The role of anthracyclines in second-line therapy of ovarian cancer

Abstract

Anthracyclines (ANTs) have been in clinical practice since the 1960s and represent one of the most commonly used classes of anticancer drugs. In the 1990s, meta-analyses showed a favorable impact of doxorubicin (DOX/A) on the survival of patients with advanced ovarian cancer, when it was combined with cyclophosphamide and cisplatin (CAP) and compared to CP alone. With the acceptance of paclitaxel-carboplatin (TCb) as the new reference arm for first-line treatment, testing the addition of ANTs to TCb seems a logic next step. Trials presently testing this, make use of either epirubicin (EPI) or pegylated liposomal doxorubicin (PLD: Doxil(R)/Caelyx(R)). These are the two most favorable ANTs, based on data obtained with various ANTs in ovarian cancer failing platinum-based chemotherapy. EPI has not been evaluated in direct comparison with other antineoplastic agents. PLD has been compared with both paclitaxel and topotecan. No difference in efficacy parameters could be observed, but the toxicity profile of PLD scored favorably against those of the comparator in both trials, despite the fact that palmar-plantar erythrodysesthesia can be troublesome, and sometimes lead to treatment discontinuation. Data from four randomized trials evaluating the role of ANT combinations in patients with relapsed ovarian cancer suggest that the addition of EPI or DOX to paclitaxel does not lead to better outcomes in patients with platinum- refractory or resistant disease. In platinum-sensitive disease, any benefit of EPI-platinum or DOX-platinum combinations over platinum alone is uncertain. There are no randomized trials with PLD combinations in the second-line setting. It is concluded that both EPI and PLD can be recommended as a reasonable single-agent treatment option for relapsed patients, with a preference for PLD taking into account its more favorable toxicity profile.

Using the Expected Survival to Explain Differences Between the Results of Randomized Trials: A Case in Advanced Ovarian Cancer

“…Other trials that are ongoing will provide further evidence on any added benefits of anthracyclines. 19 The comparison of survival curves across different experiments requires knowledge of prognostic factors for individual patients in both experiments. 20 Indeed, as shown in Fig 3, the expected survival curve depends heavily on the prognostic factors found to be significant in the survival model for advanced ovarian cancer (extent of residual disease, age, FIGO stage, and histologic grade).…”

Genotoxic Effect of Epirubicin in Mouse Bone Marrow in vivo

“…Anthracycline antibiotics are among the most important antitumour agents and have been in clinical practice since the 1960's. The fi rst generation anthracyclines, doxorubicin and daunorubicin, are produced by some Streptomyces species (Vermorken et al, 1999). Although epirubicin differs from doxorubicin only in the orientation of the 4'-hydroxy group, this minor difference has important consequences on the spectrum of their activity (Minotti et al, 2004).…”

“…It has been approved by Food and Drug Administration (FDA, 2000). Epirubicin has been used extensively in the treatment of a wide range of cancers, including breast, ovarian, gastric, bladder, and colorectal carcinomas, lymphomas, leukemias, and multiple myelomas (Cersosimo and Hong, 1986;Muggia and Green, 1991;Coukell and Faulds, 1997;Vermorken et al, 1999). It is used alone or in combination with other drugs.…”

Randomised controlled trial comparing single agent paclitaxel vs epidoxorubicin plus paclitaxel in patients with advanced ovarian cancer in early progression after platinum-based chemotherapy: an Italian Collaborative Study from the ‘Mario Negri’ Institute, Milan, G.O.N.O. (Gruppo Oncologico Nord Ovest) group and I.O.R. (Istituto Oncologico Romagnolo) group

“…In a review analysis, Vermorken et al (1999) showed that 25 out of 75 (33%) chemotherapy patients from several trials achieved an objective response to single agent doxorubicin. The results of single agent epirubicin appear to be better in prior platinumexposed patients.…”