Surg Endosc DOI 10.1007/s00464-015-4215-9
and Other Interventional Techniques
Comparison of the long-term results of patients who underwent laparoscopy versus open distal gastrectomy Jun Ho Lee1 • Byung-Ho Nam2 • Keun Won Ryu3 • Seong Yeop Ryu4 Young Woo Kim3 • Young Kyu Park4 • Sung Kim1
•
Received: 12 December 2014 / Accepted: 6 April 2015 Ó Springer Science+Business Media New York 2015
Abstract Background Survival data of patients who underwent laparoscopy assisted distal gastrectomy (LADG) compared with those of patients who underwent open distal gastrectomy (ODG) for gastric cancer are rarely presented. We compared long-term outcomes of LADG with those of ODG in patients with EGC who met the current indication for LADG. Methods A total of 2410 patients with early gastric cancer who underwent curative-intent gastric cancer surgery in three Korean tertiary hospitals between January 2003 and June 2009 were included in this multicenter, retrospective, propensity-score-matched cohort study. Cox proportional hazard regression models were used to evaluate the association between operation methods and survival. Results In the matched cohort, there were no significant differences in overall survival [hazard ratio (HR) for the LADG group 0.990; 95 % confidence interval (CI) 0.675–1.453] or recurrence-free survival (HR 0.989; 95 % CI 0.480–2.038). The patterns of recurrence were not different between the two groups. The most common pattern & Jun Ho Lee [email protected] Sung Kim [email protected] 1
Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea
2
Center for Clinical Trial, National Cancer Center, Goyang, Korea
3
Center for Gastric Cancer, National Cancer Center, Goyang, Korea
4
Department of Surgery, Chunnam National University Whasoon Hospital, Gwangjoo, Korea
of recurrence was liver metastasis followed by metastasis to distant lymph nodes. The rate of complications in the LADG group was higher than that of the ODG group (6.7 vs. 4.6 %, P = 0.045). Grade III or worse complications that required surgical intervention or were life-threatening showed a marginal difference between the two groups (1.7 vs. 2.2 %, P = 0.052). There were no postoperative mortalities in either group. Conclusion Laparoscopy assisted distal gastrectomy for patients with early gastric cancer is feasible in terms of the long-term results including survival and recurrence. Keywords Gastric cancer Laparoscopy Subtotal gastrectomy Abbreviations LADG Laparoscopy assisted distal gastrectomy ODG Open distal gastrectomy HR Hazard ratio RFS Recurrence-free survival
Early gastric cancer (EGC) is defined as gastric cancer in which tumor invasion is limited to the mucosa or submucosa, regardless of lymph node metastasis [1]. D2 lymph node dissection is recommended for patients with advanced gastric cancer [2, 3], whereas for patients with EGC, less than D2 lymph node dissection is recommended because EGC rarely metastasizes to extra-perigastric lymph nodes [4]. Laparoscopy assisted distal gastrectomy (LADG) has been used for the treatment of patients with EGC since 1990 [5–7]. LADG is safe, and the quality of life of patients has been reported to be superior to that of patients
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who undergo open distal gastrectomy (ODG) [8]. As advances have been made in laparoscopic instruments and the surgeons have accumulated experience with laparoscopic surgery, LADG has become a widespread treatment option for patients with EGC. The most important outcome of cancer surgery is survival. Some investigators have reported that the survival of patients who have undergone LADG is not inferior to that of patients who have undergone ODG [9–11]. However, past studies had limitations, including small sample sizes or inclusion of advanced tumors which did not meet the current indication of LADG. LADG for advanced tumor is an investigational treatment; there are little data supporting whether D2 lymph node dissection is feasible during LADG [12]. Thus, the aim of the present study was to investigate whether long-term outcomes from LADG are comparable to those from ODG for EGC.
Patients and methods Study cohort and data sources The study cohort consisted of patients with gastric cancer who were treated by open or laparoscopic gastric cancer surgery between January 2003 and June 2006 at one of three institutions in Korea: Chunnam Whasoon Hospital, National Cancer Center, and Samsung Medical Center. Patients who (i) had a histologically confirmed gastric adenocarcinoma, (ii) had a mucosa or submucosa tumor, and (iii) had newly diagnosed cancer without previous treatment were included in the analysis. Patients who had another cancer or a tumor located in the upper one-third of the stomach that needed total gastrectomy were excluded. All information was obtained with the appropriate Institutional Review Board waivers, and the data were collected without revealing any personal information.
main lesion and all others were regarded as accessory lesions. The clinicopathological characteristics of the main lesion were used for the analysis.
Operative procedures The indications of LADG were patients with early gastric cancer according to the preoperative examinations including esophagogastroduodenoscopy (EGD) and abdominopelvic computed tomogram (CT). The surgical procedures and reconstruction methods were as follows. Gastrectomy was performed if the tumor-free margin was 2 cm. The extent of lymph node dissection was determined using recommendations of the Japanese Research Society for Gastric Carcinoma [4]. After the laparotomy or laparoscopy, the surgeons examined the intra-abdominal cavities and inspected the peritoneum, diaphragm, liver capsule, and pelvic cavity. All patients enrolled in the present study underwent gastrectomy with D1 ? b or more lymph node dissection [4]. Tumors were staged in accordance with the sixth UICC/AJCC tumor node metastasis (TNM) classification [13].
Follow-up schedule The follow-up schedule and discharge plan were not standardized among three institutions. However, most patients with early gastric cancer were followed up as follows, and the patients were discharged after soft diet was possible. The patients’ follow-up was conducted according to the accepted clinical practice procedures at each institution. In general, the follow-up consisted of abdominopelvic CT every 6 months for 5 years after surgery and EGD annually for 5 years after surgery. Cancer recurrence was defined as positive radiological evidence of recurrence. Outcome data
Personal characteristics and clinical data All characteristics of the patients were obtained from a review of the medical records. Demographic characteristics included age, sex, and body mass index. Clinicopathological characteristics included tumor location, tumor size, differentiation, gross type, depth of invasion, lymphatic invasion, lymph node metastasis, stage at diagnosis, and operation method. Stage at diagnosis was determined with adherence to the sixth edition of the Union International Centre Cancer (UICC)/American Joint Committee on Cancer (AJCC) classification system [12]. In patients with multiple synchronous gastric cancers, the lesion with the deepest infiltration of the gastric wall was regarded as the
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The primary end points of the study were death and tumor recurrence. Death was defined as death from any cause. Peritoneal recurrences were defined as carcinomatosis or ovarian metastasis. The other metastases were defined as lymph node recurrence outside the lymph node dissection field, liver metastases, or metastases at other extra-abdominal sites without other sites of malignancy. All cases of recurrence were documented pathologically and/or by radiologic imaging. Morbidity was defined as complications that required extended hospital stay or readmission. Morbidity was classified according to the Clavien-Dindo classification [14].
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Statistical methods and analyses Continuous variables were compared by using the t test or Wilcoxon rank-sum test, and categorical variables were compared by using the x2 test or Fisher’s exact test, as was appropriate. To reduce the effect of treatment-selection bias and potential confounding, we adjusted for significant differences in the patients’ baseline characteristics with propensity-score matching [15]. For generating the propensity score, a multiple logistic regression model was employed. The dependent variable was the treatment received, and the variables included in the multivariate model were age, sex, differentiation and depth of tumor invasion, size, and the presence of lymphatic invasion. Using the SAS Greedy 5 ? 1 digit match macro, we created propensityscore-matched pairs without replacement (1:1 match). After all the propensity-score matches were performed, we compared the baseline covariates of the LADG and ODG groups by using the random-effects models with matched-pair effects as random. Statistical significance and the effect of treatment on the outcomes were estimated by using the appropriate statistical methods for the matched data. In the propensity-score-matched cohort, continuous variables were compared using the mixed linear model, and categorical variables were compared using the conditional logistic regression. The risks of death, recurrence, and metachronous gastric cancer were compared by Cox proportional hazards’ regression models with robust standard errors that accounted for the clustering of matched pairs. The proportional hazards’ assumption was confirmed by examination of log [-log (survival)] curves, and no relevant violations were found. The follow-up of patients was completed until death or until the cutoff date of December 31, 2012. At the time of the last follow-up, 14 patients (0.6 %) had been lost to follow-up. The median follow-up interval for patients alive at the cutoff date was 71 months (range 1–120 months). The lost cases and operative mortality cases were treated as censored. Overall survival (OS) was defined as the time from surgery to death from any cause. In addition, recurrence-free survival (RFS) was defined as the time from surgery to tumor recurrence, death with evidence of recurrence, or occurrence of a new primary gastric tumor. For RFS, patients who died without known tumor recurrence were censored at the last documented evaluation.
Results Patient characteristics of the study population A total of 2410 patients after the propensity-score matching was performed were included in this study. The clinical
and pathological characteristics of the tumors are shown in Table 1. The median age was 57 years, and approximately 59.8 % of the patients were men. The major location of the gastric cancers was in the lower one-third of the stomach (61.8 %). There were no significant differences in the baseline characteristics between the ODG and LADG groups.
Effect of the operation method on short-term outcomes The number of dissected lymph nodes was similar in both groups (Table 2). The proportion of patients with less than 15 lymph nodes retrieved was not different between the two groups. Morbidities were more found in the LADG group (Table 2). The most common complication in the ODG group was wound infection (11 patients, 0.9 %) followed by wound dehiscence (4 patients, 0.3 %). Intra-abdominal or anastomotic bleeding (19 patients, 1.6 %) was the most common complication in the LADG group followed by anastomotic leakage (9 patients, 0.7 %). Grade III or more complications, which required surgical intervention or were life-threatening, were similar between the two groups (1.7 vs. 2.2 %, P = 0.052). There were no postoperative mortalities in either group.
Effect of the operation method on the long-term outcomes The median follow-up period was 59 months [inter-quartile range (IQR) 46–78 months] for the ODG group and 53 months (IQR 42–68 months) for the LADG group. During follow-up, 104 patients from the two groups (4.3 %) died. In the two groups, thirty-three patients experienced recurrences (Table 2). The rate or the patterns of recurrence were not different between the two groups. Liver metastases were the most common form of recurrence followed by distant lymph node metastases in both groups (Table 3). Figure 1 shows the risk of death for this matched cohort. The risk of death did not differ significantly between the ODG and LADG groups (hazard ratio [HR] for the LADG group was 0.990; 95 % CI 0.675–1.453, P = 0.960). The 5-year OS rates were 98.7 % in the ODG group and 98.4 % in the LADG group. There was no significant difference in the risk of recurrence during the follow-up period (HR 0.989; 95 % CI 0.480–2.038, P = 0.977) (Fig. 2). The 5-year RFS rates were 99.7 % in the ODG group and 99.9 % in the LADG group.
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Surg Endosc Table 1 Baseline characteristics of the propensity-score-matched patients (1:1 matching) Variables
Matched cohort (N = 2410)
Demographic characteristics
Open group (n = 1205)
Laparoscopy group (n = 1205)
56.5 (12.0)
56.5 (12.0)
Age Mean [years (SD)] Median [years (range)] Male sex [no. (%)]
0.933 57 (23–84) 721 (59.8)
58 (23–84) 721 (59.8)
Body mass index (kg/m2) Mean (SD) Median (range) Tumor characteristics
P value
1.000 0.482
23.7 (3.0)
23.6 (3.0)
23.6 (15–37)
23.6 (15–37) 0.675
Location [no. (%)] Mid 1/3
455 (37.8)
465 (38.6)
Low 1/3
750 (62.2)
740 (61.4)
Mean [cm (SD)]
2.7 (1.6)
2.6 (1.5)
Median [cm (range)]
2.4 (0.1–9.0)
2.4 (0.1–16)
Differentiated
596 (49.5)
585 (49.5)
Undifferentiated
609 (50.5)
620 (51.5)
49 (4.1)
47 (3.9)
1128 (93.6)
1124 (93.3)
Size
0.105
Histology [no. (%)]
0.654
Morphology [no. (%)] Elevated Flat Depressed
0.730
28 (2.3)
34 (2.8)
1107 (91.9)
1107 (91.9)
Mucosa
767 (63.7)
767 (63.7)
Submucosa
438 (36.3)
438 (33.6)
47 (3.9)
53 (4.4)
No lymphovascular invasion [no. (%)] Depth of tumor invasion [no. (%)]
Lymph node metastasis Yes
1.000 1.000
0.540
Table 2 Short-term surgical outcomes after open and laparoscopic surgery among the propensity-score-matched patients Outcomes
Matched cohort (N = 2410) Open group (n = 1205)
Laparoscopy group (n = 1205)
36.4 (14.1)
36.0 (13.6)
Number of dissected lymph nodes, no. Mean (SD)
0.475
Median (range)
35 (4-103)
35 (3-100)
\15 of dissected lymph nodes (%)
29 (2.4)
39 (3.2)
Complications None
0.217 0.045
1150 (95.4)
1124 (93.3)
I
16 (1.3)
13 (1.1)
II
19 (1.6)
41 (3.4)
III
19 (1.6)
26 (2.1)
IV
1 (0.1)
1 (0.1)
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P value
Surg Endosc Table 3 Long-term outcomes after open and laparoscopic surgery among the propensityscore-matched patients
Outcomes
Matched cohort (N = 2410) Open group (n = 1205)
Laparoscopy group (n = 1205)
P value
Death [no. (%)]
55 (4.6)
49 (4.1)
0.805
Recurrence [no. (%)]
19 (1.6)
14 (1.2)
0.681
Site of recurrence Peritoneum
0.669 0
Liver
7 (0.6)
Distant lymph node
4 (0.3)
Lung
1 (0.1)
0 5 (0.4) 0 2 (0.2)
Bone
1 (0.1)
1 (0.1)
Operation bed
1 (0.1)
1 (0.1)
Spleen
1 (0.1)
1 (0.1)
Others
2 (0.2)
3 (0.2)
Fig. 1 Kaplan–Meier curve for the probability of death after open or laparoscopy assisted distal gastrectomy. The risk of death did not differ significantly between the ODG and LADG groups [hazard ratio (HR) for the LADG group was 0.990; 95 % CI 0.675–1.453, P = 0.960]. The 5-year overall survival rates were 98.7 % in the ODG group and 98.4 % in the LADG group, respectively
Discussion In this study, we compared the long-term results of patients with EGC after ODG and LADG. The main findings of the present study are as follows: (1) the OS and RFS after ODG and LADG are similar, and (2) the short-term surgical outcomes including the number of dissected lymph nodes and grade III or more complications were similar in both groups. Some investigators have reported that the survival of patients who have undergone LADG is not inferior to that
of patients who have undergone ODG [9–11]. However, those studies were limited by the numbers of included patients and by baseline differences between the ODG and LADG groups. To minimize the effect of selection bias, we adjusted for significant differences in patient baseline characteristics by propensity-score matching [14]. A recent study that compared long-term outcomes of LADG with those of ODG showed that OS rates were not significantly different between groups [11]. Kim et al. performed a retrospective study comparing LADG with ODG for gastric cancer by propensity-score matching
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Surg Endosc Fig. 2 Kaplan–Meier curve for the probability of recurrence after open or laparoscopy assisted distal gastrectomy. There was no significant difference in the risk of recurrence during the follow-up period [HR 0.989; 95 % CI 0.480–2.038, P = 0.977]. The 5-year recurrence-free survival rates were 99.7 % in the ODG group and 99.9 % in the LADG group, respectively
analysis. The authors found that 5-year OS rates were not significantly different between the LADG group and the surgery group. However, this study had several limitations. First, the proportion of EGC was less than 75 % in the both groups. Therefore, a large number of patients did not meet the current indication criteria for LADG. Second, this study included patients who received laparoscopy assisted total gastrectomy, which is a different type of surgery from LADG. A large-scale single-arm study on patients after LADG from Japan showed similar long-term outcomes with this study [15]. Kitano et al. showed that the 5-year DFS rate was more than 98 %. The reason for the good prognoses after LADG might be the lower rate of lymph node metastasis in patients after LADG. The presence of lymph node metastasis is the most important prognostic factor in patients with early gastric cancer. The rate of lymph node metastasis after LADG in this study and in the Japanese study was 4.1 and 6.1 %, respectively. This rate of lymph node metastasis is similar to that of mucosa cancer and the 5-year OS rate of patients with mucosa cancer, which have been reported to be approximately 92 % [16, 17]. In the early period of this study, surgeons performing LADG were still in the learning period in most hospitals, and thus, there might have been patient selection for LADG. Our study showed a higher rate of recurrence after surgery compared with that in Japanese studies, which may
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due to the longer follow-up period of this study. The median follow-up period of our study was 71 months, while the median follow-up period of the Japanese study was 36 months. However, the pattern of recurrence was consistent with that from previous studies [18, 19]. Liver metastases were the most common form of recurrence in this study. Postoperative complications were more common in the LADG group than the ODG group in this study. Most investigators have reported a lower rate of morbidities in the LADG group than those in the ODG group [20, 21]. This discrepancy might be due to different experiences with laparoscopic surgery. Most surgeons in Korea started LADG in early 2000, so as a result, outcomes when the learning period was still undergoing were included in this study. However, surgeons included in this study performed thousands of open gastrectomies. In spite of that, we found that the complications of grade III or higher were not different between the two groups. Although all patients in this study underwent D1 ? b or more lymph node dissection, the median number of retrieved lymph nodes was more than 35 and the proportion of patients with less than 15 dissected lymph nodes was 3.2 % in the LADG group and 2.4 % in the ODG group. More than 25 lymph nodes retrieved might be regarded as D2 lymph node dissection, and for proper TNM staging, more than 15 lymph nodes is needed [12, 22]. Therefore,
Surg Endosc
the surgical quality of LADG was not inferior compared with ODG in terms of the oncological outcome. The major limitation of this study is that it was a retrospective study, and as such, the treatment strategy was not based on random assignment. In other words, selection bias for choosing the treatment modality might have occurred in spite of the use of a propensity-matching cohort. Another limitation of this study was that we analyzed data from high-volume centers in Korea. The inclusion of data from high-volume centers might have influenced the results. According to our results, LADG was not inferior compared to ODG in terms of the surgical quality and the longterm outcomes. Laparoscopy assisted distal gastrectomy for patients with early gastric cancer is feasible in terms of survival. Disclosures Jun Ho Lee, Byung-Ho Nam, Keun Won Ryu, Seong Yeop Ryu, Young Woo Kim, Young Kyu Park, and Sung Kim have no conflicts of interest, financial or otherwise.
References 1. Murakami T (1971) Pathomorphological diagnosis. Definition and gross classification of early gastric cancer. Gann Monogr Cancer Res 11:53–55 2. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ (2010) Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1 D2 trial. Lancet Oncol 11:439–449 3. Sasako M, Sano T, Yamamoto S, Kurokawa Y, Nashimoto A, Kurita A, Hiratsuka M, Tsujinaka T, Kinoshita T, Arai K, Yamamura Y, Okajima K, Japa Clinical Oncology Group (2008) D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med 359:453–462 4. Japanese Gastric Cancer Association (2011) Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 14:113–123 5. Ohashi S (1995) Laparoscopic intraluminal (intragastric) surgery for early gastric cancer. A new concept in laparoscopic surgery. Surg Endosc 9:169–171 6. Watson DI, Devitt PG, Game PA (1995) Laparoscopic Billroth II gastrectomy for early gastric cancer. Br J Surg 82:661–662 7. Nagai Y, Tanimura H, Takifuji K, Kashiwagi H, Yamoto H, Nakatani Y (1995) Laparoscope-assisted Billroth I gastrectomy. Surg Laparosc Endosc 5:281–287 8. Kim YW, Baik YH, Yun YH, Nam BH, Kim DH, Choi IJ, Bae JM (2008) Improved quality of life outcomes after laparoscopyassisted distal gastrectomy for early gastric cancer: results of a prospective randomized clinical trial. Ann Surg 248:721–727
9. Fujiwara M, Kodera Y, Misawa K, Kinoshita M, Kinoshita T, Miura S, Ohashi N, Nakayama G, Koike M, Nakao A (2008) Long term outcomes of early-stage gastric carcinoma patients treated with laparoscopy-assisted surgery. J Am Coll Surg 206:138–143 10. Strong VE, Devaud N, Allen PJ, Gonen M, Brennan MF, Coit D (2009) Laparoscopic versus open subtotal gastrectomy for adenocarcinoma: a case-control study. Ann Surg Oncol 16:1507–1513 11. Kim HH, Han SU, Kim MC, Hyung WJ, Kim W, Lee HJ, Ryu SW, Cho GS, Song KY, Ryu SY (2014) Long-term results of laparoscopic gastrectomy for gastric cancer: a large-scale case control and case-matched Korean multicenter study. J Clin Oncol 32:627–633 12. Sobin LH, Wittekind C (2002) International Union Against Cancer (UICC) TNM classification of malignant tumours, 6th edn. Wiley-Liss, New York, pp 65–68 13. Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, de Satibanes E, Pekoli J, Slankmenac K, Bassi C, Graf R, Vonlanthen R, Padbury R, Cameron JL, Makuuchi M (2009) The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 250:187–196 14. D’Agostino RB Jr (1998) Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 17:2265–2281 15. Kitano S, Shiraishi N, Uyama I, Sugihara K, Tanikawa N, Japanese Laparoscopic Surgery Study Group (2007) A multicenter study on oncologic outcome of laparoscopic gastrectomy for early cancer in Japan. Ann Surg 245:68–72 16. Ho¨lscher AH, Drebber U, Mo¨nig SP, Schulte C, Vallbo¨hmer D, Bollschweiler E (2009) Early gastric cancer: lymph node metastasis starts with deep mucosal infiltration. Ann Surg 250:791–797 17. Moreaux J, Bougaran J (1993) Early gastric cancer. A 25-year surgical experience. Ann Surg 217:347–355 18. Lai JF, Kim S, Kim K, Li C, Oh SJ, Hyung WJ, Rha SY, Chung HC, Choi SH, Wang LB, Noh SH (2009) Prediction of recurrence of early gastric cancer after curative resection. Ann Surg Oncol 16:1896–1902 19. Ikeda Y, Saku M, Kishihara F, Maehara Y (2005) Effective follow-up for recurrence or a second primary cancer in patients with early gastric cancer. Br J Surg 92:235–239 20. Kim HH, Hyung WJ, Cho GS, Kim MC, Han SU, Kim W, Ryu SW, Lee HJ, Song KY (2010) Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: an interim report-a phase III multicenter, prospective, randomized Trial (KLASS Trial). Ann Surg 251:417–420 21. Lee JH, Park do J, Kim HH, Lee HJ, Yang HK (2012) Comparison of complications after laparoscopy-assisted distal gastrectomy and open distal gastrectomy for gastric cancer using the Clavien-Dindo classification. Surg Endosc 26:1287–1295 22. Siewert JR, Bottcher K, Stein HJ, Roder JD (1998) Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 228:449–461
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and Other Interventional Techniques
Comparison of the long-term results of patients who underwent laparoscopy versus open distal gastrectomy Jun Ho Lee1 • Byung-Ho Nam2 • Keun Won Ryu3 • Seong Yeop Ryu4 Young Woo Kim3 • Young Kyu Park4 • Sung Kim1
•
Received: 12 December 2014 / Accepted: 6 April 2015 Ó Springer Science+Business Media New York 2015
Abstract Background Survival data of patients who underwent laparoscopy assisted distal gastrectomy (LADG) compared with those of patients who underwent open distal gastrectomy (ODG) for gastric cancer are rarely presented. We compared long-term outcomes of LADG with those of ODG in patients with EGC who met the current indication for LADG. Methods A total of 2410 patients with early gastric cancer who underwent curative-intent gastric cancer surgery in three Korean tertiary hospitals between January 2003 and June 2009 were included in this multicenter, retrospective, propensity-score-matched cohort study. Cox proportional hazard regression models were used to evaluate the association between operation methods and survival. Results In the matched cohort, there were no significant differences in overall survival [hazard ratio (HR) for the LADG group 0.990; 95 % confidence interval (CI) 0.675–1.453] or recurrence-free survival (HR 0.989; 95 % CI 0.480–2.038). The patterns of recurrence were not different between the two groups. The most common pattern & Jun Ho Lee [email protected] Sung Kim [email protected] 1
Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea
2
Center for Clinical Trial, National Cancer Center, Goyang, Korea
3
Center for Gastric Cancer, National Cancer Center, Goyang, Korea
4
Department of Surgery, Chunnam National University Whasoon Hospital, Gwangjoo, Korea
of recurrence was liver metastasis followed by metastasis to distant lymph nodes. The rate of complications in the LADG group was higher than that of the ODG group (6.7 vs. 4.6 %, P = 0.045). Grade III or worse complications that required surgical intervention or were life-threatening showed a marginal difference between the two groups (1.7 vs. 2.2 %, P = 0.052). There were no postoperative mortalities in either group. Conclusion Laparoscopy assisted distal gastrectomy for patients with early gastric cancer is feasible in terms of the long-term results including survival and recurrence. Keywords Gastric cancer Laparoscopy Subtotal gastrectomy Abbreviations LADG Laparoscopy assisted distal gastrectomy ODG Open distal gastrectomy HR Hazard ratio RFS Recurrence-free survival
Early gastric cancer (EGC) is defined as gastric cancer in which tumor invasion is limited to the mucosa or submucosa, regardless of lymph node metastasis [1]. D2 lymph node dissection is recommended for patients with advanced gastric cancer [2, 3], whereas for patients with EGC, less than D2 lymph node dissection is recommended because EGC rarely metastasizes to extra-perigastric lymph nodes [4]. Laparoscopy assisted distal gastrectomy (LADG) has been used for the treatment of patients with EGC since 1990 [5–7]. LADG is safe, and the quality of life of patients has been reported to be superior to that of patients
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who undergo open distal gastrectomy (ODG) [8]. As advances have been made in laparoscopic instruments and the surgeons have accumulated experience with laparoscopic surgery, LADG has become a widespread treatment option for patients with EGC. The most important outcome of cancer surgery is survival. Some investigators have reported that the survival of patients who have undergone LADG is not inferior to that of patients who have undergone ODG [9–11]. However, past studies had limitations, including small sample sizes or inclusion of advanced tumors which did not meet the current indication of LADG. LADG for advanced tumor is an investigational treatment; there are little data supporting whether D2 lymph node dissection is feasible during LADG [12]. Thus, the aim of the present study was to investigate whether long-term outcomes from LADG are comparable to those from ODG for EGC.
Patients and methods Study cohort and data sources The study cohort consisted of patients with gastric cancer who were treated by open or laparoscopic gastric cancer surgery between January 2003 and June 2006 at one of three institutions in Korea: Chunnam Whasoon Hospital, National Cancer Center, and Samsung Medical Center. Patients who (i) had a histologically confirmed gastric adenocarcinoma, (ii) had a mucosa or submucosa tumor, and (iii) had newly diagnosed cancer without previous treatment were included in the analysis. Patients who had another cancer or a tumor located in the upper one-third of the stomach that needed total gastrectomy were excluded. All information was obtained with the appropriate Institutional Review Board waivers, and the data were collected without revealing any personal information.
main lesion and all others were regarded as accessory lesions. The clinicopathological characteristics of the main lesion were used for the analysis.
Operative procedures The indications of LADG were patients with early gastric cancer according to the preoperative examinations including esophagogastroduodenoscopy (EGD) and abdominopelvic computed tomogram (CT). The surgical procedures and reconstruction methods were as follows. Gastrectomy was performed if the tumor-free margin was 2 cm. The extent of lymph node dissection was determined using recommendations of the Japanese Research Society for Gastric Carcinoma [4]. After the laparotomy or laparoscopy, the surgeons examined the intra-abdominal cavities and inspected the peritoneum, diaphragm, liver capsule, and pelvic cavity. All patients enrolled in the present study underwent gastrectomy with D1 ? b or more lymph node dissection [4]. Tumors were staged in accordance with the sixth UICC/AJCC tumor node metastasis (TNM) classification [13].
Follow-up schedule The follow-up schedule and discharge plan were not standardized among three institutions. However, most patients with early gastric cancer were followed up as follows, and the patients were discharged after soft diet was possible. The patients’ follow-up was conducted according to the accepted clinical practice procedures at each institution. In general, the follow-up consisted of abdominopelvic CT every 6 months for 5 years after surgery and EGD annually for 5 years after surgery. Cancer recurrence was defined as positive radiological evidence of recurrence. Outcome data
Personal characteristics and clinical data All characteristics of the patients were obtained from a review of the medical records. Demographic characteristics included age, sex, and body mass index. Clinicopathological characteristics included tumor location, tumor size, differentiation, gross type, depth of invasion, lymphatic invasion, lymph node metastasis, stage at diagnosis, and operation method. Stage at diagnosis was determined with adherence to the sixth edition of the Union International Centre Cancer (UICC)/American Joint Committee on Cancer (AJCC) classification system [12]. In patients with multiple synchronous gastric cancers, the lesion with the deepest infiltration of the gastric wall was regarded as the
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The primary end points of the study were death and tumor recurrence. Death was defined as death from any cause. Peritoneal recurrences were defined as carcinomatosis or ovarian metastasis. The other metastases were defined as lymph node recurrence outside the lymph node dissection field, liver metastases, or metastases at other extra-abdominal sites without other sites of malignancy. All cases of recurrence were documented pathologically and/or by radiologic imaging. Morbidity was defined as complications that required extended hospital stay or readmission. Morbidity was classified according to the Clavien-Dindo classification [14].
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Statistical methods and analyses Continuous variables were compared by using the t test or Wilcoxon rank-sum test, and categorical variables were compared by using the x2 test or Fisher’s exact test, as was appropriate. To reduce the effect of treatment-selection bias and potential confounding, we adjusted for significant differences in the patients’ baseline characteristics with propensity-score matching [15]. For generating the propensity score, a multiple logistic regression model was employed. The dependent variable was the treatment received, and the variables included in the multivariate model were age, sex, differentiation and depth of tumor invasion, size, and the presence of lymphatic invasion. Using the SAS Greedy 5 ? 1 digit match macro, we created propensityscore-matched pairs without replacement (1:1 match). After all the propensity-score matches were performed, we compared the baseline covariates of the LADG and ODG groups by using the random-effects models with matched-pair effects as random. Statistical significance and the effect of treatment on the outcomes were estimated by using the appropriate statistical methods for the matched data. In the propensity-score-matched cohort, continuous variables were compared using the mixed linear model, and categorical variables were compared using the conditional logistic regression. The risks of death, recurrence, and metachronous gastric cancer were compared by Cox proportional hazards’ regression models with robust standard errors that accounted for the clustering of matched pairs. The proportional hazards’ assumption was confirmed by examination of log [-log (survival)] curves, and no relevant violations were found. The follow-up of patients was completed until death or until the cutoff date of December 31, 2012. At the time of the last follow-up, 14 patients (0.6 %) had been lost to follow-up. The median follow-up interval for patients alive at the cutoff date was 71 months (range 1–120 months). The lost cases and operative mortality cases were treated as censored. Overall survival (OS) was defined as the time from surgery to death from any cause. In addition, recurrence-free survival (RFS) was defined as the time from surgery to tumor recurrence, death with evidence of recurrence, or occurrence of a new primary gastric tumor. For RFS, patients who died without known tumor recurrence were censored at the last documented evaluation.
Results Patient characteristics of the study population A total of 2410 patients after the propensity-score matching was performed were included in this study. The clinical
and pathological characteristics of the tumors are shown in Table 1. The median age was 57 years, and approximately 59.8 % of the patients were men. The major location of the gastric cancers was in the lower one-third of the stomach (61.8 %). There were no significant differences in the baseline characteristics between the ODG and LADG groups.
Effect of the operation method on short-term outcomes The number of dissected lymph nodes was similar in both groups (Table 2). The proportion of patients with less than 15 lymph nodes retrieved was not different between the two groups. Morbidities were more found in the LADG group (Table 2). The most common complication in the ODG group was wound infection (11 patients, 0.9 %) followed by wound dehiscence (4 patients, 0.3 %). Intra-abdominal or anastomotic bleeding (19 patients, 1.6 %) was the most common complication in the LADG group followed by anastomotic leakage (9 patients, 0.7 %). Grade III or more complications, which required surgical intervention or were life-threatening, were similar between the two groups (1.7 vs. 2.2 %, P = 0.052). There were no postoperative mortalities in either group.
Effect of the operation method on the long-term outcomes The median follow-up period was 59 months [inter-quartile range (IQR) 46–78 months] for the ODG group and 53 months (IQR 42–68 months) for the LADG group. During follow-up, 104 patients from the two groups (4.3 %) died. In the two groups, thirty-three patients experienced recurrences (Table 2). The rate or the patterns of recurrence were not different between the two groups. Liver metastases were the most common form of recurrence followed by distant lymph node metastases in both groups (Table 3). Figure 1 shows the risk of death for this matched cohort. The risk of death did not differ significantly between the ODG and LADG groups (hazard ratio [HR] for the LADG group was 0.990; 95 % CI 0.675–1.453, P = 0.960). The 5-year OS rates were 98.7 % in the ODG group and 98.4 % in the LADG group. There was no significant difference in the risk of recurrence during the follow-up period (HR 0.989; 95 % CI 0.480–2.038, P = 0.977) (Fig. 2). The 5-year RFS rates were 99.7 % in the ODG group and 99.9 % in the LADG group.
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Surg Endosc Table 1 Baseline characteristics of the propensity-score-matched patients (1:1 matching) Variables
Matched cohort (N = 2410)
Demographic characteristics
Open group (n = 1205)
Laparoscopy group (n = 1205)
56.5 (12.0)
56.5 (12.0)
Age Mean [years (SD)] Median [years (range)] Male sex [no. (%)]
0.933 57 (23–84) 721 (59.8)
58 (23–84) 721 (59.8)
Body mass index (kg/m2) Mean (SD) Median (range) Tumor characteristics
P value
1.000 0.482
23.7 (3.0)
23.6 (3.0)
23.6 (15–37)
23.6 (15–37) 0.675
Location [no. (%)] Mid 1/3
455 (37.8)
465 (38.6)
Low 1/3
750 (62.2)
740 (61.4)
Mean [cm (SD)]
2.7 (1.6)
2.6 (1.5)
Median [cm (range)]
2.4 (0.1–9.0)
2.4 (0.1–16)
Differentiated
596 (49.5)
585 (49.5)
Undifferentiated
609 (50.5)
620 (51.5)
49 (4.1)
47 (3.9)
1128 (93.6)
1124 (93.3)
Size
0.105
Histology [no. (%)]
0.654
Morphology [no. (%)] Elevated Flat Depressed
0.730
28 (2.3)
34 (2.8)
1107 (91.9)
1107 (91.9)
Mucosa
767 (63.7)
767 (63.7)
Submucosa
438 (36.3)
438 (33.6)
47 (3.9)
53 (4.4)
No lymphovascular invasion [no. (%)] Depth of tumor invasion [no. (%)]
Lymph node metastasis Yes
1.000 1.000
0.540
Table 2 Short-term surgical outcomes after open and laparoscopic surgery among the propensity-score-matched patients Outcomes
Matched cohort (N = 2410) Open group (n = 1205)
Laparoscopy group (n = 1205)
36.4 (14.1)
36.0 (13.6)
Number of dissected lymph nodes, no. Mean (SD)
0.475
Median (range)
35 (4-103)
35 (3-100)
\15 of dissected lymph nodes (%)
29 (2.4)
39 (3.2)
Complications None
0.217 0.045
1150 (95.4)
1124 (93.3)
I
16 (1.3)
13 (1.1)
II
19 (1.6)
41 (3.4)
III
19 (1.6)
26 (2.1)
IV
1 (0.1)
1 (0.1)
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P value
Surg Endosc Table 3 Long-term outcomes after open and laparoscopic surgery among the propensityscore-matched patients
Outcomes
Matched cohort (N = 2410) Open group (n = 1205)
Laparoscopy group (n = 1205)
P value
Death [no. (%)]
55 (4.6)
49 (4.1)
0.805
Recurrence [no. (%)]
19 (1.6)
14 (1.2)
0.681
Site of recurrence Peritoneum
0.669 0
Liver
7 (0.6)
Distant lymph node
4 (0.3)
Lung
1 (0.1)
0 5 (0.4) 0 2 (0.2)
Bone
1 (0.1)
1 (0.1)
Operation bed
1 (0.1)
1 (0.1)
Spleen
1 (0.1)
1 (0.1)
Others
2 (0.2)
3 (0.2)
Fig. 1 Kaplan–Meier curve for the probability of death after open or laparoscopy assisted distal gastrectomy. The risk of death did not differ significantly between the ODG and LADG groups [hazard ratio (HR) for the LADG group was 0.990; 95 % CI 0.675–1.453, P = 0.960]. The 5-year overall survival rates were 98.7 % in the ODG group and 98.4 % in the LADG group, respectively
Discussion In this study, we compared the long-term results of patients with EGC after ODG and LADG. The main findings of the present study are as follows: (1) the OS and RFS after ODG and LADG are similar, and (2) the short-term surgical outcomes including the number of dissected lymph nodes and grade III or more complications were similar in both groups. Some investigators have reported that the survival of patients who have undergone LADG is not inferior to that
of patients who have undergone ODG [9–11]. However, those studies were limited by the numbers of included patients and by baseline differences between the ODG and LADG groups. To minimize the effect of selection bias, we adjusted for significant differences in patient baseline characteristics by propensity-score matching [14]. A recent study that compared long-term outcomes of LADG with those of ODG showed that OS rates were not significantly different between groups [11]. Kim et al. performed a retrospective study comparing LADG with ODG for gastric cancer by propensity-score matching
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Surg Endosc Fig. 2 Kaplan–Meier curve for the probability of recurrence after open or laparoscopy assisted distal gastrectomy. There was no significant difference in the risk of recurrence during the follow-up period [HR 0.989; 95 % CI 0.480–2.038, P = 0.977]. The 5-year recurrence-free survival rates were 99.7 % in the ODG group and 99.9 % in the LADG group, respectively
analysis. The authors found that 5-year OS rates were not significantly different between the LADG group and the surgery group. However, this study had several limitations. First, the proportion of EGC was less than 75 % in the both groups. Therefore, a large number of patients did not meet the current indication criteria for LADG. Second, this study included patients who received laparoscopy assisted total gastrectomy, which is a different type of surgery from LADG. A large-scale single-arm study on patients after LADG from Japan showed similar long-term outcomes with this study [15]. Kitano et al. showed that the 5-year DFS rate was more than 98 %. The reason for the good prognoses after LADG might be the lower rate of lymph node metastasis in patients after LADG. The presence of lymph node metastasis is the most important prognostic factor in patients with early gastric cancer. The rate of lymph node metastasis after LADG in this study and in the Japanese study was 4.1 and 6.1 %, respectively. This rate of lymph node metastasis is similar to that of mucosa cancer and the 5-year OS rate of patients with mucosa cancer, which have been reported to be approximately 92 % [16, 17]. In the early period of this study, surgeons performing LADG were still in the learning period in most hospitals, and thus, there might have been patient selection for LADG. Our study showed a higher rate of recurrence after surgery compared with that in Japanese studies, which may
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due to the longer follow-up period of this study. The median follow-up period of our study was 71 months, while the median follow-up period of the Japanese study was 36 months. However, the pattern of recurrence was consistent with that from previous studies [18, 19]. Liver metastases were the most common form of recurrence in this study. Postoperative complications were more common in the LADG group than the ODG group in this study. Most investigators have reported a lower rate of morbidities in the LADG group than those in the ODG group [20, 21]. This discrepancy might be due to different experiences with laparoscopic surgery. Most surgeons in Korea started LADG in early 2000, so as a result, outcomes when the learning period was still undergoing were included in this study. However, surgeons included in this study performed thousands of open gastrectomies. In spite of that, we found that the complications of grade III or higher were not different between the two groups. Although all patients in this study underwent D1 ? b or more lymph node dissection, the median number of retrieved lymph nodes was more than 35 and the proportion of patients with less than 15 dissected lymph nodes was 3.2 % in the LADG group and 2.4 % in the ODG group. More than 25 lymph nodes retrieved might be regarded as D2 lymph node dissection, and for proper TNM staging, more than 15 lymph nodes is needed [12, 22]. Therefore,
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the surgical quality of LADG was not inferior compared with ODG in terms of the oncological outcome. The major limitation of this study is that it was a retrospective study, and as such, the treatment strategy was not based on random assignment. In other words, selection bias for choosing the treatment modality might have occurred in spite of the use of a propensity-matching cohort. Another limitation of this study was that we analyzed data from high-volume centers in Korea. The inclusion of data from high-volume centers might have influenced the results. According to our results, LADG was not inferior compared to ODG in terms of the surgical quality and the longterm outcomes. Laparoscopy assisted distal gastrectomy for patients with early gastric cancer is feasible in terms of survival. Disclosures Jun Ho Lee, Byung-Ho Nam, Keun Won Ryu, Seong Yeop Ryu, Young Woo Kim, Young Kyu Park, and Sung Kim have no conflicts of interest, financial or otherwise.
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