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Prostate Cancer Update 2005 (3)

DR ANTHONY L ZIETMAN: Two randomized trials have compared high-dose to conventional-dose external beam radiation therapy. The MD Anderson trial evaluated approximately 300 patients.

For the patients with a PSA > 10 ng/mL, a clear advantage appeared in terms of freedom from biochemical or disease failure at five years with high-dose radiation (78 Gray) compared to conventional-dose radiation (70 Gray). They didn’t see an advantage for high-dose radiation in patients with a PSA ≤ 10 ng/mL.

The second randomized trial — the Massachusetts General Hospital/Loma Linda University trial — compared high-dose (79 Gray) to conventional-dose (70 Gray) radiation in men who mainly had low-risk disease. Of the 393 patients randomly assigned, approximately 250 had low-risk disease. The number of biochemical failure events at five years was halved for the patients with low-risk and intermediate-risk disease who were treated with high-dose radiation therapy.

Prostate Cancer Update 2005 (2)

DR ANTHONY V D’AMICO: The validation that the combination of hormonal therapy and external beam radiation therapy provides a survival benefit compared to radiation therapy alone is an important clinical message.

A number of randomized studies have evaluated this question, particularly in men with localized, high-risk disease. “High risk” in this scenario is defined as a Gleason score of 7 or higher or a PSA level greater than 10 ng/mL.

A study published in JAMA in August 2004 demonstrated a 10 percent survival benefit at five years for men who received six months of hormonal therapy in combination with radiation therapy compared to men who received radiation therapy alone.

Hormonal therapy consisted of flutamide with either leuprolide or goserelin. Two questions remain in this scenario: (1) Is combined hormonal blockade necessary? and (2) Are six months of hormonal therapy adequate for patients with Gleason 8, 9 or 10 disease, even if it is T1c or T2?

The studies preceding the trial published in JAMA were RTOG-9202 and the Bolla trial. The Bolla trial — an EORTC study — found that three years of hormonal therapy is better than no hormonal therapy.

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RTOG-9202 found that two years and four months was better than just four months of hormonal therapy. It was not an overall survival benefit but a cancer-specific survival benefit of 3.4 percent at five years.

The question remains whether long-term hormonal therapy is necessary and safe. A European randomized study comparing three years to six months of hormonal therapy should answer the question more definitively.

If long-term hormonal therapy truly is better, I suspect that older men (over 70 years of age), in whom occult cardiovascular disease can be prevalent, will benefit least, whereas younger men who don’t have cardiovascular issues may benefit most.

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Interview, October 2006

DR SUSAN F SLOVIN: In a patient with a Gleason 8, 9 or 10 tumor, I use neoadjuvant hormones and radiation therapy, followed by hormones. If the Gleason score is 6 or less, I can get away with radiation therapy or IMRT.

Depending on what the patient wants, I’m a strong advocate of either surgery or radiation therapy. For most patients younger than age 70 who have an excellent performance status and no comorbidities, we recommend surgery because we know that they have a greater than 10-year survival and they seem to do well.

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I have used radiation therapy for patients with clinically localized disease but big, bulky prostates. Also, for patients who have disease that appears to be extending outside the capsule on MRI, I will still use radiation therapy and hormonal therapy.

The duration of hormone therapy varies. In the beginning, I use it for three to six months, depending on the size of the gland. If the gland is less than 30 cc, I might use it for two months.

It’s usually the radiation oncologist who makes the final decision as to how long to use the hormonal therapy in the neoadjuvant setting, a lot of it depending on the size of the gland. If it’s a huge gland filled with tumor or BPH, he or she may want to shrink it considerably before starting radiation therapy.

For patients with high-risk tumors, such as Gleason 8, 9 or 10, I usually continue hormonal therapy anywhere from one to two years.

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Recently, I’ve been using it for only about a year after radiation therapy because some men are concerned that their potency will not return or their testosterone will be at castrate levels permanently. It’s on a patient-by-patient basis. For patients who are more anxious, I take them off sooner, whereas for a younger man with more aggressive disease, I might go the whole two years.

I generally use bicalutamide, although a lot of my radiation colleagues are stopping the bicalutamide during the radiation therapy, leaving them off subsequently and just keeping them on a GnRH analog. I happen to like the combined blockade approach. That’s the way I was raised.

I know meta-analyses suggest combined blockade is not beneficial, yet Paul Schellhammer and several others have data that suggest a benefit with this approach.

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Prostate Cancer Update 2006 (1)

DR GREGORY S MERRICK: In our program, high-risk disease is defined as two or three adverse prognostic factors: a clinical stage greater than or equal to T2c, a PSA greater than 10 ng/mL and a Gleason score greater than or equal to 7.

In our series, all of those patients receive pelvic radiation therapy along with a palladium boost. A high percentage of those men have also received androgen deprivation therapy.

Retrospectively, we have been able to show that the men who receive androgen deprivation therapy have a statistically significant improvement in eight-year biochemical progression-free survival of approximately eight percent.

We’re strong proponents of total androgen suppression. For all of my patients, I use total androgen suppression for four months. If the PSA is undetectable at that time, we continue the LHRH alone for the remainder of the treatment.

In the community, what we often see is an LHRH agonist with a short course of an antiandrogen to block the flare. I have not been a proponent of that approach.

If you consider the RTOG studies, especially the studies that Mack Roach has conducted, they’ve all used total androgen suppression. It seems that total androgen blockade is not used in the community as much as it’s used in academia.

Prostate Cancer Update 2006 (1)

DR RICHARD G STOCK: Some of the most important findings in radiation therapy in general have been the results of the prospective randomized studies that evaluate the use of hormonal therapy combined with external beam radiation therapy.

Two of the most important published trials are the RTOG-9202 study and the EORTC-22863 study, both of which evaluated long-term hormonal therapy for patients at high risk.

The RTOG trials, and in particular the RTOG-9202 trial that examined the use of two years of hormonal therapy with external beam radiation therapy, have shown the best biochemical control rates for high-risk disease.

These trials indicate that we may be able to treat high-risk microscopic metastatic disease in many patients with long-term hormonal therapy, so I’m excited by the data.

In an effort to extrapolate some of the positive outcomes of these trials from our own data, my colleagues and I are examining our data set of patients with particularly high-risk disease treated with combination therapy and trying to analyze the outcomes for those treated with longer-term hormonal therapy.

Prostate Cancer Update — Think Tank Issue 1, 2006

DR LAURENCE KLOTZ: The data are not clear as to the optimal duration of hormonal therapy with radiation therapy. In my practice, I use six months to three years of therapy, and I titrate it according to the patient’s risk and the degree to which the patient tolerates hormonal therapy.

I believe six months of hormonal therapy is a bare minimum with these patients. In the face of the D’Amico study, the disease-free survival rate improvement was the same with six months of therapy as in other studies of two years in an intermediate-risk cohort.

I’m not aware of any comparison of six months to longer durations in patients at higher risk, but the argument to go beyond six months is not so compelling that I would do so in a patient who is experiencing difficulty with the therapy.

Prostate Cancer Update — Think Tank Issue 1, 2006

DR PAUL F SCHELLHAMMER: I feel strongly that patients with node-positive disease have a high enough risk and the data are strong enough to initiate androgen deprivation therapy. Patients at high risk, in general, are clinical trial candidates.

However, if I have a patient who is not on a clinical trial and whom I’m going to follow with observation, my inclination is to get ultra-sensitive PSAs from the get-go. Then I can determine the rising PSA before it gets to the 0.2 level that we have said is the beginning of failure. To me, that’s the absolute indication to initiate another therapeutic option.

Prostate Cancer Update 2005 (2)

DR LEONARD G GOMELLA: We generally recommend two to three years of adjuvant hormonal therapy when treating patients with locally advanced disease, which is based primarily on the data from recent trials.

Bolla’s EORTC trial showed superior outcomes in patients who received three years of hormonal therapy, and RTOG- 9202 showed two years of hormonal therapy resulted in a survival advantage.

Admittedly, the duration of hormone therapy is controversial. Some institutional studies have suggested as little as six months of hormonal therapy may be beneficial, and that’s possible, but our recommendations rely on the larger multi-institutional trials with thousands of patients.

Although the prospective randomized trials all show this approach is effective, particularly for patients with high-risk disease, it’s not advantageous for all patients. Patients with low-risk disease do not appear to benefit from the combination of hormones and radiation therapy, and the side effects may detract from the patient’s quality of life and overall outcome.

In the RTOG-9202 trial, an overall survival advantage was seen in patients with high Gleason scores. However, in the patients with lower-risk disease, although the combination may enhance PSA control, we don’t see much improvement in survival.

Interview, October 2006

DR MATTHEW R SMITH: The concern is that long-term androgen deprivation therapy increases the risk of fractures from osteoporosis, which is an important consideration for men who receive long-term treatment and have a good prognosis.

For patients who are going to receive long-term neoadjuvant or adjuvant treatment and the expectation is that they’ll be alive for a long time, I usually obtain a baseline bone density scan. I advise them about this issue, and I recommend supplemental calcium and vitamin D. I intervene with additional medications for men who have a particularly high risk of fracture or those who develop osteoporosis as revealed by DEXA scan.

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Interview, October 2006

DR SLOVIN: I believe it’s appropriate for patients with prostate cancer to see a medical oncologist at any stage. I see patients throughout the entire course of their disease.

More frequently now we’re seeing them at the time of their initial consultation, when they are diagnosed with prostate cancer and are having difficulties adjudicating whether to choose surgery or radiation therapy.

Often patients use me not quite as a tiebreaker but as someone who might be more direct or honest with nothing to be gained by selecting which treatment they would choose. They feel radiation doctors recommend radiation therapy and surgeons recommend surgery, but I’m in the middle, trying to help them make the decision that is most appropriate for them.

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Unfortunately, I don’t believe patients in the community have the benefit of seeing a medical oncologist when they are initially diagnosed. Rather, they are immediately shuttled from their primary care doctor to a radiation specialist or urologist.

I don’t think the primary care doctors, sometimes, are even aware of the role a medical oncologist plays in helping to adjudicate a treatment decision. I don’t think it’s deliberate — it’s just a lack of knowledge.

Most of the patients I see are self referred, rather than referred from the urologist or radiation doctor, although it does happen.

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Most of the time the patient has either looked me up on the internet or knows another patient of mine or one of my colleagues who tells him that the best way to deal with the treatment issue is to see a medical oncologist. That’s the norm because patients are confused about what to do.

I believe community physicians may be limited in their resources and may be naïve as to the best way to deal with this issue. Also, some patients are not interested in seeing medical oncologists. They are more interested in starting treatment and not seeing somebody as an intermediary.

In addition, the perception may be that the role of the medical oncologist is to deal with recurrent disease rather than primary therapy.

Interview, November 2006

DR MARIO A EISENBERGER: Hormonal therapy and chemotherapy are effective for treating prostate cancer, but we don’t know whether adjuvant treatment is effective, and that’s what the adjuvant trials are evaluating.

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One major study evaluates mitoxantrone and another docetaxel. Docetaxel is the standard treatment in the metastatic setting, and mitoxantrone also doesn’t improve survival, so I prefer docetaxel.

I’m the chairman for the docetaxel study, and our target accrual is nearly 1,700 patients. It’s a worldwide study.

We’re hopeful that once everyone is on board, we can finish this in two years. The primary endpoint is progression-free survival.

Interview, October 2006

DR ROBERT DREICER: I believe the international adjuvant study comparing leuprolide with or without docetaxel in patients with high-risk disease after radical prostatectomy is one of the most important trials in prostate cancer that will be conducted in the next 10 years. This study tests whether early versus later, either androgen deprivation therapy or that with chemotherapy, affects the time to disease recurrence.

The trial is open and the target accrual is 1,600 patients, so realistically it will probably be five or six years before we have data from that trial.

The treatment of prostate cancer is an evolving process. It’s a manifestation of a more educated patient population and clinicians receiving information from places they trust telling them that this is the way patient management needs to evolve.

Attendees at GU oncology meetings held in the community over the past year, which are generally urologists in a three-to-one ratio over medical oncologists, are hearing from academic urology and academic GU medical oncology groups about interdisciplinary management and the role of early systemic therapy.

I believe that over time that affects their thought process, and if you have a major eight-man urology group in the community and one or two of their major players buy into these concepts, that drives what that group does.

We have both the international trial and the adjuvant SWOG trial open at my institution. The eligibility criteria are not identical, and most of the patients we see are eligible for one or the other. We think both of these trials are important, so I offer whatever trial is most appropriate for that individual.

To date, we have enrolled approximately 25 patients on the SWOG trial. The other trial just opened at our institution, so we don’t have anyone on that yet.

We have a large neoadjuvant investigational program, so many of our patients receive chemotherapy on a protocol preoperatively, making them ineligible for the adjuvant trials. When these trials ebb, we will enroll more patients on the adjuvant studies.

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