Medical Policy: 02.04.73
Original Effective Date: June 2018
Reviewed: June 2020
Revised: June 2020
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Testing for O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation has been proposed as a method to predict which patients with malignant gliomas may benefit from the use of alkylating agent chemotherapy, such as temozolomide (TMZ). Malignant gliomas are often treated with combined therapy, including resection, chemotherapy, and radiotherapy. However, combined therapy may be too intense in the elderly population, in whom these tumors are most commonly seen.
Gliomas are diagnosed based on results of neurological exam, brain imaging (e.g., MRI, CT), and biopsy. Although, imaging is useful in distinguishing high-grade from low-grade glioma, grading is established based on both histology and molecular characteristics.
For high-grade malignant gliomas (anaplastic astrocytomas and glioblastoma multiforme (GBM), standard treatment combines maximal possible surgical resection, postoperative radiotherapy (RT), and chemotherapy. Chemotherapy may include intraoperative placement of an implantable carmustine wafer. Temozolomide (TMZ) is an oral alkylating agent. Response to TMZ has been associated with decreased O6-methylguanine-DNA methyltransferase (MGMT) activity in tumor tissue (see MGMT and Promoter Methylation section below) because a methylated MGMT promoter leads to decreased MGMT levels, which enhances the effect of the alkylating agent.
TMZ is considered standard systemic chemotherapy for malignant gliomas in patients ages 70 or younger with good performance status and a methylated MGMT promoter. This is based primarily on the results of a large, randomized multicenter trial that compared RT with or without TMZ in patients with GBM; this trial showed statistically significant better overall survival in the combination therapy group. Adjuvant options mainly depend on the performance status of the patient.
Survival with GBM declines with increasing age. Options for patients with good performance status and age older than 70 years with methylated MGMT promoter may involve hypofractionated RT alone or TMZ alone. For patients with poor performance status, options include RT alone, chemotherapy alone, or palliative or best supportive care.
For individuals who have high-grade glioma(s) who receive MGMT promoter methylation testing, the evidence includes cohort studies of prognosis, studies nested within randomized trials, and treatment trials that selected subjects based on MGMT methylation status. Relevant outcomes include overall survival, disease-specific survival, test accuracy, and changes in disease status. While there are no studies directly evaluating whether the use of MGMT methylation testing improves patient outcomes, MGMT status is consistently associated with outcomes of glioma patients. Data from randomized controlled trials have shown that MGMT promoter methylation is predictive for response to alkylating chemotherapeutic agents such as TMZ. The response rate and overall survival with the use of TMZ are higher in patients who have MGMT promoter methylation. While TMZ offers some benefit regardless of MGMT methylation status, studies have consistently suggested that MGMT methylation identifies patients who are more likely to benefit from TMZ. TMZ combined with radiotherapy remains the standard of care for most patients. TMZ is associated with a modest increase in hematologic adverse events compared with radiotherapy alone. Counseling about risks and benefits in a patient with comorbidities may result in a choice to avoid TMZ when that patient is less likely to benefit from the treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
There are 2 ways that MGMT methylation analysis may have clinical validity. The first is as a prognostic marker for survival from GBM. Pure prognostic markers, which predict outcome independent of treatment, may or may not have clinical value in terms of affecting treatment decisions. The second and considered medically necessary by this policy is as a predictive measure for response to chemotherapy, specifically TMZ. This second measure of clinical validity is more clinically relevant, because it may lead to alterations in treatment decisions based on the expected response. Futile treatments might be avoided, or more effective alternatives might be substituted in patients with poor response to TMZ.
Guidelines and Position Statements
World Health Organization
In 2016, World Health Organization revised its classification of tumors of the central nervous system so that diffusely infiltrating gliomas are grouped based on genetic driver mutations. Diffuse gliomas in the new classification include the former World Health Organization grade II and III astrocytic tumors, grade II and III oligodendrogliomas, grade IV glioblastomas, and diffuse gliomas of childhood.
The Association for Molecular Pathology
The Association for Molecular Pathology noted, “that there is sufficient evidence to support MGMT testing all glioma patients with a post-treatment imaging study suggesting progression/pseudo-progression.” The rationale for this position was that “retrospective determination of MGMT promoter methylation status in the pre-treated, original biopsies can be critical in the distinction of this post-treatment effect in patients with imaging consistent with progression/pseudo-progression to ensure that effective therapies are not inappropriately terminated under the false assumption of disease progression (versus the alternative diagnosis of transient good-prognosis pseudo-progression).”
National Comprehensive Cancer Network
Current National Comprehensive Cancer Network guidelines on central nervous system cancers (v.2.2020) support several treatment options based on the presence of methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. In patients over age 70 with good performance status and methylated MGMT promoter, the use of hypofractionated brain radiotherapy, plus concurrent and adjuvant temozolomide is a category 1 recommendation.
Testing for MGMT methylation analysis is not found in NCCN guidelines for Neuroendocrine and Adrenal tumors, Rectal Cancer, or Colon Cancer at this time.
Methylation analysis of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is medically necessary for individuals who meet the following criteria:
- They have a tumor type consistent with high-grade malignant glioma*; and
- Candidate for temozolomide therapy or radiotherapy; and
- Methylation results will be used to direct therapy choices (i.e., adjuvant therapy with temozolomide).
MGMT promoter methylation analysis is investigational in all other clinical scenarios including but not limitied to:
- Neuroendocrine and Adrenal tumors
- Colon Cancer
- Rectal Cancer
Histological characteristics of high-grade gliomas:
- Grade III: characterized by the presence of nuclear atypia with focal or dispersed anaplasia, significant proliferative activity and mitoses
- Grade IV: characterized by the presence of nuclear atypia, mitoses, microvascular proliferation, or necrosis
Grade III includes:
- Anaplastic astrocytoma, IDH-mutant (mutations in the IDH1 or IDH2 genes)
- Anaplastic oligoastrocytoma, IDH-mutant and 1p/19q codeletion
Grade IV includes:
- Glioblastoma, IDH-wildtype
- Glioblastoma, IDH-mutant
- Diffuse midline glioma, histone H3.3 K27M mutations
*For the purpose of this policy: grade III and IV glioma above also includes the following more specific classifications:
- astrocytic tumors
- anaplastic astrocytoma
- anaplastic pleomorphic xanthoastrocytoma
- ependymal tumors
- giant cell glioblastoma
- epitheliod glioblastoma
- other gliomas/mixed gliomas
- anaplastic ganglioglioma
Procedure Codes and Billing Guidelines:
To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.
- 81287 MGMT (o-6-methylguanine-DNA methyltranferase) (er, glioblastoma multiforme), methylation analysis
- Berghoff AS, Preusser M.(2012) Clinical neuropathology practice guide 06-2012: MGMT testing in elderly glioblastoma patients--yes, but how? Clin Neuropathol 2012; 31(6):405-8.
- Berghoff AS, Stefanits H, Woehrer A et al.(2013) Clinical neuropathology practice guide 3-2013: levels of evidence and clinical utility of prognostic and predictive candidate brain tumor biomarkers. Clin Neuropathol 2013; 32(3):148-58.
- Chamberlain MC.(2014) Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology. Jun 10 2014; 82(23):2147-2148. PMID 24912510
- Chen Y, Hu F, Zhou Y et al.(2013) MGMT promoter methylation and glioblastoma prognosis: a systematic review and meta-analysis. Arch Med Res 2013; 44(4):281-90.
- Collins VP, Ichimura K, Di Y, et al.(2014) Prognostic and predictive markers in recurrent high grade glioma; results from the BR12 randomised trial. Acta Neuropathol Commun. 2014; 2:68. PMID 24952577
- Dong X, Liu RY, Chen WD.(2014) Correlation of Promoter Methylation in the MGMT Gene with Glioma Risk and Prognosis: a Meta-Analysis. Mol Neurobiol. Jun 10 2014. PMID 24913835
- Elinzano H, Glantz M, Mrugala M, et al.(2015) PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244. Am J Clin Oncol. Dec 9 2015. PMID 26658237
- Fietkau R, Putz F, Lahmer G, et al.(2013) Can MGMT promoter methylation status be used as a prognostic and predictive marker for glioblastoma multiforme at the present time? A word of caution. Strahlenther Onkol. Dec 2013; 189(12):993-995. PMID 24177536
- Gilbert MR, Wang M, Aldape KD et al.(2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 2013; 31(32):4085-91.
- Hegi ME, Diserens AC, Gorlia T et al.(2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10):997-1003.
- Holdhoff M, Ye X, Blakeley JO et al.(2012) Use of personalized molecular biomarkers in the clinical care of adults with glioblastomas. J Neurooncol 2012; 110(2):279-85.
- Jain K. K. (2018). A Critical Overview of Targeted Therapies for Glioblastoma. Frontiers in oncology, 8, 419. doi:10.3389/fonc.2018.00419
- Kalkan R, Atli EI, Ozdemir M, et al.(2014) IDH1 mutations is prognostic marker for primary glioblastoma multiforme but MGMT hypermethylation is not prognostic for primary glioblastoma multiforme. Gene. Oct 14 2014; 554(1):81-86. PMID 25455102
- Kanemoto M, Shirahata M, Nakauma A, et al.(2014) Prognostic prediction of glioblastoma by quantitative assessment of the methylation status of the entire MGMT promoter region. BMC Cancer. 2014; 14:641. PMID 25175833
- Lee, A. et al. The utilization of MGMT promoter methylation testing in United States hospitals for glioblastoma and its impact on prognosis.
- Louis DN, Perry A, Reifenberger G, et al.(2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathol. Jun 2016; 131(6):803-820. PMID 27157931.
- Malmstrom A, Gronberg BH, Marosi C et al.(2012) Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 2012; 13(9):916-26.
- Minniti G, Scaringi C, Arcella A, et al.(2014) IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy. J Neurooncol. Jun 2014; 118(2):377-383. PMID 24748470
- Molenaar RJ, Verbaan D, Lamba S, et al.(2014) The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone. Neuro Oncol. Sep 2014; 16(9):1263-1273. PMID 24510240
- Myung JK, Cho HJ, Kim H, et al.(2014) Prognosis of glioblastoma with oligodendroglioma component is associated with the IDH1 mutation and MGMT methylation status. Transl Oncol. Dec 2014; 7(6):712-719. PMID 25500080
- Nabors LB, Fink KL, Mikkelsen T, et al.(2015) Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study Neuro Oncol. May 2015; 17(5):708-717. PMID 25762461
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Central Nervous System Cancers. V 1.2019
- NCCN (2020) NCCN Clinical Practice Guidelines in Oncology: Colon Cancers. Version 3.2020.;
- NCCN (2020) NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 2.2020.;
- NCCN (2020) NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. Version 1.2019.;
- NCCN (2020) NCCN Clinical Practice Guidelines in Oncology: Rectal Cancers. Version 4.2020
- Preusser M, Berghoff AS, Manzl C, et al.(2014) Clinical Neuropathology practice news 1-2014: pyrosequencing meets clinical and analytical performance criteria for routine testing of MGMT promoter methylation status in glioblastoma. Clin Neuropathol. Jan-Feb 2014; 33(1):6-14. PMID 24359605
- Preusser M, Elezi L, Hainfellner JA.(2008) Reliability and reproducibility of PCR-based testing of O6-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation status in formalin-fixed and paraffin-embedded neurosurgical biopsy specimens. Clin Neuropathol 2008; 27(6):388-90.
- Pulverer W, Hofner M, Preusser M, et al.(2014) A simple quantitative diagnostic alternative for MGMT DNA-methylation testing on RCL2 fixed paraffin embedded tumors using restriction coupled qPCR. Clin Neuropathol. Jan-Feb 2014; 33(1):50-60. PMID 23993306
- Quillien V, Lavenu A, Ducray F, et al.(2016) Validation of the high-performance of pyrosequencing for clinical MGMT testing on a cohort of glioblastoma patients from a prospective dedicated multicentric trial. Oncotarget. Sep 20,2016; 7(38):61916-61929. PMID 27542245
- Raizer JJ, Giglio P, Hu J, et al.(2015) A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients. J Neurooncol. Oct 17 2015. PMID 26476729
- Stupp R, Hegi ME, Gorlia T, et al.(2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. Sep 2014; 15(10):1100-1108. PMID 25163906
- Stupp R, Hegi ME, Mason WP et al.(2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10(5):459-66.
- Stupp R, Mason WP, van den Bent MJ et al.(2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10):987-96.
- Weathers, S. S., & Gilbert, M. R. (2017). Toward Personalized Targeted Therapeutics: An Overview. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 14(2), 256–264. doi:10.1007/s13311-016-0496-5
- Weise LM, Harter PN, Eibach S, et al.(2014) Confounding factors in diagnostics of MGMT promoter methylation status in glioblastomas in stereotactic biopsies. Stereotact Funct Neurosurg. 2014; 92(3):129-139. PMID 24776650
- Weller M, Stupp R, Reifenberger G et al.(2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 2010; 6(1):39-51.
- Wick W, Gorlia T, Bady P, et al.(2016) Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082). Clin Cancer Res. Oct 01 2016; 22(19):4797-4806. PMID 27143690
- Wick W, Meisner C, Hentschel B, et al.(2013) Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology. Oct 22 2013; 81(17):1515-1522. PMID 24068788
- Wick W, Platten M, Meisner C et al.(2012) Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 2012; 13(7):707-15.
- Wick W, Weller M, van den Bent M, et al.(2014) MGMT testing--the challenges for biomarker-based glioma treatment. Nat Rev Neurol. Jul 2014; 10(7):372-385. PMID 24912512
- Yang H, Wei D, Yang K, et al.(2014) The Prognosis of MGMT Promoter Methylation in Glioblastoma Patients of Different Race: A Meta-analysis. Neurochem Res. Dec 2014; 39(12):2277-2287. PMID 25230908
- Yin AA, Zhang LH, Cheng JX, et al.(2014) The predictive but not prognostic value of MGMT promoter methylation status in elderly glioblastoma patients: a meta-analysis. PLoS One. 2014; 9(1):e85102. PMID 24454798
- Tunthanathip T, Sangkhathat S, Tanvejsilp P, Kanjanapradit K. The clinical characteristics and prognostic factors of multiple lesions in glioblastomas [published online ahead of print, 2020 May 7]. Clin Neurol Neurosurg. 2020;195:105891. doi:10.1016/j.clineuro.2020.105891
- Marton E, Giordan E, Siddi F, et al. Over ten years overall survival in glioblastoma: A different disease?. J Neurol Sci. 2020;408:116518. doi:10.1016/j.jns.2019.116518
- Ius T, Pignotti F, Della Pepa GM, et al. Glioblastoma: from volumetric analysis to molecular predictors [published online ahead of print, 2020 Feb 4]. J Neurosurg Sci. 2020;10.23736/S0390-5616.20.04850-X. doi:10.23736/S0390-5616.20.04850-X
- Ye N, Jiang N, Feng C, et al. Combined Therapy Sensitivity Index Based on a 13-Gene Signature Predicts Prognosis for IDH Wild-type and MGMT Promoter Unmethylated Glioblastoma Patients. J Cancer. 2019;10(22):5536â€5548. Published 2019 Aug 29. doi:10.7150/jca.30614
- June 2020 - Annual Review, Policy Revised
- June 2019 - Annual Review, Policy Renewed
- June 2018 - New Policy
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