Malignant Germ Cell Tumors of the Ovary
KRISHNANSU TEWARI, MD, FABIO CAPPUCCINI, MD, PHILIP J. DISAIA, MD,
MICHAEL L. BERMAN, MD, ALBERTO MANETTA, MD, AND
MATTHEW F. KOHLER, MD
Objective: To evaluate the efficacy of adjuvant therapy for
ovarian germ cell tumors.
Methods: We reviewed records of women who had malig-
nant germ cell tumors of the ovary from 1977–1997.
Results: Seventy-two women had surgical resections of
malignant ovarian germ cell tumors and most received
adjuvant therapy. Fifty-six women (78%) presented with
stage I disease, and 16 (22%) had more advanced disease.
Tumor subtypes included dysgerminoma (n ⴝ 20), yolk sac
tumor (n ⴝ 8), immature teratoma (n ⴝ 29) and mixed germ
cell tumor (n ⴝ 15). Surgical management of the 56 with
stage I disease consisted of total abdominal hysterectomy,
bilateral salpingo-oophorectomy, and extensive surgical
staging in ten women, whereas a conservative surgical
approach, consisting of unilateral adnexectomy with or
without comprehensive surgical staging, was adopted in
later years (n ⴝ 46). Fifty-six women were treated with
postoperative chemotherapy, predominantly platinum-
based regimens. The 5-year actuarial survival rate was 93%.
None of the 36 women who presented after 1984 have died of
disease.
Conclusion: These data confirmed that platinum-based
adjuvant treatments allow most women with ovarian germ
cell malignancies to have conservative surgery without com-
promising survival. (Obstet Gynecol 2000;95:128 –33.
© 2000 by The American College of Obstetricians and
Gynecologists.)
In contrast with more common epithelial ovarian can-
cers that arise from the surface coelomic epithelium,
ovarian germ cell malignancies are believed to originate
from primordial germ cells that migrate into the go-
nadal ridge at 6 weeks of embryonic life.1 Conse-
quently, ovarian germ cell tumors might exhibit a
spectrum of histologic differentiation that mimics a
primitive developing embryo. For example, dysgermi-
noma appears to be descended from relatively undif-
From the Division of Gynecologic Oncology, Department of Obstetrics
& Gynecology, University of California, Irvine—Medical Center, Or-
ange, California.
128 0029-7844/00/$20.00
PII S0029-7844(99)00470-6
ferentiated cells, whereas yolk sac tumors show malig-
nant change in a cell line committed to extraembryonic
differentiation.1 Immature teratomas are derived from
cells predisposed to somatic (embryonic) differentiation
and recapitulate tissue from all three primitive germ
cell layers, ectoderm, endoderm, and mesoderm. When
considered together, the dysgerminoma, yolk sac tu-
mor, immature teratoma, and their hybrid—the mixed
germ cell tumor— comprise more than 90% of malig-
nant germ cell tumors.2 Nongestational choriocarci-
noma, embryonal carcinoma, and polyembryoma man-
ifest rarely as pure entities and comprise the remaining
5–10%.
Although those tumors account for less than 5% of
ovarian cancers, their importance is greater than their
numerical incidence implies because they occur in chil-
dren and young women during the prime of life. The
median age at presentation is 18 years, contrasting
dramatically with perimenopausal or postmenopausal
age associated with epithelial ovarian cancer.1–3 Symp-
toms usually indicate rapidly enlarging abdominopel-
vic masses. Approximately one-third of patients have
ascites, and 10% present with peritonitis secondary to
torsion, infection, or rupture of the ovarian tumor.
Prepubertal patients might manifest signs of precocious
puberty, such as breast development or vaginal bleed-
ing, as a result of hormone production by the tumor.
Materials and Methods
After institutional review board approval, women were
identified by tumor registry abstracts and cross-
referencing files from the Gynecologic Oncology Divi-
sion and the Departments of Pathology and Epidemiol-
ogy at the University of California, Irvine—Medical
Center and Long Beach Memorial Medical Center.
Clinical data were abstracted and follow-up informa-
tion obtained on all women up to death or for a
minimum of 1 year after diagnosis and initial treatment
Obstetrics & Gynecology
Table 1. Clinicopathologic Features
Median (range) age (y) 19 y (9 –37)
Mean (range) tumor diameter (cm) 18 (12– 40)
FIGO
Stage I n ⫽ 56 (78%)
Stage II n ⫽ 3 (4%)
Stage III/IV n ⫽ 13 (18%)
Dysgerminoma n ⫽ 20 (stage III/IV, n ⫽ 6)
Yolk sac tumor n ⫽ 8 (stage III/IV, n ⫽ 2)
Mixed germ cell tumor n ⫽ 15 (stage III/IV, n ⫽ 3)
Immature teratoma n ⫽ 29 (stage III/IV, n ⫽ 2)
Grade I n⫽6
Grade II n ⫽ 10
Grade III n ⫽ 13
FIGO ⫽ International Federation of Gynecology and Obstetrics.
for ovarian cancer. Kaplan-Meier Life Table Analysis
was used to calculate actuarial 5- and 10-year survival
rates. Tumors were classified according to the World
Health Organization System4 except that the entity
previously termed “endodermal sinus tumor” is now
categorized under the tumor subtype “yolk sac tumor.”
Histologic grading of immature teratoma was accord-
ing to criteria of Thurlbeck and Scully5 modified by
Norris et al.6 Surgical stage was assigned retroactively
as outlined by the International Federation of Gynecol-
ogy and Obstetrics (FIGO).7
Results
Seventy-two women were treated from 1977–1997 for
malignant ovarian germ cell cancer. They were classi-
fied as having had dysgerminomas (n ⫽ 20), yolk sac
tumors (n ⫽ 8), immature teratomas (n ⫽ 29), or mixed
germ cell tumors (n ⫽ 15). The median (range) age at
presentation was 19 (9 –37) years. Most women reported
symptoms of increased abdominal pain over 2– 6 weeks,
with 70% presenting with rapidly enlarging abdomino-
pelvic masses. Four women presented with menstrual
irregularities, two of whom had menarche less than 6
months before diagnosis. The median tumor diameter
was 20 cm, four women had germ cell malignancies
with diameters less than 15 cm, and twelve women
(17%) had tumors with diameters greater than 30 cm.
There was evidence of unilateral hydronephrosis on
imaging studies in seven cases, and one had radio-
graphic evidence of inferior vena cava compression.
Fifty-six (78%) presented with FIGO surgical stage I
disease, three (4%) had pelvic metastases (stage II), and
13 (18%) had advanced (stage III/IV) disease (Table 1).
With respect to individual histologic subtypes, six of
20 women with pure dysgerminoma had stage III or IV
disease with evidence of lymphatic dissemination. Five
of 10 women from whom serum lactate hydrogenase
was collected had elevated levels. There were bilateral
VOL. 95, NO. 1, JANUARY 2000
ovarian tumors in three women, all of whom had
clinically apparent contralateral ovarian metastases.
One woman had evidence of dysgenetic gonads with a
46 XY karyotype.
Two of eight women with yolk sac tumors had
advanced stage disease, manifest as hematogenous dis-
semination of tumor cells to lung or liver. All eight had
elevated pretreatment alpha-fetoprotein titers. Two of
29 women with immature teratoma presented with
extrapelvic metastases (ie, intraperitoneal spread
throughout the abdomen with omental, small bowel
mesentery or liver capsule involvement). The histologic
grade distribution among them included grade I (n ⫽
6), grade II (n ⫽ 10), and grade III (n ⫽ 13). Six women
had evidence of a mature cystic teratoma involving the
opposite ovary. The 15 women diagnosed with mixed
germ cell tumors included three who presented with
stage III/IV disease. Sixty percent of mixed tumors (n ⫽
9) contained dysgerminomatous components.
For ten women who presented with early stage
disease in the early years of the study (1977–1979),
initial surgical management included total abdominal
hysterectomy (TAH), bilateral salpingo-oophorectomy
(BSO), and staging procedures (omentectomy, perito-
neal biopsies, pelvic and para-aortic lymphadenecto-
mies, and pelvic washings). A more conservative sur-
gical approach of unilateral adnexectomy with or
without surgical staging was adopted in later years
(1980 –1997) for 46 women. Unless they were pregnant
at diagnosis (n ⫽ 1), women who presented with
advanced stage disease had TAH, BSO, and aggressive
tumor debulking (n ⫽ 15). Optimal surgical cytoreduc-
tion was accomplished in all 72 women.
With appropriate renal shielding, postoperative frac-
tionated abdominal irradiation with a pelvic boost was
administered to a mean dose of 3.2 Gy to five women
diagnosed with stage IB and above dysgerminoma from
1977–1982. There were no acute toxicities requiring
interruption of radiotherapy. Postoperative systemic
chemotherapy was administered to 56 women, includ-
ing all with yolk sac and mixed germ cell tumors and 23
with high-risk profile immature teratomas (disease be-
yond stage IA or grade II or III) and ten with dysger-
minoma who presented after 1982 (Table 2). The pri-
mary chemotherapeutic regimens included vincristine,
actinomycin-d, and cyclophosphamide (1977–1980, n ⫽
12); vinblastine, bleomycin, and cisplatin (1981–1986,
n ⫽ 21); and bleomycin, etoposide, and cisplatin (1987–
1997, n ⫽ 23).
Transient alopecia and nausea and vomiting were
universal, but only ten patients had dehydration severe
enough to warrant hospital admission, predominantly
women receiving vinblastine, bleomycin, and cisplatin.
Eight women required admission to the hospital sec-
Tewari et al Treatment of Germ Cell Tumors 129
Table 2. Adjuvant Chemotherapy implants free of immature neural elements observed
1977–1980 1981–1986 1987–1997 along the mesentery, pelvic sidewalls, and encasing
VAC VBP BEP Total regions of the liver. Two women had macroscopic
Tumors evidence of residual disease and two others had micro-
Yolk sac tumor 3 3 2 8 scopic evidence of persistent disease. All four received,
Dysgerminoma 4 6 10 at minimum, second-line systemic therapy with a plat-
Mixed tumor 5 5 5 15 inum-based regimen, and three survived.
Immature teratoma 4 9 10 23
After initial treatment (ie, surgery with or without
Total 12 21 23 56
Severe toxicities* postoperative radiotherapy-systemic chemotherapy or
Dehydration 2 6 2 10 reassessment laparotomy), there were four clinical re-
Neutropenic fever 5 3 8 currences, one 10 years after diagnosis of an early-stage,
Sepsis 1 1 grade I immature teratoma. All four women had sec-
Pulmonary injury 1 1
ondary cytoreduction (n ⫽ 2) or second-line systemic
VAC ⫽ vincristine, actinomycin-d, and cyclophosphamide; VBP ⫽ therapy (n ⫽ 4), and three survived.
vincristine, bleomycin, and cisplatin; BEP ⫽ bleomycin, etoposide, and
cisplatin. Five deaths were associated with progressive disease
* Numbers denote total number of affected women requiring hospi- during initial systemic treatment (n ⫽ 2), noncompli-
tal admission. ance (n ⫽ 1), persistent disease at reassessment laparot-
omy (n ⫽ 1), or recurrence (n ⫽ 1). The two women with
disease progression included one with an advanced-
ondary to neutropenic fever, five of whom received stage, mixed germ cell tumor that did not respond to
vinblastine, bleomycin, and cisplatin. Among 22 fourth-line salvage chemotherapy and one with a stage
women treated with vinblastine, bleomycin, and cispla- I yolk sac tumor that did not respond to therapy during
tin, there was one case each of fulminant sepsis and the vincristine, actinomycin-d, and cyclophosphamide
bleomycin-induced pulmonary injury, both of which era. A noncompliant woman with a stage IA, grade II
responded to aggressive medical management in the immature teratoma who initially refused adjunctive
intensive care unit. There were no treatment-induced treatment also died of progressive disease. A woman
deaths among the women given postoperative chemo- with an advanced-stage intraperitoneal dysgerminoma
therapy. who received primary chemotherapy and had a posi-
Six women in the study (8%) were pregnant at tive second-look laparotomy subsequently did not re-
diagnosis. Five had unilateral adnexectomies between spond to salvage therapy and died of disease. One
10 and 26 weeks’ gestation, of whom one also received woman who relapsed after radiotherapy for dysgermi-
three courses of bleomycin, etoposide, and cisplatin noma had an occult focus of radioresistant yolk sac
from 26 –35 weeks’ gestation for metastatic dysgermi- tumor discovered at autopsy.
noma. They each delivered healthy infants beyond 35 Overall, 67 women (93%) are alive without evidence
weeks’ gestation. The sixth woman was diagnosed with of disease at a median (range) follow-up of 10.5 (1–18)
a stage IIIC mixed germ cell tumor and elected preg- years. The 5- and 10-year actuarial survival rates are
nancy termination at 18 weeks to begin adjuvant sys- each 93%, including 50 women (94%) diagnosed with
temic treatment immediately. stage I disease and 11 (85%) with stage III or IV disease.
After completion of postoperative first-line systemic All six women diagnosed during pregnancy are alive
chemotherapy, 50 of 56 women had apparent complete without evidence of disease 1–16 years since diagnosis.
clinical remissions with no measurable disease. Six None of the women who received etoposide as part of
women had disease progression during first-line sys- the bleomycin, etoposide, and cisplatin regimen have
temic treatment, three of whom were rescued with experienced secondary malignancies at 1–10 years of
second-line chemotherapy totaling 53 of 56 who had follow-up.
complete clinical remission after first- or second-line
systemic therapy.
Discussion
From 1977–1992, forty-one reassessment laparoto-
mies were done on women with no clinical evidence of Before 1940, treatment for ovarian germ cell malignan-
disease within 6 weeks after completion of chemother- cies consisted primarily of surgery alone, and survival
apy, predominantly in women with high-risk profile was rare.2 During the 1940s, the use of radioisotopes
malignant teratomas (n ⫽ 23). Second-look laparoto- and postoperative radiation therapy provided a sur-
mies were negative in 37 women, nine of whom showed vival advantage to some women with dysgerminoma.2
evidence of chemotherapeutic retroconversion (or in Unfortunately, the favorable survival with postopera-
situ destruction) of immature teratomas, with benign tive radiation of women with dysgerminoma was not

130 Tewari et al Treatment of Germ Cell Tumors Obstetrics & Gynecology

experienced by women with nondysgerminomatous
tumors, all of which are radioresistant.
Prognoses for women with nondysgerminomatous
tumors did not improve until the 1970s. In 1975, Smith
and Rutledge8 reported that 15 of 20 women with
nondysgerminomatous tumors went into remission af-
ter therapy with vincristine, actinomycin-D, and cyclo-
phosphamide. In the ensuing years, combination che-
motherapy, primarily the vincristine, actinomycin-D,
and cyclophosphamide regimen, became widely used
as adjunctive management of ovarian germ cell malig-
nancies, with sustained remissions in up to 75% of
women with early-stage disease and in excess of 50%
for women with advanced disease.2 Vincristine and
actinomycin-D were associated with peripheral neuro-
pathy and myelosuppression, whereas cyclophospha-
mide was associated with potential risks of hemor-
rhagic cystitis and gonadal dysfunction.
The evolution of systemic treatment for ovarian germ
cell cancer has paralleled the advances made in the
treatment of testicular germ cell cancers because of the
biologic similarity between ovarian and testicular germ
cell tumors.1 On the basis of the testicular cancer
experiences of Einhorn and Donahue,9 the vinblastine,
bleomycin, and cisplatin regimen was made available
during the early 1980s for women with germ cell
tumors.2 A principal advantage of that regimen ap-
peared to be increased efficacy with cisplatin. The
regimen also required a far shorter course than the
standard 2 years of viscristine, actinomycin-D and
cyclophosphamine chemotherapy. However, the vin-
blastine, bleomycin, and cisplatin regimen showed in-
creased myelosuppression and peripheral neuropathy
due to combining vinblastine and cisplatin, a 2% risk of
bleomycin-induced pulmonary fibrosis, and interstitial
pneumonitis. Cisplatin also caused significant nausea
and vomiting, electrolyte aberrations, and nephrotoxic-
ity.
During the same year that Einhorn and Donahue’s
report was published, the epipodophylin derivative
etoposide was shown to have single-agent activity in
refractory testicular cancer. (Newlands ES, Bagshawe
KD. Epidodophylin derivative (VP-16-23) in malignant
teratomas and choriocarcinomas. Lancet 1977;2:87; Let-
ter). Its further efficacy as part of the bleomycin, etopo-
side, and cisplatin regimen for testicular cancer was
shown in subsequent reports.2 By eliminating vinblas-
tine and lowering the total cumulative dose of bleomy-
cin, the bleomycin, etoposide, and cisplatin regimen
had the theoretical advantage of overall decrease in
toxicities (ie, myelosuppression and peripheral neuro-
pathy) compared with the vinblastine, bleomycin, and
cisplatin regimen. It also was believed that with cispla-
tin as part of the chemotherapy regimen, efficacy would
VOL. 95, NO. 1, JANUARY 2000
not be compromised, although the need for aggressive
antiemetic prophylaxis remained. The potential for sub-
sequent leukemia secondary to etoposide was a disad-
vantage of the bleomycin, etoposide, and cisplatin reg-
imen.
Cooperative multi-institutional prospective random-
ized trials have been designed by the Gynecologic
Oncology Group to examine the efficacy of combination
chemotherapy regimens for ovarian germ cell can-
cer.10 –13 In 1985, Slayton and colleagues10 reported on
the postoperative viscristine, actinomycin-D, and cyclo-
phosphamine trial in 76 patients (protocol 10-11), with a
clear survival advantage in women whose tumors had
been debulked optimally before chemotherapy. In 1989,
Williams and coworkers11 published the Gynecologic
Oncology Group experience with vinblastine, bleomy-
cin, and cisplatin in 89 women who had advanced
nondysgerminomatous malignancies (protocol 45),
with a survival rate of 71% at 2 years’ median follow-
up. In 1991, Williams12 also reported the results of
platinum-based therapy for advanced dysgerminoma
(protocol 45:vinblastine, bleomycin, and cisplatin and pro-
tocol 90:bleomycin, etoposide, and cisplatin/viscristine,
actinomycin-D, and cyclophosphamine); 19 of 20
women were disease-free at a median follow-up of 26
months. In 1994, Williams et al13 reported on the
bleomycin, etoposide and cisplatin trial (protocol 78) in
which 91 of 93 women were alive without disease at a
minimum of 2 years’ follow-up. Of concern was the
appearance of one case each of acute myelomonocytic
leukemia and malignant lymphoma, at 22 months and
69 months after treatment, respectively.
Since 1980, additional reports have documented the
efficacy of cisplatin-based regimens in women with
ovarian germ cell cancers.2,3,14 –24 Table 3 shows primar-
ily North American and European single-institution
experiences with platinum-based systemic chemother-
apy in postoperative management of primary and re-
current nondysgerminomatous or dysgerminomatous
ovarian cancers.14 –24 The tabulated series included a
minimum of five treated women. The present series is
on the last line of the table. Most of those series contain
experiences with vinblastine, bleomycin, and cisplatin
regimen. We may anticipate the availability of addi-
tional reports as experience with the bleomycin, etopo-
side, and cisplatin regimen accumulates.
In the present series, only four of 44 women treated
with vinblastine, bleomycin, and cisplatin or bleomycin,
etoposide, and cisplatin alone did not go into remission.
Two of the women died, and two who did not respond
completely to bleomycin, etoposide, and cisplatin suc-
cessfully went into remission with vinblastine, bleomy-
cin, and cisplatin or alternating bleomycin, etoposide,
and cisplatin and viscristine, actinomycin-D, and cyclo-
Tewari et al Treatment of Germ Cell Tumors 131
Table 3. Sustained Remissions Using Platinum-Based
Chemotherapy
Institution Remission
Stanford University (California)15 9/9
Cross Cancer Institute (Canada)16 13/14
Osaka University (Japan)17 4/5
University of Brescia (Italy)18 9/13
University Hospital Groningen (The 11/13
Netherlands)†19
Royal Marsden Hospital (United 14/16
Kingdom)†20
Memorial Sloan-Kettering Cancer 21/33
Center (New York)†21
University of Barcelona (Spain)22 13/14
M.D. Anderson Hospital and Tumor 35/41
Institute (Texas)†23
Istituto Nazionale Tumori (Italy)24 16/24
Hellenic Cooperative Oncology 44/49
Group (Greece)25
University of California, Irvine 40/44
Total 229/275
* Median follow-up not given in manuscript.
†
Denotes institutions that have reported their platinum-based expe-
riences as part of two published manuscripts; the most recent citation
is listed, and the earlier publication is contained within the cited
reference (a complete list of references is available upon request from
the present authors).
phosphamine (Gynecologic Oncology Group Protocol
90). That observation is noteworthy because some of the
series listed in Table 3 had sustained remissions in
women who received platinum-based regimens as part
of second-line therapy. Salvage systemic therapy has
proven to be curative in many women with refractory
ovarian germ cell cancers, including those who were
heavily pretreated, dramatically different from the dis-
mal biologic behavior of refractory and recurrent epi-
thelial ovarian cancer.
With an actuarial survival rate of 93% at 5 and 10
years, our data confirmed that effective adjuvant treat-
ments now allow most women with ovarian germ cell
malignancies to have conservative surgery without
compromising survival. The plateau of the survival
curve beyond 5 years shows a cured population. The
observation that 11 of 13 women with metastatic stage
III and IV disease have gone into remission further
attests to the efficacy of combination chemotherapy,
particularly platinum-based regimens. None of the 36
women in our series who presented after 1984 are dead
of disease. We have observed a modern revolution in
prognoses rivaled only by the near complete curability
of gestational trophoblastic disease.
Ovarian germ cell malignancies are now highly treat-
able solid tumors. The nearly complete curability of the
disease makes identifying risk factors that portend poor
outcomes after modern chemotherapy difficult. Anec-
132 Tewari et al Treatment of Germ Cell Tumors
dotally we found that in addition to those with ad-
vanced disease, women who were noncompliant with
Median therapy or whose tumors had occult mixed elements
follow-up (y) might be at risk of treatment failure and death. Exten-
2.5 sive patient education is essential, and detailed patho-
3 logic sampling of the tumor is mandatory and should
2– 4.5* include at least one slide for every cm of maximum
2
tumor diameter.
5.5
Thorough surgical staging to confirm apparent FIGO
1.5, 2 stage I, grade I, immature teratomas or apparent FIGO
stage I dysgerminomas also is crucial because it might
1.5, 3 identify women who can safely avoid postoperative
chemotherapy. Higher-stage– higher-grade immature
4.5
0.75–7† teratomas, higher-stage dysgerminomas and all women
with yolk sac tumors and mixed germ cell tumors need
5.5 postoperative systemic treatment. Women with malig-
3.25 nant ovarian germ cell tumors in whom first-line adju-
vant therapy fails might still be salvageable. They
8
should be referred to facilities where effective second-
and third-line regimens are available.
With the evolution of modern platinum-based che-
motherapy for ovarian germ cell malignancies, most
women will be able to retain their menstrual and
reproductive potential after treatment. The efficacy of
chemotherapy now allows conservative surgery (ie,
unilateral salpingo-oophorectomy), with potential pres-
ervation of fertility. Modern treatment emphasizes
shorter courses of chemotherapy and avoidance of
prolonged exposure to alkylating agents, which charac-
terized older treatment regimens and led to substantial
ovarian toxicity. Women who retain one ovary might
avoid sterility and premature ovarian failure, and the
attendant risks of accelerated cardiovascular disease
and osteoporosis.
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Address reprint requests to:
Matthew F. Kohler, MD
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Medical University of South Carolina
171 Ashley Avenue
Charleston, SC 29425-2233
E-mail: kohlermf@musc.edu
Received March 12, 1999.
Received in revised form June 11, 1999.
Accepted July 1, 1999.
Copyright © 2000 by The American College of Obstetricians and
Gynecologists. Published by Elsevier Science Inc.
Tewari et al Treatment of Germ Cell Tumors 133