GU Cancer Treatments Advance, But Their Application Remains Unclear

Raoul Concepcion, MD

A great deal of progress has been made on the diagnosis and treatment of genitourinary cancers. For castration-resistant prostate cancer (CRPC), initiating therapy can begin prior to bone metastases.

There are now a variety of therapeutic agents available to treat advanced prostate cancer; however, how to sequence them remains somewhat unclear. For bladder cancer, enhanced immune therapies are approved in refractory disease, while genetic profiling is coming into play.

However, even as our understanding of the biology of prostate and bladder cancers improves and treatment protocols are refined, there remain many clinical scenarios in which no clear-cut answers are available.

This OncLive Peer Exchange® roundtable discussion, titled “Clinical Challenges in Genitourinary Cancers,” focuses on some of the more challenging scenarios facing oncologists and urologists in the genitourinary field, using a case-based approach to emphasize important discussion points.

In Case 1, a patient with metastatic CRPC has progressed despite aggressive definitive therapy, including therapy with the immunotherapy sipuleucel- T. The treatment strategy would depend upon whether the patient has minimal symptoms or is asymptomatic, or, if he is symptomatic despite the absence of visceral metastases, explained Michael S. Cookson, MD, MMHC. If he is minimally symptomatic or asymptomatic, active agents including enzalutamide, abiraterone, docetaxel, and sipuleucel-T would be appropriate. If the patient progressed to a more symptomatic stage, those agents would still be considered; however, the presence of bone lesions and absence of visceral metastases would suggest radium-223 as another option.

Radium-223

The panel then discussed symptoms, which encompass discomfort and quality of life, and not just pain. They noted that some patients will hide symptoms and that nurses and the patient’s spouse or caregiver may prove good sources of information about the extent of these symptoms. Early on, Daniel P. Petrylak, MD, recommended obtaining a standard computed tomography (CT) of the chest, abdomen, and pelvis with contrast “to be sure he does not have liver metastases or something else that we are missing.” If the patient is older or frail, enzalutamide might not be appropriate because its profile includes CNS effects.The panel also addressed taking advantage of the opportunity to treat with immunotherapy and to avoid complacency, said Cookson. If the patient clearly has visceral disease, consider the addition of chemotherapy. If he presents with bone-only disease or nodal disease, Cookson recommends enzalutamide or abiraterone. If the patient is experiencing pain that is related to bone and he does not have visceral metastases, there is an opportunity to administer radium-223. If radium-223 is not given at this time, and a year later the patient develops visceral metastases, the agent is not indicated for this setting. In the current case, for example, there is an opportunity to use radium-223 and the decision should be dependent upon results of a CT scan, said David I. Quinn, MBBS, PhD.

The addition of chemotherapy would be reserved for a patient who either is experiencing major pain and requires opioid agents to manage it, or, visceral metastases, said Quinn. With radium-223 therapy, Quinn says he has a low threshold for adding enzalutamide or abiraterone. For patients not taking these agents, he would conduct an additional scan between the third and fourth radium treatments. Should the identification of small liver metastases lead him to add docetaxel to the radium-223, he would not give a full dose of either.

Michael S. Cookson, MD, MMHC

However, a recent study by Neal D. Shore, MD, and colleagues, concluded that “combining abiraterone and radium-223 does not change the safety profile or the toxicity events.” Thus, Shore has become more aggressive in his treatment strategy by combining the therapies. In his experience, Shore tries to get in the full 6 cycles, as well as to give chemotherapy when appropriate.

Petrylak concurred that completing the full cycle of radium-223 treatment usually results in a survival benefit. In the patient who develops visceral disease, Petrylak would consider adding chemotherapy. If the patient has a positive response, he would consider adding radium-223 later.

In Case 2, the patient presents with very significant aggressive disease that is diagnosed during an emergency department visit. He meets the definition of low volume, androgen-sensitive metastatic disease. If we were to order “a more sensitive, more specific, more accurate newer scan—such as a PSMA gallium scan, a sodium fluoride PET scan, possibly some of the other choline- derived scans—we’d see many more lesions,” said Shore. However, the majority of US clinicians are still primarily using technetium CT.

Shore recommends taking a combined chemohormonal approach to treat this low-volume disease, while treating the oligometastatic disease aggressively with either extirpation of the node and focal radiation to the spine in combination with systemic therapy, radiation, or removal of the prostate. The likely strategy here would combine “our most effective systemic therapy, androgen deprivation, perhaps with docetaxel,” Cookson suggested.

After evaluating the patient’s response to systemic therapy, clinicians can decide if local therapy is appropriate. Petrylak and Quinn agreed with this treatment strategy.

Daniel P. Petrylak, MD

Androgen Receptor Splice Variant-7

Quinn explained that, in this case, a significant factor to consider is the size of the patient’s prostate and the nature of his urinary tract symptoms. Because the patient might live between 1 to 7 years, it is unknown “whether treating the primary [tumor] with surgery or with radiation therapy is appropriate.” Shore said that, in the future, genomic sequencing may be influential with this patient, as an oncogene target may be identified.The use of the circulating tumor cell assay for androgen receptor splice variant-7 or AR-V7, which is a mutational change of the ligand-binding domain of the androgen receptor, is gaining ground. This mutational change is associated with resistance to androgen receptor blockers like enzalutamide, and to androgen biosynthesis inhibitors like abiraterone. The presence of AR-V7 is not a universal marker of resistance because it is measured in the blood. Currently, studies are investigating the drug, galeterone, because it is not dependent on this receptor mutation.¹

In the latter stages of prostate cancer, more than two-thirds of patients who have been treated with enzalutamide, abiraterone, or both manifest AR-V7, particularly patients with progressive visceral disease, Quinn said. These patients may respond to taxane chemotherapy, to platinum regimens, to poly ADP ribose polymerase (PARP) inhibitors, and to ataxia telangiectasia mutated (ATM) inhibitors (now in clinical trials).

Neal D. Shore, MD

When using abiraterone with prednisone, clinicians should periodically monitor blood sugars, hypertension, edema, liver function, and potassium. These monitoring practices are not beyond the scope of practice for urologists, said Cookson.

He said that the side-effect component of the steroid is relatively minor, so urologists should feel comfortable administering it.

Platinum-based Therapy

Shore pointed to a recent study² showing that “it is not a long-term challenge to manage patients with long-term use of steroids.” He also suggested that “urologists who want to take care of advanced prostate cancer patients” should enter a subspecialization within the urology practice.Case 3 involves a 53-year old white female with pelvic pain. This is a case of hydronephrosis and, based on the workup, suggests a harbinger of a poor outcome that is associated with lymphadenopathy, Cookson noted. “There are many things about her features that make us think she has systemic risk and may already have regional nodes.”

Even if she does not have node involvement, he would favor platinum-based neoadjuvant chemotherapy up-front for her. The obstructed kidney described in the case will need to be addressed because it will challenge her renal function. To receive therapy she may need a nephrostomy tube. For muscle invasive bladder cancer, neoadjuvant chemotherapy has not been widely embraced at this point. But two randomized trials that investigated neoadjuvant platinum-based chemotherapy have demonstrated a survival benefit for patients with adequate renal function prior to cystectomy, said Petrylak. He noted that if the patient had a creatinine level of 2, he would bypass the platinum- based therapy and opt for cystectomy.

Quinn pointed out that patients with long-term diabetes, hypertension, or prior nephritis are much more likely to get into trouble with a modified dose of cisplatin than patients who have been obstructed. Citing a study demonstrating improved survival after 5 years with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) compared with standard MVAC, Quinn would select dose-dense MVAC. There are less data on the combination of gemcitabine and cisplatin, and with gemcitabine, a low platelet count can be problematic over time. The prospect of immunotherapy in the second-line setting, and possibly earlier, has Shore incredibly excited. He contends that the developments in immunotherapy are going to revolutionize urologists’ ability to provide better care.

Using a platinum-based therapy, even when renal function is suboptimal, “is really important,” Cookson said. “We go into the plan with the idea that cystectomy is coming once they complete their therapy.” When possible, “sparing of the gynecologic organs” is important. “We want to preserve the vagina to reduce the incidence of fistula, but also to preserve the pelvic floor support.,” he said.

David I. Quinn, MBBS, PhD

The patient in Case 4 undergoes a traditional workup and shows a normal CT scan. Cystectomy demonstrates a large broad-based tumor that is lateral to the right orifice with some questionable erythema on regular cystoscopy to the posterior wall. The patient is a candidate for a smoking cessation program.

Current guidelines recommend staging a transurethral resection with the goal to ensure that the initial resection was complete and left no deeply invasive tumor. The panelists recommend providing the pathologist with an adequate sample and adequate information. A fluorescent cystoscopy would probably also be useful. Narrow band imaging is another alternative.

For this relatively young patient, there are two options for initial therapeutic management—radical cystectomy or intravesical therapy, Cookson said. But patients may reject radical cystectomy as it is “life-changing and potentially morbid. The standard in the United States would be an induction course of Bacillus Calmette-Guerin (BCG),” he said. If the patient initially responds, follow with a maintenance course. For BCG-refractory carcinoma in situ (CIS), Valstar may be used, but the development of a vaccine looks promising.

The panelists turned to the anti-PD-1 and PD-L1 agents. They recommended to keep an eye on issues with diarrhea, colitis, and interstitial pneumonitis. Further, when multiple checkpoint inhibitors— including anti-CTLA-4 ipilimumab and any of the PD-1/PD-L1 inhibitors—are used together, there can be significant toxicity, Petrylak noted.

References

1. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT02438007.
2. Fizazi K, Chi KN, deBono JS, et al. Low incidence of corticosteroid- associated adverse events on long-term exposure to low-dose prednisone given with abiraterone acetate to patients with metastatic castration-resistant prostate cancer. Eur Urol. 2016;70(2):e41. doi:10.1016/j.eururo.2016.02.035.