Robert A. Price

Randomized Trial of Hypofractionated External-Beam Radiotherapy for Prostate Cancer

PURPOSE To determine if escalated radiation dose using hypofractionation significantly reduces biochemical and/or clinical disease failure (BCDF) in men treated primarily for prostate cancer. PATIENTS AND METHODS Between June 2002 and May 2006, men with favorable- to high-risk prostate cancer were randomly allocated to receive 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional fractionation intensity-modulated radiation therapy [CIMRT]) versus 70.2 Gy in 26 fractions at 2.7 Gy per fraction (hypofractionated IMRT [HIMRT]); the latter was estimated to be equivalent to 84.4 Gy in 2.0 Gy fractions. High-risk patients received long-term androgen deprivation therapy (ADT), and some intermediate-risk patients received short-term ADT. The primary end point was the cumulative incidence of BCDF. Secondarily, toxicity was assessed. RESULTS There were 303 assessable patients with a median follow-up of 68.4 months. No significant differences were seen between the treatment arms in terms of the distribution of patients by clinicopathologic or treatment-related (ADT use and length) factors. The 5-year rates of BCDF were 21.4% (95% CI, 14.8% to 28.7%) for CIMRT and 23.3% (95% CI, 16.4% to 31.0%) for HIMRT (P = .745). There were no statistically significant differences in late toxicity between the arms; however, in subgroup analysis, patients with compromised urinary function before enrollment had significantly worse urinary function after HIMRT. CONCLUSION The hypofractionation regimen did not result in a significant reduction in BCDF; however, it is delivered in 2.5 fewer weeks. Men with compromised urinary function before treatment may not be ideal candidates for this approach.

Dose selection for prostate cancer patients based on dose comparison and dose response studies.

PURPOSE To better define the appropriate dose for individual prostate cancer patients treated with three-dimensional conformal radiation therapy (3D CRT). METHODS AND MATERIALS Six hundred eighteen patients treated with 3D CRT between 4/89 and 4/97 with a median follow-up of 53 months are the subject of this study. The bNED outcomes were assessed by the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. The patients were grouped into three groups by prostate-specific antigen (PSA) level (<10 ng/ml, 10-19.9 ng/ml, and 20+ ng/ml) and further subgrouped into six subgroups by favorable (T1, 2A and Gleason score < or =6 and no perineural invasion) and unfavorable characteristics (one or more of T2B, T3, Gleason 7-10, perineural invasion). Dose comparisons for bNED studies were made for each of the six subgroups by dividing patients at 76 Gy for all subgroups except the favorable <10 ng/ml subgroup, which was divided at 72.5 Gy. Five-year bNED rates were compared for the median dose of each dose comparison subgroup. Dose response functions were plotted based on 5-year bNED rates for the six patient groupings, with the data from each of the six subgroups divided into three dose groups. The 5-year bNED rate was also estimated using the dose response function and compares 73 Gy with 78 Gy. RESULTS Dose comparisons show a significant difference in 5-year bNED rates for three of the six subgroups but not for the favorable <10 ng/ml, the favorable 10-19.9 ng/ml, or the unfavorable > or =20 ng/ml subgroups. The significant differences ranged from 22% to 40% improvement in 5-year bNED with higher dose. Dose response functions show significant differences in 5-year bNED rates comparing 73 Gy and 78 Gy for four of the six subgroups. Again, no difference was observed for the favorable <10 ng/ml group or the unfavorable > or =20 ng/ml group. The significant differences observed in 5-year bNED ranged from 15% to 43%. CONCLUSIONS Dose response varies by patient subgroup, and appropriate dose can be estimated for up to six subdivisions of prostate cancer patients. The appropriate use of high dose with 3D CRT results in 5-year cure rates that equal or exceed other treatments. The national practice must be upgraded to allow the safe administration of 75-80 Gy with 3D CRT.

An evidence based review of proton beam therapy: The report of ASTRO’s emerging technology committee

Proton beam therapy (PBT) is a novel method for treating malignant disease with radiotherapy. The purpose of this work was to evaluate the state of the science of PBT and arrive at a recommendation for the use of PBT. The emerging technology committee of the American Society of Radiation Oncology (ASTRO) routinely evaluates new modalities in radiotherapy and assesses the published evidence to determine recommendations for the society as a whole. In 2007, a Proton Task Force was assembled to evaluate the state of the art of PBT. This report reflects evidence collected up to November 2009. Data was reviewed for PBT in central nervous system tumors, gastrointestinal malignancies, lung, head and neck, prostate, and pediatric tumors. Current data do not provide sufficient evidence to recommend PBT in lung cancer, head and neck cancer, GI malignancies, and pediatric non-CNS malignancies. In hepatocellular carcinoma and prostate cancer and there is evidence for the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies PBT appears superior to photon approaches but more data is needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. PBT is an important new technology in radiotherapy. Current evidence provides a limited indication for PBT. More robust prospective clinical trials are needed to determine the appropriate clinical setting for PBT.

Intensity-modulated radiotherapy with mri simulation to reduce doses received by erectile tissue during prostate cancer treatment

PURPOSE The radiation doses received by erectile tissue may contribute to erectile dysfunction after treatment of prostate cancer. This is the first description of the ability to limit the dose received by the penile bulb (PB) and corporal bodies (CB) using intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS Twenty-three patients with palpation Stage T1c-T2bN0M0 prostate cancer received IMRT alone. The dose prescribed to the planning target volume was 74-78 Gy. All patients underwent CT and MRI simulation to define the target and normal structures. Three plans with identical beam arrangements and energy were generated for each patient, with varying dose constraints for the PB and CB: no dose constraint, intermediate-dose constraint (20 Gy and 15 Gy, respectively) and low-dose constraint (15 Gy and 7 Gy, respectively). All plans were normalized, such that 95% of the planning target volume received at least 100% of the prescribed dose. For each plan, the ability to meet prostate dose homogeneity criteria (PHC; prostate maximal dose </=120% prescribed dose) and rectal tolerance dose-volume histogram criteria (RTC; </=35% and </=17% of rectal volume received 40 Gy and 65 Gy, respectively) was determined. The D(90), V(50), and V(75) were determined for both PB and the CB, where D(i) was the dose received by i% of the target volume and V(i) was the target volume receiving i% of the prescribed dose. RESULTS The median PB D(90), V(50), and V(75) for the plans with no dose, intermediate-dose, and low-dose constraints was 20.8 Gy, 33.8%, and 9.9%; 8.0 Gy, 1.7%, and 0%; and 7.1 Gy, 0.1%, and 0%, respectively. The median CB D(90), V(50), and V(75) for plans with no dose, intermediate-dose, and low-dose constraints was 10.2 Gy, 3.8%, and 0%; 6.0 Gy, 0%, and 0%; and 4.9 Gy, 0%, and 0%, respectively. Overall differences in the D(90), V(50), and V(75) among the groups were significant for both the PB and the CB (p <0.0001). All plans with no dose constraint met the PHC and RTC. Twenty plans with an intermediate-dose constraint met the PHC and 21 met the RTC. Eighteen plans with a low-dose constraint met the PHC and 19 met the RTC. No statistically significant difference was found in the number of beam segments for the three groups (median of 51, 55, and 53; p = 0.8). CONCLUSION In the vast majority of cases, it is possible to limit the dose to erectile tissue with IMRT, usually by >/=50% without significantly compromising the PHC, RTC, or treatment duration. A Phase III randomized trial has been designed to test the clinical significance of the erectile tissue-sparing technique described here.

Gains From Real-Time Tracking of Prostate Motion During External Beam Radiation Therapy

PURPOSE To study the gains from real-time tracking of prostate motion and threshold-based intervention and the feasibility of margin reduction for external beam radiation therapy of prostate cancer. METHODS AND MATERIALS Prostate intrafractional motion data from 775 randomly selected treatment fractions (105 prostate patients) were analyzed. Statistical distributions of prostate intrafractional displacement from baseline were used for treatment margin calculation together with other geometrical uncertainties for all patients and a subset of 7 patient who exhibited the largest intrafractional motion. Compared with treatment without any intrafractional intervention, potential reductions in treatment margins were evaluated for treatments with 5-mm and 3-mm threshold-based intervention and four-dimensional (4D) treatments with and without prostate rotation correction. RESULTS The percentage of time of prostate displacement from the baseline by 3 mm and 5 mm in any direction was 13.4% and 1.8%, respectively, for the general patient population. The ratios were 41% and 15% for the 7 selected patients. Reductions in the posterior margin were 0.2, 0.5, 1.3, and 3.1 mm from the original 7.7 mm, respectively, for 5-mm and 3-mm threshold-based treatments and 4D treatments with and without prostate rotation correction for all patients. They were 1.3, 1.9, 3.1 and 4.9 mm from the original 9.5 mm, corresponding to the 7 selected patients. The treatment margin reductions in other directions were even smaller. CONCLUSIONS Real-time motion tracking and threshold-based intrafractional intervention may play a significant roll in treatment margin reduction for a small fraction of patients but not for the general patient population. Four-dimensional treatments with prostate rotation correction can reduce the treatment margin more significantly.

Development of a RadFET linear array for intracavitary in vivo dosimetry during external beam radiotherapy and brachytherapy

We present the details of a new linear array dosimeter consisting of a chain of semiconductors mounted on an ultra-thin (50/spl mu/m thick) flexible substrate and housed in an intracavitary catheter. The semiconductors, manufactured by NMKC Cork, have not been packaged and incorporate a passivation layer that allows them to be mounted on the substrate using flip-chip-bonding. This paper reports, for the first time, the construction of a multiple (ten) detector array suited to in vivo dosimetry in the rectum, esophagus and vagina during external beam radiotherapy, as well as being adaptable to in vivo dosimetry during brachytherapy and diagnostic radiology.

Radiotherapy Doses of 80 Gy and Higher Are Associated With Lower Mortality in Men With Gleason Score 8 to 10 Prostate Cancer

PURPOSE Men with Gleason score (GS) 8-10 prostate cancer (PCa) are assumed to have a high risk of micrometastatic disease at presentation. However, local failure is also a major problem. We sought to establish the importance of more aggressive local radiotherapy (RT) to ≥80 Gy. METHODS AND MATERIALS There were 226 men treated consecutively with RT ± ADT from 1988 to 2002 for GS 8-10 PCa. Conventional, three-dimensional conformal or intensity-modulated (IM) RT was used. Radiation dose was divided into three groups: (1) <75 Gy (n = 50); (2) 75-79.9 Gy (n = 60); or (3) ≥80 Gy (n = 116). The endpoints examined included biochemical failure (BF; nadir + 2 definition), distant metastasis (DM), cause-specific mortality, and overall mortality (OM). RESULTS Median follow-up was 66, 71, and 58 months for Groups 1, 2, and 3. On Fine and Grays competing risk regression analysis, significant predictors of reduced BF were RT dose ≥80 Gy (p = 0.011) and androgen deprivation therapy duration ≥24 months (p = 0.033). In a similar model of DM, only RT dose ≥80 Gy was significant (p = 0.007). On Cox regression analysis, significant predictors of reduced OM were RT dose ≥80 Gy (p = 0.035) and T category (T3/4 vs. T1, p = 0.041). Dose was not a significant determinant of cause-specific mortality. Results for RT dose were similar in a model with RT dose and ADT duration as continuous variables. CONCLUSION The results indicate that RT dose escalation to ≥80 Gy is associated with lower risks of BF, DM, and OM in men with GS 8-10 PCa, independently of androgen deprivation therapy.

American Society for Therapeutic Radiology and Oncology (ASTRO) Emerging Technology Committee Report on Electronic Brachytherapy

The development of novel technologies for the safe and effective delivery of radiation is critical to advancing the field of radiation oncology. The Emerging Technology Committee of the American Society for Therapeutic Radiology and Oncology appointed a Task Group within its Evaluation Subcommittee to evaluate new electronic brachytherapy methods that are being developed for, or are already in, clinical use. The Task Group evaluated two devices, the Axxent Electronic Brachytherapy System by Xoft, Inc. (Fremont, CA), and the Intrabeam Photon Radiosurgery Device by Carl Zeiss Surgical (Oberkochen, Germany). These devices are designed to deliver electronically generated radiation, and because of their relatively low energy output, they do not fall under existing regulatory scrutiny of radioactive sources that are used for conventional radioisotope brachytherapy. This report provides a descriptive overview of the technologies, current and future projected applications, comparison of competing technologies, potential impact, and potential safety issues. The full Emerging Technology Committee report is available on the American Society for Therapeutic Radiology and Oncology Web site.

Target localization for post-prostatectomy patients using CT and ultrasound image guidance.

We conducted a study comparing B‐mode acquisition and targeting (BAT) ultrasound alignments based on CT data in the postoperative setting. CT scans were obtained with a Primatom CT‐on‐rails on nine patients. Two CT scans were obtained each week, while setup error was minimized by BAT ultrasounds. For the first three patients, a direct comparison was performed. For the next six patients, a template based on the shifts from the week 1 CT during treatment was used for subsequent setup. Comparison of isocenter shifts between the BAT ultrasound and CT was made by the difference, absolute difference, and improvement (using CT alignments as the reference technique). A total of 90 image comparisons were made. The average interfraction motion was 3.2 mm in the lateral, 3.0 mm in the longitudinal, and 5.1 mm in the AP direction. The results suggest that the CT‐based ultrasound templates can improve the localization of the prostate bed when the initial displacements are greater than 4 mm. For initial displacements smaller than 4 mm, the technique neither improved nor worsened target localization. However, ultrasound alignments performed without the use of a template deteriorated patient positioning for two out of three patients, demonstrating that the use of a CT template was beneficial even at small initial displacements. PACS numbers: 87.53.‐j, 87.53.Kn, 87.53.Xd

A method for increased dose conformity and segment reduction for SMLC delivered IMRT treatment of the prostate.

PURPOSE The focus of this work is to develop a practical planning method that results in increased dose conformity and reduced treatment time for segmental multileaf collimation (sMLC) based intensity-modulated radiation therapy (IMRT) delivery. METHODS AND MATERIALS Additional regions for dose constraint are introduced within the normal tissue during the planning process by designing a series of concentric ellipsoids around the target. A dose gradient is then defined by assigning dose constraints to each concentric region. The technique was tested at two centers and data for 26 and 10 patients, respectively, are presented allowing for differences in treatment technique, beam energy, ellipsoid definition, and prescription dose. At both centers, a series of patients previously treated for prostate cancer with IMRT were selected, and comparisons were made between the original and new plans. RESULTS While meeting target dose specifications and normal tissue constraints, the average number of beam directions decreased by 1.6 with a standard error (SE) of 0.1. The average time for delivery at center 1 decreased by 29.0% with an SE of 2.0%, decreasing from 17.5 min to 12.3 min. The average time for delivery at center 2 decreased by 29.9% with an SE of 3.8%, decreasing from 11 min to 7.7 min. The amount of nontarget tissue receiving D(100) decreased by 15.7% with an SE of 2.4%. Nontarget tissue receiving D(95), D(90), and D(50) decreased by 16.3, 15.1, and 19.5%, respectively, with SE values of approximately 2% at center 1. Corresponding values for D(100), D(95), D(90), and D(50) decreased by 13.5, 16.7, 17.1, and 5.1%, respectively, with SE values of less than 3% at center 2. CONCLUSION By designating subsets of tissue as concentric regions around the target(s) and carefully defining each regions dose constraints, we have gained an increased measure of control over the region outside the target boundaries. This increased control manifests as two distinct endpoints that are beneficial to the IMRT process: increased dose conformity and decreased treatment time.