A randomised dose intensity study in ovarian carcinoma comparing chemotherapy given at four week intervals for six cycles with half dose chemotherapy given for twelve cycles

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Abstract
The importance of dose intensity has not been clearly defined in ovarian cancer and we present a prospectively randomised trial of dose intensity in patients with ovarian cancer. Ninety-nine patients with FIGO stage Ic, II, III and IV epithelial ovarian cancer were randomised to receive cycles of standard dose cyclophosphamide (600 mg/m2) and carboplatin (300 mg/m2) alternating with adriamycin (50 mg/m2) and ifosfamide (5 G/m2) for 6 cycles at monthly intervals (49 patients) or cycles of half dose cyclophosphamide (300 mg/m2) and carboplatin (150 mg/m2) alternating with adriamycin (25 mg/m2) and ifosfamide (2.5 G/m2) for 12 cycles at monthly intervals (50 patients). Patients in each arm were well balanced for major prognostic factors. The combined clinical response rate (complete response and partial response) on the 6 month arm was 76% compared with 48% on the low dose intensity arm (p = 0.009). With a median follow up of 25.7 months the median survival on the low dose intensity arm is 20.9 months. The median survival point on the 6 month arm has not yet been reached. The median progression free interval on the 12 month arm was 19.8 months, the median value has not yet been reached on the standard arm. The amount of residual tumour following initial laparotomy was the only significant independent variable affecting survival (p = 0.0001). The mean received dose intensity of each drug was greater than 80% of the planned dose intensity. More patients had clinical disease progression during treatment on the low dose intensity arm (42%) when compared to the standard dose intensity arm (8%) (p = 0.0003). Fifteen patients on the standard dose arm experienced a total of 18 delays and 5 patients on the low dose arm experienced 17 delays. Nausea, vomiting and diarrhoea were similar for both standard and low dose cycles of chemotherapy with a consequent benefit for patients receiving fewer cycles even though these were of higher dose. The combination studied was more effective when given at the higher dose intensity and the improved response and survival was not accompanied by a significant increase in toxicity.