Effect of Alvimopan on Return of Bowel Function After Robot-Assisted Radical Cystectomy

Abstract

Introduction:

Alvimopan has been shown to improve time to return of bowel function in patients undergoing bowel resection. The objective of this study is to determine if alvimopan has similar benefits for patients undergoing robot-assisted radical cystectomy (RARC).

Materials and Methods:

All RARC cases were reviewed from January 2008 to March 2012. All patients during this time were administered alvimopan unless they had been receiving narcotics preoperatively. Patients receiving alvimopan received a preoperative dose of 12 mg perorally and then were dosed twice daily for 7 days or until first bowel movement. Clinicopathologic outcomes were summarized and compared, and functional outcomes of treated patients were compared with outcomes of untreated patients.

Results:

One hundred seventeen RARCs meeting study criteria were performed. All urinary diversions used an extracorporeal approach. Urinary diversions consisted of 50 Studer neobladders, 22 Indiana pouches, and 45 ileal conduits. Fifty-four patients received alvimopan, and 63 did not. The median time to first bowel movement was 5 days in the alvimopan group and 6 days in the untreated group (P=.03). Median time to solid diet was 6 days in the treated group and 7 days in the untreated group (P=.03). There was a trend toward fewer hospital days in the alvimopan group (alvimopan, 8 days; untreated, 9 days; P=.1).

Conclusions:

Alvimopan administration appears to reduce the time to return of bowel function and initiation of diet following RARC. This was a trend toward shorter hospitalization in the alvimopan group. Alvimopan should be considered in ongoing research into protocols to aid in shorter convalescence following RARC.

Introduction

Radical cystectomy with intestinal reconstruction of the urinary tract remains the primary treatment for patients with muscle-invasive carcinoma of the bladder.^1,2 Open radical cystectomy has long been considered the gold-standard approach to this operation.³ However, since its introduction in 2003, robot-assisted radical cystectomy (RARC) has become increasingly popular in its utilization.^4–6 The drive behind this trend is the fact that cystectomy remains a relatively morbid operation with a significant complication rate and extended period of convalescence.⁷ Surgeons have therefore sought to extend the benefits of minimally invasive surgery to cystectomy, with the hope of reducing complications and promoting quicker return to normal function following surgery. There are also significant economic implications to improving outcomes following surgery given ongoing trends in reimbursements to hospitals for inpatient stays, as well as the burden of rising healthcare costs on society in general.

Despite trends toward the use of minimally invasive techniques for radical cystectomy, complication rates remain high, and hospital stays are generally long.^8,9 Intestinal-related complications are among the most common reasons for morbidity and longer length of stay following these procedures.^8,10,11 As a result, recent efforts to improve postcystectomy outcomes have primarily been focused on “fast-track” regimens aimed at reducing postoperative ileus.^10,12,13 These streamlined recovery protocols are generally derived from efforts in other disciplines such as general/colorectal surgery, where bowel resections are commonly used.^14,15

Alvimopan is a peripherally acting mu-opioid receptor antagonist. It does not cross the blood–brain barrier, so it does not compete with narcotic medications for the mu-opioid receptors in the brain responsible for the analgesic effects of these medications. However, alvimopan does compete with peripheral opioid receptors, such as those in the gastrointestinal tract, thought to be responsible for narcotic-induced constipation.¹⁶ The proposed mechanism of action for reduction of postoperative ileus is therefore that it allows patients to receive narcotics for pain control but blocks the constipating effects of these medications. Alvimopan is an oral drug that has been used perioperatively in patients undergoing bowel resection with promising results regarding reduced time to return of bowel function.^17,18 There are also reports of its effectiveness in open radical cystectomy.¹⁹ The objective of the current study is therefore to evaluate the effectiveness of alvimopan in reducing time to return of bowel function in a cohort of patients undergoing RARC.

Materials and Methods

All patients undergoing RARC for bladder cancer between January 2008 and March 2012 were considered for inclusion in this single-institution study. Patients were excluded if chart data explicitly documenting their time to return of bowel function were not available. Primary outcomes reviewed included time from surgery to first passage of flatus, first bowel movement, tolerance of solid diet, and date of discharge.

Four experienced surgeons performed >97% of the cystectomy portion of the procedure during the study time frame, although a single surgeon performed all of the urinary reconstructions. All surgeons used a similar technique, which has been previously described²⁰ but will be reviewed briefly here. A Veress needle is used to insufflate the abdomen at the umbilicus. The camera port is placed superior to the umbilicus in the midline. Three 8-mm robotic arm ports are used in a standard configuration for robotic pelvic surgery, although they are placed approximately 5 cm cephalad on the abdomen compared with prostatectomy (to aid with the extended lymphadenectomy). Two 12-mm assistant ports are used: one in the right lower quadrant above the iliac crest and the other in the midclavicular line 2 cm below the costal margin. Dissection posterior to the seminal vesicles and prostate is performed first. An extended lymphadenectomy is performed prior to cystectomy, extending from the inferior mesenteric artery at the most cephalad margin to the node of Cloquet and obturator lymph nodes at the caudal extent. The vascular pedicles to the bladder and prostate (in men) are then taken with an endoscopic stapler. In women, the anterior vagina, uterus, and ovaries are removed along with the bladder. The ureters are clipped with an identifying holding suture, and the left ureter is passed underneath the sigmoid colon mesentery. A small midline incision is made inferior to the umbilicus for specimen extraction. Through this same incision, intestinal reconstruction and ureterointestinal anastomoses are performed in an extracorporeal fashion. For neobladders, the infraumbilical incision is closed, and the urethroileal anastomosis is performed robotically.

Patients were extubated at the end of the operation at the discretion of the anesthesiologist. Nasogastric tubes were removed at the completion of the surgery or upon first extubation and were only replaced for persistent nausea and vomiting. Patients receiving chronic opioids prior to surgery were not eligible to receive alvimopan as per product labeling. All other patients received the same alvimopan regimen: a single 12-mg preoperative dose (within 5 hours of surgery) and then every 12 hours after surgery for 7 days or until their first bowel movement. Patients were also administered chewing gum daily. Patients were advanced to a clear liquid diet once they had passed flatus and then were given a solid diet once they had tolerated a clear liquid diet. Patients were discharged home when tolerating a solid diet, pain control was adequate with oral medications, and they were able to manage their activities of daily living.

Complications were graded according to the Clavien classification for postoperative complications.²¹ Clinicopathologic outcomes were summarized using frequencies and percentages for categorical data, and median and interquartile range (IQR) were used for continuous data elements. Parameters were compared between the treated and untreated patient cohorts using the chi-squared test or Fisher's test for categorical data elements and the Wilcoxon rank-sum test for continuous data.

Results

One hundred seventeen consecutive patients underwent RARC during the study time frame. Fifty-four patients (46%) received alvimopan, and 63 patients (54%) did not. Table 1 lists the preoperative demographics of the two groups. There were no significant differences with regard to gender, age, clinical stage, or American Society of Anesthesiologists class between untreated patients and those receiving alvimopan. Table 2 lists the perioperative data of the two groups. Overall, more patients underwent a continent diversion (Studer ileal neobladder, n=22 [19%]; Indiana pouch, n=50 [43%]) than ileal conduit (n=45 [38%]). However, the frequency of diversion types was similar between the alvimopan and untreated groups (P=.3) (Table 2). There were also no statistically significant differences between the two groups with respect to estimated blood loss, transfusion rates, utilization of cavernosal nerve sparing, or postoperative complications. However, patients in the alvimopan group did have longer operative times (median, 7.1 hours versus 6.6 hours; P=.02).

Table 1.

Patient Demographics and Preoperative Clinical Characteristics

	Untreated (n=63)	Alvimopan (n=54)	P value
Gender			.5
Female	11 (17.5%)	7 (13.0%)
Male	52 (82.5%)	47 (87.0%)
Age (years)	71 (64–77)	70 (62–74)	.5
ASA			.6
II	14 (22.2%)	10 (18.5%)
III	36 (57.1%)	36 (66.7%)
IV	13 (20.6%)	8 (14.8%)
Clinical T stage			.4
Ta, Tis, T1	24 (38.0%)	16 (29.6%)
T2	34 (54.0%)	34 (63.0%)
T3	4 (6.3%)	2 (3.7%)
T4	0 (0.0%)	2 (3.7%)
Clinical grade			.4
NA	9 (14.3%)	1 (1.9%)
I (Low)	3 (4.8%)	1 (1.9%)
II (Intermediate)	1 (1.6%)	0 (0.0%)
III (High)	50 (79.4%)	52 (96.3%)

Data are number (%) except for age, which is median (interquartile range).

ASA, American Society of Anesthesiologists; NA, not available.

Table 2.

Perioperative Outcomes and Complications

	Untreated (n=63)	Alvimopan (n=54)	P value
Diversion type
Ileal conduit	27 (42.9%)	18 (33.3%)	.3
Indiana pouch	9 (14.3%)	13 (24.1%)
Studor ileal neobladder	27 (42.9%)	23 (42.6%)
Operative time (hours)	6.6 (6–7.3)	7.1 (6.6–8.1)	.02
EBL (mL)	400 (300–550)	350 (250–500)	.4
Intraoperative transfusion	18 (28.6%)	12 (22.2%)	.4
Postoperative transfusion	27 (42.9%)	16 (29.6%)	.1
Nerve sparing			.9
Bilateral	21 (33.3%)	19 (35.2%)
Left	1 (1.6%)	1 (1.9%)
Right	2 (3.2%)	1 (1.9%)
None	19 (30.2%)	12 (22.2%)
Not reported	20 (31.7%)	21 (38.9%)
90-day complication incidence
Major (Clavien grade ≥3)	17 (27.0%)	17 (31.5%)	.6
All complications	48 (68.2%)	39 (72.2%)	.6

Data are number (%) except for operative time and estimated blood loss (EBL), which are median (interquartile range).

There were no significant differences in postoperative complications between the two groups (Table 2). Forty-eight patients in the untreated group (68.2%) and 39 patients in the alvimopan group (72.5%) experienced a complication of any grade. Major complications were considered those classified as Clavien grade of 3 or greater. Seventeen patients in each group (27% untreated, 31.5% alvimopan) experienced a major complication (P=.6). Pathologic data are listed in Table 3. There were no significant differences in histology, lymph node yield, pathologic stage, lymph node positivity, or positive margin rates.

Table 3.

Final Pathologic Data

	Untreated (n=63)	Alvimopan (n=54)	P value
Histology			.6
Urothelial carcinoma	56 (88.9%)	50 (92.6%)
Adenocarcinoma	4 (6.3%)	2 (3.7%)
Squamous cell carcinoma	1 (1.6%)	0 (0.0%)
Other	2 (3.2%)	2 (3.7%)
Nodal yield	33 (22–45)	31 (25–40)	.6
Pathologic T stage			.9
T0	10 (15.9%)	9 (16.7%)
TA	9 (14.3%)	4 (7.4%)
TIS	3 (4.8%)	4 (7.4%)
T1	5 (7.9%)	5 (9.3%)
T2	13 (20.6%)	14 (25.9%)
T3	16 (25.4%)	14 (25.9%)
T4	7 (11.1%)	4 (7.4%)
Pathologic node status			.9
N0	47 (74.6%)	41 (75.9%)
N1	6 (9.5%)	7 (13.0%)
N2	8 (12.7%)	4 (7.4%)
N3	1 (1.6%)	1 (1.9%)
Not assessed	1 (1.6%)	1 (1.9%)
Positive bladder margins	4 (6.3%)	1 (1.9%)	.2
Positive ureteral margins	3 (4.8%)	4 (7.4%)	.6

Data are number (%) except for nodal yield, which is median (interquartile range).

The primary postoperative return of bowel function and discharge data are listed in Table 4. Patients receiving alvimopan had a median time to first bowel movement of 5 days (IQR, 4–7 days), which was 1 day sooner than untreated patients (6 days; IQR, 5–7; P=.03). Similarly, the alvimopan group tolerated a solid diet 1 day sooner than the untreated group (6 days [IQR 5–8 days] versus 7 days [IQR, 5–9 days]; P=.03). There was a trend toward shorter median time to discharge in the alvimopan group, although this did not reach statistical significance (8 days [IQR, 6–10 days] versus 9 days [IQR, 7–12 days]; P=.1). There were no complications attributed to the use of alvimopan, and alvimopan was not discontinued for any reason other than completion of the administration protocol.

Table 4.

Comparison of Time to Return of Bowel Function, Tolerance of Regular Diet, and Time to Discharge

	Untreated (n=63)	Alvimopan (n=54)	P value
Time to first bowel movement (days)	6 (5–7)	5 (4–7)	.03
Time to solid food (days)	7 (5–9)	6 (5–8)	.03
Time to discharge (days)	9 (7–12)	8 (6–10)	.1

Data are median (interquartile range) values.

Discussion

Despite trends toward minimally invasive approaches to complex operations, cystectomy patients continue to experience relatively high complication rates and prolonged hospital stays. The present study demonstrated a 74% overall complication rate, which is not unusual for a cystectomy series with strict complication-reporting criteria.^7,8,11 A recent series⁸ from our own institution (inclusive of the patients in the present study) showed a 77.5% overall complication rate within 90 days of surgery, and 32% of these were considered major complications (Clavien grade ≥3). In that series ileus was one of the most common complications, with an incidence of 22.5%.

Because of the prevalence of postoperative ileus in patients undergoing intestinal reconstruction, investigators across several disciplines have attempted to optimize the perioperative care of these patients. Chewing gum has been shown in several studies to reduce the time to return of bowel function, and as a result we routinely offer postcystectomy patients gum several times a day starting with postoperative Day 1.^22,23 The routine use of nasogastric tubes has also been evaluated extensively in the general surgical literature. Nasogastric tubes have generally failed to show any benefit with regard to reduction in postoperative ileus—indeed, most colorectal and general surgeons no longer use them for intestinal reconstruction operations.²⁴ We routinely remove nasogastric tubes at the end of the operation unless the patient is being kept intubated at the discretion of the anesthesiologist. Another common component of postoperative “fast-track” protocols include early feeding. This can include offering patients clear liquids on postoperative Day 0 and solid foods within the first 1–2 days after surgery.²⁵ During the study time frame patient diets were advanced with a more conservative approach in an attempt to reduce the likelihood of early hospital re-admission for vomiting and/or dehydration. We feel that for the present study this approach holds significant benefits for the ability to study the effect of alvimopan, as all patients remained in the hospital until positive return of bowel function and ability to tolerate a solid diet.

In the current study, patients who received alvimopan appeared to have earlier return of bowel function and tolerance of a solid diet compared with those who did not. The median difference was 1 day. This was despite the fact that patients receiving alvimopan actually had longer operative times. Although there was a trend toward shorter hospitalization times in patients receiving alvimopan, this did not reach statistical significance. It is likely that the study was underpowered to definitively demonstrate this effect. However, a patient's readiness for hospital discharge depends on more than just his or her ability to tolerate a solid diet, and some of these factors (such as other complications, patient home support system, or need to arrange a rehabilitation stay) may have blunted the effect of alvimopan on the length of stay. Other studies have shown alvimopan to be effective in reducing postoperative ileus as well as the length of hospital stay.^26–28 Lee et al.²⁸ reported on a randomized controlled trial of alvimopan compared with placebo and also found reduced time to gastrointestinal recovery by 1 day and reduced length of stay by 2.5 days. Touchette et al.²⁹ also evaluated the potential economic impact of using a new drug such as alvimopan on the cost of hospital care for postsurgical patients; they demonstrated a potential overall savings of $1168 based on the reduction of hospital days associated with using the drug. Hilton et al.³⁰ modeled the cost impact of alvimopan in postcystectomy patients and similarly showed significant potential savings based on reports of the drug's efficacy against ileus.

There are several potential limitations to the present study. It is a retrospective review, although data were prospectively recorded in an ongoing surgical database. Patients and clinicians were not blinded to the utilization of alvimopan. However, parameters affecting the advancement of diet such as bowel movements and vomiting are quite objective and unlikely to be influenced by knowledge of taking alvimopan. Patients in this study were not randomized to the treatment arm, and there was no control arm of patients taking placebo. The exclusion criterion for patients not receiving alvimopan was chronic narcotic use prior to surgery. Chronic narcotic use in these patients may have had an impact on postoperative intestinal motility, and the magnitude of this ileus-promoting effect in comparison with the ileus-reducing effect of alvimopan is unknown.

Combining the findings of the current study with the available literature, it appears that alvimopan is effective in reducing postoperative ileus. Alvimopan also likely reduces the length of hospital stay following intestinal reconstruction, although this was not definitively shown in our study. Reducing postoperative ileus with the use of alvimopan may have economic benefits by decreasing intestinal and nutritional complications along with the cost of hospitalization. Future investigations on perioperative protocols aimed at reducing ileus and hospital stay for cystectomy patients should include prospective comparisons of the use of alvimopan.

Footnotes

Disclosure Statement

No competing financial interests exist.

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