Patient Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test. RESULTS: The study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. CONCLUSIONS: This study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

Free prostate-specific antigen improves prostate cancer detection in a high-risk population of men with a normal total PSA and digitalrectal examination.

OBJECTIVES: Uncertainty exists regarding optimal prostate cancer screening parameters for high-risk populations. The purpose of this study is to report the use of percent free prostate-specific antigen (PSA) as an indication for biopsy in men at increased risk for developing prostate cancer who have a normal digital rectal examination (DRE) and total PSA level between 2 and 4 ng/mL. METHODS: African-American men and men with at least one first-degree relative with prostate cancer are eligible for enrollment into the Prostate Cancer Risk Assessment Program (PRAP) at our institution. Between October 1996 and April 2002, 310 asymptomatic high-risk men with no history of prostate cancer, benign prostatic hyperplasia (BPH), or prostatic intraepithelial neoplasia (PIN) were screened in the PRAP with DRE and total PSA. Percent free PSA was obtained in men with a total PSA between 2 and 10 ng/mL. Men with a normal DRE and total PSA between 2 and 4 ng/mL were advised to undergo transrectal ultrasound-guided (TRUS) biopsies of the prostate if the percent free PSA was less than 27%. Other indications for biopsy included an abnormal DRE or a total PSA greater than 4 ng/mL. The primary endpoint evaluated was prostate cancer detection in high-risk men with a benign prostate examination, a normal total PSA between 2 and 4 ng/mL, and percent free PSA less than 27%. RESULTS: Of the 310 men, 174 (56%) were African American and 202 (65%) had at least one first-degree relative with prostate cancer. Sixty-two of the 310 men were referred for prostate biopsy, and 40 of 62 had biopsy performed. Twenty-one of 40 men were diagnosed with prostate cancer for a cancer detection rate of 53% in all men undergoing biopsy and an overall cancer detection rate of 6.8% in this high-risk population. Thirty-seven high-risk men (median age 54 years) with a total PSA level between 2 and 4 ng/mL (median 2.7 ng/mL) and a normal DRE were found to have a percent free PSA level of less than 27% (median 16%, range 8% to 25%). Twenty-three of these 37 men (62%) proceeded with the recommended prostate biopsy. Prostatic adenocarcinoma was diagnosed in 12 of 23 men for a cancer detection rate of 52% in men undergoing biopsy and 32% in all men with a normal DRE, a total PSA between 2 and 4 ng/mL, and a percent free PSA less than 27%. All positive biopsies demonstrated clinically significant Gleason score 6 or 7 disease. In all men electing radical prostatectomy, bilateral organ-confined disease (pT2bN0M0) was confirmed. CONCLUSIONS: In this unique population of men at high risk for prostate cancer, a percent free PSA of less than 27% was found to be useful for detecting early-stage but clinically significant cancers in men with a total PSA value between 2 and 4 ng/mL and normal DRE findings.

Impact of target volume coverage with Radiation Therapy Oncology Group (RTOG) 98-05 guidelines for transrectal ultrasound guided permanent Iodine-125 prostate implants.

PURPOSE: Despite the wide use of permanent prostate implants for the treatment of early stage prostate cancer, there is no consensus for optimal pre-implant planning guidelines that results in maximal post-implant target coverage. The purpose of this study was to compare post-implant target volume coverage and dosimetry between patients treated before and after Radiation Therapy Oncology Group (RTOG) 98-05 guidelines were adopted using several dosimetric endpoints. MATERIALS AND METHODS: Ten consecutively treated patients before the adoption of the RTOG 98-05 planning guidelines were compared with ten consecutively treated patients after implementation of the guidelines. Pre-implant planning for patients treated pre-RTOG was based on the clinical target volume (CTV) defined by the pre-implant TRUS definition of the prostate. The CTV was expanded in each dimension according to RTOG 98-05 and defined as the planning target volume. The evaluation target volume was defined as the post-implant computed tomography definition of the prostate based on RTOG 98-05 protocol recommendations. Implant quality indicators included V(100), V(90), V(100), and Coverage Index (CI). RESULTS: The pre-RTOG median V(100), V(90), D(90), and CI values were 82.8, 88.9%, 126.5 Gy, and 17.1, respectively. The median post-RTOG V(100), V(90), D(90), and CI values were 96.0, 97.8%, 169.2 Gy, and 4.0, respectively. These differences were all statistically significant. CONCLUSIONS: Implementation of the RTOG 98-05 implant planning guidelines has increased coverage of the prostate by the prescription isodose lines compared with our previous technique, as indicated by post-implant dosimetry indices such as V(100), V(90), D(90). The CI was also improved significantly with the protocol guidelines. Our data confirms the validity of the RTOG 98-05 implant guidelines for pre-implant planning as it relates to enlargement of the CTV to ensure adequate margin between the CTV and the prescription isodose lines.

Validation of a treatment policy for patients with prostate specific antigen failure after three-dimensional conformal prostate radiation therapy.

BACKGROUND: The objective of this report was to present an outcomes validation for the Fox Chase Cancer Center (FCCC) management policy for patients who demonstrate prostate specific antigen (PSA) failure after receiving three-dimensional conformal radiation therapy (3DCRT). METHODS: Eligible patients included 248 men with T1-T3N0M0 prostate carcinoma who demonstrated PSA failure (according to the American Society for Therapeutic Radiology and Oncology definition) after completing definitive 3DCRT alone or with androgen deprivation (AD) therapy between May 1989 and November 1997. The primary endpoint evaluated was freedom from distant metastasis (FDM). The secondary endpoints evaluated included cause specific survival (CSS) and overall survival (OS). The variables evaluated in the multivariate analyses (MVA) included initial PSA, Gleason score, T classification, dose, PSA nadir, time to PSA failure, PSA doubling time (PSADT), initial use of AD therapy, and the use of AD therapy upon PSA failure. RESULTS: The 5-year FDM, CSS, and OS rates for the entire group were 76%, 92%, and 76%, respectively. It was found that four variables were independent predictors of FDM: Gleason score (P = 0.0039), PSA nadir (P = 0.0001), PSADT (P = 0.0001), and the use of AD on PSA failure (P = 0.0001). One hundred forty-eight men demonstrated a PSADT < 12 months. AD therapy was started in 59 men, and 89 men refused AD therapy and were observed. The use of AD therapy was associated with a significant improvement in the 5-year FDM rate (57% vs. 78%; P = 0.0026). In the group of men with PSADT < 12 months, the median time to distant failure was significantly longer in the men who received AD therapy (6 months vs. 25 months; P = 0.02). Of the 100 men with a PSADT > or = 12 months, 89 men were observed, and 11 men received AD therapy. There was no improvement in the 5-year FDM rate with the use of AD therapy compared with observation (88% vs. 92%, respectively; P = 0.74). CONCLUSIONS: The current results validate the use of PSADT as an indicator of patients who may be observed expectantly or treated with AD therapy for PSA failure after 3DCRT. Prospective trials are needed to define further the optimal treatment for these patients.

Late morbidity profiles in prostate cancer patients treated to 79-84 Gy by a simple four-field coplanar beam arrangement.

PURPOSE: To describe the frequency and magnitude of late GI and GU morbidity in prostate cancer patients treated to high dose levels with a simple three-dimensional conformal technique. METHODS AND MATERIALS: A total of 156 intermediate- and high-risk patients were treated between January 1, 1992 and February 28, 1999 with a simple four-field three-dimensional conformal technique to 79-84 Gy. All patients were treated with a four-field conformal technique; the prostate received 82 Gy and the seminal vesicles and periprostatic tissue 46 Gy. GI and GU toxicity was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Morbidity Grading Scale and compared using Kaplan-Meier estimates. RESULTS: The late Grade 2 GI complication rate was 9% and 38% at 3 years for patients treated with and without rectal blocking, respectively (p = 0.0004). No Grade 3 late GI complications developed. The rate of Grade 2 late GU complications was 5%, 8%, and 12% at 12, 24, and 36 months, respectively. The Grade 3 late GU complication rate was 2% at 36 months. These differences were not statistically significant. CONCLUSION: The treatment method described is a simple four-field conformal technique that can be easily implemented in the general radiation community. A dose of 79-84 Gy can be safely delivered to the prostate, with a 9% rate of late Grade 2 GI, 12% rate of late Grade 2 GU, and 2% rate of late Grade 3 GU complications.

Advantages of using noncoplanar vs. axial beam arrangements when treating prostate cancer with intensity-modulated radiation therapy and the step-and-shoot delivery method.

PURPOSE: The focus of this work was to compare noncoplanar beam arrangements used for intensity-modulated radiation therapy (IMRT) step-and-shoot delivery to several axial beam arrangements used in the treatment of clinically localized prostate cancer. METHODS AND MATERIALS: A 5-field coronal crossfire beam arrangement was developed for IMRT with the objective of improving upon the rectal and bladder dose-volume histograms obtained using 5-, 7-, and 9-field axial beam arrangements. Additionally, a modified 7-field crossfire technique was developed yielding improved dose distributions. The average values of dose-volume histograms and the time for treatment delivery were evaluated for all plans for 10 randomly chosen patients. RESULTS: Both crossfire IMRT techniques exhibited a 15-25% decrease in dose to the hottest 10% and 20% of the rectum relative to all three axial IMRT techniques. The 5-field crossfire orientation yields slightly higher bladder doses when compared to the other techniques. In selected cases, the 7-field crossfire beam arrangement demonstrates decreased dose to the bladder when compared to all three axial techniques. A mean delivery time of 14 to 17.5 min is noted for the noncoplanar arrangements after positioning and localization. CONCLUSIONS: A technique is described that allows additional normal tissue sparing during dose escalation to the prostate during IMRT delivery. This technique takes advantage of the spatial orientation between the prostate, rectum, and bladder. With patient setup and target localization time aside, a mean treatment time of 14 to 17.5 min allows the delivery of the crossfire plans to conform to standard treatment times.

Biochemical failure rates in prostate cancer patients predicted to have biologically insignificant tumors treated with three-dimensional conformal radiation therapy.

PURPOSE: It has been suggested that patients with prostate cancer meeting the following criteria have pathologically determined potentially biologically insignificant (PBI) tumor and therefore should be considered for observation: clinical stage T1c, PSA density <0.1 ng/mL per gram, absence of Gleason pattern 4 or 5, three or fewer biopsy cores positive for tumor, and tumor involvement of no more than 50% of any core. We compared the biochemical control rates in men meeting the above criteria to those of all low-risk patients (clinical T1c, PSA

Relationship between prostate volume, prostate-specific antigen nadir, and biochemical control.

PURPOSE: In patients treated with definitive three-dimensional conformal radiotherapy (3D-CRT) for localized prostatic adenocarcinoma, we sought to evaluate the relationship between pretreatment prostate gland volume and posttreatment prostate-specific antigen (PSA) nadir, as well as the relationship of prostate volume and PSA nadir with biochemical control (bNED). Two subgroups were studied: favorable (PSA <10 ng/mL, Gleason score 2-6, and T1-T2A) and unfavorable (one or more: PSA >/=10 ng/mL, Gleason score 7-10, T2B-T3). MATERIALS AND METHODS: A total of 655 men (n = 271 favorable and 384 unfavorable) were treated with 3D-CRT alone between May 1989 and November 1997. All patients had information on prostate volume and a minimum follow-up of 24 months (median 56, range 24-126). Of the 655 men, 481 (n = 230 favorable and 251 unfavorable) remained bNED at time of analysis, with biochemical failure defined in accordance with the American Society for Therapeutic Radiology and Oncology consensus definition. Factors analyzed for predictors of bNED included pretreatment prostate volume, posttreatment PSA nadir, pretreatment PSA, palpation T stage, Gleason score, center of the prostate dose, and perineural invasion (PNI). We also analyzed pretreatment prostate volume and its correlation to prognostic factors. For bNED patients, the relationship between PSA nadir and prostate volume was evaluated. RESULTS: On multivariate analysis, prostate volume (p = 0.04) and palpation T stage (p = 0.02) were the only predictors of biochemical failure in the favorable group. On multivariate analysis of the unfavorable group, pretreatment PSA (p <0.0001), Gleason score (p = 0.02), palpation T stage (p = 0.009), and radiation dose (p <0.0001) correlated with biochemical failure, and prostate volume and PNI did not. For all 481 bNED patients, a positive correlation between pretreatment volume and PSA nadir was demonstrated (p <0.0001). Subgroup analysis of the favorable and unfavorable patients also demonstrated a positive correlation between prostate volume and PSA nadir (p = 0.003 and p = 0.0002, respectively). Using multiple regression analysis, the following were found to be predictive of PSA nadir in all bNED patients: prostate volume (p <0.0001), pretreatment PSA (p <0.0001), palpation T stage (p = 0.0002), and radiation dose (p = 0.0034). Gleason score and PNI were not predictive. For the favorable group, palpation T stage (p = 0.0006), pretreatment PSA (p = 0.0083), prostate volume (p = 0.0186), and Gleason score (p = 0.0592) were predictive of PSA nadir, and PNI and radiation dose were not predictive. In the unfavorable group, prostate volume (p = 0.0024), radiation dose (p = 0.0039), pretreatment PSA (p = 0.0182), and palpation T stage (p = 0.0296) were predictive of PSA nadir, and Gleason score and PNI were not predictive. CONCLUSION: This report is the first demonstration that prostate volume is predictive of PSA nadir for patients who are bNED in both favorable and unfavorable subgroups. PSA nadir did not correlate with bNED status in the favorable patients, but it was strongly predictive in the unfavorable patients. Prostate gland volume was also predictive of bNED failure in the favorable but not the unfavorable group.