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.

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.

A new algorithm for the registration of portal images to planning images in the verification of radiotherapy, as validated in prostate treatments.

The manual verification of a radiotherapy treatment, where a portal image is matched onto a planning image, is very time consuming and subject to inter- and intraobserver variability. Therefore, a fully automatic matching procedure (image registration) is required. Existing automatic matching algorithms are confounded, however, by irrelevant information in the portal images (i.e., air in the intestines). Therefore, we have developed a new method, which is an extension of chamfer matching and uses, apart from the distance to the nearest edge, additional information on the correspondence of the gradient angle and magnitude of the edges, making the method less sensitive to confounding information in the images. To validate the automatic matching procedure in clinical practice, we applied the new method on 157 images of 29 randomly selected patients treated for carcinoma of the prostate. Three experts manually matched these images in consensus. Subsequently, the same observers assessed the results of the automatic registration. When regular chamfer matching is used for the fully automatic matching procedure, only 5% of the image pairs could be matched correctly, whereas the new method successfully registered 80% by using additional information on the angle of the edges. From the results of the validation study it can be concluded that a significant reduction in workload for the physicians and technicians can be achieved with this method.