Edited comments by Anthony L Zietman, MD, MRCP, FRCR

Androgen deprivation combined with brachytherapy and external beam radiation therapy

Androgen deprivation is commonly utilized prior to brachytherapy to reduce the size of a large prostate. The Seattle group has retrospectively evaluated all of their patients treated with or without androgen deprivation and found no advantage to androgen deprivation prior to brachytherapy in patients with a favorable prognosis. In addition, for patients with an intermediate prognosis, the data suggests it may be disadvantageous, which is worrisome.

I have two concerns with Richard Stock's nonrandomized series looking at brachytherapy, external beam and androgen deprivation. First, the follow-up is relatively short, and since the effects of hormone therapy can last for months or years beyond treatment, one would expect the early data to look good. Longer-term data is necessary. Second, we know that androgen deprivation given prior to external beam therapy appears to work synergistically with radiation to enhance tumor control. However, the cell kill from low-dose rate brachytherapy is different and hasn't been well-characterized. If that cell kill is more cell-cycle dependent, which is possible, then taking cells out of cycle with androgen deprivation may actually increase resistance.

High-dose external beam radiation therapy

It is increasingly clear that eradication of cancer from the prostate requires high doses of radiation. In retrospect, the doses we routinely used well into the 1990s were inadequate and substantially inferior to radical prostatectomy. Cleveland Clinic's database evaluating patients treated with doses less than or greater than 72 Gray shows a significant divergence in outcome at eight years. MD Anderson's data suggest control for patients with intermediate prognosis is improved by high-dose radiation 78 Gray. Four other randomized trials are underway and I suspect they, too, will be positive for high-dose therapy.

My concern with ultra-high doses of radiation is the morbidity. We need a prospective study to examine doses of 80 Gray or higher. Although our delivery is more conformal and we treat less of the rectum and bladder than before, we can't avoid radiating the prostatic urethra, and I'm concerned about late urethral morbidity. At Massachusetts General Hospital we have 42 long-term survivors who were treated with doses of 77 Gray proton beam radiation in the 1980s. With a median follow-up of 13 years, approximately 50 percent have experienced an episode of hematuria. On cytoscopy, we usually find telangiectasia at the bladder neck and, in some cases, prostatic urethral restrictures requiring transurethral resection, which increases the patient’s risk for incontinence.

Radiation therapy plus androgen deprivation

The Radiation Therapy Oncology Group’s two-by-two study design (RTOG- 9413) evaluating radiation to the prostate alone versus radiation to the prostate and regional lymph nodes, with adjuvant therapy given for two months before and two months during radiation versus four months after radiation in patients with locally advanced prostate cancer. It demonstrated an advantage to whole pelvis radiation and neoadjuvant therapy, but only when the two were combined (Figure 2.1).

In RTOG-8531, patients with relatively poor prognosis locally advanced prostate cancer were randomly assigned to radiation therapy alone or radiation therapy plus total androgen blockade until relapse. A survival advantage was seen with hormonal therapy in patients with higher-grade tumors. In RTOG-9202, comparing radiation plus short-term versus long-term androgen deprivation, long-term therapy was advantageous in survival and disease-free survival, but only for those with centrally reviewed Gleason grades 8 through 10.

Patients with a favorable prognosis are generally treated with high-dose external beam radiation alone. For patients with an intermediate prognosis, we combine radiation with short-term neoadjuvant androgen deprivation. In patients with a poor prognosis, particularly those with Gleason grades 8 through 10, we continue androgen deprivation for two or three years based on the European study.

RTOG clinical trials of androgen deprivation

Data from Canada suggest it takes up to eight months to achieve maximal tumor response from androgen deprivation. RTOG has a trial in patients with an intermediate prognosis comparing four versus eight months of adjuvant androgen deprivation. In both arms, the last two months of therapy are concurrent with radiation, and the remainder is administered before radiation. The trial has accrued over a thousand patients, but it will be several years before we have results.

RTOG also conducted a trial for patients with rising PSAs after prostatectomy. The majority of patients also had positive surgical margins. Patients were randomly assigned to salvage radiation with or without high-dose bicalutamide — 150 milligrams — for two years. The trial is complete, and the first analysis is expected in a couple of years.

We know that in the short term, high-dose bicalutamide will favorably impact time-to-first-progression, but we don't know what its impact will be on survival and metastases. This trial will determine the efficacy of salvage radiation monotherapy, which I expect will only cure one-third of these patients.

LHRH agonist versus high-dose bicalutamide in patients who relapse

Matthew Smith has completed a study of bone and other effects in a trial that randomly assigned patients who relapsed after radiation or surgery to an LHRH agonist versus high-dose bicalutamide. The study included bone mineral density, body mass index, muscle mass and quality-of-life evaluations.

The data show approximately a five to seven percent bone loss with the LHRH agonist versus a one or two percent bone gain with high-dose bicalutamide during the first year of treatment. While all the patients gained fat and lost muscle, the patients on bicalutamide fared a little better. In addition, high-dose bicalutamide appeared preferable with regard to libido, general well-being and fatigue.

I use high-dose bicalutamide in patients who have failed a neoadjuvant LHRH agonist and external beam radiation, and who make it clear they do not want to experience the LHRH agonist again. Patients are happier with high-dose bicalu-tamide, and I precede it with prophylactic breast irradiation. In Smith's trial, all of the patients receiving bicalutamide developed gynecomastia.

In a Scandinavian study in which one of the randomizations was flutamide, investigators were able to reduce gynecomastia from approximately 75 percent to 25 percent by prophylactic breast irradiation. I find it reduces breast swelling, but not necessarily breast discomfort. Also, men on either LHRH agonists or high-dose bicalutamide often accumulate fat in the breast area that looks like gynecomastia, but it's fat, not breast tissue. Only weight loss will ameliorate that problem.

New techniques in the delivery of radiation

High-dose rate brachytherapy is expanding rapidly in community practices, even though we have more evidence supporting low-dose rate brachytherapy. With this newer form of brachytherapy, a temporary device is placed in the prostate, radiation is delivered and then the device is withdrawn. The process is repeated two or three times and is usually combined with external beam radiation.

It’s expensive and inconvenient, but it has the potential advantage that the radioactive source is not left in the patient — although I don’t believe there’s much risk in that. It also allows one to adjust the strength of radiation at any point and provide a relatively smooth and tight distribution of radiation to the prostate. This has aesthetic appeal, but whether it is of clinical value still needs to be determined.

Hypofractionation, which involves decreasing the number of radiation treatments while simultaneously increasing the size of the daily dose, is another potential option. Biologic evidence indicates that prostate cancer is a unique cancer and it may be advantageous to deliver larger doses over a shorter period of time. It would certainly be more convenient for patients. RTOG and the Royal Marsden Hospital are each conducting a randomized trial comparing conventional fractionation in external beam radiation with these abbreviated courses.

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Dr Zietman is a Professor of Radiation Oncology at Harvard Medical School's Massachusetts Hospital in Boston, Massachusetts.