Predictive Potential of Angiogenic Growth Factors and Circulating Endothelial Cells in Breast Cancer Patients Receiving Metronomic Chemotherapy Plus Bevacizumab.

PURPOSE: The association of chemotherapy and antiangiogenic drugs has shown efficacy in clinical oncology. However, there is a need for biomarkers that allow selection of patients who are likely to benefit from such treatment and are useful for indicating best drug combination and schedule. EXPERIMENTAL DESIGN: We investigated the predictive potential of six angiogenic molecules/transcripts and nine subpopulations of circulating endothelial cells (CEC) and progenitors (CEP) in 46 patients with advanced breast cancer treated with metronomic cyclophosphamide and capecitabine plus bevacizumab. RESULTS: Median time to progression was 281 days. Baseline CECs higher than the first quartile were associated with an increased time to progression (P = 0.021). At progression, CECs were markedly reduced (P = 0.0002). In the cohort of 15 long-term responders, who progressed later than 1 year after beginning of therapy, circulating vascular endothelial growth factor (VEGF)-A levels measured after 2 months of therapy were significantly reduced, and there were significant trends toward lower levels of PDGF-BB, CEPs, and CECs. At the time of progression, angiogenic growth factors VEGF-A and basic fibroblast growth factor were significantly increased. CONCLUSIONS: Baseline CECs (likely reflecting an active vascular turnover) predicted a prolonged clinical benefit. At the time of relapse, a pattern of decreased CECs and increased angiogenic growth factors suggested a switch toward a different type of cancer vascularization. VEGF-A and basic fibroblast growth factor levels after 2 months of therapy were also useful to identify patients whose disease was likely to progress. These biomarkers are likely to be useful for treatment selection and might be incorporated in design of future studies. (Clin Cancer Res 2009;15(24):7652-7).

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy.

The predictive role of the degree of endocrine responsiveness to preoperative chemotherapy (PCT) is unclear. We reviewed pretreatment biopsies of 553 patients with locally advanced breast cancer who were treated with PCT. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to the degree of estrogen (ER) and progesterone receptor (PgR) expression (ER and PgR absent, vs. ER or PgR 0-49%, vs. ER and PgR >or=50% of the cells positive). A statistically significant higher pCR rate was observed at the multivariate analysis for patients with ER and PgR absent tumors (17.7%) versus patients with tumors expressing high ER and PgR (0%) (OR 14.4 P < 0.001). Despite the higher incidence of pCR, a statistically significant worse disease-free survival (DFS), and overall survival (OS) was observed for patients with ER and PgR absent tumors versus patients with tumors expressing high ER and PgR (HR 6.4, 95% CI 3.5-11.6, for DFS; HR 3.6 95% CI 2.4-5.6 for OS). Response and outcome after PCT are correlated with the degree of expression of steroid hormone receptors. Studies on tailored preoperative therapies are needed.

Invasive ductal carcinoma of the breast with the "triple-negative" phenotype: prognostic implications of EGFR immunoreactivity.

Invasive ductal carcinomas (IDC) of the breast with the triple negative phenotype (steroid hormone receptor absent, negative HER2 status) are characterized by poor clinical outcome. Additional tumor markers might allow identification of patients at higher risk. We evaluated clinical and biological features of 284 consecutive patients with pT1-3, pN1-3 M0 triple-negative IDC. Median follow-up was 70 months (interquartile range 59-94 months). Statistically significant worse disease-free and overall survival were observed in multivariate analysis, for patients with EGFR immunoreactivity in >or=50% invasive tumor cells (HR 2.39, 95% CI, 1.32-4.34, P = 0.004 for DFS; HR 2.34, 95% CI, 1.20-4.59 P = 0.01 for OS). Age >or= 70 years and PVI were additional independent predictors of reduced overall survival. EGFR immunoreactivity significantly correlates with worse prognosis in patients with triple-negative IDC, supporting further studies on the correlation between the degree of EGFR expression and outcome of triple negative breast cancer.

Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer.

PURPOSE: Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies. PATIENTS AND METHODS: Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). RESULTS: In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD > or = 24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD > or = 24 weeks) of 68% (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04). CONCLUSION: Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.

Gemcitabine and vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.

BACKGROUND: Pemetrexed-cisplatin chemotherapy is the standard of care in the first-line treatment of unresectable malignant pleural mesothelioma (MPM). Second-line cytotoxic therapy is considered for a growing group of patients, but the optimal treatment has not been defined to date. Gemcitabine and vinorelbine have shown activity in the first-line setting. The objective of this study was to evaluate the activity and toxicity of the gemcitabine-vinorelbine combination in pemetrexed-pretreated patients with MPM. METHODS: From January 2004 to September 2006, 30 consecutive patients who were pretreated with pemetrexed with or without a platinum-derivative were enrolled. Gemcitabine 1000 mg/m(2) and vinorelbine 25 mg/m(2) were administered intravenously on Days 1 and 8 every 3 weeks. Treatment was repeated for a maximum of 6 cycles or until progression or unacceptable toxicity. RESULTS: A partial response was observed in 3 patients (10%; 95% confidence interval [CI], 2.1-26.5%), and 10 patients (33.3%; 95% CI, 17.3-52.8%) had stable disease after treatment. Overall, 13 patients (43.3%; 95% CI, 25.5-62.6%) achieved disease control. The median time to progression was 2.8 months (range, 0.6-12.1 months), and the median survival was 10.9 months (range, 0.8-25.3 months). Hematologic toxicity was acceptable, with grade 3 or 4 neutropenia occurring in 11% of patients and thrombocytopenia occurring in 4% of patients; no case of febrile neutropenia was observed. Nonhematologic toxicity generally was mild. CONCLUSIONS: The gemcitabine and vinorelbine combination was moderately active and had an acceptable toxicity profile in pemetrexed-pretreated patients with MPM. The role of second-line treatment in MPM needs to be evaluated in prospective trials in large series of patients who are stratified according to previous treatment and prognostic factors.

The "old drug" dacarbazine as a second/third line chemotherapy in advanced soft tissue sarcomas.

The aim of this study was to evaluate retrospectively the response rate, progression-free survival and median duration of response to dacarbazine as second/third-line chemotherapy for refractory soft tissue sarcomas. We studied 40 valuable patients with refractory soft tissue sarcomas and confirmed progressive disease (median age 54 years; range 24-73) treated between May 1997 and October 2005: 30 (75%) with metastases, and 23 (57.5%) with grade 3 disease. Dacarbazine was given as second-line chemotherapy to 29 patients (72.5%) every 21 days using three different schedules: dacarbazine 800 mg/m2 on day 1 (26 patients); dacarbazine 400 mg/m2 on days 1 and 2 (five patients); and dacarbazine 300 mg/m2 on days 1, 2 and 3 (nine patients). There were no complete responses, three (7.5%) partial responses and five (12.5%) cases of stable disease, for an overall disease control rate of 20%. Median progression-free survival was 2 months and median response duration 9 months. The 3- and 6-month progression-free rates were, respectively, 25% (SE 6.85%) and 20% (SE 6.32%). There were no cases of grade 3-4 hematological and non-hematological toxicity. In conclusion, our results suggest that second/third-line therapy with dacarbazine leads to satisfactory disease control in refractory soft tissue sarcomas; its activity seems to be comparable with other treatments, such as high dose ifosfamide or ecteinascidin-743, but it has a better toxicity profile.

Phase II trial of alternating intravenous and oral vinorelbine in combination with cisplatin in advanced non-small cell lung cancer.

Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). Several platinum-based doublets have been tested in phase II/III trials with equivalent results in terms of tumour response and survival. Our study was designed to evaluate activity, tolerability and convenience of alternating intravenous (i.v.) and oral vinorelbine in combination with cisplatin in advanced NSCLC. Forty chemo-naive patients with stage IV or relapsed unresectable disease and good performance status were enrolled to receive i.v. cisplatin 40 mg/m(2) on days 1 and 2 plus i.v. vinorelbine 25 mg/m(2) on day 1, every 3 weeks. Oral vinorelbine 60 mg/m(2) was given at home on day 5, without checking of blood cell count. A total of 175 treatment cycles were delivered. The overall response rate was 30% (one complete, 11 partial responses). Median time to progression and overall survival were 5 and 10 months, respectively. The main toxicity was haematological, with grade 3-4 neutropenia observed in 75% of patients, without febrile neutropenia. Non-haematological toxicity was mild. This schedule of cisplatin and vinorelbine treatment showed a good toxicity profile and an efficacy similar to other standard regimens. Oral vinorelbine could be administered safely at home on day 5.

Cisplatin plus gemcitabine on days 1 and 4 every 21 days for solid tumors: result of a dose-intensity study.

BACKGROUND: Three and 4-week cisplatin-gemcitabine schedules have shown similar dose-intensity (DI) and activity in non-small-cell lung cancer (NSCLC). The 3-week schedule is generally preferred because it enables better treatment compliance. To improve DI and compliance further, we delivered gemcitabine plus cisplatin over 4 days every 21 days. METHODS: Patients with any stage NSCLC or epithelial neoplasms and an ECOG PS < or = 2 were given gemcitabine 1000 mg/m(2) on days 1 and 4 plus cisplatin 70 mg/m(2) on day 2 of a 21-day cycle. Minimax design was used and a received DI for gemcitabine of > or = 580 mg/m(2)/wk was considered successful. RESULTS: Thirty-nine patients (34 NSCLC, 5 epithelial neoplasias) were enrolled. SWOG grade 3-4 neutropenia and thrombocytopenia were observed in 17.9% and 12.8% of patients, respectively. Nonhematological toxicity was minimal. Twenty-eight (18%) of 158 cycles required dose modifications and/or delays. Twenty-five patients received a gemcitabine dose intensity of > or = 580 mg/m(2)/wk. The received DIs were 601.8 mg/m(2)/wk for gemcitabine and 21.0 for cisplatin, with a relative DIs of 90.3% and 90.1%, respectively. The response rate of 27 evaluable patients with NSCLC was 44% (95% confidence interval [CI], 25.3 to 62.7%). CONCLUSIONS: The shorter schedule of gemcitabine on days 1 and 4 plus cisplatin on day 2 produces an effective DI and a toxicity profile comparable to that of weekly regimens.

EGFR tyrosine kinase inhibitors: a therapy for a few, for the majority or for all non-small cell lung cancer patients?

The EGF receptor (EGFR) is one of the most important targets for cancer treatment implicated in the control of cell survival, proliferation and metastasis. In the last few years different EGFR molecular antagonists have been evaluated in the clinical setting and some of these drugs have demonstrated clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Gefitinib or erlotinib are a new class of compounds able to inhibit the tyrosine kinase domain of EGFR (EGFR TKI) and, during recent years, clinical and biologic predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, and EGFR gene mutation or EGFR increased gene copy number represent critical biologic variables associated with an improved outcome for patients exposed to these agents. Unfortunately, cancer cells possess escape mechanisms to overcome inhibition of cell proliferation leading to drug resistance. There are several mechanisms that have been identified as responsible for intrinsic or acquired resistance. The aim of the present review is to analyze available data in order to identify an optimal paradigm for patient selection.

Short schedule of cisplatin and vinorelbine: a dose-finding study in non-small-cell lung cancer.

OBJECTIVES: A dose-finding study of a new cisplatin/vinorelbine schedule was done to increase activity of the combination, and improve compliance of non-small-cell lung cancer PATIENTS. METHODS: Beginning with cisplatin 40 mg/m(2) on days 1, 2 and vinorelbine 20 mg/m(2) on days 1, 3, increasing dose levels up to the maximum tolerated dose (MTD) were tested in a series of 6-patient cohorts. If 3 of 6 patients experienced dose-limiting toxicity in the first 3 cycles, the previous dose was considered the recommended dose (RD). Once the MTD was reached, granulocyte-colony-stimulating factor was prophylactically added to the treatment of a new patient cohort to improve the therapeutic ratio. RESULTS: We enrolled 35 stage IIIA/B or IV patients between August 2001 and February 2002. The RD was cisplatin 45 mg/m(2) and vinorelbine 25 mg/m(2), with relative dose intensities (RDIs) of 95 and 97%, respectively, and an actual received dose intensity (ARDI) of 28.62 and 16.07 mg/m(2)/week, respectively. Overall grade 3-4 toxicities were: neutropenia (71%), febrile neutropenia (25%), anemia (8%), and constipation (17%). The overall response rate was 64.3% (CI: 44.1-81.4%). CONCLUSIONS: ARDI and RDI of our modified cisplatin/vinorelbine regimen were not inferior to those of conventional weekly schedules; its acceptable toxicity profile and manageability may justify its use in clinical practice.