S40 Poster Sesswn II. Adjuvatlt systemic therapies Friday, 14 March 2003

were administered until best response was achieved by mammography and clinical assessment. The preoperative chemotherapy was well tolerated and all patients completed the treatment regimen on an outpatient basis. Dur- ing 18 courses no cardiac toxicity and no WHO-grade III or IV toxicity was observed. Response to treatment was present in all patients (100%). with 2 patients (22%) experiencing a pathological complete response of the inva- sive tumor and 7 patients (78%) showing a partial response. The residual tumor cells of these patients with a PR were HER2 negative in 3 cases and HER2 positive in 4 patients. Thus, a pCR of HER2 positive tumor cells was observed in 5 patients. In 6 patients (67%) a breast-conserving surgery was possible. Outpatient T in combination with weekly EPI and DOC is safe in the neoadjuvant treatment of patients suffering from breast cancer by showing a favourable side-effect and activity profile. We conclude from this preliminary data, that weekly T + EPI/DOC is promising for further prospective trials in the neoadjuvant as well as in the palliative clinical setting.

I P89 Pharmacokinetics of herceptin administered three-weekly compared to weekly - A simulation based on data from the clinical studies

f? Ghahramani' , C. Barton’, B. Leyland-Jones’. ‘Troche Products Ltd, Clinical Pharmacology: Welwyn Garden Ci@ United Kingdom; 2 McGill lJnivetsi& Oncolog): Montreal, Canada

Herceptin (H). when administered iv on a weekly (qw) regimen in combina- tion with chemotherapy, has been shown to increase survival in women with HER2 positive metastatic breast cancer (MBC). H is currently administered qw (approved regimen). Recent pharmacokfnetic data provides an estimated terminal half-life of about 28 days for H indicating the possibility for a dos- ing interval longer than a week. The work described here aims to compare the pharmacokinetics of H administered q3w (8 followed by 6 mg/kg every 3 weeks) vs qw (4 followed by 2 mgIkg every week). The pharmacokinetic data for the two regimens cannot be compared directly because the study design, duration and schedule of pharmacokinetic samples are very different be- tween the trials of the two regimens. As a consequence, no meaningful com- parison can be made between the two regimens without modeling the data to derive pharmacokinetic parameters independent of the differences between the studies of the two regimens of H. It has proved extremely difficult for ei- ther regimen to obtain a full pharmacokinetic profile over several months of treatment; hence, to date peaks and troughs only have been obtained for both regimens together with full profiles at 1 or 2 cycles, following the q3w regimen. Therefore, modeling of the pharmacokinetic was employed in this study to make a direct comparison between the pharmacokinetics of the two regimens. Using a population approach, pharmacokinetic data from Phase I studies of the qw regimen were used to simulate full serum concentration- time profiles of Herceptin for both qw and q3w regimen for a typical patient with a weight of 70 kg. The simulated serum concentration-time profile for the q3w regimen was consistent with the pharmacokinetic data available from two studies of the q3w regimen. The average steady state levels (Cav) for both regimens was estimated to be 80 ??g/ml, and this was reached after 15 weeks of treatment. The only differences were observed within the first 3 weeks when the average serum levels with the q3w regimen were closer to steady-state compared to the qw regimen. As expected, at steady state the trough levels for the q3w regimen were 22% lower than qw (50 vs 64 &ml) and peak levels of the q3w regimen were about 70% higher than qw (186 vs 109 mg/ml). However, the q3w regimen of H shows similar pharmacokinetic average exposure when compared to the qw regimen, and are therefore sup- portive of H being administered on a q3w schedule.

w Adjuvant hormonetherapy for slow proliferating node-negative breast cancer patients. Results of the phase Ill trial of NCI-Bari

A. Paradiso’, M. De Lena2, M. Sambiasi”, A. Mangia’, M. Brandis, F. Schittulli 3 ’ National Cancer lnstiute, Clnicaf Experimsnfal Oncology Laborator) Bari, Ita& 2 National Cancer fnstitute, Dept. Medical Oncokqx Bari, Italy; 3 National Cancer Institute, Women Dept., Bari, Ita&

Tumor proliferative acttvity has been repeatedly described as a reliable prog- nostic factor in node.-negative breast cancer patients at different risk of re- lapse and as a predictive factor for the response to chemotherapy and hor- mone therapy. On the basis of this evidence, from 1989 to 1994 we enrolled all patients with Ti -2 node-negative breast cancer who underwent surgery at the NCI-Sari and were classified according to the proliferative activity of their tumors (SH-thymidine labeling index, TLI) in two different prospective phase Ill clinical trials We previously published (Paradiso et al, JCO,2001) the clin- ical results of the Phase Ill study with rapidly proliferating node-negative breast cancer patients randomized to receive either polychemotherapy ac- cording to the FEC regimen for 6 cycles or no therapy until disease progres-

sion. Here we report the clinical results of the twin Phase Ill study in which slowly proliferating (TLI cutoff I 2.3%) node-negative breast cancer patients were randomized to receive either tamoxifen 20 mg/day for 5 years (Arm A) or no therapy until disease progression (Arm B). Overall, 1336 new diag- noses of breast cancer were made. 612/1336 (46%) patients were classified as pathological stage Tl-2NOMO; 565/612 (92.3%) had an assessable TLI assay. 278 (49.2%) and 287 (50.8%) were classified as having slowly and rapidly proliferating tumors, respectively. 125 and 130 patients with slowly proliferating node-negative breast cancer were randomized to Arm A and B, respectively. After a median follow-up of 6 years 40 relapses were observed with significant differences between the two arms. The 5-year disease-free survival 88% and 79% in Arm A and B, respectively, while the 5-year overall survival was 98% and 88%. Our result show that this type of study biological characterization of a prospective and consecutive series of breast cancer patients is highly feasible: the prognostic relevance of TLI has been con- firmed also in a prospective series of node-negative breast cancer patients; hormone therapy is an effective adjuvant approaches also for slowly prolifer- ating node-negative breast cancer patients.

El Pgl Prospective pilot study of the preoperative use of celecoxcib and FEC for the treatment of locally advanced breast cancer

L. Chow ’ , M. Toi2. ’ Univesity of Hong Kong, Surgery: Hong Kong, Hong Kong; 2 Tokyo Metropolitan Komagome Hospital, Sutgew Tokyo, Japan

Background: Neoadjuvant treatment of breast cancer with FEC is well tol- erated among Asian patients and it allows more breast-conserving surgery to be performed. COX-2 is over expressed in breast cancer and it is also a novel target of treatment. Celecoxib, a COX-2 inhibitor, has anti-angiogenic and apoptotic effects.

Objective: To study the clinical and patholooic resoonses, changes in the _ angiogenesis markers and tolerability to FEC + celecoxib or FEC alone.

Material and Methods: 3 cycles of FEC (5 FU 5OOmgIm2, Epirubicin 75mg/m2, Cyclophosphamide 5OOmq/m2) with or without celecoxib.(4OOmg b.d.) were given every 3 weeks to women with histologically proven LABC. End point assessments include clinical and pathologic responses, changes in tissue and serum angiogenesis markers and tolerability.

Results: From June 2001 to November 2001, a total of 32 patients were recruited. Sixteen patients in each arm received either a combination of FEC and celecoxib or FEC alone. The mean age was 45.6 (SE, 2.7) years. Clinical response rate of 62.5% (cCR 6.3%,cPR 56.3%). was achieved in the FEC alone arm and 81.3% (cCR l&8%, cPR 62.5%) in the combined arm of FEC and celecoxib. The pathologic response rate was 87.5% (pCR 12.5%, pPR 75%) in the combined arm and 62.5% (pCR 6.3%. pPR 56.3%) in the control arm. In the combined arm, the mean tumor size decreased from 4.52 (SE,0.32) to 2.04 (SE, 0.31) cm 31.3% of the patients chose to undergo conservative (lumpectomy) surgery and the rest opted for mastectomy. Data on COX expression, and angiogenesis-hypoxia drug resistance markers are being analyzed. The regimens were well tolerated. No clinical cardiac toxicity was detected in both arms.

Discussion: The combination treatment of celecoxib and FEC is effective and potentially allows more breast-conserving surgery to be performed in patients with LABC. This is an ongoing study and will be expanded to include more patients. Angiogenesis marker test results will be presented.

I Pg2 Stopping tamoxifen after 5 years. What’s next?

A. Keramopoullos, V. Gaki, D. Baltas, N. Bredakis, G. Vourli, A. Ghiatas, K. Pavlaki. fAS0 Hospitaf for women, Breast Oncology Department, Athens, Greece

Introduction: It is a general belief that treatment with Tamoxifen for breast cancer patients should be terminated 5 years after the surgery. Knowledge about raloxifen implies that it is similar to Tamoxifen and provides protection against breast cancer. In addition, anastrazole is a well-documented thera- peutic regiment for breast cancer patients. Our initial intention was to eval- uate the effect of the two regiments concerning the patient&bone mass as well as their prophylactic role. Additionally, we wanted to confirm that stop- ping Tamoxifen 5 years after the surgery is safe for the patients in terms of survival and disease free survival.

Materials and Methods: One hundred and ninety three postmenopausal patients with O-4 involved nodes were randomly allocated to receive either raloxifen (100 patients) or anastrazole (93 patients). The patients’mean fol- low up was 125.44 months (19-218 months). The two groups were balanced in terms of estrogen’s and progesterone’s receptors status, tumor’s size, grade, and number of involved nodes.

Results: Analyzing the data, in order to study the effect of treatments on bone mass, thickness of endometrium and DFS we observed an increased

Poster Session II. Supportive cnrdQunlity of life S4 I

I P95 Cardiac safety of 3-weekly herceptin monotherapy

J. Baselga’, N.-J. Castaneda-Soto*, M. Clemens3, M. Green4, V. Harvey5, S. Morales6, C. Barton?. ‘Hospital Universilrio Vat1 d’Hebron, Department of Medical 0ncolog)r Barcelona, Spain; 2 lnstituto National de Canceroogia, Tiafpan, Mexico; 3 Mutterhaus o’er Borromaeerihnen, Triec Germany; 4 Royal Melbourne Hospitad Melbourne, Australia; 5 Auckland Hospilal, Auckland, New Zealand; b Hospital Arnau de Villanova, Lleida, Spain; ’ Roche Products L to!, Welwyn Garden City UK

An ongoing phase II study (W016229) is evaluating q3-weekly Herceptin monotherapy in women with HERP-positive metastatic breast cancer. The qSweekly regimen is more convenient than the approved weekly schedule and is being used in the ongoing Herceptin Adjuvant (HERA) trial. Safety is a particularly important consideration in patients receiving adjuvant therapy. Here we present interim cardiac safety results.

Patients and Methods: 105 patients received Herceptin every 3 weeks by intravenous infusion over 90 minutes, at a dosage of 8mg/kg (first cycle) then Gmgikg (subsequent cycles). 47% of patients had received prior an- thracyclines, a risk factor for Herceptin-related cardiotoxicity. Left ventricular ejection fraction (LVEF) was measured by echocardiography or MUGA scan at baseline and after every 4 cycles of treatment.

Results: The median LVEF was 63% at baseline and patients had re- ceived l-19 (median 5) cycles of treatment at the time of analysis. Among patients with no prior anthracyclines (n=36). 23 (64%) had a decrease in LVEF of .15%. three (8%) had a decrease of 15% or greater and LVEF fell to 150% in two patients (6%). In patients with prior anthracyclines (n=29), LVEF fell by ~15% in 16 (55%). by 15% or greater in five (17%) and to 150% in four (14%). Only one patient (who had received prior anthracycline therapy) developed symptomatic cardiac failure, which resolved after spe- cific therapy. Her LVEF fell from 59% at baseline to 33% at cycle 8. No other serious treatment-related cardiac events were noted.

Conclusions: Three-weekly Herceptin monotherapy at a dose of Gmg/kg is associated with a low incidence of symptomatic heart failure in patients with metastatic breast cancer (11%). Asymptomatic LVEF decreases of un- certain significance were noted in a substantial proportion of patients re- gardless of whether they had received prior anlhracyclines, but reductions of -15% occurred in only a minority of patients. The incidence and severity of cardiotoxicity when Herceptin is given q3-weekly at three times the standard dose was no higher than when it is given in the standard weekly schedule. These results are reassuring for the future of the ongoing HERA trial.

number of systemic recurrences in the raloxifen group while no systemic recurrences were observed in the anastrazole group. More specifically, dis- ease free survival rate amounted to 94% in the raloxifen group (6 out of 100 patients relapsed systematically), while the disease free survival rate in the anastazole group was 100%. This difference in disease free survival rate was statistically significant (p-value=0.0294).

Conclusion: Taking into account the interim results within 18 months, our feeling was that we should terminate this protocol. However. further studies are required in order to clarify the role of these regiments concerning the above-mentioned issues.

L-J P93 Polyneuroendocrine therapy of advanced breast cancer with LHRH analogue, tamoxifen and the antiprolactinemic drug cabergoline: Phase 2 study

P. Lissoni, A. Ardizzoia, G. Cerea, M. Acquati. M. Simonelli, M. Vaghi, G. Tancini, G. Gardani. San Gerard0 Hospital, Oncolgia e Radiotempia, Monza - Milano, Italy

Despite the well known role of prolactin (PRL) as a growth factor for breast cancer (6C) and the existence of a PRL dependency in estrogen-indipendent tumors, the therapeutic role of the anti-PRL agents for BC is still obscure. This phase-2 study was performed to evaluate efficacy and tolerability of a polyneuroendocrine regimen in heavily pretreated metastatic BC, consisting of Tamoxifen (20 mg/day orally), the LHRH analogue Triptorelin (3.75 mg IM every 28 days) and the long acting antiprolactinemic drug Cabergoline (0.5 mg once/week orally). The study included 14 consecutive patients (pts), 4 of them progressed on Tamoxifen plus LHRH analogue alone. Dominant metastasis sites were, as follows: soft tissues: 4; bone: 4; visceral lesions: 6 (lung: 3; liver: 2; bone marrow: 1). Estrogen receptor (ER) was positive in 5. negative in 3 and unknown in 6 pts. The clinical response consisted of partial response (PR) in 4114 (29%) pts (median duration: 6+ months, range 4-8+), including l/4 (25%) pts, who had a progressive disease (PD) on Ta- moxifen plus LHRH alone. Response sites were soft tissues in 1, bone in 2, and visceral lesions in 1. A stable disease (SD) was achieved in 5 other pts (median duration 4+ months), whereas the other 5 pts had a PD. The treat- ment was extremely well tolerated in all pts, and in particular no cabergoline- related toxicity occurred. A complete normalization of PRL serum levels was seen in 6/6 pts with abnormally high PRL values prior to therapy. Finally, the treatment induced a significant decline in PRL mean levels, which was significantly higher in pts with PR or SD than in those with PD. This pre- liminary study shows that the polyneuroendocrine therapy with Tamoxifen, LHRH analogue and Cabergoline is a well tolerated treatment of metastatic BC, which may be effective also in pts with PD on Tamoxifen plus LHRH alone. Therefore, the association of the antiprolactinemic drug Cabergoline may further restore the hormonal dependency of BC.

0 P94 Primary chemotherapy in breast cancer shows excellent clinical and pathological response with docetaxel and epirubicin

H.R.C. Marana, J.M. Andrade, D.G. Tiezzi. M.F. Taborda, A.H. Machetti, H.H.A. Carrara, F.J.C. Reis, S. Bighetti. FacultyofMedicine ofRibeirao Preto - lJniverS& Gynecology and Obstetrics - Divion of Oncology: Ribeiro Preto, Bmzil

Introduction: Primary chemotherapy is becoming the standard of care for locally advanced breast cancer. New drugs regimens being tested are prov- ing to be more efficacious than the usual anthracycline based treatments.

Patients and Methods: Between 04198 and 04101, 56 patients (17 stage IIA; 16 stage IIB, 5 stage IIIA; 18 stage 1118) were included in the trial and received three cycles of docetaxel75 mg/m2 and epirubicin 50 mglm2 (q3w). All patients with stasis or disease progression were excluded from the trial and received alternative treatment. Patients with partial response after three cycles but still not suited for conservative surgery received up to 3 additional cycles. Following completion of the chemotherapy regimen, tumour response was assessed and appropriate surgery performed. Pathological response was assessed in excised specimens.

Results: By clinical evaluation according to the UICC criteria, 48 pts (85.7%) had objective regression (6 CR and 42 PR); 7 had stabilisation and 1 showed progression (14.3%). There were no serious complications. Fifty- three patients were eligible for surgery (947%). Of those, 30 were conserva- tive surgery (56.6%) and 23 radical modified surgery (43.4%). Total number of cycles was 184. with an average of 3.28 cycles per patient, which was according to our expectations.

Concfusions: Our study demonstrates that docetaxel and epirubicin has a high response rate in locally advanced breast cancer, enabling a high per- centage of conservative surgery without significant toxicity.

FRIDAY, 14 MARCH 2003

Supportive care/Quality of life

I P96 Undertreatment of anemia in patients with breast cancer (BC): Data from the European Cancer Anaemia Survey (ECUS)

S. Van Belle’, PJ. Barrett-Lee’. ’ Universiw Hospital Ghent, Medical Oncology: Gent, Belgium; 2 Veindre NHS TRUST Cardit United Kingdom

Anemia, which causes multiple physical and functional impairments, is one of the most serious side effects of cancer and cancer treatment (tx). ECAS was conducted to establish a comprehensive database to evaluate the preva- lence of anemia and the risk factors for development of cancer-related ane- mia, its impact on World Health Organization (WHO) performance status (PS), and anemia tx practice patterns. Between January and July 2001. 15,367 patients (3278 BC patients) were enrolled at varying times in their tx at 750 cancer centers in 24 European countries and followed for up to 6 months. Data were collected at regularly scheduled visits and included de- mographics, hemoglobin (Hb) levels, PS, tumor type, cancer tx, and anemia tx. The following are the data for the subset of 3216 BC patients evaluable at enrollment. 67% of BC patients were 160 years old. At enrollment, 57% of BC patients were newly diagnosed (43% of whom were receiving can- cer tx). 30% were persistent/recurrent. and 13% were in remission. Cancer tx status at enrollment was: no tx, 54%; radiotherapy (RT), 6%; chemother- apy (CT), 37%; or concomitant CTIRT, 3%. At enrollment. 30% of evaluable BC patients were anemic (Hb 112 g/dL). Respective anemia rates for pa- tients by disease status were: 20% newly diagnosed without cancer tx at enrollment, 34% newly diagnosed with tx, 42% with persistent/recurrent dis- ease, and 23% in remission (P ~0.001); and anemia rates for patients by tx status were: 22% receiving no tx. 43% on CT, 26% on RT, and 37% on CTIRT (P ??O.OOl). At enrollment, impaired PS with WHO scores of 3 to 4 were recorded for only 2% of patients with Hb r/=12 g/dL vs 8% for patients