Late brain recurrence of choriocarcinoma

GYNECOLOGIC ONCOLOGY31, 467--473 (1988)

Late Brain Recurrence of Choriocarcinoma JOHN P . KOULOS, M . D . , ~ AND JAMES S. I-IOFFMAN, M . D .

University of Connecticut Health Center, Department of Obstetrics and Gynecology, Division of" Gynecologic Oncology, Farmington. Connecticut 06032 Received March 10, 1987

INTRODUCTION Prior to the use of chemotherapy intervention in the treatment of gestational trophoblastic neoplasia, the outcome of women with this disease was often fatal. With the further development of chemotherapeutic trials over the past 3 decades, remissions have been reported on over 90% of patients. The availability of the fl-hCG serum determinations has been key in the overall management of patients with gestational trophoblastic neoplasia. We report a case that presents some complex clinical changes with which the physician may deal when treating highrisk gestational trophoblastic neoplasia. It also demonstrates the diagnostic values of magnetic resonance imaging in localizing recurrent disease. CASE REPORT K.W. is a 42-year-old, white female, gravida 2 para 2, who presented to an outside community emergency room on 10/13/84 with complaints of dyspnea and a 6-month history of abnormal uterine bleeding. A chest X-ray revealed left pleural effusion, multiple parenchymal lung densities, and a large mediastinal mass. Radioimmune assay for /3-hCG showed a titer of greater than 100,000 mIU/ml. Exploratory laparotomy was advised for a presumptive diagnosis of ovarian germ cell malignancy. The general surgeon performed a bilateral salpingooophorectomy and uterine wall biopsy with subsequent normal tissue histology. Postoperatively, the patient became hypovolemic, apparently from intraabdominal hemorrhage. Significant past medical history includes two normal term vaginal deliveries with the most recent having been 13 years PTA. Her husband had a vasectomy and a negative semen analysis following her second delivery. She had no major health problems prior to her current illness. The patient was transferred to our University hospital on 10/20/84 with respiratory insufficiency and hypovolemia. A repeat chest X-ray revealed a left Present address: Division of Gynecologic Oncology, OB/GYN, College of Physicians and Surgeons of Columbia University, 161 Fort Washington Avenue, AP-447, New York, NY 10032. 467 0090-8258/88 $1.50 Copyright © 1988by AcademicPress, Inc. All rightsof reproductionin any form reserved.

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pleural effusion and progression of a large mediastinal mass (15 cm), with tracheal hemorrhage. A radioimmune assay for/3-hCG was 185,000 mIU/n'fl and a diagnosis of high-risk metastatic choriocarcinoma was made. The patient was begun on MAC chemotherapy consisting of methotrexate 15 mg intravenously daily × 5, actinomycin-D 0.5 mg intravenously daily x 5, and Cytoxan 225 mg daily x 5. With her worsening respiratory status, the patient required intubation and prolonged mechanical ventilatory assistance. Computed tomography of the brain was deferred because of her poor status. Ultrasound of the liver revealed no metastasis. By the 10th hospital day, her clinical situation had improved sufficiently to be weaned from the respirator. Her/3-hCG had fallen to 8500 mIU/ml. On hospital Day 15, the patient was given a second cycle of MAC chemotherapy with subsequent developments of severe neutropenia, sepsis, and multiple mouth ulcerations. She became febrile to 105°F and blood cultures were positive for Klebsiella pneumonia. The patient was begun on cefazolin and tobramycin. The day following insertion of a left subclavian catheter, she developed swelling of her left arm and face. Venography demonstrated complete thrombosis of the left axillary, subclavian, and inominate vein, possibly resulting from her massive mediastinal mass. The subclavian line was removed and full anticoagulation with intravenous heparin was begun. On hospital Day 23, the patient underwent posterior colpotomy for drainage of a large infected cul-de-sac hematoma. After 2 days of MAC chemotherapy, she was changed to actinomycin-D only because of severe methotrexate-induced gastrointestinal toxicity. The patient showed gradual clinical improvement while in the hospital on heparin and hyperalimentation and was finally discharged on Coumadin on hospital Day 46. The patient received an additional two cycles of out-patient actinomycin-D and her /3-hCG continued to fall to a level of 21 mIU/ml on 12/24/84. However, on 1/4/85, after a subsequent rise of/3-hCG to 64, her original chemotherapy regimen of MAC was reinstituted and a hysterectomy was performed on Day 3 of therapy. Despite these measures, her/3-hCG level remained elevated and a chest X-ray of 1/17/85 revealed a new lung nodule. Computed tomography of the head did not show metastasis. A second chemotherapy regimen was begun, consisting of cis-platinum 50 mg/m 2 on Day 1, bleomycin 15 units/day by continuous infusion on Days 1-5, and etoposide (VP-16) 100 mg/m 2 on Days 1-5 [1]. Her/3-hCG level fell to undetectable levels (less than 10 mlU/ml) after two cycles with resolution of the pulmonary nodule. An additional three cycles were administered beyond the determination of a "negative" /3-hCG assay. Her/3hCG level remained at undetectable levels (less than 10 mlU/ml) for several months until 11/29/85 when her/3-hCG level rose to 15 mlU/ml. A later cerebrospinal fluid /3-hCG and repeat serum /3-hCG reported values of 64 and 48 mlU/ml, respectively. Metastatic work-up with chest tomograms, head CT-scan, and liver sonogram was negative. In view of the elevated cerebrospinal fluid/serum /3-beG ratio, the patient was evaluated by Dr. Kenneth Bagshawe of Charing Cross Hospital, in London, England. Antibody imaging was performed with 200 /zg mouse monoclonal affinity purified anti-hCG labeled with 1.3 mCi of u~I. Imaging obtained at 20, 48, 72, and 90 hr failed to show any clear-cut tumor

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localization. The patient returned to the United States to undergo a magnetic resonance imaging scan of the brain on 12/18/85. A 7-mm infiltrative lesion, consistent with recurrent tumor, appeared as a focal area of increased signal in the right parieto-occipital convexity (Fig. 1). On 12/20/86, a right parietal osteoplastic craniotomy, directed by CT and stereotactic technique, was performed under local anesthesia with removal of the lesion. Histology confirmed choriocarcinoma (Fig. 2). The patient subsequently was treated with six cycles of modified EMACO chemotherapy consisting of etoposide, methotrexate, and actinomycin-D alternating with Cytoxan, vincristine, and intrathecal methotrexate [2] (Fig. 3).The fl-hCG levels had fallen rapidly to undetectable levels following her surgery and the patient has remained clincally free of disease for over 12 months (Fig. 4). DISCUSSION

The widespread use of the radioimmune assay for fl-hCG has led to earlier diagnosis in cases of choriocarcinoma. Virtually 100% of patients presenting with either nonmetastatic or metastatic low-risk disease are cured [1]. Utilizing an optimal chemotherapy regimen is necessary for the remainder of patients with high-risk gestational trophoblastic neoplasia. Several chemotherapeutic programs have been utilized in the United States for patients with poor-prognosis gestational trophoblastic neoplasia. These programs include (1) MAC (methotrexate, actinomycin-D, and chlorambucil [3]; or methotrexate, actinomycin-D and cyclophosphamide [4]; (2) modified Bagshawe protocol (an 8-day regimen with hydroxyurea, actinomycin-D, vincristine, high-dose meth-

FIr. 1. MRI scan of the brain revealing area of metastatic tumor in the right parieto-occipital convexity.

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FI~. 2.

Histologic appearance of metastatic choriocarcinoma to the brain.

EMA/cO STUDY FOR H I G H - R I S K CHORIOCARCINOMAS

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Etoposide (VP-16) Methotrexate

Day 2

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Day 8

Vineristine

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Intrathecal Methotrexate 12.5 mg is diluted to 2 ml of 0,9% Sodium Chloride 6-day drug-free interval

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FIG. 4.

Case K.L.V. fl-hCG levels throughout the course of therapy.

otrexate with folinic acid rescue, cyclophosphamide and Adriamycin) [5]; (3) PBE (cis-platinum, bleomycin, and etoposide (VP-16) [6]; and, (4) EMACO (etoposide, actinomycin-D, high-dose methotrexate with folinic acid rescue, vincristine and cyclophosphamide) [2]. Three of the above regimens show a degree of dependence on three active drugs: methotrexate, actinomycin-D, and an alkylating agent (Cytoxan or chlorambucil). This raises the concern that patients who fail one regimen secondary to development of drug resistance would not benefit from an alternate regimen containing some of the same drugs. Nevertheless, Surwit et al. were able to achieve complete remission in five of six patients treated secondarily with the modified Bagshawe protocol when MAC chemotherapy failed [5]. In two of five cases who had complete remission, pulmonary resection had induced remission and chemotherapy was used in an adjuvant setting. The response of the other three patients did demonstrate the efficacy of this salvage problem. In a later study, Surwit administered a combination program, PBE (cis-platinum 50 mg/m 2, continuous infusion b|eomycin 15 U per day for 5 days, and etoposide (VP-16) 100 mg/m 2 daily for 5 days), to three patients who were refractory to the modified Bagshawe protocol. All three had complete remission [6]. In our patient, after initial trial with MAC failed, PBE induced a remission for 9 months. Newlands et al. treated 56 high-risk gestational trophoblastic neoplasia patients, most of whom were at risk of developing drug resistance, with EMACO (alternating weekly treatment between etoposide, methotrexate, actinomycin-D, and vincristine and cyclophosphamide), resulting in an overall survival rate of 84%. Patients who had received prior chemotherapy had a survival rate of 74% and a relapse rate of 17%, compared with 93% survival rate and 3% relapse rate in those who had not received prior chemotherapy [7]. Our patient currently has a sustained

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remission after surgical excision of an isolated central nervous system metastasis after six cycles of EMACO chemotherapy. The importance of brain metastasis must be emphasized because hemorrhage from these sites is the most common fatal event in patients with gestational trophoblastic neoplasia. When the diagnosis of brain metastasis is confirmed, it is common to administer whole brain radiation in doses of 2000-3000 rad over a period of 10-14 days with simultaneous initiation of combination chemotherapy

[81. Weed et al. reported on 23 patients with central nervous system metastases who were treated with vigorous multiagent chemotherapy and combined cerebral radiation therapy. Overall, 43% of the patients had long-term survival. However, among 13 patients who developed central nervous system metastases during multiagent chemotherapy, only 3 patients survived [9]. Charing Cross Hospital (London) experience reports six additional patients who had late central nervous system metastasis and were treated with wholebrain radiation and multiagent chemotherapy. None of the six survived. They also reported two patients who had removal of localized late central nervous system metastasis, followed by chemotherapy. At the time of the report, both patients were clinically free of disease, although one was completing chemotherapy [10]. The accessible location and focal nature of the patient's brain lesion led us to a decision to perform surgical excision and chemotherapy. Bagshawe and Harland reported the use of plasma/cerebral spinal fluid (CSF) ratio/3-hCG titers for the early diagnosis of central nervous system lesions [l 1]. Patients with central nervous system lesions have ratios less than 60:1 (~-hCG). In our patient, the elevation of serum/3-hCG followed by the abnormal plasma/CSF /3-hCG ratio raised our suspicion for metastatic central nervous system choriocarcinoma. The failure of the CT scan of the head and the antibody imaging technique, in an attempt to demonstrate central nervous system metastasis, led us to magnetic resonance imaging. The magnetic resonance imaging was helpful in demonstrating an isolated 7-mm central nervous system lesion. Routine CT scan utilizing 1-cm slices accounts for the negative finding with this diagnostic test. A subsequent CT scan utilizing 0.5-cm slides did demonstrate the central nervous system metastasis. This case study demonstrates the complexity of problems that we confronted when treating a patient with high-risk gestational trophoblastic neoplasia. Along with the severe complications associated with treatment, we demonstrated some of the failures and successes of various chemotherapeutic regimens, a treatment method of surgical excision, and combination chemotherapy in treating isolated late central nervous system metastasis, and the value of magnetic resonance imaging techniques in localizing recurrent lesions. REFERENCES 1. Hammond, C. B., Borcheut, L., Tyrey, L., Creasman, W. T., and Parker, R. T. Treatment of metastatic trophoblastic disease: Good and poor prognosis, Amer. J. Obstet. GynecoL 115, 451 (1973). 2. Newlands, E. S., Bagshawe, K. D., Begent, R. H. J., Rustin, G. J. S., Holden, L., and Dent, J.

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Developments in chemotherapy for medium and high-risk patients with gestational trophoblastic turnouts (1979-1984), Brit. J. Obstet. Gynecol. 93, 63-69 (1986). Surwit, E. A., and Hammond, C. B. Treatment of metastatic trophoblastic disease with poor prognosis, Obstet. Gynecol. 55, 565 (1980). Goldstein, D. P., and Berkowitz, R. S. Staging system for gestational trophoblastic tumors, J. Reprod. Med. 29, 792 (1984). Surwit, E. A., Suciu, T. N., Schmidt, H. S., and Hammond, C. B. A new combination chemotherapy for resistant trophoblastic disease, Gynecol. Oncol. 8, 110 (1979). Surwit, E. A., Alberts, D, S., Christian, C. D., and Graham, V. E. Poor-propgnosis gestational trophoblastic disease: An update, Obstet. Gynecol. 64, 21 (1984). Newlands, E. S. VP-16 in combinations for first-line treatment of malignant germ-cell tumors and gestational choriocarcinoma, Semin. Oncol. 12, 37-41 (1985). Jones, W. B. Treatment of chorionic tumors, Clin. Obstet. Gynecol. 18(3), 247-265 (1975). Weed, J. C., Woodward, K. T., and Hammond, C. B. Choriocarcinoma metastatic to the brain: Therapy and prognosis, Semin. Oncol. 9, 208-212 (1982). Athanassiou, A., Begent, R. H. J., Newlands, E. S., Parker, D., Rustin, G. J. S., and Bagshawe, K. D. Central nervous system metastases of choriocarcinoma: 23 years' experience at Charing Cross Hospital, Cancer 52, 1728-1735 (1983). Bagshawe, K. D., and Harland, S. Immunodiagnosis and monitoring of gonadotrophin-producing metastases in the central nervous system, Cancer 38, 112-118 (1976).