BRACHYTHERAPY FOR PROSTATE CANCER

Introduction
The optimal therapy for localized prostate cancer remains controversial. While survival data following external beam irradiation appears acceptable, many urologists remain skeptical based on post treatment PSA results. Radical prostatectomy may be the gold standard but patient perceptions regarding morbidity may be greater than previously appreciated¹.

Despite the advances made in both surgical and external beam irradiation technique, demand continues for treatment alternatives. There has been renewed interest in brachytherapy and PSA data is just beginning to mature. At this year’s American Urological meeting, no less than three brachytherapy abstracts claimed results comparable to surgery^2,3,4.

Definition
Brachytherapy is a form of radiation in which radioactive materials are placed in intimate proximity to a malignancy. Because of the short range, high doses can be delivered to a cancer with relative sparing of the surrounding normal tissue. Commercially, available radioactive seeds include Iodine-125 (half life = 60 days), Palladium - 103 (17 days), Gold (2.6 days), and Iridium (74.2 days). All are implanted permanently with the exception of Iridium, which much be removed after several days.

Historical Perspective
The modern era of brachytherapy for prostate cancer began in 1972. The initial technique described by Whitmore included a bilateral pelvic lymph node dissection and I-125 seed implantation via a retropubic approach⁵. Poor technique resulted in non-homogeneous implants, and results were inferior to those reported for XRT and surgery.

Selected patients, however, appeared to benefit from even this early form of brachytherapy. Hilaris reported a 70% survival rate at 15 years for men with B1 cancers⁶. In addition, the local control rate was 60% for men treated with over 140 Gy vs. 20% if less than 140 Gy was delivered⁷. Critical factors for success, therefore, appeared to be accurate source placement, adequate dosage, and appropriate case selection⁸.

In 1983, Holm described a less invasive and more accurate brachytherapy technique using transrectal ultrasound and a transperineal approach⁹. In the late 1980’s, Ragde and Blasko refined and popularized this technique, incorporating sophisticated treatment planning software and CT scans for post-implant imaging¹⁰.

Iverson used a combined approach with an I-125 implant to 160 Gy followed by 47.4 Gy of external beam irradiation to cover potential extracapsular disease. Since the half life of I-125 is 60 days, therapeutic radiation was given simultaneously from two separate sources. This resulted, however, in a severe complication rate of 42%¹¹.

In 1979, Critz reduced the radiation dose from the implant (40-60 Gy) and added external beam irradiation 21 days later. By 1991, this technique evolved into a transperineal approach using I-125 implants at a dose of 120 Gy followed by 45 to 50 Gy of XRT. Initial reports of serious complications were lower than reported by Iverson¹². Performing XRT after, rather than before, implantation was felt to be advantageous as the seeds provided an easily visualized prostate target facilitating a conformal approach to XRT. In addition, there was speculation that simultaneous irradiation might have a synergistic effect on tumor kill¹³.

Modern Experience as Monotherapy
D’Amico and Coleman reviewed the current literature in a paper entitled: "Role of Interstitial Radiotherapy in the Management of Clinically Organ-Confined Prostate Cancer: The Jury is Still Out"¹⁴. They found Disease Free Survival (DFS) rates to be approximately 87% at three years, comparable to early results reported for radical prostatectomy. Follow-up has generally been short, however, and the definition of DFS has been much less rigid than in surgical reports. Table I includes a summary of the largest reported series.

Experience using Transperineal Implants as Monotherapy (T1, T2 cancers)⁸

Author #Men Isotope Median F/U PSA Results (months)
Beyer	480	I-125	35	79% with PSA <4.0 (5 years)
Blasko*	197	I-125	36	93% Progression free (5 years)
Blasko	97	Pd103	37	86% with PSA <1.0 (4 years)
Wallner	62	I-125	19	83% progression free (2 years)
Stock	215	I-125, Pd103	18	65% progression free (2 years)

*Series excluded Gleason Score greater than 7, 38% with pre-treatment PSA less than or equal to 4.0

The above results were achieved for early cancers less likely to extend outside the prostate capsule. Follow-up has been no longer than the median time to recurrence after radiation, previously reported as 36 months¹⁵. In conclusion, D’Amico and Coleman suggested that the ideal candidate for seed implantation as monotherapy is a man with T1c disease, Gleason sum less than or equal to 6 (ideally less than or equal to 4) and PSA less than or equal to 10.0 ng/ml. Blasko and Stock have made similar recommendations^3,8.

Actuarial potency rates were reported as 80% at two years for those potent before implantation. Reported rectal and GU complications were 12% and 10% respectively. GU complications, including incontinence and superficial urethral necrosis, usually involved men undergoing prior TURP, which some now consider a contraindication for implantation¹⁴.

Results Using Combined Irradiation
Pathology studies following surgery indicate that only 50% of men with clinical T1c cancers actually have organ confined disease¹⁶. Accordingly, more centers are using combined irradiation with both implants and XRT, especially for men with higher Gleason scores or PSA values. Some have suggested that an isotope with a faster dose rate like Pd103 (24 CGy/hr) might be advantageous for rapidly replicating or poorly differentiated tumors, but this has not been substantiated clinically. Pd103 is more expensive than I-125 (8 CGy/hr).

Over 1000 men have been treated with combined irradiation at Dekalb Medical Center in Atlanta. When first critically reviewing our results, we found that no defined endpoint existed which reflected successful treatment of prostate cancer by irradiation. There was no precise definition of DFS, so that meaningful comparison between treatment modalities was impossible.

In an initial review of 536 men with T1, T2 disease (median PSA 8.4 ng/ml, median follow-up 40 months), PSA recurrences were scored as two successive rises above the nadir. Pretreatment PSA, tumor grade, and implant dosage all significantly affected DFS. By multi-variate analysis, however, the PSA nadir was the most significant factor indicating long term DFS. The five and ten year DFS was 95 plus or minus 4% and 84 plus or minus 12% for those achieving a PSA nadir less than or equal to 0.5 ng/ml compared to 29 plus or minus 30% at five years for a PSA nadir 0.6-1.0 ng/ml. All of those men with a PSA nadir over 1.0 ng/ml have a rising PSA. The median time to PSA nadir was 18 months. Eighty-one percent of men in this group were estimated to reach a PSA nadir less than or equal to 0.5 ng/ml¹⁵.

Based on pre and post treatment questionnaires, 57% of sexually active men remain so at five years. Of men with a prior TUR, 31% have urinary incontinence (half wear no pads); only 2% of non-TUR men have incontinence (no pads). The actuarial rate of grade 2 and 3 complications is: urinary 9%/6% (44% had a prior TUR) and rectal 3%/1%¹⁷.

A similar PSA nadir goal (less than or equal to 0.5 mg/ml) has been determined following external beam irradiation and cryosurgery, suggesting that effective local therapy must destroy most, if not all, prostate epithelium.^18,19,20,21 Crook reported a 0% positive biopsy rate in men reaching the nadir goal (less than or equal to 0.5 ng/ml) after XRT.¹⁹ Successful radiation therapy, therefore, may, in effect, be a "Radiation Prostatectomy".¹⁷

Comparative Review
Defining a short term nadir goal (less than or equal to 0.5 ng/ml) following irradiation may facilitate early comparative analysis between different radiation treatment techniques. The table below compares treatments and the percent of men reported to reach the optimum PSA nadir. Thus far, results using combined irradiation appear superior to XRT. No PSA nadir data has been reported for implants alone. A randomized study using PSA nadir as an endpoint could determine the value of brachytherapy without waiting the 10-15 years required to measure cancer specific survival.

Percent reaching the optimum PSA nadir (less than or equal to 0.5): T1, T2 prostate cancer²¹

			Pretreatment PSA (%)
Institution Therapy # Men less than or equal to 4.0 ng/ml 4.1-10.0 ng/ml 10.0-20 ng/ml
Mass General	XRT	205	77	38	24
Eastern Virginia	XRT	302	62	30	17
Dekalb Medical Center	XRT + I-125	660	96	87	77
Multiple	Implants alone	Thousands	No data reported

Defining and Evaluating DFS after Brachytherapy
DFS following radical prostatectomy can be absolutely defined as reaching and maintaining a PSA nadir in the undetectable range. The lack of an established definition for DFS following irradiation has been a source for much of the skepticism that urologists have towards radiation as a curative modality. Using PSA nadir, we have proposed a precise definition for DFS after irradiation.²

Two hundred and fifty-five men (T1, T2, median PSA 8.4 ng/ml) with a minimum of five and a median seven year (range 5-12 years) follow-up were reviewed. The median PSA nadir achieved was 0.1 ng/ml. The PSA nadir reached less than or equal to 0.5 ng/ml for 204 men and has remained less than or equal to 0.5 for 175 (86%). An additional one of 18 (6%) men with a PSA nadir 0.6-1.0 ng/ml has maintained a stable PSA. All men with a PSA nadir over 1.0 ng/ml have a rising PSA. Thus, of 175 men who remain disease free (stable PSA) 99.4%, achieved and maintained a PSA nadir less than or equal to 0.5 ng/ml.

Based on these results, we now define DFS following irradiation as reaching and maintaining a PSA nadir of less than or equal to 5 ng/ml. Treatment failure is defined as a post-irradiation nadir > 0.5 ng/ml or a rise above 0.5 ng/ml. A few progression free men with a PSA nadir > 0.5 ng/ml may be classified as treatment failures but the numbers will be insignificant; less than one percent (1/176) in this study for men with a minimum five year follow-up. Using this definition the actuarial DFS at 5 and 10 years for our updated series of 761 men is 77 plus or minus 4% and 65 4% and 65 plus or minus 8% respectively.

Realistically comparing treatment results
By precisely defining DFS after irradiation, the effectiveness of radiotherapy may be realistically evaluated for the first time in the PSA era. Combined irradiation compares favorably to other radiotherapy techniques with 10 year follow-up.

A COMPARISON OF RADIOTHERAPY TECHNIQUES FOR PROSTATE CANCER ACCORDING TO 10-YEAR DISEASE-FREE SURVIVAL RESULTS

Radiotherapy PSA 10-year

Technique Required disease-free

Survival Rate

External beam alone²² less than or equal to 0.5 ng/ml 10%

Retropubic iodine 125

implant alone²² less than or equal to 0.5 ng/ml 10%

Combined Irradiation

(Present Study)²³ less than or equal to 0.5 ng/ml 65%

For the first time, radiation can be held to a similar standard as radical prostatectomy. The table below compares DFS at five and ten years.

²⁴

Institutions	Treatment Modality	# Men	5 year (%) DFS	10 year (%) DFS
Johns Hopkins	Surgery	1623	80	68
Mayo Clinic	Surgery	3127	70	52
Cleveland Clinic	Surgery	116	61
UCLA	Surgery	601	69	47
Baylor	Surgery	500	76	73
Washington University	Surgery	925	78	65
Dekalb Medical Center	Combined irradiation	761	77	65

	5 year DFS according to pre-treatment PSA (%) 0-4 ng/ml 4-10 ng/ml 10.1-20 ng/ml >20 ng/ml
Walsh et al (surgery)24	94	82	72	54
Critz et al (combined irradiation)25	93	87	72	45

Conclusions
Technical advances have transformed brachytherapy for prostate cancer into an outpatient procedure. In properly selected patients, morbidity appears acceptable. Combined irradiation (I-125 and XRT) produces a high intra-prostatic radiation dose and compensates for potential implant inhomogeneity and extra-capsular spread.

Thus far, PSA follow-up appears to be better with combined irradiation than XRT alone. Any potential advantage of conformal beam XRT and neoadjuvant hormonal therapy is still being investigated. Using a rigid definition of DFS, comparisons can now be made to radical prostatectomy. While selected patients may be candidates for implants alone, more accurate PSA follow-up is needed.

References
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