1132 Background: The addiction of trastuzumab to standard chemotherapy has improved the outcome of HER-2-positive metastatic breast cancer (MBC) pts. Oxaliplatin and docetaxxel are among the most active agents in MBC pts pretreated with anthracyclines. In vitro studies showed synergistic effect of the combination. We investigated the feasibility and the safety of the 3-drug combination given as first line chemotherapy (CT) in HER-2-positive MBC. Methods: HER-2-positive MBC pts were prospectively enrolled to receive a first-line treatment consisting of trastuzumab 8 mg/kg loading dose iv (followed by 6 mg/kg) on day 1, docetaxel 75 mg/sqm iv on day 1, and oxaliplatin 70 mg/sqm on day 2 every 21 days. All pts received peg-filgrastim 6 mg on day 3 to prevent bone marrow toxicity. Pts received up to 9 cycles of CT. Primary end points were overall response rate (ORR) (according to RECIST criteria), clinical benefit (CB), and tolerability. Cardiac function was evaluated by echocardiography at baseline, each 3 courses and at the end of treatment. Results: To date, 13 pts have been enrolled (median age 59 yrs [range 34–70]; ECOG PS 0) representing the first-step accrual according to Minimax design. Ten pts had previously received anthracyclines as adjuvant treatment and 11 pts presented with visceral metastasis. All pts received at least 6 cycles of treatment with 7 pts continuing up to 9 cycles. Response and toxicity data are available for all pts. Two pts experienced CR, 7 pts PR, and 4 pts showed SD (lasting more than 6 months in 3 cases) with an ORR of 70% and a CB of 100%. No pts progressed during treatment. No grade 4 toxicity was observed. Most common grade 3 toxicities were diarrhea (18%), nausea/vomiting (22%), mucositis (11%). In particular, 2 episodes of febrile neutropenia were reported and no grade 4 haematologycal toxicity was observed. No significative reduction of LVEF were reported. Conclusions: The combination of trastuzumab, oxaliplatin, and docetaxel (HOT combination) showed promising activity and was well tolerated as first-line treatment in pts with HER-2-positive MBC. Peg-filgrastim profilaxis improved safety profile. No significant financial relationships to disclose.

11021 Background: women treated with tamoxifen for ER-positive early breast cancer are at a two to seven fold increased risk of endometrial cancer. Even though published data fail to support the use of transvaginal ultrasound (TVU) for screening of endometrial cancer, this is still a very common clinical practice in this subset of patients (pts). Methods: we have conducted a retrospective analysis to investigate the value of TVU in early detection of tamoxifen-related endometrial cancer. The screened population consists of pts treated with adjuvant tamoxifen in our institution from January 1999 up to December 2003 receiving a TVU annually or in case of gynaecologic symptoms. Results: 491 evaluated pts performed a total of 1634 TVUs in asymptomatic conditions. FIGO stage I endometrial cancers have been diagnosed in 3 patients (0.32%) who are still alive after total hysterectomy. A vaginal bleeding anticipated the examination in 33 women (3.2%) and represented the first symptom in two cases of tumor. Only one endometrial cancer has been detected with the screening procedure. Median increase of endometrial thickness has been 7.6 mm (range 1–34 mm) and those patients with abnormal images at TVU underwent an hysteroscopy with endometrial biopsies (169) resulting in a benign histology (polyps, cystic atrophy, hyperplasia) in most cases. Conclusions: therefore we have performed more than 1500 transvaginal ultrasound to detect only one asymptomatic cancer so we agree with literature in supporting that women receiving tamoxifen should undergo only an annual gynaecologic examination reserving the TVU to patients with vaginal bleedings or discharges. No significant financial relationships to disclose.

870 Background: Gemcitabine (G) and Capecitabine (C) are both actives in metastatic breast cancer (MBC). Methods: To define the maximum tolerated dose of this combination we designed a phase I study with escalating dose of G (from 750 mg/m2 up to 1500 mg/m2 with increments of 250 mg/m2) at day 1 and 8 every 3 weeks combined with C 2000 mg/m2/die on days 1 to 14. To better investigate the activity and toxicity at the recommended doses, a phase II study has been subsequently performed in patients (pts) pre-treated with anthracyclines and taxanes. Results: 12 pts have been enrolled in the phase I study. Dose escalation of G reached the maximum dose planned without observing dose-limiting toxicities. In fact, only 6 pts experienced a grade 2 (WHO) toxicity (anaemia, neutropenia, N/V, mucositis). So far, 21 pts have received G at the recommended dose of 1500 mg/m2 and C 2000 mg/m2/die for a total of 125 cycles with a median of 6 cycles for pt (range1–12). Main characteristics included: median age 51 (range 35–71), median PS 1 (range 0–2) and median sites of metastasis 2 (range 1–4) (14 pts liver, 9 lung, 12 skin/lymphnodes and 14 bone). No G3–4 non-haematological toxicities have been observed except for a G3 dermatitis in one pt. G2 toxicities are diarrhoea, nausea/vomiting and mucositis in 2.4%, 4.8% and 1.6% of cycles, respectively. A reduced dose of G (75% of total dose) was administered at day 8 in 4.8% of cycles because of G3 neutropenia. A G2 neutropenia was observed in 11% of cycles. So far 22 pts are evaluable for response (12 pts in the phase I and 10 in the phase II): 9 pts (41%) obtained an OR (5 CR and 4 PR), 12 (55%) a SD and 1 (4%) progressed. Median duration of response is 5+ months (range 2–13) and median progression-free survival is 7+ months (range 2–16). Conclusion: The combination we used shows a favourable toxicity profile and promising activity in pre-treated MBC. Accrual is continuing to include 39 pts in the phase II study.(Partially supported by Fondazione ARCO) No significant financial relationships to disclose.

BACKGROUND The purpose of this study was to evaluate the impact of a dose-dense primary chemotherapy on pathological response rate (pCR) in patients with locally advanced breast cancer (LABC) treated with combined modality therapy. PATIENTS AND METHODS Stage IIIA/IIIB patients received three courses of induction chemotherapy (ICT) with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) followed by local therapy (total mastectomy or segmental mastectomy with axillary nodes dissection) and adjuvant chemotherapy (ACT) with three courses of CEF alternated with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Patients were randomized to receive ICT and ACT every 3 weeks (arm A, 'standard treatment') or every 2 weeks with granulocyte-macrophage colony-stimulating factor (GM-CSF) support (arm B, 'dose-dense treatment'). In both arms radiotherapy was administered after the end of chemotherapy (in selected cases) and patients with hormonal receptor-positive tumors received tamoxifen for 5 years. RESULTS A total of 150 patients were randomized (77 arm A and 73 arm B) and demographics were well balanced between the two arms. Compliance to treatment was excellent: 95% and 93% of patients in arms A and B, respectively, completed the treatment program with no modification or delay. Median duration of treatment (ICT+local+ACT) was 183 days (range 0-265) in arm A and 139 days (0-226) in arm B. The average relative dose intensity (ARDI) of chemotherapy was 1.3 with a 30% increase in the dose intensity in arm B in comparison with arm A. No difference in clinical [62%; 95% confidence interval (CI) 49% to 73.2%] and pathological response rates to ICT was observed between the two arms. Median follow-up was 5 years (range 1-96 months); median disease-free survivals were 4.8 years in arm A and 4.5 years in arm B. Median overall survival was 7.8 years in standard therapy: this figure has not yet been reached in the dose-dense treatment. CONCLUSIONS In LABC a dose-dense regimen, while allowing a 30% increase in the dose intensity of chemotherapy, did not provide significant improvement in pathological response rates. However, accelerated chemotherapy reduced the duration of the combined-modality program (6.1 versus 4.6 months) with no additional toxicities.

C-type lectin-like proteins (CTLs) as found in snake venoms fulfill various physiological functions. They play a role in hemostasis and have helped elucidate mechanisms involved in blood coagulation and platelet activation. Their basic structure consists of the subunits α and β, which form heterodimers via a typical domain-swapping motif. These heterodimers can form oligomers such as the tetrameric flavocetin-A and convulxin, which arrange into cyclic structures. Rhodocetin is a selective α2β1 integrin antagonist consisting of four distinct subunits forming a novel cruciform structure. Along with EMS16 and VP12, rhodocetin inhibits collagen-binding to the α2A-domain. These integrin-specific antagonists are lead structures for the development of antimetastatic and antiangiogenic drugs.

Cisplatin is the most active agent currently employed in epithelial ovarian cancer. A meta-analysis of the Advanced Ovarian Cancer Trialists Group suggested that in terms of immediate survival platinum-based therapy was superior to nonplatinum regimens and that regimens including cisplatin were superior to single agent cisplatin given at the same doses. Intraperitoneal cisplatin seems to offer some clinical benefit when compared to systemic cisplatin in patients with minimal residual disease after initial surgery. An overview on the role of anthracyclines using data from the Advanced Ovarian Cancer Trialists Group and the Ovarian Cancer Meta-Analysis Project suggested that the addition of doxorubicin significantly improves survival and that the size of this benefit is of a similar magnitude to that of platinum. Carboplatin and cisplatin are equiactive, and the different spectrum of toxicities could offer an appropriate criterion for the choice of the platinum analogue to use in the individual patient. At present, there is no conclusive evidence that cisplatin dose intense regimens are beneficial, and the issue of dose intensity must still be considered experimental. The combination of cisplatin + paclitaxel is able to obtain a better progression-free survival and survival than the association cisplatin + cyclophosphamide. Phase I-II trials on regimens including platinum compounds, anthracyclines and paclitaxel are currently ongoing.

From June 1990 to October 1994, 111 advanced ovarian cancer patients with minimal (less than 2 cm) residual disease after platinum-based front-line chemotherapy and second-look laparotomy entered a cooperative randomized study aimed at evaluating the effectiveness and the toxicity of the addition of interferon-alpha2 to carboplatin, both intraperitoneally (ip) administered. Patients were randomized to receive either 3 courses of ip Carboplatin 400 mg/m2 Day 1 q 28 days (54 pts) (CBDCA) or ip interferon-alpha 25 x 10(6) U Day 1 + ip carboplatin 400 mg/m2 Day 2 q 28 days (57 pts) (CBDCA + IFN). Patients treated with interferon experienced more severe (WHO grade 3-4) leukopenia (28% vs 17.1%) and anemia (14% vs 4.2%). Fever (P = 0.000) and flu-like syndrome (P = 0.02) were significantly more frequent in the combination arm. No difference in gastroenteric, neurologic, or renal toxicity was observed. At a median follow-up time of 13 months (range 1-72) 71 patients showed a disease progression (31 CBDCA, 40 CBDCA + IFN) and 44 patients died (21 CBDCA, 23 CBDCA + IFN). Median progression-free survival was 11 months in the CBDCA group and 10 months in the CBDCA + IFN arm. Median survival was 22 and 29 months in CBDCA and CBDCA + IFN arm, respectively. In conclusion, intraperitoneal interferon-alpha does not seem to improve the results achievable with intraperitoneal carboplatin in this subset of patients, while the toxicity and the costs of the combination are consistently higher than with chemotherapy alone.

Thirty-two patients with advanced breast cancer have been treated with epirubicin 90 mg/m2, immediately followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) infused over 3 hours, every 21 days. The starting paclitaxel dose was 135 mg/m2, increased in subsequent triplets of patients until the maximum tolerated dose was reached at 200 mg/m2. One hundred seventy-six courses have been administered; dose-related grade 4 neutropenia was observed in 66% of the courses, with 12 episodes of febrile neutropenia. Two patients showed a decline of left ventricular ejection fraction below 50% after six courses, but no signs of congestive heart failure have been reported. The response rate is 76% (95% confidence interval, 56% to 90%), with 14% complete remissions. This level of activity is encouraging considering that 84% of the patients had failed adjuvant chemotherapy (with anthracyclines in 14 cases), and 19 had progressive disease following hormone therapy for metastasis. In another study, the toxicity and activity of a salvage regimen consisting of paclitaxel 135 mg/m2 over 3 hours plus vinorelbine 25 mg/m2 in an intravenous bolus on day 1 were evaluated; vinorelbine was given again on day 8 (in 14 patients) or on day 3 (in 20 patients), and the courses were repeated every 3 weeks. Thirty-four previously treated patients with advanced breast cancer entered the study; 20 had received one prior line of chemotherapy, II had two lines, and three patients had three lines. Thirty-two patients had been exposed to anthracyclines. Grade 4 neutropenia was observed in 64% of the courses, with 13 episodes of febrile neutropenia; four episodes of grade 3 mucositis have been reported with vinorelbine days 1 and 3. A delay in the administration of chemotherapy was necessary in 17% of the courses with vinorelbine days 1 and 8 and 16% of the courses with vinorelbine days 1 and 3; moreover, the vinorelbine dose was reduced or the drug omitted on day 8 in 86% of the courses and on day 3 in 16% of the course. An objective response was achieved in 43% of the patients. In conclusion, the combination of paclitaxel plus vinorelbine is an active salvage regimen and can be administered at greater dose intensity with the day 1 and 3 schedule.

It has been demonstrated, both in breast cancer cell lines and in metastatic breast cancer patients with cutaneous lesions that could be biopsied, that treatment with interferon beta (IFN-B) can increase expression of both estrogen (ER) and progesterone receptors (PgR). To evaluate the efficacy and toxicity of the combination of IFN and tamoxifen, 33 metastatic breast cancer patients were treated with the following regimen: IFN-B, 6.0 million units intramuscularly IU 3 times a week for two consecutive weeks followed by IFN-B 6.0 million IU im 3 times a week with concomitant tamoxifen 20 mg orally daily. Patients were pre and postmenopausal with median age of 60 years, median ECOG PS of 0, either ER positive or unknown, and had not received prior hormone therapy for metastatic disease. Overall objective response was observed in 9 (27%) patients. Complete response was observed in 2 cases and partial response in 7 patients. Median duration of response was 7 months (range 2-10). A higher response rate was observed in patients with predominantly soft tissue disease (38%) compared to patients with either dominant bone (18%) or visceral lesions (17%). Toxicity was mild and reversible: low grade fever in 30% of patients and flu-like symptoms in 9% of cases. It appears that IFN-B does not improve the efficacy of tamoxifen in an unselected population of metastatic breast cancer.

Annals of the New York Academy of SciencesVolume 784, Issue 1 p. 419-426 Effects of Primary Chemotherapy on Biological Parameters of Locally Advanced Breast Cancera P. COLLECCHI, P. COLLECCHI Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorP. G. GIANNESSI, P. G. GIANNESSI Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorE. BALDINI, E. BALDINI Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorA. G. NACCARATO, A. G. NACCARATO Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorA. PASSONI, A. PASSONI Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorG. BEVILACQUA, G. BEVILACQUA Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorP. F. CONTE, P. F. CONTE Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this author P. COLLECCHI, P. COLLECCHI Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorP. G. GIANNESSI, P. G. GIANNESSI Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorE. BALDINI, E. BALDINI Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorA. G. NACCARATO, A. G. NACCARATO Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorA. PASSONI, A. PASSONI Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorG. BEVILACQUA, G. BEVILACQUA Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this authorP. F. CONTE, P. F. CONTE Institute of Pathology University of Pisa, Pisa, Italy Department of Medical Oncology St. Chiara Hospital Pisa, ItalySearch for more papers by this author First published: April 1996 https://doi.org/10.1111/j.1749-6632.1996.tb16256.xCitations: 5 a This work was supported by Consiglio Nazionale Ricerche (CNR) Grant No. 93.02290.PF39. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume784, Issue1Basis for Cancer ManagementApril 1996Pages 419-426 RelatedInformation

Encouraging results with Paclitaxel are reported in ovarian cancer patients relapsing and progressing after platinum-based chemotherapy; however, the two populations have different probabilities of a response to a second-line treatment. Here we report the results achieved in 39 patients with platinum-refractory ovarian cancer, treated with Paclitaxel 175 mg/qm(2) (or 135 mg/m(2) if heavily pretreated) using 3-hour intravenous infusion every 3 weeks, in an attempt to verify the activity of this drug in platinum-resistant patients. The toxicity was mild to moderate and primarily hematologic and neurologic. The objective response rate is 12.8% with no complete responses. The response duration was brief and the median survival 6 (range 1-17) months. An accurate cost-benefit balance is necessary before routinely use of Paclitaxel in platinum-refractory patients. Further research is needed to determine the optimal role of Paclitaxel in the whole therapeutic strategy for ovarian cancer.

We performed a dose-escalation study to evaluate the maximum tolerated dose (MTD) of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus a fixed dose of epirubicin. Epirubicin was administered as a 90 mg/m2 bolus immediately followed by a 3-hour infusion of paclitaxel starting at 135 mg/m2 and escalating by 20mg/m2 for each triplet of patients as long as no dose-limiting toxicity had occurred; courses were repeated every 3 weeks. The MTD was defined as that at which any of the following toxicities occurred in at least two of six patients: absolute neutrophil count less than 500/microliter for more that 7 days or less than 100/microliter for more than 3 days; any episode of febrile neutropenia requiring intravenous antibiotics and hospitalization; grade 4 thrombocytopenia requiring platelet transfusion; failure to recover absolute neutrophil count to > or = 1,500/microliter and/or platelets to > or = 100,000/microliter by day 28; and any grade > or = 3 nonhematologic toxicity. Two MTDs were defined: the first without granulocyte colony-stimulating factor (MTD 1) and the second with granulocyte colony-stimulating factor given either to accelerate recovery of grade 4 neutropenia lasting more than 72 hours or immediately in case of febrile neutropenia (MTD 2); granulocyte colony-stimulating factor was never used prophylactically. To date, 22 patients have been entered into the study; the median patient age was 55 years (age range, 30 to 66 years). Nineteen (86%) patients had received adjuvant chemotherapy that included anthracyclines in 12 cases (55%). The viscera were the dominant sites of disease in 55% of patients. Median baseline ventricular ejection fraction was 58% (range, 53% to 67%). Short-lasting grade 4 neutropenia occurred in 61% of courses; however, only four episodes of febrile neutropenia were recorded. Grade 4 thrombocytopenia was reported in 8% and grade 3 anemia in 3% of courses; four patients experienced peripheral neuropathy (three patients grade 1, one patient grade 2); complete alopecia was universal. The cardiac effects of the combination were surprisingly low: median ejection fraction at study entry was 58%, and after a cumulative dose 1,080 mg/m2 it was 56%. Three complete responses and 12 partial responses have been documented for an overall response rate of 83.3% (95% confidence interval, 58% to 96%). In conclusion, neutropenia is the most frequent toxicity of this novel combination. However, the MTD has not yet been reached. The combination of epirubicin plus paclitaxel is highly active, and no signs of cumulative myocardiopathy have been observed.

This phase II study combined paclitaxel (Taxol; Bristol Myers Squibb Company, Princeton, NJ) 135 mg/m2 by 3-hour infusion on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 (in the first 14 patients) or on days 1 and 3 (in the subsequent 20 patients). The courses were repeated every 3 weeks. The second vinorelbine dose (on days 3 or 8) was reduced or omitted according to the toxicities encountered. Thirty-four patients have been treated to date; 21 had received one prior regimen of chemotherapy, 11 had two prior regimens, and two had three prior regimens. Only two patients (6%) had not been exposed to anthracyclines. One hundred twenty-six courses have been administered: 52 with vinorelbine given on days 1 and 8, and 74 with vinorelbine administered on days 1 and 3. The most frequent toxicity was grade 4 neutropenia, which occurred in 64% of the courses; 13 episodes of febrile neutropenia have been reported in eight patients. Filgrastim was administered in 43% of the courses because of febrile neutropenia or delayed recovery (> 72 hours) from grade 4 neutropenia. Mucositis was observed in 18% of the courses (12% grade 1, 3% grade 2, and 3% grade 3). The dose of vinorelbine was reduced or omitted in 86% of courses with the days 1 and 8 schedule, and in 48% of courses with the days 1 and 3 schedule. Among 28 evaluable patients, two complete and 10 partial responses have been observed (response rate, 43%, 95% confidence interval, 19% to 51%). Median duration of response is 5+ months (range, 1 to 15 months). In conclusion, this combination is active and has acceptable toxicities in anthracycline-pretreated breast cancer patients. The delivered dose intensity of vinorelbine is higher with the schedule adopted later in the study, with vinorelbine given on days 1 and 3.