Alpha particle microdosimetry calculations using a shallow neural network.

A shallow neural network was trained to accurately calculate the microdosimetric parameters, 〈z1〉 and 〈z12〉 (the first and second moments of the single-event specific energy spectra, respectively) for use in alpha-particle microdosimetry calculations. The regression network of four inputs and two outputs was created in MATLAB and trained on a data set consisting of both previously published microdosimetric data and recent Monte Carlo simulations. The input data consisted of the alpha-particle energies (3.97-8.78 MeV), cell nuclei radii (2-10µm), cell radii (2.5-20µm), and eight different source-target configurations. These configurations included both single cells in suspension and cells in geometric clusters. The mean square error (MSE) was used to measure the performance of the network. The sizes of the hidden layers were chosen to minimize MSE without overfitting. The final neural network consisted of two hidden layers with 13 and 20 nodes, respectively, each with tangential sigmoid transfer functions, and was trained on 1932 data points. The overall training/validation resulted in a MSE = 3.71 × 10-7. A separate testing data set included input values that were not seen by the trained network. The final test on 892 separate data points resulted in a MSE = 2.80 × 10-7. The 95th percentile testing data errors were within ±1.4% for 〈z1〉 outputs and ±2.8% for 〈z12〉 outputs, respectively. Cell survival was also predicted using actual versus neural network generated microdosimetric moments and showed overall agreement within ±3.5%. In summary, this trained neural network can accurately produce microdosimetric parameters used for the study of alpha-particle emitters. The network can be exported and shared for tests on independent data sets and new calculations.

Microdosimetry-based determination of tumour control probability curves for treatments with 225Ac-PSMA of metastatic castration resistant prostate cancer.

We performed Monte Carlo simulations in order to determine, by means of microdosimetry calculations, tumour control probability (TCP) curves for treatments with 225Ac-PSMA of metastatic castration resistant prostate cancer (mCRPC). Realistic values of cell radiosensitivity, nucleus size and lesion size were used for calculations. As the cell radiosensitivity decreased, the nucleus size decreased and the lesion size increased, the absorbed dose to reach a given TCP increased. The widest variations occurred with regard to the cell radiosensitivity. For the Monte Carlo simulations, in order to address a non-uniform PSMA expression, different 225Ac-PSMA distributions were considered. The effect of these different PSMA distributions resulted in small variations in the TCP curves (maximum variation of 5%). Absorbed doses to reach a TCP of 0.9 for a uniform 225Ac-PSMA distribution, considering a relative biological effectiveness (RBE) of 5, ranged between 35.0 Gy and 116.5 Gy. The lesion absorbed doses per administered activity reported in a study on treatments with 225Ac-PSMA of mCRPC ranged between 1.3 Gy MBq-1 and 9.8 Gy MBq-1 for a RBE = 5. For a 70 kg-patient to whom 100 kBq kg-1 of 225Ac-PSMA are administered, the range of lesion absorbed doses would be between 9.1 Gy and 68.6 Gy. Thus, for a single cycle of 100 kBq kg-1, a number of lesions would not receive an absorbed dose high enough to reach a TCP of 0.9.

Comparison of microdosimetry-based absorbed doses to control tumours and clinically obtained tumour absorbed doses in treatments with 223Ra.

We performed Monte Carlo simulations in order to determine by means of microdosimetry calculations the average number of hits to the cell nucleus required to reach a tumour control probability (TCP) of 0.9, [Formula: see text], for the source geometry of a nucleus embedded in a homogeneous distribution of 223Ra atoms. From the results obtained and following the MIRD methodology, we determined the values of lesion absorbed doses needed to reach a TCP of 0.9, [Formula: see text], for different values of mass density, cell radiosensitivity, nucleus radius and lesion volume. The greatest variation of those absorbed doses occurred with cell radiosensitivity and no dependence was found on mass density. The source geometry used was chosen because we aimed to compare the values of [Formula: see text] with the lesion absorbed doses obtained from image-based macrodosimetry in treatments of metastatic castration-resistant prostate cancer with 223Ra which were obtained assuming a homogeneous distribution of 223Ra atoms within the lesion. In a comparison with a study including 29 lesions, results showed that even for the case of the most radiosensitive cells simulated, 45% of the lesions treated following a schedule of two cycles of 110 kBq kg-1 body mass would receive absorbed doses below the values of [Formula: see text] determined in this study.

Post-treatment prostate biopsies in the era of three-dimensional conformal radiotherapy: what can they teach us?

BACKGROUND: The ability to discriminate between therapeutic success and failure after radiotherapy (RT) for prostate cancer (PCa) remains a clinical challenge. Post-treatment biopsies would seem ideal for evaluating innovations such as dose escalation protocols or combination treatments involving brachytherapy or hormones. OBJECTIVE: Correlate post-treatment biopsy results with prostate-specific antigen (PSA) and clinical outcome in PCa patients treated with three-dimensional conformal radiotherapy (3DCRT) in a dose-escalation study. DESIGN, SETTING, AND PARTICIPANTS: This study included 160 patients with clinical stage T1c to T3b PCa treated between 1995 and 2005 in Hospital Universitario la Princesa with 3DCRT who consented to and underwent a transrectal ultrasound (TRUS)-guided prostate biopsy 24-36 mo after RT. The median follow-up was 78 mo (range 27-171 mo). INTERVENTION: The median radiation dose was 74 gray (Gy; range 66.0-84.1). Risk-adapted short-term androgen deprivation (STAD) and long-term androgen deprivation (LTAD) were associated in 25 and 106 patients, respectively. Right and left systematic biopsies were carried out by the same urologist and were examined by a genitourinary pathologist. MEASUREMENTS: Biochemical disease-free survival (bDFS) according to American Society for Therapeutic Radiology and Oncology (ASTRO) 1997 and Phoenix definition criteria as well as histologic control using post-treatment prostate biopsies. RESULTS: Twenty-one percent of patients (34 of 160) had post-treatment-positive biopsies (PB). The 5-yr bDFS according to the Phoenix definition was 87%, 65%, and 92% for the whole series (PB and negative biopsies [NB] patients, respectively [p<0.001]). Multivariate analysis showed that biopsy status at 24-36 mo was an independent predictor of bDFS (p<0.0005) and of clinical failure-free survival (p=0.043). CONCLUSION: The results of the present study show a strong correlation between a post-treatment PB and the 5-yr probability of bDFS, confirming that PSA control can be an adequate surrogate for local control, as assessed by post-treatment biopsies.

Is hormone therapy a protective factor for late hematuria after high-dose radiotherapy in prostate cancer?

OBJECTIVES: To identify potential clinical and dosimetric factors predictive of a higher risk of grade 2 or higher late hematuria in patients with prostate cancer treated with high-dose radiotherapy. METHODS: For this purpose, we have analyzed 229 T1c-T3b prostate cancer patients treated with 3-dimensional conformal radiotherapy (3DCRT) in a prospective dose escalation study and with a minimum follow-up of 1 year. The mean radiation dose was 79 Gy (range 72.1 to 84.14 Gy) and the mean follow-up was 47 months (range 14 to 95). One hundred eighteen patients also received androgen deprivation (AD) for high-risk disease. Univariate and multivariate analysis (MVA) were performed to identify variables significantly associated with late hematuria. RESULTS: Of the 31 (14%) patients with grade 2 or higher genitourinary toxicity, hematuria was the main symptom in 24 (10.5%) with only 1 patient (0.5%) experiencing grade 3 hematuria. On statistical analysis, all the dosimetric parameters failed to show a significant correlation with grade 2 or higher hematuria. On MVA, prior transurethral resection of the prostate (TURP) was significantly associated with a higher risk of late hematuria (relative risk [RR] = 2.8; P = 0.026), whereas long-term AD was correlated with a significantly decreased risk (RR = 0.21; P = 0.019). CONCLUSIONS: TURP was a relevant factor increasing 3 times the risk of late hematuria in prostate cancer patients treated with 3DCRT. Conversely, long-term AD resulted in a protective factor decreasing 5 times the risk of late hematuria. To our knowledge, this is the first study reporting a protecting effect of long-term hormones in late toxicity after radiotherapy.