Patient Selection for Prostate Brachytherapy: More Myth Than Fact: Review 2

Drs. Merrick, Wallner, and Butler have compiled information regarding patient selection for prostate brachytherapy[1] and conclude that, "While there is no shortage of opinions regarding symptoms or circumstances that render the use of brachytherapy inadvisable, most are baseless." They go on to say that, "Reports to date have failed to establish any firm contraindication." I am impressed with the certainty such a statement projects for a disease as heterogeneous as prostate cancer.

Is Prostate Brachy-monotherapy for Everyone?
In the subsection entitled, "Adverse Pathologic Features," the authors state that, "an aggressive locoregional approach that includes generous periprostatic brachytherapy treatment margins and/or the addition of supplemental external-beam therapy can result in a high likelihood of cancer eradication." This theory is supported by some evidence from surgical series[2,3] in which the radial extent of extraprostatic extension was found to be within 5 mm of the prostatic capsule in the vast majority (90%) but not all cases. I believe that the theory regarding maximizing local control is true when combining external-beam radiation therapy (EBRT) and brachytherapy. In fact, this type of combination therapy is a commonly used technique in radiation oncology that has also been applied to certain gynecologic malignancies.[4]

However, evidence from centers experienced in prostate brachytherapy[5,6] clearly defines who is at high risk for prostate-specific antigen (PSA) progression despite generous periprostatic brachytherapy, with or without supplemental EBRT. Specifically, in men whose pretherapy PSA exceeded 20 ng/mL or who had biopsy Gleason scores of 8 to 10 or bilateral palpable disease (clinical category T2c), PSA control rates of only 45% to 57% at 8 to 10 years after prostate brachytherapy were noted despite supplemental EBRT. Clearly, many of these men are in need of more than aggressive local therapy to optimize cancer control.

What then becomes of the authors' conclusion that, "Reports to date have failed to establish any firm contraindication"? This statement needs to be tempered along the following lines: In select patients in whom localized disease alone is likely, the use of aggressive local therapy may afford a high likelihood of cancer control.

Is PSA Failure the Correct End Point?
One could argue that not all PSA failure translates into prostate cancer- specific mortality and that the rate of rising PSA after local therapy (ie, PSA doubling time) is a much more important predictor of this outcome.[7] As recently reported by the Patterns of Care Study of Radiotherapy in the United States,[8] patients treated with prostate brachytherapy are younger than those managed with EBRT. The difference in age provides more time for PSA failure to translate into distant recurrence and death among brachytherapy-treated men.

Management of High-Risk Prostate Cancer
Randomized trials[9,10] have evaluated the impact of adding long-term androgen-suppression therapy (AST) to EBRT, as compared to adding no AST or short-term AST to EBRT. These studies include a European Organization for Research and Treatment of Cancer (EORTC) trial (3 years of AST vs none) and the Radiation Therapy Oncology Group (RTOG) 9202 trial (2 years and 4 months of AST vs 4 months of AST). Patients enrolled in these studies generally had clinical category T3 or T4 disease, meaning they had palpable evidence of extraprostatic extension on digital rectal examination. However, a minority (9%) in the EORTC study had highrisk disease (clinically localized but high grade).[9] Both studies showed a cancer-specific survival benefit; the EORTC study also demonstrated an overall survival benefit for men who received long-term AST in addition to EBRT.

Two additional randomized studies have been completed for patients with clinically localized disease (clinical category T1c-T2) and are in follow- up. In these studies, patients were randomized to EBRT with or without 4 months (RTOG 9408) or 6 months (Dana-Farber Cancer Institute [DFCI] 95096) of AST. Patient selection for the DFCI study was generally limited to patients whose pretreatment PSA was > 10 ng/mL but less than 40 ng/mL or who had a biopsy Gleason score of 7 or higher. Patient selection for the RTOG study was limited to patients with a PSA < 20 ng/mL and any biopsy Gleason score. The results of these studies will establish the utility of short-term AST for patients with clinically localized prostate cancer.

To date, no published randomized studies have evaluated the impact of AST on patients managed with prostate brachytherapy, and the results of the retrospective studies are conflicting- some suggest a benefit in highrisk patients,[11] whereas others do not.[6] Therefore, we will need to await the results of randomized studies to adequately address this question.

A Word of Caution
In conclusion, while carefully designed and delivered prostate brachytherapy may successfully sterilize local disease within and perhaps juxtaposed to the prostatic capsule, careful attention to the known pretreatment predictors of outcome should be heeded in order to avoid a 50% PSA recurrence rate in high-risk patients. This large PSA recurrence rate likely reflects the occult micrometastatic disease that is present at diagnosis and left unaddressed by the initial aggressive local therapy. Therefore, an aggressive local therapy- only approach to high-risk prostate cancer could lead to distant recurrence and, ultimately, the patient's death. While we await the results of randomized trials, perhaps the addition of AST to radiation therapy should also be considered in such patients. I believe the high PSA recurrence rates in high-risk patients from the published literature provide a valuable lesson.[5,6,9,10]

References:

1. Merrick GS, Wallner KE, Butler WM: Patient selection for prostate brachytherapy: More myth than fact. Oncology 18:000-000, 2004.
2. Sohayda C, Kupelian PA, Levin HS, et al: Extent of extracapsular extension in localized prostate cancer. Urology 55:382-386, 2000.
3. Davis BJ, Pisansky TM, Wilson TM, et al: The radial distance of extraprostatic extension of prostate carcinoma: Implications for prostate brachytherapy. Cancer 85:2630-2637, 1999.
4. Eifel PJ, Moughan J, Erickson B, et al: Patterns of radiotherapy practice for patients with carcinoma of the cervix (1996-1999): A patterns of care study. Int J Radiat Oncol Biol Phys 57(2 suppl):S190, 2003.
5. Sylvester JE, Blasko JC, Grimm PD, et al: Ten-year biochemical relapse-free survival after external beam radiation and brachytherapy for localized prostate cancer; the Seattle experience. Int J Radiat Oncol Biol Phys 57:944- 952, 2003.
6. Kollmeier MA, Stock RG, Stone N: Biochemical outcomes after prostate brachytherapy with 5-year minimum follow-up: Importance of patient selection and implant quality. Int J Radiat Oncol Biol Phys 57:645-653, 2003.
7. D’Amico AV, Moul J, Carroll P, et al: Surrogate marker for prostate cancer specific mortality following radical prostatectomy or radiation therapy. J Natl Cancer Inst 95:1376- 1383, 2003.
8. Lee WR, Moughan J, Owen JB, et al: The 1999 patterns of care study of radiotherapy in localized prostate carcinoma: A comprehensive survey of prostate brachytherapy in the United States. Cancer 98:1987-1994, 2003.
9. Bolla M, Collette L, Blank L, et al: Longterm results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomized trial. Lancet 360:103-106, 2002.
10. Hanks GE, Pajak TF, Porter A, et al: Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group protocol 92-02. J Clin Oncol 21:3972-3978, 2003.
11. Merrick GS, Butler WM, Galbreath RW, et al: Does hormonal manipulation in conjunction with permanent interstitial brachytherapy, with or without supplemental external beam irradiation, improve biochemical outcome for men with intermediate or high-risk prostate cancer? BJU Int 91:23-29, 2003.