Full title: Phase 3 Assessment of the Automated Bone Scan Index as a Prognostic Imaging Biomarker of Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Full title: Role of bone scan index in the prognosis and effects of therapy on prostate cancer with bone metastasis: Study design and rationale for the multicenter Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index (PROSTAT-BSI) study.

Full title: Editorial Comment to Role of bone scan index in the prognosis and effects of therapy on prostate cancer with bone metastasis: Study design and rationale for the multicenter Prostatic Cancer Registry of Standard Hormonal and Chemotherapy Using Bone Scan Index (PROSTAT-BSI) study.

Full title: Influence of the Different Primary Cancers and Different Types of Bone Metastasis on the Lesion-based Artificial Neural Network Value Calculated by a Computer-aided Diagnostic System, BONENAVI, on Bone Scintigraphy Images.

Introduction: We evaluated bone scan index (BSI) as a predictive biomarker for time to castration-resistant prostate cancer (CRPC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). 

Materials and Methods: We identified 85 consecutive mHSPC patients treated with first-line androgen deprivation therapy. We analyzed the correlations between time to CRPC and clinicopathological characteristics, including age, prostate-specific antigen (PSA) level, Gleason score, clinical TNM stage, hemoglobin, lactate dehydrogenase, C-reactive protein, and BSI. 

Results: The median BSI was 2.7%. Progression to CRPC occurred in 55 (64.7%) patients and the median time to CRPC was 12.9 months. In multivariate analysis, 3 significant risk factors for time to CRPC were identified: age (>73 vs. ≤ 73 years; hazard ratio [HR] 0.53), p = 0.038, PSA level (>270 vs. ≤ 270 ng/mL; HR 0.53, p = 0.038), and BSI (>2.7 vs. ≤ 2.7%; HR 2.97, p < 0.001). 

Conclusion: Age, PSA level, and BSI were found to be significant predictive factors for time to CRPC in patients with mHSPC.

We retrospectively assessed the bone scan index as a predictor of overall survival in patients with metastatic
castration-resistant prostate cancer treated with enzalutamide or abiraterone acetate. Improved bone scan index after these treatments independently predicted longer overall survival.

Purpose: Bone scan index (BSI) is an objective tool for quantifying bone metastasis load. We assessed its prognostic usefulness in patients with metastatic castration-resistant prostate cancer (CRPC) treated with enzalutamide (ENZ) or abiraterone acetate (AA). Materials and Methods: We analyzed 40 patients who received ENZ or AA treatment (ENZ/AA) for metastatic CRPC. The Cox proportional hazards model and a C-index were used to investigate associations between overall survival (OS) and BSI, and patient age, prostate-specific antigen, time to CRPC, previous docetaxel use, and pain. Results: Median OS after ENZ/AA was 17.8 months. All patient deaths (n ¼ 19; 47.5%) were from prostate cancer. In multivariate analysis, decreased BSI was an independent predictor for longer OS (hazard ratio, 8.97; P ¼ .011). Inclusion of BSI improved the C-index from 0.721 to 0.792 in predicting OS after ENZ/AA.
Conclusions: Decreased BSI after ENZ/AA independently predicts longer OS.

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.

BACKGROUND:
We sought to identify potential clinical variables associated with outcomes after radium-223 therapy in routine practice.
METHODS:
Consecutive non-trial mCRPC patients who received ≥1 dose of radium dichloride-223 at four academic and one community urology-specific cancer centers from May 2013 to June 2014 were retrospectively identified. Association of baseline and on-therapy clinical variables with number of radium doses received and clinical outcomes including overall survival were analyzed using chi-square statistics, cox proportional hazards, and Kaplan-Meier methods. Bone Scan Index (BSI) was derived from available bone scans using EXINI software.
RESULTS:
One hundred and forty-five patients were included. Radium-223 was administered for six cycles in 74 patients (51%). One-year survival in this heavily pre-treated population was 64% (95%CI: 54-73%). In univariate and multivariate analysis, survival was highly associated with receiving all six doses of Radium-223. Receipt of six doses was associated with ECOG PS of 0-1, lower baseline PSA & pain level, no prior abiraterone/enzalutamide, <5 BSI value, and normal alkaline phosphatase. In patients who reported baseline pain (n = 72), pain declined in 51% after one dose and increased in 7%. PSA declined ≥50% in 16% (18/110). Alkaline phosphatase declined ≥25% in 48% (33/69) and ≥50% in 16/69 patients. BSI declined in 17 (68%) of the 25 patients who had bone scan available at treatment follow-up. Grade ≥3 neutropenia, anemia, and thrombocytopenia occurred in 4% (n = 114), 4% (n = 125), and 5% (n = 123), respectively.
CONCLUSIONS:
Patients earlier in their disease course with <5 BSI, low pain score, and good ECOG performance status are optimal candidates for radium-223. Radium-223 therapy is well tolerated with most patients reporting declines in pain scores and BSI.

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.

Background:
The bone scan index (BSI), which is obtained using a computer-aided bone scan evaluation system, is anticipated to become an objective and quantitative clinical tool for evaluating bone metastases in prostate cancer. Here, we assessed the usefulness of the BSI as a prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC) treated using docetaxel.

Methods:
We analyzed 41 patients who received docetaxel for mCRPC. The Bonenavi system was used as the calculation program for the BSI. The utility of the BSI as a predictor of overall survival (OS) after docetaxel was evaluated. The Cox proportional hazards model was used to investigate the association between clinical variables obtained at docetaxel treatment, namely PSA, patient age, liver metastasis, local therapy, hemoglobin (Hb), lactase dehydrogenase (LDH), albumin (Alb), PSA doubling time, and BSI and OS.

Results:
The median OS after docetaxel therapy was 17.7 months. Death occurred in 22 (53.7 %) patients; all deaths were caused by prostate cancer. In multivariate analysis, three factors were identified as significant independent prognostic biomarkers for OS after docetaxel; these were liver metastases (yes vs no; HR, 3.681; p = 0.026), Alb (<3.9 vs ≥3.9; HR, 3.776; p = 0.020), and BSI (>1 % vs ≤1 %; HR, 3.356; p = 0.037). We evaluated the discriminatory ability of our models including or excluding the BSI by quantifying the c-index. The BSI improved the c-index from 0.758 to 0.769 for OS after docetaxel. CRPC patients with a BSI >1 had a significantly shorter OS than patients with a BSI ≤1 (p = 0.029).

Conclusions:
The BSI, liver metastases and Alb were independent prognostic factors for OS after docetaxel. The BSI might be a useful tool for risk stratification of mCRPC patients undergoing docetaxel treatment.

Background
Abiraterone acetate (AA) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. To accurately measure treatment response in bone, quantitative methods are needed. Bone Scan Index (BSI), a prognostic imaging biomarker, reflects the tumour burden in bone as a percentage of the total skeletal mass calculated from bone scintigraphy.

Objective
To evaluate the value of BSI as a biomarker for outcome evaluation in mCRPC patients on treatment with AA according to clinical routine. Design, setting and participants: We retrospectively studied 104 mCRPC patients who received AA following disease progression after chemotherapy. All patients underwent whole-body bone scintigraphy before and during AA treatment. Baseline and follow-up BSI data were obtained using EXINI Bone ^BSI software.

Measurements and statistical analysis
Associations between BSI-change, clinical parameters at follow up, and overall survival (OS) were evaluated using the Cox proportional hazards regression models and Kaplan-Meier estimates. Discrimination between variables was assessed using the concordance index (C index).

Results and limitations
Patients with an increase in BSI at follow-up of at most 0.30 (n=54) had a significantly longer median-survival-time than those with an increase of BSI> 0.30 (n=50) (median 16 vs. 10 months, p=0.001). BSI-change was also associated with OS in a multivariate Cox analysis including commonly used clinical parameters for prognosis (C-index=0.7, Hazard ratio= 1.1 and p=0.03). The retrospective design was a limitation.

Conclusions
BSI-change was significantly associated with OS in mCRPC patients undergoing AA treatment, following disease progression in a post-chemotherapy setting. BSI may be a useful imaging biomarker for outcome evaluation in this group of patients, and it could be a valuable complementary tool in monitoring patients with mCRPC on second-line therapies.

Patient summary
BSI-change is related to survival time in mCRPC patients on AA. BSI may be a valuable complementary decision-making tool supporting physicians monitoring patients with mCRPC on second-line therapies.