Assessing the DNA Damaging Effectiveness of Ionizing Radiation Using Plasmid DNA.

Plasmid DNA is useful for investigating the DNA damaging effects of ionizing radiation. In this study, we have explored the feasibility of plasmid DNA-based detectors to assess the DNA damaging effectiveness of two radiotherapy X-ray beam qualities after undergoing return shipment of ~8000 km between two institutions. The detectors consisted of 18 µL of pBR322 DNA enclosed with an aluminum seal in nine cylindrical cavities drilled into polycarbonate blocks. We shipped them to Toronto, Canada for irradiation with either 100 kVp or 6 MV X-ray beams to doses of 10, 20, and 30 Gy in triplicate before being shipped back to San Diego, USA. The Toronto return shipment also included non-irradiated controls and we kept a separate set of controls in San Diego. In San Diego, we quantified DNA single strand breaks (SSBs), double strand breaks (DSBs), and applied Nth and Fpg enzymes to quantify oxidized base damage. The rate of DSBs/Gy/plasmid was 2.8±0.7 greater for the 100 kVp than the 6 MV irradiation. The 100 kVp irradiation also resulted in 5±2 times more DSBs/SSB than the 6 MV beam, demonstrating that the detector is sensitive enough to quantify relative DNA damage effectiveness, even after shipment over thousands of kilometers.

Development of a novel high quantum efficiency MV x-ray detector for image-guided radiotherapy: A feasibility study.

PURPOSE: To develop a new scintillating fiber-based electronic portal imaging device (EPID) with a high quantum efficiency (QE) while preserving an adequate spatial resolution. METHODS: Two prototypes were built: one with a single pixel readout and the other with an active matrix flat-panel imager (AMFPI) for readout. The energy conversion layer of both prototypes was made of scintillating fiber layers interleaved with corrugated lead sheets to form a honeycomb pattern. The scintillating fibers have a diameter of 1 mm and the distance between the centers of neighboring fibers on the same layer is 1.35 mm. The layers have 1.22 mm spacing between them. The energy conversion layer has a thickness of 2 cm. The modulation transfer function (MTF), antiscatter properties and sensitivity of the detector with a single pixel readout were measured using a 6-MV beam on a LINAC machine. In addition, a Monte Carlo simulation was conducted to calculate the zero-frequency detective quantum efficiency (DQE(0)) of the proposed detector with an active matrix flat-panel imager for readout. RESULTS: The DQE(0) of the proposed detector can be 11.5%, which is about an order of magnitude higher than that of current EPIDs. The frequency of 50% modulation ( f 50 ) of the measured MTF is 0.2 mm - 1 at 6 MV, which is comparable to that of video-based EPIDs. The scatter to primary ratio (SPR) measured with the detector at 10 cm air gap and 20 × 20 cm 2 field size is approximately 30% lower than that of ionization chamber-based detectors with a comparable QE. The detector noise which includes the x-ray quantum noise and absorption noise is much larger than the electronic noise per pixel of the flat-panel imager at a dose of less than two LINAC pulses. Thus, the proposed detector is quantum noise limited down to very low doses (∼a couple of radiation pulses of the LINAC). A proof-of-concept image has been obtained using a 6-MV beam. CONCLUSIONS: This work indicates that by using scintillating fibers and lead layers it is possible to increase the thickness of the detecting materials, and therefore the QE or the DQE(0) of the detector, while maintaining an adequate spatial resolution for MV x-ray imaging. Due to the use of lead as the spacing material, the new detector also has antiscatter property, which will help improve the signal-to-noise ratio of the images. Further investigation to optimize the design of the detector and achieve a better combination of DQE and spatial resolution is warranted.

Impact of a 1.5 T magnetic field on DNA damage in MRI-guided HDR brachytherapy.

PURPOSE: Some studies have suggested that the presence of a static magnetic field (SMF) during irradiation alters biological damage. Since MRI-guided radiotherapy is becoming increasingly common, we constructed a DNA-based detector to assess the effect of a 1.5 T SMF on DNA damage during high dose rate (HDR) brachytherapy irradiation. METHODS: Block phantoms containing a small cavity for the placement of plasmid DNA (pBR322) samples were 3-D printed with biocompatible tissue equivalent material. The phantom was CT scanned and an HDR brachytherapy treatment plan was designed to deliver 20 Gy and 30 Gy doses to the DNA samples in the presence and absence of a 1.5 T SMF. Relative yields of single- and double-strand breaks (SSBs and DSBs, respectively) were computed from gel electrophoresis images of the DNA band intensities and averaged over sample sizes ranging from 12 to 30. Radiation dose was also measured in the presence and absence of the 1.5 T SMF using GafChromic™ EBT3 film placed in the coronal, sagittal, and axial planes. RESULTS: The average yield of DNA with SSBs and DSBs in the presence and absence of the SMF showed no statistically significant differences (all p ≥ 0.17). Differences in the net optical densities of the EBT3 films for each plane were within experimental uncertainty, suggesting no dose difference in the presence and absence of the SMF. CONCLUSIONS: HDR irradiation in the presence of the 1.5 T SMF did not alter dose deposition to the DNA cavity nor change SSB and DSB DNA damage.

Maximum RBE change in 192Ir, 125I, and 169Yb brachytherapy and the corresponding effect on treatment planning.

PURPOSE: The purpose of this study was to examine RBE variation as a function of distance from the radioactive source, and the potential impact of this variation on a realistic prostate brachytherapy treatment plan. METHODS: Three brachytherapy sources (125I, 192Ir, and 169Yb) were modelled in Geant4 Monte Carlo code, and the resulting electron energy spectrum in water in 3D space around these sources was scored (voxel size of 2 mm3). With this energy spectrum, microdosimetric techniques were used to calculate the maximum RBE, RBEM, as a function of distance from the source. RBEM of 125I relative to 192Ir was calculated in order to validate simulations against literature; all other RBEM calculations were done by normalizing electron fluence at various distances to the source position. In order to examine the impact of RBEM variation in treatment planning, a realistic 192Ir prostate plan was re-evaluated in terms of RBE instead of absorbed dose. RESULTS: The RBEM of 125I, 192Ir, and 169Yb at 8 cm away from the source was 0.994 (+/-0.002), 1.030 (+/-0.003), and 1.066 (+/-0.008), respectively. RBEM in the HDR prostate treatment plan exhibited several hot (+3.6% in RBEM) spots. CONCLUSIONS: The large increase RBEM observed in 169Yb has not yet been described in the literature. Despite the presence of radiobiological hotspots in the HDR treatment, these variations are likely nominal and clinically insignificant.

Accelerating prostate stereotactic ablative body radiotherapy: Efficacy and toxicity of a randomized phase II study of 11 versus 29 days overall treatment time (PATRIOT).

BACKGROUND: Prostate stereotactic ablative radiotherapy (SABR) regimens differ in time, dose, and fractionation. We report an update of a multicentre, Canadian randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL), efficacy, and toxicity. METHODS: Men with intermediate risk prostate cancer were randomized to 40 Gy in 5 fractions delivered every other day (EOD) versus once per week (QW). Primary outcome was proportion of patients experiencing a minimally clinically important change (MCIC) in acute bowel QOL using EPIC. Secondary outcomes were toxicity, biochemical failure (BF), other QOL domains, and the rate of salvage therapy. FINDINGS: 152 men from 3 centers were randomized; the median follow-up was 62 months. Results are described for EOD versus QW. Acute bowel and urinary QOL was reported previously. Late changes in QOL were not significantly different between the two arms. There were 1 (1.3%) vs 3 (2.7%) late grade 3 + GI toxicities (p = 0.36) and 5 (6.7%) vs 2 (2.7%) late grade 3 GU toxicities (p = 0.44). Two and 5 patients had BF (5-year failure rate 3.0 vs 7.2%, p = 0.22); 0 and 4 patients received salvage therapy (p = 0.04). 5-Year OS and CSS was 95.8% and 98.6% with no difference between arms (p = 0.49, p = 0.15). 3 patients in the QW arm developed metastases. INTERPRETATION: Although we previously reported that weekly prostate SABR had better bowel and urinary QOL compared to EOD, the updated results show no difference in late toxicity, QOL, BF, or PSA kinetics. Patients should be counseled that QW SABR reduces short-term toxicity compared to QW SABR.

Dosimetric predictors of toxicity and quality of life following prostate stereotactic ablative radiotherapy.

PURPOSE: SABR offers an effective treatment option for clinically localized prostate cancer. Here we report the dosimetric predictors of late toxicity and quality of life (QOL) in a pooled cohort of patients from four phase II trials. METHODS: The combined cohort included all three prostate cancer risk groups. The prescription dose was 35-40 Gy in 5 fractions. Toxicity (CTCAE) and QOL (EPIC) were collected. Multiple dosimetric parameters for the bladder, rectum and penile bulb were collected. Univariate (UVA) followed by multivariate (MVA) logistic regression analysis was conducted to search for significant dosimetric predictors of late GI/GU toxicity, or minimal clinically important change in the relevant QOL domain. RESULTS: 258 patients were included with median follow up of 6.1 years. For QOL, bladder Dmax, V38, D1cc, D2cc, D5cc and rectal V35 were predictors of urinary and bowel MCIC on UVA. On MVA, only bladder V38 remained significant. For late toxicity, various parameters were significant on UVA but only rectal Dmax, V38 and bladder D2cc were significant predictors on MVA. CONCLUSIONS: This report confirms that the high-dose regions in the bladder and rectum are more significant predictors of late toxicity and QOL after prostate SABR compared to low-dose regions. Caution must be taken to avoid high doses and hotspots in those organs.

Quantifying the impact of lead doping on plastic scintillator response to radiation.

PURPOSE: Through the addition of high-Z dopants, the sensitivity of plastic scintillators to low-energy radiation can be increased. This study quantifies this change in sensitivity as a function of dopant concentration. METHODS: Measurements were conducted using four different lead-doped scintillators (0%, 1%, 1.5%, and 5% Pb) in high-energy electrons (6 to 15 MeV) and low-energy photon (100 to 300 kVp) radiation fields. High-energy and low-energy irradiations were done using a clinical linear accelerator and an orthovoltage unit, respectively. Light emitted by the scintillator was quantified using a photosensor module. The experimental setup was replicated in Geant4.10.3 Monte Carlo and scintillator parameters (Quenching parameter: kB and the light yield: L0 ) were varied until agreement between measured and simulated results was reached. Monoenergetic electrons were used to simulate the high-energy electron beam while a spectrum generated using SpekCalc® software was used in the low-energy simulations. Light produced by the scintillator was quantified using a flux scorer sensitive only to photons in the visible wavelength range. In order to compare measured and simulated results, the light produced by the scintillator was normalized to the absorbed dose-to-water at the point of measurement. RESULTS: At high lead dopant concentrations, the scintillator's sensitivity to the 100 kVp beam increased by 474% relative to the 15 MeV electron beam; the scintillator's kB parameter increased from 0.126 to 0.27 mm/MeV. A model quantifying the change in kB and L0 as a function of Zeff was derived; presenting a modified Birks' Law for metal-doped plastic scintillators. CONCLUSION: The impact of high-Z doping on plastic scintillator response was quantified; this can allow for the controlled induction of energy dependence in plastic scintillator detectors.

5-Year Outcomes of a Prospective Phase 1/2 Study of Accelerated Hypofractionated Radiation Therapy to the Prostate Bed.

PURPOSE: To report the 5-year outcomes from a single institution, prospective, phase 1/2 study on hypofractionated, accelerated radiation therapy to the prostate bed after radical prostatectomy. METHODS AND MATERIALS: Patients enrolled in this study were all eligible for postoperative radiation therapy and received a prescribed dose of 51 Gy in 17 fractions to the prostate bed. On follow-up, gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0; prostate-specific antigen (PSA) was evaluated and quality of life was assessed using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: A total of 30 patients were enrolled between 2008 and 2011. Median age was 65 (52-75) years. Median pretreatment PSA was 0.12 ng/mL (0.01-1.42). Twenty-six (93%) patients had Gleason ≤7 disease, 13 (43%) had pT3 disease, and 20 (67%) had positive margins. Twenty-six patients (87%) underwent radiation therapy as salvage treatment. After a median follow-up of 6.4 (2.1-8.1) years, no patient experienced Common Terminology Criteria for Adverse Events grade 3/4 toxicity. Eleven patients (37%) had grade 2 genitourinary and 2 (7%) had grade 2 gastrointestinal toxicity. At baseline and 5 years after radiation therapy, mean EPIC urinary domain score was 80% (standard deviation, 18%) and 82% (17%). Mean EPIC bowel domain score was 93% (13%) and 93% (15%). One patient (4%) had a minimally clinically important change in urinary domain score and 1 patient (4%) had a minimally clinically important change in bowel domain score. Nelson-Aalen estimated cumulative incidence of biochemical failure was 31% (nadir +0.2) and 18% (nadir +2.0) at 5 years. Four-year PSA ≥0.4 was predictive of subsequent androgen deprivation therapy use (Nelson-Aalen cumulative incidence: 1.45; P < .0001). Five patients (17%) received hormonal therapy for biochemical failure. Nelson-Aalen estimated cumulative incidence of hormone therapy use was 14% at 5 years. All patients who received hormone therapy had PSA >0.4 at 4 years. CONCLUSIONS: In this phase 1/2 study, hypofractionated postoperative radiation therapy seems to have good clinical efficacy without significant late toxicity. Phase 3 studies are warranted.

Two versus five stereotactic ablative radiotherapy treatments for localized prostate cancer: A quality of life analysis of two prospective clinical trials.

PURPOSE: Stereotactic ablative radiotherapy (SABR) is appealing for prostate cancer (PCa) due to low α/ß, and increasing the dose per fraction could improve the therapeutic index and lead to a better quality of life (QOL). Here we report the outcomes of a QOL comparison between two phase II clinical trials: two vs. five fraction prostate SABR. METHODS: Patients had low or intermediate risk PCa. The doses prescribed were 26 Gy/2 and 40 Gy/5. Expanded prostate cancer index composite was collected. Urinary, bowel and sexual domains were analyzed. Minimal clinically important change (MCIC) was defined as >0.5 standard deviation. RESULTS: 30 and 152 patients were treated with 2-fraction and 5-fraction SABR. Median follow-up was 55 and 62 months. Five-year biochemical failure rate was 3.3% and 4.6%. The 2-fraction cohort had a significantly better mean QOL over time in the bowel domain (p = 0.0004), without a significant difference in the urinary or sexual domains. The 2-fraction cohort had a significantly lower rate of bowel MCIC (17.8% vs 42.3%, p = 0.01), but there was no difference in urinary (24.1% vs 35.7%) or sexual (15.3% vs 29.2%) MCIC. For MCIC x2 (moderate QOL change), the 2-fraction trial had significantly lower MCIC rates in both the bowel (7.1% vs 24%, p = 0.04) and sexual (0 vs 17.6%, p = 0.01) domains. CONCLUSIONS: 2-Fraction SABR is feasible to deliver and well tolerated, with significant signals of improved bowel and sexual QOL. A randomized trial of two vs. five fractions for prostate SABR is needed to confirm the promising findings of this study.

Hypofractionated accelerated radiotherapy using concomitant intensity-modulated radiotherapy boost technique for localized high-risk prostate cancer: acute toxicity results.

PURPOSE: To evaluate the acute toxicities of hypofractionated accelerated radiotherapy (RT) using a concomitant intensity-modulated RT boost in conjunction with elective pelvic nodal irradiation for high-risk prostate cancer. METHODS AND MATERIALS: This report focused on 66 patients entered into this prospective Phase I study. The eligible patients had clinically localized prostate cancer with at least one of the following high-risk features (Stage T3, Gleason score >or=8, or prostate-specific antigen level >20 ng/mL). Patients were treated with 45 Gy in 25 fractions to the pelvic lymph nodes using a conventional four-field technique. A concomitant intensity-modulated radiotherapy boost of 22.5 Gy in 25 fractions was delivered to the prostate. Thus, the prostate received 67.5 Gy in 25 fractions within 5 weeks. Next, the patients underwent 3 years of adjuvant androgen ablative therapy. Acute toxicities were assessed using the Common Terminology Criteria for Adverse Events, version 3.0, weekly during treatment and at 3 months after RT. RESULTS: The median patient age was 71 years. The median pretreatment prostate-specific antigen level and Gleason score was 18.7 ng/L and 8, respectively. Grade 1-2 genitourinary and gastrointestinal toxicities were common during RT but most had settled at 3 months after treatment. Only 5 patients had acute Grade 3 genitourinary toxicity, in the form of urinary incontinence (n = 1), urinary frequency/urgency (n = 3), and urinary retention (n = 1). None of the patients developed Grade 3 or greater gastrointestinal or Grade 4 or greater genitourinary toxicity. CONCLUSION: The results of the present study have indicated that hypofractionated accelerated RT with a concomitant intensity-modulated RT boost and pelvic nodal irradiation is feasible with acceptable acute toxicity.

Dose escalation for prostate stereotactic ablative radiotherapy (SABR): Late outcomes from two prospective clinical trials.

PURPOSE: Optimal prostate SABR dose-fractionation is unknown. This study compares long-term outcomes from two prospective trials. METHODS: Study1 patients had low-risk PCa and received 35 Gy/5. Study2 patients had low/intermediate-risk PCa and received 40 Gy/5. Biochemical failure (BF) was defined as nadir + 2. RESULTS: 114 patients were included (study1, n = 84; study2, n = 30). Median follow-up was 9.6 years and 6.9 years. Median nPSA was 0.4 and 0.1 ng/ml. Nine patients had BF (8 in study1, 1 in study2); two were managed with ADT and four had local salvage. The BF rate was 2.5% and 12.8% at 5 and 10 years for study1 and 3.3% at 5 years for study 2. BF probability was 0% if PSA <0.4 at 4 years, and 20.5% at 10 years if PSA ≥0.4 (p = 0.02). Nine patients died, none of PCa. No patient has metastases or castrate-resistance. At 10 years, OS and CSS were 90.4% (p = 0.25) and 100%. CONCLUSIONS: Dose-escalated prostate SABR was associated with lower nPSAs but no difference in BF, OS, CSS or MFS. PSA <0.4 at 4 years was a predictor of biochemical control. Half of patients with BF were successfully salvaged. Given that this is a favorable-risk cohort, longer follow-up will be needed to see if the lower nPSA translates into lower BF rates.

Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): A phase 2 randomized trial.

BACKGROUND AND PURPOSE: Prostate stereotactic body radiotherapy (SBRT) regimens differ in time, dose, and fractionation. We completed a multicentre, randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL). MATERIAL AND METHODS: Men with low and intermediate-risk prostate cancer were randomly assigned to 40 Gy in 5 fractions delivered once per week (QW) vs. every other day (EOD). QOL was assessed using the Expanded Prostate Cancer Index Composite. The primary endpoint was the proportion with a minimum clinically important change (MCIC) in bowel QOL during the acute (≤12 week) period, and analysis was by intention-to-treat. ClinicalTrials.gov NCT01423474. RESULTS: 152 men from 3 centres were randomized with median follow-up of 47 months. Patients treated QW had superior acute bowel QOL with 47/69 (68%) reporting a MCIC compared to 63/70 (90%) treated EOD (p = 0.002). Fewer patients treated QW reported moderate-severe problems with bowel QOL during the acute period compared with EOD (14/70 [20%] vs. 40/70 [57%], p < 0.001). Acute urinary QOL was also better in the QW arm, with 52/67 (78%) vs 65/69 (94%) experiencing a MCIC (p = 0.006). There were no significant differences in late urinary or bowel QOL at 2 years or last follow-up. CONCLUSION: Prostate SBRT delivered QW improved acute bowel and urinary QOL compared to EOD. Patients should be counselled regarding the potential for reduced short-term toxicity and improved QOL with QW prostate SBRT.

Lag correction model and ghosting analysis for an indirect-conversion flat-panel imager.

Cone-beam digital tomosynthesis (CBDT) is a new approach that was recently proposed for rapid tomographic imaging of soft-tissue targets in the radiotherapy treatment room. One of the potential problems in implementing CBDT using, for example, megavoltage (MV) X rays is the possibility of artifacts caused by image lag and ghosting of the X-ray detector used. In the present work, we developed a model to correct for image lag with indirect-conversion flat-panel imagers (FPIs) used for MV-CBDT. This model is based on measurement and analysis of image lag in an indirect-conversion FPI irradiated with a 6-MV X-ray beam. Our results demonstrated that image lag is amenable to correction. In addition, we measured the ghosting effect for an indirect-conversion FPI and found it to be insignificant.

The dosimetric impact of gadolinium-based contrast media in GBM brain patient plans for a MRI-Linac.

Dosimetric effects of gadolinium based contrast media (Gadovist) were evaluated for the Elekta MRI linear accelerator using the research version of the Monaco treatment planning system (TPS). In order to represent a gadolinium uptake, the contrast was manually assigned to a phantom as well as to the gross tumour volume (GTV) of 6 glioblastoma multiforme (GBM) patients. A preliminary estimate of the dose enhancement, due to gadolinium, was performed using the phantom irradiated with a single beam. A more complicated assessment was performed for the GBM patients using a 7 field IMRT technique. The material table in Monaco was modified in order to identify the presence of a non-biological material. The dose distribution was modelled using GPUMCD (MC algorithm in Monaco) for an unmodified (or default) material table (DMT) as well as for a modified (or custom) material table (CMT) for both the phantom and patients. Various concentrations ranging between 8 and 157 mg ml-1 were used to represent the gadolinium uptake in the patient's GTV. It was assumed that the gadolinium concentration remained the same for the entire course of radiation treatment. Results showed that at the tissue-Gadovist interface, inside the phantom, dose scored using the DMT was 7% lower compared to that using the CMT for 157 mg ml-1 concentration of gadolinium. Dosimetric differences in the case of the patient study were measured using the DVH parameters. D 50% was higher by 6% when the DMT was used compared to the CMT for dose modelling for a gadolinium concentration of 157 mg ml-1. This difference decreased gradually with decreasing concentration of gadolinium. It was concluded that dosimetric differences can be quantified in Monaco if the tumour-gadolinium concentration is more than 23 mg ml-1. If the gadolinium concentration is lower than 23 mg ml-1, then a correction for the presence of gadolinium may not be necessary in the TPS.

Dose-Escalated Stereotactic Body Radiation Therapy for Prostate Cancer: Quality-of-Life Comparison of Two Prospective Trials.

INTRODUCTION: The optimal prostate stereotactic body radiation therapy (SBRT) dose-fractionation scheme is controversial. This study compares long-term quality of life (QOL) from two prospective trials of prostate SBRT to investigate the effect of increasing dose (NCT01578902 and NCT01146340). MATERIAL AND METHODS: Patients with localized prostate cancer received SBRT 35 or 40 Gy delivered in five fractions, once per week. QOL was measured using the Expanded Prostate Cancer Index Composite at baseline and every 6 months. Fisher's exact test and generalized estimating equations were used to analyze proportions of patients with clinically significant change and longitudinal changes in QOL. RESULTS: One hundred fourteen patients were included, 84 treated with 35 Gy and 30 treated with 40 Gy. Median QOL follow-up was 56 months [interquartile range (IQR) 46-60] and 38 months (IQR 32-42), respectively. The proportion of patients reporting clinically significant declines in average urinary, bowel, and sexual scores were not significantly different between dose levels, and were 20.5 vs. 24.1% (p = 0.60), 26.8 vs. 41.4% (p = 0.16), and 42.9 vs. 38.5% (p = 0.82), respectively. Similarly, longitudinal analysis did not identify significant differences in QOL between treatment groups. CONCLUSION: Dose-escalated prostate SBRT from 35 to 40 Gy in five fractions was not associated with significant decline in long-term QOL.

Individualized planning target volumes for intrafraction motion during hypofractionated intensity-modulated radiotherapy boost for prostate cancer.

PURPOSE: The objective of the study was to access toxicities of delivering a hypofractionated intensity-modulated radiotherapy (IMRT) boost with individualized intrafraction planning target volume (PTV) margins and daily online correction for prostate position. METHODS AND MATERIALS: Phase I involved delivering 42 Gy in 21 fractions using three-dimensional conformal radiotherapy, followed by a Phase II IMRT boost of 30 Gy in 10 fractions. Digital fluoroscopy was used to measure respiratory-induced motion of implanted fiducial markers within the prostate. Electronic portal images were taken of fiducial marker positions before and after each fraction of radiotherapy during the first 9 days of treatment to calculate intrafraction motion. A uniform 10-mm PTV margin was used for the first phase of treatment. PTV margins for Phase II were patient-specific and were calculated from the respiratory and intrafraction motion data obtained from Phase I. The IMRT boost was delivered with daily online correction of fiducial marker position. Acute toxicity was measured using National Cancer Institute Common Toxicity Criteria, version 2.0. RESULTS: In 33 patients who had completed treatment, the average PTV margin used during the hypofractionated IMRT boost was 3 mm in the lateral direction, 3 mm in the superior-inferior direction, and 4 mm in the anteroposterior direction. No patients developed acute Grade 3 rectal toxicity. Three patients developed acute Grade 3 urinary frequency and urgency. CONCLUSIONS: PTV margins can be reduced significantly with daily online correction of prostate position. Delivering a hypofractionated boost with this high-precision IMRT technique resulted in acceptable acute toxicity.

Prostatic displacement during extreme hypofractionated radiotherapy using volumetric modulated arc therapy (VMAT).

BACKGROUND: To determine prostate displacement during extreme hypofractionated volume modulated arc radiotherapy (VMAT) using pre- and post-treatment orthogonal images with three implanted gold seed fiducial markers. METHODS: A total of 150 image pairs were obtained from 30 patients who underwent extreme hypofractionated radiotherapy to a dose of 40 Gy in five fractions on standard linear accelerators. Position verification was obtained with orthogonal x-rays before and after treatment and were used to determine intra-fraction prostate displacement. RESULTS: The mean prostate displacements were 0.03 ± 1.23 mm (1SD), 0.18 ± 1.55 mm, and 0.37 ± 1.95 mm in the left-right, superior-inferior, and anterior-posterior directions, respectively. The mean 3D displacement was 2.32 ± 1.55 mm. Only 6 (4%) fractions had a 3D displacement of >5 mm. The average time of treatment delivery for a given fraction was 195 ± 59 seconds. CONCLUSIONS: The mean intra-fraction prostate displacement during a course of extreme hypofractionated radiotherapy delivered via VMAT, continues to be small. Clinical margins typically used in a similar fixed-angle IMRT treatment are adequate. The use of VMAT in further extreme hypofractionation may limit prostatic motion uncertainties that would be otherwise be associated with longer treatment times.

A prospective study on pain score with transperineal prostatic gold seed fiducial implantation under local anesthetic alone.

BACKGROUND: The purpose of this study was to monitor patient pain score with transperineal prostatic gold seed implantation in the absence of conscious sedation. METHODS: All patients who were scheduled for image-guided external beam radiation (IGRT) and referred for gold seed fiducials were eligible to participate. Gold seed implants were performed by two radiation oncologists between December 2007 and April 2008. Patients received only local and deep anesthetic. No patients had prophylactic IV cannulation for the procedure. Three gold seeds were inserted transperineally into the prostate. A visual analogue scale from 0 to 10 was used to assess the pain at baseline, local and deep anesthetic infiltration, with each seed drop, and after the completion of the procedure. RESULTS: A total of 30 patients were accrued to this study. The highest recorded increase in pain score was at the time point of deep local anesthesia, at which the mean pain score was 3.8. The mean pain scores at each seed drop were 0.8 (standard deviation [SD]=1.24), 1 (SD=1.26), and 0.5 (SD=0.90), respectively. All gold seed insertion procedures were well-tolerated, with no patients having significant pain post-procedure, and no significant procedural complications. There were only slight increases in dysuria, urinary frequency, constipation, urinary retention and flatulence in 7 patients - none of which required intervention. INTERPRETATION: Transperineal ultrasound-guided gold seed implantation without conscious sedation is well-tolerated and associated with a low complication rate. It is a convenient outpatient procedure obviating the need for resource intensive postoperative monitoring.

Prostate stereotactic ablative body radiotherapy using a standard linear accelerator: toxicity, biochemical, and pathological outcomes.

BACKGROUND AND PURPOSE: Biological dose escalation through stereotactic ablative radiotherapy (SABR) holds promise of improved patient convenience, system capacity and tumor control with decreased cost and side effects. The objectives are to report the toxicities, biochemical and pathologic outcomes of this prospective study. MATERIALS AND METHODS: A phase I/II study was performed where low risk localized prostate cancer received SABR 35 Gy in 5 fractions, once weekly on standard linear accelerators. Common Terminology Criteria for Adverse Events v3.0 and Radiation Therapy Oncology Group late morbidity scores were used to assess acute and late toxicities, respectively. Biochemical control (BC) was defined by the Phoenix definition. RESULTS: As of May 2012, 84 patients have completed treatment with a median follow-up of 55 months (range 13-68 months). Median age was 67 years and median PSA was 5.3 ng/ml. The following toxicities were observed: acute grade 3+: 0% gastrointestinal (GI), 1% genitourinary (GU), 0% fatigue; late grade 3+: 1% GI, 1% GU. Ninety-six percent were biopsy negative post-treatment. The 5-year BC was 98%. CONCLUSIONS: This novel technique employing standard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible, well tolerated and shows excellent pathologic and biochemical control.

Cone beam CT (CBCT) evaluation of inter- and intra-fraction motion for patients undergoing brain radiotherapy immobilized using a commercial thermoplastic mask on a robotic couch.

Patients receiving fractionated intensity-modulated radiation therapy (IMRT) for brain tumors are often immobilized with a thermoplastic mask; however, masks do not perfectly re-orient the patient due to factors including the maximum pressure which can be applied to the face, deformations of the mask assembly, patient compliance, etc. Consequently, ~3-5mm PTV margins (beyond the CTV) are often recommended. We aimed to determine if smaller PTV margins are feasible using mask immobilization coupled with 1) a gantry mounted CBCT image guidance system and 2) position corrections provided by a full six-degree of freedom (6-DOF) robotic couch. A cohort of 34 brain tumor patients was treated with fractionated IMRT. After the mask set-up, an initial CBCT was obtained and registered to the planning CT. The robotic couch corrected the misalignments in all 6-DOF and a pre-treatment verification CBCT was then obtained. The results indicated a repositioning alignment within our threshold of 1.5 mm (3D). Treatment was subsequently delivered. A post-treatment CBCT was obtained to quantify intra-fraction motion. Initial, pre-treatment and post-treatment CBCT image data was analyzed. A total of 505 radiation fractions were delivered to the 34 patients resulting in ~1800 CBCT scans. The initial median 3D (magnitude) set-up positioning error was 2.60 mm. Robotic couch corrections reduced the 3D median error to 0.53 mm prior to treatment. Intra-fraction movement was responsible for increasing the median 3D positioning error to 0.86 mm, with 8% of fractions having a 3D positioning error greater than 2 mm. Clearly CBCT image guidance coupled with a robotic 6-DOF couch dramatically improved the positioning accuracy for patients immobilized in a thermoplastic mask system; however, such intra-fraction motion would be too large for single fraction radiosurgery.