When the College of American Pathology recently surveyed 17 assays over 4 years to gauge their reliability, reviewers noted that 2 assays underperformed 50% of the time at levels below 0.2 ng/mL.² It's potentially dangerous to base treatment decisions on the results of ultrasensitive PSA tests. None of them are currently approved by the FDA for identifying clinical recurrence in the postprostatectomy setting.

Pruthi: When we see a low PSA level, we need to know several things before we can make any decisions about treatment. First, is it a detectable level? Is it a real number? Second, we need to understand the dynamics of that value. Is it going up and, if so, what is the doubling time? When you are dealing with extremely low levels, the variability is normally 20% to 30%—but it can be as high as 70%. That would truly affect the decision-making process.

Smith: Dr Keane, would you tell this patient that it's possible you didn't remove all his benign prostate cells?

Keane: You have to consider the PSA level before surgery. Because of the half-life, the level might not have completely dropped. I'd certainly tell the patient that he needs another test in 6 or 8 weeks. Of course, I'd also look at the original pathology. Even so, if the PSA level was 0.14 ng/mL 2 months after prostatectomy, I'd be worried about a positive margin and residual tissue I might not have resected.

We know that only about 30% of patients with positive margins are going to have a recurrence. But it isn't very clear what happens to patients who have a recurrence but who also have favorable pathologic parameters—as in our example case. I'd tell him that in series of nearly 2000 men, only 103 (33%) out of 315 selected patients with recurrences after surgery developed metastatic disease at 8 years, and only 50 of those were dead 5 years later.³ About 80% of patients who experienced a recurrence were still alive at 13 years. I'd probably tell a patient with a PSA level of 0.14 ng/mL that I would watch him very carefully.

Smith: Many of these men do well for an extended period of time. Does radical prostatectomy affect the natural history of the disease? Or is this simply a manifestation of the slow progression of prostate cancer, meaning that the situation would have been the same without surgery?

Keane: I have a somewhat controversial view—I believe that radical prostatectomy does change the course of this disease. I strongly recommend surgery in young men because it serves a great purpose—it tells us the extent of the disease. That's information that none of the other available treatment modalities gives us. That's especially important at the present time, because our staging techniques for prostate cancer are so poor. I think men who are young, perhaps in their 50s, should know exactly what issues they are dealing with over the long term. The pathology tells you the exact location, extent, and characteristics of the disease.

I would offer a young man with high-risk disease, who may or may not have the parameters of extensive local disease, the option of having a radical prostatectomy. While I have no data to back that up, it would certainly be in my algorithm because the combination of metastatic and local disease is a horrible way to die. The mortality for radical prostatectomy is below 0.2%, and fewer than 1% of these patients require placement of an artificial urinary sphincter. If the patient has aggressive prostate cancer, he is going to be impotent anyway because he's going to need hormone therapy in the very near future—so the issue of the surgery causing erectile dysfunction is irrelevant. So I recommend surgery, clearly noting that it is not going to cure him but that I think it will improve his outlook in the long run and will largely eliminate the problem of local disease. In a man with extensive stage T4 disease, this would probably not be an option straight off but could be considered as part of an adjuvant protocol following a chemo/hormonal protocol.

Smith: Would you offer radical prostatectomy to a man with demonstrated metastatic disease?

Keane: I'm not at that point yet, but I'd certainly debate it. The outlook for that man in his 50s is pretty dismal. Up to now, we've been concerned about side effects, but the procedure has been modified so much that the side effects are relatively minimal. In cases of breast cancer, most people remove the breast. In some of the other cancers, the primary tumor is removed. There's evidence now for doing that for renal cell carcinoma.⁴ No one's ever considered that for prostate cancer. I'm not sure if it's right or wrong, but I don't think we should limit a patient's options. That viewpoint may be controversial, but it's certainly something we need to start looking at.

Smith: That is a controversial stance. Let me rephrase the question. Dr Cookson, do you think the debulking effect of radical prostatectomy affects the course of the disease in a patient who has demonstrated metastasis outside the prostate?

Cookson: That's a very difficult question. I don't think we could definitively answer Yes or No without a randomized clinical trial. But, unfortunately, the scenario where a patient has an otherwise removable primary in the face of widely metastatic disease is so infrequent that the clinical scenario rarely presents itself. Therefore, removal of the prostate is currently not advocated in the setting of widely metastatic disease.

Keane: But we're not talking about a patient with widely metastatic disease, we're talking about a young man with poor parameters. You've documented that his disease may be aggressive, and there may be a possibility of disease elsewhere, which would often exclude him from having a radical prostatectomy. The question is whether we should be excluding this group of patients from radical prostatectomy. Widely metastatic disease is a separate issue. I'm concerned about the young man with aggressive disease, stage T3 or maybe early stage T4, and who may have positive nodes. We'd normally send him for radiation therapy plus hormones, and we might consider him for chemo. But we wouldn't advocate radical prostatectomy. Again, we need to investigate this issue further.

Intervention with radiation: Who and when?

Smith: There are many treatment options for these patients. Let's start with radiation. Under most circumstances, when we suggest radiation therapy, we're assuming the disease is still localized to the periprostatic region or the prostate bed. How do you make that determination? What are the indications you use?

Hall: The Johns Hopkins series provided substantial insight on the natural history of biochemical relapse, and specifically in regard to which prostatectomy patients are most likely to develop clinical metastasis.³ The high-risk group includes men who have a persistently detectable PSA following surgery, develop PSA recurrence in the first year after surgery, and/or have a PSA doubling time of less than a year. Poorly differentiated tumors and seminal vesicle invasion also predict development of disease outside the pelvis.

Smith: Would you withhold a recommendation for radiation in a younger man who had seminal vesicle invasion in his primary lesion and whose PSA level became detectable 6 months after surgery?

Hall: That's a very important question. I haven't recommended adjuvant radiation therapy in years because, with PSA testing, there's really no need. However, data on salvage radiation therapy in the pre-PSA era is being replaced by newer experience. A recent pooled analysis examined whether or not these men are appropriate candidates for radiation therapy.⁵ The conclusion was that selected patients who were previously thought to be destined to develop progressive metastatic disease may achieve a durable response to salvage radiotherapy.

In the past, we would not have recommended radiation therapy in men with organ-confined disease if they had factors suggesting distant disease. That might have been a mistake. Some recent data suggest there's a subset of patients—even with a rapid PSA doubling time or seminal vesicle invasion—who have a complete PSA response to treatment. We don't yet have survival data, but we do know that the PSA response is durable, with limited follow-up. This new information has changed the way I think about radiation therapy. I believe that radiation needs to be done early to be effective. The chance of complete response is substantially lower when the PSA level is above 2 ng/mL. The recent combined analysis showed that survival was higher when radiation was done when the PSA was 0.6 ng/mL or less.⁵

Keane: That's where the problem lies. The American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Conference stated that greater than 60 Gy must be delivered, but also that there is no evidence that it affects survival in these patients. All we know is that half of these men will have a PSA of 0 at 5 years. A study showed that there was no survival difference between patients with a rising PSA and those with a PSA that reached a nadir and remained there at 10 years.⁶

I would have difficulty recommending radiation in a patient with high-risk disease and seminal vesicle invasion. A number of studies have shown a survival advantage for a combination of radiation and hormones versus radiation alone.^7-9 Why would you offer radiation alone to somebody whom you've staged surgically and you know has seminal vesicle invasion? There is a high possibility that disease has metastasized to the nodes, probably outside the pelvis, so radiation to the prostate bed isn't going to work.

Smith: Dr Cookson, at what PSA level would you recommend radiation in someone with the proper parameters?

Cookson: I usually wait until functional status returns or at least stabilizes. Potency generally returns around 6 months—but may take as long as 1 year—while return of continence usually occurs much sooner. Once functional status is established and you have confirmed that the PSA level is rising, you want to do it as soon as possible—certainly before the level rises above 2 ng/mL—when outcomes have been shown to be significantly worse.⁵

We all would recommend radiation for patients at high risk for local recurrence with favorable parameters. Traditionally, I would not have recommended radiation for men with Gleason score 8 tumors, but recent multicenter analysis showed that some of these patients would likely benefit, particularly if they had associated positive margins.⁵

Smith: Dr Pruthi, in a patient with a PSA of 0.4 ng/mL, is there any reason to wait for the level to rise higher before recommending radiation (assuming it's a patient for whom you'd be recommending it)?

Pruthi: The potential benefit in waiting, aside from allowing the patient to get back to his functional baseline, is to get a handle on the PSA kinetics before you decide whether to radiate that patient or not. If this is an older patient, with a possibly decreased functional status, whose PSA level is going to rise at a very slow rate, he may be a better candidate for observation—if you could determine early that the PSA level will rise slowly. In a younger patient, however, you want to be more aggressive and consider multimodal therapy, keeping in mind our concerns that the ultra-sensitive assays may be too sensitive. We're learning that if we are going to do salvage radiation therapy, the lower the PSA value, the better.

Side effects of radiation therapy

Smith: Radiation in a postoperative setting can have some adverse effects. Theoretically, it can affect continence, but the potential effect on potency is even more problematic in this group. Dr Cookson, let's say you do a successful nerve-sparing procedure, and the patient has fairly good return of erectile function 9 months or so after surgery, yet his PSA is detectable. Will that influence your decision about radiation?

Cookson: I would probably still recommend radiation—I wouldn't withhold radiation just because a man was potent. I would counsel the patient that radiation definitely could impact his outcome in terms of erectile function, and he would have to take that into consideration before making his treatment decision.

Smith: What would you tell this patient, Dr Pruthi?

Pruthi: From personal experience and discussions with others, we would probably all say that salvage radiation affects potency and possibly continence. However, a recent study revealed that salvage intensity-modulated radiotherapy (IMRT) has less of an impact on erectile function than we might have thought. According to a recent study, men who were potent after surgery remained potent after IMRT.¹⁰ That was a bit of a surprise, because these findings differ from my experience.

Keane: Dr Pruthi is correct—there is very little in the literature that would lead you to say that potency is going to be affected. To be honest, I don't necessarily believe that.

The effect on continence is marginal. A recent review looked at 470 series of salvage radiation and put 47 in a meta-analysis.¹¹ The reviewers could not recommend salvage radiation definitively for any recurrence. They did recommend radiation for patients with stage T3 disease and a positive margin. When looking at side effects, one study suggested a 20% rate of bladder neck contracture, but the the finding was not supported by other articles in the series.

Pruthi: It has been my observation that patients who are on the fence with regard to their potency or voiding function after surgery will be the ones that will do worse.

Keane: That has been my experience as well.

Smith: At least 20% or 30% of patients who undergo radical prostatectomy will develop a detectable PSA level at some point, and therefore these patients have the potential to be considered for radiation treatment. An increasing number of radical prostatectomies are being performed with an intraperitoneal approach, either laparoscopically or with robotic assistance. Will the surgical approach affect eligibility for postoperative radiation, Dr Cookson?

Cookson: If you change from a retropubic to an intraperitoneal approach, there's a chance that some of the small bowel can end up in the pelvis and be in the radiated field, so there is the potential for small bowel-related radiation toxicity. Currently, with an extraperitoneal approach, most bowel-related toxicity is rectal. The risk is only theoretic at this point—I haven't seen any cases. It's too early to know for sure because so few patients have failed following the laparoscopic approach.

Hall: It certainly is a major concern, but there are no data whatsoever regarding that yet.

Androgen deprivation: Triggers and timing

Smith: Let's move on to another option—androgen deprivation therapy. We've mentioned that if one is going to use radiation, then the earlier the better—within certain parameters. Do we have the same sort of time sensitivity with regard to initiation of hormone therapy? Does it make any difference if you start androgen deprivation when the PSA level is 0.8 ng/mL as opposed to 0.22 ng/mL?

Keane: I don't think it does, but I can't be sure. The decision to use androgen deprivation is a difficult one, especially in a setting where there is a rise in the PSA value, but we don't know if there's any metastatic disease. The best data we have is from the Early Prostate Cancer (EPC) program.¹² The findings from the 5-year analysis were unclear, and I think it's going to take another 10 years before we get any conclusive data from that series.

In my mind, the question is what to use if you decide to use it? And are you going to use it continuously or intermittently? This is a difficult decision for patients and they need as much guidance as we can give them. But there isn't a whole lot of information. The literature is fraught with questions. A few studies are ongoing, but they haven't matured. We can tell a patient we can get his PSA down to 0 with hormones if he's prepared to tolerate the side effects.

Smith: The patient often drives the decision when he becomes uncomfortable about a rising PSA level. But let's say you have a patient who's relying totally upon your recommendation. Dr Hall, how long are you comfortable waiting before you tell a patient that something needs to be done?

Hall: The most important issue with regards to biochemical relapse and the timing of hormone therapy is individualization. You've got to make recommendations for each particular patient because each has his own priorities. Ultimately, my goal is to start hormone therapy before a patient develops clinical evidence of disease and metastasis. While there's no absolute number that would trigger therapy, I'd certainly treat a man who has a PSA doubling time of 4 months. If his PSA level rises from 0.4 to 5 ng/mL over 2 years, I know this patient is likely to have clinical metastasis within the next year or two, so I would recommend he start on hormones. However, if he's sexually active and that's important, that consideration would influence the starting point. Certainly a luteinizing hormone-releasing hormone agonist would be problematic and adversely affect his quality of life. If his PSA is low and not rising rapidly, indicating a more protracted clinical course, he might be more appropriately managed with observation.

Smith: We all know that we need to individualize therapy and that many variables enter into that process. But if you were writing a protocol today regarding when to initiate hormonal therapy based upon PSA alone, what value would you use, Dr Pruthi?

Pruthi: We don't know for sure that early hormonal therapy provides a survival advantage, but we do know it has side effects. So, in theory, I prefer to wait until just before patients have clinical evidence of disease, such as a positive bone scan. A study showed that if a hormone-nave patient's PSA value is under 40 ng/mL, there is only a 5% chance that he will have a positive finding on a bone scan.¹³ So I begin to be concerned about a positive result from a bone scan when the PSA level reaches 40 ng/mL. But I also consider the PSA doubling time. If a patient has a rapid doubling time—less than 12 months, certainly less than 6 months—I will not wait until the PSA reaches 40 ng/mL before instituting therapy, because we know he will very shortly develop overt metastatic disease and may come in with a pathologic fracture. Waiting doesn't save patients very much time off hormonal therapy.

Smith: The value of 40 ng/mL seems high to me. I'm not challenging you, I'm just not aware of that data. Would you wait until the PSA level reaches 40 ng/mL, Dr Cookson?

Cookson: I would not wait that long. If I were on a panel trying to devise recommendations for this situation, I would avoid using an absolute number. Instead, I would try to stratify different groups based on risk. In men with a Gleason score of 8, 9, or 10, for example, any detectable PSA level in the early period is probably a sentinel sign of future relapse and later systemic metastasis. So in those patients, my threshold for initiating treatment would be quite low.

This rationale is derived from several sources. A recent study compared early versus delayed hormonal therapy using the Department of Defense Center for Prostate Disease Research observational database and concluded that early therapy delayed the time to presentation of clinical metastases, but only in high-risk patients—those with a Gleason score greater than 7 or a PSA doubling time of 12 months or less.¹⁴ The data from another study is a bit harder to extrapolate to PSA recurrence because that dealt with node-positive patients.¹⁵ But 80% of those patients had an undetectable PSA level when they underwent hormonal therapy and there was a survival advantage. So, if a patient had a high Gleason score, my PSA threshold would be quite low. But if the patient had risk stratification parameters in favor of local recurrence, including a slow doubling time, then I would be much more willing to delay the hormonal therapy.

Smith: You have all appropriately avoided my efforts to pin you down to an absolute PSA number. I think the message is simply that timing of treatment needs to be individualized based upon a number of factors, and there is no single PSA value that fits everyone.

Intermittent androgen therapy

Smith: Dr Keane, do you use intermittent hormonal therapy earlier in this setting?

Keane: I do, but without a shred of evidence that it benefits the patient or his survival. It certainly may be beneficial in terms of reducing the side effects, but there are a few things that worry me. First, the model that it was based on is the Shinogi mouse tumor, which is an endocrine-dependent breast cancer. Second, the patient's testosterone level will hopefully drop to castrate levels and then return to normal when he comes off treatment. The return of a normal testosterone level restores potency, which is one of the biggest benefits of intermittent therapy. But as soon as potency returns, the PSA level is more than likely going to be rising again.

Hall: I only rarely use intermittent therapy. To me, the term intermittent is a misnomer. Let's say you use leuprolide, whether it's combined or as monotherapy, and you give the patient two 4-month injections and then stop. The recovery of testosterone function is highly variable, and it may take some men over a year to recover. But just because you stop giving the injections doesn't mean it's intermittent therapy. The patient's testosterone is still at castrate levels. Patients essentially get their next injection once the testosterone (and PSA) level rises. So until that time, these men are still maintaining a castrate level of testosterone. That time period is a proper dose interval, because 4-month leuprolide will last substantially longer in most men.

Cookson: If you start men with a PSA recurrence on early hormone deprivation therapy, you're looking at perhaps more than a decade of osteoporosis, anemia, and other side effects. But the injections seem efficacious well beyond the duration mentioned in the product insert, so if you monitor testosterone and PSA levels, these patients can be off the drug perhaps 30% to 40% of the time. It's important to remember that we don't yet have data about whether intermittent therapy is equivalent to continued therapy in terms of cancer control.

Pruthi: The rationale behind intermittent therapy is appropriate. The potential benefits include a cost savings, a decreased side-effect profile, and improved health status. Castration may have detrimental effects on bone density, cholesterol levels, fat indices, and even cognition. Correspondingly, time off from androgen deprivation provided by intermittent therapy may help reduce these side effects. Some early research should help answer this question.

Antiandrogen monotherapy

Smith: What about a man who needs androgen deprivation therapy but who expresses concerns about potency preservation? What role does antiandrogen monotherapy play in this patient group, Dr Hall?

Hall: Of the 3 nonsteroidal antiandrogens—bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron), only bicalutamide, 150 mg/d, has been fairly well-studied in comparison to castration. I don't have many patients who can afford this bicalutamide regimen, which costs about $1200 to $1500 a month. That is a huge issue. It's not FDA-approved as monotherapy, either.

Although bicalutamide monotherapy is inferior to castration in terms of survival in the setting of metastatic prostate cancer, at 150 mg/d, bicalutamide may be equivalent to castration in nonmetastatic disease. So in the setting of nonmetastatic disease from a survival standpoint, I think bicalutamide monotherapy is fine and may be associated with quality-of-life advantages.

Pruthi: There is also the concern about potential adverse effects, including higher mortality rates, especially in the absence of proof of a clear survival benefit. This has led to the withdrawal of bicalutamide for this indication, both in Canada and the United Kingdom.

The evolution of chemotherapy

Smith: The role of cytotoxic chemotherapy for prostate cancer has really changed in recent years. It's used much more commonly in patients with established metastatic, hormone-refractory disease. Is there a rationale for incorporating it even earlier, in men with a rising PSA level, either prior to or in conjunction with hormonal therapy? While there are protocols evaluating this, what would you tell the patient in your office today about incorporating chemotherapy early in the course of their treatment?

Hall: Again, for many cancers, the standard of care is adjuvant therapy. However, the chemotherapy that is used as adjuvant therapy, including that for breast cancer, is not curative in the setting of metastatic disease. As reported at this year's ASCO meeting, taxane-based regimens are showing a survival benefit for the first time in hormone-refractory cancer. That is going to be a huge stimulus to move chemotherapy earlier in the disease course. But I don't think there's a role for it in current clinical practice, either in the adjuvant setting or in cases of PSA relapse. I don't think it is standard of care to use chemotherapy in those settings.

Smith: A young patient of yours with a rising PSA and an aggressive tumor says he wants to do everything he can and he wants to do it early. What would you tell him about chemotherapy?

Pruthi: We need to study this approach in a trial setting because that's the only way we're going to get real answers. When we get to the next step as far as chemotherapy is concerned—better agents with less toxicity—it may be appropriate to use it earlier or off protocol. But as it stands now, I'd encourage a patient with a PSA recurrence, instead, to join an in-house COX-2 inhibitor trial. It's a relatively innocuous therapy, which makes the decision-making easier. Other similar trials, which employ less toxic oral agents, are likewise recommended—especially for the low-risk patient. Clearly, for high-risk patients, we are headed in the direction of using multimodal therapy.

Smith: Dr Keane, outside of a clinical protocol, do you believe chemotherapy should be used in a patient with a detectable or rising PSA value after radical prostatectomy who has not yet received hormonal therapy?

Keane: At the present, I would have to say No because there are not enough data to support it. As Dr Pruthi mentioned, we need to rethink how we treat prostate cancer. To me, multimodal therapy seems to be the key to beating this disease. I hope that someday soon, we'll be able to give patients a 4- or 6-cycle course of a taxane or some other chemotherapy.

Dr Cookson discloses that he is a consultant/advisor for Aventis and Sanofi, and has participated in scientific studies and trials for Bayer, Cytogen, and PhotoCure ASA.

Dr Keane discloses that he is on the speakers' bureaus of AstraZenica, Aventis, and Novartis.

Dr Pruthi has received a research grant from Pfizer.

Drs Smith and Hall disclose that they have no financial relationship with any manufacturer in this area of medicine.

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