GYNECOLOGIC

ONCOLOGY

45, 26-31 (1992)

Ovarian Germ Cell Malignancies: The Yale University Experience PETER E. SCHWARTZ,

M.D.,*,’

SETSUKOK. CHAMBERS,M.D.,* KOHORN, M.D.,*

*Department

of Obstetrics

and Gynecology

and TDepartment

JOSEPHT. CHAMBERS, PH.D.,

AND SUE MCINTOSH, of Pediatrics, Connecticut

Yale University 06510

M.D. ,* ERNEST

M.D.? School

of Medicine,

333 Cedar

Street,

New Haven,

Received July 22, 1991

Eighty-one patients with ovarian germ cell malignancies(immature teratoma29, dysgerminoma26, endodermalsinustumors 15, mixed germ cell tumor 8, other 3) seenor consultedon at Yale University over a 15 year period are presented.Initial therapy was successfulin 70 of 81 (86.4%) patients and 75 (92.6%) are currently alive and diseasefree. Early stagedysgerminomas may be safely treated with surgery whereasadvanced diseaseis exquisitely sensitive to vincristine, actinomycin D, and cyclophosphamide(VAC) therapy. Early stageimmature teratoma is uniformly successfullytreated with short-term VAC whereasadvanceddiseaserequireslongertreatment. Early stageendodermal sinustumor (EST) and mixed germcell tumorsmay be effectively treated with VAC or platinum-basedtherapy but advanceddiseaseshouldbetreated with paltinum-basedregimens.Serialalpha fetoproteinassaysshoulddetermineduration of therapy in tumors containing EST elements.Conservative surgery to preserve reproductive function is appropriatefor all patientswith early stage ovarian germ cell malignanciesand selectedpatients with advanced disease. 0 1992 Academic Press, Inc. INTRODUCTION

The evolution of modern chemotherapy management for the treatment of ovarian germ cell malignancies has resulted in changing these most virulent malignancies occurring in young women into highly curable malignancies. Chemotherapy as part of the primary treatment for patients with ovarian germ cell malignancies was introduced at Yale University School of Medicine in 1975. Initially the emphasis was on reducing the duration of very toxic treatment. However, review of our initial experience suggested that patients with ovarian germ cell malignancies could be managed by using tumor histology to determine the type of chemotherapy and determining treatment duration by serial assays of circulating tumor markers or by the International Federation of Gynecologists and Ob1 To whom correspondence and reprint requests should be addressed. 26 009&8258/92 $1.50 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.

stetricians (FIGO) staging if there were no measureable circulating tumor markers [l]. Preservation of reproductive function was viewed as appropriate for all patients with early-stage disease and selected patients with more advanced disease. Following the publication of our initial institutional experience in treating patients with these malignancies a number of physicians consulted us regarding the management of their ovarian germ cell malignancy patients [l]. This report reviews the overall experience of patients treated or on whom consultations were made at Yale University School of Medicine. MATERIALS

AND

METHODS

From October 1975 through September 1989, 81 women with ovarian germ cell malignancies were seen or consulted on at the Yale University School of Medicine. Fifty-one underwent surgery or received postoperative chemotherapy at this institution. Physicians for 28 patients consulted the senior author (P.E.S.) beginning in 1984 for recommendations regarding additional management after the diagnosis was established at other institutions. Two patients were consulted on for the possibility of attempting pregnancy following therapy. All medical records were reviewed for patients treated at Yale University. Operative, pathology, and chemotherapy records were requested for review for patients treated elsewhere. Consulting physicians completed a detailed questionnaire to update medical records. The follow-up time from diagnosis ranged from 11 to 208 months (median, 68 months). All living patients have been followed a minimum of 2 years from diagnosis. Three patients lost to follow-up were alive and disease-free at last contact (two stage I dysgerminomas at 36 and 54 months and one stage I mixed germ cell tumor at 57 months). All histologic specimens have been reviewed by gynecologic pathologists at Yale-New Haven Hospital and

OVARIAN

TABLE 1 Ovarian Germ Cell Malignancies No. pts. Figo stage

IMMT

DYSG

IA IB IC

14 1 4

8 5 4

IIA IIB IIC

-

2 1

Mixed

Other

Total

5

2

2 -

6

-

31 6 14

-

2 2 2

1

4 3 15

3

2 81

EST -

1

2

-

-

IIIA IIIB IIIC

3 1 4

-

-

IV Total

29

5

2

1 2 3

1 26

1 15

8

27

GERM CELL MALIGNANCIES

Note. IMMT, Immature teratoma; DYSG, dysgerminoma; EST, endodermal sinus tumor; Mixed, mixed germ cell tumor; Other, embryonal carcinoma (stage IA, IX); polyembryoma (stage IA).

other major institutions (Massachusetts General Hospital, Armed Forces Institute of Pathology, Brigham and Women’s Hospital, Memorial-Sloan Kettering Medical Center, Roswell Park Memorial Institute, Mount Sinai Medical Center, NY, and the University of Alabama). The FIG0 stage and histology of the entire series of patients are presented in Table 1. Three of twenty-nine patients with immature teratomas had grade 1 lesions but only one of the three had a stage IA lesion. Two patients with advanced-stage immature teratoma were not graded. For the entire series, 51 of 81 (62.9%) patients had stage I disease, 6 (7.4%) patients had stage II disease, 22 (27.2%) patients had stage III disease, and 2 (2.5%) patients had stage IV disease. The age distribution was from 6 to 47 years. No endodermai sinus tumors or mixed germ cell tumors occurred in patients 10 years of age or younger but three dygerminomas and three immature teratomas occurred in patients aged 6-9 years. Our current management of germ cell malignancies is based upon accumulated experience. Thus, the treatments have evolved over a 15year period. In reviewing our initial experience no patient with stage I disease treated with vincristine, actinomycin D, and cyclophosphamide (VAC) chemotherapy failed primary therapy, despite reducing the duration of treatment systematically from 18 to 6 cycles [l]. Therefore, short-term VAC was recommended routinely in all subsequent patients with stage I disease treated at this institution. Similarly, experience with the c&platinum, vinblastine, and bleomycin (PVB) regimen became available and was quite successful in treating patients with ovarian germ cell malignancies, and

the morbidity and mortality were less than anticipated [2,3]. Thus, some patients with early-stage disease consulted on at Yale University received PVB at other institutions from the consulting physicians. The PVB regimen was modified recently. Patients now receive etoposide (VP-16) instead of vinblastine in order to reduce bone marrow suppression and the neuropathy associated with vinblastine [4]. &-Platinum is given over a 24-hr infusion rather than over 5 days and bleomycin is given as a continuous iv infusion over 4 days every 3 weeks to reduce the risks for bleomycin lung toxicity [4]. This regimen is referred to as BEP. In general, staging procedures were not routinely performed by community gynecologists who operated on patients for what was believed to be benign ovarian cysts. In such cases it was our routine postoperatively to obtain a computerized tomography scan of the abdomen and pelvis and obtain serum tumor markers. Patients were then placed on combination chemotherapy without undergoing a second laparotomy. The only exception to this approach was for patients with dysgerminoma in whom intraoperative staging was incomplete and postoperative therapy could be avoided if proper surgical staging were performed. Patients with advanced-stage disease, whether or not surgically debulked, were placed on chemotherapy as soon as they were evaluated at Yale University. Second-look surgery has not been routinely recommended since 1984 [l]. Patients who were clinically free of disease at completion of their planned program of chemotherapy underwent computerized tomography studies and serum tumor markers assays. If these diagnostic studies were normal, patients were followed clinically. RESULTS Conservative surgery was performed whenever appropriate in this series of patients. Preservation of reproductive function was accomplished in 62 of 81 (76.5%) women, 61 of whom underwent unilateral oophorectomy and 1 of whom underwent an ovarian cystectomy for a stage IA grade 1 immature teratoma. Among the 19 women who underwent bilateral oophorectomy a retrospective review suggests that only 3 might have been spared unnecessary loss of fertility. Four of the nineteen had dysgenetic gonads. The remaining 12 had obvious bilateral involvement or advanced disease such that preservation of life became the critical issue in management. The primary therapy administered to the patients is presented in Table 2. The majority of patients received VAC. Most VAC-treated patients (21/47, 44.6%) received six cycles. Nine patients received two to five cycles without any loss of efficacy. PVB-treated patients received three to six cycles. BEP patients received three to

28

SCHWARTZ

ET AL.

TABLE 2 Ovarian Germ Cell Malignancies:Primary Therapy Rx Surgery VAC

PVB

BEP

No. courses

IMMT

DYSG

EST

Mixed

Other

Succ. Prim. Rx”

Total No. pts

2-5 6 8-12 13-18

2 1 11 I 2

9 2 9

1 5 1 2 1

1

1

10

13

-

2

-

5 20 9 2 40

9 21 10 3 47

3 4 5 6

1

1 2 -

1 2 1

-

2 3 4 1 10

2 3 5 1 11

1

-

-

1 1

2 1

-

1’

1’

-

15

8

3 5 6

-

lb -

2

1 -

-

1

1

1

-

Other

2

2d

Total

29

26

a Succ. prim. Rx, successful primary treatment. b VAC and radiation therapy. ’ PVB/BEP (1) vincristine, actinomycin D, cyclophosphamide, d Radiation. ’ VAC x 3, PVB x 3. ’ C&platinum, vinblastine, bleomycin, adriamycin.

1 1

1

3

2

2

70

81

4 6

5 6

adriamycin (1).

six cycles. Primary treatment was successful in 70 of the 81 (86.4%) patients treated in this series (Table 2). Ten of the thirteen patients who failed primary therapy were recognized to have recurrent or persistent disease in a median time of 5 months (range, 2 to 9 months). Five of sixty-three patients who had preservation of reproductive function recurred. Four of the five were salvaged with chemotherapy (Table 3). Two of thirty-three patients who underwent second-look operations were found to have asymptomatic persistent disease, one at 3 months after initiation of BEP therapy for an immature teratoma and the other at 15 months after completing a course of cyclophosphamide and &-platinum therapy for an ovarian ependymoma. One stage IB patient who had microscopic dysgerminoma found on biopsy of the contralateral ovary retained that ovary. She was recognized to have recurrent dysgerminoma that involved the remaining ovary and paraaortic lymph nodes 33 months following diagnosis. That patient has completed a course of combination chemotherapy at another institution and is currently alive and disease free at 33 weeks gestation. No patient undergoing a negative second-look operation recurred, including 6 patients found to have mature teratoma implants. The

latter patients received no additional therapy and are alive and disease free 35 to 145 months (median, 98 months) following surgery. The current disease status of the patients in this series can be seen in Fig. 1. Seventy-five patients (92.6%) are alive and disease free, four patients died of disease, and two patients died of other causes, each free of disease. Eighteen patients have been followed more than 10 years from initial diagnosis. No adverse chemotherapy sequelae have been noted in this long-term follow-up group. Chemotherapy toxicity data are available for 54 patients (VAC, 40; PVB, 10; BEP, 4) receiving primary postoperative chemotherapy. Thirty-five VAC-treated patients experienced total white blood cell counts of less than 3000 cells/PI, usually with the first course of therapy, and twenty-three patients were hospitalized for neutropenia and fever. A syndrome of myalgias, particularly low back pain, lethargy, and stomatitis usually preceded the fever and neutropenia by 2 to 4 days. Dose reductions were necessary for 24 patients on VAC who experienced neutropenia. Mild neurosensory toxicity was routinely observed in association with vincristine therapy. Severe neurosensory or neuromotor toxicity required early discon-

OVARIAN

29

GERM CELL MALIGNANCIES

-/

tinuation of treatment in 3 patients. Nausea and vomiting were routinely experienced by all patients receiving VAC therapy but 5 patients had to be hospitalized specifically for persistent nausea, vomiting, and dehydration. Seven of ten PVB-treated patients experienced luekopenia of less than 3000 cells/p1 and three of ten had total white blood cell counts of less than 1000 cells/pi. Five PVBtreated patients were hospitalized for neutropenia and fever, one of whom experienced a second episode requiring hospitalization. Hospitalization was also necessary for 1 patient experiencing severe myalgias and a second patient required psychiatric hospitalization for a reactive depression. Two of four patients treated with BEP had leukopenia less than 3000 cells/p1 and one of these patients had a leukopenia less than 1000 cells/pi. One patient experienced severe bladder pain and urinary frequency that required hospitalization and discontinuation of BEP therapy. Five of sixty-two women in whom preservation of reproductive function was attempted had metastases documented in paraaortic lymph nodes (three dysgerminomas, one endodermal sinus tumor, one embryonal carcinoma). One additional patient had benign glial metastases in paraaortic lymph nodes. Five of these six are alive and well 63-116 months following diagnosis. One committed suicide. No cancer was found at the postmortem examination. Only one of these six patients has attempted to conceive and that patient delivered normal twins. Fourteen additional patients in this series who have had preservation of reproductive function (12 following VAC, 2 following PVB) have conceived at this time. Nine patients have had one, four have had two, and one patient

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