Quality of life end points in cancer clinical trials: review and recommendations.

In this presentation, issues that influenced the development of policies for inclusion of quality of life end points in certain Southwest Oncology Group clinical trials are reviewed. The key policies recommended by us and adopted by the Cancer Control Research Committee of the Southwest Oncology Group are as follows: (a) Begin assessment of quality of life in specific types of phase III protocols. (b) Always measure physical functioning, emotional functioning, symptoms (general and protocol specific), and global quality of life separately. (c) Include measures of social functioning and additional protocol-specific measures if resources permit. (d) Use patient-based questionnaires with psychometric properties that have been documented in published studies. In this review, we also recommend specific questionnaires. Our recommendations may prove useful for other cancer clinical trials groups and for multi-institution trials of treatment for chronic diseases.

Quality of life in advanced prostate cancer: results of a randomized therapeutic trial.

BACKGROUND: For patients with metastatic prostate cancer, treatment is primarily palliative, relying mainly on the suppression of systemic androgen hormone levels. To help document the achievement of palliation and to characterize positive and negative effects of treatment, we evaluated quality-of-life (QOL) parameters in patients with metastatic prostate cancer who were randomly assigned to two methods of androgen deprivation. METHODS: Patients (n = 739) with stage M1 (bone or soft tissue metastasis) prostate cancer were enrolled in a QOL protocol that was a companion to Southwest Oncology Group INT-0105, a randomized double-blind trial comparing treatment with bilateral orchiectomy (surgical castration) plus either flutamide or placebo. Patients completed a comprehensive battery of QOL questionnaires at random assignment to treatment and at 1, 3, and 6 months later. Data were collected on three treatment-specific symptoms (diarrhea, gas pain, and body image), on physical functioning, and on emotional functioning. All P values are two-sided. RESULTS: Questionnaire return rates for this study never dropped below 80%; only 2% of the patients did not submit baseline QOL assessments. Cross-sectional analyses (corrected for multiple testing) identified statistically significant differences that favored orchiectomy plus placebo for two of the five primary QOL parameters as follows: patients receiving flutamide reported more diarrhea at 3 months (P = .001) and worse emotional functioning at 3 and 6 months (both P<.003). Longitudinal analyses replicated these findings. Other analyzed QOL parameters favored the group receiving placebo but were not statistically significant after adjustment for multiple testing. CONCLUSIONS: We found a consistent pattern of better QOL outcomes at each follow-up assessment during the first 6 months of treatment for orchiectomized patients with metastatic prostate cancer who received placebo versus flutamide. Improvement over time was evident in both treatment groups but more so for patients receiving placebo.

Profile of men randomized to the prostate cancer prevention trial: baseline health-related quality of life, urinary and sexual functioning, and health behaviors.

PURPOSE: To describe men who agreed to be randomized to the Prostate Cancer Prevention Trial (PCPT), a 7-year, double-blind placebo-controlled study of the efficacy of finasteride in preventing prostate cancer. METHODS: Comprehensive health-related quality-of-life data are presented for 18,882 randomized PCPT participants. RESULTS: PCPT participants are highly educated, middle to upper income, and primarily white (92%). Participants reported healthy lifestyles. The mean American Urological Association Symptom Index score was well below the maximum entry score of less than 19; existing urinary symptoms were generally not bothersome. The scores for two sexual functioning scales could range from 0 to 100, with higher scores reflecting worse sexual functioning. The mean score for the Sexual Problem Scale was 19.2 out of 100, and the mean Sexual Activities Scale was 44.1 out of 100. Scores for seven of the eight Medical Outcomes Study 36-item Short-Form Health Survey scales (higher scores are better) were 10 to 20 points higher than those reported by a general population sample and differed minimally by race but not by age. Previously reported associations between sexual dysfunction and hypertension, diabetes, and depression were also observed. Men who never smoked reported less sexual dysfunction than did those who either had quit or still smoked. CONCLUSION: Individuals who are likely to enroll in primary prevention trials have a high socioeconomic status, healthy lifestyle behaviors, and better health than the general population. These data help oncologists design chemoprevention trials with respect to the selection of health-related quality-of-life assessments and recruitment strategies.

Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial.

PURPOSE: This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non--small-cell lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization. PATIENTS AND METHODS: Two hundred two patients received VC (vinorelbine 25 mg/m(2)/wk and cisplatin 100 mg/m(2)/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m(2) over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months. RESULTS: Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P =.002) and neutropenia (P =.008) occurred more frequently on the VC arm. Grade 3 nausea and vomiting were higher on the VC arm (P =.001, P =.007), and grade 3 peripheral neuropathy was higher on the PC arm (P <.001). More patients on the VC arm discontinued therapy because of toxicity (P =.001). No difference in QOL was observed. Overall costs on the PC arm were higher than on the VC arm because of drug costs. CONCLUSION: PC is equally efficacious as VC for the treatment of advanced non--small-cell lung cancer. PC is less toxic and better tolerated but more expensive than VC. New treatment strategies should be pursued.

Costs of quality-of-life research in Southwest Oncology Group trials.

Quality-of-life (QOL) research in Southwest Oncology Group (SWOG) trials has achieved increasing support over the past 5 years. The purpose of this paper is to estimate the cost of performing QOL research in SWOG trials. During the month of January 1995, we tracked staff time expended for QOL tasks at the SWOG's Operations Office and Statistical Center. Of interest was a description of average costs per patient enrolled in existing SWOG trials (both open and closed), including protocol development, ongoing data monitoring, and QOL data analysis. The findings emphasize the personnel-intensive nature of this research and highlight the role of "start-up" costs, especially in terms of programmer time. It is estimated that average monthly direct costs associated with implementing a QOL study and monitoring and analyzing QOL data over the life cycles of current and closed SWOG QOL protocols are $7304; a $443 per QOL patient total cost figure is also presented. Costs associated with initiating QOL research in cooperative groups are substantial (4-5-year start-up investment) but are expected to decline after systems for monitoring, retrieving, and analyzing QOL data are in place. Funding issues are addressed.

Measuring quality of life: an emerging science.

Quality of life (QOL) variables are increasingly included as end points in cancer therapy trials, supplementing such traditional end points as survival time in evaluating the effects of cancer treatments. Consensus has been reached that a number of QOL components (symptom status and physical, emotional, role, and social functioning) should be measured. Assessing multiple health-related QOL dimensions, as compared with a global score, provides a more detailed accounting of specific effects of cancer treatment on patient functioning. Southwest Oncology Group QOL assessment policies emphasize patient reports and the need for systematic quality control procedures. The Southwest Oncology Group QOL questionnaire comprises a battery of categorical scales with established psychometric properties. A set of generic core scales is always included in the battery, and treatment- and disease-specific scales are developed for each trial. Other frequently used QOL questionnaires, such as the European Organization for Research and Treatment of Cancer QLQ-C30, the Cancer Rehabilitation Evaluation System questionnaire, and the Functional Assessment of Cancer Therapy are alternative instruments in current use. Quality of life findings from lung cancer clinical trials indicate a prevalence of symptom distress, fatigue, and decline in functional status, although patients also experience symptom management problems without treatment. A summary of preliminary QOL findings for two vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) trials (randomized and single-arm) in patients with non-small cell lung cancer show that symptom status was as good or better for patients receiving vinorelbine compared with those receiving 5-fluorouracil/leucovorin in the randomized study. Differences in other QOL dimensions were not detected. Findings for the single-arm trial of oral vinorelbine were generally consistent with those of the randomized trial.

Minority recruitment in the prostate cancer prevention trial.

PURPOSE: African American men have a higher prostate cancer risk profile than that of other men in the United States. The purpose of this manuscript is to summarize the challenges associated with enrolling and randomizing African American and other minority participants in the Prostate Cancer Prevention Trial (PCPT). METHODS: The PCPT is a randomized trial of finasteride versus placebo for preventing prostate cancer in healthy men age 55 years and older; it is coordinated by the Southwest Oncology Group. The manuscript describes demographic and lifestyle characteristics of the PCPT randomized sample (18,882 men) by four racial and ethnic groups (Caucasian, African American, Hispanic, and other). African American men comprised 4% of the total randomized sample compared to our goal of 8%. Minority recruitment was emphasized through the Study Manual and training that occurred at trial activation. Supplemental minority recruitment activities were initiated a year after study activation and continued through the end of the accrual period. Minority recruitment was emphasized as follows: minority recruitment presentations at PCPT training seminars (held during twice yearly Southwest Oncology Group meetings); distribution of additional minority recruitment materials; engagement of four consultants for minority recruitment; production of a Minority Recruitment Manual; and a small pilot study involving minority outreach recruiters at five PCPT sites. RESULTS: The consultants were helpful in implementing the pilot project and in suggesting and reviewing materials for minority recruitment. The five-site pilot project did not increase either enrollment or randomization of minorities (with a possible exception at one site). CONCLUSIONS: We suggest that a long-term perspective is required for successful recruitment of minority participants in clinical trials. Likewise, extensive minority recruitment efforts must be ready to implement at trial activation.

Quality of life assessment in Southwest Oncology Group trials.

The Southwest Oncology Group Quality of Life Questionnaire is based on six policy recommendations adopted by the Group: 1. Always measure physical functioning, emotional functioning, symptoms, and global quality of life separately. 2. Include measures of social functioning and additional protocol-specific measures if resources permit. 3. Use patient-based questionnaires. 4. Use categorical rather than visual analogue scales. 5. Select brief questionnaires (not interviews). 6. Select quality of life measures with published psychometric properties. Three additional policy recommendations deal with procedures and issues associated with the assessment of quality of life in a Southwest Oncology Group prostate cancer trial. Communication among investigators and groups can improve access to newly developed QOL measures and assure consistent quality control procedures across cooperative group trials.

Impact of a randomized, controlled trial of liberal vs conservative hospital discharge criteria on energy, protein, and fluid intake in patients who received marrow transplants.

OBJECT: To determine if adult patients who received marrow transplants had faster resumption of oral energy and nutrient intake and shorter duration of intravenous (i.v.) fluid requirement if discharged from the hospital earlier than is customary. DESIGN: Randomized, controlled trial of patients remaining hospitalized because of inadequate oral intake. Consenting patients were assigned randomly to remain hospitalized (hospital group) or be discharged to an ambulatory setting (ambulatory group). SUBJECTS: Seventy-eight patients of the Fred Hutchinson Cancer Research Center who were consuming less than 33% of estimated energy requirement and requiring up to 3,000 mL of fluids per day intravenously. INTERVENTION: Participants received nutrition counseling by a registered dietitian to promote resumption of oral intake. Daily oral intake records were analyzed to determine energy and nutrient content. MAIN OUTCOME MEASURES: Days after study enrollment to consume 33% of energy and protein requirements and total number of days of i.v. fluid support were analyzed by group until discharge from the center, approximately 100 days after transplantation. STATISTICAL ANALYSES: Demographic data were defined by group means. Differences between treatment procedures were determined by Cox regression analysis. No variables were confounding. RESULTS: The hospital group took fewer days than the ambulatory group to resume oral energy intake (4.5 vs 8.0, P = .004) and to discontinue i.v. fluids (30.5 vs 48.5, P = .019). There was no difference between groups in days of parenteral nutrition support (P = .817) or days to resume oral protein intake (P = .470). APPLICATIONS/CONCLUSIONS: Oral and gastrointestinal complications delay resumption of oral energy and protein intakes after transplantation. Earlier hospital discharge can achieve cost savings but may delay resumption of oral energy intake. Because of continued high-risk nutrition status and potential for rapid change in medical status, nutrition assessment and counseling are necessary in both the hospital and ambulatory setting to promote resumption of oral intake and discontinuation of i.v. fluids.

Inclusion of black Americans in oncology clinical trials: the Louisiana State University Medical Center experience.

Recruitment of patients from diverse ethnic, racial, and socioeconomic backgrounds for clinical trials is desirable for both scientific and ethical reasons. Participation rates in clinical trials are low for minorities and especially for black Americans. This report summarizes the experience at Louisiana State University Medical Center in Shreveport, Louisiana, in enrolling black Americans in oncology treatment and prevention trials. Barriers to enrollment are identified and discussed. Although major strides must still be made in the area of cancer prevention, the university's experience demonstrates that black Americans can be encouraged to participate in and can be enrolled in cancer clinical trials.

Pitfalls in quality-of-life assessment: lessons from a Southwest Oncology Group breast cancer clinical trial.

There is increasing interest in evaluating the impact of cancer treatment and medical intervention on patient quality of life (QOL). This article reports the findings of a substudy that incorporated the Functional Living Index--Cancer in an ongoing adjuvant breast cancer clinical trial sponsored by the Southwest Oncology Group. The companion study had to be terminated prior to the end of the two-armed, randomized trial because of poor reporting rates over time. Problems with missing data items also occurred. Poor reporting rates in this trial motivated several recommendations for conducting QOL assessment in the cooperative group setting: (a) build support for QOL assessment among the group's leadership, (b) involve physicians and oncology nurses in the study design, (c) identify a QOL liaison at each participating institution, and (d) aggressively monitor the quality and timeliness of data submission.

Physician participation in research surveys. A randomized study of inducements to return mailed research questionnaires.

The authors randomly selected 400 physicians from a population of 1,545 practicing physicians providing follow-up care to patients who received bone marrow or blood stem cell transplants at the Fred Hutchinson Cancer Research Center to determine interest in receiving Internet-based transplant information. In a two-factor completely randomized factorial design, the 400 physicians were assigned to receive mailed surveys with either no compensation or a $5 check and either no follow-up call or a follow-up call 3 weeks after mailing. Overall, 51.5% of the physicians returned the mailed surveys. Comparison of logit models showed that inclusion of a $5 check in the mailer significantly (p = .016) increased the probability of returning the surveys (57.5% vs. 45.5%). In contrast, the telephone follow-up had no overall effect. The authors concluded a modest financial reward can significantly improve physician response rates to research surveys but a telephone follow-up may be inefficient and even ineffective.

A comparison of visual analogue and numerical rating scale formats for the Lung Cancer Symptom Scale (LCSS): does format affect patient ratings of symptoms and quality of life?

PROBLEM AND PURPOSE: The Lung Cancer Symptom Scale (LCSS), a site-specific health-related quality of life measure for patients with lung cancer, was originally developed using a Visual Analogue Scale (VAS) format. However, the VAS format is not readily compatible with data management and software programs using scanning. The primary aim of this study was to evaluate the convergence of ratings obtained with a Numerical Rating Scale (NRS), with an 11-pt response category format, to those obtained with a VAS format. The intent was to determine the degree of agreement between two formats to generalize the existing psychometric properties for the original measure to the new presentation. DESIGN/SETTING: This methodological study evaluated the feasibility, reliability, and validity of a NRS format for the LCSS. The study was conducted at two cancer centers in New York City. PATIENTS/PROCEDURES: Sixty-eight patients with non-small cell lung cancer (NSCLC) completed both versions of the LCSS along with demographic and feasibility questions on a single occasion. The VAS form was administered first, followed by the NRS form to prevent bias. The intraclass correlation coefficient (ICC), Lin's concordance correlation coefficient (CCC), and Bland-Altman plots were used to evaluate agreement and to characterize bias. RESULTS: Cronbach's alpha for the NRS format total score was 0.89 for the 68 patients with NSCLC. Agreement was excellent, with both the ICC and CCC > or = 0.90 for the two summary scores (total score and average symptom burden index) for the LCSS. Only five of the nine individual items showed this level of strict agreement. An agreement criterion of > or = 0.80 (representing excellent) was observed for seven of the nine individual items (all but appetite loss and hemoptysis). Mean differences tended to be slightly lower for the VAS format compared to the NRS format (more so for the appetite and hemoptysis items), with evidence of scale shift for the same two items. The summary measures showed good concordance as measured by the ICC and CCC, but did display mean differences (VAS - NRS) of -2.7 and -3.1, respectively. CONCLUSIONS: Overall, the NRS format for the LCSS suitable for scanning has good feasibility, reliability (internal consistency), and convergent validity. The complete set of concordance evaluation measures supports the reproducibility of VAS scores by NRS scores, particularly for the two summary scores.

Do quality of life assessments make a difference in the evaluation of cancer treatments?

The question posed by this set of quality of life papers is whether or not quality of life assessments in cancer clinical trials help evaluate the effects of cancer treatment on patient functioning. In this discussion, missing data problems, particularly those commonly found in advanced stage disease trials, are highlighted. Researchers are encouraged to investigate the extent of bias associated with missing data and to select analysis approaches accordingly. In the worst case, it may not be possible to analyze data longitudinally; descriptive or graphical portrayals of the data may be more appropriate. The importance of instrument reliability (minimizing measurement error) is emphasized for clinical trials research, particularly with respect to enhancing a trial's ability to detect quality of life differences by treatment arm. One strategy for addressing missing data is evaluated with respect to its impact on the measurement properties of the quality of life questionnaire. Clinical trials groups have been successful in obtaining quality of life data in multi-site settings and patients, by and large, appreciate the effort to include a systematic and standardized report of the effects of treatment on their functioning.

Ensuring the quality of quality of life data: the Southwest Oncology Group experience.

The Southwest Oncology Group (SWOG) has successfully included quality of life (QOL) questionnaires in selected oncology treatment trials. Extensive quality control procedures have been necessary for obtaining and maintaining good questionnaire submission rates. Since the first QOL study was activated in SWOG in 1990, the Group has found it increasingly necessary to incorporate centralized monitoring of the QOL assessment schedule. Successful quality control strategies are presented. Current submission rates for five SWOG phase III treatment trials (both open and closed) and one chemoprevention trial are presented for those scheduled QOL assessments for which we have follow-up data. Reasons for missing QOL questionnaires and the extent of missing data within submitted QOL questionnaires are described for two different disease contexts: a trial for patients with advanced stage disease, and a trial for patients with earlier stage disease.

Factors affecting place of death of hospice and non-hospice cancer patients.

We identified factors associated with death at home for 28,828 hospice and non-hospice cancer patients in 13 counties of western Washington State. Hospice participation was found to be the variable most strongly associated with death at home. Admission to hospice appears to override the tendency for certain subgroups of patients, such as the extreme elderly and those diagnosed close to death, to die in an institutional setting. These findings are discussed with respect to the problem of selection bias.

Substituting proxy ratings for patient ratings in cancer clinical trials: an analysis based on a Southwest Oncology Group trial in patients with brain metastases.

In studies of the effect of cancer treatment in the advanced disease setting, researchers have attempted to avoid missing data for quality of life (QOL) assessments by either substituting proxy for patient assessments from the outset or by interspersing proxy measures when patients are unable to respond. Although poor agreement between patient and proxy assessments has been amply demonstrated in the literature, interest in using proxy measures persists. Completion of the Spitzer QL-Index by a small sample of patients with brain metastases and family member proxies provided data for evaluating the ability to substitute proxy for patient QOL assessments. These data cannot address treatment efficacy due to the modest sample size. Rather, the analyses serve to alert researchers to the important distinction (in a clinical trial setting) between agreement and the use of the proxy as a surrogate. We present several methods for evaluating the accuracy of proxy measures and for identifying other sources of error and bias that may vary with time or with treatment arm. Lin's concordance correlation coefficient suggests that proxies are generally a poor substitute for capturing a patient's perspective of his/her QOL. A longitudinal analysis suggests that the use of proxy rather than patient responses could lead to different conclusions concerning radiation therapy's effect on QOL.