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Adenocarcinoma of the endometrium
GYNECOLOGIC
ONCOLOGY
2,71-80
(1974)
Adenocarcinoma Role
of Preoperative
of the Endometrium Radiation
in Stage
PAUL B. UNDERWOOD, JR., M.D., J. 0. KEENE WALLACE, M.D., AND ELIZABETH Medical Uniuersity of South Obstetrics and Gynecology Charleston, South Received
I Disease FENN, TRAVIS,
Carolina Departments and Radiation Therapy Carolina 29401
February
M.S.,
M.S.
of
4, 1974
A prospective study was reported evaluating the effectiveness of preoperative radiation focused on the vaginal apex followed immediately by abdominal hysterectomy and bilateral salpingo-oophorectomy as a means of therapy for Stage I adenocarcinoma of the endometrium. Eighty-three consecutive patients over a 53/4-yr span of time were studied. This technique resulted in a predicted 5-yr survival of 91.8%. Complications were low and patient acceptance excellent. The precise dosages and schedules were discussed in detail.
In this cancer-awareness age, women seek early medical advice for abnormal vaginal bleeding, and physician’s evaluations are oriented toward cancer as an etiology. In most clinics including ours, adenocarcinoma of the uterine cropus is rapidly approaching an incidence rate equal to that of the uterine cervix (Table I)[I,Z]. This decreasing ratio may be related to such factors as improved nutritional and living standards, liberal use of hormones, increased longevity, and/or improved diagnostic and reporting techniques. As a result, more advanced and less expensive diagnostic techniques have been developed with emphasis on outpatient evaluations. The addition of radiation to surgery either pre or postoperative, whether delivered by radium or external beam has been accepted by most gynecological oncologists as the proper mode of therapy. The combined contributions of these two modalities, earlier diagnosis and the addition of radiation to surgery, have played a valuable role in improving survival from endometrial carcinoma. Although many studies [3-101 have been reported comparing surgery alone to radiation combined with surgery, few represent a study from the same department in which stage I adenocarcinoma of the endometrium was treated by surgery alone for a period of time followed by a similar number of patients treated by a combination of radiation and surgery. Since the techniques of delivering the radiation and the dosages administered as well as the timing of surgery vary so greatly in other reports, a prospective study was organized to evaluate the adjunctive use of radiation with surgery. The purpose of the study was to determine the accuracy of the following hypothesis for stage I adenocarcinoma of the endometrium: 71 Copyright All rights
@ 1974 by Academic Press, Inc. of reproduction in any form reserved.
72
UNDERWOOD
ET
AL.
TABLE I NUMBER OF NEW INVASIVE UTERINE CANCERS PER YEAR SINCE OPENING MEDICAL UNIVERSITY HOSPITAL, EXCLUSIVE OF INTRAEPITHELIAL TUMORS
Year 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972
Uterine
cervix 27 71 69 94 126 82 98 73 73 59 65 83 85 118 87 105 114 122
Uterine (sarcomas
Fundus included) 5 11 0 13 18 17 15 13 16 13 16 22 17 21 31 40 43 47
1. Radiation combined with surgery offers an improved prognosis over surgery alone. 2. Preoperative irradiation focused on vaginal apex will decrease local recurrences. 3. A hysterectomy and bilateral salpingo-oophorectomy within a few days after preoperative radium (same hospitalization) is a safe and effective mode of therapy. METHOD From the opening of the Medical University Hospital of South Carolina in 1955 through July 1967, patients with stage I adenocarcinoma of the endometrium were treated by abdominal hysterectomy, bilateral salpingo-oophorectomy, and attempted removal of the upper one third of the vagina. The surgery-alone series, which has been previously reported [Ill, will be compared to the patients treated from August 1967 to May 1973 (5 314 yr). During this time, the prospective study was established to treat all patients with stage I adenocarcinoma of the endometrium with a combination of radiation and surgery. A favorable comparison exists between the two groups since they reside within the same geographic area, were treated within the Medical University Hospital, and consist of a similar number of patients. All patients were staged as recommended by the Cancer Committee of International Federation of Obstetrics and Gynecology in January 1971 [12]. Information was ex-
STAGE
I ENDOMETRIAL
tracted from the charts by a trained ture recall and analysis.
73
CANCER
technician
and stored
in a computer
for fu-
PROCEDURE All untreated patients were entered into the protocol except for two women who were severe medical risks. Two other patients who died after radium removal and before surgery were also not included in the survival rate of a technique aimed to evaluate the effectiveness of preoperative irradiation focused on the vaginal apex followed by a short waiting period for hysterectomy. These two deaths will be discussed later. This prospective protocol (Table II) utilizes the afterloading uterine tandem and vaginal ovoids of the Fletcher-Suit applicator in clinical stage I disease in a uterus of lo-wk gestational size or less. This applicator was loaded with radium sources so as to deliver a surface dose of 7000 rads to the vaginal apex and 3000 mg hr to the uterine corpus over a period of 60-70 hr. The vaginal mucosa dose was calculated by computer after the applicator was introduced using the individual patient’s X-rays. If the uterus was larger than 10 wk gestational size due to fibromyomas with a uterine cavity of 10 cm or less in depth, she was treated by the same method. However, patients with uteri 12 wk in size or over received 4000 rads external beam megavoltage radiation through a 15 x 15-cm port followed by a similar radium application except that the dosage was decreased to 4000 rads surface dose to the vagina and 2000 mg hr to the corpus. In either case an abdominal hysterectomy and bilateral salpingo-oophorectomy was performed 2-5 days after completion of radium and usually during the same hospitalization. When the microscopic evaluation of the excised uterus demonstrated the neoplasm to extend more than one half way through the myometrium and the patient had received radium only, 2000 rads to the total pelvis through similar ports followed by’another 2000 rads with a 4-cm midline shield was administered.
TABLE
II
PROTOCOL FOR PREOPERATIVE RADIATION IN STAGE I DISEASE Uterus 10 wk Radium
7000 3000
size less than pregnancy 1 R surface dose mg/hr fundus
L Hysterectomy and bilateral salpingooophorectomy 2-5
Uterus size greater 10 wk pregnancy L 4000 R total pelvis by external beam
vagina
Radium days
than
4000 I 2000
I R surface dose vagina mg/hr to fundus
later
i If myometrium invaded over l/z way thickness, 2000 R total pelvis plus 2000 R with 4 cm midline shield
I Hysterectomy and bilateral salpingo-oophorectomy 2-5
days
later
74
UNDERWOOD
ET
AL.
RESULTS Ninety-five patients with stage I adenocarcinoma of the endometrium completed therapy (Table III). The majority (75 patients, or 74%) received only one radium application followed within 2-5 days by the abdominal surgery. Fpur very obese women with clinical early disease underwent a vaginal hysterectomy without removal of the ovaries or tubes immediately postradium and all were living and well. In the stage I patients, eight received external beam radium, and then surgery indicating extensive disease; however, seven of these remain free of disease. The 10 patients who received radiation postoperatively and the two treated with radium only will be discussed later. These remaining 83 unselected patients with stage I adenocarcinoma of the endometrium diagnosed pretreatment were managed as outlined in the protocol and represent the heart of this paper. Of the 83 patients with stage I disease who received preoperative radiation treatment, only 32 have been followed for 36 or more months. A life table as calculated by the Burkson and Gage method [13] predicts a 5-yr survival of 91.8% with a mean error of 3.9% at the 95% confidence level [14] (Fig. 1). The predicted 5-yr survival without recurrence was 87.3% with a standard error of 7% (Fig. 2). A comparison of this predicted survival rate with the survival rate of the surgery-alone series (Table IV) illustrated a 17% increased survival when preoperative radiation was administered (P = <0.05). Of greater importance was that to date, no vaginal apex recurrences have occurred in the group that received preoperative irradiation whereas 18% of the surgery-alone series developed the apical recurrence.
STAGE
TABLE III I DISEASE: METHODS BY WHICH RADIATION WAS DELIVERED No. pt. treated
Method Radium External Surgery Radium Total
STAGE
plus surgery beam, radium, then radium only
and surgery
TABLE IV I DISEASE: COMPARISON OF SURVIVALS RECURRENCES (FOUR PATIENTS WHO OF OTHER CAUSES EXCLUDED) Surgery
Result 5-Yr survival Vaginal recurrence
alone series
75% 18%
75 8 10 2 95
AND VAGINAL DIED
Combined therapy series 91.8% 0%
STAGE
I ENDOMETRIAL
75
CANCER
L 6
12
IS
24
30
36
42
48
54
60
TIME mtcNTHS)
FIG.
1. Survival
curve
as predicted
by Burkson
and Gage
[13].
4s
60
I 8
I2
IS
24
30
36
42
54
TIME WoNrHS)
FIG.
2. Survival
curve
as predicted
by Burkson
and Gage
[13].
Five of these 83 patients who received preoperative radiation have developed a recurrence (Table V). One patient had recurrent disease at 45 mo but survived more than 5 yr. Four died of cancer at 13,18,20, and 26 mo, respectively. A review of these five deaths did not reveal any predictable failure characteristic. The patient who received external beam therapy did have neoplasm extending to the serosal surface of the uterus. A positive right inguinal node was discovered 4. mo postoperatively. One patient had a moderately well-differentiated lesion extending almost half way through myometrium, one had a malignant polyp, and the two others had only superficial myometrial involvement although one lesion a poorly differentiated papillary neoplasm. All recurrences developed at distant sites-one in an inguinal node, one abdominal carcinomatosis, and three pulmonary. No vaginal cuff recurrences were evident in any patient even at death. Four other patients have died of other causes but without any clinical evidence of recurrent neoplasm.
76
UNDERWOOD
STAGE
ET
AL.
TABLE V I DISEASE: RECURRENCES ACCORDING TO METHOD OF IRRADIATION No. pt. with recurrence
Radium External Surgery Radium Total
plus surgery beam, radium, then radium only
and surgery
Major postoperative complications were minimal (Table VI). Our code sheet was not designed to include all patients who had.morbidity as defined by a temperature of 100.6 F or greater on two consecutive days; therefore, complications listed represent only those significant enough to be diagnosed either on the discharge summary or the front of the chart. These complications could possibly have been related to the two anesthesias and procedures in close proximity; however, they do not seem excessive when one considers the high percentage of elderly, obese patients. There was no known posthysterectomy thrombophlebitis or emboli. Although not included in our preoperative protocol series and only presented for information, 10 patients who had undergone a hysterectomy elsewhere for various reasons and found coincidentally to have adenocarcinoma of the endometrium, were referred shortly after operation for follow-up therapy. Each received radium in the form of two ovoids placed against the vaginal apex between 10 and 20 days postoperatively. A surface ‘dose of 7000 rads was delivered within 60-70 hr. Eight patients remain free of disease. One developed pulmonary metastasis and the other abdominal carcinomatosis. Both have died. TABLE VI STAGE I DISEASE: MAJOR POSTOPERATIVE COMPLICATION AFTER HYSTERECTOMY Complication Abdominal wound Abscesses Gastrointestinal Ileus Pulmonary Atelectasis Pneumonia Renal Pyelonephritis Thrombophlebitis
No. pt.
2 (one 2 1 1 4 0
evisceration)
STAGE
I ENDOMETRIAL
CANCER
77
COMMENTS Adequate irradiation focused on the vaginal apex can essentially eliminate recurrences in the vaginal cuff. Our protocol was to administer radiation preoperatively in all known cases of adenocarcinoma of the endometrium; however, 10 patients were given postoperative radiation to the vaginal apex without any local recurrence. The deliverance of a tumorostatic dose to the neoplasm prior to surgical manipulation appears preferable; in addition, the uterus serves as a perfect stabilizer of the radium apparatus and displacer of the bladder and rectum. The dose delivered by our study did not prevent later external beam therapy when more extensive disease was discovered at operation. Heyman capsules obviously deliver a more symmetrical distribution of radiation to the uterine corpus than the tandem used in this study. However, from a radiation-protection standpoint, Heyman capsules deliver 15-20 mrads to the technician as compared to none with the afterloading tandem, not to mention the danger of live radium to the operating room personnel. The removal of the uterus soon after the radium implant appears worthy since a curative dose of radiation was not delivered to the corpus by this technique. Postponement of surgery would only permit the neoplasm time to grow. When one considers that the majority of the patients were over 50 yr of age and over 150 lb of weight, the postsurgical complications were not excessive. Although these complications did not represent every temperature elevation or minor problem, they did represent complications worthy of mention in discharge summary or diagnosis on the front of the chart. From the subjective standpoint of the senior author who has participated in all of these patients’ care, postoperative complications have not been a problem. Antibiotics were not routinely used, however, pelvic and wound irrigation with normal saline at the time of surgery was emphasized. From the patient’s standpoint, the complete therapy during one hospitalization has been far superior to delay. The performance of surgery immediately after a radium implant revealed no clinical evidence of radiation changes in the parauterine tissues. No attempt was made to remove an excessive vaginal cuff. The fallopian tubes were tied imediately upon opening the abdomen. Elective appendectomies were performed when applicable. An aspect that may contribute to the improved survival has been our policy to diagnose endometrial carcinoma with the least minimal trauma [15]. As outlined (Figs. 3, 4, and 5), outpatient diagnosis was emphasized. Only one adenocarcinoma of the endometrium has been missed by this technique at the Medical University of South Carolina since April 1971. That patient continued to bleed; therefore, a dilatation and curettage was performed 1 mo later for the diagnosis. The increased number of malignant cells found in the peripheral blood after a diagnostic dilatation and curettage upon a uterus which contained adenocarcinoma could possibly contribute to distant metastasis, not to mention patient cost, risk, and inconvenience. All patients with endometrial carcinoma received an endocervical curettage as a means of
78
UNDERWOOD
ABNORMAL
ET
AL.
UTERINE BLEEDING AFTER 40
Endonwrirl
Biopsy
Cerricsl Biepsy [if lesion I FIG. 3. 05ce
procedure
used in diagnosing
etiology
of abnormal
uterine
bleeding
after
age 40.
staging. By this technique, only one stage II endometrial carcinoma was missed, and in this patient, a microscopic metastatic implant was found deep in the cervical stroma and could easily have been missed by a conization. Adenocarcinoma of the endometrium results in early abnormal uterine bleeding; therefore, without patient or physician delay, the majority should be diagnosed as a clinical stage I disease. Lymphatic spread occurs late as indicated by indirect evidence of excellent survival rates without therapy to regional lymph nodes. Ur results would indicate that there is no need for pelvic lymph node dissection in this disease. The two women who died soon after radium removal and prior to the hysterectomy need comment. From August 1,1967, to present, over 1406 radium applications have been performed at the Medical University of South Carolina by the author or by a member of the resident staff under his supervision. Three deaths in the postradium period have occurred-one patient with cervical and two with an endometrial carcinoma. All three patients developed chest pain and their condition rapidly deteriorated. Two deaths occurred within less than 6 hr after radium removal and the other on the second day, ALL
STUDIE:
/
I
A
Premenowusal
I
i NEGATIVE I
-\
Continues to had
Post-mmmpwul b O&C
Cyclic HormoMs Observe FIG. uterine
4. Method bleeding.
of managing
negative
outpatient
studies
in women
over
40 with
abnormal
STAGE
I ENDOMETRIAL
ABNORMAL
STUDIES
/
\
Endometrial
Abnormal but not rAopstic Corded 4 Cldpotcopy 0 L c and/or cone FIG. uterine
5. Methods bleeding.
of managing
abnormal
79
CANCER
I
Cmctr
Concr
\ 4 Trut as such Tnrt OS such outpatient studies in women
over
40 with
abnormal
Neither patient survived long enough to clarify the differential diagnosis. This mortality rate was probably not excessive when one considers that the patient population involved was elderly, frequently obese, and had cancer. In 1971, a policy was established that all radium patients have their beds elevated from the buttocks to the feet. No further deaths have occurred. If these two deaths were included in our survival rate, it would fall to 89%. SUMMARY 1. Adenocarcinoma of the endometrium should be diagnosed with the least minimal trauma to the uterus and a dilatation and curettage avoided if possible. 2. Preoperative irradiation should be focused on the vaginal apex rather than the uterine corpus. 3. Abdominal hysterectomy and bilateral salpingo-oophorectomy can be performed safely and effectively immediately postradium. 4. Improved patient acceptance of therapy exists by completion during one hospitalization. ACKNOWLEDGMENTS The authors acknowledge and Dr. Don Frey.
the computer
and statistical
assistance
provided
by Carol
Wallace
REFERENCES 1. REAGAN, J. W., AND NG, A. B. P. Endometrial cancer: Rising incidence, detection and treatment. J. Reprod. Med. 10,53-74 (1973). 2. HELWIG, P. C. Changing ratio of cervical to corpus carcinoma-A 32-year survey. Amer. J. Obstet.
Gynecol.
81,277-280
(1961).
WADE, M. E., KOHORN, E. I., AND MORRIS, J. M. Adenocarcinoma ofthe endometrium. Amer. J. Obstet. Gynecol. 99,869-876 (1967). 4. BORONOW, R. C. Carcinoma of corpus: Treatment at M. D. Anderson Hospital, in Cancer of the uterus and ouary, Year Book Publ., Chicago pp. 35-54 (1969). 5. SHAH, C. A., AND GREEN, T. H. Evaluation of current management of endometrial carcinoma. Obstet. Gynecol. 39,500-509 (1972). 6. LEWIS, B. V., AND STALLWORTH, J. A. Adenocarcinoma of the body of the uterus,]. Obstet. 3.
Gynaecol.
Brit.
Commonw.
77, 343-348
(1970).
7. COPENHAVER, E. H., AND BARSANICAN, M. Management of stage I adenocarcinoma dometrium. Amer. Obstet. Gynecol. 99,864-868 (1967).
of the en-
80
STAGE
8. GUSBERG,
S. B., AND
10. 11. 12. 13. 14. 15.
CANCER
YANNOPOULOS, D. Therapeutic decisions in corpus cancer. Amer. (1964). GRAHAM, j. Value of preoperative or postoperative treatment by radium for carcinoma of the uterine body, Surg. Gynecol. Obstet. 132,855-860 (1971). WHETHAM, J. C. G., AND BEAN, J. C. M. Carcinoma of the endometrium. Amer. J. Obstet. Gynecol. 112,339-343 (1972). UNDERWOOD, P. B., AND PURCELL, J. L. Adenocarcinoma of the endometrium-lo-Year study at the Medical College of South Carolina. S. Med. J. 64,961-966 (1971). Report presented by the Cancer Committee to the General Assembly of F.I.G.O., New York April 1970, Znt. J. Gynecol. Obstet. 9,72-179 (1971). BURKSON, J., AND GAGE, R. P. Calculation of survival rates for cancer. Proc. StuffMeet. Mayo Clin. 25,270 (1950). GREENWOOD, M. Reports on public health and medical subjects, No. 33, Appendix 1, The “Errors of Sampling” of the Survivorship Tables, London, 1926, H. M. Stationery Office. UNDERWOOD, P. B. The jet wash: Can it replace the diagnostic D&C? Presented at the South Atlantic Association of Obstetricians and Gynecologists Meeting, Hot Springs, Va., February 1973, and submitted to the Amer. J. Obstet. Gynecol. for consideration of publication.
J. Obstet. Gynecol. 88, 157-162
9.
I ENDOMETRIAL
ONCOLOGY
2,71-80
(1974)
Adenocarcinoma Role
of Preoperative
of the Endometrium Radiation
in Stage
PAUL B. UNDERWOOD, JR., M.D., J. 0. KEENE WALLACE, M.D., AND ELIZABETH Medical Uniuersity of South Obstetrics and Gynecology Charleston, South Received
I Disease FENN, TRAVIS,
Carolina Departments and Radiation Therapy Carolina 29401
February
M.S.,
M.S.
of
4, 1974
A prospective study was reported evaluating the effectiveness of preoperative radiation focused on the vaginal apex followed immediately by abdominal hysterectomy and bilateral salpingo-oophorectomy as a means of therapy for Stage I adenocarcinoma of the endometrium. Eighty-three consecutive patients over a 53/4-yr span of time were studied. This technique resulted in a predicted 5-yr survival of 91.8%. Complications were low and patient acceptance excellent. The precise dosages and schedules were discussed in detail.
In this cancer-awareness age, women seek early medical advice for abnormal vaginal bleeding, and physician’s evaluations are oriented toward cancer as an etiology. In most clinics including ours, adenocarcinoma of the uterine cropus is rapidly approaching an incidence rate equal to that of the uterine cervix (Table I)[I,Z]. This decreasing ratio may be related to such factors as improved nutritional and living standards, liberal use of hormones, increased longevity, and/or improved diagnostic and reporting techniques. As a result, more advanced and less expensive diagnostic techniques have been developed with emphasis on outpatient evaluations. The addition of radiation to surgery either pre or postoperative, whether delivered by radium or external beam has been accepted by most gynecological oncologists as the proper mode of therapy. The combined contributions of these two modalities, earlier diagnosis and the addition of radiation to surgery, have played a valuable role in improving survival from endometrial carcinoma. Although many studies [3-101 have been reported comparing surgery alone to radiation combined with surgery, few represent a study from the same department in which stage I adenocarcinoma of the endometrium was treated by surgery alone for a period of time followed by a similar number of patients treated by a combination of radiation and surgery. Since the techniques of delivering the radiation and the dosages administered as well as the timing of surgery vary so greatly in other reports, a prospective study was organized to evaluate the adjunctive use of radiation with surgery. The purpose of the study was to determine the accuracy of the following hypothesis for stage I adenocarcinoma of the endometrium: 71 Copyright All rights
@ 1974 by Academic Press, Inc. of reproduction in any form reserved.
72
UNDERWOOD
ET
AL.
TABLE I NUMBER OF NEW INVASIVE UTERINE CANCERS PER YEAR SINCE OPENING MEDICAL UNIVERSITY HOSPITAL, EXCLUSIVE OF INTRAEPITHELIAL TUMORS
Year 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972
Uterine
cervix 27 71 69 94 126 82 98 73 73 59 65 83 85 118 87 105 114 122
Uterine (sarcomas
Fundus included) 5 11 0 13 18 17 15 13 16 13 16 22 17 21 31 40 43 47
1. Radiation combined with surgery offers an improved prognosis over surgery alone. 2. Preoperative irradiation focused on vaginal apex will decrease local recurrences. 3. A hysterectomy and bilateral salpingo-oophorectomy within a few days after preoperative radium (same hospitalization) is a safe and effective mode of therapy. METHOD From the opening of the Medical University Hospital of South Carolina in 1955 through July 1967, patients with stage I adenocarcinoma of the endometrium were treated by abdominal hysterectomy, bilateral salpingo-oophorectomy, and attempted removal of the upper one third of the vagina. The surgery-alone series, which has been previously reported [Ill, will be compared to the patients treated from August 1967 to May 1973 (5 314 yr). During this time, the prospective study was established to treat all patients with stage I adenocarcinoma of the endometrium with a combination of radiation and surgery. A favorable comparison exists between the two groups since they reside within the same geographic area, were treated within the Medical University Hospital, and consist of a similar number of patients. All patients were staged as recommended by the Cancer Committee of International Federation of Obstetrics and Gynecology in January 1971 [12]. Information was ex-
STAGE
I ENDOMETRIAL
tracted from the charts by a trained ture recall and analysis.
73
CANCER
technician
and stored
in a computer
for fu-
PROCEDURE All untreated patients were entered into the protocol except for two women who were severe medical risks. Two other patients who died after radium removal and before surgery were also not included in the survival rate of a technique aimed to evaluate the effectiveness of preoperative irradiation focused on the vaginal apex followed by a short waiting period for hysterectomy. These two deaths will be discussed later. This prospective protocol (Table II) utilizes the afterloading uterine tandem and vaginal ovoids of the Fletcher-Suit applicator in clinical stage I disease in a uterus of lo-wk gestational size or less. This applicator was loaded with radium sources so as to deliver a surface dose of 7000 rads to the vaginal apex and 3000 mg hr to the uterine corpus over a period of 60-70 hr. The vaginal mucosa dose was calculated by computer after the applicator was introduced using the individual patient’s X-rays. If the uterus was larger than 10 wk gestational size due to fibromyomas with a uterine cavity of 10 cm or less in depth, she was treated by the same method. However, patients with uteri 12 wk in size or over received 4000 rads external beam megavoltage radiation through a 15 x 15-cm port followed by a similar radium application except that the dosage was decreased to 4000 rads surface dose to the vagina and 2000 mg hr to the corpus. In either case an abdominal hysterectomy and bilateral salpingo-oophorectomy was performed 2-5 days after completion of radium and usually during the same hospitalization. When the microscopic evaluation of the excised uterus demonstrated the neoplasm to extend more than one half way through the myometrium and the patient had received radium only, 2000 rads to the total pelvis through similar ports followed by’another 2000 rads with a 4-cm midline shield was administered.
TABLE
II
PROTOCOL FOR PREOPERATIVE RADIATION IN STAGE I DISEASE Uterus 10 wk Radium
7000 3000
size less than pregnancy 1 R surface dose mg/hr fundus
L Hysterectomy and bilateral salpingooophorectomy 2-5
Uterus size greater 10 wk pregnancy L 4000 R total pelvis by external beam
vagina
Radium days
than
4000 I 2000
I R surface dose vagina mg/hr to fundus
later
i If myometrium invaded over l/z way thickness, 2000 R total pelvis plus 2000 R with 4 cm midline shield
I Hysterectomy and bilateral salpingo-oophorectomy 2-5
days
later
74
UNDERWOOD
ET
AL.
RESULTS Ninety-five patients with stage I adenocarcinoma of the endometrium completed therapy (Table III). The majority (75 patients, or 74%) received only one radium application followed within 2-5 days by the abdominal surgery. Fpur very obese women with clinical early disease underwent a vaginal hysterectomy without removal of the ovaries or tubes immediately postradium and all were living and well. In the stage I patients, eight received external beam radium, and then surgery indicating extensive disease; however, seven of these remain free of disease. The 10 patients who received radiation postoperatively and the two treated with radium only will be discussed later. These remaining 83 unselected patients with stage I adenocarcinoma of the endometrium diagnosed pretreatment were managed as outlined in the protocol and represent the heart of this paper. Of the 83 patients with stage I disease who received preoperative radiation treatment, only 32 have been followed for 36 or more months. A life table as calculated by the Burkson and Gage method [13] predicts a 5-yr survival of 91.8% with a mean error of 3.9% at the 95% confidence level [14] (Fig. 1). The predicted 5-yr survival without recurrence was 87.3% with a standard error of 7% (Fig. 2). A comparison of this predicted survival rate with the survival rate of the surgery-alone series (Table IV) illustrated a 17% increased survival when preoperative radiation was administered (P = <0.05). Of greater importance was that to date, no vaginal apex recurrences have occurred in the group that received preoperative irradiation whereas 18% of the surgery-alone series developed the apical recurrence.
STAGE
TABLE III I DISEASE: METHODS BY WHICH RADIATION WAS DELIVERED No. pt. treated
Method Radium External Surgery Radium Total
STAGE
plus surgery beam, radium, then radium only
and surgery
TABLE IV I DISEASE: COMPARISON OF SURVIVALS RECURRENCES (FOUR PATIENTS WHO OF OTHER CAUSES EXCLUDED) Surgery
Result 5-Yr survival Vaginal recurrence
alone series
75% 18%
75 8 10 2 95
AND VAGINAL DIED
Combined therapy series 91.8% 0%
STAGE
I ENDOMETRIAL
75
CANCER
L 6
12
IS
24
30
36
42
48
54
60
TIME mtcNTHS)
FIG.
1. Survival
curve
as predicted
by Burkson
and Gage
[13].
4s
60
I 8
I2
IS
24
30
36
42
54
TIME WoNrHS)
FIG.
2. Survival
curve
as predicted
by Burkson
and Gage
[13].
Five of these 83 patients who received preoperative radiation have developed a recurrence (Table V). One patient had recurrent disease at 45 mo but survived more than 5 yr. Four died of cancer at 13,18,20, and 26 mo, respectively. A review of these five deaths did not reveal any predictable failure characteristic. The patient who received external beam therapy did have neoplasm extending to the serosal surface of the uterus. A positive right inguinal node was discovered 4. mo postoperatively. One patient had a moderately well-differentiated lesion extending almost half way through myometrium, one had a malignant polyp, and the two others had only superficial myometrial involvement although one lesion a poorly differentiated papillary neoplasm. All recurrences developed at distant sites-one in an inguinal node, one abdominal carcinomatosis, and three pulmonary. No vaginal cuff recurrences were evident in any patient even at death. Four other patients have died of other causes but without any clinical evidence of recurrent neoplasm.
76
UNDERWOOD
STAGE
ET
AL.
TABLE V I DISEASE: RECURRENCES ACCORDING TO METHOD OF IRRADIATION No. pt. with recurrence
Radium External Surgery Radium Total
plus surgery beam, radium, then radium only
and surgery
Major postoperative complications were minimal (Table VI). Our code sheet was not designed to include all patients who had.morbidity as defined by a temperature of 100.6 F or greater on two consecutive days; therefore, complications listed represent only those significant enough to be diagnosed either on the discharge summary or the front of the chart. These complications could possibly have been related to the two anesthesias and procedures in close proximity; however, they do not seem excessive when one considers the high percentage of elderly, obese patients. There was no known posthysterectomy thrombophlebitis or emboli. Although not included in our preoperative protocol series and only presented for information, 10 patients who had undergone a hysterectomy elsewhere for various reasons and found coincidentally to have adenocarcinoma of the endometrium, were referred shortly after operation for follow-up therapy. Each received radium in the form of two ovoids placed against the vaginal apex between 10 and 20 days postoperatively. A surface ‘dose of 7000 rads was delivered within 60-70 hr. Eight patients remain free of disease. One developed pulmonary metastasis and the other abdominal carcinomatosis. Both have died. TABLE VI STAGE I DISEASE: MAJOR POSTOPERATIVE COMPLICATION AFTER HYSTERECTOMY Complication Abdominal wound Abscesses Gastrointestinal Ileus Pulmonary Atelectasis Pneumonia Renal Pyelonephritis Thrombophlebitis
No. pt.
2 (one 2 1 1 4 0
evisceration)
STAGE
I ENDOMETRIAL
CANCER
77
COMMENTS Adequate irradiation focused on the vaginal apex can essentially eliminate recurrences in the vaginal cuff. Our protocol was to administer radiation preoperatively in all known cases of adenocarcinoma of the endometrium; however, 10 patients were given postoperative radiation to the vaginal apex without any local recurrence. The deliverance of a tumorostatic dose to the neoplasm prior to surgical manipulation appears preferable; in addition, the uterus serves as a perfect stabilizer of the radium apparatus and displacer of the bladder and rectum. The dose delivered by our study did not prevent later external beam therapy when more extensive disease was discovered at operation. Heyman capsules obviously deliver a more symmetrical distribution of radiation to the uterine corpus than the tandem used in this study. However, from a radiation-protection standpoint, Heyman capsules deliver 15-20 mrads to the technician as compared to none with the afterloading tandem, not to mention the danger of live radium to the operating room personnel. The removal of the uterus soon after the radium implant appears worthy since a curative dose of radiation was not delivered to the corpus by this technique. Postponement of surgery would only permit the neoplasm time to grow. When one considers that the majority of the patients were over 50 yr of age and over 150 lb of weight, the postsurgical complications were not excessive. Although these complications did not represent every temperature elevation or minor problem, they did represent complications worthy of mention in discharge summary or diagnosis on the front of the chart. From the subjective standpoint of the senior author who has participated in all of these patients’ care, postoperative complications have not been a problem. Antibiotics were not routinely used, however, pelvic and wound irrigation with normal saline at the time of surgery was emphasized. From the patient’s standpoint, the complete therapy during one hospitalization has been far superior to delay. The performance of surgery immediately after a radium implant revealed no clinical evidence of radiation changes in the parauterine tissues. No attempt was made to remove an excessive vaginal cuff. The fallopian tubes were tied imediately upon opening the abdomen. Elective appendectomies were performed when applicable. An aspect that may contribute to the improved survival has been our policy to diagnose endometrial carcinoma with the least minimal trauma [15]. As outlined (Figs. 3, 4, and 5), outpatient diagnosis was emphasized. Only one adenocarcinoma of the endometrium has been missed by this technique at the Medical University of South Carolina since April 1971. That patient continued to bleed; therefore, a dilatation and curettage was performed 1 mo later for the diagnosis. The increased number of malignant cells found in the peripheral blood after a diagnostic dilatation and curettage upon a uterus which contained adenocarcinoma could possibly contribute to distant metastasis, not to mention patient cost, risk, and inconvenience. All patients with endometrial carcinoma received an endocervical curettage as a means of
78
UNDERWOOD
ABNORMAL
ET
AL.
UTERINE BLEEDING AFTER 40
Endonwrirl
Biopsy
Cerricsl Biepsy [if lesion I FIG. 3. 05ce
procedure
used in diagnosing
etiology
of abnormal
uterine
bleeding
after
age 40.
staging. By this technique, only one stage II endometrial carcinoma was missed, and in this patient, a microscopic metastatic implant was found deep in the cervical stroma and could easily have been missed by a conization. Adenocarcinoma of the endometrium results in early abnormal uterine bleeding; therefore, without patient or physician delay, the majority should be diagnosed as a clinical stage I disease. Lymphatic spread occurs late as indicated by indirect evidence of excellent survival rates without therapy to regional lymph nodes. Ur results would indicate that there is no need for pelvic lymph node dissection in this disease. The two women who died soon after radium removal and prior to the hysterectomy need comment. From August 1,1967, to present, over 1406 radium applications have been performed at the Medical University of South Carolina by the author or by a member of the resident staff under his supervision. Three deaths in the postradium period have occurred-one patient with cervical and two with an endometrial carcinoma. All three patients developed chest pain and their condition rapidly deteriorated. Two deaths occurred within less than 6 hr after radium removal and the other on the second day, ALL
STUDIE:
/
I
A
Premenowusal
I
i NEGATIVE I
-\
Continues to had
Post-mmmpwul b O&C
Cyclic HormoMs Observe FIG. uterine
4. Method bleeding.
of managing
negative
outpatient
studies
in women
over
40 with
abnormal
STAGE
I ENDOMETRIAL
ABNORMAL
STUDIES
/
\
Endometrial
Abnormal but not rAopstic Corded 4 Cldpotcopy 0 L c and/or cone FIG. uterine
5. Methods bleeding.
of managing
abnormal
79
CANCER
I
Cmctr
Concr
\ 4 Trut as such Tnrt OS such outpatient studies in women
over
40 with
abnormal
Neither patient survived long enough to clarify the differential diagnosis. This mortality rate was probably not excessive when one considers that the patient population involved was elderly, frequently obese, and had cancer. In 1971, a policy was established that all radium patients have their beds elevated from the buttocks to the feet. No further deaths have occurred. If these two deaths were included in our survival rate, it would fall to 89%. SUMMARY 1. Adenocarcinoma of the endometrium should be diagnosed with the least minimal trauma to the uterus and a dilatation and curettage avoided if possible. 2. Preoperative irradiation should be focused on the vaginal apex rather than the uterine corpus. 3. Abdominal hysterectomy and bilateral salpingo-oophorectomy can be performed safely and effectively immediately postradium. 4. Improved patient acceptance of therapy exists by completion during one hospitalization. ACKNOWLEDGMENTS The authors acknowledge and Dr. Don Frey.
the computer
and statistical
assistance
provided
by Carol
Wallace
REFERENCES 1. REAGAN, J. W., AND NG, A. B. P. Endometrial cancer: Rising incidence, detection and treatment. J. Reprod. Med. 10,53-74 (1973). 2. HELWIG, P. C. Changing ratio of cervical to corpus carcinoma-A 32-year survey. Amer. J. Obstet.
Gynecol.
81,277-280
(1961).
WADE, M. E., KOHORN, E. I., AND MORRIS, J. M. Adenocarcinoma ofthe endometrium. Amer. J. Obstet. Gynecol. 99,869-876 (1967). 4. BORONOW, R. C. Carcinoma of corpus: Treatment at M. D. Anderson Hospital, in Cancer of the uterus and ouary, Year Book Publ., Chicago pp. 35-54 (1969). 5. SHAH, C. A., AND GREEN, T. H. Evaluation of current management of endometrial carcinoma. Obstet. Gynecol. 39,500-509 (1972). 6. LEWIS, B. V., AND STALLWORTH, J. A. Adenocarcinoma of the body of the uterus,]. Obstet. 3.
Gynaecol.
Brit.
Commonw.
77, 343-348
(1970).
7. COPENHAVER, E. H., AND BARSANICAN, M. Management of stage I adenocarcinoma dometrium. Amer. Obstet. Gynecol. 99,864-868 (1967).
of the en-
80
STAGE
8. GUSBERG,
S. B., AND
10. 11. 12. 13. 14. 15.
CANCER
YANNOPOULOS, D. Therapeutic decisions in corpus cancer. Amer. (1964). GRAHAM, j. Value of preoperative or postoperative treatment by radium for carcinoma of the uterine body, Surg. Gynecol. Obstet. 132,855-860 (1971). WHETHAM, J. C. G., AND BEAN, J. C. M. Carcinoma of the endometrium. Amer. J. Obstet. Gynecol. 112,339-343 (1972). UNDERWOOD, P. B., AND PURCELL, J. L. Adenocarcinoma of the endometrium-lo-Year study at the Medical College of South Carolina. S. Med. J. 64,961-966 (1971). Report presented by the Cancer Committee to the General Assembly of F.I.G.O., New York April 1970, Znt. J. Gynecol. Obstet. 9,72-179 (1971). BURKSON, J., AND GAGE, R. P. Calculation of survival rates for cancer. Proc. StuffMeet. Mayo Clin. 25,270 (1950). GREENWOOD, M. Reports on public health and medical subjects, No. 33, Appendix 1, The “Errors of Sampling” of the Survivorship Tables, London, 1926, H. M. Stationery Office. UNDERWOOD, P. B. The jet wash: Can it replace the diagnostic D&C? Presented at the South Atlantic Association of Obstetricians and Gynecologists Meeting, Hot Springs, Va., February 1973, and submitted to the Amer. J. Obstet. Gynecol. for consideration of publication.
J. Obstet. Gynecol. 88, 157-162
9.
I ENDOMETRIAL