Ann Surg Oncol DOI 10.1245/s10434-014-4172-x
ORIGINAL ARTICLE – COLORECTAL CANCER
Laparoscopic Versus Open Surgery for Colorectal Cancer in Elderly Patients: A Multicenter Matched Case–Control Study Takao Hinoi, MD, PhD1, Yasuo Kawaguchi, MD2, Minoru Hattori, PhD1, Masazumi Okajima, MD, PhD3, Hideki Ohdan, MD, PhD1, Seiichiro Yamamoto, MD, PhD4, Hirotoshi Hasegawa, MD, PhD5, Hisanaga Horie, MD, PhD6, Kohei Murata, MD, PhD7, Shigeki Yamaguchi, MD, PhD8, Kenichi Sugihara, MD, PhD9, Masahiko Watanabe, MD, PhD10 and the Japan Society of Laparoscopic Colorectal Surgery 1
Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; 2Department of Surgery, Tsuchiya General Hospital, Hiroshima, Japan; 3 Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan; 4Department of Surgery, Hiratsuka City Hospital, Kanagawa, Japan; 5Department of Surgery, Keio University School of Medicine, Tokyo, Japan; 6 Department of Surgery, Jichi Medical University, Shimotsuke, Japan; 7Department of Surgery, Suita Municipal Hospital, Osaka, Japan; 8Department of Gastroenterological Surgery, Saitama Medical University International Medical Center, Saitama, Japan; 9Department of Surgical Oncology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan; 10 Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan
ABSTRACT Background. The safety of laparoscopic surgery (LAP) in elderly patients with colorectal cancer has not been demonstrated. The aim of this study was to compare the outcomes of LAP and open surgery (OP) and estimate the feasibility of LAP in colorectal cancer patients aged C80 years. Methods. We conducted a propensity scoring matched case–control study of colon and rectal cancer patients aged C80 years using data from 41 hospitals between 2003 and 2007. A total of 1,526 colon cancer patients and 282 rectal cancer patients underwent surgery and were included in the analysis. The primary end point was 3-year overall survival (OS). Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), and postoperative complications. Results. LAP and OP were compared in 804 colon cancer patients (402 pairs) and 114 rectal cancer patients (57 pairs) after all covariates were balanced, and no significant differences were observed, except for tumor size in colon
Ó Society of Surgical Oncology 2014 First Received: 16 December 2013 T. Hinoi, MD, PhD e-mail: [email protected]
cancer. OS, DFS, and CSS did not differ between the groups for either colon cancer (P = 0.916, 0.968, and 0.799, respectively) or rectal cancer (P = 0.765, 0.519, and 0.950, respectively). In colon cancer cases, LAP was associated with fewer morbidities than was OP (24.9 vs. 36.3 %, P \ 0.001); no such difference was observed for rectal cancer patients (47.4 vs. 40.4 %, P = 0.450). Conclusions. LAP is an acceptable alternative to OP in elderly patients with colorectal cancer.
Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide, and it is the second leading cause of cancer-related deaths in many developed countries.1 The incidence of colorectal cancers that necessitate surgical intervention continues to increase because of the prolonged life expectancy in most countries.2 Several studies have reported that in colorectal cancer cases, laparoscopic surgery (LAP) shows comparable oncologic results and improved short-term outcomes compared to open surgery (OP).3–10 However, postoperative morbidities and mortalities increase with age in older patients.11–15 Therefore, surgery needs to be modified for geriatric patients. Thus far, it remains unclear whether elderly patients respond to LAP as they do to OP. Because of this uncertainty, investigators have been unwilling to include frail patients in randomized studies, and no study has investigated the
T. Hinoi et al.
feasibility of LAP in a large cohort of elderly patients with colorectal cancer. Hence, the important issue of whether the laparoscopic approach can serve as well as OP in elderly patients with colorectal cancer remains to be elucidated. In this study, we compared the surgical outcomes between elderly patients with colorectal cancer who underwent either LAP or OP and assessed whether LAP is an acceptable alternative to OP. Moreover, we evaluated the results to determine whether the survival data justify the implementation of laparoscopic techniques in geriatric oncology. METHODS Study Design and Participants We conducted a matched case–control study by using data from 41 hospitals that are members of the Japan Society of Laparoscopic Colorectal Surgery. To be included in the study, patients were required to have a clinical diagnosis of adenocarcinoma of the colon or rectum, age of at least 80 years, and Union for International Cancer Control stage 0–III disease. Exclusion criteria included the presence of distant metastases, multiple primary tumors, appendix cancer, or a concurrent malignant tumor. The study was approved by the institutional review board of each participating hospital. Between January 1, 2003, and December 31, 2007, a total of 2,065 patients aged C80 years underwent surgery for colon and rectal cancer at the participating hospitals. However, 257 patients were ineligible because they failed to meet the inclusion criteria. For each patient, we obtained the following data: age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) class, and performance status (Eastern Cooperative Oncology Group/World Health Organization). In addition to the type of surgery, we noted the nature of admission (i.e., elective or emergency) in addition to the occurrence of postoperative morbidities and mortalities. The data of all patients were collected in December 2010. Morbidities were assessed using the Common Terminology Criteria for Adverse Events version 4.0. Bowel preparation, antibiotic prophylaxis, and thrombosis prophylaxis were performed in accordance with the standards of the participating institutions. Each surgeon followed a treatment policy for elderly patients, outlining the level of mesenteric ligation, lymph node dissection, and postoperative chemotherapy. The time until fluid intake and solid intake was similar for OP and LAC patients in each institution. The primary end point in this study was 3-year overall survival (OS). In view of the life expectancy of elderly
patients, the minimum requirements stipulated a recruitment period of 3 years. Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), postoperative complications, and postoperative recovery. Statistical Analyses Summary statistics were calculated using the frequencies and proportions for categorical data and the medians and interquartile ranges for continuous variables. Mann– Whitney U tests were used for continuous data, whereas the Chi square and Fisher’s exact tests were used for categorical data. Patients with a cause of death other than colorectal cancer were right-censored for the CSS analysis to obtain specific estimates of colorectal-disease-related survival. Kaplan–Meier analyses and Cox’s proportional hazards modeling were used to assess unadjusted survival analyses. The resulting survival curves were compared using the log-rank test. Moreover, the hazard ratios (HR) were estimated and expressed with 95 % confidence intervals (CI) because all surviving patients were followed up for unequal periods. Because patients with colorectal cancer were not randomly assigned to LAP or OP, we used a propensity score method to balance the observed covariates between the treatment groups. Propensity scores reflect the probability that a patient will receive therapy based on observed covariates, and propensity analysis seeks to identify patients who resemble one another except for the treatments assigned.16,17 By assigning a propensity score to each patient and incorporating these scores into model construction, we were able to reduce the selection bias inherent in retrospective nonrandomized regression analyses; thus, the propensity analysis mimicked the conditions of randomized controlled trials (RCTs). Logistic regression analyses were used to select baseline variables associated with LAP or OP. Covariates were selected based on a priori selection (i.e., interactions known to be clinically plausible).2,3,7,18 Included covariates were age, sex, BMI, ASA class, performance status, elective or emergency admission, previous abdominal surgery, tumor size, tumor site, T stage, N stage, and tumor, node, metastasis classification system (TNM) stage. This model yielded a C index of 0.719 (95 % CI 0.692–0.746) with colon cancer and 0.728 (95 % CI 0.662–0.793) with rectal cancer, indicating an appropriate ability to differentiate between patients who underwent LAP and OP. We matched each patient who underwent LAP with another patient who underwent OP and had the closest propensity score within 0.03 on a scale of 0–1. This procedure was continued until all possible pairs were identified.
Laparoscopic Surgery for Elderly CRC Patients TABLE 1 Patient characteristics overall and after propensity score matching (colon cancer) Characteristic
Overall OP (n = 970)
After matching LAP (n = 556)
P
\0.001
OP (n = 402)
LAP (n = 402)
P
83
83
0.649
81.0–85.0 190 (47.3)
81.0–85.0 187 (46.5)
0.832 0.707
Age, y Median
83
82
81.0–86.0 440 (45.4)
81.0–85.0 268 (46.2)
0.150
Median
21.20
21.80
0.005
IQR
18.90–23.60
19.60–23.80
1
106 (10.9)
2 3
IQR Male sex Body mass index
21.49
21.61
19.12–23.93
19.13–23.71
86 (15.5)
53 (13.2)
48 (11.9)
580 (59.8)
354 (63.7)
260 (64.7)
266 (66.2)
242 (24.9)
101 (18.2)
88 (21.9)
96 (21.4)
4
7 (0.7)
2 (0.4)
1 (0.1)
2 (0.5)
5
2 (0.2)
0 (0.0)
0 (0.0)
0 (0.0)
ASA class
0.003
0.880
\0.001
WHO/ECOG performance status
0.236
0
359 (37.0)
260 (46.8)
190 (47.3)
169 (42.0)
1
312 (32.2)
197 (35.4)
130 (32.3)
161 (40.0)
2
200 (20.6)
70 (12.6)
66 (16.4)
57 (14.2)
3 4
65 (6.7) 8 (0.8)
14 (2.5) 3 (0.5)
14 (3.5) 2 (0.5)
12 (3.0) 3 (0.7)
2 (0.5)
1 (0.2)
400 (99.5)
401 (99.8)
123 (30.6)
128 (31.8)
0.704
40.0 (28.0–60.0)
39.0 (25.0–50.0)
0.007
66 (16.4)
61 (15.2)
Emergency surgery
52 (5.4)
2 (0.4)
Elective surgery
914 (94.2)
552 (99.3)
Previous abdominal surgery
361 (37.2)
161 (29.0)
\0.001 0.005
0.563
Tumor size, mm \0.001
Median
46.0
35.0
IQR
30.0–65.0
21.0–49.0
Caecum
114 (11.8)
89 (16.0)
Ascending
278 (28.7)
152 (28.2)
109 (27.1)
115 (28.6)
Transverse
175 (18.0)
63 (11.3)
45 (11.2)
51 (12.7)
\0.001
Tumor site
0.954
Descending
52 (5.4)
19 (3.4)
17 (4.2)
15 (3.7)
Sigmoid
237 (24.4)
167 (30.0)
110 (27.4)
110 (27.4)
Rectosigmoid
114 (11.8)
66 (11.9)
55 (13.7)
50 (12.4)
is 1
28 (2.9) 67 (6.9)
34 (6.1) 117 (21.0)
16 (4.0) 42 (10.4)
16 (4.0) 33 (8.2)
2
106 (10.9)
89 (16.0)
62 (15.4)
70 (17.4)
3
508 (52.4)
252 (45.3)
220 (54.7)
223 (55.5)
4a
186 (19.2)
55 (9.9)
52 (12.9)
51 (12.7)
4b
75 (7.7)
9 (1.6)
10 (2.5)
9 (2.2)
\0.001
T
N
0.895
0.416
0.541
0
655 (67.5)
392 (70.5)
277 (68.9)
277 (68.9)
1a
138 (14.2)
82 (14.7)
57 (14.2)
58 (14.4)
1b
107 (11.0)
46 (8.3)
50 (12.4)
36 (9.0)
1c
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
2a
44 (4.5)
25 (4.5)
15 (3.7)
21 (5.2)
2b
26 (2.7)
11 (2.0)
3 (0.7)
10 (2.5)
T. Hinoi et al. TABLE 1 continued Characteristic
Overall
After matching
OP (n = 970)
LAP (n = 556)
0
28 (2.9)
I II III
OP (n = 402)
LAP (n = 402)
33 (5.9)
16 (4.0)
16 (4.0)
152 (15.7)
174 (31.3)
96 (23.9)
96 (23.9)
475 (49.0) 315 (32.5)
185 (33.3) 164 (29.5)
165 (41.0) 125 (31.1)
165 (41.0) 125 (31.1)
N = 315
N = 164
N = 125
N = 125
Yes
0
4 (2.4)
0
1 (1.8)
No
311 (98.7)
158 (96.3)
123 (98.4)
124 (99.2)
Unknown
4 (1.3)
2 (1.2)
2 (1.6)
0
\0.001
UICC 7th disease stage
Postoperative chemotherapy
P
0.013
P
1.000
1.000
(stage III)
Data are presented as n (%) unless otherwise indicated OP open surgery, LAP laparoscopic surgery, IQR interquartile range, ASA American Society of Anesthesiologists, ECOG Eastern Cooperative Oncology Group, UICC Union for International Cancer Control
The matched cohort was evaluated for differences between the treatment groups for each of the potential the confounding factors. Using both the matched and entire study cohorts, we examined the association between confounding factors and surgical approach. All statistical analyses were performed by SPSS Statistics software, version 19 (IBM, Armonk, NY). RESULTS Overall, 1,808 patients were included in the study. Of these, 1,526 and 282 patients underwent surgery for colon and rectal cancer, respectively. Among the colon cancer cases, 970 patients underwent OP and 556 underwent LAP. The LAP group was younger and had a significantly higher BMI compared to the OP group. In addition, significant differences were observed between the two groups in terms of the distribution of ASA class, performance status, admission, previous abdominal surgery, tumor size, tumor site, T stage, and TNM stage (Table 1). Among the rectal cancer cases, 202 and 80 patients underwent OP and LAP, respectively. Significant differences were found between the two groups in terms of the distribution of sex, tumor size, tumor site, T stage, and TNM stage (Table 2). After propensity score matching, all covariates were balanced and showed no statistically significant differences between the colon and rectal cancer cases, except for tumor size. Cox’s regression analysis confirmed that the tumor size did not have a statistical influence on OS or the occurrence of postoperative complications (data not shown). In addition, after the matching all comorbidities were balanced and no longer showed statistically significant differences between
OP and LAP for either colon or rectal cancer cases, except for the presence of hypertension in colon cancer patients. Consequently, 804 patients in 402 pairs were treated with OP or LAP for colon cancer, and 114 patients in 57 pairs were treated for rectal cancer. For the colon cancer cases, the median follow-up period was 39.5 (interquartile range 27.0–53.0) months and 39.0 (interquartile range 34.0– 52.0) months for the OP and LAP groups, respectively. For the rectal cancer cases, the median follow-up was 36.0 (interquartile range 18.0–54.0) months and 37.0 (interquartile range 25.0–44.0) months for the OP and LAP groups, respectively. No statistically significant differences in the surgical procedures were noted between the OP and LAC groups after adjusting for tumor site as a covariate (Table 3). This is particularly important for rectal cancer because a midrectal versus lower rectal location of the cancer may affect sphincter preservation. With regard to postoperative results, the operative times were significantly longer in the LAP group than in the OP group for both cancer types (Table 3). However, blood loss was lower in the LAP group than in the OP group for both cancer types, and colon cancer patients undergoing LAP showed a faster return of postoperative bowel function and a shorter hospital stay than those undergoing OP. In addition, the time until initiation of fluid intake was significantly shorter in the LAP than in the OP group for both cancer types. The mean length of stay for LAP and OP group after colon cancer surgery was 12 and 13 days, respectively, while that after rectal cancer surgery was 19 and 18 days, respectively. The longer hospital stay in rectal cancer patients might be partially explained by differences in
Laparoscopic Surgery for Elderly CRC Patients TABLE 2 Patient characteristics overall and after propensity score matching (rectal cancer) Characteristic
Overall
After matching
OP (n = 202)
LAP (n = 80)
P
OP (n = 57)
LAP (n = 57)
P
82
83
0.149
81.0–84.0 119 (58.9)
81.0–86.0 34 (42.5)
83
83
0.863
81.0–85.0 32 (56.1)
81.0–85.5 28 (49.1)
0.017
0.296
Median
21.30
21.90
0.597
IQR
18.80–23.60
18.30–23.90
0.496
1
26 (12.9)
16 (20.0)
2
125 (61.9)
52 (65.0)
34 (59.6)
42 (73.7)
3
46 (22.8)
11 (13.8)
15 (26.3)
8 (14.0)
4
1 (0.5)
1 (1.3)
0 (0.0)
1 (1.8)
5
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Age, y Median IQR Male sex Body mass index
ASA class
21.78
21.0
18.51–23.33
17.93–23.60
8 (14.0)
6 (10.5)
0.191
WHO/ECOG performance status
0.235
0.448
0.491
0
78 (38.6)
37 (46.3)
25 (43.9)
23 (40.4)
1
62 (30.7)
23 (28.7)
15 (26.3)
21 (36.8)
2
43 (21.3)
16 (20.0)
12 (21.1)
11 (3.5)
3 4
15 (7.4) 1 (0.5)
2 (2.5) 1 (1.3)
5 (8.8) 0 (0.0)
2 (3.5) 0 (0.0)
Emergency surgery
1 (0.5)
0 (0.0)
0 (0.0)
0 (0.0)
Elective surgery
200 (99.0)
79 (98.8)
57 (100.0)
57 (100.0)
Previous abdominal surgery
70 (34.7)
20 (25.0)
0.246
10 (17.5)
16 (28.1)
0.18
Median
45.0
40.0
0.024
0.365
IQR
31.0–60.0
27.0–54.75
Mid
87 (43.1)
44 (55.0)
Lower
115 (56.9)
35 (43.8)
0.652
–
Tumor size, mm
Tumor site
43.0
40.0
35.0–59.0
30.0–55.0
33 (57.9)
31 (54.4)
23 (40.4)
26 (45.6)
0 (0.0)
0 (0.0)
0.046
T
0.536
0.007 3 (3.8)
0.893
is
4 (2.0)
1
9 (4.5)
11 (13.8)
5 (8.8)
4 (7.0)
2
43 (21.3)
26 (32.5)
14 (24.6)
18 (31.6)
3
60 (29.7)
20 (25.0)
18 (31.6)
19 (33.3)
4a 4b
79 (39.1) 7 (3.5)
19 (23.8) 1 (1.3)
19 (33.3) 1 (1.8)
15 (26.3) 1 (1.8)
0
134 (66.3)
56 (70.0)
35(61.4)
35 (61.4)
1a
26 (12.9)
8 (10.0)
6 (10.5)
6 (10.5)
1b
24 (11.9)
10 (12.5)
6 (10.5)
10 (17.5)
1c
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
2a
9 (4.5)
3 (3.8)
7 (12.3)
3 (5.3)
2b
9 (4.5)
3 (3.8)
3 (5.3)
3 (5.3)
N
0.956
UICC 7th disease stage
0.627
0.010
1.000
0
4 (2.0)
3 (3.8)
0 (0.0)
0 (0.0)
I
45 (22.3)
32 (40.0)
17 (29.8)
17 (29.8)
II
85 (42.1)
21 (26.3)
18 (31.6)
18 (31.6)
T. Hinoi et al. TABLE 2 continued Characteristic
Overall OP (n = 202)
III Postoperative chemotherapy
After matching LAP (n = 80)
68 (33.7)
24 (30.0)
(n = 68)
(n = 24)
1 (1.5) 67 (98.5)
0 24 (100)
P
OP (n = 57)
LAP (n = 57)
22 (38.6)
22 (38.6)
1.000
(n = 22)
(n = 22)
0 22 (100)
0 22 (100)
P
1.000
(stage III) Yes No
Data are presented as n (%) unless otherwise indicated OP open surgery, LAP laparoscopic surgery, IQR interquartile range, ASA American Society of Anesthesiologists, ECOG Eastern Cooperative Oncology Group, UICC Union for International Cancer Control
surgical damage between the two cancer types. Moreover, approximately 40 % of patients underwent a Hartmann’s operation or abdominoperineal resection and 3.5 and 8.8 % of patients underwent anterior resection with diverting stoma in open and laparoscopic surgery, respectively. Thus, almost 50 % of rectal cancer patients had some type of stoma (Table 3). The longer hospital stay for elderly rectal cancer patients might be due to a time needed to learn proper stoma management. Our data suggest that the length of the hospital stay for rectal cancer patients may depend on the type of operation, although LAP might be less invasive with limited complications as compared to OP. In colon cancer cases, the overall postoperative morbidity rates were 36.3 and 24.9 % in the OP and LAP groups, respectively (P \ 0.001, Table 4). A significant reduction in the occurrence of delirium, organ/space surgical site infection, and pneumonia was observed in the LAP group as compared to the OP group (P = 0.034, 0.033, and 0.019, respectively). In rectal cancer cases, the overall morbidity rates were 40.4 and 47.4 % in the OP and LAP group, respectively; however, this difference was not significant (P = 0.450). Postoperative mortalities included three patients who underwent OP for colon cancer. For colon cancer patients, the OS, DFS, and CSS did not significantly differ between LAP and OP patients (P = 0.916, 0.968, and 0.799, respectively), and the 3-year OS for the OP and LAP groups were 81.2 and 85.5 %, respectively. In addition, no significant differences were found between rectal cancer patients who underwent LAP and OP in terms of OS (HR 0.895; 95 % CI 0.432–1.857; P = 0.765), DFS (HR 0.800; 95 % CI 0.406–1.574; P = 0.516), and CSS (HR 0.967; 95 % CI 0.339–2.760; P = 0.950) (Fig. 1). In addition, OS, DFS, and CSS analyses showed no significant differences between the OP and LAP groups when the colon and rectal cancers were classified by stage (data not shown). With regard to effect of the postoperative chemotherapy on survival analysis in 479
stage III colon cancer patients, none (0 %) of 315 patients and 4 (2.4 %) of 164 patients received 5-FU based postoperative chemotherapy in OP and LAP group, respectively. However, only one patient was selected from LAP group after matching (Table 1). In rectal cancer one out of overall 92 stage III patients and none of 44 patients after matching received postoperative chemotherapy (Table 2). These results suggest that infrequent use of postoperative chemotherapy did not make any impact on our results. DISCUSSION In our study, no statistically significant differences in long-term outcomes were found in elderly colorectal cancer patients who underwent OP and LAP. To our knowledge, this is the first large-scale cohort study involving elderly patients (median age of 83.0 years in both the OP and LAP groups) that also studied the clinical feasibility of LAP for colon and rectal cancer, consistent with previous RCT studies in the general population with mean patient ages of 69–71 years and 68–71 years in the OP and LAP groups, respectively.3–9,19,20 Although an RCT would be ideal for confirming the feasibility of LAP in elderly patients, the increase in the incidence of postoperative morbidities and mortalities with advancing age may lead to investigators avoiding the inclusion of frail patients in prospective randomized trials.11–13 To circumvent the impracticability of RCT, we conducted a multicenter matched case–control study using a propensity scoring method. This method can reduce the selection bias inherent in retrospective nonrandomized regression analyses and simulate the conditions of RCTs.16,21–24 In addition, the differing percentage (0.0– 96.1 %) of the operative procedures in the enrolled elderly patients, giving priority to LAP, indicates the diversity of the selected facilities, which supports the validity of our analysis (data not shown).
Laparoscopic Surgery for Elderly CRC Patients TABLE 3 Operative results Characteristic
Colon cancer
Rectal cancer
OP (n = 402)
LAP (n = 402)
Ileocecal resection
11 (2.7)
20 (5.0)
Right hemicolectomy Transverse colectomy
178 (44.3) 31 (7.7)
168 (41.8) 35 (8.7)
Left hemicolectomy
81 (20.1)
92 (22.9)
Surgical procedure
P
OP (n = 57)
LAP (n = 57)
0.380
Sigmoidectomy
90 (22.4)
80 (19.9)
Hartmann operation
11 (2.7)
7 (1.7)
0.263
8 (14.0)
9 (15.8)
Abdominoperineal resection
15 (26.3)
13 (22.8)
High anterior resection
0 (0)
4 (7.0)
34 (59.6)
31 (54.4)
Low anterior resection Stoma
P
0.451
0.782
Permanent stoma
11 (2.7)
7 (1.7)
23 (40.4)
22 (38.6)
Diverting stoma
4 (1.0)
5 (1.2)
2 (3.5)
5 (8.8)
–
384 (95.5)
389 (96.8)
32 (56.1)
30 (52.6)
Unknown
4 (1.0)
1 (0.2)
1 (1.8)
Operative time, min Median IQR Blood loss, mL
148.0
201.0
114.0–186.0
155.0–240.0
Median
80.0
27
IQR
30.0–200.0
10.0–70.0
Median
14.0
14.0
IQR
8.0–22.0
9.0–21.0
\0.001
\0.001
189
291
149.0–237.5
204.0–350.5
299
70
145.0–4,350.0
40.0–202.5
11
12.5
7.0–19.0
6.25–16.0
Median
15.5
5.5
IQR
7.5–59.5
0–20.0
\0.001
\0.001
No. of resected lymph nodes 0.674
0.995
Circumferential resection margin, mm
Resection margin
0.156
0.121 0.850
R0
384 (99.2)
388 (98.2)
54 (94.7)
54 (96.4)
R1
2 (0.5)
7 (1.8)
2 (3.5)
1 (1.8)
R2
1 (0.3)
0 (0.0)
1 (1.8)
1 (1.8)
Unknown
15 (3.7)
7 (1.8)
0 (0.0)
1 (1.8)
Duration of hospital stay after surgery, d 13.0 11.0–20.0
12 9.0–15.0
\0.001
18 14.0–25.0
19 13.0–28.0
0.990
Median
3.0
2
\0.001
2
1
0.002
IQR
2.0–4.0
1.0–2.0
1.0–4.0
1.0–2.0
Median
5.0
3
4
3
IQR
3.0–6.0
3.0–5.0
3.0–6.0
2.0–6.0
Median
5.0
4
5
4
IQR
3.0–6.0
3.0–5.0
3.0–7.75
2.0–6.0
Median IQR Days to fluid diet
Days to solid diet \0.001
0.100
Days to feces after surgery
Data are presented as n (%) unless otherwise indicated OP open surgery, LAP laparoscopic surgery, IQR interquartile range
\0.001
0.033
T. Hinoi et al. TABLE 4 Comorbidities and postoperative morbidities Characteristic
Colon cancer
Rectal cancer
OP (n = 402)
LAP (n = 402)
Overall comorbidities
342 (85.1)
340 (84.6)
Diabetes mellitusa
52 (12.9)
57 (14.2
Respiratoryb Cardiacc
15 (3.7) 76 (18.9)
23 (5.7) 76 (18.9)
119 (29.6)
163 (40.5)
41 (10.2)
40 (10.0)
0.907
4 (7.0)
6 (10.5)
0.508
8 (2.0)
5 (1.2)
0.662
1 (1.8)
0 (0.0)
0.315
Hypertensiond Cerebrovascular
e
Steroid usef Overall postoperative morbidity
P
OP (n = 57)
LAP (n = 57)
0.981
47 (82.5)
49 (86.0)
0.456
0.606
7 (12.3)
6 (10.5)
0.768
0.184 1.000
2 (3.5) 10 (17.5)
7 (12.3) 12 (21.1)
0.082 0.635
0.001
11 (19.3)
16 (28.1)
0.271
\0.001
P
145 (36.3)
100 (24.9)
23 (40.4)
27 (47.4)
0.45
Delirium
39 (9.7)
23 (5.7)
0.034
4 (7.0)
5 (8.8)
0.918
Postoperative ileus
28 (7.0)
21 (5.2)
0.302
5 (8.8)
4 (7.0)
0.525
Pneumonia
12 (3.0)
3 (0.7)
0.019
2 (3.5)
0 (0.0)
0.118 0.274
Bleeding
3 (0.7)
5 (1.2)
0.477
1 (1.8)
0 (0.0)
39 (9.7)
32 (8.0)
0.384
4 (7.0)
5 (8.8)
0.918
Organ/space SSI
7 (1.7)
1 (0.2)
0.033
2 (3.5)
1 (1.8)
0.459
Anastomotic leak
2 (0.5)
4 (1.0)
0.412
0 (0.0)
4 (7.0)
0.054
Cardiovascular occurrence
2 (0.5)
1 (0.2)
0.563
0 (0.0)
0 (0.0)
–
Incisional SSI
Data are presented as n (%) OP open surgery, LAP laparoscopic surgery, SSI surgical site infection a
Diabetes mellitus include history of oral agents or insulin
b
Respiratory conditions include chronic obstructive pulmonary disease or current pneumonia
c
Cardiac conditions include: history of heart failure, arrhythmia or ischemic heart disease; previous coronary intervention or cardiac surgery
d
Hypertension requiring medication
e
Cerebrovascular conditions include hemiplegia, history of transient ischemic attacks, and cerebrovascular event with or without neurological deficit
f
Steroid use for any chronic condition
Although the current study is in agreement with previous prospective studies reporting that OS and DFS did not differ between LAP and OP patients, elderly patients are more likely to die of causes other than cancer, which can result in an apparent decrease in OS. Therefore, we evaluated the CSS, wherein the survival curve reached a state of equilibrium as time advanced. Ultimately, no significant differences were demonstrated in CSS between the OP and LAP groups. The short-term outcomes of this study demonstrated the benefits of using LAP in elderly patients. The overall morbidities and the number of cases of postoperative delirium, organ/space surgical site infection, and pneumonia were significantly reduced in the LAP group as compared to the OP group for colon cancer patients, while no differences in these parameters were observed among rectal cancer patients. These findings are also consistent with those of previous prospective trials.3–5,19,20 Elderly patients with colon cancer may receive greater benefits from LAP because there is a linear correlation between increasing age and the frequency of postoperative
morbidities, such as respiratory, cardiovascular, and neurological complications.11–15 We recognize that our data are not adequate for demonstrating a statistically significant benefit of LAP for rectal cancer in elderly patients, which has been reported in the general population.4 In the present study, a relatively small number of rectal cancer patients were studied as compared with colon cancer patients, indicating that further research is needed to determine the benefit of LAP in elderly patients with rectal cancer. With regard to the oncological quality of the surgery, the number of resected lymph nodes and resection margins did not differ significantly between the OP and LAP groups. Although the operative strategy was individualized and may have been somewhat restricted for elderly patients (e.g. limited lymphadenectomy) in approximately half of the participating institutions (data not shown), the median number of removed lymph nodes was between 11.0 and 14.0 in each group, which is consistent with other studies.3,4,25,26 Regarding conversion of LAP to OP, our data indicated conversion rates of 5.8 and 19.3 % in patients
Laparoscopic Surgery for Elderly CRC Patients Rectum
Colon LAP OP
0.8 0.6 0.4 3-year survival OP 81.2% LAP 85.5%
0.2
LAP OP
1.0
HR: 1.016 (0.749–1.380) P = 0.916
0.8
Overall Survival
1.0
Overall Survival
FIG. 1 Survival rate in different procedure groups for colon or rectal cancer. For colon cancer, the OS, DFS, and CSS did not differ between LAP and OP patients (P = 0.916, 0.968, and 0.799, respectively). The 3-year OS for the OP and LAP groups were 81.2 % and 85.5 %, respectively. No significant differences were found in the OS, DFS, and CSS for rectal cancer patients between the treatment groups (P = 0.765, 0.516, and 0.950, respectively)
0.6 0.4 3-year survival OP 70.2% LAP 78.6%
0.2 0.0
0.0 0
20
40
60
0
80
20
402 402
337 359
201 191
73 62
12 15
OP LAP
0.6 0.4 3-year survival OP 75.6% LAP 74.4%
0.2
HR: 1.006 (0.765–1.322) P = 0.968
Disease-Free Survival
Disease-Free Survival
0.8
57 57
42 49
28 25
8 7
2 3
0.8 0.6 0.4 3-year survival OP 63.4% LAP 74.6%
0.2
HR: 0.800 (0.405–1.574) P = 0.516
0.0
0
20
40
60
0
80
20
391 394
310 331
40
60
80
7 7
2 3
Time (Months)
Time (Months) Number of patients at risk
Number of patients at risk 196 175
72 58
12 14
OP LAP
55 55
38 43
27 24
1.0
0.8 0.6 0.4 3-year survival OP 92.3% LAP 93.4%
0.2
HR: 1.065 (0.657–1.726) P = 0.799
Cancer-specific survival
1.0
Cancer-specific survival
80
1.0
0.0
0.8 0.6 0.4 3-year survival OP 86.5% LAP 89.6%
0.2
HR: 0.967 (0.339–2.760) P = 0.950
0.0
0.0 0
20
40
60
0
80
20
337 359
60
80
8 7
2 3
Number of patients at risk
Number of patients at risk 402 402
40
Time (Months)
Time (Months) OP LAP
60
Number of patients at risk
1.0
OP LAP
40
Time (Months)
Time (Months) Number of patients at risk OP LAP
HR: 0.895 (0.432–1.857) P = 0.765
201 191
with colon and rectal cancer, respectively. The combined conversion rate for colon and rectal cancer was 7.4 %, which was lower than that described in previous reports (COST, 21 %; COLOR, 17 %; Asian, 23.2 %; and CLASICC, 29 %).3–5,26 This difference might be attributed to the learning curve of LAP because most of our surgeons performed LAP in elderly patients after adequate experience with the general population.
73 62
12 15
OP LAP
57 57
42 49
28 25
Our study has certain limitations. First, the retrospective data analyses were affected by selection bias. The propensity score method seeks to adjust for multiple covariates simultaneously and adequately; however, even this matching method cannot adjust for unobserved or unmeasured factors. Second, the use of postoperative chemotherapy for elderly patients and preoperative chemoradiotherapy for rectal cancer varied according to the
T. Hinoi et al.
facility. Almost half of the participating facilities were reluctant to use postoperative chemotherapy according to standard protocols for elderly patients (data not shown). In this study, the number of the colon cancer patients who received postoperative chemotherapy was 0 and 2.4 % overall and 0 and 0.8 % after matching in OP and LAP group, respectively. In rectal cancer, only one of overall 92 stage III patients received postoperative chemotherapy. Only two out of 114 rectal cancer patients received preoperative chemoradiotherapy after matching, which is not a standard practice in Japan because the efficacy of this treatment remains under debate. Therefore, the effects of preoperative chemoradiotherapy and postoperative chemotherapy are considered to be limited and may not have a significant influence on the conclusion of this study. Third, the number of patients in the rectal cancer group was lower than that in the colon cancer group in this study. Although, the feasibility of LAP for rectal cancer has been reported in the institutions that are members of the Japan Society of Laparoscopic Colorectal Surgery, the results of the present study may represent a learning curve for LAP in geriatric rectal cancer patients.27 A larger cohort study would therefore be ideal for confirming the efficacy of LAP in elderly patients with rectal cancer. Despite these limitations, our observations indicated that LAP in elderly patients has fewer incidences of postsurgical morbidities and is oncologically feasible, consistent with the results of previous RCTs in the general population. Hence, we believe that these results justify the implementation of LAP in the routine treatment practices for elderly patients with colorectal cancer. CONCLUSIONS Our matched case–control study suggested that the laparoscopic approach is not inferior to the open approach and that LAP can be an acceptable alternative to OP in extremely elderly patients with colon and rectal cancer. ACKNOWLEDGMENT We acknowledge the cooperation of the following doctors: Eiji Kanehira, Kunihisa Shiozawa, Ageo Central General Hospital; Hiroyuki Bando, Daisuke Yamamoto, Ishikawa Prefectural Central Hospital; Seigo Kitano, Masafumi Inomata, Tomonori Akagi, Oita University; Junji Okuda, Keitaro Tanaka, Osaka Medical College; Masayoshi Yasui, Osaka National Hospital; Kosei Hirakawa, Kiyoshi Maeda, Osaka City University; Akiyoshi Kanazawa, Osaka Red Cross Hospital; Junichi Hasegawa, Junichi Nishimura, Osaka Rosai Hospital; Ichio Suzuka, Kagawa Prefectural Central Hospital; Shintaro Akamoto, Kagawa University; Yosuke Fukunaga, Hiroya Kuroyanagi, Cancer Institute Ariake Hospital; Masaki Naito, Kitasato University; Takashi Ueki, Kyushu University; Takashi Yamaguchi, Koya Hida, Kyoto Medical Center; Yousuke Kinjo, Kyoto University; Yukihito Kokuba, Kyoto Prefectural University; Madoka Hamada, Kochi Health Sciences Center; Norio Saito, Masaaki Ito, National Cancer Hospital East; Jou Tashiro, Saitama Medical University; Toshimasa Yatsuoka, Saitama Cancer Center;
Tomohisa Furuhata, Kenji Okita, Sapporo Medical University; Yoshiro Kubo, Shikoku Cancer Center; Shuji Saito Yosuke Kinugasa, Shizuoka Cancer Center; Fumio Konishi, Saitama medical Center Jichi Medical University; Michitoshi Goto, Juntendo University; Junichi Tanaka, Shungo Endo, Showa University Northern Yokohama Hospital; Nobuyoshi Miyajima, Tadashi Suda, Tsukasa Shimamura, St. Marianna University; Yoshihisa Saida, Toshiyuki Enomoto, Toho University Ohashi Medical Center; Takeshi Naito, Tohoku University; Yasuhiro Munakata, Souichi Tagami, Nagano Municipal Hospital; Satoshi Maruyama, Niigata Cancer Center Hospital; Takao Ichihara, Nishinomiya Municipal Central Hospital; Hitoshi Idani, Fukuyama Municipal Hospital; Yasuhiro Miyake, Minoh City Hospital; Shoichi Hazama, Yamaguchi University; and Kazuteru Watanabe, Yokohama City University Medical Center. This study was supported by the Japanese Society for Cancer of the Colon and Rectum. DISCLOSURE
The authors declare no conflict of interest.
REFERENCES 1. Center MM, Jemal A, Ward E. International trends in colorectal cancer incidence rates. Cancer Epidemiol Biomarkers Prev. 2009;18:1688–94. 2. Law WL, Chu KW, Tung PH. Laparoscopic colorectal resection: a safe option for elderly patients. J Am Coll Surg. 2002;195:768– 73. 3. Clinical Outcomes of Surgical Therapy Study Group. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med. 2004;350:2050–9. 4. Guillou PJ, Quirke P, Thorpe H, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC Trial): multicentre, randomised controlled trial. Lancet. 2005;365:1718–26. 5. Veldkamp R, Kuhry E, Hop WC, et al. Laparoscopic surgery versus open surgery for colon cancer: short-term outcomes of a randomised trial. Lancet Oncol. 2005;6:477–84. 6. Jayne DG, Guillou PJ, Thorpe H, et al. Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J Clin Oncol. 2007;25:3061–8. 7. Buunen M, Veldkamp R, Hop WC, et al. Survival after laparoscopic surgery versus open surgery for colon cancer: long-term outcome of a randomised clinical trial. Lancet Oncol. 2009;10: 44–52. 8. Hemandas AK, Abdelrahman T, Flashman KG, et al. Laparoscopic colorectal surgery produces better outcomes for high risk cancer patients compared to open surgery. Ann Surg. 2010;252: 84–9. 9. Bagshaw PF, Allardyce RA, Frampton CM, et al. Long-term outcomes of the Australasian randomized clinical trial comparing laparoscopic and conventional open surgical treatments for colon cancer: the Australasian Laparoscopic Colon Cancer Study Trial. Ann Surg. 2012;256:915–9. 10. Cummings LC, Delaney CP, Cooper GS. Laparoscopic versus open colectomy for colon cancer in an older population: a cohort study. World J Surg Oncol. 2012;10:31. 11. Colorectal Cancer Collaborative Group. Surgery for colorectal cancer in elderly patients: a systematic review. Lancet. 2000; 356:968–74. 12. Rutten HJ, den Dulk M, Lemmens VE, van de Velde CJ, Marijnen CA. Controversies of total mesorectal excision for rectal cancer in elderly patients. Lancet Oncol. 2008;9:494–501.
Laparoscopic Surgery for Elderly CRC Patients 13. Turrentine FE, Wang H, Simpson VB, Jones RS. Surgical risk factors, morbidity, and mortality in elderly patients. J Am Coll Surg. 2006;203:865–77. 14. Al-Refaie WB, Parsons HM, Habermann EB, et al. Operative outcomes beyond 30-day mortality: colorectal cancer surgery in oldest old. Ann Surg. 2011;253:947–52. 15. Panis Y, Maggiori L, Caranhac G, Bretagnol F, Vicaut E. Mortality after colorectal cancer surgery: a French survey of more than 84,000 patients. Ann Surg. 2011;254:738–43. 16. Austin PC. The relative ability of different propensity score methods to balance measured covariates between treated and untreated subjects in observational studies. Med Decis Making. 2009;29:661–77. 17. Joffe MM, Rosenbaum PR. Propensity scores [invited commentary]. Am J Epidemiol. 1999;150:327–33. 18. Stocchi L, Nelson H, Young-Fadok TM, Larson DR, Ilstrup DM. Safety and advantages of laparoscopic vs open colectomy in the elderly: matched-control study. Dis Colon Rectum. 2000;43:326–32. 19. Lacy AM, Garcı´a-Valdecasas JC, Delgado S, et al. Laparoscopyassisted colectomy versus open colectomy for treatment of nonmetastatic colon cancer: a randomised trial. Lancet. 2002;359: 2224–9. 20. Kang SB, Park JW, Jeong SY, et al. Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an openlabel randomized controlled trial. Lancet Oncol. 2010;11:637–45.
21. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification on the propensity score. J Am Stat Assoc. 1984;79:516–24. 22. D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998;17:2265–81. 23. Austin PC, Mamdani MM. A comparison of propensity score methods: a case-study estimating the effectiveness of post-AMI statin use. Stat Med. 2006;25:2084–106. 24. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–107. 25. Veldkamp R, Gholghesaei M, Bonjer HJ, et al. Laparoscopic resection of colon cancer: consensus of the European Association of Endoscopic Surgery (EAES). Surg Endosc. 2004;18:1163–85. 26. Leung KL, Kwok SP, Lam SC, et al. Laparoscopic resection of rectosigmoid carcinoma: prospective randomised trial. Lancet. 2004;363:1187–92. 27. Miyajima N, Fukunaga M, Hasegawa H, Tanaka J, Okuda J, Watanabe M; Japan Society of Laparoscopic Colorectal Surgery. Results of a multicenter study of 1,057 cases of rectal cancer treated by laparoscopic surgery. Surg Endosc. 2009;23:113–8.
ORIGINAL ARTICLE – COLORECTAL CANCER
Laparoscopic Versus Open Surgery for Colorectal Cancer in Elderly Patients: A Multicenter Matched Case–Control Study Takao Hinoi, MD, PhD1, Yasuo Kawaguchi, MD2, Minoru Hattori, PhD1, Masazumi Okajima, MD, PhD3, Hideki Ohdan, MD, PhD1, Seiichiro Yamamoto, MD, PhD4, Hirotoshi Hasegawa, MD, PhD5, Hisanaga Horie, MD, PhD6, Kohei Murata, MD, PhD7, Shigeki Yamaguchi, MD, PhD8, Kenichi Sugihara, MD, PhD9, Masahiko Watanabe, MD, PhD10 and the Japan Society of Laparoscopic Colorectal Surgery 1
Department of Gastroenterological and Transplant Surgery Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; 2Department of Surgery, Tsuchiya General Hospital, Hiroshima, Japan; 3 Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan; 4Department of Surgery, Hiratsuka City Hospital, Kanagawa, Japan; 5Department of Surgery, Keio University School of Medicine, Tokyo, Japan; 6 Department of Surgery, Jichi Medical University, Shimotsuke, Japan; 7Department of Surgery, Suita Municipal Hospital, Osaka, Japan; 8Department of Gastroenterological Surgery, Saitama Medical University International Medical Center, Saitama, Japan; 9Department of Surgical Oncology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan; 10 Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan
ABSTRACT Background. The safety of laparoscopic surgery (LAP) in elderly patients with colorectal cancer has not been demonstrated. The aim of this study was to compare the outcomes of LAP and open surgery (OP) and estimate the feasibility of LAP in colorectal cancer patients aged C80 years. Methods. We conducted a propensity scoring matched case–control study of colon and rectal cancer patients aged C80 years using data from 41 hospitals between 2003 and 2007. A total of 1,526 colon cancer patients and 282 rectal cancer patients underwent surgery and were included in the analysis. The primary end point was 3-year overall survival (OS). Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), and postoperative complications. Results. LAP and OP were compared in 804 colon cancer patients (402 pairs) and 114 rectal cancer patients (57 pairs) after all covariates were balanced, and no significant differences were observed, except for tumor size in colon
Ó Society of Surgical Oncology 2014 First Received: 16 December 2013 T. Hinoi, MD, PhD e-mail: [email protected]
cancer. OS, DFS, and CSS did not differ between the groups for either colon cancer (P = 0.916, 0.968, and 0.799, respectively) or rectal cancer (P = 0.765, 0.519, and 0.950, respectively). In colon cancer cases, LAP was associated with fewer morbidities than was OP (24.9 vs. 36.3 %, P \ 0.001); no such difference was observed for rectal cancer patients (47.4 vs. 40.4 %, P = 0.450). Conclusions. LAP is an acceptable alternative to OP in elderly patients with colorectal cancer.
Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide, and it is the second leading cause of cancer-related deaths in many developed countries.1 The incidence of colorectal cancers that necessitate surgical intervention continues to increase because of the prolonged life expectancy in most countries.2 Several studies have reported that in colorectal cancer cases, laparoscopic surgery (LAP) shows comparable oncologic results and improved short-term outcomes compared to open surgery (OP).3–10 However, postoperative morbidities and mortalities increase with age in older patients.11–15 Therefore, surgery needs to be modified for geriatric patients. Thus far, it remains unclear whether elderly patients respond to LAP as they do to OP. Because of this uncertainty, investigators have been unwilling to include frail patients in randomized studies, and no study has investigated the
T. Hinoi et al.
feasibility of LAP in a large cohort of elderly patients with colorectal cancer. Hence, the important issue of whether the laparoscopic approach can serve as well as OP in elderly patients with colorectal cancer remains to be elucidated. In this study, we compared the surgical outcomes between elderly patients with colorectal cancer who underwent either LAP or OP and assessed whether LAP is an acceptable alternative to OP. Moreover, we evaluated the results to determine whether the survival data justify the implementation of laparoscopic techniques in geriatric oncology. METHODS Study Design and Participants We conducted a matched case–control study by using data from 41 hospitals that are members of the Japan Society of Laparoscopic Colorectal Surgery. To be included in the study, patients were required to have a clinical diagnosis of adenocarcinoma of the colon or rectum, age of at least 80 years, and Union for International Cancer Control stage 0–III disease. Exclusion criteria included the presence of distant metastases, multiple primary tumors, appendix cancer, or a concurrent malignant tumor. The study was approved by the institutional review board of each participating hospital. Between January 1, 2003, and December 31, 2007, a total of 2,065 patients aged C80 years underwent surgery for colon and rectal cancer at the participating hospitals. However, 257 patients were ineligible because they failed to meet the inclusion criteria. For each patient, we obtained the following data: age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) class, and performance status (Eastern Cooperative Oncology Group/World Health Organization). In addition to the type of surgery, we noted the nature of admission (i.e., elective or emergency) in addition to the occurrence of postoperative morbidities and mortalities. The data of all patients were collected in December 2010. Morbidities were assessed using the Common Terminology Criteria for Adverse Events version 4.0. Bowel preparation, antibiotic prophylaxis, and thrombosis prophylaxis were performed in accordance with the standards of the participating institutions. Each surgeon followed a treatment policy for elderly patients, outlining the level of mesenteric ligation, lymph node dissection, and postoperative chemotherapy. The time until fluid intake and solid intake was similar for OP and LAC patients in each institution. The primary end point in this study was 3-year overall survival (OS). In view of the life expectancy of elderly
patients, the minimum requirements stipulated a recruitment period of 3 years. Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), postoperative complications, and postoperative recovery. Statistical Analyses Summary statistics were calculated using the frequencies and proportions for categorical data and the medians and interquartile ranges for continuous variables. Mann– Whitney U tests were used for continuous data, whereas the Chi square and Fisher’s exact tests were used for categorical data. Patients with a cause of death other than colorectal cancer were right-censored for the CSS analysis to obtain specific estimates of colorectal-disease-related survival. Kaplan–Meier analyses and Cox’s proportional hazards modeling were used to assess unadjusted survival analyses. The resulting survival curves were compared using the log-rank test. Moreover, the hazard ratios (HR) were estimated and expressed with 95 % confidence intervals (CI) because all surviving patients were followed up for unequal periods. Because patients with colorectal cancer were not randomly assigned to LAP or OP, we used a propensity score method to balance the observed covariates between the treatment groups. Propensity scores reflect the probability that a patient will receive therapy based on observed covariates, and propensity analysis seeks to identify patients who resemble one another except for the treatments assigned.16,17 By assigning a propensity score to each patient and incorporating these scores into model construction, we were able to reduce the selection bias inherent in retrospective nonrandomized regression analyses; thus, the propensity analysis mimicked the conditions of randomized controlled trials (RCTs). Logistic regression analyses were used to select baseline variables associated with LAP or OP. Covariates were selected based on a priori selection (i.e., interactions known to be clinically plausible).2,3,7,18 Included covariates were age, sex, BMI, ASA class, performance status, elective or emergency admission, previous abdominal surgery, tumor size, tumor site, T stage, N stage, and tumor, node, metastasis classification system (TNM) stage. This model yielded a C index of 0.719 (95 % CI 0.692–0.746) with colon cancer and 0.728 (95 % CI 0.662–0.793) with rectal cancer, indicating an appropriate ability to differentiate between patients who underwent LAP and OP. We matched each patient who underwent LAP with another patient who underwent OP and had the closest propensity score within 0.03 on a scale of 0–1. This procedure was continued until all possible pairs were identified.
Laparoscopic Surgery for Elderly CRC Patients TABLE 1 Patient characteristics overall and after propensity score matching (colon cancer) Characteristic
Overall OP (n = 970)
After matching LAP (n = 556)
P
\0.001
OP (n = 402)
LAP (n = 402)
P
83
83
0.649
81.0–85.0 190 (47.3)
81.0–85.0 187 (46.5)
0.832 0.707
Age, y Median
83
82
81.0–86.0 440 (45.4)
81.0–85.0 268 (46.2)
0.150
Median
21.20
21.80
0.005
IQR
18.90–23.60
19.60–23.80
1
106 (10.9)
2 3
IQR Male sex Body mass index
21.49
21.61
19.12–23.93
19.13–23.71
86 (15.5)
53 (13.2)
48 (11.9)
580 (59.8)
354 (63.7)
260 (64.7)
266 (66.2)
242 (24.9)
101 (18.2)
88 (21.9)
96 (21.4)
4
7 (0.7)
2 (0.4)
1 (0.1)
2 (0.5)
5
2 (0.2)
0 (0.0)
0 (0.0)
0 (0.0)
ASA class
0.003
0.880
\0.001
WHO/ECOG performance status
0.236
0
359 (37.0)
260 (46.8)
190 (47.3)
169 (42.0)
1
312 (32.2)
197 (35.4)
130 (32.3)
161 (40.0)
2
200 (20.6)
70 (12.6)
66 (16.4)
57 (14.2)
3 4
65 (6.7) 8 (0.8)
14 (2.5) 3 (0.5)
14 (3.5) 2 (0.5)
12 (3.0) 3 (0.7)
2 (0.5)
1 (0.2)
400 (99.5)
401 (99.8)
123 (30.6)
128 (31.8)
0.704
40.0 (28.0–60.0)
39.0 (25.0–50.0)
0.007
66 (16.4)
61 (15.2)
Emergency surgery
52 (5.4)
2 (0.4)
Elective surgery
914 (94.2)
552 (99.3)
Previous abdominal surgery
361 (37.2)
161 (29.0)
\0.001 0.005
0.563
Tumor size, mm \0.001
Median
46.0
35.0
IQR
30.0–65.0
21.0–49.0
Caecum
114 (11.8)
89 (16.0)
Ascending
278 (28.7)
152 (28.2)
109 (27.1)
115 (28.6)
Transverse
175 (18.0)
63 (11.3)
45 (11.2)
51 (12.7)
\0.001
Tumor site
0.954
Descending
52 (5.4)
19 (3.4)
17 (4.2)
15 (3.7)
Sigmoid
237 (24.4)
167 (30.0)
110 (27.4)
110 (27.4)
Rectosigmoid
114 (11.8)
66 (11.9)
55 (13.7)
50 (12.4)
is 1
28 (2.9) 67 (6.9)
34 (6.1) 117 (21.0)
16 (4.0) 42 (10.4)
16 (4.0) 33 (8.2)
2
106 (10.9)
89 (16.0)
62 (15.4)
70 (17.4)
3
508 (52.4)
252 (45.3)
220 (54.7)
223 (55.5)
4a
186 (19.2)
55 (9.9)
52 (12.9)
51 (12.7)
4b
75 (7.7)
9 (1.6)
10 (2.5)
9 (2.2)
\0.001
T
N
0.895
0.416
0.541
0
655 (67.5)
392 (70.5)
277 (68.9)
277 (68.9)
1a
138 (14.2)
82 (14.7)
57 (14.2)
58 (14.4)
1b
107 (11.0)
46 (8.3)
50 (12.4)
36 (9.0)
1c
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
2a
44 (4.5)
25 (4.5)
15 (3.7)
21 (5.2)
2b
26 (2.7)
11 (2.0)
3 (0.7)
10 (2.5)
T. Hinoi et al. TABLE 1 continued Characteristic
Overall
After matching
OP (n = 970)
LAP (n = 556)
0
28 (2.9)
I II III
OP (n = 402)
LAP (n = 402)
33 (5.9)
16 (4.0)
16 (4.0)
152 (15.7)
174 (31.3)
96 (23.9)
96 (23.9)
475 (49.0) 315 (32.5)
185 (33.3) 164 (29.5)
165 (41.0) 125 (31.1)
165 (41.0) 125 (31.1)
N = 315
N = 164
N = 125
N = 125
Yes
0
4 (2.4)
0
1 (1.8)
No
311 (98.7)
158 (96.3)
123 (98.4)
124 (99.2)
Unknown
4 (1.3)
2 (1.2)
2 (1.6)
0
\0.001
UICC 7th disease stage
Postoperative chemotherapy
P
0.013
P
1.000
1.000
(stage III)
Data are presented as n (%) unless otherwise indicated OP open surgery, LAP laparoscopic surgery, IQR interquartile range, ASA American Society of Anesthesiologists, ECOG Eastern Cooperative Oncology Group, UICC Union for International Cancer Control
The matched cohort was evaluated for differences between the treatment groups for each of the potential the confounding factors. Using both the matched and entire study cohorts, we examined the association between confounding factors and surgical approach. All statistical analyses were performed by SPSS Statistics software, version 19 (IBM, Armonk, NY). RESULTS Overall, 1,808 patients were included in the study. Of these, 1,526 and 282 patients underwent surgery for colon and rectal cancer, respectively. Among the colon cancer cases, 970 patients underwent OP and 556 underwent LAP. The LAP group was younger and had a significantly higher BMI compared to the OP group. In addition, significant differences were observed between the two groups in terms of the distribution of ASA class, performance status, admission, previous abdominal surgery, tumor size, tumor site, T stage, and TNM stage (Table 1). Among the rectal cancer cases, 202 and 80 patients underwent OP and LAP, respectively. Significant differences were found between the two groups in terms of the distribution of sex, tumor size, tumor site, T stage, and TNM stage (Table 2). After propensity score matching, all covariates were balanced and showed no statistically significant differences between the colon and rectal cancer cases, except for tumor size. Cox’s regression analysis confirmed that the tumor size did not have a statistical influence on OS or the occurrence of postoperative complications (data not shown). In addition, after the matching all comorbidities were balanced and no longer showed statistically significant differences between
OP and LAP for either colon or rectal cancer cases, except for the presence of hypertension in colon cancer patients. Consequently, 804 patients in 402 pairs were treated with OP or LAP for colon cancer, and 114 patients in 57 pairs were treated for rectal cancer. For the colon cancer cases, the median follow-up period was 39.5 (interquartile range 27.0–53.0) months and 39.0 (interquartile range 34.0– 52.0) months for the OP and LAP groups, respectively. For the rectal cancer cases, the median follow-up was 36.0 (interquartile range 18.0–54.0) months and 37.0 (interquartile range 25.0–44.0) months for the OP and LAP groups, respectively. No statistically significant differences in the surgical procedures were noted between the OP and LAC groups after adjusting for tumor site as a covariate (Table 3). This is particularly important for rectal cancer because a midrectal versus lower rectal location of the cancer may affect sphincter preservation. With regard to postoperative results, the operative times were significantly longer in the LAP group than in the OP group for both cancer types (Table 3). However, blood loss was lower in the LAP group than in the OP group for both cancer types, and colon cancer patients undergoing LAP showed a faster return of postoperative bowel function and a shorter hospital stay than those undergoing OP. In addition, the time until initiation of fluid intake was significantly shorter in the LAP than in the OP group for both cancer types. The mean length of stay for LAP and OP group after colon cancer surgery was 12 and 13 days, respectively, while that after rectal cancer surgery was 19 and 18 days, respectively. The longer hospital stay in rectal cancer patients might be partially explained by differences in
Laparoscopic Surgery for Elderly CRC Patients TABLE 2 Patient characteristics overall and after propensity score matching (rectal cancer) Characteristic
Overall
After matching
OP (n = 202)
LAP (n = 80)
P
OP (n = 57)
LAP (n = 57)
P
82
83
0.149
81.0–84.0 119 (58.9)
81.0–86.0 34 (42.5)
83
83
0.863
81.0–85.0 32 (56.1)
81.0–85.5 28 (49.1)
0.017
0.296
Median
21.30
21.90
0.597
IQR
18.80–23.60
18.30–23.90
0.496
1
26 (12.9)
16 (20.0)
2
125 (61.9)
52 (65.0)
34 (59.6)
42 (73.7)
3
46 (22.8)
11 (13.8)
15 (26.3)
8 (14.0)
4
1 (0.5)
1 (1.3)
0 (0.0)
1 (1.8)
5
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Age, y Median IQR Male sex Body mass index
ASA class
21.78
21.0
18.51–23.33
17.93–23.60
8 (14.0)
6 (10.5)
0.191
WHO/ECOG performance status
0.235
0.448
0.491
0
78 (38.6)
37 (46.3)
25 (43.9)
23 (40.4)
1
62 (30.7)
23 (28.7)
15 (26.3)
21 (36.8)
2
43 (21.3)
16 (20.0)
12 (21.1)
11 (3.5)
3 4
15 (7.4) 1 (0.5)
2 (2.5) 1 (1.3)
5 (8.8) 0 (0.0)
2 (3.5) 0 (0.0)
Emergency surgery
1 (0.5)
0 (0.0)
0 (0.0)
0 (0.0)
Elective surgery
200 (99.0)
79 (98.8)
57 (100.0)
57 (100.0)
Previous abdominal surgery
70 (34.7)
20 (25.0)
0.246
10 (17.5)
16 (28.1)
0.18
Median
45.0
40.0
0.024
0.365
IQR
31.0–60.0
27.0–54.75
Mid
87 (43.1)
44 (55.0)
Lower
115 (56.9)
35 (43.8)
0.652
–
Tumor size, mm
Tumor site
43.0
40.0
35.0–59.0
30.0–55.0
33 (57.9)
31 (54.4)
23 (40.4)
26 (45.6)
0 (0.0)
0 (0.0)
0.046
T
0.536
0.007 3 (3.8)
0.893
is
4 (2.0)
1
9 (4.5)
11 (13.8)
5 (8.8)
4 (7.0)
2
43 (21.3)
26 (32.5)
14 (24.6)
18 (31.6)
3
60 (29.7)
20 (25.0)
18 (31.6)
19 (33.3)
4a 4b
79 (39.1) 7 (3.5)
19 (23.8) 1 (1.3)
19 (33.3) 1 (1.8)
15 (26.3) 1 (1.8)
0
134 (66.3)
56 (70.0)
35(61.4)
35 (61.4)
1a
26 (12.9)
8 (10.0)
6 (10.5)
6 (10.5)
1b
24 (11.9)
10 (12.5)
6 (10.5)
10 (17.5)
1c
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
2a
9 (4.5)
3 (3.8)
7 (12.3)
3 (5.3)
2b
9 (4.5)
3 (3.8)
3 (5.3)
3 (5.3)
N
0.956
UICC 7th disease stage
0.627
0.010
1.000
0
4 (2.0)
3 (3.8)
0 (0.0)
0 (0.0)
I
45 (22.3)
32 (40.0)
17 (29.8)
17 (29.8)
II
85 (42.1)
21 (26.3)
18 (31.6)
18 (31.6)
T. Hinoi et al. TABLE 2 continued Characteristic
Overall OP (n = 202)
III Postoperative chemotherapy
After matching LAP (n = 80)
68 (33.7)
24 (30.0)
(n = 68)
(n = 24)
1 (1.5) 67 (98.5)
0 24 (100)
P
OP (n = 57)
LAP (n = 57)
22 (38.6)
22 (38.6)
1.000
(n = 22)
(n = 22)
0 22 (100)
0 22 (100)
P
1.000
(stage III) Yes No
Data are presented as n (%) unless otherwise indicated OP open surgery, LAP laparoscopic surgery, IQR interquartile range, ASA American Society of Anesthesiologists, ECOG Eastern Cooperative Oncology Group, UICC Union for International Cancer Control
surgical damage between the two cancer types. Moreover, approximately 40 % of patients underwent a Hartmann’s operation or abdominoperineal resection and 3.5 and 8.8 % of patients underwent anterior resection with diverting stoma in open and laparoscopic surgery, respectively. Thus, almost 50 % of rectal cancer patients had some type of stoma (Table 3). The longer hospital stay for elderly rectal cancer patients might be due to a time needed to learn proper stoma management. Our data suggest that the length of the hospital stay for rectal cancer patients may depend on the type of operation, although LAP might be less invasive with limited complications as compared to OP. In colon cancer cases, the overall postoperative morbidity rates were 36.3 and 24.9 % in the OP and LAP groups, respectively (P \ 0.001, Table 4). A significant reduction in the occurrence of delirium, organ/space surgical site infection, and pneumonia was observed in the LAP group as compared to the OP group (P = 0.034, 0.033, and 0.019, respectively). In rectal cancer cases, the overall morbidity rates were 40.4 and 47.4 % in the OP and LAP group, respectively; however, this difference was not significant (P = 0.450). Postoperative mortalities included three patients who underwent OP for colon cancer. For colon cancer patients, the OS, DFS, and CSS did not significantly differ between LAP and OP patients (P = 0.916, 0.968, and 0.799, respectively), and the 3-year OS for the OP and LAP groups were 81.2 and 85.5 %, respectively. In addition, no significant differences were found between rectal cancer patients who underwent LAP and OP in terms of OS (HR 0.895; 95 % CI 0.432–1.857; P = 0.765), DFS (HR 0.800; 95 % CI 0.406–1.574; P = 0.516), and CSS (HR 0.967; 95 % CI 0.339–2.760; P = 0.950) (Fig. 1). In addition, OS, DFS, and CSS analyses showed no significant differences between the OP and LAP groups when the colon and rectal cancers were classified by stage (data not shown). With regard to effect of the postoperative chemotherapy on survival analysis in 479
stage III colon cancer patients, none (0 %) of 315 patients and 4 (2.4 %) of 164 patients received 5-FU based postoperative chemotherapy in OP and LAP group, respectively. However, only one patient was selected from LAP group after matching (Table 1). In rectal cancer one out of overall 92 stage III patients and none of 44 patients after matching received postoperative chemotherapy (Table 2). These results suggest that infrequent use of postoperative chemotherapy did not make any impact on our results. DISCUSSION In our study, no statistically significant differences in long-term outcomes were found in elderly colorectal cancer patients who underwent OP and LAP. To our knowledge, this is the first large-scale cohort study involving elderly patients (median age of 83.0 years in both the OP and LAP groups) that also studied the clinical feasibility of LAP for colon and rectal cancer, consistent with previous RCT studies in the general population with mean patient ages of 69–71 years and 68–71 years in the OP and LAP groups, respectively.3–9,19,20 Although an RCT would be ideal for confirming the feasibility of LAP in elderly patients, the increase in the incidence of postoperative morbidities and mortalities with advancing age may lead to investigators avoiding the inclusion of frail patients in prospective randomized trials.11–13 To circumvent the impracticability of RCT, we conducted a multicenter matched case–control study using a propensity scoring method. This method can reduce the selection bias inherent in retrospective nonrandomized regression analyses and simulate the conditions of RCTs.16,21–24 In addition, the differing percentage (0.0– 96.1 %) of the operative procedures in the enrolled elderly patients, giving priority to LAP, indicates the diversity of the selected facilities, which supports the validity of our analysis (data not shown).
Laparoscopic Surgery for Elderly CRC Patients TABLE 3 Operative results Characteristic
Colon cancer
Rectal cancer
OP (n = 402)
LAP (n = 402)
Ileocecal resection
11 (2.7)
20 (5.0)
Right hemicolectomy Transverse colectomy
178 (44.3) 31 (7.7)
168 (41.8) 35 (8.7)
Left hemicolectomy
81 (20.1)
92 (22.9)
Surgical procedure
P
OP (n = 57)
LAP (n = 57)
0.380
Sigmoidectomy
90 (22.4)
80 (19.9)
Hartmann operation
11 (2.7)
7 (1.7)
0.263
8 (14.0)
9 (15.8)
Abdominoperineal resection
15 (26.3)
13 (22.8)
High anterior resection
0 (0)
4 (7.0)
34 (59.6)
31 (54.4)
Low anterior resection Stoma
P
0.451
0.782
Permanent stoma
11 (2.7)
7 (1.7)
23 (40.4)
22 (38.6)
Diverting stoma
4 (1.0)
5 (1.2)
2 (3.5)
5 (8.8)
–
384 (95.5)
389 (96.8)
32 (56.1)
30 (52.6)
Unknown
4 (1.0)
1 (0.2)
1 (1.8)
Operative time, min Median IQR Blood loss, mL
148.0
201.0
114.0–186.0
155.0–240.0
Median
80.0
27
IQR
30.0–200.0
10.0–70.0
Median
14.0
14.0
IQR
8.0–22.0
9.0–21.0
\0.001
\0.001
189
291
149.0–237.5
204.0–350.5
299
70
145.0–4,350.0
40.0–202.5
11
12.5
7.0–19.0
6.25–16.0
Median
15.5
5.5
IQR
7.5–59.5
0–20.0
\0.001
\0.001
No. of resected lymph nodes 0.674
0.995
Circumferential resection margin, mm
Resection margin
0.156
0.121 0.850
R0
384 (99.2)
388 (98.2)
54 (94.7)
54 (96.4)
R1
2 (0.5)
7 (1.8)
2 (3.5)
1 (1.8)
R2
1 (0.3)
0 (0.0)
1 (1.8)
1 (1.8)
Unknown
15 (3.7)
7 (1.8)
0 (0.0)
1 (1.8)
Duration of hospital stay after surgery, d 13.0 11.0–20.0
12 9.0–15.0
\0.001
18 14.0–25.0
19 13.0–28.0
0.990
Median
3.0
2
\0.001
2
1
0.002
IQR
2.0–4.0
1.0–2.0
1.0–4.0
1.0–2.0
Median
5.0
3
4
3
IQR
3.0–6.0
3.0–5.0
3.0–6.0
2.0–6.0
Median
5.0
4
5
4
IQR
3.0–6.0
3.0–5.0
3.0–7.75
2.0–6.0
Median IQR Days to fluid diet
Days to solid diet \0.001
0.100
Days to feces after surgery
Data are presented as n (%) unless otherwise indicated OP open surgery, LAP laparoscopic surgery, IQR interquartile range
\0.001
0.033
T. Hinoi et al. TABLE 4 Comorbidities and postoperative morbidities Characteristic
Colon cancer
Rectal cancer
OP (n = 402)
LAP (n = 402)
Overall comorbidities
342 (85.1)
340 (84.6)
Diabetes mellitusa
52 (12.9)
57 (14.2
Respiratoryb Cardiacc
15 (3.7) 76 (18.9)
23 (5.7) 76 (18.9)
119 (29.6)
163 (40.5)
41 (10.2)
40 (10.0)
0.907
4 (7.0)
6 (10.5)
0.508
8 (2.0)
5 (1.2)
0.662
1 (1.8)
0 (0.0)
0.315
Hypertensiond Cerebrovascular
e
Steroid usef Overall postoperative morbidity
P
OP (n = 57)
LAP (n = 57)
0.981
47 (82.5)
49 (86.0)
0.456
0.606
7 (12.3)
6 (10.5)
0.768
0.184 1.000
2 (3.5) 10 (17.5)
7 (12.3) 12 (21.1)
0.082 0.635
0.001
11 (19.3)
16 (28.1)
0.271
\0.001
P
145 (36.3)
100 (24.9)
23 (40.4)
27 (47.4)
0.45
Delirium
39 (9.7)
23 (5.7)
0.034
4 (7.0)
5 (8.8)
0.918
Postoperative ileus
28 (7.0)
21 (5.2)
0.302
5 (8.8)
4 (7.0)
0.525
Pneumonia
12 (3.0)
3 (0.7)
0.019
2 (3.5)
0 (0.0)
0.118 0.274
Bleeding
3 (0.7)
5 (1.2)
0.477
1 (1.8)
0 (0.0)
39 (9.7)
32 (8.0)
0.384
4 (7.0)
5 (8.8)
0.918
Organ/space SSI
7 (1.7)
1 (0.2)
0.033
2 (3.5)
1 (1.8)
0.459
Anastomotic leak
2 (0.5)
4 (1.0)
0.412
0 (0.0)
4 (7.0)
0.054
Cardiovascular occurrence
2 (0.5)
1 (0.2)
0.563
0 (0.0)
0 (0.0)
–
Incisional SSI
Data are presented as n (%) OP open surgery, LAP laparoscopic surgery, SSI surgical site infection a
Diabetes mellitus include history of oral agents or insulin
b
Respiratory conditions include chronic obstructive pulmonary disease or current pneumonia
c
Cardiac conditions include: history of heart failure, arrhythmia or ischemic heart disease; previous coronary intervention or cardiac surgery
d
Hypertension requiring medication
e
Cerebrovascular conditions include hemiplegia, history of transient ischemic attacks, and cerebrovascular event with or without neurological deficit
f
Steroid use for any chronic condition
Although the current study is in agreement with previous prospective studies reporting that OS and DFS did not differ between LAP and OP patients, elderly patients are more likely to die of causes other than cancer, which can result in an apparent decrease in OS. Therefore, we evaluated the CSS, wherein the survival curve reached a state of equilibrium as time advanced. Ultimately, no significant differences were demonstrated in CSS between the OP and LAP groups. The short-term outcomes of this study demonstrated the benefits of using LAP in elderly patients. The overall morbidities and the number of cases of postoperative delirium, organ/space surgical site infection, and pneumonia were significantly reduced in the LAP group as compared to the OP group for colon cancer patients, while no differences in these parameters were observed among rectal cancer patients. These findings are also consistent with those of previous prospective trials.3–5,19,20 Elderly patients with colon cancer may receive greater benefits from LAP because there is a linear correlation between increasing age and the frequency of postoperative
morbidities, such as respiratory, cardiovascular, and neurological complications.11–15 We recognize that our data are not adequate for demonstrating a statistically significant benefit of LAP for rectal cancer in elderly patients, which has been reported in the general population.4 In the present study, a relatively small number of rectal cancer patients were studied as compared with colon cancer patients, indicating that further research is needed to determine the benefit of LAP in elderly patients with rectal cancer. With regard to the oncological quality of the surgery, the number of resected lymph nodes and resection margins did not differ significantly between the OP and LAP groups. Although the operative strategy was individualized and may have been somewhat restricted for elderly patients (e.g. limited lymphadenectomy) in approximately half of the participating institutions (data not shown), the median number of removed lymph nodes was between 11.0 and 14.0 in each group, which is consistent with other studies.3,4,25,26 Regarding conversion of LAP to OP, our data indicated conversion rates of 5.8 and 19.3 % in patients
Laparoscopic Surgery for Elderly CRC Patients Rectum
Colon LAP OP
0.8 0.6 0.4 3-year survival OP 81.2% LAP 85.5%
0.2
LAP OP
1.0
HR: 1.016 (0.749–1.380) P = 0.916
0.8
Overall Survival
1.0
Overall Survival
FIG. 1 Survival rate in different procedure groups for colon or rectal cancer. For colon cancer, the OS, DFS, and CSS did not differ between LAP and OP patients (P = 0.916, 0.968, and 0.799, respectively). The 3-year OS for the OP and LAP groups were 81.2 % and 85.5 %, respectively. No significant differences were found in the OS, DFS, and CSS for rectal cancer patients between the treatment groups (P = 0.765, 0.516, and 0.950, respectively)
0.6 0.4 3-year survival OP 70.2% LAP 78.6%
0.2 0.0
0.0 0
20
40
60
0
80
20
402 402
337 359
201 191
73 62
12 15
OP LAP
0.6 0.4 3-year survival OP 75.6% LAP 74.4%
0.2
HR: 1.006 (0.765–1.322) P = 0.968
Disease-Free Survival
Disease-Free Survival
0.8
57 57
42 49
28 25
8 7
2 3
0.8 0.6 0.4 3-year survival OP 63.4% LAP 74.6%
0.2
HR: 0.800 (0.405–1.574) P = 0.516
0.0
0
20
40
60
0
80
20
391 394
310 331
40
60
80
7 7
2 3
Time (Months)
Time (Months) Number of patients at risk
Number of patients at risk 196 175
72 58
12 14
OP LAP
55 55
38 43
27 24
1.0
0.8 0.6 0.4 3-year survival OP 92.3% LAP 93.4%
0.2
HR: 1.065 (0.657–1.726) P = 0.799
Cancer-specific survival
1.0
Cancer-specific survival
80
1.0
0.0
0.8 0.6 0.4 3-year survival OP 86.5% LAP 89.6%
0.2
HR: 0.967 (0.339–2.760) P = 0.950
0.0
0.0 0
20
40
60
0
80
20
337 359
60
80
8 7
2 3
Number of patients at risk
Number of patients at risk 402 402
40
Time (Months)
Time (Months) OP LAP
60
Number of patients at risk
1.0
OP LAP
40
Time (Months)
Time (Months) Number of patients at risk OP LAP
HR: 0.895 (0.432–1.857) P = 0.765
201 191
with colon and rectal cancer, respectively. The combined conversion rate for colon and rectal cancer was 7.4 %, which was lower than that described in previous reports (COST, 21 %; COLOR, 17 %; Asian, 23.2 %; and CLASICC, 29 %).3–5,26 This difference might be attributed to the learning curve of LAP because most of our surgeons performed LAP in elderly patients after adequate experience with the general population.
73 62
12 15
OP LAP
57 57
42 49
28 25
Our study has certain limitations. First, the retrospective data analyses were affected by selection bias. The propensity score method seeks to adjust for multiple covariates simultaneously and adequately; however, even this matching method cannot adjust for unobserved or unmeasured factors. Second, the use of postoperative chemotherapy for elderly patients and preoperative chemoradiotherapy for rectal cancer varied according to the
T. Hinoi et al.
facility. Almost half of the participating facilities were reluctant to use postoperative chemotherapy according to standard protocols for elderly patients (data not shown). In this study, the number of the colon cancer patients who received postoperative chemotherapy was 0 and 2.4 % overall and 0 and 0.8 % after matching in OP and LAP group, respectively. In rectal cancer, only one of overall 92 stage III patients received postoperative chemotherapy. Only two out of 114 rectal cancer patients received preoperative chemoradiotherapy after matching, which is not a standard practice in Japan because the efficacy of this treatment remains under debate. Therefore, the effects of preoperative chemoradiotherapy and postoperative chemotherapy are considered to be limited and may not have a significant influence on the conclusion of this study. Third, the number of patients in the rectal cancer group was lower than that in the colon cancer group in this study. Although, the feasibility of LAP for rectal cancer has been reported in the institutions that are members of the Japan Society of Laparoscopic Colorectal Surgery, the results of the present study may represent a learning curve for LAP in geriatric rectal cancer patients.27 A larger cohort study would therefore be ideal for confirming the efficacy of LAP in elderly patients with rectal cancer. Despite these limitations, our observations indicated that LAP in elderly patients has fewer incidences of postsurgical morbidities and is oncologically feasible, consistent with the results of previous RCTs in the general population. Hence, we believe that these results justify the implementation of LAP in the routine treatment practices for elderly patients with colorectal cancer. CONCLUSIONS Our matched case–control study suggested that the laparoscopic approach is not inferior to the open approach and that LAP can be an acceptable alternative to OP in extremely elderly patients with colon and rectal cancer. ACKNOWLEDGMENT We acknowledge the cooperation of the following doctors: Eiji Kanehira, Kunihisa Shiozawa, Ageo Central General Hospital; Hiroyuki Bando, Daisuke Yamamoto, Ishikawa Prefectural Central Hospital; Seigo Kitano, Masafumi Inomata, Tomonori Akagi, Oita University; Junji Okuda, Keitaro Tanaka, Osaka Medical College; Masayoshi Yasui, Osaka National Hospital; Kosei Hirakawa, Kiyoshi Maeda, Osaka City University; Akiyoshi Kanazawa, Osaka Red Cross Hospital; Junichi Hasegawa, Junichi Nishimura, Osaka Rosai Hospital; Ichio Suzuka, Kagawa Prefectural Central Hospital; Shintaro Akamoto, Kagawa University; Yosuke Fukunaga, Hiroya Kuroyanagi, Cancer Institute Ariake Hospital; Masaki Naito, Kitasato University; Takashi Ueki, Kyushu University; Takashi Yamaguchi, Koya Hida, Kyoto Medical Center; Yousuke Kinjo, Kyoto University; Yukihito Kokuba, Kyoto Prefectural University; Madoka Hamada, Kochi Health Sciences Center; Norio Saito, Masaaki Ito, National Cancer Hospital East; Jou Tashiro, Saitama Medical University; Toshimasa Yatsuoka, Saitama Cancer Center;
Tomohisa Furuhata, Kenji Okita, Sapporo Medical University; Yoshiro Kubo, Shikoku Cancer Center; Shuji Saito Yosuke Kinugasa, Shizuoka Cancer Center; Fumio Konishi, Saitama medical Center Jichi Medical University; Michitoshi Goto, Juntendo University; Junichi Tanaka, Shungo Endo, Showa University Northern Yokohama Hospital; Nobuyoshi Miyajima, Tadashi Suda, Tsukasa Shimamura, St. Marianna University; Yoshihisa Saida, Toshiyuki Enomoto, Toho University Ohashi Medical Center; Takeshi Naito, Tohoku University; Yasuhiro Munakata, Souichi Tagami, Nagano Municipal Hospital; Satoshi Maruyama, Niigata Cancer Center Hospital; Takao Ichihara, Nishinomiya Municipal Central Hospital; Hitoshi Idani, Fukuyama Municipal Hospital; Yasuhiro Miyake, Minoh City Hospital; Shoichi Hazama, Yamaguchi University; and Kazuteru Watanabe, Yokohama City University Medical Center. This study was supported by the Japanese Society for Cancer of the Colon and Rectum. DISCLOSURE
The authors declare no conflict of interest.
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