Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments.

BACKGROUND: This open-label study compared docetaxel/gemcitabine vs. paclitaxel/gemcitabine and a weekly (W) vs. 3-weekly (3 W) schedule in metastatic breast cancer (MBC). METHODS: Patients relapsed after adjuvant/neoadjuvant anthracycline-containing chemotherapy were randomized to: A) gemcitabine 1000 mg/m2 Day 1,8 + docetaxel 75 mg/m2 Day 1 q3W; B) gemcitabine 1250 mg/m2 Day 1,8 + paclitaxel 175 mg/m2 Day 1 q3W; C) gemcitabine 800 mg/m2 Day 1,8,15 + docetaxel 30 mg/m2 Day 1,8,15 q4W; D) gemcitabine 800 mg/m2 Day 1,15 + paclitaxel 80 mg/m2 Day 1,8,15 q4W. Primary endpoint was time-to-progression (TTP). Secondary endpoints were overall survival (OS) and overall response rate (ORR). RESULTS: Interim analysis led to accrual interruption (241 patients enrolled of 360 planned). Median TTP (months) was 8.33 (95% CI: 6.19-10.16) with W and 7.51 (95% CI: 5.93-8.33) with 3 W (p=0.319). No differences were observed in median TTP between docetaxel and paclitaxel, with 85.6% and 87.0% of patients progressing, respectively. OS did not differ between regimens/schedules. ORR was comparable between regimens (HR: 0.882; 95% CI: 0.523-1.488; p=0.639), while it was significantly higher in W than in the 3 W (HR: 0.504; 95% CI: 0.299-0.850; p=0.010) schedule. Grade 3/4 toxicities occurred in 69.2% and 71.9% of patients on docetaxel and paclitaxel, and in 65.8% and 75.2% in W and 3 W. CONCLUSIONS: Both treatment regimens showed similar TTP. W might be associated with a better tumour response compared with 3 W. TRIAL REGISTRATION: Clinicaltrial.gov ID NCT00236899.

Gemcitabine and carboplatin treatment in advanced NSCLC: a retrospective evaluation including elderly patients.

BACKGROUND: Carboplatin-containing regimens are sometimes preferred for patients with advanced non-small cell lung cancer. METHODS: Eighty-three patients with stage III-IV non-small cell lung cancer received 3 to 4 cycles of carboplatin AUC 5 on day 2 and gemcitabine 1250 mg/m2 on days 1 and 8 every 21 days. RESULTS: The overall response rate was 43.4%. Results obtained from elderly and non-elderly groups were compared using the logrank method. Median overall survival and progression-free survival were 11 and 7 months, respectively (12 and 7 months, non-elderly group; 6.5 and 5 months, elderly group, P = 0.28 and 0.25 respectively). Grade 3-4 toxicity included neutropenia, thrombocytopenia, anemia, nausea/vomiting, and diarrhea. Incidences of grade 3-4 toxicity were similar for elderly and non-elderly patients. CONCLUSIONS: Data confirm that carboplatin-gemcitabine is an active and well-tolerated regimen in advanced non-small cell lung cancer and could be investigated in elderly patients.

Immunotherapy with dendritic cells for cancer.

Dendritic cells are professional antigen-presenting cells with a key role in both immunity induction and tolerance maintenance. Dendritic cells are highly specialized in antigen capture, processing and presentation, and express co-stimulation signals which activate T lymphocytes and NK cells. Dendritic cells generated in culture and loaded with an antigen efficiently induce antigen-specific immunity after injection. More recently, methods have been developed that target antigens to dendritic cells in vivo, bypassing the need for ex vivo cell manipulations. Numerous ongoing studies aim to evaluate the effectiveness of dendritic cell vaccines in preventing tumor relapses and extending patients' survival. Further implementation of this form of immunotherapy is expected following the identification of the mechanisms controlling dendritic cell immunogenicity, and from a better understanding of the cell dynamics whereby immune responses are orchestrated. Here, we discuss these new insights together with an overview of the dendritic cell-based clinical studies carried out to date.

The use of dendritic cells in cancer immunotherapy.

Cancer immunotherapy aims at eliciting an immune response directed against tumor antigens to help fight off residual tumor cells and thereby improve survival and quality of life of cancer patients. Different immunotherapeutic approaches share the use of dendritic cells (DCs) to present tumor-associated antigens to T-lymphocytes. Ex vivo generated DCs can be loaded with antigens and re-infused to the patients, or they can be used for ex vivo expansion of antitumor lymphocytes. Alternatively, methods exist to target antigens to DCs in vivo without need for ex vivo cell manipulations. The clinical studies have shown that DC administration to patients is safe and induces antigen-specific immunity. However, it seldom elicits objective clinical responses in patients with advanced-stage malignancies. Novel insights into DC and lymphocyte regulation are expected to lead to more effective vaccines in the near future. Meanwhile, efforts are directed at identifying the most appropriate clinical targets for active specific immunotherapies. Data suggests that vaccinations may indeed be beneficial when given in the adjuvant setting rather than to treat metastatic cancers. These issues are discussed here together with an overview of the DC-based antitumor immunotherapy studies.

Pegfilgrastim compared with filgrastim after autologous peripheral blood stem cell transplantation in patients with solid tumours and lymphomas.

To evaluate the safety and efficacy of pegfilgrastim administered as haematological support after autologous peripheral blood stem cell transplantation, we compared 44 patients with solid tumours and lymphomas receiving a 6-mg single dose of pegfilgrastim on day +5 after transplantation to a historical control group of 25 patients receiving filgrastim 5 microg kg(-1) day(-1) starting on day +5. There were no significant differences in haematological recovery nor in the incidence and duration of neutropenic fever. Median duration of grade 4 neutropenia in the pegfilgrastim and filgrastim group was similar. The incidence of grade III-IV mucositis was lower in pegfilgrastim than in filgrastim group due to the significant difference observed among the patients with solid tumours (p = 0.00). The only adverse event considered to be cytokine related was mild to moderate bone pain occurring during haematological recovery. According to the present study design and taking into account the current prices in our institution, the cost of the two drugs was similar in both treatment groups. In conclusion, a single injection of pegfilgrastim administered at day +5 post-transplantation shows comparable safety and efficacy profiles to daily injections of filgrastim and may be cost effective.

Cooperative cytotoxicity of proteasome inhibitors and tumor necrosis factor-related apoptosis-inducing ligand in chemoresistant Bcl-2-overexpressing cells.

PURPOSE: Bcl-2 overexpression is frequently detected in lymphoid malignancies, being associated with poor prognosis and reduced response to therapy. Here, we evaluated whether Bcl-2 overexpression affects the cytotoxic activity of proteasome inhibitors taken alone or in association with conventional anticancer drugs or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). EXPERIMENTAL DESIGN: Jurkat cells engineered to overexpress Bcl-2 were treated with proteasome inhibitors (MG132, epoxomicin, and bortezomib), anticancer drugs (etoposide and doxorubicin), TRAIL, or combinations of these compounds. Cell death and loss of mitochondrial transmembrane potential were detected by flow cytometry. Cytosolic relocalization of cytochrome c and SMAC/Diablo, caspase cleavage, and Bcl-2 and Mcl-1 levels were determined by immunoblotting. Nuclear factor-kappaB inhibition was done by retroviral transduction with a dominant-negative mutant of IkappaBalpha. RESULTS: Bcl-2 overexpression results in significant inhibition of apoptosis in response to proteasome inhibitors, antiblastics, and TRAIL. Addition of TRAIL to proteasome inhibitors results in a synergistic cytotoxic effect in Bcl-2-overexpressing cells, whereas this result is not reproduced by the combination of proteasome inhibitors with antiblastic drugs. Importantly, proteasome inhibitors plus TRAIL induce mitochondrial dysfunction irrespective of up-regulated Bcl-2. Bcl-2 cleavage to a fragment with putative proapoptotic activity and elimination of antiapoptotic Mcl-1 may both play a role in proteasome inhibitors-TRAIL cooperation. Conversely, nuclear factor-kappaB inhibition by proteasome inhibitors is per se insufficient to explain the observed synergy. CONCLUSIONS: Combined proteasome inhibitors and TRAIL overcome the apoptotic threshold raised by Bcl-2 and may prove useful in the treatment of chemoresistant malignancies with up-regulated Bcl-2.

Tumor necrosis factor-related apoptosis-inducing ligand cooperates with anticancer drugs to overcome chemoresistance in antiapoptotic Bcl-2 family members expressing jurkat cells.

PURPOSE: Overexpression of antiapoptotic Bcl-2 family members has recently been related to resistance to chemo/radiotherapy in several human malignancies, particularly lymphomas. Hence, innovative approaches bypassing this resistance mechanism are required in the therapeutic approach. This study evaluated whether chemoresistance associated with Bcl-2 and Bcl-x(L) overexpression would be overcome by activating the death receptor pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the Jurkat cell model EXPERIMENTAL DESIGN: We made use of genetically modified Jurkat cells to evaluate the effect of Bcl-2 or Bcl-x(L) overexpression on the cytotoxic effect produced by the anticancer drugs doxorubicin, etoposide, and oxaliplatin and TRAIL. Caspase activation was detected by cleavage of caspase-8 and -3. The mitochondrial transmambrane potential was assessed by staining with DiOC(6) and flow cytometry. Caspase activity was blocked by the broad-spectrum caspase inhibitor zVAD-fmk. RESULTS: Bcl-2 and Bcl-x(L) overexpression but not lack of caspase-8 protects the Jurkat cells from the anticancer drug-induced cytolysis. However, Bcl-2/Bcl-x(L) Jurkat cells retained some susceptibility to TRAIL-induced cytolysis. A highly synergistic cytotoxic effect of the combination of TRAIL with any of the antiblastic used in this study was detected in the chemoresistant cells. This effect was associated with mitochondrial disassemblage and dependent on caspase activation CONCLUSIONS: The combination of TRAIL with conventional anticancer drugs may prove to be useful in the treatment of antiapoptotic Bcl-2 family proteins-expressing malignancies.

Sequential dose-dense 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel in patients with early breast cancer with four or more positive lymph nodes.

AIM: The aim of present study was to investigate the feasibility of a densified sequence of FEC75 (5-fluorouracil 600 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2) and docetaxel 100 mg/m2 (D100) in patients with primary operable high-risk breast cancer. METHODS: Fifty-one consecutive patients with resectable breast cancer and 4 or more positive axillary lymph nodes were enrolled. After a common regimen of 4 cycles of FEC75 given every 14 days, patients received 4 cycles of D100 every 14 days. Prophylactic granulocyte colony-stimulating factor was administered subcutaneously at 5 mg/kg daily from days 5 to 10 to each patient. RESULTS: The primary endpoint was the proportion of subjects receiving at least 85% of the relative dose intensity (rDI) both in the FEC and docetaxel parts of the regimen. In view of the high percentage of grade 3-4 skin toxicity (32%) observed in the first 25 patients (Group A) during D100 treatment, it was decided to continue the study using a docetaxel dose reduced by 15% (85 mg/m2; D85). This second group of 26 patients was defined as Group B. Of the total 51 patients, 38 (75%) received docetaxel rDI ≥85%, 23/26 patients (88.5%) and 15/25 patients (60.0%) in Group B and Group A, respectively. The observed grade 3-4 hematological and nonhematological toxicities were in line with data from the literature. The only significant difference was the higher percentage of grade 3-4 skin toxicity experienced with D100. CONCLUSION: This study failed to demonstrate the feasibility of a dose-dense FEC-D regimen with docetaxel 100 mg/m2. Docetaxel 85 mg/m2 seems to allow a higher rDI than docetaxel 100 mg/m2 but this should be confirmed in a larger cohort of patients.

Squamous cell carcinoma of the breast: a case report.

INTRODUCTION: Pure primary squamous cell carcinoma of the breast is uncommon and it's debated the correct management of this disease. CASE PRESENTATION: A 54-years-old woman presented with signs and symptoms of mastitis of left breast. A palpable well circumscribed and firm mass, measuring about 40 mm, was present in the left lower lateral quadrant. She underwent antibiotic therapy without benefit. She performed an ultrasound and mammographic scan of the left breast. Fine needle aspiration cytology revealed an infiltrative poorly differentiated squamous cell carcinoma. Total body CT scan and bone scan excluded distant metastasis. Subsequently wide local excision of the left breast with ipsilateral axillary lymph nodes dissection was performed. The pathological examination revealed an infiltrative poorly differentiated squamous cell carcinoma of the breast. Adjuvant chemotherapy cisplatin and 5-fluorouracil based was administered. Patient refused locoregional radiotherapy. Twenty-eight months after surgery the patient was disease free. CONCLUSIONS: Pure primary squamous cell carcinoma of the breast is a rare and aggressive disease often treatment-refractory. An optimal systemic treatment is needed to improve patient's outcome.