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Carcinoma of the endometrium in Saskatchewan
Carcinoma of the endometrium in Saskatchewan A review patients
J. A. H.
of 603 cases with a suggested with
Stage 1 disease
CARMICHAEL,
A. BEAN,
Regina,
B.A.,
scheme of management
and regarded
M.D.,
C.M.,
as good
surgical
for risks
F.R.C.S.(C)
M.D.
Saskatchewan
A review of 603 cases of adenocarcinoma of endometrium is presented. A comparison has been made of the results of various types of treatment in 469 cases in Stage I and operable from a medical standpoint (Group I). The efiect of the surgical pathology on the subsequent spread of disease in patients treated has been examined. A proposed scheme of management is ofiered for cases of carcinoma of the endometrium,classed as Stage I and operable (Group 1).
I T I s T H E purpose of this paper to review and compare the different methods of treatment of carcinoma of endometrium in the Province of Saskatchewan for a 21 year period ( 1939-1959). Particular reference will be made to operable casesclassified as Stage I, Group 1 to determine the incidence and type of spread of diseaseand finally on the basis of these observations ~0 propose a scheme of management for patients with Stage I, Group 1 disease. The Province of Saskatchewan has a population slightly less than one million people. Consultive diagnostic and treatment clinics for cancer were established in -two centers in Saskatchewan in 1930. Ninety per cent of all cancer patients in this Province are referred to a cancee clinic. Regular re-
view examinations are done on all patients with only 0.6 per cent being lost to followup.l Adequate records are maintained on all patients. This program, therefore, provides excellent material for incidence studies and for appraisal of treatment methods. Material
and
methods
The material analyzed consistsof 603 patients with carcinoma of endometrium seen in the Saskatchewan cancer clinics from 1939 to 1959 inclusive. Histologic classification is shown in Table I. Staging has been done according to the system used for reporting of material for the Annual Report of Results of Treatment Carcinoma of the Uterus and Vagina.”
in
Stage I includes caseswith operable disease,i.e., diseaseconfined to the uterus. Table I. Histologic classification
From the Radiotherapy Department, Allan Blair Memorial Clinic, and the Department of Obstetrics and Gynecology, Medical Arts Clinic.
Adenocarcinoma Adenocarcinoma Adenoacanthoma Carcinosarcoma
Presented at the Twenty-second Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada, Jasper, Alberta, June 17-19, 1966.
Total
294
Well-differentiated Anaplastic
518 62 18 5 603
Volume Number
97 3
Carcinoma
Stage I is divided into two groups: Stage I, Group 1 includes cases suitable for surgical treatment; Stage I, Group 2 includes cases where the anatomical spread of the growth does not hinder a radical removal but which are bad operative risks; Stage II includes cases in which the growth has spread outside the uterus; Corpus and cervix includes cases with involvement of cervix and corpus; Unstaged were not staged at initial examination. The distribution of cases
Table II. Staging (International of Obstetrics and Gynecology)
Federation
Stage I, Group 1 Stage I, Group 2 Stage II Corpus and cervix Not stared
469 39 58 5 32
Total
603
Fig.
1. Age
distribution.
in this series according in Table II. Age
of endometrium
295
to staging is shown
distribution
Fig. 1 shows the age distribution which is comparable to other series of this size. Age of menopause is shown in Fig. 2 for 395 patients whose symptoms began in the postmenopausal period (6 months amenorrhea prior to onset of symptoms). The observation that the average age of the menopause is delayed” in patients subsequently developing carcinoma of endometrium is not confirmed. (It is the impression of the gynecologists in this area that the average age of the menopauseis 50 years.) Associated
medical
conditions
Fifty-nine per cent of all patients had one or more of the triad of diabetes, obesity, and hypertension. Careful review of the his-
296
Carmichael
-40
40
and
41
February 1, 1967 Am. J. Obst. & Gynec.
Bean
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
bit
AGE
Fig.
2. Age of menopause in the 395 patients symptoms (amenorrhea x 6 months).
tories failed to reveal any characteristic preceding gynecologic pattern. Fifty-three patients gave a history of abnormal menstrual bleeding, 47 had an abnormal menopause (requiring dilatation and curettage or hormonal therapy), 40 had some form of hormone therapy, and 28 had had a previous diagnosis of endometrial hyperplasia. None of these problems appeared frequently enough in this series to justify any conclusions. Thirty-three patients had had previous radiotherapy for gynecologic problems. Symptoms
Table III lists the first symptom or symptoms experienced by the patient. Eighty per cent experienced someform of abnormal bleeding (irregular menstrual, postmenopausal, etc.). In reviewing this series, vaginal discharge appeared more significant than the figure of 10 per cent would suggest. A number of patients complained of intractable vaginal discharge many months before the telltale symptoms of postmenopausal bleeding occurred.
completing
their
menopause
before
the onset
of
Duration of symptoms. Fig. 3 shows the duration of symptoms (from first symptoms to first treatment). Treatment was started within 6 months in over 50 per cent of patients. Fig. 4 showsthe relationship between duration of symptoms and crude 5 year survival. Despite the recognized desirability of early detection and treatment, this series fails to show that duration of symptoms influences survival. This observation has been made previously for carcinoma of uterus4 and for other sites.5 The accuracy of the history, particularly when recalling the onset of irregular bleeding, vaginal discharge or postmenopausal bleeding must always reTable III.
First symptom of symptoms %
Bleeding Discharge Bleeding Pain None Other
and
discharge
78.9 10.3 1.1 90.3 4.6 1.1 4.0
52.5
% )
f 25
-1
1-3
4-6
7-9 DURATION
Fig.
3. Duration
of symptoms
to first
10-12 OF
13.24
SYMPTOMS
IN
MONTHS
treatment.
30
-1 -1
1-3
7.0 7.0
4.4
to-12 DURATION
63 63
142
53
va
Fig. 4. Duration of symptoms in each time interval.
and
survival.
13-34
Of
SYWYOMS
NUMMR
Of
37.48 37.48
4w 4w
37
17
36
IN MONTNS
60
The
2%a6 2%a6
77
bottom
PATIENTS
figures
give
the
number
of patients
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and Bean
February 1, 1967 Am. J. Obst. & Gym.
main suspect. However, it is clearly shown that survival rates are greatly influenced by extent of spread of disease (Table IV) and stage of disease(Table VII) indicating that for any individual case the earlier the diagnosis is made and adequate treatment initiated, the better the prognosis will be. Treatment
Treatment methods were numerous and were classified under twenty-five separate categories. These fall into three main groupings; surgery alone, radiotherapy alone, and combined surgery plus radiotherapy (Table V)* Table IV. Crude 5 year survival by surgical pathology Iti
No remainingtumor
90.8 192 93.8/ 85.5 65.2
Endometriumonly Myometrium minimal Myometrium gross Upper segmentonly Upper
+ lower
84.6 64.5
segments
Description of radiotherapy procedures. Heyman packing. In 1934 Heyman developed the “packing technique.” This consisted of packing as many as possible Heyman applicators enclosed in suitable filters or capsules into the uterine cavity. Each applicator contained 8 to 10 mg. of radium element. Four sizesof capsule or filter were available, small capsules being used for small uterine cavities and larger capsules for larger cavities so that at least four and not more than twelve capsules were used. This method of loading maintains a constant total filtration of 3 mm. lead equivalent. An empirical dose of 1,500 mg. hours for a No. 1 shield using ten applicators was arrived at by Professor Heyman. Corrections were made for fewer applicators and larger sizes of shields.In addition to uterine applicators, vaginal applicators were used to radiate the vaginal vault. In the present study applicators were loaded with 8 to 10 mg. of Coso wire. The number of mg. hours for different numbers of irradiators of different sizes is shown in Table VI. The use of Coeowire has necessi-
Table V. Methods of treatment Surgeryalone
182
Total abdominalhysterectomy bilateral
Less than total and bilateral Radiotherapy
Combined
147
abdominal hysterectomy salpingo-oophorectomy
35
alone
104
Suitable for surgery Inoperable disease Poor surgical risk Unclassified
treatment
298
Preoperative Heyman packing + total abdominal hysterectomy + bilateral salpingo-oophorectomy
146
Preoperative line source radium + total abdominal hysterectomy + bilateral salpingo-oophorectomy
55
Other radiotherapy+ + Total abdominal hysterectomy + bilateral salpingo-oophorectomy
47
Radiotherapy
50
No treatment Total *External
and
salpingo-oophorectomy
radiation,
vault
radium.
+ less radical
25 35 32 12
surgery
19
19
603
603
Volume Number
97 3
Carcinoma
Table VI. Heyman applicators (milligram hours for different numbers of irradiators of different sizes) Size No.
I (mg.hr.)
985
4 5 6
Table
hr.)
1,480 1,585
1,610 1,730 1,815 1,880
2,000 2,080 2,100
1,650 1,745 1.800
1,760 1,835 1.905
1,915 1,985
2,115 2,155
2.070
2.170
Crude
5 year
survival
Stage I, Group 1 Stage I, Group 2 Stage II Corpus + coli Not staned Total
VIII.
IV (mg.
1,385 1,505 1,615 1,705
No.
Table
III (mg. hr.)
-
1,370
VII.
hr.)
-
1,145 1,255
7 8 9 10 11 12
II (mg.
369 12
58 5 32
6 3 8
Complications
Perforated uterus Fistulas Bowel or ureteral Total
obstruction
by stages
Surviving 5 years
469 39
603
1,905
% 78.67 30.77 18.75 -
398
66
of treatment 8 4 6
18 f3.8%\
tated a constant correction factor for decay. Two insertions were carried out at 3 to 4 week intervals. In one clinic, vault radium was inserted with one packing using small vaginal ovoids each loaded with 20 mg. of radium. In the other clinic, vault radium was applied as a postoperative procedure in selected cases only where there was evidence of lower uterine segment involvement or deep penetration of myometrium. This application consisted of vaginal ovoids of three sizes loaded as for treatment of carcinoma of the cervix. Line source or tandem radium was administered using a thick rubber tube 1 cm. in diameter loaded with two to four 25 mg. tubes of radium (depending on the length of the uterine cavity). Treatment time was 96 hours in 2 insertions, one week apart.
of
endometrium
299
Vault radium was applied in some cases, using vaginal ovoids. Pre- and postoperative external radiation were given by orthovoltage and Co60 teletherapy and varied in dosage-but approximated in the majority of incidences 3,000 rads to the whole pelvis. A few patients with advanced disease received Betatron treatment. Crude 5 year survival for the total series is shown in Table VII. Complications of Treatment are shown in Table VIII. Stage
1, Group
1
A detailed analysis has been made of the 469 cases which were classified as Stage I, Group 1. Treatment methods for this group are shown in Table IX. The two main forms of treatment were preoperative intrauterine radiation with or without vault radium plus total abdominal hysterectomy and bilateral salpingo-oophorectomy and surgery (total abdominal hysterectomy and bilateral salpingo-oophorectomy) alone. Before comparing results of treatment in these two groups it is necessary to establish a reasonable similarity in the patient material in each group. Table X compares the age, incidence of medical complications and the histologic distribution to be found in each form of therapy. These tables show comparable patient material in each treatment group. Fig. 5 shows the yearly incidence of the main forms of therapy used. It cannot be denied that there is a natural and understandable selection of favorable cases for primary surgery alone. However, Fig. 5 suggests a certain trend or selection according to “la mode” rather than a continual selection of favorable patients for primary surgery. Table XI compares the results of the different types of preoperative intrauterine radiation. There appears to be little difference in the incidence and direction of extension of disease postoperatively, and no difference in 5 year survival rates. There is a 10 per cent decrease in residual tumor in those patients who had Heyman
300
Carmichael
and
February 1, 1967 Am. J. Obrt. & Gynec.
Bean
packing. This difference is not reflected in survival figures. To have residual tumor in 52.8 per cent of uteri with Heyman packing was disappointing. The time of surgery may have influenced this to some extent. Surgery was originally done at 6 weeks to 2 months following the second Heyman packing. This time interval was shortened to one month in one clinic, and in the other clinic, surgery
Table IX. Methods Surgery
of treatment
alone
Radiotherapy Surgery
for Stage I, Group
1
Total abdominal
160
alone
was done immediately following the second Heyman packing. When surgery is done immediately it is probable that residual tumor will be present. The high incidence of residual tumor may also be due to insufficient dosage, insufficient filling of the uterine cavity, or to exceptional diligence on the part of the pathologist. Because of the similarity of patient ma-
hysterectomy + bilateral salpingo-oophorectomy Less than adequate surgery
140 20
30
+ radiotherapy
30
276
Heyman packing + total abdominal hysterectomy + bilateral salpingo-oophorectomy Heyman packing + vault radium + total abdominal hysterectomy + bilateral salpingo-oophorectomy
82L
142
60A
Line source radium + total abdominal hysterectomy + bilateral salpingo-oophorectomy Line source radium + vault radium t total abdominal hysterectomy bilateral salpingo-oophorectomy Other radiotherapy*+ total abdominal hysterectomy bilateral salpingo-oophorectomy Other No
treatment
+
+ 67 16 3
combinations
3
Total
469
469
*External
radiation,
vault
Table X. Comparison
Treatment Heyman
packing
radium
+ line
of patient
abdominal
+ surgery*
hysterectomy
material
treatment
groups
w
82
59.2
63.4
74
8
0
0
60
55.5
65
57
2
0
1
34
59.5
65
28
2
0
4
56.4
70.6
15
57.2
59.3
120
12
4
4
l7 140 plus
in different Per cent with hyfiertension and/or obesity and/or diabetes
No. of patients
groups
Heyman packing + surgery+ and vault radium Line source + surgery* Line source and vault radium + surgery* *Surgery alone “Total
source.
bilateral
Average
salpingo-oophorectomy.
Histolonv
Volume Number
97 3
Carcinoma
terial and therapeutic results of all forms of preoperative intrauterine radiation, these groups have been combined to give a total group of 193 cases. This group has been compared with the 140 cases treated by surgery alone. Th e results are shown in Table XII. The incidence of pelvic extension, lymph node and blood spread and 5 year survival rates are essentially the same. The only significant difference is the incidence of vaginal vault recurrence or vaginal implant. The final line in Table XII compiles all other combinations of surgery and radiotherapy. Again, a decrease in incidence of va.ginal extension is noted. Table XIII lists the yearly incidence of both vaginal and pelvic spread of tumor for primary surgery and for preoperative intrauterine radiation plus surgery. All vaginal recurrence in the surgical group appeared within the first 3 years; in the preoperative irradiation group within the first 4 years with the exception of one case. Pelvic
KING
WITH
extension tended both groups.
of endometrium
to occur
at a later
5. Yearly
census
of
major forms
of therapy
time in
Correlation of surgical pathology and subsequent spread of carcinoma of endometrium Analysis of surgical pathology and subsequent spread of carcinoma of endometrium in the 140 cases treated by surgery alone (total abdominal hysterectomy and bilateral salpingo-oophorectomy) shows a significant increase in the incidence of pelvic recurrence where the disease has progressed beyond minimal invasion of the myometrium (Table XIV). Table XIV also correlates lymph node and blood spread with surgical pathology in the 140 cases treated by surgery alone. Again there is a significant increase in incidence when there is greater than minimal invasion of myometrium. There was also an increase in vaginal recurrence with gross myometrial involvement. There is also an increase in vaginal recur-
OR
WITHOUT
YEAR Fig.
301
used for
Stage
I, Group
I patients.
302
Carmichael
and
Bean
February 1, 1967 J. Obst. & Gynec.
Am.
Comment
rence with minimal myometrial involvement when tumor is in the lower uterine segment. This observation does not stand up to statistical analysis because of the small numbers involved but does indicate that both spread and position are a factor in subsequent vaginal recurrence.
Heyman packing technique versus tandem radium. In the Saskatchewan experience Heyman packing with or without vault radium shows no advantage over line source with or without vault radium, except that with Heyman packing 10 per cent less
Table XI. Results
of preoperative intrauterine radiation hysterectomy and bilateral salpingo-oophorectomy
abdominal
Spread
Treatment Heyman
No. of patients
of method packing
with
total
at 5 years
Pelvic and intraabdominal
Vaginal alone
combined
Continuing disease
Residual tumor in operative sfiecimen
5 year survival
Metastases
82
3
6
2
3
67 (81.7%)
60
2
2
2
2
50 (83.3%)
source
34
1
1
0
3
25
Line source + vault radium
17
0
1
1
0
15
5 (2.6%)
7 (3.6%)
81.35%
Heyman with Line
>
packing vault radium
Total
193
Table XII.
Comparison
6 (3.1%)
10 (5.2%)
of results in different
treatment
Method treatment Surgery*
of
Treatment method
%
No.
%
No.
No.
%
8.6
10
7.4
0
0
5
3.6
85
193
6
3.1
10
5.2
5
2.6
7
3.6
81.35
3.0
6
9.0
1
1.5
3
4.5
76.1
67
2 plus
incidence
Spread
Surgery* alone
bilateral
of disease
Vaginal
*Total
plus abdominal
Vaginal Pelvic and/or intra-abdominal hysterectomy plus
bilateral
%
salpingo-oophorectomy.
of vaginal
Pelvic and/or intra-abdominal Intrauterine radiation suraerv*
5 year crude survival %
Metastases
12
hysterectomy
Yearly
Continuing disease
No.
Other radiotherapy + surgery*
Table XIII.
at 5 years
Pelvic and intra-abdominal
140
alone
abdominal
107(55.4%)
No. of patients
Surgery* plus intrauterine radiation
*Total
32(62.7%)
groups
S#read Vaginal only
> 78.6%
75(52.8%)
I
and pelvic
and abdominal
2
3
68
2
2
6
2
4
1
4
3
sirlpingo-oophorectomy.
1
Years
after
4
5
:
spread treatment 6
7
8
2
1
1
1
9
) IO+
1 1
Volume Number
97 3
Carcinoma
Table XIV.
Surgical
pathology
and subsequent Endometrium only
No disease Pelvic No
spread disease
of endometrium
303
spread Myometrium, minimal
Myomet Gum, gross
Serosa
Adnexa
0” 11
Upper
uterine
segment Lower
uterine
segment Uterus
+ cervix
Metastases-lymph No disease
nodes
and
blood
0
1
3
8
37
17
1
0
i
i
1
1
3
0
5
22
20
0
0
0
1
0
0
i
3
0
1 r 1 i
borne 0 11
Upper uterine segment
0
0
3
s
37
17
Lower uterine segment
1
0
5
5
22
20
Uterus
0
0
0
0
-i
3
+ cervix
Vaginal spread No disease
0 11
Upper
uterine
0
segment Lower
s
uterine
segment Uterus
+ cervix
*Numerator denotes pathologic group.
number
of
cases
of
spread,
1 3s
2
0
14
0
1 t
0
4
3
0
0
4
21
19
0
0
0
0
0
0
0
0
r
?
0
0
denominator
specimens have residual tumor. This difference, however, is not reflected in 5 year survival rates or in recurrence of disease (Table XI).
Primary surgery versus all forms of preoperative intrauterine irradiation with or without vault radiation. The single advantage of preoperative intrauterine radiation is a significant decrease in the incidence of vaginal vault recurrences and vaginal implants (see Table XII). The incidence of pelvic recurrence, metastases and, the 5 year survival rates are the same.
denotes
number
of
cases
in
that
surgical
Pelvic extension and surgical pathology. Postoperative pelvic extension and metastases are a direct function of the extent of myometrial involvement (Table XIV).
Vaginal extension and surgical pathology. Table XIV suggests that vaginal implants and vaginal vault recurrences are a factor both of myometrial penetration and tumor site. In this series surgery alone has produced as good 5 year survival as combined treatment for Stage I, Group 1 disease but does carry a greater risk of vaginal recurrence
304
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February 1, 1967 Am. J. Obst. & Gynec.
Bean
where there is more than minimal penetration of myometrium by tumor and when the tumor involves lower uterine segment. It has been shown that postoperative vaginal vault radiation can satisfactorily limit the incidence of vault recurrences.G Intrauterine radiation procedures do not adequately radiate tissue beyond the uterus itself and it would seem more reasonable to use external radiation to the pelvis postoperatively when the risk of pelvic spread is present as indicated by the pathologic site and spread of tumor.rv 8 On the basis of this analysis the following scheme of management for Stage I, Group 1 carcinoma of endometrium is proposed:
A. Total abdominal hysterectomy and bilateral salpingo-oophorectomy. B. Additional treatment on the basis of surgical pathology. When there is ( 1) no remaining disease, (2) endometrial involvement only, or (3) minimal involvement of myometrium in the upper uterine segment, no additional therapy to be given. With (4) minimal involvement of myometrium in the lower uterine segment, postoperative vault radium to be administered. With (5) gross myometrial involvement, postoperative vault radium plus external radiation to the whole pelvis to be administered.
REFERENCES
Report of the Saskatchewan Cancer Commission, 1963. Kottmeier, H. L., editor: Annual Report on the Results of Treatment in Carcinoma of the Uterus and Vagina, Stockholm, 1963, vol. 13, pp. 11-16. Waterman, G. W., Sumner, I. R., and Moskosky, W.: AM. J. OBST. & GYNEC. 64: 1073, 1952. Corscaden, J. A.: Gynecological Cancer, ed. 2, Baltimore, 1956, The Williams & Wilkins Company, pp. 382, 383.
Discussion DR. R. P. BECK, Edmonton, Alberta, Canada. The Saskatchewan paper provides tables for the various histologic types of carcinoma encountered, but no mention is made of Broders’ grading of the tumor. Histologic staging of these tumors is of some importance. Dr. Roman, Dr. Latour, and I reviewed the pathology slides of 266 cases of endometrial adenocarcinoma at the Royal Victoria Hospital, Montreal, correlating a Broders’ grading of these tumors with 5 year survival
tologic
rate.
Table
grading
I indicates
the
of these tumors
value
of his-
in helping
to
formulate a prognosis for the patient. In 1962, Beck and Latour presented the results of a necropsy study on 36 patients with endometrial adenocarcinoma. This study revealed
that when
the tumor
was limited
to the endo-
metrium or superficial myometrium it was confined to the uterus in 75 per cent of the cases. Dr. Carmichael has shown that when the tumor
5. 6.
7.
8.
Barclay T. H. C.: Glasgow M. J. 33: 331, 1952. Dobbie, B. M. W., Taylor, C. W., Waterhouse, J. A. H. A.: J. Obst. & Gynaec. Brit. Comm. 72: 659, 1965: Silverstone. S. M.: In Pack. G. T.. and Ariel. I. M., editors: Treatment of Cance; and Allied Diseases, ed. 2, New York, 1962, Harper & Brothers, vol. VI, pp. 195-196. Meredith, W. B.: Radium Dosage, Edinburgh, 1947, E. & S. Livingstone Ltd.
involved oniy the endometrium there was a 92 per cent 5 year survival, and when the myometrium was superficially invaded there was an 85 per cent 5 year survival. The Saskatchewan study has shown that when the tumor “grossly” involves the myometrium the 5 year survival
drops to 65 per cent in what were thought to be Stage I, Group 1 cases. A necropsy study showed that when into, or perforating,
the tumor was the myometrium,
either deep there was
spread outside the pelvis in 92.5 per cent of the cases. The necropsy study also showed that when the
pelvic
lymph
nodes
were
involved
the
tumor
had spread out of the pelvis in 90.5 per cent of cases. The Saskatchewan study has demonstrated that when endometrial carcinoma is confined to the upper uterine segment there is a better prognosis for the patient. Five of 64 patients (l/13) with tumor in the upper uterine segment showed
Volume 97 Number 3
Carcinsma
lymphatic or blood-borne metastases whereas 7 in 49 (1,/7) patients with tumor in the lower uterine segment showed these types of spread. Five of the 64 (l/13) patients with disease confined to the upper segment showed pelvic spread of disease whereas 6 of 48 (l/8) patients with lower segment disease showed pelvic spread of disease. It is interesting that none of the 5 cases with spread to the cervix showed lymphatic or blood borne spread, and that two of these cases showed local pelvic spread characteristic of primary carcinoma of the cervix. Gusberg and Yannopoulos have reported a significant difference in the net cure rate according to the size of the uterus (normal size-83.1 per cent, 2!/2 month size or 10 cm. in depth69.5 per cent; and 3 months plus or more than 10 cm.422 per cent). Although these results speak for themselves there is some difficulty in making a correlation of uterine size with cure rates because fibroids, parity, and menopausal atrophy can deceptively alter the size of the uterus. Also, one is reluctant to probe the depth of an enlarged uterus filled with necrotic tumor. My experience has been that patients with endometrial adenocarcinoma very seldom have a uterus as large as a two month pregnancy unless uterine fibroids coexist, even when there is extensive disease present. In summary it would seem that a high Broder’s
Grade
No. of cases
1 2 3 4 -__
Total
Table
38 56 a9 a3
33 46 65 38
266
182
II. Five-year
survival
Per cent 5 year survival 86.8 82.4 73.03 45.8 68.4
correlated
with
Stage
70
(I 939-59) / Total
305
stage of disease Royal
Saskatchewan
endometrium
grading, deep penetration or perforation of the myometrium, involvement of the lower uterine segment, involvement of the pelvic lymph glands, and tumor enlargement of the uterus, especially beyond a 10 cm. depth each carry an ominous prognosis for a patient with endometrial adenocarcinoma. The 66 per cent over-all survival rate reported by the Saskatchewan unit is extremely good. The over-all 5 year survival rate of 116 contributors to the annual report of the International Federation of Obstetrics and Gynaecology collated in 1963 was 62.5 per cent. The Saskatchewan group have excellent records and excellent follow-up with patients. Two years ago Beck, Latour and Bourne reported the results of treatment from the Royal Victoria Hospital in Montreal and these are compared with the Saskatchewan results in Table II. It is assumed that Dr. Carmichael is presenting his treatment results according to the results laid down by the International Federation and that Stage I, Group 1 contains no Stage 0 cases. Excluding Stage 0 cases from the Royal Victoria Hospital results, the over-all 5 year survival would be 62.34 per cent. Advances in therapy techniques and general medicine are steadily improving 5 year results. Of the 152 patients seen at the Royal Victoria Hospital Cancer Clinic from 1949 to 1956 the over-all 5 year survival was 69.34 per cent whereas it was only 59.3 per cent for 209 cases treated from 1926 to 1948. The Saskatchewan 5 year survival results using different types of therapy are remarkably similar to those reported from the Royal Victoria Hospital (see Table III). The Saskatchewan results, taken from Table XII of Dr. Carmichael’s paper, I surmise represent only Stage I, Group 1 cases whereas the Royal Victoria Hospital results represent all cases receiving treatment. The Saskatchewan surgical results would have been more significant if the 20 cases who re-
Table I. Broders’ classification of 266 cases of endometrial carcinoma correlated with 5 year survival Five-year survival rate
of
patients
Stage I, Group 1
78.67
469
Stage I, Group 2 Stage 2 Others
30.77 18.75 29.73
39 58 37
Over-all --
66.00
603
Stage
Stage Stage Stage Stage
70
0 IA IB II
81.81 74.88 39.13 33.90
Others
0 64.26
Victoria (1926-56)
Hospital
1 Total
patients 37
219 46
59 0 361
306
Carmichael
and
February J. Obst.
Bean Am.
Table III. Comparison of 5 year survival with different Saskatchewan and Royal Victoria Hospital series Saskatchewan-5 (Stage I. Group Mode
Surgery Radium Surgery Surgery other ‘Does
of
therapy
not
include
20
Total
85.00 ? 81.35 76.10 patients
who
received
partial
types of therapy in
year survival 1 patients)* 1
%
alone only and radium plus x-ray or radiotherapy
surgery
and
1, 1967 b Gynec.
Royal
Victoria
Hospital 5 year stages)
survival (all
cases
%
1
Total
cases
140 30 193
82.35 44.36 71.11
119 133 90
67
68.42
19
16 cases.
Table IV. Five-year survivals with various forms of therapy in various stagesof diseaseRoyal Victoria Hospital series 1926 Stage
Treatment
Total cases
to 1948
1949
to 1956
Survivals
Total cases
Survivals
1926 Total cases
to 1956 Survivals
1926 to 1956 % survivals
Per
cent
by stage
0
Surgery Radium Surgery and radiation
6 7 13
6 5 10
9 1 1
8 1 0
15 8 14
14 6 10
93.33 75.00 1 71.43
81.81
IA
Radium Surgery Surgery and radiation
43 18 55
27 13 37
10 75 18
7 66 14
53 93 73
34 79 51
64.15 84.94 69.86 I
74.88
IB
Radium Surgery Surgery and radiation
27 03
9 03
16 00
6 00
43 03
15 03
34.89 0 I 100.00
39.13
II
Radium Surgery Surgery and radiation
19 117
5 54
10 48
0 51
29 11 19
5 69
17.24 54.54 47.37 1
33.90
209
124
152
108
361
232
64.26
64.26
Total
ceived “partial” surgery had been included. I do, however, agree with the Saskatchewan group that surgery alone gives “at least” as good results as preoperative radium plus surgery in Stage I, Group 1 cases. Table IV shows the results with various forms of therapy in the various stages of disease in the Royal Victoria Hospital series. This table indicates an 85 per cent 5 year survival in 93 surgically treated cases and a 70 per cent 5 year survival in 73 patients treated by preoperative radium and surgery. Both treatment groups were comprised of patients with Stage IA or Stage I, Group 1 disease. One must realize, however, that most of the former cases were treated in the 19491956 era and that most of the latter caseswere treated in the 1926-1948 period.
The observations
5
year survival
on vault recurrence
are very
interesting in the Saskatchewanpresentation. The vault recurrent rate in the “surgery only” group was 8.6 per cent and about 3 per cent in the group treated by radiotherapy and surgery. It was pointed out that although the radiation cut down the number of vault recurrences it did not improve the 5 year survival. In my opinion, the reason for the latter finding is that in most cases the vault recurrence is an extension of pelvic disease into the vault and radiotherapy, of course, will do little to improve the 5 year survival in these cases. Latour, in Montreal, distinguishes between tumor recurring in the vault and tumor which appears to extend into the vault from elsewhere in the pelvis, and he classifies only the former as a vault recurrence. In
Volume Number
97 3
the Royal Victoria Hospital series from 19491956 only 2 patients treated by surgery alone developed a vault recurrence. There were 88 cases surgically treated; 9 Stage 0, 75 Stage IA, and 4 Stage II cases. In the same period 2 patients receiving preoperative radium plus surgery developed a vault recurrence. These were 17 cases so treated; one Stage 0, 14 Stage IA and 2 Stage II cases. The four vault recurrences in the two treatment groups were all Stage II cases. Vault recurrence of tumor can be treated by radiotherapy when it develops and in my opinion this is preferable to the use of preoperative radium in all Stage I, Group 1 cases. Why does surgery alone give at least as good results as preoperative radium plus surgery in view of the fact that surgery and radiation each have been used with success in treating endometrial adenocarcinoma? The incidence of radioresistant endometrial adenocarcinoma varies
Carcinoma
of endometrium
307
from 15 to 75 per cent according to Kottmeier and Corscaden. The Saskatchewan group have reported a 55 per cent incidence of residual tumor after radiation. Even in the hands of an experienced radiotherapist like Chau of the M. D. Anderson Hospital the incidence of socalled radioresistant tumor is from 20 to 30 per cent. Preoperative radium insertion followed by surgery in 6 weeks would constitute a delay in effective treatment in radioresistant cases and would only serve to disseminate these tumors. This explanation is the only answer to the question posed assuming that the case selection in the two treatment groups is unbiased. The proposed management of Stage I, Group 1 patients by the Saskatchewan group represents sound logic. I think the value of their very good paper would be enhanced by an inclusion of the treatment results in all cases.
J. A. H.
of 603 cases with a suggested with
Stage 1 disease
CARMICHAEL,
A. BEAN,
Regina,
B.A.,
scheme of management
and regarded
M.D.,
C.M.,
as good
surgical
for risks
F.R.C.S.(C)
M.D.
Saskatchewan
A review of 603 cases of adenocarcinoma of endometrium is presented. A comparison has been made of the results of various types of treatment in 469 cases in Stage I and operable from a medical standpoint (Group I). The efiect of the surgical pathology on the subsequent spread of disease in patients treated has been examined. A proposed scheme of management is ofiered for cases of carcinoma of the endometrium,classed as Stage I and operable (Group 1).
I T I s T H E purpose of this paper to review and compare the different methods of treatment of carcinoma of endometrium in the Province of Saskatchewan for a 21 year period ( 1939-1959). Particular reference will be made to operable casesclassified as Stage I, Group 1 to determine the incidence and type of spread of diseaseand finally on the basis of these observations ~0 propose a scheme of management for patients with Stage I, Group 1 disease. The Province of Saskatchewan has a population slightly less than one million people. Consultive diagnostic and treatment clinics for cancer were established in -two centers in Saskatchewan in 1930. Ninety per cent of all cancer patients in this Province are referred to a cancee clinic. Regular re-
view examinations are done on all patients with only 0.6 per cent being lost to followup.l Adequate records are maintained on all patients. This program, therefore, provides excellent material for incidence studies and for appraisal of treatment methods. Material
and
methods
The material analyzed consistsof 603 patients with carcinoma of endometrium seen in the Saskatchewan cancer clinics from 1939 to 1959 inclusive. Histologic classification is shown in Table I. Staging has been done according to the system used for reporting of material for the Annual Report of Results of Treatment Carcinoma of the Uterus and Vagina.”
in
Stage I includes caseswith operable disease,i.e., diseaseconfined to the uterus. Table I. Histologic classification
From the Radiotherapy Department, Allan Blair Memorial Clinic, and the Department of Obstetrics and Gynecology, Medical Arts Clinic.
Adenocarcinoma Adenocarcinoma Adenoacanthoma Carcinosarcoma
Presented at the Twenty-second Annual Meeting of the Society of Obstetricians and Gynaecologists of Canada, Jasper, Alberta, June 17-19, 1966.
Total
294
Well-differentiated Anaplastic
518 62 18 5 603
Volume Number
97 3
Carcinoma
Stage I is divided into two groups: Stage I, Group 1 includes cases suitable for surgical treatment; Stage I, Group 2 includes cases where the anatomical spread of the growth does not hinder a radical removal but which are bad operative risks; Stage II includes cases in which the growth has spread outside the uterus; Corpus and cervix includes cases with involvement of cervix and corpus; Unstaged were not staged at initial examination. The distribution of cases
Table II. Staging (International of Obstetrics and Gynecology)
Federation
Stage I, Group 1 Stage I, Group 2 Stage II Corpus and cervix Not stared
469 39 58 5 32
Total
603
Fig.
1. Age
distribution.
in this series according in Table II. Age
of endometrium
295
to staging is shown
distribution
Fig. 1 shows the age distribution which is comparable to other series of this size. Age of menopause is shown in Fig. 2 for 395 patients whose symptoms began in the postmenopausal period (6 months amenorrhea prior to onset of symptoms). The observation that the average age of the menopause is delayed” in patients subsequently developing carcinoma of endometrium is not confirmed. (It is the impression of the gynecologists in this area that the average age of the menopauseis 50 years.) Associated
medical
conditions
Fifty-nine per cent of all patients had one or more of the triad of diabetes, obesity, and hypertension. Careful review of the his-
296
Carmichael
-40
40
and
41
February 1, 1967 Am. J. Obst. & Gynec.
Bean
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
bit
AGE
Fig.
2. Age of menopause in the 395 patients symptoms (amenorrhea x 6 months).
tories failed to reveal any characteristic preceding gynecologic pattern. Fifty-three patients gave a history of abnormal menstrual bleeding, 47 had an abnormal menopause (requiring dilatation and curettage or hormonal therapy), 40 had some form of hormone therapy, and 28 had had a previous diagnosis of endometrial hyperplasia. None of these problems appeared frequently enough in this series to justify any conclusions. Thirty-three patients had had previous radiotherapy for gynecologic problems. Symptoms
Table III lists the first symptom or symptoms experienced by the patient. Eighty per cent experienced someform of abnormal bleeding (irregular menstrual, postmenopausal, etc.). In reviewing this series, vaginal discharge appeared more significant than the figure of 10 per cent would suggest. A number of patients complained of intractable vaginal discharge many months before the telltale symptoms of postmenopausal bleeding occurred.
completing
their
menopause
before
the onset
of
Duration of symptoms. Fig. 3 shows the duration of symptoms (from first symptoms to first treatment). Treatment was started within 6 months in over 50 per cent of patients. Fig. 4 showsthe relationship between duration of symptoms and crude 5 year survival. Despite the recognized desirability of early detection and treatment, this series fails to show that duration of symptoms influences survival. This observation has been made previously for carcinoma of uterus4 and for other sites.5 The accuracy of the history, particularly when recalling the onset of irregular bleeding, vaginal discharge or postmenopausal bleeding must always reTable III.
First symptom of symptoms %
Bleeding Discharge Bleeding Pain None Other
and
discharge
78.9 10.3 1.1 90.3 4.6 1.1 4.0
52.5
% )
f 25
-1
1-3
4-6
7-9 DURATION
Fig.
3. Duration
of symptoms
to first
10-12 OF
13.24
SYMPTOMS
IN
MONTHS
treatment.
30
-1 -1
1-3
7.0 7.0
4.4
to-12 DURATION
63 63
142
53
va
Fig. 4. Duration of symptoms in each time interval.
and
survival.
13-34
Of
SYWYOMS
NUMMR
Of
37.48 37.48
4w 4w
37
17
36
IN MONTNS
60
The
2%a6 2%a6
77
bottom
PATIENTS
figures
give
the
number
of patients
298
Carmichael
and Bean
February 1, 1967 Am. J. Obst. & Gym.
main suspect. However, it is clearly shown that survival rates are greatly influenced by extent of spread of disease (Table IV) and stage of disease(Table VII) indicating that for any individual case the earlier the diagnosis is made and adequate treatment initiated, the better the prognosis will be. Treatment
Treatment methods were numerous and were classified under twenty-five separate categories. These fall into three main groupings; surgery alone, radiotherapy alone, and combined surgery plus radiotherapy (Table V)* Table IV. Crude 5 year survival by surgical pathology Iti
No remainingtumor
90.8 192 93.8/ 85.5 65.2
Endometriumonly Myometrium minimal Myometrium gross Upper segmentonly Upper
+ lower
84.6 64.5
segments
Description of radiotherapy procedures. Heyman packing. In 1934 Heyman developed the “packing technique.” This consisted of packing as many as possible Heyman applicators enclosed in suitable filters or capsules into the uterine cavity. Each applicator contained 8 to 10 mg. of radium element. Four sizesof capsule or filter were available, small capsules being used for small uterine cavities and larger capsules for larger cavities so that at least four and not more than twelve capsules were used. This method of loading maintains a constant total filtration of 3 mm. lead equivalent. An empirical dose of 1,500 mg. hours for a No. 1 shield using ten applicators was arrived at by Professor Heyman. Corrections were made for fewer applicators and larger sizes of shields.In addition to uterine applicators, vaginal applicators were used to radiate the vaginal vault. In the present study applicators were loaded with 8 to 10 mg. of Coso wire. The number of mg. hours for different numbers of irradiators of different sizes is shown in Table VI. The use of Coeowire has necessi-
Table V. Methods of treatment Surgeryalone
182
Total abdominalhysterectomy bilateral
Less than total and bilateral Radiotherapy
Combined
147
abdominal hysterectomy salpingo-oophorectomy
35
alone
104
Suitable for surgery Inoperable disease Poor surgical risk Unclassified
treatment
298
Preoperative Heyman packing + total abdominal hysterectomy + bilateral salpingo-oophorectomy
146
Preoperative line source radium + total abdominal hysterectomy + bilateral salpingo-oophorectomy
55
Other radiotherapy+ + Total abdominal hysterectomy + bilateral salpingo-oophorectomy
47
Radiotherapy
50
No treatment Total *External
and
salpingo-oophorectomy
radiation,
vault
radium.
+ less radical
25 35 32 12
surgery
19
19
603
603
Volume Number
97 3
Carcinoma
Table VI. Heyman applicators (milligram hours for different numbers of irradiators of different sizes) Size No.
I (mg.hr.)
985
4 5 6
Table
hr.)
1,480 1,585
1,610 1,730 1,815 1,880
2,000 2,080 2,100
1,650 1,745 1.800
1,760 1,835 1.905
1,915 1,985
2,115 2,155
2.070
2.170
Crude
5 year
survival
Stage I, Group 1 Stage I, Group 2 Stage II Corpus + coli Not staned Total
VIII.
IV (mg.
1,385 1,505 1,615 1,705
No.
Table
III (mg. hr.)
-
1,370
VII.
hr.)
-
1,145 1,255
7 8 9 10 11 12
II (mg.
369 12
58 5 32
6 3 8
Complications
Perforated uterus Fistulas Bowel or ureteral Total
obstruction
by stages
Surviving 5 years
469 39
603
1,905
% 78.67 30.77 18.75 -
398
66
of treatment 8 4 6
18 f3.8%\
tated a constant correction factor for decay. Two insertions were carried out at 3 to 4 week intervals. In one clinic, vault radium was inserted with one packing using small vaginal ovoids each loaded with 20 mg. of radium. In the other clinic, vault radium was applied as a postoperative procedure in selected cases only where there was evidence of lower uterine segment involvement or deep penetration of myometrium. This application consisted of vaginal ovoids of three sizes loaded as for treatment of carcinoma of the cervix. Line source or tandem radium was administered using a thick rubber tube 1 cm. in diameter loaded with two to four 25 mg. tubes of radium (depending on the length of the uterine cavity). Treatment time was 96 hours in 2 insertions, one week apart.
of
endometrium
299
Vault radium was applied in some cases, using vaginal ovoids. Pre- and postoperative external radiation were given by orthovoltage and Co60 teletherapy and varied in dosage-but approximated in the majority of incidences 3,000 rads to the whole pelvis. A few patients with advanced disease received Betatron treatment. Crude 5 year survival for the total series is shown in Table VII. Complications of Treatment are shown in Table VIII. Stage
1, Group
1
A detailed analysis has been made of the 469 cases which were classified as Stage I, Group 1. Treatment methods for this group are shown in Table IX. The two main forms of treatment were preoperative intrauterine radiation with or without vault radium plus total abdominal hysterectomy and bilateral salpingo-oophorectomy and surgery (total abdominal hysterectomy and bilateral salpingo-oophorectomy) alone. Before comparing results of treatment in these two groups it is necessary to establish a reasonable similarity in the patient material in each group. Table X compares the age, incidence of medical complications and the histologic distribution to be found in each form of therapy. These tables show comparable patient material in each treatment group. Fig. 5 shows the yearly incidence of the main forms of therapy used. It cannot be denied that there is a natural and understandable selection of favorable cases for primary surgery alone. However, Fig. 5 suggests a certain trend or selection according to “la mode” rather than a continual selection of favorable patients for primary surgery. Table XI compares the results of the different types of preoperative intrauterine radiation. There appears to be little difference in the incidence and direction of extension of disease postoperatively, and no difference in 5 year survival rates. There is a 10 per cent decrease in residual tumor in those patients who had Heyman
300
Carmichael
and
February 1, 1967 Am. J. Obrt. & Gynec.
Bean
packing. This difference is not reflected in survival figures. To have residual tumor in 52.8 per cent of uteri with Heyman packing was disappointing. The time of surgery may have influenced this to some extent. Surgery was originally done at 6 weeks to 2 months following the second Heyman packing. This time interval was shortened to one month in one clinic, and in the other clinic, surgery
Table IX. Methods Surgery
of treatment
alone
Radiotherapy Surgery
for Stage I, Group
1
Total abdominal
160
alone
was done immediately following the second Heyman packing. When surgery is done immediately it is probable that residual tumor will be present. The high incidence of residual tumor may also be due to insufficient dosage, insufficient filling of the uterine cavity, or to exceptional diligence on the part of the pathologist. Because of the similarity of patient ma-
hysterectomy + bilateral salpingo-oophorectomy Less than adequate surgery
140 20
30
+ radiotherapy
30
276
Heyman packing + total abdominal hysterectomy + bilateral salpingo-oophorectomy Heyman packing + vault radium + total abdominal hysterectomy + bilateral salpingo-oophorectomy
82L
142
60A
Line source radium + total abdominal hysterectomy + bilateral salpingo-oophorectomy Line source radium + vault radium t total abdominal hysterectomy bilateral salpingo-oophorectomy Other radiotherapy*+ total abdominal hysterectomy bilateral salpingo-oophorectomy Other No
treatment
+
+ 67 16 3
combinations
3
Total
469
469
*External
radiation,
vault
Table X. Comparison
Treatment Heyman
packing
radium
+ line
of patient
abdominal
+ surgery*
hysterectomy
material
treatment
groups
w
82
59.2
63.4
74
8
0
0
60
55.5
65
57
2
0
1
34
59.5
65
28
2
0
4
56.4
70.6
15
57.2
59.3
120
12
4
4
l7 140 plus
in different Per cent with hyfiertension and/or obesity and/or diabetes
No. of patients
groups
Heyman packing + surgery+ and vault radium Line source + surgery* Line source and vault radium + surgery* *Surgery alone “Total
source.
bilateral
Average
salpingo-oophorectomy.
Histolonv
Volume Number
97 3
Carcinoma
terial and therapeutic results of all forms of preoperative intrauterine radiation, these groups have been combined to give a total group of 193 cases. This group has been compared with the 140 cases treated by surgery alone. Th e results are shown in Table XII. The incidence of pelvic extension, lymph node and blood spread and 5 year survival rates are essentially the same. The only significant difference is the incidence of vaginal vault recurrence or vaginal implant. The final line in Table XII compiles all other combinations of surgery and radiotherapy. Again, a decrease in incidence of va.ginal extension is noted. Table XIII lists the yearly incidence of both vaginal and pelvic spread of tumor for primary surgery and for preoperative intrauterine radiation plus surgery. All vaginal recurrence in the surgical group appeared within the first 3 years; in the preoperative irradiation group within the first 4 years with the exception of one case. Pelvic
KING
WITH
extension tended both groups.
of endometrium
to occur
at a later
5. Yearly
census
of
major forms
of therapy
time in
Correlation of surgical pathology and subsequent spread of carcinoma of endometrium Analysis of surgical pathology and subsequent spread of carcinoma of endometrium in the 140 cases treated by surgery alone (total abdominal hysterectomy and bilateral salpingo-oophorectomy) shows a significant increase in the incidence of pelvic recurrence where the disease has progressed beyond minimal invasion of the myometrium (Table XIV). Table XIV also correlates lymph node and blood spread with surgical pathology in the 140 cases treated by surgery alone. Again there is a significant increase in incidence when there is greater than minimal invasion of myometrium. There was also an increase in vaginal recurrence with gross myometrial involvement. There is also an increase in vaginal recur-
OR
WITHOUT
YEAR Fig.
301
used for
Stage
I, Group
I patients.
302
Carmichael
and
Bean
February 1, 1967 J. Obst. & Gynec.
Am.
Comment
rence with minimal myometrial involvement when tumor is in the lower uterine segment. This observation does not stand up to statistical analysis because of the small numbers involved but does indicate that both spread and position are a factor in subsequent vaginal recurrence.
Heyman packing technique versus tandem radium. In the Saskatchewan experience Heyman packing with or without vault radium shows no advantage over line source with or without vault radium, except that with Heyman packing 10 per cent less
Table XI. Results
of preoperative intrauterine radiation hysterectomy and bilateral salpingo-oophorectomy
abdominal
Spread
Treatment Heyman
No. of patients
of method packing
with
total
at 5 years
Pelvic and intraabdominal
Vaginal alone
combined
Continuing disease
Residual tumor in operative sfiecimen
5 year survival
Metastases
82
3
6
2
3
67 (81.7%)
60
2
2
2
2
50 (83.3%)
source
34
1
1
0
3
25
Line source + vault radium
17
0
1
1
0
15
5 (2.6%)
7 (3.6%)
81.35%
Heyman with Line
>
packing vault radium
Total
193
Table XII.
Comparison
6 (3.1%)
10 (5.2%)
of results in different
treatment
Method treatment Surgery*
of
Treatment method
%
No.
%
No.
No.
%
8.6
10
7.4
0
0
5
3.6
85
193
6
3.1
10
5.2
5
2.6
7
3.6
81.35
3.0
6
9.0
1
1.5
3
4.5
76.1
67
2 plus
incidence
Spread
Surgery* alone
bilateral
of disease
Vaginal
*Total
plus abdominal
Vaginal Pelvic and/or intra-abdominal hysterectomy plus
bilateral
%
salpingo-oophorectomy.
of vaginal
Pelvic and/or intra-abdominal Intrauterine radiation suraerv*
5 year crude survival %
Metastases
12
hysterectomy
Yearly
Continuing disease
No.
Other radiotherapy + surgery*
Table XIII.
at 5 years
Pelvic and intra-abdominal
140
alone
abdominal
107(55.4%)
No. of patients
Surgery* plus intrauterine radiation
*Total
32(62.7%)
groups
S#read Vaginal only
> 78.6%
75(52.8%)
I
and pelvic
and abdominal
2
3
68
2
2
6
2
4
1
4
3
sirlpingo-oophorectomy.
1
Years
after
4
5
:
spread treatment 6
7
8
2
1
1
1
9
) IO+
1 1
Volume Number
97 3
Carcinoma
Table XIV.
Surgical
pathology
and subsequent Endometrium only
No disease Pelvic No
spread disease
of endometrium
303
spread Myometrium, minimal
Myomet Gum, gross
Serosa
Adnexa
0” 11
Upper
uterine
segment Lower
uterine
segment Uterus
+ cervix
Metastases-lymph No disease
nodes
and
blood
0
1
3
8
37
17
1
0
i
i
1
1
3
0
5
22
20
0
0
0
1
0
0
i
3
0
1 r 1 i
borne 0 11
Upper uterine segment
0
0
3
s
37
17
Lower uterine segment
1
0
5
5
22
20
Uterus
0
0
0
0
-i
3
+ cervix
Vaginal spread No disease
0 11
Upper
uterine
0
segment Lower
s
uterine
segment Uterus
+ cervix
*Numerator denotes pathologic group.
number
of
cases
of
spread,
1 3s
2
0
14
0
1 t
0
4
3
0
0
4
21
19
0
0
0
0
0
0
0
0
r
?
0
0
denominator
specimens have residual tumor. This difference, however, is not reflected in 5 year survival rates or in recurrence of disease (Table XI).
Primary surgery versus all forms of preoperative intrauterine irradiation with or without vault radiation. The single advantage of preoperative intrauterine radiation is a significant decrease in the incidence of vaginal vault recurrences and vaginal implants (see Table XII). The incidence of pelvic recurrence, metastases and, the 5 year survival rates are the same.
denotes
number
of
cases
in
that
surgical
Pelvic extension and surgical pathology. Postoperative pelvic extension and metastases are a direct function of the extent of myometrial involvement (Table XIV).
Vaginal extension and surgical pathology. Table XIV suggests that vaginal implants and vaginal vault recurrences are a factor both of myometrial penetration and tumor site. In this series surgery alone has produced as good 5 year survival as combined treatment for Stage I, Group 1 disease but does carry a greater risk of vaginal recurrence
304
Carmichael
and
February 1, 1967 Am. J. Obst. & Gynec.
Bean
where there is more than minimal penetration of myometrium by tumor and when the tumor involves lower uterine segment. It has been shown that postoperative vaginal vault radiation can satisfactorily limit the incidence of vault recurrences.G Intrauterine radiation procedures do not adequately radiate tissue beyond the uterus itself and it would seem more reasonable to use external radiation to the pelvis postoperatively when the risk of pelvic spread is present as indicated by the pathologic site and spread of tumor.rv 8 On the basis of this analysis the following scheme of management for Stage I, Group 1 carcinoma of endometrium is proposed:
A. Total abdominal hysterectomy and bilateral salpingo-oophorectomy. B. Additional treatment on the basis of surgical pathology. When there is ( 1) no remaining disease, (2) endometrial involvement only, or (3) minimal involvement of myometrium in the upper uterine segment, no additional therapy to be given. With (4) minimal involvement of myometrium in the lower uterine segment, postoperative vault radium to be administered. With (5) gross myometrial involvement, postoperative vault radium plus external radiation to the whole pelvis to be administered.
REFERENCES
Report of the Saskatchewan Cancer Commission, 1963. Kottmeier, H. L., editor: Annual Report on the Results of Treatment in Carcinoma of the Uterus and Vagina, Stockholm, 1963, vol. 13, pp. 11-16. Waterman, G. W., Sumner, I. R., and Moskosky, W.: AM. J. OBST. & GYNEC. 64: 1073, 1952. Corscaden, J. A.: Gynecological Cancer, ed. 2, Baltimore, 1956, The Williams & Wilkins Company, pp. 382, 383.
Discussion DR. R. P. BECK, Edmonton, Alberta, Canada. The Saskatchewan paper provides tables for the various histologic types of carcinoma encountered, but no mention is made of Broders’ grading of the tumor. Histologic staging of these tumors is of some importance. Dr. Roman, Dr. Latour, and I reviewed the pathology slides of 266 cases of endometrial adenocarcinoma at the Royal Victoria Hospital, Montreal, correlating a Broders’ grading of these tumors with 5 year survival
tologic
rate.
Table
grading
I indicates
the
of these tumors
value
of his-
in helping
to
formulate a prognosis for the patient. In 1962, Beck and Latour presented the results of a necropsy study on 36 patients with endometrial adenocarcinoma. This study revealed
that when
the tumor
was limited
to the endo-
metrium or superficial myometrium it was confined to the uterus in 75 per cent of the cases. Dr. Carmichael has shown that when the tumor
5. 6.
7.
8.
Barclay T. H. C.: Glasgow M. J. 33: 331, 1952. Dobbie, B. M. W., Taylor, C. W., Waterhouse, J. A. H. A.: J. Obst. & Gynaec. Brit. Comm. 72: 659, 1965: Silverstone. S. M.: In Pack. G. T.. and Ariel. I. M., editors: Treatment of Cance; and Allied Diseases, ed. 2, New York, 1962, Harper & Brothers, vol. VI, pp. 195-196. Meredith, W. B.: Radium Dosage, Edinburgh, 1947, E. & S. Livingstone Ltd.
involved oniy the endometrium there was a 92 per cent 5 year survival, and when the myometrium was superficially invaded there was an 85 per cent 5 year survival. The Saskatchewan study has shown that when the tumor “grossly” involves the myometrium the 5 year survival
drops to 65 per cent in what were thought to be Stage I, Group 1 cases. A necropsy study showed that when into, or perforating,
the tumor was the myometrium,
either deep there was
spread outside the pelvis in 92.5 per cent of the cases. The necropsy study also showed that when the
pelvic
lymph
nodes
were
involved
the
tumor
had spread out of the pelvis in 90.5 per cent of cases. The Saskatchewan study has demonstrated that when endometrial carcinoma is confined to the upper uterine segment there is a better prognosis for the patient. Five of 64 patients (l/13) with tumor in the upper uterine segment showed
Volume 97 Number 3
Carcinsma
lymphatic or blood-borne metastases whereas 7 in 49 (1,/7) patients with tumor in the lower uterine segment showed these types of spread. Five of the 64 (l/13) patients with disease confined to the upper segment showed pelvic spread of disease whereas 6 of 48 (l/8) patients with lower segment disease showed pelvic spread of disease. It is interesting that none of the 5 cases with spread to the cervix showed lymphatic or blood borne spread, and that two of these cases showed local pelvic spread characteristic of primary carcinoma of the cervix. Gusberg and Yannopoulos have reported a significant difference in the net cure rate according to the size of the uterus (normal size-83.1 per cent, 2!/2 month size or 10 cm. in depth69.5 per cent; and 3 months plus or more than 10 cm.422 per cent). Although these results speak for themselves there is some difficulty in making a correlation of uterine size with cure rates because fibroids, parity, and menopausal atrophy can deceptively alter the size of the uterus. Also, one is reluctant to probe the depth of an enlarged uterus filled with necrotic tumor. My experience has been that patients with endometrial adenocarcinoma very seldom have a uterus as large as a two month pregnancy unless uterine fibroids coexist, even when there is extensive disease present. In summary it would seem that a high Broder’s
Grade
No. of cases
1 2 3 4 -__
Total
Table
38 56 a9 a3
33 46 65 38
266
182
II. Five-year
survival
Per cent 5 year survival 86.8 82.4 73.03 45.8 68.4
correlated
with
Stage
70
(I 939-59) / Total
305
stage of disease Royal
Saskatchewan
endometrium
grading, deep penetration or perforation of the myometrium, involvement of the lower uterine segment, involvement of the pelvic lymph glands, and tumor enlargement of the uterus, especially beyond a 10 cm. depth each carry an ominous prognosis for a patient with endometrial adenocarcinoma. The 66 per cent over-all survival rate reported by the Saskatchewan unit is extremely good. The over-all 5 year survival rate of 116 contributors to the annual report of the International Federation of Obstetrics and Gynaecology collated in 1963 was 62.5 per cent. The Saskatchewan group have excellent records and excellent follow-up with patients. Two years ago Beck, Latour and Bourne reported the results of treatment from the Royal Victoria Hospital in Montreal and these are compared with the Saskatchewan results in Table II. It is assumed that Dr. Carmichael is presenting his treatment results according to the results laid down by the International Federation and that Stage I, Group 1 contains no Stage 0 cases. Excluding Stage 0 cases from the Royal Victoria Hospital results, the over-all 5 year survival would be 62.34 per cent. Advances in therapy techniques and general medicine are steadily improving 5 year results. Of the 152 patients seen at the Royal Victoria Hospital Cancer Clinic from 1949 to 1956 the over-all 5 year survival was 69.34 per cent whereas it was only 59.3 per cent for 209 cases treated from 1926 to 1948. The Saskatchewan 5 year survival results using different types of therapy are remarkably similar to those reported from the Royal Victoria Hospital (see Table III). The Saskatchewan results, taken from Table XII of Dr. Carmichael’s paper, I surmise represent only Stage I, Group 1 cases whereas the Royal Victoria Hospital results represent all cases receiving treatment. The Saskatchewan surgical results would have been more significant if the 20 cases who re-
Table I. Broders’ classification of 266 cases of endometrial carcinoma correlated with 5 year survival Five-year survival rate
of
patients
Stage I, Group 1
78.67
469
Stage I, Group 2 Stage 2 Others
30.77 18.75 29.73
39 58 37
Over-all --
66.00
603
Stage
Stage Stage Stage Stage
70
0 IA IB II
81.81 74.88 39.13 33.90
Others
0 64.26
Victoria (1926-56)
Hospital
1 Total
patients 37
219 46
59 0 361
306
Carmichael
and
February J. Obst.
Bean Am.
Table III. Comparison of 5 year survival with different Saskatchewan and Royal Victoria Hospital series Saskatchewan-5 (Stage I. Group Mode
Surgery Radium Surgery Surgery other ‘Does
of
therapy
not
include
20
Total
85.00 ? 81.35 76.10 patients
who
received
partial
types of therapy in
year survival 1 patients)* 1
%
alone only and radium plus x-ray or radiotherapy
surgery
and
1, 1967 b Gynec.
Royal
Victoria
Hospital 5 year stages)
survival (all
cases
%
1
Total
cases
140 30 193
82.35 44.36 71.11
119 133 90
67
68.42
19
16 cases.
Table IV. Five-year survivals with various forms of therapy in various stagesof diseaseRoyal Victoria Hospital series 1926 Stage
Treatment
Total cases
to 1948
1949
to 1956
Survivals
Total cases
Survivals
1926 Total cases
to 1956 Survivals
1926 to 1956 % survivals
Per
cent
by stage
0
Surgery Radium Surgery and radiation
6 7 13
6 5 10
9 1 1
8 1 0
15 8 14
14 6 10
93.33 75.00 1 71.43
81.81
IA
Radium Surgery Surgery and radiation
43 18 55
27 13 37
10 75 18
7 66 14
53 93 73
34 79 51
64.15 84.94 69.86 I
74.88
IB
Radium Surgery Surgery and radiation
27 03
9 03
16 00
6 00
43 03
15 03
34.89 0 I 100.00
39.13
II
Radium Surgery Surgery and radiation
19 117
5 54
10 48
0 51
29 11 19
5 69
17.24 54.54 47.37 1
33.90
209
124
152
108
361
232
64.26
64.26
Total
ceived “partial” surgery had been included. I do, however, agree with the Saskatchewan group that surgery alone gives “at least” as good results as preoperative radium plus surgery in Stage I, Group 1 cases. Table IV shows the results with various forms of therapy in the various stages of disease in the Royal Victoria Hospital series. This table indicates an 85 per cent 5 year survival in 93 surgically treated cases and a 70 per cent 5 year survival in 73 patients treated by preoperative radium and surgery. Both treatment groups were comprised of patients with Stage IA or Stage I, Group 1 disease. One must realize, however, that most of the former cases were treated in the 19491956 era and that most of the latter caseswere treated in the 1926-1948 period.
The observations
5
year survival
on vault recurrence
are very
interesting in the Saskatchewanpresentation. The vault recurrent rate in the “surgery only” group was 8.6 per cent and about 3 per cent in the group treated by radiotherapy and surgery. It was pointed out that although the radiation cut down the number of vault recurrences it did not improve the 5 year survival. In my opinion, the reason for the latter finding is that in most cases the vault recurrence is an extension of pelvic disease into the vault and radiotherapy, of course, will do little to improve the 5 year survival in these cases. Latour, in Montreal, distinguishes between tumor recurring in the vault and tumor which appears to extend into the vault from elsewhere in the pelvis, and he classifies only the former as a vault recurrence. In
Volume Number
97 3
the Royal Victoria Hospital series from 19491956 only 2 patients treated by surgery alone developed a vault recurrence. There were 88 cases surgically treated; 9 Stage 0, 75 Stage IA, and 4 Stage II cases. In the same period 2 patients receiving preoperative radium plus surgery developed a vault recurrence. These were 17 cases so treated; one Stage 0, 14 Stage IA and 2 Stage II cases. The four vault recurrences in the two treatment groups were all Stage II cases. Vault recurrence of tumor can be treated by radiotherapy when it develops and in my opinion this is preferable to the use of preoperative radium in all Stage I, Group 1 cases. Why does surgery alone give at least as good results as preoperative radium plus surgery in view of the fact that surgery and radiation each have been used with success in treating endometrial adenocarcinoma? The incidence of radioresistant endometrial adenocarcinoma varies
Carcinoma
of endometrium
307
from 15 to 75 per cent according to Kottmeier and Corscaden. The Saskatchewan group have reported a 55 per cent incidence of residual tumor after radiation. Even in the hands of an experienced radiotherapist like Chau of the M. D. Anderson Hospital the incidence of socalled radioresistant tumor is from 20 to 30 per cent. Preoperative radium insertion followed by surgery in 6 weeks would constitute a delay in effective treatment in radioresistant cases and would only serve to disseminate these tumors. This explanation is the only answer to the question posed assuming that the case selection in the two treatment groups is unbiased. The proposed management of Stage I, Group 1 patients by the Saskatchewan group represents sound logic. I think the value of their very good paper would be enhanced by an inclusion of the treatment results in all cases.