At the Third Annual Interdisciplinary Prostate Cancer Congress in March, the audience viewed presentations of real prostate cancer cases treated by the speakers. How would you treat the patient in this case study? Compare your responses with those of the attendees and the expert panel.
A case study presented by Roy E. Berger, MD, was discussed by a panel that included doctors Daniel Petrylak, David Crawford, Howard Sandler, and Robert Dreicer. This real-life scenario consisted of four parts, and the audience was invited to vote for the treatment option they would use.
The patient is a 65-year-old, moderately obese man (115 kg), who is hypertensive and has hypercholesterolemia. Seven years ago, he had an iPSA level of 6.3, a Gleason score of 3 + 3 = 6, and underwent radical prostatectomy for adenocarcinoma. He experienced PSA failure 3.5 years after surgery and underwent salvage radiotherapy when his PSA level reached .85 ng/mL. After an initial decline, PSA values have increased over the past 3 years and are now 15.5 ng/mL, with a PSA doubling time of 4.5 months. The patient is asymptomatic but is worried and wants something done. He notes he has two primary goals in life: to see Ireland in the World Cup and to get his PSA down.
Which of the following do you recommend?
A. Bone scan and CT scan of the abdomen and pelvis
B. Androgen deprivation therapy (with a plan to go to intermittent therapy)
C. PET-CT scanning
E. Pelvic MRI
Berger: Half the audience basically recommend an extended disease workup, and ~50% say they would treat with intermittent androgen therapy.
Sandler: My question is do you really need the abdomen when you are doing this? Doesn’t that cost twice as much?
Dreicer: Well, depending on how your center operates, it can cost more if they are billed as two separate procedures. I think you do need the abdomen because it is not uncommon for nodes to show up above the bifurcation, even in the absence of nodes in the pelvis.
Petrylak: One of the first patients I imaged with ProstaScint, in 1993, was a 38-year-old man whose supraclavicular lymph nodes lit up like a Christmas tree. We really did not know what to do with him at that point. We had a long discussion about whether he should be on hormones or whatever else. About 3 years ago, I received a letter from him saying he never relapsed in that spot, so there are clearly false positives with ProstaScint.
The physician involved in this patient’s care ordered a bone scan and a CT scan of the abdomen and pelvis. The bone scan showed no evidence of metastatic disease—only degenerative joint disease. The CT scan showed a positive right pelvic node.
What would you recommend next?
A. Androgen deprivation therapy (ADT) + LHRH agonist to maximum response, then intermittently
B. Radiosurgery to the node
C. Expectant management
D. ADT plus 6 cycles of docetaxel
E. ADT + LHRH agonist continuously
Petrylak: There is not an indication for docetaxel in this situation. If this were a trial, I would say it is appropriate. Outside the context of a clinical trial, there is no evidence that giving up-front chemotherapy is going to improve somebody’s survival. An ECOG study is looking at the question of whether to give ADT with or without docetaxel. This is not a patient I would give docetaxel to.
Sandler: The logic for radiosurgery to the node might be that although he had salvage radiation, he had unifocal nodal disease that has grown out and because it is his only site of disease, you can attack it with radiosurgery to try to minimize any radiation overlap. It is a nice story, but pretty much a fable at this point. I would like it to be true, but I think it is unlikely. I am not saying radiosurgery would be wrong, but I would only do it in the context of long-term androgen ablation if you are trying to make a survival argument.
LHRH agonist therapy is initiated, and the PSA nadirs to .9 ng/mL. Over the next 38 months, the patient receives 3 cycles of intermittent androgen blockade. Now the patient has PSA progression up to 22 ng/mL in the setting of serum testosterone of 22 ng/mL. The patient remains completely asymptomatic. A CT scan shows a mild increase in adenopathy, and a bone scan is obtained, which is positive throughout the axial skeleton and pelvis.
Which of the following would you do at this point?
A. Start bicalutamide at ≥50 mg/day
D. Refer to a clinical trial
E. Expectant management
Petrylak: This is an asymptomatic patient, and I think it’s appropriate to consider secondary hormonal manipulations or something like Provenge (sipuleucel T). The issue is when it is optimal to give chemotherapy. It is somewhat controversial as to whether you should administer chemotherapy when patients are progressing rapidly but remain asymptomatic or wait until they develop symptoms. I would probably hold off on chemotherapy at this point. It is certainly appropriate to consider a clinical trial. I am a little perplexed by the 13% who selected mitoxantrone/prednisone. In 2010, I do not really think that has a role for this patient in front-line therapy.
Berger: This would be the ideal patient for Provenge, in line with the indication for it. Bob [Dreicer], would you start other secondary hormonal therapies first and what would they be?
Dreicer: I’m not a big fan of second-line antiandrogens; I’ve been unimpressed with the first generation over the years. I would consider ketoconazole today if I did not have access to any experimental drugs. I think that has been far better in terms of the likelihood of obtaining a response. It is not wrong to use bicalutamide, but I am a little less impressed with it. I hope that in a relatively short period of time we will have better compounds to use in this context so the discussion goes away.
Petrylak: In the face of a positive bone scan, and as long as the patient’s renal function and teeth are okay, I would also start zoledronic acid right away, at 4 mg every 3 to 4 weeks. We are still waiting for the randomized trial data to come back on denosumab, but from what I have heard, it will be very similar or better than zoledronic acid as far as skeletal-related events go. Until that data is in front of the FDA, however, zoledronic acid is the primary choice.
Berger: About 8 to 10 years ago, Nicholas Volgelzang did a study involving ~14 patients that showed a 60% response rate to nilutamide (Nilandron). In my practice, I have found using nilutamide was beneficial to patients that failed almost every hormone and ketoconazole.
Petrylak: I have used it, but if I remember correctly, Vogelzang’s study was with a select group of patients who had responded to antiandrogen withdrawal. Nonetheless, my impression is the same as yours—it is probably a more active drug in the second-line setting than bicalutamide. As to whether that is selection factor, we saw from the ASCO Genitourinary meeting this year that patients who respond to multiple hormonal manipulations will respond to multiple hormonal manipulations—you tend to get response again and again. I think that we need a marker that will tell us when to use these treatments. Clearly, the antiandrogens are not as good as the newer generation of treatments, and hopefully these will get approved shortly.
Berger: But it is something that one can consider if the patient is asymptomatic and the PSA doubling time is relatively slow.
Dreicer: And if he does not drive a bus at night. Not infrequently, this compound is associated with visual impairment at night, so you have to know that.
Petrylak: The other problem is you need to make sure they do not like a glass of wine at night because they can develop an antabuse type of reaction. So, you have to be careful with niltuamide.
Dreicer: That is why nilutamide is not widely used; its side effect profile is a little dicier.
The patient is referred into a phase II trial with an investigational lyase inhibitor. Following a partial response, at 13 months he develops mild back pain. He has a 3-kg weight loss and fatigue. Docetaxel/ prednisone is initiated; following cycle 1, his pain has resolved and he has regained 2 kg of weight. Following cycle 8, his PSA is nadir 2.2 ng/mL. He is fatigued and requests a break in therapy. Eight months after completing chemotherapy, he has new back pain and now rib pain. His appetite is poor, and his ECOG status is 1 to 2. His PSA has risen to 56 ng/mL.
4. Which of the following would you recommend?A. Start bicalutamide (any dose)
D. Refer to a clinical trial
E. Expectant management
F. HospiceBerger: Overwhelmingly, the audience chooses “Refer to a clinical trial.” This is followed by docetaxel/prednisone. Few people would start hormones at this point, which I think is right, and 11% said expectant management. I have to ask the panel, would you allow his PSA to go up to 56 ng/mL before he has pain prior to reinitiating therapy?Dreicer: Normally, in this setting, I follow PSA as infrequently as possible. Second-line therapy is purely palliative, so in the absence of evidence in the natural history that I do something, all I care about is how he feels. Needless to say, had I followed him with minute-to-minute PSA testing, he might have been worse 3 weeks after he finished docetaxel. I follow PSAs as infrequently as possible and remind patients it is about quality of life, that we are managing expectantly, and we will reinitiate therapy when it will improve how he feels. That will obviously change if we get data showing additional therapy can improve survival.Petrylak: The interesting thing about this is that you are getting into the question of when you should reinstitute docetaxel-based therapy. Just like intermittent therapy for hormone-sensitive prostate cancer, there are many different ways to skin that particular cat, that is, giving intermittent chemotherapy. Published data looking at when patients’ PSAs start to rise again show ~60% of patients re-respond. In our phase II trial of docetaxel and estramustine, we restarted chemotherapy when PSAs reached 20 ng/mL, which was slightly higher. You are more likely to get symptoms at that particular point. It is a difficult issue. Yes, PSA may be one way of basing this, but we do not have any standard way of doing this.I think it is appropriate to retry docetaxel/prednisone. If you had a patient who really did not want to go on chemotherapy at this point, the other thing we really have neglected to mention are radioisotopes. You can get significant palliation, particularly in someone who has diffuse bone pain and is on pain medications. Some worry about maintaining blood counts, particularly with drugs such as strontium. I do not use strontium; I go primarily with samarium at this point. Morris has shown you can give chemotherapy and a radioisotope safely, at the same time, so that is something you can consider, though it is not necessarily standard.