M. Maenhout

Focal salvage iodine-125 brachytherapy for prostate cancer recurrences after primary radiotherapy: a retrospective study regarding toxicity, biochemical outcome and quality of life.

PURPOSE Whole-gland salvage for recurrent prostate cancer (PCa) shows high failure and toxicity rates. Early and adequate localization of recurrences enables focal salvage, thereby potentially improving functional outcomes, while maintaining cancer control. MATERIALS AND METHODS Retrospective analysis yielded 20 focal salvage I125 brachytherapy patients for locally recurrent PCa after primary radiotherapy. Tumor was defined by multiparametric MRI and correspondence with transrectal biopsies. Dose data were obtained intra-operatively. The tumor was prescribed ⩾144 Gy. Toxicity was scored by the Common Terminology Criteria for Adverse Events version 4 (CTCAE-4). Biochemical failure (BF) was defined using the Phoenix criteria (PSA-nadir + 2.0 ng/ml). Quality of life (QoL) was measured by SF-36 Health Survey and European Organization of Research and Treatment of Cancer (EORTC) C30+3 and PR25 questionnaires. RESULTS With a median follow-up of 36 months (range 10-45), six patients experienced BF, of which three had no initial response. Grade 3 genitourinary (GU) toxicity occurred in one patient (a urethral stricture). The five previously potent patients retained erectile function. QoL remained decreased with regard to urinary symptoms. CONCLUSION Focal salvage I125 brachytherapy showed one grade 3 GU toxicity in the 20 treated patients. Biochemical response and QoL were acceptable.

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.

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 ratios (HRs) 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.

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.

An automated optimization tool for high-dose-rate (HDR) prostate brachytherapy with divergent needle pattern

Focal high-dose-rate (HDR) for prostate cancer has gained increasing interest as an alternative to whole gland therapy as it may contribute to the reduction of treatment related toxicity. For focal treatment, optimal needle guidance and placement is warranted. This can be achieved under MR guidance. However, MR-guided needle placement is currently not possible due to space restrictions in the closed MR bore. To overcome this problem, a MR-compatible, single-divergent needle-implant robotic device is under development at the University Medical Centre, Utrecht: placed between the legs of the patient inside the MR bore, this robot will tap the needle in a divergent pattern from a single rotation point into the tissue. This rotation point is just beneath the perineal skin to have access to the focal prostate tumor lesion. Currently, there is no treatment planning system commercially available which allows optimization of the dose distribution with such needle arrangement. The aim of this work is to develop an automatic inverse dose planning optimization tool for focal HDR prostate brachytherapy with needle insertions in a divergent configuration. A complete optimizer workflow is proposed which includes the determination of (1) the position of the center of rotation, (2) the needle angulations and (3) the dwell times. Unlike most currently used optimizers, no prior selection or adjustment of input parameters such as minimum or maximum dose or weight coefficients for treatment region and organs at risk is required. To test this optimizer, a planning study was performed on ten patients (treatment volumes ranged from 8.5 cm(3)to 23.3 cm(3)) by using 2-14 needle insertions. The total computation time of the optimizer workflow was below 20 min and a clinically acceptable plan was reached on average using only four needle insertions.

Fiber Bragg gratings-based sensing for real-time needle tracking during MR-guided brachytherapy

PURPOSE The development of MR-guided high dose rate (HDR) brachytherapy is under investigation due to the excellent tumor and organs at risk visualization of MRI. However, MR-based localization of needles (including catheters or tubes) has inherently a low update rate and the required image interpretation can be hampered by signal voids arising from blood vessels or calcifications limiting the precision of the needle guidance and reconstruction. In this paper, a new needle tracking prototype is investigated using fiber Bragg gratings (FBG)-based sensing: this prototype involves a MR-compatible stylet composed of three optic fibers with nine sets of embedded FBG sensors each. This stylet can be inserted into brachytherapy needles and allows a fast measurement of the needle deflection. This study aims to assess the potential of FBG-based sensing for real-time needle (including catheter or tube) tracking during MR-guided intervention. METHODS First, the MR compatibility of FBG-based sensing and its accuracy was evaluated. Different known needle deflections were measured using FBG-based sensing during simultaneous MR-imaging. Then, a needle tracking procedure using FBG-based sensing was proposed. This procedure involved a MR-based calibration of the FBG-based system performed prior to the interventional procedure. The needle tracking system was assessed in an experiment with a moving phantom during MR imaging. The FBG-based system was quantified by comparing the gold-standard shapes, the shape manually segmented on MRI and the FBG-based measurements. RESULTS The evaluation of the MR compatibility of FBG-based sensing and its accuracy shows that the needle deflection could be measured with an accuracy of 0.27 mm on average. Besides, the FBG-based measurements were comparable to the uncertainty of MR-based measurements estimated at half the voxel size in the MR image. Finally, the mean(standard deviation) Euclidean distance between MR- and FBG-based needle position measurements was equal to 0.79 mm(0.37 mm). The update rate and latency of the FBG-based needle position measurement were 100 and 300 ms, respectively. CONCLUSIONS The FBG-based needle tracking procedure proposed in this paper is able to determine the position of the complete needle, under MR-imaging, with better accuracy and precision, higher update rate, and lower latency compared to current MR-based needle localization methods. This system would be eligible for MR-guided brachytherapy, in particular, for an improved needle guidance and reconstruction.

Focal MRI-Guided Salvage High-Dose-Rate Brachytherapy in Patients With Radiorecurrent Prostate Cancer

Introduction: Whole-gland salvage treatment of radiorecurrent prostate cancer has a high rate of severe toxicity. The standard of care in case of a biochemical recurrence is androgen deprivation treatment, which is associated with morbidity and negative effects on quality of life. A salvage treatment with acceptable toxicity might postpone the start of androgen deprivation treatment, might have a positive influence on the patients’ quality of life, and might even be curative. Here, toxicity and biochemical outcome are described after magnetic resonance imaging–guided focal salvage high-dose-rate brachytherapy in patients with radiorecurrent prostate cancer. Materials and Methods: Seventeen patients with pathologically proven locally recurrent prostate cancer were treated with focal high-dose-rate brachytherapy in a single 19-Gy fraction using magnetic resonance imaging for treatment guidance. Primary radiotherapy consisted of external beam radiotherapy or low-dose-rate brachytherapy. Tumors were delineated with Ga-68–prostate-specific membrane antigen or F18-choline positron emission tomography in combination with multiparametric magnetic resonance imaging. All patients had a prostate-specific antigen level of less than 10 ng/mL at the time of recurrence and a prostate-specific antigen doubling time of ≥12 months. Toxicity was measured by using the Common Terminology Criteria for Adverse Events version 4. Results: Eight of 17 patients had follow-up interval of at least 1 year. At a median follow-up interval of 10 months (range 3-40 months), 1 patient experienced a biochemical recurrence according to the Phoenix criteria, and prostate-specific membrane antigen testing revealed that this was due to a distant nodal metastasis. One patient had a grade 3 urethral stricture at 2 years after treatment. Conclusion: Focal salvage high-dose-rate brachytherapy in patients with radiorecurrent prostate cancer showed grade 3 toxicity in 1 of 17 patients and a distant nodal metastasis in another patient. Whether this treatment option leads to cure in a subset of patients or whether it can successfully postpone androgen deprivation treatment needs further investigation.

A novel adaptive needle insertion sequencing for robotic, single needle MR-guided high-dose-rate prostate brachytherapy

MR-guided high-dose-rate (HDR) brachytherapy has gained increasing interest as a treatment for patients with localized prostate cancer because of the superior value of MRI for tumor and surrounding tissues localization. To enable needle insertion into the prostate with the patient in the MR bore, a single needle MR-compatible robotic system involving needle-by-needle dose delivery has been developed at our institution. Throughout the intervention, dose delivery may be impaired by: (1) sub-optimal needle positioning caused by e.g. needle bending, (2) intra-operative internal organ motion such as prostate rotations or swelling, or intra-procedural rectum or bladder filling. This may result in failure to reach clinical constraints. To assess the first aforementioned challenge, a recent study from our research group demonstrated that the deposited dose may be greatly improved by real-time adaptive planning with feedback on the actual needle positioning. However, the needle insertion sequence is left to the doctor and therefore, this may result in sub-optimal dose delivery. In this manuscript, a new method is proposed to determine and update automatically the needle insertion sequence. This strategy is based on the determination of the most sensitive needle track. The sensitivity of a needle track is defined as its impact on the dose distribution in case of sub-optimal positioning. A stochastic criterion is thus presented to determine each needle track sensitivity based on needle insertion simulations. To assess the proposed sequencing strategy, HDR prostate brachytherapy was simulated on 11 patients with varying number of needle insertions. Sub-optimal needle positioning was simulated at each insertion (modeled by typical random angulation errors). In 91% of the scenarios, the dose distribution improved when the needle was inserted into the most compared to the least sensitive needle track. The computation time for sequencing was less than 6 s per needle track. The proposed needle insertion sequencing can therefore assist in delivering an optimal dose in HDR prostate brachytherapy.

Second salvage high-dose-rate brachytherapy for radiorecurrent prostate cancer

Purpose Salvage treatments for localized radiorecurrent prostate cancer can be performed safely when a focal and image guided approach is used. Due to the low toxicity, the opportunity exists to investigate a second salvage treatment when a second locally recurrent prostate cancer occurs. Here, we describe a second salvage treatment procedure of 4 patients. Material and methods Four patients with a pathologically proven second local recurrence were treated in an outpatient magnetic resonance imaging (MRI)-guided setting with a single fraction of 19 Gy focal high-dose-rate brachytherapy (HDR-BT). Delineation was performed using choline-PET-CT or a 68Ga-PSMA PET in combination with multiparametric 3 Tesla MRI in all four patients. Toxicity was measured using common toxicity criteria for adverse events (CTCAE) version 4.0. Results With a median follow-up of 12 months (range, 6-15), there were 2 patients with biochemical recurrence as defined by the Phoenix-definition. There were no patients with grade 3 or more toxicity. In all second salvage HDR-BT treatments, the constraints for rectum, bladder, and urethra were met. Median treatment volume (GTV) was 4.8 cc (range, 1.9-6.6 cc). A median of 8 catheters (range, 6-9) were used, and the median dose to the treatment volume (GTV) was a D95: 19.3 Gy (SD 15.5-19.4 Gy). Conclusions Second focal salvage MRI-guided HDR-BT for a select group of patients with a second locally recurrent prostate cancer is feasible. There was no grade 3 or more acute toxicity for these four patients.

Adaptive planning strategy for high dose rate prostate brachytherapy—a simulation study on needle positioning errors.

The development of magnetic resonance (MR) guided high dose rate (HDR) brachytherapy for prostate cancer has gained increasing interest for delivering a high tumor dose safely in a single fraction. To support needle placement in the limited workspace inside the closed-bore MRI, a single-needle MR-compatible robot is currently under development at the University Medical Center Utrecht (UMCU). This robotic device taps the needle in a divergent way from a single rotation point into the prostate. With this setup, it is warranted to deliver the irradiation dose by successive insertions of the needle. Although robot-assisted needle placement is expected to be more accurate than manual template-guided insertion, needle positioning errors may occur and are likely to modify the pre-planned dose distribution.In this paper, we propose a dose plan adaptation strategy for HDR prostate brachytherapy with feedback on the needle position: a dose plan is made at the beginning of the interventional procedure and updated after each needle insertion in order to compensate for possible needle positioning errors. The introduced procedure can be used with the single needle MR-compatible robot developed at the UMCU. The proposed feedback strategy was tested by simulating complete HDR procedures with and without feedback on eight patients with different numbers of needle insertions (varying from 4 to 12). In of the cases tested, the number of clinically acceptable plans obtained at the end of the procedure was larger with feedback compared to the situation without feedback. Furthermore, the computation time of the feedback between each insertion was below 100 s which makes it eligible for intra-operative use.