Robot-Assisted Radical Cystectomy for Bladder Cancer in Octogenarians

Abstract

Objective:

To evaluate perioperative morbidity and mortality rate, a 3-year recurrence-free survival, and cancer-specific mortality rate in patients older than 80 years undergoing robot-assisted radical cystectomy (RARC).

Materials and Methods:

We retrospectively collected data of 155 consecutive patients who received RARC for muscle-invasive or high-risk nonmuscle-invasive urothelial carcinoma of the bladder between 2003 and 2014 at a high-volume robotic center. Diversion was performed intra- or extracorporeally according to the surgeon's preferences. Complications were graded according to the Clavien–Dindo system. Logistic regression analyses were used to assess the impact of age on postoperative outcomes.

Results:

Of 155 consecutive patients, 22 (14.2%) patients were 80 years or older. Octogenarians did not significantly differ from younger patients in ASA score (p = 0.4) and Charlson comorbidity index (p = 0.4). Prevalence of any grade and high-grade complications was similar in both groups (all p ≥ 0.6). Older patients had a significantly higher pathologic tumor grade (p = 0.04) and a lower use of pelvic lymphadenectomy (p < 0.001). No perioperative mortality rate was recorded within 90 days from surgery. Elderly patients had a similar risk of 3-year oncologic recurrence after surgery compared with their younger counterparts (odds ratio [OR] 1.63; p = 0.2). Conversely, the risk of cancer-specific mortality rate was significantly higher (OR 2.78; p = 0.02).

Conclusions:

Patients 80 years or older undergoing RARC for bladder cancer did not have a higher risk of peri- and postoperative morbidity and mortality rate and had a similar 3-year recurrence-free survival, suggesting that RARC can be safely performed in selected elderly patients by experienced surgeons.

Introduction

Nearly three-quarters of incident bladder cancers (BCas) are diagnosed in patients aged ≥65 years¹ and 40% of them are older than 75 years at the time of diagnosis.² Of note, BCa is one of the leading causes of cancer-related mortality rate in people aged more than 80 years.² Radical cystectomy (RC) with pelvic lymphadenectomy (PLND) and urinary diversion is the standard of care for both high-risk nonmuscle-invasive and muscle-invasive BCa.^3
–5 Figures from the United States show that a significant survival advantage associated with RC compared with bladder-sparing treatments, namely transurethral resection (TUR) of the bladder tumor with additional radiation, is observed especially in younger patients. Conversely, the overall and cancer-specific survival advantage associated with RC in patients older than 80 years is ∼3 and 15 months, respectively.² Of note, not all patients are appropriate candidates for RC and age is often a major consideration when considering the benefits and potential side effects of each treatment option.⁶ Despite the survival advantage of RC, it can be noted that this therapeutic approach is currently considered only in 14% of the BCa patients aged more than 80 years. Conversely, this figure is 49.4% in the age group of 65 to 79 years.⁷ This discrepancy is likely related to the fear of perioperative morbidity and mortality rate counterbalanced by a reduced survival benefit. With the aging of the European population, surgery in the elderly will become a pertinent and relevant issue.

Robot-assisted minimally invasive procedures offer the advantage of three-dimensional vision, precision, and ergonomics for the surgeon. This results in decreased estimated blood loss (EBL), decreased blood transfusion rates, diminished pain and opioid requirements, earlier time to oral intake, shorter hospital stay, fewer wound complications, and expedited perioperative and postoperative convalescence and recovery compared with traditional approaches.^8

–11 Nonetheless, limited data are available on the outcomes of robot-assisted radical cystectomy (RARC) in elderly patients.^12,13 A recent report evaluating 24 octogenarians who underwent RARC showed significant postoperative morbidity and mortality rate, thus questioning the safety of this surgical treatment.¹³ Conversely, a retrospective study of 23 patients who underwent RARC for BCa demonstrated acceptable perioperative outcomes associated with RARC, eventually supporting the feasibility of this approach.¹² However, this study did not report oncologic outcomes.

Under this light, we sought to comprehensively evaluate perioperative outcomes and the long-term cancer-specific mortality rate of RARC in BCa patients older than 80 years and to compare these results to their younger counterparts.

Materials and Methods

Study population

We retrospectively reviewed 155 consecutive patients who underwent RC for nonmetastatic BCa at the Onze-Lieve-Vrouw Hospital, Aalst, Belgium, from January 2004 to May 2014. Indications for RC were tumor invasion of the muscularis propria, high-grade invasive BCa associated with or without carcinoma in situ refractory to intravesical immunotherapy, or recurrent multifocal nonmuscle-invasive disease refractory to TUR and intravesical therapy. Neoadjuvant chemotherapy was selectively adopted, according to the treating physician's preference. Indications for an orthotopic ileal neobladder were absent locally advanced disease, absent disease at the level of the bladder neck and prostatic urethra, normal renal function, and patient request for orthotopic bladder substitution. Third-generation cephalosporin, low-molecular-weight heparin, and elastic compressive stockings were used as prophylaxis for infection and thromboembolic events in all patients. Mechanical bowel preparation was not routinely administered. RARC was performed by two surgeons, as previously reported.^14

–17 Postoperatively all patients had a nasogastric tube left in place for 24 to 48 hours and total parenteral nutrition was done until complete recovery of bowel motility after surgery, usually until postoperative day 3 or 4. Patients with a neobladder underwent a pouchogram on postoperative day 14 with the urethral catheter removed when there was no significant leakage. Double-J stents were typically left in place for 4 weeks after neobladder and 10 days after conduit.

Covariates and outcomes

Clinical stage was based on the histologic report of the TUR specimen, chest X-rays, and abdominal CT. Concomitant upper urinary tract transitional-cell carcinoma was evaluated by excretory urography or CT. Bone scans and brain CT were performed when suggested by signs and symptoms. Comorbidities were assessed by nonage adjusted Charlson comorbidity index. Clinical and pathologic staging was reported according to the 2002 TNM system.¹⁸ The WHO 1998 classification was used to assign the histologic tumor grade.¹⁹ All complications within 90 days of surgery were recorded, defined, and graded according to an established five-grade modification of the original Clavien system, including grade 0—no complications, grade 1—complications needing only oral medications or bedside intervention, grade 2—complications needing only intravenous medications, total parenteral nutrition, enteral nutrition, or blood transfusion, grade 3—complications needing interventional radiology, therapeutic endoscopy, intubation, angiography, or operation, grade 4—complications causing residual and lasting disability requiring major rehabilitation or organ resection, and grade 5—complications causing death.^15,20,21 Data on complications that developed after hospital discharge were collected by reviewing the electronic medical records at our outpatient clinic, where most patients were evaluated after discharge home, and by individually contacting patients, relatives, general practitioners, or local physicians.

Follow-up regimen

Patients were generally seen 2 months after discharge and then at least every 3 to 4 months for the first year, semiannually for the second year, and annually thereafter. Follow-up visits consisted of a physical examination and serum chemistry evaluation, including electrolytes, liver function tests, and alkaline phosphatase. Diagnostic imaging of the upper tracts and chest radiography were performed at least annually or when clinically indicated. Additional radiographic evaluations were performed at the discretion of the treating physician.

Statistical analysis

The chi-square test was used to assess differences in categoric variables between the two groups. Differences in variables with a continuous distribution across dichotomous categories were assessed using the Mann–Whitney test. Univariable and multivariable logistic regression models addressed the association of intracorporeal diversion with prolonged operative time, EBL, prolonged length of stay, postoperative any grade and high-grade complications. All multivariable regression analyses were adjusted for age, gender, Charlson comorbidity index, presence of hydronephrosis, clinical T stage (nonmuscle invasive vs muscle invasive), clinical N stage (No vs N+), tumor grade in TUR specimen, adoption of neoadjuvant chemotherapy, and diversion type (conduit vs neobladder/continent cutaneous). Odds ratio (OR) with 95% confidence intervals was used to report regression analyses. Statistical significance in this study was set as p < 0.05. All reported p-values are two sided. Analyses were performed with SPSS ver. 20.0 (SPSS, Inc., Chicago, IL).

Results

Patient characteristics

Table 1 shows the demographic, preoperative, and pathologic characteristics in this cohort. Twenty-two patients (14.2%) were 80 years or older with a median age of 82 years. Charlson comorbidity index (p = 0.4) and ASA score (p = 0.4) were similar in younger and older patients. Only the use of PLND (p < 0.001), the number of removed nodes (p < 0.001), and pathologic T stage (p = 0.04) were different between the groups. Surgical margins were positive in 9% of the patients. When stratified according to the pathologic tumor stage, this was 3% for pT0–1, 2.9% for pT2, and 20% for pT3–4.

Table 1.

Demographic, Preoperative, and Pathologic Characteristics of 155 Patients Treated with Robot-Assisted Radical Cystectomy for Bladder Cancer

		Age at surgery
Variable	Overall	<80 years, 133 (85.8%)	≥80 years, 22 (14.2%)	p
Age (years), median (IQR)	70 (61–77)	66 (60–74)	82 (80–84)	<0.001
BMI	26.5 (23.2–28.6)	26.6 (23.4–28.8)	24.6 (22.5–28.3)	0.48
Male gender, n (%)	128 (83)	113 (85)	15 (68.2)	0.059
Charlson comorbidity index, n (%)
0	52 (33.5)	47 (35.3)	5 (22.7)	0.4
1	37 (23.9)	31 (23.3)	6 (27.3)
≥2	66 (42.6)	55 (41.4)	11 (50)
ASA score, n (%)
1	13 (8.4)	13 (9.8)	0 (0)	0.4
2	81 (52.3)	69 (51.9)	12 (54.5)
3	60 (38.7)	50 (37.6)	10 (45.5)
4	1 (0.6)	1 (0.8)	0 (0)
Clinical ≥T2 stage, n (%)	101 (65)	43 (32.3)	11 (50)	0.2
Grade 3 urothelial cancer in TUR specimen, n (%)	119 (83)	101 (82.9)	18 (85.7)	0.9
Clinical N positive disease, n (%)	11 (7)	10 (7.8)	1 (4.5)	0.4
Presence of hydronephrosis, n (%)	43 (28)	36 (27.9)	7 (33.3)	0.3
Neoadjuvant chemotherapy, n (%)	32 (21)	29 (21.8)	3 (13.6)	0.3
Type of diversion, n (%)
Bricker	132 (85.2)	110 (82.7)	22 (100)	0.1
Neobladder	21 (13.5)	23 (15.8)	0 (0)
Continent cutaneous diversion	2 (1.3)	2 (1.5)	0 (0)
Diversion technique, n (%)
Intracorporeal	105 (67.7)	91 (68.4)	14 (63.6)	0.6
Extracorporeal	50 (32.3)	42 (31.6)	8 (36.4)
PLND, n (%)
Omitted	45 (29.6)	30 (23.1)	15 (68.2)	<0.001
Performed	110 (70.4)	103 (76.9)	7 (31.8)
Pathologic T stage, n (%)
≤T1	66 (43)	59 (43.5)	7 (31.8)	0.04
T2	34 (22)	32 (24.4)	2 (9.1)
≥T3	55 (35)	42 (32.1)	13 (59.1)
Number of removed nodes, median (IQR)	11 (6–17)	9.5 (1–15)	0 (0–2)	<0.001
Pathologic N positive disease, n (%)	28 (18)	26 (19.5)	2 (9.1)	0.19
High-grade cancer in RARC specimen, n (%)	118 (76)	102 (89.5)	16 (84.2)	0.4
Positive surgical margin, n (%)	14 (9)	12 (9)	2 (9.1)	0.9

ASA = American Society of Anesthesiologists; BMI = body mass index; IQR = interquartile range; PLND = pelvic lymphadenectomy; RARC = robot-assisted radical cystectomy; TUR = transurethral resection.

Perioperative outcomes

Table 2 summarizes the perioperative outcomes and complications stratified according to age at surgery. Overall, median operative time, EBL, length of stay, and reoperation rate were similar in both groups (all p > 0.05). No differences were noted between groups with respect to perioperative complications for low-grade as for high-grade and overall complications when subdivided accorded to the Clavien–Dindo system. There was no mortality rate in the first 90 postoperative days in the whole series.

Table 2.

Perioperative Outcomes and Complications

		Age at surgery
Variable	Cases (%)	<80 years	≥80 years	p
Operative time, median (IQR)^a	325 (247–371)	330 (270–370)	240 (220–240)	0.05
Estimated blood loss, median (IQR)^b	350 (240–500)	300 (200–437)	375 (260–460)	0.45
Length of stay, median (IQR)	13 (11–17)	13 (11–16)	14 (11–23)	0.18
Complications according to Clavien–Dindo, n (%)
0	71 (45.8)	62 (46.6)	9 (40.9)	0.7
1–2	58 (37.4)	48 (36.1)	10 (45.5)
3–5	26 (16.8)	23 (17.3)	3 (13.6)
Reoperation	18 (11.6)	15 (11.3)	3 (13.6)	0.7

Data available for 30 patients.

Data available for 102 patients.

Table 3 shows the impact of age (<80 years vs ≥80 years) on the risk of prolonged operative time, high-grade complications (Clavien–Dindo 3–5), and prolonged hospitalization. The risk of high blood loss (OR 0.73; p = 0.7) and high-grade complications (OR 0.69; p = 0.6) was not increased in the elderly.

Table 3.

Impact of Age (<80 vs ≥80) on the Risk of Prolonged Operative Time, High-Grade Complications (Clavien–Dindo 3–5), and Length of Hospitalization

	Odds ratio	95% Confidence interval	p
Blood loss >500 mL	0.73	0.13, 4.06	0.7
High-grade complications	0.69	0.17, 2.81	0.6
Length of stay >18 days	2.81	0.94, 8.41	0.06

Model adjusted for CCI, clinical stage, use of PLND, and diversion technique.

CCI = Charlson comorbidity index.

Survival analyses

Figure 1 shows the Kaplan–Meier analysis assessing BCa recurrence rates according to age at surgery (<80 years vs ≥80 years). Three-year recurrence-free survival estimates were 62.1% and 43.1% in younger and older patients (p = 0.06), respectively. Table 4 depicts Cox multivariable regression analyses assessing the impact of age on the risk of BCa recurrence. Patients older than 80 years did not have a significant higher risk of recurrence compared with younger patients after RARC (OR 1.63; p = 0.2). Only pathologic tumor stage ≥T3 (OR 2.39; p = 0.01) and positive lymph node status pN1–3 (OR 2.24; p = 0.01) were significant predictors of oncologic recurrence.

FIG. 1.

Kaplan–Meier analyses predicting recurrence according to age at surgery (<80 vs ≥80). Color images available online at www.liebertpub.com/end

Table 4.

Multivariable Cox Regression Analyses Predicting Recurrence

	Odds ratio	95% Confidence interval	p
Age ≥80 years	1.63	0.79, 3.38	0.18
Pathologic stage
≤T1	1 (Ref.)
T2	1.75	0.82, 3.71	0.14
≥T3	2.39	1.87, 4.84	0.01
pN1–3	2.24	1.21, 4.16	0.01
Positive margins	1.20	0.51, 2.84	0.6

Figure 2 shows the Kaplan–Meier analysis assessing cancer-specific mortality rates according to age at surgery (<80 years vs ≥80 years). Table 5 shows the multivariable Cox regression analyses predicting the cancer-specific mortality rate. Multivariable analyses indicate that the cancer-specific mortality rate was significantly higher in patients older than 80 years (OR 2.78; p = 0.02). Similarly, pathologic tumor stage pT3–4 (OR 3.33; p = 0.02) and positive lymph node status pN1–3 (OR 2.33; p = 0.045) were independent predictors of cancer-specific mortality rate.

FIG. 2.

Kaplan–Meier analyses predicting cancer-specific mortality rate according to age at surgery (<80 vs ≥80). Color images available online at www.liebertpub.com/end

Table 5.

Multivariable Cox Regression Analyses Predicting Cancer-Specific Mortality Rate

	Odds ratio	95% Confidence interval	p
Age ≥80 years	2.78	1.11, 7.04	0.02
Pathologic stage
≤T1	1 (Ref.)
T2	2.35	0.74, 7.54	0.14
≥T3	3.33	1.13, 9.83	0.029
pN1–3	2.33	1.02, 5.24	0.045
Positive margins	0.98	0.27, 3.47	0.97

Discussion

We analyzed the perioperative morbidity and mortality rate, recurrence, and cancer-specific mortality rate of RARC in patients older than 80 years performed by two experienced surgeons in a high-volume robotic center. We found that in carefully selected elderly patients undergoing RARC for high-risk, nonmuscle-invasive, and muscle-invasive BCa, peri- and postoperative morbidity and mortality rate, and 3-year recurrence-free survival rates were similar when compared with younger patients. Therefore, age by itself cannot be the only consideration for the indication for RARC in elderly.

The treatment of BCa in elderly patients remains a difficult issue for primary care physicians, oncologists, and urologists. Although multiple reports advocate consideration of cystectomy in the elderly,^7,22

–26 population-based data from the United States suggest that avoidance of cystectomy because of age still represents an issue. Significant comorbidities and shortened life expectancy often drive patients and physicians away from surgical management. Indeed, the overall complication rate of elderly patients undergoing open RC has been reported by several authors ranging up to 60%,^27

–30 with mortality rates exceeding 10%.³¹ The use of robot-assisted minimally invasive procedures could reduce morbidity. For example, Wang and colleagues found a significant decrease in blood loss and transfusion requirements as well as time to resumption of regular diet and length of hospital stay in their analysis of open vs robotic cystectomy.¹⁰ The current results of this series support the concept that RARC can be offered safely to carefully selected elderly.

In a retrospective review of 1142 patients, Donat and colleagues evaluated the morbidity and survival outcomes of octogenarians treated with RC at a tertiary cancer center. They found that octogenarians had a higher rate of minor (55% vs 50%) and major (17% vs 13%) complications than younger patients. However, this did not reach statistical significance. After adjusting for baseline characteristics, the risk of any complication was roughly flat across all ages. For major complications, risk appeared to increase slightly up to age 65 years and then plateau.³² After adjusting for deaths from other causes, the cumulative incidence of death from BCa in octogenarians was comparable to that in younger patients.³²

When RC is avoided in elderly because of fear of postoperative morbidity, TUR of the bladder tumor with additional external radiotherapy is often offered as an alternative treatment. Although lower than in the younger population, there is a marked overall survival benefit and cancer-specific survival advantage for RC compared with this bladder-sparing approach.² It appears that competing causes of mortality rate have a disproportionately negative effect in octogenarians relative to younger patients.² In this series, we tend to prove that RARC can be a valid option for elderly patients with both high-risk, nonmuscle-invasive and muscle-invasive BCa. With respect to per- and perioperative morbidity and mortality rate and low- and high-grade complications, we were not able to find a significant difference. Only pathologic tumor stage and lymph node status, but not age, were significant predictors of oncologic recurrence.

It should be mentioned that 3-year recurrence-free survival rates were lower in octogenarians although this was not statistically significant. Of note, we cannot exclude that larger series might lead to a significant difference in recurrence-free survival rates between octogenarians and younger patients. Further investigations are therefore needed to better address this issue. It is also important that the cancer-specific mortality rate was markedly higher in elderly. These observations can be at least, in part, explained by the significant higher pathologic tumor stage in elderly patients at one side and by the lower use of PLND in these patients on the other side. As already indicated, high pathologic tumor stage is an independent predictor of oncologic recurrence. Chamie and colleagues suggested that the survival benefit of RC in the elderly is mainly obtained by the performance of PLND. This is slightly in contrast to the younger patients who also benefit from an RC without PLND.² The lower use of PLND in octogenarians in this series was mainly the result of a multidisciplinary discussion between urologists, anesthesiologists, and patients. The aim of not performing the PLND was to lower the perioperative morbidity and to shorten the operative time in this fragile population. In constrast, our study shows that indications to RARC for both high-risk, nonmuscle-invasive and muscle-invasive BCa should not be based on chronologic age but based on a clinical selection of the fit geriatric patients. This study is also socially relevant. Indeed, the progressive aging of the population, major surgery in the elderly patient is a growing topic and the correct management of these patients is critical in this setting.

The main limitation of this study is represented by its retrospective nature. Moreover, the inclusion of a higher number of patients might have strengthened our results. In this light, further studies in a prospective, multicenter setting with larger numbers of patients are needed to validate our findings. It should also be noted that our study includes the learning curve period of surgeons performing RARC. Therefore, it might be hypothesized that after the widespread diffusion of the robotic approach in the treatment of BCa, further studies would report lower rates of complications even in the setting of elderly patients.

Conclusions

Patients of 80 years or older undergoing RARC for both high-risk, nonmuscle-invasive and muscle-invasive BCa did not have a higher risk of peri- and postoperative morbidity and mortality rate. Only pathologic tumor stage and pelvic lymph node status, and not age, were able to predict oncologic recurrence. In conclusion, RARC performed by experienced surgeons can be offered safely to carefully selected elderly patients.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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