Raoul Concepcion, MD, director, Comprehensive Prostate Center, recently sat down with <em>Targeted Oncology </em>to discuss his treatment decisions for 2 patient scenarios in prostate cancer.
Raoul Concepcion, MD
Raoul Concepcion, MD, director, Comprehensive Prostate Center, recently sat down withTargeted Oncologyto discuss his treatment decisions for 2 patient scenarios in prostate cancer. Concepcion discussed these cases at a live case-based peer perspective event during the Large Urology Group Practice Association (LUGPA) Annual Meeting.
In the first case, the patient was a 79-year-old male who was referred to urology with an elevated PSA of 12.9 ng/dl. Prior PSA values had been between 4.0 to 5.0 ng/dl from 2007 to 2011. The patient was an ex-smoker, who smoked 2 packs per day for 35 years. He also had a positive family history of prostate cancer, however, he did not have any voiding symptoms at the time he was referred to urology.
The patient was positive for hypertension, CAD, and COPD, but did not have evidence of metastatic disease at the time of diagnosis.
TARGETED ONCOLOGY:What are the treatment options for this patient?
The gentleman we discussed was an elderly gentleman, 79 years old. He presented with prostate cancer, but because of his advancing age, he was started initially on luteinizing hormone-releasing hormone (LHRH) therapy, and was then lost to follow-up. Then, when he went back to his original urologist, at that point [he was found] to have castration-resistant prostate cancer with metastatic disease. He was elderly, but he was relatively asymptomatic.
Your treatment options now in patients who have metastatic castration-resistant prostate cancer (mCRPC) really do follow certain guidelinesboth American Urological Association Allied (AUAA) and National Comprehensive Cancer Network (NCCN). The options for therapy include immunotherapies, which would be sipuleucel-T (Provenge); oral agents, including abiraterone acetate (Zytiga), which is a androgen synthesis inhibitor; an androgen receptor inhibitor, which would include enzalutamide (Xtandi); an alpha emitter radiopharmaceutical, which is radium-223, as well as traditional taxane therapies, which would be docetaxel (Taxotere), and for men who have failed docetaxel, it would be cabazitaxel (Jevtana).
In this particularl gentleman, what the guidelines do not tell us is particularly which agents to use. All the studies for these agents have been monotherapy trials. They were not used in combination. They were not done head to head. We know that in patients who are asymptomatic, who have a good performance status, who have a life expectancy greater than 1 year, what the guidelines might indicate is that that patient might be ideally suited for sipuleucel-T, which again is an autologous immunotherapy.
However, when patients progress beyond that, you have to take a look at the patient’s individual characteristics, you have to take into account all of his comorbidities, his functional status, whether he has heart disease or neurological deficits, does he have a history of seizures, does he have a history of strokes, does he have significant cardiovascular disease, is he symptomatic, and is he having a lot of bone pain, because 90% of people who have metastatic prostate cancer will have bone metastases. So all of those things will come into play when we determine the optimal therapy.
[With] traditional cytotoxic chemotherapy vis-à-vis docetaxel or cabazitaxel, a lot of patients do want to steer away from those because of the side effect profile of those medicines. They’re associated with myelosuppression and significant neuropathies. People, if given the choice between an oral therapya pill, like abiraterone acetate or enzalutamide—versus an intravenous cytotoxic chemotherapy, they will pretty much try to go with a pill.
Radium-223, the indication for that drug is for patients with bone metastases who are minimally symptomatic and who have very little soft tissue disease.
In this particular patient, he was elderly, and by the time he had progressed he was already in his mid-80s and he had already failed androgen depravation therapy (ADT), although we continue to treat patients with ADT, and with LHRH analogs, because that continues to be part of the treatment scheme. The best choice for this patient, given his history, was really abiraterone acetate, which is [given] 1000-mg daily, taken with prednisone (Deltasone), 5 mg, BID.
TARGETED ONCOLOGY:What are the next steps? When would you order scans?
Once a patient has started on treatment for mCRPC, the follow-up is somewhat dependent on what agent you use. For abiraterone acetate, because it can cause an element of hepatotoxicityliver dysfunction—the follow-up for patients on abiraterone is that every 2 weeks for the first 3 months, you have to check liver function, potassium, blood pressure, and basically do a more aggressive monitoring because it can potentially be a hepatotoxic agent. That’s one of the difficulties in monitoring patients with abiraterone acetate.
If you choose enzalutamide therapy, which again, is an oral androgen receptor inhibitor, it doesn’t have the hepatotoxic effects, so the monitoring scheme is a little less intense. It doesn’t require every 2-week monitoring of liver enzymes, as well as potassium.
I think most of us, generally, when we start patients on therapy, we like to get PSAs, testosterone levels, alkaline phosphatase every month, pretty much for the first few months because PSA, although we follow it, is not a great surrogate marker for death. The other problem is that 2 of the therapies, including sipuleucel-T and radium-223, do not necessarily have a profound effect on PSA. Laboratory monitoring is somewhat dependent upon therapy.
In terms of radiographic follow-up, I personally, in my practice, tend to do a lot of what we call sodium fluoride PET CTs about every 6 months, or if a patient comes in with new complaints.
When to change therapies should not be predicated on PSA changes only. As I mentioned before, 2 of the therapies do not result in a reduction of PSA. You might actually see PSAs go up in patients who have been treated with sipuleucel-T or radium-223. I personally believe that the indication to stop a new therapy, add a new therapy, or switch to a new therapy, is really based upon progression radiographically.
In the second case Concepcion discussed, the patient was a 61-year-old Caucasian male who presented to his urologist with lower urinary track symptoms (LUTS). The patient has metastatic hormone-sensitive disease.
TARGETED ONCOLOGY:How would would you manage this patient with metastatic hormone-sensitive disease?
Many people believe, because of the US ‘D’ recommendation of PSA screening, and because we’re not doing aggressive early detection programs, that we will begin to see more and more patients walking through our doors with metastatic prostate cancer who are previously undiagnosed and are now hormone-naïve. The problem with those patients is that they already have advanced disease.
In this particular patient, this gentleman presented with a high PSA, had high-grade prostate cancer, and again, had significant boney disease. Historically, we would have treated that patient with ADT and then watched him closely. Now, in this very unique patient, I think it’s critical to understand that hormone-sensitive metastatic disease is different from patients with CRPC.
Many of us feel, because of the article that Chris Sweeney published a few years ago and presented, that in patients with high-volume metastatic hormone-sensitive disease, the treatment of choice should be the institution of ADT, plus 6 cycles of docetaxel chemotherapy. High-volume metastatic disease is defined as more than 4 lesions on bone scan, one of which is outside the axial skeleton, and/or nodal soft tissue disease or visceral disease. In low-volume metastatic diseaseless than 4 lesions of bone scan, all confined within the axial skeleton—it has not been shown that the addition of ADT plus docetaxel was of significant benefit versus ADT alone. I think the standard for people with high-volume metastatic hormone-sensitive disease should be ADT, plus 6 cycles of docetaxel chemotherapy.
TARGETED ONCOLOGY:Do you consider bone-targeted therapy for this patient?
In the patient who presents with hormone-naïve metastatic disease, a few things need to come into play. Obviously number 1, we have to drive down the testosterone level and make sure they’re in castration range. We have to follow their PSAs and see what their PSA does because if a patient has a very good response to ADT plus docetaxel with a PSA reduction of less than 4, they actually have a better prognosis versus a patient who has started on therapy whose PSA stays above 4.
What we also know is that the addition of ADT does result in bone marrow density loss because we’re lowering testosterone levels, which also results in a lowering of estrogen. In patients with boney metastatic disease, we should also be instituting antiresorptive therapy. There are 2 drugs approved for this, one is zoledronic acid (Zometa), which is an intravenous osteoclast, as well as denosumab (Xgeva), which is a fully human monoclonal antibody. Both are approved for patients with metastatic disease to the bone for the prevention of a skeletal-related event. Denosumab actually was superior to zoledronic acid in a head-to-head trial.
In this particular patient where he is hormone sensitive, there should be definite consideration of him being on bone-targeted therapy, not to treat his cancer, but to prevent a skeletal-related event. Once the patient moves from hormone-sensitive metastatic disease, and he’s started on ADT, and in this case, 6 cycles of docetaxel, he will progress, he will develop mCRPC.
It’s important to understand that hormone-sensitive metastatic prostate cancer is a different phenotype than CRPC. When the patient progresses on ADT, we will monitor their PSAs. Once the patient’s PSA starts to go above their nadir, by that point he then goes into this mCRPC phase, which then opens up a number of different therapies, which would include abiraterone acetate, enzalutamide, sipuleucel-T, radium-223, and even though he’s been exposed to taxanes before, you could even challenge him with taxane therapy. If the patient progresses, even though he has gotten docetaxel therapy, and if he continues to have high-volume metastatic disease with bone metastases, and he’s minimally symptomatic, at that point, a good agent to use would be radium-223, which is an alpha emitting radiopharmaceutical.