Epidermal growth factor receptor and anaplastic lymphoma kinase testing and mutation prevalence in patients with advanced non-small cell lung cancer in Switzerland: A comprehensive evaluation of real world practices.

In order to improve outcomes, identification of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes has become crucial in advanced non-small-cell lung cancer (NSCLC). The aim of the present study is to analyse time trends and frequency of testing, factors affecting testing as well as prevalence of mutations in the Swiss population. We analysed EGFR and ALK testing in a cohort of patients with newly diagnosed metastasised non-squamous NSCLC in the catchment area of the cancer registry Eastern Switzerland in the years 2008-2014. We analysed prevalence of mutations and studied clinicopathological characteristics and survival of tested and non-tested patients and of patients with and without mutations. Among 718 patients identified, 11% (51/447) harboured an EGFR mutation in the exons 18, 19 or 21 and further 12% (31/265) showed a positive test result for ALK rearrangements. In non-smokers the proportions of mutations were 31% and 23% respectively. Testing rates increased over time and reached 79% in 2014. We observed significantly lower testing rates and poorer survival in elderly, patients with limited life expectancy and patients treated at hospitals not involved in clinical research. Outcomes can be further improved in a considerable proportion of patients with advanced non-squamous NSCLC.

The Range of Neurological Complications in Chikungunya Fever.

BACKGROUND: Chikungunya fever is a globally spreading mosquito-borne disease that shows an unexpected neurovirulence. Even though the neurological complications have been a major cause of intensive care unit admission and death, to date, there is no systematic analysis of their spectrum available. OBJECTIVE: To review evidence of neurological manifestations in Chikungunya fever and map their epidemiology, clinical spectrum, pathomechanisms, diagnostics, therapies and outcomes. METHODS: Case report and systematic review of the literature followed established guidelines. All cases found were assessed using a 5-step clinical diagnostic algorithm assigning categories A-C, category A representing the highest level of quality. Only A and B cases were considered for further analysis. After general analysis, cases were clustered according to geospatial criteria for subgroup analysis. RESULTS: Thirty-six of 1196 studies were included, yielding 130 cases. Nine were ranked as category A (diagnosis of Neuro-Chikungunya probable), 55 as B (plausible), and 51 as C (disputable). In 15 cases, alternative diagnoses were more likely. Patient age distribution was bimodal with a mean of 49 years and a second peak in infants. Fifty percent of the cases occurred in patients <45 years with no reported comorbidity. Frequent diagnoses were encephalitis, optic neuropathy, neuroretinitis, and Guillain-Barré syndrome. Neurologic conditions showing characteristics of a direct viral pathomechanism showed a peak in infants and a second one in elder patients, and complications and neurologic sequelae were more frequent in these groups. Autoimmune-mediated conditions appeared mainly in patients over 20 years and tended to show longer latencies and better outcomes. Geospatial subgrouping of case reports from either India or Réunion revealed diverging phenotypic trends (Réunion: 88% direct viral vs. India: 81% autoimmune). CONCLUSIONS: Direct viral forms of Neuro-Chikungunya seem to occur particularly in infants and elderly patients, while autoimmune forms have to be also considered in middle-aged, previously healthy patients, especially after an asymptomatic interval. This knowledge will help to identify future Neuro-Chikungunya cases and to improve outcome especially in autoimmune-mediated conditions. The genetics of Chikungunya virus might play a key role in determining the course of neuropathogenesis. With further research, this could prove diagnostically significant.

Off-label use of anticancer drugs in eastern Switzerland: a population-based prospective cohort study.

PURPOSE: Prevalence data on the off-label use (OLU) of anticancer drugs are limited despite OLU being controversial for medical, pharmaco-economic, and ethical reasons. We therefore quantified and characterized the OLU of anticancer drugs and compared OLU based on the national drug label with international treatment recommendations. METHODS: We prospectively collected data on patients receiving systemic anticancer therapy between October and December 2012 at hospitals affiliated with the Eastern Switzerland Oncology Network. Individual data on patient characteristics, tumor disease, and systemic treatment were collected, and each individual treatment was compared with the national drug label and international treatment guidelines. RESULTS: A total of 985 consecutive patients receiving 1,737 anticancer drug treatments were included in the study. Overall, 32.4 % of all patients received at least one off-label drug, corresponding to 27.2 % of all anticancer drugs administered. Major reasons for OLU were the lack of approval for the specific disease entity (15.7 %) and modified application of the anticancer drug (10 %). OLU that was unsupported by the current European Society for Medical Oncology (ESMO) treatment recommendations was rare (6.6 %) but higher for bevacizumab (29.6 %) due to its use in treating advanced ovarian cancer beyond the second-line setting and advanced breast cancer beyond the first-line setting and for lenalidomide (22.6 %) due to its use in treating Non-Hodgkin lymphoma. CONCLUSIONS: Based on data collected on our patient cohort, OLU of anticancer drugs in a European clinical setting applies to one-third of all cancer patients. ESMO-unsupported use of chemotherapies or molecularly-targeted drugs is rare, opposing concerns that the off-label use of newer anticancer drugs is a substantial clinical problem.

Management of elderly patients with advanced non-small cell lung cancer: a single-center experience.

BACKGROUND: Optimal management of elderly patients (≥70 years) with non-small cell lung cancer (NSCLC) remains debatable. We compared survival and treatment of advanced NSCLC between elderly and younger patients. METHODS: From the cancer registry, we identified 188 patients treated with chemotherapy for stage IV NSCLC. Patient characteristics, survival, toxicity, chemotherapy regimen and response were compared between age groups (patients 50-69 vs. ≥70 years). RESULTS: There were 96 young and 92 elderly patients. The majority were male (70%) and had adenocarcinoma (53%). More elderly had an ECOG performance status >1 (59 vs. 42%, p = 0.04). Median survival was longer for young patients (11.5 vs. 10.8 months, hazard ratio, HR 1.43, p = 0.04). Patients ≥75 years had a significantly worse outcome compared to the young and patients aged 70-74 years (11.5 vs. 12.8 vs. 7.7 months, HR 1.71, p = 0.01). Hospitalization rate did not differ. Elderly had more hematological toxicities (56 vs. 32%, p = 0.01) and less frequently received first-line platinum combinations (96 vs. 69%, p < 0.001). CONCLUSIONS: Elderly patients had a marginally worse survival compared to young patients. Despite the less frequent use of combination chemotherapy, elderly patients experienced toxicity more often. Survival of those ≥75 years was significantly worse, indicating the urgent need of further research particularly in this age group.

Elevated preoperative CEA is associated with worse survival in stage I-III rectal cancer patients.

BACKGROUND: The objective of this investigation was to assess whether preoperative carcinoembryonic antigen (CEA) level is an independent predictor of overall survival in rectal cancer patients. METHODS: All patients (n=504) undergoing a resection for stage I-III rectal cancer at the Kantonsspital St Gallen were included into a database between 1991 and 2008. The impact of preoperative CEA level on overall survival was assessed using risk-adjusted Cox proportional hazard regression models and propensity score methods. RESULTS: In risk-adjusted Cox proportional hazard regression analyses, preoperative CEA level (hazard ratio (HR): 1.98, 95% confidence interval (CI): 1.36-2.90, P<0.001), distance from anal verge (<5 cm: HR: 1.93, 95% CI: 1.11-3.37; P=0.039), older age (HR: 1.07, 95% CI: 1.05-1.09; P<0.001), lower body mass index (HR: 0.94, 95% CI: 0.89-0.98; P=0.006), advanced tumour stage (stage II HR: 1.41, 95% CI: 0.85-2.32; stage III HR: 2.08, 95% CI: 1.31-3.31; P=0.004), R 1 resection (HR: 5.65, 95% CI: 1.59-20.1; P=0.005) and chronic kidney disease (HR: 2.28, 95% CI: 1.03-5.04; P=0.049) were all predictors for poor overall survival. CONCLUSION: This is one of the first investigations based on a large cohort of exclusively rectal cancer patients demonstrating that preoperative CEA level is a strong predictor of decreased overall survival. Preoperative CEA should be used as a prognostic factor in the preoperative assessment of rectal cancer patients.

Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial.

BACKGROUND: This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUC(HD-MTX)) in patients with primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n=30) or HD-MTX and high-dose cytarabine (HD-AraC) (n=25). Individual AUC(HD-MTX) from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling. RESULTS: AUC(HD-MTX), the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUC(HD-MTX) did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUC(HD-MTX) was associated with better event-free survival (EFS) (P=0.01) and overall survival (OAS) (P=0.02). Both the AUC(HD-MTX) and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100 micromol l(-1) h(-1) increase in AUC(HD-MTX). CONCLUSIONS: Individualised dosing of HD-MTX might have the potential to improve clinical outcome in patients with PCNSL, even when administered concurrently with HD-AraC. In the future, this could be carried out by using first-cycle PK modelling with determination of potential dose adaptations for later cycles using Bayesian analysis.

Two-weekly gemcitabine fixed dose rate and oxaliplatin combination chemotherapy for advanced non-small-cell lung cancer.

PURPOSE: Combination chemotherapy with gemcitabine and oxaliplatin (GEMOX) is active in patients with advanced non-small-cell lung cancer (NSCLC). Oxaliplatin has a favourable toxicity profile compared to cisplatin. Gemcitabine's cellular uptake mechanism is saturable and fixed dose rate (FDR) infusion results in higher intracellular concentrations. We evaluated the feasibility, response rate and toxicity of bi-weekly GEMOX. PATIENTS AND METHODS: Eligible patients with inoperable stage IIIB and IV NSCLC were treated with gemcitabine 1200mg/m(2) FDR and oxaliplatin 85mg/m(2), both given on d1 and d15 every 4 weeks for a maximum of six cycles. Tumour response was assessed every 8 weeks using RECIST criteria. RESULTS: Forty eligible patients initiated treatment between December 2002 and December 2004. There were nine partial responses (23%). An additional 23 patients (58%) had stable disease, resulting in a disease stabilization rate of 81%. The time to progression was 7.3 months (95% CI, 6.0-8.2 months). Median survival time was 10.4 months (95% CI, 8.7-13.2 months). The 1 and 2-year survival rates were 42% and 12%, respectively. The time to treatment response was 2.2 months (95% CI, 1.8-3.5 months) with a median response duration of 4 months. The most common grade 3 or higher toxicities were leucopenia (20%), asthenia (15%) and neurotoxicity (10%). There were no treatment-related deaths. Patients with performance status (PS) of 0 had a significantly longer survival than patients with higher PS (12.9 months versus 9.4 months, HR 0.45, P=0.03). CONCLUSION: Bi-weekly GEMOX is active and well tolerated for chemotherapy-naïve patients with advanced NSCLC. This regimen merits consideration for further investigation.

Fear, Pain, Denial, and Spiritual Experiences in Dying Processes.

PURPOSE: Approaching death seems to be associated with physiological/spiritual changes. Trajectories including the physical-psychological-social-spiritual dimension have indicated a terminal drop. Existential suffering or deathbed visions describe complex phenomena. However, interrelationships between different constituent factors (e.g., fear and pain, spiritual experiences and altered consciousness) are largely unknown. We lack deeper understanding of patients' inner processes to which care should respond. In this study, we hypothesized that fear/pain/denial would happen simultaneously and be associated with a transformation of perception from ego-based (pre-transition) to ego-distant perception/consciousness (post-transition) and that spiritual (transcendental) experiences would primarily occur in periods of calmness and post-transition. Parameters for observing transformation of perception (pre-transition, transition itself, and post-transition) were patients' altered awareness of time/space/body and patients' altered social connectedness. METHOD: Two interdisciplinary teams observed 80 dying patients with cancer in palliative units at 2 Swiss cantonal hospitals. We applied participant observation based on semistructured observation protocols, supplemented by the list of analgesic and psychotropic medication. Descriptive statistical analysis and Interpretative Phenomenological Analysis (IPA) were combined. International interdisciplinary experts supported the analysis. RESULTS: Most patients showed at least fear and pain once. Many seemed to have spiritual experiences and to undergo a transformation of perception only partly depending on medication. Line graphs representatively illustrate associations between fear/pain/denial/spiritual experiences and a transformation of perception. No trajectory displayed uninterrupted distress. Many patients seemed to die in peace. Previous near-death or spiritual/mystical experiences may facilitate the dying process. CONCLUSION: Approaching death seems not only characterized by periods of distress but even more by states beyond fear/pain/denial.

Relationships among cell survival, O6-alkylguanine-DNA alkyltransferase activity, and reactivation of methylated adenovirus 5 and herpes simplex virus type 1 in human melanoma cell lines.

O6-Alkylguanine-DNA alkyltransferase (ATase) activity and host cell reactivation (HCR) of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC)-methylated viruses were compared in human melanoma cell lines that were sensitive or resistant to killing by the antitumor DNA-methylating agent MTIC. Enhanced HCR of adenovirus 5 (defined as the Mer+ phenotype) generally showed a semiquantitative correlation with the natural or induced resistance of the host cells to the toxic effects of MTIC and to the level of ATase activity. However, one MTIC-resistant cell line was found (MM170) which had a low level of ATase and intermediate HCR of adenovirus. The HCR of herpes simplex virus type 1 (HSV-1) was enhanced in the Mer+ cells that had natural resistance to MTIC compared with Mer- cells. On the other hand, HCR of HSV-1 in Mer+ cells with induced resistance to MTIC was similar to that in Mer- cells. Neither adenovirus 5 nor HSV-1 infection induced ATase activity in Mer- cells. This indicates that resistance to the toxic effects of methylating agents is not invariably associated with high levels of ATase activity in human melanoma cells. Furthermore, while induction of the Mer+ phenotype from Mer- cells was usually accompanied by the recovery of ATase activity, induced Mer+ cells had less proficient repair than natural Mer+ cells, as judged quantitatively by slightly lower cellular resistance and qualitatively by deficient HCR response for HSV-1. These results suggest that the Mer- and induced Mer+ cells lack an ATase-independent DNA repair mechanism. No differences in MTIC-induced DNA repair synthesis or strand breaks were found between the Mer-, natural Mer+, and induced Mer+ phenotypes. However, UV-induced DNA repair synthesis was higher in the natural Mer+ than in the Mer- or induced Mer+ cells, both of which had increased cellular sensitivity to the antimetabolites methotrexate and hydroxyurea. These differences may be related to the effects observed with MTIC. A wide range of ATase activities was found in human melanoma biopsy material.

Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma.

20 patients with advanced non-small cell lung cancer were treated with ifosfamide and mesna 1.5 g/m2 daily for 5 days; 10 received the drug by mouth and 10 i.v. Both schedules resulted in a reduction in the elimination half-life with an increased total and nonrenal clearance of ifosfamide over the 5-day period. Oral administration resulted in an unacceptably high incidence of encephalopathy(5/10) which was not seen in the i.v. group. In two patients this encephalopathy manifested itself as coma which lasted for 24 to 48 h but was fully reversible and in the other three cases as somnolence occurring for more than 50% of the patients' waking hours. Nadir blood counts and response rates were similar in both arms. The encephalopathy suggests that there are metabolic differences between the i.v. and oral routes and that a metabolite rather than the parent drug is responsible for this syndrome. In addition it was shown that the total and nonrenal clearance of the drug was significantly less when the drug was administered orally. None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creatinine clearance and ifosfamide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot be given orally at the conventionally employed i.v. doses.

Prostate stem cell antigen is a promising candidate for immunotherapy of advanced prostate cancer.

Immunotherapy of prostate cancer (CaP) may be a promising novel treatment option for the management of advanced CaP. However, the lack of suitable tumor antigens remains a major obstacle for the rational design of vaccines. To characterize potential CaP antigens, we determined the mRNA expression of the prostate-specific genes C1, C2, C5, PAGE-1, and prostate stem cell antigen (PSCA) in hormone-refractory CaP, benign prostatic hyperplasia, CaP cell lines, and CaP specimens. Among these gene products, only expression of PSCA appears to be retained in the majority of advanced CaP samples, as shown by reverse transcription-PCR analyses. Peptide fragments of PSCA presented in the context of major histocompatibility molecules could serve as recognition targets for CD8 T cells, provided these lymphocytes were not clonally deleted or peripherally tolerized. Our goal was to determine whether the human T-cell repertoire could recognize PSCA-derived peptide epitopes in the context of a common class I allele, HLA-A0201. Of nine peptides that, according to HLA-A0201 binding motifs, were candidate ligands of A0201 class I molecules, three peptides were able to stabilize HLA-A0201 molecules on the cell surface. One of the latter peptides, encompassing amino acid residues 14-22, was capable of generating a PSCA-specific T-cell response in a human lymphocyte culture from a patient with metastatic CaP. PSCA-specific CTLs recognized peptide-pulsed targets as well as three prostate carcinoma lines in cytotoxicity assays, indicating that this peptide could be endogenously processed. In conclusion, our findings establish PSCA as a potential target for antigen-specific, T cell-based immunotherapy of prostate carcinoma.

Assessment of P-glycoprotein, glutathione-based detoxifying enzymes and O6-alkylguanine-DNA alkyltransferase as potential indicators of constitutive drug resistance in human colorectal tumors.

Drug resistance is a major problem in cancer chemotherapy. Treatment protocols generally include a number of different cytotoxic drugs given in combination. Therefore, drug resistance in the tumor is likely to result from the coexpression of several cellular activities able to prevent cell killing by any of the drugs used. In this study we have measured several potential drug resistance mechanisms consisting of the multidrug resistance gene product P-glycoprotein, glutathione, glutathione-transferase and -peroxidase, and the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase in samples of colon carcinoma and normal adjacent mucosa from 23 untreated patients. All of these, with the exception of P-glycoprotein, showed significant increases in tumor tissue levels when compared with normal tissue from the same patient. The significance was highest for glutathione peroxidase (P less than or equal to 0.0005). Individual patients, however, showed very different patterns, with none, several, or all monitored resistance mechanisms elevated in the tumor. The implications both in the choice of drugs and in the use of resistance modifying agents to improve therapy for the individual patient are discussed.

Erlotinib has comparable clinical efficacy to chemotherapy in pretreated patients with advanced non-small cell lung cancer (NSCLC): A propensity-adjusted, outcomes research-based study.

OBJECTIVES: Controversy exists about the integration of erlotinib in patients with EGFR wildtype, advanced NSCLC. MATERIALS AND METHODS: We included patients with advanced NSCLC receiving at least two lines of palliative systemic treatment between January 2005 and December 2014 and not harbouring targetable driver mutations. Primary study endpoint was overall survival (OS), secondary endpoint progression-free survival (PFS). We used Kaplan-Meier statistics, multivariate Cox regression and Propensity score or Inverse Probability Weights (IPW) matching to compare clinical outcome between patients receiving erlotinib in second or further line and those receiving chemotherapy only. The study had a power of 90% to detect a survival superiority of 30%. RESULTS: From a total of 827 patients, we excluded 171 patients with potentially curative treatment, 189 receiving treatment outside of our institute, 206 receiving no or only one line of systemic treatment, 6 with ALK translocations and 28 with EGFR mutations. From 227 patients in the final efficacy analysis, 125 patients received erlotinib in second (89 patients), third (28) or further-line (8), and 102 patients received chemotherapy only. Women and never smokers were significantly overrepresented in the erlotinib group. Both OS (hazard ratio (HR)=1.14, 95% CI 0.80-1.63, P=0.448) and PFS (HR=1.20, 95% CI 0.95-1.52, P=0.119) were similar in the erlotinib compared to the chemotherapy group using IPW-adjusted Cox regression analysis treating the use of erlotinib as a time-dependent covariate starting from second-line treatment and stratified for ECOG performance status and treatment line. ECOG performance status was the most powerful covariate to select patients for erlotinib treatment. CONCLUSION: The present study suggests erlotinib to have similar clinical efficacy compared to chemotherapy in patients with pretreated advanced NSCLC and no known molecular targetable alterations.

Phase I clinical and pharmacokinetic study of oral etoposide phosphate.

PURPOSE: To determine the bioavailability (F) and the pharmacokinetic profile of both etoposide and its prodrug, etoposide phosphate, after oral and intravenous administration of etoposide phosphate, and to determine the maximum-tolerable dose (MTD) of oral etoposide phosphate administered daily for 5 consecutive days every 3 weeks. In addition, we sought to develop and validate two limited-sampling models (LSMs) to predict the etoposide area under the curve (AUC) 24 hours after administration of oral and intravenous etoposide phosphate. PATIENTS AND METHODS: In the F part of the study, patients were assessed for pharmacokinetic studies after one oral and one intravenous administration of the same dose of etoposide phosphate. Etoposide phosphate and etoposide plasma concentrations were assayed by high-performance liquid chromatography (HPLC). To develop LSMs after oral and intravenous administration, patients were randomized between the training and validation data sets. In the phase I part of the study, which followed the F part, the dose of etoposide phosphate was escalated from 50 mg/m2/d for etoposide equivalents for 5 days to 220 mg/m2/d for 5 days. RESULTS: Forty adult patients with solid tumors or lymphoma entered the study and 35 were assessable for toxicity. The MTDs were defined as 175 mg/m2 and 220 mg/m2 in previously treated and untreated patients, respectively. Neutropenia was dose-limiting, with high interpatient variability. Within 15 minutes after intravenous administration, etoposide phosphate was no longer detectable in plasma, and it was never detectable after oral administration. Plasma concentrations and pharmacokinetic parameters of etoposide following etoposide phosphate were comparable to those reported for etoposide. The relative F (mean +/- SD) of etoposide after oral etoposide phosphate was 76 +/- 27%, with a range of 37% to 144%. CONCLUSION: The clinical and pharmacokinetic results of this study confirm the prodrug hypothesis of etoposide phosphate. Although firm conclusions cannot be drawn, the F of oral etoposide phosphate seems to be comparable to or only slightly better than that of oral etoposide.

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-Hodgkin's lymphoma or relapsed Hodgkin's 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.

Fewer infections, but maintained antitumor activity with lower-dose versus standard-dose cladribine in pretreated low-grade non-Hodgkin's lymphoma.

PURPOSE: To study the efficacy and the safety of cladribine (2-chlorodeoxyadenosine [2-CDA]) administered at two different dosages. PATIENTS AND METHODS: In this two-cohort study, patients with low-grade refractory/relapsing non-Hodgkin's lymphoma (NHL) received 2-CDA at a dose of 0.7 mg/kg per cycle as a continuous intravenous (i.v.) infusion (group 1, n = 44) or at a reduced dose of 0.5 mg/kg per cycle as a subcutaneous (s.c.) bolus injection (group 2, n = 60). Three 2-CDA cycles at > or = 4-week intervals were planned, then treatment could be pursued until six cycles. RESULTS: A total of 300 cycles were administered (group 1, 114 cycles; group 2, 186). Patient characteristics in both groups were comparable. The median dose-intensities were 0.17 mg/kg/wk and 0.13 mg/kg/wk for groups 1 and 2, respectively (P < or = .0001). The overall response rate for all 104 patients was 54% (95% confidence interval [CI], 45% to 66%; 15% complete response [CR] and 39% partial response [PR]). Response was similar in both patient groups (57% in group 1 and 53% in group 2; P = .72), and no association between 2-CDA dose-intensity and response rate was found (P = .35). Median remission duration was 7 and 12 months in groups 1 and 2, respectively (P = .21). Toxicity, in particular opportunistic infections (> or = grade 2, 30% in group 1 v 7% in group 2; P = .003) and myelosuppression (> or = grade 3 neutropenia, 33% v 8% of 2-CDA cycles, P < .0001), were more frequent in group 1. Multiple logistic regression analysis showed that the infection risk (grade > or = 2) was decreased by 81% with 2-CDA dose reduction in group 2 after adjusting for number of pretreatment regimens and time since diagnosis (P = .01). CONCLUSION: When administered as a s.c. bolus injection, 2-CDA at 0.5 mg/kg per cycle is safe and this dose level should not be exceeded in this patient population.

Anti-nicotine vaccination: where are we?

Nicotine is the main substance responsible for dependence on tobacco-containing, products, which have a heavy impact on the public health of developed as well as non-developed countries by being a main etiologic factor for the induction of cardiovascular diseases and tobacco-related cancer. A vaccine against nicotine induces antibodies against the molecule, intercepting the nicotine on its way to its specific receptors. The binding of the antibody to nicotine in turn significantly diminishes the nicotine concentration in the brain shortly after smoking. This approach therefore interrupts the vicious circle between smoking and nicotine-related gratification. The preclinical data of our animal experiments are briefly summarized. At the end of 2003, three companies were in early clinical development of an anti-nicotine vaccine: Xenova (TA-NIC), Nabi (NicVAX) and Cytos (Nicotine-Qbeta). The carrier molecules are recombinant cholera toxin B (TA-NIC), an especially selected carrier protein (Nabi) and a virus-like particle VLP (Cytos). Another carrier is additionally used by Chilka in an advanced preclinical model, which showed superiority to cholera toxin B carrier. Cytos has successfully completed a phase I study with 40 healthy non-smoking volunteers. So far, results of a phase I trial by Cytos have shown no unexpected toxicities and phase II trials have now started in Switzerland (Cytos).

Hypertriglyceridemia as a possible risk factor for prostate cancer.

We retrospectively studied anthropometric and laboratory parameters (including serum triglycerides, cholesterol), as well as comedication in 504 patients diagnosed with prostate cancer between January 1997 and August 2002 at a single referral center, and compared these patients with 565 age-matched patients with benign prostatic hyperplasia. A positive correlation was found between serum triglycerides and prostate cancer (odds ratio: 1.148/mmol/l; 95% confidence interval (CI) 1.003-1.315; P<0.05) after correcting for age, body mass index, diabetes and comedication with statins. Hypertriglyceridemia may increase the risk of prostate cancer, and the prognostic relevancy of serum triglycerides should be studied prospectively.

Spiritual experiences of transcendence in patients with advanced cancer.

PURPOSE: Spirituality encompasses a wide range of meanings between holistic wellbeing and mysticism. We explored advanced cancer patients' spiritual experiences of transcendence. METHODS: A total of 251 patients with advanced cancer were included and observed (participant observation) over 12 months by a psycho-oncologist/music-therapist. She recorded and documented patients' spontaneously expressed spiritual experiences during hospitalisation. Interpretative Phenomenological Analysis was applied. RESULTS: 135 patients communicated a spiritual experience, as expressed by altered body-awareness, less pain, less anxiety, higher acceptance of illness/death, new spiritual identity. Spiritual experiences were communicated by patients across different religious affiliations/attitudes. We identified types of spiritual experiences. CONCLUSION: The occurrence of spiritual experiences seems to be frequent and associated with profound, powerful reactions. Our results indicate that experienced-based spiritual care may complement current needs-based approaches.

Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy.

PURPOSE: This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies. METHODS: We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24 h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. RESULTS: Patients with a low clearance of 5FU were at increased risk of neutropenia (P < 0.05) and hand-foot syndrome (P = 0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P < 0.05) and HFS (P < 0.02), and IVS14+1G>A additionally with diarrhea (P < 0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR = 2.0, P < 0.01) and GEC group (HR = 5.4, P < 0.001) and worse OS in the GEC group (HR = 4.7, P < 0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR = 0.55, P = 0.001) and OS (HR = 0.60, P = 0.002) in the CRC group. CONCLUSIONS: Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.