Individualized PER
KOLSTAD,
MARGARET KARI
H@EG,
treatment of ovarian cancer M.D.
DAVY,
M.R.C.O.G.
M.D.
Oslo, Norway During the years 1968 to 1974, 418 patients with Stage I and Stage II malignant epithelial tumors of the ovary entered a controlled clinical trial. The purpose was to compare the results of postoperative external irradiation with intraperitoneal instillation of radioactive colloidal gold (AIF). The Stage I series comprised 175 invasive carcinomas and 83 tumors of low potential malignancy. The Stage II series comprised 160 invasive carcinomas and five cases of potentially malignant tumors. No significant difference in the five-year survival rate was found for the patients with Stage I lesions. A lower number of cancer deaths among those treated with AP was outweighed by a higher number of deaths from complications. However, patients with Stage IA serous and mutinous tumors, Stage IB and IC turnon+ (all histologic types), and ruptured tumors did significantly better when treated with Au’“. The five-year survival rate for patients with Stage II lesions treated with gold was 54.1 per cent as compared to 40.0 per cent for those receiving external irradiation. In agreement with these observations, a new treatment protocol is proposed which includes a randomized trial to study the value of adjuvant chemotherapy. (AM. J. OBSTET. GYNECOL. 128:617,
1977.)
I N MANY Western countries, ovarian cancer ranks first among the lethal cancers developing in the genital tract. In Scandinavia, it appears that the incidence of this malignancy is increasing. The age-adjusted incidence rate is now close to that of carcinoma of the cervix. In Norway, compulsory cancer registration was established in 1952. Since 1932, the Norwegian Radium Hospital has been the main referral center for gynecologic cancer. During the last two decades, an increasing number of patients with malignant ovarian neoplasia have been admitted to the hospital for primary therapy, postoperative radiotherapy, or chemotherapy (Fig. 1). In the period from 1967 to 1975, 2,175 new cases have been treated, of which about 50 per cent belonged to the earlier Stages I and II and 50 per cent belonged to the late Stages III and IV (Fig. 2). Malignant ovarian neoplasia comprises a het-
erogeneous group of diseases. It has been stressed repeatedly that studies on the results of treatment must be based on histologically and biologically homogeneous series. No standard treatment can or should be used for all the different types and stages of the disease. Surgery is still the keystone in the treatment of ovarian carcinoma. However, several reports in the literature indicate that, for example, additional radiotherapy or chemotherapy may improve the results.‘-4 In 1971, a retrospective clinical and histopathologic study of 990 cases of malignant epithelial tumors was published.5 In agreement with the experience of earlier investigators, 6-8 large differences in the results of treatment were observed according to histologic type and grading. Among true carcinomas of Miillerian origin, endometrioid and mutinous types had the best prognosis, followed by serous and ultimately undifferentiated carcinomas. The so-called potentially malignant tumors did not always behave as benign disease. With a sufficiently long follow-up period, extending from 15 to 20 years, more than 10 per cent of such patients died from recurrence of cancer.’ Radioactive colloidal gold has been employed in the treatment of ovarian carcinoma in the department since 1954. In the earlier years, including the period from 1954 to 1957, external radiotherapy was given by
From the Department of Gynecology and the Department of Pathology, The Nonwgian Radium Hospital. The Annual Guest Lecture, presented at the Forty-fourth Ann& Meeting of the Central Association of Obstetricians and Gynecologists, Houston, Texas, October 14-16, 1976. Reprint requests: Dr. Per Kolstad, Department Gynecology, The Norwegian Radium Hospital, Norway.
of Oslo 3,
617
618
Kolstad, Davy, and Haeg
Reported the
Table I. Five-year survival rate in relation tu type of radiotherapy and stage in carcinoma of the ovary. tumor completely removed (Aurrb and associates”)
to
Cancer
Romtgtw (250 kil.) I
:
Treated
1501
in the
Norwegian
Radium
Hospital
100 1. I
,
-40
1930
-50
-70
-60
150
Stage
No.
Alizje
100
I
55
2X
II
17
7
III
-
1. The total number of new cases of carcinoma of the detected in Norway and the number of patients treated in the Norwegian Radium Hospital, 1932 to 1975.
Fig. ovary
No.
A&w
62
63
51
.43
x4
7
30
15
8
53
2
22
15
6
38
d41iue
51
98
41
23 9
-
Roentgen (250 ku.)
WI-
Per c’mt
No.
STAGE
IV
STAGE
III
Beta&on (31 7nex)
Radioactira Au’*8
,i_,,.,
Stage
soIO-
PIT cent
Table II. Five-year survival rate in relation to type of radiotherapy and stage in ovarian carcinoma, nonradical operation (Aure and associates”)
too-
u
Per cent
-75
Year
l3
Betatron ( ? I rw.)
II
COso-
STAGE II
.o-
III IV
K L
3o xl-
STAGE I
10 o-
1%1
1968
I%9
Fig. 2. Stage distribution
,970
1971
of 2,175
1972
1973
1974
1975
new cases of ovarian
cancer
treated in the Norwegian Radium Hospital during the period 1967 to 1975. Total number of patients treated each year is shown on the top of the columns. conventional 250 kv. roentgen machines. From 1957, megavoltage betatron irradiation was brought into use. A comparison between the results achieved with these three types of irradiation therapy disclosed significantly better results for Stage I and Stage II cases in which radioactive colloidal gold was given.s However, it should be stressed that this statement held true only for those cases where the tumor was completely removed (Tables I and II). Furthermore, when the results were presented, it was emphasized that the investigation was retrospective and that definite conclusions about the advantages of radioactive gold could be reached only by controlled clinical trials in which both the stage and tumor type were taken into consideration.Y In 1968, it was decided to carry out such a trial, and the present report is an up-to-date survey of the observations made.
Mstsrlsl and methods Clinical staging and histologic typing were performed according to the rules proposed by the Cancer Committee of the International Federation of Gynecology and Obstetrics (FIGO). The FIG0 histopathologic classification agrees in principle with that of the World Health Organization. Only Stage I and Stage II malignant epithelial tumors were included in the study. In all cases. initial therapy consisted of bilateral salpingo-oophorectomy, hysterectomy, and omentectomy. Intraperitoneal instillation of radioactive gold was always performed in connection with laparotomy. If extensive intra-abdominal adhesions were found, the patient was taken out of the trial. Furthermore. young patients with unilateral tumors of so-called IOU potential malignancy did not receive any type 01‘ radiotherapy. A few patients were considered too old to enter the trial, and some patients were excluded because
of
various
medical
conditions.
Otherwise.
there was no selection in the series. The patients randomized to radioactive gold received an intraperitoneal dose of 100 mCi of Au’“’ dissolved in 1,000 ml. of physiologic saline. In addition, they were given 3,000 radb of external megavoltage radiation
against
a pelvic
field.
The
other
group
rc’-
Volume
128
Number
6
Individualized treatment of ovarian cancer
Table III. Age distribution in the randomized series of Stage I and Stage II ovarian carcinoma Stage I Age (yr.) 529 30-39 40-49 50-59
60-69 70-79
80-89 Total
No.
Table
Stage II
Gold
Radiation
Gold
Radiation
8 11 16 44 35 10
9 12 34 35 33 11
3 5 20 22 15 9
-
-
21 29 95 133 103 36 1
124
134
74
1 1 25 32 20 6 1
86
418
IV. Distribution
Stage IA IB
IC IIA IIB IIC
Total
SURGERY:
2.
POSTOPERATIVE RADIOTHERAPY
BILATERAL SAlPlNGO-OOPHORECTOMY, HYSTERECTOMY AND OMENTECTOYY
: RANDOMIZED A.
group Radiation
94
97
191
100mCi VOLTAGE
+ 3OObrad EXTERNAL RADIATION, PELVIC
FIELD
’ RADIATION’ 5000 rad EXTERNAL RADIATION, PELVIC
HIGH FIELD
VOLTAGE
Fig. 3. Treatment protocol followed during the study period 1968 to 1972 for Stage I and Stage II malignant epithelial tumors of the ovary.
Total No.
23 7 15 54 5
22 15 17 58
45 22 32 112
11
16
Treatment
220
:
‘GOLD’ Au”* HIGH
a.
TRIAL
Table V. Number of invasive carcinomas and potentially malignant tumors in the two treatment groups, Stage I lesions
Gold
198
PRIMARY
Total No.
by stages
Treatment
1.
619
418
Histology
Invasive Potentially tumors Total
ceived postoperative external megavoltage radiation against a pelvic field with a tumor dose of 5,000 rads. A summary of the treatment protocol is shown in Fig. 3. The youngest patient was 20 years of age; the oldest 8 1 years. The majority were in the age groups of 50 to 59 and 60 to 69 (Table III). The number of cases in the different age ranges was almost identical in the two treatment groups for both the Stage I and the Stage II cases. The slightly lower total number of patients in the series receiving radioactive gold is mainly due to exclusion of patients with intra-abdominal adhesions. Altogether, 10 patients were taken out of the trial because of this reason or some other factor which made the use of colloidal gold contraindicated. The total number with a sufficient follow-up time comprised 418 patients. Distribution by clinical stages is shown in Table IV. Apparently, the randomization has been satisfactory except for the fact that there were slightly more patients with ascites (Stages IC and IIC) receiving external irradiation. As mentioned previously, potentially malignant tumors were included in the series except for those in young women of childbearing age. A more conservative attitude was taken in such cases with some of the young women having only the tumor-involved ovary removed. Altogether, 258 cases were classified as Stage
cancer malignant
Stage
group
Gold
Radiation
IA IB IC
68 14
64
IA IB IC
26 9
33
2
4
5
124
13 11 9 134
Total No.
132 27 16
59 18 6
175
83 258
I lesions, of which 175 were invasive carcinomas and 83 were potentially malignant tumors (Table V). From a statistical point of view, the allocation by random numbers to the two treatment groups was satisfactory. As mentioned previously, only malignant epithelial tumors were included. Histology of the Stage I invasive carcinomas is shown in Table VI. Altogether, 87 patients were treated with radioactive gold and 88 patients received external radiation. There was a slightly higher number of patients with serous carcinomas in the external radiation group, which, however, was compensated for by a higher number of endometrioid lesions in the radioactive gold group. Among the potentially malignant tumors, there were found no examples of mesonephroid or undifferentiated lesions, and only one case was classified as an endometrioid lesion of low potential malignancy (Table VII). The majority belonged to the serous type. The microscopic examination of the Stage II lesions revealed a much higher number of serous carcinomas in the radiation group than in the gold group. On the other side, mesonephroid tumors was a more frequent finding in the gold group (Table VIII). Only five cases of potentially malignant tumors were classified as Stage II carcinomas, of which two were allocated to the
620
Kolstad, Davy, and Hpeg
/Ext. 100r-V-V-”
-v
O\
90-
-100
‘v
o-o-o-
Au
- 90
198
-80
70-
-
STAGE I, POTENTIALLY MALIGNANT
40
-
40
30
-
30
20
-20
10 I
-
4
Fig. 4. Actuarial survival curves for patients with Stage 1 potentially malignant tumors treated with external radiation (Ext.) and radioactive colloidal gold (Au’“*).
Treatment Histology oj invasive carcinoma
Gold
group
18 22 28 18 1
24 26 23 14 1
42 48 51 32 2
Total
87
88
175
radioactive gold group and three were placed in the external radiation group. There were three serous and two mutinous tumors. These five cases have not been included in the evaluation of the results of treatment. All five patients are alive with no signs of disease after 4 to 6 years of follow-up.
Follow-up The follow-up has been performed in the outpatient department of the Norwegian Radium Hospital, in the hospital,
or by the patient’s
private
physician.
No case has been lost to follow-up. Usually, the patients have been examined every second month the first year, every third month the second year, and then at increasing intervals with one visit each year after 5 years of follow-up. patients
When have
been
recurrences readmitted
have to the
27
16
19
I
0
37
46
Total
Table VIII. Distribution by histologic Stage II invasive carcinoma
Hzstology
Gold
Serous Mutinous Endometrioid Mesonephroid Undifferentiated
17 12 26 16 3
type.
group Radzation
Total No.
39 16 20 7 4
56 28 46 23 7
Total
Total No.
Serous Mutinous Endometrioid Mesonephroid Undifferentiated
referring
20
Mucinoos
Table IX. Observed number of deaths from carcinoma during the follow-up period in the two treatment groups for Stages IA, IB, and IC lesions, all histologic types
type of
Radiation
Radiation
Gold
Sewus
10
YEARS
Table VI. Distribution by histologic Stage I invasive carcinomas
gyoup
Treatment
5
type.
tumors
Trratmrnt
TLMOURS
3
by histologic malignant
Endometroid 50
2
Distribution
Potcvztial(7~ malignant tumors
-60 -
1
I potentially
70
50 c
olo
VII.
Stage
(46) O (37)
2
80-
60-
Table
been
detected,
hospital,
and
the as a
IA
Y4
IB
2.‘1
IC
7
14
11.3
Total
12
124
12.8
97
14
14.4
2
8.7
0
0
22
5
22.6
15
3
20.0
22
16.4
134
rule chemotherapy with an alkylating agent (thio-tepa) has been started. When the present study was closed, the follow-up time had been from five to eight years for the Stage I cases and from three to eight. years for the Stage II cases. Survival curves have been constructed according to the actuarial life-table method, which means that intercurrent deaths have been included. However, with this method, the inclusion of intercurrent deaths is partly compensated
for
by the
mathematic
formula
used.
Re8ults
Pote&idly tumors
of low
malignant potential
tumors. malignancy.
Of 83 patients 46 received
with exter-
Volume Number
Individualized treatment of ovarian cancer
128 6
-1
loo
-100
90
- 90
80 70 60
E d
40
50
INVASIVE
t
- 80 z 0’
70-
\
0
ag
60 _
\
”\
Au’96
Olo
CARCINOMA 40 30
g 2
50-
2 L
40 30-
-
70
-
60
0 (74)
\
STAGE I,
50
621
- so
“\ -
“lv
(86)
-40
z
Ext.
20
-
30
-
20
10 01
I
I
1
2
1
YE:RS
4
I
4
5
d
0
01
, 1
I 2
1
I 5
t 4
1 0
YE:RS Fig. 5. Actuarial sive carcinoma
survival curves of the ovary.
for patients
with
Stage I inva-
nal irradiation and 37 radioactive gold. The five-year survival rates were 92.5 and 87.2 per cent, respectively (Fig. 4). The difference is not statistically significant. The slightly poorer result for the gold series is due to two patients who died from complications related to the instillation of the radioactive material. Two patients, one in each treatment group, died from cancer. They both had mutinous tumors. Stage I invasive carcinoma. Survival curves for the Stage I lesions classified as true invasive carcinomas are shown in Fig. 5. The total number comprised 175 cases, in 87 of which gold and 88 external irradiation were given. The five-year survival rate for the first group was 77.8 per cent as compared to 75.0 per cent for those receiving external irradiation. The two curves run close together, and the difference observed at any point of follow-up is not statistically significant. It should be mentioned, however, that in the gold group six patients as compared to only one patient in the external radiation group died of intercurrent disease. Moreover, four patients treated with radioactive gold died of complications. They were all recurrence free. It is well established that the prognosis for ovarian cancer limited to one ovary (Stage IA) is better than if both ovaries are involved (Stage IB) or if’ ascites is present at the time of operation (Stage IC). The histopathologic pattern and the degree of differentiation are also prognostically significant factors. Therefore, it was found of interest to compare the number of deaths from cancer in the different subgroups related to stage and histology. In the series treated with external ir-
Fig. 6. Actuarial ovarian carcinoma (Alias) or external
survival curves treated with radiation (Ext.)
for patients radioactive
with Stage II colloidal gold
Table X. The relationship between histologic and cancer deaths in Stage I lesions
type
Histology of invasive carcinoma Serous Mutinous Endometrioid Mesonephroid Undifferentiated
‘:9 28 18 1
1 1 6 5 0
56 4:6 21.5 27.6 0
24 26 23 14 1
7 3 4 6 1
29.1 11.5 17.4 42.8 100
Total
87
13
14.9
88
21
23.9
radiation, the poorer prognosis for the patients with Stage IB and Stage IC lesions was confirmed (Table IX). In striking contrast to this, the patients with Stage IB and IC lesions treated with radioactive gold seemed to have an even better prognosis than those with Stage IA lesions. Although the number of patients is small, the figures are suggestive. It should be pointed out that in Table IX intercurrent deaths and deaths from complications are not included. The relationship between the histopathologic pattern of the tumor and death from cancer is shown in Table X. The number of patients in each subgroup is small. Therefore, any conclusion should be drawn with great care. Nevertheless, it is tempting to suggest that especially the serous, but also the mutinous, tumors respond better to intraperitoneal instillation of radioactive colloidal gold than to external radiation, at
622
Kolstad,
Davy,
and Hpeg
Table XI. The relationship between histologic and cancer deaths in Stage II lesions
Serous Mutinous Endometrioid Mesonephroid Undifferentiated Total
17 12 26 16 5
7 3 8 6 2
74
26
type
41.1 25.0 30.7 37.3 66.7
39 16 20 7 3
18 6 9 3 2
35.1
86
38
46.1 37.5 45.0 43.0 50.0 44.2
Table XII. The number of deaths in the two treatment groups with Stage II carcinomas and ascites or residual tumor after operation
jk Ascites (Stage IIC) Residual tumor
Table
XIII.
carcinoma
5 24
3
60
11
11
46
24
6 17
The frequency of deaths from in cases with ruptured tumor Gold
Radiatmn Deaths
Sta,ge
I Ii Total
55 71
Total No.
19 21
40
Death .
NO.
1 9 10
Prr cent
Total NV.
‘Via.
Pertrut
5.3 42.9
16
6
19
10
37.5 52.6
25.0
35
16
45.7
least if the radiation is restricted to a pelvic field. Only one of 18 patients with carcinoma of the serous type died from cancer in the course of the follow-up period as compared to seven deaths of 24 patients treated with external radiation. The difference is not so clear fol tumors of the mutinous type. For the endometrioid. mesonephroid, and undifferentiated lesions, the end result does not seem to depend upon the type of radiotherapy. As can he seen from Table X, 14.9 per cent of the patients in the gold series died from carcinoma as compared to 25.9 per cent in the radiation group. The difference is statistically significant. The almost identical course of the survival curves shown in Fig. 5 can be explained by the larger number of intercurrent deaths and deaths from complications in the series of patients treated with radioactive gold.
Stage II invasive carcinoma. During the years from 1968 to 1974. 165 patients \\ith Stage II lesions IVCI’( seen. of which five belonged to the potentially malignant tumors. These live have not brcn intriutlcd in the analysis of the material, and the panrnrs a~ all alivt without signs of recurrence. Of the remaining 160 patients, 7-l were treated with radioactive gold and 86 received exrernal irradiation. The f’ollo\~-up period varies from three to eight years. Fig. 6 sho\vs the actuarial survival curves for the two groups. -l’hc tivcyear sur\,ival rate for those receiving gold was 54.1 per cent as compared to 40.0 per cent for those receiving external irradiation. Only one patient in the radioactive gold series compared to three patients in the external radiation group died from intercurrent disease. On the olher hand. four patients treated with gold as compared to only one in the radiation group died from c.c)mpliratiorls. At the end of the follow-up period, ti\:e patients (6.8 pel- cent) in the gold group and scvcn (X.1 per cent) in the radiation group were alive with proved recurrence. The relationship betkveen histology and cancer deaths ti)r the Stage II c,arcinomas ic shown in Table XI. The differences in prognosis hctween the two treatment series according to histologic type are not as striking as those for the Stage 1 lesions. ‘44ltogether. 35.1 per Lent in the gold group as compared to 44.2 per cent in the radiation group died from cancer. It seems as if patients with mutinous tumors, closely filllo\t.ed b! the endometrioicl tumors, treated with gold have the best prognosis. The number of cases in each histologic subgroup is too small to reach any definite conclusion with regard to whit.h therapy should he preferred. It might be anticipated that instillation of radioactive gold would gi1.e better rrsults in Stage II lesions with ascites (Stage IIC). while external radiation possibly should be preferred when macroscopic tissue is behind after operation. However, this was not the case. Table XII shows the relationship between the occurrence of ascites. nonradical removal
KOLSTAD,
MARGARET KARI
H@EG,
treatment of ovarian cancer M.D.
DAVY,
M.R.C.O.G.
M.D.
Oslo, Norway During the years 1968 to 1974, 418 patients with Stage I and Stage II malignant epithelial tumors of the ovary entered a controlled clinical trial. The purpose was to compare the results of postoperative external irradiation with intraperitoneal instillation of radioactive colloidal gold (AIF). The Stage I series comprised 175 invasive carcinomas and 83 tumors of low potential malignancy. The Stage II series comprised 160 invasive carcinomas and five cases of potentially malignant tumors. No significant difference in the five-year survival rate was found for the patients with Stage I lesions. A lower number of cancer deaths among those treated with AP was outweighed by a higher number of deaths from complications. However, patients with Stage IA serous and mutinous tumors, Stage IB and IC turnon+ (all histologic types), and ruptured tumors did significantly better when treated with Au’“. The five-year survival rate for patients with Stage II lesions treated with gold was 54.1 per cent as compared to 40.0 per cent for those receiving external irradiation. In agreement with these observations, a new treatment protocol is proposed which includes a randomized trial to study the value of adjuvant chemotherapy. (AM. J. OBSTET. GYNECOL. 128:617,
1977.)
I N MANY Western countries, ovarian cancer ranks first among the lethal cancers developing in the genital tract. In Scandinavia, it appears that the incidence of this malignancy is increasing. The age-adjusted incidence rate is now close to that of carcinoma of the cervix. In Norway, compulsory cancer registration was established in 1952. Since 1932, the Norwegian Radium Hospital has been the main referral center for gynecologic cancer. During the last two decades, an increasing number of patients with malignant ovarian neoplasia have been admitted to the hospital for primary therapy, postoperative radiotherapy, or chemotherapy (Fig. 1). In the period from 1967 to 1975, 2,175 new cases have been treated, of which about 50 per cent belonged to the earlier Stages I and II and 50 per cent belonged to the late Stages III and IV (Fig. 2). Malignant ovarian neoplasia comprises a het-
erogeneous group of diseases. It has been stressed repeatedly that studies on the results of treatment must be based on histologically and biologically homogeneous series. No standard treatment can or should be used for all the different types and stages of the disease. Surgery is still the keystone in the treatment of ovarian carcinoma. However, several reports in the literature indicate that, for example, additional radiotherapy or chemotherapy may improve the results.‘-4 In 1971, a retrospective clinical and histopathologic study of 990 cases of malignant epithelial tumors was published.5 In agreement with the experience of earlier investigators, 6-8 large differences in the results of treatment were observed according to histologic type and grading. Among true carcinomas of Miillerian origin, endometrioid and mutinous types had the best prognosis, followed by serous and ultimately undifferentiated carcinomas. The so-called potentially malignant tumors did not always behave as benign disease. With a sufficiently long follow-up period, extending from 15 to 20 years, more than 10 per cent of such patients died from recurrence of cancer.’ Radioactive colloidal gold has been employed in the treatment of ovarian carcinoma in the department since 1954. In the earlier years, including the period from 1954 to 1957, external radiotherapy was given by
From the Department of Gynecology and the Department of Pathology, The Nonwgian Radium Hospital. The Annual Guest Lecture, presented at the Forty-fourth Ann& Meeting of the Central Association of Obstetricians and Gynecologists, Houston, Texas, October 14-16, 1976. Reprint requests: Dr. Per Kolstad, Department Gynecology, The Norwegian Radium Hospital, Norway.
of Oslo 3,
617
618
Kolstad, Davy, and Haeg
Reported the
Table I. Five-year survival rate in relation tu type of radiotherapy and stage in carcinoma of the ovary. tumor completely removed (Aurrb and associates”)
to
Cancer
Romtgtw (250 kil.) I
:
Treated
1501
in the
Norwegian
Radium
Hospital
100 1. I
,
-40
1930
-50
-70
-60
150
Stage
No.
Alizje
100
I
55
2X
II
17
7
III
-
1. The total number of new cases of carcinoma of the detected in Norway and the number of patients treated in the Norwegian Radium Hospital, 1932 to 1975.
Fig. ovary
No.
A&w
62
63
51
.43
x4
7
30
15
8
53
2
22
15
6
38
d41iue
51
98
41
23 9
-
Roentgen (250 ku.)
WI-
Per c’mt
No.
STAGE
IV
STAGE
III
Beta&on (31 7nex)
Radioactira Au’*8
,i_,,.,
Stage
soIO-
PIT cent
Table II. Five-year survival rate in relation to type of radiotherapy and stage in ovarian carcinoma, nonradical operation (Aure and associates”)
too-
u
Per cent
-75
Year
l3
Betatron ( ? I rw.)
II
COso-
STAGE II
.o-
III IV
K L
3o xl-
STAGE I
10 o-
1%1
1968
I%9
Fig. 2. Stage distribution
,970
1971
of 2,175
1972
1973
1974
1975
new cases of ovarian
cancer
treated in the Norwegian Radium Hospital during the period 1967 to 1975. Total number of patients treated each year is shown on the top of the columns. conventional 250 kv. roentgen machines. From 1957, megavoltage betatron irradiation was brought into use. A comparison between the results achieved with these three types of irradiation therapy disclosed significantly better results for Stage I and Stage II cases in which radioactive colloidal gold was given.s However, it should be stressed that this statement held true only for those cases where the tumor was completely removed (Tables I and II). Furthermore, when the results were presented, it was emphasized that the investigation was retrospective and that definite conclusions about the advantages of radioactive gold could be reached only by controlled clinical trials in which both the stage and tumor type were taken into consideration.Y In 1968, it was decided to carry out such a trial, and the present report is an up-to-date survey of the observations made.
Mstsrlsl and methods Clinical staging and histologic typing were performed according to the rules proposed by the Cancer Committee of the International Federation of Gynecology and Obstetrics (FIGO). The FIG0 histopathologic classification agrees in principle with that of the World Health Organization. Only Stage I and Stage II malignant epithelial tumors were included in the study. In all cases. initial therapy consisted of bilateral salpingo-oophorectomy, hysterectomy, and omentectomy. Intraperitoneal instillation of radioactive gold was always performed in connection with laparotomy. If extensive intra-abdominal adhesions were found, the patient was taken out of the trial. Furthermore. young patients with unilateral tumors of so-called IOU potential malignancy did not receive any type 01‘ radiotherapy. A few patients were considered too old to enter the trial, and some patients were excluded because
of
various
medical
conditions.
Otherwise.
there was no selection in the series. The patients randomized to radioactive gold received an intraperitoneal dose of 100 mCi of Au’“’ dissolved in 1,000 ml. of physiologic saline. In addition, they were given 3,000 radb of external megavoltage radiation
against
a pelvic
field.
The
other
group
rc’-
Volume
128
Number
6
Individualized treatment of ovarian cancer
Table III. Age distribution in the randomized series of Stage I and Stage II ovarian carcinoma Stage I Age (yr.) 529 30-39 40-49 50-59
60-69 70-79
80-89 Total
No.
Table
Stage II
Gold
Radiation
Gold
Radiation
8 11 16 44 35 10
9 12 34 35 33 11
3 5 20 22 15 9
-
-
21 29 95 133 103 36 1
124
134
74
1 1 25 32 20 6 1
86
418
IV. Distribution
Stage IA IB
IC IIA IIB IIC
Total
SURGERY:
2.
POSTOPERATIVE RADIOTHERAPY
BILATERAL SAlPlNGO-OOPHORECTOMY, HYSTERECTOMY AND OMENTECTOYY
: RANDOMIZED A.
group Radiation
94
97
191
100mCi VOLTAGE
+ 3OObrad EXTERNAL RADIATION, PELVIC
FIELD
’ RADIATION’ 5000 rad EXTERNAL RADIATION, PELVIC
HIGH FIELD
VOLTAGE
Fig. 3. Treatment protocol followed during the study period 1968 to 1972 for Stage I and Stage II malignant epithelial tumors of the ovary.
Total No.
23 7 15 54 5
22 15 17 58
45 22 32 112
11
16
Treatment
220
:
‘GOLD’ Au”* HIGH
a.
TRIAL
Table V. Number of invasive carcinomas and potentially malignant tumors in the two treatment groups, Stage I lesions
Gold
198
PRIMARY
Total No.
by stages
Treatment
1.
619
418
Histology
Invasive Potentially tumors Total
ceived postoperative external megavoltage radiation against a pelvic field with a tumor dose of 5,000 rads. A summary of the treatment protocol is shown in Fig. 3. The youngest patient was 20 years of age; the oldest 8 1 years. The majority were in the age groups of 50 to 59 and 60 to 69 (Table III). The number of cases in the different age ranges was almost identical in the two treatment groups for both the Stage I and the Stage II cases. The slightly lower total number of patients in the series receiving radioactive gold is mainly due to exclusion of patients with intra-abdominal adhesions. Altogether, 10 patients were taken out of the trial because of this reason or some other factor which made the use of colloidal gold contraindicated. The total number with a sufficient follow-up time comprised 418 patients. Distribution by clinical stages is shown in Table IV. Apparently, the randomization has been satisfactory except for the fact that there were slightly more patients with ascites (Stages IC and IIC) receiving external irradiation. As mentioned previously, potentially malignant tumors were included in the series except for those in young women of childbearing age. A more conservative attitude was taken in such cases with some of the young women having only the tumor-involved ovary removed. Altogether, 258 cases were classified as Stage
cancer malignant
Stage
group
Gold
Radiation
IA IB IC
68 14
64
IA IB IC
26 9
33
2
4
5
124
13 11 9 134
Total No.
132 27 16
59 18 6
175
83 258
I lesions, of which 175 were invasive carcinomas and 83 were potentially malignant tumors (Table V). From a statistical point of view, the allocation by random numbers to the two treatment groups was satisfactory. As mentioned previously, only malignant epithelial tumors were included. Histology of the Stage I invasive carcinomas is shown in Table VI. Altogether, 87 patients were treated with radioactive gold and 88 patients received external radiation. There was a slightly higher number of patients with serous carcinomas in the external radiation group, which, however, was compensated for by a higher number of endometrioid lesions in the radioactive gold group. Among the potentially malignant tumors, there were found no examples of mesonephroid or undifferentiated lesions, and only one case was classified as an endometrioid lesion of low potential malignancy (Table VII). The majority belonged to the serous type. The microscopic examination of the Stage II lesions revealed a much higher number of serous carcinomas in the radiation group than in the gold group. On the other side, mesonephroid tumors was a more frequent finding in the gold group (Table VIII). Only five cases of potentially malignant tumors were classified as Stage II carcinomas, of which two were allocated to the
620
Kolstad, Davy, and Hpeg
/Ext. 100r-V-V-”
-v
O\
90-
-100
‘v
o-o-o-
Au
- 90
198
-80
70-
-
STAGE I, POTENTIALLY MALIGNANT
40
-
40
30
-
30
20
-20
10 I
-
4
Fig. 4. Actuarial survival curves for patients with Stage 1 potentially malignant tumors treated with external radiation (Ext.) and radioactive colloidal gold (Au’“*).
Treatment Histology oj invasive carcinoma
Gold
group
18 22 28 18 1
24 26 23 14 1
42 48 51 32 2
Total
87
88
175
radioactive gold group and three were placed in the external radiation group. There were three serous and two mutinous tumors. These five cases have not been included in the evaluation of the results of treatment. All five patients are alive with no signs of disease after 4 to 6 years of follow-up.
Follow-up The follow-up has been performed in the outpatient department of the Norwegian Radium Hospital, in the hospital,
or by the patient’s
private
physician.
No case has been lost to follow-up. Usually, the patients have been examined every second month the first year, every third month the second year, and then at increasing intervals with one visit each year after 5 years of follow-up. patients
When have
been
recurrences readmitted
have to the
27
16
19
I
0
37
46
Total
Table VIII. Distribution by histologic Stage II invasive carcinoma
Hzstology
Gold
Serous Mutinous Endometrioid Mesonephroid Undifferentiated
17 12 26 16 3
type.
group Radzation
Total No.
39 16 20 7 4
56 28 46 23 7
Total
Total No.
Serous Mutinous Endometrioid Mesonephroid Undifferentiated
referring
20
Mucinoos
Table IX. Observed number of deaths from carcinoma during the follow-up period in the two treatment groups for Stages IA, IB, and IC lesions, all histologic types
type of
Radiation
Radiation
Gold
Sewus
10
YEARS
Table VI. Distribution by histologic Stage I invasive carcinomas
gyoup
Treatment
5
type.
tumors
Trratmrnt
TLMOURS
3
by histologic malignant
Endometroid 50
2
Distribution
Potcvztial(7~ malignant tumors
-60 -
1
I potentially
70
50 c
olo
VII.
Stage
(46) O (37)
2
80-
60-
Table
been
detected,
hospital,
and
the as a
IA
Y4
IB
2.‘1
IC
7
14
11.3
Total
12
124
12.8
97
14
14.4
2
8.7
0
0
22
5
22.6
15
3
20.0
22
16.4
134
rule chemotherapy with an alkylating agent (thio-tepa) has been started. When the present study was closed, the follow-up time had been from five to eight years for the Stage I cases and from three to eight. years for the Stage II cases. Survival curves have been constructed according to the actuarial life-table method, which means that intercurrent deaths have been included. However, with this method, the inclusion of intercurrent deaths is partly compensated
for
by the
mathematic
formula
used.
Re8ults
Pote&idly tumors
of low
malignant potential
tumors. malignancy.
Of 83 patients 46 received
with exter-
Volume Number
Individualized treatment of ovarian cancer
128 6
-1
loo
-100
90
- 90
80 70 60
E d
40
50
INVASIVE
t
- 80 z 0’
70-
\
0
ag
60 _
\
”\
Au’96
Olo
CARCINOMA 40 30
g 2
50-
2 L
40 30-
-
70
-
60
0 (74)
\
STAGE I,
50
621
- so
“\ -
“lv
(86)
-40
z
Ext.
20
-
30
-
20
10 01
I
I
1
2
1
YE:RS
4
I
4
5
d
0
01
, 1
I 2
1
I 5
t 4
1 0
YE:RS Fig. 5. Actuarial sive carcinoma
survival curves of the ovary.
for patients
with
Stage I inva-
nal irradiation and 37 radioactive gold. The five-year survival rates were 92.5 and 87.2 per cent, respectively (Fig. 4). The difference is not statistically significant. The slightly poorer result for the gold series is due to two patients who died from complications related to the instillation of the radioactive material. Two patients, one in each treatment group, died from cancer. They both had mutinous tumors. Stage I invasive carcinoma. Survival curves for the Stage I lesions classified as true invasive carcinomas are shown in Fig. 5. The total number comprised 175 cases, in 87 of which gold and 88 external irradiation were given. The five-year survival rate for the first group was 77.8 per cent as compared to 75.0 per cent for those receiving external irradiation. The two curves run close together, and the difference observed at any point of follow-up is not statistically significant. It should be mentioned, however, that in the gold group six patients as compared to only one patient in the external radiation group died of intercurrent disease. Moreover, four patients treated with radioactive gold died of complications. They were all recurrence free. It is well established that the prognosis for ovarian cancer limited to one ovary (Stage IA) is better than if both ovaries are involved (Stage IB) or if’ ascites is present at the time of operation (Stage IC). The histopathologic pattern and the degree of differentiation are also prognostically significant factors. Therefore, it was found of interest to compare the number of deaths from cancer in the different subgroups related to stage and histology. In the series treated with external ir-
Fig. 6. Actuarial ovarian carcinoma (Alias) or external
survival curves treated with radiation (Ext.)
for patients radioactive
with Stage II colloidal gold
Table X. The relationship between histologic and cancer deaths in Stage I lesions
type
Histology of invasive carcinoma Serous Mutinous Endometrioid Mesonephroid Undifferentiated
‘:9 28 18 1
1 1 6 5 0
56 4:6 21.5 27.6 0
24 26 23 14 1
7 3 4 6 1
29.1 11.5 17.4 42.8 100
Total
87
13
14.9
88
21
23.9
radiation, the poorer prognosis for the patients with Stage IB and Stage IC lesions was confirmed (Table IX). In striking contrast to this, the patients with Stage IB and IC lesions treated with radioactive gold seemed to have an even better prognosis than those with Stage IA lesions. Although the number of patients is small, the figures are suggestive. It should be pointed out that in Table IX intercurrent deaths and deaths from complications are not included. The relationship between the histopathologic pattern of the tumor and death from cancer is shown in Table X. The number of patients in each subgroup is small. Therefore, any conclusion should be drawn with great care. Nevertheless, it is tempting to suggest that especially the serous, but also the mutinous, tumors respond better to intraperitoneal instillation of radioactive colloidal gold than to external radiation, at
622
Kolstad,
Davy,
and Hpeg
Table XI. The relationship between histologic and cancer deaths in Stage II lesions
Serous Mutinous Endometrioid Mesonephroid Undifferentiated Total
17 12 26 16 5
7 3 8 6 2
74
26
type
41.1 25.0 30.7 37.3 66.7
39 16 20 7 3
18 6 9 3 2
35.1
86
38
46.1 37.5 45.0 43.0 50.0 44.2
Table XII. The number of deaths in the two treatment groups with Stage II carcinomas and ascites or residual tumor after operation
jk Ascites (Stage IIC) Residual tumor
Table
XIII.
carcinoma
5 24
3
60
11
11
46
24
6 17
The frequency of deaths from in cases with ruptured tumor Gold
Radiatmn Deaths
Sta,ge
I Ii Total
55 71
Total No.
19 21
40
Death .
NO.
1 9 10
Prr cent
Total NV.
‘Via.
Pertrut
5.3 42.9
16
6
19
10
37.5 52.6
25.0
35
16
45.7
least if the radiation is restricted to a pelvic field. Only one of 18 patients with carcinoma of the serous type died from cancer in the course of the follow-up period as compared to seven deaths of 24 patients treated with external radiation. The difference is not so clear fol tumors of the mutinous type. For the endometrioid. mesonephroid, and undifferentiated lesions, the end result does not seem to depend upon the type of radiotherapy. As can he seen from Table X, 14.9 per cent of the patients in the gold series died from carcinoma as compared to 25.9 per cent in the radiation group. The difference is statistically significant. The almost identical course of the survival curves shown in Fig. 5 can be explained by the larger number of intercurrent deaths and deaths from complications in the series of patients treated with radioactive gold.
Stage II invasive carcinoma. During the years from 1968 to 1974. 165 patients \\ith Stage II lesions IVCI’( seen. of which five belonged to the potentially malignant tumors. These live have not brcn intriutlcd in the analysis of the material, and the panrnrs a~ all alivt without signs of recurrence. Of the remaining 160 patients, 7-l were treated with radioactive gold and 86 received exrernal irradiation. The f’ollo\~-up period varies from three to eight years. Fig. 6 sho\vs the actuarial survival curves for the two groups. -l’hc tivcyear sur\,ival rate for those receiving gold was 54.1 per cent as compared to 40.0 per cent for those receiving external irradiation. Only one patient in the radioactive gold series compared to three patients in the external radiation group died from intercurrent disease. On the olher hand. four patients treated with gold as compared to only one in the radiation group died from c.c)mpliratiorls. At the end of the follow-up period, ti\:e patients (6.8 pel- cent) in the gold group and scvcn (X.1 per cent) in the radiation group were alive with proved recurrence. The relationship betkveen histology and cancer deaths ti)r the Stage II c,arcinomas ic shown in Table XI. The differences in prognosis hctween the two treatment series according to histologic type are not as striking as those for the Stage 1 lesions. ‘44ltogether. 35.1 per Lent in the gold group as compared to 44.2 per cent in the radiation group died from cancer. It seems as if patients with mutinous tumors, closely filllo\t.ed b! the endometrioicl tumors, treated with gold have the best prognosis. The number of cases in each histologic subgroup is too small to reach any definite conclusion with regard to whit.h therapy should he preferred. It might be anticipated that instillation of radioactive gold would gi1.e better rrsults in Stage II lesions with ascites (Stage IIC). while external radiation possibly should be preferred when macroscopic tissue is behind after operation. However, this was not the case. Table XII shows the relationship between the occurrence of ascites. nonradical removal
