Search

To evaluate the cardiotoxicity, general toxicity, and activity of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first-line therapy in metastatic breast cancer. Thirty-one patients with metastatic human epidermal growth factor receptor 2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50mg/m 2 ), docetaxel (75mg/m 2 ) and trastuzumab (2mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) to below 45%, or a decrease in LVEF of at least 20% from baseline. Mean LVEF was maintained at baseline level also in the subset of patients who had received anthracycline previously. Cardiotoxicity developed in three patients during the treatment cycles, and in two further patients after the end of the study. The most common adverse events were haematological toxicity, alopecia, asthenia and fever. The best overall response rate was 65.5%. Median time to progression was 13.0 months. The combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab combines acceptable cardiac and general toxicity and promising activity as first-line therapy in metastatic breast cancer.

Lung cancer represents the leading cause of cancer mortality worldwide, accounting for ∼1.2 million deaths each year. Improving survival in lung cancer is a major challenge for modern oncology considering that 5-year survival remains

Background Estrogens, environmental chemicals with carcinogenic potential, as well as oxidative and carbonyl stresses play a very important role in breast cancer (BC) genesis and progression. Therefore, polymorphisms of genes encoding enzymes involved in estrogen biosynthesis pathway and in the metabolic activation of pro-carcinogens to genotoxic intermediates, such as cytochrome P450C17α (CYP17), endogenous free-radical scavenging systems, such as glutathione S-transferase (GSTP1) and paraoxonase 1 (PON1), and anti-glycation defenses, such as glyoxalase I (GLO1), could influence individual susceptibility to BC. In the present case-control study, we investigated the possible association of CYP17 A1A2, GSTP1 ILE105VAL, PON1 Q192R or L55M, and GLO1 A111E polymorphisms with the risk of BC. Methods The above-said five polymorphisms were characterized in 547 patients with BC and in 544 healthy controls by PCR/RFLP methods, using DNA from whole blood. To estimate the relative risks, Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression after adjusting for the known risk factors for BC. Results CYP17 polymorphism had no major effect in BC proneness in the overall population. However, it modified the risk of BC for certain subgroups of patients. In particular, among premenopausal women with the A1A1 genotype, a protective effect of later age at menarche and parity was observed. As to GSTP1 and PON1 192 polymorphisms, the mutant Val and R alleles, respectively, were associated with a decreased risk of developing BC, while polymorphisms in PON1 55 and GLO1 were associated with an increased risk of this neoplasia. However, these findings, while nominally significant, did not withstand correction for multiple testing. Conclusion Genetic polymorphisms in biotransformation enzymes CYP17, GSTP1, PON1 and GLO1 could be associated with the risk for BC. Although significances did not withstand correction for multiple testing, the results of our exploratory analysis warrant further studies on the above mentioned genes and BC.

Background In the attempt to optimize the efficacy of chemotherapy in advanced non-small cell lung cancer (NSCLC) several strategies need to be investigated including the use of non-platinum combinations and the sequential use of different agents. Patients and methods In a phase II randomised study 165 patients with stage IIIB or IV NSCLC were assigned to receive docetaxel 40 mg/m2 days 1 and 8 plus gemcitabine 1200 mg/m2 days 1 and 8 every 21 days (arm A, N = 54) or docetaxel 50 mg/m2 days 1 and 15 plus gemcitabine 1600 mg/m2 days 1 and 15 every 28 days (arm B, N = 57) or gemcitabine 1200 mg/m2 days 1 and 8 plus cisplatin 100 mg/m2 day 2 every 21 days for 3 cycles followed by docetaxel 75 mg/m2 day 1 every 21 days for 3 cycles (arm C, N = 54). The primary endpoint of the trial was overall response rate. Secondary end points included safety, progression-free and overall survival. Results Response rate was 22.2%, 23.2% and 33.3% after 3 cycles, whereas at the end of treatment was 24.1%, 12.5% and 27.8% in arm A–C, respectively. Median time to progression was similar in all the 3 arms: 6.7 months in arm A (95% CI: 4.8–9.7), 5.6 in arm B (5.0–7.9) and 6.6 in arm C (5.7–9.1). The median survival time was 10.7 months in arm A (95% CI: 6.8–15.6), 8.9 in arm B (7.4–12.5) and 14.6 in arm C (8.0–22.4) and 1-year survival rate was 46.3%, 37.9% and 53.9%, respectively. Grade 3–4 haematological toxicities were more frequent in arm C while non-haematological were more common in the gemcitabine and docetaxel arms. Conclusions The results of this phase II randomised clinical trial do not indicate a clear superior efficacy of one of the tested combinations according to the planned statistical design and none of these regimens is sufficiently active or less toxic to warrant further investigation in a phase III study.

Purpose This phase II, open-label, parallel-group study compared gefitinib with vinorelbine in chemotherapy-naïve elderly patients with advanced non–small-cell lung cancer (NSCLC). Methods Chemotherapy-naïve patients (age ≥ 70 years) were randomly assigned to gefitinib (250 mg/d orally) or vinorelbine (30 mg/m2 infusion on days 1 and 8 of a 21-day cycle). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and tolerability. Exploratory end points included epidermal growth factor receptor (EGFR) gene copy number by fluorescent in situ hybridization (FISH). Results Patients were randomly assigned to gefitinib (n = 97) or to vinorelbine (n = 99). Hazard ratios (HR; gefitinib v vinorelbine) were 1.19 (95% CI, 0.85 to 1.65) for PFS and 0.98 (95% CI, 0.66 to 1.47) for OS. ORR and disease control rates were 3.1% (95% CI, 0.6 to 8.8) and 43.3% (for gefitinib) and 5.1% (95% CI, 1.7 to 11.4) and 53.5% (for vinorelbine), respectively. Overall QOL improvement and PSI rates were 24.3% and 36.6% (for gefitinib) and 10.9% and 31.0% (for vinorelbine), respectively. In the 54 patients who were EGFR FISH-positive, HRs were 3.13 (95% CI, 1.45 to 6.76) for PFS and 2.88 (95% CI, 1.21 to 6.83) for OS. There were fewer treatment-related grade 3 to 5 adverse events with gefitinib (12.8%) than with vinorelbine (41.7%). Conclusion There was no statistical difference between gefitinib and vinorelbine in efficacy in chemotherapy-naïve, unselected elderly patients with advanced NSCLC, but there was better tolerability with gefitinib. Individuals who were EGFR FISH-positive benefited more from vinorelbine than from gefitinib; this unexpected finding requires further study.

Background: Erlotinib demonstrated significantly prolonged survival versus placebo in patients with advanced NSCLC who had progressed after standard chemotherapy. TRUST is a phase IV trial initiated to provide erlotinib access to patients with advanced NSCLC. We report the interim analysis for patients enrolled in the TRUST trial in Italy. Patients and methods: Eligible patients had stage IIIB/IV NSCLC and had failed or were unsuitable for chemotherapy. Erlotinib (150 mg/day orally) was given until disease progression or unacceptable toxicity. Patients were monitored monthly. Results: At time of this analysis, data from 651 patients were available. Patient characteristics were: median age 66 years (range 30-87), male 69%, former or current smoker 71%, ECOG PS 0-1 81%, adenocarcinoma histology 52% and stage IV 82%. Erlotinib was administered as first-, second-, third- or other-line in 12, 45,43 and

Trastuzumab, a monoclonal antibody against the HER2 receptor, is currently approved as a part of adjuvant therapy for patients with HER2-overexpressing breast tumors. The Short-HER study is a phase III randomized, multicentric Italian trial aimed at testing the optimal duration of adjuvant trastuzumab. In this trial, 2500 patients with HER2-positive breast cancer will be randomized to receive the following: (arm A, long) 4 courses of anthracycline- based chemotherapy (doxorubicin/cyclophosphamide or epidoxorubicin/cyclophosphamide) followed by 4 courses of docetaxel or paclitaxel in combination with trastuzumab, followed by 14 additional courses of trastuzumab administered every 3 weeks (for a total of 18 3-weekly doses of trastuzumab); or (arm B, short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab (for a total of 9 weekly doses of trastuzumab) followed by 3 courses of 5-fluorouracil/epirubicin/cyclophosphamide. The primary objective is disease-free survival.

Sorafenib is an orally available multikinase inhibitor active on vascular endothelial growth factor receptor-2 and -3, platelet-derived growth factor receptor-beta, B-RAF, C-RAF, flt3 and C-Kit. Phase I studies showed its activity on renal cell carcinoma (RCC) and other neoplasms and identified the schedule of 400 mg (two tablets) b.i.d. as better tolerated and potentially active. The original design selected for the principal phase II trial, randomization discontinuation trial, showed the particular activity profile of this drug: low objective response rates but significant increases in progression-free survival [PFS, which frequently translate in increased overall survival (OS)]. A pattern of response completely agrees with an antiangiogenic (cytostatic) agent. The potential efficacy of sorafenib was confirmed in immunotherapy-refractory advanced RCC cases by 'TARGETs', the largest randomized double-blind study ever carried out in kidney cancer. With a doubled PFS, a trend in OS and a modest toxicity profile, mainly grade 1-2 skin toxicity and diarrhea, sorafenib has been recently approved from the Food and Drug Administration and European Agency for the Evaluation of Medicinal Products for the second-line treatment of advanced RCC. Numerous trials are ongoing to test new schedules and drug combinations, while promising results were recently achieved also in hepatocellular carcinoma. With drugs such as sorafenib, angiogenesis could become an Achilles's heel for RCC.

Background. A higher incidence of central nervous system (CNS) metastases in HER-2–positive metastatic breast cancer (MBC) has recently been reported. Materials and Methods. Aims of this observational study were to evaluate the incidence of CNS metastases in HER-2–positive MBC patients, to define the outcome of patients with CNS metastases, and to identify the risk factors for CNS relapse. Results. Between April 1999 and June 2005 we treated 122 consecutive HER-2–positive MBC patients with chemotherapy and trastuzumab. At a median follow-up of 28 months from the occurrence of metastatic disease, 43 patients (35.2%) developed CNS metastases. The median time to death from the diagnosis of CNS metastases was 23.46 months. At multivariate analysis we found that only premenopausal status at diagnosis of breast cancer and visceral metastases as the dominant site at relapse were significantly associated with a higher risk for CNS metastases. Conclusion. The CNS metastasis incidence is very high in HER-2–positive MBC, but the survival after CNS relapse in these patients is longer than in patients unselected for HER-2 status, because of the better control of extracranial disease obtained by trastuzumab. The identified risk factors for CNS relapse could allow us to select a subgroup of HER-2–positive MBC patients as candidates for active surveillance for CNS progression (by computed tomography or magnetic resonance imaging) and/or as candidates for accrual in trials of prevention of CNS relapse.

Background: Tissues are heterogeneous in terms of cell composition and the percentage of tumor epithelium can vary tremendously in any clinical biopsy. Given the importance and focus on the cancer phosphoproteome due to the mechanism of action of nearly all targeted therapies, we and others have shown the importance of upfront cellular enrichment strategies such as laser capture microdissection (LCM). However, despite the improved data quality, retention of dynamic range, and correlations with IHC and genomic data shown with LCM based analysis; questions remained about the overall impact of LCM on protein and phosphoprotein measurements. The aim of the study was to investigate whether a real-world tissue processing workflow using infrared (IR) based LCM for the isolation of pure cell populations affect the overall expression and activation/deactivation levels of protein signaling molecules that are important in druggable target analysis and companion diagnosis. Materials and methods: Five Non Small Cell Lung Cancer samples were used for this study. Eight micron sections were cut and mounted on glass slides. Samples were microdissected or lysed within 30 minutes once stained. For each sample, using alternating adjacent slides, three different protein lysates were collected: the first lysate was generated after tumor epithelium enrichment was performed via LCM, the second one was obtained by lysing of the undissected whole tissue directly from the glass slide (TL) and the last was obtained by microdissecting the entire tissue slide (LCM-TL) without regard to the underpinning cell population. Lysates were then analyzed by Reverse Phase Protein Microarray to evaluate the expression/activation levels of 87 proteins. Unsupervised hierarchical clustering analysis was used to compare the expression/activation of the 87 analytes across the different collection methods. Results: Tumor percentage was estimated as 50% (n = 1), 60% (n = 1) and 70% (n = 3). Unsupervised hierarchical clustering analysis showed that for all five pairs (100%), the TL and matched LCM-TL samples clustered within the same arm of the dendrogram while only one of the LCM samples (with tumor percentage of 70%) clustered in the same arm of the dendrogram as the matched LCM-TL. On the other hand, two of the five LCM samples were contained in the same cluster. Conclusion: These results confirm the importance of using LCM for upfront cellular enrichment for the accurate measurement of the expression/activation levels of proteins for biomarker discovery, even when the tumor cells percentage in the specimen is high. Importantly, based on this pilot study we conclude, that the LCM process, using an IR based direct capture laser system, itself does not appear to have a significant impact on the integrity of proteome and phosphoproteome. Citation Format: Elisa Baldelli, Vienna Ludovini, Lucio Crinò, Lance Liotta, Emanuel Petricoin, Mariaelena Pierobon. Impact of laser capture microdissection on cancer signaling proteins and phosphoproteins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1994. doi:10.1158/1538-7445.AM2015-1994

e19149 Background: the association of venous thromboembolic events (VTE) and lung cancer has a high prevalence. Limited data are available in the adenocarcinoma subtype population especially in rel...

3034 Background: TG4010 is an immunotherapy using an attenuated and modified poxvirus (MVA) coding for MUC1 and interleukin-2. A previous study showed that the baseline level of Triple Positive Act...

8059 Background: In the ASCEND-1 study ceritinib showed clinical activity in pts with ALK+ NSCLC, including in brain metastases (BM). ASCEND-2 (NCT01685060) evaluated efficacy and safety of ceritin...

7540 Background: Adjuvant chemotherapy for NSCLC has reached a plateau. The use of the tyrosine kinase inhibitor (TKI), E, was explored in the adjuvant setting given success in advanced setting.We ...

Purpose: Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non–small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression]. Experimental Design: EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens. Results: EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P < 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35). Conclusion: EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.

Background: Oligodendroglial tumors are rare and chemosensitive diseases; but the overall results with current chemotherapy regimens cannot be considered satisfactory and other active treatments are necessary. We decided to determine the efficacy and toxicity profile of the carboplatin and etoposide (CE) regimen in this setting. Methods: In this phase II trial we evaluated the response rate of first or second line CE regimen (Carboplatin AUC 5 on day 1 and Etoposide 120 mg/m 2 on days 1-3 every 28 days) in patients with recurrent/progressive oligodendroglial tumors. Results: Thirty-two patients were enrolled. Median age was 42 years (range 22-66); median ECOG PS was 0 (range 0-2); 9 patients had oligodendroglioma, 3 patients had oligoastrocytoma, 11 patients had anaplastic oligodendroglioma, 9 patients had anaplastic oligoastrocytoma. CE regimen showed a response rate of 46.9% with 5 complete responses (15.6%) and 10 partial responses (31.3%). Eleven patients (34.4%) had stable disease. Median time to progression was 8 months, progression-free survivals at 6 and 12 months were 80% and 46.9%, respectively. Toxicity was mainly hematological, with grade 3-4 neutropenia in 5 (15.6%) patients. Conclusions: In this trial CE regimen has shown relevant activity with a favourable safety profile. © Springer Science+Business Media B.V. 2006.

Metastatic bone lesions are exceptional at diagnosis in germ cell tumors (GCTs). Bone involvement is usually a late event combined with synchronous metastasis in the retroperitoneal lymph nodes, lung and liver. Bone examination is not considered a standard procedure in the staging of GCTs, and this may contribute to underestimation of the real proportion of bone metastases. Here we report a case of nonseminomatous GCT of the testis with a synchronous, symptomatic, solitary pubic bone metastasis that was completely controlled by systemic chemotherapy and locoregional radiation therapy. Solitary bone metastases from GCTs seem to be chemosensitive and radiosensitive, but we do not know their prognostic value. We reviewed the literature where 3 similar cases have been reported. We propose individualized management for symptomatic GCT patients including bone scintigraphy and/or PET examination at diagnosis and a combined cytotoxic approach with chemotherapy and radiation therapy

Pre-clinical data suggested a relationship between inactivation of hMLH1 and hMSH2 and resistance to drugs like cisplatin and carboplatin, but not oxaliplatin. We then hypothesised that NSCLC showing loss of expression of the mismatch repair system (MMR), could be refractory to cisplatin-based, but not to oxaliplatin-based chemotherapy. Immunoistochemical. expression of hMLH1 and hMSH2 was analysed on tumour samples from 93 advanced NSCLC, receiving chemotherapy with either cisplatin or oxaliplatin in combination with gemcitabine. Patients showing loss of hMLH1 or hMSH2 expression in >= 50% of tumour cells were deemed MMR-negative (Group A), whereas cases with a normal, hMLH1 or hMSH2 expression in > 50% of the tumour cells were defined MMR-positive (Group B). No differences in the response and progression rate were found in the whole patients population and in the gemcitabine/cisplatin group for both hMLH1 and hMSH2. In the gemcitabine/oxaliplatin group response rate was 38% and 0% (p = 0.04) for patients with or without loss of hMSH2 expression. Median survival according to MMR status in Groups A and B, respectively was: 17 months versus 9 months for hMLH1 (p=0.031) and 10 months versus 9 months for hMSH2 (p=0.8330). Both the difference in response rate and in median survival observed according to MMR status seem to confirm what has been suggested by preclinical studies. (c) 2006 Elsevier Ireland Ltd. All rights reserved. RI Rossi, Giulio/C-5576-2011

Life expectancy of patients affected by glioblastoma multiforme is extremely low. The therapeutic use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been proposed to treat this disease based on its ability to kill glioma cell lines in vitro and in vivo. Here, we show that, differently from glioma cell lines, glioblastoma multiforme tumors were resistant to TRAIL stimulation because they expressed low levels of caspase-8 and high levels of the death receptor inhibitor PED/PEA-15. Inhibition of methyltransferases by decitabine resulted in considerable up-regulation of TRAIL receptor-1 and caspase-8, down-regulation of PED/PEA-15, inhibition of cell growth, and sensitization of primary glioblastoma cells to TRAIL-induced apoptosis. Exogenous caspase-8 expression was the main event able to restore TRAIL sensitivity in primary glioblastoma cells. The antitumor activity of decitabine and TRAIL was confirmed in vivo in a mouse model of glioblastoma multiforme. Evaluation of tumor size, apoptosis, and caspase activation in nude mouse glioblastoma multiforme xenografts showed dramatic synergy of decitabine and TRAIL in the treatment of glioblastoma, whereas the single agents were scarcely effective in terms of reduction of tumor mass, apoptosis induction, and caspase activation. Thus, the combination of TRAIL and demethylating agents may provide a key tool to overcome glioblastoma resistance to therapeutic treatments. (Cancer Res 2005; 65(24): 11469-77)

Platinum-based chemotherapy offers a modest survival advantage over best supportive care in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Despite the survival benefit associated with first-line chemotherapy, the majority of patients will experience relapse or disease progression. In clinicalpractice, an increasing number of patients maintain a good performance status after first-line treatment and are eligible for further treatments. Docetaxel (Taxotere) at 75 mg/m2 given once every 3 weeks has been the standard of care for second-line chemotherapy since the year 2000. Pemetrexed (Alimta) is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. A large phase 111 study comparing docetaxel to pemetrexed in second-line therapy demonstrated that pemetrexed is equally active and less toxic than docetaxel. Based on these results, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC. Progress made in the field of molecular biology has led to the identification of drugs active against specific cellular targets. Gefitinib (Iressa) and erlotinib (Tarceva) are both orally active tyrosine kinase inhibitors of the epidermal growth factor receptor. Phase II and III trials have demonstrated that these agents are active particularly in a subgroup of patients with specific biologic characteristics. Both drugs have been approved for the treatment of pretreated NSCLC. Other drugs, such as cetuximab (Erbitux) and bevacizumab (Avastin) have shown promising activity in NSCLC and are currently being tested in clinical trials.

Gefitinib is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks signal transduction pathways involved in cell proliferation. This drug demonstrated impressive and durable responses in patients with heavily pretreated non-small cell lung cancer (NSCLC). In two large phase II trials, responses were observed in 9-19% of unselected patients, along with symptom improvement and benefit in quality of life. Biological mechanisms underlying TKI sensitivity have recently been discovered. There is evidence that specific EGFR gene mutations and/or amplification confer a particularly sensitive phenotype, especially in individuals with tumors demonstrating activation of the anti-apoptotic protein Akt. However, in all so far conducted clinical trials, no patient selection has been made, providing a logical explanation for the negative results observed in large phase III studies. In the present review, we will summarize the results observed in clinical trials with gefitinib. We will present results obtained in NSCLC and in other solid tumor, focusing on biological and clinical markers predicting drug sensitivity.

PURPOSE: Gemcitabine-platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally. DESIGN: Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes. RESULTS: A significant reduction in overall mortality in favor of gemcitabine-platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84-0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine-platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine-platinum regimens, HR 0.84 (CI: 0.71-0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93 (CI: 0.86-1.01). There was a significant decrease in the risk of disease progression in favor of gemcitabine-platinum regimens, HR 0.88 (CI: 0.82-0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine-platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine-platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77-0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82-0.96).

Aims and background In addition to bone marrow suppression and renal toxicity, neurotoxicity is a commonly occurring side effect of widely used chemotherapeutic agents like taxanes, cisplatin and vinca alkaloids. Neurotoxicity can cause antitumor therapy discontinuation or dose regimen modification. The aim of the present exploratory study was to investigate the activity of acetyl-L-carnitine in reversing peripheral neuropathy in patients with chemotherapy-induced peripheral neuropathy. Methods and study design Twenty-seven patients (16 males and 11 females) with paclitaxel and/or cisplatin-induced neuropathy (according to WHO recommendations for the grading of acute and subacute toxic effects) were enrolled. Patients received at least one cisplatin- (n = 5) or one paclitaxel- (n = 11) based regimen, or a combination of both (n = 11). Patients with chemotherapy-induced peripheral neuropathy were treated with acetyl-L-carnitine 1 g/die iv infusion over 1-2 h for at least 10 days. Results Twenty-six patients were evaluated for response having completed at least 10 days of acetyl-L-carnitine therapy (median, 14 days; range, 10-20). At least one WHO grade improvement in the peripheral neuropathy severity was shown in 73% of the patients. A case of insomnia related to ALC treatment was reported in one patient. Acetyl-L-carnitine seems to be an effective and well-tolerated agent for the treatment of chemotherapy-induced peripheral neuropathy. Conclusions Our preliminary results should be confirmed in double-blind, placebo controlled studies.

Purpose: The aim of this study was to assess serum extracellular binding domains of epidermal growth factor receptor (EGFR) and HER2 as surrogate markers of Gefitinib (Iressa, ZD1839, AstraZeneca, London, United Kingdom) activity in patients with non-small cell lung cancer. Experimental Design: Serum EGFR and HER2 levels were monitored in blood samples taken within 1 week of starting Gefitinib at day 28 and at every computed tomography scan evaluation. EGFR and HER-2 were assayed in duplicate using commercial sandwich enzyme-linked immunosorbent assay kits (Oncogene Science Bayer Corporation, Cambridge, UK). A logistic regression analysis was performed to evaluate: (1) the relationship between best overall tumor response and basal EGFR and HER2 levels, and (2) the association between best overall tumor response and the differences of EGFR and HER2 levels obtained at the best overall tumor response and at baseline. Results: Forty-six pretreated patients were evaluated, including F/M:11/35, Eastern Cooperative Oncology Group performance status 0–1/2:39/7, IIIB/IV:11/35, and adenocarcinoma/nonadenocarcinoma 29/17. Five partial responses (11%) and 14 stable disease responses (30%) were observed. Median pretreatment EGFR and HER2 were 83.3 ng/ml and 13.7 ng/ml. For baseline EGFR and HER2, the odds ratio of progression was 0.95 [95% confidence interval (CI), 0.91–0.98; P = 0.01] and 0.87 (95% CI, 0.74–1.03; P = 0.11), respectively. The difference between the best overall tumor response and basal EGFR value was predictive for response with a 6% increase in the odds of progression for an increase of 1 ng/ml (odds ratio, 1.06; 95% CI, 1.01–1.11; P = 0.009) and for progression-free survival with a hazard ratio of 1.03 (95% CI, 1.01–1.04; P = 0.003). Conclusion: Modifications of EGFR serum values during treatment seem to reflect Gefitinib activity.

In our case report, strong evidence indicates hyperamylasemia as a paraneoplastic phenomenon: Firstly, the marked salivary-type hyperamylasemia in the absence of inflammatory conditions of both the salivary glands and pancreas; secondly, the dramatic fall of the amylase level soon after the start of chemotherapy; and thirdly, the evidence of the strong cytoplasmic positivity with antisalivary gland type amylase antibody in the neoplastic tissue. More interestingly, in this instance, the paraneoplastic hyperamylasemia behaved like a specific tumor marker because it paralleled tumor response to chemotherapy and disease relapse.

Herein we describe the case of a patient with primary diffuse leptomeningeal gliomatosis (PDLG). After surgery and ventriculoperitoneal shunt placement, due to poor general conditions, the patient was not eligible for radiotherapy. For this reason we decided to start a systemic chemotherapy treatment with Temozolomide (150 mg/m2 per day for 5 days every 4 weeks). After three cycles a partial response was achieved with a clear improvement of general conditions. In our knowledge, this is the first time that PDLG treatment with Temozolomide has been described.

Lung cancer is the leading cause of cancer death in the world. Therapeutic improvements caused by recent cytotoxic agents seem to have reached a plateau. New therapeutic strategies are, therefore, necessary to improve the cure rate. These include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gene therapy and vaccines. The antiepidermal growth factor receptor (EGFR) group includes compounds acting on the extracellular domain of EGFR, such as IMC-C225 and trastuzumab; small molecules inhibiting EGFR phosphorylation, such as ZD 1839 and OSI-774; or compounds that interfere with one of the downstream steps, such as mitogen-activated protein kinase kinase (MEK) inhibitors. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumour activity. Antiangiogenesis inhibitors include matrix metalloprotease inhibitors (MMPIs), suchs as marimastat, AG3340, BAY 12-9566, BMS-275291 and Col-3. Antiangiogenic agents offer great potential for the treatment of lung cancer, as shown in preclinical models, whereas emerging data suggest that there are limits to their use as monotherapy in advanced disease. Molecules targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) also seem to control tumour progression and may prolong survival. COX-2 inhibitors are another class of agents currently under evaluation in clinical trials for their chemoprevention role in subjects at high lung cancer risk, and also in patients with non-small cell lung cancer (NSCLC) in combination with standard chemotherapeutics. Genetic and immunologic therapies represent two additional promising modalities. All of these therapies are in different phases of clinical testing and have shown encouraging activity alone or in combination with chemotherapy drugs.

Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low beta-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by beta-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between beta-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.

Purpose: Our objective was to determine the activity in terms of response rate, surgical resectability, and the tolerability of the new three-drug combination gemcitabine–cisplatin–paclitaxel (GCP) in unresectable stage IIIA(N2) and IIIB non-small cell lung cancer (NSCLC). Patient and methods: Forty-two chemo-naive patients with stage IIIA(N2)–IIIB NSCLC, median age of 59 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and the ability to tolerate pneumectomy, received gemcitabine (Gem) 1000 mg/m2 IV days 1 and 8, cisplatin (CDDP) 50 mg/m2 IV days 1 and 8, paclitaxel 125 mg/m2 1 h infusion IV days 1 and 8, every 21 days for 3 cycles. After induction chemotherapy, patients were evaluated for surgery or definitive radiotherapy. Results: Grade 3–4 neutropenia was the main hematologic toxicity, occurring in 28% of patients. Grade 3–4 thrombocytopenia was observed in only 11% of cases. No neutropenic fever or bleeding episodes were recorded. Severe non-hematologic toxicity was uncommon. Thirty (71%, 95% CI: 57.2–84.7%) of the 42 eligible patients had objective responses (1 complete and 29 partial responses). After induction chemotherapy, 21 patients (50%) went to surgery. Complete resection was obtained in 16 patients (38%). Viable tumor was present in 18 of 21 resection specimens. In three cases only necrotic tumor cells were identified, for a pathological complete response of 7%. With a median follow-up of 13.9 months, median time to progression was 17.4 months, median survival 21.7 months and estimated 1-year survival 92%. Conclusions: GCP combination is active and well tolerated in locally-advanced, non-resectable NSCLC. The activity profile, in terms of response and surgical resection rate, is comparable to that obtained with standard doublets.

A significant number of small cell lung carcinomas shows overexpression of the proto-oncogene c-kit product, a tyrosine kinase known as Kit or CD117. This molecular pathway seems somewhat implicated in promoting the neoplastic growth of small cell lung carcinoma. The current pharmacological availability of its selective inhibitor, together with the promising clinical results in the management of CD117-positive neoplasms such as advanced gastrointestinal stromal tumors, aroused great interest among oncologists in also adopting this therapeutic strategy in other CD117-positive tumors. We evaluated a series of 27 small cell lung carcinomas, comparing the expression of CD117 of the primary naive tumor (before first-line chemotherapy) with the expression of the same neoplasm after postchemotherapy relapse. All the patients underwent similar chemotherapeutic regimens (cisplatin/carboplatin plus etoposide). At diagnosis, 21 of 27 cases (78%) showed strong immunoreactivity for CD117. Among these 21 originally positive tumors, CD117 remained overexpressed in 10 after relapse (48%), whereas the other 11 cases became negative. No originally CD117-negative small cell carcinomas displayed immunoreactivity after chemotherapy. CD117 expression was not statistically correlated with overall survival, occurrence of chemoresistance, or clinical response to chemotherapy. We also evaluated CD117 expression in a series of 46 surgically resected non-small cell lung carcinomas (8 squamous cell carcinomas, 10 adenocarcinomas, 5 pleomorphic carcinomas, 10 typical and 3 atypical carcinoids, and 10 large cell neuroendocrine carcinomas). Apart from small cell carcinomas, CD117 overexpression was observed in 6 of 10 large cell neuroendocrine carcinomas, whereas all the other histotypes resulted unstained. We speculate that loss of CD117 expression after chemotherapy in a high proportion of SCLC indicates that in this tumor, Kit unlikely represents the product of a constitutive mutation, as instead shown in gastrointestinal stromal tumors. Keeping this finding in mind, oncologists could re-test CD117 expression in relapsing small cell lung carcinomas in order to establish the best candidates for enrollment in ongoing clinical trials with Kit inhibitors. Practically speaking, CD117 may be helpful in discriminating between pulmonary high-grade neuroendocrine tumors and other histotypes, but pathologists should be aware that treated small cell lung carcinomas may remain unstained in a not insignificant number of cases.

The overall cure rate in non-small cell lung cancer is still below 15% despite years of research and clinical trials [1]. In recent years, significant improvement has been achieved and current treatments are able to reduce the hazard rate of death by nearly one third. Surgical resection is still considered the treatment of choice in early stage NSCLC, but a 5 year survival rate over 50% is obtained only in stage 1A patients, mainly because of distant dissemination of disease [2]. It is clear that NSCLC should be considered a systemic illness and clinical research should be focused on the development of effective systemic treatment. Indeed all the attempts to improve survival through a better management of local disease with more aggressive surgery or postoperative radiotherapy did not obtain their goal [3,4]. Distant relapses cause the failure of local treatment in over two-third of the patients and this evidence has determined, as in other neoplasia such as breast and colon cancer, the introduction of systemic adjuvant chemotherapy. The value of postoperative adjuvant chemotherapy has been assessed by a meta-analysis of randomised trials in 1995, which demonstrated a marginal survival benefit using platinum-based chemotherapy in a patient population mainly in early (I / II) stage NSCLC [5]. On the basis of these results two large randomised trials have been recently completed in North America and Europe and hopefully will address the question as to whether adjuvant chemotherapy may add some benefit in the treatment of this disease. In the past 15 years a different approach, protochemotherapy or neo-adjuvant chemotherapy, has also been evaluated in the management of stage IIIA NSCLC in many phase II and in a few small phase III trials. Despite a lack of consistent evidence of survival benefit, neo-adjuvant chemotherapy has become a widely employed preoperative treatment of locally advanced unresectable stage IIIA (N2) NSCLC [6] and it is under current investigation in early stage NSCLC too. As with stage IIIA tumors, also in earlier stages of NSCLC the most common sites of recurrence are distant, and there are a number of theoretical advantages of neo-adjuvant chemotherapy to control micrometastatic dissemination: chemotherapy prior to surgery is usually better tolerated than adjuvant chemotherapy and can be given at full dosage according to planned treatment; micrometastases are more likely to be eradicated by an earlier rather than later treatment. On the basis of these theoretical considerations platinum-based neo-adjuvant chemotherapy in association with either old or new drugs has been studied in prospective phase III and in phase II studies. At the 1999 ASCO meeting Depierre and other French investigators presented the first data of a prospective phase III study assessing the impact on survival of two cycles of a neo-adjuvant MIC regimen (Mitomycin, Ifosfamide Cisplatin) and surgery, versus surgery alone in stage I, II and selected III A NSCLC. In the Cox regression test adjusted for stage, the effect of pre-operative chemotherapy was favorable with a relative risk of 77 (P /0.05) [7]. In a multicentre phase II trial conducted in the USA in 94 pts with T2NO: T1/2N1 and T3N0/1 NSCLC, the investigators showed evidence of activity and feasibility of both preoperative (two cycles) and adjuvant (three cycles) chemotherapy with carboplatin and paclitaxel and surgery [8]. After these studies, a number of randomised studies have been designed and are currently on the way in Europe and USA evaluating the new chemotherapy E-mail address: lucio.crino@ausl.bologna.it (L. Crino). Lung Cancer 38 (2002) S31 /S32

PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 2 every 21 days (GC arm), or paclitaxel 225 mg/m2 (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL·min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m2/wk for 12 weeks then every other week plus cisplatin 100 mg/m2 day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, PCb, and VC groups was 9.8, 9.9, and 9.5 months, respectively. Neutropenia was significantly higher on the VC arm (GC 17% or PCb 35% v VC 43% of cycles, P < .001), as was thrombocytopenia on the GC arm (GC 16% v VC 0.1% of cycles, P < .001). Alopecia and peripheral neurotoxicity were most common on the PCb arm, as was nausea/vomiting on the VC arm (P < .05). CONCLUSION: Efficacy end points were not significantly different between experimental and reference arms, although toxicities showed differences. These findings suggest that chemotherapy in NSCLC has reached a therapeutic plateau.

Background: ALK gene rearrangement occurs in 2–7% of NSCLC cases. Pts with ALK+ NSCLC respond modestly to chemotherapy, and crizotinib (CRZ) is the only targeted agent currently widely approved for the treatment of ALK+ NSCLC. Ceritinib is a novel oral ALK inhibitor with 20-fold greater potency than CRZ in enzymatic assays, and sustained activity against both CRZ-resistant and CRZ-naive NSCLC in preclinical studies. In a phase I clinical study (Shaw et al NEJM 2014), the maximum tolerated dose of ceritinib was determined to be 750 mg/day and the overall response rate in 78 pts treated at this dose was 59%. In this study, substantial clinical activity was shown in both CRZ-naive and CRZ-treated pts with ALK+ NSCLC. Nausea, vomiting, diarrhea and fatigue were the most common toxicities. Trial design: Here we describe two phase III, prospective, multicenter, randomized open-label studies designed to compare the anti-tumor activity of ceritinib with that of chemotherapy in adult pts with ALK+ advanced NSCLC who are either chemotherapy- and CRZ-naive (ASCEND-4; NCT01828099) or who have received prior chemotherapy and CRZ (ASCEND-5; NCT01828112). Pts participating in either trial must have stage IIIB or IV NSCLC and ≥1 measurable lesion, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Pts will be randomized to oral ceritinib 750 mg/day or to chemotherapy every 21 days (ASCEND-4: pemetrexed 500 mg/m2 in combination with either cisplatin 75 mg/m2 or carboplatin AUC 5-6; ASCEND-5: pemetrexed 500 mg/m2 or docetaxel 75 mg/m2). The primary objective of both studies is to compare ceritinib with chemotherapy by analysis of progression-free survival. Secondary objectives include comparison of ceritinib with chemotherapy by evaluation of overall survival, overall response rate, duration of response, disease control rate and time to response. Enrolment is ongoing. Disclosure: A. Shaw: Advisory board: Novartis, Pfizer, Ariad, Chugai, Genentech; L. Crino: Advisory board and honoraria:Novartis; E. Felip: Sat on advisory boards for Novartis, Roche, BMS, BI and Lilly; T.S.K. Mok: Employee of The Chinese University of Hong Kong. Research grant: AZ; Ad board & Honoraria: AZ, Roche, Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, BI, Novartis, GSK, Clovis, Amgen, Janssen, BioMarin; M. Nishio: Received honoraria from Pfizer, Chugai and Novartis; L. Paz-Ares: Consultant and Speakers bureau: Lilly. Honoraria: Lilly, Roche, Pfizer, Bayer, BI; G. Scagliotti: Honoraria: Lilly, AZ, Pfizer, Roche, Clovis SB: Lilly Ad board: Lilly, Roche, AZ, Clovis; D.R. Spigel: Consultant: BMS and Novartis; J. Wolf: Employee of University Hospital of Cologne; Advisory Boards, speakers bureau and research funding: AZ, Novartis, Roche, Pfizer, BI, BMS, Clovis; Research support: Novartis, Roche, BI; Y. Wu: Speaker fees: Roche, Lilly, Sanofi, Pfizer; G. Castro: Speakers bureau and Advisory board for Novartis; P. Sen: Employee of, employee remuneration and stock options from: Novartis; C. Zheng: Cheng Zheng is an employee of Novartis; A. Joe: Employee, Employee remuneration and stock options: Novartis; J. Soria: Advisory board compensated by Novartis. All other authors have declared no conflicts of interest.

Aim: NSCLC in NS often harbors proto-oncogene aberrations, showing enrichment for targetable alterations compared to unselected populations. Objectives of this study were to define the proportions of the driver gene alterations and to examine survival in genotype-specific subsets of NS NSCLC. Methods: We identified 243 NS NSCLC pts treated at our Institution from October 2003 to January 2014. Pts with tissue available for biological analysis were as follows: 207 pts (85.1%) assessable for EGFR/KRAS mutation, 77 (31.6%) for ALK rearrangement, 37 (15.2%) for ROS1 rearrangement, 33 (13.5%) and 32 (13.1%) for RET fusion and HER2 mutation. The cohort comprised 58% women, median age 62, 86% advanced adenocarcinomas (10% brain metastases at diagnosis). Results: Out of 207 tumors, frequency of EGFR and KRAS mutation was 42.5% (88 pts) and 7.7% (16), respectively. Among pts screened for ALK, ROS1, RET, HER2, the proportion of individual testing, were 25.9% (20), 13.5% (5), 9% (3), 0%. 228 pts were evaluable for treatment and outcomes.158 pts (69%) received at least one line of an EGFR tyrosine kinase inhibitor (TKI), of which 42 (27%) as first line. 16 pts (7%) received an ALK/ROS1 inhibitor, and 8 pts (4%) had both treatments, 50 pts (21%) received exclusively chemotherapy. Median progression-free survival (PFS) after treatment with first line EGFR TKI was 13.2 months (mo) vs 5.3 mo for chemotherapy (p Conclusions: The study confirmed the clinical and outcome features which make lung cancer in NS a distinct disease. Of particular note is the marked increase in OS with EGFR TKI therapy when evaluating this subset in contrast to previous studies not specifically focusing on NS. Disclosure: All authors have declared no conflicts of interest.

11099 Background: Surgically resected early-stage non-small lung cancer (NSCLC) display a highly variable outcome in terms of PFS and OS. Currently used clinico-pathological parameters may not prec...

10063 Background: Retinoblastoma is the most common ocular tumor of childhood. Diagnosis times differ across the word, with diagnosis occurring significantly earlier in developed countries. Necrosi...

e19086 Background: Tyrosine kinase inhibitors (TKIs) are the first choice of treatment in a subset of patients with non- small cell lung cancer (NSCLC) harboring specific epidermal growth factor re...

11035 Background: ROS1 chromosomal rearrangement (ROS1+) was described as an oncogenic driver in approximately 1% of non-small cell lung cancers (NSCLC). Due to the structural analogy of ROS1 and A...

e19054 Background: Identification of oncogenic drivers has dramatically changed current therapeutic strategies for lung cancer, initiating the era of personalized therapy. "Pan-negative" NS non-sma...

The 5-year survival for pancreatic cancer is usually less than 5%, and no treatment has demonstrated consistent effect on patient survival and disease-related symptoms. Early studies with gemcitabine suggested a modest antitumor activity with significant improvement in disease-related symptoms. This phase II study reports the activity of gemcitabine on 33 consecutive patients with unresectable pancreatic carcinoma. Twenty-three patients had metastatic and 10 locally advanced unresectable disease. Twenty-six patients had not received any previous treatment and seven had received first-line chemotherapy with 5-fluorouracil. Gemcitabine 1,000 mg/m 2 was administered intravenously in 30 minutes in the first cycle once weekly for up to 7 weeks followed by 1 week rest; then in subsequent cycles, once weekly for 3 of every 4-week cycle. Four patients obtained partial response (12%). Fifteen patients (45%) had stable disease with a median duration of 32 weeks (range: 16-75 weeks), and 14 patients experienced progressive disease. Median duration of response was 34.5 weeks (range: 19-50 weeks). Median survival was 33 weeks (range: 2-91 weeks). All 4 responding patients and 14 of 15 (93%) patients with stable disease had improvement in performance status and decrease in daily analgesic requirement. Toxicity was mild and mainly consisted of moderate and rapidly reversible myelosuppression. We conclude that gemcitabine chemotherapy was very well tolerated and determined a significant clinical improvement with modest antitumoral activity in patients with advanced pancreatic cancer.

Introduction: This phase II study was designed to assess the activity and tolerability of the carboplatin–paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. Patients and methods: Sixty patients (15 stage IIIb and 45 stage IV) received paclitaxel 225 mg/ml on day 1, followed by carboplatin AUC 6 mg/ml per minute (Calvert formula) every 3 weeks. Paclitaxel was administered as a 3-h intravenous infusion followed by carboplatin over 30 min, on completion of paclitaxel administration. Results: The combination showed a good safety profile with Grade 4 neutropenia occurring in 31% of patients without any serious infectious episodes requiring hospitalization. Moderate to severe anemia and thrombocytopenia seldom occurred. Sensorimotor peripheral neuropathy (Grade 2–3) and myalgia (Grade 3–4) were documented in 34 and 20% of the patients, respectively. Among 59 evaluable patients, there was one complete response and 26 partial responses for an overall response rate of 46% (95% C.I.: 34–59%). With a minimum follow-up duration of 16.5 months, the median overall survival time is 52 weeks and the 1-year survival rate is 50%. Median duration of response is 20 weeks (range: 4–52) and progression-free survival is 22 weeks (range: 5–77). Conclusion: In advanced NSCLC, the combination carboplatin–paclitaxel at doses of AUC 6 mg/ml per minute and 225 mg/ml every 3 weeks, is both active and relatively well-tolerated.

Introduction: This phase I study was designed to establish the maximum tolerated dose (MTD) of the carboplatin–paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer. Patients and methods: Fifty patients (one stage IIIa, 31 stage IIIb and 18 stage IV) were sequentially assigned to one of 14 treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 235 mg/m 2 and from 230 to 375 mg/m 2 , respectively. Paclitaxel was administered as a 3-h intravenous infusion using non-polyvinylchloride tubing and connectors. The carboplatin infusion, over 30 min, was administered at the completion of the paclitaxel infusion. Results: The MTD for the combination has been reached at 235 mg/m 2 of paclitaxel and at 375 mg/m 2 of carboplatin. The combination shows a good safety profile with very few and brief episodes of neutropenia without any infectious episodes. At the doses tested thrombocytopenia did not occur at all. Among 47 assessable patients there was one complete response and 17 partial responses for an overall response rate of 38%. There has been a tendency to a dose–response relationship for the combination with only six partial responses (27%) reported in 22 patients who received paclitaxel at doses ≤195 mg/m 2 and carboplatin at doses 2 and 12 partial responses in 25 patients (48%) receiving paclitaxel >195 mg/m 2 and carboplatin ≥350 mg/m 2 , respectively. The median event-free survival time is 33 weeks (range, 4–156+). With a minimum follow up duration of 57 weeks the median overall survival time is 51.81 weeks (range, 7–162+) and the 1-year survival rate is 49%. Conclusion: In advanced NSCLC the carboplatin–paclitaxel combination can be safely administered at the doses of 375 and 225 mg/m 2 every 4 weeks, it appears to be active and well tolerated.