Neoadjuvant Therapy With Gemcitabine in Breast Cancer
Neoadjuvant Therapy With Gemcitabine in Breast Cancer
In early breast cancer, primary systemic
and adjuvant (postoperative) chemotherapy
are equally effective with
regard to effects on disease-free and
overall survival. Primary systemic
therapy, however, increases the possibility
for breast-conserving surgery,
and tumor response may be a surrogate
marker for chemotherapy efficacy
Patients with pathologic complete remission
(pCR) after primary systemic
therapy experience significantly improved
survival as compared with patients
with persistent, invasive
tumor. A significant increase in the
pCR rate might translate into improved
Rationale for Combining
As a single agent, gemcitabine
(Gemzar) is active in chemotherapynaive
and previously treated patients
with metastatic breast cancer. Because
of its favorable toxicity profile[
6] and lack of complete
cross-resistance, particularly with anthracyclines[
7-10] and taxanes,
gemcitabine has been evaluated in different
combination regimens for the
treatment of advanced breast cancer.
In particular, results of two trials of
the triplet combination of gemcitabine,
anthracycline, and paclitaxel administered
as first-line therapy showed
remarkable overall response rates of
92% and 83% and complete response
rates of 31% and 44%, respectively.[
12,13] Therefore, it seemed reasonable
to evaluate this combination
as primary systemic therapy in patients
with primary breast cancer in
an attempt to improve the pCR rate
Thus far, results of four phase II
studies evaluating gemcitabine-containing
regimens as primary systemic
therapy in primary breast cancer are
available.[14-17] All investigators reported
promising clinical and pathologic
response rates (Table 1). Gomez
et al treated 39 patients with stage
IIIB breast cancer with gemcitabine
at 1,200 mg/m2/d on days 1 and 8 and
doxorubicin at 60 mg/m2 on day 1
every 3 weeks for three cycles.
The overall clinical response (cR) rate
was 95% (clinical complete response
[cCR] rate, 18%), and the pCR rate
was 13% (3 of 23 evaluable patients).[
Silva et al reported cR, cCR, and
pCR rates of 91%, 21%, and 17%
(4 of 23 evaluable patients), respectively,
among 34 patients with stage
IIIA-IIIB primary breast cancer who
received gemcitabine at 1,200 mg/m2
on days 1 and 8 plus epirubicin (Ellence)
at 75 mg/m2 on day 1 every
3 weeks * 3.
Snchez-Rovira and colleagues
completed a phase II study with preoperative
biweekly gemcitabine at 2,000
mg/m2, doxorubicin at 40 mg/m2, and
paclitaxel at 150 mg/m2 for six cycles,
with granulocyte colony-stimulating
factor [G-CSF] support. Doses
were modified after the first six patients
had received gemcitabine (2,500
mg/m2), doxorubicin (30 mg/m2), and
paclitaxel (135 mg/m2). Among 45
evaluable patients, the cR, cCR, and
pCR rates were 98%, 42%, and 18%,
Conte et al presented preliminary
results of a phase II study using gemcitabine
at 1,000 mg/m2 on days 1 and
8, epirubicin at 90 mg/m2 on day 1,
and paclitaxel at 175 mg/m2 on day 1
every 3 weeks for four cycles in patients
with stage II-III primary breast
cancer. In the first 22 evaluable patients,
the cR, cCR, and pCR rates
were 96%, 32%, and 23%, respectively.[
17] In all studies, toxicity was
mild to moderate and manageable.
All investigators used paclitaxel as
the taxane compound. In randomized
trials comparing doxorubicin and taxane
as monotherapy in advanced
breast cancer, however, paclitaxel
showed similar or inferior efficacy as
compared with doxorubicin,[18,19]
whereas docetaxel (Taxotere)
achieved higher response rates than
did doxorubicin. Therefore, it
seemed reasonable to substitute paclitaxel
with docetaxel and evaluate
docetaxel in combination with gemcitabine
and anthracycline as primary
systemic therapy in patients with primary
Phase I/II Study of
Patients and Methods
We initiated a multicenter phase I/II study in January 2002 to evaluate the triplet combination of gemcitabine, epirubicin, and docetaxel (GEDoc) as primary systemic therapy in patients with biopsy-proven primary breast cancer stage T2-4, N0-2, M0. Partici- pating institutions were the University of Heidelberg, University of Tuebingen, and the Community Hospital Weinheim in Germany. Patients were treated with gemcitabine on days 1 and 8, epirubicin on day 1, and docetaxel on day 1, every 3 weeks at escalating dose levels of 800/60/60 mg/ m2 (dose level 0), 800/60/75 mg/m2 (dose level 1), 800/75/75 mg/m2 (dose level 2), and 800/90/75 mg/m2 (dose level 3), for up to six cycles. Prophylactic filgrastim (Neupogen) was administered from day 2 to day 6 and from day 9 until neutrophil recovery (Figure 1). Primary study end points were to define the maximum tolerated dose and to evaluate clinical and pathologic response rates of GEDoc as primary systemic therapy. Secondary end points included the rate of breast-conserving surgery and toxicity. In addition, snap frozen tissue of pretreatment tumor biopsies were collected, and DNA microarray analyses will be performed in the future to ascertain any predictive and prognostic gene expression signatures. This aspect of the study is based on data from van de Vijver et al, who described a gene expression signature in primary breast cancer with prognostic value superior to that of currently used clinical parameters.[ 21] The DNA microarray analyses will be performed in a blinded fashion regarding clinical outcomes by Peter Lichter, PhD, at the German Cancer Research Center in Heidelberg, Germany. Results of these analyses will be correlated with clinical and pathologic responses, time to progression, survival, and toxicity. Results
Through March 2003, 80 patients had been enrolled in the study; 3 patients were not eligible due to primary bone metastases, an uncontrolled psychiatric disorder, or chronic infectious disease. A total of 77 patients were evaluable for clinical and pathologic response, type of surgery, and toxicity. Baseline patient and tumor characteristics are shown in Table 2. The median patient age was 48 years (range: 30 to 65 years), and tumor size was a median of 3.0 cm (as assessed sonographically). The majority of paients had ductal carcinoma, with a negative nodal status in 32, a positive nodal status in 41, and data not available in 4 patients. The majority of tumors were grade 2 or 3, and approximately three-fourths of tumors were hormone-receptor positive. HER2/neu status (Herceptest) was ≤ 2+ in 49, 3+ in 26, and not available in 2 patients. A total of 3 patients were treated at dose level 0, 4 patients at level 1, 7 patients at level 2, and 63 patients at dose level 3 (Table 3). The maximum tolerated dose was reached at dose level 3, when three of nine patients developed dose-limiting toxicity during the first cycle. Dose-limiting toxicities consisted of grade 3 febrile neutropenia (n = 1) and grade 3 diarrhea (n = 2), with toxicities graded according to National Cancer Institute- Common Toxicity Criteria (NCICTC), version 2.0. Among 63 patients treated at the maximum tolerated dose, 56 patients received the six scheduled treatment cycles, 5 patients stopped after the fifth cycle (4 patients due to toxicity and 1 patient refused to proceed), and 2 patients stopped after the fourth cycle due to toxicity. According to the study protocol, doses of epirubicin, docetaxel, or gemcitabine were reduced due to toxicity in 30 patients (48%) after a median of three cycles (range: 1 to 5 cycles). Thirtyfive patients began receiving erythropoietin during chemotherapy. Besides alopecia, NCI-CTC grade 3/4 events that occurred in more than 10% of 63 patients treated at the MTD were leukopenia, 56%/32%; febrile neutropenia, 13%/0%; fatigue, 30%/5%; stomatitis, 27%/0%; lung toxicity, 16%/0%; and diarrhea, 11%/0% (Figure 2A). The most common NCI-CTC grade 3/4 events among all 369 cycles given at the MTD were leukopenia, 32%/6%; febrile neutropenia, 2%/0%; fatigue, 10%/1%; stomatitis, 7%/0%; lung toxicity, 3%/0%; and diarrhea, 2%/0% (Figure 2B). The mean (± standard deviation) and median (range) relative dose intensities, as measured by the summation dose intensity product (SDIP) of the chemotherapy administered divided by the SDIP of the chemotherapy scheduled, were 93% (± 9%) and 97% (66%-100%), respectively. The SDIP that accounted for all three relevant factors of combination chemotherapy in breast cancer, namely, dose intensity, activity, and cumulative dose of each drug, was calculated as described by Hryniuk et al.[22,23] Assessment of response by ultrasound and mammography showed that 17 of 77 patients (22%) achieved a complete remission and 54 patients (70%) a partial remission, for an overall response rate of 92%. No tumor progression occurred. Breast-conserving surgery was possible in 61 patients (79%), with repeat excision required in only 9 patients. In 10 of 77 patients, no invasive or in situ residual tumor was found in resected breast tissue (pCR rate, 13%). Another 10 patients had only in situ residual tumor in the resected breast tissue (pCRINV breast, 13%), for an overall pCR rate in the breast (pCR + pCRINV breast) of 26%. Fifty-five patients (71%) had no lymph node involvement. In 19 of 77 patients, no malignant tumor cells were detected in the resected breast and lymph nodes (pCR + pCRINV breast + nodes). Conclusion Gemcitabine-containing doublets with anthracyclines and gemcitabinecontaining triplets with anthracyclines and taxanes are safe and remarkably active as primary systemic therapy in primary breast cancer. In particular, the triplet combination GEDoc (gemcitabine, 800 mg/m2 on days 1 and 8; epirubicin, 90 mg/m2 on day 1; and docetaxel, 75 mg/m2 on day 1) administered every 3 weeks for six cycles with prophylactic use of filgrastim is well tolerated and highly active as primary systemic therapy, with a clinical response rate as measured by ultrasound and mammography of 92%, a pCR rate in the breast of 26%, and a breast-conserving surgery rate of 79%. Additional assessments will correlate clinical outcomes with results of DNA microarray analyses to identify genetic parameters with prognostic or predictive value.
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