A.G. Martin

An Eight-Year Experience of HDR Brachytherapy Boost for Localized Prostate Cancer: Biopsy and PSA Outcome

PURPOSE To evaluate the biochemical recurrence-free survival (bRFS), the 2-year biopsy outcome and the prostate-specific antigen (PSA) bounce in patients with localized prostate cancer treated with an inversely planned high-dose-rate (HDR) brachytherapy boost. MATERIALS AND METHODS Data were collected from 153 patients treated between 1999 and 2006 with external beam pelvic radiation followed by an HDR Ir-192 prostate boost. These patients were given a boost of 18 to 20 Gy using inverse-planning with simulated annealing (IPSA).We reviewed and analyzed all prostate-specific antigen levels and control biopsies. RESULTS The median follow-up was 44 months (18-95 months). When categorized by risk of progression, 74.5% of patients presented an intermediate risk and 14.4% a high one. Prostate biopsies at 2 years posttreatment were negative in 86 of 94 patients (91.5%), whereas two biopsies were inconclusive. Biochemical control at 60 months was at 96% according to the American Society for Therapeutic Radiology and Oncology and the Phoenix consensus definitions. A PSA bounce (PSA values of 2 ng/mL or more above nadir) was observed in 15 patients of 123 (9.8%). The median time to bounce was 15.2 months (interquartile range, 11.0-17.7) and the median bounce duration 18.7 months (interquartile range, 12.1-29). The estimate of overall survival at 60 months was 97.1% (95% CI, 91.6-103%). CONCLUSIONS Considering that inverse planned HDR brachytherapy prostate boosts led to an excellent biochemical response, with a 2-year negative biopsy rate, we recommend a conservative approach in face of a PSA bounce even though it was observed in 10% of patients.

Brachytherapy improves biochemical failure-free survival in low- and intermediate-risk prostate cancer compared with conventionally fractionated external beam radiation therapy: a propensity score matched analysis.

PURPOSE To compare, in a retrospective study, biochemical failure-free survival (bFFS) and overall survival (OS) in low-risk and intermediate-risk prostate cancer patients who received brachytherapy (BT) (either low-dose-rate brachytherapy [LDR-BT] or high-dose-rate brachytherapy with external beam radiation therapy [HDR-BT+EBRT]) versus external beam radiation therapy (EBRT) alone. METHODS AND MATERIALS Patient data were obtained from the ProCaRS database, which contains 7974 prostate cancer patients treated with primary radiation therapy at four Canadian cancer institutions from 1994 to 2010. Propensity score matching was used to obtain the following 3 matched cohorts with balanced baseline prognostic factors: (1) low-risk LDR-BT versus EBRT; (2) intermediate-risk LDR-BT versus EBRT; and (3) intermediate-risk HDR-BT+EBRT versus EBRT. Kaplan-Meier survival analysis was performed to compare differences in bFFS (primary endpoint) and OS in the 3 matched groups. RESULTS Propensity score matching created acceptable balance in the baseline prognostic factors in all matches. Final matches included 2 1:1 matches in the intermediate-risk cohorts, LDR-BT versus EBRT (total n=254) and HDR-BT+EBRT versus EBRT (total n=388), and one 4:1 match in the low-risk cohort (LDR-BT:EBRT, total n=400). Median follow-up ranged from 2.7 to 7.3 years for the 3 matched cohorts. Kaplan-Meier survival analysis showed that all BT treatment options were associated with statistically significant improvements in bFFS when compared with EBRT in all cohorts (intermediate-risk EBRT vs LDR-BT hazard ratio [HR] 4.58, P=.001; intermediate-risk EBRT vs HDR-BT+EBRT HR 2.08, P=.007; low-risk EBRT vs LDR-BT HR 2.90, P=.004). No significant difference in OS was found in all comparisons (intermediate-risk EBRT vs LDR-BT HR 1.27, P=.687; intermediate-risk EBRT vs HDR-BT+EBRT HR 1.55, P=.470; low-risk LDR-BT vs EBRT HR 1.41, P=.500). CONCLUSIONS Propensity score matched analysis showed that BT options led to statistically significant improvements in bFFS in low- and intermediate-risk prostate cancer patient populations.

Dose Escalation to the Dominant Intraprostatic Lesion Defined by Sextant Biopsy in a Permanent Prostate I-125 Implant: A Prospective Comparative Toxicity Analysis

PURPOSE Using real-time intraoperative inverse-planned permanent seed prostate implant (RTIOP/PSI), multiple core biopsy maps, and three-dimensional ultrasound guidance, we planned a boost volume (BV) within the prostate to which hyperdosage was delivered selectively. The aim of this study was to investigate the potential negative effects of such a procedure. METHODS AND MATERIALS Patients treated with RTIOP/PSI for localized prostate cancer with topographic biopsy results received an intraprostatic boost (boost group [BG]). They were compared with patients treated with a standard plan (reference group [RG]). Plans were generated using a simulated annealing inverse planning algorithm. Prospectively recorded urinary, rectal, and sexual toxicities and dosimetric parameters were compared between groups. RESULTS The study included 120 patients treated with boost technique who were compared with 70 patients treated with a standard plan. Boost technique did not significantly change the number of seeds (55.1/RG vs. 53.6/BG). The intraoperative prostate V150 was slightly higher in BG (75.2/RG vs. 77.2/BG, p = 0.039). Urethra V100, urethra D90, and rectal D50 were significantly lower in the BG. No significant differences were seen in acute or late urinary, rectal, or sexual toxicities. CONCLUSIONS Because there were no differences between the groups in acute and late toxicities, we believe that BV can be planned and delivered to the dominant intraprostatic lesion without increasing toxicity. It is too soon to say whether a boost technique will ultimately increase local control.

The prostate cancer risk stratification (ProCaRS) project: recursive partitioning risk stratification analysis.

BACKGROUND The Genitourinary Radiation Oncologists of Canada (GUROC) published a three-group risk stratification (RS) system to assist prostate cancer decision-making in 2001. The objective of this project is to use the ProCaRS database to statistically model the predictive accuracy and clinical utility of a proposed new multi-group RS schema. METHODS The RS analyses utilized the ProCaRS database that consists of 7974 patients from four Canadian institutions. Recursive partitioning analysis (RPA) was utilized to explore the sub-stratification of groups defined by the existing three-group GUROC scheme. 10-fold cross-validated C-indices and the Net Reclassification Index were both used to assess multivariable models and compare the predictive accuracy of existing and proposed RS systems, respectively. RESULTS The recursive partitioning analysis has suggested that the existing GUROC classification system could be altered to accommodate as many as six separate and statistical unique groups based on differences in BFFS (C-index 0.67 and AUC 0.70). GUROC low-risk patients would be divided into new favorable-low and low-risk groups based on PSA ⩽6 and PSA >6. GUROC intermediate-risk patients can be subclassified into low-intermediate and high-intermediate groups. GUROC high-intermediate-risk is defined as existing GUROC intermediate-risk with PSA >=10 AND either T2b/c disease or T1T2a disease with Gleason 7. GUROC high-risk patients would be subclassified into an additional extreme-risk group (GUROC high-risk AND (positive cores ⩾87.5% OR PSA >30). CONCLUSIONS Proposed RS subcategories have been identified by a RPA of the ProCaRS database.

RTOG 0518: randomized phase III trial to evaluate zoledronic acid for prevention of osteoporosis and associated fractures in prostate cancer patients

Background:RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT).Methods:Eligible patients with T-scores of the hip (<−1.0, but >−2.5 vs >−1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years.Results:Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm 1 and 34.8 months for Arm 2. Only two patients experienced a bone fracture (one in each arm) resulting in no difference in freedom from any bone fracture (P=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs −5%, P<0.0001), left total hip (1% vs −8%, P=0.0002), and left femoral neck (3% vs −8%, P=0.0007).Conclusions:For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL.

Calcifications in low-dose rate prostate seed brachytherapy treatment: Post-planning dosimetry and predictive factors

BACKGROUND AND PURPOSE The brachytherapy dose algorithm of the American Association of Physicists in Medicine Task Group (TG) Report 43 overrides all tissue materials with water. In reality, dose discrepancies will occur around tissue calcifications. This study investigates these perturbations in low dose rate prostate brachytherapy dosimetry. MATERIALS AND METHODS 43 cancer patients with prostatic calcifications are identified. Geant4 Monte Carlo (MC) simulations are made with materials assigned based on TG186 recommendations. Five dose calculation scenarios are presented: MC in water (MCW), MCW with calcifications, (MCCA), MCCA with seeds (MCCASEED) and full tissue definition and seeds with dose to medium in medium (FMC) and dose to water in medium (FMC-Dw,m). RESULTS The mean FMC prostate D90 (V100) difference relative to TG43 is -6.4% (range [-1.8, -14.1]) (-2.6% [-0.3, -6.7]). For MCCA we obtained -3.9% [-1.0, -8.7] (-1.5% [-0.2, -4.1]). The mean urethra D10 difference is -4.5% [-1.3, -9.9] for FMC, -2.4% [-0.7, -5.1] with MCCA. FMC-Dw,m D90 has a -0.45% smaller dose difference than FMC on average. The calcification/prostate volume ratio is a good predictor of dose perturbation (R(2)=0.75). CONCLUSION Based on these results, calcifications alter the dose coverage and may have severe dose perturbation that requires recalculation.

Randomized non-inferiority trial of Bicalutamide and Dutasteride versus LHRH agonists for prostate volume reduction prior to I-125 permanent implant brachytherapy for prostate cancer

OBJECTIVE To determine the efficacy and toxicity of a 3-month regimen of Dutasteride and Bicalutamide compared to LHRH agonists for prostate volume (PV) reduction prior to permanent implant prostate brachytherapy (PIPB). MATERIAL AND METHODS Patients with low-risk or low-tier intermediate risk prostate cancer eligible for PIPB with a prostate volume greater than 50 cc were randomized to either Dutasteride 0.5 mg Bicalutamide 50 mg daily and Tamoxifen 10 mg daily for 3 months (D+B group) or to a 3 month dose of an LHRH agonist and Bicalutamide daily for 1 month (LHRH group). Their PV was measured at baseline and at pre-implant. Non-inferiority analysis was completed for the relative (%) PV reduction. IPSS and EPIC questionnaires were completed at baseline, pre-implant and at 1, 3, 6, 12, 18 and 24 months post-treatment. IPSS and EPIC comparisons were based on superiority analysis RESULTS 60 patients were randomized (31 to LHRH group and 29 to D+B group). Mean relative PV reduction (SD) was 35.5% (8.9) in the LHRH group and 31.7% (9.6) in the D+B group. The upper bound of the 95% confidence for the interval for the difference between groups favouring LHRH agonists for PV reduction was 8.6 which did not cross the 10% non-inferiority margin meaning D+B is non-inferior to LHRH agonist for PV reduction, although 5/29 (17%) of those in the D+B group required longer duration of D+B to achieve adequate volume reduction. There were no statistically significant differences in IPSS scores over the entire follow-up period. EPIC sexual summary score was significantly better in the D+B group at pre-implant, 1 month, 3 months post-implant. CONCLUSION Dutasteride and Bicalutamide is a regimen of non-inferior efficacy to LHRH agonist based regimens for prostate volume reduction prior to permanent implant prostate brachytherapy. D+B has less sexual toxicity compared to LHRH agonists prior to implant and for the first 6 months after implant. D+B is therefore an option to be considered for prostate volume reduction prior to PIPB.

Quantifying the effect of seed orientation in postplanning dosimetry of low-dose-rate prostate brachytherapy

PURPOSE Radioactive seed orientations are usually ignored in clinical brachytherapy dosimetry for prostate implants. Associated with the anisotropic dose distribution of seeds, these orientations could cause dose differences between the planning configurations and the clinical postplanning dosimetry. This study will quantify the impact of seed orientation on the dosimetry. METHODS 3D seed positions and θ and φ polar angles were obtained using five independent fluoroscopic images for 287 patients. Five dose calculation methods are compared: TG43-1D (1), TG43-2D parallel to implant axis (2) and with orientations (3), Monte Carlo (MC) simulations parallel (4), and MC simulations with orientations (5). GEANT4 v4.9.6 MC simulations were made in 1 mm(3) voxelized geometries based on the DICOM-RT information. Materials were assigned using thresholds based on the HU number, as recommended in TG186 reports. Seed voxels are overridden with prostatic materials and the layered mass geometry [Enger et al., Phys. Med. Biol. 57(19), 6269-6277 (2012)] allows subsequent placement of the source geometry. 500 million histories were used per patient. 3D dose and DVHs for each structure were calculated. RESULTS The various seed orientations do not result in statistically significant differences on the dose metrics for the clinical target volume (CTV) or the urethra, based on the Student t-test p-value. Difference as low as -0.238% and 0.059% has been seen on the CTV D90, respectively, for the MC and the TG43. The difference between parallel and oriented calculations for the organs at risk (OARs) can differ by 2% on average. CONCLUSIONS Based on the results from this study, seed orientations have no significant impact of CTV and urethra dose metrics but can affect OARs that are external to the CTV.

Development of ProCaRS Clinical Nomograms for Biochemical Failure-free Survival Following Either Low-Dose Rate Brachytherapy or Conventionally Fractionated External Beam Radiation Therapy for Localized Prostate Cancer

Purpose: Although several clinical nomograms predictive of biochemical failure-free survival (BFFS) for localized prostate cancer exist in the medical literature, making valid comparisons can be challenging due to variable definitions of biochemical failure, the disparate distribution of prognostic factors, and received treatments in patient populations. The aim of this investigation was to develop and validate clinically-based nomograms for 5-year BFFS using the ASTRO II “Phoenix” definition for two patient cohorts receiving low-dose rate (LDR) brachytherapy or conventionally fractionated external beam radiation therapy (EBRT) from a large Canadian multi-institutional database. Methods and Materials: Patients were selected from the GUROC (Genitourinary Radiation Oncologists of Canada) Prostate Cancer Risk Stratification (ProCaRS) database if they received (1) LDR brachytherapy ≥ 144 Gy (n=4208) or (2) EBRT ≥ 70 Gy (n=822). Multivariable Cox regression analysis for BFFS was performed separately for each cohort and used to generate clinical nomograms predictive of 5-year BFFS. Nomograms were validated using calibration plots of nomogram predicted probability versus observed probability via Kaplan-Meier estimates. Results: Patients receiving LDR brachytherapy had a mean age of 64 ± 7 years, a mean baseline PSA of 6.3 ± 3.0 ng/mL, 75% had a Gleason 6, and 15% had a Gleason 7, whereas patients receiving EBRT had a mean age of 70 ± 6 years, a mean baseline PSA of 11.6 ± 10.7 ng/mL, 30% had a Gleason 6, 55% had a Gleason 7, and 14% had a Gleason 8-10. Nomograms for 5-year BFFS included age, use and duration of androgen deprivation therapy (ADT), baseline PSA, T stage, and Gleason score for LDR brachytherapy and an ADT (months), baseline PSA, Gleason score, and biological effective dose (Gy) for EBRT. Conclusions: Clinical nomograms examining 5-year BFFS were developed for patients receiving either LDR brachytherapy or conventionally fractionated EBRT and may assist clinicians in predicting an outcome. Future work should be directed at examining the role of additional prognostic factors, comorbidities, and toxicity in predicting survival outcomes.

A More Efficient, Radiation-Free Alternative to Systematic Chest X-Ray for the Detection of Embolized Seeds to the Lung

PURPOSE To evaluate the efficacy of a seed-migration detector and to compare its performance to fluoroscopy and postoperative chest radiographs. METHODS AND MATERIALS A gamma scintillation survey meter was converted to a seed-migration detector by adding a shield on the probe detection window. The detector response to three (125)I seed activities was characterized for different source-to-detector distances in water. The detector was used to perform a chest evaluation on 737 patients at their first postoperative visit. When the detector showed positive activity, seed migration was confirmed by taking a chest radiograph and by looking at the region with fluoroscopy. RESULTS One hundred and three patients (14.0%) presented at least one embolized seed. This accounts for 123 of the 39,887 seeds. Eighty-seven, 12, and 4 patients had respectively one, two, and three seed embolization. Compared with the seed-migration detector, detection based on fluoroscopy would have led to 13 false-negative detections (of 103, or 12.6%), and the radiograph would have resulted in 31 or 30.1%. More important, standard chest X-ray would have required a survey and extra radiation dose to lung to 100% of the patients, rather than the 14% who required it. CONCLUSIONS The usual recommendation to perform chest radiographs at the first follow-up visit to scan lungs for embolized seeds should be revised because of the high false-negative rate. Scintillator-based gamma counter detector provides superior detection sensitivity and should be adopted as a standard of practice. Chest X-ray could be limited to documenting cases of positive migration.