Adjuvant chemotherapy of choriocarcinoma

Adjuvant chemotherapy of choriocarcinoma Presentation of 2 cases with 5 year survival

GILBERT A. WEBB, M.D. San Francisco, California

with nitrogen mustard. Both patients have survivC'd 5 years and are now living and well. The surgical specimens have been extensively reviewed by many pathologists with complete unanimity of opinion as to the diagnosis in both cases.

T HE use of the term ''adjuvant" in the title implies that there is a primary form of therapy which needs assistance to enable it to effect a cure. The primary attack on this disease has bet.>n surgical extirpation of all available lesions. The failure of this approach alone is evident by the report by No,·ak and Seah~ published in 1954 in which the results of therapy used in the cases referred to the Albert Mathieu Chorionepithelioma Registry. Fifty-nine cases were treated with opt'ration alone or with operation and x-ray. In 7 cases there was no treatment. The survival rate was 17.5 per cent. Smalbraak, 1 in his scholarly book Trophobla>lic Growths, covers in detail many of the a.l(ents which have been used in the therapy of choriocarcinoma (Table I). Hertz"' has rfported fxtensively on his experiences with methotrexate. Rfcently he has also reported on the use of vinblastine sulfate, a new chemotherapeutic agent which has proved to he of ,·aluc in cases which are resistant to methotrexate. 11 In the Asian literature, 1" sarkomycin has been reported as used without success. ThC' purpose of this present paper is to pn:sent 2 cases of true nonvillous choriocarcinoma which received primary surgical treatment. followed by adjunctive therapy

Case 1. Mrs. F. de los R., a Filipino, was aged 32, gravida iv, para iii. Her illness began with a last normal menstrual period on April 22, 1955. On July 15, 1955, the patient had a curettage for evacuation of a hydatidiform mole. Following this, the chorionic gonadotropin tt·st (hereinafter called CGT) was positive. On September 8, she had a heavy menstrual period. On October 3, the CGT test was negative. The patient had a second heavy flow on October 17. On Nov. 2, 1955, she began to bleed and continued until November 15 when a curettage was don<'. The pathology report was that of endometrium, late sPcrrtory phase, with stromal areas showing marked progestin t:>tfect. A quantitative CGT test was obtained and was rPported as positive at 1 : 80. This was the rat Zondek test and the dilution factor alone \\·as calculated. A second test was reported December 30, positive at 1:200. The plan at that timr was to admit the patient for elective hyst('rrctomy which a probable diagnosis of eitlwr chorioadenoma destrucns or rhoriorpithelioma. However, on January 2, thr patient was admittrd in severe shock with rvidence of intraJl<'ritoneal hPmorrhagt~. It was at this time that f first saw the patient. A prcopcr;1tivc dia.gnosis of lllt-rint' JJt'rforation from l'ither choriocarcinollla or chorioadt•noma dPstruPIIS was made. At tlw time of operation, approximatt'!y 2,001] c.c. of fn•sh clotted blood was revealt•d in tlw abdominal cavity. Pelvic exploration n'v<'al('(l both tubes and ovaries to be of normal sizf~ and

From the Department of Obstetrics and Gynecology, University of California School of Medid11e and Children's Hosj>ital Presented b1' i>witation at the Twenty-eighth Annual Meeting of the Pacific Coast Obstetrical and Gynecological Society, Yosemite National Park, California, Sept. 20-23, 1961.

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Adjuvant chemotherapy of choriocarcinoma

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symmetry. On the left ovary were two small cysts which appeared to be follicul ar in origin. The uto•rus was found to be asymmetrically enlarged by a 6 em. rather soft mass. Fresh bleeding was occurring through a 2 em. defect. At this time, it was my impression because of the rising 1iter that this probably represented a malignant tumor. Consequently, an extended hysterectomy with excision of the upper third of the vagina and both tubes and ovaries was carried out. The pat ient survived the operation, receiving 5 units •,f whole blood. Her condition at the end of the operation was fair; however, she had an uneventful postoperative course. Pathologic examination of the removed speci•n rn (Fig. I ) revealed a choriocarcinoma which had invaded the posterior aspect of the uterus a nd eroded into the uterine vessels. There were 110 placental villi found in any of the removed tissue. The slides were reviewed by Dr. Herbert Traut, Dr. Ludwig Emge, and Dr. Arthur Hertig, all of whom concurred in the above diaguosis. Inasmuch as there was no evidence of llletastatic spread within the peritoneal cavity, th e use of radiation therapy was deemed inad,·isab le. Therefore, it was planned, because of rhe type of tumor, to give the patient chemotherapy. A Friedman test, done on the sixth postopt•rative day, was still positive. As a result, the patient was given 0.4 mg. nitrogen mustard pt'r kilogram of body weight, or 25 mg., intravenously. Chest x-ray films at this time were negative. The patient was subsequently followed with serial rat Zondek quantitative CGT tests. As can be seen in Fig. 2, the CGT became negative after the second course but again became positive one month later. After the third course, it again lwcame negative and has remained so to date. Case 2. Mrs. M. T. , was a 24-year-old Negro woman, gravida ii, para ii. She was first seen as a

Table I. Methods of therapy from Smalbraak I. Hormonal

II. III. IV. V.

Estrogen Parahydroxyprophine Testosterone Thyroxin Blood transfusions Syncytolysins from pregnant woman Immunization Chorionic extracts Radioactive phosphorus Nitrogen mustard plus x-ray

1479

Fig. 1. Case 1. Choriocarcinoma in wall of uterus.

patient in August, 1956, with a chief complaint of steady vaginal bleeding which had started in September, 1955. H er menstrual cycles had been regular until the spring of 1955. At that time, they gradually became longer in duration, going from 5 to 7 to 10 to 14 days in duration, and finally in September, 1955, she began to bleed daily. In February, 1956, the patient had been hospitalized at a local hospital with a diagnosis of incomplete abortion and a curettage was carried out. The tissue removed revealed only decidual reaction, but she was told that she had a positive pregnancy test. On April 30, she was seen again with bleeding and a positive pregnancy test. She continued to bleed intermittently and in June of that year had a profuse hemorrhage which necessitated her being hospitalized. Curettage resulted in a pathology report of placental polyps. The patient hemorrhaged again and was readmitted to the hospital on July 25, 1956, at which time a third curettage was done. This time, the pathologic study revea led atypical hyperplasia of placental tissue consistent with

1480 Webb

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choriocarcinoma. A repeat pregnancy test was reported as positiw. The patient signed out of the hospital before the above reports were final, and she was seen in my office on August 3. Past medical history revealed that she had bt>('ll married 5 Yz years. She had 2 full-term deliveries, and her children were 4Yz and 2Y:z years of age, respectively. At no time had there been any period of amenorrhea following the birth of the last child. Examination showed a well-developed, very nervous young Negro woman. The abdomen was relaxed with no tumors, masses, or tenderness palpable. Breast examination revealed a 1.5 em. fully mobile, hard lump in the upper outer quadrant of the left breast. Pelvic examination revealed a slightly relaxed pelvic outlet. The Bartholin and Skene glands were within normal limits. The vagina contained a small amount of dark, bloody discharge. The vulva was normal. The cervix was slightly patulous but well epithrliz<'d. The uterus was third-degree retroflexed, fl'lt symmetrical, hut was enlarged to the size of about a 3 months' gPstation. The adnexa wcrr nontender with no masses detected. Rectal PXamination confirmed the above findings. TPntative diagnosis at this time was that the patiC'nt had either chorioadenoma destruens or

choriocarcinoma. She was hospitalized on August 7 for further study. A quantitative CGT determination was positive at a dilution of 1 : 200. Chest x-ray was normal. Curettage and excision of the cyst in the left breast were done. The pathologic study confirmed the diagnosis of fibroadenoma of the left breast. There was considerable discussion as to the diagnosis of the endometrial material. The pathologist first made a diagnosis of "malignant hydatidiform mole ( chorioadenoma destruens) ,'' but, because no definite villi were found, the impression of some of the tissue examiners, including myself, was that of choriocarcinoma. Therefore, on August 11, an extended panhysterectomy was carried out, with wedge biopsy of both ovaries. Examination of the patient at the time of operation showed no evidence of upper abdominal pathologic conditions. Pelvic examination revealed the uterus to be approximately three times normal size and retrocessed. Both ovaries were small, with numerous small follicle cysts. The broad ligaments were markedly distended by large varicosities. The upper third of the vagina was removed at operation, and the patient tol<'rated the procedure well. Pathologic study of the material revealed a polypoid hemorrhagic mass (Fig. 3) in the left

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Adjuvant chemotherapy of choriocarcinoma

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uterine cornu, measuring 3 by 3 em. The tumor appeared to invade into the midportion of the myometrium but showed no evidence of serosal spread. The histologic appearance of the trophoblastic tissue (Figs. 4 and 5) in the uterine wall forced the pathologist into the conclusion that the lesion represented choriocarcinoma rather than chorioadenoma destruens. The ovarian wedge biopsies showed no evidence of pathologic c,mditions. Tissue was submitted to Dr. Emil Novak, Dr. H erbert Traut, and Dr. Ludwig Emgc, all of whom concurred in the diagnosis of r horiocarcinoma. On August 18, the patient was given the first course of nitrogen mustard, 0.4 mg. per kilogram of weight, intravenously. A quantitative Zondek rat test done on August 20 was reported as positive undiluted, but negative in each of th e dilutions. Fig. 6 outlines the subsequent follow-up. Comment

The first case represents the most common sequence of events in choriocarcinoma; namely, the occurrence of the disease following a previously diagnosed hydatidiform mole. Novak and Seah2 found this to be true in 39.2 per cent of their cases. This case also points out the feeling of Acosta-Sison8 that a negative curettage does not exclude a primary intramural growth. It also shows that it is necessary to run frequent chorionic gonadotropin tests, preferably with quantitative

Fig. 3. Case 2. Uterus with intramural choriocarcinoma.

Fig. 4. Case 2. Choriocarcinoma in wall of uterus.

evaluation, rather than to rely on the qualitative alone. Delfs 3 has demonstrated the value in following all moles with the quantitative test. The decision to give the patient chemotherapy was made in spite of the failure to demonstrate any lung or pelvic metastases. The presence of trophoblastic cells in the large uterine sinuses draining the tumor and the depressing percentages of survivals from this disease were strong influences in the decision. The choice of nitrogen mustard was made after consultation with Dr. Nicholas Petrakis, a chemotherapist at the University of California Medical School. Our reasoning went as follows: 1. Nitrogen mustard is described as being radiomimetic/ and choriocarcinoma Is thought by some physicians5 to be radiosensitive. 2. As the metastatic trophoblastic cells are blood-borne, an agent working in the vascular system was required. 3. Isolated reports 6 • 7 were appearing on the use of nitrogen mustard in conjunction

1482 Webb

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F ig. 5. Case 2. H igh-power photomicrograph of choriocarcinoma in wall of uterus.

with x-ray in the treatment of lung metastases from choriocarcinoma with the suggestion tha t it gave transient improvement although there were no definite proved cures. 4 . We had no knowledge of a better agent . ...... ~

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The giving of three courses of nitrogen mustard was dictated by the course of the chorionic gonadotropin tests in the first cas<~ . The drop in titers after the operation, followed by further reduction to negative after the second course, was encouraging. However, a later return of chorionic gonadotropin to hig-her levels was interpreted as indicating viable trophoblastic tissue remained a nd was being rejuvenated. Therefore, the patient was given a third dose with prompt n·tmn to negative when it was received. Admittedly, this was a large dose for this type of drug; however, the patient tolerated it well , with only a transient drop in white blood ce ll count. She also had transient nausea. controlled by the use of intravenous chlorpromazine sim ultaneously administered. She later developed ra ther bothersome menopausal symptoms and these were effect ivel y treated with stilbestrol, 0.1 mg. three times a day, with gradual reduction of dosage to once a day. I do not feel that this small dosage of stilbestrol played any role in the patient's survival, inasmuch as Stearns 7 has pointed out that, to be effective, stilbestrol

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Volume 111 Number 11

Adjuvant chemotherapy of choriocarcinoma

must be given in doses of 100 mg. intramuscularly. The precursor of the second case is impossible to state. Whether it followed an abortion (the patient was separated from her husband and repeatedly denied sexual exposure) or followed her last normal pregnancy 2Yz years before is subject to speculation. In our patient, a review of all of the curettings failed to reveal any villi. After the first case had stimulated my interest in the problem of choriocarcinoma, I became aware of the theory, championed by Stearns, 7 of leaving the ovaries as a protective mechanism. Consequently, wedge resection was done for biopsy purposes only. The use of nitrogen mustard in the same fashion as in the first case was done empirically. It was gratifying to see the chorionic gonadotropin titers level at zero after the first course. It is quite possible that the second and third courses were not necessary. It is impossible to be sure of the role of nitrogen mustard in the cure of the first 2 cases described. However, there is reason to believe it did play a part, particularly in the first case. The fact that choriocarcinoma is spread by the hematogenous route necessi-

1483

tates sterilization of the bloodstream by an agent which will successfully attack this spread. The earlier an agent is given, the greater the chance of success, as a chemotherapeutic agent is more effective against small lesions than large. Nitrogen mustard has proved to be lacking in alleviating cases with visible lung metastases. However, it has been used successfully12 to "sterilize" the bloodstream from cellular metastases. Also, it has fewer side effects than the newer, morl' powerful agents. Therefore, its use is advocated after extirpative operations if obvious metastases are not present. If metastases arl' present, then the more powerful agents, methotrexate or vinblastine sulfate, are indicated. Summary

Two cases of authenticated choriocarcinoma are reviewed. These were treated with primary operation followed by nitrogen mustard therapy. Both patients have survived 5 years.

I would like to thank Dr. Herbert F. Traut and Dr. Ludwig Emge for their suggestions and support.

REFERENCES

J.: Trophoblastic Growths, Amsterdam, 1957, Elsevier Press, Inc., p. 209. 2. Novak, E., and Seah, C. S.: AM. J. OBsT. & GYNEC. 67: 933, 1954. 3. Delfs, E.: Obst. & Gynec. 9: 1, 1957. +. Barnes, H.: AM. J. 0BsT. & GYNEC. 69: 519, 1. Smalbraak,

1955. 5. Acosta-Sison, H., and Espinola, N. A.: AM. 0BST. & GYNEC. 42: 878, 1941.

J.

6. Beecham, C. T., Peale, A. R., and Robbins, R.: AM. J. OssT. & GYNEC. 69: 510, 1955. 7. Stearns, H. C.: West. J. Surg. 61: 368, 1953. 8. Acosta-Sison, H.: Asiatic Congress of Obstetricians and Gynecologists, 1957, p. 135.

Discussion DR. A. C. GARDNER FRosT, Vancouver, British Columbia. I have looked up the cases in our city, Vancouver, British Columbia, and there has only been one patient who has received adjuvant chemotherapy. This is a 38-year-old gravida viii,

9. Novak, E.: Gynecological and Obstetrical Pathology, Philadelphia, 1947, W. B. Saunders Co., p. 501. 10. Hertz, R.: Ann. New York Acad. Sc. 80: 282,

1959. 11. Hertz, R., Lipsett, M. B., and Moy, R. H.: Canad. Res. 20: 1050, 1960. 12. Cole, W. H.· Roberts, S., Watne, G., Mc-

Donald, G., and McGrew, E.: Bull. New York Acad. Med. 34: 163, 1958. 13. Hsua, C. H., Lin, C., Na, Y., and Lai, Y.: Asiatic Congress of Obstetricians and Gynecologists, 1957, p. 159.

para 0, Hospital Number 33-8540. Her last menstrual period was Nov. 29, 1958. About Jan. 10, 1959, she began to have abdominal cramps and vaginal bleeding and noticed that the abdom<'n was swelling. On Jan. 24, 1959, she developt'ci

1484 Webb

acute abdominal symptoms and was operated upon for a ruptured ectopic pregnancy in a small hospital on Vancouver Island. The fundus of the uterus was found to be perforated and the operator was of the opinion that this was a bleeding m~crotic fibroid. A wedge resection of the uterus, as well as a right salpingo-oophorectomy, \vas done. The pathologic diagnosis was choriocarcmoma. On February 6, 13 days after operation, it was noted that there was some transient paresthesia and hyperesthesia of the right arm and leg and a distinct reduction in sensation to the touch of the right leg, extending up to the mid-thigh. She was transported to the Vancouver General Hospital on the same day. X-ray examination of the chest on admission revealed multiple densities scattered throughout both lung fields. The admission diagnosis was consequently one of choriocarcinoma with probable metastases to the lungs and brain. On February 7, a panhysterectomy was donr by the late Dr. A. M. Agnew, head of the Department of Obstetrics and Gynf'cology, University of British Columbia. At the time of operation, a blood smear was taken from the antecubital vPin and cancer cells were seen. On the evening of the same day, her condition deteriorated rapidly and she developed a rig-ht spastic hemiplegia and became semicomatose. In addition, she developed Jacksonian type convulsions involving the left leg and arm and she became comatose. At this time, she was started on 20 mg. methotrexate. In addition, in order to control the seizures, phenobarbital sodium and dilantin were given. Hydrocortisone succinate was also given. In 2 days' time, she was found much improved and able to answer questions. No further convulsions occurred. Methotrexate was continued in large dosage. Her clinical condition showed a gradual but steady improvement of the right hemiplegia. There was also a rapid clearing of the sensorium. l\1ethotrexate was continued until February 13, a total of 145 mg. having been given. On this day, it was noted the white blood count dropped to 4,200 and also tl1f're was a severe oropharyngitis from which monilia was cultured. Th<' white blood count reached a maximal drop to 1,500 and the platelrts to 88,400 on February 19. On February 13, a qualitative Friedman trst was positive. A dilution test was not reported. On February 13, there ,,·as a dehiscence of the

Am.

June I, 1%2 J. Ohst. & Oynec,

abdominal wound which was closed under local anesthesia. By February 26, the white blood count and platelet count were normal. Howewr, on February 27, her clinical cottdition seemed to deteriorate and she was again given l.'i mg. mrthotrexatr daily and this was mntinued until March 7. She again showed a marked clinical improvement \\·ith complete restoration of the state of consciousness and a steady improvement of the right hemiplegia. Chest x-ray studies showed a marked resolution of the previously observrd scattered densities. A qualitative Friedman test on Febmary 20 was negative. A quantitative test February 28 showed a trace. On March 18 and April II, the qualitative tests were negative. At thr time of presentation of the case at th·~ medical rounds March 26, the patient was able to walk with the assistance of a cane and was mentally normal. Chest x-ray examination on this date showed the densities appreciably smaller and possibly not so numerous. She was discharged from the hospital April II, 64 days after admission. There was still somr' hemiplegia of thP right leg. She was again admitted on May 24, at the request of the Medical Department, for reassessmrnt and furthrr treatment. She had no complaints. By June 6 she had received 10 mg. methotrexate daily for 5 days. One Friedman test on May 30 showed the qualitative test positive and the quantitative nrgativc in I : 10 dilution, and again on June 8 the qualitative tl'st was positive and the quantitative test was twg:lt.iw.

X-ray of the chest taken on May 26 revealed both lung fields were now clear and within limits of normal. Blood test findings were normal on dischargt~ from the hospital .June 8. The patient still required the usc of the cane to walk. She was requested to return in one month for treatmt•nt and reassessment of her condition. Unfortunately. she refused to return to the hospital in VanCOllV('f.

On September 2, at 4 P.M., she was admitted to the hospital on Vancouver Island unconscious, with twitching of the arms and legs. The blood prt>ssurr was recorded at :200/90. She died 12 homs latt'r. The husband states that one wrek prior to this, he had tried to persuade her to comr to the hospital but she refused. The family refused permission for autopsy. I wish to thank Dr. Fred Bryans, Professor of

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Obstetrics and Gynecology of the University of British Columbia; also Dr. John R. Boyd of the Gynecological Pathology Department and Dr. R. E. Beck of the Medical Department, for the privilf'ge of reporting this case. DR. KARL L. ScHAUPP, ]R., San Francisco, California. It has been well demonstrated, I think, that surgical procedures may squeeze cells into the general circulation. Would it not be wise

Adjuvant chemotherapy of choriocarcinoma

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to give your chemotherapeutic agent, if you have a diagnosis, just before the operation. DR. WEBB (Closing). There is more and more literature on the use of chemotherapy in various other types of malignant tumors, particularly ovarian carcinoma. At the time these cases were seen, there was not much literature available. I really do not know whether chemotherapy is better before or right after the operative procedure.