ROUTINE PROSTATE BIOPSIES FOLLOWING

RADIOTHERAPY FOR PROSTATE CANCER:

RESULTS FOR 226 PATIENTS
J.M. CROOK, M.D.
G.A. PERRY, M.D.
S. ROBERTSON, M.D.
B.A. ESCHE, M.D.

From the Department of Radiation Oncology, Ottawa Regional Cancer Centre,

and the Department of Pathology, Ottawa General Hospital, Ottawa, Canada

ABSTRACT-Objectives. To determine the time course of histologic resolution of

prostate cancer following radiotherapy (RT) and to correlate biopsy results with clinical
outcome.
Methods. Since July 1990, all patients treated with radical external beam RT for
prostate cancer at the General Division of the Ottawa Regional Cancer Centre have had
systematic transrectal ultrasound (TRUS) and TRUS-guided biopsies beginning 12
months after RT and then every 6 months until negative or until clinical failure. Thus,
226 patients have had 375 TRUS with four to seven specimens per examination. Stage
distribution was Tl b: 32, Tl c: 1 1, T2a: 45, T2b: 82, T3: 50, and T4: 6. Median fol-
low-up was 33 months.
Results. Biopsy results were negative in 69.5% of patients by 30 months of follow-
up. Thirty-two (14%) had local failure (Tl b: 12.5%, Tl c: 0%, T2a: 1 1 %, T2b: 15%, T3:
18%, T4: 33%). Seven (3%) had chemical failure, and 47 (21%) had biopsy-only fail-
ure. Median follow-up for the biopsy-only failure group is only 19.5 months and mean
prostate-specific antigen (PSA) is 1 .O ng/mL. Thirty-nine patients, initially with biopsy-
only failure, have converted to negative biopsies at a median of 26 months. Nadir PSA
for patients with local failure was 3.9 ng/mL at 14 months versus 0.7 ng/mL at 23
months for those without failure. Patients with late conversion to negative biopsy re-
sults had a later nadir PSA of 1.3 ng/mL at 27.3 months. \ ~\_ \
Conclusions. Routine prostate biopsy specimens after RT in an unselected ‘population
show tumor clearance that is in agreement with long-term clinical follow-up, although
tumor may take more than 30 months to resolve. Nadir PSA can be used to predict
outcome.

External beam radiotherapy CRT) is the most Clinical follow-up after RT may be unreliable.
commonly used potentially curative treatment for The use of prostate-specific antigen (PSA) is rou-
carcinoma of the pr0state.i In general, patients se- tine, but a rising PSA may signal either local or
lected for radiation are 5 to 10 years older than distant recurrence. Prostate biopsy is logically the
those selected for radical prostatectomy,2 have gold standard for determination of local failure
more advanced local disease, and are of unknown but both the indications and interpretation of
nodal status. Despite a clearly less favorable pa- biopsy specimens are controversial.4 Several re-
tient population, clinical results at 10 years are ports on selective post-RT biopsies, often includ-
equivalent to those for surgery.lm3 ing patients who had biopsies a few months after
treatment or in whom residual disease is sus-
Submitted (Rapid Communication): November 17, 1994, pected, have shown very high positive biopsy
accepted (with revisions): December 5, 1994 rates.5-7 Such reports cast doubts on the efficacy

624 U ROLOGP /APRIL 1995 I VOLUME45, NUMBER4

 TABLE I. TNM staging for prostate cancer (1 992)21
Stage Definition or Criteria for Inclusion
Tl Clinically inapparent tumor, not palpable nor visible by imaging
Tla Tumor an incidental histologic finding; <5% of tissue resected
Tlb Tumor an incidental histologic finding; > 5% of tissue resected
Tic Tumor identified by needle biopsy (eg, because of elevated serum PSA)
T2 Confined within the prostate
T2a Tumor involves half of a lobe or less
T2b Tumor involves more than half of a lobe but not both lobes
T2c Tumor involves both lobes
T3 Tumor extends through the prostate capsule
T3a Unilateral extracapsular extension
T3b Bilateral extracapsular extension
T3c Tumor invades seminal vesicle(s)
T4 Tumor is fixed or invades adjacent structures other than seminal vesicles
T4a Tumor invades bladder neck and/or external sphincter and/or rectum
T4b Tumor invades levator muscles and/or is fixed to pelvic wall

of radiation in the curative management of pros-
tate cancer.
Positive biopsy specimens are of concern because
they are associated with distant failure and death
from prostate cancer. 8-13However, the difficulty in
interpretation of post-RT biopsy results is often un-
derstated. Histologic clearance of tumor following
RT may take 18 months or longer.gv14-16Even when
biopsies are performed at an appropriate interval
following treatment, major pitfalls exist.
Radiation atypia in benign prostate glands may
be confused with residual or recurrent tumor,
leading to overcall of positive biopsy resu1ts.l’
Immunohistochemical stains for high molecular
weight keratin can differentiate radiation atypia
from residual tumor, since the basal cell layer of
benign glands stains positive, whereas malignant
glands are negative. l8 Most series, however, do
not document staining for high molecular weight
keratin.
Tumor resolution after RT may leave scattered
nests of cells showing marked radiation change.
Since there is no identifiable glandular morphol-
ogy, these remnants would be given a high Glea-
son score. Recently developed immunohisto-
chemical stains can differentiate between rapidly
proliferating poorly differentiated residual tumor
and degenerated nonproliferating cells. Prolifera-
tive cell nuclear antigen (PCNA) is a nonhistone
nuclear protein elaborated on the nuclear mem-
brane of actively cycling cells, but absent in those
cells that are not proliferating. Levels correlate
well with other indices of proliferative activity,
such as in vivo 5bromodeoxyuridine (BuDR)
staininglg and tumor grade.20
In this prospective study, routine transrectal ul-
trasound (TRUS)-guided biopsies were done sys-
tematically on 226 unselected patients to deter-
mine the time course of histologic resolution and
to correlate biopsy results at intervals following
RT with clinical outcome.
MATERIAL AND METHODS
In July 1990, a policy of obtaining routine post-
RT-TRUS-guided prostate biopsy specimens was
introduced at the General Division of the Ottawa
Regional Cancer Centre for all prostate cancer pa-
tients treated by pelvic RT with curative intent.
Biopsies were scheduled 12 months following RT,
then every 6 months until negative or until the
development of clinical recurrence. Patients with
initial negative biopsy results at 12 months had
another biopsy at 36 months. We report the re-
sults on 226 patients aged 49 to 87 years (median,
70), treated from July 1987 to February 1993, all
with histologically confirmed adenocarcinoma of
the prostate. Data were updated in March 1994
and analyzed with the Kwikstat 3.3 statistical data
analysis program (TexaSoft).
All patients had a complete history and physi-
cal examination at the time of initial consulta-
tion. Local tumor stage was determined by digi-
tal rectal examination (DRE), performed by both
the radiation oncologist and the referring urolo-
gist. If hormonal intervention had been initiated
before referral, the tumor stage assigned was as
described by the referring urologist. Investiga-
tions included complete hlood count, renal and
hepatic function tests, serum alkaline and acid
phosphatases, PSA (since November 1989, Abbot
IMX assay: normal range to 5.3 ng/mL), chest ra-
diograph, technetium-99m bone scan, and pelvic
computed tomography (CT) scan. Thirty-three
patients (14.6%) had a staging pelvic lymphade-
nectomy. Staging is according to International
Union Against Cancer-TNM classification of
199221 (Table I). Distribution by stage and grade
is shown in Table II.

UROLOGY@ I APRIL 1995 I VOLUME 45, NUMBER 4 625

 All biopsy results were reviewed by one pathol-
TABLE II. Distribution of patients by
ogist (S.R.) and stained for PSA and prostatic acid
stage and grade
phosphatase. Immunohistochemical stain for high
Grade molecular weight keratin (keratin 903) was used
Stage WD MD PD GX to distinguish residual carcinoma from radiation
Tl ti- 14 13 5 0 atypia in benign glands. Biopsies were considered
Tic 8 3 0 0 positive if hematoxylin and eosin staining showed
T2a 30 11 1 3 any evidence of residual malignancy, regardless of
T2b 33 40 4 5
the scarcity of malignant cells or the degree of ra-
T3 14 30 4 2
diation effect. Positive biopsies were then subdi-
T4 2 - 1 2 1
vided into “clearly positive” and “indeterminate”
Total 101 98 16 11
categories, based on the degree of radiation-
KEY: WD = well dif~ereerentiated (Gleason scow 2-4); MD = moderately induced degenerative change.
d$Jereerentiated (Gleason scox 5-7); PD = poorly differentiated (Gleason SCDIC
8-10); GX = unknown grade. Positive or indeterminate biopsies were also
processed with an immunohistochemical stain for
PCNA, using the NovoCastra PC10 antibody. Fix-
Forty-two percent of patients (94 of 226) had ation time in formalin was limited to 12 hours.
hormonal intervention (median duration, 5 PCNA staining was expressed as the percentage of
months; range, 1 to 60 months) before referral for tumor cells staining positive.
definitive RT. Hormonal treatment was discontin- Patient status was considered as no evidence of
ued before RT and not reinstituted except for doc- disease (NED) if both serum PSA and DRE were
umented failure. Patients with orchiectomy were normal and the biopsy results were negative. Pos-
excluded. Patients who failed distantly in the first itive and indeterminate biopsy results were classi-
year of follow-up also had a biopsy if they were fied as biopsy failures if both DRE and serum PSA
close to the 12-month mark. values were normal. If either PSA or DRE was ab-
All patients were treated with 18 MV photons normal, together with a positive or indeterminate
using a four-field box technique. The treatment biopsy result, the patient was classified as having
volume was limited to the prostate and seminal a local failure. An elevated PSA level, with no ev-
vesicles for small well-differentiated tumors and idence of tumor on either DRE or a biopsy spec-
those that were pathologically node negative. Most imen was deemed a chemical failure. Patients with
patients were treated to the first echelon (external distant metastases were classified as distant fail-
and internal iliac) nodes with fields extending su- ures only if the prostate biopsy result was normal;
periorly to the bottom of the sacroiliac joints. otherwise they were considered to have combined
Treatment to the whole pelvis was rarely used. local and distant failure, even if the DRE was clin-
Standard fractionation of 1.8 to 2.0 Gy/day was ically normal.
used. Lymph nodes received 45 to 46 Gy, the pros-
tate and seminal vesicles received 65 to 66 Gy R&ULTS
(range, 60 to 68 Gy). Three hundred seventy-five biopsies were per-
The mean follow-up is 33 months (range, 12 to formed on 226 patients: 117 patients had one
78 months). Patients were seen every 3 to 4 months biopsy, 76 patients had two biopsies, 26 patients
for the first 2 years, every 6 months until 5 years, had three biopsies, and seven patients had four
and yearly thereafter, with a PSA determination at biopsies. Status of the 226 patients as of March
each visit. The first post-treatment biopsy was 1994 is shown in Table III. Of the 226 patients,
scheduled 12 months after RT. Prostates with resid- 51% (115 of 226) had an abnormal initial biopsy
ual tumor had a biopsy every 6 months until nega- result at a median time of 13 months after RT. Sev-
tive or until clinical evidence of failure (rising PSA enty of the 115 (61%) showed malignant cells with
values or abnormal DRE). Repeat biopsies were also apparently minimal treatment effect. Of these, 24%
performed to investigate a rising PSA or abnormal (17 of 70) progressed to local failure at a median
DRE. All biopsies were performed under TRUS guid- of 30 months, and 33% (23 of 70) converted to
ance with antibiotic prophylaxis (ciprofloxacin, negative at a median of 26 months. Of 115 pa-
500 mg every 12 hours for three doses). All quad- tients, 45 (39%) were considered indeterminate
rants of the prostate were sampled, as well as the because of marked degenerative changes. Of these,
site of the original tumor, which was targeted for an only 9% (4 of 45) progressed to local failure and
additional two or three passes. In total four to seven 29% (13 of 45) converted to negative. Delayed
samples were taken per biopsy session. conversion to negative occurred in all T stages

626 LJ ROLOCY@ /APRIL 1995 i VOLUME 45, NUMBER 4

 *Vander Wed Messing=
FIGURE 1. Percent positive
$-Herr rs biopsy versus time from comple-
*Crook (present series) tion of radiation therapy [RT).
14 [Modified from Crook et aLz2)
* cox
10
* Schellhammer

~0 3 6 9 12 15 18 21 24 27 30 33 i-5
Months post RT

TABLE III. Status of patients as of March 1994 according to stage

Stage NED BF CF LF* LF + DF DF+ Total
Tlb 21 5 1 2 2 1 32
Tic 6 5 0 0 0 0 11
T2a 28 9 1 4 1 2 45
T2b 46 15 3 10 2 6 82
T3 21 10 2 6 3 8 50
T4 0 3 0 0 2 1 6
Total 122 47 7 22 10 18 226
% 54.0 20.8 3.1 9.7 4.4 8 100
KEY: NED = no evidence of disease; BF = biopsy failure; CF = chemicaljaihue; LF = isolated local failure; DF = isolated
distant failure; L.F + DF = simultaneous local and distant failures.
“Total local failures were 32 (14%).
‘Total distant failures were28 (12.5%).

(Tlb: 6, Tic: 1, T2a: 12, T2b: 14, T3: 6). The pro- 100
portion of normal and abnormal biopsies as a func-
tion of time is shown in Figure 1. By 30 months, 90
69.5% of patients had achieved a negative biopsy. a0
Eleven (7%) of the 150 patients with negative post-
treatment biopsy results progressed to local failure 70

at a median time of 36 months. 60

Overall, 14% of patients (32 of 226) had a local
50
failure. The local failure rate by stage is 12.5% %
Tlb, 0% Tic, 11% T2a, 15% TZb, 18% T3, and 40
33% T4. Of local failures, 28% (9 of 32) were 30
based on a positive biopsy and elevated PSA level
with a normal DRE, and were thus “preclinical.” 20
Actuarial local control is shown in Figure 2. 10
Twenty-one percent of patients (47 of 226) re-
main in the biopsy failure category, with a normal 0 I I I I I I I I

0 6 12 18 24 30 36 42 48
PSA and DRE. This has occurred in 16% of Tlb
(5 of 32), 45% of Tic (5 of ll), 20% of T2a (9 of Months
45), 17% of T2b (14 of 82), 20% of T3 (10 of 50), FIGURE 2. Actuarial local control by stage.

UROLOGY@ /APRIL 1995 I VOLUME 45, NUMBER 4


12 18 24
TimepostRT (month)
FIGURE 3. Proliferative cell nuclear antigen (PCNA)
counts (number of PCNApositive nuclei per 100 tumor
nuclei) in three consecutive biopsies for 2 individual
patients. (Modified from Crook et a1.24)
and 50% of T4 (3 of 6). This includes both posi-
tive and indeterminate biopsy results, regardless
of PCNA status or apparent tumor viability. The
median follow-up on these patients is only 19.5
months, and the median PSA level is 1.0 ng/mL.
Only 30% (14 of 47) of the biopsy failure group
has a PSA level of 1.5 ng/mL or greater.
We classified the positive biopsies (clearly posi-
tive versus indeterminate) based on the degree of
radiation effect, in order to predict eventual con-
version to negative. Forty-five patients had an ini-
tial indeterminate biopsy. Of these, 14 have had
only one biopsy, and 10 have continued to be clas-
sified as indeterminate after subsequent biopsies,
for a total of 53% (24 of 45) who require further fol-
low-up to determine outcome. Sixteen (36%) have
resolved to negative at a mean time of 24 months
after RT, and 5 (11%) have progressed to a clearly
positive biopsy result at a mean of 20 months
(4 with local failure).
The mean PSA nadir for the study population
was 2.0 ng/mL at a mean time of 19.3 months.
Nadir PSA was higher in patients with local fail-
ure (mean, 3.9 ng/mL) than those without failure
(mean, 0.7 ng/mL) (P <O.OOl). Time to nadir PSA
was 14.4 months in patients with local failure
compared with 23.1 months in patients without
failure (P = 0.012). Patients with abnormal biopsy
result that resolved had a nadir of 1.3 ng/mL at
628
27.3 months, whereas those who progressed had
a nadir of 4.7 ng/mL at 14.9 months.
Staining for PCNA was attempted in all biopsies
suspicious for residual tumor. For the 39 patients
showing late conversion to negative, 27 (69%) of
the initial post-treatment biopsy specimens were
stained for PCNA and 18 of these (67%) were ini-
tially negative, indicating a loss of proliferative
capability. The 9 patients who had initially PCNA-
positive residual tumor showed decreasing PCNA
counts with subsequent biopsies (Fig. 3). All lo-
cal failures that could be stained for PCNA (26 of
32) were PCNA positive, with a mean count of
13.7 cells per 100 tumor cells, confirming their
biologic activity.
Forty-two percent of patients (94 of 226) had
hormonal treatment before RT. The effect on
local outcome was examined as a function of du-
ration of hormones. Negative biopsy rates at 18
months are 53% (56 of 106) for those who did
not receive prior hormones and 74% for those
treated for more than 4 months (P = 0.047). Pa-
tients with stage T2b or T3 disease showed no in-
fluence of prior hormone therapy in the rate of
local failure.
COMMENT
Prostate cancer is a disease with a long natural
history. Overall survival is not an appropriate mea-
sure of treatment efficacy in an aging population
with multiple competing causes of mortality.25
Even disease-specific survival can be misleading,
given the high risk of subclinical microscopic dis-
semination at the time of diagnosis. Efficacy of lo-
cal therapy must be judged by local tumor eradi-
cation. Therefore, prostate biopsy should be the
ultimate measure of treatment success. Unfortu-
nately, the prolonged time to histologic tumor
clearance and the microscopic changes caused by
irradiation of nonmalignant glands can make in-
terpretation of biopsy results difficult. Other series
that may not have taken these factors into account
have reported very high rates of residual tumor
following RT.5-7 We have tried to eliminate selec-
tion bias by performing biopsies on all patients.
Thirty-two patients (14%) have had local fail-
ures, 10 with concurrent distant metastases.
Twenty-eight percent of these local failures were
detected by the combination of a positive biopsy
and a rising PSA level without abnormality on
DRE. Thus, although our follow-up is relatively
short, our criteria for local failure are strict, and
failures are diagnosed earlier than they would be
clinically. Surgical series reporting results for rad-
ical prostatectomy show that biochemical failure
UROLOGY@ / APRK 1995 I VOWME 45, NUMBER 4
at 3 years is equivalent to clinical failure at 10
years26,27 and the same may be true for RT.
The 7% false-negative rate (defined as patients
with a negative post-treatment biopsy that later
converts to positive) is comparable to other se-
ries9 and is likely due to sampling error. We have
tried to minimize sampling error by using TRUS
guidance, taking multiple samples, and preferen-
tially targeting the original tumor site.
Biopsy failures, by definition, have no support-
ing evidence for biologically active disease.
Whether the biopsy shows apparently viable tu-
mor or degenerated cells showing marked radia-
tion change, continued resolution over time may
occur. So far, only 18% of patients (21 of 115)
with an initially positive post-treatment biopsy
have developed local failure, whereas 34% (39 of
115) have demonstrated delayed conversion to
negative at a mean of 26 months (range, 17 to 65
months). This rate of late tumor clearance agrees
well with Scardino’s16 rate of 32% of positive 12-
month biopsy results becoming negative by 24
months. For patients not achieving complete tu-
mor clearance, one can expect a continued toll of
local failures. Schellhammer et al.1° have reported
local failures developing in 25% of patients with
a positive post-treatment biopsy by 3 years, 50%
by 5 years, and 65% by 8 years.
Histologic resolution correlates well with PSA
nadir. Patients with local failure had a higher PSA
nadir, 3.9 ng/mL, and reached the nadir earlier (14
months) than patients without failure (0.7 ng/mL
at 23 months). These values are similar to those re-
ported by Ritter et al. 28.. 2.9 ng/mL for patients with
isolated local failure and 0.9 ng/mL for patients
with no failure (Proschek assay: normal upper limit
of 3.2 ng/mL). Our patients with delayed tumor
clearance reached a nadir PSA level of 1.3 ng/mL at
27 months, an interval almost identical to the mean
time for biopsy conversion.
It remains unclear what constitutes a normal
PSA after RT. Since the prostate has not been re-
moved, one cannot expect the serum PSA level to
become undetectable or to fall below 0.6 ng/mL.2T29
Most authors continue to define chemical failure
as a PSA level above the upper limits of normal for
their laboratory Levels associated with long-term
disease-free survival are 1.1 to 1.2 ng/mL,13,28,29 al-
though Stamey et al.ll reported stable values as
high as 2.9 ng/mL in radiation-treated patients. In
our series, the current median PSA in the patients
with NED is 0.7 ng/mL.
Forty-seven of our 226 patients (21%) are
presently classified as biopsy failures. These pa-
tients have no clinical or PSA abnormalities. Al-
U ROLOCYO / APIUL 1995 I VOLUME 45, NUMBER 4
though some will undoubtedly fail, many of these
biopsies may eventually convert to negative. The
median follow-up of this group is only 19.5 months,
which is short compared with the time course for
tumor resolution, and the mean nadir PSA level is
1.0 ng/mL, which indicates an overall favorable
prognosis. However, 14 of the 47 patients (30%)
presently have a serum PSA over 1.5 ng/mL and
this subgroup is at higher risk for eventual failure.
PCNA was found to correlate with tumor via-
bility after radiotherapy The absence of PCNA in
residual tumor is predictive of eventual resolu-
tion, since no patient with negative PCNA had lo-
cal progression. Unfortunately, the converse is not
true, since PCNA positivity may decrease with
time. RT causes postmitotic cell death, allowing
fatally damaged prostate carcinoma cells to un-
dergo a limited number of cell divisions.30,31 Since
tumor doubling times are many months, residual
proliferative activity may be seen up to 24 months
after RT. All local failures showed high PCNA
counts (mean, 13.7 per 100 tumor cells), indica-
tive of retained proliferative potential. Other
markers of cell proliferative capacity are available
(Ki-67, MoAb, AgNor)31-33 and are currently be-
ing investigated.
The correct interpretation of post-RT prostate
biopsies requires a certain expertise. Pathologists
should be encouraged to grade the therapy ef-
fect 34*35as this can be helpful in interpretation of
the ‘report. Gleason grading should be avoided,
since it was designed for untreated prostate can-
cer and may not be applicable to irradiated can-
cers where tumor gland morphology can be
markedly altered. As with androgen deprivation
therapy, invasive cell clusters or single cells can
mimic a high Gleason grade.36 Gleason grading
may, however, be appropriate in biopsies showing
no apparent therapy effect. Staining for high mo-
lecular weight keratin is essential to avoid mis-
taking radiation atypia in benign glands for resid-
ual tumor. Such overcall may have contributed to
uncertainty about the clinical relevance of posi-
tive biopsies,18 since patients with radiation atypia
alone are unlikely to develop distant metastases
or die of prostate cancer.
There is no doubt that true residual tumor of
proven biologic activity (abnormal DRE or rising
PSA levels) will eventually progress and dissemi-
nate. Prestidge et a1.37 report that the most im-
portant predictive factor for the outcome of a pos-
itive post-radiation prostate biopsy is the DRE. In
their series, 52% of patients with an abnormal
DRE developed distant metastases compared with
26% of patients with no palpable abnormality. At
629
a median follow-up of 13.8 years, 50 of 116 pa-
tients (43%) are alive with no evidence of disease
other than a positive prostate biopsy result. PSA
levels for these patients were not reported.
Contrary to the experience of other authors,12
rapidly rising PSA values in our population of ir-
radiated patients were seen only in those with dis-
seminated disease. Local failures had a mean PSA
doubling time of 8.1 months compared with 3.4
months for patients with distant failure. Zagars
amd Pollack38 reported mean doubling times of 6
months for metastatic disease and 10.8 months
for locoregional failure. Although PSA doubling
times appear to be related more to grade than to
site of failure,25 higher grade tumors have a higher
metastatic potential. This may account for the
consistently shorter doubling times for patients
with metastases rather than isolated local failure.
Cox et ~1.~~ have proposed an alternative theory
that, since the more rapidly dividing cells are more
radiosensitive, radiation may select more slowly
proliferating clones, accounting for the slower
rise in PSA levels with local failure.
There was a higher rate of negative biopsies at 18
months in patients who received more than 4
months of prior hormonal therapy (75%) compared
with no hormonal treatment (53%) (P = 0.047).
However, there was no corresponding difference in
local failure rates. This should not be interpreted as
a failure of cytoreductive therapy Patients receiving
hormones before RT were selected for many reasons
and referred for RT at times often unrelated to op-
timal cytoreduction. Furthermore, the hormonal
therapy was not uniform. No conclusions should be
drawn when such heterogeneity exists. Prospective
randomized trials of hormonal cytoreduction are
presently under way
We do not recommend routine post-treatment
biopsies in the follow-up of prostate cancer after
RT. However, TRUS-guided biopsies may be use-
ful if further local treatment is considered for lo-
cal failure. A positive biopsy result after 30
months, especially one showing PCNA positivity,
likely represents true local treatment failure. Al-
though our follow-up is short, we recommend
that treatment decisions should not be based on a
positive biopsy result alone, in the absence of ei-
ther a palpable abnormality or a rising PSA level.
Currently, efforts are under way to reduce the
failure rate. Fiducial markers inserted under ultra-
sound guidance can be used to track prostate mo-
tion during RT and ensure optimal centering of
the radiation beam throughout therapy, reducing
the risk of geographic miss. Conformal therapy
may allow dose escalation without increasing tox-
630
icity. Finally, cytoreduction prior to radiotherapy
may reduce the number of clonogenic cells and
improve the dose/response relationship.
CONCLUSION
Prostate biopsies following radical radiotherapy
may take 2 l/2 to 3 years to resolve. Staining for
proliferative cell nuclear antigen can help differ-
entiate viable from nonviable tumor cells. Al-
though longer follow-up is required, it appears
that an abnormal prostate biopsy without other
evidence of disease is insufficient to make the di-
agnosis of local failure.
J. M. Crook, M.D.
Department of Radiation Oncology
Ottawa Regional Cancer Centre
Ottawa, Canada
ACKNOWLEDGMENT. To Carolle Brazeau for secretarial as-
sistance, and to Dr. V. Zaleski for his expertise in ultra-
sonography and the Ottawa Regional urologists for referral
of patients, especially Dr. N. Futter, Dr. D. McKay, Dr. W.
Walsh (Ottawa General Hospital), Dr. G. Chenard (Riverside
Hospital), Dr. N. Saliba and Dr. S. Faddoul (Centre hospi-
talier de Gatineau), Dr. G. Bourdeau and Dr. C. Lajeunesse
(Montfort Hospital).
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EDITORIAL COMMENT
This study reports the results of a remarkable 6-year effort
by the authors to define the time course of histologic resolu-
tion of prostate cancer after radiotherapy. Of great importance
is that it was conducted prospectively in consecutive patients.
Seventy percent of 226 patients achieved negative biopsy
status by 30 months follow-up and the conversion from early
positivity to later negative biopsies was clearly shown. Im-
portantly, prostate-specific antigen (PSA) response predicted
biopsy outcome but conversion to late negative status was
frequently accompanied by a later PSA response in those pa-
tients. Rapidly rising PSAs after radiation failure were ob-
served only in a small group of patients with documented
metastatic disease.
These data have established the new standard that extends
and more accurately defines previous reports concerning the
accuracy of postirradiation biopsies by Cox et al.’ and
Scardino et nl.* They also show, along with other recent ar-
ticles,3-5 that the previous statement by Kabalin et al.,‘j “Resid-
ual prostate cancer was proven by biopsy in 25 of 27 patients
(93%) 18 months to 12 years after completion of radiation
therapy” and Stamey et al7 “...approximately 20% of the pa-
tients...can be cured by irradiation therapy. The remaining
80% of the patients in whom radiotherapy fails appear to have
an accelerated growth rate...” were observations made in highly
selected patient groups that do not represent the results ob-
tained in unselected radiotherapy patients. Unfortunately,
their comments have been interpreted by many physicians as
representing the results of radiation therapy as a whole.
Dr. Crook and her colleagues have reminded us that there
is a role for institution-based clinical research where care-
fully planned and conducted clinical studies in large groups
of consecutive patients can provide valuable information that
can help to guide us in patient management.
Gerald E. Hanks, M.D.
Fox Chase Cancer Center
7701 Burholme Avenue
Philadelphia, PA I91 I I
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