The acceptability of smokeless tobacco products depends on nicotine levels.

Understanding the role nicotine plays in initiating and sustaining addiction has been of interest for the scientific community and general population, with the idea that low levels of nicotine will reduce abuse liability associated with smokeless tobacco products. Previously, research has relied on subjective assessments to determine consumer acceptability, but these measures cannot provide a characterization of the physiological responses associated with nicotine use. Consumer acceptability arises from psychological and neurophysiological factors, thus establishing the need to use subjective and objective measurements in conjunction. This study provides a comprehensive characterization of the subjective and objective effects of smokeless tobacco product use with varying levels of nicotine. EEG data were recorded before and after the use of four different smokeless tobacco products and one control product over five separate visits, with participants arriving to each visit after 12 h of tobacco abstinence. These products have distinct consumer acceptability levels and patterns of use characteristics ranging from starter products to those used primarily by established users. Subjective results showed that smokeless tobacco products with higher levels of nicotine were more successful in reducing craving and more reinforcing than those with lower levels. These results were concordant with the activity present in the EEG recordings where products with high nicotine levels produced larger changes in the amplitude of the event-related signal than those with low levels. This study is fundamental in understanding the relationship between subjective and objective smokeless tobacco acceptability measurements, as mediated by the different levels of nicotine in each product.

Effect of cigarette menthol content on mainstream smoke emissions.

The 2009 Family Smoking Prevention and Tobacco Control Act empowered the U.S. Food and Drug Administration to study "the impact of the use of menthol in cigarettes on the public health, including such use among children, African Americans, Hispanics and other racial and ethnic minorities," and develop recommendations. Current scientific evidence comparing human exposures between menthol and nonmenthol smokers shows mixed results. This is largely because of the many differences between commercial menthol and nonmenthol cigarettes other than their menthol content. We conducted an innovative study using two types of test cigarettes: a commercial nonmenthol brand that we mentholated at four different levels, and Camel Crush, a commercial cigarette containing a small capsule in the filter that releases menthol solution into the filter when crushed. Cigarettes were machine-smoked at each of the menthol levels investigated, and the total particulate matter (TPM) was collected on a quartz fiber filter pad and analyzed by gas chromatography/mass spectrometry for menthol, nicotine, tobacco-specific nitrosamines (TSNAs), polycyclic aromatic hydrocarbons (PAHs), cotinine, and quinoline. The mainstream smoke was also monitored continuously in real time on a puff-by-puff basis for seven gas-phase constituents (acetaldehyde, acetonitrile, acrylonitrile, benzene, 1,3-butadiene, isoprene, and 2,5-dimethylfuran), using a proton transfer reaction-mass spectrometer. Average yields (in micrograms/cigarette) for the analytes were determined. Menthol in the TPM samples increased linearly with applied menthol concentration, but the amounts of nicotine along with the target TSNAs, PAHs, cotinine, and quinoline in the cigarettes remained essentially unchanged. Similarly, yields of the targeted volatile organic compounds (VOCs) in whole smoke from the mentholated nonmenthol cigarettes that were measured in real-time were largely unaffected by their menthol levels. In the Camel Crush cigarettes, however, the VOC yields appeared to increase in the presence of menthol, especially in the gas phase. Although we succeeded in characterizing key mainstream smoke constituents in cigarettes that differ only in menthol content, further study is needed to definitively answer whether menthol affects exposure to selected cigarette constituents and thereby influences harm.

Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: a prospective randomised controlled single centre study.

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.

Development of a model of the tobacco industry's interference with tobacco control programmes.

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.

How tobacco companies ensure prime placement of their advertising and products in stores: interviews with retailers about tobacco company incentive programmes.

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 trial of a 5-day schedule of intravenous topotecan and etoposide in previously untreated patients with small-cell lung cancer.

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

Factors associated with tobacco sales to minors: lessons learned from the FDA compliance checks.

CONTEXT: Tobacco products continue to be widely accessible to minors. Between 1997 and 1999, the US Food and Drug Administration (FDA) conducted more than 150,000 tobacco sales age-restriction compliance checks. Data obtained from these checks provide important guidance for curbing illegal sales. OBJECTIVE: To determine which elements of the compliance checks were most highly associated with illegal sales and thereby inform best practices for conducting efficient compliance check programs. DESIGN AND SETTING: Cross-sectional analysis of FDA compliance checks in 110,062 unique establishments in 36 US states and the District of Columbia. MAIN OUTCOME MEASURE: Illegal sales of tobacco to minors at compliance checks; association of illegal sales with variables such as age and sex of the minor. RESULTS: The rate of illegal sales for all first compliance checks in unique stores was 26.6%. Clerk failure to request proof of age was strongly associated with illegal sales (uncorrected sales rate, 10.5% compared with 89.5% sales when proof was not requested; multivariate-adjusted odds ratio [OR], 0.03; 95% confidence interval [CI], 0.03-0.04). Other factors associated with increased illegal sales were employment of older minors to make the purchase attempt (adjusted ORs for 16- and 17-year-old minors compared with 15-year-olds were 1.52 [95% CI, 1.46-1.63] and 2.43 [95% CI, 2.31-2. 59], respectively), attempt to purchase smokeless tobacco (adjusted OR, 2.16 [95% CI, 1.90-2.45] vs cigarette purchase attempts), and performing checks at or after 5 PM (adjusted OR, 1.28 [95% CI, 1. 21-1.35] vs before 5 PM). Female sex of clerk and minor, Saturday checks, type of store (convenience store selling gas, gas station, drugstore, supermarket and general merchandise), and rural store locations also were associated with increased illegal sales. CONCLUSIONS: This analysis found that a request for age verification strongly predicted compliance with the law. The results suggest several ways in which the process of compliance checks might be optimized. JAMA. 2000;284:729-734

Low-dose continuous-infusion ceftazidime monotherapy in low-risk febrile neutropenic patients.

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.

Prognostic factors in patients progressing after cisplatin-based chemotherapy for malignant non-seminomatous germ cell tumours.

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.

Anti-tobacco socialization in homes of African-American and white parents, and smoking and nonsmoking parents.

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.

Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

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.

Current role of oral etoposide in the management of small cell lung cancer.

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.

Response error in self-reported current smoking frequency by black and white established smokers.

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.

Effect of menthol cigarettes on biochemical markers of smoke exposure among black and white smokers.

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.

Continuing clozapine despite neutropenia.

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.

Treatment of carcinomas of the uterine cervix which remain bulky after initial external beam radiotherapy: a pilot study using integrated cytotoxic chemotherapy prior to brachytherapy.

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.

Predicting etoposide toxicity: relationship to organ function and protein binding.

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.