PROMIS - Multi-Parametric MRI and Prostate Cancer Diagnosis

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Ahmed HU, et al. "Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study". The Lancet. 2017. 289(10071):815-822.
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Clinical Question

In patients being investigated for prostate cancer, can MP-MRI discriminate between men with and without clinically significant cancer based on a template prostate mapping biopsy as a reference test?

Bottom Line

Using MP-MRI as an initial triage for men who presented with an elevated PSA may result in 27% fewer patients receiving a prostate biopsy, and the diagnosis of 5% fewer clinically insignificant cancers. Furthermore, if the triage MP-MRI was used to direct TRUS biopsies, 18% more cases of clinically significant cancer would be identified, compared to a standard pathway where TRUS is conducted when an elevated PSA is observed.

Major Points

TRUS biopsies to diagnose prostate cancer can cause side effects including bleeding, pain and infection. One way to reduce the number of unnecessary TRUS biopsies would be to implement a triage such as MP-MRI. This multi-center, paired cohort, confirmatory study tested the diagnostic accuracy of MP-MRI and TRUS biopsy, using template prostate mapping biopsy as the reference standard. 740 men from 11 centers in the UK were enrolled between 2012 and 2015 with 576 completing all imaging and biopsy studies. MP-MRI achieved higher sensitivity (93%) compared with TRUS biopsy (48%), however TRUS achieved higher specificity (96%) compared with MP-MRI (41%). If MP-MRI was used to triage for biopsies, 27% of TRUS biopsies could be avoided. In a best-case scenario, where TRUS was guided by MP-MRI after triage, over-diagnosis of clinically insignificant cancers would be increased by 5%, while the correct diagnosis of significant cancers fould increase by 18%

Guidelines

The following comments are made in current guidelines regarding the investigation of men with elevated cancer risk:

  • EAU - The EAU guidelines make reference to multi-parametric MRI in the setting of triaging candidates for biopsy. At the time of printing (April 2014), results had not been confirmed and the cost-effectiveness had not been assessed. The need for a biopsy should be determined based on PSA and DRE findings. Patient age, co-morbidities and therapeutic options should all influence the decision to biopsy. The guidelines state that the first elevated PSA should not trigger a biopsy, by a confirmatory PSA test a few weeks later under standard conditions. Biopsies are typically ultrasound guided and can be transrectal or perineal. The cancer detection rate is similar between the two approaches. Saturation biospies further increase the cancer detection rate (but have increased adverse effects).
  • NCCN -NCCN recommends biopsy where PSA is >3.0 ng/mL, a DRE is suspicious or workup for benign disease is underway. Initial biopsy is transrectal and US guided. The panel did not recommend the routine use of advanced biopsy methods (MRI guided, saturation, transperineal approach) in the initial setting, though these may be useful in a repeat biopsy setting.

Design

  • Design: prospective, multi-center, paired cohort, confirmatory study.
  • N=740 (men enrolled). 576 received MP-MRI followed by TRUS-biopsy and TPM-biopsy.
  • Setting: 11 centers in the UK
  • Enrollment: 2012-2015
  • Mean follow-up: Not applicable
  • Analysis: per protocol, a pre-specified analysis plan is referred to.
  • Primary outcome: to establish the proportion of men who could safely avoid biopsy and the proportion of men correctly identified by MP-MRI to have clinically significant prostate cancer.

Population

Inclusion Criteria

  • Men who had:
    • Never had a prostate biopsy before
    • Clinical suspicion of prostate cancer (elevated PSA up to 15 in the past 3 months, DRE suspected stage T2 or lower disease)
    • Family history of prostate cancer
    • Over 18 years old
    • Fit enough to undergo all procedures in the protocol including spinal anaesthesia

Exclusion Criteria

  • Men using 5-alpha reductase inhibitors at registration or in the previous six months
  • Previous history of prostate biopsy, prostate surgery, or treatment for prostate cancer (interventions for benign prostatic hyperplasia or bladder outflow obstruction were acceptable);
  • Had evidence of a urinary tract infection or history of acute prostatitis within the last 3 months;
  • Had any contraindication to MRI (e.g. claustrophobia, pacemaker, estimated glomerular filtration rate ≤50);
  • Had any other medical condition precluding procedures
  • Described in the protocol; or had previous history of hip replacement surgery, metallic hip replacement, or extensive pelvic orthopaedic metal work.

Baseline Characteristics

  • Mean PSA – 7.1 (SD 2.9)
  • Mean BMI – 27.8 (SD 4.4)
  • Family history - 127 (22%)
  • Mean age – 63.4 (SD 7.6)
  • Ethnicity – White (87%), Mixed (1%), Asian or British Asian (3%), Black or Black British (7%), Other (2%).

Interventions

  • Men who were referred on clinical suspicion of prostate cancer were enrolled;
  • After registration, a MP-MRI test was conducted with the imaging results kept blinded from patient and clinicians;
  • Patients were biopsied within three months of the imaging study;
  • The biopsy procedure included:
    • Firstly, a template prostate mapping biopsy; and
    • Secondly a trans-rectal ultrasound (TRUS) biopsy.
  • Patients were then given the results of all tests and treatment proceeded along standard care pathways.

Outcomes

Primary Outcomes

Detection of significant cancer
Defined as a Gleason score >=4+3 or cancer core length >=6mm.
For MP-MRI the following was observed:
Prevalence of clinically significant cancer 40% (36-44%)
Sensitivity: 93 (88-96)
Specificity: 41 (36-46)
PPV: 51 (46-56)
NPV: 89 (83-94)

Secondary Outcomes

Alternative definitions of significant cancer
Gleason score ≥3+4 or cancer core length ≥4 mm:
Prevalence of clinically significant cancer 57% (53-62%)
Sensitivity: 87 (83-90)
Specificity: 47 (40-53)
PPV: 69 (64-73)
NPV: 72 (65-79)
Any Gleason score 7 (≥3+4):
Prevalence of clinically significant cancer 53% (49-58%)
Sensitivity: 88 (84-91)
Specificity: 45 (39-51)
PPV: 65 (60-69)
NPV: 76 (69-82)
The test ratio between MP-MRI and TRUS-biopsy (using the primary definition of clinically significant cancer) was as follows
Sensitivity: 0.52 (0.45-0.60), p<0.0001
Specificity: 2.34 (2.08-2.68), p<0.0001
PPV: 8.2 (4.7-14.3), p<0.0001
NPV: 0.34 (0.21-0.55),p<0.0001

Subgroup Analysis

If MP-MRI is used as a triage, there is a 27% reduction in biopsies. In a best-case, worst-case scenario mapping, the following scenarios were reported:

Best case – all biopsies are TRUS, guided by MP-MRI (This was assumed to have the same accuracy as template mapping MRI)
Over diagnosis of clinically insignificant cancers is increased by 5%
Correct diagnosis of significant cancers increased by 18%
Worst case – standard TRUS biopsy was performed.
Over diagnosis of clinically insignificant cancers is reduced by 5%
Correct diagnosis of significant cancers reduced by 1%

Inter-observer rating of MP-MRI calls achieved a Kappa of 0.5 (moderate agreement)

Adverse Events

Side effects are reported in the supplementary material. Most side effects related to the biopsy procedure. In all, 88% of patients reported having any side effect. It is unclear how many of these side effects resolved with time, and the period over which they were experienced. Approximately 4% of side effects related to the MP-MRI procedure including pain/discomfort (2%), allergic reaction to the contrast medium (<1%) and ‘other’ (<1%).

Criticisms

  • The MP-MRI used for triage was not subsequently used to guide prostate biopsy
  • The MP-MRI used a 1.5T rather than 3T (with endo-rectal coil) which may be more contemporary
  • The report did not use a minimum cut-off for PSA for referral to triage (where PSA was the only indicator for biopsy)
  • No use of the now standardised PIRADS score for MRI reporting
  • Economic data is yet to be reported. The reality of implementing this new pathway will depend on service availability, local expertise, wait times and cost.
  • The TRUS biopsy could have been performed before the prostate mapping biopsy (or randomisation to either TRUS or Transperineal mapping first)

Funding

  • UK Government Department of Health, National Institute of Health Research–Health Technology Assessment Programme, (Project number 09/22/67).
  • UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre
  • Coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL.
  • Sponsored by University College London (UCL).

Further Reading