Factors influencing the participation of older people in clinical trials - data analysis from the MAVIS trial.

BACKGROUND: Older people are less likely to be included in clinical trials. Little is known about factors influencing older people's decisions about participating in clinical trials. OBJECTIVES: To examine the views of older people about participating in clinical trials. METHODS: Postal questionnaire to 801 participants who had completed the MAVIS nutrition trial, aged 65 yrs and older. Closed and open questions sought participants' views about factors important to them when deciding to take part in a trial, features of the MAVIS trial they liked and disliked and changes they would suggest. RESULTS: 540 (59% of MAVIS trial participants) returned the questionnaire. The most important reasons reported for taking part in the trial were helping the research team and medical knowledge, and helping other older people. Participants valued good communication with the trial staff and good organisation. Participants reported concerns about swallowing pills and taking a placebo. Participants reported that future participation in trials could be influenced by poor health status. LIMITATIONS: This questionnaire surveyed older participants who had taken part in a randomised controlled trial. It did not elicit the views of people who had withdrawn or never decided to take part in the trial. CONCLUSIONS: Older people report altruistic reasons for taking part in trials. Simple trial designs, which minimise demands on participants and maintain good communications should be preferred. Explaining the need for older people, despite poor health, to participate in trials may help the generalisability of clinical trials.

Pitfalls in the diagnosis of prostatic cancer: retrospective review of 1791 cases with clinical outcome.

AIMS: To assess the possible reasons for error in the diagnosis of prostatic cancer with available follow-up data. METHOD AND RESULTS: A cohort of 1791 cases of prostatic cancer diagnosed in the UK between 1990 and 1996 was examined. All cases were clinically localized at presentation, treated by non-curative methods and detailed follow-up was available. A panel of genitourinary pathologists reviewed the pathology of all cases. One hundred and thirty-three (7.5%) of cases were reassigned to a non-malignant diagnosis. Where possible, reasons for the initial diagnosis were given. These included severe atrophy, inflammatory induced atypia, sclerosing adenosis, atypical adenomatous hyperplasia and basal cell hyperplasia. Follow-up of these patients showed an extremely low death rate from prostatic cancer: lower than that for the Gleason combined score of five or less tumours diagnosed in this series. CONCLUSIONS: Many morphological entities potentially mimic prostatic cancer and may be responsible for misdiagnosis in routine specimens. Continuing education in prostatic morphology and immunohistochemistry may have helped reduce this error rate.

Long-term outcome among men with conservatively treated localised prostate cancer.

Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of <10, 10-30, and >30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients.

The role of external radiotherapy in patients treated with permanent prostate brachytherapy.

To examine the difference in Prostate Specific Antigen (PSA)-Relapse Free Survival (RFS) in patients (pts) with prostate cancer treated with permanent prostate brachytherapy (PPB) alone (monotherapy) or combined modality PPB and external radiotherapy (CMT) by a matched pair analysis. There were 1476 pts who were treated loosely based on the American Brachytherapy Society criteria for monotherapy or CMT. PSA-RFS was based upon the Kattan modification of the ASTRO consensus panel definition. A computer generated matching process was undertaken to produce two equally weighted pairs of patients divided by treatment methodology and Kaplan-Meier PSA-RFS curves were generated and compared by chi(2) testing. All pts were treated between 1992 and 2000 with a 6-y PSA-RFS of 81.9%. The median follow-up was 34.7 months. Patients treated with CMT presented with higher pre-treatment PSA values, Gleason sum score, clinical stage, risk classification, and were more likely to be treated with neoadjuvant hormones. A matched-pair analysis with 314 pts in each group was created stratified by the addition of neoadjuvant hormones, Gleason score sum and the pretreatment PSA value. Actuarial 5-y PSA-RFS was 77.0% for the monotherapy group and 81.1% for the combined therapy group (P=0.54).chi(2) testing by pretreatment PSA value, Gleason score sum, risk stratification, isotope and the addition of neoadjuvant hormones failed to identify any group with a significant difference in 5-y PSA-RFS. In conclusion, this retrospective study presents a large cohort of patients treated with PPB that failed to identify a significant advantage for the addition of combined therapy. A matched pair analysis performed also failed to identify any significant difference based on treatment modality.

Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer.

OBJECTIVES: To develop a prognostic nomogram to predict the freedom from recurrence for patients treated with permanent prostate brachytherapy for localized prostate cancer. METHODS: We performed a retrospective analysis of 920 patients treated with permanent prostate brachytherapy between 1992 and 2000. The clinical parameters included clinical stage, biopsy Gleason sum, pretreatment prostate-specific antigen (PSA) value, and administration of external beam radiation. Patients who received neoadjuvant androgen deprivation therapy were excluded. Failure was defined as any post-treatment administration of androgen deprivation, clinical relapse, or biochemical failure, defined as three PSA rises. Patients with fewer than three PSA rises were censored at the time of the first PSA rise. Data from two outside institutions served as validation. RESULTS: A nomogram that predicts the probability of remaining free from biochemical recurrence for 5 years after brachytherapy without adjuvant hormonal therapy was developed using Cox proportional hazards regression analysis. External validation revealed a concordance index of 0.61 to 0.64, and calibration of the nomogram suggested confidence limits of +5% to -30%. CONCLUSIONS: The pretreatment nomogram we developed may be useful to physicians and patients in estimating the probability of successful treatment 5 years after brachytherapy for clinically localized prostate cancer.

Potency after permanent prostate brachytherapy for localized prostate cancer.

PURPOSE: The evaluation of potency preservation after treatment of localized prostate cancer with transperineal permanent prostate brachytherapy (PPB) and the efficacy of sildenafil were studied. METHODS AND MATERIALS: This study comprised 482 patients who were able to maintain an erection suitable for intercourse before treatment from a cohort of 1166 patients with clinically localized prostate cancer treated with PPB. All patients have been followed prospectively, and actuarial analysis was performed to assess potency preservation over time. Patients treated with sildenafil were evaluated as to its efficacy. RESULTS: The median follow-up of this cohort was 34 months (6--92), with a median age of 68 years (47--80). Potency was preserved in 311 of the 482 patients, with a 5-year actuarial potency rate of 52.7%. The 5-year actuarial potency rate for patients treated with PPB as monotherapy was 76%, and, for those treated with combination external beam radiotherapy (EBT) + PPB, 56% (p = 0.08). Patients treated with neoadjuvant androgen deprivation (NAAD) + PPB had a 5-year potency rate of 52%, whereas those with combination EBT + PPB + NAAD had a potency rate of 29% (p = 0.13). Cox regression analysis identified that pretreatment use of NAAD and patient age predicted for impotence (p = 0.0001 and 0.04, respectively). Of 84 patients treated with sildenafil, 52 had a successful outcome (62%). The response to sildenafil was significantly better in those patients not treated with NAAD (p = 0.04). CONCLUSIONS: The actuarial potency rates at 5 years for patients treated with PPB are lower than generally acknowledged, except for those patients treated with PPB as monotherapy. Patients who received sildenafil exhibited improved potency in a majority of cases.

A comprehensive review of CT-based dosimetry parameters and biochemical control in patients treated with permanent prostate brachytherapy.

PURPOSE: The American Brachytherapy Society recommends that postprostate implant dosimetry be performed on all patients undergoing transperineal interstitial permanent prostate brachytherapy (TIPPB) utilizing CT scan clinical target volume reconstructions. This study was undertaken to assess the recommended dosimetry parameters from a large cohort of patients undergoing TIPPB that would predict for PSA relapse-free survival (PSA-RFS). METHODS AND MATERIALS: Seven hundred nineteen consecutive patients with clinical stage T1/T2 adenocarcinoma of the prostate underwent TIPPB using either I-125 or Pd-103. Postimplant dosimetry was performed at 2 to 3 weeks with CT scan 3-dimensional reconstructions obtained on all patients. The D90 and D100 doses (defined as the minimum dose covering 90% and 100% of the prostate volume, respectively) and the V100 (defined as the percent of the prostate receiving 100% of the prescribed dose) were obtained for each patient. Regression analysis was performed on the D90 dose, D100 dose, and V100 to test for cutoff points that would predict for PSA-RFS, defined by a modification of the American Society for Therapeutic Radiology and Oncology consensus panel statement. A cutoff value was found and was subjected to subset analysis to assess for its robustness. Treatment-related factors were tested for their ability to achieve dosimetry at or above the cutoff dose. RESULTS: The median follow-up from this cohort is 30 months (7-71 months) with a 48-month PSA-RFS of 89.5%. A D90 dose-response cutoff value > or =90% of the prescribed dose was identified. Prostate implants with a D90 dose <90% of the prescribed dose had an 80.4% 4-year PSA-RFS, while those with a D90 dose > or =90% of the prescribed dose had a 92.4% 4-year PSA-RFS (p = 0.001). No cutoff value was found for the V100 and D100 dose that predicted for PSA-RFS. Using the cutoff value, the D90 dose at 90% of the prescribed dose, a difference in 4-year PSA-RFS survival was identified for patients treated with I-125 (p = 0.04), Pd-103 (p = 0.01), TIPPB as monotherapy (p = 0.001), the addition of hormone therapy (p = 0.005), and TIPPB without hormone therapy (p = 0.001). The D90 dose was not significant for the group of patients treated with external beam radiotherapy and TIPPB (p = 0.15). The only significant finding from Cox regression analysis to predict for a poor D90 dose (<90% of the prescribed dose) was a CT/TRUS volume ratio >1.5 (p = 0.02). CONCLUSIONS: The American Brachytherapy Society recommends that postimplant CT-based dosimetry be performed for all patients treated with TIPPB. This prospective study identified that the D90 dose > or =90% of the prescribed dose can be used as a factor for predicting PSA-RFS in patients treated with brachytherapy. A dose-response using the D90 dose was observed for several typical clinical treatment variations used in the practice of TIPPB. Using the D90 dose appears to be a satisfactory parameter for predicting outcome in patients treated with TIPPB.

Time trade-off utility modified to accommodate degenerative and life-threatening conditions.

The time trade-off is often argued to be the preferred utility assessment method. When measuring current health in its classic form, it involves a comparison of two certainties: perfect health and current health, each for a fixed period of time and followed by death. This makes the time trade-off insensitive to patient fears regarding premature death or worsening health. We suggest the classic time trade-off be modified to include subjective rather than actuarial life expectancy, and relaxation of the current health option to include uncertainty in quantity and quality of life. We illustrate the mechanics of this modified time trade-off and report a preliminary application to 122 men presenting to a prostate cancer screening program. Further analysis of this modified time trade-off appears warranted.

The definition of biochemical failure in patients treated with definitive radiotherapy.

PURPOSE: The American Society for Therapeutic Radiology and Oncology (ASTRO) published a definition for biochemical failure following treatment of prostate cancer. Others have noted difficulties with interpreting this definition and recommended modifications to accommodate special recurrence patterns. We have compared various modifications to the original ASTRO definition on our series of 1213 patients treated with transperineal permanent prostate brachytherapy. METHODS AND MATERIALS: The ASTRO modifications we considered adjusted for (1) early censoring of nonrecurrent patients with rising prostate-specific antigen levels (PSA), (2) cumulative rather than consecutive rises (without a decrease) as evidence of recurrence, (3) both of the above, and (4) waiting 2 years before data analysis. The Kaplan-Meier method was used to compute the effects on recurrence rate for patients treated with and without neoadjuvant hormones. RESULTS: With the original ASTRO definition, freedom from recurrence in our series of men who did not receive neoadjuvant hormones was 83% at 4 years. All of the modifications considered had statistically insignificant effects on freedom from recurrence rates, varying from 80% to 83% at 4 years. Patients treated with neoadjuvant hormones also showed very little sensitivity to the recurrence definition employed. CONCLUSION: Early censoring of equivocal patients and counting cumulative rather than consecutive rises in PSA (without a decrease) had little empiric effect on the ASTRO recurrence rates. However, we favor the addition of both these modifications to the ASTRO definition on conceptual grounds for evaluating patients following any modality (radiation or surgery), whereby a trend over multiple PSA values is used to judge failure.

Telephone interviews vs. workstation sessions for acquiring quality of life data.

Patient quality of life data can be acquired in a variety of ways, including over the telephone and through computerized questionnaires. However, if the method of collection produces different results, medical decisions regarding appropriate and cost-effective care may be influenced by collection method. We conducted an experiment where subjects had two quality of life measures, the time trade-off and rating scale utilities, assessed both in telephone interivews and via computer touchscreens. The order of telephone and touchscreen was randomized. We found that rating scale utilities were similar whether obtained via the telephone or via touchscreen regardless of which was done first. However, patients who had their time trade-off utilities assessed over the telephone first did not provide as consistent responses as those elicited first via touchscreen (p = 0.01). Caution is suggested when considering eliciting time trade-off over the telephone with subjects who have not had time trade-off elicited previously.