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CORRESPONDENCE
Dose-Dense and/or Metronomic Schedules of Specific Chemotherapies Consolidate the Chemosensitivity of Triple-Negative Breast Cancer: A Step Toward Reversing Triple-Negative Paradox
Rita S. Mehta Departments of Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California at Irvine School of Medicine, Irvine, CA
Liedtke et al
1 report a progression-free survival of 63% in
patients with triple-negative breast cancer predominantly treated
with anthracyline-based first and second regimens in the neoadjuvant
setting. They suggest that third generation regimen are important
considerations in triple-negative subtypes of breast cancer
in their discussion, but we feel it needs to be emphasized that
third generation regimens should be standard in treatment of
triple-negative breast cancer.
Combining the four subgroups
(based additionally on progesterone receptor status and human
epidermal growth factor receptor 2 [HER-2] status) of 483 patients
with estrogen receptor–negative breast cancer, the 3-year
progression-free survival is similarly 63% and overall survival
is 74%.
1 These combined group results are comparable with the
5-year progression-free survival of 63% and overall survival
of 68% in 327 patients with estrogen receptor–negative
breast cancer updated by Citron et al
2 in the adjuvant setting
(possibly smaller tumors, but longer time outcome) using the
standard once-every-3-weeks doxorubicin, cyclophosphamide, and
paclitaxel.
In the comparator arm, the 5-year progression-free
survival improved statistically significantly to 70% and overall
survival to 75% in 336 patients with estrogen receptor–negative
(includes triple-negative subset) breast cancer with use of
dose-dense (once every 2 weeks) administration of doxorubicin,
cyclophosphamide, and paclitaxel—a third generation regimen
(23% hazard reduction).
2
Another trial showed an estimated 5-year
event-free survival of 71% in the triple-negative cohort treated
with two cycles of dose-dense epirubicin and cyclophosphamide
followed by high-dose cyclophosphamide, thiotepa, and epirubicin
chemotherapy compared with only 26% in the four cycles of dose-dense
epirubicin and cyclophosphamide followed by dose-dense cyclophosphamide,
methotrexate, and flurouracil arm, but the poor survival in
comparator arm suggest that
rapid cycling to an alternate effective regimen may be the underlying mechanism of superiority of dose-dense and dose-intensified regimen.
3
Similarly, weekly paclitaxel
significantly improved the 5-year progression-free hazard rate
by 40% in hormone receptor–negative (including triple-negative
subset) breast cancer and 20% in hormone receptor–positive
subsets compared with these subsets treated with once-every-3-weeks
scheduling.
4
A parallel phase III neoadjuvant study demonstrated
a
pathologic complete response of 43% with denser doxorubicin (weekly) and cyclophosphamide (continuous) compared with 26% with once-every-3-weeks doxorubicin and cyclophosphamide, both
arms receiving weekly paclitaxel in locally advanced breast
cancer, suggesting an additive benefit of denser administration
doxorubicin and cyclophosphamide, in addition to the denser
administration of paclitaxel.
5 Taken together, studies show benefit of accelerated schedules (weekly or once every 2 weeks) of doxorubicin, cyclophosphamide, and paclitaxel. Importantly,
comparing across trials, weekly paclitaxel achieves a higher
hazard rate reduction than once-every-2-weeks paclitaxel when
both accelerated schedules are compared to once-every-3-weeks
paclitaxel.
2,4
Of note, Liedtke et al
1 show that 22% of patients who achieved
pathologic complete response had an overall survival of 94%,
and 78% of patients who did not achieve a pathologic complete
response had a 68% overall survival—a 26% difference.
An absolute 50% increment in pathologic complete response over
a baseline of 22% would move an additional 50% of patients from
68% to 94% survival (an absolute 26% improvement for the 50%
patients), a 13% increment in survival above a baseline 3-year
survival of 74% for 100 patients would result in overall survival
improvement to 87% (a 25% increment in pathologic complete response
would move 25% of patients from 68% to 94% survival, netting
a 6.5% improvement in 3-year survival; ie, each 10% increment
in pathologic complete response will translate into an absolute
2.6% 3-year survival). Green et al
6 show doubling of pathologic
complete response from 23% to 48% with weekly paclitaxel, and
an absolute 25% improvement of pathologic complete response
in the hormone receptor–negative subset. On projecting,
this will translate into an absolute 6.5% survival benefit,
that is an improved 3-year overall survival of 81.5%, a 25%
hazard reduction at a minimum. Speculatively, additional survival
benefit may accrue with increase in the minimal residual disease.
6 Indeed, the actual benefit in the trial reported by Sparano
et al
4 was 40% hazard reduction with weekly paclitaxel compared
to once-every-3-weeks paclitaxel in hormone receptor–negative
subset.
Of the prospectively maintained database of 14 patients with
stage IIA-IIIB (including inflammatory breast cancer) or local
relapse HER-2–negative, estrogen receptor–negative,
and progesterone receptor–negative, infiltrating ductal
carcinoma (excluding two patients with metaplastic carcinoma)
of breast who received dose-dense doxorubicin and cyclophosphamide
(maximum four doses, except one who relapsed after doxorubicin,
cyclophosphamide, and flurouracil) followed either by dose-dense
paclitaxel (n = 2; four doses), or by weekly paclitaxel (cremophor
[80 mg/m
2] or albumin bound [100 mg/m
2]) with carboplatin (at
area under the curve of 2, both 3 weeks on, 1 week off; maximum
12 doses, n = 12) plus or minus maximum eight doses of bevacizumab
every 2 weeks (n = 4; maximum 8 doses), 10 of 14 patients (71%;
95% CI, 42% to 92%) achieved pathologic complete response. Two
additional patients had scattered cells in the breast with no
lymph node involvement. Thus, 13 of 14 (93%; 95% CI, 66% to
100%) patients had no evidence of residual lymph node involvement.
The progression-free survival of 86% (95% CI, 57% to 98%) and
overall survival of 93% (95% CI, 66% to 100%) of 14 patients
at a median follow-up of 36 months (range, 22 to 68 months)
compared with the projected survival improvement of 87% based
on pathologic complete response of 71% is promising.
Assessed
another way, a reversal of pathologic response incidence from
22% reported by Liedtke et al
1 to 71% is likely to show improvement
in survival closer to 94% for the majority of patients, a result
seen with our data—a 73% hazard reduction. Therefore,
the
high pathologic complete response reported by us parallels the benefit of once-every-2-weeks anthracyclines (or denser), and once-every-2-weeks or once-weekly paclitaxel scheduling
in phase III trials.
5,6 F
aster delivery of anthracyclines allows administration of targeted or alternate effective treatment earlier. For example, hormone receptor blocker for hormone receptor–positive breast cancer, trastuzumab for HER-2–positive breast cancer, and once-weekly paclitaxel, an alternate effective treatment for all subsets of breast cancer, specifically triple-negative
subset. Therefore,
for patients with triple-negative tumors, optimally scheduled doxorubicin and cyclophosphamide (once every 2 weeks) and paclitaxel (once weekly) should be standard.
2,4
As 12 of 14 patients also received carboplatin, the use of carboplatin
may be considered in any patient with large (as seen in neoadjuvant
setting) triple-negative breast cancer.
7,8 While carboplatin
based adjuvant phase III studies are limited to docetaxel, trastuzumab,
and carboplatin combination, extrapolation of docetaxel, trastuzumab,
and carboplatin combination to paclitaxel and carboplatin (and
trastuzumab in HER-2–positive breast cancer) after anthracyclines
may be reasonable pending large adjuvant or neoadjuvant trials
in triple-negative breast cancer. Importantly, carboplatin is
standard treatment for ovarian and lung cancer, and therefore
long-term outcome is known. Moreover, the BRCA-ness of the triple-negative
tumors makes these tumors specifically susceptible to the DNA-damaging
action of carboplatin give support to our use of carboplatin
in triple-negative breast cancer.
9
Additional small studies that used platinums have similarly shown a promising outcome either in pathologic complete response (20% with single-agent cisplatin to 67% with platinum combination regimens) or in progression-free survival (75% to 84%) in triple-negative breast cancer.
10-12,14-15 We did not see any progression while patients were receiving chemotherapy, unlike the studies by Torissi et al10,13 where they show a substantial progression while patients were either on weekly paclitaxel or dose-dense docetaxel regimen. This may be secondary to delayed switch to alternate effective therapy of weekly paclitaxel in the first case, or switch to a less effective dose-dense docetaxel switch in the second case.
The potential additional benefit of bevacizumab over optimum
scheduling of standard chemotherapy needs to be tested in randomized
trials, as the follow-up is shortest for the four patients receiving
bevacizumab. While the small number, short follow-up, and heterogeneity
of chemotherapy are limitations of our small study, the chemotherapy
was uniformly delivered in accelerated fashion. Achievement
of high pathologic complete response and the corresponding survival
benefit tied to high pathologic complete response are the strengths
of the study. Despite a short follow-up, the follow-up would
be considered adequate for progression-free survival in triple-negative
subtype of breast cancer as the hazard rates of relapse are
highest in the first year, and taper off quickly after 3 years.
1 We emphasize that third generation chemotherapeutic regimens
are the most important treatment regimens for triple-negative
breast cancer in achieving a higher pathologic complete response,
and thereby higher survival, where the only current targeted
treatment is the accelerated and optimized chemotherapy that
targets the Gompertzian growth model as first shown by Norton
et al.
16 Moreover,
poor clinical outcome seen in patients with triple-negative despite initial chemosensitivity as demonstrated by Carey et al17 can be overcome by consolidating the gains obtained by initial chemosensitiviy of accelerated anthracyclines with accelerated optimal chemotherapy, which at a minimum should include weekly paclitaxel.
Int J Exp Pathol. 2010 Feb;91(1):10-6.
Low-dose metronomic chemotherapy with cisplatin: can it suppress angiogenesis in H22 hepatocarcinoma cells?
Shen FZ,
Wang J,
Liang J,
Mu K,
Hou JY,
Wang YT.
Department of Oncology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
fangzhenshen@126.com
Low-dose chemotherapy drugs can suppress tumours by restraining tumour vessel growth and preventing the repair of damaged vascular endothelial cells. Cisplatin is a broad-spectrum, cell cycle-non-specific drug, but has serious side effects if used at high doses. There have been few reports on the anti-angiogenic effects of low-dose cisplatin and hence the effect of low-dose metronomic (LDM) chemotherapy on the proliferation and neovascularization of H22 hepatocarcinoma cells is discussed in this research. The influence of LDM chemotherapy with cisplatin on human umbilical vascular endothelial cells (HUVECs) and proliferation of the HepG(2) human hepatocarcinoma cell line were measured using MTT assays.
The LDM group was treated with cisplatin 0.6 mg/kg/day; the control group with saline 0.2 ml; the maximum tolerated dose (MTD) group with cisplatin 9 mg/kg/day. Vascular endothelial growth factor (VEGF) and matrix metallopeptidase 2 (MMP-2) were detected using immunohistochemical staining. A chicken chorio-allantoic membrane (CAM) model was used to check the inhibitory effect of LDM chemotherapy with cisplatin on neovascularization in vivo.
Low-dose cisplatin inhibited HUVEC proliferation in a dose- and time-dependent manner, but was ineffective in inhibiting HepG(2) cell proliferation. Tumour growth was delayed in mice receiving LDM cisplatin, without apparent body weight loss, compared with mice that received MTD cisplatin. Microvessel density and expression of VEGF and MMP-2 were much lower in mice receiving LDM cisplatin than in the control and MTD groups. Continuous low-dose cisplatin suppressed CAM angiogenesis in vivo. LDM chemotherapy with cisplatin can inhibit the growth of blood vessel endothelial cells in vitro and shows anti-angiogenic ability in vivo.
PMID: 20096070 [PubMed - in process]