Local Coverage Determination (LCD)

MolDX: DecisionDx-UM (Uveal Melanoma)

L37033

Expand All | Collapse All
Proposed LCD
Proposed LCDs are works in progress that are available on the Medicare Coverage Database site for public review. Proposed LCDs are not necessarily a reflection of the current policies or practices of the contractor.

Document Note

Note History

Contractor Information

LCD Information

Document Information

Source LCD ID
N/A
LCD ID
L37033
Original ICD-9 LCD ID
Not Applicable
LCD Title
MolDX: DecisionDx-UM (Uveal Melanoma)
Proposed LCD in Comment Period
N/A
Source Proposed LCD
DL37033
Original Effective Date
For services performed on or after 07/10/2017
Revision Effective Date
For services performed on or after 06/30/2022
Revision Ending Date
N/A
Retirement Date
N/A
Notice Period Start Date
05/25/2017
Notice Period End Date
07/09/2017

CPT codes, descriptions, and other data only are copyright 2023 American Medical Association. All Rights Reserved. Applicable FARS/HHSARS apply.

Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of CPT, and the AMA is not recommending their use. The AMA does not directly or indirectly practice medicine or dispense medical services. The AMA assumes no liability for data contained or not contained herein.

Current Dental Terminology © 2023 American Dental Association. All rights reserved.

Copyright © 2024, the American Hospital Association, Chicago, Illinois. Reproduced with permission. No portion of the AHA copyrighted materials contained within this publication may be copied without the express written consent of the AHA. AHA copyrighted materials including the UB‐04 codes and descriptions may not be removed, copied, or utilized within any software, product, service, solution, or derivative work without the written consent of the AHA. If an entity wishes to utilize any AHA materials, please contact the AHA at 312‐893‐6816.

Making copies or utilizing the content of the UB‐04 Manual, including the codes and/or descriptions, for internal purposes, resale and/or to be used in any product or publication; creating any modified or derivative work of the UB‐04 Manual and/or codes and descriptions; and/or making any commercial use of UB‐04 Manual or any portion thereof, including the codes and/or descriptions, is only authorized with an express license from the American Hospital Association. The American Hospital Association (the "AHA") has not reviewed, and is not responsible for, the completeness or accuracy of any information contained in this material, nor was the AHA or any of its affiliates, involved in the preparation of this material, or the analysis of information provided in the material. The views and/or positions presented in the material do not necessarily represent the views of the AHA. CMS and its products and services are not endorsed by the AHA or any of its affiliates.

Issue

Issue Description

This LCD outlines limited coverage for this service with specific details under Coverage Indications, Limitations and/or Medical Necessity.

Issue - Explanation of Change Between Proposed LCD and Final LCD

CMS National Coverage Policy

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary.

42 CFR 410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Changes

Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

This Medicare contractor will provide limited coverage for the DecisionDx-UM (Castle Bioscience, Inc.) test for the management of newly diagnosed uveal melanoma. This test is intended for the determination of metastatic risk, and to guide surveillance and referral to medical oncology (preferably an oncologist with expertise in melanoma) in patients who have a confirmed diagnosis of uveal melanoma (UM) and no evidence of metastatic disease.

Summary of Evidence

UM is a rare cancer, affecting ~1600-1700 patients per year in the United States, but it is the most common intra-ocular cancer in adults. UM arises in the middle layer of the eye, the uvea tract, which consists of the iris, ciliary body, and choroid. Eye-sparing radiation (brachytherapy or proton beam therapy) is the most common treatment approach, but approximately 10% of patients will undergo enucleation due to large and/or aggressive tumors that cannot be managed with radiation or due to eye pain or vision loss. Local treatment by radiation or enucleation is highly successful at controlling the primary tumor, with only ~5% chance of local recurrence. Most patients present with local disease and no evidence of metastases, however, as many as 50% of patients will ultimately experience distant metastasis, most commonly to the liver.

Clinicopathologic staging cannot reliably identify patients at low or high risk of metastasis, as even early stage patients (AJCC Stage I-II) have a substantial risk of metastasis and mortality. Historically, most UM patients were managed with high intensity surveillance, including frequent imaging and laboratory tests, with the goal of diagnosing early metastasis. Systematic imaging has been shown to be effective at identifying asymptomatic metastases, which is important because treatment of liver metastases with surgical resection or regional therapy is more effective and achieves better outcomes when tumor burden is low. However, since approximately 50% of patients will not experience metastasis, a substantial proportion of patients were subjected to unnecessary imaging, laboratory tests, and clinical visits, resulting in patient burden, undo exposure to radiation and over-utilization of healthcare resources.

An accurate determination of metastatic risk at diagnosis allows for a risk-appropriate surveillance program. Patients at high-risk of metastasis can continue to be followed with a high intensity program as previously prescribed, such as quarterly ultrasound, magnetic resonance imaging (MRI) or computerized tomography (CT) scans alternating with liver function tests (LFTs), and consideration of adjuvant treatment. These patients benefit from early detection of metastatic disease when it can be most effectively treated. Patients with low metastatic risk can be removed from this traditional intensive surveillance and instead followed with a low intensity program, such as yearly exams, imaging, and LFTs.

DecisionDx-UM Test Description and Intended Use

DecisionDx-UM is an ribonucleic acid (RNA) gene expression classifier that is based on the expression levels of 15 mRNA transcripts (3 control and 12 discriminating genes). DecisionDx-UM is performed on tissue from a fresh-frozen fine needle aspirate biopsy (FNAB), formalin-fixed paraffin embedded (FFPE) sections from an enucleated tumor, or, in rare cases, fresh-frozen resection material. Results are reported as a 5-year risk classification for metastasis: low risk (Class 1A), intermediate risk (Class 1B), or high risk (Class 2).

The DecisionDx-UM test is intended for determination of metastatic risk, and to guide surveillance and referral to medical oncology in patients who have a confirmed diagnosis of UM and no evidence of metastatic disease. The test discriminates patients with high risk (class 2) for early distal recurrent disease from those with minimal risk of distal metastasis (class 1A). Identification of high-risk patients allows early referral to a medical oncologist with expertise in the management of UMs, which includes intensified metastatic surveillance and/or metastasis intervention, and stratification for entry into clinical trials with adjuvant therapy. In rare cases where the patient cannot realistically see a medical oncologist due to geographic location (long distance to travel), and/or are among underserved patient populations, if they cannot feasibly see a medical oncologist, surveillance testing for class 2 patients can be directed by an ophthalmologist with specific training in treating patients with UM.

Clinical Validation

In both prospective and retrospective multicenter studies, DecisionDX-UM has been shown to be a more accurate prognostic indicator of metastasis compared to any other factor.1-4

Onken et al1 reported the migration of the RNA expression profile from a hybridization-based microarray platform to a polymerase chain reaction (PCR)-based 15 gene assay and analyzed the technical performance of the assay in a prospective study of FNAB tumor samples from multiple centers. The gene expression profile distinguished between low metastatic risk (class 1 signature) and high metastatic risk (class 2 signature). The role of RNA quality and tumor heterogeneity was evaluated. A clinically annotated training set of 28 UMs was used to support the vector machine algorithm for classification. One hundred seventy-two patients from a single center with a median follow-up of 16 months were utilized to evaluate prognostic performance which demonstrated technical performance of 94.8%. Kaplan–Meier analysis showed an accuracy of risk-classification with 5-year metastatic-free survival (MFS) rates of 98% and 24% for predicted Class 1 and 2 cases, respectively (P < 0.0001).1

The Collaborative Ocular Oncology Group study was a prospective, multi-center, blinded study to assess clinical validity of the DecisionDx-UM test.2 Comparison with other genetic and clinicopathologic variables was evaluated. Of 494 patients, 446 were considered evaluable. The 50-month metastasis-free survival was 97% vs 20% for Class 1 and 2 respectively (p<0.0001). By Cox multivariate proportional hazards analysis, Class 2 identified metastasis better than any other prognostic factor (p<0.006). The Net Reclassification Improvement study showed improvement of gene expression profiling over TNM (T describes size of primary tumor, N describes regional lymph nodes status, M describes distant metastasis) classification of 37% at 2 years (p=0.008) and 43% at 3 years (p=0.001). When compared to chromosome 3 status, the improvement of gene expression profiling over TNM was 36% at 2 years (p= 0.006) and 38% at 3 years (p=0.004).2

In a retrospective, single-center clinical study designed to assess clinical validity of the DecisionDx-UM test, in 187 patients, Chappell, et al3 showed disease specific survival was predicted with high accuracy. Kaplan-Meier analysis for 5-year disease specific survival was 93% and 38% for Class 1 vs 2 cases, respectively (p<0.0001). By multivariate Cox modeling, the DecisionDx-UM class was the only independent significant predictor of outcome for both metastasis-free survival (HR=8.4, p<0.0001) and disease-specific survival (HR=12.3, p<0.0001).

Another prospective, single-center clinical study evaluated the clinical validity of the DecisionDx-UM test in 299 UM patients. In this study, Cox multivariate analyses confirmed that the 15-gene expression profile was the only significant predictor of metastatic risk (p=0.0013).4

A step-down algorithm analysis of two genes in Class 1 patients has since been performed to identify those patients with Class I classification at risk for late metastasis. Due to this refinement, Class 1 includes low-risk Class 1A patients and a small number of intermediate-risk Class 1B subjects with late relapse.

Clinical Utility

A retrospective chart review study showed that the DecisionDx-UM test results direct appropriate surveillance and treatment plans by matching an individual patient’s risk for metastasis to informed medical management decisions. Aaberg et al6 reported on 88 Medicare beneficiaries in which all Class 1 patients received low-intensity surveillance while Class 2 patients received high intensity surveillance plans (imaging and/or liver function testing every 3-6 months). Test results also influenced referral decisions with 29% of Class 2 patients being referred to medical oncology for follow-up and 10% recommended for adjuvant therapy consideration whereas no Class 1 patients were referred.

In a prospective, multi-center study of 70 patients, the majority (81%) of Class 1 patients had low-intensity surveillance and all (100%) Class 2 patients received high-intensity surveillance (p<0.0001); four Class 2 patients were recommended for systemic adjuvant therapy.

A decision tree analysis was performed to model the impact of DecisionDx-UM on resource utilization, comparing the previous framework in which all patients received high-intensity surveillance regimens with one in which the surveillance regimen is guided by DecisionDx-UM. Strict compliance with DecisionDx-UM results was associated with a 50% reduction in the number of surveillance procedures performed at two years compared to the previous framework, and a 63% reduction at five years. These results indicate that use of DecisionDx-UM can help avoid high intensity, imaging-based surveillance in patients with a low risk of metastasis, thereby reducing resource utilization in the management of UM patients, which is associated with overall cost savings.

Summary of Analytical and Clinical Performance

General

Intended Use The DecisionDx-UM test is intended for the determination of metastatic risk, and to guide surveillance and referral to medical oncology in patients who have a confirmed diagnosis of uveal melanoma (UM) and no evidence of metastatic disease.
Validated Specimen Type(s) Fresh frozen fine needle aspirate biopsies (FNAB), frozen resections, and formalin-fixed, paraffin-embedded (FFPE) specimens

 

Analytical Performance

Description

Results                            (with 95% Confidence Intervals if applicable)1

Repeatability (within run precision)
4 samples (in triplicate) twice on a single PCR card, 1 instrument, 1 operator, 1 run, 1 day, 1 manufacturing reagent lot; repeated on a separate card.
100% (63.1-100%)
Intermediate precision (between run precision)
Inter-operator/instrument: 28 samples, 2 instruments, 2 operators, 2 runs, 1 day, 1 manufacturing reagent lot (3 discordances: 1 class 2 vs 1A; 2 class 1A-1B)
Inter-assay: 16 samples, 1 instrument, 2 operators, 3 runs, 3 consecutive days, 1 manufacturing lot (0 discordances)
89.3% (71.8-97.7%)
100% (79.4-100%)
Reproducibility (between sites) Not applicable
Minimum input cDNA quantity 125 ng
Minimum tumor content (for FFPE specimens) 80% by histomorphology
Limit of blank (LOB) CT undetermined for blank
Limit of detection (LOD) Not applicable
Limit of quantitation (LOQ) Not applicable
Linearity Not applicable
Interfering substances Not applicable2
Specimen stability, primary FNAB 96 hours at -80 °C (Onken et al., 2010)
FFPE 4 years at RT (Onken et al., 2012)
Specimen stability, intermediate (extracted RNA) 96 hours when stored at -80 °C per manufacturer and literature
Specimen stability, intermediate (cDNA) 24 hours when stored at 4 °C per manufacturer
30 days when stored at -20 °C
Critical reagent closed/shelf-life stability Applied Biosystems TaqMan® Low Density Array, 24 months at -20 7deg;C per manufacturer

Arcturus PicoPure® RNA Extraction Kit, 10 months at RT per manufacturer

Applied Biosystems High-Capacity cDNA Reverse Transcription Kit, 8 months at -20 °C per manufacturer

Applied Biosystems TaqMan® PreAmp Master Mix Kit, 9 months at 4 7deg; C per manufacturer

Applied Biosystems TaqMan® Gene Expression Master Mix, 12 months at -20 °C per manufacturer

Applied Biosystems RNAse Inhibitor, 42 months at -20 °C per manufacturer
Critical reagent open/in use stability Per manufacturer’s specifications

 

1Using Clopper-Pearson method

2Since the gene expression profile is based on ratios of gene to controls, rather than an absolute value, the effect of an interfering agent is expected to affect all genes equally and result in failed amplification.

 

Clinical Performance: Validity

 

Description 5-year metastasis-free (a) or disease-specific (b) survival rates1
(Non-censored recurrence rate; 95% Confidence Intervals of event rates)2
  Class 1A Class 1B Class 2
Onken et al2 (n=514)* 98%a
(0.8%; 0.1-3%; 2/241)
79%a
(10.4%; 4.3-20.3%; 7/67)
28%a
(29.6%; 23.5-36.4%; 61/206)
Chappell et al3 (n=187)* 93%b
(2.5%; 0.5-7.3%; 3/118)
38%b
(28.9%; 18.7-41.2%; 20/69)
Correa et al4 (n = 158) 92%b
(4.58%; 1.5-10.4%; 5/109)
55%b
Correa et al5 (n = 299)† 92%b 55%b

 

 

1Survival rates according to Kaplan-Meier analysis


2Overall non-censored recurrence rates and 95% Confidence Intervals (Coppler-Pearson method) not accounting for censored patients.


*Tests performed at Washington University (Wash U);

 

†Tests performed at Wash U and Castle Biosciences Inc.

 

**Published survival rates but not event numbers so cannot calculate confidence intervals

 

Clinical Performance: Utility

 

Description Clinical Use Outcomes
(with 95% Confidence Intervals if applicable)1
  Class 1A Class 1B Class 2
Aaberg et al6
(n = 88 with documentation)
(Note: Retrospective decision impact study of Medicare beneficiaries)
100% (92.6-100.0%; 48/48) received low intensity surveillance. None referred to medical oncology or adjuvant trials.1 100.0%
(91.2-100.0%; 40/40) received high intensity surveillance, referral to medical oncology or adjuvant trials.
Plasseraud et al7 (n = 70) (65.3-94.4%; 25/30)
received low intensity management
(29-96.3%; 5/7)
received low intensity management
(89.4-100.0%; 33/33) received high intensity management
16.7%
(5.6-34.7%; 5/30) received high intensity management
28.6%
(3.7-71.0%; 2/7) received high intensity management
10.0%
(2.1-26.5%; 3/30) received referral to medical oncology
  33.3%
(18.0-51.8%; 11/33) received referral to medical oncology

 

1Low intensity management is defined LFTs and/or imaging studies annually. High intensity management is defined LFTs and/or imaging studies every 3-6 months.

 

 

Analysis of Evidence (Rationale for Determination)

Level of Evidence

Quality – Moderate

Strength – Limited

Weight – Limited


This contractor recognizes that evidence for clinical utility for the DecisionDX-UM assay in patients with UM with no evidence of distant metastatic disease at the time of diagnosis is promising at the current time.  However, this contractor believes a prospective registry currently in progress will generate sufficient data to demonstrate improved patient outcomes.  Registry endpoints will demonstrate that ≥ 80% of class 2 patients are referred to medical oncology for management, and that Class 1A/1B patients do not undergo more intensive surveillance testing compared to Class 2 patients. Continued coverage of this assay will depend on semi-annual review of interim data and publications demonstrating the above clinical utility. 

Proposed Process Information

Synopsis of Changes
Changes Fields Changed
N/A
Associated Information
Sources of Information
Bibliography
Open Meetings
Meeting Date Meeting States Meeting Information
N/A
Contractor Advisory Committee (CAC) Meetings
Meeting Date Meeting States Meeting Information
N/A
MAC Meeting Information URLs
N/A
Proposed LCD Posting Date
Comment Period Start Date
Comment Period End Date
Reason for Proposed LCD
Requestor Information
This request was MAC initiated.
Requestor Name Requestor Letter
View Letter
N/A
Contact for Comments on Proposed LCD

Coding Information

Bill Type Codes

Code Description

Please accept the License to see the codes.

N/A

Revenue Codes

Code Description

Please accept the License to see the codes.

N/A

CPT/HCPCS Codes

Please accept the License to see the codes.

N/A

ICD-10-CM Codes that Support Medical Necessity

Group 1

Group 1 Paragraph:

N/A

Group 1 Codes:

N/A

N/A

ICD-10-CM Codes that DO NOT Support Medical Necessity

Group 1

Group 1 Paragraph:

N/A

Group 1 Codes:

N/A

N/A

Additional ICD-10 Information

General Information

Associated Information
N/A
Sources of Information
N/A
Bibliography
  1. Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn. 2010;12(4):461-468.
  2. Onken MD, Workley LA, Char DH, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119(8):1596-1603.
  3. Chappell MC, Char DH, Cole TB, et al. Uveal melanoma: molecular pattern, clinical features, and radiation response. Am J Ophthalmol. 2012;154(2):227-232 e2.
  4. Correa ZM, Augsburger JJ. Sufficiency of FNAB aspirates of posterior uveal melanoma for cytologic versus GEP classification in 159 patients, and relative prognostic significance of these classifications. Graefe’s Arch Clin Exp Ophthalmol. 2014;252(1):131-135.
  5. Correa ZM, Augsburger JJ. Independent prognostic significance of gene expression profile class and largest basal diameter of posterior uveal melanomas. Am J Ophthalmol. 2016;162:20-27.
  6. Aaberg Jr TM, Cook RW, Oelschlager K, Maetzold D, Rao PK, Mason JO 3rd. Current clinical practice: differential management of uveal melanoma in the era of molecular tumor analyses. Clin Ophthalmol. 2014;8:2449-2460.
  7. Plasseraud KM, Cook RW, Tsai T, et al. Clinical performance and management outcomes with the DecisionDx-UM Gene Expression Profile test in a prospective multicenter study. J Oncol. 2016;2016:5325762.

Revision History Information

Revision History Date Revision History Number Revision History Explanation Reasons for Change
06/30/2022 R9

Under Bibliography changes were made to citations to reflect AMA citation guidelines. Formatting, punctuation, and typographical errors were corrected throughout the LCD. Acronyms were inserted where appropriate throughout the LCD.

  • Provider Education/Guidance
07/08/2021 R8

Under CMS National Coverage Policy revised the verbiage for the regulation CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15 by removing §80.2. Under Bibliography changes were made to citations to reflect AMA citation guidelines.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Provider Education/Guidance
10/31/2019 R7

This LCD is being revised in order to adhere to CMS requirements per chapter 13, section 13.5.1 of the Program Integrity Manual, to remove all coding from LCDs. There has been no change in coverage with this LCD revision. Regulations regarding billing and coding were removed from the CMS National Coverage Policy section of this LCD and placed in the related Billing and Coding: MolDX: DecisionDx-UM (Uveal Melanoma) A56906 Article.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Provider Education/Guidance
08/22/2019 R6

All coding located in the Coding Information section has been moved into the related Billing and Coding: MolDX: DecisionDx-UM (Uveal Melanoma) A56906 article and removed from the LCD.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Provider Education/Guidance
02/21/2019 R5

Added 0081U to CPT/HCPCS Codes Group 1. Deleted 81599. The change is due to the Q1:2019 CPT/HCPCS Quarterly Update and is effective 1/1/2019.

Deleted the Demirci reference in the Clinical Performance Validity Table.

  • Revisions Due To CPT/HCPCS Code Changes
01/10/2019 R4

Removed bibliography #5 and references in the policy.

  • Provider Education/Guidance
02/26/2018 R3 The Jurisdiction "J" Part B Contracts for Alabama (10112), Georgia (10212) and Tennessee (10312) are now being serviced by Palmetto GBA. The notice period for this LCD begins on 12/14/17 and ends on 02/25/18. Effective 02/26/18, these three contract numbers are being added to this LCD. No coverage, coding or other substantive changes (beyond the addition of the 3 Part B contract numbers) have been completed in this revision.
  • Change in Affiliated Contract Numbers
01/29/2018 R2 The Jurisdiction "J" Part A Contracts for Alabama (10111), Georgia (10211) and Tennessee (10311) are now being serviced by Palmetto GBA. The notice period for this LCD begins on 12/14/17 and ends on 01/28/18. Effective 01/29/18, these three contract numbers are being added to this LCD. No coverage, coding or other substantive changes (beyond the addition of the 3 Part A contract numbers) have been completed in this revision.
  • Change in Affiliated Contract Numbers
07/20/2017 R1

Revised policy to add Summary of Evidence, Analysis of Evidence, and Bibliography. No changes were made to the coverage.

  • Other
N/A

Associated Documents

Attachments
N/A
Related National Coverage Documents
N/A
Public Versions
Updated On Effective Dates Status
06/20/2022 06/30/2022 - N/A Currently in Effect You are here
Some older versions have been archived. Please visit the MCD Archive Site to retrieve them.

Keywords

N/A

Read the LCD Disclaimer