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Improved survival in patients with locally advanced prostate cancer treated
radiotherapy and goserelin
Bolla, M.; González González, D.; Warde, P.; Dubois, J.B.; Mirimanoff, R-O.; Storme, G.;
Bernier, J.; Kuten, A.; Sternberg, C.; Gil, T.; Collette, L.; Pierart, M.
DOI
10.1056/NEJM199707313370502
Publication date
1997
Published in
The New England journal of medicine
Link to publication
Citation for published version (APA):
Bolla, M., González González, D., Warde, P., Dubois, J. B., Mirimanoff, R-O., Storme, G.,
Bernier, J., Kuten, A., Sternberg, C., Gil, T., Collette, L., & Pierart, M. (1997). Improved
survival in patients with locally advanced prostate cancer treated radiotherapy and goserelin.
The New England journal of medicine
,
337
, 295-300.
https://doi.org/10.1056/NEJM199707313370502
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Download date:10 Aug 2022
Volume 337 Number 5
295
IMPROVED SURVIVAL WITH RADIOTHERAPY AND GOSERELIN IN LOCALLY ADVANCED PROSTATE CANCER
IMPROVED SURVIVAL IN PATIENTS WITH LOCALLY ADVANCED PROSTATE
CANCER TREATED WITH RADIOTHERAPY AND GOSERELIN
M
ICHEL
B
OLLA
, M.D., D
IONISIO
G
ONZALEZ
, M.D., P
ADRAIG
W
ARDE
, M.D., J
EAN
B
ERNARD
D
UBOIS
, M.D.,
R
ENÉ
-O
LIVIER
M
IRIMANOFF
, M.D., G
UY
S
TORME
, M.D., J
ACQUES
B
ERNIER
, M.D., A
BRAHAM
K
UTEN
, M.D.,
C
ORA
S
TERNBERG
, M.D., T
HIERRY
G
IL
, M.D., L
AURENCE
C
OLLETTE
, M.S
C
.,
AND
M
ARIANNE
P
IERART
A
BSTRACT
Background
We conducted a randomized, pro-
spective trial comparing external irradiation with
external irradiation plus goserelin (an agonist ana-
logue of gonadotropin-releasing hormone that re-
duces testosterone secretion) in patients with locally
advanced prostate cancer.
Methods
From 1987 to 1995, 415 patients with lo-
cally advanced prostate cancer were randomly as-
signed to receive radiotherapy alone or radiotherapy
plus immediate treatment with goserelin. The pa-
tients had a median age of 71 years (range, 51 to 80).
Patients in both groups received 50 Gy of radiation
to the pelvis over a period of five weeks and an ad-
ditional 20 Gy over an additional two weeks as a
prostatic boost. Patients in the combined-treatment
group received 3.6 mg of goserelin (Zoladex) subcu-
taneously every four weeks starting on the first day
of irradiation and continuing for three years; those
patients also received cyproterone acetate (150 mg
orally per day) during the first month of treatment to
inhibit the transient rise in testosterone associated
with the administration of goserelin.
Results
Data were available for analysis on 401
patients. The median follow-up was 45 months. Kap-
lan–Meier estimates of overall survival at five years
were 79 percent (95 percent confidence interval, 72
to 86 percent) in the combined-treatment group and
62 percent (95 percent confidence interval, 52 to 72
percent) in the radiotherapy group (P
0.001). The
proportion of surviving patients who were free of
disease at five years was 85 percent (95 percent con-
fidence interval, 78 to 92 percent) in the combined-
treatment group and 48 percent (95 percent confi-
dence interval, 38 to 58 percent) in the radiotherapy
group (P
0.001).
Conclusions
Adjuvant treatment with goserelin,
when started simultaneously with external irradia-
tion, improves local control and survival in patients
with locally advanced prostate cancer. (N Engl J Med
1997;337:295-300.)
©1997, Massachusetts Medical Society.
From University Hospital, Grenoble, France (M.B.); Akademisch Me-
disch Centrum, Amsterdam, the Netherlands (D.G.); Princess Margaret
Hospital, Toronto (P.W.); Centre Régional de Lutte contre le Cancer Val
d’Aurelle, Montpellier, France (J.B.D.); Centre Hospitalier Universitaire
Vaudois, Lausanne, Switzerland (R.-O.M.); Oncologisch Centrum, Brus-
sels (G.S.); Ospedale San Giovanni, Bellinzona, Switzerland (J.B.); Ram-
bam Medical Center, Haifa, Israel (A.K.); Ufficio Sternberg & Pansadoro,
Rome (C.S.); and the European Organization for Research and Treatment
of Cancer Data Center, Brussels (T.G., L.C., M.P.). Address reprint re-
quests to Dr. Bolla at the Radiotherapy Department, University Hospital,
B.P. 217 38043 Grenoble CEDEX 9, France.
HE role of external irradiation in patients
with locally advanced prostate cancer is
controversial.
1,2
At this stage of the disease
the tumor extends beyond the capsule of
the prostate; it may infiltrate neighboring structures
and involve regional lymph nodes, but there are no
distant metastases (stage T3–4, N0–2, M0, accord-
T
ing to the tumor–node–metastasis [TNM] classifica-
tion system of the International Union against Can-
cer). In a study begun in 1973, the overall survival
after 15 years for 287 patients with locally ad-
vanced prostate cancer who were treated with con-
ventional external irradiation was 23 percent.
3
Achiev-
ing local control after radiotherapy improved the
prognosis; among patients who did not have in-
volvement of regional lymph nodes at the time of
diagnosis, 70 percent of those who attained local
control survived for 20 years free of distant metasta-
ses, as compared with 13 percent of those who had
a local relapse (P
0.001).
4
Hormonal therapy often prolongs the suppression
of the primary tumor by radiotherapy,
5
but the
question remains whether hormonal therapy should
be reserved for relapse or used early in asymptomatic
patients with locally advanced disease who are receiv-
ing external radiation treatment. Three controlled
clinical trials have failed to demonstrate the value of
prophylactic therapy with diethylstilbestrol, orchi-
ectomy, or both in patients treated with external
radiotherapy.
6-8
A study of 277 patients found no
differences among those undergoing orchiectomy,
radiotherapy, or combined treatment; orchiectomy,
however, whether alone or combined with radio-
therapy, significantly delayed metastases as compared
with radiotherapy alone.
9
Goserelin is an agonist analogue of gonadotropin-
releasing hormone that induces hypogonadism by
reducing the secretion of gonadotropin and there-
fore testosterone. The purpose of this trial was to
determine whether treatment with goserelin, when
initiated during the first week of irradiation, increas-
es disease-free survival and prolongs overall survival
in patients at high risk for metastatic prostate cancer.
Copyright © 1997 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at UNIVERSITEIT VAN AMSTERDAM on July 18, 2006 .
296
July 31, 1997
The New England Journal of Medicine
METHODS
Eligibility Criteria
Patients were eligible if they were under 80 years of age, with
histologically proved prostatic adenocarcinoma that was intracap-
sular (T1) or confined to the gland (T2), without detectable in-
volvement of regional lymph nodes (N0-X), and of World Health
Organization (WHO) histologic grade 3; or if they had prostate
cancer of any histologic grade that extended beyond the capsule
(T3) or infiltrated neighboring structures (T4) without involving
regional lymph nodes. The clinical evaluation included bone
scanning, chest radiography, and ultrasonography or computed
tomography (CT) of the liver. Lymph nodes were evaluated by
CT, bipedal lymphangiography, or extraperitoneal lymphadenec-
tomy. Laboratory studies included complete blood counts and
measurements of creatinine, serum prostatic acid phosphatase, se-
rum testosterone, and prostate-specific antigen (PSA), as assessed
by radioimmunometric or immunoenzyme assays. Eligible patients
had had no previous treatment for prostate cancer and gave writ-
ten informed consent. Patients with a previous malignant disease,
except for treated basal-cell carcinoma of the skin, and those with
evidence of distant metastases, including metastases to common
iliac or paraaortic lymph nodes, were excluded. Pathological spec-
imens were reviewed centrally.
Techniques of Treatment
Radiotherapy
Photons of 10 MV and above were recommended; when they
were not available, the use of cobalt-60 was acceptable provided
the skin-to-source distance was more than 80 cm and patients
had a maximal anterior–posterior pelvic diameter of less than 22
cm. Planning target volume I was the whole pelvis, and planning
target volume II the prostate and seminal vesicles. The whole pel-
vis was irradiated with a four-field technique, with one anterior–
posterior field, one posterior–anterior field, and two parallel op-
posed lateral fields. In the craniocaudal direction the upper limit
was the L5–S1 interspace, the lower limit was the ischial tuberos-
ities, and the lateral margins were 1 cm beyond the maximal width
of the bony pelvis; some centers preferred to irradiate a smaller tar-
get volume by using anterior–posterior fields averaging 12 by 12
cm and lateral fields averaging 12 by 10 cm. Planning target vol-
ume II was irradiated with either the same technique or with three
fields: one anterior–posterior and two lateral fields with wedge fil-
ters. The anterior and posterior security margins on the lateral
fields were at least 2 cm. The specification of the dose was given
at the intersection of the beam axes according to Report 29 of the
International Commission on Radiation Units and Measurements.
10
The dose per fraction was 2 Gy. Patients were treated once a day,
five days a week, for seven weeks; planning target volume I was ir-
radiated during a five-week period with up to 50 Gy, and planning
target volume II was treated during the last two weeks with an ad-
ditional 20 Gy.
Hormonal Treatment
Goserelin (Zoladex, Zeneca-Pharma) was supplied by the man-
ufacturer in a disposable syringe loaded with 3.6 mg of the drug
and fitted with a 16-gauge needle. The drug was administered
subcutaneously every four weeks, starting on the first day of pel-
vic irradiation and continuing for three years; 150 mg of a steroi-
dal antiandrogen, cyproterone acetate (Androcur, Schering), was
given orally for one month, starting one week before the first
dose of goserelin, to inhibit the transient rise of testosterone
caused by goserelin.
Toxicity
Acute side effects of radiotherapy were scored according to the
WHO scale.
11
Late toxicity was scored according to the Radio-
therapy Oncology Group scale: 0, no symptoms; 1, minor tran-
sient symptoms; 2, distressing, persistent, or recurring symptoms
requiring occasional prolonged medical treatment; 3, symptoms
requiring prolonged medical treatment, surgical intervention, or
both; or 4, fatal complications. For patients receiving goserelin,
adverse reactions were registered as hot flashes and gynecomastia.
There was no quality-of-life study.
Assessment of Progression
Local failure was defined as an increase of more than 50 per-
cent in the product of the two maximal perpendicular diameters
of the primary lesion as measured digitally, by CT or transabdom-
inal ultrasonography; in case of doubt, biopsy was highly recom-
mended. Local progression was defined as the recurrence of a pal-
pable tumor after initial regression. Regional failure, in the pelvic
or paraaortic lymph-node areas, was demonstrated by ultrasonog-
raphy or CT and was confirmed by biopsy. Distant metastases in
bones, parenchymal organs, or soft tissues were identified radio-
logically and then by biopsy if deemed necessary.
Quality Assurance
The calibration of every linear accelerator was obtained by
mailed thermoluminescence dosimetry checks. Individual clinical,
biologic, pathological, and follow-up procedures for the main
participating centers were reviewed individually to reconcile dis-
crepancies between local data and data registered at the European
Organization for Research and Treatment of Cancer (EORTC)
Data Center. Protocol compliance was checked by a dummy-run
procedure to evaluate differences in the definition of target vol-
ume, in treatment technique, and in dose specification and ho-
mogeneity.
12
End Points and Statistical Analysis
Overall survival was measured from the date of randomization
to the date of death or the most recent follow-up. The disease-
free interval was measured from the date of randomization to the
date of local or regional failure, the first appearance of distant me-
tastases, or the last follow-up, whichever occurred first. The time
until the first treatment failure after a biologic response was meas-
ured from the date of randomization to the date of clinically de-
termined progression, PSA-determined progression, or the most
recent follow-up; PSA-determined progression was defined as a
PSA level greater than 1.5 ng per milliliter and increasing on two
consecutive measurements.
The protocol was designed to detect a minimal increase from
40 percent to 55 percent in the 5-year disease-free rate, corre-
sponding to an increase from 3.8 to 5.8 years in the median dis-
ease-free interval (assuming exponential distribution). To detect
this difference, 75 patients in each treatment group had to be fol-
lowed until relapse (
a
0.05,
b
0.2). Survival curves were esti-
mated by using the Kaplan–Meier technique.
13
All comparisons
were made by means of a two-sided log-rank test with a 0.05 sig-
nificance level.
14
Data were analyzed according to the intention-
to-treat principle.
Randomization
Randomization was centralized at the EORTC Data Center.
Patients were stratified according to institution, the clinical stage
of the disease, the results of extraperitoneal pelvic lymph-node bi-
opsy, and the irradiation technique. The randomization was per-
formed by the minimization technique.
15
RESULTS
Characteristics of the Patients
From May 1987 through September 1995, 415
patients entered the study — 208 in the pelvic-
radiotherapy group and 207 in the combined-treat-
Copyright © 1997 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org at UNIVERSITEIT VAN AMSTERDAM on July 18, 2006 .
IMPROVED SURVIVAL WITH RADIOTHERAPY AND GOSERELIN IN LOCALLY ADVANCED PROSTATE CANCER
Volume 337 Number 5
297
ment group. The median duration of follow-up was
45 months. At the time of analysis, all but 14 pa-
tients had been evaluated. For the analysis, these 14
patients were considered eligible. Ten patients — six
in the radiotherapy group and four in the com-
bined-treatment group — were ineligible because of
bone metastases (two patients), paraaortic lymph-
node metastases (one), thrombocytopenia (one), in-
appropriate clinical stages (T1G1, one; T2G1, one;
and T2G2, three; and T2 without mention of grade,
one). The two groups of patients were well balanced
with regard to age, WHO performance status, clini-
cal stage, presence or absence of pelvic lymph-node
metastases, WHO histologic grade, Gleason grade,
serum acid phosphatase level, and base-line PSA lev-
el (Table 1). Cardiovascular disease was present in
29 percent of the patients in the radiotherapy group
and 24 percent of those in the combined-treatment
group; no chronic disease was mentioned for 48
percent of the patients in the radiotherapy group as
compared with 53 percent in the combined-treat-
ment group.
Compliance
Information about treatment was available for
401 patients — 198 in the radiotherapy group and
203 in the combined-treatment group. Of the pa-
tients in the radiotherapy group, 99 percent re-
ceived external irradiation; 80 percent of these pa-
tients received large-field and 20 percent small-field
radiotherapy. Three of the 198 patients refused the
treatment.
Of the 203 patients in the combined-treatment
group, 2 refused any treatment and 6 refused hor-
monal therapy. At the time of analysis, not all the pa-
tients in this group had completed the three-year
treatment with goserelin, but 15 patients continued
that treatment for more than three years (Table 2).
Eighty-one percent of the patients in this group re-
ceived large-field and 19 percent small-field radio-
therapy.
Toxicity
Of the acute toxic effects listed in Table 3, none
with a grade of 3 or 4 affected more than 5 percent
of either group except for diarrhea. With a median
follow-up of 45 months, not more than 1 percent
of either group had grade 3 late toxic effects, in-
cluding hematuria, chronic diarrhea, proctitis, cysti-
tis, small-bowel obstruction, incontinence, and ure-
thral stricture. Data on erectile function were not
collected systematically. Among the patients receiv-
ing goserelin, 62 percent had hot flashes, but only
34 percent had more than three per day. During
follow-up, more patients in the combined-treat-
ment group than in the radiotherapy group had late
grade 1–3 incontinence (29 percent vs. 16 percent,
P
0.002); the proportions of patients with late
grade 1–3 urethral stricture (20 percent in the com-
bined-treatment group vs. 13 percent in the radio-
therapy group) were not significantly different (P
0.09). Thirty-eight patients (19 percent) had adverse
reactions to the gonadotropin-releasing hormone
analogue: hot flashes (22 patients), gynecomastia
(4), mastodynia (1), breast pain and galactorrhea
(1), sweating (2), weakness (2), depression (1),
deep venous thrombosis (1), and unspecified reac-
tions (4).
Efficacy
The Kaplan–Meier estimate of overall survival at
five years in the combined-treatment group was 79
*T denotes tumor and N node, according to the TNM
(tumor–node–metastasis) classification system; PSA denotes
prostate-specific antigen.
T
ABLE
1.
A
GE
, P
ERFORMANCE
S
TATUS
, WHO G
RADE
,
G
LEASON
S
CORE
,
AND
T
UMOR
AND
N
ODE
C
LASSIFICATION
AMONG
P
ATIENTS
E
LIGIBLE
FOR
THE
T
RIAL
.
C
HARACTERISTIC
*
R
ADIOTHERAPY
(N
198)
C
OMBINED
T
REATMENT
(N
203)
Age (yr)
Median
Range
70
51–80
71
54–80
number (percent)
Performance status
0
1
2
157 (79)
37 (19)
4 (2)
158 (78)
38 (19)
7 (3)
WHO grade
1
2
3
X
37 (19)
90 (45)
67 (34)
4 (2)
44 (22)
96 (47)
62 (31)
1 (
1)
Gleason score
2–4
5–6
7–10
Unknown
16 (8)
38 (19)
71 (36)
73 (37)
10 (5)
49 (24)
66 (33)
78 (38)
T classification
T1
T2
T3
T4
0
17 (9)
163 (82)
18 (9)
2 (1)
15 (7)
167 (82)
19 (9)
T according to grade
T1–T2, G3
T3–T4, any G
17 (9)
181 (91)
17 (8)
186 (92)
N classification
N0
N
Unknown
175 (88)
6 (3)
17 (9)
181 (89)
8 (4)
14 (7)
PSA (no. of times the upper
limit of normal)
1
1–2
2–5
5–10
10
Unknown
10 (5)
11 (6)
46 (23)
48 (24)
62 (31)
21 (11)
15 (7)
12 (6)
40 (20)
47 (23)
72 (35)
17 (8)
Copyright © 1997 Massachusetts Medical Society. All rights reserved.
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298
July 31, 1997
The New England Journal of Medicine
percent (95 percent confidence interval, 72 to 86
percent), as compared with 62 percent (95 percent
confidence interval, 52 to 72 percent) in the radio-
therapy group (P
0.001) (Fig. 1). For overall sur-
vival, the hazard ratio was 0.50 (95 percent confi-
dence interval, 0.33 to 0.76). There were 58 deaths
in the radiotherapy group and 35 in the combined-
treatment group. Of these deaths, 26 in the radio-
therapy group and 6 in the combined-treatment
group were due to prostate cancer. Among the pa-
tients who survived for five years, the disease-free
rate was 85 percent (95 percent confidence interval,
78 to 92 percent) in the combined-treatment group
and 48 percent (95 percent confidence interval, 38
to 58 percent) in the radiotherapy group (hazard
ratio
0.22; 95 percent confidence interval, 0.15
to 0.32; P
0.001) (Fig. 2). Seventy-eight patients
had disease progression in the radiotherapy group,
as compared with 20 in the combined-treatment
group. Table 4 shows the sites of progression. In the
radiotherapy group, the treatment given after pro-
gression included goserelin in 56 cases (72 percent)
and another hormonal treatment in 17 cases and
was unspecified in 5 cases. The 17 other treatments
were orchiectomy (eight patients), another hormo-
nal treatment (two), delayed treatment (five), and
no treatment, because of intercurrent death (one)
and the patient’s refusal (one). The five-year local-
control rate was 97 percent in the combined-treat-
ment group and 77 percent in the radiotherapy
group (hazard ratio
0.19; 95 percent confidence
interval, 0.10 to 0.37; P
0.001). The combined-
treatment group had a longer time until the first
treatment failure after a biologic response than the
radiotherapy group (6.6 years [95 percent confi-
dence interval, 3.5 to 5.3] vs. 4.4 years [95 percent
confidence interval, 5.8 to 9.0]; hazard ratio
0.17;
95 percent confidence interval, 0.11 to 0.48; P
0.001). The five-year failure-free rate after biologic
response was 81 percent for the combined-treat-
ment group and 43 percent for the radiotherapy
group.
DISCUSSION
We found that adjuvant therapy with an analogue
of gonadotropin-releasing hormone (goserelin), start-
ed at the beginning of external irradiation treatment
and continuing for three years, can improve the five-
year overall survival of patients with locally advanced
prostate cancer. Two previous studies have compared
short-term hormonal therapy before and during ex-
ternal irradiation, or long-term hormonal therapy af-
ter external irradiation, with radiation therapy alone
for locally advanced prostatic carcinoma. The hor-
monal therapy included flutamide and goserelin for
the former and goserelin alone for the latter; both
protocols showed advantages over radiotherapy alone
in terms of local control, the incidence of distant
metastases, and progression-free survival.
16,17
How-
ever, it is difficult to compare these three trials, since
the eligibility criteria, the timing and duration of ad-
ministration of goserelin, the definition of local con-
trol, and the results in the radiotherapy groups are
not quite comparable. In our study, we assessed lo-
cal control by endorectal examination; a second bi-
*Five patients declined further treatment because
of hot flashes (after 3, 8, 11, 14, and 16 months).
Two patients had their treatment stopped because of
depression (after 3 and 19 months). One patient
stopped because of mastodynia and galactorrhea (af-
ter 4 months).
†One patient underwent orchiectomy because of
poor compliance with goserelin treatment (after 20
months). One patient stopped taking goserelin to
undergo urethrotomy because of recurrent strictures
(after 4 months). One patient was lost to follow-up
(after 15 months). Two patients stopped the radio-
therapy and goserelin treatment for reasons unrelat-
ed to the potential side effects of the drug.
T
ABLE
2.
C
OMPLIANCE
WITH
THE
G
OSERELIN
R
EGIMEN
AMONG
195 P
ATIENTS
IN
THE COMBINED-TREATMENT GROUP.
COMPLIANCE NO. (%)
Continued goserelin for 3 yr 15 (8)
Received goserelin for 3 yr 93 (48)
Received goserelin until progression
or death
21 (11)
Stopped in 3 yr because of toxicity* 8 (4)
Stopped in 3 yr for other reasons† 5 (3)
In study for 3 yr, still receiving
treatment
53 (27)
*Only grade 3 toxic effects were observed.
TABLE 3. GRADE 3 OR 4 TOXIC EFFECTS
R
EPORTED DURING RADIOTHERAPY
AMONG ALL ELIGIBLE PATIENTS
WHO UNDERWENT RADIOTHERAPY.
TOXIC EFFECT
RADIOTHERAPY
(N 195)
C
OMBINED
T
REATMENT
(N 201)
no. of patients (%)
Leukopenia* 1 (1) 0
Thrombocytopenia* 1 (1) 0
Anemia* 0 3 (1)
Nausea or vomiting* 0 1 (1)
Diarrhea* 22 (11) 11 (5)
Urinary frequency 10 (5) 10 (5)
Dysuria 6 (3) 4 (2)
Radiation dermatitis* 4 (2) 1 (1)
Hematuria* 1 (1) 0
Performance status 3 (2) 3 (1)
Copyright © 1997 Massachusetts Medical Society. All rights reserved.
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