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
administered in a metronomic fashion (i.e., at a continu- all treatment courses, the median time to onset of grade4
ouslowdose without drug-free intervals) topatients with a neutropeniawas10days,comparedwith15daysforgrade4
variety of persistent solid tumours were presented at thrombocytopenia and 13 days for grade3/4 anaemia. The
ASCO 2008
27
. Oral topotecan was shown to be well tol- median durations of severe toxicities were 7 days for
eratedwhenadministeredmetronomically,andthisdosing grade4 neutropenia, 5 days for thrombocytopenia (range:
regimen therefore warrants further investigation in 2–7 days) and 7 days for anaemia (range: 4–7.5 days). In
patients with relapsed ovarian cancer. course1, the median time to onset of grade4 neutropenia
Avariety ofdosesandschedules have been investigated was 13 days, the duration of which was greater than 1week
in order to find the optimal therapeutic index of topote- in 37% of affected patients. However, in subsequent
can, and daily as well as weekly schedules have produced courses, the median time to onset per course was generally
encouraging results in patients with ovarian cancer
4
.As 9 days, with a duration greater than 1week in 21–43% of
stated above, a regimen consisting of 1.5mg/m
2
/day i.v.
affected patients
29
. Serious adverse events, such as neutro-
topotecan for days 1–5 of a 21-day cycle is approved for
penic fever and sepsis, are rare with topotecan treatment:
the treatment of relapsed ovarian cancer in most Western
in a comparative study of topotecan and PLDH, 3.8% of
countries
7
. However, in the clinic, a dose of 1.25mg/m
2
/
patients treated with topotecan experienced treatment-
day for days 1–5 is widely accepted in the cancer commu-
related sepsis and 0.9% of patients experienced treat-
nity, as it is associated with a better toxicity profile.
ment-related neutropenic fever
21
. Furthermore, topote-
Certain studies suggest that this dose is as effective as the
can-induced thrombocytopenia seemed to become less
higher dose
43
; however, there are no randomized studies
pronounced in the subsequent cycles
33
.
that have compared the efficacy of both topotecan doses.
Topotecan 1.5mg/m
2
administered on days 1–5 has
greater haematological toxicity (largely neutropenia)
than both PLDH
21
and paclitaxel; however, this is largely
Safety profile
without clinical sequelae or consequences. By effectively
managing topotecan-related toxicities, the impact on
Chemotherapy is frequently associated with severe side
patients’ QoL can be minimized
28
. At the recommended
effects that can have a profound impact on patients’
dose,PLDHcan cause stomatitis andPPE, whilepaclitaxel
QoL
28
. Many of the serious toxicities associated with the
can cause neuropathy. PPE is a cutaneous reaction seen on
use of chemotherapy can be effectively managed through
the palmsofthe handsandsolesofthefeet thatcan leadto
either pre-treatment (with anti-emetics, antidiarrhoeals
severe pain and cracking of the skin; there is currently no
and corticosteroids) or post-treatments (with growth
definitive evidence that pharmacological intervention
factor support), dosing modifications or the use of
effectively manages PPE
21
. When compared with PLDH,
alternative schedules, routes of delivery, or combination
the incidence of stomatitis and PPE seen with topotecan is
regimens
28
. Alopecia and polyneuropathy can reduce
lower
21
, and compared with paclitaxel, topotecan is asso-
patients’ QoL; therefore, alternative anti-cancer drugs
ciated with less peripheral neuropathy, alopecia, arthralgia
are warranted that offer improved safety without compro-
and myalgia
3,19
.
mising the tumour control rate.
Extensive clinical trials in patients with ovarian
cancer have shown that topotecan is effective and
Intravenous weekly topotecan
generally well tolerated
29
. The main toxicities
associated with topotecan are haematological, including
Topotecan is generally well tolerated in patients with
neutropenia, thrombocytopenia and anaemia. Non- relapsed ovarian cancer; however, administration as a
haematological toxicity associated with topotecan use is 5-day i.v. regimen can result in significant haematological
generally mild and mainly consists of gastrointestinal toxicities
29
, which frequently necessitate dose reduction
events, hairlossandfatigue
19,30,31
. Thedose-limiting toxi- and treatment interruption
18
. Many patients with ovarian
city of i.v. topotecan, as established in early dose-finding cancerhavesignificantco-morbidities,andthoserequiring
studies, is haematological (largely neutropenia)
29
. Grade4 second-line treatment often have cumulative toxicities
neutropenia is generally highest during the first course of from prior courses of chemotherapy; these factors may
treatment (57% of patients receiving second-line therapy make these patients more susceptible to haematological
and 59.3% of patients receiving third-line therapy), but toxicities
34
.
decreases in subsequent courses. Haematological toxicity Several alternative topotecan dosing schedules have
isthusnon-cumulative
20
,reversibleandgenerallymanage- been explored with the aim of improving tolerability as
able with dose reduction, treatment delays and growth well as treatment convenience, without compromising
factor support
32
. anti-tumour efficacy
18
. Regimens investigated included:
In a pooled analysis of patients with either relapsed C15 21-day, 24-hour continuous i.v. infusion
35
small-cell lung cancer or relapsed ovarian cancer, across C15 3-day i.v. bolus
35
!
2009 Informa UK Ltd
www.cmrojournal.com Topotecan for relapsed ovarian cancer Sehouli & Oskay-O
¨
zcelik
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