Arun Rai, Thiri Khin, Teresa Gray Hayes, and Jennifer Marie Taylor

INTRODUCTION

Bladder cancer is the most common cancer arising from the urothelial tract, and the ninth most common cancer worldwide. In the United States, it is the fifth most common cancer behind breast, lung, prostate, and colorectal cancer. It accounts for 77,000 new cases each year and 16,000 deaths (1). Urothelial or transitional cell carcinoma comprises 90% of all bladder cancer cases in the United States and Western Europe, of which approximately 25% to 30% of cases are muscle invasive bladder cancer (MIBC).

Despite the utilization of radical cystectomy (RC) for MIBC, the early dissemination of micrometastases frequently results in failure to cure with surgery alone. American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging is the definitive staging criteria used for bladder cancer (see Table 24.1) (2).

The recurrence rate after surgery is 20% to 30% in pT1 and pT2 disease and 50% to 90% in pT3 or pT4 (3,4). Clinical understaging has been well documented, and ranges from 31% to 61% (4). Pathologic staging shows extravesical disease (pT3–T4) rates between 25% and 35%, and 5-year survival of patients with MIBC is at best 65%. Approximately 50% of patients will develop metastatic disease within 2 years. Metastatic bladder cancer is aggressive. The efficacy of chemotherapy in metastatic disease has led to the investigation of its 178use in the perioperative setting with the intent of eradicating micrometastatic disease.

CLINICAL CONSIDERATIONS AND DISEASE PROGRESSION

Of those with muscle invasive disease diagnosed at resection, the majority of patients are diagnosed de novo. Approximately 20% of patients will have progressed from previously diagnosed nonmuscle-invasive disease. The risk of progression is highest within the first 2 years after diagnosis with increasing risk of progression with higher initial stage and grade. As noted in the previous section, T1 tumors have a recurrence rate as high as 50% at 2 years and up to 50% likelihood at 5 years of progression to MIBC. Carcinoma in situ (CIS) is associated with both high rates of recurrence and progression, with the greatest 5-year risk of progression (74%) in a patient with T1 high grade (HG) disease with CIS present (5).

Certain genetic changes have been correlated with earlier incidence of more aggressive, muscle-invasive disease. This includes allelic loss of chromosome 9, loss of Rb1 and p53, and abnormalities in proliferation genes such as Ki67. On review of transurethral resection of the bladder tumor (TURBT) pathologic samples, the presence and loss of these genetic markers can help to indicate likelihood of progression to muscle invasive disease. Emerging molecular data from The Cancer Genome Atlas (TCGA) and other characterization studies will provide new insights into the molecular drivers of recurrence and progression and provide avenues to guide treatment.

Pure variant histology tumors other than urothelial bladder cancer are associated with statistically significantly poorer outcomes when compared to primary urothelial carcinoma. However, mixed histology cases, with urothelial and variant histology, occur commonly as the tumors de-differentiate. The incidence of pure squamous cell carcinoma of the bladder is 3% to 7% in the United States, and adenocarcinoma <2%. Other nonurothelial tumors (small cell, carcinosarcoma, lymphoma, neurofibroma, and sarcoma) each occur in less than 1% of bladder cancers in the United States (6).

179STAGING CONSIDERATIONS IN BLADDER CANCER

Clinical understaging of T stage, by both resection and physical and radiographic examination, remains a common problem. Up to 40% of patients clinically diagnosed with T1 disease who undergo cystectomy are found to have pathologic T2 disease at surgery. Re-resection of initially diagnosed T1 high-grade disease is required within 2 to 6 weeks to assure appropriate staging. The presence of persistent T1 carcinoma on re-resection is a statistically significant predictor of poor outcome in patients treated with Bacillus Calmette-Guérin (BCG), and an indication for “early” RC. (7) On re-resection, approximately 50% of patients are found to have residual tumor, and 25% of patients will be upstaged from Ta to T1 or from T1 to T2 (7). Certain risk factors increase the likelihood of concomitant or metachronous upper tract urothelial disease. These include high-grade tumor, periureteral location, multiple tumors, bladder CIS, and the presence of vesicoureteral reflux.

On cystoscopy, muscle invasive tumors are often more nodular or sessile in appearance and may have more elements of tissue necrosis (see Figure 25.1). At the time of tumor resection, bimanual exam under anesthesia forms the basis of the TNM clinical T stage, with higher non-organ-confined stage suggested by asymmetric thickening (cT3) or palpable 180extension to pelvic sidewall or adjacent organ (cT4). By imaging such as CT urography (CTU), muscle invasive tumors often show focal bladder wall thickening or can cause obstruction with resulting hydronephrosis if located near the ureteral orifice. Perivesical stranding on axial imaging, when obtained prior to transurethral resection, is highly suspicious for microscopic or macroscopic extravesical extension (stage cT3).

Indications for RC include resectable muscle invasive disease (clinical stages T2–T4a N0 M0), BCG-unresponsive CIS, high-risk histology with persistent T1 disease on repeat resection, or T1 tumors with associated CIS, lymphovascular invasion (LVI), or variant histology (the latter being a Grade C American Urological Association [AUA] recommendation) (7).

RATIONALE FOR NEOADJUVANT CHEMOTHERAPY

Giving chemotherapy prior to surgery has several advantages. Chemotherapy is better tolerated when the patient has a better performance status than in the postoperative state. Neoadjuvant chemotherapy can downstage the tumor, which may lead to a better surgical outcome. The ability to assess pathologic response to chemotherapy in the surgical specimen can be used for prognostication, and the effectiveness of chemotherapy can help guide the use of later lines of treatment if needed. The major downside of neoadjuvant chemotherapy is the need to rely on clinical stage, which may be inaccurate and can either downstage or upstage the tumor. There is also a concern for morbidity caused by neoadjuvant chemotherapy, which could cause a delay to RC, although recent reports suggest no statistical difference. A lack of predictable data for survival benefit may lead to overtreatment of a portion of patients who otherwise would not need chemotherapy (8–10).

181BENEFITS OF NEOADJUVANT CHEMOTHERAPY

A pivotal Southwest Oncology Group (SWOG) 8701/US Intergroup trial compared neoadjuvant MVAC (methotrexate, vinblastine, Adriamycin, cisplatin), followed by RC versus RC alone (11) and found the chemotherapy group to have a median overall survival of 77 months compared to 46 months for those undergoing RC alone. The 5-year overall survival did not reach statistical significance at 57% versus 43% (P = .06). Pathological complete response (pCR) rates were 38% versus 15%.

The International Collaboration of Trialists Study is the largest phase 3 randomized prospective trial of neoadjuvant chemotherapy for bladder cancer. This trial enrolled 976 patients and compared neoadjuvant CMV (cisplatin, methotrexate, vinblastine) followed by local therapy versus local therapy alone. The updated report shows a 10-year overall survival of 36% versus 30% for local therapy alone, with a hazard ratio (HR) of 0.84 (12).

The Nordic cystectomy trials I and II compared neoadjuvant chemotherapy with cisplatin and doxorubicin in Nordic I and CMV in Nordic II followed by cystectomy. The trials failed to show an overall survival or cancer specific survival benefit. However, subgroup analysis of the patients with T3 and T4 disease showed an absolute survival benefit of 15% in the patients who received chemotherapy (13). Meta-analysis of 11 prospective trials using neoadjuvant chemotherapy was conducted by the Medical Research Council Clinical Trials unit and reported by the Advanced Bladder Cancer Meta-Analysis Collaboration. It included 3,005 patients and demonstrated a 5% absolute survival benefit with HR 0.86 (P = .003) and 9% absolute disease-free survival benefit, HR 0.78 (P < .0001) (14).

Across multiple trials, the lowest long-term recurrence and best survival outcomes are seen in patients who achieve pathologic T0 stage after chemotherapy (15,16).

HOW TO CHOOSE NEOADJUVANT CHEMOTHERAPY REGIMENS

There is no evidence of superiority of one chemotherapy regimen over another, since none of the conventional regimens have been compared head-to-head. However, better tolerability 182and comparable efficacy of gemcitabine and cisplatin (GC) in metastatic disease have led to its adoption for neoadjuvant chemotherapy, and GC has become the most commonly used regimen. Zargar et al. reported retrospective data of comparison of neoadjuvant MVAC, GC, and other regimens in MIBC (9). There was no statistically significant difference in pathological response between MVAC and GC (24.5% vs. 23.9%) or overall survival.

Dose-dense MVAC, which increases the dose intensity of MVAC by administering treatment every 2 weeks along with granulocyte colony-stimulating factor (G-CSF) support, has been studied in metastatic urothelial cancer, but there is no randomized trial evaluating efficacy in the neoadjuvant setting. Two single arm phase 2 studies showed the feasibility of administering three to four cycles of dose-dense MVAC in the neoadjuvant setting, with a pathological complete response rate (pCR) up to 38% (8,11). Given a shortened time to surgery, dose-dense MVAC remains a reasonable alternative and continues to be actively studied in trials.

Multiple phase 2 trials have been conducted to add novel agents such as bevacizumab, lapatinib, and erlotinib to combination cisplatin-based chemotherapy. The addition of bevacizumab led to increased surgical complications. Data for targeted therapy are still at large.

REGIMENS TO USE IN PATIENTS WITH RENAL INSUFFICIENCY

The median age at diagnosis of bladder cancer is 69 years in men and 71 years in women. Comorbidities and functional status are major factors influencing the choices of treatment modality. Renal insufficiency is often encountered in bladder cancer patients due to urinary outflow tract obstruction, advanced age, and/or coexisting medical conditions. In patients with renal insufficiency, there is an unmet need for effective chemotherapy other than the nephrotoxic agent cisplatin. Carboplatin-based neoadjuvant chemotherapy was evaluated in several phase 2 trials, with a pCR rate up to 30% to 40%. Compared to cisplatin, there was more myelosuppression 183and a higher treatment related mortality. In the therapy of metastatic disease, carboplatin has been shown to be inferior to cisplatin (8,10). Therefore, carboplatin-based chemotherapy is not currently recommended in the neoadjuvant setting. In patients with mild to moderate renal insufficiency who are good surgical candidates, upfront RC is recommended in clinical practice.

ROLE OF SURGERY

RC is critical in the management of local tumor control. Similar to the results found with neoadjuvant chemotherapy, optimizing the likelihood of complete pathologic response in the final tumor specimen has been shown to improve overall survival (3). Resection in men includes prostate, seminal vesicles, distal ureters, pelvic peritoneum, and bladder. For women, the uterus, cervix, ovaries, anterior vagina, distal ureters, pelvic peritoneum, and bladder are removed. During RC, a bilateral pelvic lymph node dissection should be performed, to include lymph nodes in the external iliac, internal iliac, obturator, and common iliac stations. The oncologic efficacy and comparative benefit of minimally invasive (robotic-assisted) cystectomy, relative to open surgery, continues to be studied.

Although neoadjuvant therapy is key to the achievement of a pathologic T0 specimen, some patients can achieve pT0 status from the initial TURBT. On the other hand, restaging with cystoscopy and biopsies cannot always detect occult persistent disease, and RC is required to achieve survival benefit due to the persistence of microscopic disease. Relapse has been demonstrated in up to 64% of patients who maintained their bladders despite apparent complete neoadjuvant response (16). During RC, a bilateral pelvic lymph node dissection should be performed. The oncologic efficacy and comparative benefit of minimally invasive (robotic-assisted) cystectomy, relative to open surgery, continues to be studied. For patients who are not deemed to be cystectomy candidates, trimodal bladder preservation therapy is an option (see section on Bladder Preservation).

184SURGICAL CONSIDERATIONS

Perioperative (90-day) mortality rates are 1% to 3% at large centers, but can be significantly higher in community hospitals. Up to 64% of patients, even in high-volume centers of expertise, experience at least one perioperative complication within 90 days, and 13% experience a high-grade (grade 3 or higher) complication (17). Patients older than 70 years have a baseline 3- to 5-fold increase in perioperative mortality even when they are without significant comorbidities (18). In general, patients with significant medical comorbidity are best served by alternative approaches, albeit with potentially less durable benefit. The risk of complications can be minimized by proper patient selection, using objective assessment instruments when possible, and protocols to standardize perioperative management. These include principles known as Enhanced Recovery after Surgery (ERAS), covering elements of physical conditioning, nutrition, fluid management, postoperative diet, and other subjects (see Figure 25.2). The risk of venous thromboembolic events (VTE) is known to be increased in cancer patients undergoing pelvic surgery, and recent data have described 185much higher rates of VTE in patients receiving platinum-based chemotherapy. Surgeons are increasingly aware of these risks and may incorporate preoperative and extended postoperative VTE prophylaxis to reduce the risk of a potentially fatal complication such as pulmonary embolism.

In the SWOG 8710 trial, negative surgical soft tissue margins and removal of 10 or more lymph nodes were significantly associated with longer survival and decreased local recurrence. Achieving negative soft tissue margins is critical in resection, and positive soft tissue margins carry a significant risk of recurrence and progression (19). Further analysis demonstrated that improved surgical outcomes could be achieved by centralizing the treatment of locally advanced bladder cancer at high-volume institutions with experienced surgeons.

A typical postoperative course generally consists of a 4 to 7 day hospital stay, allowing for recovery of bowel function, along with adequate ambulation and pain control. Patients often take several months to recover their strength and appetites fully, and many benefit from postoperative rehabilitation, either in a facility or at home. Optimal perioperative care incorporates the patient’s family members and considers their physical, psychosocial, and functional needs. A multidisciplinary team could include a nutritionist, social worker, psychologist, physical/occupational therapist, and patient navigator, along with the medical and surgical clinicians, and the integration of these varied aspects of care can contribute to better recovery and quality of life.

Intraoperative Frozen Section: The urothelial margin status at the urethral stump is important if orthotopic diversion is considered. Prostatic urethral involvement by urothelial cancer, particularly at the urethral margin of resection, is associated with risk of urethral and pelvic recurrence. In general, tumors involving the bladder neck carry increased risk of urethral involvement and often preclude orthotopic neobladder construction (20).

Urinary Diversion Overview: The type of urinary tract reconstruction is determined after careful preoperative evaluation of the patient’s comorbidities and functional status. The types can be broadly classified into incontinent (ileal/colonic segment) or continent diversions (summarized in Table 25.1). All diversions lead to chronic bacteriuria due to persistent bowel flora in the urinary system (21).

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Chronic bacterial urinary colonization, metabolic derangements, and hypercalciuria can predispose patients with intestinal diversion to the development of magnesium ammonium phosphate stones (3). The incidence of urolithiasis in patients with colon conduits is 3% to 5% and 10% to 12% in ileal conduits, and up to 20% with continent cecal reservoirs. Metabolic derangements can occur due to bowel segment absorption of electrolytes in urine. Nutritional problems can result from loss of significant intestinal absorptive surface. In patients with ileal and colonic-derived diversions, vitamin B₁₂ malabsorption has been reported. If more than 60 to 100 cm of ileum is resected (increased risk in orthotopic neobladders), the risk of malabsorption of bile acids increases.

189Role for Adjuvant Chemotherapy

To date, no prospective comparison between neoadjuvant and adjuvant chemotherapy in muscle-invasive bladder cancer has been carried out. Given the survival benefit with neoadjuvant chemotherapy, treatment before surgery is recommended for eligible patients with MIBC. Patients who undergo RC and are found to have high-risk features, defined as pathologic stage T3 and T4, positive soft tissue margins, and/or positive nodal disease, are offered adjuvant chemotherapy. However, a significant proportion of patients who undergo RC develop complications, which may preclude them from getting additional therapy in a timely fashion.

The benefit of adjuvant chemotherapy is shown in a meta-analysis of nine trials with 945 patients total (22), which showed improvement in overall survival (HR 0.77, 95% confidence interval [CI] 0.59–0.99) and also improvement in disease-free survival (HR 0.66, 95% CI 0.45–0.91). However, this meta-analysis had multiple flaws: all studies had lower accrual than planned and several studies terminated prematurely. The largest and most recent European Organisation for Research and Treatment of Cancer (EORTC) 30994 trial, not included in the meta-analysis, randomized 284 patients to four cycles of adjuvant chemotherapy versus observation, with administration of six cycles of chemotherapy upon relapse (23). This study showed a trend toward improvement in overall survival of 53.6% versus 47.7%, which did not reach statistical significance (HR 0.78, 95% CI 0.56–1.08). More clinical trials are needed to identify the patient population that will benefit the most from neoadjuvant/adjuvant chemotherapy and regimens that minimize the adverse effects of chemotherapy.

Bladder Preservation

RC has long been the standard of care in the management of MIBC. However, due to substantial perioperative morbidity in an older patient population that often has underlying medical comorbidities, bladder preservation techniques have been 190explored. Though there are no prospective randomized control trials comparing RC to bladder sparing techniques, many clinicians believe bladder-sparing techniques have inferior oncologic outcomes. The major drawback is disease recurrence in the retained bladder, which is estimated to be 50% or more by 3 to 5 years after surgery.

Options for a bladder preservation approach include radical transurethral resection (TUR), partial cystectomy and radiation therapy (RT), and combined chemoradiation. A retrospective study showed TUR had a similar 10-year survival rate compared to RC in muscle invasive cancer that was stage T0 to T1 at the time of TUR restaging (24). For solitary tumors, partial cystectomy is another viable option. A series of 58 highly selected patients reported a 5-year survival rate of 69%, with 74% alive with bladder intact (25). One must be cautioned that such series are done in large-volume centers with very strict selection criteria, very close follow-up, and lifelong cystoscopy. For patients who are not candidates for RC due to comorbidities and those who wish to retain their bladders, optimal candidates for bladder preservation techniques include those with a single tumor less than 5 cm in size, absence of CIS (Tis), clinical T2 or T3a disease, absence of hydronephrosis, and good bladder and renal function.

Role of RT

RT for MIBC is commonly used as a palliative approach to control local symptoms in frail, medically unfit patients. External beam radiation therapy (EBRT) and brachytherapy combined with EBRT are two available options. The local recurrence rate for EBRT when used alone is estimated as high as 70%, and thus this modality alone should not be used in otherwise healthy patients. In patients with a single tumor less than 5 cm, a large European study showed that there was no difference in 5- or 10-year disease-free survival when brachytherapy combined with EBRT was compared to RC (26). The 10-year overall survival was better in the RC group (42% vs. 33% with brachytherapy). Results may have been confounded by a younger patient population in the cystectomy group (26).

191Maximal transurethral resection followed by combined chemotherapy and RT, also called trimodal therapy, is an appropriate alternative for patients who are not candidates for radical cystectomy. In patients who are surgical candidates, trimodal therapy is employed frequently outside the United States and in select centers in the United States. When done at centers with experience and with careful post-treatment surveillance, patients can derive similar cancer and quality of life outcomes. Combined chemotherapy with RT has shown superior outcomes in local and regional control and trends toward improvement in survival when compared to RT alone (27). Most commonly used chemotherapy regimens are cisplatin-based, but a 5-fluorouracil and mitomycin combination may be employed in patients with impaired renal function. A Radiation Therapy Oncology Group (RTOG)-pooled analysis of six trials showed a 10-year disease-specific survival of 65% and a 10-year overall survival of 36% (28). One U.S. center with experience treating 465 patients over 25 years (29) has reported steadily improving survival outcomes over time, with an initial complete response rate of 76% and salvage RC performed in 27% for either incomplete response or recurrence. Long-term follow-up among complete responders shows 5- and 10-year disease-specific survival rates of 66% and 59%, with good patient-reported quality of life outcomes (30).

SURVEILLANCE

Careful surveillance should be undertaken for all bladder cancer patients, consisting of surveillance cystoscopy in patients with intact bladder; upper tract monitoring with CT urogram, retrograde pyelograms, or renal ultrasound; and urinary cytology. The schedule and intensity of surveillance depends on risk stratification and recurrence history (31). Following cystectomy, interval abdominal imaging with CT or MRI is warranted to monitor for pelvic or visceral metastatic recurrence. Cytology samples should include a diversion specimen biannually and urethral wash annually if ileal conduit diversion was performed.

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Bone Health and Use of Adjunctive Agents Controversies in the Surgical Management of Renal Cell Carcinoma Reproductive Considerations and Long-Term Complications of Therapy Controversies in the Management of Upper Tract Urothelial Cancer Treatment of Metastatic Bladder Cancer: Chemotherapy and Checkpoint Inhibitors Treatment of Metastatic Penile Cancer: Chemotherapy

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