Despite major progress achieved in the last decades, epithelial ovarian cancer is still not curable in the majority of patients. Therefore, development of further more active therapy regimens is of crucial importance. The addition of a third active drug to standard TC is one option for improving activity. For this purpose and based on previous work of a Scandinavian group, the Arbeitsgemeinschaft Gynakologische Onkologie Studdiengruppe Ovarialkarziom (AGO-OVAR) developed a triple-drug regimen (TCG) within a multicenter, nonrandomized, two-cohort phase II study (AGO-OVAR 8). This regimen was then taken to a prospectively randomized phase III Intergroup study and was compared to standard TC (protocol AGO-OVAR 9). The phase II protocol AGO-OVAR 8 recruited 55 chemonaive patients after radical debulking surgery for primary epithelial ovarian cancer stages FIGO IC–IV. They received paclitaxel 175 mg/m2, carboplatin area under curve 5, and gemcitabine 800 mg/m2 on day 1 and gemcitabine 800 mg/m2 on day 8, every 3 weeks for six courses. Main toxicities were hematologic with National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grade 3/4 anemia 12.7%, leukopenia 70.9%, neutropenia 76.3%, and thrombocytopenia 45.5%. However, febrile neutropenia occurred only in 1.8%. Grade 3/4 nonhematologic toxicities were rare and occurred in less than 10% of patients. Toxicity-induced treatment delays occurred in 3.1% of cycles and resulted in early treatment cessation in four patients. Dose intensity reached 90.8% for carboplatin and paclitaxel and 73.3% for gemcitabine. Due to the rather high compliance rate and the moderate toxicity profile of the TCG regimen, a prospectively randomized phase III Intergroup study was initiated within the GCIG network. This protocol, AGO-OVAR 9, started in August 2002 and recruitment was completed with 1742 patients in April 2004. Patients who were 18 years or older had to have epithelial ovarian cancer FIGO stages IC–IV and had to be randomized within 6 weeks after primary surgery. The treatment schedule was the same as that evaluated within the preceding phase II protocol. Exclusion criteria contained the common limits with respect to organ functions and medical history. Overall, 1091, 323, and 328 patients were recruited by AGO-OVAR, Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), and Nordic Society of Gynecological Oncology (NSGO), respectively. A total of 882 patients were assigned standard TC (175 mg/m2 3 h/area under curve 5 day1 q 21 × 6) and 860 TCG, respectively. Preliminary data with respect to patient characteristics, treatment compliance, and toxicity were available: 175 (10.1%) patients had FIGO stage IC–IIA and the remaining suffered from advanced disease FIGO stage IIB–IV. Twofold stratification was based on center and on disease characteristics defined as follows: stratum I contained only early ovarian cancer stages FIGO IC–IIA, stratum II was based on stage and residual tumor with FIGO IIB–IIIC and residual tumor 0–1 cm, and stratum III consisted of FIGO IV or residual tumor >1 cm independent from FIGO stage. The strata distribution showed 175, 891, and 676 patients in stratum I, II, and III, respectively. First analysis of safety will be presented and based on 10,367 courses in 1724 patients. A total of 5256 cycles were administered in the TC arm and 5111 cycles in the TCG arm. Most of the patients received a minimum of six cycles of chemotherapy, 86.7% in the TC arm and 86.0% in the TCG arm, respectively.
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