Local Coverage Article Response to Comments

Response to Comments: Prostate Cancer Detection with IsoPSA®


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Response to Comments: Prostate Cancer Detection with IsoPSA®
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Response to Comments
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This article contains the responses to comments submitted regarding IsoPSA® Prostate Cancer Detection test based on revised draft policy DL39284 presented at open meeting on 6/21/22.

Response To Comments


Broaden the range of patient total PSA values covered to 4-100 ng/mL

Cleveland DX requests to broaden the range of patient total PSA values covered to 4-100 ng/mL. As a ratio metric test, IsoPSA diagnostic performance is unaffected by absolute PSA value. IsoPSA has been proven to be effective across a broad range of total PSA values (4 ng/mL – 100 ng/mL), exhibiting consistent performance in patients across the breadth of PSA values seen in routine clinical practice. A new study by Klein et al (2022) was submitted and they referred to Lotan 2021, Stovasky 2019, Klein 2017 as well.

Klein et al (2022) is a prospective, multi-center validation study of the diagnostic performance of IsoPSA for Prostate Cancer (PcA). For IsoPSA, diagnostic performance was evaluated only in patients within the intended use population of the test of men age > 50 years and PSA > 4ng/mL. In this study sub-group analysis was conducted for PSA levels of 4-10 ng/mL and PSA >10 ng/mL. The authors report that IsoPSA maintained statical accuracy across a broad range of elevated total PSA ranging from 4-100 ng/mL in 888 subjects. 24% (217/888) of study subjects had a PSA >10 ng/mL. 54 subjects (14.8%) of the sub-set with PSA >10-25 ng/mL had a negative biopsy while 44 (21.3%) has low grade PCa and 96 (30.4%) had high-grade PCa (Table 1). The NCCN Guidelines algorithm considers biomarkers in this population to potential aid in evaluation as well.


However, only 23 subjects or 2.5% (23/888) had total PSA values >25 ng/mL with 20 of those predictably having high grade PCa (Gleason >7). Specificity (SP) and NPV (negative predictive value) decreased modestly in the group with total PSA >10 ng/mL and further breakdown of the small sub-set with PSA> 25 (n=23) was not reported in the study (Table 6). In this population higher SP and NPV are desired as the risk of malignancy is increase with PSA >25 ng/mL making need for additional evaluation and/or biopsy more likely. Further evaluation of the IsoPSA test at the higher PSA levels with a larger number of patients to ensure the test is appropriately triaging those these high-risk individuals is necessary and malignancy is not missed. Additionally, long-term follow-up with an understanding of rate of missed cancers in this population and necessary follow-up has not been determined. Therefore, the range was broadened to upper limit of ≤25 ng/mL. 


Expand range of patient biopsy status to include those with previous negative biopsy

Cleveland DX requests to expand the range of patient-specific biopsy status to include also those patients having had previous negative biopsy. IsoPSA has been proven to perform consistently among patients with prior negative biopsy results as well as among those prior to their initial biopsies.

In Klein et al. (2022) 40% (354/888) of study subjects had a prior negative biopsy. In the group with at least 1 prior negative biopsy, IsoPSA yielded a moderate AUC (0.82), a modest specificity = 46% and good NPV=95% for High-Grade PCa on subsequent biopsy in 202 subjects with prior negative biopsies.

This demonstrates diagnostic performance of IsoPSA was consistent regardless of prior biopsy status.

In the study protocol exclusion criteria included recent prostate biopsy (≤ 30 days prior to study participation), however in Scovell et al. (2021) in a real-world population 44% (324/734) had prior negative biopsies without this exclusion criteria.

This is a diagnostically challenging group and the high NPV in this population is clinical useful to aid in management therefore the policy will be expanded to allow prior negative biopsy. This is consistent with NCCN Guidelines for evaluation of patients with at least one negative biopsy where the panel recommends multiparametric MRI and allows biomarkers if clinically indicated. Therefore the limitation to initial biopsy was removed.


Remove restrictions regarding patients with symptomatic BPH (benign prostate condition) and, accordingly, the use of medications such as 5α reductase (5-ARIs) and alpha blockers

Cleveland DX requests remove restrictions regarding patients with symptomatic BPH, a benign prostate condition which often precipitates the use of medications such as 5-ARIs and/or alpha blockers. Because structural changes in cancer-related PSA are unaffected by drugs that lower PSA level, medications including 5ARIs and alpha blockers do not interfere with the diagnostic performance of IsoPSA. They reference Klein et al. (20220 as well as other published studies on IsoPSA patients with symptomatic BPH taking 5_ARIs (Klein 2017, Stovsky 2019, Scovell 2021).

New Evidence was submitted in Klein et al. (2022) reported that IsoPSA is unaffected by the use of 5a-reductase inhibitors or alpha blockers consistent with the other referenced studies. The same author, Klein (2017), stated “because IsoPSA measures PSA structure rather than concentration, men on 5-ARIs, which are known to affect PSA concentration, were not excluded.” Therefore, this limitation will be removed. 


IsoPSA definition – B&C article

Cleveland DX believes that the code initially proposed by CGS (89240) is inappropriate as it does not properly describe IsoPSA. IsoPSA is a lab procedure and not a pathology procedure. Note that 89240 is listed under the physician fee schedule, whereas IsoPSA should be listed under the lab fee schedule. IsoPSA is not a tissue- or fluid-based based pathology evaluation, rather it is a blood-based immunoassay with proprietary algorithm. recommends instead using the unlisted MAAA code 81599.

CGS has reviewed CPT 81599 and agree this is the most accurate code until a specific code is issued and B&C has been modified.


Cleveland DX - minor typographical errors

These have been corrected.

Associated Documents

Related Local Coverage Documents
L39284 - Prostate Cancer Detection with IsoPSA®
Related National Coverage Documents
Public Versions
Updated On Effective Dates Status
09/30/2022 10/06/2022 - N/A Currently in Effect You are here