Case-Based Discussion: Integrating Novel Agents Into the Treatment of Prostate Cancer
In the wake of the approval of several novel treatments for prostate cancer, physicians must now focus on how best to integrate new therapies into the treatment of patients with prostate cancer.
Case 1
Gomella
: The patient is a 55-year-old white male. His father died of prostate cancer at 65 years of age, and no other family members have any history of prostate cancer. The patient is worried and wants to be checked, although he’s done some reading and is doubtful about the value of the prostate-specific antigen (PSA) test. What do you tell him?
Dreicer
: The patient is at risk, since he had a first-degree relative who was impacted. Screening is reasonable for him.
Petrylak
: I’d tell him that PSA has its implications. If it’s elevated, he’ll need a biopsy, and then he’ll have to choose either local therapy or observation. I would do it if I were him. But he needs to know what the studies say.
Slovin
Leonard Gomella, MD
Crawford
: I would explain the pros and cons and then leave it up to him, although I probably would give him the strong arm because his risk is at least two-fold higher than Joe Blow’s next door as a result of his family history. I’d also make sure he’s had a screening colonoscopy.< br />: One family member probably doesn’t increase risk a lot. You’ve got to have two or three to be at a higher risk.
Gomella
: The patient has his PSA tested and it’s deemed normal at 1.1 His digital rectal exam is normal. Can you tell him he doesn’t have prostate cancer?
Crawford
: No. Based on the results of the Prostate Cancer Prevention Trial [in which 15% of men with PSAs of <4 ng/ mL were found to have prostate cancer], he still faces a risk.1I’d do a Prostate Cancer Gene 3 (PCA3) test on him.
Gomella
: Even though he hasn’t had a biopsy yet, you would jump the fence on the PCA3 and use it sort of off-label? The labeled indication is to see if a second biopsy is needed.
Crawford
: Yes.
Gomella
: What I tell my residentsand my patients— is that we’re finding our way with PCA3, but that we have a lot of questions. Still, I’d rather have a PCA3 in the bank in case some breakthrough comes up over the next couple of years.
So, you can’t tell the patient he doesn’t have prostate cancer. What would you do next?
Slovin
: I would ask him to repeat a PSA in a short period of time to get a sense of how rapidly it’s going up.
Gomella
: Let’s assume he had a biopsy a year ago that was completely normal. Now he comes in and his PSA has gone up to 5. He still has a normal digital rectal exam. What would you do next?
Petrylak
: He needs a repeat biopsy. I would do a saturation biopsy.
Gomella
: How about PCA3, if he didn’t have it before?
Petrylak
: It probably would be appropriate, but I still think he’s going to need a biopsy. Gomella: What about freeto- total PSA? Is anyone using that anymore? We asked this question two years ago and just about everybody put their hands up, and now, as I look around, there seems to be a lot of cooled enthusiasm.
What would the audience do in this setting? The choices are: (1) perform a biopsy; (2) repeat the PSA test; (3) check free-to-total PSA; or (4) check PCA3. Okay, 61% said biopsy, 22% repeat PSA, 7% free-to-total PSA, and 9% PCA3.
Dreicer
: I’d do a PCA3 first, though.
Gomella
: I agree, although it does scare me a little bit that his PSA had had such a rapid rise.
Crawford
: The PCA3 would make me feel better about doing another biopsy.
Gomella
: The patient comes back three years later and his PSA is up to 8. He’s had at least three sets of 12-core biopsies, and they’ve all been negative. Now where are we?
Crawford
: This is a guy that I would get the MRI on, and the mapping biopsies. I’d also consider the fact that, every time you have one negative biopsy, your risk goes down. If the guy is tired of biopsies or his insurance company won’t pay for more, I’d also think about putting him on dutasteride to see what his PSA does, because I’ve seen people like this go from 8 to 1 again, or at least cut their PSA in half.
Gomella
: Dave, what about transurethral (TUR) biopsy? We used to do that in the ’90s when we ran into this situation. It was sort of an anterior biopsy. Is this a dead issue now because of MRIs?
Daniel P. Petrylak, MD
Crawford
: A lawyer told me the other day that he’s defending a urologist for that very thinking. The patient was just like this one: negative biopsy, negative biopsy, negative biopsy, PSA not even up this high, and so he didn’t do anything. A couple of years later he’s got metastatic disease, and they’re saying he should have had a TUR biopsy. But to me, what takes the place of the TUR biopsy are the staging and mapping biopsies. We’ve actually shown that if you take those biopsies and you correlate them to whole mount radical prostatectomy specimens, they’re just as accurate, if not more accurate, at predicting what’s there.
Audience member: I have a question about PSA leaks in people who’ve had multiple biopsies. I’ve certainly done three or four biopsies on people, but I worry that I have created the [elevated] PSA with all the [needle] sticks.
Gomella
: Dave, with all those needle sticks in the prostate, are you making a leaky prostate, making neovascular channels when it heals, and sending more PSA out to the bloodstream?
Crawford
: I don’t buy it.
Gomella
: There’s some data out there now saying that the more biopsies you have, the more difficult it may be to spare nerves when you get treated definitively with a radical prostatectomy. What do you think about that, Dave?
Crawford
: Well, I’ve had a lot of experience in going in after mapping. Since the mapping is done transperineally, it’s not much more difficult to do. In the people that have had a couple of what you described as saturation biopsies, which are transrectal, that has been difficult.
Gomella
: So what can a patient like this do to prevent prostate cancer, and what should you recommend?
Slovin
: There are data that there is some benefit to changing the diet, limiting the amount of red meat. And while I recommend that for some patients who are on the heavier side, I don’t know that it’s something we would do for everybody. The question is, do I put him on dutasteride or finasteride? I’d be a little worried, but you can make an argument that if the prostate shrinks down a little bit more, it’s going to be easier to find a Gleason 8 or 9 cancer sitting there waiting for us.
Gomella
: It’s kind of disappointing that we don’t have this as an approved prevention strategy, since we have two large clinical trials that show a 20% to 25% relative risk reduction with 5 alphareductase inhibitors, and data from trials such as CombAT demonstrating no increased risk of high-grade cancer.2Dr. Dreicer, you’ve been involved in some drug discussions at the FDA level. Do you think there’s any chance that this thing could get resurrected?
Dreicer
: None.
Crawford
: Less than none. We’ve been through so many things on the prevention of prostate cancer: vitamin E, and selenium, and saw palmetto, and the 5-alpha reductase inhibitors, and Vioxx. I think the benefit of 5-alpha reductase inhibitors is real, but we also need to document the risk of high-grade cancer, which is probably volume-related. In my opinion, chemo prevention trials in prostate cancer are dead, because it’s too risky.
Gomella
: You may also be familiar with the data that came out a few years ago that patients with advanced prostate cancer who went on hyper-vitamin therapy actually had a worse outcome. They progressed more rapidly. So we have to convince our patients that more is not necessarily better.
Petrylak
: That was demonstrated in the SELECT trial, too.3The trial took all comers, and you wonder what giving these vitamins at high dosages to somebody who has a normal level is going to do to their prostate tissue. A lot of these agents are yin-yang: In low doses they may be inhibitory, in high doses they may be stimulatory. So when designing these studies in the future, you’re going to have to look at levels and see whether you’re supplementing something that doesn’t need to be supplemented.
Gomella
Case 2
Gomella
: And despite this data, we still find all our patients taking vitamin E and selenium to prevent prostate cancer, which is really sad.: The patient is a 62-year-old who develops urinary frequency. His primary care doctor detects a nodule on rectal exam and a PSA of 82. A urologist does a biopsy and finds Gleason 7 cancer. A bone scan shows four lesions in the lumbar sacral spine, and a CT scan of the abdomen shows retroperitoneal lymphadenopathy. The patient undergoes combined androgen blockade. His PSA bottoms out at less than 0.1 seven months after the blockade is started, and he remains on continuous androgen blockade for about three years. His PSA then begins to slowly rise from 0.2 to 0.8 to 1.0 over a six-month period. On bone scan, progression is noted with two more spots in the ribs. A CT scan of the abdomen and pelvis shows resolution of retroperitoneal adenopathy, and the patient feels pretty good. He’s not in any pain, and he has a good appetite and a good performance status. At this point, what would you do? Audience choices are: (1) discontinue bicalutamide and monitor for antiandrogen withdrawal syndrome; (2) start second- line hormonal therapy with ketoconazole and hydrocortisone; (3) give him sipuleucel-T; (4) do numbers 1 and 2; or (5) do numbers 1 and 3. The results are pretty even. Twenty-eight percent would stop the bicalutamide and monitor for antiandrogen withdrawal, 24% would give him sipuleucel- T, 12% would do 1 and 2, and 30% would do antiandrogen withdrawal and sipuleucel-T. At 6 %, it looks like ketoconazole and hydrocortisone do not have a lot of traction right now.
Petrylak
: The only times I’ve used ketoconazole in a patient who’s castrateresistant is when the patient has nonmetastatic disease. Except in that situation, abiraterone has superseded ketoconazole in this clinical state.
Slovin
: I’ve gone back to ketoconazole, because abiraterone is not always covered by insurance. Ketoconazole is not as effective, and it has more toxicity, but if you’re in a dither it’s the best one to use. On this particular patient, though, I could make the argument that if he went into a complete biochemical radiographic remission, I would have radiated his prostate for local control and maybe used adjuvant hormones for an extra year, and then gotten him off everything. He’s a young guy, and the law does not say one should stay on hormones for ever and ever.
Dreicer
: Clearly we’re going to stop his bicalutamidethat’s a no brainer—and if you’re going to think about immunomodulatory therapy, this might be a very good patient to use it in. Even if he has an antiandrogen withdrawal response, you could argue that that’s okay, and may make him even a better candidate.
Gomella
: The patient’s testosterone is 55 and he’s been getting leuprolide. What would you do at that point?
Petrylak
: One option would be to put him on abiraterone, which would reduce his testosterone even further. A second would be to put him on degarelix, which could also lower his testosterone. Of course, the final option is simply to do an orchiectomy.
Gomella
: An important point, and one that Dr. Crawford has been out in the lead on, is that our LHRH analog therapies are one-size-fits-all. If you have a 98-pound gentleman and a 300-pound gentleman, they get the same dose of the LHRH analog, and there are some issues now to suggest that the mode of administration and obesity can actually affect absorption and utility. So, at our shop, we’ve flipped people from goserelin to triptorelin, or triptorelin to leuprolide, and I have to say that we’ve always gotten their testosterone to come down.
Crawford
: In a study, we looked at patients with T (testosterone) less than 50 who went on sipuleucel-T, and then [investigational] GTx-758 and a couple of other agents, and watched T levels. Twenty-one percent of participants had T levels above about 20. Orchiectomy gets you to 14 to 17. And so, theoretically, these patients aren’t castrate. And maybe the reason 20% to 30% of people respond to secondary androgen ablation is because they weren’t totally suppressed to begin with.
Slovin
: While we’re getting serum testosterone levels down, we still are never 100% sure of intratumoral testosterone levels. That’s always sitting in the background.
Dreicer
: And the testosterone assays most of us use in the hospitals are not very sensitive, especially at the low level.
Crawford
: You’ve got to also measure the free T level.
Gomella
: In this case, the patient was put on abiraterone and prednisone. Do you think he needed to be there, Rob?
Dreicer
: I would have been concerned that, in a relatively short period of time, he was going to become symptomatic, and I’d want to obviate that, so I think it’s eminently reasonable to have treated him.
Robert Dreicer, MD, MS
Gomella
: So the patient is put on the abiraterone/ prednisone regimen, and his PSA goes down. Eight months after treatment, it’s down to 3. However, it then goes up to 5 and then, four weeks later, to 9. He has new or recurring retroperitoneal adenopathy. His bone scan shows more lesions, and he has lumbosacral spine pain. He’s failed hormonal therapy, sipuleucel-T, and abiraterone. What would the audience do for this gentleman? The choices are to give (1) enzalutamide, (2) docetaxel/prednisone, or (3) cabazitaxel. Okay, 12% of you said enzalutamide, 72% said docetaxel and prednisone, and 16% said cabazitaxel. It looks like the clear winner here is standard docetaxel and prednisone. Dan, any comments about using it in the setting of having pain?
Petrylak
Case 3
Gomella
: The right situation to use it is when the patient is symptomatic. As far as your alternatives, there’s no data for using cabazitaxel in the frontline setting. With enzalutamide, we don’t know what the response rate is after abiraterone. Also, at this point, it’s not approved for that indication.: The patient is 69 years old and has Gleason 4+3 prostate cancer. His PSA is 9, and his rectal exam shows a T2a nodule. He is staged negative on bone scan and CAT scan, has good GU function, and is sexually active without PDE-5 inhibitors. He has had no previous pelvic radiation or irritable bowel disease, and his prostate size is about 40 ccs on transrectal ultrasound. Since he prefers radiation therapy, his options are brachytherapy, external-beam radiation, brachytherapy plus external-beam, protons, or all of the above. The audience selected all of the above (48%), external-beam (24%), brachytherapy plus external- beam (18%), brachytherapy (8%), and protons (2%). Dr. Crawford, what are your thoughts on this gentleman?
Crawford
: I think he has all of those things available. The current “sexy treatment” seems to be focusing on brachytherapy and how high the dose can go. So that’s what a lot of people are doing.
Gomella
: Probably mixing brachytherapy with external-beam would be a top option for him. But it’s almost dealer’s choice.
Gomella
: So the next question is: What’s the benefit of adding hormonal therapy in this patient who’s getting radiation therapy? Would people do that? Eighty percent of you say yes, 20% say no. We’re going to assume this man is intermediate or higher-intermediate risk, and that’s probably a reasonable choice. Dave, do you have any thoughts about using an LHRH agonist or antagonist in these settings? Are you still using combined androgen blockade?
Susan Slovin, MD
Crawford
: I still believe in combined androgen blockade. If you give an agonist, you get a flare, testosterone goes up, the tumor gets bigger, and the prostate gets bigger. If you’re trying to downsize, you’re wasting time. So combined androgen blockade makes sense. There’s pretty good evidence about using an antagonist where you don’t get that, and some other advantages. So, we tend to use more antagonist activity. The other trend that’s interesting is that the hormone therapy is kind of going away, except in really high-risk patients, and that it’s being continued for less than two years, while the radiation dose is going up. The claim is that there’s less local failure because we’re able to get the gray up so high. But I don’t buy that. My argument is that a lot of these people who are getting hormones and radiation with intermediate and advanced disease are actually benefiting from treatment of micrometastatic disease with hormone therapy.
Gomella
: The other question that has been unanswered is: How many of these patients actually recover their testosterone level to some reasonableness? That’s something that the radiation/ oncology community has not been enthusiastic about studying, because they think it’s not an important issue.
Crawford
: Another thing that never gets talked about is that when you radiate the prostate, you have radiation scatter that hits the testes and lowers testosterone. If you look at a few studies that have been done, the bump in testosterone down is not huge. It’s 10%, 20%, maybe even more. What effect does that have?
Gomella
: Here’s a question for the audience. If you were going to treat this man with external-beam radiation monotherapy, what is the optimum dose he should receive for localized prostate cancer? The choices are (1) 66.6 gray (Gy) at 1.8 Gy/fraction; (2) 72 Gy at 1.8 Gy/fraction; (3) 79.2 Gy at 1.8 Gy/ fraction; or (4) 80 Gy at 2.0 Gy/fraction. Thirty percent of you say 80 Gy, 23% say 72 Gy, and 6% say 66.6 Gy. Forty percent say 79.2 Gy, and that’s about right. Once you start getting to 80 Gy with external-beam radiation, the toxicity goes up dramatically. Audience member: What’s your opinion about local radiation at this point? Not the complete gland, but focal radiation?
Crawford
: I think it’s a good idea to do extra loading of the seeds in the area that is involved, and then not as much to cover the rest of the gland.
Gomella
: It might make theoretic sense from a standard-of-care standpoint, but it’s nowhere in any kind of guidelines.
Crawford
: They’re actually doing it at Memorial Sloan-Kettering. And we’re going to be joining them in a trial that will involve targeting, loading it to the lesion.
Gomella
Case 4
Gomella
: High-dose radiation therapy is being reconsidered in localized prostate cancer as well. We’re not talking about focal therapy there, but it’s just another way of getting the radiation into the gland.: Here’s another high-risk patient, an 83-year-old gentlemen with urinary retention and an inability to walk. His PSA is over 1000. An MRI of the spine shows a T12 epidural spinal cord compression. He undergoes a decompressive laminectomy that shows metastatic carcinoma of the prostate. His bone scan is extensively positive, with lesions in the left femur, axial and appendicular skeleton, the T12 vertebra, and the ribs. A CAT scan of the abdomen and pelvis shows no evidence of any visceral metastases. The patient is treated with androgen blockade, and seven months after therapy, his PSA is 12. Three months later he has pain in his back. A bone scan shows new lesions. His PSA has bounced up to 80 and he’s put on abiraterone, and now is also given denosumab. The bone scan continues to progress six months after treatment, and his pain worsens. He then goes on docetaxel and prednisone. He gets a good response after eight cycles. His pain improves. However, after two more cycles, his PSA goes up to 10 and then to 20. He gets very bad pain. He has a repeat bone scan and now he has a lot of problems in his thoracic spine, but no epidural lesions. What would you do for this gentleman who’s wracked with pain and has failed multiple therapies? The choices are to give (1) isotope therapy with samarium; (2) isotope therapy with radium- 223; (3) palliative focal radiation to the thoracic spine; (4) abiraterone; or (5) enzalutamide. Okay, 60% of the group says radium-223. Twenty-three percent went with palliative care, 11% with samarium, and 6% with enzalutamide. No one chose abiraterone. Radium-223 is only available on compassionate release at a few centers around the US. Susan, what are your thoughts?
Slovin
: I could probably make an argument for any of these. The only reason I would be reluctant to use enzalutamide is because he is symptomatic and you want to get him out of his misery. If one were to assume radium-223 was FDA-approved, I probably would be using that, either alone or in concert with another chemotherapy, if we had it, in a clinical trial. Cabazitaxel would be very reasonable, as well.
Petrylak
: There is a clinical trial available for this patient in the early stages of his disease. For those patients who do not normalize their PSA to less than 4, SWOG is looking at early abiraterone prior to progression. Second, Susan’s right: You can make an argument for anything here. I wouldn’t be so sure about using enzalutamide, though, because you’ve had already a short initial response to hormones, and you’ve seen abiraterone, so I don’t think he’s going to respond to that. I would agree with going with radium-223.
E. David Crawford, MD
Gomella
: Are there any questions from the audience?
Audiencemember: We never really talked about intermittent androgen therapy. What do the panelists think about that?
Dreicer
: The intermittent therapy question has been addressed by two randomized trials. If a patient has nonmetastatic disease, had radiation, and is deemed appropriate for hormones, I think there’s reasonable data from the Canadian trial, which suggests that it’s equivalent.4The US intergroup trial led by SWOG addressed the question of intermittent therapy versus continuous in metastatic patients.5I think the data are reasonably obvious that intermittent therapy is likely to be inferior to continuous therapy in a majority of those patients. And I think, for the majority of patients, continuous therapy should be the standard of care.
Audiencemember: What are your thoughts on the role of the sodium fluoride PET/CT bone scan?
Dreicer
REFERENCES
: The problem with these new technologies is that they’re beginning to define what we’ve always known was happening. For example, we know that many patients with rapidly shortening PSA doubling time have systemic disease. We have clinically managed these patients for a long time using the technology that we have. So, if you have a positive bone scan or CT, you say you have radiographic evidence of metastases. So the question is: As we have better tests that resolve things earlier, have we gotten smart enough to intervene and use that information meaningfully? And I would argue right now we’re in a sort of in-between, and it’s going to screw things up for a while. We do trials for nonmetastatic disease based on bone scans. But Mr. X who’s on a trial could go over to the neighborhood mobile PET imaging store and learn that he has metastaseseven though he was on the trial because we thought he didn’t have metastases. The larger issue that will play out is that, if we are in a value-based care environment and the test helps us take care of people and they do better, it’ll likely get used. If it doesn’t, and it’s a lot more expensive, I think we’ll have to make a choice.
- National Cancer Institute. The Prostate Cancer Prevention Trial. National Cancer Institute at the National Institutes of Health. http://www.cancer. gov/clinicaltrials/noteworthy-trials/pcpt/Page1. Accessed March 27, 2013.
- Roehrborn CG, Barkin J, Siami P, et al. Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial.BJU Int. 2011;107(6): 946-954.
- Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).JAMA. 2009; 301(1):39-51.
- Crook JM, O’Callaghan CJ, Graeme D, et al. Intermittent androgen suppression for rising PSA level after radiotherapy.N Engl J Med. 2012;367: 895-903.
- Hussain M, Tangen CM, Higano CS, et al. Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): results of S9346 (INT-0162), an international phase III trial.J Clin Oncol. 2012;30 (suppl; abstr 4).
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