Revision Effective Date: 12/14/2020
Revision Explanation: Under LCD Title changed the LCD title from MolDX: DecisionDX Melanoma to MolDX: Melanoma Risk Stratification Molecular Testing.
Under CMS National Coverage Policy regulations regarding billing and coding were removed from this section and placed in the related billing and coding article.
Under Coverage Indications, Limitations and/or Medical Necessity the verbiage was revised and now reads:
Molecular diagnostic tests used to assist in risk stratification of melanoma patients are covered when:
1. The patient has a personal history of melanoma AND:
Has Stage T1b and above OR
Has T1a with documented concern about adequacy of microstaging
Is undergoing workup or being evaluated for treatment, AND
Does not have metastatic disease AND
Presumed risk for a positive Sentinel Lymph Node Biopsy (SLNB) based on clinical, histological, or other information is >5% AND
Has a disease stage, grade, and Breslow thickness (or other qualifying conditions) within the intended use of the test
2. The TEST has demonstrated, as part of a Technical Assessment:
Clinical validity of analytes tested in predicting metastatic disease in peer-reviewed scientific literature
Utility beyond clinical, histological, and radiographical factors in the ability to accurately stratify patients into risk groups to manage patient care
Appropriate analytical validity
Performance characteristics equivalent to other covered, similar tests
Under Summary of Evidence the verbiage was revised and now reads:
Cutaneous melanoma (CM) is increasing in incidence in the U.S., with an estimated 96,480 cases expected to be diagnosed in 2019 with 7,230 deaths.1
In the treatment of CM, the risk that a patient has or will develop metastatic disease is central to many of the decision management choices in cutaneous melanoma, with more aggressive management or treatment strategies recommended for patients who are at a higher risk.2 Per current national guidelines, a SLNB procedure is considered for all patients with melanoma pathologic Stage T1b and above, as well as those patients with T1a tumors in whom there is significant uncertainty about the adequacy of microstaging.2,3 Patients with a positive SLN are at substantially increased risk for distant metastatic disease and death,4 however, the procedure only provides prognostic information, and the MSLT-II study showed no survival benefit associated with completion lymphadenectomy in SLN positive patients.5 Currently, the identification of SLN positive patients helps identify Stage III patients who can potentially benefit from targeted and immunotherapeutic agents in the adjuvant setting.6-8 The procedure can be associated with complications in a substantial proportion of patients such as pain, seromas, nerve damage and edema, and requires a large team of dedicated personnel, including nuclear medicine physicians, surgeons, and pathologists.9-11 It has been estimated that the cost of a SLNB can be 10 times that of a wide excision alone, and the cost per life saved in a patient population with low prevalence of positive SLN can approach 1 million dollars.12 Overall, the likelihood of a positive SLN after the SLNB procedure is 16%,4,13 but this is variable for specific populations.13-16 Elderly patients account for a substantial proportion of CM patients, and 60% of melanoma-related deaths occur in patients ≥65 years-old. While older age is associated with a poor prognosis, fewer elderly patients are SLN positive,14-18 which indicates that the prognostic value of SLNB is limited in this population.19,20In general, a 5% likelihood for a positive SLN is recommended as a threshold for performing this procedure in a patient population.13
Molecular diagnostic tests have been proposed to help managing clinicians risk stratify patients for selecting their most appropriate management based on their probability of developing metastatic disease; these tests may score patients’ probabilities of resultant metastatic disease by measuring tumor biomarkers such as relevant gene expression. 21-24 One gene expression profile (GEP) test (DecisionDx Melanoma, Castle Biosciences) was evaluated in a retrospective cohort (n=782) to evaluate its ability to predict metastasis and ability to predict SLNB status with tumors with a Breslow thickness <2.0 mm (AJCC T1 T2).25
The ability of the test to identify a low risk group was assessed and compared to SLNB in two contemporary, multi-center, prospective study cohorts: a 584 patient cohort from two published prospective studies (overall 14% SLN positive rate)23,26 and a 837 patient cohort from prospectively tested patients at 5 large academic institutions (overall 12% SLN positive rate).25 The rate of SLN positivity in both prospective study cohorts aligns with the SLN positivity rate in the general population of melanoma patients who have undergone SLNB. The results show that in patients from the Medicare-eligible population (65 years old and over) who were determined to be low risk by this test, the concordance of a negative SLNB was 98.4%. These studies showed improved performance in other patient groups as well.
SLNB positivity rates for T3 tumors with low risk score for this test is 8.7%. Importantly, the 5-year melanoma specific survival (MSS) rate for T1/T2 low risk group remains favorable; with 99% MSS, comparable to that observed in T1a tumors and for which current guidelines do not recommend SLNB.2,27 Furthermore, T1/T2 low risk patients patients show 5-year overall survival (OS) of 97% and distant metastasis free survival (DMFS) of 93%.28 The MSLT-II study demonstrated that a delay in lymph node dissection does not adversely affect survival, thus clinical follow up of low-risk patients and lymphadenectomy for those few who develop clinically detectable nodal disease should achieve similar outcomes to those who currently undergo a planned SLNB.5 Thus, the test identifies a patient population with <5% likelihood of a positive SLN and high survival rates and therefore has utility in guiding SLNB decisions in patients 65 years-old and over with T1-T2 CM tumors. In this population, the test could potentially reduce the rate of SLNB by up to 78% while still maintaining a MSS survival rate of 99% in those patients with low-risk tumor biology who can safely avoid the procedure.
Clinical validation of this same test as a prognostic test for CM patients was performed in three multicenter, prospectively designed archival tissue studies including 782 patients.21,22,24 These studies have shown that the test accurately predicts risk for local/regional recurrence, distant metastasis, melanoma-related mortality, and all-cause mortality independent of clinicopathologic factors used in staging and that the test shows improved sensitivity and negative predictive value (NPV) for recurrence-free (RFS), distant metastasis-free (DMFS), melanoma-specific (MSS) and overall (OS) survival individually or in conjunction with established clinicopathologic factors. A study focused on patients with melanoma of the head and neck (H&N) has been recently published. Patients with H&N melanoma have poorer outcomes and lower rates of SLN positivity which makes the prognostic value of the SLNB procedure limited and thus additional prognostic information provided by this test is important in this group of patients.28 Four prospective, independent studies (n= 510) and an interim analysis of two prospective registries (n=322) have confirmed the prognostic accuracy of the assay.23,29-32 This suggests that the test may be useful in stratifying risk and patient treatment decisions.
A recent retrospective study directly compared the ability of DecisionDX Melanoma with the ability of American Joint Committee on Cancer (AJCC) melanoma staging to predict longer term outcomes.33 This study looked at 205 archived formalin-fixed, paraffin-embedded primary melanoma tissue blocks from 6 centers. This included 109 Stage I and 96 Stage II cancers, and median time to follow-up was 6.9 years. The median time to recurrence was 1.7 years, and the median time to distant metastasis was 1.6 years. In general, the test scoring alone had greater sensitivity to recurrence, distant metastasis, and death than AJCC staging. Alternatively, AJCC staging had greater specificity for these outcomes. The use of this assay with AJCC staging had a higher sensitivity to these adverse outcomes than either prognostic measurement alone. Lastly, a number of recent studies have suggested that clinicians value and use this test in their medical decision making regarding aggressiveness of melanoma management.34-36
Under Analysis of Evidence the verbiage was revised and now reads:
For cutaneous melanoma, a well-established set of clinical pathways is available for the management of cutaneous melanoma, which are heavily based on risk stratification of patients with higher risk patients being recommended to have a more intense diagnostic workup or more intensive treatment. While the consensus guidelines also give specific clinical, pathologic, and imagining findings that can help to risk stratify a patient, additional evidence suggests that molecular diagnostic tests can be used to further improve risk stratification, thereby improving the accuracy of the risk stratification that is key to deciding on the optimal patient management plan in these clinical pathways. This is particularly the case for identifying the patients at a higher risk of adverse outcomes as a result of the melanoma. As such, tests such as the one evaluated above are considered reasonable and necessary for indications where it has both shown an ability to enhance accuracy of risk stratification and where this risk stratification may be used to select among a number of different consensus recommended management approaches.
Since the clinical utility of this test is dependent upon consensus-based management recommendations based on risk, this coverage decision is subject to change pending changes in the consensus recommended use of risk strata for patient management and the accuracy of alternative risk-stratification tools. This coverage decision will be periodically re-evaluated.
Updated link for #39 in bibliography section.
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.