ASCO 2009-CAELYX AND CARBOPLATIN MORE TOXIC THAN PACLITAXEL CARBOPLATIN BUT WITH THE SAME EFFICACY

Preliminary results from the Multicentre Italian Trials in Ovarian Cancer (MITO-2) (Abstract LBA5508) presented during Sunday’s Gynecologic Cancer Oral Abstract Session showed that combination therapy with carboplatin plus pegylated liposomal doxorubicin (C+PLD) has a similar effect on disease activity but markedly different toxicities compared with carboplatin plus paclitaxel (C+P), the standard first-line therapy for advanced ovarian cancer.

Sandro Pignata, MD, PhD, of the Istituto Nazionale Tumori, Italy, presented this multicenter, randomized phase III study in which 820 patients with advanced ovarian cancer were randomized 1:1 to C+P (C area under the curve [AUC] = 5 + P 175 mg/m², day 1 every 21 days) or to C+PLD (C AUC5 + PLD 30 mg/m², day 1 every 21 days). The treatments were repeated every 3 weeks, rather than the more standard interval of 4 weeks, for six cycles. Although patients with International Federation of Gynecology and Obstetrics stage IC through stage IV disease were included, slightly more than 80% of patients had stage III or IV disease in both study arms. In the experimental and control arms, 82% and 88% of patients, respectively, completed all six cycles of treatment.

The toxicity profiles of the chemotherapy regimens differed considerably. C+PLD was associated with a significantly higher incidence of anemia (68% vs. 59% for C+P, respectively; p = 0.007) and thrombocytopenia (48% vs. 19% for C+P; p < 0.001), although transfusions rarely were required. However, delays in treatment cycles as a result of hematologic toxicities were higher with C+PLD. There also was a significantly higher incidence of stomatitis (20% vs. 9% for C+P, respectively; p < 0.001) and skin toxicity (20% vs. 6%; p < 0.001) for patients in the experimental arm compared with the control group, although these were rarely severe. However, there was a significantly lower incidence of hair loss (14% vs. 63%, respectively; p < 0.001) and neurotoxicity (15% vs. 47%, p<0.001) with C+PLD.

Both therapies showed similar effects on disease activity. Of the subset of women eligible for analysis using Response Evaluation Criteria in Solid Tumors (RESIST) criteria (having ? 1 target lesion), 59% (92/156) who received C+P and 57% (76/134) who received C+PLD had an objective complete or partial response, demonstrating no significant difference in response rate between treatments (p = 0.70). Similarly, there were no significant differences observed for women whose disease activity could not be analyzed using RECIST criteria: complete response was observed in 33% (27/83) of patients taking C+P and in 29% of patients (29/99) taking C+PLD (p = 0.64). Among women with elevated CA125 only, 83% (73/88) on standard treatment and 86% (69/80) receiving the experimental therapy experienced normalization of CA125 (p = 0.56).

The primary endpoint of this study, progression-free survival, was not presented because the number of events required for final analysis (632) has not been reached yet. As of May 4, 2009, 531 progressions have been recorded (median follow-up, 35 months). Dr. Pignata noted that the final analysis for progression-free survival will be conducted as soon as the required number of events has been reached.

Discussant Jonathan A. Ledermann, MD, of Cancer Research UK, United Kingdom, commented on the preliminary results of the MITO-2 study. He said that it was not surprising to learn that giving C+PLD every 3 weeks produced more hematologic toxicities, but he noted the benefit of less hair loss and neurotoxicity. Without having seen the results for progression-free survival, he noted, it is difficult to predict final results. Dr. Ledermann concluded that when looking at MITO-2 in the context of the many previous trials of triplet therapies in ovarian cancer, it is “a moderate-sized fish in very big sea of studies that have so far been entirely negative…The concern is, what do we do if MITO-2 is positive? How do we interpret those data?”