With less than a 3-month doubling time I would administer androgen deprivation therapy (ADT) to the 65-year-old patient with a PSA level of 10- ng/mL. A 6-month doubling time in the 10 to 20-ng/mL PSA range is a gray area. I would evaluate comorbidities, and if they were low I might treat. At 20 ng/mL and above I would treat. For a 12-month PSADT and PSA level of 10 ng/mL, I would probably not treat but have a long discussion with the patient.

The life expectancy of an older patient, such as a 78-year-old, may be 5 to 10 years. If his PSADT were less than 3 months, it would be the prostate cancer, if left untreated, that would be life threatening. In such a case, with a PSA level of 10 ng/mL I would administer ADT. With a PSADT of 6 months and PSA of 10 ng/mL I would not treat, at 20 ng/mL I would have a long discussion and for higher PSA levels I would treat. For older patients with a 12-month PSADT I probably would not treat unless PSA level were above 50 ng/mL.

The time between primary treatment and PSA relapse does not affect my decision to treat as much as does PSA level and PSADT. Certainly men with rapid relapse are at higher risk. PSA level, PSADT, imaging results and comorbidities are the major factors that affect my decision to treat.

We have to individualize our approach in this setting. The ASCO guidelines are reasonable — they recommend discussion of combined androgen blockade for some men because some are good candidates for that. There’s not much evidence here for specific PSA thresholds. But on average, bone metastases and imaging evidence of metastases tend to happen between PSA 20 and 40 ng/mL.

Gleason score alone does not determine whether I offer treatment. If the initial score is high grade, PSA becomes less reliable. Some aggressive tumors don’t make as much PSA. I’m more likely to follow that patient with imaging over time and not rely only on the PSA. Men with high-grade tumors tend to develop metastatic disease sooner. So I may be more conservative and use hormonal therapy at a lower trigger for higher-grade tumors.

With a PSADT of less than 3 months, I would probably administer treatment to the 65-year-old patient if he had a PSA of 10 ng/mL. I would prefer to treat on a clinical trial or offer abiraterone or enzalutamide if I could obtain either. But these agents are not approved in this space, so in our practice we would offer bicalutamide or dexamethasone or a low-dose steroid.

With a PSADT of 6 months, I would again prefer a clinical trial, but in the absence of that I would likely administer treatment to this patient at a PSA level of 10 ng/mL or higher. If the patient didn’t want hormonal therapy to maintain sexual potency, I would probably watch and wait. So I believe there’s some equipoise in this situation. There is also equipoise if the doubling time is 12 months. I would not rush into anything. The higher the PSA, the more likely I would be to initiate treatment. I would administer the same treatment if the patient were 78 years old. I don’t believe that age matters. Younger patients are more likely to want to maintain sexual potency, but apart from that, age doesn’t usually affect my treatment decisions.

The other thing is that we know that bone scans are pretty poor at detecting bone metastases, so I’d probably conduct a whole-body MRI scan or a choline C-11 PET scan to truly evaluate in my workup whether the patient had metastatic disease or not.

With PSA-only relapse, if the patient had a rapidly rising PSA and a high PSA, then I guess I would speak to the patient, see whether they were concerned about their sexual potency, whether they would be willing to consider hormonal deprivation. If the patient were keen to go ahead with that therapy, then I would go ahead with it. I would argue that we do not have clear evidence whether one should treat and that’s why there are trials ongoing.

In northern Europe there is reluctance to initiate treatment. It’s a complex issue. If the patient would be willing to accept no treatment, because it has probably no effect on his survival, then we will probably wait on the initiation of ADT. Metastatic disease is the paradigm for initiating ADT.

Age would not affect my treatment decision-making. My approach would be the same for the 65-year-old and for an older, 78-year-old patient. The dominating factor for me is patient anxiety. That’s going to drive my decision to treat more than PSA level or PSADT. If the patient were concerned that his PSA was high at levels higher than 50 ng/mL and the doubling time was so short that it was viewed as imminent further disease progression, I would be willing to have a discussion and consider initiating treatment.

So whether to initiate treatment or not is driven more by the anxiety of the patient and where you practice. In northern Europe we are less likely to start treatment than in southern Europe and the United States. The approach in northern Europe is to initiate ADT only in the setting of metastatic disease. In that scenario, I would ask for a total body MRI to confirm that no metastases were present. We do have guidelines from the EAU and ESMO. Both options are listed because northern and southern countries are all part of the European Union. In the United States and in southern Europe, many patients will simply be initiated on ADT. So in those countries we have many patients with castration-resistant nonmetastatic disease because the physicians initiate the hormone treatment too early.

The driver would be the PSADT, regardless of what the absolute PSA is. In the setting of a doubling time of less than 3 months, I would be concerned and I would administer treatment to this patient. If the doubling time is 6 months, that, to me, is still a nerve-wracking number. With a 12-month doubling time and a PSA of 10 ng/mL, I would probably watch that gentleman, but for any others with a PSA of more than 20, across the board I would probably go ahead and treat.

I would treat a 78-year-old in the same manner as a 65-year-old. In terms of factors that go into my decision-making, checking baseline testosterone is important, knowing exactly where you’re starting from to make sure that you actually have somebody who has the opportunity to have the testosterone level lowered. The overall health and life expectancy of the patient is the second consideration. And that can be measured by a whole variety of means. Certainly, a lot of us measure it by absolute calendar age, but other factors go into that. Life expectancy is evaluating cardiovascular disease, renal disease, diabetes and things like that. If a patient has a short life expectancy, I may not treat as aggressively as I would someone who perhaps has a longer life expectancy, knowing that we don’t have the solid data.

For some patients, anxiety is such that they simply can’t live with knowing that their PSA is going up or that it’s not being treated. This destroys their quality of life and has to be considered, including factors such as the patient’s wishes, desires, reasonable expectations and family history. It is not a simple discussion. But clearly, the strongest data we have suggest that the patients who have doubling times of less than 3 to 6 months are going to be in trouble quickly and rapidly develop metastatic disease. And I believe that at least administering ADT will slow that down in some men. But again, we don’t have strong data to say that this is the standard.

This particular patient group with PSA recurrence alone is probably the most underserved in all of urologic oncology when it comes to exactly what’s the best thing to do. Should we be administering secondary hormonal therapy? Should we be administering ketoconazole? Should we be withdrawing antiandrogens before committing to LHRH analog therapy? In Europe, a lot of these patients receive high doses of bicalutamide as a secondary hormonal manipulation before primary androgen deprivation. So I think it’s a “do what you think is right” area. A lot of the guidelines leave it up to your clinical judgment in the absence of any guidance from randomized clinical trials.

I would administer treatment to a 65-year-old patient with a PSADT of less than 3 months and PSA level of 10 ng/mL. With a 6-month PSADT, I would still administer treatment to all of these patients with PSA levels of 10 ng/mL and above. If the PSADT were 12 months and the patient had a PSA level of 10 ng/mL, I would have a discussion with the patient, but I would tend not to administer treatment. The PSA level affects my decision. I’d be pretty suspect if the patient had a PSA level of 500 but the imaging was negative.

I would treat a 78-year-old in the same manner as the 65-year-old. The most important factor in my treatment decision-making is the PSADT. But if the patient were anxious and wanted treatment, regardless of the PSADT, I would offer treatment. In that case I would recommend intermittent therapy.

I would administer treatment to a 65-year-old patient with a PSADT of less than 3 months and a PSA level of 10 ng/mL. If the PSADT is 6 months and the PSA level is 10 ng/mL, I may or may not treat. If the patient had a PSADT of 12 months, I would not treat.

For a 78-year-old patient, I would only treat if the doubling time were less than 3 months. I’d be a little more conservative with 78-year-olds, because these patients have a pretty good prognosis unless the doubling time is less than 3 months.

The reason I would treat a rapid “PSA doubler” with a PSADT of less than 3 months is for the prevention of metastatic disease. Such a patient is likely to develop metastatic disease quickly, and you can delay that in exchange for the side effects of ADT.

I take side effects into consideration. I would talk to the patient about side effects and see how he reacts to that. I do consider the patient’s age, and I tend to be more conservative in treatment for older patients. Gleason score probably would not affect my decision to treat or not. Some guidelines address the issue of treatment for PSA-only relapse. However, in the scenarios described we do not have a lot of guidance, and what is available is not clear.

I think PSA level of 10 ng/mL and a doubling time of less than 3 months is a harbinger that the 65-year-old patient is going to develop radiographic evidence of disease soon. I would generally administer treatment to this patient or tell him that it’s highly likely that within the next year he will have a positive scan that will make me want to start ADT. We can do it now or wait and perform scans frequently.

A PSADT of 6 months is more borderline. That’s when I start paying attention, and I discuss the options with the patient. I will say, “This is a sign that things may be progressing now and we want to keep a closer eye on things. If you develop a positive scan, I will definitely recommend treatment. You may decide to start treatment now, or we can wait until the scan turns positive.” I watch all patients with a PSADT of 12 months, regardless of what the PSA level is.

I would administer treatment to a 78-year-old patient in the same manner as the 65-year old, assuming that he doesn’t have a lot of other comorbidities and isn’t about to die of heart failure or something else. Someone who’s lived to 78 years actually has a 10-year life expectancy. It’s not unreasonable to treat for the same triggers as I did for the previous patient.

The absolute value of the PSA doesn’t make any difference to me. The PSADT is far more important. Three months or less for sure would be a trigger. I have a couple of surveillance patients who have slow PSADTs, and I have followed their PSA levels up until they’re in the thousands. Age doesn’t play into that so much, other than thinking about what the life expectancy is. It’s more about life expectancy than it is about age.

The patient’s anxiety level, performance status and other lifestyle issues are all also important. It depends on what need you’re fulfilling for the patient. If the patient doesn’t have an urgent cancer need to go on ADT, then you must consider what need you’re fulfilling. For example, a PSADT of more than 6 months is not an urgent need. I tell the patients, “Starting ADT now is not likely to make you live any longer than waiting until your PSADT becomes more rapid or you develop symptoms or have a positive scan.” There are better ways to treat anxiety than with ADT, such as with diazepam, counseling and support groups. That’s generally how I counsel the patients.

In someone who is older and frail, I might be less likely to start ADT unless the patient has a positive scan or disease symptoms. ADT does cause known side effects, such as sarcopenia, lethargy and cognitive changes. Not all patients will tolerate that. If they’re already debilitated and if they’re not mobile, then the risk of a fall and a fracture because of osteopenia or osteoporosis, in addition to sarcopenia, are all considerations. So in those patients who have a less robust performance status, it would not be doubling time that would trigger treatment. It would be symptoms or radiographic disease progression. We do not have any real guidelines to follow because no one knows for certain what the correct approach is.

I would administer treatment to a 65-year-old patient with a PSA level of 10 ng/mL and a PSADT of 6 months or less than 3 months. I would prefer to place the patient on a clinical trial, but otherwise you could administer bicalutamide or ketoconazole. None of the newer agents, such as sipuleucel-T, abiraterone or enzalutamide, have an indication in this setting. Because it’s unlikely that I’ll be able to do anything differently, I administer treatment to all these patients.

For a doubling time of 12 months, you could observe, but my patient population probably wouldn’t accept that. Generally, I would continue treatment with antiandrogen or ketoconazole. I would administer treatment to a 78-year-old patient basically in the same way as I did for the 65-year-old, with the exception that with a PSADT of 12 months and a PSA level of 10 ng/mL, I would observe that patient and not treat.

In all scenarios, my treatment decision will be tempered by the overall medical condition of the patient. Specifically, in a patient who either has a history of cardiovascular disease or is at high risk for cardiovascular disease, I am slower to treat PSA-only relapse. I generally evaluate the patient as a whole in that situation.

I believe that patients with rapid doubling times are the ones who would receive hormone therapy. I’m not so convinced that the people who have doubling times of more than 10 months need androgen blockade. My treatment algorithm is based on PSADT and not only on the PSA level. The issue of the level of the PSA has been studied and found not to be as important as the doubling time.

Pertaining to an older patient, one of the things that I also consider is the patient’s physique, such as leanness. A certain body physique will not be seriously affected by side effects. Not only do I worry about cardiovascular complications, but I also worry about fatigue and functional abilities. I certainly believe that a lean patient who is in fairly good shape will tend not to gain weight and not to have some of the other complications related to androgen blockade. Hot flashes are difficult to control, but I don’t believe that correlates with androgen blockade. One factor that plays a role is how the patient physically looks. Some 78-year-olds are fit and look like they could run a marathon, and some 50-year-olds look terribly debilitated. I believe there’s a correlation between tolerating treatment and leanness, in terms of fatigue. These are things that I have observed in my practice. I have no data in support of these observations.

I would administer treatment to a 65-year-old patient who has a PSADT of less than 3 months or 6 months and a PSA level of 10 ng/mL. With a PSADT of 12 months and a PSA level of 10 ng/mL, I might put the patient on observation. If the PSA level is 500 ng/mL, I’m probably administering treatment because I know he’s going to turn positive soon.

The older a patient is, the more cautious I am about hormonal therapy. I tilt a little bit more toward no treatment in the older patient. But again, it kind of depends on the comorbidities, how the patient is feeling and the patient’s anxiety level.

The Gleason score does not affect my treatment decision much, nor does the time from local therapy until relapse develops. There’s a great paper by Steve Freedland that evaluated the time between the initial treatment and relapse and the Gleason score. Basically, 99% of the information is in the PSADT. The Gleason score and the time to relapse do not add a huge amount of information. Both factors can predict and correlate with the PSADT. So I almost always try to obtain a PSADT before I start treatment.

I consider the patient’s age, anxiety level, performance status and comorbidities. I take into account a lot of patient preference considerations. I find it difficult to be dogmatic when the data we have don’t allow me to do so. If somebody’s pushing to receive treatment, I’ll say, “That’s fine.” For all my patients I use intermittent therapy, which is another important factor. So I administer 6 months of therapy and then I see how the patient responds. If the patient has pretty benign disease and a great response, I may not treat again for 2 or 3 years. The intermittent nature of the therapy is an important element that has to be captured.

We don’t have a prospective randomized trial that addresses this issue in a clear and distinct fashion. An old MRC trial concluded that how you diminish certain things and not others doesn’t prolong survival. You have retrospective data that suggest that you can predict who will fare poorly. We know the natural history well. The patient who experiences rapid disease progression with a less than 3-month PSADT has a poor prognosis.

I would recommend treatment for a 65-year-old patient with a PSA level of 10 ng/mL and a PSADT of less than 3 months. With a PSADT of 6 months, my treatment choice would be the same.

I would have a discussion with the patient with a PSADT of 12 months. I would review the safety/tolerability issues and take a shared decision-making approach. Assuming the patient had no symptoms and potentially had some level of sexual function, I would discuss this point with the patient. With a 78-year-old patient, I would probably be more inclined not to treat. I’m still going to follow the patient closely. Once the PSA level rises above 20 ng/mL, it creates anxiety, not just for the patient but also for me. However, no one ever died of an elevated PSA level. People die of tumor burden and the symptoms associated with it.

Currently, the factor that has the biggest impact on my treatment decision-making is the PSADT. I also take into consideration and review factors such as absolute PSA level, patient age, anxiety level, performance status and other lifestyle issues in my own mind and discuss openly with the patient and his family and caregiver. I discuss the option to institute a testosterone-lowering therapy, any potential clinical study or continued observation. I don’t have a perfect answer. All of those variables must be carefully reviewed before I make a decision. I’m not aware of any clinical guidelines in the PSA-relapse setting.