XML Template (2009) [5.9.2009–3:06pm] [1–12]
{TANDF_FPP}CMO/CMO_A_370883(NEW).3d (CMO) [First Proof]
Current Medical Research and Opinion
C213
Volume 25, Number 3 2008
dependent on the stage of disease at the initiation of Topotecan is currently approved for the treatment
treatment and the postoperative tumour residuals
5
: of relapsed ovarian cancer (i.e., for the second-line
5-year survival for patients with advanced disease is low, or subsequent treatment of platinum-sensitive or
at about 45%
1
. platinum-resistant cancer that has recurred following
The standard of care for management of ovarian cancer initial treatment); a regimen of 1.5mg/m
2
/day 1–5 has
includes surgery for staging and maximal cytoreduction, been approved in the USA and many other western
followed by systemic chemotherapy with a platinum/ countries.
paclitaxel combination for all advanced stages
3
. While
most patients with ovarian cancer respond to first-line
treatment, the majority experience disease relapse and
Topotecan in the first-line setting
50–80% require second-line therapy
3,6
. Currently avail-
able therapies in the second-line setting are not curative,
There is great interest in incorporating a third agent into
andtheaimsoftreatmentare,therefore,tocontroldisease,
the current gold standard of first-line chemotherapy with
prolong survival, and maintain quality of life (QoL)
3
.
carboplatin and paclitaxel, in order to circumvent resis-
Several agents are available for the treatment of relapsed
tance to platinum chemotherapy and improve the clinical
disease, including topotecan, gemcitabine, and pegylated
outcome. A number of different study groups have
liposomal doxorubicin (PLDH)
6
. Given the comparable
explored various agents, including epirubicin
8,9
, gemcita-
efficacy of available second-line therapies, the choice of
bine
10
and topotecan
11,12
. Four different strategies for
salvage therapy depends on a range of factors, including
incorporating topotecan into first-line treatment have
treatment-related toxicities, administration schedule, and
been considered: a replacement strategy (substituting
treatment-free interval
7
.
topotecan for paclitaxel); triplet chemotherapy (adding
topotecan to carboplatin/paclitaxel); sequential doublet
therapy (carboplatin/topotecan followed by carboplatin/
paclitaxel); and topotecan maintenance (after carbopla-
Research design and methods
tin/paclitaxel)
4
. The feasibility and efficacy of topotecan
In preparing this article, literature searches were con-
when used in the aforementioned strategies have been
ducted in the MEDLINE database on articles published
evaluated in a number of clinical trials (Table 1). While
between January 1996 and June 2008. Articles were iden-
theresultsshowedsignificantanti-tumouractivity,mostof
tified that included the search terms ‘topotecan’ and
the trials – two of which are at the preliminary reporting
‘ovarian cancer’; ‘topotecan’ and ‘relapsed/recurrent/
stage – demonstrated no clinical benefit in prolongation of
advanced ovarian cancer’; or ‘chemotherapy’ and
progression-free survival or overall survival, when topote-
‘relapsed/recurrent/advanced ovarian cancer’ within the
can was used in the first-line setting
3
. Thus, there are
title or abstract. From the results of the literature searches,
currently no randomized data to support the role of topo-
articles were chosen for inclusion based upon their rele-
tecan in the first-line treatment of ovarian cancer.
vance to the purpose of this article, i.e. to review the
current and future role of topotecan in primary and
relapsed ovarian cancer. Reference lists of related papers
Topotecan for relapsed ovarian cancer
andrecentreviewarticleswerescannedforadditionalcita-
Topotecan is an established second-line therapy for
tions. The literature search was further supplemented by
relapsed ovarian cancer
3
. The efficacy of 5-day i.v. topo-
congress abstracts from the American Society of Clinical
tecan has been demonstrated in several phase II clinical
Oncology (ASCO) between January 1996 and June 2008.
trials in patients with relapsed ovarian cancer who have
previously received chemotherapy with a platinum-based
Topotecan
regimen
13–18
.Theresultsofthesestudiesindicatethat,asa
single agent, topotecan is an active compound. Overall
Topotecan is a semi-synthetic camptothecin analogue, response rates ranged from 14% to 33%, with 18–48% of
a plant alkaloid present in the Asian tree Camptotheca patients achieving stable disease; response rates observed
acuminata. It functions as a potent inhibitor of inpatients with platinum-sensitive disease (19–33%) were
topoisomeraseI, an enzyme that relieves torsional strain higher compared with rates seen in platinum-resistant dis-
on supercoiled DNA. TopoisomeraseI creates single- ease(14–18%).Themediandurationofresponsetosingle-
strand breaks and then re-ligates the broken strands, agent topotecan (daily i.v.) ranged between 4.5 months
thereby restoring the integrity of the double helix. By and 11.2 months, with median survival among
inhibiting topoisomeraseI, topotecan induces double- treatment responders of 6–21 months
4
. Based on the
strand breaks when DNA is replicated, resulting in apop- proven efficacy of topotecan in phase II trials, phase III
totic cell death
4
. trials were performed to compare the efficacy and
2
Topotecan for relapsed ovarian cancer Sehouli & Oskay-O
¨
zcelik
www.cmrojournal.com
!
2009 Informa UK Ltd
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