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The Prostate 39:151–152 (1999)
Commentary
Effect of Combined Transient Androgen
Deprivation and Irradiation Following Radical
Prostatectomy for Prostatic Cancer
Adjunctive irradiation of the prostatic region following radical prostatectomy in patients with suspected or proven locally residual disease has long
been the subject of investigation in the Department of
Radiation Oncology at Stanford University [1–3].
Early experience demonstrated that postoperative irradiation was feasible and tolerated, although there
was a slight increase in morbidity which has disappeared with improvements in technique and case selection. It also demonstrated that patients with more
advanced disease, i.e., those with seminal vesicle or
lymph node involvement, were less likely to have a
disease-free posttherapeutic survival than those with
only capsular penetration, and that patients at higher
risk were more likely to fail because of the development of distant metastases, as well as residual disease
in the prostatic fossa [4].
In the contribution by Eulau et al. under review, 105
consecutive patients were treated with pelvic irradiation after radical retropubic prostatectomy between
August 1985–December 1995 [1]. Seventy-four patients received radiation alone and 31 were also
treated with transient androgen blockade and/or androgen receptor blocker (flutamide). Twenty-four received gonadotropin-releasing hormone (GnRH) and
flutamide, 4 GnRH alone, and 1 flutamide only. Two
patients were eliminated because hormonal management extended to 1 year. While the study was not
prospectively randomized, the patients referred from
the Stanford University Department of Urology received adjuvant androgen deprivation, while those referred from other sources were treated with radiation
only. Thus, two patient groups were identified which
did not differ significantly in terms of Gleason score,
lymph node status, seminal vesicle involvement, preoperative prostate-specific antigen (PSA), or other indications for treatment. Hormone deprivation was initiated for 2 months prior to irradiation, and was continued for 2 months during irradiation, and for 2
months thereafter. Radiation consisted of a prostatic
fossa dose of 60–70 Gy at 2 Gy per fraction, and 47
patients also received pelvic nodal irradiation to a median dose of 50 Gy. Biochemical relapse after prosta© 1999 Wiley-Liss, Inc.
tectomy or after combined treatment was defined as
two consecutive elevations of PSA values above the
equivalent of 0.07 ng/ml by either the TOSOH or Hybritech Incorporated assay.
Survival, freedom from clinical relapse (FFCR), and
freedom from biochemical relapse (FFBR) were monitored. A total of 1,820 PSA determinations was obtained on the patients analyzed in this report, with a
mean of 12.6 PSA values per patient. Ten of 103 patients died of prostatic cancer and 1 from intercurrent
disease. The 5-year actuarial survival of all patients
was 92%, FFCR was 78%, and FFBR was 34%. None of
12 patients at risk more than 5 years after irradiation
has developed clinical or biochemical recurrence. For
patients at risk for less than 5 years, 20 have had clinical recurrence, with distant metastases in 16, and local
recurrence in 4. Interestingly, the 4 local recurrences
were seen after radiotherapy alone; no local recurrences have been observed after combined androgen
suppression and irradiation. To date, 30 patients have
had biochemical relapse without clinical signs, and
among those, clinical relapse was preceded by biochemical failure by 22.3 months. Freedom from clinically evident local or distant recurrence was significantly superior among patients treated with transient
androgen deprivation compared to those receiving radiation alone (P = 0.014).
Similarly, patients who received both transient androgen deprivation and irradiation had a significantly
better freedom from biochemical relapse compared to
patients who received radiotherapy alone. At 3 years,
FFBR was 76% vs. 45%, and at 5 years the FFBR was
56% for those receiving combined therapy, vs. 27% for
those receiving radiation alone (P = 0.004).
On multivariate analysis, which included presurgical PSA values >10, seminal vesicle involvement, marginal involvement, capsular penetration, or summed
Gleason score >6, the only predictor for biochemical
relapse was transient androgen therapy.
*Correspondence to: Malcolm A. Bagshaw, M.D., 922 Lathrop Place,
Stanford, CA 94305.
Received 14 January 1999; Accepted 15 January 1999
152
Bagshaw
In several earlier studies of prostatic bed irradiation, even though local recurrence was reduced, this
approach did not significantly increase the probability
of enhanced long-term survival. This led several authors, some of whom are tabulated in the article under
review, to speculate that the lack of survival benefit
following irradiation of the prostate bed alone may be
secondary to progression of occult metastases undetected at the time of irradiation of the postsurgical
prostatic fossa.
It has been suggested that androgen deprivation
induces apoptosis or programmed cell death of prostatic cancer cells irrespective of their anatomical site.
Irradiation of prostatic cancer cells induces both apoptosis and mutational cell death in the irradiated volume. The combination of hormone deprivationinduced apoptosis for systemically disseminated prostate cancer cells and radiation-induced cell death of
prostatic cancer cells residual at the surgical site may
be responsible for this apparent improvement in the
survival of patients following surgical resection, irradiation, and systemic androgen deprivation.
Clearly a long and careful follow-up of these data
and confirmation of this evidence will be required to
verify the efficacy of this triple attack on prostatic
cancer.
REFERENCES
1. Eulau SJ, Tate DJ, Stamey TA, Bagshaw MA, Hancock SL. Effect
of combined transient androgen deprivation and irradiation following radical prostatectomy for prostatic cancer. Int J Radiat
Oncol Biol Phys 1998;41:735–740.
2. Ray GR, Cassady JR, Bagshaw MA. External-beam megavoltage
radiation therapy in the treatment of post-radical prostatectomy
residual or recurrent tumor: preliminary results. Urology 1975;
114:98–101.
3. Ray GR, Bagshaw MA, Freiha FS. External beam radiation salvage for residual or recurrent local tumor following radical
prostatectomy. Urology 1984;132:926–930.
4. Kaplan ID, Bagshaw MA. Serum prostate-specific antigen after
post-prostatectomy radiotherapy. Urology 1992;39:401–406.
Malcolm A. Bagshaw*
Departments of Radiation Oncology and Urology
Stanford University Medical Center
Stanford, California
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