Quality of life in advanced non-small-cell lung cancer: results of a Southwest Oncology Group randomized trial.

PURPOSE: The main purpose of this paper is to present the results of a randomized trial comparing the effects of two chemotherapy regimens on the Quality of life (QOL) of patients with advanced non-small-cell lung cancer (NSCLC). Trials in advanced stage disease represent an important treatment context for QOL assessment. A second purpose of this paper is to examine methods for handling the level of missing data commonly observed in the advanced stage disease context. METHODS: Patients were randomized to receive cisplatin plus vinorelbine or carboplatin plus paclitaxel. The QOL of 222 patients was assessed with the Functional Assessment of Cancer Therapy-Lung (FACT-L) prior to randomization; follow-up assessments occurred at 13 and 25 weeks. Three methods were used to analyze the QOL data: (1) cross-sectional analysis of four patient categories (improved, stable, missing, and declined) based on changes in the FACT-L score, (2) a mixed linear model, and (3) a pattern mixture model. The longitudinal analyses addressed two potential data biases. RESULTS: Questionnaire submission rates were 91% at baseline, 68% at 13 weeks, and 47% at 25 weeks. The cross-sectional and mixed linear model analyses did not show significant differences by treatment arm in patient-reported QOL. The pattern mixture model analysis, more appropriate given non-ignorable missing data, also found no statistically significant effect of treatment on patient QOL. CONCLUSION: We present a sensitivity analysis approach with multiple methods for analyzing treatment effects on patient QOL in the presence of substantial, non-ignorable missing data in an advanced stage disease clinical trial. We conclude that the two treatment arms did not differ statistically in their effects on patient QOL over a 25-week treatment period.

Challenges posed by non-random missing quality of life data in an advanced-stage colorectal cancer clinical trial.

Effects of variations in agent, dose, and route of treatment administration on patient reported quality of life (QOL) were examined for 279 patients enrolled on a seven-arm randomized clinical trial (S8905) of 5-FU and its modulation for advanced colorectal cancer. Patients completed QOL questionnaires at randomization and weeks 6, 11, and 21 post-randomization with five QOL endpoints considered primary: three treatment-specific symptoms (stomatitis, diarrhea, and hand/foot sensitivity); physical functioning; and emotional functioning. Patient compliance with the QOL assessment schedule was good, supporting the feasibility of including QOL measures in cooperative group trials. However, death and deteriorating health produced substantial missing data. Cross-sectional analyses indicated that the seven therapeutic arms did not differ in their impact on QOL. Unfortunately, longitudinal analyses of the QOL data were inappropriate given non-random missing data. Graphical presentation of non-random missing data identified the seriousness of this problem and its effect on potential conclusions about QOL during treatment. This problem appears to be particularly challenging in the context of advanced-stage disease. Failure to recognize the presence of non-random missing data can lead to serious overestimates of patient QOL over time.

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.

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.

Mass mailing and staff experience in a total recruitment program for a clinical trial: the SHEP experience. Systolic Hypertension in the Elderly Program. Cooperative Research Group.

The Systolic Hypertension in the Elderly Program (SHEP) staff contacted 447,921 screenees, of whom 11,919 (2.7%) were originally eligible and 4,736 (1.1%) maintained eligibility and were randomized. The total number of participants enrolled at the 16 clinical centers ranged from 133 to 559. The low yield of screenees to randomizations resulted from the study design, not from low levels of agreement to participate, and required the employment of a variety of recruitment strategies in a prudent overall plan. SHEP was one of the first clinical trials to use mass mailing as a primary strategy of recruitment. The study used mailing lists from seven generic sources. More than 3.4 million letters of invitation were mailed; they yielded an overall response rate of 4.3%. Motor vehicle and voter registration lists provided the greatest numbers of names. Mailings to members of health maintenance organizations (HMOs) and registrants of the Health Care Finance Administration (HCFA) provided the greatest response rates. Considerable variability in response rates existed among clinical centers using generically similar mailing lists. Generally, the number of hours spent on recruitment showed a positive, but not statistically significant, association with randomization yields. The recruitment yield was statistically significantly higher in clinics with experienced recruitment coordinators than in clinics with inexperienced ones (p = 0.0008). From these findings we conclude that mass mailing is an important strategy in an overall recruitment program, that the involvement of experienced recruitment staff is important, and that although the total time spent by staff on recruitment may also improve results, it matters less than the staff's level of recruiting experience.

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.

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.

Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study.

We assessed Ki-ras mutations by single-strand conformation polymorphism followed by DNA sequencing, p53 expression by immunohistochemistry, ploidy status, and S-phase fraction in 66 stage II and 163 stage III colon cancer patients enrolled on a randomized trial of surgery followed by observation or adjuvant levamisole or 5-fluorouracil (5FU) plus levamisole (Intergroup Trial 0035) to see whether these factors were independently associated with survival or with differential effects of adjuvant therapy. A Cox proportional hazards survival model was used to describe marker effects and therapy by marker interactions, with adjustment for the clinical covariates affecting survival. A Bonferroni adjustment was used to account for multiple testing. Mutation of the Ki-ras gene was found in 41% of the cancers and was associated with a poor prognosis in stage II but not stage III. In stage II, 7-year survival was 86% versus 58% in those with wild type versus Ki-ras mutations. After adjustment for treatment and clinical variables, the hazard ratio (HR) for death was 4.5; 95% confidence interval (CI), 1.7-12.1 (P = 0.012). p53 overexpression was found in 63% of cancers and was associated with a favorable survival in stage III but not stage II. Seven-year survival in stage III was 56% with p53 overexpression versus 43% with no p53 expression (HR, 2.2; 95% CI, 1.3-3.6; P = 0.012). Aneuploidy was more common in stage III than in stage II (66 versus 47%; P = 0.009) but was not independently related to survival in either group. The proliferative rate was greater in aneuploid than in diploid cancers but was not related to survival. There was no benefit of adjuvant therapy in stage II nor in any of the stage II subgroups defined by mutational status. In stage III, adjuvant therapy with 5FU plus levamisole improved 7-year survival in patients with wild-type Ki-ras (76 versus 44%; HR, 0.4; 95% CI, 0.2-0.8) and in those without p53 overexpression (64 versus 26%; HR, 0.3; 95% CI, 0.1-0.7). Adjuvant therapy did not benefit those with Ki-ras mutations or p53 overexpression. The effects of adjuvant therapy did not differ according to ploidy status or proliferative rate. Ki-ras mutation is a significant risk factor for death in stage II, and the absence of p53 expression is a significant risk factor for death in stage III colon cancer after adjustment for treatment and clinical covariates. Exploratory analyses suggest that patients with stage III colon cancer with wild-type Ki-ras or no p53 expression benefit from adjuvant 5FU plus levamisole, whereas those with Ki-ras mutations or p53 overexpression do not. An independent study will be required to determine whether response to adjuvant therapy in colon cancer depends on mutational status.

Recruitment for controlled clinical trials: literature summary and annotated bibliography.

This article is a literature summary and annotated bibliography of research on recruitment for controlled clinical trials published through 1995. It extends and revises a similar review published in this journal a decade ago. The current commentary focuses on intervening developments in recruitment, including diverse populations, HIV trials, primary prevention trials, recruitment strategies, overall planning and management, patient and physician attitudes, adherence, generalizability, and cost. Profound barriers may exist in the recruitment of diverse populations, involving language, cultural factors, beliefs about medical research, and the appropriateness of available protocols. Extensive literature exists on patient and physician barriers to participation. Trials in HIV-infected or AIDs-diagnosed individuals introduce special considerations, including issues of confidentiality, parallel track design, and populations difficult to define and track. Recruitment strategies such as patient registries, occupational screening, direct mail, and the media are now prominent in the literature. Successful planning and management of an overall recruitment plan include piloting strategies, monitoring recruitment by data tracking systems, and hiring quality staff. Generalizability of study results is influenced by the characteristics of participants and by their adherence to study protocol. With increasingly limited funding to conduct clinical trials, efforts to quantify and reduce recruitment costs are being made. While over 4000 titles were identified, primarily by MEDLINE literature search, the articles summarized emphasize data-supported and -confirmed conclusions, and broad coverage of disease areas. We annotate here 91 outstanding articles useful for formulation of overall recruitment approaches in clinical trials.