Trials Of New Therapies Research Articles

EXTRACORPOREAL MEMBRANE OXYGENATION 2001: The Odyssey Continues

Extracorporeal membrane oxygenation was established as a standard of care by demonstrating its ability to save lives in moribund infants. The designs of early studies provided no living cohorts of similarly ill patients by which to measure accurately other (and perhaps to many more important) outcomes of interest: long-term neurodevelopmental outcomes or cost. Prospective cohort studies of neurodevelopmental outcomes post-ECMO demonstrate: (1) because ECMO, as used, saves lives, there will be an increase in the absolute number of handicapped children surviving; (2) there is little evidence that ECMO creates a relative increase in the percent of handicapped children surviving severe respiratory failure. The high direct costs of an ECMO program are measured and well publicized. When such costs are compared with similar therapies in other fields (in such terms as cost per survivor), the cost of ECMO does not seem to be an outlier. Trials of newer therapies, such as iNO, show the capacity to decrease the use of ECMO but have failed to demonstrate either cost-effectiveness or better long-term outcomes. It has not been shown that either society or individual patients have benefited from the decreased need for ECMO.

Clinical trials in cardiovascular medicine.

The practice of cardiology is increasingly driven by evidence-based medicine centering around the results of clinical trials.1 In this inaugural article of Clinical Cardiology: Physician Update , I will focus on the design, analysis, and interpretation of clinical trials in cardiovascular medicine. Armed with the tools described herein, clinicians will be better equipped to understand and synthesize the results of the multitude of clinical trials appearing in the cardiology literature. A major goal of this effort is to shorten the delay between the publication of trial results and the translation of their findings into clinical practice. Trials of new therapies in cardiology typically compare the new treatment to a control. The control group receives the treatment against which the test intervention is being compared. Control and test treatments must be both medically justifiable and compatible with the healthcare needs of study patients. Either treatment must be acceptable to study patients and to the physicians administering them; there must be a reasonable doubt regarding the efficacy of the test treatment; and there should be reason to believe that the benefits will outweigh the risks of treatment. When the control treatment is a placebo, the trial is referred to as a placebo-controlled trial.2 Given the burgeoning supply of new treatments in the cardiovascular armamentarium, more and more trials compare the test therapy to a standard therapy. This is referred to as an active controlled trial.3 4 Randomized controlled trials typically involve the randomization of patients to either the control or test treatment (ie, randomized concurrent control). These trials are the gold standard for evaluating new therapies, and they form the foundation for the highest level of recommendations in practice guideline documents that stress evidence-based medicine5 (Figure 1⇓). Randomization has 3 important influences that explain why it is …

Introduction to Commentaries on the Use of Placebo-Controlled Trials of New Therapies in the Treatment of Type 2 Diabetes

As the editor in chief of Diabetes Care , I was stimulated by the thoughtful letter of David S.H. Bell (1) questioning the value and ethics of placebo-controlled trials in the development of new therapeutic agents for the treatment of hyperglycemia in type 2 diabetes, and I decided to look into this issue more in depth. I asked three people to give their perspectives on this issue. The first response, …

Inpatient costs of major cardiovascular events.

Many trials of new therapies for cardiovascular disease include economic measures to assess the impact of treatment on healthcare costs, however, it is difficult to compare results between trials due to variation in methods for assigning costs. Therefore we developed a standard library of inpatient hospital costs for major cardiovascular events commonly reported in trials for new cardiovascular therapies. Mean and median hospital charges for each event were calculated from Medicare admissions selected by ICD-9-CM codes from the most recent Healthcare Cost and Utilisation Project (HCUP) Nationwide Inpatient Sample (NIS) database available. Charges were converted to costs using the cost-to-charge ratio from the most recent Medicare cost report data and updated to 1999 using a model derived from the Medicare Payment Advisory Commission (MedPAC) forecast to recommend annual updates to Medicare. Total hospital costs for medical events ranged from $US3654 (1999 values) to $US7833; total hospital costs for surgery and procedures ranged from $US7054 to $US46 317. The distribution of hospital costs is skewed with median costs and lengths of stay lower than mean values. Costs for patients who died in the hospital were generally higher than costs for patients who were discharged. The library of costs was calculated using a uniform method based on publicly available and easily accessible data and may be updated from year to year. This method provides standardised estimates of hospital costs that can be used in economic analyses of cardiovascular clinical trials.

Pancreatic cancer.

Optimal therapy for pancreatic adenocarcinoma requires surgical removal with tumor-free margins. Superior outcomes have been reported for high-volume centers incorporating a multidisciplinary approach. Postoperative ("adjuvant") chemotherapy and radiation should be considered in patients with successfully resected primary tumors. Combined modality treatment with chemotherapy and radiation should be considered for locally advanced, unresectable tumors. Gemcitabine can provide symptom relief and a modest improvement in survival for patients with metastatic disease. Strict attention to relief of symptoms such as pain, depression, anorexia/cachexia, and jaundice is essential in all patients with pancreatic cancer. All patients with pancreatic cancer should be encouraged to enter clinical trials of new therapies, given that long-term survival for all stages remains poor.

The potential use of ECG-based prognostic instruments in clinical trials and cost-effectiveness analyses of new therapies in acute cardiac ischemia

The dramatic improvements in outcomes in acute cardiac ischemia because of therapeutic advances has led to “diminishing returns” with increasingly intensive therapies. This article explores the potential of electrocardiograph (ECG)-based prognostic instruments to identify patients likely to benefit from intense regimens, even in the absence of overall average benefit in the population, with 2 clinical examples; 1) Reperfusion therapy in acute myocardial infarction (AMI); and 2) anticoagulation/antiplatelet therapy in unstable angina. Based on previously developed, ECG-based prognostic instruments we explored the distribution of potential benefits in individual patients from increasingly intense therapy in both AMI and unstable angina. Predictions were obtained on community-based patient samples with both AMI and unstable angina to examine the distribution of effectiveness and cost-effectiveness. For both AMI and unstable angina, much of the benefit of intensifying therapy can be obtained by targeting a subgroup of patients that can be identified in multivariable dimensions by clinical and ECG characteristics. Treatment of these patients with more potent agents (such as hirudin or the glycoprotein inhibitors in unstable angina) is likely to be both effective and cost-effective. However, treatment of “low benefit” patients is unlikely to be effective or cost-effective, and some candidates for therapy are more likely to be harmed, than to benefit, by the more intensive regimens. Multivariable stratification can improve clinical and economic outcomes in acute cardiac ischemia, particularly when such models help identify “high benefit” patients early in their clinical course. Additionally, using validated models in the planning and execution of clinical trials of new therapies can improve the power of the trial and help target the therapies to patients most likely to benefit.

Psycho-oncology: where have we been? Where are we going?

This article reviews the development of the subspeciality of psycho-oncology and its contributions to patient care, encouraging more attention to and research into the care of the total patient: the physical, psychological, social and spiritual aspects of care. The result is enhanced quality of life as the patient is studied in the domains of living that are important, extending across the continuum of care from diagnosis to palliative care. In addition, cancer prevention and early detection depends largely on changing attitudes and behaviours that put people at greater risk. This is an important area of research for psycho-oncologists. In the past two decades, research has contributed to our understanding of the psychological responses that accompany a cancer diagnosis. Oncologists better recognise psychological distress and psychiatric disorders such as anxiety, depression and delirium (in hospitalised patients) as frequent comorbid disorders. The development of valid assessment tools for the patients' self-report has been important. Increasingly, outcome measures in controlled trials of new therapies include quality of life, and no longer look at survival alone. The future will continue to bring new challenges to psycho-oncology as patients face new challenges in treatment. A major aim of the next century will be to bring this integrated approach to all patients in an affordable manner.

New chemotherapy options for the treatment of malignant gliomas.

Chemotherapy remains part of the treatment triad that includes surgery and radiation therapy for the management of malignant gliomas. In recent years there has been an increased understanding of the molecular pathways of malignant transformation. Based on this research, new drugs have been evaluated, with specific cellular targets in mind that can be modified or inhibited. Many of these agents are now being tested in phase I and II clinical trials and have shown some promising results. Clearly, not all patients with malignant gliomas respond equally to chemotherapy. Recent evidence suggests that certain molecular markers may predict chemosensitivity in some tumor types, particularly anaplastic oligodendroglioma. This article reviews recent trends in the use of chemotherapy and clinical trials of new therapies for adults with malignant gliomas.

Measurement of health-related quality of life in patients with amyotrophic lateral sclerosis in clinical trials of new therapies.

Recent trials of amyotrophic lateral sclerosis (ALS) therapies have included the Sickness Impact Profile (SIP) to evaluate health-related quality of life (HQL). The purpose of this study was to assess the feasibility, psychometric properties, and interpretation of the Sickness Impact Profile in this setting. The Sickness Impact Profile was administered at baseline, 3, 6, and 9 months during a double-blind, placebo-controlled study of recombinant human insulin-like growth factor I. The frequency of missing Sickness Impact Profile data and administration time were recorded. Patients' scores on the Appel ALS (AALS) Rating Scale were used to identify a stable subgroup for reliability testing and clinically distinct groups for validity testing. Internal consistency reliability and reproducibility were evaluated using Cronbach's alpha and intraclass correlation coefficients, respectively. Analysis of variance (ANOVA) models and t tests were used to assess validity. Effect sizes and the responsiveness index were used to assess responsiveness. At baseline, 259 (97%) patients completed a 30-minute Sickness Impact Profile interview. At subsequent assessments, response rates ranged from 92% to 97% and mean administration times ranged from 25 to 27 minutes. The overall Sickness Impact Profile score demonstrated alpha reliability and 3-month stability coefficients of 0.94 and 0.80, respectively. Baseline overall Sickness Impact Profile scores discriminated between patients in the two AALS-defined groups with a mean of 13.0+/-7.8 and 24.0+/-11.7 in the better and worse AALS groups, respectively. Similarly, mean overall SIP change scores discriminated patients progressing at different rates (slow to moderate = 4.00+/-7.97; rapid = 10.74+/-8.76). With few exceptions, dimension and category scores met similar criteria. Responsiveness statistics for the physical and overall Sickness Impact Profile scores were lower at 3 months and higher at 6 and 9 months. The feasibility, psychometric, and interpretive findings support the validity of the Sickness Impact Profile for assessing outcomes of amyotrophic lateral sclerosis and its treatment. Based on these findings, we recommend including the Sickness Impact Profile in future amyotrophic lateral sclerosis clinical trials.

Improved device for measuring scratching activity in patients with pruritus.

Pruritus is an inherently subjective perception that cannot be quantified. However, in trials of new therapies for pruritus, it is necessary to base assessments of therapeutic efficacy on objective quantitative criteria. This can be achieved by measuring the behavioural consequence of pruritus, scratching activity, and using an index of scratching activity as an efficacy endpoint. A portable device to monitor scratching activity in patients with pruritus is described. The key feature of this device is a piezo-element attached to a fingernail. Vibrations of the fingernail in the act of scratching induce electrical impulses in the piezo-element. Electrical signals from the device are filtered and measured. The measurements, which are not absolute, have nevertheless been shown to provide an objective index of scratching activity that is independent of arm and hand movements. An advantage of the device is that recordings can be made while the patient is in a normal, non-hospital environment, thereby obviating effects of change of environment (e.g. hospitalisation) on the intensity of pruritus. Application of the device enables data on scratching activity during periods of treatment with a test drug and with a placebo to be compared in individual patients.

SURGICAL OPTIONS FOR PATIENTS WITH ADVANCED EMPHYSEMA

Since the early 1900s, a variety of operations have been suggested for emphysema but, with the exception of giant bullectomy, an option in only a small fraction of patients, none has proven effective. Data collected by a number of academic medical centers indicate that LVRS may ameliorate symptoms and improve pulmonary physiology, function, and quality of life in appropriately selected patients with emphysema. Accordingly, LVRS may provide an opportunity to intervene in a rapid, effective, and, possibly, cost-effective manner in a debilitating, chronic disease. That is an extraordinarily attractive proposition for both patients and physicians alike. But a number of questions remain: (1) What is the effect of LVRS compared with maximal medical therapy? (2) What is the duration of any beneficial effect of LVRS? (3) What is the best operative approach? (4) What patient characteristics predict good and bad outcomes? (5) What is the role of pre- and, possibly, postoperative pulmonary rehabilitation? (6) Does LVRS adversely affect the rate of loss of lung function over time, as some have suggested? (7) What is the cost of LVRS compared with standard medical therapy? (8) Can the procedure be performed safely in nontransplant centers? (9) What is the effect on disease-specific quality of life? (10) Does it affect mortality? A prospective, randomized controlled trial involving 18 selected centers will begin in the fall of 1997 under the sponsorship of the Health Care Financing Corporation (the administrators of Medicare) and the National Institutes of Health. We strongly support the creative, collaborative approach that has been taken by those two government agencies to stimulate this study. The need for controlled trials of new therapies cannot be overstated; only with such trials can the questions enumerated above be answered with certainty.

The interstitial cystitis symptom index and problem index

Objectives To develop 2 brief self-administered indices for measuring lower urinary tract symptoms and their impact in patients with interstitial cystitis (IC). Methods An initial set of questions was developed and evaluated in focus groups. The index was revised, shortened, and validated with patients diagnosed in 3 large urologic practices with experience in interstitial cystitis (N = 45). Controls were recruited from a group of healthy volunteers in a gynecology clinic (N = 67). Internal consistency, construct validity, and test-retest reliability were evaluated. Results The IC symptom index and the IC problem index measure urinary and pain symptoms and assesses how problematic symptoms are for patients with interstitial cystitis. Psychometric performance of both instruments is good, with the symptom index demonstrating excellent ability to discriminate characteristics between patients and controls. Conclusion Both indices should be useful in the evaluation and management of patients with IC and should be particularly useful in clinical trials of new therapies for this condition, where reliable, validated, and reproducible outcome measures are critically important.

The Time Course of Acute Hypoxemic Respiratory Failure in Children: Improvement or Deterioration Occurs Rapidly 186

The timely institution of therapy as well as the appropriate design of clinical trials of new therapies depend on an accurate understanding of the time course for evolution of acute hypoxemic respiratory failure. Methods: We analyzed the data collected at 12 hour intervals from 331ECMO-eligible patients in 32 centers (Crit Care Med 24:323-9, 1996) as part of the PCCSG study of Acute Hypoxemic Respiratory Failure (Chest 108:789-97, 1995). Data collection began when patients received at least 50% FiO2 and end expiratory pressure of 6 cm H2O or greater. The time courses to the primary positive outcome of interest (successful tracheal extubation) and primary negative outcomes (death in the PICU or the need for extracorporeal membrane oxygenation) were determined. Measures of oxygenation and ventilation as well as ventilator pressures were compared as predictors of outcomes. Results: Thirty six per cent of patients died and 11% received ECMO. The worst value for oxygenation index (OI)was the strongest predictor of death(P<.0001). An OI of 40 or above predicted a 48% probability of death and was selected as a third negative outcome (24% of patients). 42% of patients reached one or more negative outcome - 50% of these outcomes occurred within 24 hours of enrollment, 75% within 96 hours. Positive outcomes also occurred rapidly after enrollment: 25% of patients were extubated within 72 hours, 50% within 7 days. Conclusions: Acute respiratory failure in children improves or evolves to critical stages rapidly in the majority of children. Therapeutic trials must enroll and randomize patients within a narrow time window. Critical phases in the pathophysiology of lung injury probably occur early in the course when ventilator settings are low.

Why Sepsis Trials Fail

FEW CRITICAL conditions in medicine are as paradoxical as the events occurring during sepsis. The response of the patient's body to an insult such as infection or severe injury may initially be appropriate, but such defenses can lose their usual balance and destroy the patient. If the defense forces could be down-regulated after they have responded to the initial insult but before they begin destroying the body itself, we could prevent sepsis from developing—or at least reduce the associated mortality. Deceptively simple, a viable way to accomplish this downregulation has eluded intense clinical research scrutiny for more than 10 years. All the trials of new therapies for sepsis conducted to date have failed to show efficacy (Table). Conducted under the rigorous conditions of the double-blind, randomized, placebo-controlled trial, their uniformly negative results have provoked great disappointment. I believe the trials have reached the correct conclusion. The problem has not been

Predicting the Duration of Mechanical Ventilation: The Importance of Disease and Patient Characteristics

To analyze the determinants of an individual patient's duration of mechanical ventilation and assess interhospital variations for average durations of ventilation. Prospective, multicenter, inception, cohort study. Forty-two ICUs at 40 US hospitals. A total of 5,915 patients undergoing mechanical ventilation on ICU day 1 selected from the acute physiology and chronic health evaluation (APACHE) III database of 17,440 admissions. None. Utilizing APACHE III data collected on the 5,915 patients, multivariate regression analysis was performed on selected patients and disease characteristics to determine which variables were significantly associated with the duration of mechanical ventilation. An equation predicting duration of ventilation was then developed using the significant predictor variables and its accuracy was evaluated. Variables significantly associated with duration of ventilation included primary reason for ICU admission, day 1 acute physiology score (APS) of APACHE III, age, prior patient location and hospital length of stay, activity limits due to respiratory disease, serum albumin, respiratory rate, and PaO2/FIo2 measurements. Using an equation derived from these variables, predicted durations of ventilation were then calculated and compared with actual observed durations for each of the 42 ICUs. Average duration of ventilation for the 42 ICUs ranged from 2.6 to 7.9 days, but 60% of this variation was accounted for by differences in patient characteristics. For patients admitted to the ICU and ventilated on day 1, total duration of ventilation is primarily determined by admitting diagnosis and degree of physiologic derangement as measured by APS. An equation developed using multivariate regression techniques can accurately predict average duration of ventilation for groups of ICU patients, and we believe this equation will be useful for comparing ventilator practices between ICUs, controlling for patient differences in clinical trials of new therapies or weaning techniques, and as a quality improvement mechanism.

Replacing DXA scanners: Cross-calibration with phantoms may be misleading

The high precision and stable calibration of dual X-ray absorptiometry (DXA) has led to its widespread use in clinical trials of new therapies for osteoporosis. Daily scanning of phantoms provides a check on the continuity of the bone mineral density (BMD) calibration and allows for correction of minor changes. However, because clinical trials may last up to 5 years, it is likely that the scanner will need replacing during the course of a study. We report the upgrade of a Hologic QDR-2000 to a QDR-2000plus. The new scanner was cross-calibrated with the old according to the manufacturer's instructions using the Hologic spine phantom. The accuracy of cross-calibration was checked by in vivo scans of patients in clinical trials and also using the European spine phantom (ESP). Daily QC scans with the Hologic phantom over the 6-week period of the in vivo study showed that the new scanner agreed within 0.2% with the old. However, in vivo scans at 10 sites in the spine, hip, total body, and forearm showed significant mismatch between the two systems with five sites differing by more than 2%. Results for the ESP phantom lay closer to the in vivo spine data than the Hologic phantom. The mismatch revealed was larger than anticipated and emphasized the importance of performing adequate in vivo cross-calibration studies whenever DXA systems are replaced. Typically, scans of 20-30 subjects are required at each scan site to achieve an accuracy of 1%. Such studies require careful planning and make significant demands on space, patient cooperation, scanning time, scientific resources, and, not least, the implementation of the findings.

Target Heart Failure Populations for Newer Therapies

The scarcity of donor hearts has created a large population of heart failure patients who are unlikely to undergo transplantation. Newer surgical therapies that might sustain such patients at home previously have been applied in critical situations in which early outcome is jeopardized by multiorgan failure. The optimal population for studies of extended support would be ambulatory patients with low operative risk but high risk of later unfavorable outcome. Baseline clinical, echocardiographic, and hemodynamic data were collected prospectively between 1988 and 1993 in 500 patients who were discharged on tailored medical therapy after evaluation for transplantation. Specific criteria were examined to identify high risk of death or need for urgent transplantation during the next 2 years. In 265 patients with ejection fraction < or = 25% and initial New York Heart Association class IV symptoms, survival at 2 years was 55% (without urgent transplantation, 45%). Lower cardiac index or higher filling pressures at the time of referral did not confer higher risk, which was predicted by persistence of higher pressures after therapy. Serum sodium below 133 was associated with 34% 2-year survival without urgent transplantation, and ventricular dimension > 80 mm with a rate of 25%. Patients with initial peak oxygen consumption > 10 mL/kg per minute had a 2-year event-free rate of 72% compared with 48% for those with < 10 mL/kg per minute and 32% for those unable to exercise at referral. Demonstration of a 30% decrease in mortality with a controlled trial of new therapy in patients with ejection fraction < or = 25% would require 600 patients with class III symptoms or almost 300 patients with class IV symptoms unless another criterion were added. Ambulatory populations with high predicted event rates can be identified at initial evaluation, when hemodynamic criteria may be less useful than ventricular dimension, serum sodium, and ability to exercise. The use of outcome data from previous eras may lead to overestimation of benefits from newer therapies and underestimation of the sample size required in a prospective trials.

Prostate‐specific antigen and prognosis in patients with metastatic prostate cancer — a multivariable analysis of prostate cancer mortality

To analyse the prognostic significance of pre- and post-treatment serum prostate-specific antigen (PSA) levels, together with a variety of other factors, in a multivariable analysis of survival in men with stage D2 prostate cancer. Cox's proportional hazards model was used to compare survival in 134 men with stage D2 metastatic prostate cancer followed prospectively over a 4 year period, using both univariable and multivariable models. The influence of the following factors on survival was analysed: pre- and post-treatment PSA (both absolute and percentage values), age, treatment, testosterone, pre- and post-treatment alkaline phosphatase (absolute and percentage values), acid phosphatase, haemoglobin, symptom score and performance status and extent of disease on bone scan. Pre-treatment PSA levels did not significantly influence survival. Similarly, a low absolute post-treatment PSA level at 3 months after the start of treatment conferred no survival advantage relative to patients with a high PSA level at this time. A post-treatment percentage PSA of < 10% at 2, 3 and 6 months after commencement of treatment was associated with prolonged survival. Low pre-treatment alkaline phosphatase (less than the upper limit of normal) and high pre-treatment testosterone levels (> or = 10 nmol/L) were similarly associated with prolonged survival. The strong influence of post-treatment percentage PSA on survival in patients with stage D2 prostate cancer suggests that the percentage change in bulk of metastatic deposits is more important in determining survival than the absolute volume of tumour. Pre-treatment alkaline phosphatase seems to be a better indicator of tumour activity than pre-treatment PSA. These findings have important implications for the design and analysis of clinical trials of new therapies in men with stage D2 prostate cancer and for the future selection of alternative treatments for patients with this stage of the disease.

Paclitaxel (Taxol) and Docetaxel (Taxotere): active chemotherapeutic agents in lung cancer

Paclitaxel (Taxol ®), the prototype of a new class of plant-derived antineoplastic compounds, is a natural product isolated from the Pacific yew. Docetaxel (Taxotere ®) is a hemisynthetic product derived from the European yew. These agents share a unique mechanism of cytotoxic action by promoting assembly of microtubules and rendering the microtubules resistant to depolymerization. In vitro studies suggest a possible role for radiation sensitization. In Phase I trials, the dose-limiting toxicity was neutropenia for both agents. Other toxicities include infusion-related hypersensitivity reactions, alopecia, neurotoxicity, mucositis, diarrhoea and myalgias. To prevent infusion-related reactions, routine premedication is recommended. Noncumulative cardiac toxicity has been observed with paclitaxel. Fluid retention and rash have been reported with docetaxel. In Phase II studies of paclitaxel in advanced non-small cell lung cancer, response rates of 21% and 24% were observed. In Phase II studies of docetaxel in similar patients, response rates ranging from 28–38% were reported, including patients previously treated with cisplatin. The most common toxicity in these studies was neutropenia. Combination studies with cisplatin and other agents are in progress. Paclitaxel and docetaxel are among the most active chemotherapeutic agents for non-small cell lung cancer patients. Their testing will dominate trials of new therapies in this disease for years to come.

Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Psychometric assessment of the lung cancer symptom scale

This study continued the development and psychometric testing of the Lung Cancer Symptom Scale (LCSS), a disease- and site-specific instrument primarily measuring the physical and functional dimensions of quality of life for individuals with lung cancer. The instrument contains two scales, one for patients and a counterpart for health professionals as observers. Feasibility, reliability, construct validity, and criterion-related validity were evaluated with 207 patients with non-small cell lung cancer (NSCLC) from six cancer centers. Within an interview with an observer, patients completed part of a battery of instruments by self-report and were interviewed for the remaining measures. Observers also completed measures after the interview. Feasibility, reliability, and validity were well supported for this lung cancer population. Feasibility was demonstrated by patient and staff compliance in completion at all six cancer centers. Internal consistency was good, with coefficient alphas of 0.82 for the patient scale and 0.75 for the observer scale. Construct validity was supported by 1. contrasted groups approach: regression lines (with 95% confidence bands) were obtained between the Karnofsky performance scale (KPS) and each of the two LCSS scales; 2. as a refinement, relationship testing: significant correlations between the LCSS and KPS for each item (except hemoptysis for the patient scale); and 3. multitrait-multimethod approach: good reliability (alphas ranging from 0.75 to 0.93), good convergent validity for the two LCSS scales (r = 0.77), and a good discriminant validity pattern from the Brief Symptom Inventory (BSI). Criterion-related validity with relevant gold standard measures (American Thoracic Society Questionnaire [ATS] and McGill Pain questionnaire, KPS, Profiles of Mood States [POMS], and Sickness Impact Profile [SIP]) was supported with significant correlations (0.40-0.67 for the LCSS patient scale; 0.54-0.65 for the LCSS observer scale). These psychometric properties demonstrate that the LCSS patient and observer scales are feasible, reliable, and valid quality of life measures that are ready for research and clinical use with lung cancer populations.