Measuring quality of life in clinical trials: a taxonomy and review.

Measurement of quality of life is becoming increasingly relevant to controlled clinical trials. Two basic types of instrument are available: generic instruments, which include health profiles and utility measurements based on the patient''s preferences in regard to treatment and outcome; and specific instruments, which focus on problems associated with individual diseases, patient groups or areas of function. The two approaches are not mutually exclusive; each has its strengths and weaknesses and may be suitable under different circumstances. We surveyed 75 randomized trials published in three medical journals in 1986 and categorized them according to the importance of quality of life as a measure of outcome and the extent to which quality of life was actually measured. Although a number of the investigators used quality-of-life instruments in a sophisticated manner, in only 10 of 55 trials in which the measurement had been judged to be crucial or important were instruments with established validity and responsiveness used. We conclude that although accurate measurement of quality of life in randomized trials is now feasible it is still not widely done. Using the framework we have outlined, investigators can choose generic or specific instruments according to the purpose and the focus of their trial.     

Paradigm shifts in cancer vaccine therapy

Cancer vaccines constitute a unique therapeutic modality in that they initiate a dynamic process involving the host's immune response. Consequently, (a) repeated doses (vaccinations) over months may be required before patient clinical benefit is observed and (b) there most likely will be a "dynamic balance" between the induction and maintenance of host immune response elements to the vaccinations vs. host/tumor factors that have the potential to diminish those responses. Thus "patient response" in the form of disease stabilization and prolonged survival may be more appropriate to monitor than strictly adhering to "tumor response" in the form of Response Criteria In Solid Tumors (RECIST) criteria. This can be manifested in the form of enhanced patient benefit to subsequent therapies following vaccine therapy. This article will review these phenomena unique to cancer vaccines with emphasis on prostate cancer vaccines as a prototype for vaccine therapy. The unique features of this modality require the consideration of paradigm shifts both in the way cancer vaccine clinical trials are designed and in the way patient benefit is evaluated.     

Quality of life and disease-specific functional status following microvascular reconstruction for advanced (T3 and T4) oropharyngeal cancers

In an effort to evaluate quality-of-life benefits of ablative head and neck cancer surgery and microvascular reconstruction, a longitudinal study was undertaken in which patients with T3 or T4 oropharyngeal cancers without systemic metastases at presentation were administered both general and disease-specific quality-of-life instruments preoperatively and postoperatively. In an initial prospective pilot study, 17 cancer patients were evaluated both preoperatively and postoperatively using the Medical Outcomes Short-Form Health Survey questionnaire (SF-36) and the Performance Status Scale for Head and Neck Cancer Patients. In the second part of the study, the need was recognized for a different disease-specific measure, for more frequent intervals of longitudinal follow-up (rather than be limited by a single data collection point), and for a noncancer control group. Since then, 17 more cancer patients were evaluated in the second part of the study and were compared with patients who had similar reconstructions after suffering head and neck trauma and also with age-matched controls. Instead of the performance status scale, the University of Washington Head and Neck Quality of Life questionnaire was substituted. Interval assessments were done at 1, 3, 6, and 12 months and preoperatively. Whereas many of the general and disease-specific quality of life subclasses initially worsened following extensive surgery and radiation therapy, most returned to the preoperative baseline by 6 months following conclusion of treatment and surpassed pretreatment values at 1 year. It can be concluded, based on this study, that large resections and reconstructions for head and neck cancer patients are justified in terms of outcome; the resection controls the local disease, and the microvascular reconstruction restores quality of life and functional status.     

Measuring outcomes in aesthetic surgery: a comprehensive review of the literature

Outcomes research examines the end results of medical interventions, taking into account patients' experiences, preferences, and values. The purpose of assessing outcomes is to provide evidence on which to base clinical decisions. The assessment of outcomes in aesthetic surgery is especially pertinent because patient satisfaction is the predominant factor in determining success. In cosmetic surgery, various scales have been used to assess outcomes. Unfortunately, none of these methods has achieved widespread use. The adoption of broadly accepted, relevant scales to measure outcomes would be advantageous, because this would allow the comparison of techniques, quantification of positive effects, and identification of patients unlikely to benefit from surgery. The purpose of this study was to critically review the present literature to identify the appropriate instruments to assess outcomes in aesthetic surgery. After a comprehensive review of aesthetic surgery outcome instruments, the authors identified body-image and quality-of-life measures to be of the greatest value in determining aesthetic surgery outcomes. These conclusions were based on a critical evaluation of the feasibility, validity, reliability, and sensitivity to change of these measures. The Multidimensional Body-States Relations Questionnaire (MBSRQ), a psychological assessment of body image, was selected as a potential candidate for further study. Two additional body-image assessment instruments, the Facial Appearance Sorting Test (FAST) and the Breast Chest Ratings Scale (BCRS), may be useful in the assessment of rhinoplasty and breast surgery, respectively. The Derriford Scale (DAS59), an instrument that assesses appearance-related quality of life, was also selected. In addition, the authors recommend the use of a generic, utility-based quality-of-life instrument, such as the Health Utilities Index (HUI) or the EuroQol (EQ-5D).     

Combined mutational analysis of KRAS, NRAS and BRAF genes in Indian patients with colorectal carcinoma

The epidermal growth factor receptor (EGFR) is an excellent candidate for targeted therapy in colorectal cancer. Recent studies have demonstrated that apart from wild-type KRAS, a wild-type BRAF and NRAS genotype is required for response to anti-EGFR therapy. This suggests that NRAS and BRAF genotype criteria should be used together with KRAS genotype to select patients who will likely benefit from anti-EGFR therapy. We investigated the prevalence of mutations in the KRAS, BRAF and NRAS genes and its correlation with demographic characteristics, tumor location and stage in 100 colorectal carcinoma patients from India. The frequency of KRAS, BRAF and NRAS mutations was found to be 23%, 17% and 2.0%, respectively. There was no significant difference in KRAS, NRAS and BRAF mutation with respect to gender, age, tumor location (colon vs rectum) and clinicopathological stage. In addition, we found a novel point variant (T20I) of unknown significance in NRAS exon 1 in addition to a KRAS codon 12 mutation in one of the rectal carcinoma patients. In the present study, combined evaluation of genetic biomarkers (KRAS, NRAS and BRAF) was able to classify 42% of colorectal cancer patients as likely non-responders to anti-EGFR therapy.     

Évaluation de la réponse au traitement des lymphomes : rôle de la TEP-FDG

Positron emission tomography (PET) with FDG has a prominent role in the staging of lymphoma, including Hodgkin's lymphoma and aggressive non Hodgkin's lymphoma. Its value in the assessment of end therapy response is also well established, especially with residual masses on CT scan to differentiate between fibrosis (scar) and active tissue. International experts with the International Harmonization Project of lymphoma have proposed a set of interpretation criteria. Finally, FDG-PET looks very promising in the early response assessment; it has shown to be predictive of chemosensitivity and of therapy response. Interpretation criteria have been improved and proposed. FDG-PET usefulness is being evaluated in national and international research protocols where therapeutic strategies are based on FDG-PET results.     

An estimator for treatment comparisons among survivors in randomized trials

In clinical trials of advanced-stage disease it is often of interest to perform treatment comparisons for endpoints which are defined only for survivors. Examples include time on ventilation in ventilation studies, change in quality of life in health-related quality-of-life studies, and duration of response to therapy in therapeutic trials. Randomized treatment comparisons for these endpoints cannot be performed because the outcomes are only defined in the nonrandomly selected subgroup of survivors. We propose a new evaluation of the survivor average causal effect (SACE) for treatment comparisons of this nature. We provide an estimator of SACE in the presence of no unmeasured confounders, a nontestable assumption, which identifies SACE. We also outline a sensitivity analysis for exploring robustness of conclusions to deviations from this assumption. We apply this method to duration of ventilation in a clinical trial of acute respiratory distress syndrome.     

Évaluation de la réponse au traitement du lymphome avec la TEP F-FDG : existe-t-il un consensus dans l’évaluation de la réponse ?

The concept of risk-adapted therapy in lymphoma is increasingly accepted as a way to achieve higher cure rates with a lower or equal risk of treatment-related morbidity and mortality. Tailoring and individualizing therapy according to the need of the patient is a therapeutic option which could maybe soon become the standard of care. However, it is still not proven that modifying therapy based on interim-PET can improve patient outcomes. Therefore, this issue must be analyzed in appropriately designed clinical trials. ¹⁸F-FDG PET enables evaluation of the early metabolic changes rather than the morphologic changes which occur later during therapy. In lymphoma these early metabolic changes are highly predictive of the final treatment response. PET performed after a few courses of standard chemotherapy is a reliable prognostic tool to identify poor responders to therapy. Interim-PET is a powerful prognostic tool when compared to other well-established clinical parameters in lymphoma. However, the major drawback in the literature appeared to be related to the lack of uniform and reliable criteria for interim-PET scan interpretation. Therefore, in April 2009 an international meeting took place in Deauville (France), where uniform criteria were established for interim-PET scan interpretation. On the other hand, when PET is used to assess treatment response after completion of therapy, the criteria established in the International Harmonization Project in 2007 must be applied. These recommendations were designed to standardize the interpretation of interim PET and PET at the conclusion of therapy of patients with lymphoma both in clinical practice and clinical trials.     

Health outcome measures in atopic dermatitis: a systematic review of trends in disease severity and quality-of-life instruments 1985-2010

Background

A number of disease-severity and quality-of-life (QoL) instruments have emerged in atopic dermatitis (AD) in the last decade.

Objectives

To identify trends in outcomes instruments used in AD clinical trials and to provide a useful summary of the dimensions and validation studies for the most commonly used measures.

Method

All randomized control trials (RCTs) from 1985 to 2010 in the treatment of AD were examined.

Results

Among the 791 RCTs reviewed, we identified 20 disease-severity and 14 QoL instruments. Of these outcomes instruments, few have been validated. SCORAD, EASI, IGA and SASSAD were the most commonly used disease-severity instruments and CDLQI, DFI, DLQI and IDQOL were the most frequently used QoL measures.

Limitations

The small number of RCTs using QoL scales makes identifying trends for QoL instruments difficult.

Conclusion

Overall, there is an increase in the use of disease-severity and QoL instruments in AD clinical trials.     

Labeled release — An experiment in radiorespirometry

The Labeled Release extraterrestrial life detection experiment onboard the Viking spacecraft is described as it will be implemented on the surface of Mars in 1976. This experiment is designed to detect heterotrophic life by supplying a dilute solution of radioactive organic substrates to a sample of Martian soil and monitoring for evolution of radioactive gas. A significantly attenuated response by a heat-sterilized control sample of the same soil would confirm a positive metabolic response. Experimental assumptions as well as criteria for the selection of organic substrates are presented. The Labeled Release nutrient has been widely tested, is versatile in eliciting terrestrial metabolic responses, and is stable to heat sterilization and to the long-term storage required before its use on Mars. A testing program has been conducted with flight-like instruments to acquire science data relevant to the interpretation of the Mars experiment. Factors involved in the delineation of a positive result are presented and the significance of the possible results discussed.     

Adaptive two-stage designs for single-arm phase IIA cancer clinical trials

The main purpose of a phase IIA trial of a new anticancer therapy is to determine whether the therapy has sufficient promise against a specific type of tumor to warrant its further development. The therapy will be rejected for further investigation if the true response rate is less than some uninteresting level and the test of hypothesis is powered at a specific target response rate. Two-stage designs are commonly used for this situation. However, in many situations investigators often express concern about uncertainty in targeting the alternative hypothesis to study power at the planning stage. In this article, motivated by a real example, we propose a strategy for adaptive two-stage designs that will use the information at the first stage of the study to either reject the therapy or continue testing with either an optimistic or a skeptic target response rate, while the type I error rate is controlled. We also introduce new optimal criteria to reduce the expected total sample size.     

Frequency analysis of atrial fibrillation from the surface electrocardiogram

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Neither the natural history of AF nor its response to therapy are sufficiently predictable by clinical and echocardiographic parameters. Atrial fibrillatory frequency (or rate) can reliably be assessed from the surface electrocardiogram (ECG) using digital signal processing (filtering, subtraction of averaged QRST complexes, and power spectral analysis) and shows large inter-individual variability. This measurement correlates well with intraatrial cycle length, a parameter which appears to have primary importance in AF domestication and response to therapy. AF with a low fibrillatory rate is more likely to terminate spontaneously, and responds better to antiarrhythmic drugs or cardioversion while high rate AF is more often persistent and refractory to therapy. In conclusion, frequency analysis of AF seems to be useful for non-invasive assessment of electrical remodeling in AF and may subsequently be helpful for guiding AF therapy.     

Evaluating markers for selecting a patient's treatment

Selecting the best treatment for a patient's disease may be facilitated by evaluating clinical characteristics or biomarker measurements at diagnosis. We consider how to evaluate the potential impact of such measurements on treatment selection algorithms. For example, magnetic resonance neurographic imaging is potentially useful for deciding whether a patient should be treated surgically for Carpal Tunnel Syndrome or should receive less-invasive conservative therapy. We propose a graphical display, the selection impact (SI) curve that shows the population response rate as a function of treatment selection criteria based on the marker. The curve can be useful for choosing a treatment policy that incorporates information on the patient's marker value exceeding a threshold. The SI curve can be estimated using data from a comparative randomized trial conducted in the population as long as treatment assignment in the trial is independent of the predictive marker. Estimating the SI curve is therefore part of a post hoc analysis to determine whether the marker identifies patients that are more likely to benefit from one treatment over another. Nonparametric and parametric estimates of the SI curve are proposed in this article. Asymptotic distribution theory is used to evaluate the relative efficiencies of the estimators. Simulation studies show that inference is straightforward with realistic sample sizes. We illustrate the SI curve and statistical inference for it with data motivated by an ongoing trial of surgery versus conservative therapy for Carpal Tunnel Syndrome.     

Diagnosis and management of binge eating disorder

This paper addresses current issues regarding the diagnosis and management of binge eating disorder (BED). Controversies in diagnosis include the lack of empirically validated criteria, the lack of a universally recognized operational definition of a "binge episode", and the lack of age-appropriate assessment instruments in light of growing reports of BED among children and adolescents. For adults with BED, several pharmacological and behavioral treatments have shown promise in reducing binge frequency and related psychological symptoms of disordered eating (i.e., disinhibition, hunger, depressed mood). Second-generation antidepressants and cognitive behavioral therapy are among the most widely studied treatments. However, no behavioral interventions have demonstrated efficacy with respect to weight loss (which is a critical concern for many BED sufferers who are overweight). Furthermore, randomized controlled trials for BED have been plagued by high drop out and placebo response rates, as well as by insufficient follow-up after active treatment ends to determine long-term outcomes. Therefore, the long-term utility of the various intervention strategies studied thus far remains unclear. More research is needed on innovative medications and behavioral treatments that explore novel modalities to reduce the subjectively reinforcing properties of binge eating. In addition, expanded use of information technologies may be particularly instrumental in the treatment of patients who experience marked shame, denial, and interpersonal deficits, or who face limited access to specialty care. Ultimately, examining BED within the broader context of the current obesity epidemic will be an important area of study.     

The use of expert opinion to assess the risk of emergence or re-emergence of infectious diseases in Canada associated with climate change

Global climate change is predicted to lead to an increase in infectious disease outbreaks. Reliable surveillance for diseases that are most likely to emerge is required, and given limited resources, policy decision makers need rational methods with which to prioritise pathogen threats. Here expert opinion was collected to determine what criteria could be used to prioritise diseases according to the likelihood of emergence in response to climate change and according to their impact. We identified a total of 40 criteria that might be used for this purpose in the Canadian context. The opinion of 64 experts from academic, government and independent backgrounds was collected to determine the importance of the criteria. A weight was calculated for each criterion based on the expert opinion. The five that were considered most influential on disease emergence or impact were: potential economic impact, severity of disease in the general human population, human case fatality rate, the type of climate that the pathogen can tolerate and the current climatic conditions in Canada. There was effective consensus about the influence of some criteria among participants, while for others there was considerable variation. The specific climate criteria that were most likely to influence disease emergence were: an annual increase in temperature, an increase in summer temperature, an increase in summer precipitation and to a lesser extent an increase in winter temperature. These climate variables were considered to be most influential on vector-borne diseases and on food and water-borne diseases. Opinion about the influence of climate on air-borne diseases and diseases spread by direct/indirect contact were more variable. The impact of emerging diseases on the human population was deemed more important than the impact on animal populations.     

Cardiac resynchronisation therapy in daily practice and loss of confidence in predictive techniques to response

Cardiac resynchronisation therapy (CRT) aims to restore left ventricular electrical/mechanical dyssynchrony, which can underlie impaired systolic left ventricular (LV) function and congestive heart failure. Several large prospective studies were able to document clearly that chronic electrical synchronisation does improve the systolic dysfunction and ameliorates symptoms, patient functioning and prognosis. If the conventional criteria are applied, this positive response can be observed in roughly 70% of patients, depending on the definition used for ‘positive response’.     

Antiretroviral drug therapy alters the profile of human immunodeficiency virus type 1-specific T-cell responses and shifts the immunodominant cytotoxic T-lymphocyte response from Gag to Pol

Antiretroviral drug therapy and cytotoxic T lymphocytes (CTL) both exert selective pressures on human immunodeficiency virus type 1, which influence viral evolution. Compared to chronically infected, antiretroviral-untreated patients, most chronically infected, treated patients with detectable viremia lack a cellular immune response against the Gag 77-85(SL9) epitope but show a new immunodominant response against an epitope in protease PR 76-84. Hence, mutations induced by antiretroviral therapy likely alter the profile of epitopes presented to T cells and thus the direction of the response. The consequences of dual pressures from treatment and CTL need to be considered in monitoring of drug therapy.     

Chronic lymphocytic leukaemia: when and how to treat

In the 4th International Workshop on Chronic Lymphocytic Leukaemia (CLL), staging and response criteria were proposed to help physicians make decisions on when and how to treat patients with CLL. The most important factor is prolonging survival. There are several promising new treatment approaches under investigation, and the criteria proposed should facilitate future therapy trials.     

c-erbB-2 in serum of patients receiving fractionated paclitaxel chemotherapy.

Humanized anti-c-erbB-2 antibodies (Herceptin) in a weekly schedule are a new therapeutic option for the treatment of c-erbB-2-positive, advanced breast cancer (ABC). Addition of Herceptin to first-line chemotherapy for c-erbB-2 overexpressing ABC increased anticancer activity in a randomized phase III trial. However, except from standard UICC response criteria, there are hitherto no recommendations as to how to monitor Herceptin therapy. In a therapy optimizing study with weekly dose-intensified paclitaxel monotherapy (schedule: 90 mg/m2 weekly x 6, q9w), we correlated the clinical course of stage IV breast cancer in UICC criteria with the course of the shed c-erbB-2 protein fragment and the CA 27.29 serum level. Serum samples were taken weekly from 35 patients to measure the serum c-erbB-2 and CA 27.29 protein levels over time. Up to now, 10 patients (28.5%) are c-erbB-2 positive (> 15 U/mL), with a median baseline protein expression of 65 U/mL. While the overall response rate in the study is 36%, the response rate among c-erbB-2-positive patients is 62%, indicating a high sensitivity of c-erbB-2 positive patients to dose-intense paclitaxel treatment. In all responders the c-erbB-2 serum level decreased below the detection limit either before the clinical diagnosis of response or by the end of the next cycle. However, the normalization of the c-erbB-2 serum level was not specific for responders as patients with stable or progressive disease presented normalized levels or a > 50% decrease of the baseline level, too. The courses of the c-erbB-2 protein levels correlated closely with the courses of CA 27.29. The decrease in the serum c-erbB-2 oncoprotein level might indicate a regression of c-erbB-2 positive tumor load. This may even happen in progressive disease according to UICC criteria when the c-erbB-2-negative tumor fraction progresses while the c-erbB-2-positive fraction is controlled. Another explanation would be that the mechanisms of c-erbB-2 shedding change under chemotherapy, with less of the c-erbB-2 protein fragment being released to the serum, which would make the c-erbB-2 positive tumor cells a better target for anti-c-erbB-2 antibody treatment.     

Leukemic chromosome clone. I. Risk factor in the acute lymphatic leukemia of children]

As long as the aetiology of acute lymphatic leukaemia of children is not known its therapy is based on clinical experience. Among the values of experience those factors will play a part, the evidence of which during the ALL initial stage will be a risk for successful therapy and survival rate. This results in a choice of more aggressive variants of modern therapy schemes. In a cytogenetic study made in 35 children with ALL it was tested, whether even leukaemic chromosome clones will be a risk for the course of acute leukaemia. The duration of the first remission and survival rate were considered as criteria. The evidence of a leukaemic chromosome clone could be shown to be followed by a short survival rate, irrespective of the stage of the disease where the clone had been observed first. Thus, cytostatic therapy in those ALL patients who are affected with luekaemic chromosome aberration of stem line character should be aimed at the complete annihilation of the clone, irrespective of other remission criteria. The failure of blood and bone-marrow cultures as early as during the untreated initial stage indicated a primary cellular immuno-insufficiency. This combination of cell immuno-depression with high peripheral leukocytes connts and a primary mediastinal tumour or a generalizing lymphosarcoma respectively, was the highest risk up till now for the course of the disease. Judging from the duration of the first remission and the survival rates, the consecutive schemes of therapy did not differ in their effect on leukaemia with pathological stem lines. On the basis of the present study the impression could not be excluded that up till now long term survival rates could be attributed rather to individual manners of response than to the modern therapy scheme.