Advances in radiotherapy and its impact on second primary cancer risk: A multi-center cohort study in prostate cancer patients.

BACKGROUND: Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and characteristics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa). METHODS: We collected EBRT protocol characteristics (2000-2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were calculated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT. RESULTS: From 2000-2006, 3D-CRT with 68-78 Gy in 2 Gy fractions, delivered with 10-23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imaging protocols. Sixteen percent (N = 1268) developed ≥ 1 SPC. SIRs for pelvis and non-pelvis SPC (all institutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00-1.36) vs 1.39 (1.21-1.59), and 1.01 (0.89-1.07) vs 1.03 (0.94-1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01-1.13) vs 1.02 (0.98-1.07). Other RT protocol characteristics did not correlate with SPC endpoints. CONCLUSION: None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important.

Impact of Advanced Radiotherapy on Second Primary Cancer Risk in Prostate Cancer Survivors: A Nationwide Cohort Study.

PURPOSE: External Beam Radiotherapy (EBRT) techniques dramatically changed over the years. This may have affected the risk of radiation-induced second primary cancers (SPC), due to increased irradiated low dose volumes and scatter radiation. We investigated whether patterns of SPC after EBRT have changed over the years in prostate cancer (PCa) survivors. MATERIALS AND METHODS: PCa survivors diagnosed between 1990-2014 were selected from the Netherlands Cancer Registry. Patients treated with EBRT were divided in three time periods, representing 2-dimensional Radiotherapy (RT), 3-dimensional conformal RT (3D-CRT), and the advanced RT (AdvRT) era. Standardized incidence ratios (SIR) and absolute excess risks (AER) were calculated to estimate relative and excess absolute SPC risks. Sub-hazard ratios (sHRs) were calculated to compare SPC rates between the EBRT and prostatectomy cohort. SPCs were categorized by subsite and anatomic region. RESULTS: PCa survivors who received EBRT had an increased risk of developing a solid SPC (SIR=1.08; 1.05-1.11), especially in patients aged <70 years (SIR=1.13; 1.09-1.16). Pelvic SPC risks were increased (SIR=1.28; 1.23-1.34), with no obvious differences between the three EBRT eras. Non-pelvic SPC were only significantly increased in the AdvRT era (SIR=1.08; 1.02-1.14), in particular for the 1-5 year follow-up period. Comparing the EBRT cohort to the prostatectomy cohort, again an increased pelvic SPC risk was found for all EBRT periods (sHRs= 1.61, 1.47-1.76). Increased non-pelvic SPC risks were present for all RT eras and highest for the AdvRT period (sHRs=1.17, 1.06-1.29). CONCLUSION: SPC risk in patients with EBRT is increased and remained throughout the different EBRT eras. The risk of developing a SPC outside the pelvic area changed unfavorably in the AdvRT era. Prolonged follow-up is needed to confirm this observation. Whether this is associated with increased irradiated low-dose volumes and scatter, or other changes in clinical EBRT practice, is the subject of further research.

Dosimetric impact of contouring and image registration variability on dynamic 125I prostate brachytherapy.

PURPOSE: The quality of permanent prostate brachytherapy can be increased by addition of imaging modalities in the intraoperative procedure. This addition involves image registration, which inherently has inter- and intraobserver variabilities. We sought to quantify the inter- and intraobserver variabilities in geometry and dosimetry for contouring and image registration and analyze the results for our dynamic 125I brachytherapy procedure. METHODS AND MATERIALS: Five observers contoured 11 transrectal ultrasound (TRUS) data sets three times and 11 CT data sets one time. The observers registered 11 TRUS and MRI data sets to cone beam CT (CBCT) using fiducial gold markers. Geometrical and dosimetrical inter- and intraobserver variabilities were assessed. For the contouring study, structures were subdivided into three parts along the craniocaudal axis. RESULTS: We analyzed 165 observations. Interobserver geometrical variability for prostate was 1.1 mm, resulting in a dosimetric variability of 1.6% for V100 and 9.3% for D90. The geometric intraobserver variability was 0.6 mm with a V100 of 0.7% and D90 of 1.1%. TRUS-CBCT registration showed an interobserver variability in V100 of 2.0% and D90 of 3.1%. Intraobserver variabilities were 0.9% and 1.6%, respectively. For MRI-CBCT registration, V100 and D90 were 1.3% and 2.1%. Intraobserver variabilities were 0.7% and 1.1% for the same. CONCLUSIONS: Prostate dosimetry is affected by interobserver contouring and registration variability. The observed variability is smaller than underdosages that are adapted during our dynamic brachytherapy procedure.

Cone-beam CT-based adaptive planning improves permanent prostate brachytherapy dosimetry: An analysis of 1266 patients.

PURPOSE: To evaluate adaptive planning for permanent prostate brachytherapy and to identify the prostate regions that needed adaptation. METHODS AND MATERIALS: After the implantation of stranded seeds, using real-time intraoperative planning, a transrectal ultrasound (TRUS)-scan was obtained and contoured. The positions of seeds were determined on a C-arm cone-beam computed tomography (CBCT)-scan. The CBCT-scan was registered to the TRUS-scan using fiducial gold markers. If dose coverage on the combined image-dataset was inadequate, an intraoperative adaptation was performed by placing remedial seeds. CBCT-based intraoperative dosimetry was analyzed for the prostate (D90, V100, and V150) and the urethra (D30). The effects of the adaptive dosimetry procedure for Day 30 were separately assessed. RESULTS: We analyzed 1266 patients. In 17.4% of the procedures, an adaptation was performed. Without the dose contribution of the adaptation Day 30 V100 would be < 95% for half of this group. On Day 0, the increase due to the adaptation was 11.8 ± 7.2% (1SD) for D90 and 9.0 ± 6.4% for V100. On Day 30, we observed an increase in D90 of 12.3 ± 6.0% and in V100 of 4.2 ± 4.3%. For the total group, a D90 of 119.6 ± 9.1% and V100 of 97.7 ± 2.5% was achieved. Most remedial seeds were placed anteriorly near the base of the prostate. CONCLUSION: CBCT-based adaptive planning enables identification of implants needing adaptation and improves prostate dose coverage. Adaptations were predominantly performed near the anterior base of the prostate.

Edema and Seed Displacements Affect Intraoperative Permanent Prostate Brachytherapy Dosimetry.

PURPOSE: We sought to identify the intraoperative displacement patterns of seeds and to evaluate the correlation of intraoperative dosimetry with day 30 for permanent prostate brachytherapy. METHODS AND MATERIALS: We analyzed the data from 699 patients. Intraoperative dosimetry was acquired using transrectal ultrasonography (TRUS) and C-arm cone beam computed tomography (CBCT). Intraoperative dosimetry (minimal dose to 40%-95% of the volume [D40-D95]) was compared with the day 30 dosimetry for both modalities. An additional edema-compensating comparison was performed for D90. Stranded seeds were linked between TRUS and CBCT using an automatic and fast linking procedure. Displacement patterns were analyzed for each seed implantation location. RESULTS: On average, an intraoperative (TRUS to CBCT) D90 decline of 10.6% ± 7.4% was observed. Intraoperative CBCT D90 showed a greater correlation (R(2) = 0.33) with respect to Day 30 than did TRUS (R(2) = 0.17). Compensating for edema, the correlation increased to 0.41 for CBCT and 0.38 for TRUS. The mean absolute intraoperative seed displacement was 3.9 ± 2.0 mm. The largest seed displacements were observed near the rectal wall. The central and posterior seeds showed less caudal displacement than lateral and anterior seeds. Seeds that were implanted closer to the base showed more divergence than seeds close to the apex. CONCLUSIONS: Intraoperative CBCT D90 showed a greater correlation with the day 30 dosimetry than intraoperative TRUS. Edema seemed to cause most of the systematic difference between the intraoperative and day 30 dosimetry. Seeds near the rectal wall showed the most displacement, comparing TRUS and CBCT, probably because of TRUS probe-induced prostate deformation.

Multivariable model development and internal validation for prostate cancer specific survival and overall survival after whole-gland salvage Iodine-125 prostate brachytherapy.

BACKGROUND: Whole-gland salvage Iodine-125-brachytherapy is a potentially curative treatment strategy for localised prostate cancer (PCa) recurrences after radiotherapy. Prognostic factors influencing PCa-specific and overall survival (PCaSS & OS) are not known. The objective of this study was to develop a multivariable, internally validated prognostic model for survival after whole-gland salvage I-125-brachytherapy. MATERIALS AND METHODS: Whole-gland salvage I-125-brachytherapy patients treated in the Netherlands from 1993-2010 were included. Eligible patients had a transrectal ultrasound-guided biopsy-confirmed localised recurrence after biochemical failure (clinical judgement, ASTRO or Phoenix-definition). Recurrences were assessed clinically and with CT and/or MRI. Metastases were excluded using CT/MRI and technetium-99m scintigraphy. Multivariable Cox-regression was used to assess the predictive value of clinical characteristics in relation to PCa-specific and overall mortality. PCa-specific mortality was defined as patients dying with distant metastases present. Missing data were handled using multiple imputation (20 imputed sets). Internal validation was performed and the C-statistic calculated. Calibration plots were created to visually assess the goodness-of-fit of the final model. Optimism-corrected survival proportions were calculated. All analyses were performed according to the TRIPOD statement. RESULTS: Median total follow-up was 78months (range 5-139). A total of 62 patients were treated, of which 28 (45%) died from PCa after mean (±SD) 82 (±36) months. Overall, 36 patients (58%) patients died after mean 84 (±40) months. PSA doubling time (PSADT) remained a predictive factor for both types of mortality (PCa-specific and overall): corrected hazard ratio's (HR's) 0.92 (95% CI: 0.86-0.98, p=0.02) and 0.94 (95% CI: 0.90-0.99, p=0.01), respectively (C-statistics 0.71 and 0.69, respectively). Calibration was accurate up to 96month follow-up. Over 80% of patients can survive 8years if PSADT>24months (PCaSS) and >33months (OS). Only approximately 50% survival is achieved with a PSADT of 12months. CONCLUSION: A PSADT of respectively >24months and >33months can result in >80% probability of PCa- specific and overall survival 8years after whole-gland salvage I-125-brachytherapy. Survival should be weighed against toxicity from a salvage procedure. Larger series and external validation are necessary.

Rectal dose constraints for salvage iodine-125 prostate brachytherapy.

PURPOSE: Organ-confined prostate cancer recurrences after primary radiotherapy can be treated with salvage iodine-125 brachytherapy. Options include total salvage (TS) or focal salvage (FS). TS often leads to severe late gastrointestinal (GI) toxicity. Differences in rectal dosimetry between TS and FS are presented and dose constraints proposed to reduce late severe GI toxicity (>90 days). METHODS AND MATERIALS: Intraoperative dosimetry and 30-day CT-dosimetry of 20 FS and 28 TS patients were evaluated. GI toxicity was evaluated using the common terminology criteria for adverse events-4. With receiver operating characteristic analysis, dosimetry cutoff values to prevent severe late GI toxicity were assessed. RESULTS: FS reduces rectal dose significantly. Median D(0.1cc), D(1cc), D(2cc), and V100 reductions were 38 Gy (p = 0.002), 46 Gy (p < 0.0001), 46 Gy (p < 0.0001), and 0.41 cc (p = 0.0001), respectively, compared with TS. FS patients had no late severe GI toxicity. TS patients with severe GI toxicity (41%, n = 11) showed significantly higher rectal doses than TS patients without GI toxicity (59%, n = 16). Median D(0.1cc), D(1cc), D(2cc), and V100 differences were 29 Gy (p < 0.001), 17 Gy (p = 0.001), 28 Gy (p < 0.001), and 0.45 cc (p = 0.001). With receiver operating characteristic analysis, restrictions for the D(0.1cc), D(1cc), D(2cc), and V100 are <160 Gy (area under the curve [AUC], 0.88; 95% confidence interval [CI] 0.76-1.00), <119 Gy (AUC, 0.87; 95% CI, 0.74-1.00), <102 Gy (AUC, 0.89; 95% CI, 0.77-1.00), and <0.38 cc (AUC, 0.88; 95% CI, 0.75-1.00), respectively. Thirty-day CT dosimetry showed minor overestimation of intraoperative D(2cc) (median, 10 Gy [p = 0.02]). CONCLUSIONS: FS reduces rectal dose compared with TS. D(0.1cc), D(1cc), D(2cc), and V100 restrictions were 160 Gy, 120 Gy, 100 Gy, and 0.35 cc. Taking correlation into account, the D2cc <100 Gy might be sufficient for clinical practice. Larger series and multivariable models are necessary to further assess the found restrictions.

Urethral and bladder dosimetry of total and focal salvage Iodine-125 prostate brachytherapy: Late toxicity and dose constraints.

INTRODUCTION: Salvage Iodine-125 brachytherapy (I-125-BT) constitutes a curative treatment approach for patients with organ-confined recurrent prostate cancer after primary radiotherapy. Currently, focal salvage (FS) instead of whole-gland or total salvage (TS) is being investigated, to reduce severe toxicity associated with cumulative radiation dose. Differences in urethral and bladder dosimetry and constraints to reduce late (> 90 days) genitourinary (GU) toxicity are presented here. MATERIALS AND METHODS: Dosimetry on intraoperative ultrasound (US) of 20 FS and 28 TS patients was compared. The prostate, bladder, urethra and bulbomembranous (BM) urethra were delineated. Toxicity was assessed using the CTCAE version 4.0. Dose constraints to reduce toxicity in TS patients were evaluated with receiver operating characteristic (ROC) analysis. RESULTS: FS I-125 BT significantly reduces bladder and urethral dose compared to TS. Grade 3 GU toxicity occurred once in the FS group. For TS patients late severe (⩾ grade 3) GU toxicity was frequent (38% in the total 61 patients and 56% in the 27 analyzed patients). TS patients with ⩾ grade 3 GU toxicity showed higher bladder D2 cc than TS patients without toxicity (median 43 Gy) (p = 0.02). The urethral V100 was significantly higher in TS patients with several toxicity profiles: ⩾ grade 3 urethral strictures, ⩾ grade 2 urinary retention and multiple ⩾ grade 2 GU toxicity events. Dose to the BM urethra did not show a relation with stricture formation. ROC-analysis indicated a bladder D2 cc <70 Gy to prevent ⩾ grade 3 GU toxicity (AUC 0.76, 95%CI: 0.56-0.96, p = 0.02). A urethral V100 < 0.40 cc (AUC from 0.73-0.91, p = 0.003-0.05) could prevent other late GU toxicity. CONCLUSION: FS I-125 BT reduces urethral and bladder dose significantly compared to TS. With TS, there is an increased risk of cumulative dose and severe GU toxicity. Based on these findings, bladder D2 cc should be below 70 Gy and urethral V100 below 0.40 cc.

High-dose-rate prostate brachytherapy based on registered transrectal ultrasound and in-room cone-beam CT images.

PURPOSE: To present a high-dose-rate (HDR) brachytherapy procedure for prostate cancer using transrectal ultrasound (TRUS) to contour the regions of interest and registered in-room cone-beam CT (CBCT) images for needle reconstruction. To characterize the registration uncertainties between the two imaging modalities and explore the possibility of performing the procedure solely on TRUS. METHODS AND MATERIALS: Patients were treated with a TRUS/CBCT-based HDR brachytherapy procedure. For 100 patients, dosimetric results were analyzed. For 40 patients, registration uncertainties were examined by determining differences in fiducial marker positions on TRUS and registered CBCT. The accuracy of needle reconstruction on TRUS was investigated by determining the position differences of needle tips on TRUS and CBCT. The dosimetric impact of reregistration and needle reconstruction on TRUS only was studied for 8 patients. RESULTS: The average prostate V100 was 97.8%, urethra D10 was 116.3%, and rectum D1 cc was 66.4% of the prescribed dose. For 85% of the patients, registration inaccuracies were within 3 mm. Large differences were found between needle tips on TRUS and CBCT, especially in cranial-caudal direction, with a maximum of 10.4 mm. Reregistration resulted in a maximum V100 reduction of 0.9%, whereas needle reconstruction on TRUS only gave a maximum reduction of 9.4%. CONCLUSIONS: HDR prostate brachytherapy based on TRUS combined with CBCT is an accurate method. Registration uncertainties, and consequently dosimetric inaccuracies, are small compared with the uncertainties of performing the procedure solely based on static TRUS images. CBCT imaging is a requisite in our current procedure.

Objective automated assessment of time trends in prostate edema after (125)I implantation.

PURPOSE: To present an objective automated method to determine time trends in prostatic edema resulting from iodine-125 brachytherapy. METHODS AND MATERIALS: We followed 20 patients, implanted with stranded seeds, with seven consecutive CT scans to establish a time trend in prostate edema. Seed positions were obtained automatically from the CT series. The change in seed positions was used as surrogate for edema. Two approaches were applied to model changes in volume. (1) A cylindrical model: seeds from the compared distribution were linked to the reference distribution of Day 28. After alignment, the compared distribution was scaled in cylindrical coordinates, leading to the changes in radial and craniocaudal directions. The volume changes were calculated using these scaling factors. (2) A spherical model: distances of seeds to the center of gravity of all seeds were used as a measure to model volume changes. RESULTS: With Day 28 as reference, the observed volume changes were smaller than 18% ± 6% (1 standard deviation) for the cylindrical model and 12% ± 7% for the spherical model. One day after implantation, the implanted prostate was less than 10% larger than in the reference scan for both models. Apart from Day 0, both models showed similar volume changes. CONCLUSIONS: We present an objective automated method to determine changes in the implanted prostate volume, eliminating the influence of an observer in the assessment of the prostate size. The implanted volume change was less than 18% ± 7% for the studied group of 20 patients. Edema was 9% ± 5% from 1 day after implantation onward.

Regional radiotherapy versus an axillary lymph node dissection after lumpectomy: a safe alternative for an axillary lymph node dissection in a clinically uninvolved axilla in breast cancer. A case control study with 10 years follow up.

BACKGROUND: The standard treatment of the axilla in breast cancer used to be an axillary lymph node dissection. An axillary lymph node dissection is known to give substantial risks of morbidity. In recent years the sentinel node biopsy has become common practice. Future randomized study results will determine whether the expected decrease in morbidity can be proven. METHODS: Before the introduction of the sentinel node biopsy, we conducted a study in which 180 women of 50 years and older with T1/T2 cN0 breast cancer were treated with breast conserving therapy. Instead of an axillary lymph node dissection regional radiotherapy was given in combination with tamoxifen (RT-group). The study group was compared with 341 patients, with the same patient and tumour characteristics, treated with an axillary lymph node dissection (S-group). RESULTS: The treatment groups were comparable, except for age. The RT-group was significantly older than the S-group. The median follow up was 7.2 years. The regional relapse rates were low and equal in both treatment groups, 1.1% in RT-group versus 1.5% in S-group at 5 years. The overall survival was similar; the disease free survival was significant better in the RT-group. CONCLUSION: Regional recurrence rates after regional radiotherapy are very low and equal to an axillary lymphnode dissection.

Intraoperative adaptive brachytherapy of iodine-125 prostate implants guided by C-arm cone-beam computed tomography-based dosimetry.

PURPOSE: (1) To demonstrate the feasibility of C-arm cone-beam computed tomography (CBCT)-based postplanning and subsequent adaptation of underdosed critical areas by adding remedial seeds during the transrectal ultrasound (TRUS)-guided implantation of (125)I seeds and (2) to assess the duration of this procedure. METHODS AND MATERIALS: After finishing the implant, three fiducial markers were implanted and a TRUS study was performed to delineate the prostate. A C-arm CBCT unit with isocentric design was used to generate a CT data set to localize the seeds. The TRUS and CBCT data sets were coregistered by the radiation oncologist to assess the dosimetry of the implant. If underdosages existed at critical areas, dosimetry was adapted by adding remedial seeds while the patient was still under anesthesia. RESULTS: Of 20 patients studied, 9 demonstrated underdosage in critical areas. On average four additional seeds were implanted, resulting in a mean D(90) of 100.7% (increase 4.9%) and 117.5% (increase 17.8%) of the prescribed dose of 145 and 110 Gy, respectively. The average additional time involved in performing the adaptation procedure was less than 30 min. CONCLUSIONS: C-arm CBCT-guided intraoperative postplanning during TRUS-guided brachytherapy for prostate cancer is both feasible and time efficient. The adaptation resulted in improved dosimetry of the prostate implants.