Adjuvant Treatment

Adjuvant therapy decisions are based on stage, histology, and grade of the tumor. For example, stage IA dysgerminomas and stage IA, grade 1 immature teratomas can be observed without the need for further therapy.47 Currently, it is recommended that those with all other stages and grades (regardless of histology) should receive adjuvant chemotherapy.

For dysgerminomas, adjuvant therapy has consisted of radiation therapy or chemotherapy. Before the advent of platinum-based chemotherapy, dysgerminomas were successfully managed with external-beam radiation therapy, with the major side effect being nearly universal ovarian failure, despite attempts at surgically displacing the ovaries.94 Given the success of platinum-based chemotherapy, and the observation that most patients demonstrate normal ovarian function after treatment, chemotherapy has essentially replaced radiation in the setting of adjuvant treatment for dysgerminomas.93

Modern chemotherapy for malignant germ cell tumors of the ovary incorporates BEP. In the 1970s, initial chemotherapy experience in ovarian germ cell tumors came from the GOG, which demonstrated the value of combination chemotherapy with vincristine, dactinomycin and cyclophosphamide (VAC),107 followed later by cisplatin, vinblastine and bleomycin (PVB), which proved superior.109 BEP had been shown to be superior in testicular tumors, and its activity in ovarian germ cell tumors was evaluated in GOG 90, which demonstrated that BEP was superior to PVB in this setting.110 The importance of bleomycin as a component of BEP was proved later in an Eastern Cooperative Oncology Group (ECOG) trial, in which patients treated with BEP had an overall survival rate of 95% compared with 86% for patients treated with etoposide and cisplatin alone.111

Reflecting on data collected in testicular cancer trials, the optimal number of cycles of chemotherapy with BEP is not predetermined but can be altered by the clinical picture of the patient. One trial, which compared three cycles with four cycles of BEP in patients with low-risk testicular cancer, found that the outcomes were generally similar.112 The advantage of one less cycle of chemotherapy is a reduction of early and late side effects of therapy, not the least of which are the pulmonary toxicity associated with bleomycin and the potential late onset of treatment-related leukemias. Studies looking at treatment of favorable (i.e., surgically staged, little to no residual disease) ovarian germ cell tumors have also reported good outcomes with three cycles of BEP.113 However, patients with bulky residual disease should receive four cycles of chemotherapy because no other regimen to date has proved

superior.

Increasingly, surgery has been advocated as the sole primary therapy for selected cases of germ cell tumors. In a prospective, single-institution study, Bonazzi and associates114 followed up 32 patients with pure ovarian immature teratomas, all stages I-II, grades 1-2. In this series, 22 were treated with surgery alone. There were two recurrences, both salvaged with chemotherapy. Marina and colleagues115 reviewed 50 patients with pure immature teratomas, 23 of whom had malignant foci (grades 1-3) and were treated with surgical excision alone. There were four recurrences in this group, and all were salvaged by chemotherapy. Dark and associates116 recently updated their experience with surgery followed by close observation, with chemotherapy reserved for recurrent disease. Briefly, the original study examined a surveillance policy that followed surgical excision in 24 patients with malignant ovarian germ cell tumors stage IA, including nine dysgerminomas, nine immature teratomas, and six endodermal sinus tumors. Seven of eight recurrences were salvaged with chemotherapy, and the only death was due to pulmonary embolism while undergoing treatment. In the updated dataset, the relapse rate was 22% for dysgerminomas and 36% for nondysgerminomas. Ten of 11 recurrences were successfully salvaged; one death was due to chemoresistant disease. All recurrences were noted within 13 months of initial surgery, and the overall disease-specific survival rate was 94%.117 Results such as these from single-institution studies have prompted the Children's Oncology Group to study surgical excision alone in stage I tumors. The data are forthcoming.

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