Thomas Cerny

Mediastinal Lymph Node Clearance After Docetaxel-Cisplatin Neoadjuvant Chemotherapy Is Prognostic of Survival in Patients With Stage IIIA pN2 Non–Small-Cell Lung Cancer: A Multicenter Phase II Trial

PURPOSE A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

Platinum-Based Versus Non-Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis of the Published Literature

PURPOSE This meta-analysis was performed to compare the activity, efficacy and toxicity of platinum-based versus non-platinum-based chemotherapy in patients with advanced non-small-cell lung cancer. METHODS Randomized phase II and III clinical trials comparing first-line palliative platinum-based chemotherapy with the same regimen without platinum or with platinum replaced by a nonplatinum agent were identified by electronic searches of Medline, Embase, and Cancerlit, and hand searches of relevant abstract books and reference lists. Response rates, 1-year survival, and toxicity were analyzed. Subgroups of trials using third-generation agents were compared. RESULTS Thirty-seven assessable trials were identified including 7,633 patients. A 62% increase in the odds ratio (OR) for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46 to 1.8; P < .0001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% v 29%; OR, 1.21; 95% CI, 1.09 to 1.35; P = .0003). No statistically significant increase in 1-year survival was found when platinum therapies were compared to third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96 to 1.28; P = .17). The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nephrotoxicity, and nausea and vomiting, but not for neurotoxicity, febrile neutropenia rate, or toxic death rate. CONCLUSION Response is significantly higher with platinum-containing regimens. One-year survival was not significantly prolonged when platinum-based therapies were compared with third-generation-based combination regimens. Toxicity is generally higher for platinum-based regimens.

A Vaccine against Nicotine for Smoking Cessation: A Randomized Controlled Trial

Background Tobacco dependence is the leading cause of preventable death and disabilities worldwide and nicotine is the main substance responsible for the addiction to tobacco. A vaccine against nicotine was tested in a 6-month randomized, double blind phase II smoking cessation study in 341 smokers with a subsequent 6-month follow-up period. Methodology/Principal Findings 229 subjects were randomized to receive five intramuscular injections of the nicotine vaccine and 112 to receive placebo at monthly intervals. All subjects received individual behavioral smoking cessation counseling. The vaccine was safe, generally well tolerated and highly immunogenic, inducing a 100% antibody responder rate after the first injection. Point prevalence of abstinence at month 2 showed a statistically significant difference between subjects treated with Nicotine-Qβ (47.2%) and placebo (35.1%) (P = 0.036), but continuous abstinence between months 2 and 6 was not significantly different. However, in subgroup analysis of the per-protocol population, the third of subjects with highest antibody levels showed higher continuous abstinence from month 2 until month 6 (56.6%) than placebo treated participants (31.3%) (OR 2.9; P = 0.004) while medium and low antibody levels did not increase abstinence rates. After 12 month, the difference in continuous abstinence rate between subjects on placebo and those with high antibody response was maintained (difference 20.2%, P = 0.012). Conclusions Whereas Nicotine-Qβ did not significantly increase continuous abstinence rates in the intention-to-treat population, subgroup analyses of the per-protocol population suggest that such a vaccination against nicotine can significantly increase continuous abstinence rates in smokers when sufficiently high antibody levels are achieved. Immunotherapy might open a new avenue to the treatment of nicotine addiction. Trial Registration Swiss Medical Registry 2003DR2327; ClinicalTrials.gov NCT00369616

Effect of Single-Agent Rituximab Given at the Standard Schedule or As Prolonged Treatment in Patients With Mantle Cell Lymphoma: A Study of the Swiss Group for Clinical Cancer Research (SAKK)

PURPOSE To evaluate the effect of single-agent rituximab given at the standard or a prolonged schedule in patients with newly diagnosed, or refractory or relapsed mantle cell lymphoma (MCL). PATIENTS AND METHODS After induction treatment with the standard schedule (375 mg/m2 weekly x 4), patients who were responding or who had stable disease at week 12 from the start of treatment were randomly assigned to no further treatment (arm A) or prolonged rituximab administration (375 mg/m2) every 8 weeks for four times (arm B). RESULTS The trial enrolled 104 patients. After induction, clinical response was 27% with 2% complete responses. Among patients with detectable t(11;14)-positive cells in blood and bone marrow at baseline, four of 20, and one of 14, respectively, became polymerase chain-reaction-negative after induction. Anemia was the only adverse predictor of response in the multivariate analysis. After a median follow-up of 29 months, response rate and duration of response were not significantly different between the two schedules in 61 randomly assigned patients. Median event-free survival (EFS) was 6 months in arm A versus 12 months in arm B; the difference was not significant (P = .1). Prolonged treatment seemed to improve EFS in the subgroup of pretreated patients (5 months in arm A v 11 months in arm B; P = .04). Thirteen percent of patients in arm A and 9% in arm B presented with grade 3 to 4 hematologic toxicity. CONCLUSION Single-agent rituximab is active in MCL, but the addition of four single doses at 8-week intervals does not seem to significantly improve response rate, duration of response, or EFS after treatment with the standard schedule.

Long-Term Follow-Up of Patients With Follicular Lymphoma Receiving Single-Agent Rituximab at Two Different Schedules in Trial SAKK 35/98

PURPOSE We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. PATIENTS AND METHODS Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). RESULTS At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed. CONCLUSION An important proportion of patients experienced long-term remission after prolonged exposure to rituximab, particularly if they had no prior treatment and responded to rituximab induction.

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-Year follow-up of a phase II study

The aim was to investigate the efficacy of neoadjuvant docetaxel–cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m−2 (day 1) plus cisplatin 40 or 50 mg m−2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel–cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Cancer genetics-guided discovery of serum biomarker signatures for diagnosis and prognosis of prostate cancer

A key barrier to the realization of personalized medicine for cancer is the identification of biomarkers. Here we describe a two-stage strategy for the discovery of serum biomarker signatures corresponding to specific cancer-causing mutations and its application to prostate cancer (PCa) in the context of the commonly occurring phosphatase and tensin homolog (PTEN) tumor-suppressor gene inactivation. In the first stage of our approach, we identified 775 N-linked glycoproteins from sera and prostate tissue of wild-type and Pten-null mice. Using label-free quantitative proteomics, we showed that Pten inactivation leads to measurable perturbations in the murine prostate and serum glycoproteome. Following bioinformatic prioritization, in a second stage we applied targeted proteomics to detect and quantify 39 human ortholog candidate biomarkers in the sera of PCa patients and control individuals. The resulting proteomic profiles were analyzed by machine learning to build predictive regression models for tissue PTEN status and diagnosis and grading of PCa. Our approach suggests a general path to rational cancer biomarker discovery and initial validation guided by cancer genetics and based on the integration of experimental mouse models, proteomics-based technologies, and computational modeling.

Randomized study of recombinant human granulocyte colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation for high-risk lymphoid malignancies.

PURPOSE The aim of this prospective randomized trial was to examine the efficacy and safety of filgrastim after high-dose chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS Patients with poor-risk non-Hodgkins lymphoma or relapsed Hodgkins disease were treated in a randomized, open-label trial to study the use of filgrastim as an adjunct to high-dose chemotherapy and ABMT. Of 43 assessable patients, 19 were randomized to receive filgrastim by continuous subcutaneous infusion at a dose of 10 micrograms/kg/d, 10 to filgrastim 20 micrograms/kg/d, and 14 to a parallel control group that received no filgrastim after ABMT. RESULTS For all filgrastim-treated patients analyzed together, the median time to neutrophil recovery > or = 0.5 x 10(9)/L after the day of ABMT was significantly accelerated to 10 days compared with 18 days in control patients (P = .0001). The median number of platelet transfusions was identical in both groups. Clinical parameters, including the median number of days with fever (1 v 4, P = .0418) and neutropenic fever (5 v 13.5, P = .0001) were significantly shorter in the filgrastim than in the control group. The number of days on intravenous antibiotics and duration of hospitalization were also shorter in the treated groups; however, the differences did not reach statistical significance. For patients treated with the two different dose levels of filgrastim, the neutrophil recovery and clinical results were similar. Filgrastim-associated toxicity appeared to be minimal, with five adverse events considered at least possibly related to filgrastim: two in the higher-dose group and three in the lower-dose group. All of these were rated moderate, except one case of severe bone pain that did not preclude continued filgrastim treatment at a lower dose. Survival and relapse-free survival were similar for control and filgrastim-treated patients. CONCLUSION Taken together, the results of this first randomized study support the role of filgrastim given as an adjunct to ABMT in accelerating neutrophil recovery, as well as in reducing treatment-related morbidity and overall duration of the treatment procedure.

Depletion of total cysteine, glutathione, and homocysteine in plasma by ifosfamide/mesna therapy.

The sulfhydryl status of cells, particularly the intracellular concentration of glutathione, is a critical determinant of the response of tumor and normal cells to cytostatic drugs. Recent data indicate that the administration of mercaptoethane sulfonate (mesna), which is often combined with ifosfamide, markedly decreases the circulating concentration of total cysteine and could thereby influence the response of the organism to the cytotoxic effects of chemotherapy. The aim of the present study was to assess the effects of the combination of ifosfamide/mesna on sulfhydryl and disulfide homeostasis in tumor patients. Ifosfamide was infused into 14 patients with advanced sarcoma for 5 days at a dose of 2.4–3.2 g/m2 per day together with mesna. The plasma concentrations of total mesna, cysteine, glutathione, and homocysteine were measured before and on days 1 and 6 of the first course of ifosfamide/mesna therapy and prior to the next course of chemotherapy, and the urinary excretion of cysteine and mesna was monitored daily using a high-performance liquid chromatography (HPLC) method. Ifosfamide/mesna resulted in a marked depletion of circulating total cysteine, i.e., cysteine, cystine, and cysteine mixed disulfides [from 245±36 to 50±14 nmol/ml (mean±95% CI) on day 6], total glutathione (from 6.9±1.1 to 2.5±1.1 nmol/ml), and total homocysteine (from 12.3±2.1 to 1.4±1.1 nmol/ml). The values returned to baseline levels prior to the next course of chemotherapy. The urinary excretion of cysteine increased significantly from 0.28 to 1.82 mmol/day on the 1st day, whereupon it returned toward baseline. An average of 62%±6% of the delivered dose of mesna was recovered in urine. The combination of ifosfamide/mesna results in depletion of circulating total cysteine, glutathione, and homocysteine. This marked derangement of sulfhydryl and disulfide homeostasis could modulate the efficacy and toxicity of ifosfamide/mesna therapy.

Vaccines against nicotine

Medications against any dependence-inducing drug face a dilemma: if they are efficient, they will induce withdrawal symptoms and the patient is likely to stop taking his medication. Anti drug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting rather with the drug in the blood than with a receptor in the brain, the vaccines are in addition free of side effects due to central interaction. For drugs like nicotine interacting with different types of receptors in many organs, this is a further advantage. There are three reasons, that anti drug vaccines have first been developed against nicotine. Firstly, in most parts of the world 20- to 50% of the adult population smoke and any smoking cessation treatment will have an important impact on public health and be commercially a very attractive product. The second reason are the smokers themselves, which would like to quit in significant numbers and which have shown good compliance for any form of treatment. Thirdly, the quantities of cocaine or heroine taken by dependant persons are higher than the quantity of nicotine per cigarette, which makes an anti nicotine vaccine the easier vaccine project. Three anti nicotine vaccines are today in an advanced stage of clinical evaluation. We report here how those vaccines work, on the progress of the trials and future developments to expect. Results show that the efficiency of the vaccines is directly related to the antibody levels of the probates, a fact which will help to optimize further the vaccine effect. We expect the vaccines to appear on the market during a time window between 2009 and 2011.