“Instead of just offering a select-few treatment options, ideally you would like to be able to offer patients a whole menu of treatments and have an educated conversation regarding the risks and benefits for each of these treatment options," says Rian Dickstein, MD.
Urologic cancer care is quickly changing with the widespread use of a growing number of immunotherapy drug options. The shifting treatment paradigm is impacting not only patients’ lives but also urology practices, as more practices look to incorporate immunotherapy treatment for prostate, bladder, and kidney cancers.
Urologists actually were among the pioneers in immunotherapy treatment, dating back to the 1980s.
“Urologists have been using [BCG] immunotherapy in bladder cancer for over 3 decades,” said Neal D. Shore, MD, director of the Carolina Urologic Research Center at Atlantic Urology Clinics in Myrtle Beach, South Carolina.
BCG offered one of the first options for cancer treatment in which the patient’s immune system could be stimulated to help fight the cancer, minimizing cytotoxic adverse effects of treatment.
“This new era of cancer therapy really focuses on optimally treating cancer while maximizing quality of life during treatment,” said Tom Jayram, MD, codirector of the Advanced Therapeutics Center for Urology Associates in Nashville, Tennessee.
Another immunotherapy used by urologists is sipuleucel-T (Provenge), which was FDA approved in 2010 for patients with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer.
Sipuleucel-T was a game changer for prostate cancer and the specialty of urology, said Rian Dickstein, MD, a urologist at Chesapeake Urology and chairman of urology at the University of Maryland Baltimore Washington Medical Center.
“Provenge was the first autologous cellular immunotherapy [for metastatic disease] and the first immunotherapy to prolong overall survival in the setting of advanced prostate cancer,” Dickstein said.
The FDA has since approved 5 checkpoint inhibitors: pembrolizumab (Keytruda) for bladder and kidney cancers, nivolumab (Opdivo) for bladder and kidney cancers, atezolizumab (Tecentriq) for bladder cancer, avelumab (Bavencio) for bladder cancer and in combination with a tyrosine kinase inhibitor for kidney cancer, and durvalumab (Imfinzi) for bladder cancer.
“Since 2015, we have witnessed a breakthrough pace of approvals of an additional class of immunotherapeutics called checkpoint inhibitors, [which] either directly block [PD-1] or block [PD-L1], which interacts with the [PD-1] receptor,” Shore said. “These 5 therapeutics have gained widespread global usage in patients with advanced bladder cancer.”
The thinking is that many tumors grow and spread by turning off the host’s immune system. Checkpoint inhibitors target this ability, essentially turning back on the body’s natural tendency to fight the cancer. This “natural” defense also spares patients of some of the adverse effects of older chemotherapy drugs, according to Jayram.
“Chemotherapy is still very effective,” Jayram said. “But what we’re seeing, especially in genitourinary cancers, is immunotherapy can work just as well while being easier to administer and safer for patients.”
Ongoing trials are investigating checkpoint inhibitors as maintenance therapy for patients with advanced bladder cancer. According to Shore, these agents are being well utilized for patients with advanced renal cancer, in addition to incorporating the CTLA4 antibody inhibitor ipilimumab (Yervoy) as a second immunotherapy.
Urologists are particularly interested in investigators studying these same checkpoint inhibitors in trials examining their activity in neoadjuvant therapy prior to cystectomy, in lieu of or in combination with platinum-based chemotherapy. Researchers are also investigating these checkpoint inhibitors in combination with chemo-radiation as part of the trimodal bladder-sparing approach to avoid cystectomy for patients who have T2 or greater disease, as well as to treat BCG-naive, high-risk non–muscle invasive bladder cancer patients with concomitant BCG, with or without a course of maintenance BCG, Shore said.
“Of note, in 2020, pembrolizumab received FDA approval for high-risk BCG-unresponsive patients with carcinoma in situ,” Shore said.
Incorporating immunotherapy into your practice
Given the tremendous advancements in urologic cancer care with immunotherapeutic and other drug options, Shore added that it is incumbent upon urologists to develop their expertise in the different therapy types and to consider launching advanced prostate, bladder, and possibly kidney cancer clinics in their practices.
Currently, providers administer immunotherapy intravenously, with the exception of BCG, which is administered intravesically.
“Trials are ongoing looking at subcutaneous administration of checkpoint inhibitors, which may be appealing to some urologic clinics that are not as comfortable with an intravenous administration,” Shore said.
But for now, the newer PD-1 and PD-L1 inhibitors are administered intravenously and carry risk for systemic toxicities. Medical oncologists typically administer these immunotherapies, but a number of urology practices have implemented or are looking at implementing immunotherapy options, especially in the setting of non–muscle invasive bladder cancer, according to Dickstein.
Collaborating with a medical oncologist is ideal for urology practices launching infusion or immunotherapy centers, but if that is not an option for a community urology practice, it is possible to offer immunotherapy treatment safely and successfully, Dickstein said.
Because immunotherapy is different than other drugs in respect to adverse events, monitoring, and disease progression, Jayram said that most urology practices are going to need an experienced cancer team, consisting of a centralized treating physician and nurses and nurse practitioners familiar with infusion therapies, as well as cancer navigation systems to appropriately identify patients.
Shore said that he believes the biggest barrier to entry for urologists in this space is their comfort level in understanding the etiology and management of immune-related adverse events from checkpoint inhibitors.
“These are immune-related inflammatory type syndromes,” Shore said. “The most common ones we see include dermatitis, pneumonitis, colitis, [and] transaminitis, but there are other very important adverse immune events that need to be recognized and can include thyroiditis, pancreatitis, and very uncommon observations of encephalitis or myocarditis. It is incumbent upon the health care provider to be absolutely familiar with the mechanism of action, the appropriate indications, and how to assuredly educate patients and their families on identification of adverse events as early as possible and to manage them as early as possible with appropriate interventions, which can oftentimes involve medical subspecialty consultation.”
Telemedicine has been a boon to urologists’ management of many patients with cancer, including those on immunotherapy. Urologists and staff members can talk more often with patients, asking important questions about how they are feeling and potential adverse effects. They can also use the time on telemedicine visits to review lab work and radiographic imaging. But telemedicine does not take the place of the physical exam, which must still be done, according to Shore.
To monitor for adverse events from immunotherapies, Jayram’s staff schedules telehealth appointments between the infusions.
“With checkpoint inhibitors, small things can become big things in terms of [adverse] effects. The treatment team needs to be proactive in monitoring response and prioritize patient-provider communication,” Jayram said. “Telehealth has proven to be a great tool for monitoring, especially during [coronavirus disease 2019], when patients do not want to be coming to the office very frequently.”
Regarding reimbursement for FDA-approved immunotherapies, it has not been a problem for Shore’s practice.
“For appropriate FDA-approved indications, I have had no difficulty getting reimbursement for all 5 of the checkpoint inhibitors that have come onto the market since 2015. I have used all of them [including] ipilimumab,” Shore said.
Although reimbursement is not usually a major concern, private groups outside a hospital setting still have some operational considerations. Margins tend to be small, and there is some risk because groups generally buy the drugs first and bill the patient’s insurance later, according to Jayram.
Nevertheless, given the trend in urologic cancer therapy to include immunotherapy when appropriate in patients’ treatment, broadening treatment offerings is something that all urology practices should consider.
“Instead of just offering a select-few treatment options, ideally you would like to be able to offer patients a whole menu of treatments and have an educated conversation regarding the risks and benefits for each of these treatment options,” Dickstein said.
Undoubtedly, it is an exciting time in uro-oncology and urology.
“Systemic therapies for cancer historically were utilized the most at the end stages of cancer. Now, because these treatments have fared so well, we are seeing novel new applications being brought into the localized setting,” Jayram said.
Immunotherapy will begin to replace some, but not all, therapeutic regimens used to treat urologic cancers.
“There seems to be less of a role in prostate cancer for checkpoint inhibitors than in bladder or kidney [cancers], but there is still a lot of ongoing work to try and figure that out,” Jayram said. “The bigger trend is [that] we are bringing these agents earlier into cancer pathways and combining them with other established local and systemic treatments. This approach is allowing more patients to receive and potentially benefit from these life-altering therapies.”