LCD Reference Article Response To Comments Article

Response to Comments: Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis

A56115

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Article ID
A56115
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Article Title
Response to Comments: Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis
Article Type
Response to Comments
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12/01/2018
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As an important part of Medicare Local Coverage Determination (LCD) development, National Government Services solicits comments from the provider community and from members of the public who may be affected by or interested in our LCDs. The purpose of the advice and comment process is to gain the expertise and experience of those commenting.

We would like to thank those who suggested changes to the Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis LCD. The official notice period for the final LCD begins on October 16, 2018, and the final determination will become effective on December 1, 2018.

 

Response To Comments

Number Comment Response
1

A joint comment by the College of American Pathologists (CAP) and the Association for Molecular Pathology (AMP)- “We appreciate NGS’ willingness to provide limited coverage for biomarker testing as part of emerging efforts to both improve detection of prostate cancer and help guide treatment decisions. Given the limited evidence at this time for the clinical use of these assays, we agree with the coverage limitations that are outlined in NGS’ proposed policy.”

NGS appreciates the supportive comment.

2

The American Urological Association (AUA)- “while noble in its intent…the LCD should be altered to allow repeat testing to be done at intervals indicated by the patient's clinical condition and should not be limited based upon a prior prostate biopsy.” Regarding repeat testing, they note: “Although the optimal frequency of marker testing is not yet clear, choosing an arbitrary interval such as every 1 to 2 years or creating an exception for a status change (such as continued PSA rise, new finding on imaging or exam) would help minimize the concern” (with) “overuse yet still allow a thoughtful approach to a patient's condition.” It is not entirely clear if this comment is only meant to be in the context of a repeat biopsy.

Regarding the “prior prostate biopsy” exclusion, biomarker testing prior to initial biopsy versus repeat biopsy seemed to be distinct enough topics to warrant separate treatment. We, therefore, chose to confine the scope of the draft LCD to “biomarker testing used to refine selection of patients for initial (not repeat) biopsy.” To clarify this, the LCD title will be changed to “Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis.” Regarding repeat testing, there seems to be some linkage with repeat biopsy; obviously, multiple testing is more an issue in the setting of multiple biopsies. However, even if confined to initial biopsy, as outlined in the draft Analysis of Evidence, NGS feels only very circumscribed coverage is warranted; this excludes patients with relative indications for biopsy, such as the cited “status changes” would most likely represent.

3

Mayo Clinic submitted a PHI specific comment which was overall supportive but echoed the AUA’s requested changes.

See the AUA response.

4

Beckman Coulter, the PHI test manufacturer, also requested the same two changes as the AUA, even though acknowledging the LCD scope limitation: (“We understand that DL37733 proposes to address coverage for biomarker testing used to refine selection of patients for initial (not repeat) biopsy.”). They note that NCCN guidelines recommend a PHI score > 35 as potentially informative for men with total serum PSA > 3.0 ng/mL who have never undergone a biopsy or who have had a previous negative biopsy.” They cite two recently published studies (1,2)

See the AUA response. The new studies will be detailed in the revised final LCD.

  1. Tosoian JJ, Druskin SC, Andreas D, et al. Prostate Health Index density improves detection of clinically significant prostate cancer. BJU Int. 2017;120(6):793-798.
  2. White J, Shenoy BV, Tutrone RF, et al. Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting. Prostate Cancer Prostatic Dis. 2018;21(1):78-84.

 

5

OPKO, the 4Kscore test manufacturer, submitted comments, the primary focus of which was to request standalone coverage criteria by highlighting “important differences in the clinical performance and level of evidence for the 4Kscore test compared to %fPSA and PHI,” citing a number of (mostly new) studies not cited in the draft (1-6). The three criteria singled out are frequency of testing, men with a prior negative biopsy, and selective use in men over the age of 75.

  1. Frequency- The comment notes that latest AUA guidelines recommend PSA screening interval of two years for men with a PSA > 1.0 ng/mL, presumably implying the “once/bene” limitation should be changed to align with frequency of PSA screening.
  2. Prior Negative Bx- The comment notes that 18% of study patients had a prior negative biopsy and that NCCN 2018 Prostate Cancer Early Detection Guidelines “indicate that the use of the 4Kscore is appropriate in both biopsy naïve as well as prior negative biopsy patients.”
  3. Selective use in men >75 years old- The comment again cites NCCN guidelines that recommend screening in men >75 (and consideration of biopsy) if PSA ≥4 ng/mL.

NGS disagrees with standalone indications for 4Kscore. While we appreciate the new peer-reviewed, published studies brought to our attention (now detailed in the final LCD), NCCN and other guidelines still generally equate %fPSA, PHI, and 4Kscore testing, as outlined in the draft Analysis of Evidence section. Regarding the frequency and prior negative biopsy request, see the prior AUA response. NGS agrees with the request for selective coverage in men >75 years old (i.e., those with a PSA >4 ng/mL and otherwise healthy with a >10 year life expectancy), consistent with NCCN, particularly as this type of patient would most benefit from avoiding unnecessary procedures, and be least harmed by a false negative. 

  1. Vickers A, Nordstrom T, Assel M, Lilja H, Gronberg H, Eklund M. Re: Tobias Nordstrom, Andrew Vickers, Melissa Assel, Hans Lilja, Henrik Gronberg, Martin Eklund. Comparison Between the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol 2015;68:139-46. Eur Urol. 2018;74(2):e35-e36.
  2. Zappala SM, Scardino PT, Okrongly D, Linder V, Dong Y. Clinical performance of the 4Kscore Test to predict high-grade prostate cancer at biopsy: A meta-analysis of us and European clinical validation study results. Rev Urol. 2017;19(3):149-155.
  3. Punnen S, Freedland SJ, Polascik TJ, et al. A Multi-Institutional Prospective Trial Confirms Noninvasive Blood Test Maintains Predictive Value in African American Men. J Urol. 2018;199(6):1459-1463.
  4. Braun K, Sjoberg DD, Vickers AJ, Lilja H, Bjartell AS. A Four-kallikrein Panel Predicts High-grade Cancer on Biopsy: Independent Validation in a Community Cohort. Eur Urol. 2016;69(3):505-511.
  5. Stattin P, Vickers AJ, Sjoberg DD, et al. Improving the Specificity of Screening for Lethal Prostate Cancer Using Prostate-specific Antigen and a Panel of Kallikrein Markers: A Nested Case-Control Study. Eur Urol. 2015;68(2):207-213.
  6. Sjoberg DD, Vickers AJ, Assel M, et al. Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men. Eur Urol. 2018;73(6):941-948.
6

Exosome Diagnostics, the EPI test manufacturer, submitted comments largely centered around the upcoming publication of a second validation study, and its potential positive NCCN guideline implications. They also refer to a “recently completed” RCT, which apparently has not yet been submitted for publication. Unlike any other commenters, they also object to the draft limitation “to patients with no other relative indication for prostate biopsy,” citing their own data where “biopsies performed in a population inclusive of these risk factors proved unnecessary.”

NGS will incorporate consideration of these publications, and any consequent NCCN changes, when published. Regarding the broader issue excluding coverage when other relative indications for biopsy exist, NGS outlined in some detail, and stands by, the basis of “very circumscribed coverage” in the LCD Analysis of Evidence.

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