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Focus groups were conducted in 2005-2006 with 25 urban methadone-maintained outpatients to examine beliefs about the role of spirituality in addiction and its appropriateness in formal treatment. Thematic analyses suggested that spirituality and religious practices suffered in complex ways during active addiction, but went "hand in hand" with recovery. Participants agreed that integration of a voluntary spiritual discussion group into formal treatment would be preferable to currently available alternatives. One limitation was that all participants identified as strongly spiritual. Studies of more diverse samples will help guide the development and evaluation of spiritually based interventions in formal treatment.

Introduction: This exploratory study was designed to assess the availability, price, and point-of-purchase marketing strategies for new smokeless tobacco products in 4 test market areas., Methods: A random sample of 50 gas stations, convenience and food stores, and tobacco shops was selected in each of 4 test market areas. Pairs of observers visited each store, recorded product information, and engaged vendors in conversation about product demand., Results: Snus was available in 64% of the stores, but availability and price differed by brand. Point-of-purchase marketing also varied by brand on a variety of dimensions and all brands appeared to be marketed primarily to smokers. Camel Snus was described by store attendants as having the highest demand and was also the most expensive of the observed products. In light of the number of test market cities and intensity of promotion at retail locations, Camel Snus was the most intensively marketed product., Discussion: The results appear to reflect differences in marketing strategy by American snus manufacturers. These strategies may help to predict future marketing of snus and other tobacco products and may provide a baseline for later assessments of product acceptance.

Purpose: OEO2 is a randomized, controlled trial of preoperative chemotherapy in patients undergoing radical surgery for esophageal cancer. Random assignment was to surgery alone (S) or to two cycles of combination cisplatin and fluorouracil before surgery (CS). Initial results reported in 2002 demonstrated an advantage for both disease-free and overall survival in the CS group. The analysis has now been updated after a median follow-up of 6 years., Patients and Methods: OEO2 recruited 802 patients, 400 on CS and 402 on S. The nature of the first recurrence event and cause of death are detailed. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Survival by extent of resection is presented., Results: There were 655 deaths, 335 for S and 320 for CS. The survival benefit has been maintained with a hazard ratio (HR) of 0.84 (95% CI, 0.72 to 0.98; P = .03) which in absolute terms is a 5-year survival of 23.0% for CS compared with 17.1% for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma. The first disease-free survival event was macroscopic residual disease from incomplete resection (R2) or no resection in 26.4% of the S group versus 14.3% of the CS P < .001. Three-year survival by type of resection was R0 42.4%, R1 was 18.0%, and R2 was 8.6%., Conclusion: Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.

Improving population health requires understanding and changing societal structures and functions, but countervailing forces sometimes undermine those changes, thus reflecting the adaptive complexity inherent in public health systems. The purpose of this paper is to propose systems thinking as a conceptual rubric for the practice of team science in public health, and transdisciplinary, translational research as a catalyst for promoting the functional efficiency of science. The paper lays a foundation for the conceptual understanding of systems thinking and transdisciplinary research, and will provide illustrative examples within and beyond public health. A set of recommendations for a systems-centric approach to translational science will be presented.

Objective: To identify the level of effort state tobacco control programmes and partners have expended on interventions recommended by the community guide and how those efforts have changed over time between 1999 and 2004., Design: Longitudinal study., Setting: United States., Participants: State tobacco control partners, including the state health department, voluntary agencies and tobacco control coalitions., Main Outcome Measure: We used the Strength of Tobacco Control survey responses in 1999, 2002 and 2004 to calculate the mean proportion of state tobacco control partners working on recommended interventions and subsequently analysed changes in effort over time., Results: The proportion of state tobacco control partners working to promote clean indoor air legislation remained at more than 70% in all three years. The proportion working to increase taxes on tobacco rose significantly between 1999 and 2002 (from 54% to 70%), and those working to reduce patient costs for tobacco cessation treatments never exceeded 31% in any year. Use of mass media targeting youths decreased significantly in all years (from 40% to 32% to 26%), and the proportion of state tobacco control partners participating in a quitline has increased steadily and significantly in all years (from 24% to 36% to 41%). The level of effort in each area varied widely between states and over time., Conclusions: State tobacco control partners are implementing evidence based interventions, but more focus is needed on the tobacco cessation and mass media campaign components of comprehensive tobacco control programmes.

Study Objective: To examine whether young, especially low socioeconomic status (SES), females are influenced by tobacco control policies in terms of smoking initiation and transition to more adverse stages of smoking behaviour from adolescence to young adulthood., Design and Setting: Data from 2697 young female respondents to the national longitudinal study of adolescent health wave 1 (1994-1995) and wave 3 (2001-2002)., Measurements: The following factors were used to predict the likelihood of smoking initiation and transition to heavier tobacco use between adolescence and young adulthood among females of low, middle, and high SES groups: state level tobacco control policy scores, developed by the US National Cancer Institute, state cigarette excise tax, smoking rate at school, cigarette availability at home, and number of best friends smoking., Main Results: Stronger state level tobacco policies were associated with lower likelihood of smoking initiation and adverse transition among low SES women, although the effect sizes were small. Adolescents who attended schools with higher student smoking rates; adolescents who had easier access to cigarettes at home; and adolescents who had more friends smoking were all more likely to be adverse transitioners by young adulthood., Conclusions: State level tobacco control policies and individual level factors during adolescence are independently associated with smoking initiation and adverse transition by the onset of young adulthood, especially for low SES females. While states may have very little direct influence on individual level behaviours, through their policies they do have the potential to exert considerable influence on smoking behaviour that persists through adolescence into young adulthood.

Introduction: Smoking restrictions in public places have been shown to reduce cigarette consumption and may reduce smoking prevalence. Evidence is emerging that smoke-free policies in nonpublic places may have a similar effect. The purpose of this study was to determine whether an association exists between household smoking rules and smoking patterns among adolescents (aged 15 to 18 years) and young adults (aged 19 to 24 years) living in parental homes (i.e., the homes of their parents, grandparents, or foster parents)., Methods: Cross-sectional data from the 1998-1999 Tobacco Use Supplement to the Current Population Survey were analyzed for the association between household smoking rules and smoking behaviors among adolescents and young adults. We used a probability sample of noninstitutionalized adolescents (aged 15 to 18 years) and young adults (aged 19 to 24 years) living in the United States and assessed smoking status, attempts to quit, and smoking intensity., Results: After controlling for smoking status of others in the household, the odds of ever having smoked, being a current smoker, and smoking more than five cigarettes per day were significantly smaller in households with strict no-smoking policies than in households where smoking was permitted anywhere. These results were relevant for adolescents and young adults., Conclusion: Household smoking rules are a type of antitobacco socialization that help deter adolescents from smoking. The influence of household smoking rules seems to extend beyond adolescence into the young adult years among people who continue to live at home with their parents, grandparents, or foster parents.

The availability of tobacco products purported to reduce toxin exposure or potentially reduce health risks necessitates the development of methods and identification of biomarkers that can be used to assess these products. These assessments occur on multiple levels and stages, from identifying constituents in the tobacco products and smoke, to human exposure and health effects trials, to postmarketing surveillance. A conference of multidisciplinary experts was convened to present and discuss methods and biomarkers to assess these products and to consider the infrastructure necessary to facilitate the evaluation process. Although no currently available set of measures was thought to be sufficient for determining the relative health risk of potential reduced exposure products, this paper provides a blueprint for future research toward this end.

Purpose: Ifosfamide, carboplatin, etoposide, and vincristine, alone and in combination, are highly active against small-cell lung cancer (SCLC). This trial was designed to investigate whether survival could be improved by a regimen of all four drugs (ICE-V) compared with standard chemotherapy in patients with SCLC and good performance status, and to assess the patients' quality of life (QL)., Patients and Methods: Patients were randomly assigned to receive six cycles of either ICE-V at 4-week intervals without dose reduction or standard chemotherapy administered according to local practice. The recommended standard control regimens were cyclophosphamide, doxorubicin, and etoposide; and cisplatin and etoposide., Results: A total of 402 patients were randomly assigned, and 350 (87%) patients have died. Overall survival was longer in the ICE-V group (hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P = .0049), median survival was 15.6 months in the ICE-V group and 11.6 months in the control group, and 2-year survival rates were 20% and 11%, respectively. There was no evidence that the relative survival benefit for ICE-V was less in extensive-stage than in limited-stage patients. An increased rate of septicemia was reported in the ICE-V group (15% v 7% in the control group), but this did not result in an increase in reported treatment-related deaths (four patients [2%] in both groups). The findings on QL were broadly similar in both groups, with some benefit in favor of ICE-V., Conclusion: Compared with standard chemotherapy, the ICE-V regimen improves overall survival without QL penalties, despite an increased but manageable level of toxicity.

Purpose: The retail outlet is the cigarette companies' major marketing channel to reach present and future customers. Of the $11.2 billion spent by them to market their products in 2001, approximately 85% was spent on retailer and consumer incentives to stimulate sales. This study examines the extent of retailer participation in these incentive programs, and the relationship between participation and the amount and placement of cigarette marketing materials and products, and prices in stores., Methods: Observational assessments of cigarette marketing materials, products, and prices were conducted in 468 stores in 15 U.S. states. Telephone interviews were conducted with store owners or managers of these stores to determine the details of their participation in incentive programs., Results: Cigarette companies engaged 65% of retailers in an incentive program. Nearly 80% of participating retailers reported cigarette company control over placement of marketing materials in their stores. Stores that reported receiving over $3,000 from incentive programs in the past 3 months averaged 19.5 cigarette marketing materials, and stores receiving no money averaged only 8.2 marketing materials. In multivariate analyses, participation in incentive programs offered by Philip Morris and R.J. Reynolds was positively related to the number of cigarette marketing materials for each of these companies' brands in stores and the placement of their cigarettes on the top shelf. The price of Newports was significantly lower in stores that received incentives; no price difference was found for Marlboro., Conclusions: Stores that participate in cigarette company incentive programs feature more prominent placement of cigarettes and advertising, and may have cheaper cigarette prices.

Neutropenic sepsis remains a potentially life-threatening complication of anticancer chemotherapy. However, it is possible to identify patients who are at low risk for serious complications and for whom less-intensive, more-convenient treatment may be appropriate. The aim of this study was to assess the efficacy and safety of oral antibiotics in conjunction with early hospital discharge in comparison with standard in-patient intravenous antibiotics in patients with low-risk neutropenic fever. In all, 126 episodes of low-risk neutropenic fever occurred in 102 patients. Patients were randomised to receive either: an oral regimen of ciprofloxacin (750 mg 12 hourly) plus amoxicillin-clavulanate (675 mg 8 hourly) for a total of 5 days, or a standard intravenous regimen of gentamicin and tazocin (piperacillin/tazobactam) until hospital discharge. Patients randomised to oral antibiotics were eligible for discharge following 24 h of hospitalisation, if clinically stable and symptomatically improved. The efficacy of the two arms was similar: initial treatment was successful without antibiotic modification in 90% of episodes in the intravenous arm and 84.8% of episodes in the oral arm, P=0.55, absolute difference between the groups 5.2%; 95% confidence interval (CI) for the difference -7 to 17.3%. Only one episode in the oral arm was associated with significant clinical deterioration: this occurred within the initial in-patient assessment period. The median in-patient stay was 4 days in the intravenous arm (range 2-8) and 2 days in the oral arm (range 1-16 days), P&<0.0005. The reduction in hospital stay led to significant cost-savings in the oral arm. In conclusion, this study suggests that oral antibiotics in conjunction with early hospital discharge for patients who remain stable after a 24 h period of in-patient monitoring offers a feasible and cost-effective alternative to conventional management of low-risk neutropenic fever.

Objective: To construct a conceptual model of tobacco industry tactics to undermine tobacco control programmes for the purposes of: (1) developing measures to evaluate industry tactics, (2) improving tobacco control planning, and (3) supplementing current or future frameworks used to classify and analyse tobacco industry documents., Design: Web based concept mapping was conducted, including expert brainstorming, sorting, and rating of statements describing industry tactics. Statistical analyses used multidimensional scaling and cluster analysis. Interpretation of the resulting maps was accomplished by an expert panel during a face-to-face meeting., Subjects: 34 experts, selected because of their previous encounters with industry resistance or because of their research into industry tactics, took part in some or all phases of the project., Results: Maps with eight non-overlapping clusters in two dimensional space were developed, with importance ratings of the statements and clusters. Cluster and quadrant labels were agreed upon by the experts., Conclusions: The conceptual maps summarise the tactics used by the industry and their relationships to each other, and suggest a possible hierarchy for measures that can be used in statistical modelling of industry tactics and for review of industry documents. Finally, the maps enable hypothesis of a likely progression of industry reactions as public health programmes become more successful, and therefore more threatening to industry profits.

Background: About 81% of cigarette manufacturers' marketing expenditures in the USA is spent to promote cigarette sales in stores. Relatively little is known about how these expenditures help the manufacturers achieve their marketing goals in stores. A better understanding of how tobacco companies influence the retail environment would help researchers and tobacco control activists to monitor industry presence in stores., Objective: To describe the types of tobacco company incentive programmes offered to retailers, how these programmes impact the store environments, and possible visual indicators of retailer participation in incentive programmes., Study Design: In-depth qualitative interviews with a convenience sample of 29 tobacco retailers were conducted in 2001., Setting: USA., Main Outcome Measures: The types and requirements of retailer incentive programmes provided by tobacco companies, and how participation in a programme alters their stores., Results: The retailers provided insights into how tobacco companies convey promotional allowances and special offers to them and how these incentives shape the retail environment. Retailers noted that tobacco companies exert substantial control over their stores by requiring placement of products in the most visible locations, and of specific amounts and types of advertising in prime locations in the store. Retailers also described how tobacco companies reduce prices by offering them volume based discounts, "buy two, get one free" specials, and "buying down" the price of existing product., Conclusions: Tobacco companies are concentrating their marketing dollars at the point-of-sale to the extent that the store is their primary communication channel with customers. As a result, all shoppers regardless of age or smoking status are exposed to pro-smoking messages. Given the financial resources spent by tobacco companies in stores, this venue warrants closer scrutiny by researchers and tobacco control advocates.

A phase I dose-escalation study was undertaken to determine the maximum tolerated dose of the intravenous combination of topotecan and etoposide in previously untreated patients with small-cell lung cancer. Nineteen patients were treated with 30-min infusions of topotecan (0.5 mg/m(2)/day for cohort 1; 0.75 mg/m(2)/day for cohort 2) followed by 1-hour infusions of a fixed daily dose of etoposide (60 mg/m(2)/day) for 5 consecutive days every 3 weeks. Patient cohort 1 (n = 7) received a total of 41 courses of chemotherapy. Grade 4 neutropenia occurred after 17% of the courses of therapy, and there was 1 episode of dose-limiting toxicity in this patient cohort. In patient cohort 2 (n = 12), a total of 64 courses of chemotherapy were administered. Grade 3 or 4 neutropenia occurred following 41 and 37% of the courses of therapy, respectively. Grade 3 thrombocytopenia occurred following 19% of the courses of therapy, and there were 3 episodes of dose-limiting toxicity in this patient cohort. There were no toxic deaths, and all nonhematologic toxicity (except hair loss) was

One hundred and thirty-five cancer patients admitted with low-risk neutropenic fever received a low-dose schedule of ceftazidime as infusional monotherapy over a total of 180 episodes. Ceftazidime was administered as a 1-g bolus followed by a continuous infusion of 2 g per day. In this patient population the ceftazidime was both practical and well tolerated. Sixty-eight percent of patients responded with clinical improvement and complete resolution of fever within 48 h. Overall, 95% of patients responded, although 18% subsequently required antibiotic modification for persistent fever. Only 5% of episodes were considered failures due to clinical deterioration, and over the study period there was only 1 fatality due to respiratory failure. The median duration of hospitalisation was only 4 days (2-20). In conclusion, monotherapy with low-dose infusional ceftazidime appears safe and highly effective in this low-risk population of neutropenic patients and may reduce antibiotic costs appreciably.

The aim of this study was to define prognostic parameters for survival in patients with malignant germ cell tumours progressing after platinum-based induction chemotherapy with or without surgery. A total of 164 progressing patients (testicular: 83%, extragonadal: 17%) were identified out of 795 patients treated with platinum-based induction chemotherapy for metastatic germ cell malignancy with or without surgery. 'Progressive disease' included patients who had progressed after a previous partial or complete remission as well as patients who failed primary therapy. Salvage chemotherapy consisted of 'conventional' platinum-based chemotherapy. Prognostic factors for survival were assessed by uni- and multivariate analyses. The resulting prognostic model was validated in an independent data set of 66 similar patients. For all 164 patients the median time from start of induction chemotherapy to progression was 10 months (range: 0-99). Thirty-eight (23%) patients relapsed after 2 years. The 5-year survival rate for all progressing patients was 30% (95% confidence interval 23-38%). In the univariate analysis the following factors most importantly predicted a poor prognosis: progression-free interval < 2 years: initial poor prognosis category (MRC criteria), < CR to induction chemotherapy, initial treatment early in the 1980s and treatment given at a 'small' centre. Three prognostic factors remained in the multivariate analysis: progression-free interval, response to induction treatment and the level of serum human chronic gonadotrophin (hCG) and alpha fetoprotein (AFP) at relapse. One hundred and twenty-four patients could be classified on the basis of these characteristics, Those patients with progression-free interval < 2 years, < CR to induction chemotherapy and high markers at relapse (AFP >100 kU l(-1) or hCG >100 IU l(-1)) formed a poor prognosis group of 30 patients, none of whom survived after 3 years. Patients with at most two of these three risk factors formed a good prognosis group of 94 patients (76%) with a 47% (37-56%) 5-year survival. Thirty-eight patients from the good prognosis group with a progression-free interval of >2 years had a 2-year survival of 74% (60-88%) and 5-year survival of 61%. These prognostic groups were validated in the independent data set, in which 5-year survival rates in the good and poor risk groups were 51% and 0% respectively. One-third of patients progressing during or after platinum-based induction chemotherapy for metastatic germ cell malignancy may be cured by repeated 'conventional' platinum-based chemotherapy. Good prognosis parameters are: progression-free interval of > 2 years, CR to induction treatment and normal or low serum markers at relapse (hCG < 100 IU l(-1) and AFP < 100 kU l(-1)). The results of high-dose salvage chemotherapy should be interpreted on the background of these prognostic factors.

Purpose: To examine parental perceptions and behaviors with regard to teen smoking, comparing African-American and white parents, and those who did and did not smoke., Methods: Focus groups consisting of African-American and white parents who smoked provided initial in-depth information. A computer-assisted telephone survey of a biracial sample of 311 parents of children ages 8 to 17 years provided more generalizable information regarding parental beliefs and behaviors., Results: Nearly 50% of households either allowed teen smoking, had no ground rules, or had set restrictive rules but never communicated them to the children. Compared to white parents, African-American parents felt more empowered to affect their children's behaviors and were more likely to actively participate in anti-tobacco socialization within the home (all p values < 0.01). Among the African-American parents, 98% reported 18 years or older to be an appropriate age for teens to make up their own minds about using tobacco, whereas 26% of white parents thought 16 years to be an appropriate age (p < 0.001). Parents who smoked reported more frequent rule-making than those who did not smoke (p = 0.02), but were more likely to believe that childhood tobacco use is inevitable (p = 0.01)., Conclusions: Many parents are not engaged in antitobacco socialization in the home. Differences in the degree of parental participation may contribute to the variance in smoking prevalence between African-American and white children.

Purpose: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy., Patients and Methods: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review., Results: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens., Conclusion: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.

Etoposide is part of first-line chemotherapy for patients with small cell lung cancer (SCLC) and is one of the few cytotoxic drugs available in an oral formulation. There have been 3 major avenues of investigation of the role of oral etoposide in SCLC: the optimal schedule of administration, its potential as single agent therapy, and its incorporation into combination chemotherapy. Current evidence suggests that, in SCLC, the optimal schedule of administration is over 3 to 5 days. Its use as a single agent for palliation cannot be supported, but it has a continued use within combination chemotherapy for most patients. In addition, it is likely to be incorporated into regimens with new agents that may offer significant advantages over current combinations.

Study Objectives: Black smokers have been reported to have higher serum cotinine levels than do white smokers, and have higher rates of most smoking-related diseases, despite smoking fewer cigarettes per day. Another striking racial difference is the preference for mentholated cigarettes among black smokers. The contribution of menthol to variability in biochemical markers of cigarette smoke exposure (end-expiratory carbon monoxide and serum cotinine) was evaluated in a biracial sample., Design: Descriptive cross-sectional., Setting: A university smoking research laboratory., Participants: Sixty-five black and 96 white adult established smokers who were paid for their participation., Measurements: Information was obtained through direct observation, self-report (interview and self-administered questionnaires), measurement of butts collected for a week, and laboratory analyses of the biochemical markers of exposure., Results: Compared with the white smokers, the black smokers had significantly higher cotinine and carbon monoxide levels per cigarette smoked and per millimeter of smoked tobacco rod (both p < 0.001). After adjusting for race, cigarettes per day, and mean amount of each cigarette smoked, menthol was associated with higher cotinine levels (p = 0.03) and carbon monoxide concentrations (p = 0.02)., Conclusions: The use of menthol may be associated with increased health risks of smoking. Menthol use should be considered when biochemical markers of smoke exposure are used as quantitative measures of smoking intensity or as indicators of compliance with smoking reduction programs. In addition, the effect of menthol on total "dose" should be considered in any efforts to regulate the amount of nicotine in cigarettes.

As compared with white smokers, black smokers, although they report using fewer cigarettes per day, are at higher risk for most smoking-related diseases. Among black smokers serum cotinine levels are also higher in proportion to cigarettes per day; this observation has led to suggestions of bias in self-reporting. The purpose of this study was to evaluate and compare the extent of errors in self-reported smoking patterns among black and white established smokers. Ninety-seven white and 66 black smokers participated in structured telephone interviews, filled out two self-administered questionnaires one week apart, and collected all of their cigarette butts for a week. Group differences in the validity of self-reported smoking patterns were assessed by comparison with cigarette butt counts and the measured butt lengths. Both black and white smokers significantly overestimated smoking on our measure of smoking frequency (both P < 0.001); the group difference in bias was not significant (P = 0.13). There was no evidence that underreporting was more common among blacks than among whites (P = 0.67). Test-retest reliability was not significantly different in the two groups (P = 0.09). Both groups performed poorly when asked to categorize their smoking frequency according to the cutpoints of the Fagerström Test for Nicotine Dependence. Black smokers smoked more of each cigarette and smoked longer cigarettes, but they smoked fewer total millimeters of cigarettes per day (all P < 0.001). Contrary to an earlier report, the disproportionately high cotinine levels could not be attributed to reporting error.

Background: A 40-year-old chronic schizophrenic patient whose psychosis and associated violent behaviour resolved on clozapine, required chemotherapy for a testicular teratoma with pulmonary metastases. His treatment was initially delayed due to refusal to consent., Treatment: The patient finally agreed to orchidectomy and cytotoxic therapy, and following agreement by the CPMS, clozapine continued to be dispensed despite neutropenia and 'red alert' status on full blood count., Discussion: This is the only patient to continue clozapine despite 'red alert' status, and as such is an exceptional case, but may open the way for such patients in the future.

The use of cytotoxic chemotherapy (CT) between external beam radiotherapy (EBRT) and intracavitary brachytherapy (BT) in patients with bulky carcinomas of the uterine cervix which regress poorly after initial EBRT has been evaluated in a pilot study. The aim of CT was to limit tumour clonogen repopulation while awaiting further tumour regression in order to improve the BT dose distribution. Between 1989 and 1992, 22 patients with FIGO Stage IIA, IIB and IIIB cervical carcinomas were given two to three cycles of cisplatin-based CT between EBRT and intracavitary BT. Patients were selected for CT if there was bulky residual tumour extending beyond the range of point "A" after completion of EBRT. The median survival of patients with Stage IIA/B and Stage IIIB disease was 24 months and 13 months, respectively. The 5 year actuarial survival rate for patients with Stage IIA/B disease was 42%. There were no long-term survivors among patients with Stage IIIB disease. Survival difference between Stage IIA/B patients and Stage IIIB patients was statistically significant (p < 0.04). 5 year actuarial pelvic control rates were 38% and 0% for Stage IIA/B and Stage IIIB patients, respectively. There were no serious late radiation complications in the entire study group. Bulky carcinomas of the cervix which respond poorly to initial EBRT have a particularly poor prognosis. For Stage IB-IIB patients with persistent bulky disease after EBRT, published reports suggest that a 5 year actuarial survival rate of around 40% can be obtained using higher doses of radiation alone, but the risk of serious late morbidity is considerable. The results of our study suggest that in Stage IIA/B carcinomas of the cervix which remain bulky after initial EBRT, the use of integrated cytotoxic chemotherapy prior to intracavitary BT can give similar 5 year survival rates but with minimal treatment related morbidity.

Purpose: To investigate the effect of organ function on total and free etoposide pharmacokinetics and hematologic toxicity., Patients and Methods: Seventy-two patients who received single-agent intravenous (i.v.) etoposide over 5 or 8 days (total dose, 500 mg/m2) were studied. Pharmacokinetic parameters were derived after analysis of total plasma etoposide by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection, and etoposide protein binding by ultrafiltration of an etoposide-spiked, pretreatment serum sample, followed by HPLC analysis. Free etoposide area under the concentration-time curve (AUC) was derived from the total AUC and protein binding., Results: Patients with renal impairment (serum creatinine level > 130 mumol/L) had a lower plasma etoposide clearance (13.6 v 18.5 mL/min/m2; P = .016), resulting in an increased total-drug and free-drug AUC (total etoposide AUC 615 v 452 micrograms/mL.hr; P = .016; free etoposide AUC 26.0 v 17.6 micrograms/mL.hr; P = .026) and increased hematologic toxicity (nadir neutrophil count 0.3 v 1.9 x 10(9)/L; P = .005). Patients with albumin levels less than 35 g/L had no change in total etoposide kinetics but had an increase in unbound etoposide (5.2% v 4.1%; P = .01), resulting in an increase in free etoposide AUC (27.5 v 16.5 micrograms/mL.hr; P = .003) and more profound toxicity (nadir neutrophil count 0.6 v 1.9 x 10(9)/L; P = .004). In patients with normal albumin and creatinine, increased toxicity in those older than 65 years was associated with a reduced drug clearance, and in those with increased liver enzymes by a trend toward an increase in free etoposide AUC., Conclusion: Increased hematologic toxicity after etoposide in patients with abnormal organ function is mediated by an increase in free etoposide AUC. A reduction in dose is clearly indicated in such patients.

Etoposide is a widely used cytotoxic drug that requires complex formulation for both the i.v. and oral preparation to ensure drug stability. Data on the stability of the i.v. formulation when diluted in infusion fluids are contradictory, and there is little information on the stability of the oral preparation in gastric or intestinal fluids. The stability of both i.v. and oral etoposide was therefore evaluated in the present investigation. The stability of the i.v. preparation was investigated across a range of concentrations in infusion fluids, being determined by regular sampling for high-performance liquid chromatography (HPLC) analysis and by visual inspection. The stability of the oral preparation was studied in both artificial gastric and intestinal fluids, again with regular sampling for HPLC analysis, and the influence of pH, concentration and the addition of ethanol and bile salts on oral stability was determined. The i.v. preparation showed a marked decrease in stability with increasing drug concentration, but stability was additionally reduced in i.v. bags regularly sampled with a syringe and needle as compared with bags that were inspected visually only (minimal stability in sampled bags, 24 h at 0.5 mg/ml and 5 h at 1.0 mg/ml, as compared with 10 days and 18 h at the respective concentrations in unsampled bags). Stability was also greater at room temperature, 20-23 degrees C, as compared with 8-12 degrees C. Loss of stability was indicated by a decrease in etoposide concentration (measured by HPLC) and the appearance of a fine white precipitate, shown to be pure etoposide. Importantly, the appearance of precipitate was as sensitive as a specific HPLC assay in detecting loss of stability and was in many cases apparent when the etoposide concentration was within 5% of the starting concentration. The oral formulation also showed a marked concentration-dependent decrease in stability in artificial intestinal fluid at pH 7.5 (percentage of etoposide in solution after 2 h at 0.5, 1.0, 1.5 and 2.0 mg/ml, 94 +/- 2%, 80 +/- 5%, 68 +/- 13% and 41 +/- 9%, respectively). There was no concentration effect on stability in gastric fluid at pH 3.0, although stability was much greater at pH 3 and pH 5 as compared with pH 1 or in intestinal fluid at pH 7.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Etoposide demonstrates incomplete and variable bioavailability after oral dosing, which may be due to its concentration and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a number of clinical studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concentration-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4 +/- 20.3 micrograms ml-1 h, versus 74.3 +/- 25.9 micrograms ml-1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concentration tmax from 1.1 to 3.5 h (P < 0.01), but again without a significant improvement in drug AUC or bioavailability across the 24-h study period (AUC with etoposide alone 78.3 +/- 19.1 micrograms ml-1 h, versus 88.1 +/- 23.6 micrograms ml-1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being observed after metoclopramide or propantheline administration but a significant delay in tmax being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that etoposide stability was markedly improved at pH 3-5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in laboratory studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clinical setting.

We report on a 49-year-old woman with relapsing ovarian cancer who developed a hypersensitivity reaction (HSR) to carboplatin and, subsequently, to cisplatin. This patient was known to be allergic to Co-Amoxiclav and talc, both giving rise to a transient macular skin rash, but had no other history of atopy. Similar cases, including some of life-threatening severity, have been reported in the literature. These severe reactions may prevent a small population of young patients from receiving effective therapy with cisplatin or its analogues, treatment known to be associated with a significant improvement in survival in germ-cell tumours, ovarian cancer and osteogenic sarcoma.

The aim of this Phase II study was to test the feasibility of intensifying standard chemotherapy in the treatment of small cell lung cancer (SCLC) by reducing the interval between cycles from 3 to 2 weeks by adding recombinant human methionyl granulocyte colony-stimulating factor (G-CSF; filgrastim) to shorten the duration of neutropenia following each cycle. Thirty-two patients with SCLC were prescribed six cycles of 2-weekly doxorubicin 50 mg/m2 and cyclophosphamide 1 g/m2 on day 1, and etoposide 120 mg/m2 i.v. on days 1, 2 and 3 (ACE), plus filgrastim in a fixed dose of 300 micrograms s.c. on days 4-14 of each cycle. Three patients died during the treatment period and a further nine had chemotherapy terminated before the sixth cycle, all nine because of toxicity. All 32 patients have been followed up for at least 21 months; 14 (44%) were alive at 12 months and the median survival period was 356 days. Of the 127 intervals between cycles of chemotherapy, 74 (58%) were of the prescribed 14 days, 18 (14%) of 15-20 days, 25 (20%) of 21 days, and 10 (8%) were longer. The results were best during the first four cycles, during which 71% of the 83 intervals were of 14 days and a further 10% were less than 21 days. The main reason for delay was haematological toxicity in 37 of the 53 instances. Symptoms of myelosuppression occurred in 23 patients, but at 14 days after a cycle of chemotherapy, all 127 available neutrophil granulocyte counts were normal. Twenty-one patients received blood transfusion and five platelet transfusion. The only adverse effects attributed to filgastrim were episodes of rash, throat swelling, anorexia and shivering, affecting one patient. We conclude that the policy of adding filgrastim allows the dose intensity of ACE chemotherapy to be increased by reducing the intervals between cycles. The findings reinforce those of a parallel study involving lenograstim.

One hundred and fifty-six patients with multiple myeloma were treated over a period of 12 years at St. Bartholomew's Hospital. The progress of the disease was affected in 96/156 patients (61%). Response was defined as achieving a plateau of M component. A partial or complete response was seen in 68/120 patients treated conventionally (56.5%), and in 28/36 patients treated with high-dose therapy (77.7%). The median survival of the group as a whole was 20 months, with a 2-year survival of just over 40%. In the 36 patients treated with high-dose therapy, median survival was 6 years, and in a small group who have had maintenance Interferon therapy, the median has not yet been reached. In a univariate analysis, age, intensity of therapy, haemoglobin and creatinine levels were significant, but multivariate analysis showed that only age and intensity of therapy were independent predictors for survival. The outlook for relapsed patients who showed progression of disease remains poor, but palliation was best achieved by steroid and Interferon in combination. Patients who achieve complete responses and are maintained on Interferon appear to be doing better both in terms of freedom from symptoms and in survival, and methods to enable an elderly population to tolerate this form of therapy need to be explored.

Purpose: Etoposide is a schedule-dependent drug, as demonstrated by the superiority of 5 consecutive daily infusions over a continuous 24-hour infusion in patients with small-cell lung cancer. A randomized trial has therefore been conducted to compare an extended 8-day regimen with the 5-day schedule., Patients and Methods: Ninety-four patients with small-cell lung cancer (35 limited disease, 59 extensive disease) were randomized to receive single-agent etoposide 500 mg/m2, either as 5 daily 2-hour infusions of 100 mg/m2 or as 8 daily 75-minute infusions of 62.5 mg/m2, both repeated every 3 weeks for six cycles. Single-agent carboplatin was administered at relapse in both arms of the study. Patients were stratified at randomization according to extent of disease and Karnofsky performance status (KPS)., Results: The overall response rate was 81% in the 5-day arm and 87% in the 8-day arm, with median survival durations of 7.1 and 9.4 months, respectively (no significant differences). The time over which plasma etoposide exceeded low plasma concentrations was significantly longer in patients who responded compared with patients who did not respond. This was most significant for time at concentrations greater than 1, 1.5, and 2 micrograms/mL. Hematologic toxicity was significantly worse in the 5-day arm of the study (cycle no. 1 nadir neutrophil count, 0.8 x 10(9)/L v 1.7 x 10(9)/L). Stepwise regression analysis found duration of exposure to plasma etoposide greater than 3 micrograms/mL to be predictive of nadir neutrophil count and duration of exposure to plasma etoposide greater than 2 micrograms/mL to be predictive of nadir WBC count., Conclusion: The 5-day and 8-day regimens had equivalent activity in small-cell lung cancer. A pharmacokinetic association between concentrations of etoposide and response and toxicity was found. Antitumor activity was associated with the maintenance of lower levels of etoposide than found to be associated with hematologic toxicity. This supports the hypothesis that the schedule of etoposide administration may affect efficacy and toxicity, and that prolonged exposure to low concentrations of etoposide may improve the therapeutic ratio for this drug.

Pharmacologic studies in patients with small cell lung cancer treated with differing schedules of intravenous etoposide over 1 to 8 days have suggested that etoposide's antitumor cytotoxicity is related to duration of exposure to low plasma levels of drug. Three phase II studies have been performed in 78 patients with extensive small cell lung cancer examining the efficacy and toxicity of 50-mg doses of oral etoposide given twice daily for 14 days every 3 weeks, once daily for 21 days every 4 weeks, and twice daily for 10 days every 3 weeks. Partial response rates were observed in 76%, 52%, and 70% of patients, respectively. Median response duration appeared similar in all three schedules, but the time to achieve a response appeared longer in the 21-day, once-daily schedule. Bone marrow toxicity was generally mild, but occasionally severe nadir blood counts were observed. These studies demonstrate that prolonged administration of low-dose oral etoposide is very active in small cell lung cancer, and that a twice-daily regimen is preferable in view of the greater rapidity of response and possibly higher response rate. The optimal duration of a twice-daily, 50-mg dosage schedule remains to be determined.

A 27-year-old woman had a large hepatic tumor and a markedly increased serum alpha-fetoprotein (AFP) level. A diagnosis of endodermal sinus tumor was made after a needle biopsy was performed on the liver. Clinical and radiologic examinations did not show an alternative primary site. Treatment with cisplatin, etoposide, and bleomycin was started, but, after three cycles, was changed to cisplatin, vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, and etoposide because the serum AFP level was decreasing too slowly. After additional chemotherapy was given, the patient was well but had an increased AFP level and a large residual mass in the liver. A right hemihepatectomy was performed, but no viable tumor was present. The patient is alive and disease-free 5 years later. Thus, AFP levels may be misleading in the presence of large necrotic tumors. The authors stress the need to make a diagnosis of these rare tumors early because aggressive treatment with combination chemotherapy may result in cure.

Etoposide and teniposide are closely related derivatives of podophyllotoxin, and both have a phase-specific action in the late S and early G2 phases of the cell cycle. Etoposide has attracted more widespread use and study, although no evidence suggests a differing mode of action or spectrum of anticancer activity. The drugs have significant differences in their clinical pharmacology, however. Teniposide exhibits greater protein-binding affinity, has a longer plasma terminal elimination half-life, and has reduced plasma and renal clearances. Little is accurately known about the metabolism of either drug, but the fact that 40% to 60% of administered etoposide is accounted for by excretion or metabolism, whereas the range is only 10% to 25% for teniposide, reflects a further difference between the drugs. Renal dysfunction impairs etoposide excretion, but the effect of hepatic impairment on drug clearance is unclear. A specific oral formulation exists only for etoposide, although the unpalatable intravenous preparations of both drugs can be taken orally. The bioavailability of oral etoposide is about 50% at doses of 200 mg or less and decreases as drug doses increase. There is considerable intrapatient and interpatient variation in etoposide absorption, but the reasons for this are unknown. In vitro, the efficacy of etoposide is highly dependent on the schedule of administration. The superior efficacy without increased toxicity of more prolonged schedules of etoposide administration has been demonstrated recently in patients with small cell lung cancer (SCLC). Although the optimal schedule in any specific tumor is not known, current pharmacodynamic evidence suggests that the efficacy of etoposide, at least in SCLC, is related to the maintenance of prolonged low blood concentrations of drug.

For nearly 30 years clinicians have assumed that diuretic therapy, per se, even in the absence of clinical hypokalemia, can cause false-positive exercise ST-segment responses. The precept has stubbornly persisted in the literature and in the day-to-day interpretation of exercise tests in clinical settings. The assumption probably originated with very early studies of patients on diuretics, in which other causes of false-positive tests were not excluded. This study was undertaken to show that diuretic therapy alone is not sufficient to cause ST depression. Twenty healthy male volunteers, aged 18 to 35, with normal history and physical examinations, echocardiograms, electrocardiograms, serum electrolytes, renal function tests and exercise tests, took 50 mg of hydrochlorothiazide daily for four weeks. Exercise tests, serum electrolytes, and renal function tests were repeated at Weeks 2 and 4. The administration of the diuretic resulted in a statistically significant reduction in serum potassium (from 4.37 +/- 0.37 to 3.96 +/- 0.28, and 3.94 +/- 0.31 mEq/l at 2 and 4 weeks, respectively). There were no abnormal ST-segment shifts on any of the exercise tests. It is concluded that exercise-induced ST-segment shifts in otherwise healthy young male normokalemic subjects who are taking diuretics should not be ascribed to a false-positive response to diuretics.

Because the safety of withholding standard therapy and enrolling patients with stable angina in placebo-controlled trials is not known, we identified all events leading to dropout from trials of 12 antianginal drugs submitted in support of new drug applications to the US Food and Drug Administration. Persons who dropped out of the trials were classified as cause due to adverse cardiovascular events or other causes without knowledge of drug assignment. There were 3161 subjects who entered any randomized, double-blind phase of placebo-controlled protocols; 197 (6.2%) withdrew because of cardiovascular events. There was no difference in risk of adverse events between drug and placebo groups. A prospectively defined subgroup analysis showed that groups who received calcium antagonists were at an increased risk of dropout compared with placebo groups (P = .04), primarily because of a disproportionate number of adverse events in studies of one drug. In conclusion, there were few adverse experiences associated with short-term placebo use. Withholding active treatment does not increase the risk of serious cardiac events.

Evaluation of the physiologic responses to exercise can greatly enhance the information gained by consideration of the electrocardiogram alone. Interpretation of chest pain patterns, blood pressure and heart rate responses, and changing physical examinations is essential for complete interpretation of the exercise stress test.

Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin and are increasingly used in cancer medicine. Teniposide is more highly protein-bound than etoposide, and its uptake and binding to cells is also greater. Etoposide and teniposide are phase-specific cytotoxic drugs acting in the late S and early G2 phases of the cell cycle. They appear to act by causing breaks in DNA via an interaction with DNA topoisomerase II or by the formation of free radicals. Teniposide is more potent as regards the production of DNA damage and cytotoxicity. Most studies show a biexponential decay following intravenous administration of etoposide and teniposide. The terminal elimination half-life of etoposide is less than that of teniposide, and the plasma and renal clearances of etoposide are greater. The peak plasma concentrations of drug and the area under the concentration versus time curve are linearly related to the intravenous dose of both drugs. Considerable interpatient variability of pharmacokinetic parameters exists following intravenous etoposide and teniposide. Various metabolites of etoposide and teniposide have been identified but their detection and quantitation are disputed. Approximately 30 to 70% of a dose of etoposide is accounted for by excretion, whereas the figure appears to be only 5 to 20% for teniposide. The bioavailability of oral etoposide is about 50% but its absorption is not linear with increasing dose within the range in clinical use. There is considerable inter- and intrapatient variability in the pharmacokinetics of oral etoposide. There is no evidence of accumulation of etoposide and teniposide after multiple consecutive doses by the intravenous or oral routes. The exact roles of the liver and kidney in metabolism and excretion of etoposide and teniposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This together with the phase-specific action of etoposide and teniposide and their increasingly widespread use in cancer medicine make the clinical pharmacology of these drugs of great clinical importance.

The correlation of symptoms (SX) with major arrhythmias (ARS) occurring during 24-hour ambulatory monitoring (AM) was investigated in a goup of patients referred because of dizziness or syncope. Ninety-eight consecutive patients, ages 25 to 82, who had adequate diaries of activities and SX, wre included. The ARS considered to be major were ventricular and supraventricular ectopy grade 2, 3, and 4 (Lown classification), sinus arrest and block, atrioventricular block, and sinus bradycardia less than or equal to 40/minute. Although all patients were referred because of dizziness and/or syncope, only 41 (42%) had their symptoms during the recording period. The ARS were recorded in 63 (64%). There was no statistically significant difference in the incidence or in the type of ARS in the group with, and the group without, symptoms (x2 = 1.64). Of the 23 subjects with both major ARS and recorded SX, only two had SX and ARS occurring concomitantly. It is concluded that (1) this is a group with a high prevalence of major ARS, (2) there was correlation between major ARS recorded and SX reported in a very small percent of cases (2%), (3) treating the ARS in the others could not be expected to abolish the SX, and (4) the high cost of monitoring should be considered in this context.

In order to delineate the frequency of arrhythmias and conduction abnormalities in a group of apparently healthy elderly people, 24-hour ambulatory ECG recordings were obtained on subjects recruited from the Veterans Administration Voluntary Service. Their ages ranged from 60--84 (average 69). It is concluded from this preliminary study that complex supraventricular and ventricular arrhythmias occur in an apparently healthy elderly population. These findings must be taken into account in assessing the clinical significance of arrhythmias in an elderly population.

Sixty-five patients with advanced colorectal cancer were randomised to one of two schedules of recombinant alpha-2 interferon (IFN). In the first study, 36 patients received single-agent IFN, either 50 X 10(6) U/m2 intravenously on 5 consecutive days every 4 weeks, or 20 X 10(6) U/m2 subcutaneously three times per week. No tumour responses were seen and toxicity was unacceptable. In the second study, 29 patients received IFN in two similar schedules, but the dose of IFN was reduced to 20 X 10(6) U/m2 per day in the intravenous arm and to 5 X 10(6) U/m2 per day in the subcutaneous arm. In addition these patients were administered intravenous 5-Fluorouracil (5-FU), 250-500 mg/m2 per day on the first 5 days of each 4-weekly cycle. Although the toxicity of this second study was tolerable, only one short-lived partial remission was observed. Alpha-2 interferon, alone or in combination with 5-FU, is ineffective in advanced colorectal cancer.

Arrhythmias and conduction disturbances can greatly influence the diagnostic and prognostic value of the exercise test. In addition, the results of testing can have an impact on the long-term management of patients with arrhythmias.