Urothelial cell carcinomas arise from the transitional epithelium that lines the urethra, bladder, ureter, and renal pelvis. More than 90% of patients with bladder cancer have transitional cell carcinoma (TCC), which is not uncommonly found admixed with limited squamous cell, adenocarcinoma, or neuroendocrine carcinoma elements. Pure adenocarcinomas, squamous cell carcinomas, and neuroendocrine (small cell) cancers represent 5% to 10% of bladder cancers. TCC of the bladder can be considered as presenting in two disease states, non-muscle invasive and muscle invasive (MIBC).

Approximately two-thirds of patients have low-grade, noninvasive tumors characterized most commonly by FGFR3 mutations, and one-third have high-grade and/or invasive disease characterized by loss of critical tumor suppressor genes such as p53, pRB, and p21. The significant improvement in our understanding of the underlying molecular biology of bladder cancer derives from the publication of the Human Cancer Genome Atlas’s molecular characterization of urothelial bladder cancer.¹

Whereas the vast majority of lethal events occur among patients with high-grade/invasive tumors, most patients have noninvasive, low-grade forms of bladder cancer, and many live for years after the initial diagnosis with evidence of recurrent tumors, making bladder cancer among the most prevalent cancers as well as the most costly to treat.

Patients with bladder cancer typically present with painless hematuria, with or without irritative voiding symptoms including frequency, urgency, and dysuria. Patients with more advanced disease may present with progressive flank or pelvic pain from direct extension of disease or as a consequence of ureteral obstruction.

The bladder wall consists of four layers, the urothelium, the innermost epithelial lining, the lamina propria, muscularis propria (detrusor muscle), and the adventitia (serosa). Most (75% to 85%) bladder tumors are non-muscle invasive at diagnosis and are typically low-grade, stage Ta tumors (TaLG) or stage T1 tumors, which have penetrated the epithelial basement membrane but have not invaded the muscle. The remaining 20% to 30% present with de novo invasion of the muscle wall of the bladder (stages T2 to T4).
The TNM staging system for bladder cancer is summarized in the 7th edition of the AJCC Cancer Staging Manual.²

Patients who present with a clinical picture worrisome for bladder cancer should undergo an evaluation including cystoscopy with the collection of urine cytology and evaluation of renal function. Findings on cystoscopic evaluation may lead to a transurethral resection of bladder tumor (TURBT), a procedure performed under anesthesia to obtain tissue for histologic diagnosis. Inclusion of muscle in the pathologic specimen is required to evaluate the potential for muscle invasion. Evidence of the presence of muscle-invasive disease on biopsy should be followed by a metastatic evaluation with CT imaging of the chest and abdomen/pelvis (if not obtained prior to TURBT), assessment of complete blood cell count, and serum chemistries.

The guiding principle of the management of non-muscle invasive disease is to diminish the frequency of recurrent disease while at the same time minimizing the potential for disease progression to muscle-invasive and potentially lethal disease. The vast majority of patients with TaLG have a nonlethal form of bladder cancer that is likely to recur but is far less likely to progress to high-grade and/or muscle-invasive disease (<10%). The therapeutic goals for these patients are to monitor for bladder tumor recurrences, typically by surveillance cystoscopies with collection of urine cytology at 3-month intervals. Level I evidence supports the use of post-TURBT (within 24 hours) administration of intravesical chemotherapy with agents such as mitomycin-C to attempt to reduce the risk of tumor recurrences for those with multiple or large (>3 cm) tumors for whom a bladder preservation strategy is planned.

For patients with Ta high-grade (TaHG), carcinoma in situ (CIS) or T1 bladder cancer, the goals of therapy are to prevent progression to clinical metastasis while preserving quality of life through bladder preservation or reconstructive strategies that are consistent with the patients’ preferences. The primary therapeutic dilemma is determining which patients should be considered for immediate cystectomy and which are suitable candidates for a bladder preservation approach using intravesical BCG (Bacillus Calmette-Guérin). Cystectomy should be the primary therapeutic approach for patients with TaHG, CIS, or TI bladder cancer with a long (>10 to 15 years) life expectancy with other high-risk features including large or multifocal T1 tumors, evidence of variant histology such as micropapillary, and or lymphovascular invasion. For other patients and those who refuse cystectomy, intravesical BCG is a reasonable approach.

Full-dose induction BCG is administered weekly for 6 weeks, starting at least 2 weeks after TURBT. Patients with negative cystoscopy and cytology at restaging at 3 months are appropriate candidates for maintenance BCG typically given as three-weekly installations at 3, 6, 12, 18, 24, 30, and 36 months after diagnosis. Patients who manifest persistent or recurrent disease may be considered for a second induction course of BCG based on their clinical status; however, cystectomy remains the preferred management approach.

Patients with muscle-invasive disease (T2 to T4, N0, M0) are usually managed by radical cystectomy or radiotherapy. There is increasing evidence that an extended lymphadenectomy as part of the radical cystectomy is associated with an improvement in 5-year progression-free survival.³ Appropriate patients may be offered continent diversions instead of an ileal loop diversion. Despite appropriate local therapy, the recurrence rates of patients with MIBC range from 40% to 100%. Systemic chemotherapy administered in the perioperative setting has the potential to improve the cure rates of patients undergoing cystectomy. The role of cisplatin-based neoadjuvant therapy has been tested prospectively in two large randomized trials providing definitive evidence of a survival benefit in patients undergoing radical cystectomy and is the standard of care for patients who are suitable to receive cisplatin.⁴,⁵ Patients with high-risk pathology who did not receive neoadjuvant chemotherapy may benefit from cisplatin-based adjuvant therapy.

In patients with MIBC, cisplatin-based combination chemotherapy followed by radical cystectomy has been demonstrated to improve survival compared with surgery alone.⁶ It is important to note that survival benefit has not been demonstrated with non-cisplatin-based regimens, and for patients unfit or unwilling to receive cisplatin-based chemotherapy, the standard of care remains surgery alone. Although in some clinical settings, it may be reasonable to consider cisplatin-based chemotherapy in the adjuvant setting, there is no level I evidence that therapy in this setting improves overall survival.⁷ The only regimens that have been tested in the phase III settings include the MVAC regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) (Table 12.1) and the CMV regimen (cisplatin, methotrexate, vinblastine), though the latter regimen is rarely used. Many oncologists have adopted the gemcitabine, cisplatin regimen (GC) (Table 12.1) for use in the neoadjuvant setting extrapolating from the results of a phase III study in metastatic urothelial cancer,
which compared GC with MVAC, which demonstrated comparable efficacy, duration of response, and less toxicity with GC.⁸ More recently, several phase II trials have demonstrated the potential utility and safety of administering accelerated/dose-dense MVAC (Table 12.1) in the neoadjuvant setting.⁹,¹⁰ The optimal number of cycles remains unknown, but three to four cycles are most commonly administered. Upon completion of therapy, most patients go on to radical cystectomy 3 to 6 weeks postchemotherapy.

External-beam radiation therapy is widely used in parts of the world as the standard curative-intent local therapy, with recent level I evidence demonstrating an improvement in survival in those patients receiving chemo-radiotherapy versus radiotherapy alone.¹¹ Patients who undergo radiotherapy do require ongoing bladder surveillance with periodic cystoscopic evaluations.

Chemotherapy and radiation can be offered to patients with MIBC who desire bladder preservation or are not candidates for radical cystectomy. Cisplatin chemotherapy
concurrent with radiation increases local control. Approximately 30% of patients are free of recurrence 5 years after combined modality therapy for muscle-invasive disease. Salvage cystectomy has been used in some patients who do not achieve a complete response or recur after a bladder-sparing approach. There have been no randomized trials comparing bladder preservation therapy with radical cystectomy. Local symptoms from radiation including urinary frequency, incontinence, and proctitis usually resolve, but can persist in some patients. Candidates for a bladder-sparing approach are patients with favorable tumors (e.g., no involvement of the trigone or ureter) or patients who are unfit for radical cystectomy due to comorbidities.

The management of transitional cell cancer of the renal pelvis is primarily surgical with nephroureterectomy the procedure of choice, and the role of perioperative chemotherapy in this setting is the subject of ongoing clinical trials.

The prognosis for locally advanced and metastatic urothelial bladder cancer has changed little over the past 30 years. In the untreated metastatic settings, favorable prognostic factors include good performance status, the absence of visceral metastases, and normal albumin and hemoglobin values.¹² Randomized trials of cisplatin-based combination regimens have demonstrated the ability to cure a small subset of patients ranging from 5% to 15%.¹³,¹⁴

As noted above, the MVAC (standard/dose dense) and GC regimens are the most widely used in the management of advanced urothelial cancers (Table 12.1). Although cisplatin is the most active single agent in advanced urothelial cancers many patients as a consequence of the disease or other comorbidities are not appropriate candidates for cisplatin-based regimens.¹⁵ Agents such as carboplatin, docetaxel, paclitaxel, and gemcitabine as single agents and in combination have demonstrated overt antitumor activity, but none have demonstrated curative potential.

Cisplatin-based multiagent chemotherapy produces median progression-free and overall survival rates in the 7-to-8-month and 14-to-15-month ranges, respectively.⁸ The toxicity of these regimens can be substantial and patient selection in regard to medical comorbidities and performance status is important. Response to chemotherapy is monitored by periodic assessment of tumor responses typically with CT imaging, with the expectation that most patients who will respond will do so within the first one or two cycles of treatment.

Patients with disease progression following initial platinum-based chemotherapy currently have very poor outcomes with no established standard of care. Antitumor activity has been demonstrated with a large number of chemotherapeutic agents primarily in phase II studies but to date, no evidence of improved survival has been demonstrated.¹⁶ Goals of therapy need to be carefully reviewed with patients before initiating therapy. Enrolling fit patients onto next-generation clinical trials should be a primary consideration for those patients desiring additional therapy.

Recently, next-generation immunomodulatory (anti-PD1/PDL1) agents have demonstrated significant activity in advanced urothelial cancer. Several phase II trials have demonstrated objective response rates in the 30 to 40 range with subsets of patients having sustained responses with a good safety profile. Phase III studies to define the role of these agents are underway.¹⁷

Management of the non-TCC histologies, typically adenocarcinoma, squamous cell, or small cell carcinomas, is challenging. Primary adenocarcinomas and squamous cancers of the bladder are managed surgically, as there is no defined role for chemotherapy in the neoadjuvant or adjuvant settings. Patients with metastatic disease should be considered for phase I studies, as there is no evidence of meaningful response rates to standard chemotherapeutic agents. Neuroendocrine tumors of the bladder are usually treated similar to small cell lung cancer with cisplatin and etoposide chemotherapy and bladder radiotherapy or cystectomy in selected patients with bladder-confined disease. Subsets of these patients with clinically organ-confined disease may be long-term survivors; however, patients with metastatic disease have similar outcomes to patients with extensive small cell lung cancer, demonstrating a relatively high response rate to chemotherapy, but very poor survival rates.

Carcinoma of the prostate is the second most common cancer in the United States after non-melanoma skin cancer. Following the introduction of prostate-specific antigen (PSA) into clinical practice in the late 1980s a significant increase in prostate cancer diagnoses as a consequence of a broadly applied screening paradigm led to a dramatic increase in the number of men with low-grade and low-stage disease undergoing curative-intent therapy with surgery or radiotherapy. Large randomized prostate cancer screening
trials from the United States and Europe have reported mixed results, leading to much more nuanced recommendations for prostate cancer screening from major medical societies in the United States¹⁸,¹⁹,²⁰,²¹ Active surveillance (AS) as a management strategy for low-risk patients and recent developments in genomic- based diagnostics may improve our ability to risk-stratify patients to enable curative-intent therapy for patients at risk of dying from prostate cancer while minimizing the side effects of therapy for those patients destined to die with, but not of prostate cancer.²²,²³

Definitive pathologic staging of prostate cancer requires surgical excision of the prostate and regional nodes, whereas clinical staging of prostate cancer uses pretreatment clinical parameters to predict the extent of disease and the patient’s prognosis as well as to inform the therapeutic decision process. Pretreatment modalities used to predict disease extent in prostate cancer patients include the digital rectal exam, prostate cancer features obtained from needle biopsy, PSA, and imaging with prostate MRI. Pathologic staging more accurately estimates disease burden and is more useful than clinical staging for outcome prediction. The most important pathologic criteria in the assessment of a radical prostatectomy specimen are tumor grade, the presence or absence of seminal vesicle invasion and extracapsular disease, surgical margin status, and pelvic lymph node involvement. The most commonly used staging for prostate cancer is the TNM system.²

As a consequence of widespread prostate cancer screening, the potential for clinical understaging, and the heterogeneity of prostate cancer, the therapeutic decision process for men with localized prostate cancer is complex. The guiding principal of disease management should be to offer curative-intent therapy to men who need to be cured and to avoid the side effects of the intervention in men who are not destined to die of prostate cancer.²⁴