Linkage of clinical trial and administrative data: a survey of cancer patient preferences.

BACKGROUND: Personal health information, including diagnoses and hospital admissions, is routinely collected in administrative databases. Patients enrolling on clinical trials consent to separate collection and storage of their personal health information. We evaluated patient preferences for linking long-term data from administrative databases with clinical trials. METHODS: Adults with cancer attending outpatient clinics at 3 Ontario hospitals were surveyed about their willingness, when faced with the hypothetical scenario of participating in a clinical trial, to provide potentially identifying information such as initials and date of birth to facilitate long-term research access to normally deidentified publicly collected databases. RESULTS: Of 569 patients surveyed, 335 (59%) were women, 452 (79%) were white, 385 (68%) had a post-secondary education, and 386 (68%) had never participated in a clinical trial. Median age in the group was 59 years. Most participants (93%, cohort 1) would allow long-term access to their information and allow personal information to be used to match clinical trial with administrative data. At the time of clinical trial closure, two thirds of participants (68%, cohort 2) preferred to make additional clinical information available through linkage with administrative databases, and 8 (9%) preferred to have no further information made available to researchers. No significant differences were found in the subset of patients who were part of a clinical trial and those who had never participated (p = 0.65). INTERPRETATION: Almost all patients would allow a clinical trial research team to access their confidential information, providing a more comprehensive assessment of an intervention's long-term risks and benefits.

Estimation of drug cost avoidance and pathology cost avoidance through participation in NCIC Clinical Trials Group phase III clinical trials in Canada.

BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.

Interpreting the Significance of Changes in Health-Related Quality-of-Life Scores.

PURPOSE: To determine the significance to patients of changes in health-related quality-of-life (HLQ) scores assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). PATIENTS AND METHODS: A subjective significance questionnaire (SSQ), which asks patients about perceived changes in physical, emotional, and social functioning and in global quality of life (global QL) and the QLQ-C30 were completed by patients who received chemotherapy for either breast cancer or small-cell lung cancer (SCLC). In the SSQ, patients rated their perception of change since the last time they completed the QLQ-C30 using a 7-category scale that ranged from "much worse" through "no change" to "much better." For each category of change in the SSQ, the corresponding differences were calculated in QLQ-C30 mean scores and effect sizes were determined. RESULTS: For patients who indicated "no change" in the SSQ, the mean change in scores in the corresponding QLQ-C30 domains was not significantly different from 0. For patients who indicated "a little" change either for better or for worse, the mean change in scores was about 5 to 10; for "moderate" change, about 10 to 20; and for "very much" change, greater than 20. Effect sizes increased in concordance with increasing changes in SSQ ratings and QLQ-C30 scores. CONCLUSION: The significance of changes in QLQ-C30 scores can be interpreted in terms of small, moderate, or large changes in quality of life as reported by patients in the SSQ. The magnitude of these changes also can be used to calculate the sample sizes required to detect a specified change in clinical trials.

Future research and methodological approaches.

This supplement has explored the evidence for benefits from the participation of healthcare institutions and their patients in clinical research. The questions have been clarified. There is some encouragement that research active healthcare institutions may deliver improved outcomes compared to less research-active or research-inactive institutions but there is a pressing need for further research. In this chapter we explore the methodological challenges to evaluating the impact of the process of clinical research on hospitals and other healthcare organizations. The postulated mechanisms by which benefits may be accrued are important drivers of the types of research needed and these are emphasized. Study designs are explored including formal randomized trials, the stepped wedge randomized design, approaches to the design and analysis of observational studies particularly to examine whether a temporal or spatial relationship exists between changes in research activity and patients' outcomes. It is acknowledged that in most future studies the data available will be cross-sectional and observational, and such studies are susceptible to many types of bias. The importance of identifying and addressing such biases in multivariate analysis is discussed and examples of successful studies are given.

A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women.

We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.

The economic impact of the transition from branded to generic oncology drugs.

Background: Economic evaluations are an integral component of many clinical trials. Costs used in those analyses are based on the prices of branded drugs when they first enter the market. The effect of genericization on the cost-effectiveness (ce) or cost-utility (cu) of an intervention is unknown because economic analyses are rarely updated using the costs of generic drugs. Methods: We re-examined the ce or cu of regimens previously evaluated in Canadian Cancer Trials Group (cctg) studies that included prospective economic evaluations and where genericization has occurred or is anticipated in Canada. We incorporated the new costs of generic drugs to characterize changes in ce or cu. We also determined acceptable cost levels of generic drugs that would make regimens reimbursable in a publicly funded health care system. Results: The four randomized controlled trials included (representing 1979 patients) were cctg br.10 (early lung cancer, adjuvant vinorelbine-cisplatin vs. observation, n = 172), cctg br.21 (metastatic lung cancer, erlotinib vs. placebo, n = 731), cctg co.17 (metastatic colon cancer, cetuximab vs. best supportive care, n = 557), and cctg ly.12 (relapsed or refractory lymphoma, gemcitabine-dexamethasone-cisplatin vs. cytarabine-dexamethasone-cisplatin, n = 619). Since the initial publication of those trials, the genericization of vinorelbine, erlotinib, cetuximab, and cisplatin has taken place or is expected in Canada. Costs of generics improved the ces and cus of treatment significantly. For example, genericization of erlotinib ($1460.25 per 30 days) resulted in an incremental cost-effectiveness ratio (icer) of $45,746 per life-year gained compared with $94,638 for branded erlotinib. Likewise, genericization of cetuximab ($275.80 per 100 mg) produced an icer of $261,126 per quality-adjusted life-year (qaly) gained compared with $299,613 for branded cetuximab. Decreases in the cost of generic cetuximab to $129.39 and $63.51 would further improve the icer to $150,000 and $100,000 per QALY respectively. Conclusions: Genericization of a costly oncology drug can modify the ce and cu of a regimen significantly. Failure to revisit economic analyses with the costs of generics could be a missed opportunity for funding bodies to optimize value-based allocation of health care resources. At current levels, the costs of generics might not be sufficiently low to sustain publicly funded health care systems.

Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17.

BACKGROUND: MA.17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease-free survival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008]. The trial was unblinded and placebo patients were offered letrozole. PATIENTS AND METHODS: An intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out. RESULTS: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16-95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55-0.83, P = 0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62-1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39-0.97, P = 0.033). CONCLUSIONS: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.

Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans.

AIMS: Type 2 diabetes is frequently associated with infectious complications. Swift activation of leucocytes is important for an adequate immune response. We determined the selective effects of hyperglycaemia and hyperinsulinaemia on lipopolysaccharide (LPS)-induced proinflammatory gene expression and cytokine production in leucocytes and on neutrophil functions. METHODS: Six healthy humans were studied on four occasions for 6 h during: (i) lower insulinaemic euglycaemic clamp, (ii) lower insulinaemic hyperglycaemic clamp, (iii) hyperinsulinaemic euglycaemic clamp, and (iv) hyperinsulinaemic hyperglycaemic clamp. Target levels of plasma glucose were 12.0 mmol/l (hyperglycaemic clamps) or 5.0 mmol/l (euglycaemic clamps). Target plasma insulin levels were 400 pmol/l (hyperinsulinaemic clamps) or 100 pmol/l (lower insulinaemic clamps). RESULTS: Hyperglycaemia reduced LPS-induced mRNA expression of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha (NFKBIA), interleukin-1 alpha (IL1A) and chemokine (C-C motif) ligand 3 (CCL3), whereas during hyperinsulinaemia enhanced mRNA levels occurred in six out of eight measured inflammation-related genes, irrespective of plasma glucose levels. Combined hyperglycaemia and hyperinsulinaemia led to enhanced IL1A, interleukin-1 beta (IL1B) and CCL3 mRNA levels upon LPS stimulation. Neither hyperglycaemia nor hyperinsulinaemia altered cytokine protein production, neutrophil migration, phagocytic capacity or oxidative burst activity. CONCLUSIONS: These results suggest that short-term hyperglycaemia and hyperinsulinaemia influence the expression of several inflammatory genes in an opposite direction, that the acute effects of hyperinsulinaemia on inflammatory mRNA levels may be stronger than those of hyperglycaemia, and that the effects of insulin, in particular, may be relevant in the concurrent presence of hyperglycaemia.

The National Cancer Institute of Canada Clinical Trials Group MAP.3 trial: an international breast cancer prevention trial.

Several large phase III trials have demonstrated that tamoxifen-and more recently, raloxifene-can effectively reduce the incidence of invasive breast cancer by 50%. However, these selective estrogen receptor modulators can also be associated with several rare, but serious, adverse events. Recently, the third-generation aromatase inhibitors (AIS) have demonstrated excellent efficacy in adjuvant breast cancer trials, and they show particular promise in the breast cancer prevention setting. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has developed a randomized phase III study to determine the efficacy of an ai (exemestane) to reduce the incidence of invasive breast cancer in postmenopausal women at an increased risk for developing breast cancer. The NCIC CTG map.3 (ExCel) trial is a double-blind placebo-controlled multicentre, multinational trial. Based on the known preclinical and clinical profile of the ais, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifene.

Communicating quality of life information to cancer patients: a study of six presentation formats.

PURPOSE: To determine which formats for presenting health-related quality of life (HRQL) data are interpreted most accurately and are most preferred by cancer patients. Patients often want a great deal of information about cancer treatments, including information relevant to HRQL. Clinical trials provide methodologically sound HRQL data that may be useful to patients. PATIENTS AND METHODS: In a multicenter study, 198 patients with previously treated cancer participated in a structured interview. Participants judged HRQL information presented in one textual and five graphical formats. Outcome measures included the accuracy of patients' interpretations and ease-of-use and helpfulness ratings for each format. RESULTS: Correct interpretations ranged from 85% to 98% across formats (F = 10.3, P < .0001) with line graphs of mean HRQL scores over time being interpreted correctly most often. Older patients and less-educated patients were less likely to interpret graphs accurately (F = 7.3, P = .008; and F = 10.6, P = .001, respectively), but all groups were most accurate on simple line graphs. Multivariate analysis revealed that format type, participant age and education were independent predictors of accuracy rates. Patients' ratings also varied across formats both for ease of understanding scores (F = 12.1, P < .0001) and for helpfulness scores (F = 13.2, P < .0001), with line graphs being rated highest on both outcomes. CONCLUSION: Patients generally prefer a simple linear representation of group mean HRQL scores, and can accurately interpret data presented in this format more than 98% of the time irrespective of their age group and educational level. The findings have important implications for the communication of clinical trial HRQL results.

Virilization of the external genitalia and severe mental retardation in a girl with an unbalanced translocation 1;18.

A female infant with dysmorphic facial features, psychomotor retardation, and clitoris hypertrophy is described. Molecular cytogenetic analyses revealed a de novo unbalanced translocation, causing partial monosomy 1p36 and partial trisomy 18q22. Monosomy 1p was confirmed by FISH, and trisomy of the distal part of chromosome 18q was demonstrated by microFISH. Gene copy number changes in these chromosomal regions were determined by array-CGH. The absence of a number of facial dysmorphic signs, and the presence of clitoris hypertrophy indicate that the combination of a del(1p36->pter) with a dup(18q22->qter) may lead to a unique phenotypic constellation. The findings at birth and at age 12 years in our patient are compared with genotype-phenotype correlations discussed in the literature.

Assessing the reliability of two toxicity scales: implications for interpreting toxicity data.

BACKGROUND: The toxicity of a given cancer therapy is an important end point in clinical trials examining the potential costs and benefits of that therapy. Treatment-related toxicity is conventionally measured with one of several toxicity criteria grading scales, even though the reliability and validity of these scales have not been established. PURPOSE: We determined the reliability of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) expanded toxicity scale and the World Health Organization (WHO) standard toxicity scale by use of a clinical simulation of actual patients. METHODS: Seven experienced data managers each interviewed 12 simulated patients and scored their respective acute toxic effects. Inter-rater agreement (agreement between multiple raters of the same case) was calculated using the kappa (kappa) statistic across all seven randomly assigned raters for each of 18 toxicity categories (13 NCIC-CTG and five WHO categories). Intra-rater agreement (agreement within the same rater on one case rated on separate occasions) was calculated using kappa over repeated cases (where raters were blinded to the repeated nature of the subjects). Proportions of agreement (estimate of the probability of two randomly selected raters assigning the same toxicity grade to a given case) were also calculated for inter-rater agreement. Since minor lack of agreement might have adversely affected these statistics of agreement, both kappa and proportion of agreement analyses were repeated for the following condensed grading categories: none (0) versus low-grade (1 or 2) versus high-grade (3 or 4) toxicity present. RESULTS: Modest levels of inter-rater reliability were demonstrated in this study with kappa values that ranged from 0.50 to 1.00 in laboratory-based categories and from -0.04 to 0.82 for clinically based categories. Proportions of agreement for clinical categories ranged from 0.52 to 0.98. Condensing the toxicity grades improved statistics of agreement, but substantial lack of agreement remained (kappa range, -0.04-0.82; proportions of agreement range, 0.67-0.98). CONCLUSIONS: Experienced data managers, when interviewing patients, draw varying conclusions regarding toxic effects experienced by such patients. Neither the NCIC-CTG expanded toxicity scale nor the WHO standard toxicity scale demonstrated a clear superiority in reliability, although the breadth of toxic effects recorded differed.

Quality-of-life assessment: patient compliance with questionnaire completion.

BACKGROUND: Previous investigators have found that compliance with quality-of-life data collection on cancer clinical trials is poor. There is general belief that collecting complete quality-of-life data is at present an unachievable goal. PURPOSE: We assessed the completeness of quality-of-life data collection on trials instituted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), since incorporation of quality-of-life outcomes into trials became mandatory for the group. METHODS: Data from three NCIC CTG trials in which quality of life was a study end point were examined to determine the extent to which protocol specifications were met with respect to questionnaire completion. Two of the studies examined adjuvant therapies, and one examined anti-emetics. In two trials, the quality-of-life questionnaire of the European Organization for Research and Treatment of Cancer was used; in the other, the Breast Cancer Chemotherapy Questionnaire. RESULTS: Patient compliance with questionnaire completion was unexpectedly high: More than 95% of the scheduled questionnaires were returned, and more than 99% of the questions were answered. CONCLUSIONS: We attribute this success to a comprehensive set of measures taken to enhance compliance on these studies. Which of these measures was most contributory requires further investigation, as does the issue of whether similar results can be obtained in other circumstances. IMPLICATIONS: It seems that the commonly held belief that quality-of-life data cannot be successfully collected in multicenter cancer trials is incorrect.

Trimetrexate: predictors of severe or life-threatening toxic effects.

In four phase II trials of trimetrexate given iv daily for 5 days, we noted marked variability among patients in the development of severe or life-threatening toxic effects. In an effort to define which of 15 patient characteristics were associated with toxic effects of this degree, we have carried out single-factor and multifactor analyses on toxic effects during the first cycle of therapy in 68 patients. The final logistic regression model identified both low pretreatment serum protein levels and metastatic liver disease as significant correlates of severe toxic effects (P = .02 and P = .0005, respectively). While drug dose was an important element of the best logistic model, its statistical significance was only borderline. Trimetrexate is extensively protein bound and is cleared primarily by hepatic metabolism, so it is not unreasonable to believe that alteration in protein binding of the drug or in metabolic capacity of the liver could produce enhanced toxic effects. Although the validity of these predictors should be confirmed, it seems prudent to recommend lower starting doses of trimetrexate for patients with metastatic liver disease and/or low protein levels and dose escalation if toxic effects allow it.

Reporting the results of randomized trials of empiric antibiotics in febrile neutropenic patients--a critical survey.

Twenty-one randomized trials of empiric antibiotic therapy in febrile neutropenic patients were reviewed and scored by methods suggested by Chalmers. In general, the scores were low, indicating that many of these articles failed to meet currently suggested methodologic standards for publication of results of clinical trials. Particularly striking was the lack of attention paid to statistical issues, such as power, exclusions, and repeated analyses. In addition, there appears to be a need for a better-developed system for assessing response in these circumstances.

Methodologic issues in trials of antiemetics.

Studies of antiemetics require consideration of methodologic issues that may not be of concern in trials of antineoplastics. This paper illustrates how the strength of the results of these studies can be affected by (1) the types of patients studied, (2) the sample size, (3) the trial design, (4) the choice and definition of outcome measures, and (5) the method of analysis.

Does knowledge guide practice? Another look at the management of non-small-cell lung cancer.

PURPOSE: To describe Canadian doctors' beliefs about the appropriate role of chemotherapy and radiotherapy in the management of non-small-cell lung cancer (NSCLC). METHODS: A mail survey of a random sample of Canadian respirologists, thoracic surgeons, radiation oncologists, and medical oncologists was performed. Three cases of NSCLC were described and respondents were asked to estimate the prognosis in each case and to give their treatment recommendations. RESULTS: Responses were obtained from 234 of 330 eligible subjects (74%). Doctors' treatment recommendations varied widely. After a complete resection for stage II NSCLC, 68% recommended no adjuvant treatment, 28% recommended radiotherapy, 1% recommended chemotherapy, and 3% recommended both radiotherapy and chemotherapy. For an asymptomatic patient with stage IIIb NSCLC, 17% recommended no active treatment, 65% recommended radiotherapy alone, 16% recommended radiation and chemotherapy, and 2% recommended chemotherapy alone. For an asymptomatic patient with a stage IV NSCLC, 80% recommended no active treatment and 20% recommended chemotherapy. Doctors' beliefs about the natural history of NSCLC and its response to treatment varied widely. Seventy-five percent of respondents believed that adjuvant radiotherapy did not increase survival in stage II disease, but 25% believed that it did. Thirty percent believed that the addition of chemotherapy to radiotherapy in stage III increased survival, but 70% believed that it did not. Fifty-five percent believed that chemotherapy increased the median survival in stage IV, but 45% believed that it did not. Doctors' beliefs about the efficacy of treatment were strongly associated with their treatment recommendations. CONCLUSION: Personal beliefs, rather than universal knowledge, currently guide the management of NSCLC in Canada.

Cost-effectiveness of cancer chemotherapy: an economic evaluation of a randomized trial in small-cell lung cancer.

An economic evaluation of a randomized trial of cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and vincristine alone or alternating with etoposide (VP-16) and cisplatin in extensive small-cell lung cancer (SCLC) was undertaken. A survival benefit of 1.6 months in favor of alternating chemotherapy was associated with an additional cost of $450 (1984 Canadian dollars) per patient. This translated to a cost of $3,370 per year of life gained. Sensitivity analyses demonstrated that the cost-effectiveness (CEA) of alternating chemotherapy was greatest when treatment was given on an outpatient basis. The results of the evaluation were sensitive to hospitalization rates, but even the most unfavorable analyses revealed the CEA of alternating chemotherapy to be comparable to that of treatments of common nonmalignant diseases. It is concluded that the CEA of alternating chemotherapy for SCLC was favorable when compared with accepted treatments for nonmalignant diseases. The survival benefit seen with alternating chemotherapy was felt to be clinically significant and alternating chemotherapy is recommended as routine therapy for extensive SCLC.

Determinants of postchemotherapy nausea and vomiting in patients with cancer. Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To assess whether prechemotherapy health-related quality-of-life (HQL) variables are associated with postchemotherapy nausea and vomiting (PCNV), and to determine their relationship to patient and treatment variables. PATIENTS AND METHODS: Eight hundred thirty-two chemotherapy-naive patients scheduled to receive antiemetic regimens containing a 5-hydroxytryptamine (5-HT3) antagonist with or without dexamethasone for moderately or highly emetogenic chemotherapy were enrolled. HQL was measured by the self-report European Organization for Research and Treatment of Cancer (EORTC) Care Quality of Life Questionnaire (QLQ-C30) within 7 days before chemotherapy. Prechemotherapy HQL scores, as well as other patient, disease, and treatment variables were compared in the groups of patients who had PCNV and those who did not have PCNV. All variables were assessed initially in a univariate analysis and then together in a multivariate analysis using step-wise logistic regression. The final model generated by the multivariate analyses was used in a risk factor analysis to predict PCNV. RESULTS: Univariate analyses identified 10 HQL variables and five patient and treatment characteristics that were associated with PCNV. In the multivariate analysis, the variables remaining in the final model included low social functioning, prechemotherapy nausea, female gender, highly emetogenic chemotherapy, and the lack of maintenance antiemetics (5-HT3 antagonists with or without dexamethasone) after chemotherapy. A history of low alcohol use was also associated with PCV, whereas increased fatigue and lower performance status were associated with PCN. In the risk factor analysis, the incidence of PCV increased from 20% in those having no risk factors to 76% in those having any four of the six risk factors. CONCLUSION: Several pretreatment HQL, patient, and treatment characteristics are associated with the occurrence of PCNV. Patients about to receive moderately or highly emetogenic chemotherapy should be screened for these factors and additional measures, such as behavior modification and modification of antiemetic therapy, should be considered in attempts to improve the control of PCNV.

Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer.

PURPOSE: The Canadian multicenter trial for advanced non-small-cell lung cancer (NSCLC) reported survival benefit for chemotherapy when best supportive care was compared with vindesine-cisplatin (VP) and the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). We examined received drug delivery to document dose-intensity (DI) and total dose of drugs given to various groups in this patient population. PATIENTS AND METHODS: Plots of cumulatively received chemotherapy against time were used to evaluate drug delivery by regimen, major prognostic factors, and response status. RESULTS: Individual CAP patients show a narrow range of received DI, with the median similar to protocol. Drug delivery analysis exposed a wide range of received DI for both drugs in the more intensive VP regimen, and the median received DI was below protocol. The median received DI for cisplatin was still higher for VP than CAP, but only during the first 8 weeks of protocol treatment (20 v 10 mg/m2/wk); thereafter, the ongoing received cisplatin DI was the same (10 mg/m2/wk). The median received DI for cisplatin in each regimen was not influenced by stage, performance status, prior weight loss, sex, or response status. VP-treated patients received a higher total dose of cisplatin than CAP patients (median, 255 mg/m2 v 112.5 mg/m2; P < .0001). Median cisplatin total dose was similar for patients with a chemotherapy response or stable disease and threefold greater than for patients with progressive disease for both regimens. Although patients with chemotherapy response and stable disease had similar survival outcomes for both CAP and VP, the VP regimen had a higher proportion of patients without progressive disease (P = .004), which resulted in an overall survival advantage (P = .01). CONCLUSION: The major prognostic factors for advanced NSCLC do not exert their influence on outcome by affecting deliverable chemotherapy DI. Regimen and treatment response determined total dose. Because stable disease patients usually outnumber responding patients in advanced NSCLC trials, controlled studies should be performed that allow assessment of the impact of total received dose on outcome according to response status.