Podcast Transcript: Managing Biochemical Recurrence After Prostatectomy

[Dr. Aditya Bagrodia]:
Perfect. All right, so we've got our patient. They're in the office, they had their PSA drawn a couple days prior. For some period of time, it's been undetectable. Now it's detectable. When you're digging into that patient's chart and trying to sort out what comes next, what are the critical elements? Let's say they're functional and all of that. What are the critical elements of their history, physical, pathology, et cetera, that to you are the most important drivers here?

[Dr. James Eastham]:
Pathology I think can help. Positive margins are more likely to be a local issue. Seminal vesicle invasion can be a local issue, perhaps a little more likely to be metastatic. Obviously, if they had node-positive disease, that suggests node positivity, but it doesn't preclude local recurrence either. Pathology can give a little bit of information. How far they are out from their surgery? Two years before or after?

That's a general landmark. If they're more than two years, more likely local recurrence. If it's before two years, more likely distant recurrence. Then imaging. I don't rely just on one PSA level, of course. We've had several situations where a PSA has been checked, it's been detectable, and then you simply repeat the PSA test and it's gone back to undetectable, and it's just a lab error. It happens.

Always confirm the test, if not just once, twice. I don't necessarily do it immediately. Depending upon the value, I usually wait a few weeks and say, "Look, sometimes there's just these blips and things we don't understand, but we're not going to treat until there's an obvious trend going upwards, and then we will be guided by all the information that we have." Pathology reports, time from surgery, what imaging shows.

[Dr. Aditya Bagrodia]:
I think these are the tried and true risk factors, grade, margins, nodes, obviously clinical factors, making sure that they've got some gas left in the tank, some years left. Doubling time, can you talk a little bit about that?

[Dr. James Eastham]:
We typically aren't getting so many PSAs unless it's someone who's rising very slowly, and then you know they have a long doubling time. In terms of is this a patient who's a candidate for salvage radiation therapy, should I get three to six PSA levels so I can calculate a doubling time? I'm not sure that's a practical way of doing things. I think in more advanced disease, sure, but I think in selecting a patient for consideration of salvage radiation, I think the absolute value of the PSA is far more important with other clinical variables than waiting for a doubling time.

I might be wrong about that, but I don't use doubling times in terms of I have a very low threshold to send folks to radiation therapy for the conversation. I'd rather refer too early than too late. As you have at your place, we have a great relationship with our radiation oncologist. It's not adversarial at all. No one's trying to have the patient and say, "The other treatment's awful. You shouldn't have surgery. You shouldn't have radiation therapy." It's a group effort. It's multidisciplinary.

I have no trouble sending them off to the radiation oncology folks who will give them very sound advice. It may be a little different advice than I might have given them, but no one's right. It's just different advice. Timing might be a little different, those types of things, but I have a low threshold to just send them to get another opinion.

[Dr. Aditya Bagrodia]:
Totally. I think there historically used to be this thought process that if they see a radiation oncologist, they're going to get radiated. I think that's historical interest only as long as you have good patient-centric care. I couldn't agree more with that assessment. I also think it's important for patients to really get a firsthand look at what does radiation look like, number of sessions, bladder filling, time per day as they're trying to sort this out in the context of their whole life.

For me, I would say that the doubling time really comes into play when I'm trying to talk patients off the ledge who've had a nice long interval undetectable PSA, it goes from .01 undetectable to 0.1, and they're freaking out. First of all, I go through my, "Here, you got 13 years, don't freak out." They want to do something. I'm like, "Let's just monitor this and we'll check it at three months." If it's barely creeping, we're obviously talking about the actual management here. Broad strokes, I'm thinking observation if they don't have a dangerous cancer, XRT, radiation therapy, monotherapy, or radiation therapy plus ADT, or systemic therapy only. Those are the four buckets I've organized things in.

Maybe we can start taking your input on that, starting with observation. Are there people that you're generally saying, "Yes, your PSA is detectable, but let's just hang tight"?

[Dr. James Eastham]:
One thing I think that has improved dramatically over the last several years anyway, maybe many years, is the side effect profile of salvage radiation therapy has markedly improved. The negatives about receiving radiation therapy after surgery are far less than what they were 15 or 20 years ago. It becomes much easier to recommend a treatment if the side effect profile is fairly bland. That's why I have a low threshold.

In terms of who might I observe following biochemical recurrence, someone with a limited life expectancy, if they're already, based on age or medical condition, probably not going to live much longer than five years, especially if their PSA is just trickling up, and their imaging is negative. I have several of those patients that were just watching, and they're content with that.

That's the main group that I do with observation. The other, there are some patients that they have a bias against receiving radiation therapy for some reason, and if their PSA is not going up very quickly, I'll still have them meet with the radiation oncologist, I'll even have them meet with a medical oncologist, even though they're probably not going to get systemic therapy, but just for patients like hearing from someone who doesn't have the infamous dog in the fight so to speak, to give them advice.

Medical oncologists aren't selling surgery or selling radiation therapy, and sometimes the medical oncologist can be a good arbiter of what comes next. There are selected patients, primarily older, less healthy patients, those with shorter life expectancy, patients who are averse to getting salvage anything, they're willing to monitor things. This is where I think you can look at doubling times because you'll have more time to get more PSA values and can get a better calculation of doubling time.

Systemic therapy, obviously if they have metastatic disease on their imaging, and if they have a local disease only, or they're being treated as if they're local recurrence only, and their PSA is a little higher than what we like to see, or they have some other risk factors, I leave that guidance to the radiation oncologist, whether or not hormonal therapy is included with prostatic fossa radiation therapy.

If there's any nodal disease or [unintelligible 00:41:38] disease, other types of metastatic disease, I get the medical oncology folks involved early, not because they're necessarily going to be continuously on hormonal therapy, but again, just to establish the relationship so that if that service is needed down the road, they at least know the person that will be delivering that care.

[Dr. Aditya Bagrodia]:
I think it's going to evolve and maybe become continually more complicated, true multi-D. Taking a walk down memory lane, it used to be like a node-positive patient, ADT for the rest of your life, messing trial, boom. Now I would say that that's largely fallen out of favor in a major way. We've got extrapolation from stampede, ADT, abiraterone radiation. We've got the EMBARK study of enzalutamide.

I think looping in the whole gang and hopefully, they've seen them in some form or fashion for their pre-treatment counseling makes a lot of sense and it goes back to nothing, i.e. observation or kitchen sink. Radiation, ADT, Enza or Abi, fossa plus nodes potentially are the gamut as I see it today. Is that fair?

[Dr. James Eastham]:
I think that's incredibly accurate and yes, we're getting better at detecting systemic disease and we're getting better at determining what therapies are useful in a particular systemic disease. I think yes, it's not all or none anymore. It's not we're going to do nothing versus we're going to do everything. This will happen as time goes on. I think we'll be better able to select what type of therapy is most appropriate for a given type of patient.

That'll involve genetics, that will involve targeted therapies, and as is the trend now, I'm not saying anything that's mind-boggling by any means, is we're going to, as we're doing, shift away from treating cancer by their cell of origin but by their genetic makeup. We won't treat prostate cancer, we won't treat bladder cancer, we won't treat kidney cancer. We'll treat a cancer of this type of genetic makeup is managed with this approach.

It may only be in the classic sense, that's only 5% of prostate cancers and you'll say that's great because, in these patients, this drug works wonderful. it's like olaparib, it's the PARP inhibitors. It's a very small percentage of patients that will benefit, but there is a benefit. Actually, I think surgery will probably be used more and not necessarily as they call it debulking. It's not just taking out or treating the primary perhaps with both surgery and radiation therapy, using appropriate systemic therapy guided by genetics, the clinical situation, et cetera.

I think surgery is not going to go away. I think it's going to be a critical part of a multi-D management to try to cure patients with metastatic disease. That's the goal. I think surgery will play a key role in that.

[Dr. Aditya Bagrodia]:
I couldn't have asked for a better plug. You all have a neoadjuvant PARP inhibitor trial, olaparib in high-risk patients with BRCA mutations. Yes, the incidence is only 5%, but you better believe for those 5%, it could be a total game changer. I totally love that. Of course, you spearheaded the CalGB trial of neoadjuvant docetaxel. I think we ought to keep looking and there's going to be the subsets that benefit. Since you mentioned personalized medicine, tailored medicine, are you using any genomic classifiers to help inform timing of radiation, PSA levels, and whether or not to use ADT as well like Decipher, for instance?

[Dr. James Eastham]:
Primarily an unfavorable intermediate risk, the 4+3s, typically they will get a Decipher test to help guide whether or not the patient will or won't benefit from the addition of ADT. Haven't used it much post-radical to say a patient should or should not receive early radiation therapy. I still use PSA testing and let that guide me. I have not used the Decipher testing post-radical to say, "Oh, your PSA is just detectable. We're going to give you radiation therapy early rather than waiting to 0.2."

I don't know if I'm right or wrong in that. I just don't think the data is convincing enough to say that particular use of genetic testing alters what I'm going to do with the patient. Where I think patients certainly, and some physicians, we use the term genetic testing. There's germline testing, there's somatic testing, there's the specific, you mentioned Decipher, Oncotype Prolaris, they all measure different things.

I think that we have to be very clear when we say, "Oh, we're going to get a genetic test." What genetic test, why are you getting it, and what's the purpose of it? What I try to teach the fellows, if you're going to order a test, is it going to change your management even if it's a hemoglobin? Why do you get a hemoglobin at eight hours? The guy's hemodynamically stable, you had one four hours ago, and it's normal. Why are you getting it? What are you going to do with that test? If it goes down, what are you going to do with it? If it goes up, what are you going to do with it? Why are you doing the test?

We have to have a reason to do the test. There's so many tests we have available today. It's why are you doing it and how are you going to react to the result? If it's not going to change management, don't do the test. All my low-risk patients, I don't get genetic testing on them, just the ones that are borderline. Even those patients, I'm really trying to convince them to have active surveillance, but I many times will get a genetic test if they're saying, "I want treatment", hoping the genetic test comes back favorable, so it gives me more reason to help them make a shared decision about choosing active surveillance.

[Dr. Aditya Bagrodia]:
I absolutely appreciate that. It's going to remain a dynamic process. The way I see it is we just need to stay up to date. There used to be the Stevenson paper where the Holy Grail magic number was 0.5, and there was the update of 0.2 to pull the trigger, so to speak. I think there's evolution in the management to get node-positive ADT for everybody. Now it's another way of thinking, as you described earlier.

[Dr. James Eastham]:
That's the exciting part of it. If everything stayed the same, it would get boring.

[Dr. Aditya Bagrodia]:
Absolutely.

[Dr. James Eastham]:
Heck, we're operating on seminoma now, my God.

[Dr. Aditya Bagrodia]:
There you go. It is exciting. We talked about observation. We talked about maybe the other end of the spectrum, the grade groups, 4s, 5s, high PSAs, persistently positive that are going to be more [unintelligible 00:48:52], Abi, ADT, plus radiation, [unintelligible 00:48:55]. Intermittent ADT, is that something that you're doing much in your practice?

[Dr. James Eastham]:
I have to punt because Memorial is a different place. I've not given ADT for the whole time I've been here. The reason for that is a bit historical. Back in the day, giving ADT may have made patients ineligible for clinical trials. The agreement at Memorial was that if someone had a biochemical recurrence after surgery or radiation therapy, we would not give ADT and have the medical oncologist evaluate the patient. That is perpetuated.

I have to back off a little bit in terms of whom I recommend radiation or hormonal therapy for because I don't give it. I know our medical oncologists use intermittent hormonal therapy in some situations. They use continuous in some situations. It just depends but I punt to the experts on systemic therapy. I don't give it.

[Dr. Aditya Bagrodia]:
I think that's totally fair. I personally think that even this clinical stage is getting increasingly complex. There's opportunity for clinical trials. There's opportunities for escalation, enzalutamide, abiraterone, et cetera. Perhaps in the community setting, a large urology group practice setting where there's not the support infrastructure to really run through everything. It makes sense for a urologist to say, "Hey, let me prescribe your ADT and your enzalutamide, which isn't rocket science and we'll get you well taken care of."

I would tend to agree, that's a patient in my hands that I want to loop in the team to make sure we're doing it perfectly. The baseline DEXA scans, the vitamin D, the calcium, all of it. It's not just here's your ADT, have a good time.

[Dr. James Eastham]:
I think there's many urologists who do that. It's just I'm not one of them. I realize my limitations and I do have the benefit of having folks around me who are interested and do it a lot better than I do. My bar for referral is very low. As you mentioned, there are some practices where there are urologists who focus on systemic therapy and they're great at it.

I think as long as one is comfortable doing all the things that you mentioned, pre-evaluation, DEXA scans, making sure patients get their vitamin D and calcium and do especially weight-bearing exercise, that they take their medications appropriately, they're monitored appropriately, then have at it. I don't care if a urologist is giving the right treatment or a medical oncologist is giving the right treatment, as long as it's the right treatment. I'm not the urologist that does that. I'm not comfortable doing it, so I refer. If there is a urologist that's comfortable doing it, great. That's fine. The patient just needs a good doctor. It doesn't matter what their moniker is.