# 20 - 91 Cancer of the Bladder and Urinary Tract ### 91 Cancer of the Bladder and Urinary Tract TABLE 90-3  Commonly Used Systemic Regimens for Metastatic Renal Cell Carcinoma CLASS DRUG Antiangiogenic: TKIs Sunitinib Advanced RCC, first line Pazopanib Advanced RCC, first line Axitinib Advanced RCC, pretreated Cabozantinib Tivozanib Advanced RCC, pretreated with two or more prior systemic therapies Immunotherapy: checkpoint inhibitor Nivolumab Advanced RCC, pretreated with antiangiogenic therapy Combination therapies   TKI + mTOR inhibitor Lenvatinib + everolimus Advanced RCC, pretreated with one antiangiogenic therapy   PD-1 inhibitor + CTLA-4 inhibitor Nivolumab + ipilimumab Advanced intermediate-risk or poor-risk RCC, first line   PD-1 inhibitor + TKI Pembrolizumab + axitinib Advanced RCC, first line Nivolumab + cabozantinib Advanced RCC, first line Pembrolizumab + lenvatinib Advanced RCC, first line Abbreviations: CTLA-4, cytotoxic T lymphocyte-associated protein; FDA, U.S. Food and Drug Administration; mTOR, mammalian target of rapamycin; PD-1, programmed cell death-1; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor. PART 4 Oncology and Hematology whether and why treatments are working. Although a multitude of candidate biomarkers have been investigated for their predictive value in metastatic RCC, none have been validated for clinical use to date. Projected overall survival in patients starting systemic therapies for newly diagnosed metastatic disease has tripled over the past 15–20 years; this can largely be attributed to the successful drug developments discussed here. ■ ■GLOBAL CONSIDERATIONS Worldwide, >400,000 patients are diagnosed each year with malignant tumors arising from the kidney, resulting in >175,000 deaths annu­ ally. Kidney cancer is the sixth most common cancer in men and the 10th most common cancer in women. Higher incidence is observed in developed countries, including the United States, Canada, Europe, Australia, New Zealand, and Uruguay. Lower rates are reported in Southeast Asia and Africa, though it is speculated that these rates may be underreported due to lack of disease-reporting structure and reduced access to diagnostic facilities. The incidence of kidney cancer has been steadily increasing over the past four decades. Mortality trends have stabilized in Europe and the United States, but not in less developed countries. This is likely related to differences in access to optimal therapies. Treatment guidelines for both localized and meta­ static renal cancer are similar between U.S. and European documents and contingent on the access to adequate health care and availability of targeted drugs to treat metastases. ■ ■FURTHER READING Choueiri TK et al: Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 385:683, 2021. Choueiri TK et al: Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 384:829, 2021. Huang J et al: A global trend analysis of kidney cancer incidence and mortality and their associations with smoking, alcohol consumption, and metabolic syndrome. Eur Urol Focus 8:200, 2022. Jonasch E et al: Belzutifan for renal cell carcinoma in von Hippel– Lindau Disease. N Engl J Med 385:2036, 2021. Moch H et al: The 2022 WHO classification of tumours of the urinary system and male genital organs—Part A: renal, penile, and testicular tumours. Eur Urol 82:458, 2022. Motzer RJ et al: Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. Cancer Cell 38:803, 2020. Motzer RJ et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277, 2018. FIRST FDA APPROVAL FOR RCC CURRENTLY USED FOR Advanced RCC, pretreated with antiangiogenic therapy Advanced RCC, first line Noah M. Hahn Cancer of the Bladder and Urinary Tract GLOBAL CONSIDERATIONS Within the United States, urothelial carcinomas of the bladder and urinary tract are most closely related to tobacco smoking history. However, within developing countries, water supplies contaminated with arsenic or schistosomiasis parasites also are major carcinogenic contributors. INTRODUCTION Cancers of the urinary tract including the bladder, renal pelvis, ureter, and urethra occur frequently, and they represent the second most com­ mon class of genitourinary cancers. Bladder cancer alone represents the sixth most common cancer diagnosis annually in the United States with 82,290 new cases and 16,710 deaths every year. Because cancers of the renal pelvis are often lumped in with all kidney cancers, the true incidence and mortality from nonbladder urinary tract cancers are less precise. While less frequent than bladder cancer, an additional 20,000 new cases and 5000 deaths are estimated every year. An accelerated understanding of the molecular underpinnings of bladder and uri­ nary tract cancer biology has led to a significant increase in urothelial cancer clinical trials resulting in U.S. Food and Drug Administration (FDA) approval of multiple new therapeutic agents since 2016 with more expected to follow. This chapter reviews the established, current, and emerging evidence that serves as the basis for the rapidly evolving standards of care for patients with bladder and urinary tract cancers. ■ ■CLINICAL EPIDEMIOLOGY AND RISK FACTORS Bladder cancer typically affects older patients with a median age at diagnosis of 73 years. Males are four times more frequently affected than females. Similarly, bladder cancer is more common in Caucasians than in Asian patients. Inheritable germline genetic risk factors have been observed in up to one-seventh of patients with bladder or urinary tract cancers. However, a predominant, singular germline genetic alter­ ation has not been identified. Patients with defects in mismatch repair genes leading to microsatellite instability (MLH1, MSH2, MSH6, etc.) as part of the familial cancer Lynch syndrome are at particular risk of upper urinary tract cancers of the renal pelvis and ureter. Additionally, patients with Cowden disease (PTEN mutations) or retinoblastoma (RB1 mutations) are at increased risk for developing bladder cancer. Historically, associations have existed between environmental toxic exposures and higher rates of developing bladder cancer. The aromatic amines benzidine and β-naphthylamine that can be present in indus­ trial dyes as well as arsenic that can be found in drinking water supplies in underdeveloped countries have been associated with increased blad­ der cancer risk. Other chemicals in the leather, paint, rubber, textiles, and printing industries have been associated with bladder cancer. Associations with exposures to hair dyes and hair sprays in workers in the hairstyling field have been suggested. Additionally, concern has been raised regarding use of the antidiabetic medication, pioglitazone, and bladder cancer risk. Extensive reviews and meta-analyses have produced differing conclusions. The data suggest a small risk of blad­ der cancer from long-term pioglitazone use, which has led to inclusion of bladder cancer risk within the pioglitazone prescribing information. An association between chronic inflammatory states and the develop­ ment of squamous bladder cancer clearly exists in underdeveloped countries in patients chronically infected with the parasitic disease schistosomiasis and in paraplegic patients with chronic indwelling catheters. Above and beyond each of these associations, however, smoking of tobacco products (cigarettes, cigars, pipes, etc.) remains the overwhelming leading risk factor for development of bladder cancer. Among new bladder cancer diagnoses, 90% of cases occur in current or former smokers. Toxicologists have estimated that >70 confirmed car­ cinogenic toxins are present within tobacco smoke. It is estimated that one-third of bladder cancer cases could be prevented through simple modification of lifestyle choices, in particular cessation of smoking. ■ ■CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP Occasionally, patients will present with flank pain in association with an upper tract renal pelvis or ureter cancer or due to hydronephrosis in association with a bladder tumor obstructing the orifice of the ureter within the bladder. Only in rare cases do patients present with sig­ nificant cachexia and widespread metastatic disease. For most patients, painless hematuria (either gross or microscopic) represents the ini­ tial manifestation of an underlying urinary tract cancer. In females, hematuria due to malignancy can often be mistaken for a urinary tract infection or menstrual bleeding. While treatment with antibiotics is warranted if a concurrent urinary tract infection is noted on initial urinalysis, persistent hematuria requires further workup. Painless hematuria in males is almost always abnormal and should be worked up. Initial investigations in patients of either sex should include urine cytology and visual examination of the bladder by cystoscopy. Cytology is successful in identifying cancer in only 50% of individuals with highgrade bladder cancers. In addition to urine cytology, radiographic eval­ uation of the kidneys and upper urinary tract by CT urogram should be performed. A magnetic resonance (MR) urogram may be substituted in patients with poor renal function. Additional diagnostic testing of the urine to assess for cancer-associated chromosomal changes by fluorescent in situ hybridization, increased levels of nuclear mitotic proteins, increased bladder tumor–associated antigens, or higher levels of staining on cells shed by the bladder may identify some cancers missed by traditional cytology testing. However, they may also produce abnormal results in patients who do not have cancer. For now, these adjunct molecular tests are primarily utilized in detecting recurrent cancer in patients with a prior diagnosis of urinary tract cancer. Small tumors, particularly flat noninvasive tumors of the bladder, may be detected at higher rates with the use of blue light cystoscopy or narrowband imaging cystoscopy. Both blue light and narrow-band imaging cystoscopies are now used routinely in the monitoring of patients with bladder cancer. For patients with no bladder abnormalities in whom upper tract tumors are suspected, visualization of the upper urinary tracts and renal pelvises should be performed by ureteroscopy or ret­ rograde pyelography. In all patients with abnormalities noted in the bladder or upper urinary tracts, complete endoscopic resection for histologic diagnosis and staging should be performed when possible via either transurethral resection of bladder tumor (TURBT) or endoscopic resection of upper tract tumors. All metastatic patients should have genomic sequencing performed on their tumor tissue, circulating tumor DNA (ctDNA), or both. The role of genomic sequencing in earlier stages of disease is evolving. ■ ■HISTOLOGY Urothelial carcinoma, often called transitional cell carcinoma in the past, is the most common urinary tract cancer histology and is observed in ~90% of cases. Squamous, glandular, micropapillary, plas­ macytoid, sarcomatoid, and other variant features can often be found in portions of urothelial carcinoma tumors; however, pure variant histologies are rare. The presence of some variant histologies includ­ ing micropapillary and plasmacytoid has been associated with worse surgical outcomes compared to urothelial carcinoma. Nonurothelial variant histologies including squamous cell carcinoma, adenocarci­ noma, small-cell carcinoma, and carcinosarcoma collectively account for ≤10% of urinary tract tumors. Examples of traditional urothelial carcinoma and some of the variant histologies are shown in Fig. 91-1. ■ ■MOLECULAR BIOLOGY Clinically, urothelial carcinoma of the bladder displays a biphasic phe­ notype characterized by (1) low-grade papillary tumors that frequently recur but rarely invade or metastasize and (2) high-grade sometimes flat tumors that invade early leading to lethal metastatic disease. In both of these phenotypes, loss of portions of chromosomes 9q and 9p by loss of heterozygosity is an early molecular event, whose exact significance is not clear. Potential candidate regulatory genes in these genomic regions include CDNK2A, a cyclin-dependent kinase inhibi­ tor, and TSC1, a gene encoding hamartin mutated in tuberous sclerosis. Genomic investigations have demonstrated that low-grade tumors are characterized by alterations in the RAS/RAF signaling pathway with activating FGFR3 mutations or gene fusions present in 60–80% of patients. In contrast, the high-grade invasive phenotype is notable for early deleterious mutations in TP53 and RB1, alterations in CDH1 (E-cadherin), and increased expression of VEGFR2. In urothelial car­ cinoma of the renal pelvis and ureter, 10–20% of cases may be associ­ ated with Lynch syndrome hereditary defects in the MLH1, MSH2, or MSH6 mismatch repair genes, leading to microsatellite instability and frequent DNA mutations. Testing for germline mutations in these genes is recommended in patients with upper urinary tract urothelial carcinoma under the age of 60 at diagnosis, with a first-degree relative with a Lynch syndrome–associated cancer diagnosed under the age of 50, or with two first-degree relatives with a Lynch syndrome–associated cancer regardless of the age at diagnosis. CHAPTER 91 Cancer of the Bladder and Urinary Tract As genomic analysis technologies have improved, so has our under­ standing of the molecular biology unique to urothelial carcinoma. In 2017, the full bladder cancer results of The Cancer Genome Atlas (TCGA) project were published. This effort comprehensively analyzed gene mutations, fusions, expression, copy number variations, meth­ ylation, and microRNA across the genome of patients with bladder urothelial carcinoma treated with surgery. Key findings from this effort include (1) genomic alterations in genes (e.g., FGFR3, EGFR, ERBB2, ERBB3, PIK3CA, TSC1, etc.) targetable by currently approved drugs or drugs in development in 71% of patients; (2) genomic alterations in chromatin-modifying genes (KMT2D, KDM6A, KMT2C, EP300, CREBBP, etc.) in the majority of patients; (3) hypermethylation with epigenetic silencing of gene expression in one-fourth of patients; and (4) the identification by RNA sequencing of five distinct intrinsic molecular subtypes (luminal papillary, luminal infiltrated, luminal, basal squamous, and neuronal) closely resembling luminal and basal subclassifications of breast cancers. These bladder TCGA findings have led to clinical trial designs enriching for patients with specific gene mutation profiles as well as interrogation of candidate biomarkers according to intrinsic molecular subtypes. ■ ■STAGING AND OUTCOMES BY STAGE The staging of bladder cancer is dependent on the depth of invasion within the bladder wall, involvement of lymph nodes, and spread to A B PART 4 Oncology and Hematology C D FIGURE 91-1  Bladder and urinary tract cancer histologies. A. Urothelial carcinoma. B. Squamous cell carcinoma. C. Small-cell carcinoma. D. Plasmacytoid variant. (Courtesy of Alex Baras, MD, PhD, Johns Hopkins University Department of Pathology.) surrounding and distant organs as depicted in Fig. 91-2. Approxi­ mately 75% of bladder cancer presents with non–muscle-invasive bladder cancer (NMIBC), 18% with disease invading into or through the muscular wall of the bladder, and only 3% with metastatic spread to distant organs. NMIBC is defined by tumors that involve only the immediate epithelial layer of cells (carcinoma in situ [CIS] and Ta) or that only penetrate into the connective tissue below the urothelium (T1) but not into the muscular layer known as the muscularis propria. Muscle-invasive bladder cancer (MIBC) is defined by tumors that invade into the muscularis propria (T2), through the muscularis propria to involve the surrounding serosa (T3), or into immediately adjacent pelvic organs such as the rectum, prostate, vagina, or cervix (T4). Lymph node staging is classified according to involvement of a solitary node within the true pelvis (N1), two nodes involved in the true pelvis (N2), or involvement of the common iliac nodes (N3). Any disease that has spread beyond the common iliac nodes is considered metastatic (M1). The staging of bladder cancer is driven primarily by the T stage of the tumor, with stages 0a–II defined entirely by the T stage in the absence of nodal or metastatic disease. Involvement of regional lymph nodes in the true pelvis or along the common iliac artery qualifies as stage III disease, whereas involvement of any distant metastases qualifies as stage IV disease. Clinical outcomes of patients with bladder cancer correlate closely with staging at diagnosis with 5-year overall survival rates of 70–90% for disease confined to the bladder (stage I–II), 39–50% for disease that penetrates through the bladder or has spread to regional lymph nodes (stage III), and only 8% for disease extending to metastatic sites (stage IV). ■ ■TREATMENT APPROACHES Early-Stage Disease  For NMIBC, removal of all visible tumors by TURBT in the operating room is considered the mainstay of surgical treatment. Risk of recurrence can be classified as low, intermediate, or high depending on the presence of features summarized in Table 91-1. For patients with low-risk disease, meta-analyses have demonstrated a 12% reduction in early relapses when a single chemotherapy treatment of mitomycin C, epirubicin, or gemcitabine was instilled directly into the bladder (intravesical therapy) within 24 hours of the TURBT. For patients with intermediate- or high-risk tumors, weekly intravesical instillations for 6 consecutive weeks of the attenuated mycobacte­ rium strain known as Bacille Calmette-Guérin (BCG) reduce the risk of recurrence from 50 to 29%. In addition, BCG treatment has been shown to decrease the rate of progression to MIBC by 27%. Intravesical BCG is generally well tolerated. Side effects can include dysuria, uri­ nary frequency, bladder spasms, hematuria, and, in rare cases (<5%), a systemic inflammatory response that can mimic disseminated BCG infection. Following a 6-week induction BCG schedule, additional maintenance BCG treatments given according to the Southwest Bladder T-staging Bladder lymph node staging T2 T3 Muscularis propria Lamina propria T1 N3 N3 Ta N3 T4 Urothelium Tis Internal iliac artery External iliac artery Prostate* Obturator artery *Direct tumor extension into other adjacent pelvic organs (rectum, vagina, cervix) or the pelvic or abdominal walls also qualifies as T4 True pelvis border Bladder cancer prognosis according to stage N1 - Cancer spread to 1 lymph node in the true pelvis T N M Stage 5-yr survival 0is/0a M0 M0 M0 M0 M0 M1 N0 N0 N0 N0 N1-N3 Any N 96% 90% 70% 50% 36% 5% Tis/Ta T1 T2 T3 T1-T4 Any T N2 - Cancer spread to 2 lymph nodes in the true pelvis N3 - Cancer spread to lymph nodes along the common iliac artery FIGURE 91-2  Bladder cancer staging and prognosis. TNM, tumor-node-metastasis. Oncology Group schedule further reduce the risk of recurrent NMIBC compared to induction BCG alone. In patients with NMIBC that recurs long after initial BCG treatment, a repeat course of BCG can be considered. For patients with recurrence after a second adequate course of BCG or with relapsed NMIBC within 6 months of initial BCG exposure, surgical removal of the entire bladder by cystectomy is recommended due to the high risk of progression to MIBC and poten­ tially metastatic disease. For patients who are not fit enough for or who refuse cystectomy, non-BCG alternative intravesical agents (nadofara­ gene firadenovec, mitomycin C, gemcitabine, docetaxel, valrubicin) or systemically administered agents that inhibit the PD-1/PD-L1 immune checkpoint pathway (pembrolizumab) can achieve durable tumor responses in a small fraction of patients. Upper Tract Disease  In patients with urothelial carcinoma of the renal pelvis or ureter, endoscopic tissue acquisition and staging are TABLE 91-1  Non–Muscle-Invasive Bladder Cancer Recurrence Risk Groups RISK GROUP CHARACTERISTICS Low risk Initial tumor, solitary tumor, low grade, <3 cm, no CIS Intermediate risk All tumors not defined in the two adjacent categories (between the category of low and high risk) High risk Any of the following: • T1 tumor • High-grade • CIS • Multiple and large (>3 cm) Ta low-grade tumors in patients over age 70 (all conditions must be met for this point on Ta low-grade tumors) Abbreviation: CIS, carcinoma in situ. more challenging than primary tumors located in the bladder. Tumors possessing all of the following are considered low risk: solitary tumor, low grade, size <1 cm, and no invasive component on imaging. Lowrisk tumors can successfully be treated by laser ureteroscopic ablation or surgical resection and reanastomosis of the remain­ ing ureter ends in tumors that cannot be successfully eradicated endoscopically. Aorta Common iliac artery Muscle-Invasive Disease  In patients with urothelial carcinoma of the bladder that invades into or through the muscularis propria but with no evidence of metastatic spread, more aggressive therapy options summarized in Table 91-2 are required to achieve cure. In carefully selected patients with no evidence of CIS or hydronephro­ sis, bladder-sparing combined-modality therapy with concurrent chemotherapy and radiation can achieve cure in ~65% of patients. Various chemotherapy regimens have been utilized in combination with radiation including cisplatin, carboplatin, 5-fluorouracil, mitomycin C, paclitaxel, and gemcitabine. It is important to note that a maximal debulking of all visible tumor by TURBT is required prior to ini­ tiation of combined-modality therapy. In patients who achieve a complete response to combined-modality therapy, regu­ lar cystoscopic monitoring of the blad­ der is required with salvage cystectomy offered to patients who develop MIBC in follow-up. N2 N2 N1 CHAPTER 91 Cancer of the Bladder and Urinary Tract In a similar fashion, bladder-sparing partial cystectomy can be performed in a very small subset of MIBC patients. The ideal patient for partial cystectomy is the patient with a solitary, clinical T2 urothelial carcinoma in the dome of the bladder. In such patients, the tumor and immediate surrounding urothelium can TABLE 91-2  Treatment Approaches to MIBC Patients TREATMENT PATIENT SELECTION CLINICAL OUTCOMES Bladder-sparing chemoradiation No CIS, no hydronephrosis, maximal TURBT required 65% cure, 55% bladder intact, highly dependent on patient selection Bladder-sparing partial cystectomy Solitary tumors in dome of bladder are ideal Variable, highly dependent on patient selection Cystectomy Any MIBC patient 50% cure with surgery alone, highly dependent on pathologic stage Neoadjuvant cisplatin-based chemotherapy Cisplatin-eligible MIBC patients 5–10% improvement in overall survival compared to cystectomy alone Adjuvant cisplatin-based chemotherapy Cisplatin-eligible, highrisk, postcystectomy MIBC patients (pT3-4, N+) Similar improvement as neoadjuvant treatment, data less robust, many patients not suitable for adjuvant treatment Adjuvant nivolumab anti–PD-1 immunotherapy Postsurgery, high-risk MIBC and UTUC patients (pT3-4, N+, cisplatineligible after neoadjuvant therapy OR pT2-4, N+, cisplatin-ineligible who did not receive neoadjuvant therapy) 30% improvement in diseasefree survival compared to surgery alone Abbreviations: CIS, carcinoma in situ; MIBC, muscle-invasive bladder cancer; TURBT, transurethral resection of bladder tumor; UTUC, upper tract urothelial carcinoma. be resected with reconstruction of the remaining bladder to maintain near physiologic urinary function. In the majority of patients, however, resection of the entire bladder is required. In males, a cystoprostatectomy with removal of the bladder, prostate, and pelvic lymph nodes is performed, whereas in females, an anterior exenteration with removal of the bladder, uterus, ovaries, cer­ vix, and pelvic lymph nodes is performed. With the bladder removed, three options exist to reroute the urine outflow. In an ileostomy, the bilateral ureters are connected to a portion of ileum that is brought through an incision in the abdominal wall to create a stoma that drains urine into an affixed bag outside of the body. In a continent urinary reservoir or “Indiana pouch,” the ureters are connected to a portion of ileum that has been separated on both ends from the rest of the smallbowel transit to form a urinary reservoir. The remaining small bowel is reanastomosed, and the urinary reservoir is brought up just beneath the abdominal wall muscles with patients catheterizing the urinary res­ ervoir several times per day via a small stoma tract. Last, in a neoblad­ der, the same urinary reservoir described previously is brought down into the pelvis and is anastomosed to the remaining urethra to provide the opportunity to the patient to void urine through the urethra. The choice of which urinary reconstruction to perform is affected not only by patient choice but also by anatomic tumor considerations and urolo­ gist experience with each procedure. Regardless of the type of surgery performed, all patients undergo a significant catabolic change in their metabolism following removal of the bladder. While many MIBC patients are affected by weight loss preoperatively, it is not uncommon for postcystectomy patients to lose an additional 10–15 pounds in the first month postoperatively. In addition, patients can experience longterm nutritional changes such as low B12 levels due to alterations in small-bowel physiology caused by all of the urinary diversion options. PART 4 Oncology and Hematology Despite aggressive surgery, only half of patients undergoing cystec­ tomy are cured by surgery alone. Therefore, many clinical trials have investigated the role of systemic chemotherapy and immunotherapy before (neoadjuvant) or after (adjuvant) surgery. Meta-analyses have shown a 5–10% absolute overall survival advantage when combination chemotherapy regimens utilizing cisplatin have been used before sur­ gery. Importantly, non–cisplatin-containing chemotherapy regimens have proven inferior to cisplatin-containing regimens. Therefore, if patients are not suitable candidates for cisplatin administration due to poor functional status or comorbidities (e.g., poor renal function), patients should proceed directly to surgery and forego neoadjuvant therapy. A similar benefit exists with cisplatin-based combination che­ motherapy given after surgery. However, in the postoperative setting, some patients may not recover sufficiently from their surgery within a time frame optimal for chemotherapy administration. In bladder and upper tract urothelial cancer patients with high-risk postsur­ gery pathology features, adjuvant treatment with the PD-1–targeting immune checkpoint inhibitor, nivolumab, has demonstrated a 30% improvement in disease-free survival compared to observation and is considered a standard treatment option. For patients with high-risk urothelial carcinoma of the upper urinary tract, resection of the kidney and ureter (including the ureter bladder cuff) by nephroureterectomy is preferred. Segmental ureterectomy may be appropriate in patients with decreased renal function in which nephron-sparing outcomes are critical to prevent the need for dialysis. Similarly, in CIS patients, administration of BCG therapy via a nephros­ tomy tube can be considered to preserve intact renal function. The use of cisplatin-based neoadjuvant chemotherapy has been associated with a pathologic complete response at surgery of 14% in upper tract urothe­ lial carcinoma patients. Similarly, in the post-nephroureterectomy set­ ting, adjuvant platinum-based chemotherapy (carboplatin or cisplatin) reduced recurrence rates by 55% compared to surgery alone. The use of perioperative chemotherapy (before or after surgery) or PD-1–tar­ geting immunotherapy (after surgery) is now recommended for upper tract urothelial carcinoma patients in national guidelines. Metastatic Disease  For patients with metastatic urothelial carci­ noma regardless of primary tumor origin, systemic platinum-based chemotherapy remained the established initial treatment for decades. However, the regimen of a nectin-4–targeting antibody-drug con­ jugate, enfortumab vedotin, carrying the monomethyl auristatin E (MMAE) cytotoxic payload combined with the PD-1 immune check­ point inhibitor pembrolizumab (EV+P) supplanted platinum-based chemotherapy in 2023 as the preferred first-line therapy for meta­ static urothelial carcinoma patients. In a randomized, phase 3 clini­ cal trial, EV+P treatment resulted in a highly significant improved median overall survival of 31.5 months compared to 16.2 months with platinum-based chemotherapy. These results led to the FDA approval of the EV+P regimen in first-line metastatic urothelial carcinoma patients. The optimal second-line therapy for patients who experience disease progression on front-line EV+P is not defined. Second-line options include platinum-based chemotherapy or fibroblast growth factor receptor (FGFR) inhibitor therapy (erdafitinib) for patients with activating FGFR genomic alterations. For patients with progres­ sion after receiving both platinum-based chemotherapy and a PD-1/ PD-L1 immune checkpoint inhibitor, the Trop-2–targeting antibodydrug conjugate sacituzumab govitecan, containing a topoisomerase- inhibiting cytotoxic payload, SN-38, remains a third-line option. Prior to the approval of EV+P in the metastatic front-line setting, maintenance treatment with the PD-L1 immune checkpoint inhibitor avelumab had demonstrated an improvement in overall survival com­ pared to platinum-based chemotherapy alone in patients demonstrat­ ing stable disease or objective response to their front-line treatment. The role of maintenance PD-1/PD-L1 immune checkpoint inhibitor therapy in the second-line and beyond settings is undefined and is being evaluated in ongoing clinical trials. Additional novel urothelial carcinoma therapeutics are under ongoing investigation. With the increased number of therapeutic agents for metastatic urothelial cancer patients now available, differing toxicity profiles between treatment regimens commonly impact treatment decisions for individual patients. With platinum-based chemotherapy, renal insufficiency, myelosuppression, nausea, and neuropathy are common. With enfortumab vedotin, myelosuppression can occur; however, neuropathy is dose-limiting with rare but serious skin toxicity and new-onset diabetes events. Myelosuppression and significant diarrhea requiring intravenous fluid support are common with sacituzumab govitecan. In contrast, myelosuppression is uncommon with PD-1/ PD-L1 immune checkpoint inhibitors. Rare immune-related toxicities can be severe and may include colitis, pneumonitis, hepatitis, nephri­ tis, myocarditis, rash, hypothyroidism, Guillain-Barré syndrome, idiopathic thrombocytopenia purpura, and adrenal insufficiency. Lastly, erdafitinib side effects are notable for hyperphosphatemia, dystrophic nail changes, and rare central serous retinopathy. Thus, ophthalmologic evaluations are recommended for patients receiving FGFR inhibitor therapies. ■ ■FURTHER READING American Cancer Society: Cancer Facts & Figures 2023. Atlanta, GA: Available from https://www.cancer.org/cancer/bladder-cancer/ detection-diagnosis-staging/survival-rates.html. Carlo MI et al: Cancer susceptibility mutations in patients with urothelial malignancies. J Clin Oncol 38:5, 2020. Chou R et al: Intravesical therapy for the treatment of nonmuscle invasive bladder cancer: A systemic review and meta-analysis. J Urol 197:5, 2017. Coleman JA et al: Diagnosis and management of non-metastatic upper tract urothelial carcinoma: AUA/SUO guideline. J Urol 209:6, 2023. Dyrskjøt L et al: Bladder cancer. Nat Rev Dis Primers 9:1, 2023. Howlader N et al: SEER Cancer Statistics Review, 1975-2017. Avail­ able from https://seer.cancer.gov/csr/1975_2017/. Based on November 2019 SEER data submission, posted to the SEER website, April 2020. Powles T et al: Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med 390:10, 2024. Robertson AG et al: Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171:3, 2017.