Giovanni Palazzolo

New Targeted Therapies and Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) accounts for almost 15% of lung carcinomas. Chemotherapy is the cornerstone of treatment of patients with SCLC. In limited disease, median survival is about 12-20 months, with no more than 6%-12% of patients surviving beyond 5 years. In extensive disease, median survival is 7-12 months, with < 5% of patients living beyond 2 years and a 5-year survival rate of just 2%. Several therapeutic approaches have been used in an attempt to improve the outcome of SCLC. Among these, a better understanding of tumor biology and the subsequent development of novel therapeutic strategies have been identified as a possible approach for increasing the survival rate of patients with SCLC. Several targeted agents have been introduced into clinical trials in SCLC, and a few phase III studies, including matrix metalloproteinase inhibitors, thalidomide, and vaccines, have already produced definitive results. Currently, negative results are more commonly reported than positive ones. However, this first generation of clinical trials represents only the beginning of clinical research in this field. To date, no targeted therapy has been approved for use in the treatment of patients with SCLC. Nevertheless, clinical research in this field is still in progress considering that several new targeted agents, such as antiangiogenic agents and mammalian target of rapamycin inhibitors, offer a promise of improved outcomes. This review will focus on the reported results and the future development of the main novel biologic agents for the treatment of patients with SCLC.

Treatment of advanced non-small-cell lung cancer in the elderly.

Lung cancer in the older individual is an increasingly common problem faced by the oncologist. Elderly patients have more co-morbidities and tend to tolerate toxic medical treatments more poorly than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of non-selected elderly patients with non-small-cell lung cancer (NSCLC). The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients comes from studies in advanced disease. In elderly advanced NSCLC patients single-agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered as the standard treatment for unselected patients, based on several phase II and III trials specifically designed for this special population. Retrospective analyses found no differences in survival between elderly and younger patients treated with cisplatin-based chemotherapy, with a small but significant increase in toxicity in the elderly. Cisplatin-based chemotherapy with cisplatin at attenuated doses has demonstrated to be an active and feasible option in phase II trials and deserves prospective phase III comparison against monochemotherapy. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib are the most promising agents and have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the anti-vascular endothelial growth factor monoclonal antibody bevacizumab, particular care must be taken for elderly patients because of a possible higher incidence of cardiovascular co-morbidities. However its role in this population remains controversial and specific prospective studies are warranted to clarify this topic. Further specifically designed phase III randomized trials are needed to optimize medical treatment of NSCLC in elderly patients.

Recent Developments of Targeted Therapies in the Treatment of Non-Small Cell Lung Cancer

Non small cell lung cancer (NSCLC) is a lethal disease with poor prognosis. The main percentage of NSCLC patients are diagnosed to have an advanced disease. Standard treatment, such as chemotherapy and radiotherapy, has apparently reached a plateau of effectiveness in improving survival of advanced NSCLC patients. Hence, considerable efforts have started to be made in order to identify novel targets for new biological agents which may safely and effectively be administered to advanced NSCLC patients. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) and its receptors play an essential role in tumour proliferation. Approaches targeting EGFR and VEGF include monoclonal antibodies (mAbs) and small molecules inhibiting the corresponding receptor-tyrosine kinase activity. Erlotinib is a small molecule inhibitor of EGFR tyrosine-kinase which has brought significant improvements in median survival, quality of life and related symptoms, in an unselected population of advanced NSCLC patients in the second- or third-line setting. Bevacizumab, an anti-VEGF recombinant humanized mAb, is the first targeted agent which, when combined with chemotherapy, reported superior efficacy versus chemotherapy alone in the treatment of advanced NSCLC. ZD6474, a small molecule targeting VEGF tyrosine-kinase activity, showing early evidence of antitumour activity and the excellent toxicity profile, seems to be a promising agent for the treatment of advanced NSCLC. This review shows the latest and the future developments of erlotinib, bevacizumab and ZD6474 in the treatment of advanced NSCLC patients.

Carboplatin plus vinorelbine, a new well-tolerated and active regimen for the treatment of extensive-stage small-cell lung cancer: a phase II study. Gruppo Oncologico Centro-Sud-Isole.

PURPOSE To evaluate the activity and toxicity of the combination carboplatin plus vinorelbine in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS A two-stage optimal Simon design was applied. To proceed after the first stage, responses from 8 of 11 treated patients were needed. Overall, 31 responses of 43 treated patients were required to comply with the design parameters. Inclusion criteria were cytohistologically proven SCLC; extensive disease; age of 70 years or less; Eastern Cooperative Oncology group performance status (ps ECOG) of 2 or less; normal cardiac, hepatic, renal, and bone marrow functions; and no previous chemotherapy. Patients were staged by physical examination; biochemistry; chest radiograph; brain, thoracic; and abdominal computed tomographic (CT) scans, and bone scan. All patients received carboplatin 300 mg/m2 intravenously (i.v.) day 1 and vinorelbine 25 mg/m2 i.v. on days 1 and 8 every 4 weeks up to six cycles. Of 43 enrolled patients, 36 were men and 7 women, with a median age of 63 years (range, 46 to 70 years). RESULTS All patients were assessable for response and toxicity. We observed 32 (74%) objective responses, with 23% complete responses. Median time to progression was 25 weeks, and median survival was 37 weeks. The treatment was well tolerated. The reported main toxicities were leukopenia grade 3 in 21% of patients and grade 4 in 5% of patients, anemia grade 2 in 11% of patients and grade 3 in 2% of patients, and thrombocytopenia grade 3 in 7% of patients. CONCLUSION These data show that carboplatin plus vinorelbine is an active and well-tolerated regimen in extensive SCLC. In view of the activity, low toxicity, and ease of administration, it may be a reasonable alternative to more toxic cisplatin-containing regimens.

Anti PD-1 and PDL-1 Immunotherapy in the Treatment of Advanced Non- Small Cell Lung Cancer (NSCLC): A Review on Toxicity Profile and its Management

The better understanding of immunology and antitumor immune responses have prompted the development of novel immunotherapy agents like PD-1 checkpoint inhibitors (anti-PD-1 and anti- PDL-1 antibodies) that improve the capacity of the immune system to acknowledge and delete tumors, including lung cancer. Currently, two anti-PD-1 (nivolumab and pembrolizumab) and one anti- PD-L1 (MPDL-3280A) agents are in advanced stages of development in advanced or metastatic non-small cell lung cancer (NSCLC). Among these, nivolumab demonstrated a survival benefit versus docetaxel in refractory squamous NSCLC, reporting 41% reduction in risk of death (median overall survival: 9.2 versus 6.0 months; objective response rate: 20% versus 9%), and better safety profile than standard-of-care chemotherapy (grade 3-4 adverse events: 7% versus 55%). However, the enhancement of immune response to cancer targeting specific immune regulatory checkpoints is associated with a toxicity profile different from that related to traditional chemotherapeutic agents and molecularly targeted therapies. The success of immunotherapy is related to ongoing evaluation/identification and treatment of these immunerelated side effects. Herein, first clinical results of PD-1 agents in lung cancer are reviewed, focusing on toxicity profile and its management.

Mitomycin C plus vindesine or cisplatin plus epirubicin in previously treated patients with symptomatic advanced non-small-cell lung cancer

SummaryA total of 40 previously treated patients with symptomatic advanced non-small-cell lung cancer (NSCLC) were subjected to second-line chemotherapy with mitomycin C plus vindesine (MV) or cisplatin plus epirubicin (PE). The 12 patients treated with the MV regimen showed no objective response (OR) or symptom palliation. In the 28 patients who received the PE regimen, we obtained a 25% partial response rate, with amelioration of tumor-related symptoms occurring in 35.7% of cases and improvement in the performance status being noted in 25% of subjects. Both regimens were well tolerated. These data show that the administration of cisplatin-based secondline chemotherapy to patients with symptomatic advanced NSCLC may be useful.

Management of unfit older patients with advanced NSCLC

Lung cancer in the older individual is an increasingly common problem faced by the oncologist. Elderly patients over 70 years account about 40% of lung cancer patients. Performance Status 2 patients represent a significantly high proportion of advanced non-small cell lung cancer (NSCLC) patients (30-40%) when population-based surveys are conducted. Thus, unfit older patients represent a significant proportion of advanced NSCLC patients, for whom specific prospective data are very scarce. Elderly cancer patients often present with medical and physiological challenges that make the selection of their optimal treatment daunting. Single-agent chemotherapy should be considered the standard treatment for unfit older patients with advanced NSCLC. Molecularly targeted therapies as erlotinib and gefitinib, if approved for use in the next future also in the first-line treatment of advanced NSCLC, may represent a valid alternative to single-agent chemotherapy for a large proportion of unfit older patients because of their more favourable safety profile. However, specific prospective investigation is absolutely warranted for this special population.

Phase I study of epirubicin plus vinorelbine with or without G-CSF in advanced non-small cell lung cancer

The present phase I study was designed to determine the maximum tolerated dose (MTD) of epirubicin, administered every 3 weeks to patients with advanced non-small cell lung cancer (NSCLC), and combined with a conventional dose of vinorelbine [25 mg/m2 intravenously (i.v.) days 1 and 8] with or without the support of granulocyte-colony stimulating factor (G-CSF). 18 patients entered the study. The patients received the following four dose levels of epirubicin (i.v., day 1): 50 mg/m2 (3 patients) and 60 mg/m2 (6 patients) without G-CSF, 75 mg/m2 (3 patients) and 90 mg/m2 (6 patients) with G-CSF (5 micrograms/kg days 4-6 and 9-15). In the patients treated without G-CSF the MTD of epirubicin was 60 mg/m2 and leukopenia was the dose-limiting toxicity. In the patients treated with G-CSF the MTD was 90 mg/m2, myelotoxicity being the dose-limiting toxicity. We observed 1/3 partial response (PR) with epirubicin at the dose of 75 mg/m2 and 2/6 PR at 90 mg/m2. These results would indicate the usefulness of a phase II study with epirubicin at the dose of 90 mg/m2 in association with conventional dose of vinorelbine with the support of G-CSF in advanced NSCLC.

Combination of radiotherapy and targeted therapies in the treatment of locally advanced non-small cell lung cancer

Lung cancer is the most common cancer in the world. One third of patients with non-small cell lung cancer (NSCLC) are diagnosed with locally or regionally advanced unresectable disease at presentation. Currently, in this stage of disease, a combination of chemotherapy and radiotherapy is the standard treatment approach for patients with good performance status, and concomitant chemo-radiotherapy has demonstrated to be the best therapeutic approach. However, despite improvements in treatment, local tumor control remains suboptimal and distant metastases remain the major site of failure. The diversity of molecular abnormalities in NSCLC may partly contribute to its resistance to therapy. It is therefore widely accepted that one approach to improve the efficacy of cancer therapy is the development of rational combinations of anticancer agents that may exhibit synergistic interactions. The introduction of several biologic agents represents an important advance in the management of NSCLC and some of them have shown to have a synergistic effect when given in combination with radiotherapy and chemotherapy in preclinical and in clinical models. In the present review we discuss the rationale and the feasibility of these combinations and the first results available from clinical trials.

Mitomycin C and vindesine: an ineffective combination chemotherapy in the treatment of malignant pleural mesothelioma.

Twelve patients with malignant pleural mesothelioma were subjected to mitomycin C (MMC) and vindesine (VDS) chemotherapy (MMC 10 mg/m2, i.v., d 1; VDS, 3 mg/m2, i.v., d 1–8, every 4 weeks). No objective response was obtained; 3 (25%) patients had stable disease and 9 (75%) progression of disease. We conclude that MMC plus VDS is an ineffective combination chemotherapy in the treatment of malignant pleural mesothelioma.