Granulosa-Theca Cell Tumors Medication

Surgical treatment is considered first-line therapy for patients with GCTs. Chemotherapy can be used as adjuvant therapy in patients with advanced or recurrent disease and has been effective for improving the disease-free survival. The rarity of this tumor has precluded randomized control trials; therefore, no prospective data are available regarding overall survival in high-risk patients who receive adjuvant chemotherapy compared to those who have not.

The optimal chemotherapy regimen has been hard to identify given that the overall incidence of GCTs is relatively low. Various chemotherapy regimens have been used in patients with GCTs, with varying toxicity and response rates.

Single-agent chemotherapy with alkylating agents has been used in patients with GCTs with only modest partial response rates. Current chemotherapy regimens usually consist of multidrug regimens and most commonly include platinum as one of the agents.

Bleomycin, etoposide, and cisplatin regimen

Bleomycin, etoposide, and cisplatin (BEP) regimen also has been studied in patients with advanced and recurrent GCTs. In 1999, Homesley et al reported the Gynecologic Oncology Group's experience using this regimen and included patients with all types of ovarian sex cord–stromal tumors, although 48 patients had GCTs. Patients with gross residual disease, positive findings on peritoneal cytology, and recurrent tumors were included.^[16]

Of patients undergoing second-look surgery, 14 of 38 (37%) had a complete response on second look laparotomy. Additionally, 40% of the 25 patients with measurable disease had an objective response to this regimen. No recurrence or progression of disease was observed in 11 of 16 patients with primary advanced disease (68%) and 21 of 41 patients with recurrent disease (51%). However, only half the patients had follow-up of 3 years or longer. Only measurable disease was found to be a predictor of both overall survival and progression-free interval. Again, significant toxicity was noted, with bone marrow suppression being most common (79%), followed by GI toxicity.

The BEP regimen is bleomycin at 20 U/m² (not to exceed 30 U) IV q3wk for 4 courses, etoposide at 75 mg/m² IV on days 1-5 q3wk for 4 courses, and cisplatin at 20 mg/m² IV on days 1-5 q3wk for 4 courses.

Cisplatin, vinblastine, and bleomycin regimen

The cisplatin (Platinol), vinblastine, and bleomycin (PVB) regimen has been studied most recently and shows moderately high response rates. Pecorelli et al showed complete and partial response rates of 28% and 24%, respectively, with 25.4-month median survival in patients who had not received prior chemotherapy or radiation. An additional 13 patients in their study received prior radiation. Their complete, partial, and overall response rates were 38%, 38%, and 77%, respectively. Median survival in this group was 41.1 months. Hematologic toxicity, nausea, vomiting, and peripheral neuropathy were common, and pulmonary toxicity due to bleomycin was observed in a few patients.^[31] Earlier studies by Zambetti et al^[45] and Colombo et al^[7] showed similar response rates but with severe bone marrow and pulmonary toxicity.

The PVB regimen is cisplatin at 20 mg/m²/d IV for 5 days q3wk for 3-4 courses; bleomycin at 20 U/m² (not to exceed 30 U) IV qwk for 7 courses, followed by an 8th course during the 10th week; and vinblastine at 12 mg/m² IV q3wk for 3-4 courses.

Other regimens

Older multidrug regimens included (1) cyclophosphamide, doxorubicin (Adriamycin), and cisplatin regimen, which includes cyclophosphamide at 500 mg/m² IV, Adriamycin at 40-50 mg/m² IV, and cisplatin at 40-50 mg/m² IV all given q4wk for 4-6 courses; (2) cisplatin and doxorubicin; and (3) cyclophosphamide, actinomycin, and 5-fluorouracil. These regimens have the benefit of fewer and less serious adverse effects. However, response rates often were poorer than for those of the newer cisplatin-based regimens.

Much less information is available for JGCTs with regard to treatment of advanced disease and recurrences. These tumors tend to behave more aggressively, with earlier recurrences and poorer responses to chemotherapeutic agents. Case reports detailing complete responders can be found for patients treated with carboplatin and etoposide; methotrexate, actinomycin D, and chlorambucil; and methotrexate, actinomycin D, and cyclophosphamide. However, long-term survival rates in patients with JGCTs have been disappointing.

Current research includes the activity of taxanes in the treatment of GCTs, particularly for recurrence in patients previously treated with BEP. A retrospective review from the MD Anderson Cancer Center suggests that response to taxanes with or without platinum may be similar to that of the BEP regimen with less toxicity. Further studies are ongoing.

Experimental medications

Several recent case reports have raised the possibility of the use of hormonal therapy in the management of recurrent granulose-theca cell tumors. Responses to medroxyprogesterone acetate, GnRH agonists, and megestrol (Megace)^[3] have all been reported in a small number of patients with progressive disease not responsive to chemotherapy.

Several recent reports have documented the use of the aromatase inhibitor anastrozole, which inhibit the conversion of androstenedione to estrone, in the management of patients who previously received surgery and chemotherapy.^[19] Several patients with recurrent disease demonstrated normalization of their serum inhibin, decrease in tumor size, and an increase in disease-free survival. Several authors have recommended aromatase inhibitors as a treatment strategy for recurrent and refractory disease. Currently, however, the number of cases are too small to draw any conclusions, and the use of aromatase inhibitors should be considered strictly experimental.

Class Summary

Adjunct chemotherapy for GCTs that are higher than stage Ia and for recurrent tumors.

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA crosslinks and denaturation of double helix. Platinum-based alkylating agent. Found in most currently prescribed regimens for ovarian sex cord–stromal tumors. Treatment should be delayed if leukocyte count is < 4000/µL or if platelet count is < 100,000/µL.

Vinblastine (Velban)

Plant-based vinca-alkaloid. Inhibits microtubule formation, which, in turn, disrupts the formation of mitotic spindle, causing cell proliferation to arrest at metaphase.

Bleomycin (Blenoxane)

Glycopeptide antibiotic that inhibits DNA synthesis.

Cyclophosphamide (Cytoxan)

Alkylating agent that inhibits tumor growth by binding to DNA. Limited use currently, but could be tried in second-line regimens.

Doxorubicin (Adriamycin)

Antitumor antibiotic that works by irreversibly binding to DNA, thereby inhibiting transcription.

Actinomycin D (Dactinomycin, Cosmegen)

Antitumor antibiotic that is second-line treatment for ovarian germ cell tumors. Mechanism of action is through binding to guanine, thereby preventing DNA transcription.

5-Fluorouracil (Adrucil)

Cycle-specific antimetabolite that interferes with DNA synthesis by blocking methylation of deoxyuridylic acid. Used in various dosages in a variety of combination chemotherapy regimens.

Etoposide (VP-16, VePesid)

Plant-alkaloid derivative that exerts inhibitory activity at S-G2 phase of the cell cycle.

Class Summary

Prevention of hemorrhagic cystitis in patients being treated with ifosfamide and cyclophosphamide.

Mesna (Mesnex)

Detoxifies metabolites of ifosfamide and cyclophosphamide.

Somewhat controversial but commonly accepted that total dose should be at least 60% of total dose of alkylating agent.

Class Summary

Prevention and treatment of nausea and vomiting associated with chemotherapy.

Ondansetron (Zofran)

Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy.

Granisetron (Kytril)

5-HT3-receptor antagonist.

Palonosetron (Aloxi)

Selective 5-HT3 receptor antagonist with long half-life (40 h). Indicated for prevention and treatment of chemotherapy-induced nausea and vomiting. Blocks 5-HT3 receptors peripherally and centrally in chemoreceptor trigger zone.

Dexamethasone (Decadron)

Used as antiemetic in low doses during chemotherapy. Usually used in multiagent antiemetic regimens with 5HT-3 receptor antagonists.