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1.  Narrow safety range of intraoperative rectal irradiation exposure volume for avoiding bleeding after seed implant brachytherapy 
Background & Purpose
Rectal toxicity is less common after 125I seed implant brachytherapy for prostate cancer, and intraoperative rectal dose-volume constraints (the constraint) is still undetermined in pioneering studies. As our constraint failed to prevent grade 2 or 3 rectal bleeding (bled-pts) in 5.1% of patients, we retrospectively explored another constraint for the prevention of rectal bleeding.
Materials and methods
The study population consisted of 197 patients treated with the brachytherapy as monotherapy using real-time intraoperative transrectal ultrasound (US)-guided treatment at a prescribed dose of 145 Gy. Post-implant dosimetry was performed on Day 1 and Day 30 after implantation using computed tomography (CT) imaging. Rectal bleeding toxicity was classified by CTC-AE ver. 3.0 during a mean 29-month (range, 12-48 months) period after implantation. The differences in rV100s were compared among intraoperative, Day 1 and Day 30 dosimetry, and between that of patients with grade 2 or 3 rectal bleeding (the bled-pts) and of the others (the spared-pts). All patients were divided into groups based on provisional rV100s that were increased stepwise in 0.1-cc increments from 0 to 1.0 cc. The difference in the ratios of the bled-pts to the spared-pts was tested by chi-square tests, and their odds ratios were calculated (bled-OR). All statistical analyses were performed by t-tests.
The mean values of rV100us, rV100CT_1, and rV100CT_30 were 0.31 ± 0.43, 0.22 ± 0.36, and 0.59 ± 0.68 cc, respectively. These values temporarily decreased (p = 0.020) on Day 1 and increased (p = 0.000) on Day 30. There was no significant difference in rV100s between the bled-pts and spared-pts at any time of dosimetry. The maximum bled-OR was identified among patients with an rV100us value above 0.1 cc (p = 0.025; OR = 7.8; 95% CI, 1.4-145.8); an rV100CT_1 value above 0.3 cc (p = 0.014; OR = 16.2; 95% CI, 3.9-110.7), and an rV100CT_30 value above 0.5 cc (p = 0.019; OR = 6.3; 95% CI, 1.5-42.3).
By retrospective analysis exploring rV100 as intraoperative rectal dose-volume thresholds in 125I seed implant brachytherapy for prostate cancer, it is proved that rV100 should be less than 0.1 cc for preventing rectal bleeding.
PMCID: PMC3293044  PMID: 22293400
prostate cancer; brachytherapy; dose-volume histogram
2.  The Incidence of Late Rectal Bleeding in High-Dose Conformal Radiotherapy of Prostate Cancer using EUD- and Dose-Volume Based NTCP Models 
Accurate modelling of rectal complications based on DVH data is necessary to allow safe dose escalation in radiotherapy of prostate cancer. We applied different EUD- and dose-volume based NTCP models to rectal wall DVHs and follow-up data of 319 prostate cancer patients in order to identify the dosimetric factors most predictive for grade 2 or higher rectal bleeding.
Materials and Methods
Data of 319 patients, treated at the William Beaumont Hospital with 3D-CRT under an adaptive radiotherapy protocol, were used for this study. The following models were considered: (1) Lyman model and (2) logit-formula with DVH reduced to generalized EUD, (3) serial reconstruction unit (RU) model, (4) Poisson-EUD-model, (5) mean dose- and (6) cutoff dose-logistic regression model. The parameters and their confidence intervals were determined using maximum likelihood estimation.
51 patients (16.0%) showed grade 2 or higher bleeding. As assessed qualitatively and quantitatively, the Lyman- and Logit-EUD, serial RU and Poisson-EUD model fitted the data very well. Rectal wall mean dose did not correlate to grade 2 or higher bleeding. For the cutoff dose model, the volume receiving more than 73.7 Gy showed most significant correlation to bleeding. However, this model fitted the data worse than the EUD-based models.
Our study clearly confirms a volume effect for late rectal bleeding. This can be described very well by the EUD-like models, where the serial RU- and Poisson-EUD model can describe the data with only two parameters. Dose-volume based cutoff-dose models performed worse.
PMCID: PMC1991336  PMID: 17258870
Prostate cancer; Rectal toxicity; NTCP; Volume effects; Dose-volume histograms; EUD
Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard “closed-bore” 1.5T scanner.
Methods and Materials:
Patients with intermediate-risk and high-risk localized prostate cancer received MRI-guided high-dose-rate brachytherapy boosts before and after a course of external beam radiotherapy. Using a custom visualization and targeting program, the brachytherapy catheters were placed and adjusted under MRI guidance until satisfactory implant geometry was achieved. Inverse treatment planning was performed using high-resolution T2-weighted MRI.
Ten brachytherapy procedures were performed on 5 patients. The median percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) achieved was 94% (mean, 92%; 95% confidence interval, 89–95%). The urethral V125 ranged from 0% to 18% (median, 5%), and the rectal V75 ranged from 0% to 3.1% (median, 0.3%). In all cases, lesions highly suspicious for malignancy could be visualized on the procedural MRI, and extracapsular disease was identified in 2 patients.
High-dose-rate prostate brachytherapy in a standard 1.5T MRI scanner is feasible and achieves favorable dosimetry within a reasonable period with high-quality image guidance. Although the procedure was well tolerated in the acute setting, additional follow-up is required to determine the long-term safety and efficacy of this approach.
PMCID: PMC2396328  PMID: 15275727
Prostate cancer; Brachytherapy; MRI; Image guidance
4.  Comparison of rectal volume definition techniques and their influence on rectal toxicity in patients with prostate cancer treated with 3D conformal radiotherapy: a dose-volume analysis 
To evaluate the impact of four different rectum contouring techniques and rectal toxicities in patients with treated with 3D conformal radiotherapy (3DCRT).
Clinical and dosimetric data were evaluated for 94 patients who received a total dose 3DCRT of 70 Gy, and rectal doses were compared in four different rectal contouring techniques: the prostate-containing CT sections (method 1); 1 cm above and below the planning target volume (PTV) (method 2); 110 mm starting from the anal verge (method 3); and from the anal verge to the sigmoid flexure (method 4). The percentage of rectal volume receiving RT doses (30–70 Gy) and minimum, mean rectal doses were assessed.
Median age was 69 years. Percentage of rectal volume receiving high doses (≥ 70 Gy) were higher with the techniques that contoured smaller rectal volumes. In methods 2 and 3, the percentage of rectal volume receiving ≥ 70 Gy was significantly higher in patients with than without rectal bleeding (method 2: 30.8% vs. 22.5%, respectively (p = 0.03); method 3: 26.9% vs. 18.1%, respectively (p = 0.006)). Mean rectal dose was significant predictor of rectal bleeding only in method 3 (48.8 Gy in patients with bleeding vs. 44.4 Gy in patients without bleeding; p = 0.02).
Different techniques of rectal contouring significantly influence the calculation of radiation doses to the rectum and the prediction of rectal toxicity. Rectal volume receiving higher doses (≥ 70 Gy) and mean rectal doses may significantly predict rectal bleeding for techniques contouring larger rectal volumes, as was in method 3.
PMCID: PMC2684071  PMID: 19432953
5.  Preliminary analysis of risk factors for late rectal toxicity after helical tomotherapy for prostate cancer 
Journal of Radiation Research  2013;54(5):919-924.
The purpose of this study is to examine risk factors for late rectal toxicity for localized prostate cancer patients treated with helical tomotherapy (HT). The patient cohort of this retrospective study was composed of 241 patients treated with HT and followed up regularly. Toxicity levels were scored according to the Radiation Therapy Oncology Group grading scale. The clinical and dosimetric potential factors increasing the risk of late rectal toxicity, such as age, diabetes, anticoagulants, prior abdominal surgery, prescribed dose, maximum dose of the rectum, and the percentage of the rectum covered by 70 Gy (V70), 60 Gy (V60), 40 Gy (V40) and 20 Gy (V20) were compared between ≤ Grade 1 and ≥ Grade 2 toxicity groups using the Student's t-test. Multivariable logistic regression analysis of the factors that appeared to be associated with the risk of late rectal toxicity (as determined by the Student's t-test) was performed. The median follow-up time was 35 months. Late Grade 2–3 rectal toxicity was observed in 18 patients (7.4%). Age, the maximum dose of the rectum, V70 and V60 of the ≥ Grade 2 toxicity group were significantly higher than in those of the ≤ Grade 1 toxicity group (P = 0.00093, 0.048, 0.0030 and 0.0021, respectively). No factor was significant in the multivariable analysis. The result of this study indicates that the risk of late rectal toxicity correlates with the rectal volume exposed to high doses of HT for localized prostate cancer. Further follow-up and data accumulation may establish dose–volume modeling to predict rectal complications after HT.
PMCID: PMC3766297  PMID: 23525159
prostate cancer; helical tomotherapy; late toxicity; intensity-modulated radiation therapy; image-guided radiation therapy
6.  Comparison of Tumor Control and Toxicity Outcomes of High Dose Intensity-Modulated Radiotherapy and Brachytherapy for Patients with Favorable Risk Prostate Cancer 
Urology  2010;77(4):986-990.
To compare long-term prostate-specific antigen relapse-free survival outcome and incidence of toxicity for low-risk prostate cancer treated with brachytherapy or intensity-modulated radiotherapy.
729 consecutive patients were treated with BRT (n=448; prescription dose, 144 Gy) and intensity-modulated radiotherapy alone (n=281; prescription dose, 81 Gy). Prostate-specific antigen relapse-free survival using nadir +2 definitions, and late toxicity using the National Cancer Institute's Common Terminology Criteria for Adverse Events.
Seven-year prostate-specific antigen relapse-free survival for brachytherapy and intensity-modulated radiotherapy was 95% and 89% for low-risk patients (p=0.004). Cox regression analysis demonstrated that brachytherapy was associated with improved prostate-specific antigen relapse-free survival even when adjusted for other variables. Incidence of metastatic disease between treatments was low for both treatment groups. Late grade 2 gastrointestinal toxicities were observed in 5.1% and 1.4% of the brachytherapy and intensity-modulated radiotherapy groups, respectively (p=0.02). There were no significant differences between treatment groups for late grade ≥3 rectal complications (brachytherapy, 1.1%; intensity-modulated radiotherapy, 0%; p=0.19). Late grade 2 urinary toxicities were more often observed for brachytherapy than intensity-modulated radiotherapy (15.6% and 4.3%, respectively; p<0.0001). There were no significant differences between treatment groups for late grade 3 urinary toxicity (brachytherapy, 2.2%; intensity-modulated radiotherapy, 1.4%; p=0.62).
Among low risk prostate cancer patients, 7-year biochemical tumor control is superior for intraoperative-planning brachytherapy compared with high-dose intensity-modulated radiotherapy. While significant toxicities were minimal for both groups, modest but significant increases in grade 2 urinary and rectal symptoms were noted for brachytherapy compared with intensity-modulated radiotherapy.
PMCID: PMC4037156  PMID: 21195465
Low dose rate; Iodine-125; Prostate cancer; PSA-relapse–free survival; Brachytherapy; Toxicity
7.  An MRI-Based Dose-Response Analysis of Urinary Sphincter Dose and Urinary Morbidity after Brachytherapy for Prostate Cancer in a Phase II Prospective Trial 
Brachytherapy  2013;12(3):210-216.
To compare dose-volume histogram (DVH) variables for the internal and external urinary sphincters (IUS/EUS) with urinary quality of life after prostate brachytherapy.
Materials and Methods
Subjects were 42 consecutive men from a prospective study of brachytherapy as monotherapy with 125I for intermediate-risk localized prostate cancer. No patient received hormone therapy. Preplanning constraints included prostate V100 >95%, V150 <60%, and V200 <20% and rectal R100 < 1 cm3. Patients completed the EPIC quality of life questionnaire before and 1, 4, 8, and 12 months after implantation, and urinary domain scores were analyzed. All structures including the IUS and EUS were contoured on T2-weighted MRI at day 30, and doses received were calculated from identification of seeds on CT. Spearman's (nonparametric) rank correlation coefficient (ρ) was used for statistical analyses.
Overall urinary morbidity was worst 1 month after the implant. Urinary function declined when the IUS V285 was 0.4% (ρ =–0.32, p=0.04); bother worsened when the IUS V35 was 99% (ρ=–0.31, p=0.05) or the EUS V240 was 63% (ρ=–0.31, p=0.05); irritation increased when the IUS V35 was 95% (ρ=–0.37, p=0.02) and the EUS V265 was 24% (ρ=–0.32, p=0.04); and urgency worsened when the IUS V35 was 99.5% (ρ=–0.38, p=0.02). Incontinence did not correlate with EUS or IUS dose
Doses to the IUS and EUS on MRI/CT predicted worse urinary function, with greater bother, irritative symptoms, and urgency. Incorporating MRI-based DVH analysis into the treatment planning process may reduce acute urinary morbidity after brachytherapy.
PMCID: PMC3891368  PMID: 23466360
Health-related quality of life; Expanded Prostate cancer Index Composite (EPIC) survey; MRI/CT
8.  Treatment and prognosis of patients with late rectal bleeding after intensity-modulated radiation therapy for prostate cancer 
Radiation proctitis after intensity-modulated radiation therapy (IMRT) differs from that seen after pelvic irradiation in that this adverse event is a result of high-dose radiation to a very small area in the rectum. We evaluated the results of treatment for hemorrhagic proctitis after IMRT for prostate cancer.
Between November 2004 and February 2010, 403 patients with prostate cancer were treated with IMRT at 2 institutions. Among these patients, 64 patients who developed late rectal bleeding were evaluated. Forty patients had received IMRT using a linear accelerator and 24 by tomotherapy. Their median age was 72 years. Each patient was assessed clinically and/or endoscopically. Depending on the severity, steroid suppositories or enemas were administered up to twice daily and Argon plasma coagulation (APC) was performed up to 3 times. Response to treatment was evaluated using the Rectal Bleeding Score (RBS), which is the sum of Frequency Score (graded from 1 to 3 by frequency of bleeding) and Amount Score (graded from 1 to 3 by amount of bleeding). Stoppage of bleeding over 3 months was scored as RBS 1.
The median follow-up period for treatment of rectal bleeding was 35 months (range, 12–69 months). Grade of bleeding was 1 in 31 patients, 2 in 26, and 3 in 7. Nineteen of 45 patients (42%) observed without treatment showed improvement and bleeding stopped in 17 (38%), although mean RBS did not change significantly. Eighteen of 29 patients (62%) treated with steroid suppositories or enemas showed improvement (mean RBS, from 4.1 ± 1.0 to 3.0 ± 1.8, p = 0.003) and bleeding stopped in 9 (31%). One patient treated with steroid enema 0.5-2 times a day for 12 months developed septic shock and died of multiple organ failure. All 12 patients treated with APC showed improvement (mean RBS, 4.7 ± 1.2 to 2.3 ± 1.4, p < 0.001) and bleeding stopped in 5 (42%).
After adequate periods of observation, steroid suppositories/enemas are expected to be effective. However, short duration of administration with appropriate dosage should be appropriate. Even when patients have no response to pharmacotherapy, APC is effective.
PMCID: PMC3403958  PMID: 22691293
IMRT; Radiation proctitis; Late toxicity
9.  Gracilis muscle interposition with primary rectal without urethral repair for moderate sized rectourethral fistula caused by brachytherapy for prostate cancer: a case report 
There is a 0.16% chance of a rectourethral fistula after prostate brachytherapy monotherapy using Palladium-103 or Iodine-125 implants. We present an unusual case report of a rectourethral fistula following brachyradiotherapy monotherapy for prostate adenocarcinoma. It was also associated with unusual management of the fistula.
Case presentation
A 58-year-old Caucasian man underwent brachyradiotherapy monotherapy as definitive treatment for verified intracapsular prostate adenocarcinoma receiving 56 Iodine-125 implants using a transrectal ultrasound-guided technique. The patient started to complain of severe perineal pain and mild rectal bleeding 15Â months after brachyradiotherapy. A biopsy of mucosa of his anterior rectal wall was performed. A moderate sized rectourethral fistula was confirmed 23Â months after implantation of Iodine-125 seeds. Laparoscopic sigmoidostomy and suprapubic cystostomy were then performed. Long-term cortisone applications in combination with 30 sessions of hyperbaric oxygen therapy, and antibacterial therapies were initiated due to necrotic infection. A gracilis muscle interposition to create a partition between the patient's rectum and urethra in conjunction with primary rectal repair but without urethral repair were performed 6 months later. The 3cm rectal defect was repaired via a 3cm-long horizontal perineal incision. The 1.5cm urethral defect just below the prostate was not repaired. The patient underwent an optic internal urethrotomy 3Â months later for a 1.5cm-long urethral stricture. Several planned preventive urethral buginages were performed to avoid urethral stricture recurrence. At 12Â months postoperatively, there were no signs of a fistula and cancer recurrence. He now has a normal voiding and anal continence.
Severe rectal pain, bleeding, and local anterior necrotic proctitis are predictors of a rectourethral fistula. Urinary and fecal diversion is the first-step operation. Gracilis muscle interposition in conjunction with primary rectal repair but without urethral reconstruction is one of the reconstructive surgery options for moderate 2cm to 3cm rectourethral fistulas. Internal urethrotomy is a procedure for postoperative urethral strictures of 1.5cm in length.
PMCID: PMC3485089  PMID: 23009550
Brachytherapy; Gracilis interposition; Prostate cancer; Radiotherapy; Rectal repair; Rectourethral fistula
10.  Periodical assessment of genitourinary and gastrointestinal toxicity in patients who underwent prostate low-dose-rate brachytherapy 
To compare the periodical incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicity in patients who underwent prostate low-dose-rate brachytherapy between the monotherapy group (seed implantation alone) and the boost group (in combination with external beam radiation therapy (EBRT)).
A total of 218 patients with a median follow-up of 42.5 months were enrolled. The patients were divided into 2 groups by treatment modality, namely, the monotherapy group (155 patients) and the boost group (63 patients). The periodical incidence rates of GU and GI toxicity were separately evaluated and compared between the monotherapy group and the boost group using the National Cancer Institute - Common Terminology Criteria for Adverse Events, version 3.0. To elucidate an independent factor among clinical and postdosimetric parameters to predict grade 2 or higher GU and GI toxicity in the acute and late phases, univariate and multivariate logistic regression analyses were carried out.
Of all patients, 78.0% showed acute GU toxicity, and 7.8% showed acute GI toxicity, while 63.8% showed late GU toxicity, and 21.1% showed late GI toxicity. The incidence rates of late GU and GI toxicity were significantly higher in the boost group. Multivariate analysis showed that the International Prostate Symptom Score (IPSS) before seed implantation was a significant parameter to predict acute GU toxicity, while there were no significant predictive parameters for acute GI toxicity. On the other hand, combination with EBRT was a significant predictive parameter for late GU toxicity, and rectal volume (mL) receiving 100% of the prescribed dose (R100) was a significant predictive parameter for late GI toxicity.
The boost group showed higher incidence rates of both GU and GI toxicity. Higher IPSS before seed implantation, combination with EBRT and a higher R100 were significant predictors for acute GU, late GU and late GI toxicity.
PMCID: PMC3570431  PMID: 23363647
Prostate cancer; LDR-brachytherapy; GU toxicity; GI toxicity
11.  Dosimetric analysis and comparison of IMRT and HDR brachytherapy in treatment of localized prostate cancer 
Radical radiotherapy is one of the options for the management of prostate cancer. In external beam therapy, 3D conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) are the options for delivery of increased radiation dose, as vital organs are very close to the prostate and a higher dose to these structures leads to an increased toxicity. In brachytherapy, low dose rate brachytherapy with permanent implant of radioactive seeds and high dose rate brachytherapy (HDR) with remote after loaders are available. A dosimetric analysis has been made on IMRT and HDR brachytherapy plans. Ten cases from each IMRT and HDR brachytherapy have been taken for the study. The analysis includes comparison of conformity and homogeneity indices, D100, D95, D90, D80, D50, D10 and D5 of the target. For the organs at risk (OAR), namely rectum and bladder, V100, V90 and V50 are compared. In HDR brachytherapy, the doses to 1 cc and 0.1 cc of urethra have also been studied. Since a very high dose surrounds the source, the 300% dose volumes in the target and within the catheters are also studied in two plans, to estimate the actual volume of target receiving dose over 300%. This study shows that the prescribed dose covers 93 and 92% of the target volume in IMRT and HDR brachytherapy respectively. HDR brachytherapy delivers a much lesser dose to OAR, compared to the IMRT. For rectum, the V50 in IMRT is 34.0cc whilst it is 7.5cc in HDR brachytherapy. With the graphic optimization tool in HDR brachytherapy planning, the dose to urethra could be kept within 120% of the target dose. Hence it is concluded that HDR brachytherapy may be the choice of treatment for cancer of prostate in the early stage.
PMCID: PMC2884303  PMID: 20589121
Brachytherapy; conformity; intensity modulated radiotherapy; prostate
12.  Dosimetric comparison of intensity-modulated, conformal, and four-field pelvic radiotherapy boost plans for gynecologic cancer: a retrospective planning study 
To evaluate intensity-modulated radiation therapy (IMRT) as an alternative to conformal radiotherapy (CRT) or 4-field box boost (4FB) in women with gynecologic malignancies who are unsuitable for brachytherapy for technical or medical reasons.
Dosimetric and toxicity information was analyzed for 12 patients with cervical (8), endometrial (2) or vaginal (2) cancer previously treated with external beam pelvic radiotherapy and a CRT boost. Optimized IMRT boost treatment plans were then developed for each of the 12 patients and compared to CRT and 4FB plans. The plans were compared in terms of dose conformality and critical normal tissue avoidance.
The median planning target volume (PTV) was 151 cm3 (range 58–512 cm3). The median overlap of the contoured rectum with the PTV was 15 (1–56) %, and 11 (4–35) % for the bladder. Two of the 12 patients, both with large PTVs and large overlap of the contoured rectum and PTV, developed grade 3 rectal bleeding. The dose conformity was significantly improved with IMRT over CRT and 4FB (p ≤ 0.001 for both). IMRT also yielded an overall improvement in the rectal and bladder dose-volume distributions relative to CRT and 4FB. The volume of rectum that received the highest doses (>66% of the prescription) was reduced by 22% (p < 0.001) with IMRT relative to 4FB, and the bladder volume was reduced by 19% (p < 0.001). This was at the expense of an increase in the volume of these organs receiving doses in the lowest range (<33%).
These results indicate that IMRT can improve target coverage and reduce dose to critical structures in gynecologic patients receiving an external beam radiotherapy boost. This dosimetric advantage will be integrated with other patient and treatment-specific factors, particularly internal tumor movement during fractionated radiotherapy, in the context of a future image-guided radiation therapy study.
PMCID: PMC1471795  PMID: 16722546
13.  Virtual HDR CyberKnife SBRT for Localized Prostatic Carcinoma: 5-Year Disease-Free Survival and Toxicity Observations 
Frontiers in Oncology  2014;4:321.
Purpose: Prostate stereotactic body radiotherapy (SBRT) may substantially recapitulate the dose distribution of high-dose-rate (HDR) brachytherapy, representing an externally delivered “Virtual HDR” treatment method. Herein, we present 5-year outcomes from a cohort of consecutively treated virtual HDR SBRT prostate cancer patients.
Methods: Seventy-nine patients were treated from 2006 to 2009, 40 low-risk, and 39 intermediate-risk, under IRB-approved clinical trial, to 38 Gy in four fractions. The planning target volume (PTV) included prostate plus a 2-mm volume expansion in all directions, with selective use of a 5-mm prostate-to-PTV expansion and proximal seminal vesicle coverage in intermediate-risk patients, to better cover potential extraprostatic disease; rectal PTV margin reduced to zero in all cases. The prescription dose covered >95% of the PTV (V100 ≥95%), with a minimum 150% PTV dose escalation to create “HDR-like” PTV dose distribution.
Results: Median pre-SBRT PSA level of 5.6 ng/mL decreased to 0.05 ng/mL 5 years out and 0.02 ng/mL 6 years out. At least one PSA bounce was seen in 55 patients (70%) but only 3 of them subsequently relapsed, biochemical-relapse-free survival was 100 and 92% for low-risk and intermediate-risk patients, respectively, by ASTRO definition (98 and 92% by Phoenix definition). Local relapse did not occur, distant metastasis-free survival was 100 and 95% by risk-group, and disease-specific survival was 100%. Acute and late grade 2 GU toxicity incidence was 10 and 9%, respectively; with 6% late grade 3 GU toxicity. Acute urinary retention did not occur. Acute and late grade 2 GI toxicity was 0 and 1%, respectively, with no grade 3 or higher toxicity. Of patient’s potent pre-SBRT, 65% remained so at 5 years.
Conclusion: Virtual HDR prostate SBRT creates a very low PSA nadir, a high rate of 5-year disease-free survival and an acceptable toxicity incidence, with results closely resembling those reported post-HDR brachytherapy.
PMCID: PMC4241836  PMID: 25505732
CyberKnife; prostate cancer; dosimetry; HDR; brachytherapy; image guided; stereotactic body radiotherapy
14.  Dosimetric effects of prone and supine positions on post-implant assessments for prostate brachytherapy 
Post-implant dosimetric assessment is essential for optimal care of patients receiving prostate brachytherapy. In most institutions, post-implant computed tomography (CT) is performed in the supine position. This study aimed to assess variability in dosimetric parameters with postural changes during acquisition of post-implant CT scans.
Material and methods
In total, 85 consecutive patients were enrolled in this study. Fifty-three patients underwent seed implantation alone, and the remaining 32 received a combination of seed implantation and external beam radiotherapy. For post-implant analyses, CT scans were obtained in two patient positions, supine and prone. To evaluate differences in dosimetric parameters associated with postural change, the dosimetric data obtained in the supine position were defined as the standard.
The median prostate volume was 22.4 ml in the supine and 22.5 ml in the prone position (p = 0.51). The median prostate D90 was 120.1% in the supine and 120.3% in the prone position, not significantly different. The mean prostate V100 was 97.1% in the supine and 97.0% in the prone position, again not significantly different. Median rectal V100 in supine and prone positions were 0.42 ml and 0.33 ml, respectively (p < 0.01). Rectal D2cc was also significantly decreased in the prone as compared with the supine position (median, 59.1% vs. 63.6%; p < 0.01). A larger post-implant prostate volume was associated with decreased rectal doses in the prone position.
Though there were no significant differences among prostate D90 assessments according to postural changes, our results suggest that post-implant rectal doses decreased in the prone position.
PMCID: PMC3797408  PMID: 24143145
prostate cancer; brachytherapy; post-implant; position; prone
15.  Rectal endoscopy findings following stereotactic body radiation therapy for clinically localized prostate cancer 
Treating prostate cancer with SBRT could potentially minimize radiation proctitis by reducing high-dose rectal irradiation. In addition, it offers the potential radiobiologic benefits of hypofractionation. This study reports the endoscopic changes and the associated clinical rectal toxicity in these patients.
We reviewed the records of patients treated from 2008–2011 for localized prostate cancer who had rectal endoscopy following SBRT. SBRT was delivered either as primary treatment in 5 fractions of 7–7.25 Gy, or as an initial boost in 3 fractions of 6.5 Gy followed by conventionally fractionated radiotherapy to 45–50.4 Gy. Endoscopic changes were graded using the Vienna Rectoscopy Score (VRS). Rectal toxicity was graded via CTCAEv.4. Rectal quality of life (QOL) was assessed via the bowel domain of the EPIC-26 questionnaire.
Fifty-one patients with a median 23 months follow-up were analyzed. Thirty-five patients completed SBRT monotherapy and 16 patients received SBRT as a boost to conventionally fractionated IMRT. The median interval from SBRT to rectal endoscopy was 13 months. Endoscopy revealed VRS Grade 1–2 telangiectasias for 10 patients and VRS Grade 1–2 mucosal edema for 12 patients. No rectal ulcerations, strictures or necrosis were observed. Grade 1–2 late rectal bleeding occurred in 10 patients. There were no CTCAEv.4 Grade ≥3 toxicities. Mean EPIC bowel scores decreased from a baseline value of 96.9 to 82.3 at 1-month, but subsequently increased to 91.0 at 24 months.
In this cohort that is skewed towards patients with rectal complaints, the rate and severity of endoscopic changes following SBRT is low. Rectal toxicity and QOL were comparable to patients treated with other radiation modalities. Prospective trials examining the endoscopic outcomes following SBRT for prostate cancer are needed for confirmation of the findings of this study.
Trial registration
The Georgetown Institutional Review Board has approved this retrospective study (IRB 2009–510).
PMCID: PMC3751769  PMID: 23937800
Stereotactic body radiotherapy; Prostate cancer; SBRT; CyberKnife; Hypofractionation; Endoscopy; Rectal toxicity; Quality of life
To estimate the parameters of the Lyman normal-tissue complication probability (NTCP) model using censored time-to-event data for grade ≥2 late rectal toxicity among patients treated on Radiation Therapy Oncology Group (RTOG) 94-06, a dose-escalation trial designed to determine the maximum tolerated dose for 3D conformal radiotherapy (3D-CRT) of prostate cancer.
Methods and Materials
The Lyman NTCP model was fitted to data from 1010 of the 1084 patients accrued on RTOG 94-06 using an approach that accounts for censored observations. Separate fits were obtained using dose-volume histograms (DVH) for whole rectum and dose-wall histograms (DWH) for rectal wall.
With a median follow-up of 7.2 years, the crude incidence of grade ≥2 late rectal toxicity was 15% (N=148). The parameters of the Lyman model fitted to DVH data, with 95% profile-likelihood confidence intervals, were TD50=79.1 Gy (75.3 Gy, 84.3 Gy), m=0.146 (0.107, 0.225), and n=0.077 (0.041, 0.156). The fit based on DWH data was not significantly different. Patients with cardiovascular disease had a significantly higher incidence of late rectal toxicity (P=0.015), corresponding to a dose-modifying factor of 5.3%. No significant association with late rectal toxicity was found for diabetes, hypertension, rectal volume, rectal length, neoadjuvant hormone therapy, or prescribed dose per fraction (1.8 Gy versus 2 Gy).
These results, based on a large cohort of patients from a multi-institutional trial, are expected to be widely representative of the ability of the Lyman model to describe the long-term risk of grade ≥2 late rectal toxicity after 3D-CRT of prostate cancer.
PMCID: PMC2963659  PMID: 20598811
prostate cancer; RTOG; rectal toxicity; dose-volume histogram; Lyman model
17.  Proctitis following stereotactic body radiation therapy for prostate cancer 
Proctitis after radiation therapy for prostate cancer remains an ongoing clinical challenge and critical quality of life issue. SBRT could minimize rectal toxicity by reducing the volume of rectum receiving high radiation doses and offers the potential radiobiologic benefits of hypofractionation. This study sought to evaluate the incidence and severity of proctitis following SBRT for prostate cancer.
Between February 2008 and July 2011, 269 men with clinically localized prostate cancer were treated definitively with SBRT monotherapy at Georgetown University Hospital. All patients were treated to 35-36.25Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). Rectal bleeding was recorded and scored using the CTCAE v.4. Telangiectasias were graded using the Vienna Rectoscopy Score (VRS). Proctitis was assessed via the Bowel domain of the Expanded Prostate Index Composite (EPIC)-26 at baseline and at 1, 3, 6, 9, 12, 18 and 24 months post-SBRT.
The median age was 69 years with a median prostate volume of 39 cc. The median follow-up was 3.9 years with a minimum follow-up of two years. The 2-year actuarial incidence of late rectal bleeding ≥ grade 2 was 1.5%. Endoscopy revealed VRS Grade 2 rectal telangiectasias in 11% of patients. All proctitis symptoms increased at one month post-SBRT but returned to near-baseline with longer follow-up. The most bothersome symptoms were bowel urgency and frequency. At one month post-SBRT, 11.2% and 8.5% of patients reported a moderate to big problem with bowel urgency and frequency, respectively. The EPIC bowel summary scores declined transiently at 1 month and experienced a second, more protracted decline between 6 months and 18 months before returning to near-baseline at two years post-SBRT. Prior to treatment, 4.1% of men felt their bowel function was a moderate to big problem which increased to 11.5% one month post-SBRT but returned to near-baseline at two years post-SBRT.
In this single institution cohort, the rate and severity of proctitis observed following SBRT is low. QOL decreased on follow-up; however, our results compare favorably to those reported for patients treated with alternative radiation modalities. Future prospective randomized studies are needed to confirm these observations.
PMCID: PMC4272823  PMID: 25497602
Prostate cancer; SBRT; Rectal endoscopy; Telangiectasias; CyberKnife; Expanded prostate index composite; Bother; Proctitis; Rectal bleeding; Vienna rectoscopy score
18.  Phase I Trial of Pelvic Nodal Dose Escalation with Hypofractionated IMRT for High Risk Prostate Cancer 
Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided IMRT can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5–1/2 weeks.
Methods and Materials
Pelvic nodal and prostatic image-guided IMRT was delivered to 53 NCCN high risk patients to a nodal dose of 56 Gy in 2 Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months.
The median follow-up was 25.4 months (range 4.2–57.2). No early grade 3 (Gr3) RTOG or CTCAE v.3.0 GU or GI toxicities were seen. The cumulative actuarial incidence of Gr2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Gr2 early GI toxicity. None of the dose-volume descriptors correlated with GU toxicity, and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity (p=0.029). Maximum late grades 1,2 and 3 GU toxicities were seen in in 30%, 25% and 2%, respectively. Maximum late grade 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery), respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 ± 6.6%. No patient manifested pelvic nodal failure, while two experienced para-aortic nodal failure outside the field. The 6 other clinical failures were distant only.
Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient and well-tolerated 28 fraction schedule. Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients.
PMCID: PMC3347884  PMID: 21163590
Pelvic Lymph Node Dose Escalation; Bowel Displacement Board; Rectal Balloon; Hypofractionated Radiation Therapy; Image-Guided Prostate IMRT
19.  Efficacy and Safety of High-Dose-Rate Brachytherapy of Single Implant with Two Fractions Combined with External Beam Radiotherapy for Hormone-Naïve Localized Prostate Cancer 
Cancers  2011;3(3):3585-3600.
The purpose of this study was to evaluate the efficacy and safety of high-dose-rate (HDR) brachytherapy of a single implant with two fractions plus external beam radiotherapy (EBRT) for hormone-naïve prostate cancer in comparison with radical prostatectomy. Of 150 patients with localized prostate cancer (T1c–T2c), 59 underwent HDR brachytherapy plus EBRT, and 91 received radical prostatectomy. The median follow-up of patients was 62 months for HDR brachytherapy plus EBRT, and 64 months for radical prostatectomy. In patient backgrounds between the two cohorts, the frequency of T2b plus T2c was greater in HDR brachytherapy cohort than in prostatectomy cohort (27% versus 12%, p = 0.029). Patients in HDR brachytherapy cohort first underwent 3D conformal RT with four beams to the prostate to an isocentric dose of 50 Gy in 25 fractions and then, a total of 15–18 Gy in two fractions at least 5 hours apart. We prescribed 9 Gy/fraction for target (prostate gland plus 3 mm lateral outside margin and seminal vesicle) using CT image method for radiation planning. The total biochemical failure-free control rates (BF-FCR) at 3 and 5 years for the HDR brachytherapy cohort, and for the prostatectomy cohort were 92% and 85%, and 72% and 72%, respectively (significant difference, p = 0.0012). The 3-and 5-year BF-FCR in the HDR brachytherapy cohort and in the prostatectomy cohort by risk group was 100 and 100%, and 80 and 80%, respectively, for the low-risk group (p = 0.1418); 92 and 92%, 73 and 73%, respectively, for the intermediate-risk group (p = 0.0492); and 94 and 72%, 45 and 45%, respectively, for the high-risk group (p = 0.0073). After HDR brachytherapy plus EBRT, no patient experienced Grade 2 or greater genitourinay toxicity. The rate of late Grade 1 and 2 GI toxicity was 6% (n = 4). No patient experienced Grade 3 GI toxicity. HDR brachytherapy plus EBRT is useful for treating patients with hormone-naïve localized prostate cancer, and has low GU and GI toxicities.
PMCID: PMC3759211  PMID: 24212968
prostate cancer; high dose rate brachytherapy; external beam radiation therapy; radical prostatectomy
20.  Influence of body mass index and periprostatic fat on rectal dosimetry in permanent seed prostate brachytherapy 
We examined the influence of body mass index (BMI) and body fat distribution on rectal dose in patients treated with permanent seed brachytherapy for localized prostate cancer.
Methods and materials
We analyzed 213 patients treated with I125 seed brachytherapy for localized prostate cancer. BMI and rectal dosimetry data for all patients were available. Data on visceral and subcutaneous fat distribution at the level of the iliac crest (n = 140) as well as the distribution of periprostatic and subcutaneous fat at the symphysis pubis level were obtained (n = 117). Fat distribution was manually contoured on CT on day 30 after brachytherapy. The correlation between BMI, fat distribution and rectal dose (R100 (in cc), R150 (cc), D2 (Gy)) was analyzed using the Spearman correlation coefficient. Differences in rectal dose between tertiles of body fat distribution were calculated using nonparametric tests.
Periprostatic adipose was only weakly correlated with BMI (r = 0.0.245, p = 0.008) and only weakly correlated with the other fat measurements (r = 0.31-0.37, p < 0.001). On the other hand, BMI was correlated with all other fat measurements (≥0.58, p < 0.001). All the other fat measurements were strongly correlated with each other (r = 0.5-0.87, p < 0.001). Patients with an R100 of >1.3 cc (23% of patients) had less visceral fat (p = 0.004), less subcutaneous fat at the level of the iliac crest (p = 0.046) and a lower BMI (26.8 kg/m2 vs. 28.5 kg/m2, p = 0.02) than patients with an R100 of <1.3 cc. Results were very similar when comparing an R100 of >1.0 cc (34% of patients) across the tertiles. None of the tested linear regression models were predictive (max 12%) of dose to the rectum.
Dose to the rectum is dependent on BMI and body fat distribution. Periprostatic fat does not influence rectal dose. Dose to the rectum remains difficult to predict and depends on many factors, one of which is body fat distribution.
PMCID: PMC4002200  PMID: 24731303
Prostate cancer; Adipose tissue; Body mass index; Brachytherapy; Rectal dose
21.  Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer* 
Background and Purpose
Rectal bleeding can occur following radiotherapy for prostate cancer and negatively impacts quality of life for cancer survivors. Treatment and clinical factors do not fully predict for rectal bleeding, and genetic factors may be important.
Materials and Methods
A genome-wide association study (GWAS) was performed to identify SNPs associated with development of late rectal bleeding following radiotherapy for prostate cancer. Logistic regression was used to test association between 614,453 SNPs and rectal bleeding in a discovery cohort (79 cases, 289 controls), and top-ranking SNPs were tested in a replication cohort (108 cases, 673 controls) from four independent sites.
rs7120482 and rs17630638, which tag a single locus on chromosome 11q14.3, reached genome-wide significance for association with rectal bleeding (combined p-values 5.4×10−8 and 6.9×10−7 respectively). Several other SNPs had p-values trending towards genome-wide significance, and a polygenic risk score including these SNPs shows a strong rank-correlation with rectal bleeding (Sommers’ d = 5.0×10−12 in the replication cohort).
This GWAS identified novel genetic markers of rectal bleeding following prostate radiotherapy. These findings could lead to development of a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified.
PMCID: PMC3787843  PMID: 23719583
radiogenomics; prostate cancer; rectal toxicity; genome-wide association study
22.  Dose–volume histogram parameters of high-dose-rate brachytherapy for Stage I–II cervical cancer (≤4cm) arising from a small-sized uterus treated with a point A dose-reduced plan 
Journal of Radiation Research  2014;55(4):788-793.
We investigated the rectal dose-sparing effect and tumor control of a point A dose-reduced plan in patients with Stage I–II cervical cancer (≤4 cm) arising from a small-sized uterus. Between October 2008 and August 2011, 19 patients with Stage I–II cervical cancer (≤4 cm) were treated with external beam radiotherapy (EBRT) for the pelvis and CT-guided brachytherapy. Seven patients were treated with brachytherapy with standard loading of source-dwell positions and a fraction dose of 6 Gy at point A (conventional brachy-plan). The other 12 patients with a small uterus close to the rectum or small intestine were treated with brachytherapy with a point A dose-reduction to match D2cc of the rectum and <6 Gy as the dose constraint (‘point A dose-reduced plan’) instead of the 6-Gy plan at point A (‘tentative 6-Gy plan’). The total doses from EBRT and brachytherapy were added up and normalized to a biological equivalent dose of 2 Gy per fraction (EQD2). The median doses to the high-risk clinical target volume (HR-CTV) D90 in the conventional brachy-plan, tentative 6-Gy plan and point A dose-reduced plan were 62 GyEQD2, 80 GyEQD2 and 64 GyEQD2, respectively. The median doses of rectal D2cc in the corresponding three plans were 42 GyEQD2, 62 GyEQD2 and 51 GyEQD2, respectively. With a median follow-up period of 35 months, three patients developed Grade-1 late rectal complications and no patients developed local recurrence. Our preliminary results suggested that CT-guided brachytherapy using an individualized point A dose-reduced plan might be useful for reducing late rectal complications while maintaining primary tumor control.
PMCID: PMC4099998  PMID: 24566721
cervical cancer; CT-guided brachytherapy; small-sized uterus; late rectal complication; point A dose
23.  Permanent prostate brachytherapy extracapsular radiation dose distributions: analysis of a multi-institutional database 
Periprostatic brachytherapy doses impact biochemical control. In this study, we evaluate extracapsular volumetric dosimetry following permanent prostate brachytherapy in patients entered in a multi-institutional community database.
Material and methods
In the database, 4547 patients underwent brachytherapy (3094 – 125I, 1437 – 103Pd and 16 – 131Cs). Using the originally determined prostate volume, a 5 mm, 3-dimensional peri-prostatic anulus was constructed around the prostate (except for a 2 mm posterior margin), and evaluated in its entirety and in 90° segments. Prostate dosimetric parameters consisted of a V100 and D90 while the annular dosimetry was reported as a V100.
The intraprostatic V100 and D90 for 103Pd, and 125I were statistically comparable when stratified by isotope and/or monotherapy vs. boost. The overall mean V100 for the periprostatic annulus was 62.8%. The mean V100 at the base (51.6%) was substantially less than the apex (73.5%) and midgland (65.9%). In addition, for all patients, the anterior V100 (45.7%) was less than the lateral (68.8%) and the posterior (75.0%). The geometric V100 annular differences were consistent when evaluated by isotope. Overall, the V100 was higher in the 125I cohort.
The optimal extracapsular brachytherapy dose and radial extent remains unknown, but will prove increasingly important with reductions and/or elimination of supplemental external beam radiation therapy. The large multi-institutional community database demonstrates periprostatic annular doses that are not as robust as those in selected high volume brachytherapy centers, and may be inadequate for optimal biochemical control following monotherapeutic brachytherapy, especially in higher risk patients.
PMCID: PMC3797411  PMID: 24143144
brachytherapy; dosimetry; prostate cancer; treatment margins
To investigate whether the volumes of rectum exposed to intermediate doses, from 30-50 Gy, contribute to the risk of Grade ≥2 late rectal toxicity among patients with prostate cancer receiving radiotherapy.
Methods and Materials
Data from 1009 patients treated on Radiation Therapy Oncology Group (RTOG) protocol 94-06 were analyzed using three approaches. First, the contribution of intermediate doses to a previously published fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model was determined. Next, the extent to which intermediate doses provide additional risk information, after taking the LKB model into account, was investigated. Third, the proportion of rectum receiving doses higher than a threshold, VDose, was computed for doses ranging from 5-85 Gy, and a multivariate Cox proportional hazards (PH) model was used to determine which of these parameters were significantly associated with time to Grade ≥2 late rectal toxicity.
Doses <60 Gy have no detectable impact on the fit of the LKB model, as expected based on the small estimate of the volume parameter (n=0.077). Furthermore, there is no detectable difference in late rectal toxicity among cohorts with similar risk estimates from the LKB model but with different volumes of rectum exposed to intermediate doses. The multivariate Cox PH model selected V75 as the only value of VDose significantly associated with late rectal toxicity.
There is no evidence from these data that intermediate doses influence the risk of Grade ≥2 late rectal toxicity. Instead, the critical doses for this endpoint appear to be ≥75 Gy. It is hypothesized that cases of Grade ≥2 late rectal toxicity occurring among patients with V75 less than about 12% may be due to a “background” level of risk, likely due mainly to biological factors.
PMCID: PMC3952553  PMID: 22342302
prostate cancer; RTOG; late rectal toxicity; dose-volume histogram
25.  Stereotactic body radiation therapy via helical tomotherapy to replace brachytherapy for brachytherapy-unsuitable cervical cancer patients – a preliminary result 
OncoTargets and therapy  2013;6:59-66.
To review the experience and to evaluate the results of stereotactic body radiation therapy (SBRT) via helical tomotherapy (HT), for the treatment of brachytherapy-unsuitable cervical cancer.
Between September 1, 2008 to January 31, 2012, nine cervical cancer patients unsuitable for brachytherapy were enrolled. All of the patients received definitive whole pelvic radiotherapy with or without chemotherapy, followed by SBRT via HT.
The actuarial locoregional control rate at 3 years was 78%. The mean biological equivalent dose in 2-Gy fractions of the tumor, rectum, bladder, and intestines was 76.0 ± 7.3, 73.8 ± 13.2, 70.5 ± 10.0, and 43.1 ± 7.1, respectively. Only two had residual tumors after treatment, and the others were tumor-free. Two patients experienced grade 3 acute toxicity: one had diarrhea; and another experienced thrombocytopenia. There were no grade 3 or 4 subacute toxicities. Three patients suffered from manageable rectal bleeding in months 11, 14, and 25, respectively. One stage I VA patient experienced fistula formation in month 3.
SBRT via HT provides the possibility for treatment of locally advanced cervical cancer in patients who are unsuitable for brachytherapy. Long-term follow up and enrollment of more such patients to receive SBRT via the HT technique are warranted.
PMCID: PMC3569375  PMID: 23403975
biological equivalent dose; complication; image guidance; intensity modulated radiation therapy; rectal bleeding

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