New OrleansThe advisability of neoadjuvant hormonal
therapy in the management of prostate cancer is a hotly debated
issue. At the American Society of Therapeutic Radiology and Oncology
(ASTRO) spring refresher course, two opinion leaders in radiation
oncology squared off on opposite sides of this issue.
Speaking for the use of neoadjuvant androgen suppression was William
U. Shipley, MD, professor of radiation oncology, Harvard Medical
School, and head of genitourinary oncology, Department of Radiation
Oncology, Massachusetts General Hospital, Boston
Neoadjuvant therapy, compared with adjuvant therapy, offers a
shorter course of hormonal therapy, precedes rather than follows
radical treatment, and is aimed at increasing local control rather
than the control of micrometastases, Dr. Shipley observed.
For locally advanced prostate tumors, neoadjuvant hormonal
therapy is beneficial when combined with radiotherapy and should be
the standard of care.
Dr. Shipley believes there is a clear rationale for neoadjuvant
androgen suppression. It downstages the tumor; achieves
cytoreduction; decreases prostate volume (three studies show a 40%
reduction with 3 months of therapy); triggers apoptosis of sensitive
cells; and significantly alters histology.
There is a significantly improved biological effect, Dr.
Shipley said. This may translate into an improved clinical situation
in a number of ways:
A 40% reduction in prostate volume within 3 months of neoadjuvant
Reduction in circulating cancer cellsfrom 37% to 20% with
neoadjuvant androgen suppression.
Reduction in percentage of positive post-irradiation re-biopsy
samples, in several seriesZelefsky et al (J Clin Oncol 16:3380,
1998), for example, found 44% positive biopsies with radiotherapy
alone (70 to 76 Gy) vs 15% with radiotherapy plus neoadjuvant
Sharp decline in PSA levels due to decline in
testosteronePSA is undetectable after neoadjuvant therapy in
33% of patients at 3 months and in 70% at 6 months.
Three phase III clinical trials showed a decrease in local tumor
regrowth and occurrence of distant metastases, he said. With a median
follow-up of 6.5 years, the RTOG trial of 456 patients with large
tumors showed an advantage for neoadjuvant hormonal therapy. Use of
flutamide (Eulexin) and goserelin (Zoladex) resulted in NED (no
evidence of disease) status in 49% of patients vs 34% for
radiotherapy alone, and a significant difference in local control,
78% vs 65%, Dr. Shipley reported.
On the other hand, he said, overall survival at 8 years, although
there was a trend (P = .11), was not significantly different: 52%
survival at 8 years in the combined group vs 43% in the radiotherapy
alone group. But in the better-differentiated tumor subgroup, there
is a significant survival difference of about 12%, Dr. Shipley noted.
For T3 tumors, it stands to reason that cytoreduction is very
important. Local control is a huge issue, he remarked.
As for patients with smaller T1-T2 tumors, Dr. Shipley said the
benefits of neoadjuvant hormonal therapy occur only when a large
planning target volume increases the risk of morbidity from external
beam radiotherapy or brachy-therapy. Hormonal therapy lowers the
proportion of the organ receiving high radiation doses and spares
more of the bladder and rectum.
There are no data yet to support improved survival in unselected
stage T1-T2 patients, though clinical trials are underway to identify
T1-T2 subsets likely to benefit, he added.
Speaking against the use of neoadjuvant hormonal therapy was Gerald
Hanks, MD, chairman, Department of Radiation Oncology, Fox Chase
Cancer Center, and professor and chairman of radiation oncology,
Temple University School of Medicine, Philadelphia.
Dr. Hanks argued that there are not enough class I dataresults
based on randomized controlled clinical trialsto validate this
regimen. Currently, he sees no role, therefore, for neoadjuvant
androgen deprivation in the management of prostate cancer.
For most locally advanced prostate cancer patients, there is
already class I evidence for how they should be treated. In the
absence of a survival advantage of short-term hormones, I think the
bad outweighs the good, Dr. Hanks said. To replace or add
to the long-term strategies that are proven to have survival
advantages at this point requires new randomized trials adding the
neoadjuvant component to the proven management.
Regarding the presumed gains from neoadjuvant androgen deprivation,
he argued there is no evidence that (1) shrinking the prostate will
reduce morbidity; (2) decreasing the number of clonogens will
increase the cure rate; (3) micrometastases out of the radiation
field will be eradicated; or (4) long-term neoadjuvant hormonal
therapy is superior to short-term therapy.
Elaborating, he said that reanalysis of RTOG 86-10 and 85-31 reveals
the relative risks for cause-specific failure and distant metastases
are 1.0 each for long-term hormone therapy, but 2.1 for short-term
therapy, no different from patients receiving no hormonal therapy.
In addition, Dr. Hanks pointed to a number or potential negative
effects of androgen deprivation. Androgen deprivation could promote
resistance (as could long-term hormone therapy); weaken bone (Diamond
et al: Cancer 83:1561, 1998); suppress testosterone longer than
intended; impair recovery of potency; diminish physical activity
level and quality of life; and add to the cost of care without
demonstrating cost-effectiveness, he said.
One recent study found that 3 to 6 months of neoadjuvant hormone
therapy resulted in castrate levels of testosterone in patients and
mean hypogonadal symptoms lasting more than 1 year (Oefelein et al: J
Urol 160:1685, 1998). Another study at Fox Chase Cancer Center found
that only 36% of patients retained potency after short-term androgen
deprivation and radiotherapy vs 67% after radiotherapy alone.
I think it is quite likely that if you give 3 to 4 months of
androgen deprivation, you will cut in half the chances of recovering
potency, he commented.
Potency aside, many older patients also suffer a loss of
zipthey become sedentary, gain weight, lose muscle
mass, develop hot flashes, and lose libido. This can be a
difficult symptom complex. These are not trivial symptoms in a
70-year-old man, he observed.
Neoadjuvant androgen deprivation does, however, give a false sense of
cure and will delay PSA failure by 20 to 24 months, but no survival
benefit has been associated with this delay, he emphasized.
Dr. Hanks stressed that current treatment standards provide very good
outcomes for the vast majority of patients and shouldnt
be messed with. Even the unfavorable group, such as
T2b and T3 patients with Gleason score 7 to 10, are still 80% free of
disease at 5 years when they receive high-dose radiation therapy.