Trabectedin plus pegylated liposomal doxorubicin in the treatment of patients with partially platinum-sensitive ovarian cancer: current evidence and future perspectives
J. Sehouli
2
V. Alfaro
1
A. Gonza lez-Martn
0
0
Department of Medical Oncology, Centro Oncologico MD Anderson International
,
Madrid, Spain
1
Clinical R&D
, PharmaMar, Colmenar Viejo,
Madrid
2
Department of Obstetrics and Gynecology, Charite University Hospital
,
Berlin, Germany
The effectiveness of platinum re-treatment in relapsed ovarian cancer depends on relapse-free/treatment-free intervals. Platinum agents can be effectively readministered to platinum-sensitive patients (relapsing >12 months after platinum), but efficacy is lower in partially platinum-sensitive (PPS) disease (relapsing 6-12 months after platinum). There is no clear standard treatment challenging PPS patients. Survival data in this subset with chemotherapy combinations such as pegylated liposomal doxorubicin (PLD) plus carboplatin or gemcitabine plus PLD are available from phase II trials ranging from 16 to 21 months. Recent results from OVA-301 phase III randomized trial evaluating trabectedin plus PLD showed the longest median overall survival ever reported in PPS patients (23 months). Subsequent chemotherapy (including platinum-based regimens) was administered later and survival in patients receiving third-line platinum was longer in patients treated with trabectedin plus PLD compared with those treated with PLD alone. These results suggest that prolonging platinum-free interval (PFI) with an effective non-platinum regimen improves outcome with subsequent third-line platinum treatment. An ongoing phase III trial (INOVATYON) aims to demonstrate if the results observed with trabectedin plus PLD in PPS patients are due to PFI extension, and if PFI extension with non-platinum combination prolongs response to subsequent platinum and survival in this population.
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introduction
Platinum-containing regimens are currently the mainstay of
initial treatment of ovarian cancer and platinum-sensitive
relapsed disease. In relapsed ovarian cancer, the effectiveness of
platinum re-treatment depends on the
relapse-free/treatmentfree intervals (Table 1). Platinum agents can be effectively
readministered to patients with disease relapsing >12 months
after completion of a platinum regimen (i.e. patients with
platinum-sensitive disease), with response rates ranging from
30% to 60%, but ovarian cancer that relapses 612 months after
platinum treatment has lower response to platinum rechallenge
(25%30%) [36] and is considered partially platinum
sensitive (PPS).
These categories are based on empirical observations made
20 years ago. Ovarian cancer relapsing in the 612 months
time frame has also been defined as intermediate platinum
sensitive or simply as chemotherapy sensitive because new
non-platinum agents and combinations are being identified as
active in this setting [7, 8]. The use of non-platinum agents
in relapsed ovarian cancer to prolong platinum-free interval
(PFI) has gained interest recently, as the likelihood of
response to platinum reinduction at next relapse may increase
[9]. The acquired resistance to platinum is an unstable
phenotype over time [10]. Thus, in vitro studies [11] have
shown platinum resistance as an unstable, inducible, and
perhaps reversible phenomenon. In vitro [11] and clinical
data [9, 12, 13] suggest that PFI extension in patients with
relapsed PPS ovarian cancer through intercalation of a
nonplatinum therapy before platinum-based regimens at further
progression could be beneficial from a clinical point of view. It
has been hypothesized that platinum (or chemotherapy)
sensitivity could be restored using a PFI prolongation
strategy [6, 7]. Furthermore, most patients with
recurrent ovarian cancer will die due to tumor progression;
therefore, the definition of the best therapeutic index for
these patients including not only tumor and symptom
control but also the toxicity profile is one of the most
challenging topics in gynecologic oncology. Rechallenge with
platinum-based combinations is not only associated with risk
of development of severe allergy [1] but also polyneuropathy
and alopecia [14].
Based on these considerations, both from the clinical and the
scientific perspective, the use of platinum as the first treatment
option in patients with PPS relapse may be questioned. Limited
information exists in this regard as most clinical trials with
newer agents have been either nonrandomized phase II studies
or phase III randomized studies conducted in a heterogeneous
population of women, sometimes even including patients with
platinum-resistant disease. Unfortunately, phase III studies of
combination regimens compared with platinum monotherapy
and others comparing various non-platinum single agents
usually have not reported separate data for the PPS subset.
Therefore, interpretation of the activity of the newer agents in
the PPS population is often difficult, and this may affect
decision making in clinical practice [5].
results of clinical trials evaluating
combination regimens and including
patients with PPS ovarian canc (...truncated)