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Prostate Cancer Update 2006 (3)

DR STEPHEN J FREEDLAND: We conducted a study with Alan Partin and Patrick Walsh that observed patients who underwent radical prostatectomy at Johns Hopkins and experienced PSA failure.

Of those men, we identified a cohort of 379 who had clean doubling times, and we knew their long-term outcomes. The mean follow-up after surgery was 10 years — in some men, it was out to 15 to 20 years after surgery.

We evaluated which parameters within the first year or two were the best predictors at the time of recurrence — doubling time, how quickly the PSA became detectable to the 0.2 ng/mL level, the Gleason score and several other factors.

The doubling time was the key driving factor and by far the strongest predictor. But we also found other factors that were important: how quickly the PSA became detectable, the time to PSA recurrence (three years or less versus greater than three years) and the Gleason score.

For doubling time, the hazard ratio of 0.86 indicates that a one-month change in doubling time reduces the risk of death by 14 percent. Absolutely capturing the real doubling time involves a lot of logistical issues and difficulties such that, at the end of the day, we wanted to regard it as a categorical variable. So we considered various cut points and eventually identified four categories.

A doubling time of greater than 15 months presented the lowest risk, and a doubling time of less than three months presented a risk of dying from prostate cancer 27 times higher — these patients are at extremely high risk. With a PSA doubling time of three to nine months, patients are nine times more likely to die, and even with a PSA doubling time of nine to 15 months, patients are also at increased risk.

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What we’ve shown is that men with rapid doubling times, high Gleason scores and early recurrence are at increased risk of prostate cancer death. We’ve generated tables that can predict that. Men who experience late recurrence generally have excellent survival, and time to recurrence, in the absence of knowing the doubling time, is an important prognostic feature.

Prostate Cancer Update 2006 (2)

DR JUDD W MOUL: PSA recurrence or PSA progression continues to be a controversial topic. From a clinical standpoint, for the average urologist in the trenches, the $64,000 question is about the patient who has a rising PSA level after surgery or radiation therapy. When do you “pull the trigger” on hormones?

The answer remains controversial. Our data from 2004 indicated that you certainly couldn’t be criticized for starting hormonal therapy early for men at high risk, such as those with a rapid PSA doubling time or those with higher Gleason scores, because they’re not going to do well with watchful waiting.

More recently, Steve Freedland, who recently joined us at Duke, published a nice paper in JAMA in which he examined the Johns Hopkins data set. It was actually a follow-up to the Pound paper. The bottom line was that Steve created a nomogram that showed 10-year mortality after PSA recurrence.

In other words, he evaluated patients who had a biochemical recurrence after surgery and then asked what the chances were of dying from prostate cancer 10 years later. He found that PSA doubling time, Gleason score and time of PSA recurrence (ie, earlier versus later than three years after the surgery) were good predictors of death from prostate cancer.

The good news is that we can predict who will die of prostate cancer. The bad news is that we’re still not sure if we can alter the natural history if we put those patients on hormonal therapy.

Combining the data from Steve Freedland’s paper with those of our paper from the military would suggest that using hormonal therapy for those high-risk PSA recurrences is reasonable, but we need a randomized trial to address the question.

Prostate Cancer Update 2006 (1)

DR MERRICK: I’m relatively conservative in managing PSA recurrences. If we’re going to treat those patients with hormonal therapy, I do not recommend androgen deprivation therapy until the PSA doubling time becomes less than 12 months.

Once the PSA doubling time is less than 12 months, we have to seriously consider androgen deprivation.

The big question then is continuous versus intermittent treatment. I have always been a proponent of intermittent androgen deprivation therapy because of the better quality of life associated with it.

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The way we use intermittent therapy is we leave a patient on androgen deprivation therapy for nine to 12 months. If the PSA becomes undetectable, then we stop the androgen deprivation therapy until we see the PSA exceed some arbitrary PSA cut point, such as 10 or 15 ng/mL.

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Prostate Cancer Update 2005 (2)

DR GOMELLA: The RTOG-9601 trial evaluating radiation therapy with or without bicalutamide 150 mg is a Phase III randomized study in patients with PSA relapse following radical prostatectomy.

The study is closed to accrual, and we are anxiously awaiting the data. This will be one of the most exciting trials to be reported because it will determine whether it’s beneficial to combine hormonal manipulation with radiation therapy in the salvage setting.

RTOG-8531 showed that patients who received radiation therapy and hormones together after radical prostatectomy for unfavorable prostate cancer had a survival advantage over patients who only received radiation therapy.

I believe RTOG-9601 will also be a positive study because we know the effectiveness of bicalutamide 150 mg in the adjuvant setting. Based on the Iverson and See data, it would be a stretch to think the combination would not be more effective than radiation therapy alone.

Bicalutamide 150 mg is approved in over 50 countries around the world. However, it has not received FDA approval in the United States. In Europe, bicalutamide is commonly used as step-up therapy in which patients receive oral agents, such as a 5-alpha reductase inhibitor, with a small dose of bicalutamide. The bicalutamide dose is then increased to 150 mg before the patients are started on an LHRH analog as their definitive therapy.

Currently at our center, the medical oncologists’ standard salvage regimen for patients whose disease is failing standard androgen ablation is bicalutamide 150 mg. We have seen responses to this regimen last for more than a year and a half, so it appears to be reasonable salvage therapy and can be offered to patients. It does appear that a small percentage of men may have an increased cardiac toxicity associated with the drug.

The number of men who had adverse cardiac outcomes and the number of increased death rates in the low-risk arms of the EPC studies with bicalutamide 150 mg were low but noticeable. These findings may have been statistical aberrations or statistical noise. Nonetheless, they need to be further examined.

Although bicalutamide 150 mg is not currently approved for salvage therapy in the United States, I believe it’s appropriate to discuss it with patients for whom it may be suitable, such as those who are sexually active and want to maintain their sexual function.

Bicalutamide can preserve sexual function, whereas a high percentage of men on LHRH analog therapy experience significant sexual dysfunction. Quality of life and determining what’s important to the patient have become central issues when considering treatment alternatives in prostate cancer.

Interview, October 2006

DR SMITH: When using androgen deprivation therapy, I routinely use bicalutamide at the start of therapy because of concerns about the flare. I generally do not continue bicalutamide long term.

Occasionally, I use bicalutamide monotherapy as an alternative to a GnRH agonist, but fairly sparingly. Usually, it’s for a patient who was previously intolerant of a GnRH agonist and requires salvage treatment with hormones. I’ll consider bicalutamide monotherapy in that setting.

In a study we conducted, we found bicalutamide monotherapy spares the bone. It does not cause osteoporosis, and it actually increases bone density, probably by raising estrogen levels. It does adversely affect muscle and fat mass but less severely than a GnRH agonist.

Prostate Cancer Update 2005 (2)

DR ANTHONY V D’AMICO: When you use hormonal therapy for a man in the rising PSA setting, for how long should you administer it? Forever? Intermittently? For a short course? This question is completely unanswered.

A Portuguese study was presented at the AUA in 2005 of intermittent versus continuous therapy for men with rising PSA or node-positive or metastatic disease. While the study only included 800 men, no difference was seen in overall survival between intermittent versus continuous treatment.

I will say that with 800 patients, the trial is likely not large enough to rule out a small benefit from continuous therapy. But this is the first small study of intermittent versus continuous therapy suggesting equality. However, equality in this study is probably limited to a five to seven percent difference.

These trials have to be powered as equivalence studies, which means they need thousands of men. The SWOG study is such a study, but is not yet ready to report. So I don’t think we’re ready to say intermittent and continuous therapy are equivalent yet. But it is a big issue, because lifelong hormonal therapy in the rising PSA setting is not without consequence.

Prostate Cancer Update 2006 (1)

DR MARK S SOLOWAY: In treating patients with a postprostatectomy rise in PSA, a trend toward earlier androgen deprivation has emerged. I believe this has been impacted by the Messing study of immediate postprostatectomy hormonal therapy in patients with positive lymph nodes. Although it was a small study, it cannot be totally discounted. I believe a benefit exists with earlier, rather than later, androgen deprivation.

In the PSA screening study in Tyrol, Austria, which provided diagnoses and initiated treatment, a reduction in prostate cancer mortality was seen within just a short number of years, so I believe the impact of hormone therapy did play a part.

When we initiate androgen deprivation, one big issue is whether to administer it continuously or to provide the patient with the opportunity for intermittent therapy. I believe intermittent therapy is a reasonable approach.

I tell patients that we have yet to see randomized trial data indicating the two regimens are equivalent and that the standard has always been continuous androgen deprivation.

But my own bias, depending on the patient’s age, tolerance of the androgen deprivation and how long he’s been on therapy, is that it is reasonable to stop it at some point and monitor the PSA.

In the setting of rising PSA, in which patients will be on androgen deprivation for many years, I’m unconvinced that the benefit is substantial enough to add bicalutamide. I use initial combined therapy for one month and then only the LHRH analog.

If I had a patient with a rising PSA who was interested in maximal androgen blockade (MAB), I would indicate to him that I do believe this approach provides a slight benefit.

I am convinced by the studies, and I would follow the data. I believe Laurence Klotz has best put that information together. I would counsel a patient that MAB therapy offers some small benefit, and if he accepts the additional expense, it is reasonable to administer it.

Prostate Cancer Update 2006 (2)

DR DANIEL P PETRYLAK: I have a 46- year-old patient who underwent a radical prostatectomy four years ago for lymph node-positive, Gleason 9 disease and received MAB.

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This treatment was clearly supported by the Messing study, in which early hormone therapy was better than delayed hormone therapy. It came at the cost of losing his sexual function, but he wanted to live and he wanted to see his son grow up. He tolerated it well, with minimal hot flashes, and he gained only five pounds over the last couple of years.

When you look at the meta-analysis, you see a small — approximately four percent — but detectable difference in survival in favor of combined blockade. Other therapeutic interventions have been used for similar benefit, and I believe it’s appropriate.

Then, approximately nine months ago, his PSA level started to rise. We withdrew bicalutamide and started him on ketoconazole and cortisone, and he had a short response that lasted four or five months. Now his PSA level is rising again. In fact, it rapidly rose from about six or seven to 50 ng/mL in a four-week period and then to 70 ng/mL after another two weeks.

Based on this rapid PSA doubling, I was not comfortable with just watching and waiting until he developed metastatic disease. So I started him on docetaxel 75 mg/m² every three weeks as a single agent. He has just completed his second cycle, so it’s too early to tell how well he will respond, but he is tolerating it well.

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Interview, October 2006

DR SMITH: I believe once men have failed hormone therapy, they should be referred to a medical oncologist. I consider a rising PSA to be failure of hormone therapy. We’ve only recently seen therapy that improves survival in that setting.

Until docetaxel, a urologist could quite reasonably have said, “You don’t have anything to offer.” The challenge has been that, as a group, medical oncologists need to demonstrate that we have enough to offer these patients to make it sensible for the urologists to refer them.

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Prostate Cancer Update 2005 (1)

DR ADAM P DICKER: I usually refer patients with PSA relapse and no evidence of skeletal disease to medical oncologists who specialize in prostate diseases. I also encourage them to enroll in clinical trials that evaluate cytostatic therapy or some of the anti-androgen-type drugs.

I believe most medical oncologists would be uncomfortable using cytotoxic therapy in a patient who does not have a positive bone scan, but we don’t have any evidence that simply reducing PSA in a patient with nonradiographic metastatic disease has an impact.

Prostate Cancer Update 2005 (4)

DR HOWARD SCHER: There are very few situations in which I would use chemotherapy for PSA-only disease. For patients who have a rapid PSA doubling time who’ve had a response to hormonal therapy, the tendency has been to use a second- and third-line hormone therapy first. I’ve seen situations in which the second hormonal response exceeds the first. It doesn’t make sense, but that’s what has happened. I could probably count on one hand the number of times I’ve actually recommended chemotherapy for this group.

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Interview, December 2006

DR PETRYLAK: I agree with the statement: Clinical trials will eventually demonstrate that chemotherapy either alone or with androgen deprivation is effective in reducing the rate of clinical progression for PSA-only disease. We know there is activity. Whether it’s going to have more of a survival benefit when administered earlier, I believe, is the question.

We’re involved in SWOG-S9921, the ATLAS trial with docetaxel, the Dendreon study and the GVAX® study. We also have our own investigator-initiated trials of lenalidomide/docetaxel and docetaxel/bevacizumab/erlotinib. In the docetaxel/bevacizumab/erlotinib trial, we are shutting off two different areas of angiogenesis. The trial will be for patients with hormone-refractory disease. It is a Phase I/II trial with a targeted accrual of 35 patients.

Prostate Cancer Update 2006 (3)

DR FREEDLAND: I believe there are situations with PSA-only disease for which the use of chemotherapy off protocol is reasonable, especially in the hormone-refractory setting. Frankly, at this point we don’t have alternatives. I strongly support clinical trials, and clinical trials exist for men with hormone-refractory PSA recurrence, so a lot of options are available. Most of the trials are built off docetaxel, so it would be docetaxel with X versus X alone and docetaxel with Y versus Y alone. The docetaxel data have changed the face of clinical trials. Historically, the design was always X versus placebo. Now everything has to be compared to docetaxel or combined with docetaxel.

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Interview, October 2006

DR SLOVIN: I use chemotherapy in a variety of settings. One example is for a patient whose PSA is running rampant despite the use of multiple hormonal therapies. Another is the patient who is not thriving — not eating or drinking. The third is a patient with intractable pain, for whom I’m trying to spare the marrow and literally treat him systemically with the intent of slowing down the progression of the disease and affecting the pain.

For a patient who has failed primary hormonal therapy and his PSA doubling time is less than six months, or even less than three months, and I can’t control it with second-line hormone therapy, I’ll use chemotherapy.

If I was diagnosed with prostate cancer that recurred after local therapy, I would be willing to receive chemotherapy, with certain caveats. If I found the disease was rapidly progressing, if I had a Gleason 10 tumor or if the disease popped up in the bone and I knew my disease would be rampant, I would be in favor of receiving chemotherapy.

Prostate Cancer Update 2006 (1)

DR ANNA C FERRARI: Although the docetaxel trials established the advantage of chemotherapy in men with definite metastatic disease, previous experience with other tumors tells us that an active combination of agents against androgen-independent cells is most likely to be effective earlier rather than later.

Prostate cancer is a heterogeneous disease. We will probably eliminate the tumor cells that are more sensitive early on, and cells that emerge subsequently or that survive this initial attack may be less sensitive to treatment.

All of the time that we gain is valuable, but I don’t necessarily wait for the development of metastases. If the patient failed second- or third-line hormonal therapy and his PSA continued to rise, I believe it would be time to initiate chemotherapy, even if he might be asymptomatic, because you know where he’s heading. Once symptomatic metastatic prostate cancer is in place, it’s much harder to achieve control of symptoms and complications from the metastases.

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