chemotherapy

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					Taxanes
The taxanes, docetaxel and paclitaxel, have at least equivalent activity to
doxorubicin as single agents. Taxanes stabilize polymerized
microtubules thereby
disrupting mitoses and have signifcant activity in second- or third-line
therapy in
patients resistant to anthracyclines with response rates of 16–21% for
paclitaxel
(Seidman et al., 1995; Paridaens et al., 2000) and 42–51% for docetaxel
(Ravdin et
al., 1995; Valero et al., 1995; Trudeau et al., 1996; Sjostrom et al.,
1999). For
docetaxel the main side-efects included Xuid retention syndrome with
peripheral
oedema, skin and nail changes and febrile neutropenia in 10–20% of
patients.
Fluid retention may be abrogated by pre and posttreatment with
corticosteroids
and the subsequent use of diuretics. A compassionate use programme in
825
heavily pretreated patients (i.e. an unselected population), conWrmed
the activity
seen in trials even as third-line treatment with a response rate of 22.9%
(95% CI:
20.2%–26.2%) (Alexandre et al., 2000). This study also highlighted the
need for
dose reduction to 75 mg/m2 or less in patients with liver dysfunction or
heavy
pretreatment in whom toxicities such as leucopenia, oedema and Xuid
retention
are more frequent and severe, probably because hepatobiliary excretion
is the
major elimination routine for docetaxel.
These results in Phase II studies and a compassionate programme are
encouraging
as the options for women with anthracycline-resistant disease have been
limited. Mitomycin C and vinblastine is a commonly used palliative
regimen with
a response rate of 16% in anthracycline-resistant breast cancer compared
with30% for docetaxel in a comparative study in 392 patients (Nabholtz
et al., 1999).
In this study, time to treatment progression was superior (19 vs. 11
weeks) for
docetaxel as was survival (11.4 vs. 8.7 months). In comparison with
5-FU and
methotrexate, docetaxel was again superior with a response rate of 42%
compared
with 21% (Sjostrom et al., 1999).
Paclitaxel is commonly given at doses of 175–200 mg/m2 every three
weeks.
Higher doses (_250 mg/m2 are not associated with improved response
rates, but
do incur a sensory neuropathy (Winer et al., 1998). The response rates in
anthracycline-refractory patients between 16% and 21% appear lower
than with
docetaxel and similarly as a Wrst-line agent the response rates with
paclitaxel,
25–32%, are lower than with docetaxel (41–61%), although there are no
direct
comparative studies (Seidman, 1995; Vermoken & Ten Bokkel Huinick,
1996;
Paridaens et al., 2000). Initial concerns about cardiotoxicity with
paclitaxel have
not resulted in clinical problems in single-agent studies, although
asymptomatic
arrythmias are seen. In Wrst-line therapy doxorubicin was superior to
paclitaxel
with a response rate of 41% versus 25% and median progression-free
survival (7.5
vs. 3.9 month) (Paridaens et al., 2000). In this study the crossover
response to
doxorubicin was 30% and to paclitaxel 16%, indicating non-cross
resistance.
There is renewed interest in scheduling with both taxanes. For paclitaxel
increased duration of infusion (24 h vs. 3 h) may have a slightly
improved
response rate, but is inconvenient and associated with more
haematological and
neurotoxicity. Weekly schedules have been used for both taxanes.
Paclitaxel can be
given at 80–90 mg/m2 per week with response rates of around 30%, but
a much
lower incidence of neutropenia, neuropathy and alopecia than with the
threeweekly
scheduling possibly making this a useful schedule for patients requiring
a
taxane, but at risk of neutropenia (Seidman et al., 1998). Another
potential use of
weekly schedules may be with biological agents such as trastuzumab or
cytotoxic
drugs which are given weekly, e.g. vinorelbine, gemcitabine.
Both taxanes have been used in combination with anthracyclines (Gianni
et al.,
1995, 1997; Esposito et al., 1999; Sparano et al., 1999). There is no
pharmacokinetic
interaction between anthracyclines and paclitaxel, however docetaxel
increases plasma concentration of doxorubicin (Gianni et al., 1997)
leading to a
need for dose reduction of docetaxel to 75 mg/m2 in combination
regimens.
Despite high response rates in Phase II studies of up to 94% (Gianni et
al., 1995)
comparative studies have not demonstrated any superiority for
anthracycline/
taxane combinations over standard anthracycline/cyclophosphamide
regimens to
date. The lack of cross resistance demonstrated between paclitaxel and
doxorubicin
(Paridaens et al., 2000) makes sequential rather than combination studies
attractive.
Vinorelbine
Vinorelbine is a semisynthetic vinca alkaloid which inhibits formation of
the
mitotic spindle (in contrast to taxanes which promote and stabilize
assembly of
microtubules after spindle formation). The response rate in phase II
studies was
20–30% in previously treated patients, including those refractory to
anthracyclines
(Bertsch & Donaldson, 1995; Vermoken & Ten Bokkel Huinick, 1996).
In a
comparative study against melphalan the response rate was superior to
melphalan
at 46.5% compared with 28.2% with time to tumour progression of 12
weeks
compared with 8 weeks (Jones et al., 1995). Haematological toxicity is
doselimiting
with Grade 3 or 4 neutropenia in 75% of patients. Although this is not
cumulative it may limit planned weekly administration. Vinorelbine also
causes
mild peripheral neuropathy and autonomic neuropathy but no alopecia.
Vinorelbine
is well tolerated with a symptomatic toxicity proWle better than
conventional
regimens such as FEC or FAC in randomized trials, despite a higher
incidence of
neutropenia (Namer et al., 1997). Preclinical data indicate synergism
between
vinca alkaloids and taxanes and this has been conWrmed in a trial of 49
patients
(Romero Acna et al., 1999).
There have been no comparative trials as yet on the relative merits
between
vinorelbine and taxanes in terms of quality of life and health economics.
One
cost–utility analysis has demonstrated economic advantages for
vinorelbine compared
with taxanes with at least equivalent quality-adjusted progression-free
survival despite lower absolute response rates and time to progression.
Fluoropyrimidines
Capecitabine is a rationally designed selectively tumour-activated
Xuoropyrimidine
carbamate which is eVectively an oral 5-Xuorouracil prodrug with
intramoural activity. Interest in this arose because of the recognition that
infusional
5-Xuorouracil via central venous access, gave response rates of 20–30%
in
patients with end stage breast cancer even if they had received prior
bolus 5-FU.
However, continuous infusional treatment is inconvenient. Oral
capecitabine has
shown a response rate of 20% in 135 heavily pretreated
paclitaxel-resistant
patients, including patients who had received anthracyclines (Blum et
al., 1999).
This activity was conWrmed in a randomized phase II trial against
paclitaxel in
anthracycline-resistant patients with response rates of 36% versus 21%
and
median time to disease progression of 92 versus 95 days (Moiseyenko et
al., 1998).
Toxicities are those expected with Xuoropyramidines, with neutropenia,
gastrointestinal
problems (diarrhoea) and hand–foot syndrome.
A guiding principle in chemotherapy for breast cancer is to maximize
response
by using the best standard regimen Wrst. This approach means that most
newagents are evaluated in very advanced disease, the response rate is
low in these
resistant patients hence valuable drugs may be discarded. This approach
can be
challenged by a prospective randomized phase III trial in which the
safety and
eYcacy of using a phase II drug before standard chemotherapy was
evaluated
(Constanza et al., 1999). This study in 365 women showed that the use
of
single-agent or phase II drugs (trimetrexate, melphalan, amoniWde,
carboplatin,
elsamitrucin) for up to four cycles did not compromise response to a
standard
regimen (CAF) irrespective of the response to the experimental drug.
Dose intensification
Retrospective literature review had indicated that higher doses or dose
intensity
were associated with improved survival (Hryniuk & Bush, 1984).
Certainly a
moderate increase in dose of around twofold has been associated with
increased
response rate, but no improvement in time to progression or overall
survival
(Bastholt et al., 1996; Hortobagyi et al., 1987). These studies also
conWrmed that
chemotherapy given at suboptimal doses resulted in an inferior outcome,
emphasizing
the need for standard doses when a decision to treat is made. These data
led
to renewed interest in dose intensiWcation, with high-dose
chemotherapy supported
by growth factors and/or bone marrow transplantation or peripheral
blood
stem cell support. Phase II trials in the 1980s were promising and by
1995 breast
cancer was the most common indication for high-dose chemotherapy
and bone
marrow transplant in the United States. Few patients were in clinical
trials and any
apparently superior results may have been due to selection bias in favour
of
younger age and good performance status (Antman et al., 1997). A
retrospective
analysis by Rahman et al. (1997) emphasized this issue. This group
evaluated the
results of 1581 patients with metastatic breast cancer who were treated
with
doxorubucin containing regimens with standard doses within clinical
trials. Those
who would have met the criteria for high-dose treatment, i.e. transplant
candidates,
had a better response rate, progression-free survival and overall survival
although they only received standard chemotherapy. In a randomized
trial comparing
high-dose consolidation with maintenance chemotherapy in
conventional
doses after remission induction, there was no improvement in survival
with the
high-dose approach (Stadtmauer et al., 2000).

				
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