Clinical documentation


Expert system for bone scan interpretation improves progression assessment in bone metastatic prostate cancer

Haupt et al.Adv Ther 2017

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).
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.
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.
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.

Clinical correlates of benefit from radium-223 therapy in metastatic castration resistant prostate cancer

Alva et al.Prostate 2016

We sought to identify potential clinical variables associated with outcomes after radium-223 therapy in routine practice.

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.

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.

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.

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

Anand et al.EJNMMI Research 2016

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.
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.
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.
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.

Prognostic value of a computer-aided diagnosis system involving bone scans among men treated with docetaxel for metastatic castration-resistant prostate cancer

Uemura et al.BMC Cancer 2016

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.

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.

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).

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.

Prognostic value of the bone scan index using a computer-aided diagnosis system for bone scans in hormone-naive prostate cancer patients with bone metastases

Miyoshi et al.BMC Cancer 2016

The bone scan index (BSI) using a computer-aided diagnosis system for bone scans is expected to be an objective and quantitative clinical tool for evaluating bone metastatic prostate cancer. This study aimed to evaluate the pretreatment BSI as a prognostic factor in hormone-naive prostate cancer patients with bone metastases.

The study included 60 patients with hormone-naive, bone metastatic prostate cancer that was initially treated with combined androgen blockade therapy. The BONENAVI system was used for calculating the BSI. We evaluated the correlation between overall survival (OS) and pretreatment clinicopathological characteristics, including patients’ age, initial prostate-specific antigen (PSA) value, Gleason scores, clinical TNM stage, and the BSI. Cox proportional hazards regression models were used for statistical analysis.

The median follow-up duration was 21.4 months. Clinical or PSA progression occurred in 37 (61.7 %) patients and 18 (30.0 %) received docetaxel. Death occurred in 16 (26.7 %) patients. Of these deaths, 15 (25.0 %) were due to prostate cancer. The median OS was not reached. In multivariate analysis, age and the BSI were independent prognostic factors for OS. We evaluated the discriminatory ability of our models, including or excluding BSI by quantifying the C-index. The BSI improved the C-index from 0.751 to 0.801 for OS. Median OS was not reached in patients with a BSI ≤1.9 and median OS was 34.8 months in patients with a BSI >1.9 (p = 0.039).

The pretreatment BSI and patients’ age are independent prognostic factors for patients with 
hormone-naive, bone metastatic prostate cancer.

Bone scan index as an imaging biomarker in mCRPC: a multicentre study based on patients treated with abiraterone acetate (Zytiga™) in clinical practice

Reza et al.Eur Urol Focus 2016

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.

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.

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).

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.

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.

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.

Bone Scan Index and progression-free survival data for progressive metastatic castration-resistant prostate cancer patients who received ODM-201 in the ARADES multicentre study

Reza et al.Eur Urol Focus 2016

ODM-201, a new-generation androgen receptor inhibitor, has shown clinical efficacy in prostate cancer (PCa). Quantitative methods are needed to accurately assess changes in bone as a measurement of treatment response. The Bone Scan Index (BSI) reflects the percentage of skeletal mass a given tumour affects.

To evaluate the predictive value of the BSI in metastatic castration-resistant PCa (mCRPC) patients undergoing treatment with ODM-201.

From a total of 134 mCRPC patients who participated in the Activity and Safety of ODM-201 in Patients with Progressive Metastatic Castration-resistant Prostate Cancer clinical trial and received ODM-201, we retrospectively selected all those patients who had bone scan image data of sufficient quality to allow for both baseline and 12-wk follow-up BSI-assessments (n = 47). We used the automated EXINI Bone BSI software (EXINI Diagnostics AB, Lund, Sweden) to obtain BSI data.

We used the Cox proportional hazards model and Kaplan-Meier estimates to investigate the association among BSI, traditional clinical parameters, disease progression, and radiographic progression-free survival (rPFS).

In the BSI assessments, at follow-up, patients who had a decrease or at most a 20% increase from BSI baseline had a significantly longer time to progression in bone (median not reached vs 23 wk, hazard ratio [HR]: 0.20; 95% confidence interval [CI], 0.07–0.58; p = 0.003) and rPFS (median: 50 wk vs 14 wk; HR: 0.35; 95% CI, 0.17–0.74; p = 0.006) than those who had a BSI increase >20% during treatment.

The on-treatment change in BSI was significantly associated with rPFS in mCRPC patients, and an increase >20% in BSI predicted reduced rPFS. BSI for quantification of bone metastases may be a valuable complementary method for evaluation of treatment response in mCRPC patients.

An increase in Bone Scan Index (BSI) was associated with shorter time to disease progression in patients treated with ODM-201. BSI may be a valuable method of complementing treatment response evaluation in patients with advanced prostate cancer.

EXINI quantitative Bone Scan Index: Expanded utility for the planar radionuclide bone scan

LarsonJ Nucl Med 2016

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

Anand et al.J Nucl Med 2016

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.

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.

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.

The automated BSI provides a consistent imaging biomarker capable of standardizing quantitative changes in the bone scans of patients with metastatic prostate cancer.

Evaluation of bone scan index change over time on automated calculation in bone scintigraphy

Shintawati et al.Ann Nucl Med 2015

Bone scintigraphy (bone scan) is useful in detecting metastatic bone lesions through visual assessment of hot spots. A semi-quantitative analysis method that evaluates bone scan images has been eagerly anticipated. BONENAVI is software that enables automatic assessment of bone scan index (BSI). BSI is useful for stratifying cancer patients and monitoring their therapeutic response. The purpose of this study was to evaluate the BONENAVI reading in determining BSI and hot spots at different time intervals after radioisotope injection.

We evaluated 32 patients, including 22 males and 10 females. Ten patients had breast cancer, 20 patients had prostate cancer, and 2 had malignant pheochromocytoma. Patients were injected with 740 MBq of 99mTc-methylene diphosphonate and bone scintigraphy was performed at 2, 4, and 6 h after injection on each patient. The BSI and the number of hot spots were obtained from BONENAVI software. Bone scan images were also visually assessed to exclude false positives due to artifacts. Analyses were performed in all lesions, selected true lesions, segment based and cancer type based. Non-parametric statistical analyses for pairwise multiple group comparison were performed using Friedman test followed with post hoc analysis.

The BSIs and the number of hot spots were significantly increased with time, with significant differences between each of time points (P < 0.001). Analysis of regional BSI (rBSI) and hot spot number changes of selected 15 true lesions also showed similar increase (P < 0.001). In general, the pelvic segment was the most prone to rBSI changes and the chest segment was the most prone to hot spot number changes. Visual assessment showed that BONENAVI diagnosed some typical artifacts as metastases (hot spots).

BONENAVI reading of BSIs and hot spot numbers was highly affected by acquisition time. In serial or follow-up examinations (in particular, for monitoring therapeutic efficacy), acquisition time should be fixed for each patient. Cautious interpretation should be made on segments with high physiological uptake. BONENAVI reading was prone to misinterpretation of artifacts. Visual assessment is necessary to rule out this possibility.

Haematopoietic toxicity of radium-223 in patients with high skeletal tumour burden

Miederer et al.Nuklearmedizin 2015

In patients with metastasized, castration resistant prostate cancer (mCRPC) treatment with radium-223 (Xofigo) is an attractive therapeutic option. In particular, patients with high tumour load seem to profit from this treatment in regard of survival and quality of live. Aim of this study was to stratify mCRPC patients according to a quantitative imaging marker derived from routine bone scans (EXINI bone) and analyze haematopoietic toxicity of Xofigo in these patients.

Toxicity and oncologic outcome were investigated in a cohort of 14 patients with high tumour load. Additionally, based on a web survey, experience of toxicity in 41 high tumour load patients in Germany in 2014 was collected.

In patients with a bone scan index (BSI) greater than 5, significant toxicity occurred in more patients than expected from the ALSYMPCA trial. This was associated with application of fewer cycles. Similar experiences have been made in other centers in Germany. Approximately 7% of these patients will need very long time or will not recover from grade ≥ 3 toxicity.

Close follow-up of haematopoietic indices and, in case of toxicity, early termination of therapy is in particular necessary in late stage disease where limited bone marrow reserve is likely.

Bone Scan Index predicts outcome in patients with metastatic hormone sensitive prostate cancer

Poulsen et al.BJU Int 2015

To evaluate the Bone Scan Index (BSI) for prediction of castration resistance and prostate cancer specific survival. In a retrospective material, we used a novel computer-assisted software for automated detection/quantification of bone metastases by BSI. Prostate cancer patients are M-staged by whole-body bone scintigraphy (WBS) and categorized as M0 or M1. Within the M1 group, there is a wide range of clinical outcomes. The BSI was introduced a decade ago providing quantification of bone metastases by estimating the percentage of bone involvement. Being too time consuming, it never gained widespread clinical use.

A total of 88 patients with prostate cancer awaiting initiation of androgen deprivation due to metastases were included. WBS was performed using a two-headed gamma camera. BSI was obtained using the automated platform EXINI bone (EXINI Diagnostics AB, Lund, Sweden). In Cox proportional hazard models, time to castration resistant prostate cancer (CRPC) and prostate cancer specific survival were modelled as the dependent variables, whereas PSA, Gleason score and BSI were used as explanatory factors. For Kaplan-Meier estimates, BSI groups were dichotomously split into: BSI <1 and BSI ≥ 1. Discrimination between prognostic models was explored using the concordance index (C-index).

The mean age of the patients was 72 years (range 52-92), the median PSA level was 73 μg/L (range 4-5740), the average Gleason score was 7.7 (range 2-10), and the mean BSI was 1.0 (range 0-9.2). During a mean follow-up of 26 months (range 8-49), 48 patients became castration resistant and 15 died, the majority (13) of prostate cancer. In multivariate analysis including PSA, Gleason score and BSI, only prediction by BSI was statistically significant. This was true both in terms of time to CRPC (HR=1.45; 95%CI: 1.22-1.74; C-index increase from 0.49 to 0.69) and with regard to prostate cancer-specific survival (HR=1.34; 95%CI: 1.07-1.67; C-index increase from 0.76 to 0.95).

BSI obtained by a novel automated computer-assisted algorithm appears to be a useful predictor of outcome with regard to time to CRPC and prostate cancer specific survival in patients with hormone sensitive metastatic prostate cancer.BSI obtained by a novel automated computer-assisted algorithm appears to be a useful predictor of outcome with regard to time to CRPC and prostate cancer specific survival in patients with hormone sensitive metastatic prostate cancer.

Bone Scan Index as a prognostic imaging biomarker during androgen deprivation therapy

Reza et al.EJNMMI Research 2014

 Bone Scan Index (BSI) is a quantitative measurement of tumour burden in the skeleton calculated from bone scan images. When analysed at the time of diagnosis, it has been shown to provide prognostic information on survival in men with metastatic prostate cancer (PCa). In this study, we evaluated the prognostic value of BSI during androgen deprivation therapy (ADT). 

 Prostate cancer patients who were at high risk of a poor outcome and who had undergone bone scan at the time of diagnosis and during ADT were recruited from two university hospitals for a retrospective study. BSI at baseline and follow-up were calculated using an automated software package (EXINI Bone BSI). Associations between BSI, other prognostic biomarkers and overall survival (OS) were evaluated using a Cox proportional hazards regression model. 

One hundred forty-six PCa patients were included in the study. A total of 102 patient deaths were registered, with a median survival time after the follow-up bone scan of 2.4 years (interquartile range (IQR) =0.8 to 4.4). Both at baseline and during ADT, BSI was significantly associated with OS in univariate and multivariate analyses. When BSI was added to a prognostic base model including age, prostate-specific antigen, clinical tumour stage and Gleason score, the concordance index increased from 0.73 to 0.77 (p =0.0005) at baseline and from 0.77 to 0.82 (p <0.0001) during ADT. 

Automated BSI during ADT is an independent prognostic indicator of OS in PCa patients with bone metastasis. It represents an emerging imaging biomarker that can be used in a prognostic model for risk stratification of PCa patients at the time of diagnosis and at later stages of the disease. BSI could then help physicians identify patients who could benefit from more aggressive therapies.

Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC)

Armstrong et al.Urol Oncol 2014

Drug development and clinical decision making for patients with metastatic prostate cancer (PC) have been hindered by a lack of quantitative methods of assessing changes in bony disease burden that are associated with overall survival (OS). Bone scan index (BSI), a quantitative imaging biomarker of bone tumor burden, is prognostic in men with metastatic PC. We evaluated an automated method for BSI calculation for the association between BSI over time with clinical outcomes in a randomized double-blind trial of tasquinimod (TASQ) in men with metastatic castration-resistant PC (mCRPC).

Bone scans collected during central review from the TASQ trial were analyzed retrospectively using EXINIboneBSI, an automated software package for BSI calculation. Associations between BSI and other prognostic biomarkers, progression-free survival, OS, and treatment were evaluated over time.

Of 201 men (57 TASQ and 28 placebo), 85 contributed scans at baseline and week 12 of sufficient quality. Baseline BSI correlated with prostate-specific antigen and alkaline phosphatase levels and was associated with OS in univariate (hazard ratio [HR] = 1.42,P= 0.013) and multivariate (HR = 1.64,P<0.001) analyses. BSI worsening at 12 weeks was prognostic for progression-free survival (HR = 2.14 per BSI doubling,P<0.001) and OS (HR = 1.58,P= 0.033) in multivariate analyses including baseline BSI and TASQ treatment. TASQ delayed BSI progression.

BSI and BSI changes over time were independently associated with OS in men with mCRPC. A delay in objective radiographic bone scan progression with TASQ is suggested; prospective evaluation of BSI progression and response criteria in phase 3 trials of men with mCRPC is warranted.

Analysis of regional bone scan index measurements for the survival of patients with prostate cancer

Kalderstam et al.BMC Med Imaging 2014

BACKGROUND: A bone scan is a common method for monitoring bone metastases in patients with advanced prostate cancer. The Bone Scan Index (BSI) measures the tumor burden on the skeleton, expressed as a percentage of the total skeletal mass. Previous studies have shown that BSI is associated with survival of prostate cancer patients. The objective in this study was to investigate to what extent regional BSI measurements, as obtained by an automated method, can improve the survival analysis for advanced prostate cancer.

METHODS: The automated method for analyzing bone scan images computed BSI values for twelve skeletal regions, in a study population consisting of 1013 patients diagnosed with prostate cancer. In the survival analysis we used the standard Cox proportional hazards model and a more advanced non-linear method based on artificial neural networks. The concordance index (C-index) was used to measure the performance of the models.

RESULTS: A Cox model with age and total BSI obtained a C-index of 70.4%. The best Cox model with regional measurements from Costae, Pelvis, Scapula and the Spine, together with age, got a similar C-index (70.5%). The overall best single skeletal localisation, as measured by the C-index, was Costae. The non-linear model performed equally well as the Cox model, ruling out any significant non-linear interactions among the regional BSI measurements.

CONCLUSION: The present study showed that the localisation of bone metastases obtained from the bone scans in prostate cancer patients does not improve the performance of the survival models compared to models using the total BSI. However a ranking procedure indicated that some regions are more important than others.

Investigation of computer-aided diagnosis system for bone scans: a retrospective analysis in 406 patients

Tokuda et al.Ann Nucl Med 2014

The aim of this study was to investigate the diagnostic ability of a completely automated computer-assisted diagnosis (CAD) system to detect metastases in bone scans by two patterns: one was per region, and the other was per patient.

MATERIALS AND METHODS: This study included 406 patients with suspected metastatic bone tumors who underwent whole-body bone scans that were analyzed by the automated CAD system. The patients were divided into four groups: a group with prostatic cancer (N = 71), breast cancer (N = 109), males with other cancers (N = 153), and females with other cancers (N = 73). We investigated the bone scan index and artificial neural network (ANN), which are parameters that can be used to classify bone scans to determine whether there are metastases. The sensitivities, specificities, positive predictive value (PPV), negative predictive value (NPV), and accuracies for the four groups were compared. Receiver operating characteristic (ROC) analyses of region-based ANN were performed to compare the diagnostic performance of the automated CAD system.

RESULTS: There were no significant differences in the sensitivity, specificity, or NPV between the four groups. The PPVs of the group with prostatic cancer (51.0 %) were significantly higher than those of the other groups (P < 0.01). The accuracy of the group with prostatic cancer (81.5 %) was significantly higher than that of the group with breast cancer (68.6 %) and the females with other cancers (65.9 %) (P < 0.01). For the evaluation of the ROC analysis of region-based ANN, the highest Az values for the groups with prostatic cancer, breast cancer, males with other cancers, and females with other cancers were 0.82 (ANN = 0.4, 0.5, 0.6, 0.7, and 0.8), 0.83 (ANN = 0.7), 0.81 (ANN = 0.5), and 0.81 (ANN = 0.6), respectively.

CONCLUSION: The special CAD system "BONENAVI" trained with a Japanese database appears to have significant potential in assisting physicians in their clinical routine. However, an improved CAD system depending on the primary lesion of the cancer is required to decrease the proportion of false-positive findings.

Enhanced diagnostic accuracy for quantitative bone scan using an artificial neural network system: a Japanese multi-center database project

Nakajima et al.EJNMMI Research 2013

Background: Artificial neural network (ANN)-based bone scan index (BSI), a marker of the amount of bone metastasis, has been shown to enhance diagnostic accuracy and reproducibility but is potentially affected by training databases. The aims of this study were to revise the software using a large number of Japanese databases and to validate its diagnostic accuracy compared with the original Swedish training database.

Methods: The BSI was calculated with EXINIbone (EB; EXINI Diagnostics) using the Swedish training database (n = 789). The software using Japanese training databases from a single institution (BONENAVI version 1, BN1,n = 904) and the revised version from nine institutions (version 2, BN2,n = 1,532) were compared. The diagnostic accuracy was validated with another 503 multi-center bone scans including patients with prostate (n = 207), breast (n = 166), and other cancer types. The ANN value (probability of abnormality) and BSI were calculated. Receiver operating characteristic (ROC) and net reclassification improvement (NRI) analyses were performed.

Results: The ROC analysis based on the ANN value showed significant improvement from EB to BN1 and BN2. In men (n = 296), the area under the curve (AUC) was 0.877 for EB, 0.912 for BN1 (p = not significant (ns) vs. EB) and 0.934 for BN2 (p = 0.007 vs. EB). In women (n = 207), the AUC was 0.831 for EB, 0.910 for BN1 (p = 0.016 vs. EB), and 0.932 for BN2 (p < 0.0001 vs. EB). The optimum sensitivity and specificity based on BN2 was 90% and 84% for men and 93% and 85% for women. In patients with prostate cancer, the AUC was equally high with EB, BN1, and BN2 (0.939, 0.949, and 0.957,p = ns). In patients with breast cancer, the AUC was improved from EB (0.847) to BN1 (0.910,p = ns) and BN2 (0.924,p = 0.039). The NRI using ANN between EB and BN1 was 17.7% (p = 0.0042), and that between EB and BN2 was 29.6% (p < 0.0001). With respect to BSI, the NRI analysis showed downward reclassification with total NRI of 31.9% (p < 0.0001).

Conclusion: In the software for calculating BSI, the multi-institutional database significantly improved identification of bone metastasis compared with the original database, indicating the importance of a sufficient number of training databases including various types of cancers.

Quantitative analysis of bone scans in prostate cancer patients

KabotehDoctoral Thesis 2013

Prostate cancer (PCa) is one of the most common diseases in the world. PCa can primarily disseminate to the bone, causing bone metastases, which in turn can lead to death. To treat the disease it is important to diagnose bone metastases as soon as possible.. Bone metastases are diagnosed usually by bone scan imaging. However, interpretation of bone scan images is not always an easy task for physicians. One way of minimising the risk of misinterpretation is quantitative analysis of bone scan images in order to ascertain whether they show any metastatic lesions, and if so, to what extent. Quantification of the bone scan, i.e. the bone scan index (BSI) method, could be used for prognostication of survival, or to follow up the effect of treatment. The aim of the thesis was to develop and validate a fully automated method for the quantification of skeletal images in patients with prostate cancer based on the BSI method. This thesis is based on four papers. In Paper I, "A Novel Automated Platform for Quantifying the Extent of Skeletal Tumour Involvement in Prostate Cancer Patients Using the Bone Scan Index", we developed an automated BSI-quantification method, used it in a training group of 795 patients, compared it to a manual method and assessed the prognostic value of BSI in an evaluating group of 384 patients. The automated method showed a good correlation (r=80%) with the manual method, and BSI was strongly associated with prostate cancer death. In Paper II, "Bone Scan Index: a prognostic imaging biomarker for high-risk prostate cancer patients receiving primary hormonal therapy”, we found that BSI included prognostic information in addition to other clinical parameters such as “prostate-specific antigens”. Patients with BSI<1 had a much higher survival rate after 5 years than those with BSI>5. In Paper III, “Progression of Bone Metastases in Patients with Prostate Cancer - Automated Detection of New Lesions and Calculation of Bone Scan Index”, we further develop the automatic method to find new metastases using a training group of 266 patients. The method evaluated 31 patients who received chemotherapy. Patients with an increase in BSI during treatment had a lower two-year survival rate (18%) than those with a decrease in BSI (57%). In Paper IV, “Assessment of baseline and longitudinal bone scan index measures in the context of a randomised placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC)”, we retrospectively calculated BSI at baseline and upon treatment in 85 patients from a clinical trial. We found that BSI and BSI change on-treatment were associated with survival. BSI correlated with known biomarkers of survival, but adds independent prognostic information. In conclusion, BSI calculated using an automated method contains prognostic information and can be used to evaluate treatment effects.

Progression of bone metastases in patients with prostate cancer - automated detection of new lesions and calculation of bone scan index

Kaboteh et al.EJNMMI Research 2013 Aug

The objective of this study was firstly to develop and evaluate an automated method for the detection of new lesions and changes in bone scan index (BSI) in serial bone scans and secondly to evaluate the prognostic value of the method in a group of patients receiving chemotherapy.

The automated method for detection of new lesions was evaluated in a group of 266 patients using the classifications by three experienced bone scan readers as a gold standard. The prognostic value of the method was assessed in a group of 31 metastatic hormone-refractory prostate cancer patients who were receiving docetaxel. Cox proportional hazards were used to investigate the association between percentage change in BSI, number of new lesions and overall survival. Kaplan-Meier estimates of the survival function were used to indicate a significant difference between patients with an increase/decrease in BSI or those with two or more new lesions or less than two new lesions.

The automated method detected progression defined as two or more new lesions with a sensitivity of 93% and a specificity of 87%. In the treatment group, both BSI changes and the number of new metastases were significantly associated with survival. Two-year survival for patients with increasing and decreasing BSI from baseline to follow-up scans were 18% and 57% (p = 0.03), respectively. Two-year survival for patients fulfilling and not fulfilling the criterion of two or more new lesions was 35% and 38% (n.s.), respectively.

An automated method can be used to calculate the number of new lesions and changes in BSI in serial bone scans. These imaging biomarkers contained prognostic information in a small group of patients with prostate cancer receiving chemotherapy.

Bone scintigraphy as a new imaging biomarker: The relationship between bone scan index and bone metabolic markers in prostate cancer patients with bone metastases

Wakabayashi et al.Ann Nucl Med 2013

A computer-aided diagnosis system for bone scintigraphy with a semiquantitative index from the Bone Scan Index (BSI) has been used to quantify the spread of bone metastases. However, few papers have made clear associations among BSI, bone metabolic markers, and prostate-specific antigen (PSA). This retrospective study aimed to examine these relationships in prostate cancer patients with bone metastases.

A total of 158 scans from 52 patients (number of median examinations/person 3, range 1-8; median age 71 years, age range 46-86) were included. The intervals between bone scans and blood examinations were 0-16 days (median 0 day). The serum markers of PSA, pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (1-CTP), bone alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were examined. Subjects were divided into 4 groups according to BSI; Group A: 0 to <2, Group B: 2 to <4, Group C: 4 to <8, and Group D: over 8. BSI, which corresponded to the amount of metastatic lesion, was automatically calculated by BONENAVI® software (FUJIFILM RI Pharma, Co. Ltd., Tokyo, Japan; Exini Bone, Exini Diagnostics, Sweden).

All bone scans showed high uptake with bone metastases. BSI was correlated significantly with the serum 1-CTP, serum BAP, serum TRACP-5b, logBAP, logTRACP-5b, and logPSA (r = 0.39, 0.66, 0.69, 0.71, 0.62 and 0.41, respectively). BSI did not correlate significantly with the serum PSA. The statistical F value was 11 in the serum 1-CTP, 31 in serum BAP, 29 in logBAP, 19 in serum TRACP-5b, 14 in logTRACP-5b, 3 in serum PSA, and 9 in logPSA by analysis of variance. Comparison by Dunnett's test showed significantly higher values in Group D for all original bone metabolic markers and the logPSA, Group C for the serum BAP, logBAP, serum TRACP-5b, and logTRACP-5b, and Group B for the logTRACP-5b compared with Group A.

The changes in BSI showed a close relationship with all bone metabolic markers but not with the serum PSA. The BSI is confirmed to reflect the activity and extent of bone metastases, and can be used as an imaging biomarker.

Detection of circulating tumor cells in different stages of prostate cancer

Thalgott et al.J Cancer Res Clin Oncol 2013

To explore circulating tumor cell (CTCs) counts in different stages of prostate cancer (PC) in association with tumor burden, metastatic pattern and conventional serum biomarkers. Overall survival (OS) analyses were conducted with respect to optimized CTC cutoff levels.

Circulating tumor cell counts were assessed in healthy controls (n = 15) as well as in locally advanced high risk (LAPC, n = 20), metastatic castration resistant (mCRPC, n = 40) and taxane-refractory (mTRPC, n = 15) PC patients. CTCs were detected using the CellSearch System.

In metastatic PC (mPC), CTC counts were significantly increased compared to LAPC (p < 0.001). In LAPC, CTCs were at control level (p = 0.66). Patients with both bone and visceral lesions revealed the highest median CTC count (p = 0.004), whereas patients with sole soft tissue metastases displayed CTC counts comparable to controls (p = 0.16). No correlation was observed between CTC counts and osseous tumor burden assessed by bone lesion count (p = 0.54) or bone scan index (p = 0.81). CTC counts revealed a positive correlation with alkaline phosphatase (p < 0.001) and lactate dehydrogenase (p < 0.001) as well as a negative association with hemoglobin (p = 0.004) and PSA-doubling time (p = 0.01). Kaplan-Meier analyses demonstrated a cohort adjusted cutoff level of 3 CTCs with a shorter OS in case of ≥3 CTCs compared to <3 CTCs (p = 0.001), a cutoff level applicable in mCRPC (p = 0.003) but not in mTRPC patients (p = 0.054).

Circulating tumor cell counts are applicable as a prognostic molecular marker, especially in mCRPC patients harboring bone metastases with or without visceral metastases. For clinical practice, mPC patients with elevated CTC counts in combination with short PSA-DT, high alkaline phosphatase and lactate dehydrogenase levels as well as low hemoglobin levels are at high risk of disease progression and limited OS.

Bone Scan Index: A prognostic imaging biomarker for high risk prostate cancer patients receiving primary hormonal therapy

Kaboteh et al.EJNMMI Research 2013 Feb

The objective of this study was to explore the prognostic value of the Bone Scan Index (BSI) obtained at the time of diagnosis in a group of high-risk prostate cancer patients receiving primary hormonal therapy.

This was a retrospective study based on 130 consecutive prostate cancer patients at high risk, based on clinical stage (T2c/T3/T4), Gleason score (8 to 10) and prostate-specific antigen (PSA) (> 20 ng/mL), who had undergone whole-body bone scans < 3 months after diagnosis and who received primary hormonal therapy. BSI was calculated using an automated method. Cox proportional-hazards regression models were used to investigate the association between clinical stage, Gleason score, PSA, BSI and survival. Discrimination between prognostic models was assessed using the concordance index (C-index).

In a multivariate analysis, Gleason score (p = 0.01) and BSI (p < 0.001) were associated with survival, but clinical stage (p = 0.29) and PSA (p = 0.57) were not prognostic. The C-index increased from 0.66 to 0.71 when adding BSI to a model including clinical stage, Gleason score and PSA. The 5-year probability of survival was 55% for patients without metastases, 42% for patients with BSI < 1, 31% for patients with BSI = 1 to 5, and 0% for patients with BSI > 5.

BSI can be used as a complement to PSA to risk-stratify high-risk prostate cancer patients at the time of diagnosis. This imaging biomarker, reflecting the extent of metastatic disease, can be of value both in clinical trials and in patient management when deciding on treatment.

Prediction of survival benefit using an automated bone scan index in patients with castration-resistant prostate cancer

Mitsui et al.BJU Int 2012

What's known on the subject? and What does the study add? A bone scan index (BSI) can quantify the extent of bone involvement and response to treatment, but it has not been widely accepted, because of its time-consuming nature. The study is the first to demonstrate that automated BSI calculated with a computer-assisted diagnosis system is effective in judging the chemotherapeutic response of bone metastatic lesions in patients with castration-resistant prostate cancer.

• To evaluate the value of an automated bone scan index (aBSI), calculated using a computer-assisted diagnosis system, to indicate chemotherapy response and to predict prognosis in patients with castration-resistant prostate cancer (CRPC) with bone metastasis.

• Forty-two consecutive CRPC patients underwent taxane-based chemotherapy between November 2004 and March 2011 at our institution. • The aBSIs were retrospectively calculated at the diagnosis of CRPC and 16 weeks after starting chemotherapy. • Cox proportional hazards regression models were applied to multivariate analyses with and without aBSI response in addition to the basic model. • Based on the difference in the concordance index (c-index) between each model, the prognostic relevance of adding the aBSI response was determined.

• A decrease in aBSI was found in 28 patients (66.7%), whereas a response was shown by bone scan in only 23.8% of patients. • Patients with a reduction in aBSI had longer overall survival (OS) in comparison with the other patients (P= 0.0157). • Multivariate analysis without aBSI response showed that performance status (P= 0.0182) and PSA response (P= 0.0375) were significant prognosticators. • By adding the aBSI response to this basic model, the prognostic relevance of the model was improved with an increase in the c-index from 0.621 to 0.660.

• The aBSI reflected the chemotherapy response in bone metastasis. • The index detected small changes of bone metastasis response as quantified values and was a strong prognostic indicator for patients with CRPC.

Assessment of bone scans in advanced prostate carcinoma using fully automated and semi-automated bone scan index methods

Takahashi et al.Ann Nucl Med 2012

As metastasis of prostate carcinoma occurs in approximately 80 % of terminal prostate carcinoma patients, the prognostic value of the prediction of prostate carcinoma by bone scintigraphy is important. We compared the automated and semi-automated bone scan index (BSI) system with extent of disease (EOD) grade if there is a possibility to substitute for EOD grading.

We evaluated the bone scintigraphic images of 158 prostate carcinoma patients (mean age, 69.2 years old; range 50-97). Bone scans were obtained approximately 3 h after the intravenous injection of 740 MBq technetium-99 m-methylene diphosphonate. EOD grade was evaluated by 2 experienced radiologists using bone scintigraphy, magnetic resonance imaging, and computed tomography. We calculated the BSI using the Bonenavi(®) system (Fujifilm RI Pharma Co., Ltd.), utilizing data from a Japanese database. The semi-automated BSI of the patients was obtained by modifying the automated BSI independently by 3 radiologists (referred to as "observers" in this study) with 25, 10, and 4 years of experience. We then compared the EOD with the corresponding 4 independent BSIs for each patient. We used the Steel-Dwass test for multiple comparisons of the BSI among different EOD groups of patients. We analyzed the receiver-operating characteristics (ROC) curve to determine the cutoff values of sensitivity and specificity, which were both set at 95 %.

There were significant correlations observed among the mean EOD and BSI scores as determined using the Bonenavi(®) system for every patient group for all observers and the automated method. There was also a statistically significant difference in the mean BSI among all EOD groups (grades 0, 1, or 2-4) for all observers and the automated method. Each ROC curve showed an ideal shape and was within the optimal cutoff range.

On the basis of the present results, BSI as calculated using the Bonenavi(®) system significantly correlated with EOD. Sensitivity and specificity as measured by the fully automated method were lower than those of semi-automated BSI with modification by radiologists. Therefore, semi-automated BSI is considered to have the possibility to substitute for EOD grading to predict the survival of prostate carcinoma patients with bone metastases, with only slight interobserver variation.

A novel automated platform for quantifying the extent of skeletal tumor involvement in prostate cancer patients using the Bone Scan Index

Ulmert et al.Eur Urol 2012

There is little consensus on a standard approach to analysing bone scan images. The Bone Scan Index (BSI) is predictive of survival in patients with progressive prostate cancer (PCa), but the popularity of this metric is hampered by the tedium of the manual calculation.

Develop a fully automated method of quantifying the BSI and determining the clinical value of automated BSI measurements beyond conventional clinical and pathologic features.

We conditioned a computer-assisted diagnosis system identifying metastatic lesions on a bone scan to automatically compute BSI measurements. A training group of 795 bone scans was used in the conditioning process. Independent validation of the method used bone scans obtained ≤3 mo from diagnosis of 384 PCa cases in two large population-based cohorts. An experienced analyser (blinded to case identity, prior BSI, and outcome) scored the BSI measurements twice. We measured prediction of outcome using pretreatment Gleason score, clinical stage, and prostate-specific antigen with models that also incorporated either manual or automated BSI measurements.

The agreement between methods was evaluated using Pearson's correlation coefficient. Discrimination between prognostic models was assessed using the concordance index (C-index).

Manual and automated BSI measurements were strongly correlated (ρ=0.80), correlated more closely (ρ=0.93) when excluding cases with BSI scores≥10 (1.8%), and were independently associated with PCa death (p<0.0001 for each) when added to the prediction model. Predictive accuracy of the base model (C-index: 0.768; 95% confidence interval [CI], 0.702-0.837) increased to 0.794 (95% CI, 0.727-0.860) by adding manual BSI scoring, and increased to 0.825 (95% CI, 0.754-0.881) by adding automated BSI scoring to the base model.

Automated BSI scoring, with its 100% reproducibility, reduces turnaround time, eliminates operator-dependent subjectivity, and provides important clinical information comparable to that of manual BSI scoring.

Bone Scan Index: A quantitative treatment response biomarker for castration-resistant metastatic prostate cancer

Dennis et al.J Clin Oncol 2012

There is currently no imaging biomarker for metastatic prostate cancer. The bone scan index (BSI) is a promising candidate, being a reproducible, quantitative expression of tumor burden seen on bone scintigraphy. Prior studies have shown the prognostic value of a baseline BSI. This study tested whether treatment-related changes in BSI are prognostic for survival and compared BSI to prostate-specific antigen (PSA) as an outcome measure.

We retrospectively examined serial bone scans from patients with castration-resistant metastatic prostate cancer (CRMPC) enrolled in four clinical trials. We calculated BSI at baseline and at 3 and 6 months on treatment and performed univariate and bivariate analyses of PSA, BSI, and survival.

Eighty-eight patients were scanned, 81 of whom have died. In the univariate analysis, the log percent change in BSI from baseline to 3 and 6 months on treatment prognosticated for survival (hazard ratio [HR], 2.44; P = .0089 and HR, 2.54; P < .001, respectively). A doubling in BSI resulted in a 1.9-fold increase in risk of death. Log percent change in PSA at 6 months on treatment was also associated with survival (HR, 1.298; P = .013). In the bivariate analysis, change in BSI while adjusting for PSA was prognostic at 3 and 6 months on treatment (HR, 2.368; P = .012 and HR, 2.226; P = .002, respectively), but while adjusting for BSI, PSA was not prognostic.

These data furnish early evidence that on-treatment changes in BSI are a response indicator and support further exploration of bone scintigraphy as an imaging biomarker in CRMPC.

Introduction of a new semi-quantitative index with predictive implications in patients with painful osseous metastases after (186)Re-HEDP therapy

Zafeirakis et al.Q J Nucl Med Mol Imaging 2011

In this study, a new method has been used to predict pain response to (186)Re-HEDP therapy in patients suffering from painful osseous metastases, on the basis of a modified bone scan index and pre-therapy pain scoring.

Forty five patients received a total of 73 doses of (186)Re-HEDP during a period of pain relapse without extra-osseous disease progression. All patients were under stable regimen of zoledronic acid, far off other therapeutic manipulations. Imaging studies regarding a modified estimation of bone scan index, were applied; the value of the largest bony lesion (called mBSI), provided that it also corresponded to the most prominent site of osseous pain was taken into account, and a new semi-quantitative index called Double Product Value (DPV), equal to pre-therapy pain score times mBSI was entered in the result analyses, to investigate any possible correlations with response endpoints.

Favourable response occurred in 35/47 evaluated therapeutic doses of (186)Re-HEDP (74.5%; excellent response in 12 doses, 25.5%). Responders had significantly lower DPV (3.4 ± 2.3 vs. 10.2 ± 6.2, P=0.0029, for non-responders). Patients with pre-therapy DPV 4, and also a longer median period of pain relief (respective mean values 5.9 versus 2.1 months, HR 2.82; P=0.0001).

DPV, as developed and implemented in this study proved a valuable and reproducible pre-therapy tool for assessing degree and duration of pain response after (186)Re-HEDP therapy.

Prognostic value of baseline [18F] fluorodeoxyglucose positron emission tomography and 99mTc-MDP bone scan in progressing metastatic prostate cancer

Meirelles et al.Clin Cancer Res 2010

To compare the diagnostic and prognostic value of [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) and bone scans (BS) in the assessment of osseous lesions in patients with progressing prostate cancer.


In a prospective imaging trial, 43 patients underwent FDG-PET and BS prior to experimental therapies. Bone scan index (BSI) and standardized uptake value (SUV) on FDG-PET were recorded. Patients were followed until death (n = 36) or at least 5 years (n = 7). Imaging findings were correlated with survival.


Osseous lesions were detected in 39 patients on BS and 32 on FDG-PET (P = 0.01). Follow-up was available for 105 FDG-positive lesions, and 84 (80%) became positive on subsequent BS. Prognosis correlated inversely with SUV (median survival 14.4 versus 32.8 months if SUVmax > 6.10 versus ≤ 6.10; P = 0.002) and BSI (14.7 versus 28.2 months if BSI > 1.27 versus < 1.27; P = 0.004). Only SUV was an independent factor in multivariate analysis.


This study of progressive prostate cancer confirms earlier work that BSI is a strong prognostic factor. Most FDG-only lesions at baseline become detectable on follow-up BS, suggesting their strong clinical relevance. FDG SUV is an independent prognostic factor and provides complementary prognostic information.