Stage III and Stage IV Ovarian Epithelial Cancer Treatment
Table 2. Paclitaxel/Platinum Combinations Versus Comparator Arms in Trials
|Trial||Treatment Regimens||No. of Patients||% Early Crossover||Progression-free Survival (mo)||Overall Survival (mo)|
|AUC = area under the curve.|
|a Statistically inferior result (P< .001–< .05).|
|GOG-132||Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)||201||22%||14.2||26.6|
|Cisplatin (100 mg/m2)||200||40%||16.4||30.2|
|Paclitaxel (200 mg/m2, 24 h)||213||23%||11.2a||26|
|MRC-ICON3||Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 6||478||23%||17.3||36.1|
|Carboplatin AUC 6||943||25%||16.1||35.4|
|Paclitaxel (175 mg/m2, 3 h) and carboplatin AUC 6||232||23%||17||40|
|Cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) and cisplatin (50 mg/m2)||421||20%||17||40|
|GOG-111||Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)||184||None||18||38|
|Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)||202||None||13a||24a|
|EORTC-55931||Paclitaxel (175 mg/m2, 3 h) and cisplatin (75 mg/m2)||162||None||15.5||35.6|
|Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)||161||4%||11.5a||25.8a|
Nevertheless, for patients with ovarian cancer, the combination of cisplatin or carboplatin and paclitaxel has been used as the initial treatment (defined as induction chemotherapy) for several reasons:
- GOG-132 was regarded by many as showing that sequential treatment with cisplatin and paclitaxel was equivalent to the combination because many patients crossed over before progression; moreover, the cisplatin only arm was more toxic because it utilized a 100 mg/m2 dose.
- The Medical Research Council (MRC-ICON3) study, while having fewer early crossovers, could be interpreted similarly in regard to the impact on survival of sequential treatment.
- Data from MRC-ICON4 have shown a survival advantage for patients treated with the combination treatment regimen versus those treated with single-agent carboplatin upon recurrence (see Table 3).
- In past trials, single-agent platinums were not superior to platinum combined with an alkylating agent; therefore, the explanation of a detrimental effect of cyclophosphamide is unlikely.
Since the adoption of the platinum-plus-taxane combination as the standard nearly worldwide, clinical trials have demonstrated:
- Noninferiority for carboplatin plus paclitaxel versus cisplatin plus paclitaxel.[21,22,23]
- Noninferiority for carboplatin plus paclitaxel versus carboplatin plus docetaxel.
- No advantage but increased toxic effects by adding epirubicin to the carboplatin plus paclitaxel doublet.
- Noninferiority for carboplatin plus paclitaxel versus sequential carboplatin-containing doublets with either gemcitabine or topotecan; or, triplets with the addition of gemcitabine or pegylated liposomal doxorubicin to the reference doublet as shown below:[26,27]
- From February 2001 to September 2004, the Gynecologic Cancer InterGroup trial GOG-0182 randomly assigned 4,312 women with stage III or stage IV epithelial ovarian or primary peritoneal cancer to four different experimental arms and to a reference treatment consisting of carboplatin (AUC 6) and paclitaxel (175 mg/m2) every 3 weeks for eight cycles. Stratification factors were residual-disease status and the intention to perform interval debulking surgery. Lethal events attributable to treatment occurred in less than 1% of patients without clustering to any one regimen. None of the experimental regimens were inferior. With a median duration of follow-up of 3.7 years, the adjusted relative risk of death ranged from 0.952 to 1.114, with the control arm achieving a PFS of 16.0 months and a median OS of 44.1 months.
In this large study consisting of 84% to 87% of patients with the Féderation Internationale de Gynécologie et d'Obstétrique stage III disease, as expected, the extent of cytoreduction was an important prognostic factor in OS. Results of PFS in patients with residuum greater than 1cm, less than or equal to 1 cm, or microscopic were 13, 16, and 29 months, respectively; whereas for OS, the results were 33, 40, and 68 months, respectively.