Bisphosphonates as anticancer agents in early breast cancer: preclinical and clinical evidence.

Bisphosphonates (BPs) are approved as standard therapy in breast cancer for the treatment of bone metastases, since they were demonstrated to reduce the prevalence of skeletal-related events including fractures and hypercalcemia. In the adjuvant setting, BPs can be given to prevent and treat tumor therapy-induced bone loss in premenopausal and postmenopausal women and, owing to their beneficial effect on bone turnover, have also been evaluated for prevention of bone metastases occurrence. In this article we will review the mechanisms through which BPs have been demonstrated to prevent premetastatic niche formation and cell proliferation in bone lesions. Moreover, preclinical evidence of antitumoral effects of BPs will be presented and results from the most important clinical trials will be described critically. BPs may clearly play a clinically important role in early breast cancer in a postmenopausal adjuvant setting.

Lack of Correlation Between Liver Tests Abnormalities and Trabectedin Efficacy in the Treatment of Soft Tissue Sarcoma: a Retrospective Study.

Elevation in liver transaminases is common in patients treated with the marine antitumor agent trabectedin. However, the impact of trabectedin-related transaminase elevations on treatment outcomes is unclear. This retrospective study investigated the correlation between liver tests abnormalities and treatment outcomes in patients with unresectable advanced or metastatic soft tissue sarcomas (STS) treated with trabectedin 1.5 mg/m(2) once every 3 weeks at three reference centers in Italy. The effect of grade 3/4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) during the first two cycles and at any time during trabectedin treatment on progression-free survival (PFS) and overall survival (OS) were analyzed. Liver tests abnormalities during the first two cycles of chemotherapy or at any time during trabectedin treatment did not significantly affect PFS or OS. Nor were survival outcomes significantly different in the subgroups of patients with or without ALT/AST increases or with ALT/AST elevations ≥ 15 × the upper limit of normal (ULN) versus those with ALT/AST elevation < 15 × ULN. Although liver tests abnormalities are common in patients treated with trabectedin, elevations in ALT and AST are usually transient, occur during the first two cycles of treatment, and do not appear to affect survival.

"Impact of Smoking Cessation Treatment" on Lung Function and Response Rate in EGFR Mutated Patients: A Short-Term Cohort Study.

BACKGROUND: Erlotinib is a validated drug "for the treatment of patients affected by advanced unresectable non small cell lung cancer (NSCLC) with EGFR mutations". We want to focus on potential functional benefits deriving from a combined therapy containing TKI (erlotinib) and a nicotinic partial agonist (varenicicline) in smokers. METHODS: we analyzed the records of patients affected by NSCLC treated undergoing "first line therapy with Erlotinib" and smoking cessation (with varenicicline). Response to therapy was evaluated by CT scan. Data concerning clinical history, smoking habit, nicotine dependence were collected after three months from the beginning of the recruitment. Pulmonary function tests including spirometry with pletismographic technique and exhaled carbon monoxide (CO) were performed with recording of resistances, flows, volumes. A group of ten current smokers affected by NSCLC with EGFR activating mutation and concurrent mild COPD undergoing anti-EGFR treatment without smoking cessation was used to compare clinical and functional data. A control group of NSCLC wild type with mild COPD undergoing smoking cessation was assessed for functional data. RESULTS: Twenty-five patients were enrolled. All of them reported partial response at CT re-evaluation. All functional indexes and parameters were improved after combined treatment a significant increase of FEV1 level and a decrease of exhaled CO. In particular, a mean increase of FEV1 from 1.93 (SD 0.48) to 2.03(SD 0.46) liters was recorded. A notable reduction of sRAW (specific resistances) was also observed. The improvement of some parameters such as CO, heart rate (HR), sRAW and FEV1 resulted statistically significant. A better response to therapy was found "in the study group compared to the second group of mutated NSCLC patients". In this second group, we also observed an improvement of functional obstructive parameters although it was less remarkable than study group. Only sRAW and FEF 25/75 were significantly increased. The group of NSCLC wild type undergoing only smoking cessation showed a lower increase of FEV1 by about 50 ml compared to the first group. CONCLUSION: The combination of anti-EGFR treatment and concurrent therapy for smoking cessation seems to be more effective than erlotinib alone in improving lung function and clinical response in advanced NSCLC patients with EGFR-mutations. It is conceivable that erlotinib may potentiate the action of varenicline. We have also outlined some relevant patents concerning varenicline and EGFR-TKI.

Optimizing single agent panitumumab therapy in pre-treated advanced colorectal cancer.

PURPOSE: To improve the selection of advanced colorectal cancer patients to panitumumab by optimizing the assessment of RAS (KRAS-NRAS) mutations. EXPERIMENTAL DESIGN: Using a centralized pyrosequencing RAS assay, we analyzed the tumors of 94 patients, wild-type for KRAS mutations (codons 12 to 13) by Sanger sequencing (SS), treated with panitumumab. RESULTS: By SS analysis, 94 (62%) of 152 patients were wild-type and their objective response rate to panitumumab was 17%. We first optimized the KRAS test, by performing an accurate tissue-dissection step followed by pyrosequencing, a more sensitive method, and found further mutations in 12 (12.8%) cases. Secondly, tumors were subjected to RAS extension analysis (KRAS, exons 3 to 4; NRAS exons 2 to 4) by pyrosequencing that allowed to identify several rare mutations: KRAS codon 61, 5.3%; codon 146, 5.3%; NRAS, 9.5%. Overall, RAS mutation rate was 32.9%. All patients with additional RAS mutations had progressive or stable disease, except 3 patients with mutations at codon 61 of KRAS or NRAS who experienced partial (2 cases) or complete response. By excluding from the analysis 11 cases with mutations at codons 61, no patient was responsive to treatment (P=.021). RAS wild-type versus RAS mutated cases had a significantly better time to progression (P=.044), that resulted improved (p=.004) by excluding codon 61 mutations. CONCLUSION: This study shows that by optimizing the RAS test it is possible to significantly improve the identification of patients who do not gain benefit of panitumumab. Prospective studies are warranted to determine the clinical significance of rare mutations.

Capecitabine in elderly patients with metastatic breast cancer.

AIMS AND BACKGROUND: Capecitabine is the reference treatment for anthracycline- and/or taxane-pretreated metastatic breast cancer (MBC). This study examined its efficacy, tolerability and impact on the quality of life of elderly patients with MBC. MATERIALS AND METHODS: Between January 2002 and December 2009, 75 consecutive elderly patients with MBC received first-line chemotherapy with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks. Endpoints were efficacy, tolerability and clinical-benefit response measured every 3 cycles. RESULTS: Median age was 76 years (range 65-88); median ECOG performance status was 1 (range 0-2); 51 patients (68%) had received adjuvant chemotherapy and all patients had received hormonal therapy. Median exposure was 6 cycles. After 3 cycles, 11 patients (14.7%) had a partial response, one patient experienced a complete response, and 49 patients (65.3%) had stable disease, amounting to a disease control rate of 81.3%. Stable disease was maintained in 45 patients (60%) after 6 cycles, in 21 patients (28%) after 9 cycles, and in 13 patients (17.3%) after 12 cycles. A clinical-benefit response was experienced by 42 patients (56%), indicating a positive impact on quality of life. Treatment was well tolerated, the most common grade 3 events being diarrhea (12%) hand-foot syndrome (8%), and mucositis (8%). Adverse events were managed with dose adjustments and supportive therapy when required. CONCLUSIONS: Our results indicate that capecitabine is active and well tolerated in elderly patients with MBC. This dosing regimen warrants further study in the first-line setting for patients with less aggressive MBC who are not candidates for combination therapy.

Palonosetron plus 3-day aprepitant and dexamethasone to prevent nausea and vomiting in patients receiving highly emetogenic chemotherapy.

BACKGROUND: The combination of a neurokinin-1 receptor antagonist, dexamethasone, and a 5-HT(3) receptor antagonist is currently the standard antiemetic treatment in patients receiving cisplatin-based high emetogenic chemotherapy (HEC). The aim of this study was to evaluate the efficacy of a combination of palonosetron, a unique second-generation 5-HT(3) receptor antagonist, aprepitant, the only approved neurokinin-1 receptor antagonist, and dexamethasone as antiemetic prophylaxis in patients receiving HEC (cisplatin ≥50 mg/mq). METHODS: Chemotherapy-naïve adult patients, receiving cisplatin-based HEC, were treated with palonosetron 0.25 mg/i.v., dexamethasone 20 mg/i.v., and aprepitant 125 mg/p.o., 1-h before chemotherapy. Aprepitant 80 mg/p.o. and dexamethasone 4 mg p.o. were administered on days 2-3. Primary end point was complete response (CR; no vomiting and no use of rescue medication), during the overall study period (0-120 h). Secondary end points were complete control (CR and no more than mild nausea), emesis-free rate, and nausea-free rate during the acute (0-24 h), delayed (24-120 h), and overall (0-120 h) periods. Safety was also evaluated. RESULTS: A total of 222 patients were included in the study. Median age was 62 years, 76.6% were male and 23.4% female, and most common tumors were lung (66.7%) and head and neck (15.8%); 70.3% of patients achieved CR during the overall study period. Complete control, emesis-free rate, and nausea-free rate were 70.3%, 92.8%, and 59.9%, respectively, during the overall phase. The most commonly reported side effects were constipation (39% of patients) and headache (5%). CONCLUSIONS: This study shows that palonosetron in combination with aprepitant and dexamethasone is effective to prevent chemotherapy-induced nausea and vomiting in patients treated with cisplatin-based HEC.