Tema ProstataBoneScanIndex - BSI

Anders WidmarkProfessor, Överläkare

Umeå Universitet, Institutionen för Strålningsvetenskaper, Onkologi

Norrlands Universitetssjukhus

Cancercentrum

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Svensk Förening för NukelarmedicinVårmöte i Umeå , 18-19 maj 2017

Disclosurs

• Advisory Board Astellas

• Advisory Board Bayer

• Inbjuden av Fuji Pharma till Japanska ASCO hösten 2016 för att Presentera Xofigo (R223) och BSI (Bonavi)

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Undersökning handuppräckning

• Vilka vet vad BSI är?

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• Vilka har jobbat med BSI?

• Vilka använder det regelbundet vid bedömning av skelett scintigrafi?

Disposition

• Vad är Bone Scan Index; BSI

• Validering av BSI vid skelett metastaserad prostatacancer

• Studier i olika stadier av prostatacancer

• Studier vid olika behandlingar av prostatacancer

• Jämförelse mellan PCWG2 och BSI

Bone Scan index (BSI)

• A manual method for quantification of whole-body bone scans was presented by a group at Memorial Sloan-Kettering Cancer Center, New York

• Bone Scan Index (BSI) reflects the skeletal involvement by tumor

Imbriaco et al Clin Cancer Res 1998, Erdi et al. J Nucl Med 1997; 38:1401

Schematic of automated BSI methodology, adapted from http://exini.com/exini-bsi/.

Automated Bone Scan Index

• Automatic lesion detection and classification based on ANN (Neurala nätverk)

• Automatic tracking of old and new lesionand its location

• Automatic calculation of BSI

• Electronic Reports

The clinical value of automated BSI measurements –beyond conventional clinical and pathologic features

n=795 scint

2012

Method

• 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

The clinical value of automated BSI measurements –beyond conventional clinical and pathologic features

n=795 scint

ConclusionsPredictive accuracy increased from 0.768 to 0.825 by adding automated BSI to the base model.Patients with a baseline BSI above 1.0 had reduced prostate cancer specific survivalThis predictive imaging biomarker may prove complementary to PSA and ALP for an objective treatment response evaluation and prediction of survival in the management of patients with prostate cancer

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.

2012

Automated BSI - faster, accurate, with known analytical reproducibility threshold

Anand et al. JNM 2016

Study Design

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. (Annand et al)

Methods1.Simulation study: bone scan simulations with predefined tumor burdens were created to assess accuracy and precision.

2. 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.

3. Follow-up bone scan study: 2 follow-up bone scans of metastatic prostate cancer patients were analyzed to determine the inter observer variability between the automated BSIs and the visual interpretations in assessing changes

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

J Nucl Med. 2016 Jan;57(1):41-5.

Anand et al. JNM 2016

BSI assessed with EXINI boneBSI

correlates well and in a linear manner with known BSI

Anand et al. JNM 2016

In the BSI range from 0.10 to 13.0, the accuracy and precision of BSI is maintained independently oftumor localization

Anand et al. JNM 2016

Compared with visual assessment of changes in bone scans, theInter-observer agreement among the 3 nuclear medicine interpreters

increased significantly using the automated BSI platform

Objective: This study was an analytical validation of the BSI for use in men with metastatic prostate cancer.

Conclusion: ”The automated BSI provides a consistentimaging biomarker capable of standardizing quantitative changes in the bone scans of patients with metastatic prostate cancer.”

Artefakt

2016-05-30 Niyat Negasi 20

Vid Diagnos Efter Kastration

Objective: This retrospective study evaluated the value of BSI as a prognostic marker in men with metastatic prostate cancer on androgen deprivation therapy (ADT).

Conclusion: ”Automated BSI during ADT is an independent prognostic indicator of OS in PCa patients with bonemetastasis. 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 identifypatients who could benefit from more aggressive therapies.”

Study Design

Patients with metastatic prostate cancern = 88

Androgen deprivation1. Time to castration resistant2. Prostate cancer specific survival

BSI

Study Inclusion

Poulsen et al. BJU Int 2015

Objective: This retrospective study assessed the performance of BSI as a prognostic marker in mPCa

Conclusion: ”BSI is a useful predictor of outcome; castration resistant and prostate cancer specific survival in patients withmetastatic hormone sensitive prostate cancer. . ”

2015

Value of quantifying bone metastases in prostate cancer

Extent of bonand responsein the CHAARTED studye metastases

STAMPEDE

Sweeney C, NEJM 2015 James N The Lancet 2015

+22 mo.

+17 mo.

Study Design

Patients with metastatic CRPCn = 88

Chemotherapy

Overall Survival

0 +3mo +6mo

PSA X X XBSI X X X

Diagnosis of CRPC

Dennis et al. J Clin Oncol 2012

Studies have shown that BSI as clinical utility as a prognostic and response biomarker

J Clin Onc 2012

Objective: To study whether treatment-related changes in BSI are prognosticand to compare BSI with PSA as an outcome measure

Conclusion: ”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”.

J Clin Oncol 2012

Objective: To value of automated BSI to indicate chemotherapy response and to predict prognosis in patients with CRPC with bone metastasis

Design:The aBSIs were retrospectively calculated at the diagnosis of CRPC and 16 weeks after starting chemotherapy, n=42

Conclusions:The automated BSI method detected small changes with strong prognostic value that reflected the chemotherapy response in CPRC patient with bone metastasis.

Bone scan index as a prognostic and response biomarker in chemotherapy

BJU Int 2012

Study Design

Patients with metastatic CRPCn = 104

Abiraterone acetate (Zytiga)

Bone Scanat baseline(<6wk before start of AA therapy)

Study Inclusion

Bone Scanon indication(+3mo from start of AA therapy)

Overall Survival

Reza et al. Eur Urol Focus 2016

Objective: This retrospective study evaluated the BSI as a prognostic marker in men with metastatic CRPC on abiraterone acetate (Zytiga).

Conclusion: “Change in BSI was significantly associated with OS in mCRPC patients undergoing AA treatment following disease progression in a postchemotherapy 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 secondline therapies.”

Objective: This retrospective study evaluated the BSI as a prognostic marker in men with metastatic CRPC on enzalutamide (Xtandi).

Conclusion: ”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.”

Skåne University Hospital, Malmö

Clinical Value (response)

Patient case-study: BSI-response with enzalutamide (Xtandi)

Flare?

Value of quantifying bone metastases in CRPC

The number of bone metastases and response in the Alsympca trial

Surv

ival

Pro

bab

ility

EXINI-BSI correlation with Clinical Endpoints (N=66)

Hazard or Odds

Ratio

95% Confidence

Interval

P-value

Overall Survival 1.43 1.05 – 1.96 <0.01

PSA Response 0.94 0.60 – 1.44 0.76

ALP Response 1.59 1.04 – 2.44 0.018

Pain Response 1.10 0.84 – 1.44 0.48

BSI 0-5

BSI >5

Conclusions

Advantage of Bone Scan Index

• PSA does not work as a biomarker to follow treatment response (New HORMONES, Ra 223)

• BSI support nuclear medics to interpret treatment response on bone scans.

• Reduce inter-observer variation.

• Nuclear medics can report quantitative figures together with the subject interpretation

• BSI gives the clinician an objective answer about treatment response of the tumor burden in the skeleton

• BSI support the clinician in his assessment of prognosis both at baseline and follow-up treatment of patient with mPCa

• Makes it easier for the clinician to inform the patient of treatment result,BSI is like PSA a numerical value which the patient can relay on.

Translating Prostate Cancer Working Group 2 (PCWG2) Progression

Criteria into a Quantitative Response Biomarker in Metastatic Castration

Resistant Prostate Cancer (mCRPC)

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Aseem Anand1,2, Anders Bjartell1, Daniel C. Danila2, Danny F. Martinez2, Lars Edenbrandt1, Steven M.

Larson2, Howard I. Scher1, Michael J. Morris1

1Memorial Sloan Kettering Cancer Center, New York, NY; 2Skane University Hospital,

Malmo, Sweden

PCWG2: A validated endpoint in mCRPC trials is bone scan progression, which is semi-quantitative and rely on the appearance of new lesions as proposed by the PCWG2 criteria

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Early PD (2+2 Rule): > two new lesions within 12 weeks and > two additional new lesions at subsequent follow-up scan

Post Flare PD: > two new lesions after 12 weeks and their continued presence at a subsequent scan, but no additional new lesions were not required

PD Conf.

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The Unmet Need: A fully quantitative imaging biomarker to evaluate the change in total skeletal tumor burden during the course of meeting the PCWG2 criteria

Bone Scan Index: A quantitative analysis of bone scintigraphy, where the tumor burden is represented as the fractional weight of the total skeleton.

The EXINI automated BSI platform is available as a free of charge HIPPA compliant could service

Computer Automated BSI platform is an analytically validated quantification of Bone Scan

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OBJECTIVE

To quantify the increase in total tumor burden in the course of disease progression in patients with mCRPC

Methods

mCRPC patients from clinical trials using PCWG2 criteria to determineprogression were assessed. Patients were required to have baseline and at least two follow-up bone scans.

The EXINI automated platform was used to generate BSI at key PCWG2 landmarks: 2+2 criteria for early PD and post flare PD criteria with the appearance of 1 and ≥ 2 new lesions.

Median (M) and Interquartile range (IQR) of the relative change in BSI were calculated to quantify the increase in total tumor burden.

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Results

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Evaluable Patients (N=169)

Baseline characteristics Median (Range)

Age 70 (48 – 89)

PSA (ng/mL) 33.38 (1.12 – 1670.61)

HgB (g/dL) 12.65 (9.0 – 15.5)

ALP (U/L) 82.0 (34.0 – 1068.0)

LDH (U/L) 203.0 (88.0 – 1218.0)

BSI 0.48 (0.0 – 16.83)

Prior Treatment N (%)

Prior ADT 169 (100%)

Prior Chemo 49 (80%)

Site of Metastasis N (%)

Bone Only 68 (40%)

Bone & Soft 71 (42%)

Soft Only 30 (18%)

Deaths 144 (70%)

257 (Total Patients Assessed)

46 - Removed(Original bone-scan image in DICOM

format not available)

211(Bone scan image in DICOM format)

169(Patient with two or more follow-up bone scan available in the original DICOM format for BSI analysis)

42 - Removed(Only one follow-up bone scan)

Consort diagram detailing the total assessed patients and the evaluable patients is illustrated in Fig 2

The patient characteristics of the evaluable 169 mCRPC patients is detailed in table 1,

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ResultsOf the 169 patients, 90 (53%) were observed to meet the PCWG2 criteria of bone progression. 35 (48%) met the PCWG2 criteria for early bone progression and the remaining 55 patients progressed at subsequent time points after flare period.

Early progressionExample

An example of serial PCWG2 and BSI data of patient that met early progression and that of a patient that progressed post flare period is illustrated in Figure 3A and 3B, respectively.

Progression Post Flare Example

CONFIDENTIAL - DO NOT DISTRIBUTE (NOT PUBLISHED) 48

≥ 2 New Lesion(1st Follow-up)

2+2 New Lesion(2nd Follow-up)

BS

I C

hange in

Patie

nts

that m

et

Earl

y bone P

rogre

ssio

n (

N=

35)

≥ 2 New Lesion Confirmation

BS

I C

hange in

Patie

nts

that m

et P

ost

F

lare

bone p

rogre

ssio

n (

N=

55)

A BResults

Fig 4. The absolute BSI increase in disease burden at the meeting of PCWG2 criteria. Early Progression (A), and at subsequent time point post flare period (B)

Median=1.25

Median=2.70

Median=0.47Median=1.15

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Result

PD by PCWG2

N=90 of 169

Reference

scan at:Assessment at:

Absolute Increase

(IQR)

Median relative (%) BSI

increase (IQR)

Early PD; N=35

Baseline ≥2 new lesions 1.25(0.55 – 2.41) 79 (63 – 167)

Baseline Confirmation (≥2+≥2 new lesion) 2.70(1.89 – 6.05) 174 (94 – 539)

Post flare PD; N=55

1st Follow-up 1 New Lesion* 0.16(0.03 – 0.39) 75 (7 – 175)

1st Follow-up ≥2 new lesions 0.47(0.19 – 1.38) 95 (32 – 286)

1st Follow-upConfirmation (no additional lesion

required)1.15(0.51 – 2.49) 245 (59 – 597)

*Of the 55 patients who met the PCWG2 criteria of bone progression, 27% (15/55) had an incremental increase of 1 new lesion before meeting the PCWG2 criteria of >2 new lesions.

Table 2. The quantitative increase in disease burden at each milestone of PCWG2 criteria. (PD=Progressive Disease; IQR=Interquartile range)

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Conclusion

This is the first quantitative assessment of changes in total disease burden in patients meeting PCWG2 criteria.

Relative changes in BSI can be substantial in meeting the PCWG2 criteria.

These data build on the PCWG2 criteria by quantitating the increase both of existing lesions and the contribution of new lesions.

We are now assessing the associations with survival that these incremental increases represent.

THANK YOU!Questions?

THANK YOU!Questions?