Over the past 10 years, a shift in cancer treatment has occurred with the approvals of immune-targeted treatments. At approximately the same time that the urology community was responding to the first therapeutic cancer vaccine approval—sipuleucel-T (Provenge) for castration-resistant metastatic prostate cancer&mdash;checkpoint inhibition was found to cause tumor regression.

 Since then, immunotherapy has become a rapidly growing focus for cancer treatment.

Clinical trials have produced paradigm-shifting results, resulting in immunotherapy becoming a common treatment option in urologic cancers. Although initial approvals have been for late-stage disease after first-line therapy has failed, immunotherapy is more commonly being used earlier in the treatment plan. As immunotherapy has become increasingly utilized, urologists are more frequently participating in the management of patients who are receiving immunotherapy.

The generally well-tolerated treatments are a departure from prior aggressive cytotoxic chemotherapy regimens. The methodical movement of immunotherapy trials into earlier disease states (ie, nonmuscle-invasive bladder cancer [NMIBC]), along with the minimal or no adverse events (AEs) of immunotherapy, has generated interest among urologists who are considering management of immunotherapy agents in their own patients. In this article, we will explore some immunotherapy agents and consider the management of AEs from the urologist’s perspective.

Immunotherapy agents are often referred to as checkpoint inhibitors and include both the PD-1 and PD-L1 inhibitors along with anti—CTLA-4 agents. The first approved drug in the urologic setting was nivolumab (Opdivo), an anti–PD-1 monoclonal antibody approved for second-line therapy in metastatic renal cell carcinoma. The first approved immunotherapy agent for metastatic bladder cancer was atezolizumab (Tecentriq), a PD-L1–targeting immunotherapy.

The initial postchemotherapy approvals were unlikely to affect urology practice. Since these early approvals, however, other agents have been approved that might indeed provide options that overlap with treatments that a urologist would provide. The PD-1 inhibitor pembrolizumab (Keytruda) was approved agnostically for unresectable or metastatic microsatellite instability—high or mismatch repair deficient solid tumors without satisfactory alternative treatments. Atezolizumab and pembrolizumab have both been approved for locally advanced or metastatic bladder cancer in patients who are ineligible for cisplatin therapy but who test positive for PD-L1. Also, several ongoing clinical trials are evaluating the benefit of checkpoint inhibitors in NMIBC.

 Both the required intravenous administration and concerns about managing AEs have been considered impediments to adoption of immunotherapy for urologists. However, many urology clinics administer antineoplastic agents including immunotherapy, bacille Calmette-Guérin, and sipuleucel-T. Also, given the subtle presentation for many immunotherapy-related AEs, urologists are in a position to identify early signs of potential immune-related AEs. This is particularly true for patients with metastatic disease undergoing immunotherapy in the postoperative period, during which such symptoms as abdominal pain or diarrhea could have any of numerous potential causes.

Immunotherapy’s mechanism of action, unmasking cancer cells to facilitate identification by the immune system, is related to the development of treatment-related AEs. The immune system scans the body to identify sites of infection and potential cancer cells. To prevent erroneous attacks on normal cells, a series of cellular interactions regulate immune surveillance. Cancer cells evade detection by taking advantage of natural methods in our immune system to stop the immune response, thereby allowing growth without detection. Immune checkpoint inhibitors work by blocking the regulatory signals in the immune system, unmasking cancer cells, and allowing them to be cleared by the immune system.

When regulation of the immune system is reduced to improve recognition of cancer, the response can be nonspecific, which results in unintended off-target effects. The immune system of a patient on immunotherapy can inadvertently target any organ of the body, resulting in inflammation of an off-target system. Since nearly any organ can be targeted, a high level of vigilance is required. Severe, even fatal, AEs can occur in 15% of patients,3 but the majority of patients have minimal or no AEs. The low rate of toxicities from immunotherapy allows for treatment of patients who otherwise would not be candidates for chemotherapy regimens based on comorbidities.

The subtle presentation of AEs and the potential for a broad range of manifestations make it important for both the treating physician and other members of the team to be knowledgeable about them, and the providers must be vigilant to identify them early (

). As immunotherapy drugs have become increasingly used by oncologists who have not participated in early clinical development, guidelines have been created to help translate the safe management of immunotherapy from trial to routine practice. The first guidelines were created by the Society for Immunotherapy of Cancer in 2017.

 Since then, both the American Society of Clinical Oncology and the National Comprehensive Cancer Network have created additional clinical guidelines.

 In addition to clinical guidelines, attempts to raise awareness of potential immune-related effects have been aimed at frontline care providers including emergency department and primary care physicians and staff. Also, patients should be educated on the importance of self-reporting any new symptoms, and they should understand that they are receiving immunotherapy as opposed to chemotherapy.

The most common immune-related AEs experienced by patients on immunotherapy include gastrointestinal inflammation (ie, colitis), skin rashes, and endocrinopathies such as thyroiditis and adrenal insufficiency. The AEs can have a rapid onset or present even after a long period of treatment with no problems. Early recognition is among the most important tools to prevent progression of AEs. The longer a symptom remains unrecognized, the potentially more challenging the treatment may become. Many of the AEs require steroid treatment, and a low threshold to initiate treatment could prevent severe worsening. Unfortunately, new symptoms are not always clearly attributable to the immunotherapy treatment, so workups to rule out nonimmune-related causes are often conducted in parallel.

Depending upon the AE and the severity of the symptoms, additional testing may be required to confirm the diagnosis, determine the severity of the event, and monitor for resolution. This may include blood tests such as liver function testing for immune hepatitis, thyroid function tests for thyroiditis, or cardiac enzyme testing for suspected myocarditis. Imaging or invasive testing may be required to evaluate for pneumonitis or colitis while excluding other potential causes for symptoms, such as pneumonia or infectious colitis, respectively. The management guidelines support subspecialty referral and assistance in AE management. Early involvement by specialists can help reduce the severity of AEs and prevent permanent organ damage.

Instances of low-grade AEs can be managed conservatively, such as a topical steroid cream for a small rash or an oral antidiarrheal for low-grade diarrhea. But as the severity of the AE increases, the treatment response must increase to limit the detrimental effect. Although some moderate AEs can be managed with oral steroids and close monitoring, many patients require intravenous steroid administration, hospital admission, and specialist consultation. In such cases, the immunotherapy treatment must be stopped, and for high-grade events, therapy must be discontinued altogether. On the other hand, steroid therapy is not required for all AEs and can even worsen some conditions, such as hyperglycemia.

Immune-mediated endocrinopathies are a common AE of immunotherapy. Patients may develop a thyroiditis-like condition with reductions in thyroidstimulating hormone and elevation in T4. This is followed by a burning-out of the thyroid and reduction in the T4 levels. Eventually the patient requires thyroid replacement, which can be a permanent condition. In some instances, patients may continue therapy; however, as symptoms worsen, immunotherapy treatment may be stopped.

Urologists remain an integral part of the multidisciplinary team that is required to manage patients with cancer. Increasingly, urologists encounter patients who are candidates for immunotherapy or undergoing treatment with immunotherapy. The urologist, who may have previously provided tissue diagnosis or local resection, offers a perspective that could be useful for differentiating concomitant conditions (ie, abdominal pain) from immune-related AEs (ie, colitis). This important role should be a shared responsibility among the urology community.

The expanding role of immunotherapy in cancer treatment also provides an opportunity for select urologists to directly participate in patient care by managing immunotherapy treatment. The importance of expertise in AE management should be directly acknowledged by anyone considering immunotherapy administration. In addition to personal familiarization, staff and colleagues must be aware of potential management issues when fielding office phone calls or covering during on-call periods. The guideline-directed treatment strategies and identification of subspecialty referrals as an appropriate adjunct to direct management provide overlap to urologists who are involved in immunotherapy administration.

Kantoff PW, Higano CS, Shore ND, Berger ER, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. 

. 2010;363(5):411-422. doi: 10.1056/NEJMoa1001294.

Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. 

. 2010;28(19):3167- 3175. doi: 10.1200/JCO.2009.26.7609.

Maughan BL, Bailey E, Gill DM, Agarwal N. Incidence of immune-related adverse events with program death receptor-1- and program death receptor-1 liganddirected therapies in genitourinary cancers. 

. 2017;7:56. doi: 10.3389/ fonc.2017.00056.

Puzanov I, Diab A, Abdallah K, et al; Society for Immunotherapy of Cancer Toxicity Management Working Group. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. 

. 2017;5(1):95. doi: 10.1186/s40425-017-0300-z.

Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. 

. 2018;36(17):1714-1768. doi: 10.1200/ JCO.2017.77.6385.

Thompson JA, Schneider BJ, Brahmer J, et al. Management of immunotherapyrelated toxicities, version 1.2019. 

. 2019;17(3):255-289. doi: 10.6004/jnccn.2019.0013.

Davis ME, Francis JH. Cancer therapy with checkpoint inhibitors: establishing a role for ophthalmology. 

. 2017;33(4):415-424. doi: 10.1016/j. soncn.2017.08.003.

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As immunotherapy has become increasingly utilized, urologists are more frequently participating in the management of patients who are receiving immunotherapy.

Kelly L. Stratton, MD

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