Classical markers like ER and ki-67, but also survivin and pERK, could be involved in the pathological response to gemcitabine, adriamycin and paclitaxel (GAT) in locally advanced breast cancer patients: results from the GEICAM/2002-01 phase II study.

INTRODUCTION: The identification and validation of biomarkers of chemotherapy sensitivity is critical in order to individualise therapy in breast cancer. We evaluated pathological complete response (pCR) to GAT, and its correlation with tumour biomarkers before and after neoadjuvant chemotherapy. MATERIALS AND METHODS: Stage III (and stage II with T≥5 cm) breast cancer patients were included. Treatment consisted of adriamycin (40 mg/m(2)) day 1, and paclitaxel (150 mg/ m(2)) followed by gemcitabine (2000 mg/m(2)) day 2, every 14 days for six cycles. Tissue from pre-treatment biopsy and surgery was evaluated for biologic markers by immunohistochemistry. Two XPD single nucleotide polymorphisms (SNP) were also analysed. RESULTS: Forty-six patients entered the trial. Median age was 49.5 years (range 31-72); 25 patients (54%) were pre-menopausal; 12 (26%) were ER-PgR-negative; pCR was observed in 17% (95% CI: 6.4-28.4) of patients. Significant differences in marker expression (mean±SD) in correlation to pathological response were only found in Ki- 67. After treatment, tumours showed lower Ki-67-, surviving- and pERK-positive cells. No correlation between XPD polymorphisms and pCR was found. The overall response rate was 89% (95% CI: 80.1-98.1). Fifteen patients (33%) underwent breast-conserving surgery. The most frequent grade 3 or 4 toxicities were neutropenia (with one febrile neutropenia) and asthenia. CONCLUSION: These results show an effective regimen with acceptable tolerability. Our data suggest that not only classical markers (ER, Ki-67), but also survivin and pERK could be involved in the response to GAT, which may contribute to therapy individualisation in future study designs.

Multicenter, phase II, nonrandomized study of docetaxel plus trastuzumab every 21 days as the primary therapy in metastatic breast cancer overexpressing HER2.

Different anthracycline-free regimens have demonstrated activity, without serious cardiac events. This study was conducted to evaluate the activity and toxicity of docetaxel and trastuzumab given every 21 days in patients with metastatic breast cancer (MBC). The primary endpoint was time to progression and the secondary aims included response rate, safety, duration of response, and overall survival. Eligible patients were those with MBC human epidermal growth factor receptor-2+ (HER2+) with no previous chemotherapy for advanced disease. Patients received six cycles of docetaxel (100 mg/m) plus trastuzumab (8 mg/kg loading dose and 6 mg/kg every 21 days thereafter), followed by maintenance treatment with trastuzumab monotherapy every 21 days until disease progression. Forty-nine patients with HER2+ MBC were included. The overall response rate was 44.9% (22/49). With a median follow-up of 16.6 months, the median time to progression was 8.3 months and the median overall survival was 25.7 months. Nineteen patients did not receive treatment continuation with trastuzumab monotherapy. The most common toxicity was febrile neutropenia. A total of 10 patients were taken off the study due to treatment-related toxicity, mainly cardiac events. First-line trastuzumab combined with docetaxel is an effective and well tolerated regimen for HER2+ MBC.

Phase II clinical trial with gemcitabine and paclitaxel sequential monotherapy as first-line treatment for advanced non-small-cell lung cancer (SLCG 01-04).

BACKGROUND: In advanced-stage (IIIB or IV) non-small-cell lung cancer (NSCLC), combination chemotherapy has demonstrated response rates of 20% and a 1-year survival rate of 30%. We conducted a multicentre, open-label, nonrandomised phase II trial to determine the efficacy and tolerability of sequential monotherapy with gemcitabine followed by paclitaxel in chemotherapy-naïve patients with advanced NSCLC. MATERIALS AND METHODS: Between December 2002 and July 2004, the Spanish Lung Cancer Group (SLCG) conducted a study in which 34 patients with advanced (stage IIIB or IV) NSCLC received 1200 mg/m(2) of i.v. gemcitabine on days 1, 8 and 15 of each 28-day cycle for a total of 3 cycles followed by 100 mg/m(2) of weekly i.v. paclitaxel for a maximum of 8 weeks. If objective response or stable disease was achieved, 70 mg/m(2) of weekly i.v. paclitaxel was maintained until disease progression was evident or toxic effects were intolerable. Lung Cancer Symptom Scale (LCSS) analysis was performed. Baseline levels of serum VEGF, EGFR, telomerase reverse transcriptase (hTERT) and K-ras mutations were analysed. The primary endpoint was the objective response rate. RESULTS: The median age of the 34 patients who were enrolled was 67 years (range 46-77), but later 8 patients were excluded; 78.8% were men, 81.8% had performance status 1 and also 81.8% had metastatic disease at diagnosis. The objective response rate was 28% (95% CI, 14.2-47.8); the median overall survival was 7.2 months (95% CI, 2.1-12.3) and the median time to progression (TTP) was 3.1 months (95% CI, 2.5-5.3). Grade 3 or 4 drug-related haematological toxicities were observed in 6 patients. Patients with lower baseline serum VEGF levels had significantly longer survival. CONCLUSIONS: Sequential therapy with gemcitabine followed by paclitaxel was well tolerated with a low proportion of grade 3 or 4 adverse events, the absence of unexpected toxicity and with an improvement in quality of life. Unfortunately, the response rate did not meet the minimally required rate of 20% and the study was prematurely closed. VEGF was identified as a poor prognostic factor for TTP and survival.

A Phase II study of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of capecitabine in combination with vinorelbine in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. PATIENTS AND METHODS: In this prospective, multicenter, open-label phase II trial, patients received capecitabine (2000 mg/m2 daily, taken in 2 oral doses) on days 1-14 and vinorelbine (25 mg/m2 intravenous infusion) on days 1 and 8. Cycles were repeated every 3 weeks up to a maximum of 6 cycles, unless disease progression or unacceptable toxicity occurred or patient consent was withdrawn. RESULTS: Thirty-one patients were included and received 152 cycles of chemotherapy, with a median of 3 cycles per patient. All patients were evaluated for efficacy and toxicity in an intent-to-treat analysis. The overall response rate was 49% (95% CI, 30%-67%), including 4 complete (13%) and 11 partial (36%) responses. With a median follow-up time of 9 months, the median time to disease progression was 7.6 months (95% CI, 5.7-9.8 months), and the median survival time was 27.2 months. The most frequent severe hematologic toxicities were neutropenia (48% of patients) and leukopenia (10% of patients). Vomiting (16% of patients) was the most common nonhematologic toxicity, while asthenia, bone pain, dyspnea, plantar-palmar erythrodysesthesia, nausea, and transaminase elevation were observed in 6%-10% of patients. There was 1 death from septic shock. CONCLUSION: Capecitabine in combination with vinorelbine is an effective and safe schedule for patients with MBC pretreated with anthracycline- and taxane-containing regimens.

Thymidylate synthase expression pattern is a prognostic factor in patients of colorectal cancer treated with 5-fluorouracil.

High intratumoral expression of thymidylate synthase (TS) has been reported as a factor of poor prognosis in patients with advanced colorectal cancer (CRC), but such association is unclear in some studies. Also, TS has been stated as a typical cytosolic enzyme, but nuclear location has been occasionally reported, and data on the clinical meaning of TS intracellular location are scarce. A retrospective study was performed in paraffin-embedded sections of primary tumor from 77 CRC patients treated with surgical resection and adjuvant 5-FU-based chemotherapy. TS levels and expression patterns were determined by immunohistochemistry (IHQ) using TS-106 antibody. Qualitative and quantitative variables were compared respectively by chi2 and Kruskal-Wallis tests; overall survival (OS) and disease-free survival (DFS) were analyzed with the Kaplan-Meier method and compared using the log-rank and Wilcoxon tests. TS was cytoplasmic in 27.1% of positive tumors and both, nuclear and cytoplasmic in 72.9%; specimens from seven patients (9.1%) lacked TS expression. TS levels were high in 21.6% of tumors with nuclear expression and low in 5.6%, whereas 68.4% of cytoplasmic ones showed low immunostaining intensity (p=0.02); cytoplasmic pattern was also associated to longer OS (p<0.009) and DFS (p=0.003). In patients with nuclear expression, low TS expression was associated to shorter OS (p<0.003) and DFS (p<0.04). These results indicate that, in our study, TS immunostaining patterns were related with OS and DFS, the best prognostic corresponding to cytoplasmic one, and, within the subset of patients with nuclear expression, low TS levels were associated to worse clinical outcome.

Phase II trial of vinorelbine and estramustine in the treatment of metastatic hormone-resistant prostate cancer.

The purpose of this study was to investigate the efficacy and safety of combination chemotherapy using estramustine and vinorelbine in chemotherapy-naïve patients with hormone-resistant prostate cancer (HRPC). The patients (n = 54) received oral estramustine 840 mg/day on Days 1 to 14 and IV vinorelbine 25 mg/m(2) on Days 1 and 8 of every 3 wk cycle. The median number of cycles per patient was 9 (range, 1 to 27). Fifty-three patients were evaluable for toxicity and survival and 52 for prostate specific antigen (PSA) response. Median age was 68 (range, 46-80). PSA sustained decrease >50% was seen in 52% of patients (95% CI: 38-66%). A complete response was seen in 3 and a partial response in 12 of 25 patients with measurable disease, for an overall objective response of 60% (95% CI: 41-79%). Improvement in performance status was observed in 30 out of 43 evaluable for clinical benefit response. The median duration of response was 7 mo and median time to progression was 6 mo. The median survival time was 15 mo. The most common adverse event was mild gastrointestinal toxicity. In general, toxicity G3-4 was low: granulocytopenia Grade 3-4 (8%), thrombocytopenia Grade 3 (6%), and anemia Grade 3 (13%). Other Grade 3 toxicities included deep vein thrombosis (4%), hepatic (2%), cardiac ischemia (2%), fatigue (6%), and sensory neuropathy (2%). There were 2 treatment-related deaths (4%). We conclude that vinorelbine and estramustine as used in this trial is an efficacious and well-tolerated therapeutic regimen in the management of HRPC.

Weekly docetaxel as neoadjuvant chemotherapy for stage II and III breast cancer: efficacy and correlation with biological markers in a phase II, multicenter study.

PURPOSE: This is one of the first reports of weekly docetaxel (Taxotere) in the neoadjuvant treatment of stage II and III breast cancer. We evaluated docetaxel's efficacy and safety and analyzed correlations between response and the expression of c-erbB2, ER status, and Ki-67 labeling index. EXPERIMENTAL DESIGN: Patients with previously untreated, stage II and III breast cancer were entered into the study. Docetaxel (40 mg/m(2)) was given i.v. once weekly for the first 6 weeks of an 8-week cycle for 2 cycles. RESULTS: A total of 56 patients were evaluated by intention-to-treat analysis for efficacy and safety. The overall clinical response rate was 68% (complete and partial response, 29 and 39%, respectively). Nine patients (16%) achieved a pathological complete response. There was no correlation between response to docetaxel and the expression of molecular markers, however, the majority of the pathological complete responses were observed in patients with c-erbB2-negative tumors. Nonhematological toxicity was more common than hematological toxicity, with alopecia and asthenia the most frequently reported adverse events (89 and 77% of patients, respectively). Severe hematological toxicity was rare. CONCLUSIONS: Weekly docetaxel appears to be very effective in the neoadjuvant setting. A high pathological response rate was achieved with tolerable toxicity.