100 ng/mL CA19-9 >100 U/mL Extrahepatic metastases Prehepatectomy chemotherapy Adjuvant chemotherapy Laparoscopic procedure Blood loss >1,000 mL Major morbidity Positive operative margin
47 105 78 68 113 76 29 9 27 5 63 85 97 17 25 12
(28.7) (64.0) (47.6) (41.5) (69.3) (46.6) (18.0) (5.5) (16.9) (3.1) (37.5) (51.8) (59.1) (10.4) (15.3) (7.3)
Multivariate analyses
HR
95% CI
P value
1.25 1.11 1.25 1.90 1.46 1.50 1.44 1.83 2.23 2.36 1.67 1.26 0.88 1.87 2.06 3.23
0.80–1.92 0.73–1.71 0.92–1.71 1.27–2.84 0.94–2.38 1.00–2.24 0.85–2.34 0.64–4.08 1.32–3.60 0.83–5.27 1.11–2.49 0.84–1.90 0.59–1.33 0.97–3.95 1.16–3.43 1.42–6.37
.32 .64 .16 .002 .10 .05 .17 .23 .004 .10 .01 .27 .55 .06 .02 .007
HR
95% CI
P value
1.49
0.95–2.32
.08
1.37
0.84–2.21
.20
2.21
1.26–3.77
.007
1.37
0.86–2.17
.17
1.44 3.05
0.77–2.53 1.30–6.31
.24 .01
RFS, Recurrence-free survival.
Fig 1. (A) Overall survival curves for all patients stratified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery system preoperative score were significantly different. (B) Recurrence-free survival curves for all patients stratified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery system preoperative score were significantly different. (Color illustration of this figure is available online.)
Therefore, to overcome this limitation, we matched 168 consecutive cases using the JSHBPS nomogram, which was published in 2012 by Beppu et al4 and has been used for patient survival prediction. The advantage of this nomogram is that its detailed scoring system is subdivided on the basis of several risk factors; thus, it is suited to compare 2 groups with different backgrounds. In every
stratum, the OS and RFS of LH and OH patients were comparable. Okuno et al18 reported that prehepatectomy chemotherapy decreased the performance of the Beppu nomogram. We therefore compared the RFS rate of LH and OH patients stratified by the receipt of prehepatectomy chemotherapy. The outcomes were also comparable between LH and OH
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Table VI. Patients’ predicted survival time based on a prognostic scoring system Survival (Lap/Open) Preoperative score OS 0 1–5 6–10 11–15 $16 RFS 0 1–5 6–10 11–15 $16
n (Lap/Open)
Median, y
1-year, %
3-year, %
5-year, %
P value
11/6 30/15 41/28 15/13 3/6
— 6.3/5.0 3.3/5.3 3.3/3.9 1.6/1.4
100/100 93.3/92.9 95.0/96.4 85.7/84.6 100/80.0
90/100 71.3/71.4 52.4/63.2 52.9/51.9 33.3/
90/100 66.2/57.1 41.3/52.7 39.7/43.3 —
.44 .68 .72 .53 .76
11/6 30/15 40/28 14/13 2/5
— /2.5 1.5/1.2 0.9/1.4 0.9/0.5
81.8/100 76.7/92.3 70.3/60.7 47.1/73.9 50.0/30.0
72.7/80.0 51.3/46.2 19.5/34.4 21.0/18.5 0/0
72.7/80.0 51.3/30.1 19.5/30.1 /18.5 0/0
.63 .69 .92 .55 .79
Lap, Laparoscopic; OS, overall survival; RFS, recurrence-free survival.
Fig 2. Comparison of the overall survival curves of patients undergoing laparoscopic hepatectomy and open hepatectomy stratified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery system preoperative score. In every stratum, survival was comparable between the 2 groups.
patients (Supplementary Figs 1 and 2, and Supplementary Tables I and II). Previous studies have reported the long-term outcomes of liver resection for CRLM as follows: the 5-year OS rate was 40–53% and the 5-year RFS rate was 20–30%.1-4 In addition, the 5-year OS rate of patients undergoing LH for CRLM was 36–51%, whereas the 5-year RFS rate was 15–43%.12,13,19
Such outcomes were not much different from those in our series. Although previously reported case-matched series indicate the inferiority of LH, the evidence in oncologic high-risk patients is scarce. Therefore, the results of our study provided important and novel insights. For major hepatectomy, 20 patients underwent LH and 25 underwent OH. Blood loss was
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Fig 3. Comparison of the recurrence-free survival curves of patients undergoing laparoscopic hepatectomy and open hepatectomy stratified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery system preoperative score. In every stratum, survival was comparable between the 2 groups.
Table VII. Recurrent lesions Open Laparoscopic P hepatectomy hepatectomy (n = 41) value (n = 53) Liver, n (%) Lung, n (%) Lymph node, n (%) Peritoneum, n (%) Other/multiple, n (%)
16 12 2 4 19
(30.2) (22.6) (3.8) (7.6) (35.8)
11 14 4 2 10
(26.8) (34.1) (9.8) (4.9) (24.4)
.72 .22 .24 .60 .23
significantly less and hospitalization time tended to be less in patients with LH than in patients with OH. Other factors such as surgery time, major morbidity rate, and mortality rate were comparable. Several studies have suggested the adverse effect of intraoperative blood loss and blood transfusion on oncological outcomes.4,20,21 Therefore, laparoscopic major hepatectomy might have the potential to positively impact long-term outcomes. A positive resection margin is considered a predictor of disease recurrence after resection of CRLM. Recent publications have reported the rate of positive margins ranging from 11% to 16%.3,4,22,23 In our series, the positive operative margin rate was comparable between the LH and
OH groups (6.9% vs 8.7%, P = .67). Both preoperative simulation and intraoperative ultrasonography helped us achieve pathologically negative surgical margins not only in open laparotomy but also in laparoscopic procedure. Our findings confirmed that laparoscopic liver resection was technically adequate for treating malignant tumors. The recurrence patterns were similar between patients with LH and OH, suggesting that laparoscopic procedure would not fail to detect occult metastases. Preoperative imaging examinations such as dynamic computed tomography, gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid enhanced magnetic resonance imaging or positron emission tomography computed tomography, and intraoperative sonazoid-enhanced ultrasonography have improved rapidly in recent years, greatly advancing the detection of liver tumors or recurrences at other sites.24,25 Such an improvement may be one of the reasons why laparoscopic surgery does not have disadvantages in terms of intraoperative detection of occult metastases. This study has some limitations, such as the relatively limited number of patients, differences in patient backgrounds, and potential selection
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bias with regard to operative methods. Particularly, in the RFS analyses, the subgroups of patients with JSHBPS score of 0 and >16 was small; therefore, the comparison might not have sufficient power. To overcome these issues, future randomized controlled trials or propensity score matching analyses with more patients are needed. In conclusion, our study demonstrated that long-term survival was comparable between CRLM patients undergoing laparoscopic liver resection and those undergoing open liver resection. These results provided further evidence of LH being a valuable treatment option for CRLM. The authors thank the staff of the Department of Anesthesiology and the Division of Diagnostic Molecular Pathology, Iwate Medical University School of Medicine for their assistance. SUPPLEMENTARY DATA Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.surg.2015.01.017. REFERENCES 1. Hamady ZZ, Lodge JP, Welsh FK, Toogood GJ, White A, John T, et al. One-millimeter cancer-free margin is curative for colorectal liver metastases: a propensity score casematch approach. Ann Surg 2014;259:543-8. 2. Mavros MN, de Jong M, Dogeas E, Hyder O, Pawlik TM. Impact of complications on long-term survival after resection of colorectal liver metastases. Br J Surg 2013;100:711-8. 3. Andreou A, Aloia TA, Brouquet A, Dickson PV, Zimmitti G, Maru DM, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg 2013;257:1079-88. 4. Beppu T, Sakamoto Y, Hasegawa K, Honda G, Tanaka K, Kotera Y, et al. A nomogram predicting disease-free survival in patients with colorectal liver metastases treated with hepatic resection: multicenter data collection as a Project Study for Hepatic Surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci 2012;19:72-84. 5. Buell JF, Cherqui D, Geller DA, O’Rourke N, Iannitti D, Dagher I, et al. The international position on laparoscopic liver surgery: The Louisville Statement, 2008. Ann Surg 2009;250:825-30. 6. Kluger MD, Vigano L, Barroso R, Cherqui D. The learning curve in laparoscopic major liver resection. J Hepatobiliary Pancreat Sci 2013;20:131-6. 7. Hasegawa Y, Nitta H, Sasaki A, Takahara T, Ito N, Fujita T, et al. Laparoscopic left lateral sectionectomy as a training procedure for surgeons learning laparoscopic hepatectomy. J Hepatobiliary Pancreat Sci 2013;20:525-30. 8. Tzanis D, Shivathirthan N, Laurent A, Abu Hilal M, Soubrane O, Kazaryan AM, et al. European experience of laparoscopic major hepatectomy. J Hepatobiliary Pancreat Sci 2013;20:120-4. 9. Lin NC, Nitta H, Wakabayashi G. Laparoscopic major hepatectomy: a systematic literature review and comparison of 3 techniques. Ann Surg 2013;257:205-13.
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10. Nitta H, Sasaki A, Fujita T, Itabashi H, Hoshikawa K, Takahara T, et al. Laparoscopy-assisted major liver resections employing a hanging technique: the original procedure. Ann Surg 2010;251:450-3. 11. Sasaki A, Nitta H, Otsuka K, Takahara T, Nishizuka S, Wakabayashi G. Ten-year experience of totally laparoscopic liver resection in a single institution. Br J Surg 2009;96:274-9. 12. Kazaryan AM, Marangos IP, Rosok BI, Rosseland AR, Villanger O, Fosse E, et al. Laparoscopic resection of colorectal liver metastases: surgical and long-term oncologic outcome. Ann Surg 2010;252:1005-12. 13. Nguyen KT, Laurent A, Dagher I, Geller DA, Steel J, Thomas MT, et al. Minimally invasive liver resection for metastatic colorectal cancer: a multi-institutional, international report of safety, feasibility, and early outcomes. Ann Surg 2009;250:842-8. 14. Guerron AD, Aliyev S, Agcaoglu O, Aksoy E, Taskin HE, Aucejo F, et al. Laparoscopic versus open resection of colorectal liver metastasis. Surg Endosc 2013;27:1138-43. 15. Abu Hilal M, Di Fabio F, Abu Salameh M, Pearce NW. Oncological efficiency analysis of laparoscopic liver resection for primary and metastatic cancer: a single-center UK experience. Arch Surg 2012;147:42-8. 16. Castaing D, Vibert E, Ricca L, Azoulay D, Adam R, Gayet B. Oncologic results of laparoscopic versus open hepatectomy for colorectal liver metastases in two specialized centers. Ann Surg 2009;250:849-55. 17. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13. 18. Okuno M, Hatano E, Seo S, Taura K, Yasuchika K, Nakajima A, et al. Indication for neoadjuvant chemotherapy in patients with colorectal liver metastases based on a nomogram that predicts disease-free survival. J Hepatobiliary Pancreat Sci 2014;21:881-8. 19. Cannon RM, Scoggins CR, Callender GG, McMasters KM, Martin RCG II. Laparoscopic versus open resection of hepatic colorectal metastases. Surgery 2012;152:567-73; discussion 573-4. 20. Jiang W, Fang YJ, Wu XJ, Wang FL, Lu ZH, Zhang RX, et al. Intraoperative blood loss independently predicts survival and recurrence after resection of colorectal cancer liver metastasis. PLoS One 2013;8:e76125. 21. Acheson AG, Brookes MJ, Spahn DR. Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis. Ann Surg 2012;256:235-44. 22. Reissfelder C, Rahbari NN, Koch M, Ulrich A, Pfeilschifter I, Waltert A, et al. Validation of prognostic scoring systems for patients undergoing resection of colorectal cancer liver metastases. Ann Surg Oncol 2009;16:3279-88. 23. Saiura A, Yamamoto J, Hasegawa K, Koga R, Sakamoto Y, Hata S, et al. Liver resection for multiple colorectal liver metastases with surgery up-front approach: bi-institutional analysis of 736 consecutive cases. World J Surg 2012;36:2171-8. 24. Itabashi T, Sasaki A, Otsuka K, Kimura T, Nitta H, Wakabayashi G. Potential value of sonazoid-enhanced intraoperative laparoscopic ultrasonography for liver assessment during laparoscopy-assisted colectomy. Surg Today 2014; 44:696-701. 25. Vigano L, Ferrero A, Amisano M, Russolillo N, Capussotti L. Comparison of laparoscopic and open intraoperative ultrasonography for staging liver tumours. Br J Surg 2013;100: 535-42.
Background. Laparoscopic liver resection for liver metastases from colorectal cancer (CRLM) is performed in a relatively small number of institutions. Its operative results have been reported to be comparable with that of open laparotomy; however, information on its oncologic outcomes is scarce. This study aimed to compare the long-term outcomes of laparoscopic hepatectomy (LH) and open hepatectomy (OH) to treat CRLM at a single institution. Methods. We retrospectively reviewed data from 168 consecutive patients who underwent LH (n = 100) or OH (n = 68) for CRLM. The tumor characteristics, operative results, overall survival (OS) rate, recurrence-free survival (RFS) rate, and recurrence patterns were analyzed and compared. A previously published survival-predicting nomogram was applied to compare OS and RFS between the 2 patient groups. Results. The largest tumor diameter and the number of tumors were significantly larger in the OH group than in the LH group; however, no differences in other tumor factors were observed between the 2 groups. When matched by the nomogram, OS and RFS remained comparable between the 2 groups in every examined stratum, not only for low-risk patients but also for those with high risk. The recurrence patterns also were similar (liver: 30.2% vs 26.8%, P = .72; lung: 22.6% vs 34.1%, P = .22; peritoneum: 7.6% vs 4.9%, P = .45). Conclusion. The long-term outcomes of laparoscopic liver resection for CRLM were comparable with those of the open procedure in not only low-risk but also high-risk patients. (Surgery 2015;157:1065-72.) From the Department of Surgery, Iwate Medical University School of Medicine, Morioka City, Iwate, Japan
COLORECTAL CARCINOMA is one of the most common malignancies, and the liver is the most frequent site of metastasis. Liver metastasis occurs in approximately 50% of all patients with colorectal carcinoma. Hepatic resection is the only potential curative treatment for liver metastases from colorectal cancer (CRLM), resulting in a 5-year survival rate of 34–53%.1-4
Accepted for publication January 22, 2015. Reprint requests: Yasushi Hasegawa, MD, Department of Surgery, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka City, 020-8505 Iwate, Japan. E-mail: hasegawayas@ yahoo.co.jp. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2015.01.017
Laparoscopic hepatectomy (LH) has been established as a safe and feasible treatment option for liver tumors.5-11 Despite the clinical benefits of LH (eg, less blood loss, pain, and analgesic requirement; shorter hospital stay; and improved cosmetic results), its application remains limited because of the insufficient hepatic and laparoscopic operative experience among surgeons. Moreover, the procedure might not be accepted widely to treat CRLM, because reports on its long-term outcomes are few in umber.12-16 In a few previous case-matched series with superficially selected cases, investigators also reported the inferiority of laparoscopic liver resection. The present study aimed to compare the long-term outcomes of consecutive patients undergoing LH or open hepatectomy (OH) for the treatment of CRLM at a single institution. SURGERY 1065
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PATIENTS AND METHODS A prospective database of patients treated at our hospital was reviewed retrospectively for the purpose of this study. LH has been performed at our institution since May 1997, and the first LH for CRLM was performed in May 1998. From then until April 2013, 100 patients underwent LH for CRLM with a curative intent. During the same period, 68 patients underwent OH for CRLM with a curative intent. Thus, a total of 168 consecutive patients were included in this study. All patients were informed about the procedure, and consent was obtained before surgery. Patient and tumor characteristics, operative methods and results, overall survival (OS), recurrence-free survival (RFS), and recurrence patterns were analyzed and compared between LH and OH patients. Major hepatectomy was defined as the resection of 3 or more contiguous liver segments. Postoperative mortality was defined as any death within 90 days after liver resection. Postoperative morbidity was graded according to the Clavien-Dindo classification, and a major complication was defined as one of grade $ III severity.17 To compare the long-term survival of 2 patient groups with different tumor backgrounds, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) nomogram was used for OS and RFS. The JSHBPS preoperative scoring system was published in 2012.4 It classifies patients on the basis of 6 prognostic factors to predict patient survival: timing of liver metastases (metachronous: score 0, synchronous: score 3), primary lymph node (LN) status (absent: 0, present: 3), number of tumors (1: 0, 2–4: 4, $5: 9), largest tumor diameter (#5 cm: 0, >5 cm: 2), extrahepatic metastatic disease at hepatectomy (absent: 0, present: 4), and carbohydrate antigen (CA) 19-9 level (#100 U/ mL: 0, >100 U/mL: 4). Surgical technique. Laparoscopic liver resection was defined as pure laparoscopy, hand-assisted laparoscopy, or the hybrid technique.5 In pure laparoscopy, the operator stood to the right of the patient with the assistant and the scopist on the patient’s left. Four or five ports were placed, and a carbon dioxide pneumoperitoneum was maintained at 8 12 mm Hg. The liver parenchyma was transected by an ultrasonic dissector or clamp crush method.7,11 In the hybrid technique, the liver mobilization was performed through a laparoscope, followed by parenchymal transection being performed through a small laparotomy incision.10 In our institution, the length of the incision was 6–10 cm.
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Intraoperative ultrasonography was used routinely. with sonazoid-enhanced ultrasonography being conducted since 2008. The exclusion criteria for laparoscopic liver resection were a tumor size $10 cm, number of lesions to be resected $4, lesions spreading to other organs, and the need for bile ducts and/or vessels resection with reconstruction. Statistical analysis. Continuous data are expressed as median values with the corresponding ranges in parentheses. The Mann-Whitney U test was used to compare continuous data, whereas the v2 test was used for categorical data. Cumulative survival curves were plotted using the KaplanMeier method and statistically compared using the log-rank test. All survival-associated variables with a P value of < .05 in the univariate proportional hazards models were subsequently entered into a Cox multivariate regression model with backward elimination. All statistical analyses were performed using commercially available software (JMP version 900; SAS Institute, Cary, NC). RESULTS Patient characteristics. Between May 1998 and April 2013, 168 consecutive patients underwent hepatectomy for CRLM. Of these, 3 patients underwent 2-stage hepatectomy: 2 underwent LH, and 1 underwent OH. Thus, in total, 102 LH procedures (in 100 patients) and 69 OH procedures (in 68 patients) were performed during the study period. In the LH group, 61 (59.8%) procedures were of pure laparoscopy, whereas 41 (40.2%) were of the hybrid technique. Eight patients had extrahepatic metastatic disease at the time of their hepatectomy, 6 with lung metastases and 2 with lymph node metastases. Of these, 5 patients underwent radical resection of these metastases, whereas 3 did not. These 3 patients and another 1 who could not undergo second-stage hepatectomy were excluded from the RFS analysis. The median follow-up period of LH patients was 29.4 months (range, 1–128), and that of OH patients was 35.8 months (range, 2–185) (P = .27). At the time of analysis, 24 LH and 20 OH patients had been observed for 5 years. Patient characteristics are summarized in Table I. The largest tumor diameter was substantially larger in the OH group than in the LH group (35 vs 23 mm, P = .0002), and the median number of resected metastases was greater in the OH group (2 vs 1, P = .03); however, the LH group seemed to have more patients with primary LN metastases than the OH group (75.0% vs 61.8%, P = .07). No significant
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Table I. Patient characteristics Laparoscopic hepatectomy (n = 100) Age, y Male sex, n (%) Rectum primary, n (%) Synchronous liver metastases, n (%) Primary LN involvement, n (%) Number of liver metastases Largest tumor diameter, mm Extrahepatic metastases at hepatectomy, n (%) Serum CEA level at hepatectomy, ng/mL Serum CA19-9 level at hepatectomy, U/mL Pre-hepatectomy chemotherapy, n (%) with targeted therapy, n (%) Adjuvant chemotherapy, n (%) Preoperative score Follow-up period, mo
67 64 47 37 75 1 23 6 9.5 19.4 34 14 49 6 29.4
(24–91) (64.0) (47.0) (37.0) (75.0) (1–8) (7–95) (6.0) (0.5–712) (0–89,472) (34.0) (14.0) (51.0) (0–19) (1–128)
Open hepatectomy (n = 68) 65 43 33 31 42 2 35 2 11.7 18.5 29 13 36 7 35.8
(37–83) (63.2) (48.5) (45.6) (61.8) (1–12) (11–160) (3.0) (0.5–3,493) (0–3,573) (42.7) (19.1) (52.9) (0–21) (2–185)
P value .40 .92 .85 .27 .07 .03 .0002 .37 .31 .82 .26 .38 .81 .05 .27
CA19-9, Carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; LN, lymph node.
Table II. Operative methods Laparoscopic hepatectomy (n = 102)
Open hepatectomy (n = 69)
1 (1 6) 20 (19.6) 3 8 8 1 82 (80.4) 1 11 1 17 3 49
1 (1 7) 25 (36.2) 1 13 7 4 44 (63.8) 4 11 1 2 3 23
Number of hepatectomy during a surgery Major hepatectomy, n (%) Right trisectionectomy Right hemihepatectomy Left hemihepatectomy Central bisectionectomy Minor hepatectomy, n (%) Right anterior sectionectomy Right posterior sectionectomy Left medial sectionectomy Left lateral sectionectomy Segmentectomy Wedge resection only
differences in age, sex, site of primary tumor, timing of liver metastasis, extrahepatic metastatic disease, serum carcinoembryonic antigen level, and serum CA19-9 level at hepatectomy were observed between the 2 groups. Operative results. The proportion of LH was greater during the latter half of the study than during the first half (51.2% vs 67.9%, P = .03). The operative methods are summarized in Table II. The rate of major hepatectomy was greater in OH patients than in LH patients (36.2% vs 19.6%, P = .02). The number of hepatectomies during a surgery also tended to be higher in the OH group than in the LH group (P = .07). The operative results are summarized in Tables III and IV. LH was converted to open laparotomy
P value .07 .02
.02
in 1 patient because of little progress during surgery, and this patient was included in the LH group. The surgery time of LH patients was shorter (228 vs 277 min, P = .004), and their total blood loss was lower (127 vs 620 mL, P < .0001) than those of OH patients. In addition, the rate of major morbidity (Clavien-Dindo classification of $III) was lower (8.8% vs 24.6%, P = .005) and the hospitalization duration was less (9 vs 17 days, P < .0001) in patients with LH than in those who underwent OH. Gas embolism was not observed in patients with LH. There was 1 case of postoperative mortality in each group. The rate of pathologically positive surgical margins was comparable between the LH and OH groups (6.9% vs 8.7%, P = .66).
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Table III. Operative results Laparoscopic hepatectomy (n = 102) Surgery time, min Blood loss, mL Hospital stay, d Major morbidity, n (%) Mortality, n (%) Positive operative margin, n (%) Conversion to open laparotomy
228 127 9 9 1 7
Open hepatectomy (n = 69)
(70–591) (3–2,920) (4–256) (8.8) (0.98) (6.9) 1
277 620 16 17 1 6
(105–840) (15–2,788) (8–147) (24.6) (1.4) (8.7) —
P value .004 .0001 .0001 .005 1.00 .66
Table IV. Operative results of patients undergoing major hepatectomy Laparoscopic major hepatectomy (n = 20) Operative time, min Blood loss, mL Hospital stay, d Major morbidity, n (%) Mortality, n (%) Conversion to open laparotomy
292 283 12 5 1
(192–451) (30–1,200) (6–256) (25) (5.0) 1
The results of major hepatectomy are summarized in Table IV. The surgery time of patients with LH was comparable with that of patients with OH (292 vs 299 minutes, P = .91); however, their blood loss was less (283 vs 803 mL, P = .001), and hospitalization time tended to be less in patients with LH than in those undergoing OH (12 vs 19 days, P = .05). No greater differences were observed in the major morbidity and mortality rates between the 2 groups. Long-term outcomes. The 3- and 5-year OS rates of all patients were 62.9% and 53.0%, respectively, whereas the 3- and 5-year RFS rates were 37.3% and 34.4%, respectively. No differences in 5-year OS and RFS rates were observed between the LH and OH groups (OS: 56.8% vs 48.8%, P = .53; RFS: 39.7% vs 28.6%, P = .33). The high-risk factors for cancer recurrence are summarized in Table V. Univariate analysis revealed that the high-risk factors for cancer recurrence included synchronous liver metastasis, multiple liver metastases, CA19-9 levels of >100 U/mL, the receipt of prehepatectomy chemotherapy, the presence of major morbidity, and a positive surgical margin. In multivariate analyses, CA19-9 levels of >100 U/mL (hazard ratio: 2.21, 95% confidence interval: 1.26–3.77, P = .007) and a positive surgical margin (hazard ratio: 3.05, 95% confidence interval: 1.30–6.31, P = .01) were high-risk factors. We applied an available scoring system for all patients treated at our institution. OS and RFS were substantially different when patients were
Open major hepatectomy (n = 25) 299 803 19 8 1
(165–840) (143–2,788) (8–118) (32) (4.0)
P value .91 .001 .05 .61 .87
stratified according to their preoperative score (P < .0001 and P < .0001, respectively) (Fig 1, A and B). LH and OH patients were compared using this scoring system, and the survival curves for both procedures were similar at each score (Table VI, Figs 2 and 3). A summary of the recurrent lesions is provided in Table VII. A total of 94 recurrences were observed, 53 in the LH group and 41 in the OH group. The recurrence patterns were similar between the 2 groups. There were 16 (30.2%) liver metastases in the LH group and 11 (26.8%) in the OH group (P = .72). The corresponding numbers for lung metastases were 12 (22.6%) and 14 (34.1%) (P = .22), those for LN metastases were 2 (3.8%) and 4 (9.8%) (P = .24), and those for peritoneum dissemination were 4 (7.6%) and 2 (4.9%) (P = .60), respectively. Trocar site recurrence was not observed. DISCUSSION Despite the benefit of laparoscopic liver resection, LH for CRLM has not been accepted widely because the comparison of surgical technique and oncologic adequacy between LH and OH for CRLM remains controversial. Special concerns have been raised about the potential increase in positive margin rate or the failure to detect occult metastases when LH is performed. In this study, we performed an ‘‘intent-to-treat’’ analysis for all patients who underwent liver resection for CRLM, and the background characteristics differed between the 2 patient groups.
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Table V. Univariate and multivariate analyses of risk factors associated with RFS Univariate analyses n (%) Age >70 y Male sex Rectum primary Synchronous metastases Primary LN involvement Multiple liver metastases Tumor diameter >50 mm CEA >100 ng/mL CA19-9 >100 U/mL Extrahepatic metastases Prehepatectomy chemotherapy Adjuvant chemotherapy Laparoscopic procedure Blood loss >1,000 mL Major morbidity Positive operative margin
47 105 78 68 113 76 29 9 27 5 63 85 97 17 25 12
(28.7) (64.0) (47.6) (41.5) (69.3) (46.6) (18.0) (5.5) (16.9) (3.1) (37.5) (51.8) (59.1) (10.4) (15.3) (7.3)
Multivariate analyses
HR
95% CI
P value
1.25 1.11 1.25 1.90 1.46 1.50 1.44 1.83 2.23 2.36 1.67 1.26 0.88 1.87 2.06 3.23
0.80–1.92 0.73–1.71 0.92–1.71 1.27–2.84 0.94–2.38 1.00–2.24 0.85–2.34 0.64–4.08 1.32–3.60 0.83–5.27 1.11–2.49 0.84–1.90 0.59–1.33 0.97–3.95 1.16–3.43 1.42–6.37
.32 .64 .16 .002 .10 .05 .17 .23 .004 .10 .01 .27 .55 .06 .02 .007
HR
95% CI
P value
1.49
0.95–2.32
.08
1.37
0.84–2.21
.20
2.21
1.26–3.77
.007
1.37
0.86–2.17
.17
1.44 3.05
0.77–2.53 1.30–6.31
.24 .01
RFS, Recurrence-free survival.
Fig 1. (A) Overall survival curves for all patients stratified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery system preoperative score were significantly different. (B) Recurrence-free survival curves for all patients stratified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery system preoperative score were significantly different. (Color illustration of this figure is available online.)
Therefore, to overcome this limitation, we matched 168 consecutive cases using the JSHBPS nomogram, which was published in 2012 by Beppu et al4 and has been used for patient survival prediction. The advantage of this nomogram is that its detailed scoring system is subdivided on the basis of several risk factors; thus, it is suited to compare 2 groups with different backgrounds. In every
stratum, the OS and RFS of LH and OH patients were comparable. Okuno et al18 reported that prehepatectomy chemotherapy decreased the performance of the Beppu nomogram. We therefore compared the RFS rate of LH and OH patients stratified by the receipt of prehepatectomy chemotherapy. The outcomes were also comparable between LH and OH
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Table VI. Patients’ predicted survival time based on a prognostic scoring system Survival (Lap/Open) Preoperative score OS 0 1–5 6–10 11–15 $16 RFS 0 1–5 6–10 11–15 $16
n (Lap/Open)
Median, y
1-year, %
3-year, %
5-year, %
P value
11/6 30/15 41/28 15/13 3/6
— 6.3/5.0 3.3/5.3 3.3/3.9 1.6/1.4
100/100 93.3/92.9 95.0/96.4 85.7/84.6 100/80.0
90/100 71.3/71.4 52.4/63.2 52.9/51.9 33.3/
90/100 66.2/57.1 41.3/52.7 39.7/43.3 —
.44 .68 .72 .53 .76
11/6 30/15 40/28 14/13 2/5
— /2.5 1.5/1.2 0.9/1.4 0.9/0.5
81.8/100 76.7/92.3 70.3/60.7 47.1/73.9 50.0/30.0
72.7/80.0 51.3/46.2 19.5/34.4 21.0/18.5 0/0
72.7/80.0 51.3/30.1 19.5/30.1 /18.5 0/0
.63 .69 .92 .55 .79
Lap, Laparoscopic; OS, overall survival; RFS, recurrence-free survival.
Fig 2. Comparison of the overall survival curves of patients undergoing laparoscopic hepatectomy and open hepatectomy stratified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery system preoperative score. In every stratum, survival was comparable between the 2 groups.
patients (Supplementary Figs 1 and 2, and Supplementary Tables I and II). Previous studies have reported the long-term outcomes of liver resection for CRLM as follows: the 5-year OS rate was 40–53% and the 5-year RFS rate was 20–30%.1-4 In addition, the 5-year OS rate of patients undergoing LH for CRLM was 36–51%, whereas the 5-year RFS rate was 15–43%.12,13,19
Such outcomes were not much different from those in our series. Although previously reported case-matched series indicate the inferiority of LH, the evidence in oncologic high-risk patients is scarce. Therefore, the results of our study provided important and novel insights. For major hepatectomy, 20 patients underwent LH and 25 underwent OH. Blood loss was
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Fig 3. Comparison of the recurrence-free survival curves of patients undergoing laparoscopic hepatectomy and open hepatectomy stratified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery system preoperative score. In every stratum, survival was comparable between the 2 groups.
Table VII. Recurrent lesions Open Laparoscopic P hepatectomy hepatectomy (n = 41) value (n = 53) Liver, n (%) Lung, n (%) Lymph node, n (%) Peritoneum, n (%) Other/multiple, n (%)
16 12 2 4 19
(30.2) (22.6) (3.8) (7.6) (35.8)
11 14 4 2 10
(26.8) (34.1) (9.8) (4.9) (24.4)
.72 .22 .24 .60 .23
significantly less and hospitalization time tended to be less in patients with LH than in patients with OH. Other factors such as surgery time, major morbidity rate, and mortality rate were comparable. Several studies have suggested the adverse effect of intraoperative blood loss and blood transfusion on oncological outcomes.4,20,21 Therefore, laparoscopic major hepatectomy might have the potential to positively impact long-term outcomes. A positive resection margin is considered a predictor of disease recurrence after resection of CRLM. Recent publications have reported the rate of positive margins ranging from 11% to 16%.3,4,22,23 In our series, the positive operative margin rate was comparable between the LH and
OH groups (6.9% vs 8.7%, P = .67). Both preoperative simulation and intraoperative ultrasonography helped us achieve pathologically negative surgical margins not only in open laparotomy but also in laparoscopic procedure. Our findings confirmed that laparoscopic liver resection was technically adequate for treating malignant tumors. The recurrence patterns were similar between patients with LH and OH, suggesting that laparoscopic procedure would not fail to detect occult metastases. Preoperative imaging examinations such as dynamic computed tomography, gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid enhanced magnetic resonance imaging or positron emission tomography computed tomography, and intraoperative sonazoid-enhanced ultrasonography have improved rapidly in recent years, greatly advancing the detection of liver tumors or recurrences at other sites.24,25 Such an improvement may be one of the reasons why laparoscopic surgery does not have disadvantages in terms of intraoperative detection of occult metastases. This study has some limitations, such as the relatively limited number of patients, differences in patient backgrounds, and potential selection
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bias with regard to operative methods. Particularly, in the RFS analyses, the subgroups of patients with JSHBPS score of 0 and >16 was small; therefore, the comparison might not have sufficient power. To overcome these issues, future randomized controlled trials or propensity score matching analyses with more patients are needed. In conclusion, our study demonstrated that long-term survival was comparable between CRLM patients undergoing laparoscopic liver resection and those undergoing open liver resection. These results provided further evidence of LH being a valuable treatment option for CRLM. The authors thank the staff of the Department of Anesthesiology and the Division of Diagnostic Molecular Pathology, Iwate Medical University School of Medicine for their assistance. SUPPLEMENTARY DATA Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.surg.2015.01.017. REFERENCES 1. Hamady ZZ, Lodge JP, Welsh FK, Toogood GJ, White A, John T, et al. One-millimeter cancer-free margin is curative for colorectal liver metastases: a propensity score casematch approach. Ann Surg 2014;259:543-8. 2. Mavros MN, de Jong M, Dogeas E, Hyder O, Pawlik TM. Impact of complications on long-term survival after resection of colorectal liver metastases. Br J Surg 2013;100:711-8. 3. Andreou A, Aloia TA, Brouquet A, Dickson PV, Zimmitti G, Maru DM, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg 2013;257:1079-88. 4. Beppu T, Sakamoto Y, Hasegawa K, Honda G, Tanaka K, Kotera Y, et al. A nomogram predicting disease-free survival in patients with colorectal liver metastases treated with hepatic resection: multicenter data collection as a Project Study for Hepatic Surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci 2012;19:72-84. 5. Buell JF, Cherqui D, Geller DA, O’Rourke N, Iannitti D, Dagher I, et al. The international position on laparoscopic liver surgery: The Louisville Statement, 2008. Ann Surg 2009;250:825-30. 6. Kluger MD, Vigano L, Barroso R, Cherqui D. The learning curve in laparoscopic major liver resection. J Hepatobiliary Pancreat Sci 2013;20:131-6. 7. Hasegawa Y, Nitta H, Sasaki A, Takahara T, Ito N, Fujita T, et al. Laparoscopic left lateral sectionectomy as a training procedure for surgeons learning laparoscopic hepatectomy. J Hepatobiliary Pancreat Sci 2013;20:525-30. 8. Tzanis D, Shivathirthan N, Laurent A, Abu Hilal M, Soubrane O, Kazaryan AM, et al. European experience of laparoscopic major hepatectomy. J Hepatobiliary Pancreat Sci 2013;20:120-4. 9. Lin NC, Nitta H, Wakabayashi G. Laparoscopic major hepatectomy: a systematic literature review and comparison of 3 techniques. Ann Surg 2013;257:205-13.
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10. Nitta H, Sasaki A, Fujita T, Itabashi H, Hoshikawa K, Takahara T, et al. Laparoscopy-assisted major liver resections employing a hanging technique: the original procedure. Ann Surg 2010;251:450-3. 11. Sasaki A, Nitta H, Otsuka K, Takahara T, Nishizuka S, Wakabayashi G. Ten-year experience of totally laparoscopic liver resection in a single institution. Br J Surg 2009;96:274-9. 12. Kazaryan AM, Marangos IP, Rosok BI, Rosseland AR, Villanger O, Fosse E, et al. Laparoscopic resection of colorectal liver metastases: surgical and long-term oncologic outcome. Ann Surg 2010;252:1005-12. 13. Nguyen KT, Laurent A, Dagher I, Geller DA, Steel J, Thomas MT, et al. Minimally invasive liver resection for metastatic colorectal cancer: a multi-institutional, international report of safety, feasibility, and early outcomes. Ann Surg 2009;250:842-8. 14. Guerron AD, Aliyev S, Agcaoglu O, Aksoy E, Taskin HE, Aucejo F, et al. Laparoscopic versus open resection of colorectal liver metastasis. Surg Endosc 2013;27:1138-43. 15. Abu Hilal M, Di Fabio F, Abu Salameh M, Pearce NW. Oncological efficiency analysis of laparoscopic liver resection for primary and metastatic cancer: a single-center UK experience. Arch Surg 2012;147:42-8. 16. Castaing D, Vibert E, Ricca L, Azoulay D, Adam R, Gayet B. Oncologic results of laparoscopic versus open hepatectomy for colorectal liver metastases in two specialized centers. Ann Surg 2009;250:849-55. 17. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13. 18. Okuno M, Hatano E, Seo S, Taura K, Yasuchika K, Nakajima A, et al. Indication for neoadjuvant chemotherapy in patients with colorectal liver metastases based on a nomogram that predicts disease-free survival. J Hepatobiliary Pancreat Sci 2014;21:881-8. 19. Cannon RM, Scoggins CR, Callender GG, McMasters KM, Martin RCG II. Laparoscopic versus open resection of hepatic colorectal metastases. Surgery 2012;152:567-73; discussion 573-4. 20. Jiang W, Fang YJ, Wu XJ, Wang FL, Lu ZH, Zhang RX, et al. Intraoperative blood loss independently predicts survival and recurrence after resection of colorectal cancer liver metastasis. PLoS One 2013;8:e76125. 21. Acheson AG, Brookes MJ, Spahn DR. Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis. Ann Surg 2012;256:235-44. 22. Reissfelder C, Rahbari NN, Koch M, Ulrich A, Pfeilschifter I, Waltert A, et al. Validation of prognostic scoring systems for patients undergoing resection of colorectal cancer liver metastases. Ann Surg Oncol 2009;16:3279-88. 23. Saiura A, Yamamoto J, Hasegawa K, Koga R, Sakamoto Y, Hata S, et al. Liver resection for multiple colorectal liver metastases with surgery up-front approach: bi-institutional analysis of 736 consecutive cases. World J Surg 2012;36:2171-8. 24. Itabashi T, Sasaki A, Otsuka K, Kimura T, Nitta H, Wakabayashi G. Potential value of sonazoid-enhanced intraoperative laparoscopic ultrasonography for liver assessment during laparoscopy-assisted colectomy. Surg Today 2014; 44:696-701. 25. Vigano L, Ferrero A, Amisano M, Russolillo N, Capussotti L. Comparison of laparoscopic and open intraoperative ultrasonography for staging liver tumours. Br J Surg 2013;100: 535-42.
