Jeff M. Michalski

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.

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.

Radiation Dose–Volume Effects in Radiation-Induced Rectal Injury

The available dose/volume/outcome data for rectal injury were reviewed. The volume of rectum receiving >or=60 Gy is consistently associated with the risk of Grade >or=2 rectal toxicity or rectal bleeding. Parameters for the Lyman-Kutcher-Burman normal tissue complication probability model from four clinical series are remarkably consistent, suggesting that high doses are predominant in determining the risk of toxicity. The best overall estimates (95% confidence interval) of the Lyman-Kutcher-Burman model parameters are n = 0.09 (0.04-0.14); m = 0.13 (0.10-0.17); and TD(50) = 76.9 (73.7-80.1) Gy. Most of the models of late radiation toxicity come from three-dimensional conformal radiotherapy dose-escalation studies of early-stage prostate cancer. It is possible that intensity-modulated radiotherapy or proton beam dose distributions require modification of these models because of the inherent differences in low and intermediate dose distributions.

Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406

PURPOSE A prospective Phase I dose escalation study was conducted to determine the maximally-tolerated radiation dose in men treated with three-dimensional conformal radiation therapy (3D CRT) for localized prostate cancer. This is a preliminary report of toxicity encountered on the 3DOG/RTOG 9406 study. METHODS AND MATERIALS Each participating institution was required to implement data exchange with the RTOG 3D quality assurance (QA) center at Washington University in St. Louis. 3D CRT capabilities were strictly defined within the study protocol. Patients were registered according to three stratification groups: Group 1 patients had clinically organ-confined disease (T1,2) with a calculated risk of seminal vesicle invasion of < 15%. Group 2 patients had clinical T1,2 disease with risk of SV invasion > or = 15%. Group 3 (G3) patients had clinical local extension of tumor beyond the prostate capsule (T3). All patients were treated with 3D techniques with minimum doses prescribed to the planning target volume (PTV). The PTV margins were 5-10 mm around the prostate for patients in Group 1 and 5-10 mm around the prostate and SV for Group 2. After 55.8 Gy, the PTV was reduced in Group 2 patients to 5-10 mm around the prostate only. Minimum prescription dose began at 68.4 Gy (level I) and was escalated to 73.8 Gy (level II) and subsequently to 79.2 Gy (level III). This report describes the acute and late toxicity encountered in Group 1 and 2 patients treated to the first two study dose levels. Data from RTOG 7506 and 7706 allowed calculation of the expected probability of observing a > or = grade 3 late effect more than 120 days after the start of treatment. RTOG toxicity scores were used. RESULTS Between August 23, 1994 and July 2, 1997, 304 Group 1 and 2 cases were registered; 288 cases were analyzable for toxicity. Acute toxicity was low, with 53-54% of Group 1 patients having either no or grade 1 toxicity at dose levels I and II, respectively. Sixty-two percent of Group 2 patients had either none or grade 1 toxicity at either dose level. Few patients (0-3%) experienced a grade 3 acute bowel or bladder toxicity, and there were no grade 4 or 5 toxicities. Late toxicity was very low in all patient groups. The majority (81-85%) had either no or mild grade 1 late toxicity at dose level I and II, respectively. A single late grade 3 bladder toxicity in a Group 2 patient treated to dose level II was recorded. There were no grade 4 or 5 late effects in any patient. Compared to historical RTOG controls (studies 7506, 7706) at dose level I, no grade 3 or greater late effects were observed in Group 1 and Group 2 patients when 9.1 and 4.8 events were expected (p = 0.003 and p = 0.028), respectively. At dose level II, there were no grade 3 or greater toxicities in Group 1 patients and a single grade 3 toxicity in a Group 2 patient when 12.1 and 13.0 were expected (p = 0.0005 and p = 0.0003), respectively. Multivariate analysis demonstrated that the relative risk of developing acute bladder toxicity was 2.13 if the percentage of the bladder receiving > or = 65 Gy was more than 30% (p = 0.013) and 2.01 if patients received neoadjuvant hormonal therapy (p = 0.018). The relative risk of developing late bladder complications also increased as the percentage of the bladder receiving > or = 65 Gy increased (p = 0.026). Unexpectedly, there was a lower risk of late bladder complications as the mean dose to the bladder and prescription dose level increased. This probably reflects improvement in conformal techniques as the study matured. There was a 2.1 relative risk of developing a late bowel complication if the total rectal volume on the planning CT scan exceeded 100 cc (p = 0.019). CONCLUSION Tolerance to high-dose 3D CRT has been better than expected in this dose escalation trial for Stage T1,2 prostate cancer compared to low-dose RTOG historical experience. With strict quality assurance standards and review, 3D CRT can be safely studied in a co

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.

Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO guideline

PURPOSE The purpose of this guideline is to provide a clinical framework for the use of radiotherapy after radical prostatectomy as adjuvant or salvage therapy. MATERIALS AND METHODS A systematic literature review using the PubMed®, Embase, and Cochrane databases was conducted to identify peer-reviewed publications relevant to the use of radiotherapy after prostatectomy. The review yielded 294 articles; these publications were used to create the evidence-based guideline statements. Additional guidance is provided as Clinical Principles when insufficient evidence existed. RESULTS Guideline statements are provided for patient counseling, the use of radiotherapy in the adjuvant and salvage contexts, defining biochemical recurrence, and conducting a re-staging evaluation. CONCLUSIONS Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy (i.e., seminal vesicle invasion, positive surgical margins, extraprostatic extension) and should offer salvage radiotherapy to patients with prostatic specific antigen or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease. The offer of radiotherapy should be made in the context of a thoughtful discussion of possible short- and long-term side effects of radiotherapy as well as the potential benefits of preventing recurrence. The decision to administer radiotherapy should be made by the patient and the multi-disciplinary treatment team with full consideration of the patients history, values, preferences, quality of life, and functional status. Please visit the ASTRO and AUA websites (http://www.redjournal.org/webfiles/images/journals/rob/RAP%20Guideline.pdf and http://www.auanet.org/education/guidelines/radiation-after-prostatectomy.cfm) to view this guideline in its entirety, including the full literature review.

Adaptive modification of treatment planning to minimize the deleterious effects of treatment setup errors

PURPOSE Using daily setup variation measured from an electronic portal imaging device (EPID), radiation treatment of the individual patient can be adaptively reoptimized during the course of therapy. In this study, daily portal images were retrospectively examined to: (a) determine the number of initial days of portal imaging required to give adequate prediction of the systematic and random setup errors; and (b) explore the potential of using the prediction as feedback to reoptimize the individual treatment part-way through the treatment course. METHODS AND MATERIALS Daily portal images of 64 cancer patients, whose treatment position was not adjusted during the course of treatment, were obtained from two independent clinics with similar setup procedures. Systematic and random setup errors for each patient were predicted using different numbers of initial portal measurements. The statistical confidence of the predictions was tested to determine the number of daily portal measurements needed to give reasonable predictions. Two treatment processes were simulated to examine the potential opportunity for setup margin reduction and dose escalation. The first process mimicked a conventional treatment. A constant margin was assigned to each treatment field to compensate for the average setup error of the patient population. A treatment dose was then prescribed with reference to a fixed normal tissue tolerance, and then fixed in the entire course of treatment. In the second process, the same treatment fields and prescribed dose were used only for the initial plan and treatment. After several initial days of treatments, the treatment field shape and position were assumed to be adaptively modified using a computer-controlled multileaf collimator (MLC) in light of the predicted systematic and random setup errors. The prescribed dose was then escalated until the same normal tissue tolerance, as determined in the first treatment process, was reached. RESULTS The systematic setup error and the random setup error were predicted to be within +/-1 mm for the former and +/-0.5 mm for the latter at a > or = 95% confidence level using < or = 9 initial daily portal measurements. In the study, a large number of patients could be treated using a smaller field margin if the adaptive modification process were used. Simulation of the adaptive modification process for prostate treatment demonstrates that additional treatment dose could be safely applied to 64% of patients. CONCLUSION The adaptive modification process represents a different approach for use of on-line portal images. The portal imaging information from the initial treatments is used as feedback for reoptimization of the treatment plan, rather than adjustment of the treatment setup. Results from the retrospective study show that the treatment of individual patient can be improved with the adaptive modification process.

Toxicity after three-dimensional radiotherapy for prostate cancer on RTOG 9406 dose Level V

PURPOSE This is the first report of toxicity outcomes at dose Level V (78 Gy) on Radiation Therapy Oncology Group 9406 for Stages T1-T2 adenocarcinoma of the prostate. METHODS AND MATERIALS A total of 225 patients were entered in this cooperative group, Phase I-II dose-escalation trial of three-dimensional conformal radiotherapy for localized carcinoma of the prostate treated to a dose of 78 Gy (Level V). Of these patients, 219 were analyzed for acute and 218 for late toxicity. A minimum of 2 Gy/fraction was prescribed to the planning target volume (PTV). Patients were stratified according to the risk of seminal vesicle invasion as determined by Gleason score and presenting prostate-specific antigen level. Group 1 patients had clinical Stages T1-T2 tumors with a seminal vesicle invasion risk of <15%. Group 2 patients had clinical Stages T1-T2 tumors with a seminal vesicle invasion risk of >/=15%. Patients in Group 1 were prescribed 78 Gy to a prostate PTV. Patients in Group 2 were prescribed 54 Gy to the prostate and seminal vesicles (PTV1) followed by a boost to the prostate only (PTV2) to 78 Gy. PTV margins of between 5 and 10 mm were required. The average time at risk for late Grade 3+ toxicity after therapy completion was 23.2 and 23.1 months for Groups 1 and 2, respectively. The frequency of Grade 3 or worse late effects was compared with a similar group of patients treated in Radiation Therapy Oncology Group (RTOG) studies 7506 and 7706, with length of follow-up adjustments made for the interval from therapy completion. A second comparison was made with 170 patients treated to dose Level III (79.2 Gy in 1.8 Gy/fraction) to see whether the fraction size affected toxicity. Unlike other dose levels, patients treated at dose Level III had treatment prescribed as a minimum to the gross tumor volume. This effectively lowered the volume of the rectum treated to the study dose. RESULTS Acute toxicity at dose Level V (78 Gy) was remarkably low, with Grade 3 acute effects reported in only 4% of Group 1 and 2% of Group 2 patients. No Grade 4 or 5 acute toxicity was reported. There was no statistically significant difference in rates of acute toxicities in patients who were treated to 79.2 Gy at 1.8 Gy/fraction or 78 Gy at 2.0 Gy/fraction. Late toxicity continues to be low compared with RTOG historical controls. The observed rate of Grade 3 or worse late effects for Group 1 (6 cases) was significantly lower (p = 0.0042) than the 18.2 cases that would have been expected from the historical control. The observed rate for Group 2 (8 cases) was lower than the 15.5 cases expected, but this difference was not statistically significant (p = 0.06). A trend was noted that Group 2 patients treated on dose Level V had more late Grade 3 or worse toxicity than patients treated to a similar dose on Level III (7% vs. 1%, p = 0.06). A significantly (p < 0.0001) greater incidence of late Grade 2 or greater toxicity occurred in patients treated at dose Level V (30% and 33% for Groups 1 and 2, respectively) than at dose Level III (13% and 9% for Groups 1 and 2, respectively). The longer follow-up at dose Level III suggests these differences may increase with additional follow-up. CONCLUSION Tolerance to three-dimensional conformal radiotherapy with 78 Gy in 2-Gy fractions remains better than expected compared with historical controls. The magnitude of any effect from fraction size and treatment volume requires additional follow-up.

Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas

PURPOSE To define a male and female pelvic normal tissue contouring atlas for Radiation Therapy Oncology Group (RTOG) trials. METHODS AND MATERIALS One male pelvis computed tomography (CT) data set and one female pelvis CT data set were shared via the Image-Guided Therapy QA Center. A total of 16 radiation oncologists participated. The following organs at risk were contoured in both CT sets: anus, anorectum, rectum (gastrointestinal and genitourinary definitions), bowel NOS (not otherwise specified), small bowel, large bowel, and proximal femurs. The following were contoured in the male set only: bladder, prostate, seminal vesicles, and penile bulb. The following were contoured in the female set only: uterus, cervix, and ovaries. A computer program used the binomial distribution to generate 95% group consensus contours. These contours and definitions were then reviewed by the group and modified. RESULTS The panel achieved consensus definitions for pelvic normal tissue contouring in RTOG trials with these standardized names: Rectum, AnoRectum, SmallBowel, Colon, BowelBag, Bladder, UteroCervix, Adnexa_R, Adnexa_L, Prostate, SeminalVesc, PenileBulb, Femur_R, and Femur_L. Two additional normal structures whose purpose is to serve as targets in anal and rectal cancer were defined: AnoRectumSig and Mesorectum. Detailed target volume contouring guidelines and images are discussed. CONCLUSIONS Consensus guidelines for pelvic normal tissue contouring were reached and are available as a CT image atlas on the RTOG Web site. This will allow uniformity in defining normal tissues for clinical trials delivering pelvic radiation and will facilitate future normal tissue complication research.

Preliminary Toxicity Analysis of 3-Dimensional Conformal Radiation Therapy Versus Intensity Modulated Radiation Therapy on the High-Dose Arm of the Radiation Therapy Oncology Group 0126 Prostate Cancer Trial

PURPOSE To give a preliminary report of clinical and treatment factors associated with toxicity in men receiving high-dose radiation therapy (RT) on a phase 3 dose-escalation trial. METHODS AND MATERIALS The trial was initiated with 3-dimensional conformal RT (3D-CRT) and amended after 1 year to allow intensity modulated RT (IMRT). Patients treated with 3D-CRT received 55.8 Gy to a planning target volume that included the prostate and seminal vesicles, then 23.4 Gy to prostate only. The IMRT patients were treated to the prostate and proximal seminal vesicles to 79.2 Gy. Common Toxicity Criteria, version 2.0, and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late morbidity scores were used for acute and late effects. RESULTS Of 763 patients randomized to the 79.2-Gy arm of Radiation Therapy Oncology Group 0126 protocol, 748 were eligible and evaluable: 491 and 257 were treated with 3D-CRT and IMRT, respectively. For both bladder and rectum, the volumes receiving 65, 70, and 75 Gy were significantly lower with IMRT (all P<.0001). For grade (G) 2+ acute gastrointestinal/genitourinary (GI/GU) toxicity, both univariate and multivariate analyses showed a statistically significant decrease in G2+ acute collective GI/GU toxicity for IMRT. There were no significant differences with 3D-CRT or IMRT for acute or late G2+ or 3+ GU toxicities. Univariate analysis showed a statistically significant decrease in late G2+ GI toxicity for IMRT (P=.039). On multivariate analysis, IMRT showed a 26% reduction in G2+ late GI toxicity (P=.099). Acute G2+ toxicity was associated with late G3+ toxicity (P=.005). With dose-volume histogram data in the multivariate analysis, RT modality was not significant, whereas white race (P=.001) and rectal V70 ≥15% were associated with G2+ rectal toxicity (P=.034). CONCLUSIONS Intensity modulated RT is associated with a significant reduction in acute G2+ GI/GU toxicity. There is a trend for a clinically meaningful reduction in late G2+ GI toxicity with IMRT. The occurrence of acute GI toxicity and large (>15%) volumes of rectum >70 Gy are associated with late rectal toxicity.