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Luisella Righi,
Alessandra Cuccurullo,
Simona Vatrano,
Susanna Cappia,
Daniela Giachino,
Paolo Giuli,
Mara Ardine, Silvia Novello,
Marco Volante,
Giorgio V Scagliotti,
Mauro Papotti
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ABSTRACT: BACKGROUND: The management of advanced stage non-small cell lung cancer is increasingly based on diagnostic and predictive analyses performed mostly on limited amounts of tumor tissue. The evaluation of Epidermal Growth Factor Receptor (EGFR) mutations have emerged as the strongest predictor of response to EGFR-tyrosine kinase inhibitors mainly in patients with adenocarcinoma. Several EGFR mutation detection techniques are available, having both sensitivity and specificity issues, being the Sanger sequencing technique the reference standard, with the limitation of a relatively high amount of mutated cells needed for the analysis. METHODS: A novel nucleotide dispensation order for pyrosequencing was established allowing the identification and characterization of EGFR mutation not definable with commercially and clinically approved kits, and validated in a consecutive series of 321 lung cancer patients (246 biopsies or cytology samples and 75 surgical specimens). RESULTS: 61/321 (19%) mutated cases were detected, 17 (27.9%) in exon 21 and 44 (72.1%) in exon 19, these latter corresponding to 32/44 (72.7%) classical and 12/44 (27.3%) uncommon mutations. Furthermore, a novel, never reported, point mutation, was found, which determined a premature stop codon in the aminoacidic sequence that resulted in a truncated protein in the tyrosine kinase domain, thus impairing the inhibitory effect of specific therapy. CONCLUSIONS: The novel dispensation order allows to detect and characterize both classical and uncommon EGFR mutations. Although several phase III studies in genotypically defined groups of patients are already available, further prospective studies assessing the role of uncommon EGFR mutations are warranted.
BMC Cancer 03/2013; 13(1):114. · 3.01 Impact Factor
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Sara Pilotto,
Umberto Peretti, Silvia Novello,
Giulio Rossi,
Michele Milella,
Matteo Giaj Levra,
Ludovica Ciuffreda,
Francesco Massari,
Matteo Brunelli,
Giampaolo Tortora,
Emilio Bria
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ABSTRACT: Introduction: In the recent years, the growing attention to the molecular background of non-small-cell lung cancer (NSCLC) led to the identification of different molecular subtypes according to genetic abnormalities driving the disease development and progression. Whereas the addicted pathways were successfully inhibited (such as the mutant epidermal growth factor receptor), clinicians have witnessed a dramatic survival improvement. In this regard, the molecular portrait of adenocarcinoma was recently enriched by the identification of a specific patients' subgroup characterized by abnormalities in the anaplastic lymphoma kinase (ALK), with unclear prognostic features but impressive response to specific inhibitors. Areas covered: In this article, updated data derived from the development and the use of crizotinib (the most advanced in development among tyrosine kinase ALK inhibitors) in comparison with standard second-line chemotherapy for patients affected by ALK-altered NSCLC are reviewed. Expert opinion: Taking into account the available data, pretreated NSCLC patients carrying the ALK-translocation require a selected targeted therapy which significantly improves activity, efficacy and symptoms control versus chemotherapy. In this context, the identification of this disease entity and the availability of such impressive therapeutic targeting represent a further step toward the understanding of the molecular complexity behind the adenocarcinoma of the lung.
Expert Opinion on Pharmacotherapy 03/2013; · 3.20 Impact Factor
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ABSTRACT: The N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (MET) receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) control cellular signaling cascades that direct cell growth, proliferation, survival, and motility. Aberrant MET/HGF activation has been observed in many tumor types, can occur by multiple mechanisms, and promotes cellular proliferation and metastasis via growth factor receptors and other oncogenic receptor pathways. Thus, MET/HGF inhibition has emerged as targeted anticancer therapies. Preclinically, neoplastic and metastatic phenotypes of several tumor cells, including non-small cell lung cancer, hepatocellular carcinoma, and gastric cancer, were abrogated by MET inhibition. Ongoing clinical development with tivantinib, cabozantinib, onartuzumab, crizotinib, rilotumumab, and ficlatuzumab has shown encouraging results. These trials have established a key role for MET in a variety of tumor types. Evidence is emerging for identification of aberrant MET activity biomarkers and selection of patient subpopulations that may benefit from targeted MET and HGF inhibitor treatment.
Cancer treatment reviews 02/2013; · 5.30 Impact Factor
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ABSTRACT: Although the interpretation of the data reported in meta-analyses may hide several issues, it is undoubtable that this methodological approach may significantly contribute to implement the results of clinical trials, and represent a useful and practical tool for the evidence-based medicine process. Indeed, level-one recommendations should consider well-conducted meta-analyses as well as large and adequately powered randomized trials as the main contributors for the definition of guidelines for clinical practice. In addition, the role of meta-analyses for issues whereas conflicting data (and/or unpowered results) are provided, is well established. In the field of lung cancer, meta-analyses already participated to change the current standard, and are now facing the challenging issues of predictive biomarkers of prognosis and/or efficacy of targeted agents. With this aim, the meta-analytic approach helped in the recent years to implement the quantification of the magnitude of the benefit of targeted agents, and added new insights by interpreting the data coming from clinical trials by integrating them with biomarkers. The treatment-interaction analyses according to putative predictive factors of efficacy may clarify unknown issues and generate new hypotheses for future perspectives. The current review attempts to put in the context of the clinical data of targeted agents for lung cancer all the pros and cons of the meta-analytic process published to date, and critically analyze all the potential perspectives which this methodology may add for both current practice and forthcoming research.
Targeted Oncology 01/2013; · 3.61 Impact Factor
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ABSTRACT: BACKGROUND: This study aimed to demonstrate that patients who exhibit a tumor metabolic response to first-line chemotherapy seen on FDG-PET and computed tomography (CT) would survive longer than those who did not show such a response, comparing this evaluation with the morphologic response seen on CT. PATIENTS AND METHODS: Images were acquired in 22 consecutive patients with advanced non-small-cell lung cancer (NSCLC) randomized to receive carboplatin/paclitaxel/sorafenib or placebo. FDG-PET was performed within 4 weeks before (PET1) and 2 weeks after starting treatment (PET2). Similarly, CT (CT1) was performed at baseline and then every 2 cycles (6 weeks) during treatment (CT2). Responders and nonresponders were identified with FDG-PET, and metabolic response was then compared with morphologic changes detected by spiral CT. RESULTS: Twenty-one of 22 patients completed this study. In terms of progression-free survival (PFS) (45 vs. 22.2 weeks) and overall survival (OS) (77 vs. 47.7 weeks), we observed a trend that was not statistically significant for patients whose response after 2 weeks of treatment was seen on FDG-PET (P = .22 for PFS; P = .15 for OS). CONCLUSION: Patients with advanced NSCLC who had a positive outcome, as evidenced by prolonged survival, were those who showed a tumor metabolic response seen on FDG-PET.
Clinical Lung Cancer 12/2012; · 2.94 Impact Factor
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Carmine Pinto, Silvia Novello,
Valter Torri,
Andrea Ardizzoni,
Pier Giacomo Betta,
Pier Alberto Bertazzi,
Gianni Angelo Casalini,
Cesare Fava,
Bice Fubini,
Corrado Magnani,
Dario Mirabelli,
Mauro Papotti,
Umberto Ricardi,
Gaetano Rocco,
Ugo Pastorino,
Gianfranco Tassi,
Lucio Trodella,
Maurizio Zompatori,
Giorgio Scagliotti
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ABSTRACT: Malignant pleural mesothelioma (MPM) is a relevant public health issue. A large amount of data indicate a relationship between mesothelioma and asbestos exposure. MPM incidence has considerably and constantly increased over the past two decades in industrialized countries and is expected to peak in 2010-2020. In Italy, the standardized incidence rate in 2008 was 3.6 and 1.3 per 100,000 in men and women respectively, with wide differences from one region to another. The approach to this disease remains difficult and complex in terms of pathogenic mechanism, diagnosis, staging and treatment thus an optimal strategy has not yet been clearly defined. The Second Italian Multidisciplinary Consensus Conference on Malignant Pleural Mesothelioma was held in Turin (Italy) on November 24-25, 2011: recommendations on MPM management for public health institutions, clinicians and patients are presented in this report.
Cancer treatment reviews 12/2012; · 5.30 Impact Factor
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ABSTRACT: Lung cancer is one of the leading causes of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for at least 87% of all lung cancers and most cases present at an advanced stage, with metastatic, locally advanced or recurrent disease. With a greater understanding of tumour biology, a number of targeted agents have been investigated for the treatment of advanced NSCLC. These include insulin-like growth factor inhibitors, c-MET inhibitors, poly(adenosine diphosphate-ribose) polymerase inhibitors, histone deacetylase inhibitors, proapoptotic agents, epidermal growth factor receptor inhibitors, vaccines, immunotherapy and hedgehog inhibitors. This article aims to provide an overview of some of the emerging molecules for NSCLC that have demonstrated interesting results in the past couple of years, including descriptions of the molecular pathways of these drugs and their main location of action.
Drugs 06/2012; 72 Suppl 1:37-52. · 4.23 Impact Factor
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Clinical Lung Cancer 06/2012; 13(6):399-407. · 2.94 Impact Factor
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ABSTRACT: Evidence that supports a role for hormonal status in lung cancer has been inconsistently reported and is still unclear. We retrospectively assessed the potential correlation between sex-linked hormone receptor expression and the clinical outcome of patients with advanced-stage lung cancer treated with chemotherapy.
Based on tissue availability, 130 consecutive patients diagnosed at San Luigi Hospital from January 2008 to June 2010 were collected, including 24 small-cell lung cancer, 57 adenocarcinomas, 34 squamous cell carcinomas, 5 large-cell carcinomas, and 10 non-small-cell lung cancer-not otherwise specified. The immunohistochemical expression of estrogen receptors (ER-α and ER-β) and progesterone receptor, aromatase, epidermal growth factor receptor (EGFR), and excision repair cross-complementing 1 (ERCC1) was assessed.
ER-β nuclear expression was higher than ER-α and progesterone receptor, whose expression was null or weak (mainly in women). ER-β expression was significantly higher in patients with metastatic disease compared with all other disease stages (P = .02). EGFR expression was strongly correlated with non-small-cell lung cancer histology, being higher in squamous types and stage related. In men, aromatase positive cases had a worse outcome (P = .03) as well as in men with non-small-cell lung cancer and high ER-β expression. In the latter group, the combined aromatase negative and/or low ER-β expression and low ERCC1 and/or low ER-β expression showed a better outcome (P = .026; P = .03, respectively).
In patients with advanced-stage lung cancer treated with chemotherapy, the prognostic and predictive role of sex-linked hormone receptor expression, if any, is of borderline significance and is restricted to selected subgroups of patients.
Clinical Lung Cancer 06/2012; 13(6):416-23. · 2.94 Impact Factor
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Giorgio V Scagliotti,
Robert Ilaria, Silvia Novello,
J von Pawel,
Juergen R Fischer,
Sabine Ermisch,
Dinesh P de Alwis,
Joan Andrews,
Martin Reck,
Lucio Crino,
Corinna Eschbach,
Christian Manegold
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ABSTRACT: Tasisulam sodium (hereafter referred to as tasisulam) is a novel anticancer compound that induces apoptosis and exhibits antiangiogenesis activity in a broad range of cancer models, including non-small-cell lung cancer (NSCLC).
Tasisulam was administered as a 2-hour infusion every 21 days as third-line treatment in patients with advanced (stage IIIB/IV) NSCLC.
Thirty-two patients received a Cmax target dose of 420 µg/ml. Median time to progression was 3.12 months, median progression-free survival was 2.69 months, and median overall survival was 8.48 months. There were no objective responses; 43.8% of patients achieved stable disease. A high rate of grade-4 hematologic toxicity in the first 30 patients led to exploration of a lower Cmax target dose of 380 µg/ml. The rate of grade-4 hematologic toxicity (thrombocytopenia and/or neutropenia) at the 380-µg/ml dose (n = 20) was 20% versus 34% at the 420-µg/ml dose.
Tasisulam has only modest activity as a third-line treatment of patients with unresectable/metastatic NSCLC. The high rate of grade-4 hematologic toxicity observed with this highly albumin- bound compound in this patient population provided challenges for fixed Cmax-based dosing. Alternative dosing methods, including varying the Cmax target dose by predose albumin, are under investigation in other studies.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2012; 7(6):1053-7. · 4.55 Impact Factor
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ABSTRACT: We present the rationale and design for MARQUEE, a phase III, randomized, double-blind, placebo-controlled study of ARQ 197 plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, nonsquamous, non-small-cell lung cancer (NSCLC). The design of MARQUEE is based on preclinical data, the current understanding of the role of cellular N-methyl-N'-nitroso-guanidine human osteosarcoma (MNNG HOS) transforming gene (MET) in NSCLC, and clinical data from a randomized phase II study. The available evidence suggests that dual inhibition of MET and the epidermal growth factor receptor (EGFR) may overcome resistance to EGFR inhibitors. In the phase II study, the combination of tivantinib plus erlotinib significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus erlotinib in the subset of patients with nonsquamous histology, a population enriched for MET overexpression. The primary endpoint in MARQUEE is OS. Secondary and exploratory objectives include determination of PFS, OS in molecular subgroups (defined by EGFR and KRAS mutation status, amplification or overexpression of MET, and serum hepatocyte growth factor), and safety. All patients will be tested for biomarkers, and the results will provide a wealth of information on the role of tivantinib in treating nonsquamous NSCLC.
Clinical Lung Cancer 03/2012; 13(5):391-5. · 2.94 Impact Factor
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Suresh S Ramalingam,
David R Spigel,
David Chen,
Martin B Steins,
Jeffrey A Engelman,
Claus-Peter Schneider, Silvia Novello,
Wilfried E E Eberhardt,
Lucio Crino,
Kai Habben,
Lian Liu,
Pasi A Jänne,
Carrie M Brownstein,
Martin Reck
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ABSTRACT: R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study.
Patients with advanced-stage non-small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate.
In all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo.
The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR.
Journal of Clinical Oncology 12/2011; 29(34):4574-80. · 18.37 Impact Factor
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ABSTRACT: The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have become increasingly recognized as having a driving role in the development of malignancy, and consequently IGF-1R has become a potential target for cancer therapy. Several inhibitors of IGF-1R are in clinical development for the treatment of solid tumors, including non-small cell lung cancer (NSCLC). These IGF-1R-targeted agents include monoclonal antibodies such as cixutumumab (IMC-A12), AMG-479, AVE1642, BIIB022, dalotuzumab (MK-0646), and robatumumab (Sch717454), the ligand neutralizing antibody Medi-573, and the small molecule inhibitors BMS-754807, linsitinib (OSI-906), XL228, and AXL1717. Two phase III trials of the anti-IGF-1R monoclonal antibody, figitumumab (CP-751,871), were discontinued in 2010 as it was considered unlikely either trial would meet their primary endpoints. In light of disappointing clinical data with figitumumab and other targeted agents, it is likely that the use of molecular markers will become important in predicting response to treatment. This review outlines the role of IGF-1R signaling in solid tumors with a particular focus on NSCLC, and provides an overview of clinical data.
Cancer treatment reviews 09/2011; 38(4):292-302. · 5.30 Impact Factor
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Silvia Novello,
Carlos Camps,
Francesco Grossi,
Julien Mazieres,
Lauren Abrey,
Jean-Marc Vernejoux,
Aron Thall,
Shem Patyna,
Tiziana Usari,
Zhixiao Wang,
Richard C Chao,
Giorgio Scagliotti
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ABSTRACT: Brain metastases frequently cause significant morbidity in patients with non-small cell lung cancer (NSCLC). Sunitinib is a multitargeted inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptors and platelet-derived growth factor receptors, which has single-agent antitumor activity in refractory NSCLC. This phase II study evaluated the antitumor activity and safety of sunitinib in patients with pretreated NSCLC and irradiated brain metastases.
Patients received sunitinib 37.5 mg on a continuous daily dosing schedule. The primary end point was progression-free survival. Secondary end points included overall survival, patient-reported outcomes, and safety, including risk of intracranial hemorrhage (ICH) associated with focal neurological deficit.
Sixty-four patients received sunitinib (median age 61 years), most (83%) had received prior systemic therapy, 63% had adenocarcinoma, and 19% had squamous cell carcinoma; most (55%) were never-smokers. Median progression-free survival was 9.4 weeks (90% confidence interval [CI]: 7.5-13.1), and median overall survival was 25.1 weeks (95% CI: 13.4-35.5). The most common treatment-emergent (all-causality) nonhematologic toxicities (any grade) were fatigue (38%) and decreased appetite and constipation (both 25%). The most common grade 3/4 nonhematologic toxicities were dyspnea (9%) and fatigue (8%). Lymphopenia (20%) and neutropenia (13%) were the most common grade 3/4 hematologic abnormalities. Serious neurologic adverse events occurred in six patients (9%), and none were treatment-related. No cases of ICH were reported.
Sunitinib administration on a continuous daily dosing schedule in patients with NSCLC and brain metastases was safe and manageable, with no increased risk of ICH.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2011; 6(7):1260-6. · 4.55 Impact Factor
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ABSTRACT: Chemotherapy is the standard of care for patients with advanced stage non-small cell lung cancer (NSCLC) because of the a modest improvement in survival and quality of life but its efficacy has already reached a plateau. Several molecular targets involved in the uncontrolled growth of lung cancer cells has been recently discovered and Epidermal Growth Factor Receptor (EGFR) pathway is as a key therapeutic target. Strategies to block such pathway include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. Erlotinib and gefitinib are two EGFR-TKI active against NSCLC. Their efficacy has been proven to be definitively superior in presence of activating EGFR mutation in the tumor. This evidence does not apply to the monoclonal antibody cetuximab, which efficacy in NSCLC was recently demonstrated in a single phase III study. The good tolerability profile of EGFR inhibitors make these agents suitable for maintenance and adjuvant setting, while sequencing of EGFR-TKIs and chemotherapy seems to be preferred. This article reviews the role of EGFR inhibitors focusing mainly on compounds in phase III clinical development.
Frontiers in bioscience (Scholar edition) 01/2011; 3:501-17.
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ABSTRACT: Physicians who are responsible for the delivery of systemic treatment in lung cancer should be aware of the potential risk of drug-induced pulmonary toxicity (DIPT), because such toxicity may develop in the context of a multifactorial clinical condition. First, most patients with lung cancer may suffer from other non-neoplastic, smoking-related lung diseases, such as emphysema and chronic obstructive lung disease, which may generate pathologic changes in lung parenchyma. In addition, lung cancer itself may worsen the respiratory function, inducing atelectasis and lymphangitic carcinomatosis. The superimposed iatrogenic damage may lead to respiratory failure and, sometimes, death. The risk of DIPT from chemotherapeutic agents has been widely examined in the past; and, currently, the potential for lung toxicity has been extended by the introduction of molecular targeted therapies. Because there are no univocal criteria with which to recognize DIPT, the diagnosis often is made by exclusion; consequently, it is hard to establish an early diagnosis. The objective of this review was to describe the major DIPTs associated with antineoplastic agents against nonsmall cell lung cancer to help physicians with this difficult diagnostic challenge.
Cancer 01/2011; 117(14):3069-80. · 4.77 Impact Factor
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Silvia Novello,
Michele Milella,
Marcello Tiseo,
Giuseppe Banna,
Diego Cortinovis,
Massimo Di Maio,
Marina Garassino,
Paolo Maione,
Olga Martelli,
Tiziana Vavalà,
Emilio Bria
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ABSTRACT: Maintenance therapy is emerging as a treatment strategy in the management of advanced non small cell lung cancer (NSCLC). Initial trials addressing the question of duration of combination chemotherapy failed to show any overall survival benefit for the prolonged administration over a fixed number of cycles with an increased risk for cumulative toxicity. Nowadays several agents with different ways of administration and a different pattern of toxicity have been formally investigated in the maintenance setting. Maintenance strategies include continuing with an agent already present in the induction regimen or switching to a different one. Taking into consideration that no comparative trials of maintenance with different chemotherapy drugs or targeted agents have been conducted, the choice and the duration of maintenance agents is largely empirical. Furthermore, it is still unknown and it remains an open question if this approach needs to be proposed to every patient in the case of partial/complete response or stable disease after the induction therapy. Here, we critically review available data on maintenance treatment, discussing the possibility to tailor the right treatment to the right patient, in an attempt to optimize costs and benefits of an ever-growing panel of different treatment options.
Journal of Experimental & Clinical Cancer Research 01/2011; 30:50. · 2.15 Impact Factor
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Giuseppe Luigi Banna,
Massimo Di Maio,
Alessandro Follador,
Elena Collovà,
Jessica Menis, Silvia Novello,
Emilio Bria,
Mario Airoldi,
Domenico Amoroso,
Antonio Ardizzoia, [......],
Francesca Spinnato,
Marcello Tiseo,
Ottaviano Tomassi,
Luca Tondulli,
Giuseppe Tonini,
Salvatore Turano,
Maria Rosaria Valerio,
Franco Verderame,
Francesca Zanelli,
Elisa Zanon
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ABSTRACT: A recent pooled analysis of randomized trials indicated significant improvement in overall survival from cisplatin-based adjuvant chemotherapy for non-small cell lung cancer (NSCLC), depending on disease stage (only in stages II and III) and PS (≤ 1). Post-operative radiotherapy (RT) is optional for pN2 tumours.
To evaluate opinions and daily clinical practice of Italian Oncologists about adjuvant treatment of NSCLC, a 46-item questionnaire was delivered via e-mail.
Seventy-eight physicians from 68 Centers (out of 98 contacted) returned their questionnaire. Seventy-four, 86, 94, and 78% of them give the indication for adjuvant chemotherapy for stage IIA, IIB, IIIA, and IIIB disease, respectively and 14% in stage IB disease. Stage, PS, and age are taken into consideration evaluating adjuvant approach by 97, 95 and 73%, respectively. Cisplatin-vinorelbine (64%) and cisplatin-gemcitabine (33%), for 4 cycles (81%), are the preferred regimens, while 32% use different regimens. Ninety-two percent indicate RT in pN2 disease and/or positive resection margins. Real Number of patients Needed to Treat (NNT) is probably not completely known/understood and/or used by physicians.
A substantial adherence between clinical daily practice in Italy and scientific progresses is described in this paper, even with some discordances regarding the most appropriate adjuvant chemotherapy regimen.
Lung cancer (Amsterdam, Netherlands) 12/2010; 73(1):78-88. · 3.14 Impact Factor
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ABSTRACT: A key challenge in the treatment of advanced non-small-cell lung cancer (NSCLC) is improving outcomes for patients who have achieved at least stable disease after standard first-line therapy. Although current guidelines recommend a maximum of six cycles of first-line therapy, even in responding patients, recent trials have shown benefit with maintenance therapy.
We reviewed the English literature for randomized controlled trials on prolonged therapy for NSCLC conducted between January 1999 and January 2010. The search was supplemented by a review of abstracts presented at the American Society of Clinical Oncology annual meetings (2004 to 2010), the World Lung Cancer Conference (2007 to 2009), and the 2009 Joint European CanCer Organisation-European Society for Medical Oncology conference.
Several alternative strategies for prolongation of chemotherapy have been tested: these can be broadly categorized as continuation (prolongation of the first-line regimen until disease progression, unacceptable toxicity, or administration of a predefined greater number of treatment cycles), switch-maintenance (administration of an active agent immediately after completion of the initial course of chemotherapy), and continuation-maintenance (ongoing administration of a lower intensity version of the first-line chemotherapy regimen). These approaches differ from traditional second line, which is defined as treatment administered after documented clinical progression subsequent to first-line therapy.
There are no data to support continuation chemotherapy in advanced NSCLC. Switch-maintenance trials with erlotinib and pemetrexed have demonstrated an improvement in overall survival. Thus far, continuation-maintenance has shown an improvement in progression-free survival, without an overall survival advantage.
Journal of Clinical Oncology 11/2010; 28(34):5116-23. · 18.37 Impact Factor
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ABSTRACT: A prespecified analysis of the large, randomized, phase III study in advanced non-small cell lung cancer showed significant improvement in survival for nonsquamous patients treated with pemetrexed/cisplatin versus gemcitabine/cisplatin. Selected grade 3/4 toxicities and resource utilization favored pemetrexed in the overall population, but detailed safety results by histology have not been reported.
Treated patients were included in this analysis of safety by histology. At each cycle, adverse events were assessed, and concomitant medications, transfusions, and hospitalizations were recorded. Measures were summarized by histology and compared between arms with Fisher's exact test.
When analyzed by squamous and nonsquamous histology, safety and resource utilization for each treatment arm paralleled those of the overall population. Selected toxicities did not vary by histology. Concomitant medication use and hospitalizations were also very similar to the patterns observed in the overall population.
Although previous efficacy analyses showed a significant pemetrexed treatment advantage for nonsquamous patients, results of this analysis indicate that safety and resource utilization do not vary by histology and are consistent with the overall population. The safety and resource utilization of patients treated with pemetrexed/cisplatin are predictable, reproducible, and consistent with the established favorable safety profile of pemetrexed, regardless of histology.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 10/2010; 5(10):1602-8. · 4.55 Impact Factor
