Jpn J Clin Oncol 2014;44(7)677– 685 doi:10.1093/jjco/hyu051 Advance Access Publication 3 May 2014
Incidence and Risk Factors of 30-Day Early and 90-Day Late Morbidity and Mortality of Radical Cystectomy During a 13-Year Follow-up: A Comparative Propensity-score Matched Analysis of Complications Between Neobladder and Ileal Conduit Sung Han Kim1, Ami Yu2, Jae Hyun Jung3, Young Ju Lee3 and Eun-Sik Lee3,* 1
*For reprints and all correspondence: Eun-Sik Lee, Department of Urology, Seoul National University Hospital, 101 Daehak-ro, Yongon-dong, Jongno-gu, Seoul 110-744, Korea. E-mail: [email protected] Received October 8, 2013; accepted March 25, 2014
Objective: We report on the short and late morbidity and mortality of ileal conduit and neobladder after radical cystectomy with their associated risk factors. Methods: We retrospectively collected data on 308 non-metastatic bladder cancer patients who underwent radical cystectomy with either ileal conduit or neobladder for a curative intent from January 1999 to December 2011. Post-operative morbidity and mortality of 30-day (early) and 90-day (late) complication with their risk factors were examined in association with different types of urinary diversion. A comparative analysis using propensity-score matching was performed with matching variables of age, sex, number of underlying diseases and pathologic T and N stages, lymph node dissection, operative time and time of surgical year for comparison of the early and late morbidities between ileal conduit and neobladder. Results: During the median follow-up of 46.6 months, early and late morbidities were 29.5% (n ¼ 91) and 19.8% (n ¼ 61), and complication-related mortalities were 2.2 and 6.6%, respectively. The type of urinary diversion significantly affected only the late complications (early: neobladder 57 vs. ileal conduit 47, P ¼ 0.096; late: neobladder 67 vs. ileal conduit 37, P , 0.001). However, after propensity-score matching, no significant differences in early and late morbidities were observed between neobladder and ileal conduit. For risk factors of morbidity, number of removed lymph node states and hypertension were independently significant for both early and late complications (P , 0.05). Conclusions: The type of urinary diversion affected only late complication, however, results of the matching analysis showed no significant differences in early and late morbidities between neobladder and ileal conduit . Key words: bladder cancer – complication – mortality – cystectomy – radical – risk factor – incidence
INTRODUCTION Radical cystectomy (RC) with urinary diversion is regarded as a standard procedure for treatment of a growing number of muscle-invasive or high-risk bladder cancers (BC) (1), and a time consuming and complex surgical procedure in urology in
association with various minor and major post-operative complications (Cxm), with reported morbidity and mortality rates of 20 – 64% and 0.3 – 9.5%, respectively (2 – 7). However, considerable improvements in both surgical technique and perioperative management of RC have recently resulted in a decrease of post-operative morbidity and mortality (1,8,9).
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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Department of Urology, National Cancer Center, Goyang, 2Department of Biometric Research Branch, National Cancer Center, Goyang, and 3Department of Urology, Seoul National University Hospital, Seoul, Korea
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PATIENTS AND METHODS This study was approved by an ethics committee and institutional review board at Seoul National University Hospital (IRB No. H1208-136-423). We retrospectively reviewed the medical records of 366 consecutive patients who underwent RC with orthotopic Neo or non-orthotopic IC urinary diversion performed by a single surgeon (ESL) at a tertiary referral teaching center from January 1999 until December 2011. Those who had received neoadjuvant chemotherapy for BC were also included. However, 35 patients with RC either for palliative purposes or follow-up loss or incomplete medical records, and another 23 consecutive early cases (14 Neo and nine IC) in consideration of surgeon’s overcoming the learning curve of RC were also excluded; resulting in a total enrollment of 308 patients. Indications for a Neo included the absence of locally advanced disease, the absence of disease at the level of the bladder neck and prostatic urethra and patient request for orthotopic bladder substitution. Common contraindications of Neo were significant comorbidity and patient unwillingness, or inability to comply with the voiding habit required for the Neo. In general, men underwent either an IC or a Neo; most women underwent IC diversion because of preexisting incontinence, pelvic prolapse and surgeon preference. PERIOPERATIVE PREPARATION Patients were placed on a liquid diet and underwent bowel preparation the day before surgery. Compression leg stockings were applied routinely. All patients received a routine
intravenous antibiotic with a third generation antibiotic just one time before and continuously after RC for 3 days. Whenever feasible, patients received epidural application of local anesthetics and pain killing drugs intraoperatively in order to reduce the need for general anesthesia and postoperative pain. A nasogastric tube was placed during the operation for decompression of the stomach and bowel, and was removed at post-operative 3 – 5 days. Ureteric stents were inserted intraoperatively and removed at 7 – 14 days after surgery. Urethral catheters were removed the following day after removal of the stents. For Neo, irrigation was started from the third postoperative day (POD) and mucus was actively aspirated using 50 cc saline three times daily. Any symptomatic pyuria was treated medically until the urine was sterile and symptoms had disappeared. Patients were encouraged to drink 2 – 3 l fluid daily without ileus. Blood gases were controlled regularly and negative base excess was treated adequately with medication.
OPERATIVE TECHNIQUE OF RC Lymph node dissection (LND) and its extent of dissection (limited, standard and extended) (15,16) were decided according to surgeon decision and their clinical stages in which any nodal involvement during preoperative imaging work ups or intraoperative suspicious LN enlargements were indicated. The types of diversion were determined under the aforementioned indications. Briefly, a portion of terminal ileum measuring 40–50 cm in length for Neo or 15 cm for IC was harvested 25 cm proximal to the ileocecal valve. The ureteroileal anastomosis was formed using a serous-lined extramural tunnel technique or a freely refluxing, open end-to-side anastomosis (17). Most of our Neo techniques used a freely refluxing technique with bilateral afferent limbs and ipsilateral Wallace or Bricker anastomoses of the spatulated ureters in order to protect ureteroenteric anastomosis from obstructive stricture and urinary leakage.
POST-OPERATIVE FOLLOW-UP SCHEDULE The schedule for follow-up was determined according to the pathology results. Examinations were performed with special regard for Cxm, Neo function and oncological outcome. Regular follow-up examinations included physical examination, blood chemistry studies, complete blood count, urinary analysis, urine cytology, chest X-ray and excretory urography or enhanced computed tomography (CT) of the abdomen and pelvis. Additional imaging, including retrograde ileo-urography, was performed if warranted based on unexplained symptoms or clinical concern. In the absence of recurrence for 5 years after RC, the interval between examinations was extended based on the decision of the physician. Patients diagnosed with local recurrence of urinary upper tract recurrence underwent systemic metastatic evaluation, including bone scan or positron emissiontomography CT (PET-CT).
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These technical and perioperative advancements in management of RC have enabled both clinicians and patients to decide on urinary diversion because of its sensitive functional outcome of orthotopic reservoir of urinary reconstruction to divert urine, for control of cancer recurrence, and for protection of the upper urinary tract. Nonetheless, clinicians have still attempted to determine the predicative and prognostic risk factors associated with post-operative Cxm after RC. From previous reports on comparison of morbidity and mortality associated with Cxm after RC, differences in types of diversion have resulted in different rates of morbidity and mortality (9 – 11). Chahal et al. (12) reported that mostly two-thirds of complication-related mortality after RC occurred between post-operative 30 and 90 days. The cutoff points of 30 and 90 days have mostly been considered standard for early and late complications (10,13,14). In this study, we performed a retrospective review for comparison of our institutional perioperative morbidity and mortality of early (post-operatively within 30 days) and late (within between 30 and 90 days) Cxms between patients treated with neobladder (Neo) and ileal conduit (IC) after RC, after adjusting the inherently affecting factors with propensity-score matching analysis. In addition, we analyzed predictive risk factors for Cxms between two urinary diversions.
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EARLY AND LATE CXM Early and late Cxms were defined as Cxm that developed postoperatively within 30 days and between 30 and 90 days (12,18). Cxm were defined and graded according to a modified Dindo – Clavien classification (19) and were divided into minor (Grade 1 – 2) and major Cxms (Grade 3 – 4), separately. Major Cxm included death, cardiovascular (i.e. myocardial infarction), respiratory (i.e. pulmonary embolus, respiratory failure) and cerebrovascular accidents. Minor Cxms other than major Cxms were recorded by the treating clinicians. STATISTICAL ANALYSIS
PROPENSITY-SCORE MATCHED ANALYSIS To limit inherent baseline differences in patients and other factors between patients receiving a Neo and IC, we performed a one-to-one propensity-score matched analysis (20 – 22). Propensity scores were computed by modeling a logistic regression with the dependent variable as the odds of undergoing a Neo, and the independent variables as age, sex, body mass indices (BMI), underlying disease, pathologic T and N stages, LND, operative time and year of surgery. Subsequently, covariate balance between the matched groups of Neo and IC was examined among 247 patients after excluding those who had missing variables among nine parameters. The matching parameters were age (, 55 years, 55 – 65, 65 – 75 and 75,), sex (male and female), BMI (,25 kg/m2, 25–30 and 30,), pathologic T (T0/Ta/Tis, T1,T2,T3 and T4) and N (N0, N1, N2 and Nx) stages, performance of LND (yes or no), year of surgery (2000, 2001 – 05, 2006 – 10 and 2011), operative time (,330 min, 330 – 405, 460, for Neo ; ,280 min, 280 – 320, 410 for IC), and number of underlying diseases (0, 1, 2 and 3). Finally, within the post-propensity matched cohort, generalized linear mixed regression analyses were performed for
prediction of early and late morbidity, and their major and minor complications. All tests were two-sided with a statistical significance of P , 0.05. All analyses were performed using the statistical package for the SAS software (SAS system for Windows, version 9.2; SAS institute, Cary, NC) by a medical statistician (A.Y.).
RESULTS We identified 308 patients who underwent RC with either IC (n ¼ 161, 52.3%) or Neo (n ¼ 147, 47.7%), and their comparative demographics are described in Table 1. Age, sex ratio, total operative time, pathologic T and N stages, positive rate of resection margin, follow-up duration and survival differed significantly between Neo and IC (P , 0.05, Table 1). Overall survival was also significantly different, in that worse survival rate was observed for IC than for Neo (median survival time of Neo 96.4 vs. IC 51.6 months, P , 0.001; Fig. 1). Overall Cxm rates of early and late Cxms were 29.5% (n ¼ 91) and 19.8% (n ¼ 61) with overall mortality of 1.9% (n ¼ 6). Early Cxm-related mortality occurred in two patients whose major Cxms included one myocardial infarct, and one multi-organ failure after renal insufficiency and septicemia, whereas late mortality was observed in four patients, two who died of myocardial infarct and two who died of septicemiae (not shown in tables). Overall major and minor Cxms were 40.8 and 59.2% with a readmission rate of 56.6% (Table 2). In comparison of early and late Cxms between Neo and IC, the minor and major Cxms with their related mortalities and time to Cxm occurrence were not significantly different, except for significantly higher occurrence of late infection-related Cxm in IC, such as cholecystitis and septicemia (P ¼ 0.006). The incidence of early complication was insignificantly higher in Neo [Neo 57 (54.8%) vs. IC 47 (45.2%), P ¼ 0.339], whereas the major morbidity was higher in IC [Neo 11 (22.4%) vs. IC 16 (38.1%), P ¼ 0.569; Table 2]. More major and serious late Cxms occurred in IC, such as sepsis and cerebrovascular or cardiovascular Cxms, however, no significance was observed comparing with those of Neo (P . 0.05, Table 2). In addition, even after post-operative 90 days, five patients with four Neos and one IC were admitted to the emergency department, resulting in either surgical or interventional treatment. Those five Cxms included one adhesive ileus (POD 99) in IC, one bladder neck contracture (POD 99) in Neo, two urinary stones (POD 120 and 122) in each neo and IC, and one urinary retention .2 l (POD 366) in Neo (not shown in tables). For Cxm-related morbidities, results of Kaplan – Meier analyses showed that the type of urinary diversion did not significantly affect the early morbidity (P ¼ 0.096, Fig. 2A), whereas late Cxm was largely influenced by the types of urinary diversion of either IC or Neo in that the cumulative incidence of late Cxm was significantly different and greater in IC (P , 0.001, Fig. 2B). For the risk factors of morbidity between early and late Cxm and non-Cxm groups, number of removed LN [odds ratio (OR) 1.235, confidence interval (CI)
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Variables included preoperative patient demographics, operative parameters [operative time, type of urinary diversion (IC or Neo), LND and its extent (limited, standard and extended), number of positive LN, estimated blood loss and transfusion], post-operative parameters (minor and major Cxm, length of hospitalization, readmission, Cxm-related mortality and follow-up duration), pathological features and survival. National statistical data were used for analysis of mortality and causes of death from the Korean National Insurance Health organization, in which all cancer patients are automatically registered after their death. For statistical analysis, numerical variables with t-test and categorical variables with x 2and Fisher’s exact test were used for comparative analyses between IC and Neo. To define the overall survival and their associated risk factors for early and late Cxms, the Kaplan – Meier method, log-rank test and Cox proportional hazards analyses were applied using SPSS 17.0 (SPSS Inc., Chicago, IL, USA). All analyses were two-sided and significance was defined as P , 0.05.
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Table 1. Characteristics of total 308 patients Continent (n ¼ 161,52.3%)
Incontinent (n ¼ 147,47.3%)
Univariate P value
Male/female (n,%)
156 (96.9)/5(3.1)
115 (78.2)/32(21.8)
,0.001
Age (years)
59.4 + 9.4
67.1 + 8.9
,0.001
Body mass index (BMI) (kg/m2)
24.0 + 3.1
23.6 + 3.3
0.298
Diabetes
17 (10.6)
21 (14.3)
.0.050
Hypertension
41 (25.5)
49 (33.3)
Respiratory disease
12 (7.5)
12 (8.2)
Underlying disease (n,%)
ASA score 87 (54.0)
70 (47.6)
69 (42.9)
72 (49.0)
3
0.558
5 (3.1)
5 (3.4)
Hospital stay (days)
21.6 + 12.5
19.3 + 18.8
0.240
Follow-up duration (months)
59.3 + 32.6
47.2 + 27.5
0.032 ,0.001
Total operative time (min)
404.1 + 104.5
337.2 + 91.4
Estimated blood loss (ml)
821.3 + 496.3
843.5 + 589.3
0.731
Transfusion (n,%)
78 (48.5)
94 (63.9)
0.099
Intravesical chemotherapy (n,%)
22 (13.7)
22 (15.0)
0.748
Neoadjuvant chemotherapy (n,%)
36 (22.3)
26 (17.7)
0.276
Lymphovascular invasion (n,%)
42 (26.1)
44 (29.9)
0.504
Perineural invasion (n,%)
20 (12.4)
23 (15.6)
0.611
4 (2.4)
14 (9.5)
0.007
Resection margin positivity (n,%) Urethra
2 (1.2)
9 (6.1)
Ureter
2 (1.2)
4 (2.7)
Peribladder
0
1 (0.7)
8.7 + 6.0
8.7 + 5.4
0.291
None
36 (22.3)
40 (27.2)
0.771
Limited
37 (23.0)
31 (21.1)
Standard
85 (52.8)
72 (49.0)
Extended
3 (1.9)
4 (2.7)
Tis
12 (7.5)
10 (6.8)
Number of dissected lymph node (LN) (n,%) Extent of LN dissection (n,%)
Pathologic T stage (n,%) 0.004
Ta or T0
15 (9.3)
9 (6.1)
T1
39 (24.3)
24 (16.3)
T2
40 (24.8)
37 (25.2)
T3
48 (29.8)
38 (25.9)
T4
7 (4.3)
29 (19.7)
Low
57 (35.4)
51 (34.7)
High
104 (64.6)
96 (55.3)
Pathologic nodal positivity (n,%)
11 (6.8)
25 (17.0)
0.199
Local recurrence (n,%)
22 (13.7)
24 (16.3)
0.557 0.611
Nuclear grade (n,%)
Mean time to local recurrence (months)
19.6 + 17.1
16.7 + 13.1
Survival (n,%)
123 (76.4)
86 (59.3)
Median survival time (months)
96.4
ASA, American Society of Anesthesiologists score; Tis, T stage for carcinoma in situ.
51.6
0.518
0.004 ,0.001
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1.153 – 1.674], and hypertension variables (OR 0.339, CI 0.260 – 0.706) for early morbidity; and age (OR 1.067 CI 1.010 – 1.128), hypertension (OR 0.410, CI 0.175– 0.957), and number of removed LN (OR 1.054, CI 1.005 – 1.106) for late morbidity were suggested as being independently significant (P , 0.05). However, results of propensity-score matching analyses using nine parameters of age, sex, BMI, pathologic T and N stages, performance of LN dissection, year of surgery, operative time and number of underlying diseases showed that 46 pairs for early complications and 52 pairs for late complications were finally matched (Table 3). Comparison of morbidity and its major and minor severities graded using the Clavien – Dindo classification between Neo and IC showed that the early and late morbidities and their severities (major and minor Cxms) were not significantly different (Table 4).
DISCUSSION This retrospective study examined the clinical outcome of 30-day early and 90-day late morbidity and complicationrelated mortality with their risk factors after RC in patients with BC according to the different types of urinary diversion proportionally distributed without intra or interpersonal operative differences. A propensity-score matched analysis was used for comparison of their morbidity of major and minor Cxms between Neo and IC in order to limit inherent baseline clinicopathological differences in patients and operating factors. And the morbidity and its related mortality were not statistically different between neobladder and ileal conduit
similar to previous reports (P . 0.05, Table 2) (5,13,20,23). In addition, according to previous reports, no significant differences were observed in the overall Cxm rates of each urinary diversion, except that some predominant Cxms have been observed. The result of this study showed morbidity and mortality during early (29.5%/2.2%) and late (19.8%/6.6%) follow-up similar to results of previously reported largenumbered studies (11.0 – 57.2%/2.0 – 3.1% and 19.0 – 40.8%/ 5.7 – 8.3%, respectively) (2 – 6,10,12,18,23,24). Our result for morbidity was slightly low because Cxms in patients from follow-up loss and medical metabolic Cxms were not included in this study. Comparing between the overall Cxm and non-Cxm groups, almost all baseline clinicopathologic parameters were statistically similar between the Cxm and non-Cxm groups, except that the Cxm group had a higher rate of hypertension (Cxm 22.3% vs. non-Cxm 40.0%, P ¼ 0.021) and advanced disease states with nodal positivity (Cxm 0.7 + 1.7 vs. non-Cxm 2.0 + 0.7, P ¼ 0.040; not shown in tables). Among 91 (29.5%) early and 61 (19.8%) late patients with complications, patients who underwent Neo were significantly younger, with a greater predominance of males, and had fewer underlying diseases and longer operative time. The disease state was also less advanced in Neo (P , 0.05, Table 1). These differences had a direct influence on the different incidence rates of minor and major Cxms and different overall survival in that higher major morbidity and poorer survival were observed for IC than for Neo during the 13-year follow-up period (5-year-overall survival of IC 38% vs. Neo 59%, median survival time 51.6 vs. 96.4 months, P , 0.001, Table 1 and Fig. 1). The study showed that the early Cxm was more affected by the extent of difficulty and complexity of the operative procedure in RC, than by the type of urinary diversion (P ¼ 0.096, Fig. 2A); whereas, for the late Cxm, the type of urinary diversion was important for the different incidence of Cxm (P , 0.001, Fig. 2B). The reason that the different types did not affect development of early Cxms was that the postoperative 30 day period was a time for recovery of state, so that Cxms related to either type of continent or incontinent urinary diversion were not important risk factors for Cxm (Table 2). After post-operative 30 days, the types of urinary diversion were important for the occurrence of Cxm relating to each urinary diversion, such as stoma/conduit related Cxm in IC and voiding related Cxm in Neo. However, for the overall survival of RC patients, neither Cxm nor type of urinary diversion was an important risk factor (Fig. 1) (25). However, morbidity of RC has been significantly influenced by many factors, including age, baseline underlying diseases, operative skills and methods and disease status. Most previous studies did not include study of the morbidity of RC, after adjusting the inherent patient and provider parameters (3,9,26) and a few studies reported on the morbidity of RC after adjusting for few variables (20). Therefore, this study is significant because it used the propensity-score matched analyses with nine well-known factors for morbidities for comparison of
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Figure 1. Comparison of Kaplan-Meier survival curve between neobladder and ileal conduit after radical cystectomy.
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Morbidity of radical cystectomy in bladder cancer
Table 2. Thirty-day short- and 90-day long-term complication according to types of urinary diversion Complication parameters
Short-term complication
Long-term complication
Neobladder (n ¼ 161) Ileal conduit (n ¼ 147) P value Neobladder (n ¼ 161) Ileal conduit (n ¼ 147) P value Number of complicated patients (n,%)
49 (30.4)
42 (28.6)
0.064
25 (15.5)
36 (24.5)
0.062
Grade 1
20 (40.8)
17 (40.5)
0.339
Grade 2
18 (36.7)
9 (21.4)
5 (20.0)
13 (36.1)
0.183
3 (12.0)
5 (13.9)
Grade 3a
3 (6.2)
9 (21.4)
9 (36.0)
8 (22.2)
Grade 3b
8 (16.3)
7 (16.7)
8 (32.0)
9 (25.0)
Clavien– Dindo classification (n,%)
0
0
Minor
38 (77.6)
26 (61.9)
Major
11 (22.4)
16 (38.1)
0
1 (2.8)
0.569
8 (32.0)
18 (50.0)
17 (68.0)
18 (50.0)
0.484
8 (5.0)
14 (9.5)
0.188
Patients with multiple complication (n,%) 7 (4.3)
6 (4.1)
0.128
Readmission (n,%)
15 (9.3)
19 (12.9)
0.355
21 (13.0)
31 (21.1)
0.390
Complication-related mortality (n,%)
1 (0.6)
1 (0.7)
0.684
2 (1.2)
2 (1.4)
0.486
Time to complication occurrence (days)
11.6 + 6.5
9.4 + 5.3
0.070
49.4 + 11.6
42.7 + 10.2
0.055
Complications (n,%)
57
47
37
67
Ileus
22 (38.6)
18 (38.3)
0.835
8 (21.6)
13 (19.4)
0.257
Wound dehiscence
10 (17.5)
7 (14.9)
0.789
1 (2.7)
2 (3.0)
0.607
Respiratory complication
1 (1.8)
1 (2.1)
0.914
0
0
NA
Cardiovascular complication
1 (1.8)
5 (10.6)
0.092
0
2 (3.0)
0.227
Acute/chronic renal insufficiency
4 (7.0)
5 (10.6)
0.728
2 (5.4)
7 (10.4)
0.092
Ureteroenteric stricture/obstruction
1 (1.8)
3 (6.4)
0.332
3 (8.1)
4 (6.0)
0.713
Lymphocele or lymphedema
3 (5.3)
3 (6.4)
0.594
1 (2.7)
2 (3.0)
0.607
Urinary tract Infection/ pyelonephritis
11 (19.2)
4 (8.5)
0.156
4 (10.8)
8 (11.9)
0.241
Voiding problem including stone
2 (3.5)
0
0.498
5 (13.5)
2 (3.0)
0.451
Thromboembolism
2 (3.5)
1(2.1)
1.000
0
0
NA
Cholecystitis or sepsis
0
0
NA
0
4 (6.0)
0.006
Cerebrovascular complication
0
0
NA
0
1 (1.5)
0.477
Bladder neck or urethral stricture
0
NA
NA
5 (13.5)
NA
NA
Conduit/ chimney related complication
0
0
NA
2 (5.4)
4 (6.0)
0.430
Stoma related complication
NA
0
NA
NA
8 (11.8)
NA
Incisional or inguinal hernia
0
0
NA
5 (13.5)
6 (9.0)
0.762
Recto-vesical or ileo-cutaneous fistula
0
0
NA
1 (2.7)
4 (6.0)
0.196
early and late Cxms between Neo and IC. After controlling the nine parameters matched by propensity scores, the morbidity of major and minor early and late complications were insignificantly different (P . 0.05, Table 4). And nine parameters were age, sex, BMI, underlying disease, operating time, year of surgery, pathologic T and N stages and LND known for different risk factors affecting for post-operative complication of RC (Table 3) (2 – 7,9,10,24). The early morbidity showed higher and the major morbidity lower in Neo than in IC resulting indirectly in worse quality of life for Neo during early recovery (Table 2). This study is also meaningful in showing the clinicians’ misbelief that the
quality of life and prognosis might not be better in Neo than in IC in terms of Cxm because patients with Neo had a longer additional period of hospitalization for late Cxm (Neo 2.0 + 5.3 vs. IC 1.3 + 4.4 days, not shown in tables), and higher major morbidity (Neo 68.0% vs. IC 50.0%) during a much longer follow-up period (median survival time Neo 96.4 vs. IC 51.6 months, P , 0.001), causing difficulty and stress for clinicians after their discharge in believing that Neo might result in poorer quality of life. However, our data showed that, contrary to the belief that Neo and IC had no significant differences in morbidity and its related mortality, and the major morbidity was similar or higher in IC than in Neo treatment
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Jpn J Clin Oncol 2014;44(7)
suggesting better post-operative quality of life in Neo, similar to other studies (Table 2) (27,28). Regarding the reason for poor prognosis and quality of life of IC during late follow-up, it might be cautiously speculated that those IC patients had poorer baseline demographics and performance states, such as advanced disease states, old age, accessibility to the hospital in the case of severe Cxm and absence of caregivers, so that they did not qualify for the Neo preoperatively (26,29). Therefore, the post-recovery was expected to be poorer and major Cxms were higher in IC, especially for the
cerebrovascular/cardiovascular, infection-related Cxm and renal insufficiency, which were known to have a significant association with advancing age (13,26,28 – 30,31). According to previous reports, some predominant complications have been observed and some major Cxm rates differed according to their diversion type (5,13,20,23). In the series of 493 cases of RC from Takashige et al., they reported fewer major Cxms and more infection-related Cxms of the Neo than the IC, whereas patients in the IC group had more wound-related complications (13). In this study, the early Cxm showed insignificantly that Neo had fewer major Cxms and higher infection-related Cxms, whereas the late Cxms showed that IC had the higher major and infection-related Cxms than Neo (Table 2). The cholecystitis and infectionrelated complication such as sepsis occurred significantly higher in IC than in Neo during late follow-up (P ¼ 0.006, Table 2). The ileus and pyelonephritis were found to be the most frequently occurring Cxms, as in other studies (2,4,14), and Cxms relating to wound and renal insufficiency frequently occurred during early follow-up, whereas Cxm relating to urinary excretions, such as acute urinary retention, urinary calculi and hydronephrosis, occurred during late follow-up (10,26,30,31). Additionally for Cxms relating to the resection margin states, the positive margin rates differed significantly between Neo and IC (Table 1). IC had higher positive rates of resection margin, which referred to the advanced states of disease at the time of the operation. In spite of serial frozen analyses of resection margin at urethra and ureter until intraoperatively clear resection states, the final pathology reported the converted rates of resection margin [ureter 1.9% (n ¼ 6), and urethra 3.6% (n ¼ 12)]. These positive resection margin states would be related to local recurrences (n ¼ 5, 10.9%) of ureteroenteric (n ¼ 2) and urethro-enteric anastomosis (n ¼ 1) and pelvic local recurrences (n ¼ 2) for Neo and IC, resulting in ureteroenteric obstruction (n ¼ 2 for Neo and IC) and voiding problem (n ¼ 1 for Neo) causing hydronephrosis (n ¼ 1 for IC), acute pyelonephritis (n ¼ 1 for Neo) and gross hematuria (n ¼ 1 for Neo). As for the predictive risk factor of early (n ¼ 91) and late Cxms (n ¼ 61) after comparison with the other non-Cxm group (early n ¼ 217 and late n ¼ 247), age, hypertension and number of removed LN were commonly significant factors (P , 0.05, not shown in tables). This meant that in patients with older age with hypertension who underwent RC with a more aggressively dissected procedure due to LN extent and more advanced disease states, higher morbidity can be expected during short and late follow-up. Regarding the Cxm-related mortality of the six deaths without preoperative underlying diseases except for hypertension, renal insufficiency, cardiac (myocardial infarct, and heat failure) and infectious Cxm (multi-organ failure due to sepsis) were found to be major causes of death. Therefore, serious consideration and active management with caution would be important to lowering the mortality rates when these related clinical signs and Cxms are observed.
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Figure 2. The comparison of cumulative incidence of (A) early and (B) late morbidities between neobladder and ileal conduit.
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Morbidity of radical cystectomy in bladder cancer
Table 3. Demographics of propensity matching paired group of early and late complications according to nine parameters Matching parameters Early complication (46 matched pairs)
Table 4. Comparative results of early and late incidence of complication and their severities between neobladder and ileal conduit after propensity-score matching analysis
Late complication (51 matched pairs)
Group
Neobladder Ileal conduit Neobladder Ileal conduit Age (n,%) ,55
Neobladder
Total
P value
0.197
Ileal conduit
Early complication 5 (10.9)
4 (8.7)
8 (15.7)
5 (9.8)
Complication
19 (41.3%)
14 (30.4%)
35 (38.0%)
55, ,65
13 (28.2)
17 (37.0)
20 (39.2)
17 (33.3)
No complication
27 (58.7%)
32 (79.6%)
57 (62.0%)
65, ,75
26 (56.5)
20 (43.5)
21 (41.2)
23 (45.1)
Minor Cxm
18
12
30
2 (4.3)
5 (10.9)
2 (3.9)
6 (11.8)
Major Cxm
1
2
3
F
5 (10.9)
2 (4.3)
3 (5.9)
4 (7.8)
M
41 (89.1)
44 (95.7)
48 (94.1)
47 (92.2)
75 Sex (n,%)
Late complication
,25
32 (69.6)
32 (69.6)
33 (64.7)
36 (70.6)
25– 30
12 (26.1)
14 (30.4)
12 (23.5)
14 (27.5)
6 (11.8)
1 (1.9)
2 (4.3)
0
No. of underlying diseases (n,%) 0
22 (47.8)
30 (65.2)
22 (43.1)
22 (43.1)
1
14 (30.4)
14 (30.4)
16 (31.4)
16 (31.4)
2
5 (10.9)
1 (2.2)
13 (25.5)
13 (25.5)
3
5 (10.9)
1 (2.2)
0
0
T0,Ta,Tis
11 (23.9)
3 (6.5)
5 (9.8)
5 (9.8)
T1
10 (21.7)
9 (19.6)
13 (25.5)
11 (21.5)
T2
8 (17.4)
10 (21.7)
13 (25.5)
14 (27.5)
T3
15 (32.7)
15 (32.6)
16 (31.4)
16 (31.4)
T4
2 (4.3)
9 (19.6)
4 (7.8)
5 (9.8)
N0
27 (58.7)
25 (54.3)
33 (64.7)
30 (58.8)
N1
4 (8.7)
6 (13.0)
4 (7.8)
6 (11.8)
N2
1 (2.2)
1 (2.3)
3 (5.9)
1 (2.0)
Nx
14 (30.4)
14 (30.4)
11 (21.6)
14 (27.4)
No
10 (21.7)
10 (21.7)
10 (19.6)
13 (25.5)
Yes
36 (78.3)
36 (78.3)
41 (80.4)
38 (74.5)
Complication No complication
8 (15.7%)
13 (25.5%)
43 (84.3%)
38 (74.5%)
21 (20.6%)
0.228
81 (79.4%)
Minor Cxm
4
7
11
Major Cxm
4
6
10
0.648
method of each urinary diversion (9,11) during the 13-year follow-up period. However, the strength of the current study is the significant detail in the analyzed data with matching to exclude the inherent selection bias and quantity of variables available for the risk analysis.
pT stage (n,%)
pN stage (n,%)
LN dissection (n,%)
This study demonstrated no significant differences of early and late morbidities between Neo and IC after adjusting the propensity-score matched variables with a low Cxm-related mortality. Attention should be given to risk factors such as age, hypertension and disease state at the time of patient selection and at the time of surgery. Efforts to further reduce morbidity and improve outcomes should continue.
Conflict of interest statement None declared.
References
Operative time (n,%) ,300
CONCLUSION
5 (10.9)
13 (28.3)
11 (21.6)
16 (31.4)
300–445
28 (60.9)
23 (50.0)
35 (68.6)
27 (52.9)
445,
13 (28.3)
10 (21.7)
5 (9.8)
8 (15.7)
The current study has limited points of the non-randomized nature of the study with risk of under reporting of morbidity data from follow-up losses. Some minor Cxm (especially metabolic Cxm) may not have been recorded; however, it is not likely that major Cxm or deaths were missed. Another limitation is that we did not consider the specific operative
1. Stenzl A, Cowan NC, De Santis M, et al. The updated EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 2009;55: 815 –25. 2. Knap MM, Lundbeck F, Overgaard J. Early and late treatment-related morbidity following radical cystectomy. Scand J Urol Nephrol 2004;38:153–60. 3. Novara G, De Marco V, Aragona M, et al. Complications and mortality after radical cystectomy for bladder transitional cell cancer. J Urol 2009;182:914 –21. 4. Novotny V, Hakenberg OW, Wiessner D, et al. Perioperative complications of radical cystectomy in a contemporary series. Eur Urol 2007;51: 397–401. 5. Parekh DJ, Gilbert WB, Koch MO, Smith JA, Jr. Continent urinary reconstruction versus ileal conduit: a contemporary single-institution
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BMI (n,%)
.30
0.561
Jpn J Clin Oncol 2014;44(7)
6.
7. 8. 9. 10. 11.
12.
14.
15.
16.
17.
18.
19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205 –13. 20. Roghmann F, Becker A, Trinh QD, et al. Updated assessment of neobladder utilization and morbidity according to urinary diversion after radical cystectomy: A contemporary US-population-based cohort. Can Urol Assoc J 2013;7:E552–60. 21. 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. 22. Stukel TA, Fisher ES, Wennberg DE, Alter DA, Gottlieb DJ, Vermeulen MJ. Analysis of observational studies in the presence of treatment selection bias: effects of invasive cardiac management on AMI survival using propensity score and instrumental variable methods. JAMA 2007;297:278 –85. 23. Gore JL, Yu HY, Setodji C, Hanley JM, Litwin MS, Saigal CS. Urinary diversion and morbidity after radical cystectomy for bladder cancer. Cancer 2010;116:331– 9. 24. Clark PE, Stein JP, Groshen SG, et al. Radical cystectomy in the elderly: comparison of clinical outcomes between younger and older patients. Cancer 2005;104:36– 43. 25. Kulkarni JN. Perioperative morbidity of radical cystectomy: A review. Indian J Urol 2011;27:226– 32. 26. Froehner M, Brausi MA, Herr HW, Muto G, Studer UE. Complications following radical cystectomy for bladder cancer in the elderly. Eur Urol 2009;56:443– 54. 27. Hobisch A, Tosun K, Kinzl J, et al. Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001;19:18– 23. 28. Sogni F, Brausi M, Frea B, et al. Morbidity and quality of life in elderly patients receiving ileal conduit or orthotopic neobladder after radical cystectomy for invasive bladder cancer. Urology 2008;71: 919– 23. 29. Mogensen UM, Ersboll M, Andersen M, et al. Clinical characteristics and major comorbidities in heart failure patients more than 85 years of age compared with younger age groups. Eur J Heart Fail 2011;13:1216– 23. 30. Anderson S, Eldadah B, Halter JB, et al. Acute kidney injury in older adults. J Am Soc Nephrol 2011;22:28– 38. 31. Shimko MS, Tollefson MK, Umbreit EC, Farmer SA, Blute ML, Frank I. Long-term complications of conduit urinary diversion. J Urol 2011;185: 562– 7.
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comparison of perioperative morbidity and mortality. Urology 2000;55:852–5. Ramani VA, Bromage SJ, Clarke NW. A contemporary standard for morbidity and outcome after radical cystectomy. BJU Int 2009;104: 628 –32. Skinner DG, Crawford ED, Kaufman JJ. Complications of radical cystectomy for carcinoma of the bladder. J Urol 1980;123:640– 3. Rosario DJ, Becker M, Anderson JB. The changing pattern of mortality and morbidity from radical cystectomy. BJU Int 2000;85:427–30. Hautmann RE, Hautmann SH, Hautmann O. Complications associated with urinary diversion. Nat Rev Urol 2011;8:667– 77. Khalil el SA. Long term complications following ileal conduit urinary diversion after radical cystectomy. J Egypt Natl Canc Inst 2010;22:13 –8. Nieuwenhuijzen JA, de Vries RR, Bex A, et al. Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions. Eur Urol 2008;53:834 – 42. discussion 42– 4. Chahal R, Sundaram SK, Iddenden R, Forman DF, Weston PM, Harrison SC. A study of the morbidity, mortality and long-term survival following radical cystectomy and radical radiotherapy in the treatment of invasive bladder cancer in Yorkshire. Eur Urol 2003;43:246– 57. Abe T, Takada N, Shinohara N, et al. Comparison of 90-day complications between ileal conduit and neobladder reconstruction after radical cystectomy: a retrospective multi-institutional study in Japan. Int J Urol 2013. December 4 (online version of record published before inclusion in an issue). Stimson CJ, Chang SS, Barocas DA, et al. Early and late perioperative outcomes following radical cystectomy: 90-day readmissions, morbidity and mortality in a contemporary series. J Urol 2010;184:1296– 300. Dhar NB, Klein EA, Reuther AM, Thalmann GN, Madersbacher S, Studer UE. Outcome after radical cystectomy with limited or extended pelvic lymph node dissection. J Urol 2008;179:873 –8. Kitamura H. Editorial comment to stage-specific impact of extended versus standard pelvic lymph node dissection in radical cystectomy. Int J Urol 2013;20:398. Douglas MD, Scott McDougal W. Use of intestinal segments inurinary diversion. 10th edn. In: Kavoussi LR, Alan WP, Novick AC, Peters CA, editors. Philadelphia: WB Saunders, 2012. Liedberg F, Holmberg E, Holmang S, et al. Long-term follow-up after radical cystectomy with emphasis on complications and reoperations: a Swedish population-based survey. Scand J Urol Nephrol 2012;46:14– 8.
685
Incidence and Risk Factors of 30-Day Early and 90-Day Late Morbidity and Mortality of Radical Cystectomy During a 13-Year Follow-up: A Comparative Propensity-score Matched Analysis of Complications Between Neobladder and Ileal Conduit Sung Han Kim1, Ami Yu2, Jae Hyun Jung3, Young Ju Lee3 and Eun-Sik Lee3,* 1
*For reprints and all correspondence: Eun-Sik Lee, Department of Urology, Seoul National University Hospital, 101 Daehak-ro, Yongon-dong, Jongno-gu, Seoul 110-744, Korea. E-mail: [email protected] Received October 8, 2013; accepted March 25, 2014
Objective: We report on the short and late morbidity and mortality of ileal conduit and neobladder after radical cystectomy with their associated risk factors. Methods: We retrospectively collected data on 308 non-metastatic bladder cancer patients who underwent radical cystectomy with either ileal conduit or neobladder for a curative intent from January 1999 to December 2011. Post-operative morbidity and mortality of 30-day (early) and 90-day (late) complication with their risk factors were examined in association with different types of urinary diversion. A comparative analysis using propensity-score matching was performed with matching variables of age, sex, number of underlying diseases and pathologic T and N stages, lymph node dissection, operative time and time of surgical year for comparison of the early and late morbidities between ileal conduit and neobladder. Results: During the median follow-up of 46.6 months, early and late morbidities were 29.5% (n ¼ 91) and 19.8% (n ¼ 61), and complication-related mortalities were 2.2 and 6.6%, respectively. The type of urinary diversion significantly affected only the late complications (early: neobladder 57 vs. ileal conduit 47, P ¼ 0.096; late: neobladder 67 vs. ileal conduit 37, P , 0.001). However, after propensity-score matching, no significant differences in early and late morbidities were observed between neobladder and ileal conduit. For risk factors of morbidity, number of removed lymph node states and hypertension were independently significant for both early and late complications (P , 0.05). Conclusions: The type of urinary diversion affected only late complication, however, results of the matching analysis showed no significant differences in early and late morbidities between neobladder and ileal conduit . Key words: bladder cancer – complication – mortality – cystectomy – radical – risk factor – incidence
INTRODUCTION Radical cystectomy (RC) with urinary diversion is regarded as a standard procedure for treatment of a growing number of muscle-invasive or high-risk bladder cancers (BC) (1), and a time consuming and complex surgical procedure in urology in
association with various minor and major post-operative complications (Cxm), with reported morbidity and mortality rates of 20 – 64% and 0.3 – 9.5%, respectively (2 – 7). However, considerable improvements in both surgical technique and perioperative management of RC have recently resulted in a decrease of post-operative morbidity and mortality (1,8,9).
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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Department of Urology, National Cancer Center, Goyang, 2Department of Biometric Research Branch, National Cancer Center, Goyang, and 3Department of Urology, Seoul National University Hospital, Seoul, Korea
678
Morbidity of radical cystectomy in bladder cancer
PATIENTS AND METHODS This study was approved by an ethics committee and institutional review board at Seoul National University Hospital (IRB No. H1208-136-423). We retrospectively reviewed the medical records of 366 consecutive patients who underwent RC with orthotopic Neo or non-orthotopic IC urinary diversion performed by a single surgeon (ESL) at a tertiary referral teaching center from January 1999 until December 2011. Those who had received neoadjuvant chemotherapy for BC were also included. However, 35 patients with RC either for palliative purposes or follow-up loss or incomplete medical records, and another 23 consecutive early cases (14 Neo and nine IC) in consideration of surgeon’s overcoming the learning curve of RC were also excluded; resulting in a total enrollment of 308 patients. Indications for a Neo included the absence of locally advanced disease, the absence of disease at the level of the bladder neck and prostatic urethra and patient request for orthotopic bladder substitution. Common contraindications of Neo were significant comorbidity and patient unwillingness, or inability to comply with the voiding habit required for the Neo. In general, men underwent either an IC or a Neo; most women underwent IC diversion because of preexisting incontinence, pelvic prolapse and surgeon preference. PERIOPERATIVE PREPARATION Patients were placed on a liquid diet and underwent bowel preparation the day before surgery. Compression leg stockings were applied routinely. All patients received a routine
intravenous antibiotic with a third generation antibiotic just one time before and continuously after RC for 3 days. Whenever feasible, patients received epidural application of local anesthetics and pain killing drugs intraoperatively in order to reduce the need for general anesthesia and postoperative pain. A nasogastric tube was placed during the operation for decompression of the stomach and bowel, and was removed at post-operative 3 – 5 days. Ureteric stents were inserted intraoperatively and removed at 7 – 14 days after surgery. Urethral catheters were removed the following day after removal of the stents. For Neo, irrigation was started from the third postoperative day (POD) and mucus was actively aspirated using 50 cc saline three times daily. Any symptomatic pyuria was treated medically until the urine was sterile and symptoms had disappeared. Patients were encouraged to drink 2 – 3 l fluid daily without ileus. Blood gases were controlled regularly and negative base excess was treated adequately with medication.
OPERATIVE TECHNIQUE OF RC Lymph node dissection (LND) and its extent of dissection (limited, standard and extended) (15,16) were decided according to surgeon decision and their clinical stages in which any nodal involvement during preoperative imaging work ups or intraoperative suspicious LN enlargements were indicated. The types of diversion were determined under the aforementioned indications. Briefly, a portion of terminal ileum measuring 40–50 cm in length for Neo or 15 cm for IC was harvested 25 cm proximal to the ileocecal valve. The ureteroileal anastomosis was formed using a serous-lined extramural tunnel technique or a freely refluxing, open end-to-side anastomosis (17). Most of our Neo techniques used a freely refluxing technique with bilateral afferent limbs and ipsilateral Wallace or Bricker anastomoses of the spatulated ureters in order to protect ureteroenteric anastomosis from obstructive stricture and urinary leakage.
POST-OPERATIVE FOLLOW-UP SCHEDULE The schedule for follow-up was determined according to the pathology results. Examinations were performed with special regard for Cxm, Neo function and oncological outcome. Regular follow-up examinations included physical examination, blood chemistry studies, complete blood count, urinary analysis, urine cytology, chest X-ray and excretory urography or enhanced computed tomography (CT) of the abdomen and pelvis. Additional imaging, including retrograde ileo-urography, was performed if warranted based on unexplained symptoms or clinical concern. In the absence of recurrence for 5 years after RC, the interval between examinations was extended based on the decision of the physician. Patients diagnosed with local recurrence of urinary upper tract recurrence underwent systemic metastatic evaluation, including bone scan or positron emissiontomography CT (PET-CT).
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These technical and perioperative advancements in management of RC have enabled both clinicians and patients to decide on urinary diversion because of its sensitive functional outcome of orthotopic reservoir of urinary reconstruction to divert urine, for control of cancer recurrence, and for protection of the upper urinary tract. Nonetheless, clinicians have still attempted to determine the predicative and prognostic risk factors associated with post-operative Cxm after RC. From previous reports on comparison of morbidity and mortality associated with Cxm after RC, differences in types of diversion have resulted in different rates of morbidity and mortality (9 – 11). Chahal et al. (12) reported that mostly two-thirds of complication-related mortality after RC occurred between post-operative 30 and 90 days. The cutoff points of 30 and 90 days have mostly been considered standard for early and late complications (10,13,14). In this study, we performed a retrospective review for comparison of our institutional perioperative morbidity and mortality of early (post-operatively within 30 days) and late (within between 30 and 90 days) Cxms between patients treated with neobladder (Neo) and ileal conduit (IC) after RC, after adjusting the inherently affecting factors with propensity-score matching analysis. In addition, we analyzed predictive risk factors for Cxms between two urinary diversions.
Jpn J Clin Oncol 2014;44(7)
EARLY AND LATE CXM Early and late Cxms were defined as Cxm that developed postoperatively within 30 days and between 30 and 90 days (12,18). Cxm were defined and graded according to a modified Dindo – Clavien classification (19) and were divided into minor (Grade 1 – 2) and major Cxms (Grade 3 – 4), separately. Major Cxm included death, cardiovascular (i.e. myocardial infarction), respiratory (i.e. pulmonary embolus, respiratory failure) and cerebrovascular accidents. Minor Cxms other than major Cxms were recorded by the treating clinicians. STATISTICAL ANALYSIS
PROPENSITY-SCORE MATCHED ANALYSIS To limit inherent baseline differences in patients and other factors between patients receiving a Neo and IC, we performed a one-to-one propensity-score matched analysis (20 – 22). Propensity scores were computed by modeling a logistic regression with the dependent variable as the odds of undergoing a Neo, and the independent variables as age, sex, body mass indices (BMI), underlying disease, pathologic T and N stages, LND, operative time and year of surgery. Subsequently, covariate balance between the matched groups of Neo and IC was examined among 247 patients after excluding those who had missing variables among nine parameters. The matching parameters were age (, 55 years, 55 – 65, 65 – 75 and 75,), sex (male and female), BMI (,25 kg/m2, 25–30 and 30,), pathologic T (T0/Ta/Tis, T1,T2,T3 and T4) and N (N0, N1, N2 and Nx) stages, performance of LND (yes or no), year of surgery (2000, 2001 – 05, 2006 – 10 and 2011), operative time (,330 min, 330 – 405, 460, for Neo ; ,280 min, 280 – 320, 410 for IC), and number of underlying diseases (0, 1, 2 and 3). Finally, within the post-propensity matched cohort, generalized linear mixed regression analyses were performed for
prediction of early and late morbidity, and their major and minor complications. All tests were two-sided with a statistical significance of P , 0.05. All analyses were performed using the statistical package for the SAS software (SAS system for Windows, version 9.2; SAS institute, Cary, NC) by a medical statistician (A.Y.).
RESULTS We identified 308 patients who underwent RC with either IC (n ¼ 161, 52.3%) or Neo (n ¼ 147, 47.7%), and their comparative demographics are described in Table 1. Age, sex ratio, total operative time, pathologic T and N stages, positive rate of resection margin, follow-up duration and survival differed significantly between Neo and IC (P , 0.05, Table 1). Overall survival was also significantly different, in that worse survival rate was observed for IC than for Neo (median survival time of Neo 96.4 vs. IC 51.6 months, P , 0.001; Fig. 1). Overall Cxm rates of early and late Cxms were 29.5% (n ¼ 91) and 19.8% (n ¼ 61) with overall mortality of 1.9% (n ¼ 6). Early Cxm-related mortality occurred in two patients whose major Cxms included one myocardial infarct, and one multi-organ failure after renal insufficiency and septicemia, whereas late mortality was observed in four patients, two who died of myocardial infarct and two who died of septicemiae (not shown in tables). Overall major and minor Cxms were 40.8 and 59.2% with a readmission rate of 56.6% (Table 2). In comparison of early and late Cxms between Neo and IC, the minor and major Cxms with their related mortalities and time to Cxm occurrence were not significantly different, except for significantly higher occurrence of late infection-related Cxm in IC, such as cholecystitis and septicemia (P ¼ 0.006). The incidence of early complication was insignificantly higher in Neo [Neo 57 (54.8%) vs. IC 47 (45.2%), P ¼ 0.339], whereas the major morbidity was higher in IC [Neo 11 (22.4%) vs. IC 16 (38.1%), P ¼ 0.569; Table 2]. More major and serious late Cxms occurred in IC, such as sepsis and cerebrovascular or cardiovascular Cxms, however, no significance was observed comparing with those of Neo (P . 0.05, Table 2). In addition, even after post-operative 90 days, five patients with four Neos and one IC were admitted to the emergency department, resulting in either surgical or interventional treatment. Those five Cxms included one adhesive ileus (POD 99) in IC, one bladder neck contracture (POD 99) in Neo, two urinary stones (POD 120 and 122) in each neo and IC, and one urinary retention .2 l (POD 366) in Neo (not shown in tables). For Cxm-related morbidities, results of Kaplan – Meier analyses showed that the type of urinary diversion did not significantly affect the early morbidity (P ¼ 0.096, Fig. 2A), whereas late Cxm was largely influenced by the types of urinary diversion of either IC or Neo in that the cumulative incidence of late Cxm was significantly different and greater in IC (P , 0.001, Fig. 2B). For the risk factors of morbidity between early and late Cxm and non-Cxm groups, number of removed LN [odds ratio (OR) 1.235, confidence interval (CI)
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Variables included preoperative patient demographics, operative parameters [operative time, type of urinary diversion (IC or Neo), LND and its extent (limited, standard and extended), number of positive LN, estimated blood loss and transfusion], post-operative parameters (minor and major Cxm, length of hospitalization, readmission, Cxm-related mortality and follow-up duration), pathological features and survival. National statistical data were used for analysis of mortality and causes of death from the Korean National Insurance Health organization, in which all cancer patients are automatically registered after their death. For statistical analysis, numerical variables with t-test and categorical variables with x 2and Fisher’s exact test were used for comparative analyses between IC and Neo. To define the overall survival and their associated risk factors for early and late Cxms, the Kaplan – Meier method, log-rank test and Cox proportional hazards analyses were applied using SPSS 17.0 (SPSS Inc., Chicago, IL, USA). All analyses were two-sided and significance was defined as P , 0.05.
679
680
Morbidity of radical cystectomy in bladder cancer
Table 1. Characteristics of total 308 patients Continent (n ¼ 161,52.3%)
Incontinent (n ¼ 147,47.3%)
Univariate P value
Male/female (n,%)
156 (96.9)/5(3.1)
115 (78.2)/32(21.8)
,0.001
Age (years)
59.4 + 9.4
67.1 + 8.9
,0.001
Body mass index (BMI) (kg/m2)
24.0 + 3.1
23.6 + 3.3
0.298
Diabetes
17 (10.6)
21 (14.3)
.0.050
Hypertension
41 (25.5)
49 (33.3)
Respiratory disease
12 (7.5)
12 (8.2)
Underlying disease (n,%)
ASA score 87 (54.0)
70 (47.6)
69 (42.9)
72 (49.0)
3
0.558
5 (3.1)
5 (3.4)
Hospital stay (days)
21.6 + 12.5
19.3 + 18.8
0.240
Follow-up duration (months)
59.3 + 32.6
47.2 + 27.5
0.032 ,0.001
Total operative time (min)
404.1 + 104.5
337.2 + 91.4
Estimated blood loss (ml)
821.3 + 496.3
843.5 + 589.3
0.731
Transfusion (n,%)
78 (48.5)
94 (63.9)
0.099
Intravesical chemotherapy (n,%)
22 (13.7)
22 (15.0)
0.748
Neoadjuvant chemotherapy (n,%)
36 (22.3)
26 (17.7)
0.276
Lymphovascular invasion (n,%)
42 (26.1)
44 (29.9)
0.504
Perineural invasion (n,%)
20 (12.4)
23 (15.6)
0.611
4 (2.4)
14 (9.5)
0.007
Resection margin positivity (n,%) Urethra
2 (1.2)
9 (6.1)
Ureter
2 (1.2)
4 (2.7)
Peribladder
0
1 (0.7)
8.7 + 6.0
8.7 + 5.4
0.291
None
36 (22.3)
40 (27.2)
0.771
Limited
37 (23.0)
31 (21.1)
Standard
85 (52.8)
72 (49.0)
Extended
3 (1.9)
4 (2.7)
Tis
12 (7.5)
10 (6.8)
Number of dissected lymph node (LN) (n,%) Extent of LN dissection (n,%)
Pathologic T stage (n,%) 0.004
Ta or T0
15 (9.3)
9 (6.1)
T1
39 (24.3)
24 (16.3)
T2
40 (24.8)
37 (25.2)
T3
48 (29.8)
38 (25.9)
T4
7 (4.3)
29 (19.7)
Low
57 (35.4)
51 (34.7)
High
104 (64.6)
96 (55.3)
Pathologic nodal positivity (n,%)
11 (6.8)
25 (17.0)
0.199
Local recurrence (n,%)
22 (13.7)
24 (16.3)
0.557 0.611
Nuclear grade (n,%)
Mean time to local recurrence (months)
19.6 + 17.1
16.7 + 13.1
Survival (n,%)
123 (76.4)
86 (59.3)
Median survival time (months)
96.4
ASA, American Society of Anesthesiologists score; Tis, T stage for carcinoma in situ.
51.6
0.518
0.004 ,0.001
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Jpn J Clin Oncol 2014;44(7)
1.153 – 1.674], and hypertension variables (OR 0.339, CI 0.260 – 0.706) for early morbidity; and age (OR 1.067 CI 1.010 – 1.128), hypertension (OR 0.410, CI 0.175– 0.957), and number of removed LN (OR 1.054, CI 1.005 – 1.106) for late morbidity were suggested as being independently significant (P , 0.05). However, results of propensity-score matching analyses using nine parameters of age, sex, BMI, pathologic T and N stages, performance of LN dissection, year of surgery, operative time and number of underlying diseases showed that 46 pairs for early complications and 52 pairs for late complications were finally matched (Table 3). Comparison of morbidity and its major and minor severities graded using the Clavien – Dindo classification between Neo and IC showed that the early and late morbidities and their severities (major and minor Cxms) were not significantly different (Table 4).
DISCUSSION This retrospective study examined the clinical outcome of 30-day early and 90-day late morbidity and complicationrelated mortality with their risk factors after RC in patients with BC according to the different types of urinary diversion proportionally distributed without intra or interpersonal operative differences. A propensity-score matched analysis was used for comparison of their morbidity of major and minor Cxms between Neo and IC in order to limit inherent baseline clinicopathological differences in patients and operating factors. And the morbidity and its related mortality were not statistically different between neobladder and ileal conduit
similar to previous reports (P . 0.05, Table 2) (5,13,20,23). In addition, according to previous reports, no significant differences were observed in the overall Cxm rates of each urinary diversion, except that some predominant Cxms have been observed. The result of this study showed morbidity and mortality during early (29.5%/2.2%) and late (19.8%/6.6%) follow-up similar to results of previously reported largenumbered studies (11.0 – 57.2%/2.0 – 3.1% and 19.0 – 40.8%/ 5.7 – 8.3%, respectively) (2 – 6,10,12,18,23,24). Our result for morbidity was slightly low because Cxms in patients from follow-up loss and medical metabolic Cxms were not included in this study. Comparing between the overall Cxm and non-Cxm groups, almost all baseline clinicopathologic parameters were statistically similar between the Cxm and non-Cxm groups, except that the Cxm group had a higher rate of hypertension (Cxm 22.3% vs. non-Cxm 40.0%, P ¼ 0.021) and advanced disease states with nodal positivity (Cxm 0.7 + 1.7 vs. non-Cxm 2.0 + 0.7, P ¼ 0.040; not shown in tables). Among 91 (29.5%) early and 61 (19.8%) late patients with complications, patients who underwent Neo were significantly younger, with a greater predominance of males, and had fewer underlying diseases and longer operative time. The disease state was also less advanced in Neo (P , 0.05, Table 1). These differences had a direct influence on the different incidence rates of minor and major Cxms and different overall survival in that higher major morbidity and poorer survival were observed for IC than for Neo during the 13-year follow-up period (5-year-overall survival of IC 38% vs. Neo 59%, median survival time 51.6 vs. 96.4 months, P , 0.001, Table 1 and Fig. 1). The study showed that the early Cxm was more affected by the extent of difficulty and complexity of the operative procedure in RC, than by the type of urinary diversion (P ¼ 0.096, Fig. 2A); whereas, for the late Cxm, the type of urinary diversion was important for the different incidence of Cxm (P , 0.001, Fig. 2B). The reason that the different types did not affect development of early Cxms was that the postoperative 30 day period was a time for recovery of state, so that Cxms related to either type of continent or incontinent urinary diversion were not important risk factors for Cxm (Table 2). After post-operative 30 days, the types of urinary diversion were important for the occurrence of Cxm relating to each urinary diversion, such as stoma/conduit related Cxm in IC and voiding related Cxm in Neo. However, for the overall survival of RC patients, neither Cxm nor type of urinary diversion was an important risk factor (Fig. 1) (25). However, morbidity of RC has been significantly influenced by many factors, including age, baseline underlying diseases, operative skills and methods and disease status. Most previous studies did not include study of the morbidity of RC, after adjusting the inherent patient and provider parameters (3,9,26) and a few studies reported on the morbidity of RC after adjusting for few variables (20). Therefore, this study is significant because it used the propensity-score matched analyses with nine well-known factors for morbidities for comparison of
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Figure 1. Comparison of Kaplan-Meier survival curve between neobladder and ileal conduit after radical cystectomy.
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Morbidity of radical cystectomy in bladder cancer
Table 2. Thirty-day short- and 90-day long-term complication according to types of urinary diversion Complication parameters
Short-term complication
Long-term complication
Neobladder (n ¼ 161) Ileal conduit (n ¼ 147) P value Neobladder (n ¼ 161) Ileal conduit (n ¼ 147) P value Number of complicated patients (n,%)
49 (30.4)
42 (28.6)
0.064
25 (15.5)
36 (24.5)
0.062
Grade 1
20 (40.8)
17 (40.5)
0.339
Grade 2
18 (36.7)
9 (21.4)
5 (20.0)
13 (36.1)
0.183
3 (12.0)
5 (13.9)
Grade 3a
3 (6.2)
9 (21.4)
9 (36.0)
8 (22.2)
Grade 3b
8 (16.3)
7 (16.7)
8 (32.0)
9 (25.0)
Clavien– Dindo classification (n,%)
0
0
Minor
38 (77.6)
26 (61.9)
Major
11 (22.4)
16 (38.1)
0
1 (2.8)
0.569
8 (32.0)
18 (50.0)
17 (68.0)
18 (50.0)
0.484
8 (5.0)
14 (9.5)
0.188
Patients with multiple complication (n,%) 7 (4.3)
6 (4.1)
0.128
Readmission (n,%)
15 (9.3)
19 (12.9)
0.355
21 (13.0)
31 (21.1)
0.390
Complication-related mortality (n,%)
1 (0.6)
1 (0.7)
0.684
2 (1.2)
2 (1.4)
0.486
Time to complication occurrence (days)
11.6 + 6.5
9.4 + 5.3
0.070
49.4 + 11.6
42.7 + 10.2
0.055
Complications (n,%)
57
47
37
67
Ileus
22 (38.6)
18 (38.3)
0.835
8 (21.6)
13 (19.4)
0.257
Wound dehiscence
10 (17.5)
7 (14.9)
0.789
1 (2.7)
2 (3.0)
0.607
Respiratory complication
1 (1.8)
1 (2.1)
0.914
0
0
NA
Cardiovascular complication
1 (1.8)
5 (10.6)
0.092
0
2 (3.0)
0.227
Acute/chronic renal insufficiency
4 (7.0)
5 (10.6)
0.728
2 (5.4)
7 (10.4)
0.092
Ureteroenteric stricture/obstruction
1 (1.8)
3 (6.4)
0.332
3 (8.1)
4 (6.0)
0.713
Lymphocele or lymphedema
3 (5.3)
3 (6.4)
0.594
1 (2.7)
2 (3.0)
0.607
Urinary tract Infection/ pyelonephritis
11 (19.2)
4 (8.5)
0.156
4 (10.8)
8 (11.9)
0.241
Voiding problem including stone
2 (3.5)
0
0.498
5 (13.5)
2 (3.0)
0.451
Thromboembolism
2 (3.5)
1(2.1)
1.000
0
0
NA
Cholecystitis or sepsis
0
0
NA
0
4 (6.0)
0.006
Cerebrovascular complication
0
0
NA
0
1 (1.5)
0.477
Bladder neck or urethral stricture
0
NA
NA
5 (13.5)
NA
NA
Conduit/ chimney related complication
0
0
NA
2 (5.4)
4 (6.0)
0.430
Stoma related complication
NA
0
NA
NA
8 (11.8)
NA
Incisional or inguinal hernia
0
0
NA
5 (13.5)
6 (9.0)
0.762
Recto-vesical or ileo-cutaneous fistula
0
0
NA
1 (2.7)
4 (6.0)
0.196
early and late Cxms between Neo and IC. After controlling the nine parameters matched by propensity scores, the morbidity of major and minor early and late complications were insignificantly different (P . 0.05, Table 4). And nine parameters were age, sex, BMI, underlying disease, operating time, year of surgery, pathologic T and N stages and LND known for different risk factors affecting for post-operative complication of RC (Table 3) (2 – 7,9,10,24). The early morbidity showed higher and the major morbidity lower in Neo than in IC resulting indirectly in worse quality of life for Neo during early recovery (Table 2). This study is also meaningful in showing the clinicians’ misbelief that the
quality of life and prognosis might not be better in Neo than in IC in terms of Cxm because patients with Neo had a longer additional period of hospitalization for late Cxm (Neo 2.0 + 5.3 vs. IC 1.3 + 4.4 days, not shown in tables), and higher major morbidity (Neo 68.0% vs. IC 50.0%) during a much longer follow-up period (median survival time Neo 96.4 vs. IC 51.6 months, P , 0.001), causing difficulty and stress for clinicians after their discharge in believing that Neo might result in poorer quality of life. However, our data showed that, contrary to the belief that Neo and IC had no significant differences in morbidity and its related mortality, and the major morbidity was similar or higher in IC than in Neo treatment
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Jpn J Clin Oncol 2014;44(7)
suggesting better post-operative quality of life in Neo, similar to other studies (Table 2) (27,28). Regarding the reason for poor prognosis and quality of life of IC during late follow-up, it might be cautiously speculated that those IC patients had poorer baseline demographics and performance states, such as advanced disease states, old age, accessibility to the hospital in the case of severe Cxm and absence of caregivers, so that they did not qualify for the Neo preoperatively (26,29). Therefore, the post-recovery was expected to be poorer and major Cxms were higher in IC, especially for the
cerebrovascular/cardiovascular, infection-related Cxm and renal insufficiency, which were known to have a significant association with advancing age (13,26,28 – 30,31). According to previous reports, some predominant complications have been observed and some major Cxm rates differed according to their diversion type (5,13,20,23). In the series of 493 cases of RC from Takashige et al., they reported fewer major Cxms and more infection-related Cxms of the Neo than the IC, whereas patients in the IC group had more wound-related complications (13). In this study, the early Cxm showed insignificantly that Neo had fewer major Cxms and higher infection-related Cxms, whereas the late Cxms showed that IC had the higher major and infection-related Cxms than Neo (Table 2). The cholecystitis and infectionrelated complication such as sepsis occurred significantly higher in IC than in Neo during late follow-up (P ¼ 0.006, Table 2). The ileus and pyelonephritis were found to be the most frequently occurring Cxms, as in other studies (2,4,14), and Cxms relating to wound and renal insufficiency frequently occurred during early follow-up, whereas Cxm relating to urinary excretions, such as acute urinary retention, urinary calculi and hydronephrosis, occurred during late follow-up (10,26,30,31). Additionally for Cxms relating to the resection margin states, the positive margin rates differed significantly between Neo and IC (Table 1). IC had higher positive rates of resection margin, which referred to the advanced states of disease at the time of the operation. In spite of serial frozen analyses of resection margin at urethra and ureter until intraoperatively clear resection states, the final pathology reported the converted rates of resection margin [ureter 1.9% (n ¼ 6), and urethra 3.6% (n ¼ 12)]. These positive resection margin states would be related to local recurrences (n ¼ 5, 10.9%) of ureteroenteric (n ¼ 2) and urethro-enteric anastomosis (n ¼ 1) and pelvic local recurrences (n ¼ 2) for Neo and IC, resulting in ureteroenteric obstruction (n ¼ 2 for Neo and IC) and voiding problem (n ¼ 1 for Neo) causing hydronephrosis (n ¼ 1 for IC), acute pyelonephritis (n ¼ 1 for Neo) and gross hematuria (n ¼ 1 for Neo). As for the predictive risk factor of early (n ¼ 91) and late Cxms (n ¼ 61) after comparison with the other non-Cxm group (early n ¼ 217 and late n ¼ 247), age, hypertension and number of removed LN were commonly significant factors (P , 0.05, not shown in tables). This meant that in patients with older age with hypertension who underwent RC with a more aggressively dissected procedure due to LN extent and more advanced disease states, higher morbidity can be expected during short and late follow-up. Regarding the Cxm-related mortality of the six deaths without preoperative underlying diseases except for hypertension, renal insufficiency, cardiac (myocardial infarct, and heat failure) and infectious Cxm (multi-organ failure due to sepsis) were found to be major causes of death. Therefore, serious consideration and active management with caution would be important to lowering the mortality rates when these related clinical signs and Cxms are observed.
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Figure 2. The comparison of cumulative incidence of (A) early and (B) late morbidities between neobladder and ileal conduit.
683
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Morbidity of radical cystectomy in bladder cancer
Table 3. Demographics of propensity matching paired group of early and late complications according to nine parameters Matching parameters Early complication (46 matched pairs)
Table 4. Comparative results of early and late incidence of complication and their severities between neobladder and ileal conduit after propensity-score matching analysis
Late complication (51 matched pairs)
Group
Neobladder Ileal conduit Neobladder Ileal conduit Age (n,%) ,55
Neobladder
Total
P value
0.197
Ileal conduit
Early complication 5 (10.9)
4 (8.7)
8 (15.7)
5 (9.8)
Complication
19 (41.3%)
14 (30.4%)
35 (38.0%)
55, ,65
13 (28.2)
17 (37.0)
20 (39.2)
17 (33.3)
No complication
27 (58.7%)
32 (79.6%)
57 (62.0%)
65, ,75
26 (56.5)
20 (43.5)
21 (41.2)
23 (45.1)
Minor Cxm
18
12
30
2 (4.3)
5 (10.9)
2 (3.9)
6 (11.8)
Major Cxm
1
2
3
F
5 (10.9)
2 (4.3)
3 (5.9)
4 (7.8)
M
41 (89.1)
44 (95.7)
48 (94.1)
47 (92.2)
75 Sex (n,%)
Late complication
,25
32 (69.6)
32 (69.6)
33 (64.7)
36 (70.6)
25– 30
12 (26.1)
14 (30.4)
12 (23.5)
14 (27.5)
6 (11.8)
1 (1.9)
2 (4.3)
0
No. of underlying diseases (n,%) 0
22 (47.8)
30 (65.2)
22 (43.1)
22 (43.1)
1
14 (30.4)
14 (30.4)
16 (31.4)
16 (31.4)
2
5 (10.9)
1 (2.2)
13 (25.5)
13 (25.5)
3
5 (10.9)
1 (2.2)
0
0
T0,Ta,Tis
11 (23.9)
3 (6.5)
5 (9.8)
5 (9.8)
T1
10 (21.7)
9 (19.6)
13 (25.5)
11 (21.5)
T2
8 (17.4)
10 (21.7)
13 (25.5)
14 (27.5)
T3
15 (32.7)
15 (32.6)
16 (31.4)
16 (31.4)
T4
2 (4.3)
9 (19.6)
4 (7.8)
5 (9.8)
N0
27 (58.7)
25 (54.3)
33 (64.7)
30 (58.8)
N1
4 (8.7)
6 (13.0)
4 (7.8)
6 (11.8)
N2
1 (2.2)
1 (2.3)
3 (5.9)
1 (2.0)
Nx
14 (30.4)
14 (30.4)
11 (21.6)
14 (27.4)
No
10 (21.7)
10 (21.7)
10 (19.6)
13 (25.5)
Yes
36 (78.3)
36 (78.3)
41 (80.4)
38 (74.5)
Complication No complication
8 (15.7%)
13 (25.5%)
43 (84.3%)
38 (74.5%)
21 (20.6%)
0.228
81 (79.4%)
Minor Cxm
4
7
11
Major Cxm
4
6
10
0.648
method of each urinary diversion (9,11) during the 13-year follow-up period. However, the strength of the current study is the significant detail in the analyzed data with matching to exclude the inherent selection bias and quantity of variables available for the risk analysis.
pT stage (n,%)
pN stage (n,%)
LN dissection (n,%)
This study demonstrated no significant differences of early and late morbidities between Neo and IC after adjusting the propensity-score matched variables with a low Cxm-related mortality. Attention should be given to risk factors such as age, hypertension and disease state at the time of patient selection and at the time of surgery. Efforts to further reduce morbidity and improve outcomes should continue.
Conflict of interest statement None declared.
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Operative time (n,%) ,300
CONCLUSION
5 (10.9)
13 (28.3)
11 (21.6)
16 (31.4)
300–445
28 (60.9)
23 (50.0)
35 (68.6)
27 (52.9)
445,
13 (28.3)
10 (21.7)
5 (9.8)
8 (15.7)
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