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Progestins in the treatment of patients with endometrial adenocarcinoma
Progestins in the treatment with endometrial JULIAN
P.
FELIX
SMITH,
RUTLEDGE,
SAUL
W.
SOFFAR,
Houston,
Texas
of patients
adenocarcinoma M.D.* M.D. M.D.
THAT ADENOCARCINOMA of the endometrium may be amenable to control by means of sex steroids was first demonstrated by Kelley,l in 1951. She reported that the tumors in 2 of 3 patients regressed during a course of therapy with progesterone. Several other authors have since described their successful experiences with progestins as a treatment for endometrial hyperplasia and carcinoma. The majority used progesterone or 17a-hydroxyprogesterone caproate for this purpose. Recently, however, other agents have been introduced which are more easily administered and more potent; aho, their endocrine effects are slightly different from those of either progesterone or 17~hydroxyprogesterone caproate (Figs. 1A, lB, and 1C). Since 1959, a progestational agent has been administered to 45 patients for recurrent or metastatic adenocarcinoma of the endometrium at The University of Texas
M. D. Anderson Hospital and Tumor Institute. Among these were 3 patients who were treated between 1959 and 1961, under the direction of the department of medicine; one received ethisterone, while the other 2 received 17a-hydroxyprogesterone caproate. Although these patients failed to respond to the therapy, they are included in this study to add validity to the findings. The 42 patients who had received a progestin for adenocarcinoma of the endometrium, since 1961, have been treated by the gynecology service. Medroxyprogesterone* alone was administered to 35 of the 42 patients, AY62022t alone to 4, and medroxyprogesterone followed by AY-62022 to 3 patients. The records of all 45 patients were reviewed with respect to the clinical findings, although in the evaluation of the results only the 42 patients who have been treated since 1961 were considered. Materials
From the Section of Gynecology, Department of Surgery, The University of Texas M. D. Anderson Hosgital and Tumor Institute. *Advanced by American
and
methods
Factors related to objective progestational therapy. Various *Supplied Kalamazoo, @upplied New York,
Clinical Fellow Sponsored Cancer Society.
977
responses to authors have
by Dr. S. S. Stubbs, The Upjohn Company, Michigan. by Dr. John David Sproul, Ayerst Laboratories, New York.
978
Smith,
Rutledge,
and
Soffar
&:cH3 ETHISTERONE PRANONE 0.3 - 0.5 Index of Endometrial Activity
PROGESTERONE 1 Index of Endomstrial Activity
Fig. 1A. Structural metrial
activity
for
formulas and indexes of endoprogesterone and Pranone.
O~&O-!-(CH2)~
/
6,17 o DtMETHYL 6 DEHYDROGROGESTERONE AY62022 3.0 - 8.0 (owl) Index of Endometrial Activity
C”3
Fig. 1C. Structural metrial
activity
formulas for AY-62022.
and
indexes
of endo-
-CH3&CH3
17 o HYDROXYPROGESTERONE CAPROATE DELALUT’N 0.5 - I.0 Index of Endometriol
CH3
Activity 3.0
Fig. 1B. Structural
/ OH
formulas
and
6 METHYL 170 HYDROXY PROGESTERONE ACETATE PROVERA - 8.0 (oral) Index of Endomatriol
indexes
of endometrial
suggested factors which may influence the responseof disseminated adenocarcinoma of the endometrium to a progestin. Kennedy? observed that the responsivetumors were biologically different from the unresponsive; also, the responsive tumors were present longer before the original treatment was administered, and they recurred later. Varga and Henriksen3, 4 found that the more differentiated tumors which could be changed toward maturation responded most often. Kelley and Baker516 reported that pulmonary metastasesresponded most often, and pelvic tumors which recurred after irradiation responded poorly. In this review, the responseto treatment was correlated with age, race, parity, the age at menopause, the size and duration of the tumor, the sites of metastasesor recurrences, the presence of the “corpus cancer syndrome,” the type. of treatment, and the histologic features of the tumor before and after treatment. Age of patient. This seemed to be the single most influential factor in the responses of the tumors to progestational therapy (Fig. 2). The mean age of the patients
Activity
activity
for
Delalutin
and
Provera.
whose tumors regressedwas 57.4 years and the group whose tumors failed to respond was 63.7 years. The tumors of 4 out of 5 patients who were lessthan 50 years old regressedto a significant degree, whereas the tumor of only one of 7 patients over 70 years exhibited a response. Race of patient. Thirty-two of the 45 patients were Caucasian and 13 were Negro. Fourteen (43 per cent) of the former obtained a significant responseto treatment, as compared to only 3 (23 per cent) of the latter. Parity of patient. Twenty-two (49 per cent) of the 45 patients were nulliparous. This is the samefigure quoted by Yahia and associates7in the report of his review at the Peter Bent Brigham Hospital. Six of these 22 patients (27 per cent) had responsive tumors, while those of the remaining 16 (73 per cent) exhibited no regression. Age of patient at meuqause. In this respect, the patients with responsive and unresponsive tumors were similar. The menopausal age of the first group varied from 31 to 55 years; the mean age was 46.1 years. Five of the patients were premenopaugal at
Volume Number
94 7
Progestins
15
1
AGES
Fig. 2. Relationship
between
51-M
age of the
86-60
patient
and
(YEARS)
61-66
and
endometrial
c=13 m
66-70
response
979
Rqmdstr Non Rcrpondrrs
71-75
of the
adenocarcinoma
>75
tumor
to progestational
therapy.
the time of their original treatment. The ages of the second group at menopause varied from 32 to 56 years; the mean age was 48.9 years. Six of the latter group were premenopausal at the time of first treatment. Size of the tumor. The response of a tumor to radiotherapy and chemotherapy is believed to be related to its size. Lack of response may be attributable to poor circulation in the center of the tumor, the age of the cells in the center of the tumor, or the fact that the more numerous the cells, the greater the likelihood that some will be resistant. to therapy. The size of the tumors did not seem to influence the results of treatment in this study (Fig. 3). Duration of the tumor. The time which elapses between the appearance of the first symptom to the establishment of the diagnosis of adenocarcinoma of the endometrium is generally related to the degree of malignancy of the tumor. The interval between the appearance of the first symptom and the diagnosis of the malignant tumor in 17 patients with responsive tumors and 25 patients with unresponsive tumors was known. In the first group, this interval varied from one to 96 months; the mean was 17.4 months and the median 7.5 months. In the second group, it varied from one to 100 months; the mean was 14.9 months and the median 7 months. If tumors of a more malignant degree cause a patient to seek medical assistance earlier and less malignant tumors in the same organ system lead them to delay
in consulting a physician, from the clinical standpoint, the tumors of the 2 groups seem to have been of a similar degree of malignancy. The interval between the treatment for the primary tumor and the diagnosis of recurrence or metastasis, likewise, is related to the malignant degree of the tumor. In the patients of this series whose tumors responded to the hormonal therapy, the interval varied from less than one month to 132 months. In the group of unresponsive tumors, the interval varied from one to 72 months. Two of those whose tumors responded had recurrences 10 and 11 years after the original treatment. If these 2 were excluded, the mean interval in the responsive and the unresponsive tumors would be similar, i.e., 16.4 and 15.4 months, respectively. Eight of each group had disseminated cancer at the time of their first treatment. From these observations, the responses of recurrent or metastatic carcinoma to a progestin does not depend upon the interval which elapses between the initial treatment and their appearance. Sites of the disease. The sites of the metastases or recurrences apparently had no bearing upon the results of treatment of these patients (Fig. 4). Sixteen patients had pulmonary metastases; 5 (31 per cent) responded to the drug. A regression of clinically apparent intra-abdominal or intrapelvie disease, or both, was exhibited in 11 of 32 patients (34 per cent). Six of the 11 had
980
Smith,
Rutledge,
and
Soffar
SIZE OF LESION IN CM
<2
Fig.
3. Relationship
between
tumor
5-10
2-5
size and results
> IO
of chemotherapy.
20
5
LUNGS
Fig.
4. Relationship
between
sites
of metastases
received radiotherapy alone or in addition to surgical treatment. Hormonal medication administered to one patient subsequent to irradiation alone brought about regression of pulmonary metastases, although no change in the pelvic recurrence was noted. The “corpus cancer syndrome.” In discussing the etiology of adenocarcinoma of the endometrium, the high incidence of associated obesity, hypertension, and diabetes is often mentioned as evidence of an endocrine imbalance. Yahia and co-workers7 used the term “corpus cancer syndrome” to describe these combined states. Of 26 patients in this series who weighed more than 150 pounds, 11 (42 per cent) had responsive tumors, as did 8 (32 per cent) of the 25 patients with a blood pressure above 150/100, and 4 of the 7 diabetic patients (57 per cent).
ABD. 6 PELVIS
or
recurrences
NODES
and
results
of chemotherapy.
Type of previous therapy. Previously irradiated tumors are frequently resistant to chemotherapy. Kelley and Bake?, G observed that irradiated pelvic recurrences of adenocarcinomas of the endometrium responded poorly to progestational agents. Of 9 patients who received surgical treatment alone, 5 (55 per cent) had tumors which regressed following the postoperative administration of a progestin (Pig. 5). The tumors of 3 of 11 patients (27 per cent) who were treated with radiation alone responded to progestinal therapy, and those of 7 of 23 patients (30 per cent) who had both irradiation and surgical treatment were considered responsive. One possible explanation of the higher proportion of responsive tumors in the patients who received only surgical treatment is that 2 of the 5 in this group were less
Volume Number
94 7
Progestins
and
endometrial
adenocarcinoma
PRIMARY TREATMENT 43 Ptr.
SURGERY
Fig. with
5. Results obtained with surgery alone, radiation
;;;;;N
RADIATION
!GERY
chemotherapy in 43 patients who had alone, or by a combination of the two
HISTOLOGY
6. Results
obtained
with
chemotherapy
HlSiOLOGlCAl
Fig. 7. Histologic changes observed tained from metastases or recurrences.
in lesions
according
to the
previously
Responders
SQUAMOUS METAPLASIA
PAPILLARY
Fig.
m
been treated methods.
UNDIFF.
histologic
type
of the
lesion.
CHANGES WITH TREATMENT
in
13 patients
in whom
biopsies
could
be ob-
981
982
Smith,
Rutledge,
and
Soffar
than 50 years old. The group who was gi\Tvrl radiotherapy alone included the oldest patients in the series; undoubtedly, their ag’ was a consideration in the choice of treatment. This being true, it is difficult to determine whether the previous treatment of the patient was influential in the outcome of the hormonal medication. Histology of the tumor. The degree of differentiation of the tumors apparently had no bearing upon their responses to a progestin. The Pathology Department of The University of Texas M. D. Anderson Hospital and Tumor Institute does not use Broder’s method of grading adenocarcinoma of the endometrium. Frequently however, such descriptive terms as “papillary adenocarcinoma,” “adenocarcinoma with squamous metaplasia,” and “undifferentiated adenocarcinoma” are used. Thirty-one of the 45 tumors were so described. Of the last two types, 50 per cent responded, while only 3 (23 per cent) of the 13 papillary adenocarcinomas, the most highly differentiated type, regressed under the treatment (Fig. 6). Four of the tumors were graded by the referring pathologists. Two of these, graded as II and III, responded, while 2 which were classified as Grade I did not respond. Histologic changes in tumors incident to treatment. In view of the inaccessibility of the rnetastases and recurrences, biopsies were obtained from those of only 13 patients. Histologic changes were apparent in 3 of 6 unresponsive tumors, and in 5 of the 7 that regressed (Fig. 7). Results As stated previously, in the study of the results, the 3 earliest patients, who received ethisterone and 17a-hydroxyprogesterone caproate, were omitted. Objective response to medroxyprogesterone or AY-62022. Of the 42 patients who were treated with either or both of these agents, 17 (40 per cent) obtained a significant objective response, i.e., their tumors regressed at least 25 per cent for 3 months or longer. This group included 3 pa-
0 25 80 76 too Fig. 8. Objective response of tumors to medroxyprogesterone obtained in 17 of 42 patients. tients whose disease was classified as arrested because of their prolonged survival, although their tumors could not be measured. Two of the 3 had metastases in the intraabdominal lymph nodes, and one had metastases in the greater omentum. The tumors of 2 other patients were arrested for 10 to 12 months. Thus, the disease of 19 patients, or 45.2 per cent of the 42, exhibited a clinical response. Since 3 patients had a second lesion which regressed, they are included twice in the graph (Fig. 8). Subjective responses to medroxyprogesterone or AY-62022. With one exception, all of the 17 patients whose tumors regressed obtained an excellent subjective response to the progestational therapy. Of the 25 patients whose tumors failed to regress, 14 obtained an excellent subjective response until their disease entered the preterminal phase. Twelve of the 14 were rated 100 and 2 were rated at 80 on the Karnofsky scale.s Duration of control. The duration of the objective responses varied from 3 to 42 months, the average being 16.3 months. All of the 8 patients who obtained objective remissions lasting 9 months continued to live for a total of more than 2 years after treatment, and 7 of the 8 are still alive 2 to 3’/2 years after treatment. Duration of survival. The 17 patients with tumors which regressed under progestational therapy have survived for 4 to 42 months after treatment, the mean survival being 18 months (Fig. 9). The 3 patients with intraabdominal metastases are still living without apparent disease more than 2 years after initiation of the treatment. The 2 patients
Volume Number
94 7
Progestins
and
endometrial
adenocarcinoma
983
MONTHS
Fig. 9. Duration of survival of patients with advanced endometrial treated by chemotherapy. whose tumors were arrested for 10 and 12 months survived 14 and 21 months, respectively, after treatment. Comment The mechanism whereby the progestins affect adenocarcinoma of the endometrium is unknown. They induce maturation of normal and even hyperplastic endometrium, changing the proliferating cells to mature functional cells. If the treatment is prolonged, the cells become flattened and exhausted, then atrophic, and finally necrotic. In this series of patients, progestins seemed to be most effective in younger women whose endometrium was still, or had only recently ceased to be, under estrogenic Possibly the older women had stimulus. more autonomous tumors, despite the histologic similarity to those of the younger women. It is also possible that the effect of a progestin upon the adenocarcinoma of the endometrium is analogous to that of castration upon carcinoma of the breast. Since the treatment was more effective in younger patients, perhaps adenocarcinoma of the
adenocarcinoma
who were
endometrium, like normal endometrium, requires estrogenic stimulation before it can regress under therapy with a progestin; thus, tumors in older women become less responsive to such treatment as their production of estrogen decreases. The validity of this hypothesis is currently under investigation. The ultimate response of a tumor to a progestational agent is only remotely related to the dosage. Following cessation of an initial regression, a repeated response was induced in an occasional tumor by doubling or tripling the dosage, although the second responses were usually of short duration. The 3 patients whose treatment was changed from medroxyprogesterone to AY-62022 because of increasing growth of the tumor failed to respond to the new agent. The perineal metastases of one patient disappeared after direct injection of medroxyprogesterone into each of the tumors, despite the fact that the metastatic intrapelvic carcinoma had failed to regress under systemic medication with either progestational agent. Side effects. The patients treated with medroxyprogesterone received from 100 mg.
984
Smith,
Rutledge,
and
Soffar
to 2.7 Gm. per week with the majority rcceiving 250 mg. intramuscularly once each week. The total dosage that each patient received depended on the length of survival. The longest surviving patient has received 45.0 Gm. of medroxyprogesterone over a 42 month period of time. The patients treated with AY-62022 received from 40 to 80 mg. per day with the majority receiving 50 mg. to 60 mg. per day in 3 to 5 divided doses. The largest total dosage of AY-62022 given at this time has been 6 Gm. Medroxyprogesterone and AY-62022 have been well tolerated, regardless of dosages. No side effects were apparent in one patient who received 400 mg. of medroxyprogesterone daily. The pituitary, thyroid, adrenal, ovarian, and islet cell functions of several patients have been evaluated before and after the administration of medroxyprogesterone; all of the patients have exhibited evidence of adrenal suppression following 6 weekly doses of 250 mg. each. These aspects will be reported subsequently. Five patients with responsive tumors had side effects which could have been attributable to the medication or to the disease. One patient had nausea, vomiting, and insomnia for 5 days following each weekly injection of medroxyprogesterone. Cataracts developed in the eyes of another patient after weekly injections of 250 mg. of the same drug for 30 months. A third had
edema and retention of fluid in association with injections of 250 mg. of medroxyproaesterone twice weekly. Iliofemoral thrombophlebitis developed in a fourth patient. A fifth patient had pain in the chest and collapse of the upper lobe of one lung with regression of a hilar metastasis; she died a short time later from a myocardial infarction. Summary
Forty-five women with disseminated adenocarcinoma of the endometrium were studied in an attempt to determine the type of patient who could expect a response to treatment with a progestin. Younger patients responded more often, possibly because of the estrogen dependence of these tumors or the effects of prior stimulation of the endometrial cells by estrogen. The response of endometrial adenocarcinema to a progestin seems to be unrelated to its location or any previous treatment of the patient. In this series, 40 per cent of 42 patients who were treated with medroxyprogesterone or AY-62022 obtained an objective response for 3 to 42 months, and 2 others exhibited a significant clinical response of 10 and 12 months. Thus, the tumors of 19, or 45.2 per cent of the group, were favorably affected. Thirty, or 71 per cent of the 42 patients, obtained excellent subjective responses.
REFERENCES
1. Kelley, R. M.: Proceedings of the Second Conference on Steroids and Cancer, Council on Pharmacy and Chemistry, American Medical Association, Chicago, 1951, p. 116. 2. Kennedy, B. J.: J, A. M. A. 184: 758, 1963. 3. Varga, A., and Henriksen, E.: Obst. & Gynec. 22: 129, 1963. 4. Varga, A., and Henriksen, E.: Obst. & Gynec. 18: 668, 1961. 5. Kelley, Rita M., and Baker, W. H.: New England J. Med. 264: 261, 1961.
6.
Kelley, Rita M., and Baker, W. H.: Progress in gynecology, New York, 1963, Grune & Stratton Inc., vol. 4, p. 436. 7. Yahia, Clement, Berirschle, Kurt, and Sturgis, Somers: Progress in gynecology, New York, 1963, Grune & Stratton Inc., vol. 4, p. 410. 8. Karnofsky, D. A., Abelmann, W. H., Craver, L. F., and Burchenal, J. H.: Cancer 1: 634, 1948.
P.
FELIX
SMITH,
RUTLEDGE,
SAUL
W.
SOFFAR,
Houston,
Texas
of patients
adenocarcinoma M.D.* M.D. M.D.
THAT ADENOCARCINOMA of the endometrium may be amenable to control by means of sex steroids was first demonstrated by Kelley,l in 1951. She reported that the tumors in 2 of 3 patients regressed during a course of therapy with progesterone. Several other authors have since described their successful experiences with progestins as a treatment for endometrial hyperplasia and carcinoma. The majority used progesterone or 17a-hydroxyprogesterone caproate for this purpose. Recently, however, other agents have been introduced which are more easily administered and more potent; aho, their endocrine effects are slightly different from those of either progesterone or 17~hydroxyprogesterone caproate (Figs. 1A, lB, and 1C). Since 1959, a progestational agent has been administered to 45 patients for recurrent or metastatic adenocarcinoma of the endometrium at The University of Texas
M. D. Anderson Hospital and Tumor Institute. Among these were 3 patients who were treated between 1959 and 1961, under the direction of the department of medicine; one received ethisterone, while the other 2 received 17a-hydroxyprogesterone caproate. Although these patients failed to respond to the therapy, they are included in this study to add validity to the findings. The 42 patients who had received a progestin for adenocarcinoma of the endometrium, since 1961, have been treated by the gynecology service. Medroxyprogesterone* alone was administered to 35 of the 42 patients, AY62022t alone to 4, and medroxyprogesterone followed by AY-62022 to 3 patients. The records of all 45 patients were reviewed with respect to the clinical findings, although in the evaluation of the results only the 42 patients who have been treated since 1961 were considered. Materials
From the Section of Gynecology, Department of Surgery, The University of Texas M. D. Anderson Hosgital and Tumor Institute. *Advanced by American
and
methods
Factors related to objective progestational therapy. Various *Supplied Kalamazoo, @upplied New York,
Clinical Fellow Sponsored Cancer Society.
977
responses to authors have
by Dr. S. S. Stubbs, The Upjohn Company, Michigan. by Dr. John David Sproul, Ayerst Laboratories, New York.
978
Smith,
Rutledge,
and
Soffar
&:cH3 ETHISTERONE PRANONE 0.3 - 0.5 Index of Endometrial Activity
PROGESTERONE 1 Index of Endomstrial Activity
Fig. 1A. Structural metrial
activity
for
formulas and indexes of endoprogesterone and Pranone.
O~&O-!-(CH2)~
/
6,17 o DtMETHYL 6 DEHYDROGROGESTERONE AY62022 3.0 - 8.0 (owl) Index of Endometrial Activity
C”3
Fig. 1C. Structural metrial
activity
formulas for AY-62022.
and
indexes
of endo-
-CH3&CH3
17 o HYDROXYPROGESTERONE CAPROATE DELALUT’N 0.5 - I.0 Index of Endometriol
CH3
Activity 3.0
Fig. 1B. Structural
/ OH
formulas
and
6 METHYL 170 HYDROXY PROGESTERONE ACETATE PROVERA - 8.0 (oral) Index of Endomatriol
indexes
of endometrial
suggested factors which may influence the responseof disseminated adenocarcinoma of the endometrium to a progestin. Kennedy? observed that the responsivetumors were biologically different from the unresponsive; also, the responsive tumors were present longer before the original treatment was administered, and they recurred later. Varga and Henriksen3, 4 found that the more differentiated tumors which could be changed toward maturation responded most often. Kelley and Baker516 reported that pulmonary metastasesresponded most often, and pelvic tumors which recurred after irradiation responded poorly. In this review, the responseto treatment was correlated with age, race, parity, the age at menopause, the size and duration of the tumor, the sites of metastasesor recurrences, the presence of the “corpus cancer syndrome,” the type. of treatment, and the histologic features of the tumor before and after treatment. Age of patient. This seemed to be the single most influential factor in the responses of the tumors to progestational therapy (Fig. 2). The mean age of the patients
Activity
activity
for
Delalutin
and
Provera.
whose tumors regressedwas 57.4 years and the group whose tumors failed to respond was 63.7 years. The tumors of 4 out of 5 patients who were lessthan 50 years old regressedto a significant degree, whereas the tumor of only one of 7 patients over 70 years exhibited a response. Race of patient. Thirty-two of the 45 patients were Caucasian and 13 were Negro. Fourteen (43 per cent) of the former obtained a significant responseto treatment, as compared to only 3 (23 per cent) of the latter. Parity of patient. Twenty-two (49 per cent) of the 45 patients were nulliparous. This is the samefigure quoted by Yahia and associates7in the report of his review at the Peter Bent Brigham Hospital. Six of these 22 patients (27 per cent) had responsive tumors, while those of the remaining 16 (73 per cent) exhibited no regression. Age of patient at meuqause. In this respect, the patients with responsive and unresponsive tumors were similar. The menopausal age of the first group varied from 31 to 55 years; the mean age was 46.1 years. Five of the patients were premenopaugal at
Volume Number
94 7
Progestins
15
1
AGES
Fig. 2. Relationship
between
51-M
age of the
86-60
patient
and
(YEARS)
61-66
and
endometrial
c=13 m
66-70
response
979
Rqmdstr Non Rcrpondrrs
71-75
of the
adenocarcinoma
>75
tumor
to progestational
therapy.
the time of their original treatment. The ages of the second group at menopause varied from 32 to 56 years; the mean age was 48.9 years. Six of the latter group were premenopausal at the time of first treatment. Size of the tumor. The response of a tumor to radiotherapy and chemotherapy is believed to be related to its size. Lack of response may be attributable to poor circulation in the center of the tumor, the age of the cells in the center of the tumor, or the fact that the more numerous the cells, the greater the likelihood that some will be resistant. to therapy. The size of the tumors did not seem to influence the results of treatment in this study (Fig. 3). Duration of the tumor. The time which elapses between the appearance of the first symptom to the establishment of the diagnosis of adenocarcinoma of the endometrium is generally related to the degree of malignancy of the tumor. The interval between the appearance of the first symptom and the diagnosis of the malignant tumor in 17 patients with responsive tumors and 25 patients with unresponsive tumors was known. In the first group, this interval varied from one to 96 months; the mean was 17.4 months and the median 7.5 months. In the second group, it varied from one to 100 months; the mean was 14.9 months and the median 7 months. If tumors of a more malignant degree cause a patient to seek medical assistance earlier and less malignant tumors in the same organ system lead them to delay
in consulting a physician, from the clinical standpoint, the tumors of the 2 groups seem to have been of a similar degree of malignancy. The interval between the treatment for the primary tumor and the diagnosis of recurrence or metastasis, likewise, is related to the malignant degree of the tumor. In the patients of this series whose tumors responded to the hormonal therapy, the interval varied from less than one month to 132 months. In the group of unresponsive tumors, the interval varied from one to 72 months. Two of those whose tumors responded had recurrences 10 and 11 years after the original treatment. If these 2 were excluded, the mean interval in the responsive and the unresponsive tumors would be similar, i.e., 16.4 and 15.4 months, respectively. Eight of each group had disseminated cancer at the time of their first treatment. From these observations, the responses of recurrent or metastatic carcinoma to a progestin does not depend upon the interval which elapses between the initial treatment and their appearance. Sites of the disease. The sites of the metastases or recurrences apparently had no bearing upon the results of treatment of these patients (Fig. 4). Sixteen patients had pulmonary metastases; 5 (31 per cent) responded to the drug. A regression of clinically apparent intra-abdominal or intrapelvie disease, or both, was exhibited in 11 of 32 patients (34 per cent). Six of the 11 had
980
Smith,
Rutledge,
and
Soffar
SIZE OF LESION IN CM
<2
Fig.
3. Relationship
between
tumor
5-10
2-5
size and results
> IO
of chemotherapy.
20
5
LUNGS
Fig.
4. Relationship
between
sites
of metastases
received radiotherapy alone or in addition to surgical treatment. Hormonal medication administered to one patient subsequent to irradiation alone brought about regression of pulmonary metastases, although no change in the pelvic recurrence was noted. The “corpus cancer syndrome.” In discussing the etiology of adenocarcinoma of the endometrium, the high incidence of associated obesity, hypertension, and diabetes is often mentioned as evidence of an endocrine imbalance. Yahia and co-workers7 used the term “corpus cancer syndrome” to describe these combined states. Of 26 patients in this series who weighed more than 150 pounds, 11 (42 per cent) had responsive tumors, as did 8 (32 per cent) of the 25 patients with a blood pressure above 150/100, and 4 of the 7 diabetic patients (57 per cent).
ABD. 6 PELVIS
or
recurrences
NODES
and
results
of chemotherapy.
Type of previous therapy. Previously irradiated tumors are frequently resistant to chemotherapy. Kelley and Bake?, G observed that irradiated pelvic recurrences of adenocarcinomas of the endometrium responded poorly to progestational agents. Of 9 patients who received surgical treatment alone, 5 (55 per cent) had tumors which regressed following the postoperative administration of a progestin (Pig. 5). The tumors of 3 of 11 patients (27 per cent) who were treated with radiation alone responded to progestinal therapy, and those of 7 of 23 patients (30 per cent) who had both irradiation and surgical treatment were considered responsive. One possible explanation of the higher proportion of responsive tumors in the patients who received only surgical treatment is that 2 of the 5 in this group were less
Volume Number
94 7
Progestins
and
endometrial
adenocarcinoma
PRIMARY TREATMENT 43 Ptr.
SURGERY
Fig. with
5. Results obtained with surgery alone, radiation
;;;;;N
RADIATION
!GERY
chemotherapy in 43 patients who had alone, or by a combination of the two
HISTOLOGY
6. Results
obtained
with
chemotherapy
HlSiOLOGlCAl
Fig. 7. Histologic changes observed tained from metastases or recurrences.
in lesions
according
to the
previously
Responders
SQUAMOUS METAPLASIA
PAPILLARY
Fig.
m
been treated methods.
UNDIFF.
histologic
type
of the
lesion.
CHANGES WITH TREATMENT
in
13 patients
in whom
biopsies
could
be ob-
981
982
Smith,
Rutledge,
and
Soffar
than 50 years old. The group who was gi\Tvrl radiotherapy alone included the oldest patients in the series; undoubtedly, their ag’ was a consideration in the choice of treatment. This being true, it is difficult to determine whether the previous treatment of the patient was influential in the outcome of the hormonal medication. Histology of the tumor. The degree of differentiation of the tumors apparently had no bearing upon their responses to a progestin. The Pathology Department of The University of Texas M. D. Anderson Hospital and Tumor Institute does not use Broder’s method of grading adenocarcinoma of the endometrium. Frequently however, such descriptive terms as “papillary adenocarcinoma,” “adenocarcinoma with squamous metaplasia,” and “undifferentiated adenocarcinoma” are used. Thirty-one of the 45 tumors were so described. Of the last two types, 50 per cent responded, while only 3 (23 per cent) of the 13 papillary adenocarcinomas, the most highly differentiated type, regressed under the treatment (Fig. 6). Four of the tumors were graded by the referring pathologists. Two of these, graded as II and III, responded, while 2 which were classified as Grade I did not respond. Histologic changes in tumors incident to treatment. In view of the inaccessibility of the rnetastases and recurrences, biopsies were obtained from those of only 13 patients. Histologic changes were apparent in 3 of 6 unresponsive tumors, and in 5 of the 7 that regressed (Fig. 7). Results As stated previously, in the study of the results, the 3 earliest patients, who received ethisterone and 17a-hydroxyprogesterone caproate, were omitted. Objective response to medroxyprogesterone or AY-62022. Of the 42 patients who were treated with either or both of these agents, 17 (40 per cent) obtained a significant objective response, i.e., their tumors regressed at least 25 per cent for 3 months or longer. This group included 3 pa-
0 25 80 76 too Fig. 8. Objective response of tumors to medroxyprogesterone obtained in 17 of 42 patients. tients whose disease was classified as arrested because of their prolonged survival, although their tumors could not be measured. Two of the 3 had metastases in the intraabdominal lymph nodes, and one had metastases in the greater omentum. The tumors of 2 other patients were arrested for 10 to 12 months. Thus, the disease of 19 patients, or 45.2 per cent of the 42, exhibited a clinical response. Since 3 patients had a second lesion which regressed, they are included twice in the graph (Fig. 8). Subjective responses to medroxyprogesterone or AY-62022. With one exception, all of the 17 patients whose tumors regressed obtained an excellent subjective response to the progestational therapy. Of the 25 patients whose tumors failed to regress, 14 obtained an excellent subjective response until their disease entered the preterminal phase. Twelve of the 14 were rated 100 and 2 were rated at 80 on the Karnofsky scale.s Duration of control. The duration of the objective responses varied from 3 to 42 months, the average being 16.3 months. All of the 8 patients who obtained objective remissions lasting 9 months continued to live for a total of more than 2 years after treatment, and 7 of the 8 are still alive 2 to 3’/2 years after treatment. Duration of survival. The 17 patients with tumors which regressed under progestational therapy have survived for 4 to 42 months after treatment, the mean survival being 18 months (Fig. 9). The 3 patients with intraabdominal metastases are still living without apparent disease more than 2 years after initiation of the treatment. The 2 patients
Volume Number
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Progestins
and
endometrial
adenocarcinoma
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Fig. 9. Duration of survival of patients with advanced endometrial treated by chemotherapy. whose tumors were arrested for 10 and 12 months survived 14 and 21 months, respectively, after treatment. Comment The mechanism whereby the progestins affect adenocarcinoma of the endometrium is unknown. They induce maturation of normal and even hyperplastic endometrium, changing the proliferating cells to mature functional cells. If the treatment is prolonged, the cells become flattened and exhausted, then atrophic, and finally necrotic. In this series of patients, progestins seemed to be most effective in younger women whose endometrium was still, or had only recently ceased to be, under estrogenic Possibly the older women had stimulus. more autonomous tumors, despite the histologic similarity to those of the younger women. It is also possible that the effect of a progestin upon the adenocarcinoma of the endometrium is analogous to that of castration upon carcinoma of the breast. Since the treatment was more effective in younger patients, perhaps adenocarcinoma of the
adenocarcinoma
who were
endometrium, like normal endometrium, requires estrogenic stimulation before it can regress under therapy with a progestin; thus, tumors in older women become less responsive to such treatment as their production of estrogen decreases. The validity of this hypothesis is currently under investigation. The ultimate response of a tumor to a progestational agent is only remotely related to the dosage. Following cessation of an initial regression, a repeated response was induced in an occasional tumor by doubling or tripling the dosage, although the second responses were usually of short duration. The 3 patients whose treatment was changed from medroxyprogesterone to AY-62022 because of increasing growth of the tumor failed to respond to the new agent. The perineal metastases of one patient disappeared after direct injection of medroxyprogesterone into each of the tumors, despite the fact that the metastatic intrapelvic carcinoma had failed to regress under systemic medication with either progestational agent. Side effects. The patients treated with medroxyprogesterone received from 100 mg.
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Rutledge,
and
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to 2.7 Gm. per week with the majority rcceiving 250 mg. intramuscularly once each week. The total dosage that each patient received depended on the length of survival. The longest surviving patient has received 45.0 Gm. of medroxyprogesterone over a 42 month period of time. The patients treated with AY-62022 received from 40 to 80 mg. per day with the majority receiving 50 mg. to 60 mg. per day in 3 to 5 divided doses. The largest total dosage of AY-62022 given at this time has been 6 Gm. Medroxyprogesterone and AY-62022 have been well tolerated, regardless of dosages. No side effects were apparent in one patient who received 400 mg. of medroxyprogesterone daily. The pituitary, thyroid, adrenal, ovarian, and islet cell functions of several patients have been evaluated before and after the administration of medroxyprogesterone; all of the patients have exhibited evidence of adrenal suppression following 6 weekly doses of 250 mg. each. These aspects will be reported subsequently. Five patients with responsive tumors had side effects which could have been attributable to the medication or to the disease. One patient had nausea, vomiting, and insomnia for 5 days following each weekly injection of medroxyprogesterone. Cataracts developed in the eyes of another patient after weekly injections of 250 mg. of the same drug for 30 months. A third had
edema and retention of fluid in association with injections of 250 mg. of medroxyproaesterone twice weekly. Iliofemoral thrombophlebitis developed in a fourth patient. A fifth patient had pain in the chest and collapse of the upper lobe of one lung with regression of a hilar metastasis; she died a short time later from a myocardial infarction. Summary
Forty-five women with disseminated adenocarcinoma of the endometrium were studied in an attempt to determine the type of patient who could expect a response to treatment with a progestin. Younger patients responded more often, possibly because of the estrogen dependence of these tumors or the effects of prior stimulation of the endometrial cells by estrogen. The response of endometrial adenocarcinema to a progestin seems to be unrelated to its location or any previous treatment of the patient. In this series, 40 per cent of 42 patients who were treated with medroxyprogesterone or AY-62022 obtained an objective response for 3 to 42 months, and 2 others exhibited a significant clinical response of 10 and 12 months. Thus, the tumors of 19, or 45.2 per cent of the group, were favorably affected. Thirty, or 71 per cent of the 42 patients, obtained excellent subjective responses.
REFERENCES
1. Kelley, R. M.: Proceedings of the Second Conference on Steroids and Cancer, Council on Pharmacy and Chemistry, American Medical Association, Chicago, 1951, p. 116. 2. Kennedy, B. J.: J, A. M. A. 184: 758, 1963. 3. Varga, A., and Henriksen, E.: Obst. & Gynec. 22: 129, 1963. 4. Varga, A., and Henriksen, E.: Obst. & Gynec. 18: 668, 1961. 5. Kelley, Rita M., and Baker, W. H.: New England J. Med. 264: 261, 1961.
6.
Kelley, Rita M., and Baker, W. H.: Progress in gynecology, New York, 1963, Grune & Stratton Inc., vol. 4, p. 436. 7. Yahia, Clement, Berirschle, Kurt, and Sturgis, Somers: Progress in gynecology, New York, 1963, Grune & Stratton Inc., vol. 4, p. 410. 8. Karnofsky, D. A., Abelmann, W. H., Craver, L. F., and Burchenal, J. H.: Cancer 1: 634, 1948.