Bruno Gori

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.

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.

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.

Afatinib as first-line treatment for patients with advanced non-small-cell lung cancer harboring EGFR mutations: focus on LUX-Lung 3 and LUX-Lung 6 phase III trials

In patients with advanced or metastatic non-small-cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) positive mutations, the use of EGFR tyrosine kinase inhibitor (TKI) showed to improve survival and safety profile, when compare with standard chemotherapy. These results were reported in different randomized clinical trials with erlotinib as EURTAC and OPTIMAL (1-3), and with gefitinib IPASS, NEJ002, First-SIGNAL and the West Japan Thoracic Oncology Group Study (3-6). In these studies the median progression-free survival was around 10-12 months. After the results of the IPASS trial, gefitinib was approved for advanced NSCLC with EGFR positive mutation in all setting of treatment in Europa and Asia; while erlotinib that received in 2005 the indication in second- and third-line treatment in patients unselected for EGFR mutations after the Br.21 trial, recently was approved by FDA for the first-line treatment in patients with NSCLC harboring EGFR mutations, based on the results of the EURTAC trial in Europe, Asia and USA.

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

ObjectivesOctreotide 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. MethodsBetween 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. ResultsTreatment 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. ConclusionsThe 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.

EGFR-Driven Behavior and Intrapatient T790M Mutation Heterogeneity of Non–Small-Cell Carcinoma With Squamous Histology

Case Report 1 In October 2011, a lesion measuring 8 5 cm was found in the right upper lung lobe of a 48-year-old woman with no history of smoking. Computed tomography (CT) scanning, bone scintigraphy, and magnetic resonance imaging highlighted pleura, hilar, mediastinal, and bilateral axillary lymph node involvement along with a right femur lesion. Bronchoscopy revealed obstruction of the right upper lobe, and multiple biopsies positive for p63, p40, and cytokeratin 5/6 and negative for cytokeratin 7 and thyroid transcription factor 1 favored a diagnosis of poorly differentiated squamous cell carcinoma (SqCC) of the lung. Considering the patient’s sex and never-smoker status, EGFR assessment was requested, and an exon 19 microdeletion (L747-P753 S; 2240-2257del18) was identified. First-line treatment with gefitinib (250 mg per day) with zoledronic acid (4 mg per month) and palliative radiation therapy was preferred over conventional histotype-guided therapy. The patient had no remarkable adverse effects. A CT scan after two cycles of therapy showed an increase of the lung lesion, complete obstruction of the bronchus, consensual parenchymal atelectasis, and tumor infiltration of the right pulmonary artery, the superior vena cava, the azygos vein, and a large osteolytic area in the manubrium. Because of worsening dyspnea and severe sternal and lumbar pain, the patient was hospitalized and gefitinib was discontinued. An unblocking procedure with multiple biopsies was performed on the superior right bronchus. Morphologic and immunohistochemical features of poorly differentiated SqCC were preserved, and molecular evaluation confirmed the original exon 19 microdeletion plus a resistant T790M mutation in exon 20. Considering the rapid disease progression that the patient experienced whilereceivingtyrosinekinase inhibitor(TKI) therapy,weretrospectively reassessed the pretreatment specimen for a primary resistant mutation. A T790M mutation in exon 20 was identified. No mutations were found in normal tissue, thereby excluding germline alterations. The Eastern Cooperative Oncology Group performance status (PS) of the patient dramatically worsened (PS of 3), and palliative radiation therapy on the sternal lesionwasperformedwhilecontinuingzoledronicacid.InFebruary2012, the patient experienced a rapid worsening of dyspnea (grade 4) and PS and began receiving best supportive care. Two months later the patient died.

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.

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.

Safety and efficacy of oral vinorelbine and capecitabine combination for metastatic breast cancer

Abstract The aim of this prospective open-label study was to evaluate the efficacy and safety of oral vinorelbine in combination with capecitabine in patients with metastatic breast cancer (MBC). 51 patients with MBC received oral vinorelbine and capecitabine. the safety profile was analyzed through NCI-CTCAE v3.0 and response was evaluated using RECIST criteria. The overall response rate was 37.2%: there were four complete responders (8%) and fifteen partial responders (29.4%); practically all the responders were patients previously treated with anthracyclines and taxanes. Sixteen patients (31.3%) experienced stable disease. the clinical benefit rate was 68.5%. The median time to progression was 8 months (range 2-43; 95% CI: 6-10.8). Vinorelbine in combination with capecitabine is an effective and safe schedule for patients with MBC especially after pretreatment with anthracycline/taxane-based regimens. The clinical benefit suggests that this may be a promising schedule in the MBC initial treatment.