Faculty Bibliography

PURPOSE/OBJECTIVE:This study aimed to evaluate the toxicity of prostate and pelvic lymph node stereotactic body radiation therapy (SBRT) for high-risk prostate cancer. METHODS AND MATERIALS/METHODS:Twenty-three patients with high-risk or lymph node-positive prostate cancer were treated with SBRT that delivered 37.5 to 40 Gy in 5 fractions to the prostate and seminal vesicles, with concomitant treatment of the pelvic nodes to 25 Gy. In general, patients received neoadjuvant, concurrent, and adjuvant androgen deprivation therapy for a duration of 18 months. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events, version 3.0. The median follow-up was 19 months (range, 3-48 months). RESULTS:Acute grade 1 gastrointestinal (GI) toxicities were noted in 2 patients (9.1%). No patient experienced acute grade ≥2 GI toxicity. Acute genitourinary (GU) grade 1, 2, and 3 toxicities were observed in 7 patients (31.8%), 8 patients (36.4%), and 1 patient (4.5%), respectively. Late grade 2 GI and GU toxicities were observed in 2 patients (9.1%) and 6 patients (27.3%), respectively. No late grade ≥3 GI toxicity was noted. Late grade ≥3 GU (hemorrhagic cystitis) was noted in 1 patient (4.5%), which responded to laser fulguration. CONCLUSIONS:SBRT with pelvic lymph node radiation therapy was feasible and well tolerated. The incidence of grade ≥3 GU and GI toxicities was uncommon. Continued follow-up will be required to determine the long-term safety and efficacy of this approach for high-risk patients.

PURPOSE/OBJECTIVE:To report 15-year outcomes for dose-escalated intensity modulated radiation therapy (IMRT) for localized prostate cancer (PC) by evaluating biochemical relapse, distant metastases, cancer-specific survival, and long-term toxicity. METHODS AND MATERIALS/METHODS:A database search was conducted for the first cohort of patients treated at this institution with 81 or 86.4 Gy between 1996 and 1998 using IMRT. Toxicity data were scored according to the Common Terminology Criteria for Adverse Events version 3.0. Median follow-up was 11.6 years (range, 5-21 years). RESULTS:In the study, 301 patients were treated with 81 Gy (n = 269, 89%) or 86.4 Gy (n = 32, 11%). Patients were analyzed by National Comprehensive Cancer Network risk group, with 29% low risk (LR), 49% intermediate risk (IR), and 22% high risk (HR). Late grade 3 gastrointestinal (GI) toxicity was seen in 3 patients (1.0%). No grade 4 GI toxicity events occurred. Median time from radiation therapy to late grade 3 GI toxicity was 2.9 years. One event occurred after 10 years. Late grade 3 and 4 genitourinary (GU) toxicity was seen in 6 (2.0%) and 1 (0.3%) patient, respectively. Median time to late grade 3+ GU toxicity was 5.5 years. Two events occurred after 10 years. In addition, 38 (12.6%) developed second primary malignancies (SPMs), 8 of which were in-field malignancies. Median time from radiation therapy to all SPM and in-field SPM was 10 years. The 15-year relapse-free survival was 76%, 65%, and 55% in the LR, IR, and HR groups, respectively. Distant metastases-free survival was 88%, 75%, and 63% for LR, IR, and HR patients, respectively. PC-specific mortality was 1.9%, 7.1%, and 12.2% for LR, IR, and HR patients. CONCLUSIONS:This report represents the longest follow-up data set to our knowledge of patients treated with high-dose IMRT for PC. Our findings indicate that it is well tolerated with 1.0% and 2.3% incidence of long-term grade 3+ GI and GU toxicity, respectively. The cohort had excellent PC-specific survival.

BACKGROUND:To determine if reduced dose delivery uncertainty is associated with daily image-guidance (IG) and Prostate Specific Antigen Relapse Free Survival (PRFS) in intensity-modulated radiotherapy (IMRT) of high-risk prostate cancer (PCa). METHODS:Planning data for consecutive PCa patients treated with IMRT (n = 67) and IG-IMRT (n = 35) was retrieved. Using computer simulations of setup errors, we estimated the patient-specific uncertainty in accumulated treatment dose distributions for the prostate and for posterolateral aspects of the gland that are at highest risk for extra-capsular disease. Multivariate Cox regression for PRFS considering Gleason score, T-stage, pre-treatment PSA, number of elevated clinical risk factors (T2c+, GS7+ and PSA10+), nomogram-predicted risk of extra-capsular disease (ECD), and dose metrics was performed. RESULTS:For IMRT vs. IG-IMRT, plan dosimetry values were similar, but simulations revealed uncertainty in delivered dose external to the prostate was significantly different, due to positioning uncertainties. A patient-specific interaction term of the risk of ECD and risk of low dose to the ECD (p = 0.005), and the number of elevated clinical risk factors (p = 0.008), correlate with reduced PRFS. CONCLUSIONS:Improvements in PSA outcomes for high-risk PCa using IG-IMRT vs. IMRT without IG may be due to improved dosimetry for ECD.

PURPOSE:To investigate whether inter-institutional cohort analysis uncovers more reliable dose-response relationships exemplified for late rectal bleeding (LRB) following prostate radiotherapy. MATERIAL AND METHODS:Data from five institutions were used. Rectal dose-volume histograms (DVHs) for 989 patients treated with 3DCRT or IMRT to 70-86.4 Gy@1.8-2.0 Gy/fraction were obtained, and corrected for fractionation effects (α/β = 3 Gy). Cohorts with best-fit Lyman-Kutcher-Burman volume-effect parameter a were pooled after calibration adjustments of the available LRB definitions. In the pooled cohort, dose-response modeling (incorporating rectal dose and geometry, and patient characteristics) was conducted on a training cohort (70%) followed by final testing on the remaining 30%. Multivariate logistic regression was performed to build models with bootstrap stability. RESULTS: = 0.63), indicating a logistically shaped dose-response. CONCLUSION:We have demonstrated the importance of integrating datasets from multiple institutions, thereby reducing the impact of intra-institutional dose-volume parameters explicitly correlated with prescription dose levels. This uncovered an unexpected emphasis on sparing of the low to intermediate rectal dose range in the etiology of late rectal bleeding following prostate radiotherapy.

PURPOSE:To evaluate the difference in prostate-specific antigen (PSA) recurrence-free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). METHODS AND MATERIALS:During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75 Gy with ≥5 years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6 months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0 Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2 ng/mL. Median follow-up was 9.2 years (interquartile range, 6.9-11.3 years). RESULTS:One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6 months (interquartile range, 16.1-38.5 months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004). CONCLUSIONS:Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have improved PSA recurrence-free survival, distant metastasis-free survival, overall survival, and cancer-specific survival outcomes.