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

Andrew J. Armstrong, Aseem Anand, Lars Edenbrandt, Eva Bondesson, Anders Bjartell, Anders Widmark, Cora N. Sternberg, Roberto Pili, Helen Tuvesson, Örjan Nordle, Michael A. Carducci, Michael J. Morris

Research output: Contribution to journalArticle

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Abstract

IMPORTANCE Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m(99mTc) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data. OBJECTIVE To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS This investigationwas a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-naïve CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017. MAIN OUTCOMES AND MEASURES The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain. RESULTS Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95%CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95%CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95%CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95%CI, 1.14-1.30; P < .001). CONCLUSIONS AND RELEVANCE To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC.

Original languageEnglish (US)
Pages (from-to)944-951
Number of pages8
JournalJAMA oncology
Volume4
Issue number7
DOIs
StatePublished - Jul 1 2018

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Castration
Prostatic Neoplasms
Randomized Controlled Trials
Biomarkers
Bone and Bones
Survival
Opiate Alkaloids
Clinical Trials
Spontaneous Fractures
Bone Diseases
Technetium
Controlled Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Armstrong, Andrew J.; Anand, Aseem; Edenbrandt, Lars; Bondesson, Eva; Bjartell, Anders; Widmark, Anders; Sternberg, Cora N.; Pili, Roberto; Tuvesson, Helen; Nordle, Örjan; Carducci, Michael A.; Morris, Michael J.

In: JAMA oncology, Vol. 4, No. 7, 01.07.2018, p. 944-951.

Research output: Contribution to journalArticle

Armstrong, Andrew J. ; Anand, Aseem ; Edenbrandt, Lars ; Bondesson, Eva ; Bjartell, Anders ; Widmark, Anders ; Sternberg, Cora N. ; Pili, Roberto ; Tuvesson, Helen ; Nordle, Örjan ; Carducci, Michael A. ; Morris, Michael J. / 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. In: JAMA oncology. 2018 ; Vol. 4, No. 7. pp. 944-951.
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abstract = "IMPORTANCE Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m(99mTc) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data. OBJECTIVE To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS This investigationwas a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-na{\"i}ve CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017. MAIN OUTCOMES AND MEASURES The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain. RESULTS Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95{\%}CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95{\%}CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95{\%}CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95{\%}CI, 1.14-1.30; P < .001). CONCLUSIONS AND RELEVANCE To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC.",
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TY - JOUR

T1 - 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

AU - Armstrong, Andrew J.

AU - Anand, Aseem

AU - Edenbrandt, Lars

AU - Bondesson, Eva

AU - Bjartell, Anders

AU - Widmark, Anders

AU - Sternberg, Cora N.

AU - Pili, Roberto

AU - Tuvesson, Helen

AU - Nordle, Örjan

AU - Carducci, Michael A.

AU - Morris, Michael J.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - IMPORTANCE Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m(99mTc) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data. OBJECTIVE To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS This investigationwas a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-naïve CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017. MAIN OUTCOMES AND MEASURES The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain. RESULTS Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95%CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95%CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95%CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95%CI, 1.14-1.30; P < .001). CONCLUSIONS AND RELEVANCE To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC.

AB - IMPORTANCE Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m(99mTc) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data. OBJECTIVE To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS This investigationwas a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-naïve CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017. MAIN OUTCOMES AND MEASURES The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain. RESULTS Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95%CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95%CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95%CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95%CI, 1.14-1.30; P < .001). CONCLUSIONS AND RELEVANCE To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC.

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