New oral multitargeted antiangiogenics in non-small-cell lung cancer treatment.

Non-small-cell lung cancer is a particularly aggressive cancer. Combination chemotherapy remains the standard therapy for patients with advanced or metastatic disease. However, despite the available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process controlled by a delicate balance between pro- and antiangiogenic factors and their receptors; tumors induce angiogenesis by disrupting this balance and secreting various growth factors. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes monoclonal antibodies against VEGF and VEGF receptor and small molecule inhibitors of VEGF tyrosine kinase activity (tyrosine kinase inhibitors). Tyrosine kinase inhibitors are orally active, small molecules that represent a new class of drugs with a relatively high safety profile. They are targeted therapies that play their anticancer role interfering with specific cell signaling. This review focuses on such oral antiangiogenic agents that have been approved and are in advanced clinical development for the treatment of patients with advanced non-small-cell lung cancer.

Whole-tumor perfusion CT in patients with advanced lung adenocarcinoma treated with conventional and antiangiogenetic chemotherapy: initial experience.

PURPOSE: To determine whether wide-volume perfusion computed tomography (CT) performed with a new generation scanner can allow evaluation of the effects of chemotherapy combined with antiangiogenetic treatment on the whole tumor mass in patients with locally advanced lung adenocarcinoma and to determine if changes in CT numbers correlate with the response to therapy as assessed by conventional response evaluation criteria in solid tumors (RECIST). MATERIALS AND METHODS: Forty-five patients with unresectable lung adenocarcinoma underwent perfusion CT before and 40 and 90 days after chemotherapy and antiangiogenetic treatment. RECIST measurements and calculations of blood flow, blood volume, time to peak, and permeability were performed by two independent blinded radiologists. Pearson correlation coefficient was used to assess the correlation between baseline CT numbers. Baseline and follow-up perfusion parameters of the neoplastic lesions were tested overall for statistically significant differences by using the repeated-measures analysis of variance and then were also compared on the basis of the therapy response assessed according to the RECIST criteria. RESULTS: Pearson correlation coefficient showed a significant correlation between baseline values of blood flow and blood volume (ρ = 0.48; P = .001), time to peak and permeability (ρ = 0.31; P = .04), time to peak and blood flow (ρ = -0.66; P < .001), and time to peak and blood volume (ρ = -0.39; P = .007). Blood flow, blood volume, and permeability values were higher in responding patients than in the other patients, with a significant difference at second follow-up for blood flow (P = .0001), blood volume (P = .02), and permeability (P = .0001); time to peak was higher in nonresponding patients (P = .012). CONCLUSION: Perfusion CT imaging may allow evaluation of lung cancer angiogenesis demonstrating alterations in vascularity following treatment.

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.

management of nonhematologic toxicities associated with different EGFR-TKIs in advanced NSCLC: a comparison analysis.

INTRODUCTION: Nonhematologic toxicities are frequently observed in patients receiving epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: For the 2010-2013 period, the authors evaluated 158 patients diagnosed with advanced or metastatic NSCLC treated in first-, second-, or third-line with the EGFR-TKIs afatinib, erlotinib, or gefitinib. The study assessed the incidence of cutaneous rash, diarrhea, and mucositis/stomatitis by grade at initial assessment (< 30 days) compared with last assessment after correct management, and the authors developed a proposal for a new modality of evaluation and management of adverse events. RESULTS: The incidence of adverse events (cutaneous rash, diarrhea, and mucositis/stomatitis), classified by grade at the initial assessment and the reevaluation after management, demonstrated a reduction of about 95% from the starting toxicity grade for diarrhea, 65% for cutaneous rash, and approximately 70% for mucositis/stomatitis. CONCLUSION: These results suggest that the safety profiles regarding cutaneous rash, diarrhea, and mucositis after afatinib, erlotinib, or gefitinib treatment become similar after prompt and correct management. This analysis suggests that immediate therapeutic approaches and continuous management are required to ensure treatments without severe adverse events that could adversely affect survival and the quality of life.

Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies.

Bone and brain metastases are a very common secondary localization of disease in patients with lung cancer. The prognosis of these patients is still poor with a median survival of less than 1 year. Current therapeutic approaches include palliative radiotherapy and systemic therapy with chemotherapy and targeted agents. For bone metastasis, zoledronic acid is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events (SREs). Recently, denosumab, a fully human monoclonal antibody directed against the receptor activator of nuclear factor κB (RANK) ligand inhibiting the maturation of pre-osteoclasts into osteoclasts, showed increased time to SREs and overall survival compared with zoledronic acid. The treatment of brain metastasis is still controversial. Available standard therapeutic options, such as whole brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. More recently, novel target agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and afatinib have shown activity in patients with brain metastasis. Inter alia, in patients harboring EGFR mutations, the administration of EGFR TKIs is followed by a response rate of 70-80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. This review is focused on the evidence for therapeutic strategies in bone and brain metastases due to lung cancer.

Oral tyrosine kinase inhibitors in the first-line treatment of advanced non-small cell lung cancer.

INTRODUCTION: In EGFR mutated advanced NSCLC, tyrosine kinase inhibitors are new valid options as first-line treatment. Gefitinib appears a valid alternative to chemotherapy as first-line therapy, in EGFR mutated elderly or unfit patients too, while erlotinib remains an option for subsequent lines of treatment. AREAS COVERED: Areas covered in this review include two international trials, which evaluated erlotinib in chemo-naive EGFR mutated patients both in an Asian and caucasian population, showing a dramatic advantage in terms of progression-free survival and overall response rate as well as gefitinib. Results showed a good safety profile, with side effects of mild to moderate intensity, usually manageable with temporary interruption of treatment. EXPERT OPINION: Investigating EGFR mutations is critical in order to obtain sufficient data. It has now become mandatory for molecular characterization, as part of baseline diagnostic procedures. This approach is also becoming increasingly important during progression of the disease as a sort of 'molecular follow up'. It plays a central role in the right choice of treatment, in an aim to give the best drug to the right patients, overcoming other well known prognostic factors.

Efficacy and tolerability of long-acting octreotide in the treatment of thymic tumors: results of a pilot trial.

OBJECTIVES: Octreotide is a somatostatin analog, long-acting formulations of which have been used experimentally for the treatment of patients with invasive tumors and/or residual disease after conventional therapies. The objective of this retrospective study was to evaluate the efficacy of long-acting octreotide (Sandostatin LAR) for the treatment of thymic tumors, with a primary efficacy end point of progression-free survival. METHODS: Between 1994 and 2010, 44 patients with thymic malignancies were evaluated. Twenty-seven patients underwent an OctreoScan, and 12 OctreoScan-positive patients were treated with long-acting octreotide at a dose of 20 mg, given as an intramuscular injection, every 2 weeks. RESULTS: Treatment with long-acting octreotide gave the following results: 3 cases of partial response (25%), 5 cases of stable disease (42%), and 4 cases of progressive disease (33%), with an average progression-free survival of 8 months (range, 3 to 21). Treatment compliance and tolerability were good for all evaluated patients. CONCLUSIONS: The results of this study confirm the somatostatin receptor as a valid target for the treatment of thymic malignancies. Overall, therapy with long-acting somatostatin analogs seems to be safe and effective.

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.

New antiangiogenics in non-small cell lung cancer treatment: Vargatef™ (BIBF 1120) and beyond.

Lung cancer is the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the metastatic disease, the standard therapy is a platinum-based combination chemotherapy; however, in spite of available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process which comprises a complex, complementary, and overlapping network. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes: monoclonal antibodies against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), small molecule inhibitors of VEGF tyrosine kinase activity, VEGF Trap, and a new class named "vascular disrupting agents," tested in ongoing clinical trials which will further define their role in the management of NSCLC. BIBF 1120 is an investigational orally administered receptor tyrosine kinase inhibitor that has shown antiangiogenic and antineoplastic activity, inhibiting VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor tyrosine kinases, preventing tumor growth and interfering with the angiogenesis-signaling cascade and overcoming drug resistances.