Surgical intervention, chemotherapeutic regimens, and radiation therapy have been the primary weapons in the frontline fight against cancer. However, immunotherapy, a fourth therapeutic modality, now holds the promise of a new age in the battle against even the most resistant cancers. Bladder cancer, in particular, has carried a poor prognosis in late-stage and metastatic disease. Current treatments have been inadequate with only minimal success. The discovery of checkpoint proteins, along with a better understanding of the role they play in tumor evasion mechanisms, has opened the door to mobilizing a significant immune response in patients with cancer. Using monoclonal antibodies (mAbs) to block the inhibitory signals of the programmed death-1 (PD-1)/ programmed death-ligand 1 (PD-L1) pathway has the potential to change traditional treatment pathways. This supplement will review the traditional treatments of bladder cancer, describe PD-1 and PD-L1 pathways, and present evidence from clinical trials evaluating the specific role of drugs targeting the PD-1 pathway in bladder cancer.Bladder CancerEpidemiology
Bladder cancer is the fourth-most common cancer in the United States,1
affecting men 3 times more than women.1
In 2014, 74,690 new cases and 15,580 deaths are projected to occur in the United States.2
This represents 4.5% of all new US cancer cases and 2.7% of all US cancer deaths.2
Also, in 2011, approximately 571,518 patients were living with bladder cancer.2
The median age of diagnosis is 65 years; in fact, diagnoses in patients under the age of 40 years are considered rare.1Types of Bladder Cancer
Bladder cancer is a broad term that encompasses a variety of cancer types that involve the epithelial lining of the urinary bladder. Bladder cancers can be classified into 1 of 3 tumor types: (1) nonmuscle invasive; (2) muscle invasive; and (3) metastatic tumors.1
In the United States, 90% of urothelial tumors begin in the bladder, while only 8% originate in the renal pelvis and 2% in the ureter and urethra.1
The most common subtype of bladder cancer in the United States is urothelial or transitional cell carcinoma. This subtype develops anywhere transitional urothelial epithelium exists, including the renal pelvis, ureter, bladder, the beginning two-thirds of the urethra, and anywhere in between. The remaining section of the urethra contains squamous epithelium; tumors located here are the cause of squamous cell tumors, which comprise just 3% of tumors in the United States.1Risk Factors
According to the American Cancer Society, smoking is the leading contributing factor to a diagnosis of bladder cancer. Overall, approximately 50% of bladder cancer cases can be attributed to smoking. Carcinogens from tobacco smoke are filtered by the kidneys, thus leading to bladder cell damage due to concentrations of these carcinogens in the urine. Therefore, people who smoke are 3 times more likely to develop bladder cancer compared with nonsmokers.
Exposure to certain industrial chemicals has also been linked to developing bladder cancer. Those occupations associated with an increased risk of bladder cancer include painters, machinists, printers, hairdressers, truck drivers, and any occupation that involves handling dye. The risk of developing bladder cancer increases significantly when industrial exposure is paired with smoking.
Other risk factors include race, age, sex, bladder birth defects, genetics, long-term chemotherapy with cyclophosphamide, pelvic radiation, and having taken pioglitazone for diabetes for more than 1 year.3Pathophysiology
Non–muscle invasive disease (NMID) tumors comprise nearly 70% of newly detected cases of bladder cancer. Of these NMID tumors, 70% are confined to the mucosa, 25% are confined to the submucosa, and less than 5% are carcinoma in situ (CIS), which are flat, high-grade lesions. Characteristics of NMID tumors include being friable with high bleeding tendencies and a likely recurrence in the same area or a different area of the bladder.1 The rate of recurrence within 5 years for patients with tumors confined to the mucosa or submucosa is approximately 31% to 78%.1Diagnosis/Staging
Most often, patients with bladder cancer present with microscopic or gross hematuria. They may also present with frequent urination or a urinary tract infection as their primary complaint, albeit less frequently. Pain or an upper tract obstruction may also be a presenting symptom, but this is often indicative of a more advanced lesion.1
In-office cystoscopy is typically performed in patients presenting with pain or upper urinary tract obstruction to determine whether or not a lesion is present.