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

Patients

Bone scintigraphy

Bone scans were obtained approximately 3 hours after an intravenous injection of 600 MBq Technetium-99 m methylenediphosphonate (Tc-99 m MDP, Amersham, UK). Whole-body images, anterior and posterior views (scan speed 10 (evaluation group) or 15 (treatment group) cm/min, matrix 256 × 1024), were obtained using a gamma camera equipped with low-energy high-resolution parallel hole collimators (Maxxus; General Electric, Milwaukee, USA (evaluation group) or MultiSPECT2; Siemens Healthcare Diagnostics Inc. Deerfield, IL, USA (treatment group)). Energy discrimination was provided by a 15% window centred on the 140 keV of Tc-99 m.

Automated method

We have previously presented a completely automated method that analyses single whole-body bone scans (the anterior and posterior images) one at a time [12]. BSI is calculated by first calculating the area of a hotspot classified as a metastatic lesion and then calculating the area of the corresponding skeletal region obtained from the segmentation of the skeleton (e.g. the skull or pelvis). Dividing the former by the latter and multiplying the result by a constant representing the weight fraction of the present skeletal region with respect to the weight of the total skeleton [13] gives an estimate of the volumetric fraction of the skeletal region occupied by the hotspot. This method, which is part of the EXINI bone software (EXINI Diagnostics AB, Lund, Sweden), has now been further developed so that a comparison of two whole-body bone scans from the same patient is carried out automatically (Figure 1).

A template normal scan is used to establish correspondences between time points. As part of the method presented in a previous study [12], the template scan is warped to fit each individual scan using a non-rigid registration algorithm. Separate warps are used for anterior and posterior images. We have developed a method for connecting a point in one scan to the corresponding point in other scans in the anatomical sense using these warps. The method uses the template scan as an intermediate step in this process, since scans at all time points share this coordinate frame. Using this technique, hotspots can be marked as connected across time points using a connected-component analysis based on measures of hotspot centroid proximity and hotspot overlap. Connecting hotspots which presumably originates from a single underlying skeletal region in this fashion greatly reduces the number of hotspots to review when examining multiple time points at once. Each group of connected hotspots is then assigned a single classification as metastasis/not metastasis by an automatic algorithm. New lesions that are not present in the previous scan are marked and counted. Figure 2 shows a patient with progress of the disease resulting in new lesions in the second scan.

Visual evaluation

Visual analysis of all scans in the evaluation group was performed separately by three experienced bone scan readers. They independently classified all patients as either fulfilling the criterion of two or more new lesions, established by the PCWG2 [7], or not fulfilling it. The majority rule was applied in cases of disagreement, i.e. if at least two of the three readers found two or more new lesions in the follow-up scan the patient was defined as fulfilling the PCWG2 criterion. Clinical information, e.g. medical condition, localisation of bone pain and previous history of injury, was available to all the bone scan readers. In difficult cases, reports from other diagnostic examinations, e.g. follow-up scans using magnetic resonance imaging, X-rays or computed tomography, were considered in the re-evaluation.

Statistical methods

Cox proportional hazards with 95% confidence intervals (CI) were used to investigate the association between percentage change in BSI (BSI_follow-up/BSI_baseline), number of new lesions and survival. Kaplan-Meier estimates of the survival function were used together with the log-rank test to indicate a significant difference between patients with an increase/decrease in BSI or two or more new lesions or less than two new lesions. A p value < 0.05 was considered significant.

Results

At least two of the three readers found progression, i.e. at least two new lesions, in 120 patients and no progression in 135 patients. In 11 patients with very severe metastatic disease, the readers did not find it possible to decide about progression, and these cases were excluded. All three readers agreed in 87% (222/255) of the remaining cases, and in 13% of the cases, one found progression while the other two did not, or vice versa, i.e. several cases were difficult to classify as progression or no progression, even for experienced readers.

The automated method detected at least two new lesions in 112 of the 120 cases with progression, according to the experts, i.e. a sensitivity of 93%. In the remaining eight cases, the automated method detected one new lesion in each case. Among the 135 cases without progression according to the experts, the automated method showed a specificity of 87% (117/135). The corresponding negative and positive predictive values were 94% and 86%, respectively.

The median change in BSI from the first to the second scan was an increase of 13% (range 59% decrease to 438% increase) in the treatment group. In a univariate Cox analysis, both the ‘percentage change in BSI’ (Hazard ratio 1.005; 95% CI, 1.001 to 1.008; p = 0.008) and the ‘number of new lesions’ (Hazard ratio 1.06; 95% CI, 1.02 to 1.09; p = 0.0004) were associated with survival. A total of 17 of the 31 patients in the treatment group showed an increase in BSI during treatment. Only three (18%) of these patients were alive 2 years after the second scan. Of the 14 patients with a decrease in BSI during treatment, eight (57%) were alive after 2 years. The Kaplan-Meier curves for patients with increase and decrease in BSI were significantly different (p = 0.02) (Figure 3A). Two new lesions were found in 23 patients, and eight (35%) of these patients were alive after two years. Three of the eight (38%) patients without two new lesions were alive after two years. The Kaplan-Meier curves for patients with and without at least two new lesions were not significantly different (Figure 3B).

Discussion

The results of this study show that an automated method can be used to detect new lesions and changes in BSI in serial bone scans, and that these values contain prognostic information in a group of patients on-treatment with docetaxel. A sensitivity of 93% and a specificity of 87% for the automated method are high considering the inter-observer variability among human observers. Our gold standard was based on the classifications of three experienced observers, and they all agreed in 87% of the cases. Other studies have also shown substantial inter-observer variability. Sadik et al. studied bone scan classifications from 37 readers, and on average, found agreement between paired readers of 64% [14]. The lower value in that study can, at least partly, be explained by the fact that the classification was performed using a four-grade scale, and the fact that the readers came from 18 different hospitals. Ore et al., on the other hand, reported inter-observer agreement of 91% based on two observers in a smaller patient sample [15]. The difficulty of interpreting bone scan changes even for experienced readers is the incentive to develop an objective method in order to minimise disagreement among observers. Intra-observer variability was also found in our recent study in which one reader analysed the same bone scans twice on different occasions and calculated BSI visually [12].

In the treatment group, only 18% of the patients with an increase in BSI were alive after 2 years, while 57% of those with a decreasing BSI were alive after the same period. These results are in agreement with those of Dennis et al., who demonstrated the prognostic value of BSI as a response indicator in prostate cancer patients [11]. In this study, the PCWG2 criterion of two or more new lesions was not prognostic. The number of new lesions was, however, significantly associated with survival, indicating that a criterion other than two new lesions might be valuable. It might even be a combination of the number of new lesions and the percentage change in BSI that proves to contain the most prognostic information.

We used the subjective classifications by three experienced bone scan readers as the gold standard in the evaluation group. This is not an optimum gold standard, but no independent examinations of these patients were available that confirmed or excluded the presence of new lesions. We therefore added an evaluation group to assess the prognostic value of the automated measurements of new lesions and changes in the BSI.

The results of this study are based on a retrospectively selected group of clinical cases, and as a consequence, there is a lack of standardisation of the imaging times pre and post treatment. This lack of standardisation can be a confounding factor weakening the association between BSI and survival. In future prospective studies and retrospective studies based on cases from clinical trials, the time range between baseline scan and start of treatment as well as between baseline scan and follow-up scans should be more standardised, to strengthen the analysis.

A limitation of this study was that the treatment group was small and the analysis retrospective. The results are encouraging, but the clinical value of the automated quantitative analysis of serial bone scans needs to be confirmed in future studies. In a larger study, the imaging biomarkers, number of new lesions and percentage change in BSI could also be related to other biomarkers such as PSA. The PSA level and change during treatment are widely used, but it is well known that they are not reliable in castrate-resistant prostate cancer. Imaging biomarkers could, therefore, provide additional information in the management of prostate cancer patients.

Limitations of the bone scintigraphy method are also to be taken into consideration in a quantitative analysis. Flare response, especially early on in treatment, may result in misjudgement while measuring BSI. Lesions in a bone scan are non-specific, and they may be due to degenerative disease, fractures, etc. The automated software has proved to be as capable of interpreting bone scans and differentiating metastatic lesions from degenerative abnormalities as an experienced physician [16], but patient history is crucial to the detection of fractures after trauma.