Renal and urinary bladder cancer

KEY POINTS ABOUT BLADDER CANCER

Smoking is the leading cause of bladder cancer in the United States.
The median age at diagnosis is 73 years.
Non-muscle invasive disease is treated with cystoscopic resection and intravesical therapy.
Muscle invasive disease is treated with neoadjuvant cisplatin-based combination chemotherapy followed by cystectomy. If bladder preservation is desired or if the patient is not a surgical candidate, trimodality therapy with transuretheral resection of bladder tumor (TURBT) followed by concurrent chemoradiation is recommended.
For metastatic disease, cisplatin-based chemotherapy is the first-line therapy. Immunotherapy is indicated as the treatment of choice for some patients and has become standard second-line therapy in general.
Cardiovascular side effects of systemic treatment have been reported, especially immunotherapy-associated cardiotoxicity.

Bladder cancer

Incidence

Bladder cancer is the most common malignancy involving the urinary system and the sixth most common malignancy in the United States. Approximately 81,400 cases of bladder cancer are diagnosed each year, typically. In older individuals, with a median age at diagnosis of 73 years. Urothelial carcinoma is the most common histologic type in the United States and Western Europe.

Risk factors

The most common risk factors for bladder cancer are cigarette smoking and various occupational exposures, such as dye, arsenic, and aromatic amines, most notably in the rubber/leather industries. Schistosoma hematobium causes 50% of cases in developing countries. Other risk factors include male sex, white race, personal or family history of bladder cancer, prior chemotherapy with cyclophosphamide, pelvic radiation, chronic infection or irritation of the urinary tract, and certain medical conditions including obesity, diabetes, and human papillomavirus. ^,

Prognosis

For bladder cancer, 51% of patients present with in situ disease with a 95.8% 5-year survival, 34.1% with localized disease with a 5-year survival of 69.5%, and 7% with regional lymph node involvement with a 5-year survival of 36.3%. Five percent present with distant metastatic disease and the 5-year survival is 4.6%.

Treatment overview

Nonmuscle invasion bladder cancer is generally managed with transuretheral resection of bladder tumor (TURBT) and intravesical bacillus Calmette-Guérin (BCG) or intravesical chemotherapy to reduce recurrence or delay progression of bladder cancer to a higher grade or stage. The US Food and Drug Administration (FDA) has also approved pembrolizumab for the treatment of patients with “BCG-unresponsive, high-risk, nonmuscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.”

For muscle invasive bladder cancer, neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy with urinary diversion is considered the standard of care. A bladder-preserving approach is an alternative to cystectomy for patients who are medically unfit for surgery and those seeking an alternative to radical cystectomy. Maximal TURBT with concurrent chemoradiotherapy is recommended for this population.

Role of checkpoint inhibitors

The FDA has approved the PD-L1 inhibitors atezolizumab, durvalumab, and avelumab as well as the PD-1 inhibitors nivolumab and pembrolizumab for patients with urothelial carcinoma. Pembrolizumab, atezolizumab, nivolumab, durvalumab, and avelumab are approved for the treatment of locally advanced or metastatic urothelial cell carcinoma that has progressed during or after platinum-based chemotherapy or that has progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy, regardless of PD-L1 expression levels. Additionally, atezolizumab and pembrolizumab are approved as a first-line treatment option for patients with locally advanced or metastatic urothelial cell carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression. As above, the most recent indication for pembrolizumab is refractory nonmuscle invasive bladder cancer.

Cardiovascular risk

Cardiovascular side effects of systemic cancer treatment in bladder cancer

Cisplatin

Cisplatin is typically well tolerated from a cardiovascular standpoint. Cardiotoxicity induced by cisplatin is rare (<1%), but has been reported. Oxidative stress is an important mechanism of cardiotoxicity. The manifestations include arrhythmias, myocarditis, cardiomyopathy, and congestive heart failure. ^, Elevated cardiac blood biomarkers during treatment require further clinical evaluation. Identifying early signs of cardiac damage could optimize the management of cardiotoxicity. Arterial and venous thrombotic events are other concerns with cisplatin therapy. Hypertension has also been noted in patients on platinum-based therapy.

Gemcitabine

Gemcitabine is generally not viewed as a cardiotoxic agent. Only a few case reports exist in literature about gemcitabine-induced cardiomyopathy. Gemcitabine-associated peripheral edema is seen in 20% of patients, cardiac arrhythmia in 0.2% to 1.4%, reduction in left ventricular ejection fraction in 0.2%, and exudative pericarditis in 0.2%. Like cisplatin, gemcitabine can be toxic to the endothelium.

The development of peripheral edema is a nonspecific but multifactorial process that involves a combination of hydrostatic and oncotic forces, and/or vascular permeability changes. Other etiologies must be ruled out before attributing peripheral edema to gemcitabine.

Discontinuation of gemcitabine therapy is appropriate if cardiotoxicity develops.

Checkpoint inhibitors

Cancer immunotherapy with checkpoint inhibitors has revolutionized the management of a variety of malignancies, but can also produce immune-related adverse events. Based on the review of pharmaceutical safety databases, cardiovascular adverse events occur in less than 0.1% of patients receiving checkpoint inhibitors. The prevalence is higher (0.27%) when used in combination therapy. The cardiotoxicity related to checkpoint inhibitors includes myocardial fibrosis, cardiomyopathy, heart failure, conduction abnormalities, vasculitis, myocarditis, pericarditis, arrhythmia, myocardial infarction, and cardiac arrest.

It has been found that PD-1 and PD-L1 are expressed in human cardiomyocytes. Robust T-cell infiltration, activation, and clonal expansion have been observed in cardiomyocytes in patients receiving checkpoint inhibitors. This is thought to play a role in cardiotoxicity related to checkpoint inhibitors.

The onset of cardiovascular side effects can be as soon as 2 weeks and as long as 32 weeks with a median onset of 10 weeks after medication initiation. Signs and symptoms may include fatigue, chest pain, palpitation, peripheral edema, dyspnea, and pleural effusion.

Any grade of cardiac toxicity warrants workup and intervention. Initial workup includes an electrocardiogram, troponin, brain natriuretic peptide (BNP) and chest X-ray. Further diagnostic workup may include a stress test, cardiac catheterization, and cardiac magnetic resonance image. Checkpoint inhibitors should be held immediately and may need to be permanently discontinued. Management of cardiac symptoms should be based on American College of Cardiology/American Heart Association (ACC/AHA) guidelines. If the cardiotoxicity is felt to be caused by to immunotherapy, high-dose corticosteroids, such as methylprednisolone 1 g daily, may be necessary. The addition of mycophenolate, infliximab, or antithymocyte globulin may be considered if there is no immediate response to high-dose corticosteroids.

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