- Email: [email protected]
A comparison of medroxyprogesterone serum concentrations by the oral or intramuscular route in patients with persistent or recurrent endometrial carcinoma
GYNECOLOGY
A comparison of medroxyprogesterone serum concentrations by the oral or intramuscular route in patients with persistent or recurrent endometrial carcinoma SANFORD SALL, M.D. PHILIP D1SAIA, M.D. C. PAUL MORROW, M.D. RODRIQUE MORTEL, M.D. KON ALD PREM, M.D. TATE THIGPEN, M.D. WILLIAM CREASMAN, M.D. New York, New York
J
A randomized study, comparing serum medroxyprogesterone concentrations by the oral and intramuscular routes, was performed on 22 patients with persistent or recurrent endometrial adenocarcinoma by six institutions of the Gynecologic Oncology Group. The oral group (11 patients) received cutaneous Provera (medroxyprogesterone), 50 mg three times a day, and the intramuscular group (11 patients) received 300 mg of Depo-Provera (medroxyprogesterone) weekly for at least 2 months. Serum levels were evaluated at 0, 2, 4, 6, 8, 10, and 12 hours after administratiOn and every day for the first week and weekly thereafter for 8 weeks. The mean serum levels (nanograms per mUiiliter) of m~roxyprogesterone in the oral group were consistently higher than the corresponding mean levels of the intramuscular group. In addition, from the first through eighth weeks, the measurements (medians) for the oral group were statisticaUy higher than those for the intramuscular group. Although the study indicates a significant increase in serum levels achieved by the oral route, the follow:up period of patients under study is too early to evaluate its clinical effectiveness as compared to the intramuscular route. (AM. J. OBSTET. GYNECOL. 135:647, 1979.)
IN 1951, Kelly 1 observed regression in two of three patients with endometrial cancer treated with proges-
terone. Since Kistner's 2 first report in 1959, several reports noting the response of endometrial cancer to
From the Department of Obstetrics and Gynecology. New York Medical College.
Received for publication October .J, 1978.
Supported by the following grant awards by the National Cancer Institute, Department of Health, Education, and Welfare: 2 RIO CA 12483,2 RIO CA 13641, 1 RIO CA 16386, 1 RIO CA 23088, 5 RIO CA 13633, and 5 RIO CA 12534.
Accepted December 27, 1978.
0002-9378/79/210647+04$00.40/0
©
1979 The C. V. Mosby Co.
Revised December 5, 1978. Reprint requests: Gynecological Oncology Group Headquarters, 1234 Market St., Suite 430, Philadelphia, Pennsylvania 19107.
647
1111
648
Sail et al.
No\'ember I. 1'17!1
Am . .J. Ob,tet. (;nwcol.
Fig. l. Mean values for oral and intramuscular medroxyprogesterone. - tramuscular.
various synthetic progestins have appeared.a-H The National Cancer Institute has listed progesterone as an ef(ective antineoplastic drug in the treaiment of endometrial cancer. According to Smith and associates, i an objective response (defined in terms of a measureable deerease in tumor mass or metastatic lesions of 25% for 3 months or more) was noted in 17 of 42 patients (40%) when medroxyprogesterone (Provera) was used. Kistner9 noted a 30% to 35% objective remission rate with the same agent. In both of these studies, medroxyprogesterone was delivered intramuscularly in the form of Depo-Provera. Recently, an oral form of medroxyprogesterone (50 mg tablet) has become available. A preliminary study of the blood-level time course of Provera given by the oral and intramuscular routes has strongly suggested that very effective, in fact, higher, serum levels of medroxyprogesterone can be obtained by the oral route rather than the intramuscular form. 10 Since progestational therapy is a commonly used regimen for recurrent or persistent endometrial cancer, the Gynecologic Oncology Group developed a study to: ( l) compare the average serum concentration with the oral and intramuscular administration of medroxyprogesterone acetate; (2) compare the effectiveness of oral Provera versus the intramuscular form of DepoProvera in patients with persistent or recurrent endometrial carcinoma; and (3) establish the oral form of medroxyprogesterone acetate as an effective antineo-
Oral: - - - -
m-
plastic agent in endometrial cancer, similar to its intramuscular form known as Depo-Provera. Material and methods
Twenty-four patients were admitted to the study from six institutions (New·York Medical College, t.:niversity of Southern California, Duke University, University of Mississippi, University of Minnesota, and the M. S. Hershey Medical center of Pennsylvania State University). The Gynecologic Oncology Group Statistical Office provided randomization by means of the closed-envelope technique. The two treatments in this protocol were randomized within institutions in balanced groups of six, with limitations that no more than three consecutive entries should receive the same treatment. Patients randomized to cutaneous Prm era (Regimen A) receiYed a 50 mg tablet of drug three times a day, without interruption for at least 2 months. Patients randomized to intramuscular Depo-Provera (Regimen B) received one 300 mg (3 ml) injection by the intramuscular route weekly for at least 2 months. Eligible for the study were women with advanced adenocarcinoma of the endometrium, either recurrent or persistent, not amenable to surgery or radiation alone. In essence, any patient who had adenocarcinoma of the endometrium and who had a metastatic site not being treated by other modalities and/or a site which was accessible for determining an objective rc-
Volume
IT> :\:umher :'J
Medroxyprogesterone concentrations by oral or intramuscular route
sponse was eligible for the study. Each patient had an estimated 'urvival of at least 2 months, and, if vaginal ndf or pelvic recurrence was noted, no chemotherapy should have been given in the preceding eight weeks. Three milliliters of blood was drawn for both regimen groups at 0, 2, 4, h, 8. 10, and 12 hours after administration on the first day. daily thereafter for the first week. and weekly thereafter for the course of the study. Serum was harvested from all blood samples as soon as po,sihle and frozen. Frozen serum was shipped to The Cpjohn Co. Clinical Laboratories for assays which ,,·ere performed without knowledge of treatment regimen. Of the 24 patients originally randomized to the study, two were judged not evaluable. One died 3 weeks after study entry, and the other patient did not have serum samples obtained at the proper intervals. Results and statistical analysis
Table I indicates the mean value (nanograms per milliliter) at each time point for Regimen A (oral) and Regimen B (intramuscular). All means of the A (oral) group were consistently higher than the corresponding means of the B (intramuscular) group. Review of each case (A and B) in Fig. I indicates that there is an almost constant positive slope with the A cases having a similar slope as the B cases. Since the distribution of the values could not be determined from this small sample, it was not 1alid to test Regimen A versus Regimen B by a t test. Therefore, a nonparametric analysis was employed. There were 11 cases entered into regimen A and 11 cases into Regimen B. When the Mann-Whitney l' test is employed, the sequence of the combined A and B samples gives a U = I. The critical U for a = 0.00 I is J:j (one-tailed t test). Thus, at 12 hours, the measurement~ of the A group are statistically higher than those for the B group. Analysis for later time periods included all cases that had no more than one value missing. For each case, the median (in preference to the mean) was determined. The groups were combined and the Mann-Whitney U test was computed as "0." The critical U for a value of 0.00 I is 6. Thus, for the first through eighth weeks, the measurements for the A group were statistically higher than those for the B group. Comment
Progestational therapy by the intramuscular route has tended to be the initial systemic therapy utilized for
REFERENCES I. Kelly, R. M.: Discussion in: Proceedings of the Second
Conference on Steroids in Cancer, Council on Pharmacy
649
Table I. Mean value at each time point: Oral and intramuscular medroxyprogesterone lntramusrular
Oral Time
2 hr. 4 hr. 6 hr. 8 hr. 10 hr. 12 hr. l wk. 2 wk. 3 wk. 4 wk. 5 wk. 6 wk. 7 wk. 8 wk. 9 wk. 10 wk.
No. of values II II lI
10 II II
9 9 7 7 7 4 4 4 4 4
l
Mean (nglml)
No. of values
25.7 33.0 28.3 42.6 66.6 71.2 128.5 150.9 149.6 156.3 170.0 168.0 167.0 174.2 217.4 183.3
II ll
11 II
11 II II
11 11 11 11 9 ]{)
..,I
..,7I
I
,Wean (nglml)
5.4 6.H 8.6 9.9 9.5 11.2 16.5 24.5 30.8 62.4 46.6 53.3 51.6 58.9 68.2 73.1
persistent or recurrent endometrial adenocarcinoma, but has limited pati~nt acceptability, requires administration by health care provider's, and often necessitates considerable travel to tertiary care centers on a weekly basis. This frequently causes loss of the patient to follow-up and less than optimum chemotherapeutic management. Our results indicate that the oral route of Provera achieves a significantly higher blood level than the intramuscular route at both the 12 hour and H week time periods. This achieved increase in serum levels of Provera, however, may be of a quantitative nature, and its response on the end organ or metastatic tumor may not have a correlative increase in a qualitative effect. Although there is no significant cross-reactivity with the double-antibody radioimmunoassay, as described, with physiologic concentration of naturallv occurring steroids, measured levels may be increased by progestational metabolites. The follow-up period of this study is presently insufficient to compare the clinical effectiveness of oral Provera versus the intramuscular form of DepoProvera in patients with persistent or recurrent endometrial adenocarcinoma. We wish to thank Herbert Rich, Biostatistician at the New York Medical College, for his invaluable assistance in the evaluation and analysis of the data.
and Chemistry, Chicago, 1951, American Medical Association, p. 116. 2. Kistner, R. W.: Histologic effects of progestins on hy-
1111
650
Sail et al. Am.
3. 4. 5.
6. 7.
perplasia and carcinoma-in situ of the endometrium, Cancer 12:1106, 1959. Kelly, R. M., and Baker, W. H.: Progestational agents in the treatment of carcinoma of the endometrium, N. Engl. J Med. 264:216, 1961. Kistner, R. W., and Baginsky, S.: Progestins in endometrial cancer, surg. forum 12:424, 1961. Varga, A., and Henricksen, E.: Clinical and histopathological evaluation of the effect of 17-alpha-hydroxyprogesterone, 17-N-caproate on endometrial cancer, Obstet. Gynecol. 18:658, 1961. Wentz, B. W.: Effect of progestational agents on endometrial hyperplasia and endometrial cancer, Obstet. Gynecol. 24:370, 1964. Smith,]. P., Rutledge, F. N., and Soofar, S.: Progestins in
8. 9. 10. II.
'\ovember I. 1979 Obstet. Gvneml.
J.
the treatment of patients with endometrial adenocarcinoma, AM.]. 0BSTET. GYNECOL. 94:977, 1966. Anderson, D. G.: Management of advanced endometrial adenocarcinoma with medroxyprogesterone, AM. J. ORSTET. GYNECOL. 92:87, 1965. Kistner, R. W.: The Use of Progestins in Obstetrics and Gynecology, Chicago, 1969, Year Book Medical Publishers, Inc., p. 129. Personal communication: The Upjohn Company, C. T. Provera Study, SPSM Protocol No. 369, Kalamazoo, Michigan, 1978. Cornette, J. C., Kirton, K. T., and Duncan, G. W.: Measurement of medroxyprogesterone acetate (Provera) by radioimmunoassay, J Clin. Endocrinol. Metab. 31:459, 1971.
' (
Copyright information
The appearance of a code at the bottom of the first page of an original article in this JouRNAL indicates the copyright owner's consent that copies of the article may be made for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., P.O. Box 765, Schenectady, 1\:. Y. 12301, (518) 374-4430, for copying beyond that permitted by Section 107 or 108 of the U. S. Copyright Law. This consent does not extend to other kinds of copying, s.uch as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale.
'
A comparison of medroxyprogesterone serum concentrations by the oral or intramuscular route in patients with persistent or recurrent endometrial carcinoma SANFORD SALL, M.D. PHILIP D1SAIA, M.D. C. PAUL MORROW, M.D. RODRIQUE MORTEL, M.D. KON ALD PREM, M.D. TATE THIGPEN, M.D. WILLIAM CREASMAN, M.D. New York, New York
J
A randomized study, comparing serum medroxyprogesterone concentrations by the oral and intramuscular routes, was performed on 22 patients with persistent or recurrent endometrial adenocarcinoma by six institutions of the Gynecologic Oncology Group. The oral group (11 patients) received cutaneous Provera (medroxyprogesterone), 50 mg three times a day, and the intramuscular group (11 patients) received 300 mg of Depo-Provera (medroxyprogesterone) weekly for at least 2 months. Serum levels were evaluated at 0, 2, 4, 6, 8, 10, and 12 hours after administratiOn and every day for the first week and weekly thereafter for 8 weeks. The mean serum levels (nanograms per mUiiliter) of m~roxyprogesterone in the oral group were consistently higher than the corresponding mean levels of the intramuscular group. In addition, from the first through eighth weeks, the measurements (medians) for the oral group were statisticaUy higher than those for the intramuscular group. Although the study indicates a significant increase in serum levels achieved by the oral route, the follow:up period of patients under study is too early to evaluate its clinical effectiveness as compared to the intramuscular route. (AM. J. OBSTET. GYNECOL. 135:647, 1979.)
IN 1951, Kelly 1 observed regression in two of three patients with endometrial cancer treated with proges-
terone. Since Kistner's 2 first report in 1959, several reports noting the response of endometrial cancer to
From the Department of Obstetrics and Gynecology. New York Medical College.
Received for publication October .J, 1978.
Supported by the following grant awards by the National Cancer Institute, Department of Health, Education, and Welfare: 2 RIO CA 12483,2 RIO CA 13641, 1 RIO CA 16386, 1 RIO CA 23088, 5 RIO CA 13633, and 5 RIO CA 12534.
Accepted December 27, 1978.
0002-9378/79/210647+04$00.40/0
©
1979 The C. V. Mosby Co.
Revised December 5, 1978. Reprint requests: Gynecological Oncology Group Headquarters, 1234 Market St., Suite 430, Philadelphia, Pennsylvania 19107.
647
1111
648
Sail et al.
No\'ember I. 1'17!1
Am . .J. Ob,tet. (;nwcol.
Fig. l. Mean values for oral and intramuscular medroxyprogesterone. - tramuscular.
various synthetic progestins have appeared.a-H The National Cancer Institute has listed progesterone as an ef(ective antineoplastic drug in the treaiment of endometrial cancer. According to Smith and associates, i an objective response (defined in terms of a measureable deerease in tumor mass or metastatic lesions of 25% for 3 months or more) was noted in 17 of 42 patients (40%) when medroxyprogesterone (Provera) was used. Kistner9 noted a 30% to 35% objective remission rate with the same agent. In both of these studies, medroxyprogesterone was delivered intramuscularly in the form of Depo-Provera. Recently, an oral form of medroxyprogesterone (50 mg tablet) has become available. A preliminary study of the blood-level time course of Provera given by the oral and intramuscular routes has strongly suggested that very effective, in fact, higher, serum levels of medroxyprogesterone can be obtained by the oral route rather than the intramuscular form. 10 Since progestational therapy is a commonly used regimen for recurrent or persistent endometrial cancer, the Gynecologic Oncology Group developed a study to: ( l) compare the average serum concentration with the oral and intramuscular administration of medroxyprogesterone acetate; (2) compare the effectiveness of oral Provera versus the intramuscular form of DepoProvera in patients with persistent or recurrent endometrial carcinoma; and (3) establish the oral form of medroxyprogesterone acetate as an effective antineo-
Oral: - - - -
m-
plastic agent in endometrial cancer, similar to its intramuscular form known as Depo-Provera. Material and methods
Twenty-four patients were admitted to the study from six institutions (New·York Medical College, t.:niversity of Southern California, Duke University, University of Mississippi, University of Minnesota, and the M. S. Hershey Medical center of Pennsylvania State University). The Gynecologic Oncology Group Statistical Office provided randomization by means of the closed-envelope technique. The two treatments in this protocol were randomized within institutions in balanced groups of six, with limitations that no more than three consecutive entries should receive the same treatment. Patients randomized to cutaneous Prm era (Regimen A) receiYed a 50 mg tablet of drug three times a day, without interruption for at least 2 months. Patients randomized to intramuscular Depo-Provera (Regimen B) received one 300 mg (3 ml) injection by the intramuscular route weekly for at least 2 months. Eligible for the study were women with advanced adenocarcinoma of the endometrium, either recurrent or persistent, not amenable to surgery or radiation alone. In essence, any patient who had adenocarcinoma of the endometrium and who had a metastatic site not being treated by other modalities and/or a site which was accessible for determining an objective rc-
Volume
IT> :\:umher :'J
Medroxyprogesterone concentrations by oral or intramuscular route
sponse was eligible for the study. Each patient had an estimated 'urvival of at least 2 months, and, if vaginal ndf or pelvic recurrence was noted, no chemotherapy should have been given in the preceding eight weeks. Three milliliters of blood was drawn for both regimen groups at 0, 2, 4, h, 8. 10, and 12 hours after administration on the first day. daily thereafter for the first week. and weekly thereafter for the course of the study. Serum was harvested from all blood samples as soon as po,sihle and frozen. Frozen serum was shipped to The Cpjohn Co. Clinical Laboratories for assays which ,,·ere performed without knowledge of treatment regimen. Of the 24 patients originally randomized to the study, two were judged not evaluable. One died 3 weeks after study entry, and the other patient did not have serum samples obtained at the proper intervals. Results and statistical analysis
Table I indicates the mean value (nanograms per milliliter) at each time point for Regimen A (oral) and Regimen B (intramuscular). All means of the A (oral) group were consistently higher than the corresponding means of the B (intramuscular) group. Review of each case (A and B) in Fig. I indicates that there is an almost constant positive slope with the A cases having a similar slope as the B cases. Since the distribution of the values could not be determined from this small sample, it was not 1alid to test Regimen A versus Regimen B by a t test. Therefore, a nonparametric analysis was employed. There were 11 cases entered into regimen A and 11 cases into Regimen B. When the Mann-Whitney l' test is employed, the sequence of the combined A and B samples gives a U = I. The critical U for a = 0.00 I is J:j (one-tailed t test). Thus, at 12 hours, the measurement~ of the A group are statistically higher than those for the B group. Analysis for later time periods included all cases that had no more than one value missing. For each case, the median (in preference to the mean) was determined. The groups were combined and the Mann-Whitney U test was computed as "0." The critical U for a value of 0.00 I is 6. Thus, for the first through eighth weeks, the measurements for the A group were statistically higher than those for the B group. Comment
Progestational therapy by the intramuscular route has tended to be the initial systemic therapy utilized for
REFERENCES I. Kelly, R. M.: Discussion in: Proceedings of the Second
Conference on Steroids in Cancer, Council on Pharmacy
649
Table I. Mean value at each time point: Oral and intramuscular medroxyprogesterone lntramusrular
Oral Time
2 hr. 4 hr. 6 hr. 8 hr. 10 hr. 12 hr. l wk. 2 wk. 3 wk. 4 wk. 5 wk. 6 wk. 7 wk. 8 wk. 9 wk. 10 wk.
No. of values II II lI
10 II II
9 9 7 7 7 4 4 4 4 4
l
Mean (nglml)
No. of values
25.7 33.0 28.3 42.6 66.6 71.2 128.5 150.9 149.6 156.3 170.0 168.0 167.0 174.2 217.4 183.3
II ll
11 II
11 II II
11 11 11 11 9 ]{)
..,I
..,7I
I
,Wean (nglml)
5.4 6.H 8.6 9.9 9.5 11.2 16.5 24.5 30.8 62.4 46.6 53.3 51.6 58.9 68.2 73.1
persistent or recurrent endometrial adenocarcinoma, but has limited pati~nt acceptability, requires administration by health care provider's, and often necessitates considerable travel to tertiary care centers on a weekly basis. This frequently causes loss of the patient to follow-up and less than optimum chemotherapeutic management. Our results indicate that the oral route of Provera achieves a significantly higher blood level than the intramuscular route at both the 12 hour and H week time periods. This achieved increase in serum levels of Provera, however, may be of a quantitative nature, and its response on the end organ or metastatic tumor may not have a correlative increase in a qualitative effect. Although there is no significant cross-reactivity with the double-antibody radioimmunoassay, as described, with physiologic concentration of naturallv occurring steroids, measured levels may be increased by progestational metabolites. The follow-up period of this study is presently insufficient to compare the clinical effectiveness of oral Provera versus the intramuscular form of DepoProvera in patients with persistent or recurrent endometrial adenocarcinoma. We wish to thank Herbert Rich, Biostatistician at the New York Medical College, for his invaluable assistance in the evaluation and analysis of the data.
and Chemistry, Chicago, 1951, American Medical Association, p. 116. 2. Kistner, R. W.: Histologic effects of progestins on hy-
1111
650
Sail et al. Am.
3. 4. 5.
6. 7.
perplasia and carcinoma-in situ of the endometrium, Cancer 12:1106, 1959. Kelly, R. M., and Baker, W. H.: Progestational agents in the treatment of carcinoma of the endometrium, N. Engl. J Med. 264:216, 1961. Kistner, R. W., and Baginsky, S.: Progestins in endometrial cancer, surg. forum 12:424, 1961. Varga, A., and Henricksen, E.: Clinical and histopathological evaluation of the effect of 17-alpha-hydroxyprogesterone, 17-N-caproate on endometrial cancer, Obstet. Gynecol. 18:658, 1961. Wentz, B. W.: Effect of progestational agents on endometrial hyperplasia and endometrial cancer, Obstet. Gynecol. 24:370, 1964. Smith,]. P., Rutledge, F. N., and Soofar, S.: Progestins in
8. 9. 10. II.
'\ovember I. 1979 Obstet. Gvneml.
J.
the treatment of patients with endometrial adenocarcinoma, AM.]. 0BSTET. GYNECOL. 94:977, 1966. Anderson, D. G.: Management of advanced endometrial adenocarcinoma with medroxyprogesterone, AM. J. ORSTET. GYNECOL. 92:87, 1965. Kistner, R. W.: The Use of Progestins in Obstetrics and Gynecology, Chicago, 1969, Year Book Medical Publishers, Inc., p. 129. Personal communication: The Upjohn Company, C. T. Provera Study, SPSM Protocol No. 369, Kalamazoo, Michigan, 1978. Cornette, J. C., Kirton, K. T., and Duncan, G. W.: Measurement of medroxyprogesterone acetate (Provera) by radioimmunoassay, J Clin. Endocrinol. Metab. 31:459, 1971.
' (
Copyright information
The appearance of a code at the bottom of the first page of an original article in this JouRNAL indicates the copyright owner's consent that copies of the article may be made for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., P.O. Box 765, Schenectady, 1\:. Y. 12301, (518) 374-4430, for copying beyond that permitted by Section 107 or 108 of the U. S. Copyright Law. This consent does not extend to other kinds of copying, s.uch as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale.
'