Seungtaek Choi

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.

Risk of Late Toxicity in Men Receiving Dose-Escalated Hypofractionated Intensity Modulated Prostate Radiation Therapy: Results From a Randomized Trial

OBJECTIVE To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment. METHODS AND MATERIALS Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria. RESULTS 101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P<.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy < 20% (P=.016). CONCLUSIONS Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this hypofractionation regimen.

QUANTIFICATION OF PROSTATE AND SEMINAL VESICLE INTERFRACTION VARIATION DURING IMRT

PURPOSE To quantify the interfraction variability in prostate and seminal vesicle (SV) positions during a course of intensity-modulated radiotherapy (IMRT) using an integrated computed tomography (CT)-linear accelerator system and to assess the impact of rectal and bladder volume changes. METHODS AND MATERIALS We studied 15 patients who had undergone IMRT for prostate carcinoma. Patients had one pretreatment planning CT scan followed by three in-room CT scans per week using a CT-on-rails system. The prostate, bladder, rectum, and pelvic bony anatomy were contoured in 369 CT scans. Using the planning CT scan as a reference, the volumetric and positional changes were analyzed in the subsequent CT scans. RESULTS For all 15 patients, the mean systematic internal prostate and SV variation was 0.1 +/- 4.1 mm and 1.2 +/- 7.3 mm in the anteroposterior axis, -0.5 +/- 2.9 mm and -0.7 +/- 4.5 mm in the superoinferior axis, and 0.2 +/- 0.9 mm and -0.9 +/- 1.9 mm in the lateral axis, respectively. The mean magnitude of the three-dimensional displacement vector was 4.6 +/- 3.5 mm for the prostate and 7.6 +/- 4.7 mm for the SVs. The rectal and bladder volume changes during treatment correlated with the anterior and superior displacement of the prostate and SVs. CONCLUSION The dominant prostate and SV variations occurred in the anteroposterior and superoinferior directions. The systematic prostate and SV variation between the treatment planning CT and daily therapy as a result of the rectal and bladder volume changes emphasizes the need for daily directed target localization and/or immobilization techniques.

Patient-specific quality assurance for prostate cancer patients receiving spot scanning proton therapy using single-field uniform dose

PURPOSE To describe our experiences with patient-specific quality assurance (QA) for patients with prostate cancer receiving spot scanning proton therapy (SSPT) using single-field uniform dose (SFUD). METHODS AND MATERIALS The first group of 249 patients with prostate cancer treated with SSPT using SFUD was included in this work. The scanning-beam planning target volume and number of monitor units were recorded and checked for consistency. Patient-specific dosimetric measurements were performed, including the point dose for each plan, depth doses, and two-dimensional (2D) dose distribution in the planes perpendicular to the incident beam direction for each field at multiple depths. The γ-index with 3% dose or 3-mm distance agreement criteria was used to evaluate the 2D dose distributions. RESULTS We observed a linear relationship between the number of monitor units and scanning-beam planning target volume. The difference between the measured and calculated point doses (mean ± SD) was 0.0% ± 0.7% (range, -2.9% to 1.8%). In general, the depth doses exhibited good agreement except at the distal end of the spread-out Bragg peak. The pass rate of γ-index (mean ± SD) for 2D dose comparison was 96.2% ± 2.6% (range, 90-100%). Discrepancies between the measured and calculated dose distributions primarily resulted from the limitation of the model used by the treatment planning system. CONCLUSIONS We have established a patient-specific QA program for prostate cancer patients receiving SSPT using SFUD.

MR Imaging of Prostate Cancer in Radiation Oncology: What Radiologists Need to Know

Radiation therapy (RT) is one of the principal treatment modalities for localized or locally advanced prostate cancer. The two major forms of RT for prostate cancer are external-beam RT (EBRT) with a photon or proton beam and brachytherapy. With modern conformal techniques for EBRT (three-dimensional conformal RT, intensity-modulated RT, and image-guided RT) and advanced computer-based planning systems for brachytherapy, the dose can be more precisely delivered to the prostate while reducing unnecessary radiation to normal tissue. The dominant intraprostatic tumor can be targeted with a higher dose, so-called dose painting. Magnetic resonance (MR) imaging plays a pivotal role in pretreatment assessment of prostate cancer. Multiparametric MR imaging, a combination of anatomic and functional MR imaging techniques (diffusion-weighted imaging, dynamic contrast material-enhanced imaging, and MR spectroscopy), significantly improves the accuracy of tumor localization and local staging. For pretreatment planning, anatomic MR imaging provides highly accurate local staging information, particularly about extraprostatic extension and seminal vesicle invasion. The dominant intraprostatic tumor and local recurrence in the prostatectomy bed can be better localized with multiparametric MR imaging for dose painting. MR imaging allows excellent delineation of the contours of the prostate and surrounding structures. It can also be used in early posttreatment evaluation after brachytherapy.

Intensity modulated proton therapy treatment planning using single-field optimization: The impact of monitor unit constraints on plan quality

PURPOSE To investigate the effect of monitor unit (MU) constraints on the dose distribution created by intensity modulated proton therapy (IMPT) treatment planning using single-field optimization (SFO). METHODS Ninety-four energies between 72.5 and 221.8 MeV are available for scanning beam IMPT delivery at our institution. The minimum and maximum MUs for delivering each pencil beam (spot) are 0.005 and 0.04, respectively. These MU constraints are not considered during optimization by the treatment planning system; spots are converted to deliverable MUs during postprocessing. Treatment plans for delivering uniform doses to rectangular volumes with and without MU constraints were generated for different target doses, spot spacings, spread-out Bragg peak (SOBP) widths, and ranges in a homogeneous phantom. Four prostate cancer patients were planned with and without MU constraints using different spot spacings. Rounding errors were analyzed using an in-house software tool. RESULTS From the phantom study, the authors have found that both the number of spots that have rounding errors and the magnitude of the distortion of the dose distribution from the ideally optimized distribution increases as the field dose, spot spacing, and range decrease and as the SOBP width increases. From our study of patient plans, it is clear that as the spot spacing decreases the rounding error increases, and the dose coverage of the target volume becomes unacceptable for very small spot spacings. CONCLUSIONS Constraints on deliverable MU for each spot could create a significant distortion from the ideally optimized dose distributions for IMPT fields using SFO. To eliminate this problem, the treatment planning system should incorporate the MU constraints in the optimization process and the delivery system should reliably delivery smaller minimum MUs.

Spot Scanning Proton Beam Therapy for Prostate Cancer: Treatment Planning Technique and Analysis of Consequences of Rotational and Translational Alignment Errors

PURPOSE Conventional proton therapy with passively scattered beams is used to treat a number of tumor sites, including prostate cancer. Spot scanning proton therapy is a treatment delivery means that improves conformal coverage of the clinical target volume (CTV). Placement of individual spots within a target is dependent on traversed tissue density. Errors in patient alignment perturb dose distributions. Moreover, there is a need for a rational planning approach that can mitigate the dosimetric effect of random alignment errors. We propose a treatment planning approach and then analyze the consequences of various simulated alignment errors on prostate treatments. METHODS AND MATERIALS Ten control patients with localized prostate cancer underwent treatment planning for spot scanning proton therapy. After delineation of the clinical target volume, a scanning target volume (STV) was created to guide dose coverage. Errors in patient alignment in two axes (rotational and yaw) as well as translational errors in the anteroposterior direction were then simulated, and dose to the CTV and normal tissues were reanalyzed. RESULTS Coverage of the CTV remained high even in the setting of extreme rotational and yaw misalignments. Changes in the rectum and bladder V45 and V70 were similarly minimal, except in the case of translational errors, where, as a result of opposed lateral beam arrangements, much larger dosimetric perturbations were observed. CONCLUSIONS The concept of the STV as applied to spot scanning radiation therapy and as presented in this report leads to robust coverage of the CTV even in the setting of extreme patient misalignments.

Is androgen deprivation therapy necessary in all intermediate-risk prostate cancer patients treated in the dose escalation era?

PURPOSE The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). METHODS Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. RESULTS Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). CONCLUSIONS Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose-escalated RT did improve FFF.

Treatment margins predict biochemical outcomes after prostate brachytherapy

PURPOSEDue to the theoretical role of treatment margins (TMs) in cancer, we have correlated biochemical outcomes with post-implant TMs in patients treated with brachytherapy for early stage prostate cancer. METHODSFrom November 1998 through September 2003, 492 of a planned total of 600 patients with 1997 AJC clinical stage T1c–T2a prostatic carcinoma (Gleason score 5 or 6, PSA 4 to 10 ng/mL) have been randomized to implantation with 125I (144 Gy, TG-43) versus 103Pd (125 Gy, NIST-99). This preliminary analysis included only the first 122 analyzable patients, while accrual to the trial finishes. Isotope implantation was performed by standard techniques, using a modified peripheral loading pattern. Axial CT images at 3 mm intervals were acquired within four hours postoperatively for post-implant dosimetry. The contoured images and sources were entered into Varian Variseed™ system 7.1 (Charlottesville, VA). After completion of standard dosimetric calculations, the 100% prescription dose TMs were measured and tabulated around the prostate periphery at the 0.0, 1.0, 2.0 and 3.0 cm planes, going distal from the bladder-prostate interface. Measurements were limited to the transverse planes. Freedom from biochemical failure was defined as a serum PSA ≤ 0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum PSA was still decreasing. Patients whose serum PSA nadired at a value >0.5 ng/mL were scored as failures at the time at which their PSA nadired. The follow-up period for non-failing patients ranged from 2.1–5.0 years (median: 3.3 years). RESULTSThe average 100% prescription dose treatment margin (for individual patients) ranged from – 5.0 to 8.7 mm, with an overall average of 2.6 mm (± 3.1). In univariate analysis, the D90 was the best predictor of biochemical control for 125I, while the average TM was the best predictor for 103Pd. Similarly, in multivariate analysis using the D90, V100, and average TM as the independent variables and biochemical control as the dependent variable, the D90 was most closely related to biochemical control for 125I patients, while average TM was most closely related for 103Pd patients. In separate analysis of TM by site, the anterior TMs were the best predictors of biochemical outcomes CONCLUSIONV100, D90, and TMs all appear to have a bearing on biochemical freedom from relapse after prostate brachytherapy. Efforts to better identify and test geographic dosimetric parameters are theoretically appealing, and supported by the clinical data summarized here.

Dosimetric Changes Resulting From Patient Rotational Setup Errors in Proton Therapy Prostate Plans

PURPOSE To evaluate the dose changes to the target and critical structures from rotational setup errors in prostate cancer patients treated with proton therapy. METHODS AND MATERIALS A total of 70 plans were analyzed for 10 patients treated with parallel-opposed proton beams to a dose of 7,600 (60)Co-cGy-equivalent (CcGE) in 200 CcGE fractions to the clinical target volume (i.e., prostate and proximal seminal vesicles). Rotational setup errors of +3 degrees , -3 degrees , +5 degrees , and -5 degrees (to simulate pelvic tilt) were generated by adjusting the gantry. Horizontal couch shifts of +3 degrees and -3 degrees (to simulate longitudinal setup variability) were also generated. Verification plans were recomputed, keeping the same treatment parameters as the control. RESULTS All changes shown are for 38 fractions. The mean clinical target volume dose was 7,780 CcGE. The mean change in the clinical target volume dose in the worse case scenario for all shifts was 2 CcGE (absolute range in worst case scenario, 7,729-7,848 CcGE). The mean changes in the critical organ dose in the worst case scenario was 6 CcGE (bladder), 18 CcGE (rectum), 36 CcGE (anterior rectal wall), and 141 CcGE (femoral heads) for all plans. In general, the percentage of change in the worse case scenario for all shifts to the critical structures was <5%. Deviations in the absolute percentage of volume of organ receiving 45 and 70 Gy for the bladder and rectum were <2% for all plans. CONCLUSION Patient rotational movements of 3 degrees and 5 degrees and horizontal couch shifts of 3 degrees in prostate proton planning did not confer clinically significant dose changes to the target volumes or critical structures.