- Email: [email protected]
Methotrexate therapy of metastatic choriocarcinoma
METHOTREXATE THERAPY CHORIOCARCINOMA
OF METASTATIC JAMES F. HOLLAND, M.D., BUFFALO,N.Y.
(From
Medicine
A Service,
Roswell
Park
Memorial
Institute)
arising in the products of conception is a highly Death usually follows shortly upon the appearance of spontaneous remissions have been disseminated metastatic disease. Although reported, and often cited, they do not occur with regularity. Further, it is not certain how many patients with remissions really had chorioadenoma Choriocarcinoma destruens, a neoplastic disease with more favorable outlook. Remissions in disseminated choriois commonly refractory to x-irradiation. carcinoma after the use of testosterone propionate,l mechlorethamine (nitrogen mustard) ,2 and urethane3 have been reported, although the data, follow-up, and isolated experiences do not allow appraisal of the therapeutic effect of these drugs. the use of Methotrexate” Recently, Li, Hertz, and Spencer* reported (Amethopterin) in 2 patients for choriocarcinoma with pulmonary metastases. A third patient with chorioadenoma destruens was treated in similar fashion. Remarkable improvement was noted in each patient. Substantially elevated titers of urinary chorionic gonadotrophin were reduced progressively to levels near vanishing. Metastatic nodules in the lungs diminished greatly. The method of administration of Methotrexate to Li’s patients was unconventional, when judged by ordinary doses of this folic acid antagonist for patients with acute leukemia. Studies of Boldin measuring the therapeutic effect in mouse leukemia, and of Condit? measuring conversion of folic acid to folinic acid in man afford experimental basis for interrupted large-dose folic acid antagonist treatment. In Li’s patients, initial intravenous loading doses of Methotrexate were followed by repetitive oral courses of 3 to 5 days’ duration at a dosage of 25 mg. daily. The daily oral dose was thus 5 to 10 times the average adult dose used in acute leukemia, and the treatment was administered in an interrupted fashion. The subject of this case report is a woman with choriocarcinoma treated by a method similar to that Li has reported. The very favorable response in this case, the third successive choriocarcinoma to be benefited by the regimen, after Li’s 2 cases, supports the interpretation that a true drug effect has been observed. Since this patient was treated, Li has observed another woman with choriocarcinoma who responded favorably.7
CHORIOCARCINOMA malignant tumor.
*Methotrexate manufactured N. Y.
by
is the trade name Lederle Laboratories
for 4-amino-N-lo-methyl-pteroylglutamic Division, American Cyanamid
195
Company,
acid Pearl
and is River,
196
HOLLAND
Case Report S. 8. is a 33.year-old white married Memorial Institute for choriocarcinomatous
woman who was referred metastases to the lungs.
to the
Roswell
Park
Her first pregnancy in 1953 resulted in a stillborn infant at 7 months. A normal girl was born in 1954. On Sept. 11, 1956, a normal boy was delivered. During the course of this third pregnancy she noted intermittent vaginal bleeding, and in the postpartum period repeated vaginal hemorrhages. Abdominal pain appeared. Three liters of blood were given for continuing severe hemorrhage. A curettage was performed and the curettings were interpreted as choriocarcinoma. A total hysterectomy with salpingo-oophorectomy was performed 45 days after delivery on Oct. 26, 1956. A submucosal tumor 3 cm. in diameter Interpretation of slides from this speciinfiltrating the posterior uterine wall was present. men confirmed the diagnosis of choriocarcinoma. No villi were seen. This material has been reviewed and the diagnosis substantiated by the Armed Forces Institute of Pathology.
12gm. -.j__HGB. .~.-_y__o,o-Ic--~----~---~-Ogm.
Y-“-y”--
----So,\.‘-..,-..,
- 4%
I.000 7,000 3,000
GONADOTROPHIN
NOV.
7
Fig.
NOV.
NOV.
in
hematological Methotrexate. and white
1 .-Changes
Ii’
27
DEC.
DEC
7
17
blood
I
I
I
I
DEC.
JAN.
JAN.
JAN.
FEB
27
6
16
26
5
values and urinary Arithmetic scales cells at right.
gonadotrophin for platelets Semilogarithmic
and
I during treatment retioulocytes are s&e for gonado-
A chest x-ray disclosed multiple lesions characteristic of hematogenous metastases. At this time she was transferred to the Medicine A Service, Roswell Park Memorial Institute. On admission, on Nov. 7, 1956, no information of importance other than the present illness was elicited. She did not cough; there was no pain; she was ambulatory in so far as her postoperative condition permitted; her weight was constant at 75 kilograms (165 pounds). Physical examination disclosed no abnormalities except for a healing hysterectomy scar and a pelvic mass.” At the apex of the vaginal vault on the left side a mass was felt which measured 5 to 6 cm. in diameter. It was not certain whether this mass was a postoperative hematoma or recrudescent tumor. Urinalysis disclosed bacteriuria, pyuria, and proteinuris. A urine culture showed innumerable colonies of E. coU. The abnormal urine findings disappeared without specific antibacterial treatment. who
*I am rendered
indebted to gynecological
Dr.
Raymond consultation.
Mitchell,
who
brought
this
patient
to my
attention,
and
Volume Number
75
1
METHOTREXATE
THERAPY
OF
METASTATIC
CHORIOCAR~CINOMA
197
The hemoglobin concentrations, white blood cell, platelet, and reticulocyte counts are gonadotrophin* in the pretreatment period fell shown in Fig. 1. The levels of chorionic from a titer in excess of 100,000 to a plateau at more than 10,000 but less than 25,000 M.U. Progressive increase in the size of pulmonary lesions before treatment is seen in Figs. 2 and 3.
Fig. 7,
2.
2.-Nov.
1956.
Fig.
3.-Nov.
23, 1956.
Fig. Fig.
4.-Jan. 5.-May
10, 1957. 9, 1957.
Fig.
ond
Fig.
On
Fig.
Methotrexate day a small *The
Beginning
of
treatment.
4.
Fig. After After
third sixth
course course
of of
titers
were
performed
in
5.
Methotrexate. Methotrexate.
administration was begun at 25 mg. given vesicle was seen on the tongue, but this was
gonadotrophin
3.
admission.
the
laboratories
once per evanescent of
Dr.
day. and Roy
After the secatypical. The Hertz.
tlrug was restarted 12-i mg. in 6 days,
on t,he foIloTt-ing da,v. whereas all subsequent
The first course of Methotrexate courses were 125 mg. in 5 days.
therefore
was
I)uring
the course of administration, progressive (liminution in the pulmon:~ry lesions (Figs. 3 ant1 5). The mass detected on pelvic examination lwcame smsller nncl, on Feb. 15, 1957, was no longer i~lentifiable. A chorionic gonadotrophin titer obtainr(l after tho first course of the drug showed a fall from her pretreatment, level to less than 100 bl.l.., a normal value in the oophorectomizetl woman. Subsequent titers hare all been normal. L4ccompan;ring the administration of ,Methotrexate was eTillence of drug eRect ou the patient distinct from the effects on her tumor. A progressive fall in platelet count was noted. On two occasions the reticulocyte count dropped below 1 per cent, but at other times was well maintained. No important change in hemoglobin or leukocyte convf,ntrations ~vvxs seen. After each course of drug administration other evidence of toxicity was apparent. StaIting with the first course, ulceration of the buccal, lingual. sell pharyngeal mucosa appeared (excluding the equivocal lesion during the first course) as early as one flit>- afttv a course of administration, ant1 new lesions appeared as late as Ii (lay-s. Abdominal crampa, frequent defecation, and diarrhea began during the last days of treatment courses au11 perFisted 3 to 6 days, starting with the secon(l course. Folliculitis around the hair roots at the nape of the neck appearetl at t,he enI1 of the treatment courses, beginning a-i th the third course. Snal pruritus and dermatitis of the auditory canal were seen on isolate11 occasions The toxic 1Psions in the mouth were more severs. COW lfter allministration of the ~Irug. linuell to appear for several more clays. anI1 persisted longer after the later courses. SO toxic effect on the liver or kidneys was noted. The patient remains in remarkabl>goocl health (September 1,5, 1957 ). TIIPW is no l%viTV plan to adminirt,cr Methotresate repeatedly at intwvals drncv of tumor in lungs or pelvis. in an attempt to continue thra suppresof 30 to 60 days, (lependent on rvi(lenrca of toxicity, sion of thv tumor, if any remains.
waH
noted
Comment The administra,tion of hIcthotrcsate in this patient was associated with unequivocal remission of metastases from choriocarcinoma. A return to notima1 in urinary chorionic gonadotrophin titers was also seen. Li and his collaborator+ 7 have reported 3 cases of choriocarcinoma and une of chorioadenoma tlrstruens which responded equally dramatically. The fact that this patient is one of 4 who had choriocarciaoma, similarly treated, who have had remissions after Methotrexate administration, fortifies the impression that the responses have not, occurred by chance. It seems highly likely that several pa.tients with choriocarcinoma have bran treated with folic acid antagonists according to conventional dose regim(lns, because the effects of these xntimetabolites on the products of conception have been stressed. Such an c>xpcrience has not been found in a brief survey of the literature, however, and it is probable that, had impressive remissions occurred, they would have been reported. Whether it is the large-dose intermit,tcnt Methotrexate treatment that caused the remission in our patient, whether it is a hitherto unrecognized propensity of this neoplasm, or whether both. situat.ions must obtain cannot at this time be stated. It, has not yet been cstablishcd that the dosage regimen described by Li and used here is optimal. One can only declare pragmatically that it has worked repeatedly. In the absence of renal insufficiency, pre-existent hematopoictic tlepression, and cachesia. the doses &scribed may be given cautiously
L-‘,lrlme
ii
N11nher I
JIETHOTREXATE
THERAPY
OF
METlZHTATLC
CHORIOCARCINOMA
I$)!)
unclw daily supervision. F’or this patient, toxicity has been n~oclerately were but not life threatening. In 2 of 8 other patients with metastatic carcinoma from various other sites treated in similar fashion, howcrcr, profound toxicity evidenced by pancytopenia and ulceration of the alimentary canal was present at the time of death.s Further experience and cautious trial will be required before the best method of Methotrcsatc administration is established.
Summary A patient with choriocarcinoma estcnsircly metastatic to the lungs (and probably pelvis) 1 with elevatd urinary gonadotropin titers, has been treated with Methotresate. The drug was administered orally in intermittent highclose CoLIrscs. Regression of tumor masses and fall of gonadotrophin escretion followed. This expcriclnce confirms that reported by Li, Hertz, and Spencer.4
References 1. 9. 3. 4. 5.
Duffy, B. A.: AM. J. 0~s~. & GTR’EC. 69: S!!S, 1955. Andersqn, H. E., Bisgard, .J. D., and Greene, A. M.: A. M. A. Srch. Surg. 68: 529, 1954. DiPaola, G., Lopez Biel, R., and Open, M. M.: Obst. y ginec. latino-am. 13: 368,1955. Li, M. C., Hertz, R., and Spencer, D. B.: Proc. Sot. Exper. Biol. & Med. 93: 361, 1956. Goldin, A., Mantel, N., Greenhouse, 8. W., Venllitti, J. M., ant1 Humphreys, R. R. Cancer Res. 14: 311, 1954. Proc. Am. A. Cancer Res. 2: 194, 1957. 6. Condit, P. T.: 7. Li, M. C., Spencer, D. B., Hertz, R., and Lubs, H. A.: Proc. Am. A. Cancer Res. 2: 326, 1957. S. Holland, .J. F.: Pnpublished observation:;.
OF METASTATIC JAMES F. HOLLAND, M.D., BUFFALO,N.Y.
(From
Medicine
A Service,
Roswell
Park
Memorial
Institute)
arising in the products of conception is a highly Death usually follows shortly upon the appearance of spontaneous remissions have been disseminated metastatic disease. Although reported, and often cited, they do not occur with regularity. Further, it is not certain how many patients with remissions really had chorioadenoma Choriocarcinoma destruens, a neoplastic disease with more favorable outlook. Remissions in disseminated choriois commonly refractory to x-irradiation. carcinoma after the use of testosterone propionate,l mechlorethamine (nitrogen mustard) ,2 and urethane3 have been reported, although the data, follow-up, and isolated experiences do not allow appraisal of the therapeutic effect of these drugs. the use of Methotrexate” Recently, Li, Hertz, and Spencer* reported (Amethopterin) in 2 patients for choriocarcinoma with pulmonary metastases. A third patient with chorioadenoma destruens was treated in similar fashion. Remarkable improvement was noted in each patient. Substantially elevated titers of urinary chorionic gonadotrophin were reduced progressively to levels near vanishing. Metastatic nodules in the lungs diminished greatly. The method of administration of Methotrexate to Li’s patients was unconventional, when judged by ordinary doses of this folic acid antagonist for patients with acute leukemia. Studies of Boldin measuring the therapeutic effect in mouse leukemia, and of Condit? measuring conversion of folic acid to folinic acid in man afford experimental basis for interrupted large-dose folic acid antagonist treatment. In Li’s patients, initial intravenous loading doses of Methotrexate were followed by repetitive oral courses of 3 to 5 days’ duration at a dosage of 25 mg. daily. The daily oral dose was thus 5 to 10 times the average adult dose used in acute leukemia, and the treatment was administered in an interrupted fashion. The subject of this case report is a woman with choriocarcinoma treated by a method similar to that Li has reported. The very favorable response in this case, the third successive choriocarcinoma to be benefited by the regimen, after Li’s 2 cases, supports the interpretation that a true drug effect has been observed. Since this patient was treated, Li has observed another woman with choriocarcinoma who responded favorably.7
CHORIOCARCINOMA malignant tumor.
*Methotrexate manufactured N. Y.
by
is the trade name Lederle Laboratories
for 4-amino-N-lo-methyl-pteroylglutamic Division, American Cyanamid
195
Company,
acid Pearl
and is River,
196
HOLLAND
Case Report S. 8. is a 33.year-old white married Memorial Institute for choriocarcinomatous
woman who was referred metastases to the lungs.
to the
Roswell
Park
Her first pregnancy in 1953 resulted in a stillborn infant at 7 months. A normal girl was born in 1954. On Sept. 11, 1956, a normal boy was delivered. During the course of this third pregnancy she noted intermittent vaginal bleeding, and in the postpartum period repeated vaginal hemorrhages. Abdominal pain appeared. Three liters of blood were given for continuing severe hemorrhage. A curettage was performed and the curettings were interpreted as choriocarcinoma. A total hysterectomy with salpingo-oophorectomy was performed 45 days after delivery on Oct. 26, 1956. A submucosal tumor 3 cm. in diameter Interpretation of slides from this speciinfiltrating the posterior uterine wall was present. men confirmed the diagnosis of choriocarcinoma. No villi were seen. This material has been reviewed and the diagnosis substantiated by the Armed Forces Institute of Pathology.
12gm. -.j__HGB. .~.-_y__o,o-Ic--~----~---~-Ogm.
Y-“-y”--
----So,\.‘-..,-..,
- 4%
I.000 7,000 3,000
GONADOTROPHIN
NOV.
7
Fig.
NOV.
NOV.
in
hematological Methotrexate. and white
1 .-Changes
Ii’
27
DEC.
DEC
7
17
blood
I
I
I
I
DEC.
JAN.
JAN.
JAN.
FEB
27
6
16
26
5
values and urinary Arithmetic scales cells at right.
gonadotrophin for platelets Semilogarithmic
and
I during treatment retioulocytes are s&e for gonado-
A chest x-ray disclosed multiple lesions characteristic of hematogenous metastases. At this time she was transferred to the Medicine A Service, Roswell Park Memorial Institute. On admission, on Nov. 7, 1956, no information of importance other than the present illness was elicited. She did not cough; there was no pain; she was ambulatory in so far as her postoperative condition permitted; her weight was constant at 75 kilograms (165 pounds). Physical examination disclosed no abnormalities except for a healing hysterectomy scar and a pelvic mass.” At the apex of the vaginal vault on the left side a mass was felt which measured 5 to 6 cm. in diameter. It was not certain whether this mass was a postoperative hematoma or recrudescent tumor. Urinalysis disclosed bacteriuria, pyuria, and proteinuris. A urine culture showed innumerable colonies of E. coU. The abnormal urine findings disappeared without specific antibacterial treatment. who
*I am rendered
indebted to gynecological
Dr.
Raymond consultation.
Mitchell,
who
brought
this
patient
to my
attention,
and
Volume Number
75
1
METHOTREXATE
THERAPY
OF
METASTATIC
CHORIOCAR~CINOMA
197
The hemoglobin concentrations, white blood cell, platelet, and reticulocyte counts are gonadotrophin* in the pretreatment period fell shown in Fig. 1. The levels of chorionic from a titer in excess of 100,000 to a plateau at more than 10,000 but less than 25,000 M.U. Progressive increase in the size of pulmonary lesions before treatment is seen in Figs. 2 and 3.
Fig. 7,
2.
2.-Nov.
1956.
Fig.
3.-Nov.
23, 1956.
Fig. Fig.
4.-Jan. 5.-May
10, 1957. 9, 1957.
Fig.
ond
Fig.
On
Fig.
Methotrexate day a small *The
Beginning
of
treatment.
4.
Fig. After After
third sixth
course course
of of
titers
were
performed
in
5.
Methotrexate. Methotrexate.
administration was begun at 25 mg. given vesicle was seen on the tongue, but this was
gonadotrophin
3.
admission.
the
laboratories
once per evanescent of
Dr.
day. and Roy
After the secatypical. The Hertz.
tlrug was restarted 12-i mg. in 6 days,
on t,he foIloTt-ing da,v. whereas all subsequent
The first course of Methotrexate courses were 125 mg. in 5 days.
therefore
was
I)uring
the course of administration, progressive (liminution in the pulmon:~ry lesions (Figs. 3 ant1 5). The mass detected on pelvic examination lwcame smsller nncl, on Feb. 15, 1957, was no longer i~lentifiable. A chorionic gonadotrophin titer obtainr(l after tho first course of the drug showed a fall from her pretreatment, level to less than 100 bl.l.., a normal value in the oophorectomizetl woman. Subsequent titers hare all been normal. L4ccompan;ring the administration of ,Methotrexate was eTillence of drug eRect ou the patient distinct from the effects on her tumor. A progressive fall in platelet count was noted. On two occasions the reticulocyte count dropped below 1 per cent, but at other times was well maintained. No important change in hemoglobin or leukocyte convf,ntrations ~vvxs seen. After each course of drug administration other evidence of toxicity was apparent. StaIting with the first course, ulceration of the buccal, lingual. sell pharyngeal mucosa appeared (excluding the equivocal lesion during the first course) as early as one flit>- afttv a course of administration, ant1 new lesions appeared as late as Ii (lay-s. Abdominal crampa, frequent defecation, and diarrhea began during the last days of treatment courses au11 perFisted 3 to 6 days, starting with the secon(l course. Folliculitis around the hair roots at the nape of the neck appearetl at t,he enI1 of the treatment courses, beginning a-i th the third course. Snal pruritus and dermatitis of the auditory canal were seen on isolate11 occasions The toxic 1Psions in the mouth were more severs. COW lfter allministration of the ~Irug. linuell to appear for several more clays. anI1 persisted longer after the later courses. SO toxic effect on the liver or kidneys was noted. The patient remains in remarkabl>goocl health (September 1,5, 1957 ). TIIPW is no l%viTV plan to adminirt,cr Methotresate repeatedly at intwvals drncv of tumor in lungs or pelvis. in an attempt to continue thra suppresof 30 to 60 days, (lependent on rvi(lenrca of toxicity, sion of thv tumor, if any remains.
waH
noted
Comment The administra,tion of hIcthotrcsate in this patient was associated with unequivocal remission of metastases from choriocarcinoma. A return to notima1 in urinary chorionic gonadotrophin titers was also seen. Li and his collaborator+ 7 have reported 3 cases of choriocarcinoma and une of chorioadenoma tlrstruens which responded equally dramatically. The fact that this patient is one of 4 who had choriocarciaoma, similarly treated, who have had remissions after Methotrexate administration, fortifies the impression that the responses have not, occurred by chance. It seems highly likely that several pa.tients with choriocarcinoma have bran treated with folic acid antagonists according to conventional dose regim(lns, because the effects of these xntimetabolites on the products of conception have been stressed. Such an c>xpcrience has not been found in a brief survey of the literature, however, and it is probable that, had impressive remissions occurred, they would have been reported. Whether it is the large-dose intermit,tcnt Methotrexate treatment that caused the remission in our patient, whether it is a hitherto unrecognized propensity of this neoplasm, or whether both. situat.ions must obtain cannot at this time be stated. It, has not yet been cstablishcd that the dosage regimen described by Li and used here is optimal. One can only declare pragmatically that it has worked repeatedly. In the absence of renal insufficiency, pre-existent hematopoictic tlepression, and cachesia. the doses &scribed may be given cautiously
L-‘,lrlme
ii
N11nher I
JIETHOTREXATE
THERAPY
OF
METlZHTATLC
CHORIOCARCINOMA
I$)!)
unclw daily supervision. F’or this patient, toxicity has been n~oclerately were but not life threatening. In 2 of 8 other patients with metastatic carcinoma from various other sites treated in similar fashion, howcrcr, profound toxicity evidenced by pancytopenia and ulceration of the alimentary canal was present at the time of death.s Further experience and cautious trial will be required before the best method of Methotrcsatc administration is established.
Summary A patient with choriocarcinoma estcnsircly metastatic to the lungs (and probably pelvis) 1 with elevatd urinary gonadotropin titers, has been treated with Methotresate. The drug was administered orally in intermittent highclose CoLIrscs. Regression of tumor masses and fall of gonadotrophin escretion followed. This expcriclnce confirms that reported by Li, Hertz, and Spencer.4
References 1. 9. 3. 4. 5.
Duffy, B. A.: AM. J. 0~s~. & GTR’EC. 69: S!!S, 1955. Andersqn, H. E., Bisgard, .J. D., and Greene, A. M.: A. M. A. Srch. Surg. 68: 529, 1954. DiPaola, G., Lopez Biel, R., and Open, M. M.: Obst. y ginec. latino-am. 13: 368,1955. Li, M. C., Hertz, R., and Spencer, D. B.: Proc. Sot. Exper. Biol. & Med. 93: 361, 1956. Goldin, A., Mantel, N., Greenhouse, 8. W., Venllitti, J. M., ant1 Humphreys, R. R. Cancer Res. 14: 311, 1954. Proc. Am. A. Cancer Res. 2: 194, 1957. 6. Condit, P. T.: 7. Li, M. C., Spencer, D. B., Hertz, R., and Lubs, H. A.: Proc. Am. A. Cancer Res. 2: 326, 1957. S. Holland, .J. F.: Pnpublished observation:;.