Ingrid Spadinger

Predictive Factors for Acute and Late Urinary Toxicity After Permanent Prostate Brachytherapy: Long-Term Outcome in 712 Consecutive Patients

PURPOSE To describe the frequency of acute and late Radiation Therapy Oncology Group (RTOG) urinary toxicity, associated predictive factors, and resolution of International Prostate Symptom Score (IPSS) in 712 consecutive prostate brachytherapy patients. METHODS AND MATERIALS Patients underwent implantation between 1998 and 2003 (median follow-up, 57 months). The IPSS and RTOG toxicity data were prospectively collected. The patient, treatment, and implant factors were examined for an association with urinary toxicity. The time to IPSS resolution was examined using Kaplan-Meier curves, and multivariate modeling of IPSS resolution was done using Cox proportional hazards regression analysis. Logistic regression analysis was used to examine the factors associated with urinary toxicity. RESULTS The IPSS returned to baseline at a median of 12.6 months. On multivariate analysis, patients with a high baseline IPSS had a quicker resolution of their IPSS. Higher prostate D90 (dose covering 90% of the prostate), maximal postimplant IPSS, and urinary retention slowed the IPSS resolution time. The rate of the actuarial 5-year late urinary (>12 months) RTOG Grade 0, 1, 2, 3, and 4 was 32%, 36%, 24%, 6.2%, and 0.1%, respectively. At 7 years, the prevalence of RTOG Grade 0-1 was 92.5%. Patients with a larger prostate volume, greater number of needles, greater baseline IPSS, and use of hormonal therapy had more acute toxicity. On multivariate analysis, the significant predictors for late greater than or equal to RTOG toxicity 2 were a greater baseline IPSS, maximal postimplant IPSS, presence of acute toxicity, and higher prostate V150 (volume of the prostate covered by 150% of the dose). More recently implanted patients had less acute urinary toxicity and patients given hormonal therapy had less late urinary toxicity (all p < 0.02). CONCLUSION Most urinary symptoms resolved within 12 months after prostate brachytherapy, and significant long-term urinary toxicity was very low. Refined patient selection and greater technical experience in prostate brachytherapy were associated with less urinary toxicity.

PREDICTIVE FACTORS OF URINARY RETENTION FOLLOWING PROSTATE BRACHYTHERAPY

PURPOSE To evaluate the incidence and duration of urinary retention requiring catheterization and the factors predictive for these end points. METHODS AND MATERIALS Two hundred eighty-two patients treated with prostate brachytherapy alone were evaluated. Clinical and treatment-related factors examined included: age, baseline International Prostate Symptom Score (IPSS), presence of comorbidity, planning ultrasound target volume (PUTV), postimplant prostate CT scan volume, the CT:PUTV ratio, number of seeds inserted, number of needles used, use of neoadjuvant hormones, procedural physician, clinical stage, Gleason score, and pretreatment PSA. Dosimetric quality indicators were also examined. RESULTS Urinary obstruction after prostate brachytherapy developed in 43 (15%) patients. The median duration of catheter insertion was 21 days (mean 49, range 1-365). Univariate analysis demonstrated that presence of diabetes, preimplant volume, postimplant volume, CT:PUTV ratio, number of needles, and dosimetric parameters were predictive for catheterization. However, in multivariate analysis, only the baseline IPSS, CT:PUTV ratio, and presence of diabetes were significant independent predictive factors for catheterization. CONCLUSION Baseline IPSS was the most important predictive factor for postimplantation catheterization. The extent of postimplant edema, as reflected by the CT:PUTV ratio, predicted for need and duration of catheterization. The presence of diabetes was predictive for catheterization, but may relate to the absence of prophylactic steroids, and therefore requires further evaluation.

A robotic needle guide for prostate brachytherapy

Low dose rate prostate brachytherapy involves the permanent implant of radioactive sources into the prostate region using needles. We present a four-degree-of-freedom robot for prostate brachytherapy. The robot can translate a needle guide in the X-Y plane allowing for precise needle insertion along the Z direction. It can also rotate the guide about the X and Y axes, providing thus fine control over the needle insertion point and angle. The robot is light and mountable on a standard brachytherapy stepper. It is non- back-drivable providing a stable needle insertion direction when the power is off. It allows for manual control of each of the motor axes for fine positioning and has a quick-release mechanism for gross translation of the needle guide. We present the robot design and the performance characteristics of the prototype we built. The robot has an interface that allows the guide to be stepped through a complete treatment plan. A radiation oncologist implanted a phantom according to a treatment plan. Only 32 minutes were required for the complete implant that had 26 needles with 136 seeds. This demonstrates that, in spite of its increased flexibility of use, the robotic guide does not add to the procedure time.

Rectal toxicity and rectal dosimetry in low-dose-rate 125I permanent prostate implants: A long-term study in 1006 patients

OBJECTIVE To describe the acute and late rectal toxicity in 1006 prostate brachytherapy patients implanted 1998-2003. To determine whether rectal dose-volume histogram as well as patient and treatment factors were associated with rectal toxicity. METHODS AND MATERIALS Median followup was 60.7 months. Rectal dosimetry was calculated as dose-volume histogram of the rectum using Day 28 CT-based dosimetry and expressed as volume of the rectum in cc receiving 50%, 100%, and 150% of the prescription dose (VR(50cc), VR(100cc), and VR(150cc), respectively). Univariate and multivariate analyses were performed to examine the influence of patient, implant, dosimetry, and learning curve factors on the development of acute and late toxicities using a modified Radiation Therapy Oncology Group (RTOG) scale. Acute toxicity was analyzed using logistic regression and late toxicity using Cox proportional hazards regression. Analysis of variance was used to examine the association between rectal toxicity and rectal dose. RESULTS Rectal dosimetry in 93.5% and rectal toxicity in 96.2% have been recorded. Median VR(100)=1.05cc. Late RTOG Grades 0, 1, 2, 3, and 4 were recorded in 68%, 23%, 7.3%, 0.9%, and 0.2% patients, respectively. On multivariate analysis, acute RTOG ≥2 rectal toxicity was associated with urinary retention (p=0.036) and learning curve (p=0.015); late RTOG ≥2 was associated with the presence of acute toxicity (p=0.0074), higher VR(100) (p=0.030) and learning curve (p=0.027). CONCLUSIONS Late rectal RTOG ≥2 rectal toxicity in this cohort was 8%. Increased VR(100), presence of acute rectal toxicity, and learning curve were associated with higher rate of late RTOG ≥2 toxicity. Severe late rectal toxicity after prostate brachytherapy was rare.

Prostate brachytherapy postimplant dosimetry: a comparison of prostate quadrants

PURPOSE To investigate postimplant dosimetry for different regions of the prostate gland in patients treated with transperineal 125Iodine brachytherapy implants for low- and intermediate-risk prostate cancer. METHODS AND MATERIALS Two hundred eighty-four patients treated with permanent interstitial prostate brachytherapy comprised the study population. A nonuniform, urethral-sparing algorithm was used to plan all patients. Prostate contours were outlined on postimplant CT images. Prostate volumes were then divided into four quadrants: anterior-superior quadrant (ASQ), posterior-superior quadrant (PSQ), anterior-inferior quadrant (AIQ), and posterior-inferior quadrant (PIQ). Dose-volume histograms (DVHs) were calculated for the whole prostate and each quadrant. RESULTS The mean postimplant V(100) +/- 95% confidence (the percent prostate volume encompassed within the isodose surface comprising the prescription dose = 144 Gy) for the ASQ was 78.5 +/- 1.9, which was significantly lower than that of the PSQ, AIQ, and PIQ in which the V(100) plus minus 95% confidence values were 94.9 +/- 0.8, 92.6 +/- 1.2, and 98.7 +/- 0.3, respectively. The mean V(100) +/- 95% confidence for the whole prostate was 90.4 +/- 0.8. Mean values for V(150) and D(90) (the minimum dose in Gy received by 90% of the target volume) for the four quadrants and the whole prostate showed similar results. CONCLUSIONS Underdosed areas of the planning target volume (PTV), if present, were largely confined to the ASQ, which received a significantly lower dose, on average, compared to the other three quadrants of the prostate.

Whole prostate D90 and V100: A dose–response analysis of 2000 consecutive 125I monotherapy patients

PURPOSE To examine the relationship between whole prostate dose metrics and disease-free survival (DFS) after (125)I low-dose-rate prostate brachytherapy (LDR-PB). METHODS AND MATERIALS Data for the first 2000 LDR-PB monotherapy implants were extracted from a database containing patient, tumor, dosimetric, and outcomes information. By National Comprehensive Cancer Network criteria, half (n = 1006) had low-risk disease and half (n = 990) had intermediate-risk disease (four had high-risk disease). Most patients (58.4%) and 75.3% of intermediate-risk patients received 3 months neoadjuvant and 3 months concomitant androgen deprivation therapy (ADT). Univariate and multivariate analyses were conducted using recognized prognostic factors and the whole prostate dose metrics D90 (the minimum dose received by 90% of the postimplant CT-based prostate volume) and V100 (the percent of the postimplant CT-based prostate volume that received at least 100% of the prescription dose). RESULTS The median followup is 5 years (maximum, 12.5 years); the 5-, 7-, and 10-year actuarial DFS estimates are 96.0%, 94.4%, and 93.0%, respectively. Of the recognized prognostic factors, only pretreatment prostate-specific antigen (p = 0.012) and Gleason sum (p = 0.010) were predictive of DFS. When analyzed as continuous variables, dose metrics were not predictive of DFS. However, most nonsignificant trends favored higher doses, and D90 values <130 Gy were predictive of an increased risk of recurrence in the non-ADT subset (N = 833; log rank, p = 0.018). CONCLUSIONS Although D90 values of <130 Gy were predictive of an increased risk of recurrence in the non-ADT subset, neither D90 nor V100, when used as continuous variables, was predictive of DFS when applied to the entire cohort or in the subset analysis. This observation informs us that dose metrics are not equivalent to oncologic end points and must be calibrated against DFS for each physician and each institution offering LDR-PB.

Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: A population-based cohort study

BACKGROUND AND PURPOSE To evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency. MATERIALS AND METHODS Between 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6 months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ≤ 6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence. RESULTS Median follow-up was 60 months. Estimated 5 year bNED was 97% for patients with Gleason score ≤ 6 and 94% for patients with Gleason 7 disease (p=0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p=0.791). There was no difference in bNED between implants achieving D90 ≥ versus<the median value (150.5 Gy) or ≥ versus<140 Gy. CONCLUSIONS I-125 brachytherapy with 6 months of ADT demonstrates excellent bNED rates in Gleason 7 disease. We found no evidence of a difference between patients with Gleason 3+4 versus 4+3 disease.

Urethral and periurethral dosimetry in prostate brachytherapy: is there a convenient surrogate?

PURPOSE To assess and compare two models for a surrogate urethra to be used for postimplant dosimetry in prostate brachytherapy. METHODS AND MATERIALS Twenty men with a urinary catheter present at the time of postimplant computed tomographic imaging were studied. Urethral and periurethral volumes were defined as 5-mm and 10-mm diameter volumes, respectively. Three contours of each were used: one contour of the true urethra (and periurethra), and two surrogate models. The true volumes were centered on the catheter center. One surrogate model used volumes centered on the geometrical center of each prostate contour (centered surrogate). The other surrogate model was based on the average deviation of the true urethra from a reference line through the geometrical center of the axial midplane of the prostate (deviated surrogate). Maximum point doses and the D(10), D(25), D(50), D(90), V(100), V(120), and V(150) of the true and surrogate volumes were measured and compared (D(n) is the minimum dose [Gy] received by n% of the structure, and V(m) is the volume [%] of the structure that received m% of the prescribed dose) as well as the distances between the surrogate urethras and the true urethra. RESULTS Doses determined from both surrogate urethral and periurethral volumes were in good agreement with the true urethral and periurethral doses except in the superior third of the gland. The deviated surrogate provided a physically superior likeness to the true urethra. Certain dose-volume histogram (DVH)-based parameters could also be predicted reasonably well on the basis of the surrogates. Correlation coefficients > or =0.85 were seen for D(25), D(50), V(100), V(120), and V(150) for both models. All the other parameters had correlation coefficients in the range of 0.73 - 0.85. CONCLUSIONS Both surrogate models predicted true urethral dosimetry reasonably well. It is recommended that the simpler deviated surrogate would be a more suitable surrogate for routine clinical practice.

Point: The relationship between postimplant dose metrics and biochemical no evidence of disease following low dose rate prostate brachytherapy: Is there an elephant in the room?

Point: The relationship between postimplant dose metrics and biochemical no evidence of disease following low dose rate prostate brachytherapy: Is there an elephant in the room? W. James Morris*, Ross Halperin, Ingrid Spadinger Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada Department of Radiation Oncology, British Columbia Cancer Agency, Kelowna, BC, Canada

Decline in acute urinary toxicity: A long-term study in 2011 patients with prostate brachytherapy within a provincial institution

PURPOSE To determine whether acute urinary toxicity rates improve with the overall experience of a large prostate brachytherapy program. METHODS AND MATERIALS From 1998 to 2009, 2937 patients were treated with prostate brachytherapy at the British Columbia Cancer Agency. Baseline patient, treatment, and implant factors were recorded prospectively. Acute urinary toxicity data were prospectively recorded at baseline and each follow-up visit. Patients with ≥2 years of follow-up data were grouped into cohorts of 500 for analysis. RESULTS Two thousand eleven patients met the above criteria. Acute urinary retention (AUR) in the acute period (within 6 months of implant) occurred in 9.1% of patients overall and was prolonged (catheterization >20 days) in 3.4%. Both overall AUR and prolonged AUR decreased across implant cohorts (p ≤ 0.001 in both cases). Overall acute Radiation Therapy Oncology Group (RTOG) Grades 0 and 1 urinary toxicity rate was 57.5% and RTOG Grades 2 and 3 urinary toxicity rates were 34.3% and 8.1%, respectively. Acute toxicity improved over time for both RTOG Grades ≥2 and ≥3 toxicity (p < 0.0001). International prostate symptom score resolution to baseline was achieved in 80.5% of patients with a median time of 12.2 months. CONCLUSIONS Acute AUR and RTOG urinary toxicity rates continue to decline with the increasing experience of our provincial prostate brachytherapy program, despite its expansion to new centers and addition of members. This is likely due to better patient selection, refinement in treatment planning and implantation technique, and mentorship and training process.