Deborah A. Kuban

Quality of Life and Satisfaction with Outcome among Prostate-Cancer Survivors

BACKGROUND We sought to identify determinants of health-related quality of life after primary treatment of prostate cancer and to measure the effects of such determinants on satisfaction with the outcome of treatment in patients and their spouses or partners. METHODS We prospectively measured outcomes reported by 1201 patients and 625 spouses or partners at multiple centers before and after radical prostatectomy, brachytherapy, or external-beam radiotherapy. We evaluated factors that were associated with changes in quality of life within study groups and determined the effects on satisfaction with the treatment outcome. RESULTS Adjuvant hormone therapy was associated with worse outcomes across multiple quality-of-life domains among patients receiving brachytherapy or radiotherapy. Patients in the brachytherapy group reported having long-lasting urinary irritation, bowel and sexual symptoms, and transient problems with vitality or hormonal function. Adverse effects of prostatectomy on sexual function were mitigated by nerve-sparing procedures. After prostatectomy, urinary incontinence was observed, but urinary irritation and obstruction improved, particularly in patients with large prostates. No treatment-related deaths occurred; serious adverse events were rare. Treatment-related symptoms were exacerbated by obesity, a large prostate size, a high prostate-specific antigen score, and older age. Black patients reported lower satisfaction with the degree of overall treatment outcomes. Changes in quality of life were significantly associated with the degree of outcome satisfaction among patients and their spouses or partners. CONCLUSIONS Each prostate-cancer treatment was associated with a distinct pattern of change in quality-of-life domains related to urinary, sexual, bowel, and hormonal function. These changes influenced satisfaction with treatment outcomes among patients and their spouses or partners.

PROSTATE CANCER RADIATION DOSE RESPONSE: RESULTS OF THE M. D. ANDERSON PHASE III RANDOMIZED TRIAL

PURPOSE A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer. METHODS AND MATERIALS A total of 305 Stage T1-T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis. RESULTS There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA <or=10 ng/mL, no significant dose response was found, with an average 6-year FFF rate of about 75%. Although no difference occurred in overall survival, the freedom from distant metastasis rate was higher for those with PSA levels >10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy. CONCLUSION An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives >or=70 Gy to <25% should be used.

Predicting the Outcome of Salvage Radiation Therapy for Recurrent Prostate Cancer After Radical Prostatectomy

PURPOSE An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence. PATIENTS AND METHODS Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients. RESULTS The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69. CONCLUSION Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.

Prostate Specific Antigen Best Practice Statement: 2009 Update

PURPOSE We provide current information on the use of PSA testing for the evaluation of men at risk for prostate cancer, and the risks and benefits of early detection. MATERIALS AND METHODS The report is a summary of the American Urological Association PSA Best Practice Policy 2009. The summary statement is based on a review of the current professional literature, clinical experience and the expert opinions of a multispecialty panel. It is intended to serve as a resource for physicians, other health care professionals, and patients. It does not establish a fixed set of guidelines, define the legal standard of care or pre-empt physician judgment in individual cases. RESULTS There are two notable differences in the current policy. First, the age for obtaining a baseline PSA has been lowered to 40 years. Secondly, the current policy no longer recommends a single, threshold value of PSA, which should prompt prostate biopsy. Rather, the decision to proceed to prostate biopsy should be based primarily on PSA and DRE results, but should take into account multiple factors including free and total PSA, patient age, PSA velocity, PSA density, family history, ethnicity, prior biopsy history and comorbidities. CONCLUSIONS Although recently published trials show different results regarding the impact of prostate cancer screening on mortality, both suggest that prostate cancer screening leads to overdetection and overtreatment of some patients. Therefore, men should be informed of the risks and benefits of prostate cancer screening before biopsy and the option of active surveillance in lieu of immediate treatment for certain men diagnosed with prostate cancer.

Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer

PURPOSE To identify dosimetric, anatomic, and clinical factors that correlate with late rectal toxicity after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer. METHODS AND MATERIALS We retrospectively analyzed the dose-volume histograms and clinical records of 163 Stage T1b-T3c prostate cancer patients treated between 1992 and 1999 with 3D-CRT, to a total isocenter dose of 74-78 Gy at The University of Texas M. D. Anderson Cancer Center. The median follow-up was 62 months (range 24-102). All late rectal complications were scored using modified Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. The 6-year toxicity rate was assessed using Kaplan-Meier analysis and the log-rank test. A univariate proportional hazards regression model was used to test the correlation between Grade 2 or higher toxicity and the dosimetric, anatomic, and clinical factors. In a multivariate regression model, clinical factors were added to the dosimetric and anatomic variables to determine whether they significantly altered the risk of developing late toxicity. RESULTS At 6 years, the rate of developing Grade 2 or higher late rectal toxicity was 25%. A significant volume effect was observed at rectal doses of 60, 70, 75.6, and 78 Gy, and the risk of developing rectal complications increased exponentially as greater volumes were irradiated. Although the percentage of rectal volume treated correlated significantly with the incidence of rectal complications at all dose levels (p <0.0001 for all comparisons), the absolute rectal volume appeared to be a factor only at the higher doses of 70, 75.6, and 78 Gy (p = 0.0514, 0.0016, and 0.0021, respectively). The following variables also correlated with toxicity on the univariate analysis: maximal dose to the clinical target volume, maximal dose to rectum, maximal dose to the rectum as a percentage of the prescribed dose, and maximal dose delivered to 10 cm(3) of the rectum. Of the clinical variables tested, only a history of hemorrhoids correlated with rectal toxicity (p = 0.003). Multivariate analysis showed that the addition of hemorrhoids increased the risk of toxicity for each dosimetric variable found to be significant on univariate analysis (p <0.05 for all comparisons). CONCLUSION Dose-volume histogram analyses clearly indicated a volume effect on the probability of developing late rectal complications. Therefore, dose escalation may be safely achieved by adherence to dose-volume histogram constraints during treatment planning and organ localization at the time of treatment to ensure consistent patient setup.

Long-term multi-institutional analysis of stage T1-T2 prostate cancer treated with radiotherapy in the PSA era.

PURPOSE To report the long-term outcome for patients with Stage T1-T2 adenocarcinoma of the prostate definitively irradiated in the prostate-specific antigen (PSA) era. METHODS AND MATERIALS Nine institutions combined data on 4839 patients with Stage T1b, T1c, and T2 adenocarcinoma of the prostate who had a pretreatment PSA level and had received >or=60 Gy as definitive external beam radiotherapy. No patient had hormonal therapy before treatment failure. The median follow-up was 6.3 years. The end point for outcome analysis was PSA disease-free survival at 5 and 8 years after therapy using the American Society for Therapeutic Radiology and Oncology (ASTRO) failure definition. RESULTS The PSA disease-free survival rate for the entire group of patients was 59% at 5 years and 53% at 8 years after treatment. For patients who had received >or=70 Gy, these percentages were 61% and 55%. Of the 4839 patients, 1582 had failure by the PSA criteria, 416 had local failure, and 329 had distant failure. The greatest risk of failure was at 1.5-3.5 years after treatment. The failure rate was 3.5-4.5% annually after 5 years, except in patients with Gleason score 8-10 tumors for whom it was 6%. In multivariate analysis for biochemical failure, pretreatment PSA, Gleason score, radiation dose, tumor stage, and treatment year were all significant prognostic factors. The length of follow-up and the effect of backdating as required by the ASTRO failure definition also significantly affected the outcome results. Dose effects were most significant in the intermediate-risk group and to a lesser degree in the high-risk group. No dose effect was seen at 70 or 72 Gy in the low-risk group. CONCLUSION As follow-up lengthens and outcome data accumulate in the PSA era, we continue to evaluate the efficacy and durability of radiotherapy as definitive therapy for early-stage prostate cancer. Similar studies with higher doses and more contemporary techniques will be necessary to explore more fully the potential of this therapeutic modality.

Intrafraction prostate motion during IMRT for prostate cancer.

PURPOSE Although the interfraction motion of the prostate has been previously studied through the use of fiducial markers, CT scans, and ultrasound-based systems, intrafraction motion is not well documented. In this report, the B-mode, Acquisition, and Targeting (BAT) ultrasound system was used to measure intrafraction prostate motion during 200 intensity-modulated radiotherapy (IMRT) sessions for prostate cancer. METHODS AND MATERIALS Twenty men receiving treatment with IMRT for clinically localized prostate cancer were selected for the study. Pre- and posttreatment BAT ultrasound alignment images were collected immediately before and after IMRT on 10 treatment days for a total of 400 BAT alignment procedures. Any ultrasound shifts of the prostate borders in relation to the planning CT scan were recorded in 3 dimensions: right-left (RL), anteroposterior (AP), and superior-inferior (SI). Every ultrasound procedure was evaluated for image quality and alignment according to a 3-point grading scale. RESULTS All the BAT images were judged to be of acceptable quality and alignment. The dominant directions of intrafraction prostate motion were anteriorly and superiorly. The mean magnitude of shifts (+/-SD) was 0.01 +/- 0.4 mm, 0.2 +/- 1.3 mm, and 0.1 +/- 1.0 mm in the left, anterior, and superior directions, respectively. The maximal range of motion occurred in the AP dimension, from 6.8 mm anteriorly to 4.6 mm posteriorly. The percentage of treatments during which prostate motion was judged to be <or=5 mm was 100%, 99%, and 99.5% in the RL, AP, and SI directions, respectively. Three of the measurements were >5 mm. The extent of intrafraction motion was much smaller than that of interfraction motion. Linear regression analysis showed very little correlation between the two types of motion (r = 0.014, 0.029, and 0.191, respectively) in the RL, AP, and SI directions. CONCLUSION Using an ultrasound-based system, intrafraction prostate motion occurred predominantly in the anterior and superior directions, but was clinically insignificant. Intrafraction motion was much smaller than interfraction motion, and the two types of movement did not correlate.

LONG-TERM FAILURE PATTERNS AND SURVIVAL IN A RANDOMIZED DOSE-ESCALATION TRIAL FOR PROSTATE CANCER. WHO DIES OF DISEASE?

PURPOSE To report long-term failure patterns and survival in a randomized radiotherapy dose escalation trial for prostate cancer. MATERIALS AND METHODS A total of 301 patients with Stage T1b-T3 prostate cancer treated to 70 Gy versus 78 Gy now have a median follow-up of 9 years. Failure patterns and survival were compared between dose levels. The cumulative incidence of death from prostate cancer versus other causes was examined and regression analysis was used to establish predictive factors. RESULTS Patients with pretreatment prostate-specific antigen (PSA) >10 ng/mL or high-risk disease had higher biochemical and clinical failures rates when treated to 70 Gy. These patients also had a significantly higher risk of dying of prostate cancer. Patients <70 years old at treatment died of prostate cancer nearly three times more frequently than of other causes when they were radiated to 70 Gy, whereas those treated to 78 Gy died of other causes more frequently. Patients age 70 or older treated to 70 Gy died of prostate cancer as often as other causes, and those receiving 78 Gy never died of prostate cancer within 10 years of follow-up. In regression analysis, factors predicting for death from prostate cancer were pretreatment PSA >10.5 ng/mL, Gleason score 9 and 10, recurrence within 2.6 years of radiation, and doubling time of <3.6 months at the time of recurrence. CONCLUSIONS Moderate dose escalation (78 Gy) decreases biochemical and clinical failure as well as prostate cancer death in patients with pretreatment PSA >10 ng/mL or high-risk disease.

QUALITY OF LIFE AFTER TREATMENT FOR LOCALIZED PROSTATE CANCER: DIFFERENCES BASED ON TREATMENT MODALITY

PURPOSE Brachytherapy with 103palladium (103Pd) is an increasingly administered treatment modality for localized prostate cancer. We compared general and disease specific health related quality of life after 103Pd treatment, radical prostatectomy and external beam radiation therapy given during the same time frame. MATERIALS AND METHODS We performed a retrospective cross-sectional survey study of patients treated at a single community medical center between 1995 and 1999. We mailed 5 validated health related quality of life survey instruments to 269, 142 and 222 men who underwent radical prostatectomy, 103Pd treatment and external beam radiation therapy, respectively, with a response rate of greater than 80% in all groups. RESULTS General health related quality of life assessed by the SF-36 showed the same scores in patients who underwent prostatectomy and 103Pd treatment. The University of California-Los Angeles Prostate Cancer Index was used to assess bowel, urinary and sexual function/bothersomeness. External beam radiation therapy reported was associated with worse bowel function and greater bowel bothersomeness. Prostatectomy was associated with worse urinary function compared to 103Pd and external beam radiation therapy. Prostatectomy was associated with worse sexual function than 103Pd or external beam radiation therapy, although nerve sparing surgery and erectile aids minimized the difference. American Urological Association symptom scores were initially higher for 103Pd but became equal to those in the other groups in patients treated greater than 12 months from survey time. Disease-free men who underwent prostatectomy and 103Pd brachytherapy were equally confident that cancer would not recur in the future. Satisfaction rates were equivalent and biochemical failure significantly decreased satisfaction in all groups. CONCLUSIONS While general health related quality of life was mostly unaffected by the 3 most common treatments for prostate cancer, there were differences in bowel, urinary and sexual function. This information may aid patients in the decision making process.

Experience of ultrasound-based daily prostate localization

PURPOSE The NOMOS (Sewickley, PA) B-mode Acquisition and Targeting System (BAT) ultrasound system provides a rapid means of correcting for interfraction prostate positional variation. In this investigation, we report our experience on the clinical issues relevant to the daily use of the BAT system and the analysis of combined setup error and organ motion for 3509 BAT alignment procedures in 147 consecutive patients treated with IMRT for prostate cancer. METHODS AND MATERIALS After setup to external skin marks, therapists performed the BAT ultrasound alignment procedure before each IMRT treatment. In this study, a single physician (A.C.) reviewed all BAT images and classified image quality and accuracy of image alignment by the therapist. On a scale of 1-3, near-perfect image quality or alignment was given a 1, fair image quality or misalignment > or = 5 mm (likely within the PTV) was given a 2, and unacceptable image quality or misalignment >5 mm (potential to violate the PTV) was given a value of 3. The distribution of shifts made was analyzed in each dimension and for all patients. The time required to perform the BAT alignment was also assessed in 17 patients. RESULTS Among the 3509 attempted BAT procedures, the image quality was judged to be poor or unacceptable in 5.1% (181). Of the remaining 3328 BAT images, with quality scores of 1-2, alignments were unacceptable (>5 mm misalignment as judged by the reviewing physician) in 3% (100). The mean shift in each direction, averaged over all patients, was 0.5-0.7 mm. Interfraction standard deviation (1 SD) of prostate position based on combined setup error and internal organ motion is 4.9 mm, 4.4 mm, and 2.8 mm in the anteroposterior (AP), superior-inferior (SI), and lateral (RL) dimensions, respectively. The distribution of the shifts was a near-random Gaussian-type in all three major axes, with greater variations in AP and SI directions. The percent of BAT procedures in which the shift was >5 mm was 28.6% in AP, 23% in SI, and 9% in RL directions. The average BAT procedure took extra 5 min out of a 20-min time slot in a typical eight-field IMRT treatment. CONCLUSIONS The quality of the daily ultrasound images was deemed acceptable in 95%. Major alignment errors by therapists were only 3%. The BAT system is clinically effective and feasible in a matter of 5 min. Although the accuracy of the BAT was not addressed in this investigation, we found a significant percentage of large shifts being made from the initial alignment position.