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Carcinoma of the endometrium
Carcinoma of the endometrium HENRY
CLAY
FRICK,
EQUINN
W.
MUNNELL,
RALPH
M.
AGNES
P.
MARGARET New
I’ork,
RICHART, BERGER, F.
New
II,
M.D. M.D.
M.D. PH.D.
LAWRY,
A.B.
York
The experience in the management of 348 cases of adenocarcinoma of the corpus treated at the Presbyterian and Francis Delafield Hospitals between the years 1956 and 1965 is reviewed. The cases are classified according to the criteria outlined by the Cancer Committee of the International Federation of Gynaecology and Obstetrics. The over-all relative survival in the series is 66.1 per cent. The corrected survival computed by either the patient-years method or the Berkson-Gage estimate is 73.0 per-cent. Age, stage of disease, degree of difierentiation of tumor, and extent of myometrial penetration seem to have a definite relationship to prognosis. The policies used in treating the disease are outlined. There appears to be no difference between the cure rate in the cases receiving adjuvant radiation therapy plus hysterectomy and that in the cases treated by hysterectomy a!one. On the other hand, a greater proportion of cases with deep myometrial penetration and undifferentiated tumors received adjuvant radiation therapy. In this series of cases, localized vaginal vault recurrences are few. Complications of treatment are presented and discussed. The five-year end result in the present series is compared with a previous series of carcinoma of the endometrium treated at these institutions between 1938 and 1955 and no significant improvement in the cure rate is found.
THE EXPERIENCES in managing carcinoma of the corpus on the gynecological services of the Presbyterian and Delafield Hospitals during the years 1938-1948 and 1938-1955 have been reviewed by Corscaden and Tovelll and Gusberg and Yannopoulos.2 Because of the work of these authors, certain policies were adopted regarding the therapy
of this disease. These policies have been in effect since 1956. It was thought that a review of the cases of carcinoma of the corpus from 1956-1965 was in order to see if there had been any improvement in our five-year survival results. Materials
and
methods
This report deals with 348 casesof primary adenocarcinoma or adenoacanthoma of the corpus treated at the Presbyterian and Delafield Hospitals during the years 1956-1965. The caseswere staged according to the latest classification and staging proposed in 1950 by the Cancer Committee of the International Federation of Gynaecology and Obstetrics.3 Clinical findings preoperatively plus information obtained at operation and subsequent examination of the pathological specimen were used to aid in the classifica-
From the Departments of Obstetrics and Gynecology and Pathology of the College of Physicains and Surgeons, and Division of Biostatistics of the School of Public Health, Columbia University, the Presbyterian Hospital, and the Francis Delafield Hospital. Presented by invitation at the Eightythird Annual Meeting of the American Association of Obstetricians and Presbyterian Hospital, and the Francis September 7-9, 1972. Reprint requests: Dr. Henry Clay Frick, II, Columbia-Presbyterian Medical Center, 161 Fort Washington Ave., New York, New York 10032.
tion.
663
664
Frick et al.
Symptoms. Postmenopausal bleeding was the most common symptom, occurring in 75.0 per cent of the series; 18 per cent presented with menometrorrhagia and pain occurred in 2.0 per cent. Medical status. There were no medical contraindications to therapy in 51.7 per cent. Of the 348 patients, 87 (25.0 per cent) had hypertension or cardiovascular disease.Diabetes was found in 28 patients (8.0 per cent). Among the 38 diseaseslisted as “other conditions” were liver disease, tuberculosis, asthma, emphysema, multiple sclerosis, and syringomyelia. The incidence of diabetes in other series in the literature ranges from 5.34 to 41.0 per cent.5 Habitus. Forty-nine per cent of the patients in this series were classified as obese and 36.0 per cent as normal. Obesity was listed if the patient looked obese to the admitting physician. Parity. Of the series, 137 patients (36.5 per cent) were ntdliparous, which is higher than the figure of 17.9 per cent for the average populatior+ 7; 36.5 per cent were para 1 or 2. The remaining patients were over para 3. No relationship between five-year survival and parity could be demonstrated. History of other primary malignancies. There were 27 patients (7.7 per cent) with a history of other primary malignancies found in this series. Seventeen occurred before the diagnosisof endometrial cancer, four were diagnosed at the time of therapy, and six developed after the therapy for endometrial cancer was completed. The most common locations of the associatedmalignancies were bowel and breast. The over-all five-year survival in this group was 15 out of 27 (55.5 per cent). This incidence of 7.7 per cent compares with the findings of Davis,* 9 per cent in 525 cases;Vongtama and associates,s 11.8 per cent; MacMahon and Austin9 15.0 per cent in 869 cases;and Shah and Green,” 20.0 per cent in 122 cases. Inaccuracy of the Papanicolaou smear. In this series 155 patients had no record of a cytologic smear having been taken. The Papanicolaou smear report was recorded in
March 1, lYi3 Am. J. Obstet. Gynecol.
193 cases.In 129 (67 per cent) of the reported smears, a false-negative result was obtained. In defense of the Papanicolaou smear, it must be stated that these patients were first seenby a variety of physicians and probably the technique varied a great deal with each examiner. No intrauterine washings were obtained. The inaccuracy of the Papanicolaou smear is confirmed by others. Nahhas and colleagues’o reported only 25 per cent positive and 25 per cent suspicious smearsin 92 patients. Jones and colleagues11 reported abnormal findings in the vaginal smearsof approximately one third of 86 patients with the known diagnosis of adenocarcinoma of the corpus. Adenoacanthoma. It will be noted that there has been no separate designation of adenoacanthoma made in this paper. Although there were 44 cases of adenoacanthoma in this series,they were not tabulated separately. Over 80 per cent were classified as Stage I, and the five-year survival rate was 88.0 per cent as compared to 86.1 per cent in the Stage I, Grade I adenocarcinomas in the total series.The comparability between adenocarcinoma and adenoacanthoma of the uterus has been stressed by other authors including Gusberg and Yannopoulos,2 Davis, ’ Wade and colleagues,12 and Badib and colleagues.13 Factors influencing survival. The following factors appear to be related to five-year survival: (1) age, (2) stage of disease, (3) degree of myometrial penetration, and (4) grade. These factors may well be related to each other and we did look into the relationship between (1) age and stage, (2) grade and stage, and (3 ) grade and penetration. Age. The literature is replete with articles showing that the prognosis in endometrial cancer is much worse in the older patient.12, I41I5 The median age for this series was 60. Table I shows the age distribution in ten-year periods. The observed relative five-year survival is given. The grossor relative survival is calculated by regarding patients lost to follow-up as dead and it includes death from all causes.Age refers to age at time of diagnosis. Table II compares
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115 5
the corrected five-year survival rate observed in this series to the race-adjusted U. S. Survival Rate according to actuarial tables applied at the middle of the ten-year intervals.lG The corrected five-year survival rate is obtained by removing half of the patients lost from the number at risk in each age group. The difference between the two rates is given in the right-hand column. It can be seen that there is a marked increase in the difference between the U. S. race-adjusted survival rate and observed survival rate from the 50-59 to the 60-69 group. These findings suggest a significant difference in survival rates between the younger and older patients studied in this series not explicable by their age alone. Stages of diseaseand survival, Table III shows the relative five-year survival in the series when divided into stages. The largest number of patients were in the Stage Ia category. The difference between an 81.5 per cent survival rate in Stage Ia as compared to 3.2 per cent in Stage IV is self-evident. Degree of myometrial penetration. The relationship between survival and myometrial penetration is shown in Table IV. The degree of penetration is depicted by ( 1) no tumor seen-the tumor had been removed by either curettage or preoperative radiation therapy, (2) the disease was confined to the endometrium-it had not invaded the myometrium; (3) superficial-only one third of the myometrium was involved; (4) deepunder two thirds of the myometrium was involved ; (5) deeper-over two thirds of the myometrium was involved, and (6) no hysterectomy was performed and consequently no specimen was available for examination. Table IV shows that 48 patients in the total series had no disease in the specimen; it had been eradicated by either curettage or preoperative radium. The five-year survival rate in this group was 91.6 per cent. Fortytwo patients had deep penetration, over two thirds of the uterus, and the survival rate was 45.2 per cent. The relationship between prognosis and myometrial penetration has been confirmed by others: Corscaden and Tovell,l Gusberg and Yannopoulos,2 Wade
Table I. Carcinoma Age and survival
of endometrium
of endometrium
5 year
Ages
Total cases
20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
1 8 51 105 123 51 8 1
Total
348
:
survival
-% ..88.2 81.9 56.9 43.1 12.5 --. -__.--66.1
NO.
1 5 45 86 70 22 1 0 230
Table II. Carcinoma
665
of endometrium:
Age and survival
‘ET
40-49
50-59 60-69 70-79 old.
a%+G =
0.9783
0.901 0.854 0.582 0.431 proportion
dying
Table III. Carcinoma Stage and survival Stage
Total cases
0.07 0.10 0.30 0.30
0.9524 0.8877 0.7378 in
5 years
among
X+5 years
of endometrium: 5 year survival No.
%
Ia Ib II III IV
195 66 22 34 31
159 47 8 15 1
81.5 71.2 36.4 44.1 3.2
Total
348
zi
66.1
and associates,12 Sal1 and associates,% Shah and Green5 Nilsen and Koller,15 and Vongtama and associates.17 Grade. There appears to be a definite correlation between five-year survival and degree of differentiation of the tumor. The Stages Ia and Ib are shown separately because they comprise 75.0 per cent of the series. In addition the F.I.G.O. classification3 makes a point of dividing the Stage I cases into subgroups of Grades I, II, and III. For
March 1, 1973 Am. J. Obstet. Gynecol.
Frick et al.
666
Table IV. Carcinoma of endometrium: Degree of myometrial penetration and survival Stages Degree
of myometrial
penetration
Total
No tumor seen Confined to endometrium Superficial Deep under 2/3 Deep over 2/3 No hysterectomy specimen Total
cases 48 63 101 45 42 49
348
Z-IV
5 year survival
Died
Lost
44 50 78 33 19 6
2 8 11 10 22 38
0 5”
91
9
230
Died of intercurrent disease 2 3 7 1 1 4
1 0 1
18
5 year survival (%) 91.6 79.3 77.2 73.3 45.2 12.2 66.1
Table V. Carcinoma of endometrium: Grade of tumor and survival Stages
Grade
Totat
cases
187
I II III
52 22
Total
rsl
5 year survival
A
la
and
Zb Died of intercurrent disease
5 year survival (%)
Died
Lost
161 33 12
15 15 7
5 1 0
6 3 3
86.1 63.4 54.5
OS
37
s
12
78.9
Table VI. Carcinoma of endometrium: Grade of tumor and survival Stages 5 year survival
Z to IV
Died
Lost
I II III
218 76 54
173 41 16
30 28 33
7 2 0
Total
348
-Ki
sr
9
Grade
Total
cases
the purposes of this study, Grade I tumors adenocarcinoma. are well-differentiated Grade III tumors are composed of totally anaplastic cells with no evidence of glandular patterns. Grade II contains elements of both Grade I and Grade III. This type of separation is admittedly crude but it does give one a rough idea of the degree of differentiation in a tumor. Table V shows the relationship between survival and grading in the casesin Stages Ia and Ib. The difference between the grades is fairly apparent. Table VI shows the whole seriesand the difference between Grades I and III is more marked. The relationship between grading and survival has also been noted by other authoTS.l, 2, 6, 12,14, 15
Died of intercurrent disease 8 5 5 ii
5 year survival (%) 79.3 53.9 30.0 66.1
Interrelation of factors. The interrelated factors-age and stage, grade and stage, grade and penetration-were studied. Unfortunately, space will not allow a presentation of the statistical analysis that led to the following conclusions. Age and stage. It appears that at diagnosis the younger individuals are more apt to have a less advanced stage of their diseasethan individuals past 60. Grade and stage. It appears that at the time of diagnosis individuals with well-differentiated tumors are more apt to have their tumors in an earlier stage. Grade and penetration. Grades II and III are more apt to occur in lesionswith deeper penetration.
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Table VII. of tumor
Carcinoma
667
Carcinoma of endometrium: Results of treatment according to grade Stages Grand
total
la
No.
70
No.
Well 5 yr.
I II III
187 52 22
161 33 12
86.1 63.4 54.5
88 10 5
Total
261
20678.9103
and
Ib
Combined
Surgery
Well 5 yr.
Grade
of endometrium
Radiation
96
No.
Well 5 yr.
78 7 3
88.6 70.0 60.0 ---
86 36 14
78 25 9
90.6 69.4 66.6
ss
85.4
136
112
02.3
Methods of therapy. About 16 years ago the following pattern of treatment for operable carcinoma of the corpus was initiated. Total abdominal hysterectomy and bilateral salpingo-oophorectomy without adjuvant radiation therapy were the treatment of choice for the small uterus with superficial penetration of the myometrium and lowgrade tumor. Preoperative intrauterine packing by the Heyman l8 technique with a cervical component was prescribed for ( 1) the enlarged uterus-a uterus that sounds more than 8 cm., (2) the uterus with cervical extension of disease, and (3) the Grade III tumors. About 4,000 to 6,000 milligram-hours are given. Hysterectomy is performed either immediately following the removal of the radium or in six weeks. Postoperative radiation therapy was administered to the pelvis by supervoltage apparatus if (1) there was over one-third myometrial penetration by tumor, (2) tumor had spread outside the uterus to pelvic lymph nodes, adjacent organs, or peritoneum, or (3) Grade III tumor was found in the specimen. The dosageof external x-ray employed was 4,000 rads to the pelvis over a period of four to five weeks, administered through 15 by 15 cm. A.P. ports. Radical hysterectomy was performed, when possible,in patients with Stage II diseasefollowing preoperative intracavitary radium with a cervical component. For the most part all patients who were not candidates for operation were treated with an intrauterine packing of radium with a vaginal and cervical component as out-
%
No. 9 6 3 rs
Other--
Well 5 yr.
%
No.
5 1 0
55.5 -
4 0 Cl
s
33.34
Well 5 yr. 0 0 0 -- 0
lined, followed by external x-ray therapy to the pelvis in the dosagesalready mentioned. Treatment
and
survival
Stages Ia and Ib. Seventy-five per cent of the patients in our serieswere in Stages Ia and Ib. Table VII shows the entire Stage I seriesas related to grade, method of therapy, and survival. In the combined column are listed all patients who received radium or postoperative external x-ray therapy as adjuvant to the hysterectomy. There appears to be little difference in the five-year survival rates of the combined (82.3 per cent) vs. the surgical group (85.4 per cent). In the combined seriesof 136, there were 50 Grade II and Grade III tumors (37.0 per cent) as compared with 15 of 103 (14.0 per cent} in the surgical series. Table VIII showsdepth of penetration of the uterus in the Stages Ia and Ib casesas related to methods of therapy and survival, Again there are more caseswith over onethird penetration of the myometrium in the 44 of 136 “combined” cases (32.0 per cent) as compared with 11 of 103 (10.0 per cent) in the pure surgical series. Thirty-five per cent of the patients who received preoperative radium had no identifiable diseasein the specimen. Although there is little difference in the survival rates of the pure surgical series as compared to the “combination” series, the majority of the worst cases received adjuvant radiation therapy and the cure rates were quite similar. Stage II. There were only 22 patients classified as Stage II. These all had cervical extension of their diseaseproved by biopsy. Six received a combination of intravaginal
668
hick
et al.
Table VIII. of myometrial
Carcinoma penetration
of endometrium:
Results
of treatment
Stages
Grand Degree of myetrial penetration
No tumor seen Confined
to endometrium Superficial under l/3 Deep under 2/3 Deeper over 2/3 No hysterectomy specimen Total
Table
No.
IX.
Carcinoma
Ia and
Surgery
38 45 73 “8 16 6
Combined
206
95.0 81.8 81.1 84.8 66.6 31.5
12 33 47 6 5 -
11 “8 41 5 3 -
91.6 84.8 87.2 -
28 21! 4’ 26 18 -
78.9
103
88
85.4
136
of endometrium
Ovary unilateral Ovary bilateral Ovary and peritoneum Tube Tube and ovary Parametria Pelvic nodes Pelvic nodes and peritoneal Pelvic peritoneal seeding
: Extent
Total
Total
seeding
Radiation
27 17 32 23 13 ll?
cases 10 3 2 6 3 3 3 2 2 34
and intrauterine radium followed by external x-ray therapy to the pelvis. All six died of their disease, Two the remaining patients were treated by operation alone-total abdominal hysterectomy and bilateral salpingooophorectomy. One of these survived five years. The remaining 14 were treated by a combination of surgical and radiation therapy, with seven survivors. During these years it was planned to treat Stage II carcinoma of the endometrium by preoperative radium followed by radical hysterectomy. The radical operation was not carried out in 16 cases because of poor medical status. Stage III. The Stage III patients all had either gross or microscopic extension of their disease outside the uterus but apparently limited to the pelvis. Table IX shows the extent outside the uterus. The survival of eight of 10 patients with unilateral extension to the ovary is heartening. On the other hand, little salvage is found among the pa-
Well 5 yr.
%
No.
96.4 77.2 76.2 88.4 72.2 __-
0 0 0 0 0 18
0 0 0 0 0 6
82.3
18
:
Other %
No.
33.3 -33.3
0 0 1 1 1 1 4
Well 5 yr. 0 0 0 0 0 0 0
of disease Stage
Extent
Ib
Well 5 yr.
40 55 90 33 34 19 _--_-__~261
total
to degree
according
5 year survival
Died
8 2
1 1 2 3
2
; 2 2 1
1 1 1 15
It
III Lost -
Died intercurrent
of
disease 1
r -
-
i
i
tients with extension to the pelvic nodes or peritoneum. The majority of patients, 25 out of 34, received a combination of radiation therapy plus a total abdominal hysterectomy or radical hysterectomy. Among these 25 patients there were 13 that survived five or more years. Total abdominal hysterectomy and bilateral salpingo-oophorectomy alone were performed in four and two survived more than five years. The remaining five patients were treated by radiation alone and succumbed to their disease. Stage IV. There were 31 Stage IV patients in this series,with only one five-year survivor. The remaining 30 cases all died of their disease. Seventeen of the 31 Stage IV patients were classified as having Grade III lesions. The therapy for the most part was aimed at palliation. Preoperative clinical classification vs. pathological. According to the International
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Committee’s recommendation, the staging of carcinoma of the corpus should be made by pretreatment examination. In this series we included the findings at operation and subsequent examination of the specimen. We later re-examined the records and classified them according to the pretreatment findings alone. Table X shows the two methods of classification compared. The largest number of changes occurred in the Stages Ia and Ib groups. All these patients had clinically unsuspected microscopic extension outside the uterus and were classified as Stage III or IV in our study. Five patients in the Stage II pretreatment group had extension outside the cervix and uterus. Thus the error in pretreatment clinical staging in Stage I was 7.0 per cent and in Stage II 18.0 per cent. The cure rates in Stages I and II remain about the same. Recurrences. Gusberg and Yannopoulos reported 14.6 per cent vaginal recurrences in 191 operative cases as compared to 4.5 per cent in 219 patients treated by combined therapy. Localized vaginal vault recurrences were rare in this series-l.0 per cent in the preoperative radium-treated group and 2.0 per cent in the surgically treated group. The addition of the cervical and vaginal component to the Heymanls packing technique is difficult to appraise in that there were no localized vaginal vault recurrences in the patients treated either by the Heyman packing technique alone or with the Heyman packing technique plus the cervical and vaginal component. Complications and mortality rate. The operative mortality rate in 293 operative cases was 0.3 per cent. There were 4.0 per cent operative complications and 8.0 per cent early postoperative complications.
Comparison of end results with previous series. Corscaden and Tovelll and Gusberg and Yannopoulos* in their series published in 1954 and 1964 used different methods of staging the disease. It is therefore not possible to compare the present series with the previous experience in these hospitals on a stage-for-stage basis. The relative five-year survival rates, counting all patients who were
Carcinoma
Table X. Carcinoma Pretreatment classification
Stage
clinical
of endometrium
669
of endometrium: vs. clinicopathological
fig
Ia Ib II III IV
308 73 27 11 29
80.5 71.2 33.3 18.1 0.0
195 66 ?2 34 31
81.5 71.2 36.4 44.1 --.__ 3 ‘2
lost or who died of intercurrent disease as dead of cancer, are given at the top of Table XI. The lower portion of Table XI shows the corrected rates for these series according to the person-years method. These corrected rates show no statistical difference. These series were also compared by the BerksonGagelQ quadratic estimate and no significant difference can be shown. Table XII Iists the end results of some of the other large total series of carcinoma of the corpus found in the world literature*O during the past ten or more years. It appears that the over-all cure rate for this disease is fairly constant. Comment Carcinoma of the endometrium, like carcinoma of the ovary, is a disease primarily treated by surgery. Adjuvant external radiation therapy is administered because of surgical or pathological findings. It seems that in addition to the preclinical examination as outlined by the International Federation of Gynaecology and Obstetrics, the data obtained at operation and subsequently from the pathological examination of the specimen should be included in the staging of carcinoma of the endometrium. There has always been considerable controversy among gynecologists and radiotherapists as to the role of radiation therapy in the management of carcinoma of the corpus. Corscaden and Tovell,l in their review of the case material in our hospitals from 19381948, felt that in cancers of large size involv-
670
hick
March 1, 1973 Am. J. Obstet. Gynecol.
et al.
Table XI. Carcinoma
of endometrium:
Survival Relative
No. Authors
Years
Gusberg and Yannopoulos Present series
1938-1955 1956-1965
of cases
518 348
survival-aB
Lost or died of other disease
Died of cancer
91 27
137 91
Corrected Authors
Years
Gusberg and Yannopoulos Present series
1938-1955 1956-1965
x : =
Effective No. followed
472.5 334.5
stages
survival-all
Observed died of cancer
137 91
survival (%I
56.0 66.1
stages Corrected
No.
5 year
Corrected
survivors 5 year survival 335.5 0.71 243.5 0.73
of
0.31.
Table XII. Carcinoma of endometrium: Results from other series 5 year Year
1964 1964 1967 1969 1970 1970 1972 1966
Authors
Total
Gusberg and Yannopouloss Renning and Javertso Wade and colleagues12 Nilsen and Kolle+ Ng and Reagan14 Sal1 and colleagues6 Shah and Greens World literature; 124 clinicss”
518 507 265 634 363 307 122 14,796
ing the whole endometrium and enlarging the uterus, preoperative radium apparently gives five-year results superior to those following operation alone. Gusberg and Yannopoulos,z in their review of the same material plus an additional seven years, 19381955, stated that preoperative radium followed by total hysterectomy appeared to hold a statistically significant superiority over primary hysterectomy but also felt that preoperative radium added little in the management of the small uterus with a well-differentiated tumor. Del Regato and Chahbazia+ favored external irradiation by Cobalt-60 preoperatively over a period of five to six weeks, administering a dosage of 5,000 to 6,000 rads to the midpelvic frontal plane. These treatments were followed by hysterectomy in six to eight weeks. They reported an 83.0 per cent five-year survival in 57 patients
treated
in
this
fashion.
cases
Wade
and colleagues12 stated that preoperative radium increased survival significantly in
No. followed
427 14,650
survival
290 274 409 205 82 9,261
Relative
%
5 year survival 56.0 54.0 67.5 64.6 69.7 66.7 67.0 62.6
only Grade III tumors. They found no difference in Grade I. Nolan and colleaguesz2 reported that more favorable results were seen in those patients receiving preoperative radium. These favorable results were more apparent in patients with the anaplastic lesions or large uteri. Grahamz3 studied three seriesof cases: ( 1) those receiving operation alone, (2) those receiving preoperative intracavitary radium, and (3) those receiving postoperative radium to the vaginal vault. He concluded that superior results were obtained with the use of adjuvant radiation therapy. The postoperative use of radium in the vaginal vault seemed to him to be the superior method. Because of the policy in our institution of giving adjuvant radiation to patients with undifferentiated tumors, deep penetration of the myometrium, and enlarged uteri, we cannot make any valid comparison between our patients treated by combined therapy and those treated by operation alone. On the
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other hand, by and large, our worst cases received combination therapy and they appeared to do as well as those that were treated only surgically. We therefore intend to continue the use of preoperative radium and postoperative x-ray according to the indications already outlined. Another point made in the literature in favor of combined therapy in the management of endometrial cancer is the incidence of localized vaginal vault recurrences. Both Gusberg and Corscaden stated that there were fewer vaginal vault recurrences in the patients treated by preoperative radium. Rutledge and associatesz4also demonstrated significant reduction in vaginal vault recurrence with the use of preoperative intrauterine and intravaginal radium. Boronow25 confirmed their findings. Wade and associates,12 Ingersoll,26 Kottmeier,*’ and Rubin and associates,28 also stressedthe importance of using intravaginal radium postoperatively as a means of lesseningvaginal vault recurrences. On the other hand, Whetham and Beanzg and Renning and javertgO found no difference in the incidence of vault recurrence in the operative as compared to the combination-treated cases. In this present seriesthe incidence of recurrence limited to the vaginal vault scar was small when compared to the incidence reported in the previous series from these hospitals.’ On the other hand, the over-all survival rate remained unchanged. Our experience with the radical hysterectomy and node dissection in the treatment of Stage II endometrial carcinoma is extremely limited and precludes an assessmentof its effectiveness. When an appropriate operation has been performed within 24 to 48 hours following the removal of the radium, no demonstrable increase in complications or decreasein cure rate has been detected. It appears to be an acceptable procedure in properly selected cases. We have practically no experience with the use of postoperative intravaginal radium following hysterectomy.
Carcinoma
of endometrium
671
The use of external x-ray postoperatively in the patients with deep myometrial penetration has not increased our complications. The encouraging results in those patients treated in this fashion, especially in the Stage I group, inclines us to continue this practice. We have little experience in this series with the use of preoperative external x-ray instead of preoperative radium as is advocated by de1 Regato and Chahbazianzl and many radiation therapists. It seemsto us to be more applicable in the patients with uteri that sound greater than 10 cm, This technique adds at least an extra two to four weeks’ time to the completion of therapy. There appears to be no particular evidence in existence to relegate preoperative intrauterine packing of the uterus with radium according to the Heyman technique to medieval practices and abandon its use. The addition of a vaginal component to the Heyman packing technique appears to make good sense, but in this series no localized vaginal recurrences were found in any of the patients treated by the Heyman packing technique alone or among those treated by the Heyman technique plus intravaginal radium. It seemsto us that the most important part of the treatment of carcinoma of the corpus is total hysterectomy and bilateral salpingooophorectomy. Adjuvant radiation therapy should be used in those caseswith large uteri, deep myometrial penetration, undifferentiated tumors, cervical extension, or extension outside of the uterus. The type of radiation used should be individualized to fit the clinical problem at hand. The cure rate for carcinoma of the corpus has not changed during the past 16 to 20 years. Within limits the modalities of treatment are not critical and therefore with the existing technology it is unlikely that further progress will be made. If we want to make progress, new avenues have to be explored and it would seem that two promising avenues are early diagnosis and a better understanding of factors controlling the disease.
672
hick
et al.
REFERENCES
1. Corscaden, J. A., and Tovell, H. M. M.: Ar*r. J. OBSTET. GYNECOL. 68: 737, 1954. 2. Gusberg, S. B.. and Yannopoulos, D.: AM. J. OBSTET. GYNECOL. 88: 157, 1964. 3. F.I.G.O. News: Int. J. Gynaecol. Obstet. 9: 172, 1971. 4. Davis, E. W., Jr.: AM. J. OBSTET. GYNECOL. 88: 163, 1964. 5. Shah, C. A., and Green, T. H., Jr.: Obstet. Gynecol. 39: 500-509, 1972. 6. Sall, S., Sonnenblick, B., and Stone, M.: AM. J. OBSTET. GYNECOL. 107: 116, 1970. 7. Statistical Abstract of the United States, United States Public Health Service 87: 150, 1966. 8. Vongtama, V., Kurohara, S. S., Badib, A. O., and Webster, J. H. : Cancer 26: 842, 1970. 9. MacMahon, B., and Austin, J. H.: Cancer 23: 275, 1969. 10. Nahhas, W. A., Lund, C. J., and Rudolph, J. H.: Obstet. Gvnecol. 38: 564. 1971. 11. Jones, W. E., Kanner, H. M., Kanner, H. H., and Benson, C.: AM. J. OBSTET. GYNECOL. 113: 549, 1972. 12. Wade, M. E., Koharn, E. I., and Morris, J. M.: Am J. OBSTET. GYNECOL. 99: 869, 1967. 13. Badib, A. O., Kurohara, S. S., Vongtama, V. Y., Selim, M. A., and Webster, J. H.: AM. J. OBSTET. GYNECOL. 106: 205, 1970. 14. Ng, A. B. P., and Reagan, J. W.: Obstet. Gynecol. 35: 437, 1970. 15. Nilsen, P. A., and Keller, 0.: AM. J. OBSTET. GYNECOL. 105: 1099, 1969. 16. Vital Statistics of U. S. Vol. I. Washington, D. C., 1965, U. S. Dept. Health Education & Welfare Public Health Service. ”
Discussion
DR. MICHAEL NEWTON, Chicago, Illinois. I would first like to stipulate, as our legal friends say, (1) the superb quality of the records at Dr. Frick’s hospitals, (2) the agreeable and cooperative nature of the other members of his staff, (3) the remarkable consistency of his pathologists in their diagnoses and descriptions, (4) the compliant and cooperative behavior of his group of radiotherapists, and (5) the excellence of his follow-up system. Three particular points were of interest to me: 1. Vaginal recurrence took place in very few patients. The choice of treatment did not seem to make any difference. 2. Spread of the cancer to one or both ovaries, without other extension, did not carry a poor prognosis and 10 of 13 patients (77 per cent) survived for five years. This confirms a “gut” feel-
17. Vongtama, V., Kurohara, S. S., Badib, A. O., and Webster, J .H.: Cancer 25: 4.5, 1970. 18. Heyman, J.: J. A. M. A. 135: 412, 1947. 19. Berkson, J., and Gage, R. P.: Proc. Staff Meet., Mayo Clin. 25: 270, 1950. 20. Kottmeier, H. L., editor: .4nnual Report on the Results of Treatment in Carcinoma of the Uterus and Vagina, Stockholm, 1966, International Federation of Gynecology and Obstetrics, Vol. 14. 21. de1 Regato, J. A., and Chahbazian, C. M.: Am. J. Roentgenol. 114: 106, 1972. 22. Nolan, J. F., Dorough, M. E., and Anson, J. H.: AM. J. OBSTET. GYNECOL. 96: 663, 1967.
23. Graham, J.: Surg. Gynecol. Obstet. 132: 835, 1971. 24. Rutledge, F. N., Kan, S. K., and Fletcher, G. H.: AM. J. OBSTET. GYNECOL. 75: 167, 1958. 25. Boronow, R. C.: Carcinoma of the Corpus: Treatment at M. D. Anderson Hospital, Chicago, 1969, Year Book Medical Publishers, Inc. 26. Ingersoll, F. M.: Am. J. Surg. 121: 473, 1971. 27. Kottmeier, H. L.: Personal communication. Paper in preparation 1972. 28. Rubin, P., Gerle, R. D., Quick, R. S., and Greenlaw, R. H.: Am. J. Roentgenol. 89: 91, 1963. 29. Whetham, J. C. G., and Bean, J. L. M.: AM. J.
OBSTET.
30. Renning, J. OBSTET.
GYNECOL.
E. L.,
112:
339,
1972.
and Javert, C. T.: GYNECOL. 88: 171, 1964.
AM.
ing that I have had for some years in this matter, to the confusion of some of my colleagues. 3. When intracavitary radium was followed by hysterectomy in 24 hours, instead of the usual four to six weeks’ delay, there appeared to be no change in survival rate and no increase in complications in 19 cases. For some reason this bothers me. If you are going to use intracavitary radium, why not wait until it has had a chance to reduce infection and shrink the uterus? Rut it may be that I do not see the whole scene. Dr. Frick’s paper well illustrates some of the current problems in corpus cancer. Diagnosis. Among the 193 patients in whom cytologic studies were done suspicious or positive results were obtained in only 33 per cent. The jet-wash method appears to be a more reliable diagnostic tool,’ but the desirability and practicality of using it as a screening test have not yet, I believe, been firmly established.
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115 5
Staging. One of the problems of clinical staging has always been that the vast majority of patients fell into Stage I. This amounted to 96 per cent in the Chicago Lying-In series.* Even utilizing the 1971 modifications of F.I.G.O. classification, Dr. Frick found that 75 per cent of his patients fell into Stage I. He noted, too, that if you add the information obtained from operation and from histologic examination of the specimen, some changes in staging result. Treatment. Evaluation of treatment is complicated by the staging difficulties previously mentioned and by widely held dogmatic opinions concerning the merits of supplementary radiotherapy. A randomized study of the management of Stage I cases has not, so far as I know, been carried out. I considered it once but did not pursue it because of the relatively small number of cases on my service at that time. Pending such a study, two points should be considered. First, our data and Dr. Frick’s raise serious doubt as to the value of preoperative radiotherapy for Stage I. The important part of the treatment seems to be removal of the uterus and ovaries and the upper 1 to ‘2 cm. of vagina. Second, a logical way to handle Stage I cases is to operate initially on all patients who are good or fair operative risks, and then to re-evaluate and give postoperative radiotherapy if extended clinical staging (or, as Dr. Frick terms it, “clinicopathological classification”) indicates that further therapy is ncessary. The chief indications for such further therapy are unexpected extension to the cervix or outside the uterus or penetration of the tumor through more than half the thickness of the uterine wall. REFERENCES
1. Bibbo, M., Shanklin, D. R., and Wied, G. L.: J. Reprod. Med. 8: 90, 1972. 2. Welander, C., Griem, M. L., Newton, M., and Marks, J. E.: J. Reprod. Med. 8: 41, 1972. DR. MICHAEL J. JORDAN, New York, New York. Dr. Frick has presented an excellent review of the Presbyterian-Delafield series from 1956 to 1965 and has drawn a number of interesting conclusions. Two of these, particularly closely related, I feel are extremely important. No. 1, the inaccuracy of the Papanicolaou smear in this series and no significant improvement in the cure rate in the 1956 to 1965 series as compared to the previous series of cases treated in these institutions betwen 1938 and 1965. It is apparent in the rather sad commentary that the cure rate of endometrial carcinnoma has not kept pace
Carcinoma
of endometrium
673
with the many advances in treatment, principally because only a relatively small percentage of diagnoses are made when the disease is limited and amenable to early treatment, whichever treatment one chooses. In this series, as well as in most published series, the Papanicolaou smear was considered inaccurate yet cancer of the endometrium runs the gamut from the atypias to carcinoma-in-situ to invasive endometrial carcinoma. The techniques that have enabled cervical carcinoma to be detected early are responsible for survival rates of 85 to 95 per cent. The same modalities of early diagnosis and treatment are available to the patient with endometrial carcinoma. Cytologic studies are a mutine part of every pelvic examination, but the endometrial smear is not-and I do not mean endometrial washings. I mean the routine endometrial aspiration smear. It should be done on every patient. The accuracy of the combined vaginal-cervical and endometrial smear has been shown by Bader, Koss, and others to be as high as 76 to 84 per cent. I am sure we are all aware of the magnitude of reading the endometrial smear and I think here is where the main hitch is. These smears are being read improperly. Not infrequently, one can obtain the smears of patients taken three, four, five years prior to the time that the diagnosis of endometrial carcinoma was made and find the early changes in the single cells or small groups of cells that foreshadow an early diagnosis of carcinoma of the endometrium. Of extreme importance also is the fact that the postradiation smear is of great value in determining the interval between radiation and operation. Dr. Frick is to be congratulated for his statement that there appears to be no particular evidence in existence to relegate the use of preoperative irradiation to medieval practice and abandon its use. Surgical treatment combined with irradiation should be regarded as the optimum therapy for all stages of cancer of the endometrium. There are factors loo numerous to mention. Particularly among these are the immunologic changes that take place. When one compares a series of patients with carcinoma of the endometrium with a large uterus and a very anaplastic tumor and receiving irradiation and a similar group not receiving irradiation, there is a very marked difference in the percentage of salvage. There must be some obvious reason. I think it is about time that we spend less time rediscovering the old treatments for carcinoma of the endometrium and spend more time on early diagnosis.
674
March 1, 1973 A Am. J. Obstet. Gynecol.
Frick et al.
Table I. Endometrial
carcinoma:
Compared
methods and survival
1946-1955s
1956~1967f
No. SU7V. % Type Radiation 41 16 39 Mixed 27 15 55.5 Surgery 17 11 64.7 Combined 84 70 83.3 Total 169 *Five-year rate, 66.3 per cent; operability rate, 81.7 per cent. +Five-yearrate, 61.7 per cent; operability rate, 77.2 per cent. DR. CLAYTON T. BEECHAM, Danville, Pennsylvania. Dr. Frick and his co-workers deserve great commendation for their extensive statistical study. Like Dr. Newton, I had the privilege of reading the manuscript and studying the charts; they make a healthy addition to our information on endometrial carcinoma. I was particularly hopeful that evidence would be forthcoming to support radical hysterectomy in the treatment of corpus cancer. As you noted, there was none; nevertheless, I find it a gynecologic inconsistency to employ radical surgery in the treatment of cervical carcinoma and not extend the same principles to endometrial cancer--particularly in the advanced stages. In our moves toward optimum therapy in this disease I believe that anaplastic growths should be treated by full radiation (high-voltage external therapy4,OOO rads plus the limits in internal and vaginal radium dosage). The postradiation operation should be as radical as the patient’s condition permits. Dr. Frick was disappointed to find no improvement in salvage figures when compared to his earlier work. By extending the principles and attitudes of cervical carcinoma therapy to corpus cancer this might be changed. DR. CHARLES J. SMITH, Chicago, Illinois. I did not ask to review Dr. Frick’s paper prior to his presentation and I think that this fact will make the similarities in this brief presentation all the more striking. Table I refers to 284 patients in two comparable episodes in time. They were divided by virtue of some circumstances that affected our institution: (1) a new irradiation unit was installed in 1953 and (2) as you will all recall, 1960 was the year of Dr. Herbert Schmitz’s death. As Dr. Frick has pointed out, rates have not changed very much in terms of over-all survival. But I think these figures will show the effect of some selection, wherein the bigger percentage of patients in the
No. 28 19 38 30 115
SUTV.
4 9 32 26
%
14.2 47.3 84.2 88.6
second group were operated on but this change did not affect the outcome. Our combined therapy, or what we designate as combined, is a protocol of a complete course of radiation therapy prior to operation. As Dr. Beecham described his, we give a complete course of external therapy, follow this by intracavitary radiation, and then, when the reaction has completely subsided, do the operation. What we call mixed are those patients who were referred to us after operation for some other condition and disease found in the specimen. The only other point I would like to make is the question of the use of radiation. Whether you want to use it or not depends on what your attitude is about its effectiveness, but my plea is that if you are going to use it at all, don’t give stimulating doses of radiation. When we get a uterus without any viable tumor, we call this a sterilized tumor and our histological examiantion of this uterus is quite painstaking. It used to be that the whole uterus was sectioned. In our previously published works we have given this a great deal of detailed description but suffice it to say that there are adequate sections taken of these uteri to try to show the existence of viable tumor. There is a pretty high survival rate when you get sterilized tumor-96.5 per cent. The point is that, if you are going to use an effective means of treatment such as radiation, take advantage of all its potential and don’t give a portion of it which at the pelvic wall could actually be stimulatory to the disease. DR. SAUL B. GUSBERG, New York, New York. I do not wish to prolong this discussion but I suppose each of us sees these figures from our own particular point of view. I did have the opportunity to review this statistical report, and I do think it makes a significant contribution. I am not sure that Dr. Frick is correct in his conclusion that the protocol that he used did not improve his results, inasmuch as it seems to me
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115 5
that he improved the worst cases, meaning larger and undifferentiated ones, almost to the same rate of cure as some of the early ones. Second, though I do not wish to reiterate my own position about staging once again, I think that Dr. Frick has demonstrated that the size of the uterus makes a difference in that his cure rate was improved in Stage Ia over Stage Ib; he did not use the international classification, new as of 1971, that must include the grading and, unless one breaks down Stages Ia and Ib by grading, one does not have the advantage of this very important parameter. Third, you will notice that the Stage II cases did more poorly than the Stage III patients, that Stage III may have contained, I presume then, some that had tubal involvement without ovarian involvement-a geographic spread. I would reiterate our position about choosing a protocol of treatment from simple hysterectomy to combined treatment, whether it be by adjuvant external irradiation or preoperative radium to ralical hysterectomy. I would say here that in all cancer treatment from my point of view it is better to retract the cancer by preoperative radiation, to get better clearance by operation, then to operate, then mop up a little bit here and there with irradiation, as a general principle. Our protocol was designed not so much to improve the total cure rate but to be able to give patients with less virulent cancers restricted treatment, so to speak, with lesser complications, and give those with more virulent tumors, as, for example, those who have cervix involvement, more radical treatment. I do think, as Dr. Frick has stated, and I would surely concur, that one cannot finally evaluate the radical hysterectomy modality for those who have cervix involvement because there are too few cases that have been treated in this way in this series or in any other series that I have seen. DR. FROCK (Closing). Dr. Newton brought up the question of immediate hysterectomy following the use of intracavitary radium. This procedure was tried by us in selected cases because ( 1) it was felt that the ionizing radiation had its effect on the cancer cell, (2) immediate operation avoided the radiation reaction, and (3) there was a great saving in time and hospital bed utilization. Against immediate operation are ( 1) submitting elderly patients to anesthesia after a prolonged period of bed rest, (2) operating through a contaminated field, and (3) many people felt that the fibrosis which allegedly
Carcinoma
of
endometrium
675
develops in the uterus and parametria during the six-week waiting period following intracavitary radium application plays a large role in controlling the disease. We have limited immediate operation to good-risk patients and so far have not had any major complications. There were 19 patients treated in this fashion during the years covered by this report with a 70 per cent over-all survival and no severe complications. I am unable to answer Dr. Jordan’s comment on the endometrial aspiration smear. We have no experience with this technique. In our hands the Papanicolaou smear taken in the usual fashion was inaccurate. We are now engaged in trying to evaluate the Gravlee intrauterine washing technique. Carcinoma of the endometrium does OCCUr in younger women. The cure rate is superior to that in the older aged patient. Any unexplained abnormal vaginal bleeding ocurring in the perimenopausal period should be investigated by a dilatation and curettage. I agree with Dr. Jordan about the use of intracavitary radium preoperatively. The only time that we do not employ preoperative radium is in the management of a Stage Ia lesion with a lowgrade tumor and superficial penetration of the myometrium. The studies of both Corscaden and Gusberg showed that the cure rate in such cases was not improved hy the use of preoperative radium. We have had no experience with the use of both preoperative x-ray to the pelvis and preoperative intracavitary radium followed by hysterectomy as suggested by Drs. Smith and Beecham. We have relied on intracavitary radium preoperatively as outlined and have reserved the external x-ray therapy to the pelvis for those having histologically undifferentiated tumors or deep myometrial penetration found in the operative specimen. From the standpoint of Dr. Beecham and the radical hysterectomy, we planned to do radical hysterectomies in all Stage II cancers of the endometrium but the medical status of these patients precluded radical operation in many instances. The radical hysterectomy in the Stage II case makes good sense as a cancer operation but we are unable to assess its effect on five-year survival in any large number of cases. It was interesting to note that Dr. Smith’s cure rates in his Chicago series were very close to ours. Apparently they have not found any
676
hick et al.
marked improvement in their five-year cure rare during the past years. Dr. Gusberg mentioned the effect of uterine size on cure rate. In our series of 195 Stage Ia patients there was a relative or gross survival rate of 81.5 per cent. The survival in the 66 Stage Ib patients was 71.2 per cent. We analyzed these figures and found that there was no statistical difference between these two groups unless the relative survival rates are corrected for patients lost and patients dying of other disease. If the material is divided into two age groups, those above 60 years of age and those under 60 years of age, there is no difference in cure rate in the Stage Ia and Ib survival rates among the patients under 60 years of age. Over 60 there
March 1. 1Yi:i Am. J. Obstrt. Ggnecol.
is a difference between Stages Ia and Ib. The larger uteri seem to have a poorer survival rate. Among the Stage Ib patients in this older group, we found a much higher proportion of Grade II and Grade III tumors and a higher proportion of uteri showing deep myometrial penetration by tumor. For these reasons we cannot say that the uterine size alone is directly related to five year survival. We intend to follow the methods of therapy outlined in this paper in treating our endometrial carcinomas and feel that by individualizing our therapy we offer the best treatment possible. Despite our efforts, we have not been able to demonstrate any improvement in over-all cure rate during the past ten years.
CLAY
FRICK,
EQUINN
W.
MUNNELL,
RALPH
M.
AGNES
P.
MARGARET New
I’ork,
RICHART, BERGER, F.
New
II,
M.D. M.D.
M.D. PH.D.
LAWRY,
A.B.
York
The experience in the management of 348 cases of adenocarcinoma of the corpus treated at the Presbyterian and Francis Delafield Hospitals between the years 1956 and 1965 is reviewed. The cases are classified according to the criteria outlined by the Cancer Committee of the International Federation of Gynaecology and Obstetrics. The over-all relative survival in the series is 66.1 per cent. The corrected survival computed by either the patient-years method or the Berkson-Gage estimate is 73.0 per-cent. Age, stage of disease, degree of difierentiation of tumor, and extent of myometrial penetration seem to have a definite relationship to prognosis. The policies used in treating the disease are outlined. There appears to be no difference between the cure rate in the cases receiving adjuvant radiation therapy plus hysterectomy and that in the cases treated by hysterectomy a!one. On the other hand, a greater proportion of cases with deep myometrial penetration and undifferentiated tumors received adjuvant radiation therapy. In this series of cases, localized vaginal vault recurrences are few. Complications of treatment are presented and discussed. The five-year end result in the present series is compared with a previous series of carcinoma of the endometrium treated at these institutions between 1938 and 1955 and no significant improvement in the cure rate is found.
THE EXPERIENCES in managing carcinoma of the corpus on the gynecological services of the Presbyterian and Delafield Hospitals during the years 1938-1948 and 1938-1955 have been reviewed by Corscaden and Tovelll and Gusberg and Yannopoulos.2 Because of the work of these authors, certain policies were adopted regarding the therapy
of this disease. These policies have been in effect since 1956. It was thought that a review of the cases of carcinoma of the corpus from 1956-1965 was in order to see if there had been any improvement in our five-year survival results. Materials
and
methods
This report deals with 348 casesof primary adenocarcinoma or adenoacanthoma of the corpus treated at the Presbyterian and Delafield Hospitals during the years 1956-1965. The caseswere staged according to the latest classification and staging proposed in 1950 by the Cancer Committee of the International Federation of Gynaecology and Obstetrics.3 Clinical findings preoperatively plus information obtained at operation and subsequent examination of the pathological specimen were used to aid in the classifica-
From the Departments of Obstetrics and Gynecology and Pathology of the College of Physicains and Surgeons, and Division of Biostatistics of the School of Public Health, Columbia University, the Presbyterian Hospital, and the Francis Delafield Hospital. Presented by invitation at the Eightythird Annual Meeting of the American Association of Obstetricians and Presbyterian Hospital, and the Francis September 7-9, 1972. Reprint requests: Dr. Henry Clay Frick, II, Columbia-Presbyterian Medical Center, 161 Fort Washington Ave., New York, New York 10032.
tion.
663
664
Frick et al.
Symptoms. Postmenopausal bleeding was the most common symptom, occurring in 75.0 per cent of the series; 18 per cent presented with menometrorrhagia and pain occurred in 2.0 per cent. Medical status. There were no medical contraindications to therapy in 51.7 per cent. Of the 348 patients, 87 (25.0 per cent) had hypertension or cardiovascular disease.Diabetes was found in 28 patients (8.0 per cent). Among the 38 diseaseslisted as “other conditions” were liver disease, tuberculosis, asthma, emphysema, multiple sclerosis, and syringomyelia. The incidence of diabetes in other series in the literature ranges from 5.34 to 41.0 per cent.5 Habitus. Forty-nine per cent of the patients in this series were classified as obese and 36.0 per cent as normal. Obesity was listed if the patient looked obese to the admitting physician. Parity. Of the series, 137 patients (36.5 per cent) were ntdliparous, which is higher than the figure of 17.9 per cent for the average populatior+ 7; 36.5 per cent were para 1 or 2. The remaining patients were over para 3. No relationship between five-year survival and parity could be demonstrated. History of other primary malignancies. There were 27 patients (7.7 per cent) with a history of other primary malignancies found in this series. Seventeen occurred before the diagnosisof endometrial cancer, four were diagnosed at the time of therapy, and six developed after the therapy for endometrial cancer was completed. The most common locations of the associatedmalignancies were bowel and breast. The over-all five-year survival in this group was 15 out of 27 (55.5 per cent). This incidence of 7.7 per cent compares with the findings of Davis,* 9 per cent in 525 cases;Vongtama and associates,s 11.8 per cent; MacMahon and Austin9 15.0 per cent in 869 cases;and Shah and Green,” 20.0 per cent in 122 cases. Inaccuracy of the Papanicolaou smear. In this series 155 patients had no record of a cytologic smear having been taken. The Papanicolaou smear report was recorded in
March 1, lYi3 Am. J. Obstet. Gynecol.
193 cases.In 129 (67 per cent) of the reported smears, a false-negative result was obtained. In defense of the Papanicolaou smear, it must be stated that these patients were first seenby a variety of physicians and probably the technique varied a great deal with each examiner. No intrauterine washings were obtained. The inaccuracy of the Papanicolaou smear is confirmed by others. Nahhas and colleagues’o reported only 25 per cent positive and 25 per cent suspicious smearsin 92 patients. Jones and colleagues11 reported abnormal findings in the vaginal smearsof approximately one third of 86 patients with the known diagnosis of adenocarcinoma of the corpus. Adenoacanthoma. It will be noted that there has been no separate designation of adenoacanthoma made in this paper. Although there were 44 cases of adenoacanthoma in this series,they were not tabulated separately. Over 80 per cent were classified as Stage I, and the five-year survival rate was 88.0 per cent as compared to 86.1 per cent in the Stage I, Grade I adenocarcinomas in the total series.The comparability between adenocarcinoma and adenoacanthoma of the uterus has been stressed by other authors including Gusberg and Yannopoulos,2 Davis, ’ Wade and colleagues,12 and Badib and colleagues.13 Factors influencing survival. The following factors appear to be related to five-year survival: (1) age, (2) stage of disease, (3) degree of myometrial penetration, and (4) grade. These factors may well be related to each other and we did look into the relationship between (1) age and stage, (2) grade and stage, and (3 ) grade and penetration. Age. The literature is replete with articles showing that the prognosis in endometrial cancer is much worse in the older patient.12, I41I5 The median age for this series was 60. Table I shows the age distribution in ten-year periods. The observed relative five-year survival is given. The grossor relative survival is calculated by regarding patients lost to follow-up as dead and it includes death from all causes.Age refers to age at time of diagnosis. Table II compares
Volume Number
Carcinoma
115 5
the corrected five-year survival rate observed in this series to the race-adjusted U. S. Survival Rate according to actuarial tables applied at the middle of the ten-year intervals.lG The corrected five-year survival rate is obtained by removing half of the patients lost from the number at risk in each age group. The difference between the two rates is given in the right-hand column. It can be seen that there is a marked increase in the difference between the U. S. race-adjusted survival rate and observed survival rate from the 50-59 to the 60-69 group. These findings suggest a significant difference in survival rates between the younger and older patients studied in this series not explicable by their age alone. Stages of diseaseand survival, Table III shows the relative five-year survival in the series when divided into stages. The largest number of patients were in the Stage Ia category. The difference between an 81.5 per cent survival rate in Stage Ia as compared to 3.2 per cent in Stage IV is self-evident. Degree of myometrial penetration. The relationship between survival and myometrial penetration is shown in Table IV. The degree of penetration is depicted by ( 1) no tumor seen-the tumor had been removed by either curettage or preoperative radiation therapy, (2) the disease was confined to the endometrium-it had not invaded the myometrium; (3) superficial-only one third of the myometrium was involved; (4) deepunder two thirds of the myometrium was involved ; (5) deeper-over two thirds of the myometrium was involved, and (6) no hysterectomy was performed and consequently no specimen was available for examination. Table IV shows that 48 patients in the total series had no disease in the specimen; it had been eradicated by either curettage or preoperative radium. The five-year survival rate in this group was 91.6 per cent. Fortytwo patients had deep penetration, over two thirds of the uterus, and the survival rate was 45.2 per cent. The relationship between prognosis and myometrial penetration has been confirmed by others: Corscaden and Tovell,l Gusberg and Yannopoulos,2 Wade
Table I. Carcinoma Age and survival
of endometrium
of endometrium
5 year
Ages
Total cases
20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
1 8 51 105 123 51 8 1
Total
348
:
survival
-% ..88.2 81.9 56.9 43.1 12.5 --. -__.--66.1
NO.
1 5 45 86 70 22 1 0 230
Table II. Carcinoma
665
of endometrium:
Age and survival
‘ET
40-49
50-59 60-69 70-79 old.
a%+G =
0.9783
0.901 0.854 0.582 0.431 proportion
dying
Table III. Carcinoma Stage and survival Stage
Total cases
0.07 0.10 0.30 0.30
0.9524 0.8877 0.7378 in
5 years
among
X+5 years
of endometrium: 5 year survival No.
%
Ia Ib II III IV
195 66 22 34 31
159 47 8 15 1
81.5 71.2 36.4 44.1 3.2
Total
348
zi
66.1
and associates,12 Sal1 and associates,% Shah and Green5 Nilsen and Koller,15 and Vongtama and associates.17 Grade. There appears to be a definite correlation between five-year survival and degree of differentiation of the tumor. The Stages Ia and Ib are shown separately because they comprise 75.0 per cent of the series. In addition the F.I.G.O. classification3 makes a point of dividing the Stage I cases into subgroups of Grades I, II, and III. For
March 1, 1973 Am. J. Obstet. Gynecol.
Frick et al.
666
Table IV. Carcinoma of endometrium: Degree of myometrial penetration and survival Stages Degree
of myometrial
penetration
Total
No tumor seen Confined to endometrium Superficial Deep under 2/3 Deep over 2/3 No hysterectomy specimen Total
cases 48 63 101 45 42 49
348
Z-IV
5 year survival
Died
Lost
44 50 78 33 19 6
2 8 11 10 22 38
0 5”
91
9
230
Died of intercurrent disease 2 3 7 1 1 4
1 0 1
18
5 year survival (%) 91.6 79.3 77.2 73.3 45.2 12.2 66.1
Table V. Carcinoma of endometrium: Grade of tumor and survival Stages
Grade
Totat
cases
187
I II III
52 22
Total
rsl
5 year survival
A
la
and
Zb Died of intercurrent disease
5 year survival (%)
Died
Lost
161 33 12
15 15 7
5 1 0
6 3 3
86.1 63.4 54.5
OS
37
s
12
78.9
Table VI. Carcinoma of endometrium: Grade of tumor and survival Stages 5 year survival
Z to IV
Died
Lost
I II III
218 76 54
173 41 16
30 28 33
7 2 0
Total
348
-Ki
sr
9
Grade
Total
cases
the purposes of this study, Grade I tumors adenocarcinoma. are well-differentiated Grade III tumors are composed of totally anaplastic cells with no evidence of glandular patterns. Grade II contains elements of both Grade I and Grade III. This type of separation is admittedly crude but it does give one a rough idea of the degree of differentiation in a tumor. Table V shows the relationship between survival and grading in the casesin Stages Ia and Ib. The difference between the grades is fairly apparent. Table VI shows the whole seriesand the difference between Grades I and III is more marked. The relationship between grading and survival has also been noted by other authoTS.l, 2, 6, 12,14, 15
Died of intercurrent disease 8 5 5 ii
5 year survival (%) 79.3 53.9 30.0 66.1
Interrelation of factors. The interrelated factors-age and stage, grade and stage, grade and penetration-were studied. Unfortunately, space will not allow a presentation of the statistical analysis that led to the following conclusions. Age and stage. It appears that at diagnosis the younger individuals are more apt to have a less advanced stage of their diseasethan individuals past 60. Grade and stage. It appears that at the time of diagnosis individuals with well-differentiated tumors are more apt to have their tumors in an earlier stage. Grade and penetration. Grades II and III are more apt to occur in lesionswith deeper penetration.
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Table VII. of tumor
Carcinoma
667
Carcinoma of endometrium: Results of treatment according to grade Stages Grand
total
la
No.
70
No.
Well 5 yr.
I II III
187 52 22
161 33 12
86.1 63.4 54.5
88 10 5
Total
261
20678.9103
and
Ib
Combined
Surgery
Well 5 yr.
Grade
of endometrium
Radiation
96
No.
Well 5 yr.
78 7 3
88.6 70.0 60.0 ---
86 36 14
78 25 9
90.6 69.4 66.6
ss
85.4
136
112
02.3
Methods of therapy. About 16 years ago the following pattern of treatment for operable carcinoma of the corpus was initiated. Total abdominal hysterectomy and bilateral salpingo-oophorectomy without adjuvant radiation therapy were the treatment of choice for the small uterus with superficial penetration of the myometrium and lowgrade tumor. Preoperative intrauterine packing by the Heyman l8 technique with a cervical component was prescribed for ( 1) the enlarged uterus-a uterus that sounds more than 8 cm., (2) the uterus with cervical extension of disease, and (3) the Grade III tumors. About 4,000 to 6,000 milligram-hours are given. Hysterectomy is performed either immediately following the removal of the radium or in six weeks. Postoperative radiation therapy was administered to the pelvis by supervoltage apparatus if (1) there was over one-third myometrial penetration by tumor, (2) tumor had spread outside the uterus to pelvic lymph nodes, adjacent organs, or peritoneum, or (3) Grade III tumor was found in the specimen. The dosageof external x-ray employed was 4,000 rads to the pelvis over a period of four to five weeks, administered through 15 by 15 cm. A.P. ports. Radical hysterectomy was performed, when possible,in patients with Stage II diseasefollowing preoperative intracavitary radium with a cervical component. For the most part all patients who were not candidates for operation were treated with an intrauterine packing of radium with a vaginal and cervical component as out-
%
No. 9 6 3 rs
Other--
Well 5 yr.
%
No.
5 1 0
55.5 -
4 0 Cl
s
33.34
Well 5 yr. 0 0 0 -- 0
lined, followed by external x-ray therapy to the pelvis in the dosagesalready mentioned. Treatment
and
survival
Stages Ia and Ib. Seventy-five per cent of the patients in our serieswere in Stages Ia and Ib. Table VII shows the entire Stage I seriesas related to grade, method of therapy, and survival. In the combined column are listed all patients who received radium or postoperative external x-ray therapy as adjuvant to the hysterectomy. There appears to be little difference in the five-year survival rates of the combined (82.3 per cent) vs. the surgical group (85.4 per cent). In the combined seriesof 136, there were 50 Grade II and Grade III tumors (37.0 per cent) as compared with 15 of 103 (14.0 per cent} in the surgical series. Table VIII showsdepth of penetration of the uterus in the Stages Ia and Ib casesas related to methods of therapy and survival, Again there are more caseswith over onethird penetration of the myometrium in the 44 of 136 “combined” cases (32.0 per cent) as compared with 11 of 103 (10.0 per cent) in the pure surgical series. Thirty-five per cent of the patients who received preoperative radium had no identifiable diseasein the specimen. Although there is little difference in the survival rates of the pure surgical series as compared to the “combination” series, the majority of the worst cases received adjuvant radiation therapy and the cure rates were quite similar. Stage II. There were only 22 patients classified as Stage II. These all had cervical extension of their diseaseproved by biopsy. Six received a combination of intravaginal
668
hick
et al.
Table VIII. of myometrial
Carcinoma penetration
of endometrium:
Results
of treatment
Stages
Grand Degree of myetrial penetration
No tumor seen Confined
to endometrium Superficial under l/3 Deep under 2/3 Deeper over 2/3 No hysterectomy specimen Total
Table
No.
IX.
Carcinoma
Ia and
Surgery
38 45 73 “8 16 6
Combined
206
95.0 81.8 81.1 84.8 66.6 31.5
12 33 47 6 5 -
11 “8 41 5 3 -
91.6 84.8 87.2 -
28 21! 4’ 26 18 -
78.9
103
88
85.4
136
of endometrium
Ovary unilateral Ovary bilateral Ovary and peritoneum Tube Tube and ovary Parametria Pelvic nodes Pelvic nodes and peritoneal Pelvic peritoneal seeding
: Extent
Total
Total
seeding
Radiation
27 17 32 23 13 ll?
cases 10 3 2 6 3 3 3 2 2 34
and intrauterine radium followed by external x-ray therapy to the pelvis. All six died of their disease, Two the remaining patients were treated by operation alone-total abdominal hysterectomy and bilateral salpingooophorectomy. One of these survived five years. The remaining 14 were treated by a combination of surgical and radiation therapy, with seven survivors. During these years it was planned to treat Stage II carcinoma of the endometrium by preoperative radium followed by radical hysterectomy. The radical operation was not carried out in 16 cases because of poor medical status. Stage III. The Stage III patients all had either gross or microscopic extension of their disease outside the uterus but apparently limited to the pelvis. Table IX shows the extent outside the uterus. The survival of eight of 10 patients with unilateral extension to the ovary is heartening. On the other hand, little salvage is found among the pa-
Well 5 yr.
%
No.
96.4 77.2 76.2 88.4 72.2 __-
0 0 0 0 0 18
0 0 0 0 0 6
82.3
18
:
Other %
No.
33.3 -33.3
0 0 1 1 1 1 4
Well 5 yr. 0 0 0 0 0 0 0
of disease Stage
Extent
Ib
Well 5 yr.
40 55 90 33 34 19 _--_-__~261
total
to degree
according
5 year survival
Died
8 2
1 1 2 3
2
; 2 2 1
1 1 1 15
It
III Lost -
Died intercurrent
of
disease 1
r -
-
i
i
tients with extension to the pelvic nodes or peritoneum. The majority of patients, 25 out of 34, received a combination of radiation therapy plus a total abdominal hysterectomy or radical hysterectomy. Among these 25 patients there were 13 that survived five or more years. Total abdominal hysterectomy and bilateral salpingo-oophorectomy alone were performed in four and two survived more than five years. The remaining five patients were treated by radiation alone and succumbed to their disease. Stage IV. There were 31 Stage IV patients in this series,with only one five-year survivor. The remaining 30 cases all died of their disease. Seventeen of the 31 Stage IV patients were classified as having Grade III lesions. The therapy for the most part was aimed at palliation. Preoperative clinical classification vs. pathological. According to the International
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Ii5 5
Committee’s recommendation, the staging of carcinoma of the corpus should be made by pretreatment examination. In this series we included the findings at operation and subsequent examination of the specimen. We later re-examined the records and classified them according to the pretreatment findings alone. Table X shows the two methods of classification compared. The largest number of changes occurred in the Stages Ia and Ib groups. All these patients had clinically unsuspected microscopic extension outside the uterus and were classified as Stage III or IV in our study. Five patients in the Stage II pretreatment group had extension outside the cervix and uterus. Thus the error in pretreatment clinical staging in Stage I was 7.0 per cent and in Stage II 18.0 per cent. The cure rates in Stages I and II remain about the same. Recurrences. Gusberg and Yannopoulos reported 14.6 per cent vaginal recurrences in 191 operative cases as compared to 4.5 per cent in 219 patients treated by combined therapy. Localized vaginal vault recurrences were rare in this series-l.0 per cent in the preoperative radium-treated group and 2.0 per cent in the surgically treated group. The addition of the cervical and vaginal component to the Heymanls packing technique is difficult to appraise in that there were no localized vaginal vault recurrences in the patients treated either by the Heyman packing technique alone or with the Heyman packing technique plus the cervical and vaginal component. Complications and mortality rate. The operative mortality rate in 293 operative cases was 0.3 per cent. There were 4.0 per cent operative complications and 8.0 per cent early postoperative complications.
Comparison of end results with previous series. Corscaden and Tovelll and Gusberg and Yannopoulos* in their series published in 1954 and 1964 used different methods of staging the disease. It is therefore not possible to compare the present series with the previous experience in these hospitals on a stage-for-stage basis. The relative five-year survival rates, counting all patients who were
Carcinoma
Table X. Carcinoma Pretreatment classification
Stage
clinical
of endometrium
669
of endometrium: vs. clinicopathological
fig
Ia Ib II III IV
308 73 27 11 29
80.5 71.2 33.3 18.1 0.0
195 66 ?2 34 31
81.5 71.2 36.4 44.1 --.__ 3 ‘2
lost or who died of intercurrent disease as dead of cancer, are given at the top of Table XI. The lower portion of Table XI shows the corrected rates for these series according to the person-years method. These corrected rates show no statistical difference. These series were also compared by the BerksonGagelQ quadratic estimate and no significant difference can be shown. Table XII Iists the end results of some of the other large total series of carcinoma of the corpus found in the world literature*O during the past ten or more years. It appears that the over-all cure rate for this disease is fairly constant. Comment Carcinoma of the endometrium, like carcinoma of the ovary, is a disease primarily treated by surgery. Adjuvant external radiation therapy is administered because of surgical or pathological findings. It seems that in addition to the preclinical examination as outlined by the International Federation of Gynaecology and Obstetrics, the data obtained at operation and subsequently from the pathological examination of the specimen should be included in the staging of carcinoma of the endometrium. There has always been considerable controversy among gynecologists and radiotherapists as to the role of radiation therapy in the management of carcinoma of the corpus. Corscaden and Tovell,l in their review of the case material in our hospitals from 19381948, felt that in cancers of large size involv-
670
hick
March 1, 1973 Am. J. Obstet. Gynecol.
et al.
Table XI. Carcinoma
of endometrium:
Survival Relative
No. Authors
Years
Gusberg and Yannopoulos Present series
1938-1955 1956-1965
of cases
518 348
survival-aB
Lost or died of other disease
Died of cancer
91 27
137 91
Corrected Authors
Years
Gusberg and Yannopoulos Present series
1938-1955 1956-1965
x : =
Effective No. followed
472.5 334.5
stages
survival-all
Observed died of cancer
137 91
survival (%I
56.0 66.1
stages Corrected
No.
5 year
Corrected
survivors 5 year survival 335.5 0.71 243.5 0.73
of
0.31.
Table XII. Carcinoma of endometrium: Results from other series 5 year Year
1964 1964 1967 1969 1970 1970 1972 1966
Authors
Total
Gusberg and Yannopouloss Renning and Javertso Wade and colleagues12 Nilsen and Kolle+ Ng and Reagan14 Sal1 and colleagues6 Shah and Greens World literature; 124 clinicss”
518 507 265 634 363 307 122 14,796
ing the whole endometrium and enlarging the uterus, preoperative radium apparently gives five-year results superior to those following operation alone. Gusberg and Yannopoulos,z in their review of the same material plus an additional seven years, 19381955, stated that preoperative radium followed by total hysterectomy appeared to hold a statistically significant superiority over primary hysterectomy but also felt that preoperative radium added little in the management of the small uterus with a well-differentiated tumor. Del Regato and Chahbazia+ favored external irradiation by Cobalt-60 preoperatively over a period of five to six weeks, administering a dosage of 5,000 to 6,000 rads to the midpelvic frontal plane. These treatments were followed by hysterectomy in six to eight weeks. They reported an 83.0 per cent five-year survival in 57 patients
treated
in
this
fashion.
cases
Wade
and colleagues12 stated that preoperative radium increased survival significantly in
No. followed
427 14,650
survival
290 274 409 205 82 9,261
Relative
%
5 year survival 56.0 54.0 67.5 64.6 69.7 66.7 67.0 62.6
only Grade III tumors. They found no difference in Grade I. Nolan and colleaguesz2 reported that more favorable results were seen in those patients receiving preoperative radium. These favorable results were more apparent in patients with the anaplastic lesions or large uteri. Grahamz3 studied three seriesof cases: ( 1) those receiving operation alone, (2) those receiving preoperative intracavitary radium, and (3) those receiving postoperative radium to the vaginal vault. He concluded that superior results were obtained with the use of adjuvant radiation therapy. The postoperative use of radium in the vaginal vault seemed to him to be the superior method. Because of the policy in our institution of giving adjuvant radiation to patients with undifferentiated tumors, deep penetration of the myometrium, and enlarged uteri, we cannot make any valid comparison between our patients treated by combined therapy and those treated by operation alone. On the
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other hand, by and large, our worst cases received combination therapy and they appeared to do as well as those that were treated only surgically. We therefore intend to continue the use of preoperative radium and postoperative x-ray according to the indications already outlined. Another point made in the literature in favor of combined therapy in the management of endometrial cancer is the incidence of localized vaginal vault recurrences. Both Gusberg and Corscaden stated that there were fewer vaginal vault recurrences in the patients treated by preoperative radium. Rutledge and associatesz4also demonstrated significant reduction in vaginal vault recurrence with the use of preoperative intrauterine and intravaginal radium. Boronow25 confirmed their findings. Wade and associates,12 Ingersoll,26 Kottmeier,*’ and Rubin and associates,28 also stressedthe importance of using intravaginal radium postoperatively as a means of lesseningvaginal vault recurrences. On the other hand, Whetham and Beanzg and Renning and javertgO found no difference in the incidence of vault recurrence in the operative as compared to the combination-treated cases. In this present seriesthe incidence of recurrence limited to the vaginal vault scar was small when compared to the incidence reported in the previous series from these hospitals.’ On the other hand, the over-all survival rate remained unchanged. Our experience with the radical hysterectomy and node dissection in the treatment of Stage II endometrial carcinoma is extremely limited and precludes an assessmentof its effectiveness. When an appropriate operation has been performed within 24 to 48 hours following the removal of the radium, no demonstrable increase in complications or decreasein cure rate has been detected. It appears to be an acceptable procedure in properly selected cases. We have practically no experience with the use of postoperative intravaginal radium following hysterectomy.
Carcinoma
of endometrium
671
The use of external x-ray postoperatively in the patients with deep myometrial penetration has not increased our complications. The encouraging results in those patients treated in this fashion, especially in the Stage I group, inclines us to continue this practice. We have little experience in this series with the use of preoperative external x-ray instead of preoperative radium as is advocated by de1 Regato and Chahbazianzl and many radiation therapists. It seemsto us to be more applicable in the patients with uteri that sound greater than 10 cm, This technique adds at least an extra two to four weeks’ time to the completion of therapy. There appears to be no particular evidence in existence to relegate preoperative intrauterine packing of the uterus with radium according to the Heyman technique to medieval practices and abandon its use. The addition of a vaginal component to the Heyman packing technique appears to make good sense, but in this series no localized vaginal recurrences were found in any of the patients treated by the Heyman packing technique alone or among those treated by the Heyman technique plus intravaginal radium. It seemsto us that the most important part of the treatment of carcinoma of the corpus is total hysterectomy and bilateral salpingooophorectomy. Adjuvant radiation therapy should be used in those caseswith large uteri, deep myometrial penetration, undifferentiated tumors, cervical extension, or extension outside of the uterus. The type of radiation used should be individualized to fit the clinical problem at hand. The cure rate for carcinoma of the corpus has not changed during the past 16 to 20 years. Within limits the modalities of treatment are not critical and therefore with the existing technology it is unlikely that further progress will be made. If we want to make progress, new avenues have to be explored and it would seem that two promising avenues are early diagnosis and a better understanding of factors controlling the disease.
672
hick
et al.
REFERENCES
1. Corscaden, J. A., and Tovell, H. M. M.: Ar*r. J. OBSTET. GYNECOL. 68: 737, 1954. 2. Gusberg, S. B.. and Yannopoulos, D.: AM. J. OBSTET. GYNECOL. 88: 157, 1964. 3. F.I.G.O. News: Int. J. Gynaecol. Obstet. 9: 172, 1971. 4. Davis, E. W., Jr.: AM. J. OBSTET. GYNECOL. 88: 163, 1964. 5. Shah, C. A., and Green, T. H., Jr.: Obstet. Gynecol. 39: 500-509, 1972. 6. Sall, S., Sonnenblick, B., and Stone, M.: AM. J. OBSTET. GYNECOL. 107: 116, 1970. 7. Statistical Abstract of the United States, United States Public Health Service 87: 150, 1966. 8. Vongtama, V., Kurohara, S. S., Badib, A. O., and Webster, J. H. : Cancer 26: 842, 1970. 9. MacMahon, B., and Austin, J. H.: Cancer 23: 275, 1969. 10. Nahhas, W. A., Lund, C. J., and Rudolph, J. H.: Obstet. Gvnecol. 38: 564. 1971. 11. Jones, W. E., Kanner, H. M., Kanner, H. H., and Benson, C.: AM. J. OBSTET. GYNECOL. 113: 549, 1972. 12. Wade, M. E., Koharn, E. I., and Morris, J. M.: Am J. OBSTET. GYNECOL. 99: 869, 1967. 13. Badib, A. O., Kurohara, S. S., Vongtama, V. Y., Selim, M. A., and Webster, J. H.: AM. J. OBSTET. GYNECOL. 106: 205, 1970. 14. Ng, A. B. P., and Reagan, J. W.: Obstet. Gynecol. 35: 437, 1970. 15. Nilsen, P. A., and Keller, 0.: AM. J. OBSTET. GYNECOL. 105: 1099, 1969. 16. Vital Statistics of U. S. Vol. I. Washington, D. C., 1965, U. S. Dept. Health Education & Welfare Public Health Service. ”
Discussion
DR. MICHAEL NEWTON, Chicago, Illinois. I would first like to stipulate, as our legal friends say, (1) the superb quality of the records at Dr. Frick’s hospitals, (2) the agreeable and cooperative nature of the other members of his staff, (3) the remarkable consistency of his pathologists in their diagnoses and descriptions, (4) the compliant and cooperative behavior of his group of radiotherapists, and (5) the excellence of his follow-up system. Three particular points were of interest to me: 1. Vaginal recurrence took place in very few patients. The choice of treatment did not seem to make any difference. 2. Spread of the cancer to one or both ovaries, without other extension, did not carry a poor prognosis and 10 of 13 patients (77 per cent) survived for five years. This confirms a “gut” feel-
17. Vongtama, V., Kurohara, S. S., Badib, A. O., and Webster, J .H.: Cancer 25: 4.5, 1970. 18. Heyman, J.: J. A. M. A. 135: 412, 1947. 19. Berkson, J., and Gage, R. P.: Proc. Staff Meet., Mayo Clin. 25: 270, 1950. 20. Kottmeier, H. L., editor: .4nnual Report on the Results of Treatment in Carcinoma of the Uterus and Vagina, Stockholm, 1966, International Federation of Gynecology and Obstetrics, Vol. 14. 21. de1 Regato, J. A., and Chahbazian, C. M.: Am. J. Roentgenol. 114: 106, 1972. 22. Nolan, J. F., Dorough, M. E., and Anson, J. H.: AM. J. OBSTET. GYNECOL. 96: 663, 1967.
23. Graham, J.: Surg. Gynecol. Obstet. 132: 835, 1971. 24. Rutledge, F. N., Kan, S. K., and Fletcher, G. H.: AM. J. OBSTET. GYNECOL. 75: 167, 1958. 25. Boronow, R. C.: Carcinoma of the Corpus: Treatment at M. D. Anderson Hospital, Chicago, 1969, Year Book Medical Publishers, Inc. 26. Ingersoll, F. M.: Am. J. Surg. 121: 473, 1971. 27. Kottmeier, H. L.: Personal communication. Paper in preparation 1972. 28. Rubin, P., Gerle, R. D., Quick, R. S., and Greenlaw, R. H.: Am. J. Roentgenol. 89: 91, 1963. 29. Whetham, J. C. G., and Bean, J. L. M.: AM. J.
OBSTET.
30. Renning, J. OBSTET.
GYNECOL.
E. L.,
112:
339,
1972.
and Javert, C. T.: GYNECOL. 88: 171, 1964.
AM.
ing that I have had for some years in this matter, to the confusion of some of my colleagues. 3. When intracavitary radium was followed by hysterectomy in 24 hours, instead of the usual four to six weeks’ delay, there appeared to be no change in survival rate and no increase in complications in 19 cases. For some reason this bothers me. If you are going to use intracavitary radium, why not wait until it has had a chance to reduce infection and shrink the uterus? Rut it may be that I do not see the whole scene. Dr. Frick’s paper well illustrates some of the current problems in corpus cancer. Diagnosis. Among the 193 patients in whom cytologic studies were done suspicious or positive results were obtained in only 33 per cent. The jet-wash method appears to be a more reliable diagnostic tool,’ but the desirability and practicality of using it as a screening test have not yet, I believe, been firmly established.
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115 5
Staging. One of the problems of clinical staging has always been that the vast majority of patients fell into Stage I. This amounted to 96 per cent in the Chicago Lying-In series.* Even utilizing the 1971 modifications of F.I.G.O. classification, Dr. Frick found that 75 per cent of his patients fell into Stage I. He noted, too, that if you add the information obtained from operation and from histologic examination of the specimen, some changes in staging result. Treatment. Evaluation of treatment is complicated by the staging difficulties previously mentioned and by widely held dogmatic opinions concerning the merits of supplementary radiotherapy. A randomized study of the management of Stage I cases has not, so far as I know, been carried out. I considered it once but did not pursue it because of the relatively small number of cases on my service at that time. Pending such a study, two points should be considered. First, our data and Dr. Frick’s raise serious doubt as to the value of preoperative radiotherapy for Stage I. The important part of the treatment seems to be removal of the uterus and ovaries and the upper 1 to ‘2 cm. of vagina. Second, a logical way to handle Stage I cases is to operate initially on all patients who are good or fair operative risks, and then to re-evaluate and give postoperative radiotherapy if extended clinical staging (or, as Dr. Frick terms it, “clinicopathological classification”) indicates that further therapy is ncessary. The chief indications for such further therapy are unexpected extension to the cervix or outside the uterus or penetration of the tumor through more than half the thickness of the uterine wall. REFERENCES
1. Bibbo, M., Shanklin, D. R., and Wied, G. L.: J. Reprod. Med. 8: 90, 1972. 2. Welander, C., Griem, M. L., Newton, M., and Marks, J. E.: J. Reprod. Med. 8: 41, 1972. DR. MICHAEL J. JORDAN, New York, New York. Dr. Frick has presented an excellent review of the Presbyterian-Delafield series from 1956 to 1965 and has drawn a number of interesting conclusions. Two of these, particularly closely related, I feel are extremely important. No. 1, the inaccuracy of the Papanicolaou smear in this series and no significant improvement in the cure rate in the 1956 to 1965 series as compared to the previous series of cases treated in these institutions betwen 1938 and 1965. It is apparent in the rather sad commentary that the cure rate of endometrial carcinnoma has not kept pace
Carcinoma
of endometrium
673
with the many advances in treatment, principally because only a relatively small percentage of diagnoses are made when the disease is limited and amenable to early treatment, whichever treatment one chooses. In this series, as well as in most published series, the Papanicolaou smear was considered inaccurate yet cancer of the endometrium runs the gamut from the atypias to carcinoma-in-situ to invasive endometrial carcinoma. The techniques that have enabled cervical carcinoma to be detected early are responsible for survival rates of 85 to 95 per cent. The same modalities of early diagnosis and treatment are available to the patient with endometrial carcinoma. Cytologic studies are a mutine part of every pelvic examination, but the endometrial smear is not-and I do not mean endometrial washings. I mean the routine endometrial aspiration smear. It should be done on every patient. The accuracy of the combined vaginal-cervical and endometrial smear has been shown by Bader, Koss, and others to be as high as 76 to 84 per cent. I am sure we are all aware of the magnitude of reading the endometrial smear and I think here is where the main hitch is. These smears are being read improperly. Not infrequently, one can obtain the smears of patients taken three, four, five years prior to the time that the diagnosis of endometrial carcinoma was made and find the early changes in the single cells or small groups of cells that foreshadow an early diagnosis of carcinoma of the endometrium. Of extreme importance also is the fact that the postradiation smear is of great value in determining the interval between radiation and operation. Dr. Frick is to be congratulated for his statement that there appears to be no particular evidence in existence to relegate the use of preoperative irradiation to medieval practice and abandon its use. Surgical treatment combined with irradiation should be regarded as the optimum therapy for all stages of cancer of the endometrium. There are factors loo numerous to mention. Particularly among these are the immunologic changes that take place. When one compares a series of patients with carcinoma of the endometrium with a large uterus and a very anaplastic tumor and receiving irradiation and a similar group not receiving irradiation, there is a very marked difference in the percentage of salvage. There must be some obvious reason. I think it is about time that we spend less time rediscovering the old treatments for carcinoma of the endometrium and spend more time on early diagnosis.
674
March 1, 1973 A Am. J. Obstet. Gynecol.
Frick et al.
Table I. Endometrial
carcinoma:
Compared
methods and survival
1946-1955s
1956~1967f
No. SU7V. % Type Radiation 41 16 39 Mixed 27 15 55.5 Surgery 17 11 64.7 Combined 84 70 83.3 Total 169 *Five-year rate, 66.3 per cent; operability rate, 81.7 per cent. +Five-yearrate, 61.7 per cent; operability rate, 77.2 per cent. DR. CLAYTON T. BEECHAM, Danville, Pennsylvania. Dr. Frick and his co-workers deserve great commendation for their extensive statistical study. Like Dr. Newton, I had the privilege of reading the manuscript and studying the charts; they make a healthy addition to our information on endometrial carcinoma. I was particularly hopeful that evidence would be forthcoming to support radical hysterectomy in the treatment of corpus cancer. As you noted, there was none; nevertheless, I find it a gynecologic inconsistency to employ radical surgery in the treatment of cervical carcinoma and not extend the same principles to endometrial cancer--particularly in the advanced stages. In our moves toward optimum therapy in this disease I believe that anaplastic growths should be treated by full radiation (high-voltage external therapy4,OOO rads plus the limits in internal and vaginal radium dosage). The postradiation operation should be as radical as the patient’s condition permits. Dr. Frick was disappointed to find no improvement in salvage figures when compared to his earlier work. By extending the principles and attitudes of cervical carcinoma therapy to corpus cancer this might be changed. DR. CHARLES J. SMITH, Chicago, Illinois. I did not ask to review Dr. Frick’s paper prior to his presentation and I think that this fact will make the similarities in this brief presentation all the more striking. Table I refers to 284 patients in two comparable episodes in time. They were divided by virtue of some circumstances that affected our institution: (1) a new irradiation unit was installed in 1953 and (2) as you will all recall, 1960 was the year of Dr. Herbert Schmitz’s death. As Dr. Frick has pointed out, rates have not changed very much in terms of over-all survival. But I think these figures will show the effect of some selection, wherein the bigger percentage of patients in the
No. 28 19 38 30 115
SUTV.
4 9 32 26
%
14.2 47.3 84.2 88.6
second group were operated on but this change did not affect the outcome. Our combined therapy, or what we designate as combined, is a protocol of a complete course of radiation therapy prior to operation. As Dr. Beecham described his, we give a complete course of external therapy, follow this by intracavitary radiation, and then, when the reaction has completely subsided, do the operation. What we call mixed are those patients who were referred to us after operation for some other condition and disease found in the specimen. The only other point I would like to make is the question of the use of radiation. Whether you want to use it or not depends on what your attitude is about its effectiveness, but my plea is that if you are going to use it at all, don’t give stimulating doses of radiation. When we get a uterus without any viable tumor, we call this a sterilized tumor and our histological examiantion of this uterus is quite painstaking. It used to be that the whole uterus was sectioned. In our previously published works we have given this a great deal of detailed description but suffice it to say that there are adequate sections taken of these uteri to try to show the existence of viable tumor. There is a pretty high survival rate when you get sterilized tumor-96.5 per cent. The point is that, if you are going to use an effective means of treatment such as radiation, take advantage of all its potential and don’t give a portion of it which at the pelvic wall could actually be stimulatory to the disease. DR. SAUL B. GUSBERG, New York, New York. I do not wish to prolong this discussion but I suppose each of us sees these figures from our own particular point of view. I did have the opportunity to review this statistical report, and I do think it makes a significant contribution. I am not sure that Dr. Frick is correct in his conclusion that the protocol that he used did not improve his results, inasmuch as it seems to me
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that he improved the worst cases, meaning larger and undifferentiated ones, almost to the same rate of cure as some of the early ones. Second, though I do not wish to reiterate my own position about staging once again, I think that Dr. Frick has demonstrated that the size of the uterus makes a difference in that his cure rate was improved in Stage Ia over Stage Ib; he did not use the international classification, new as of 1971, that must include the grading and, unless one breaks down Stages Ia and Ib by grading, one does not have the advantage of this very important parameter. Third, you will notice that the Stage II cases did more poorly than the Stage III patients, that Stage III may have contained, I presume then, some that had tubal involvement without ovarian involvement-a geographic spread. I would reiterate our position about choosing a protocol of treatment from simple hysterectomy to combined treatment, whether it be by adjuvant external irradiation or preoperative radium to ralical hysterectomy. I would say here that in all cancer treatment from my point of view it is better to retract the cancer by preoperative radiation, to get better clearance by operation, then to operate, then mop up a little bit here and there with irradiation, as a general principle. Our protocol was designed not so much to improve the total cure rate but to be able to give patients with less virulent cancers restricted treatment, so to speak, with lesser complications, and give those with more virulent tumors, as, for example, those who have cervix involvement, more radical treatment. I do think, as Dr. Frick has stated, and I would surely concur, that one cannot finally evaluate the radical hysterectomy modality for those who have cervix involvement because there are too few cases that have been treated in this way in this series or in any other series that I have seen. DR. FROCK (Closing). Dr. Newton brought up the question of immediate hysterectomy following the use of intracavitary radium. This procedure was tried by us in selected cases because ( 1) it was felt that the ionizing radiation had its effect on the cancer cell, (2) immediate operation avoided the radiation reaction, and (3) there was a great saving in time and hospital bed utilization. Against immediate operation are ( 1) submitting elderly patients to anesthesia after a prolonged period of bed rest, (2) operating through a contaminated field, and (3) many people felt that the fibrosis which allegedly
Carcinoma
of
endometrium
675
develops in the uterus and parametria during the six-week waiting period following intracavitary radium application plays a large role in controlling the disease. We have limited immediate operation to good-risk patients and so far have not had any major complications. There were 19 patients treated in this fashion during the years covered by this report with a 70 per cent over-all survival and no severe complications. I am unable to answer Dr. Jordan’s comment on the endometrial aspiration smear. We have no experience with this technique. In our hands the Papanicolaou smear taken in the usual fashion was inaccurate. We are now engaged in trying to evaluate the Gravlee intrauterine washing technique. Carcinoma of the endometrium does OCCUr in younger women. The cure rate is superior to that in the older aged patient. Any unexplained abnormal vaginal bleeding ocurring in the perimenopausal period should be investigated by a dilatation and curettage. I agree with Dr. Jordan about the use of intracavitary radium preoperatively. The only time that we do not employ preoperative radium is in the management of a Stage Ia lesion with a lowgrade tumor and superficial penetration of the myometrium. The studies of both Corscaden and Gusberg showed that the cure rate in such cases was not improved hy the use of preoperative radium. We have had no experience with the use of both preoperative x-ray to the pelvis and preoperative intracavitary radium followed by hysterectomy as suggested by Drs. Smith and Beecham. We have relied on intracavitary radium preoperatively as outlined and have reserved the external x-ray therapy to the pelvis for those having histologically undifferentiated tumors or deep myometrial penetration found in the operative specimen. From the standpoint of Dr. Beecham and the radical hysterectomy, we planned to do radical hysterectomies in all Stage II cancers of the endometrium but the medical status of these patients precluded radical operation in many instances. The radical hysterectomy in the Stage II case makes good sense as a cancer operation but we are unable to assess its effect on five-year survival in any large number of cases. It was interesting to note that Dr. Smith’s cure rates in his Chicago series were very close to ours. Apparently they have not found any
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marked improvement in their five-year cure rare during the past years. Dr. Gusberg mentioned the effect of uterine size on cure rate. In our series of 195 Stage Ia patients there was a relative or gross survival rate of 81.5 per cent. The survival in the 66 Stage Ib patients was 71.2 per cent. We analyzed these figures and found that there was no statistical difference between these two groups unless the relative survival rates are corrected for patients lost and patients dying of other disease. If the material is divided into two age groups, those above 60 years of age and those under 60 years of age, there is no difference in cure rate in the Stage Ia and Ib survival rates among the patients under 60 years of age. Over 60 there
March 1. 1Yi:i Am. J. Obstrt. Ggnecol.
is a difference between Stages Ia and Ib. The larger uteri seem to have a poorer survival rate. Among the Stage Ib patients in this older group, we found a much higher proportion of Grade II and Grade III tumors and a higher proportion of uteri showing deep myometrial penetration by tumor. For these reasons we cannot say that the uterine size alone is directly related to five year survival. We intend to follow the methods of therapy outlined in this paper in treating our endometrial carcinomas and feel that by individualizing our therapy we offer the best treatment possible. Despite our efforts, we have not been able to demonstrate any improvement in over-all cure rate during the past ten years.