Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis

There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone ace...

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Veröffentlicht in:European journal of cancer (1990) Jg. 84; S. 88 - 101
Hauptverfasser: Rydzewska, Larysa H.M., Burdett, Sarah, Vale, Claire L., Clarke, Noel W., Fizazi, Karim, Kheoh, Thian, Mason, Malcolm D., Miladinovic, Branko, James, Nicholas D., Parmar, Mahesh K.B., Spears, Melissa R., Sweeney, Christopher J., Sydes, Matthew R., Tran, NamPhuong, Tierney, Jayne F.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Elsevier Ltd 01.10.2017
Elsevier Science Ltd
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ISSN:0959-8049, 1879-0852, 1879-0852
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Abstract There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III–IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53–0.71, p = 0.55 × 10−10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40–0.51, p = 0.66 × 10−36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III–IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom. •First systematic review of abiraterone acetate plus prednisone/prednisolone (AAP) in hormone-sensitive prostate cancer.•Results based on 2201 men (82% of all eligible), including unreported analyses.•Adding AAP to hormones substantially improves survival and progression-free survival.•Benefits may vary with age, but not nodal or performance status, or Gleason score.•No increased mortality with AAP, but more cardiac, vascular and hepatic toxicity.
AbstractList • First systematic review of abiraterone acetate plus prednisone/prednisolone (AAP) in hormone-sensitive prostate cancer. • Results based on 2201 men (82% of all eligible), including unreported analyses. • Adding AAP to hormones substantially improves survival and progression-free survival. • Benefits may vary with age, but not nodal or performance status, or Gleason score. • No increased mortality with AAP, but more cardiac, vascular and hepatic toxicity.
There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10 ), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10 ) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.
There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III–IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53–0.71, p = 0.55 × 10−10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40–0.51, p = 0.66 × 10−36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III–IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom. •First systematic review of abiraterone acetate plus prednisone/prednisolone (AAP) in hormone-sensitive prostate cancer.•Results based on 2201 men (82% of all eligible), including unreported analyses.•Adding AAP to hormones substantially improves survival and progression-free survival.•Benefits may vary with age, but not nodal or performance status, or Gleason score.•No increased mortality with AAP, but more cardiac, vascular and hepatic toxicity.
Background: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. Methods: Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. Findings: We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 x 10-10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 x 10-36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. Interpretation: Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.
There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT.BACKGROUNDThere is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT.Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis.METHODSUsing our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis.We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10-10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10-36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death.FINDINGSWe identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10-10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10-36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death.Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.INTERPRETATIONAdding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.
Author Burdett, Sarah
Sydes, Matthew R.
Fizazi, Karim
Tran, NamPhuong
Rydzewska, Larysa H.M.
Mason, Malcolm D.
Parmar, Mahesh K.B.
Clarke, Noel W.
Spears, Melissa R.
Vale, Claire L.
James, Nicholas D.
Miladinovic, Branko
Sweeney, Christopher J.
Tierney, Jayne F.
Kheoh, Thian
AuthorAffiliation d Janssen Research & Development, San Diego, CA, USA
b Salford Royal NHS Foundation Trust, Salford, UK
a MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
f Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
g Queen Elizabeth Hospital, Birmingham, UK
c Gustave-Roussy, University of Paris Sud, 114 Rue Edouard Vaillant, Villejuif 94800, France
e Cardiff University, School of Medicine, Cardiff, UK
h Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
i Janssen Research & Development, Los Angeles, CA, USA
AuthorAffiliation_xml – name: c Gustave-Roussy, University of Paris Sud, 114 Rue Edouard Vaillant, Villejuif 94800, France
– name: h Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
– name: e Cardiff University, School of Medicine, Cardiff, UK
– name: a MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
– name: b Salford Royal NHS Foundation Trust, Salford, UK
– name: d Janssen Research & Development, San Diego, CA, USA
– name: g Queen Elizabeth Hospital, Birmingham, UK
– name: f Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
– name: i Janssen Research & Development, Los Angeles, CA, USA
Author_xml – sequence: 1
  givenname: Larysa H.M.
  orcidid: 0000-0001-6205-7457
  surname: Rydzewska
  fullname: Rydzewska, Larysa H.M.
  email: larysa.rydzewska@ucl.ac.uk
  organization: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
– sequence: 2
  givenname: Sarah
  surname: Burdett
  fullname: Burdett, Sarah
  organization: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
– sequence: 3
  givenname: Claire L.
  surname: Vale
  fullname: Vale, Claire L.
  organization: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
– sequence: 4
  givenname: Noel W.
  surname: Clarke
  fullname: Clarke, Noel W.
  organization: Salford Royal NHS Foundation Trust, Salford, UK
– sequence: 5
  givenname: Karim
  surname: Fizazi
  fullname: Fizazi, Karim
  organization: Gustave-Roussy, University of Paris Sud, 114 Rue Edouard Vaillant, Villejuif 94800, France
– sequence: 6
  givenname: Thian
  surname: Kheoh
  fullname: Kheoh, Thian
  organization: Janssen Research & Development, San Diego, CA, USA
– sequence: 7
  givenname: Malcolm D.
  surname: Mason
  fullname: Mason, Malcolm D.
  organization: Cardiff University, School of Medicine, Cardiff, UK
– sequence: 8
  givenname: Branko
  surname: Miladinovic
  fullname: Miladinovic, Branko
  organization: Janssen Research & Development, San Diego, CA, USA
– sequence: 9
  givenname: Nicholas D.
  surname: James
  fullname: James, Nicholas D.
  organization: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
– sequence: 10
  givenname: Mahesh K.B.
  surname: Parmar
  fullname: Parmar, Mahesh K.B.
  organization: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
– sequence: 11
  givenname: Melissa R.
  surname: Spears
  fullname: Spears, Melissa R.
  organization: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
– sequence: 12
  givenname: Christopher J.
  surname: Sweeney
  fullname: Sweeney, Christopher J.
  organization: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
– sequence: 13
  givenname: Matthew R.
  surname: Sydes
  fullname: Sydes, Matthew R.
  organization: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
– sequence: 14
  givenname: NamPhuong
  surname: Tran
  fullname: Tran, NamPhuong
  organization: Janssen Research & Development, Los Angeles, CA, USA
– sequence: 15
  givenname: Jayne F.
  surname: Tierney
  fullname: Tierney, Jayne F.
  organization: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK
BackLink https://www.ncbi.nlm.nih.gov/pubmed/28800492$$D View this record in MEDLINE/PubMed
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Keywords Systematic review
Androgen deprivation therapy
Abiraterone
Prostate cancer
Metastases
Meta-analysis
Language English
License This is an open access article under the CC BY license.
Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.
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Snippet There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT)...
Background: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation...
There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT)...
• First systematic review of abiraterone acetate plus prednisone/prednisolone (AAP) in hormone-sensitive prostate cancer. • Results based on 2201 men (82% of...
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SubjectTerms Abiraterone
Acetic acid
Acute toxicity
Age Factors
Aged
Androgen Antagonists - adverse effects
Androgen Antagonists - therapeutic use
Androgen deprivation therapy
Androstenes - adverse effects
Androstenes - therapeutic use
Antineoplastic Agents, Hormonal - adverse effects
Antineoplastic Agents, Hormonal - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Cancer
Chi-Square Distribution
Clinical trials
Clinical Trials as Topic
Confidence intervals
Deprivation
Disease-Free Survival
Endocrine therapy
Endocrinology
Heart diseases
Humans
Lymphatic Metastasis
Male
Men
Meta-analysis
Metastases
Metastasis
Middle Aged
Neoplasm Grading
Neoplasms, Hormone-Dependent - drug therapy
Neoplasms, Hormone-Dependent - mortality
Neoplasms, Hormone-Dependent - pathology
Odds Ratio
Prednisolone
Prednisolone - therapeutic use
Prednisone
Prednisone - therapeutic use
Prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - mortality
Prostatic Neoplasms - pathology
Randomization
Reduction
Risk Factors
Subgroups
Survival
Systematic review
Therapy
Time Factors
Toxicity
Treatment Outcome
Title Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis
URI https://www.clinicalkey.com/#!/content/1-s2.0-S0959804917311103
https://dx.doi.org/10.1016/j.ejca.2017.07.003
https://www.ncbi.nlm.nih.gov/pubmed/28800492
https://www.proquest.com/docview/2033302366
https://www.proquest.com/docview/1928515785
https://pubmed.ncbi.nlm.nih.gov/PMC5630199
Volume 84
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