Radical Cystectomy in Women

MIRIAM HADJ-MOUSSA

JOANNE LUNDGREN

CHERYL T. LEE

TODD M. MORGAN

In 2013, 72,000 new cases of bladder cancer were diagnosed in the United States; almost 17,000 occurred in women, with 4,300 dying from their disease (1,2). Although most urothelial carcinomas are noninvasive, up to one-third of patients present with muscle-invasive disease. In addition, 15% to 30% of patients presenting with non-muscle-invasive tumors will eventually progress to muscle invasion. Radical cystectomy remains the most effective single-modality treatment for patients with muscle-invasive bladder cancer, refractory highrisk non-muscle-invasive disease, and especially lymph-node negative disease with reported 10-year recurrence-free survival of organ-confined lymph-node negative (≤pT2N0) disease between 69% and 87% (3,4). Improvements in processes of care, particularly at high-volume centers, have led to a reduction in perioperative mortality and long-term survival, further strengthening the role of cystectomy (5,6,7,8).

Historically, radical cystectomy in women has posed several technical challenges and concerns, including (a) bleeding from the paravaginal tissues and venous plexus around the urethra, which can be brisk and tedious to control; (b) an intraoperative position change for the surgeon during urethrectomy; and (c) vaginal reconstruction, which can be complex, requiring tissue flaps to maximize organ function.

More recently, additional challenges have related to female organ preservation. Radical cystectomy in women has traditionally been equated with anterior exenteration, including resection of the bladder, urethra, uterus, ovaries, and the anterior one-third of the vagina. This approach is certainly indicated for extensive posterior invasive bladder tumors at risk for reproductive organ involvement. However, tumor involvement of adjacent reproductive organs is rare, suggesting that the routine removal of female reproductive and sex organs is not necessary to achieve local cancer control (9). Studies have yet to identify female patients with skip lesions involving the urethra, allowing surgeons to proceed with nonstomal diversions when intraoperative frozen-section analysis of the urethral margin is negative (10,11). Moreover, the increasing attention to preserving quality of life after cancer surgery provides another incentive to spare part or all of the reproductive organs and urethra when feasible.

INDICATIONS FOR SURGERY

Radical cystectomy is indicated for patients with muscleinvasive urothelial malignancy or non-muscle-invasive disease refractory to transurethral resection and intravesical therapy. Additionally, select patients with high-risk non-muscle-invasive disease may elect to undergo so-called “early cystectomy” at the time of their initial presentation. The presence of intractable local symptoms, failure of bladder preservation strategies, and divergent histology are other indications for radical cystectomy.

Muscle-Invasive Disease

The standard therapy for muscle-invasive bladder cancer in women is radical cystectomy. Survival after cystectomy for muscle-invasive disease is closely related to pathologic tumor stage. In patients without lymph node involvement, Stein et al. (4) reported 10-year recurrence-free survival rates of 87% in T2, 76% in T3, and 45% in T4 disease. Lymph node involvement varies with tumor stage, ranging from 18% of patients
with T2a disease to 45% of patients with T3/T4 disease, and the 10-year recurrence-free survival rate in these patients was reported to be 34%.

Non-Muscle-Invasive Disease

Radical cystectomy should seriously be considered as an alternative to intravesical therapy in patients with high-grade T1 disease which is (a) recurrent, (b) associated with carcinoma in situ, and/or (c) combined with adverse histologic features (mixed histology, lymphovascular invasion, inverted growth pattern, or nested variant). Patients with non-muscle-invasive disease resistant or refractory to endoscopic resection and intravesical therapy (particularly bacille Calmette-Guérin) are at significant risk of progression, and repeated courses of intravesical therapy can compromise overall survival (12,13). This may be due to the 30% incidence of understaging in patients with noninvasive disease (13). Divergent histology is identified on 25% of transurethral resection of bladder tumor specimens and has been shown to correlate with high-grade and invasive disease (14).

Failure of Alternative Therapies

Alternatives to cystectomy can include systemic chemotherapy, radiation therapy, and aggressive transurethral resection of the tumor, ideally in combination. Although there are no randomized trials comparing bladder-sparing regimens with radical cystectomy, these bladder-sparing modalities have historically been offered to patients who have a solitary tumor <5 cm in size, clinical stage T2 disease without hydronephrosis, minimal or no carcinoma in situ, and no evidence of extravesical disease. Patients who are poor surgical candidates (due to age or medical comorbidities) or refuse cystectomy are also considered for organ preservation strategies.

A significant proportion of these patients will have a complete response to maximal endoscopic resection with chemoradiation (15). More recently, newer chemoradiation regimens have been proposed, even for clinical T1 tumors, in an effort to provide greater sexual and urinary quality of life in bladder cancer patients (16). Concurrent chemoradiation does appear to be more effective than radiotherapy alone, with a phase 3 trial showing 48% 5-year survival in a cohort receiving fluorouracil and mitomycin compared to 35% 5-year survival in a cohort receiving radiation alone (17). Lifelong routine surveillance is critical in this cohort, and 30% to 40% of patients will ultimately require salvage radical cystectomy for disease recurrence (15,18).

Intractable Local Symptoms

Side effects of intravesical therapies are generally mild and managed conservatively. More serious side effects including severe bladder contracture are rare, occurring in <1% of patients treated with intravesical therapy; however, these can also be managed with cystectomy (19). This decision requires an active discussion between the physician and patient to balance the risks of surgical intervention with the impact of patient symptoms on quality of life.

PREOPERATIVE CONSIDERATIONS

Age and Medical Comorbidities

While cystectomy is readily applied to younger populations, the elderly often have limited access to radical surgery and are counseled toward nonsurgical interventions. However, cystectomy is often the best treatment option for invasive bladder cancer in the elderly who are in reasonably good health, because they may be more likely to have extravesical disease at the time of cystectomy (20). Invasive urothelial carcinoma is not an indolent disease, with cancer-associated death being high in the first 3 to 4 years. Thus, for an otherwise healthy 75-year-old woman, it may represent the biggest risk to her health. Bladder cancer patients of all ages often have multiple medical comorbidities, impacting both perioperative and long-term all-cause mortality and should be discussed when considering cystectomy (21). Elderly patients, in particular, need to be extensively counseled regarding the risks of surgery because 90-day mortality is as high as 13% in individuals older than 75 years undergoing radical cystectomy (7).

Functional Outcomes and Quality of Life Measures

When proceeding to definitive surgical treatment in the female bladder cancer patient, the physician should consider the woman’s age, sexual function, and childbearing status in conjunction with her clinical stage. For premenopausal patients with carcinoma in situ, early invasive disease (T1), or anterior low-volume T2 disease, radical cystectomy should be performed with intent to preserve the vagina, uterus, ovaries, and urethra, potentially preserving sexual and urinary function. In addition, it is important to consider the need to maintain body image by offering continent and orthotopic diversions, the formation of which has been associated with continence rates between 76% and 82% (11,22,23). Even after the initial postoperative adjustment period, Gacci et al. (24) showed that incontinent diversions were associated with significantly lower rates of physical and emotional well-being in female bladder cancer patients. Table 20.1 outlines our paradigm for the extent of surgical intervention. Indications for urinary diversion are outlined in Section I of this book.

PREOPERATIVE CARE

Optimization of preoperative performance and nutritional status helps reduce the risk of perioperative complications and may be associated with improved perioperative as well as overall survival (2,25). Patients are encouraged to augment their diet with protein and caloric supplements if they have anorexia or significant unintended weight loss. Although mechanical bowel preparation was formerly the standard of care, increasing evidence over the past 10 years has suggested that this is likely unnecessary and can be safely omitted in patients undergoing urinary diversion with small intestine. Large et al. (26) showed that a GoLYTELY (polyethylene
glycol/electrolytes) bowel prep did not appear to impact rates of perioperative infection or bowel complications. In another study, where patients were prospectively randomized to undergo or not undergo mechanical bowel preparation prior to radical cystectomy and ileal urinary diversion, a nonstatistically significant increase in complication rate was observed in the group receiving a bowel preparation (27). Wound prophylaxis is achieved in the perioperative period with a second-generation cephalosporin antibiotic administered over a 24-hour period.

TABLE 20.1 INDICATIONS FOR SURGICAL EXTENT OF RADICAL CYSTECTOMY IN WOMEN

Type	Extent	Indication
I	Cystectomy alone Preserve reproductive organs/vagina/urethra (for neobladder)	≤ T2 Childbearing potential desired Potentially sexually active
II	Cystectomy plus TAH^a/BSO^b (if uterus and ovaries are present) Preserve vagina/urethra (for neobladder)	≤ T2 Postchildbearing Postmenopausal Potentially sexually active
IIa	Cystectomy plus TAH (if organs present) Preserve vagina/urethra (for neobladder)	≤ T2 Postchildbearing Premenopausal; grossly normal ovaries Potentially sexually active
III	Cystectomy plus TAH/BSO (if organs present) plus anterior vaginectomy Preserve urethra for neobladder	T2 or T3 Posterior wall tumor away from bladder neck
IIIa	Cystectomy plus TAH (if organs present) plus anterior vaginectomy Preserve urethra for neobladder	T2 or T3 Posterior wall tumor away from bladder neck Premenopausal; grossly normal ovaries
IV	Cystectomy plus TAH/BSO (if organs present) plus anterior vaginectomy and urethrectomy	T2 or T3 Tumor at bladder neck or urethra
IVa	Cystectomy plus TAH (if organs present) plus anterior vaginectomy and urethrectomy	T2 or T3 Tumor at bladder neck or urethra Premenopausal; grossly normal ovaries
^aTAH, total abdominal hysterectomy. ^bBSO, bilateral salpingo-oophorectomy.
Reprinted with permission from Lee CT, Montie JE. Orthotopic bladder replacement in women. In: Kreder KJ, Stone AR, eds. Urinary Diversion, 2nd ed. Oxfordshire, United Kingdom: Taylor & Francis, 2005:191. Copyright © 2005 by Taylor & Francis. Reproduced by permission of Taylor & Francis Books UK.

The authors of this chapter have also begun short-term perioperative administration of alvimopan (Cubist Pharmaceuticals, Inc, Lexington, Massachusetts) for most patients because it has been shown to reduce the time to return of bowel function and is well tolerated by patients (28). Alvimopan is contraindicated in patients who have taken opioids for more than a week prior to surgery and patients with end-stage renal disease. Patients should be counseled regarding a potential increase in the risk of myocardial infarction, although this has not been observed with short-term alvimopan use. Pneumatic compression stockings and 5,000 units of low-dose unfractionated subcutaneous heparin are administered prior to induction of anesthesia for deep venous thrombosis prophylaxis. Enhanced Recovery After Surgery pathways have been used to reduce complications and length of stay after colorectal surgery and are being studied for cystectomy patients to optimize perioperative care (29).

SURGICAL TECHNIQUE

Anatomic Considerations

Female Continence

An understanding of the female continence mechanism in women is critical prior to consideration of an orthotopic neobladder. There are two continence mechanisms in women (30). The first is the proximal urethra, smooth muscle fibers of which are innervated by autonomic fibers from the pelvic plexus that course adjacent to the bladder neck and vagina. These nerves often are transected during a radical cystectomy. The second is the rhabdosphincter, intermingled smooth and striated muscle fibers located in the middle to lower one-third of the urethra. Somatic innervation of the striated muscle fibers is via the pudendal nerve and appears to be the critical sphincter mechanism for continence in women (30). Because the rhabdosphincter is present in the middle to lower urethra, and the somatic nerves run below the endopelvic fascia along the levator ani, the entire bladder and bladder neck can be resected without compromising eventual continence. Importantly, complete resection of the bladder is necessary to minimize the amount of transitional epithelium left behind and thus reduce the risk of local tumor recurrence as well as hypercontinence after orthotopic urinary diversion. Alteration in
the anatomic relationships between the remnant urethra and its fascial attachments also contribute to incontinence, so care should be taken to preserve the endopelvic fascia and pubourethral ligaments in patients undergoing orthotopic neobladder creation in order to minimize the risk of longterm incontinence (10).

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