Treatment of malignant germ cell tumors of the ovary

INTRODUCTION — Ovarian germ cell tumors (OGCTs) are derived from primordial germ cells of the ovary (figure 1). They may be benign or malignant. Malignant germ cell cancers of the ovary include dysgerminomas and nondysgerminomas, which include immature teratomas, embryonal cell carcinoma, yolk sac tumors, primary ovarian (nongestational) choriocarcinomas, polyembryoma, and mixed germ cell tumors [1]. In contrast to epithelial ovarian cancer, they constitute a rare form of ovarian malignancy. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum".)

Dysgerminomas differ from other malignant OGCTs in several ways: they are more likely to be localized to the ovary at diagnosis (approximately two-thirds of cases are stage IA (table 1)), bilateral ovarian involvement is more common (10 to 15 percent), they are more likely to spread in a predictable fashion, and they are more sensitive to radiation therapy.

The management of malignant OGCTs will be reviewed here. Pathology and clinical manifestations of these neoplasms, as well as the treatment of benign OGCTs, are reviewed separately. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis".)

OVERVIEW — In general, the treatment principles for all types of malignant OGCTs are similar to those that guide the management of the more common epithelial ovarian cancer (EOC), with some exceptions:

●Many OGCTs produce tumor products (alpha fetoprotein [AFP], human chorionic gonadotropin [hCG], lactate dehydrogenase [LDH]) that can be measured in the serum. The presence of these markers provides a highly sensitive and specific indicator of the presence of certain histologic components (table 2). Testing for serum tumor markers prior to definitive treatment can provide a diagnostic clue to the presence of an OGCT. In a child, teen, or young woman, the tumor marker results may help with surgical planning, resulting in the preservation of fertility potential. Furthermore, serial assay of these tumor markers is useful for monitoring the response to chemotherapy and for subsequent post-treatment follow-up. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)

●Surgery is required for diagnosis, staging, and treatment. As with EOC, adults with OGCTs should undergo a thorough exploration of the abdomen with complete surgical staging (for apparent early-stage disease) and optimal cytoreduction (for metastatic disease) when safe and feasible.

●Most OGCTs are stage I (table 1) at initial presentation, and most patients can be safely treated with fertility-preserving surgery rather than total abdominal hysterectomy and bilateral salpingo-oophorectomy. (See 'Fertility-sparing surgery' below.)

●Malignant OGCTs occurring in adult women are highly sensitive to platinum-based chemotherapy, and treatment can be curative. This fact, coupled with the poor outcomes from surgery alone (even for stage I disease), has led to routine administration of adjuvant cisplatin-based chemotherapy to most adult patients except those with stage IA or IB dysgerminoma and stage IA, grade 1 immature teratoma.

SURGICAL STAGING AND PRIMARY CYTOREDUCTION — Surgical management of OGCTs is both diagnostic and therapeutic. In general, the scope of the operative procedure depends upon the surgical findings and the patient's desire to maintain fertility and/or avoid exogenous estrogen supplementation.

Areas of controversy include: whether hysterectomy and bilateral salpingo-oophorectomy are required for optimal outcomes in patients with apparent early-stage disease, the extent of cytoreductive surgery in patients with advanced-stage disease, and the role of minimally invasive surgery. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging", section on 'Open laparotomy versus minimally invasive surgery'.)

Staging system — The staging system used for OGCTs is identical to that used for epithelial ovarian cancer (EOC) (table 1). Malignant OGCTs spread via the lymphatics, bloodstream, or by peritoneal surface dissemination.

Staging procedure — The staging procedure for adult women with OGCTs is the same as for EOC. This is described in detail separately. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)

The standard staging procedure for ovarian cancer is total extrafascial hysterectomy with bilateral salpingo-oophorectomy and pelvic and para-aortic lymph node dissection. However, OGCTs often affect children, adolescents, or young women, and fertility-sparing surgery should be performed when possible. (See 'Children and adolescents' below and 'Fertility-sparing surgery' below.)

Peritoneal cytology is collected after the incision is made. Staging also includes omentectomy and cytology of the diaphragm. As with other intra-abdominal gynecologic malignancies, complete staging includes biopsy of any areas where metastases are suspected. Cytoreduction often is performed when metastases are evident.

Laparotomy is generally used. Laparoscopic or robot-assisted approaches are not considered prudent by some experts, but some surgeons have reported success with these techniques [2].

Lymphadenectomy — The overall prevalence of lymph node involvement varies by histology [3,4]:

●Dysgerminoma (18 to 28 percent)

●Mixed germ cell tumors (7 to 16 percent)

●Malignant teratoma (3 to 8 percent)

Lymphadenectomy is generally performed as part of the surgical procedure to guide postoperative treatment recommendations; however, it is associated with some morbidity (eg, increased intraoperative injury, lymphedema). (See 'Adjuvant treatment' below and "Pelvic and paraaortic lymphadenectomy in gynecologic cancers", section on 'Complications'.)

In one large retrospective study, while there was no difference in survival among patients who did or did not undergo lymphadenectomy, lymph node involvement was an independent predictor of poor survival (hazard ratio 2.4, 95% CI 1.0-5.53) [4]. This is consistent with other observational data [3]. In a study of 2774 patients from the National Cancer Database with apparent stage I disease, those undergoing lymphadenectomy (51.4 percent) compared with those not undergoing lymphadenectomy had similar overall survival [4]. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging", section on 'Lymph node evaluation'.)

Initial cytoreduction for advanced disease — For patients with advanced tumors, optimal cytoreductive surgery is associated with improved outcomes, particularly for nondysgerminomatous tumors. However, the benefits and risks of aggressive cytoreductive maneuvers for metastatic disease must be carefully weighed for these chemotherapy-sensitive tumors.

If advanced disease is encountered at initial exploration, cytoreductive surgery should be attempted, following the same principles as established for advanced EOC. As much tumor should be resected as is technically feasible and safe. (See "Cancer of the ovary, fallopian tube, and peritoneum: Surgical cytoreduction".)

Due to the rarity of malignant OGCTs, the benefit of cytoreductive surgery is less well-established than with EOC. However, surgical debulking of large tumor masses plays a central role in the upfront treatment of OGCTs. Despite the sensitivity of OGCTs to platinum-based chemotherapy, tumor volume is one of the most important prognostic factors for outcome. In most clinical series, prognosis is worse for women with metastatic or incompletely resected disease (table 3).

Although randomized trials have not been conducted, there is observational evidence that patients with malignant OGCTs who have optimally debulked disease (ie, all areas of residual disease less than 2 cm) have a higher complete remission rate from chemotherapy and better long-term outcomes than those with bulky unresectable disease:

●In an early trial from the Gynecologic Oncology Group (GOG), the likelihood of disease progression after postoperative chemotherapy with vincristine, dactinomycin, and cyclophosphamide (VAC) was significantly higher in patients who had incompletely as compared with completely resected disease at the time of primary surgery (68 versus 28 percent, respectively) [5].

●A subsequent GOG trial examined the benefit of cisplatin, vinblastine, and bleomycin (PVB) chemotherapy followed by restaging laparotomy in 111 women with advanced (stage II to IV (table 1)) or recurrent malignant OGCTs [6]. Eighty-nine had initial cytoreductive surgery, which was recommended but not mandated. Patients who had tumors other than dysgerminoma and clinically non-measurable disease after initial surgery had a significantly greater chance of remaining progression free than those with measurable disease (65 versus 34 percent).

●Optimal debulking may be more critical for nondysgerminoma tumors. This was shown in a case series of 33 patients with malignant OGCTs, 13 of whom had bulky (>10 cm) residual tumor after primary surgery [7]. All 11 patients with dysgerminoma achieved a complete sustained remission after bleomycin, etoposide, and cisplatin (BEP), regardless of the size of the postsurgery residual disease. Four of six patients with bulky nondysgerminomatous OGCTs were complete responders to chemotherapy; three sustained long-term. By contrast, 15 of 16 nonbulky nondysgerminomatous OGCTs achieved a complete response to chemotherapy, which was durable in 14 cases.

As a result, the majority of women with OGCTs undergo maximal surgical cytoreduction before starting chemotherapy. The central role that upfront surgery plays in OGCTs is in direct contrast to testicular cancer, where surgery is typically reserved for residual masses that remain after chemotherapy. (See "Approach to surgery following chemotherapy for advanced testicular germ cell tumors".)

Despite the importance of upfront surgical debulking, the surgeon should keep in mind the sensitivity of these tumors to cisplatin-based chemotherapy when aggressive resection of metastatic disease is considered, particularly in patients with dysgerminomas. With modern cisplatin-based adjuvant chemotherapy, approximately 80 percent of patients who present with advanced disease will be long-term survivors, even if they have residual disease remaining after cytoreductive surgery [8-12]. (See 'Adjuvant treatment' below.)

In rare instances, the extent of metastatic disease or effusions may be so great or comorbidities may be so significant that a primary surgical approach is not warranted. In such cases, neoadjuvant chemotherapy should be administered. However, little information on outcomes exists, and clinical trials are needed to evaluate outcomes [13,14].

ADJUVANT TREATMENT — We advise most women to undergo adjuvant chemotherapy after surgery for OGCTs. Exceptions to this include adult patients with stage IA, grade 1 immature teratoma and stage IA and IB dysgerminoma because their outcomes are excellent following surgery alone. Although 15 to 25 percent of such patients will recur, virtually all of these women can be treated with platinum-based chemotherapy or radiation therapy (RT) with curative intent (table 4). Long-term cure rates are >90 percent. The approach to women with de novo stage IV OGCT, as well as the approach to children with OGCTs, is discussed below. (See 'Treatment of de novo stage IV disease' below and 'Children and adolescents' below.)

Due to the rarity of these tumors, data on efficacy are limited to single-arm clinical trials [6,15] or retrospective series [9,12,16-21], often with small numbers of patients enrolled or evaluated. However, as with testicular germ cell tumors (GCTs), the receipt of adjuvant chemotherapy appears to have improved overall survival following surgery when compared with historical controls. These gains in outcome date back to one of the original studies from 1975, which reported that combination chemotherapy (vincristine, actinomycin-D, plus cyclophosphamide) resulted in the survival of 15 of 20 women with nondysgerminomas [22]. The evolution of chemotherapy to incorporate platinum agents mirrors that of testicular GCTs, and cisplatin-based chemotherapy is now considered the standard of care for patients in whom adjuvant treatment is indicated. Applying the same cisplatin-based combination chemotherapy regimens to OGCTs has resulted in dramatically improved outcomes; at least 90 percent of women with early-stage OGCTs and up to 80 percent of those with advanced disease are long-term survivors [21].

Platinum-based therapy — Multiple platinum-based regimens have been used for OGCTs, including:

●Bleomycin, etoposide, and cisplatin (BEP) (table 5)

●Etoposide and carboplatin (see 'Substitution of cisplatin with carboplatin' below)

●Etoposide and cisplatin (EP). While this regimen has very limited use given preference for BEP, it is an appropriate option for patients who cannot tolerate bleomycin. Based on data from the treatment of testicular GCTs, EP and BEP are likely to have equivalent activity. Although there are no prospective data to inform the optimal number of cycles, three cycles of EP are usually administered for patients deemed to be at a lower risk of recurrence (eg, a "good-risk" cohort). For those with a higher risk of relapse, four cycles are administered.

Unfortunately, there is no consensus definition for prognostic risk groups. One simple categorization would take into account stage at diagnosis (see 'Prognosis' below):

●Good risk – Stage IA disease

●Intermediate risk – Stage IC to III

●Poor risk – Stage IV

Although there are only limited data, carboplatin may be a reasonable alternative for women who cannot tolerate cisplatin for whatever reason.

Bleomycin, etoposide, and cisplatin — For most patients, the regimen of choice is BEP. Long-term survival rates with surgery followed by adjuvant BEP are 95 to 100 percent for early-stage nondysgerminomatous tumors and 75 to 80 percent for those with advanced disease at presentation [23,24]. Results are even more favorable for ovarian dysgerminomas regardless of stage at presentation [9,25]. However, the toxicities associated with this regimen can be significant, including risks for acute- and later-onset pulmonary toxicity associated with bleomycin, an increased risk of therapy-related myeloid neoplasms due to etoposide, and risks for long-term renal and neurotoxicity due to cisplatin. (See "Bleomycin-induced lung injury" and "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis" and "Cisplatin nephrotoxicity" and "Overview of neurologic complications of platinum-based chemotherapy".)

For patients who cannot receive bleomycin for whatever reason, alternative regimens incorporate EP, based on an extrapolation from data in men with testicular GCTs, or etoposide plus carboplatin. (See 'Substitution of cisplatin with carboplatin' below.)

Dose and schedule — As in the treatment of testicular GCTs, full doses of all agents should be administered at the scheduled time regardless of the white blood cell count; the curative potential of systemic chemotherapy may otherwise be compromised. Low blood cell counts at the beginning of a scheduled subsequent course of chemotherapy do not mandate dose reductions or treatment delay. If the previous cycle was complicated by febrile neutropenia or some other significant clinical event, the administration of hematopoietic growth factors during subsequent cycles is warranted in order to avoid dose reduction. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Secondary prophylaxis'.)

Nondysgerminomas — Although the data are limited, adjuvant BEP (table 5) for three cycles appears to prevent recurrences, especially in well-staged patients. This was shown in a single-arm study conducted by the Gynecologic Oncology Group (GOG) where 93 women with stage I, II, or III nondysgerminomatous OGCTs were treated with three courses of BEP [15]. With a range of follow-up between 4 and 90 months, 91 were alive and free of recurrence. However, two patients developed a treatment-related hematologic secondary malignancy. (See 'Secondary malignancies' below.)  

Dysgerminomas — As in the treatment of nondysgerminoma, the regimen of choice is BEP. The optimal number of cycles has not been established in randomized trials. In our practice, we administer three courses of adjuvant therapy for completely resected stage I disease and four courses for those with more advanced-stage disease. In one representative series of 26 patients with pure ovarian dysgerminoma (54 percent stage IIIC or IV (table 1)), 25 (96 percent) remained continuously disease-free following at least three cycles of BEP chemotherapy [26].

Substitution of cisplatin with carboplatin — The available data, much of them obtained in children with GCTs or in women with completely resected dysgerminoma, suggest that in contrast to testicular GCTs, carboplatin may represent an acceptable therapeutic alternative to cisplatin for the treatment of OGCTs [9,10]. In a review of 126 patients with advanced-stage dysgerminoma from six clinical trials (three pediatric and three adult), those receiving carboplatin-based (56 patients) compared with cisplatin-based (70 patients) chemotherapy had similar five-year event-free survival [27]. Although further study is needed, there is a clear trend toward the use of carboplatin-based regimens for metastatic dysgerminoma. The administration of carboplatin in younger patients is discussed below. (See 'Children and adolescents' below.)

In a study performed by the GOG, carboplatin plus etoposide was administered to 42 patients with completely resected stage IB to III dysgerminoma [28]. Treatment consisted of three 28-day courses of carboplatin (400 mg/m² on day 1) plus etoposide (120 mg/m² on days 1, 2, and 3). With a median follow-up of 7.8 years, no patient had a disease recurrence, although one died of a presumably unrelated lung adenocarcinoma.

Surveillance as an alternative option — Although surveillance following primary surgery cannot be routinely recommended for adult patients with a malignant OGCT, there are some data that surveillance might be appropriate, especially for those patients with particular subtypes of stage IA nondysgerminoma (eg, yolk sac tumor, immature teratoma, mixed GCT, embryonal carcinoma) [29-32]. In one study, the outcomes of 31 patients with stage I disease (median age, 22; range 6 to 45 years) who underwent surgery followed by surveillance were reviewed [29]. With a median follow-up of 11.4 years, the relapse rate was 23 percent (7 of 31 patients). Of these seven patients, six went into remission with chemotherapy. AGCT 1531 is an ongoing international trial sponsored by the Children's Oncology Group and in collaboration with the adult Clinical Trials Network in the United States [33]. In this trial, the low-risk cohort consisting of patients up to 50 years of age with stage I non-dysgerminoma or stage I, grade 2 or 3 immature teratoma are followed with active surveillance following primary surgery. In the standard-risk cohort, which includes children as well as adults up to age 25 years with International Federation of Gynecology and Obstetrics (FIGO) stage IC to III OGCTs, patients are randomly assigned to either cisplatin-based or carboplatin-based chemotherapy.

Radiation therapy — We reserve RT for patients with a dysgerminoma who are not candidates for chemotherapy for whatever reason [34]. RT is not effective for nondysgerminomas, which tend to be radioresistant [35,36]. Although adjuvant RT is effective in the treatment of dysgerminomas [34,37-40], it is not utilized due to the availability of chemotherapy because chemotherapy results in less long-term toxicity.

TREATMENT OF DE NOVO STAGE IV DISEASE — Patients who present with de novo stage IV disease should be offered an attempt at maximal cytoreduction, including resection of metastatic disease if applicable. Following surgery, at least four courses of bleomycin, etoposide, and cisplatin (BEP) (table 5) should be given [41]. Of note, even for women with incompletely resected disease, long-term survival can be expected in over half of these patients [23,42,43]. For patients who are not surgical candidates at the time of presentation, we offer neoadjuvant chemotherapy followed by interval debulking surgery [13,14]. There are ongoing trials, principally for patients with high-risk testicular cancer, exploring the effectiveness of more aggressive therapies, including accelerated BEP or a combination of paclitaxel and BEP.

FERTILITY PRESERVATION — Because most women with OGCTs are young and wish to preserve future childbearing potential, fertility-sparing options should be explored.

Fertility-sparing surgery — Unilateral salpingo-oophorectomy with preservation of a normal-appearing uterus and contralateral ovary is an option for women with clinically apparent early-stage disease. Even after chemotherapy, at least 80 percent of these women will resume normal menstrual function, and those who become pregnant appear to have no increase in pregnancy complications [44,45]. (See 'Premature ovarian insufficiency' below and 'Pregnant women' below.)

The ipsilateral fallopian tube is removed because of the rich lymphovascular connections between the tube and ovary. Oncologic outcomes are not compromised by conservative surgery, even in the face of bulky metastatic disease elsewhere [42,46-51].

The risk of occult contralateral ovarian involvement appears to be greatest with dysgerminomas, although it is likely no higher than 5 to 10 percent [52]. For example, in one study of 98 patients with stage IA dysgerminoma, nine developed disease in the contralateral ovary [52]. These were presumably occult primaries undetected at the time of initial surgery. While some surgeons routinely perform a wedge biopsy of a normal-appearing contralateral ovary, this practice is not universally accepted, as these tumors are particularly sensitive to chemotherapy, and salvage rates are high. (See "Ovarian germ cell tumors: Pathology, epidemiology, clinical manifestations, and diagnosis", section on 'Dysgerminoma'.)

Unnecessary surgery on normal ovaries, even a biopsy, should be avoided because postoperative adhesions are common and can impair fertility. If bilateral salpingo-oophorectomy is required, women with a uterus but no ovaries can become pregnant using an egg donor or their own cryopreserved fertilized eggs/ovarian tissue/oocytes. In addition, women with an ovary but no uterus should be counseled about the potential for use of a gestational carrier. (See "Female infertility: Treatments" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Oocyte cryopreservation — The most established method for preservation of child-bearing potential in women at risk of gonadal failure is embryo cryopreservation. For women who do not have a participating male partner and are not interested in using donor sperm, oocyte cryopreservation is also an option. The decision concerning use of assisted reproductive techniques prior to initiation of chemotherapy should be individualized and must be balanced against the delay in starting therapy. This topic is discussed in detail elsewhere. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

PROGNOSIS — Studies have addressed prognostic factors that might permit risk stratification for future treatment assignment in OGCTs [23,53-55]. As an example, the importance of stage and tumor markers was addressed in an analysis of 148 women with malignant OGCTs, 113 of whom received platinum-based chemotherapy [23]. Five-year survival rates were:

●Stage IC disease (or stage I disease with persistent/increasing tumor markers) – 100 percent

●Stage II – 85 percent

●Stage III – 79 percent

●Stage IV – 71 percent

In addition, tumor markers appear to have prognostic significance in this disease. In the study discussed above, patients who had elevations of both beta-human chorionic gonadotropin (beta-hCG) and alpha-fetoprotein (AFP) were almost five times more likely to die of their disease compared with those with initially normal levels of both markers (one-year survival 50 versus 90 percent, respectively) [23]. An unanswered clinical question is whether the poor prognosis associated with these factors can be reversed by altering the initial treatment strategy [53].

POST-TREATMENT SURVEILLANCE — Most recurrences develop within two years of initial therapy, although as with testicular seminomas, dysgerminomas may recur later (after five years or more).

The optimal post-treatment surveillance strategy has not been established. A reasonable strategy includes the following [41,56]:

●Tumor markers (alpha fetoprotein [AFP], human chorionic gonadotropin [hCG]) repeated regularly. In our practice, we repeat them every month for a period of two years and then less frequently over time.

●Review of symptoms and physical examination every two to four months for the first two years, followed by annual visits every year.

●Radiographic imaging every two to four months for the first two years only in patients whose initial tumor marker levels are not elevated.

POST-TREATMENT ISSUES — The issues for women with OGCTs after treatment has completed are similar to those for women treated for epithelial ovarian cancer (EOC). However, given that these tumors tend to occur in younger women, specific concerns may be present, which are addressed below. Further discussion of survivorship issues after treatment for EOC is covered separately. (See "Approach to survivors of epithelial ovarian, fallopian tube, or peritoneal carcinoma".)

Premature ovarian insufficiency — Although ovarian dysfunction or premature ovarian insufficiency is a risk of chemotherapy, most women who receive platinum-based therapy for three to four cycles recover normal ovarian function [6,11,12,26,44-48]. For these patients, fertility is often spared. However, premature ovarian insufficiency has been reported in women who previously received chemotherapy as children, adolescents, or young adults [57,58]. As an example, one study reported that the incidence of nonsurgical premature ovarian insufficiency was higher among survivors of childhood cancer than control siblings (8 versus 0.8 percent). These data emphasize the importance of pretreatment counseling and planning to ensure the most appropriate treatment is rendered, taking into account the age of the patient and her desires regarding future fertility. (See "Overview of infertility and pregnancy outcome in cancer survivors" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

The impact of platinum-based chemotherapy on adult women’s gonadal function was demonstrated in a representative series of 71 patients treated with fertility-sparing surgery and combination chemotherapy (including cisplatin and bleomycin). Of these, 62 (87 percent) resumed normal menstruation, and 24 of these women subsequently had 37 offspring [45].

In a review of 47 studies that included 2189 patients who underwent fertility-sparing surgery for malignant OGCTs, 79.9 percent received chemotherapy [59]. Overall, the rate of premature ovarian failure was 3.7 percent, and the fecundity rate was 24.6 percent. Of patients attempting pregnancy, 80.6 percent had at least one pregnancy.

Postmenopausal hormone therapy in ovarian cancer survivors is discussed in detail separately. (See "Approach to survivors of epithelial ovarian, fallopian tube, or peritoneal carcinoma", section on 'Menopause'.)

Secondary malignancies — An important cause of late morbidity and mortality in patients undergoing treatment for germ cell tumors (GCTs) is the development of secondary malignancies, both solid tumors and leukemia. Etoposide in particular has been implicated in the development of treatment-related leukemias. The risk is dose-related. The incidence of leukemia is <0.5 percent in patients receiving a typical three- or four-cycle course of bleomycin, etoposide, and cisplatin (BEP; cumulative etoposide dose <2000 mg/m²) [60] compared with as high as 5 percent (representing a 336-fold increase in the likelihood of leukemia) in those receiving over 2000 mg/m² [61].

Despite the risk of secondary leukemia, risk-benefit analyses have concluded that etoposide-containing chemotherapy regimens are beneficial in advanced GCTs; one case of treatment-induced leukemia would be expected for every 20 additionally cured patients who receive BEP as compared with cisplatin, vinblastine, and bleomycin (PVB). The risk-benefit balance for low-risk disease, or for high-dose etoposide in the salvage setting, is less clear. This topic is discussed in more detail elsewhere. (See "Treatment-related toxicity in testicular germ cell tumors", section on 'Second malignancies'.)

Other issues — The limited data on OGCT survivors suggest they are at risk for health disparities and chronic toxicities. For example, one study performed in the United States compared these issues among survivors who were approximately 10 years out from diagnosis (n = 132) and age-matched controls (n = 137) [62]. Of those treated for OGCT, 87 percent had received cisplatin and bleomycin. Major findings were that survivors were:

●Significantly more likely to be diagnosed with hypertension compared with age-matched controls (17 versus 8 percent, respectively).

●More likely to have hypercholesterolemia (10 versus 4 percent), though this difference was not statistically significant.

●More likely to report hearing loss (5 versus 2 percent).

●Significantly more likely to report denial for health insurance (16 versus 4 percent), though overall, health care utilization was similar.

RELAPSED DISEASE — The majority of recurrences develop in the first two years after completion of therapy. As in men with a history of testicular cancer, recurrence is usually detected by a rise in serum tumor markers or the evolution of new disease on radiographic studies. Given the rarity of these tumors, the data to inform the management of patients are of very limited quality [63]. Even small single-arm trials that were open to both male and female patients who had relapsed disease enrolled very few women [64,65]. Therefore, the approach to these patients is based on an extrapolation of the management of men with relapsed germ cell tumors. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

●Patients who were originally treated with surgery alone and then developed relapsed disease should meet with a gynecologic oncologist for consideration of secondary surgery. Regardless of whether surgery is performed, standard first-line chemotherapy should be administered. As in the adjuvant setting, the regimen of choice is bleomycin, etoposide, and cisplatin (BEP). (See 'Adjuvant treatment' above.)

●For patients who were previously treated with chemotherapy (as adjuvant therapy or first-line treatment of stage IV disease) and did not exhibit refractory disease (ie, no evidence of disease progression during or immediately after prior treatment), repeat treatment with a platinum-based regimen is indicated [64].

●For patients who relapse despite first-line treatment for recurrent disease and those with refractory disease, we utilize the approach to men with relapsed and refractory testicular cancer.

Role of surgery — The main utility of surgery for women with recurrent OGCTs is the ability to resect limited metastatic disease, which might alter the subsequent medical treatment. Although only low-quality data are available, they suggest that surgical resection may afford a survival advantage in properly selected patients [66-68]. For example, one single-institution study included 34 women, all of whom progressed after initial chemotherapy and were treated with second-line chemotherapy followed by surgical resection [68]. Compared with women who had residual disease >1 cm, the five-year survival rate was higher among those who were rendered macroscopically disease-free or who had residual tumor ≤1 cm (61 versus 14 percent, respectively). These data suggest that women with recurrent disease may benefit from surgical resection, especially if the disease appears to be resectable.

SPECIAL POPULATIONS

Children and adolescents — The treatment approach to girls with a germ cell tumor (GCT) differs from that for adult women. However, the optimal approach has not yet been characterized, primarily due to the rarity of these cancers. We agree with the position of the Children’s Oncology Group Rare Tumors Disease Committee that further evidence is needed, which will only come through international collaborations in clinical research [69]. An example of how pediatric care differs from management of these tumors in adults is that necessity for and extent of comprehensive surgical staging are controversial in children and adolescents, though not in adult women in whom staging is indicated. (See 'Surgical staging and primary cytoreduction' above.)

Primary treatment — The contemporary pediatric surgical approach tends to consist of peritoneal cytology, primary tumor removal, and biopsy or excision of suspicious implants or lymph nodes, with no further biopsies. Complete surgical staging, which is the standard approach for adult women, is generally not performed in pediatric patients. (See 'Surgical staging and primary cytoreduction' above.)

Future investigations are needed to resolve this disparity in the surgical approach to pediatric and adult patients. This disparity is illustrated in a combined retrospective study performed by the Pediatric Oncology Group and Children’s Cancer Study Group that included 131 girls (mean age, 11.9 years), all of whom underwent surgical resection (if possible for those who presented with advanced-stage disease) followed by adjuvant platinum-based chemotherapy [50]. The main findings were:

●Despite stage at presentation, complete surgical staging was seldom performed. Among the surgical omissions were no nodal sampling (97 percent), no omentectomy (36 percent), and no peritoneal cytology (21 percent).

●The six-year overall survival rates were 95, 94, 97, and 93 percent for stages I (n = 41), II (n = 16), III (n = 58), and IV (n = 16), respectively. The six-year event-free survival rates by stage were 95, 88, 97, and 87 percent.

Although this was a retrospective study, pediatric and adolescent patients appear to have an excellent outcome, likely due to the administration of adjuvant chemotherapy in all patients. However, whether chemotherapy is necessary for all patients is not answered by this study and points to the potential importance of comprehensive surgical staging as a way to help stratify patients at a higher risk of recurrence, for whom adjuvant therapy should be administered.

A study of the Surveillance, Epidemiology, and End Results database identified 2238 patients who underwent surgery for malignant OGCTs [70]. Over time, there was a decrease in the rate of omentectomy in both the pediatric and young adult groups, and a decrease in the rate of hysterectomy in the young adult group only, suggesting a trend toward less extensive surgery in young women.

Treatment after surgery — Although limited data are available, surveillance for girls with stage IA malignant OGCTs appears to be reasonable. In one study, 25 girls with International Federation of Gynecology and Obstetrics (FIGO) stage IA malignant OGCTs were enrolled in a study of the Children’s Oncology Group and underwent surveillance [31]. Although 12 patients had persistent disease or experienced recurrence, 11 were successfully treated with chemotherapy at the time of relapse. An international clinical trial for girls and women with stage IA and IB malignant OGCTs, excluding grade 1 immature teratoma and pure dysgerminoma, is actively recruiting.

Adjuvant chemotherapy is routinely offered to patients with higher-stage disease. The exception is for patients with metastatic immature teratoma, in whom postoperative chemotherapy has not been shown to decrease relapses, based on a combined data analysis of seven pediatric trials including 98 patients, of whom 90 were treated with surgery alone [71]. In general, we advocate for the use of bleomycin, etoposide, and cisplatin (BEP) if chemotherapy is indicated. However, limited data suggest that carboplatin can be used instead of cisplatin in an attempt to reduce toxicities while preserving efficacy.

●In one report, 137 children with extracranial GCTs (recurrent stage I disease and all other patients) received carboplatin (600 mg/m² on day 2), etoposide (120 mg/m² on days 1 through 3), and bleomycin (15 mg/m² on day 3) (JEB) every three to four weeks for two courses beyond clinical remission [10]. The five-year and event-free survival rates were 91 and 88 percent, respectively. No patient had significant renal toxicity, and only one had severe deafness (as a result of a middle ear hemorrhage).

●Favorable long-term outcomes with a similar regimen (carboplatin 600 mg/m² on day 2, etoposide 150 mg/m² on days 1 through 3, and bleomycin 10 mg/m² on day 3) were also noted in a series of 23 consecutive children with advanced GCTs (15 females, six primary to the ovary, 19 stage III or IV) [72]. With a median 58-month follow-up, event-free and overall survival rates were 87 and 91 percent, respectively.

Although some data support the use of carboplatin rather than cisplatin in the pediatric population, more data are needed. An international clinical trial seeking to compare cisplatin- with carboplatin-containing regimens in children and adults is ongoing. Therefore, we reserve carboplatin as a substitute for cisplatin if there are contraindications to the use of cisplatin (eg, renal failure).

Pregnant women — OGCTs often occur in women of reproductive age; therefore, these tumors are one of the more common ovarian malignancies diagnosed in pregnancy [73]. Chemotherapy treatment of OGCTs in pregnant women is discussed separately. (See "Chemotherapy of ovarian cancer in pregnancy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer".)

SUMMARY AND RECOMMENDATIONS

●Malignant ovarian germ cell tumors (OGCTs) include dysgerminomas (analogous to the male testicular seminoma) and nondysgerminomatous tumors. Nondysgerminomatous tumors include immature teratomas, embryonal cell carcinoma, yolk sac tumors, primary ovarian (nongestational) choriocarcinomas, polyembryoma, and mixed germ cell tumors. (See 'Introduction' above.)

●The treatment principles for all types of malignant OGCTs are generally similar and include surgery for diagnosis and staging, cytoreductive surgery if advanced disease is present, and adjuvant chemotherapy in most cases (table 6). (See 'Overview' above.)

●OGCTs occur predominantly in children and young women. For these patients, unilateral salpingo-oophorectomy with preservation of the uterus and the contralateral ovary may be performed if these organs appear normal. Standard surgical staging with total extrafascial hysterectomy and bilateral salpingo-oophorectomy is generally performed on women who have completed childbearing. (See 'Children and adolescents' above and 'Fertility-sparing surgery' above.)

●For most adult women with a newly diagnosed OGCT, we recommend adjuvant chemotherapy (Grade 1B). Our regimen of choice is bleomycin, etoposide, and cisplatin (BEP). Women with stage IA or IB dysgerminoma or stage IA, grade 1 immature teratomas have an excellent prognosis following surgical treatment alone, and therefore, we recommend against administering adjuvant chemotherapy (Grade 1B). (See 'Adjuvant treatment' above.)

●All women should be followed by history and physical exam after the completion of treatment for OGCTs. Serum tumor markers should be followed serially as well. In keeping with the guidelines from the Society of Gynecologic Oncologists, we only perform radiographic surveillance within the first two years if tumor markers were not elevated initially. Given the risk for late relapse, dysgerminomas require annual follow-up for at least 10 years. (See 'Post-treatment surveillance' above.)

●For women who relapse and did not receive chemotherapy previously (ie, in the adjuvant setting), we recommend platinum-based chemotherapy (Grade 1A). As in the adjuvant setting, our regimen of choice is BEP. (See 'Relapsed disease' above.)

●The approach to treatment for women with relapsed disease despite prior treatment with chemotherapy is extrapolated from the approach to men with relapsed or refractory testicular germ cell tumors. (See "Diagnosis and treatment of relapsed and refractory testicular germ cell tumors".)

●For pediatric and adolescent girls (see 'Children and adolescents' above):

•We suggest postoperative surveillance for those with International Federation of Gynecology and Obstetrics (FIGO) stage IA and IB OGCTs (Grade 2C).

•With the exception of patients with immature teratomas regardless of grade, we suggest adjuvant chemotherapy for those with more advanced disease (stage IC to IV) (Grade 2C). For those with immature teratomas regardless of grade, we suggest observation rather than adjuvant chemotherapy (Grade 2C).

•As in adult women, our regimen of choice is BEP. However, carboplatin-based treatment appears to be a reasonable and less toxic regimen for use in this population, especially if there is a contraindication to cisplatin.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to recognize Eva Chalas, MD, FACOG, FACS, Fidel A Valea, MD, and William Mann, Jr, MD, who contributed to an earlier version of this topic review.