Patients with superficial non–muscle invasive cancers (Tis, Ta, T1) are treated with complete transurethral resection with selective use of a single dose intravesical chemotherapy immediately following resection. The subset of patients with carcinoma in situ (Tis) and those undergoing resection of large, high-grade, recurrent Ta lesions or T1 cancers (or both) are good candidates for additional intravesical therapy.
Patients with muscle invasive (T2+) but still localized cancers are at risk for both nodal metastases and progression and require more aggressive treatment. The gold standard treatment is neoadjuvant chemotherapy followed by radical cystectomy, which confers a survival advantage versus cystectomy alone. This is particularly important for higher-stage or bulky tumors to improve their surgical resectability. Trimodal bladder preservation therapy consisting of complete transurethral resection, sensitizing systemic chemotherapy, and external beam radiotherapy can offer similar outcomes in optimally selected patients.
Immunotherapeutic or chemotherapeutic agents delivered directly into the bladder via a urethral catheter can reduce the likelihood of recurrence in those who have undergone complete transurethral resection. Most agents are administered weekly for 6–12 weeks. Efficacy may be increased by prolonging contact time to 2 hours. The use of maintenance therapy after the initial induction regimen is beneficial. Common agents include gemcitabine, mitomycin, doxorubicin, valrubicin, and bacillus Calmette–Guérin (BCG), with the last being the only agent effective in reducing disease progression. Side effects of intravesical chemotherapy include irritative voiding symptoms and hemorrhagic cystitis. Patients in whom symptoms or infection develop from BCG may require antituberculous therapy.
Although transurethral resection is the initial form of treatment for all bladder tumors (since it is diagnostic, allows for proper staging, and controls superficial cancers), muscle-invasive cancers require more aggressive treatment. Partial cystectomy can be considered in selected patients with solitary lesions at the bladder dome or those with cancer in a bladder diverticulum. Radical cystectomy in men entails removal of the bladder, prostate, seminal vesicles, and surrounding fat and peritoneal attachments and in women removal of the bladder, uterus, cervix, urethra, anterior vaginal vault, and usually the ovaries. In women with anterior tumors, vaginal and reproductive organ–sparing surgery can be considered. Bilateral pelvic lymph node dissection is performed in all patients. Randomized trials have demonstrated similar oncologic outcomes and risks of complications with both open and robot-assisted laparoscopic cystectomy; however, robot-assisted techniques result in significantly less blood loss, lower need for blood transfusion, and slightly shorter convalescence. Urinary diversion is performed in all. In most patients, it uses a conduit of ileum or colon. However, continent forms of diversion avoid the necessity of an external appliance; it can be considered in a significant percentage of patients.
External beam radiotherapy delivered in fractions over a 6- to 8-week period is generally well tolerated, but approximately 10–15% of patients will develop bladder, bowel, or rectal complications. Local recurrence is common after radiotherapy alone (30–70%) and it is therefore combined with radiosensitizing systemic chemotherapy to improve complete response and to decrease recurrence rates. Bladder-preserving chemoradiation can be offered to those patients seeking to keep their bladder and is best suited for those with solitary T2 or limited T3 tumors without ureteral obstruction. Radiation with or without chemotherapy can be offered to patients with localized cancers and to patients who are poor candidates for radical cystectomy or to patients with metastatic disease seeking palliation of local symptoms. Salvage cystectomy following primary bladder radiotherapy is more challenging with greater risk of complications.
Metastatic disease is present in 15% of patients with newly diagnosed bladder cancer. Furthermore, metastases develop in up to 40% of patients within 2 years of cystectomy, including those patients who were believed to have localized disease at the time of treatment. Cisplatin-based combination chemotherapy results in partial or complete responses in 15–45% of patients (see Table 39–2) and is the preferred approach.
Combination chemotherapy has been used to decrease recurrence rates in patients treated both with surgery and with radiotherapy. Neoadjuvant chemotherapy appears to benefit all patients with muscle-invasive disease prior to planned cystectomy. Chemotherapy should also be considered before surgery in those with bulky lesions or those in whom regional metastases are suspected. Alternatively, adjuvant chemotherapy has been used after cystectomy in patients at high risk for recurrence, such as those who have lymph node involvement or extravesical local invasion. For patients with Stage 3B and Stage 4 disease, molecular/genetic testing should be considered to identify actionable mutations to target with second-line targeted therapies.
The FDA has now approved several checkpoint inhibitors as immunotherapy for metastatic urothelial cancer. Approved anti–PDL-1 inhibitors include atezolizumab, durvalumab, and avelumab (Table 39–2). Approved anti-PD1 inhibitors include nivolumab and pembrolizumab. All are approved for second-line treatment of locally advanced or metastatic urothelial cancer that progressed during or after platinum-based chemotherapy. Additionally, atezolizumab and pembrolizumab are approved as first-line therapy in cisplatin-ineligible patients whose tumors express PD-L1 or in patients ineligible for any platinum-based chemotherapy regardless of PD-L1 expression status. Overall response rates of these agents are similar and range from 17% to 25% in locally advanced and metastatic urothelial bladder cancer. In many cases, responses to therapy are durable.