Pd-103 Dose De-Escalation for Early Stage Prostate Cancer: A Prospective Randomized Trial

In calendar year 2003, approximately 220, 000 men will be diagnosed with prostate cancer and
approximately 30,000 will die. The vast majority of men will be diagnosed with clinically
organ-confined disease with potentially curative treatments including radical prostatectomy,
external beam radiation therapy and brachytherapy. Within the uro-oncology community, the
selection of one modality over another remains controversial.

Over the past decade, transperineal ultrasound-guided permanent prostate brachytherapy using
either Pd-130 or I-125 has been increasingly utilized as definitive management for early
stage carcinoma of the prostate gland. This resurgence of interest in prostate brachytherapy
was the result of several technologic advances including the evolution of transrectal
ultrasonography, the development of a closed transperineal approach and the availability of
sophisticated treatment planning computers. These imaging and planning advances
significantly improved the accuracy of seed placement. In addition, the advent of CT-based
postoperative dosimetry in the early 1990's provided a unique opportunity to evaluate
quality and proactively predict outcome and complications.

Prostate brachytherapy represents the ultimate 3-dimensional conformal therapy and permits
dose escalation far exceeding other modalities. Following permanent prostate brachytherapy
with or without supplemental external beam radiation therapy, favorable long term
biochemical outcomes have been reported for patients with low, intermediate and high risk
features with a morbidity profile that compares favorably with competing local modalities
(1,2)2).

Although there is no definitive evidence suggesting that either Pd-103 or I-125 is more
efficacious than the other in terms of cure or side effects/complications, preliminary
results of a prospective randomized trial suggests that Pd-103 may be more "dose forgiving"
than I-125 (3). Long-term results demonstrate cancer eradication is highly correlated with
delivered radiation dose. To date, postoperative dosimetry has primarily been described in
terms of V 100/150/200 (volume of the gland receiving 100%, 150% and 200% of the
prescription dose) and the D90 (the dose delivered to 90% of the prostate gland). Following
I-125 monotherapy, A D90 greater than or equal to 140 Gy (day 30 dosimetry) is required for
optimal long-term biochemical control (4,5)4)5). A dose of 140 Gy represents 96% of the
standard I-125 prescription dose (145 Gy). In contrast, following Pd-103 monotherapy, A D90
greater than or equal to 100 Gy (day 30 dosimetry) and a D90 greater than or equal to 108 Gy
(median day 22 dosimetry) have been reported to predict optimal biochemical outcomes
(6,7)6)7). These Pd-103 doses represent 80% and 86% of the standard monotherapy prescription
dose (125 Gy). In addition, a prospective randomized trial demonstrated that coverage of 90%
or more of the prostate by 124 Gy of Pd-103 yields 98% change of being cancer-free three
years following treatment (3).

Because of some seed placement uncertainty, however, the pre-plans are designed to deliver a
higher radiation dose than necessary to most of the prostate gland (8). Additionally, there
is a variable amount of edema that occurs from the implant procedure, moving seeds farther
away from each other, again requiring a higher planned dose than actually needed.

Delivered radiation dose is paramount to securing long-term freedom from biochemical
progression. Previously Merrick and colleagues reported that postoperative dosimetric
quality for Pd-103 and I-125 in terms of V 100/150/200 and D90 were independent of prostate
size, isotope selection, radiation implant dose prescription, the use of supplemental
external beam radiation therapy, neoadjuvant androgen deprivation therapy and patient age
(8-12)8)9)10)11)12). These results demonstrate the dosimetric reproducibility of Pd-103
across all implant scenarios. A review of the last 200 consecutive Pd-103 implants at the
Schiffler Cancer Center illustrates similar dosimetric outcomes for patients implanted with
125 Gy versus 115 Gy.

Although the morbidity profile of permanent prostate brachytherapy compares favorably with
competing local modalities, side effects and complications do occur. Delivered radiation
dose to the urethra, rectum and proximal penis strongly correlate with brachytherapy-related
morbidity (2, 13-18)13)14)15)16)17)18).

In summary, the available literature suggests that the Pd-103 doses necessary for cure care
substantially less than currently prescribed, postoperative dosimetry has consistently
demonstrated high intraprostatic doses and brachytherapy-related morbidity is related to
radiation doses to normal surrounding structures. As such, we proposed to conduct a
prospective randomized trial evaluating the effect of a 12% reduction in prescription dose
(125 Gy vs. 110 Gy) on the ultimate cure and complication rates for low risk prostate cancer
(PSA greater than or equal to 10 ng/mL, Gleason score greater than or equal to 6 and
clinical stage T1b-T2b). To assure that the dose is adequate, intraoperative and
postoperative dosimetry will be performed. Intraoperative dose evaluation will allow
additional seeds to be implanted if needed to achieve minimum required dose.

Inclusion Criteria:

- Low risk patients: Gleason score less than or equal to 6, PSA less than or equal to
10 ng/mL and clinical stage T1b-T2b (2002 AJCC.

- An enzymatic prostatic acid phosphatase must be obtained prior to implantation.

- No pelvic external beam radiation therapy for either prostate cancer or other
malignancies.

- Androgen deprivation therapy less than 4 month duration for size reduction is
allowable.

- No surgical staging for prostate cancer.

- A minimum of 5 year life expectancy.

- No other invasive cancer diagnosis other than non-melanoma skin cancer within the
last 5 years.

Exclusion Criteria:

- Exclusion criteria will be limited to patients who do not meet the above eligibility
criteria.