Novel nomogram developed for determining suitability of metastatic castration-resistant prostate cancer patients to receive maximum benefit from radium-223 dichloride treatment-Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial.

PURPOSE: To develop a novel nomogram for determining radium-223 dichloride (Ra-223) treatment suitability for metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: This Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial was a retrospective multicenter investigation enrolled 258 mCRPC patients in Japan with Ra-223 treatment between June 2016 and August 2020, with bone scintigraphy findings before treatment, clinical data, and survival outcome available. A nomogram was constructed using prognostic factors for overall survival (OS) based on a least absolute shrinkage and selection operator Cox regression model. A sub-analysis was also conducted for patients meeting European Medicines Agency (EMA) guidelines. RESULTS: Within a median of 17.4 months after initial Ra-223 treatment, 124 patients (48.1%) died from prostate cancer. Predictive factors included (1) sum of prior treatment history (score 0, never prior novel androgen receptor-targeted agents (ARTA) therapy, never prior taxane-based chemotherapy, and ever prior bisphosphonate/denosumab treatment), (2) Eastern Cooperative Oncology Group (ECOG) performance status, (3) prostate-specific antigen doubling time (PSADT), (4) hemoglobin, (5) lactate dehydrogenase (LDH), and (6) alkaline phosphatase (ALP) levels, and (7) automated bone scan index (aBSI) value based on bone scintigraphy. The nomogram using those factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.748 and 0.734, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.771, 0.818, and 0.771, respectively. In 227 patients meeting EMA recommendation, the nomogram with seven factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.722 and 0.704, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.747, 0.790, and 0.759, respectively. CONCLUSION: This novel nomogram including aBSI to select mCRPC patients to receive Ra-223 with significantly prolonged OS possibility was found suitable for assisting therapeutic decision-making, regardless of EMA recommendation.

New index to assess the extent of bone disease in patients with prostate cancer using SPECT/CT.

OBJECTIVE: Assessing the extent of bone metastases in patients with prostate cancer is very important to predict patient prognosis. Therefore, the bone scan index (BSI), which is easy to use, has been used; however, the accuracy is not that high. In this study, we proposed a new index for the extent of bone disease using single-photon emission computed tomography with computed tomography (SPECT/CT) images and assessed the accuracy of calculation. METHODS: In this study, a total of 46 bone scans from 12 patients with prostate cancer treated for bone metastases with Radium-223 were included. Whole-body planar images were obtained 150-180 min after an intravenous injection of 99mTc-methylene diphosphonate, and cervical-to-pelvic SPECT/CT was immediately obtained. The total bone volume (TBV) and regional metabolic bone volume (MBV) were defined as Hounsfield unit of > 120, standardized uptake value (SUV) of > 0.5, and SUV of > 5-8 in four levels, respectively. Bone metabolism volumetric index (BMVI) was calculated as the percentage of the total MBV divided by TBV. The variability of the TBV measurement was evaluated by the percentage coefficient of variance (%CV) of TBV within individual patients. We evaluated the correlation of TBV with age, height, weight, and body mass index and the correlation and agreement between BSI and BMVI. RESULTS: The mean and %CV of TBV were 4661.7 cm3 and 2.8%, respectively, and TBV was strongly correlated with body weight. BMVI was significantly higher than BSI and correlated with alkaline phosphatase. For patients with progressive bone metastases, BSI was clearly underestimated, whereas BMVI was elevated. CONCLUSIONS: Although assessed in a small number of cases, the new index for assessing the extent of bone disease using SPECT/CT imaging was highly value than BSI and was significantly correlated with alkaline phosphatase. Therefore, this study suggests that BMVI could improve the low sensitivity of BSI in patients with low extent of disease grade.

Bone scan index of the jaw: a new approach for evaluating early-stage anti-resorptive agents-related osteonecrosis.

OBJECTIVE: A computer-aided diagnosis of bone scintigraphy using a bone scan index (BSI) has not been applied to a diagnosis of anti-resorptive agents-related osteonecrosis of the jaw (ARONJ). The aim of this study was to validate a diagnostic ability of BSI for early-stage ARONJ. METHODS: A total of 44 cancer patients treated with anti-resorptive drugs were evaluated retrospectively. All patients underwent bone scintigraphy and the tracer uptakes were analyzed by BSI. The software BONENAVI (FUJIFILM RI Pharma; EXINIbone, EXINI Diagnostics) could automatically detect abnormal intensities and calculate each regional BSI (rBSI). Among the rBSIs, the largest one in the jaw was manually selected and defined as maximum BSI of the jaw (BSIJmax). Uptake ratio (UR) between the maximum jaw count-to-average forehead count was also calculated. Screening accuracy of ARONJ based on 2 parameters was compared. Receiver operating characteristic analysis and Fisher's exact test were performed. RESULTS: The BSIJmax was significantly higher in patients who developed ARONJ than in those who did not, 3 months before the diagnosis of stage 2 ARONJ (p < 0.0001 and p = 0.02 in the maxilla and mandible, respectively). Using the cutoff values of 0.09% in the maxilla and 0.06% in the mandible, BSIJmax for predicting stage 2 ARONJ showed sensitivity and specificity of 88 and 96%, respectively, in the maxilla and 64 and 89%, respectively, in the mandible at 3 months before the diagnosis. The BSIJmax >0.09% and BSIJmax >0.06% in the maxilla and mandible, respectively, were much more frequently observed in patients who subsequently developed stage 2 ARONJ 3 months after the bone scintigraphy than in those who did not (p < 0.0001 and odds ratio = 182 in the maxilla and p < 0.005 and odds ratio = 14 in the mandible). The UR showed comparable diagnostic ability. CONCLUSION: The BSIJ provided a new index for evaluating ARONJ. For predicting occurrence of ARONJ, the thresholds of BSIJmax = 0.09 and 0.06% in the maxilla and mandible, respectively, may be used in patients treated with anti-resorptive drugs, and a differential diagnosis including ARONJ is recommended.

Expert System for Bone Scan Interpretation Improves Progression Assessment in Bone Metastatic Prostate Cancer.

INTRODUCTION: The bone scan index (BSI) was introduced as a quantitative tool for tumor involvement in bone of patients with metastatic prostate cancer (mPCa). The computer-aided diagnosis device for BSI analysis EXINIboneBSI seems to represent technical progress for the quantitative assessment of bone involvement. But it is not yet clear if the automated BSI (aBSI) could contribute to improved evaluation of progression in patients under antiandrogens or chemotherapy in contrast to the visual interpretation and/or conventional biomarkers such as the prostate-specific antigen (PSA). METHODS: In 49 mPCa patients, bone scans were performed initially and during different therapy courses. Scans were evaluated visually and by the artificial-neural-network-based expert system EXINIboneBSI. Progression of metastatic bone involvement was defined according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria in the visual interpretation. The computer-assisted interpretation was based on different cutoff values in relative changes of the aBSI. Additionally, assessments according to bone scanning were compared to changes in the PSA value as a potential surrogate for treatment response. RESULTS: Using a sensitive cutoff value (5% or 10%) for the relative aBSI increase led to significantly increased progression determination compared to the visual interpretation of bone scans (49% and 43% vs. 27%, p < 0.001). In 63% of the cases PSA and BSI changes matched, whereas in 18% progression was only indicated by the aBSI. A relative cutoff of 5% for the aBSI decrease could reclassify 47 serial scan pairs which were visually interpreted as stable into 22 progressive and 25 remissive scans. CONCLUSION: Distinct thresholds of the relative aBSI could help to better assess disease progression in mPCa patients. Manual corrections of the BSI values are not required in most cases. The aBSI could serve as a useful additional parameter for therapy monitoring in mPCa patients in the future.

Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide.

BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the automated BSI in predicting overall survival (OS) in mCRPC patients being treated with enzalutamide. METHODS: Retrospectively, we included patients who received enzalutamide as a clinically approved therapy for mCRPC and had undergone bone scan prior to starting therapy. Automated BSI, prostate-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI Bone(BSI) version 2. Kendall's tau (τ) was used to assess the correlation of BSI with other blood-based biomarkers. Concordance index (C-index) was used to evaluate the discriminating strength of automated BSI in predicting OS. RESULTS: Eighty mCRPC patients with baseline bone scans were included in the study. There was a weak correlation of automated BSI with PSA (τ = 0.30), with HgB (τ = -0.17), and with ALP (τ = 0.56). At baseline, the automated BSI was observed to be predictive of OS (C-index 0.72, standard error (SE) 0.03). Adding automated BSI to the blood-based model significantly improved the C-index from 0.67 to 0.72, p = 0.017. Treatment follow-up bone scans were available from 62 patients. Both change in BSI and percent change in PSA were predictive of OS. However, the combined predictive model of percent PSA change and change in automated BSI (C-index 0.77) was significantly higher than that of percent PSA change alone (C-index 0.73), p = 0.041. CONCLUSIONS: The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated with enzalutamide.

Analytic Validation of the Automated Bone Scan Index as an Imaging Biomarker to Standardize Quantitative Changes in Bone Scans of Patients with Metastatic Prostate Cancer.

UNLABELLED: A reproducible and quantitative imaging biomarker is needed to standardize the evaluation of changes in bone scans of prostate cancer patients with skeletal metastasis. We performed a series of analytic validation studies to evaluate the performance of the automated bone scan index (BSI) as an imaging biomarker in patients with metastatic prostate cancer. METHODS: Three separate analytic studies were performed to evaluate the accuracy, precision, and reproducibility of the automated BSI. Simulation study: bone scan simulations with predefined tumor burdens were created to assess accuracy and precision. Fifty bone scans were simulated with a tumor burden ranging from low to high disease confluence (0.10-13.0 BSI). A second group of 50 scans was divided into 5 subgroups, each containing 10 simulated bone scans, corresponding to BSI values of 0.5, 1.0, 3.0, 5.0, and 10.0. Repeat bone scan study: to assess the reproducibility in a routine clinical setting, 2 repeat bone scans were obtained from metastatic prostate cancer patients after a single 600-MBq (99m)Tc-methylene diphosphonate injection. Follow-up bone scan study: 2 follow-up bone scans of metastatic prostate cancer patients were analyzed to determine the interobserver variability between the automated BSIs and the visual interpretations in assessing changes. The automated BSI was generated using the upgraded EXINI bone(BSI) software (version 2). The results were evaluated using linear regression, Pearson correlation, Cohen κ measurement, coefficient of variation, and SD. RESULTS: Linearity of the automated BSI interpretations in the range of 0.10-13.0 was confirmed, and Pearson correlation was observed at 0.995 (n = 50; 95% confidence interval, 0.99-0.99; P < 0.0001). The mean coefficient of variation was less than 20%. The mean BSI difference between the 2 repeat bone scans of 35 patients was 0.05 (SD = 0.15), with an upper confidence limit of 0.30. The interobserver agreement in the automated BSI interpretations was more consistent (κ = 0.96, P < 0.0001) than the qualitative visual assessment of the changes (κ = 0.70, P < 0.0001) was in the bone scans of 173 patients. CONCLUSION: The automated BSI provides a consistent imaging biomarker capable of standardizing quantitative changes in the bone scans of patients with metastatic prostate cancer.