Operationalizing immunotherapy in urologic practice

Dr. Jayram is a urologic oncologist and co-director of the Advanced therapeutics Center in Nashville.  

The impact of checkpoint inhibitors (CPIs) in oncology over the past decade cannot be overstated. These treatments are providing patients with advanced cancers the opportunity to live longer and better than ever before. Urologic oncology has been especially fortunate in this era, with a flurry of recent FDA approvals and clinical trials with CPIs in prostate, kidney, and bladder cancer.

Currently, there are three approved disease states in genitourinary oncology for CPI utilization: (1) metastatic urothelial cancer (first-line therapy with cisplatin ineligibility and PD-L1 expression; second line, post-platinum failures); (2) metastatic renal cell carcinoma; and (3) those with bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ of the bladder (FDA approved January 2020). Many urologists are generally familiar with CPIs; however, this most recent indication has the opportunity to bring our specialty in much closer contact with these novel therapies.

Shift in practice patterns

The debate regarding whether urologists should bring CPIs into their treatment realm has been rather spirited. Provider-specific factors such as practice setting, clinical volume, and hospital affiliation will likely drive this decision. Since sipuleucel-T (Provenge) entered the prostate cancer arena in 2010, many large independent urology groups have centralized advanced prostate cancer care and have implemented infrastructure to administer systemic therapies. This move has led to a shift in practice patterns for advanced prostate cancer, with an increasing proportion of patients with castration-resistant prostate cancer in the community setting being treated primarily by urologists.

This has brought with it opportunities for large groups to participate in clinical trials, in-office dispensing, multidisciplinary treatments, and other high-value resources for patients with cancer. Immuno-oncology, specifically CPIs, likely represent the next step in this cascade.

Similar to other large groups, our practice has a dedicated cancer facility with an infusion suite, in-office dispensary, and full research staff. Over the years, our program has evolved to include cancer navigation, bone health and nutrition clinics, and clinical trials across multiple tumor types. We began administering CPIs for patients with advanced urothelial cancers in 2017 after significant internal discussion. Through the success of our advanced prostate cancer program and patient feedback, we have learned that patients want to stay in a familiar environment, even in the setting of advanced disease. Patients with bladder cancer are unique in that they have special urologic needs ranging from ostomy/diversion care to treatment of bladder symptoms and unique cancer surveillance protocols.

Centralizing these patients’ needs, improving continuity of care, and providing low-cost, convenient, and efficient cancer care was our main rationale to start offering this service to our patients.

We use two urologic oncology–focused physicians as champions of our immuno-oncology program. Our program has been bolstered by the implementation of an advanced bladder cancer clinic, where patients with metastatic disease, BCG-unresponsive bladder cancer, or complex (atypical histology) cases are sent for secondary consultation. Furthermore, all requests for BCG throughout the practice are centrally reviewed, providing quality-control measures during the BCG shortage and also appropriately escalating care for patients who do not respond to BCG treatment. These measures along with cancer navigation have allowed us to identify a large pool of patients who could potentially benefit from CPIs.

At our center, the champion provider meets with all potential patients and has a thorough discussion of indications, treatment protocol, adverse events (AEs), and alternative treatments for the patient’s cancer, including clinical trials or referral to a medical oncologist. Before starting CPIs, each patient undergoes a baseline laboratory panel of tests including those for complete blood count, a comprehensive metabolic panel, thyroid-stimulating hormone, and cortisol levels. 

Patients who demonstrate endocrine abnormalities or have pre-existing thyroid or adrenal disease are required to obtain a referral from the endocrinology department before starting therapy. Similarly, appropriate specialists are consulted for patients with significant cardiac or pulmonary disease at baseline. Patients meeting all criteria are precertified for treatment and given a treatment schedule. 

Treatment considerations

On the day of treatment, patients are seen by the physician before their infusion, and their lab test results and clinical responses are reviewed. The patient completes a validated adverse event (AE) questionnaire, which is indicative of ongoing morbidity from therapy. Vital signs are obtained before and after the infusion, which takes about 30 minutes, and the patient is then allowed to leave with a companion. Depending on the agent, CPIs are given on a fixed schedule every 2 to 6 weeks, with treatment discontinued for drug intolerance or radiographic disease progression and lasting a total of up to 2 years. While on treatment, patients are routinely monitored for disease progression with cross-sectional imaging with or without cystoscopy and cytology given their disease process and clinical stage.

Managing treatment-related AEs has been cited in numerous surveys as the biggest obstacle for urologists in embracing CPI administration. In our experience, administering PD-1 and PD-L1 inhibitors for patients with advanced cancer has been safe and manageable with a team-based approach and appropriate practice awareness. On the group level, it is important that all physicians (not just the champions) who may come in contact with patients be made aware of the potential systemic AEs from CPIs and their basic management.

Group physicians and treatment team members need to understand that seemingly small AEs from treatment (rash, cough, diarrhea) may blossom into severe issues if not monitored and treated appropriately. Physician- and patient-specific resources (pamphlets, hotlines, and treatment expectations) have been made available by most immune-oncology manufacturers and are valuable educational tools. Although most nontreating urologists fear the isolated late-night call concerning CPI AEs, in our experience, with good patient selection and education, it has not been a frequent occurrence.

Patient monitoring

On the day-to-day level, establishing a protocol of monitoring (laboratory and telephone) and setting triggers for evaluation and treatment is necessary. In our practice, clinical questionnaires and laboratory values are reviewed before each treatment. Patients with any AEs are clinically and radiographically evaluated to determine severity.

The table shows the management of AEs caused by CPIs. Low-grade AEs are managed by withholding the next infusion and active monitoring. The hallmark of management for significant AEs is corticosteroid administration, which can usually be managed as an outpatient. This treatment usually entails a 3- to 4-week steroid taper, during which our clinical staff is in contact with the patient to ensure clinical improvement.

Providers administering CPIs need to understand patients can develop toxicity immediately after the first dose and/or months after completing treatment. As reflected by the literature, the majority of patients can return to CPIs after steroid treatment for mild to moderate AEs. Patients with severe, life-threatening issues are rare but need urgent hospitalization, intravenous steroids, and medical consultation. CPIs should not be restarted in these patients even after a full recovery.

Patient selection

Patient selection is important for success, especially in the early stages of a new program with systemic therapy. Patients with more severe comorbidities, a higher disease burden (when treating in the metastatic setting), and prior chemotherapy will have a higher risk of both disease-specific and treatment-specific morbidity early on during therapy. As these therapies move into localized disease processes (such as for high-risk nonmuscle-invasive bladder cancer), the hope is that the treatment morbidity will be even less, and this has been supported by safety data in the KEYNOTE-057 trial. Our experience has told us that although patients will certainly develop AEs necessitating treatment, severe toxicity is very rare, and the majority of patients do quite well on treatment.

From an operational standpoint, the burden on the busy group practice is fairly low, especially on those with advanced therapeutic capabilities. Obtaining the medication already compounded helps avoid concerns about USP <800> and bypasses the need for special facilities (storage, hood, etc). We have one infusion nurse who performs the infusions, calls the patient post-treatment, and triages messages of concern to the physicians.

Although there is valid debate concerning the financial toxicity of these treatments, our experience with billing and payers has been straightforward, and the therapies seem to be reimbursed on a schedule and scale consistent with other cancer medicines in urologic oncology.

Conclusion

In summary, CPIs have emerged as a therapeutic option in multiple urologic cancers and continue to move earlier in treatment algorithms, evidenced by the recent approval of pembrolizumab (KEYTRUDA) in patients with BCG-unresponsive bladder carcinoma in situ. This new indication will push all urologists to gain a deeper understanding of the risks and benefits of these treatments.

Nontreating urologists should prioritize understanding disease indications, treatment morbidity, and a general approach to AE management. A centralized, team-based approach is key to safely and appropriately dispensing these therapies. The AE profile and management is new to urologists but can be simplified via structured monitoring and treatment protocols.

Although not all urologists are equipped to administer these medications, urology groups active and experienced in cancer treatment with dedicated facilities and staff will be well positioned to incorporate these therapies into their clinical armamentarium.