Dr. Potters has provided an excellent and timely overview of
transperineal interstitial permanent prostate brachytherapy (TIPPB).
The historical context, as the title suggests, nicely illustrates the
lessons already learned and those still to be learned. There are a
few points I would like to discuss in further detail.
Importance of Local Control
As Dr. Potters pointed out, the poorer results in the earlier
retropubic series may have been due to technically inadequate
implants, ie, suboptimal dose. Studies have demonstrated that not
only was local control inferior with lower-dose implants but freedom
from distant metastases and overall survival was compromised as
well. Conversely, in prospective randomized trials using
fast-neutron radiation therapy, enhanced local control has been
associated with significant increases in overall survival.
Recently at Fox Chase, improvements in biochemical and local control
using high-dose three-dimensional (3D) conformal external-beam
radiation therapy have translated into better survival rates as well.
The importance of technically sound permanent implants cannot be
overstated and, as these data demonstrate, adequate dose is directly
related to local control, which, in turn, correlates with
survivala situation not always observed in radiation oncology.
Role of Androgen Deprivation
Dr. Potters contends that neoadjuvant androgen deprivation does not
add much benefit as seen in his own data. However, another
interpretation of the same data could be that the therapy was, in
fact, quite successful. The prostate volumes in the cohort that
received neoadjuvant androgen deprivation were nearly 80 cc, in
contrast to 35 cc in patients who did not receive this therapy.
The fact that the disease control outcomes were equivalent could mean
that neoadjuvant androgen deprivation successfully downsized the
prostates in these patients, making TIPPB feasible. The lack of
difference in biochemical no-evidence-of-disease rates suggests that
the downsized glands were implanted with technical adequacy.
The fact that no benefit in disease control was observed with
neoadjuvant androgen deprivation may, in part, be due to patient
selection. Low-risk patients have not been shown to benefit
conclusively from adjuvant hormonal therapy when combined with
external-beam radiation therapy; there may also be no reason to
expect a benefit when the therapy is combined with TIPPB in low-risk patients.
In high-risk patients, the prospective randomized trials that have
revealed a benefit to hormonal therapy with external-beam radiation
therapy have used either prolonged (at least 3 years) luteinizing
hormone-releasing hormone (LHRH) agonists[5,6] or a neoadjuvant
approach with total androgen blockade (ie, an LHRH-agonist and an
androgen-receptor blocker). Whether brachytherapy combined with
prolonged LHRH-agonist therapy or combined with neoadjuvant total
androgen blockade would be more effective than the short-term
neoadjuvant LHRH-agonist therapy typically used is presently unknown.
Role of External-Beam Radiation
The importance of radiation dose escalation in prostate cancer is now
well established. Techniques employed to achieve this include 3D
treatment planning with conformal techniques (3D CRT),
intensity-modulated radiation therapy (IMRT), and proton therapy.
Brachytherapy can also be considered as a means of escalating the
dose further. When a brachytherapy boost is used in
conjunction with external-beam radiation therapy, the highest
physical doses of radiation for prostate cancer are attained.
Although Dr. Potters own data do not support the addition of
external-beam radiation therapy to TIPPB; other data do support the
combination. Ragde et al have observed equivalent disease control
in patients who received external-beam radiation therapy along with
TIPPB compared to those who received implants alone, despite
significantly worse prognostic features in the former group. When
they used a stricter definition of biochemical control
(prostate-specific antigen [PSA] < 0.4 ng/mL), the addition of
external-beam radiation therapy proved significantly better despite
the worse prognosis of these patients.
Critz et al employed a similarly strict definition of biochemical
control (PSA < 0.5 ng/mL) and reported excellent actuarial
biochemical control rates (92% at 5 years) using TIPPB combined with
external-beam radiation therapy. This group has been performing the
implants before beginning external-beam radiation.
We have also been using a similar reverse sequence. With
this strategy, the tumor receives more radiation per day than with
the conventional sequence since the implanted seeds are still
emitting radiation at the time of external irradiation.
There is a theoretical radiobiological advantage; the low-dose
radiation may sensitize the tumor cells to the subsequent high-dose
external-beam radiation therapy. The sequence also permits some
flexibility in that the external-beam radiation therapy dose can be
adjusted to compensate for a suboptimal implant. Perhaps most
significantly, during TIPPB, we have been implanting fiducial seed
markers that are visible on both simulation and port films to assure
precise tumor localization and setup reproducibility during conformal
external-beam radiation therapy.
Radiation Dose From TIPPB With Palladium-103
Finally, as Dr. Potters points out, Blasko et al have recently
reported excellent results using palladium-103 (103Pd)
implants alone. Considering that the average volume of the prostate
expands 70% after TIPPB with iodine-125 (125I) or 103Pd
and shrinks back down with a half-life of well over a week, one
might expect poorer results with 103Pd. That is, the
shorter half-life of 103Pd implies that most of the
prescribed dose is actually being delivered to a target significantly
larger than initially assumed. During the time in which the bulk of
the dose is delivered, the individual seeds are farther apart than
initially anticipated and, thus, areas within the gland are receiving
less than the planned dose.
The fact that the clinical results are as good as they are suggests
that the actual dose of radiation from standard 103Pd
implants may be considerably higher than the prescribed 115 Gy. A
reanalysis of the actual dose from 103Pd seeds is underway.
James S. Welsh, MD
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