Mayer_edit.qxp 8/8/08 02:21 Page 100
Breast Cancer
past few years, changes in scheduling—including the superiority of weekly was seen in 37 patients.
23
Finally, ixabepilone monotherapy has been
paclitaxel over every-three-week dosing—have introduced small evaluated at 40mg/m
2
every three weeks in a highly refractory population
improvements.
13
Both combination and single-agent strategies have been used resistant to anthracycline, taxane, and capecitabine. In this phase II study of
in the treatment of metastatic breast cancer. In general, combination treatment 126 patients by Perez et al., an independent radiology facility (IRF)-assessed
leads to a higher response rate or longer time to progression. However, this response rate of 11.5% (18.3% for investigator assessed) was observed,
activity typically does not translate into significant survival benefits, likely due with 25% having either a partial response (PR) or stable disease (SD)
to washout from cross-over to subsequent lines of therapy.
4
Combination >6 months. All of the patients with responses had visceral metastatic disease
regimens also incorporate additional toxicity compared with sequential single- at baseline, with a substantial number resistant to all prior chemotherapeutic
agent therapy, an important caveat given the goal of symptom palliation. Two treatment.
24
In all of these trials, the most significant toxicities seen were
combination regimens to date, paclitaxel ± gemcitabine and docetaxel ± sensory neuropathy, fatigue, cytopenias, nausea, and myalgias. The
capecitabine, have demonstrated improved overall survival in randomized trials frequency of neuropathy appears to be greater with every-three-week
compared with the single-agent comparator arm.
14,15
These regimens can be dosing, and in the above trials led to frequent dose reductions on the every-
useful in the setting of visceral crisis, when obtaining a rapid response to three-week schedule. Weekly dosing may reduce the occurrence of this
therapy is of utmost importance. Otherwise, in usual practice sequential single- toxicity and is being studied in ongoing trials. Therefore, ixabepilone
agent therapy preferably offers both improved tolerability and the ability to monotherapy represents an attractive new chemotherapeutic option,
identify emerging resistance to treatment. particularly for patients with highly refractory disease.
The past few years have brought two new agents into the armamentarium. Thomas et al. have studied the role of ixabepilone combination therapy in
Nanoparticle albumin-bound paclitaxel does not require cremaphor for the phase III setting. Ixabepilone 40mg/m
2
every three weeks and
preparation, thus significantly reducing the risks of hypersensitivity reaction capecitabine 2,000mg/m
2
was compared with capecitabine 2,500mg/m
2
during administration associated with other taxanes. Additionally, pre- monotherapy in 752 patients with anthracycline- and taxane-pre-treated
clinical work suggests improved delivery of albumin-bound paclitaxel to disease. The combination arm demonstrated an improved response rate of
tumor tissue, possibly leading to enhanced efficacy.
16
In a phase III trial in the 35 versus 14%, with a 1.6-month improvement in median progression-free
metastatic setting comparing every-three-week nanoparticle albumin- survival. Both neuropathy and hematological toxicity were more significant
bound paclitaxel at 260mg/m
2
versus every-three-week paclitaxel at in the combination arm, in addition to a greater number of deaths.
25
Based
175mg/m
2
, results demonstrated a higher response rate and longer time on the results of these studies, the FDA approved ixabepilone monotherapy
to progression in the nanoparticle albumin-bound paclitaxel arm.
17
The and in combination with capecitabine for treatment of metastatic breast
toxicity profile differed from traditional paclitaxel, with less hematological cancer in October 2007. Multiple ongoing studies are examining the role of
toxicity but more neuropathy. ixabepilone in combination with other chemotherapeutics, with human
epidermal growth factor receptor (HER)-2-directed therapy, and with
Data from this study supported drug approval by the US Food and Drug angiogenesis inhibitors. Additionally, the subset of ‘triple-negative’
Administration (FDA) in 2005 for the treatment of anthracycline-refractory tumors—negative for estrogen receptor, progesterone receptor, and
metastatic breast cancer. Subsequently, weekly nanoparticle albumin-bound HER2—appear to derive substantial benefit from ixabepilone,
26
and ongoing
paclitaxel (100mg/m
2
, three weeks on/one week off) appears to have work will further explore the role of this new agent for this tumor subset.
increased activity compared with every-three-week dosing in the first-line
setting.
18
A phase III comparison of weekly nanoparticle albumin-bound Another evolving paradigm in the treatment of metastatic disease is the
paclitaxel and every-three-week docetaxel is expected. combination of traditional chemotherapeutics with biologic therapies.
Almost a decade ago, the pivotal phase III study of paclitaxel ± trastuzumab
The newest chemotherapeutic available for treatment of metastatic breast in the first-line metastatic setting heralded the entry of antibody-based
cancer is ixabepilone, an epothilone analog. Epothilones bind tubulin, targeted therapy.
27
Currently, the treatment paradigm for women with
leading to stabilization of microtubules, causing cell-cycle arrest and HER2-positive disease includes early use of trastuzumab in combination
subsequent apoptotic cell death. Pre-clinical study of epothilones has with chemotherapy. Other agents with demonstrated efficacy in
demonstrated activity in both taxane-sensitive and taxane-refractory combination with trastuzumab include vinorelbine, docetaxel, gemcitabine,
tumors, suggesting a role for this class of agent in refractory disease.
19
Four and capecitabine.
28–32
The question of whether trastuzumab should be
phase II trials have examined the role of ixabepilone monotherapy in continued after disease progression has not been answered in clinical trials,
patients with metastatic breast cancer refractory to anthracyclines, taxanes, although in general practice treatment typically consists of sequential
or both. Using the primary dosing schedule of 40mg/m
2
every three weeks, trastuzumab/chemotherapy doublets. Lapatinib, an oral reversible HER2
a response rate of 41.5% was observed in 65 anthracycline pre-treated tyrosine kinase inhibitor, has been evaluated in the setting of trastuzumab-
patients. Similarly, this dosing schedule resulted in a response rate of 21% refractory disease. In a phase III trial, 324 patients pre-treated with
in a cohort of 49 taxane-refractory patients. Notably, of the six responders, anthacycline, taxane, and trastuzumab were randomized to capecitabine
five had not responded to prior taxane treatment.
20,21
alone at 2,500mg/m
2
/day or capecitabine 2,000mg/m
2
/day plus lapatinib
1,250mg/day. The trial was terminated early to report a 51% reduction
A second dosing schedule, 6mg/m
2
daily for five days every three weeks, has in the risk of disease progression,
33
leading to FDA approval for lapatinib in
also been explored. In the first-line metastatic setting, without prior taxane March 2007. Ongoing trials will evaluate next-generation HER2-directed
exposure, a response rate of 57% was observed in 23 patients.
22
Using the therapy, including irreversible tyrosine kinase inhibitors of HER2 such as
same regimen in a taxane-pre-treated population, a response rate of 22% HKI-272 or BIBW 2992.
100 US OBSTETRICS & GYNECOLOGY
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