Subject:
Alkylating Agent(s) [Temozolomide intravenous (Temodar®)]
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Temozolomide (Temodar®) is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine. Temodar® capsules for oral administration was first approved on 11th August 1999 for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine. Subsequently, in March 2005, it received its second indication for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. A 100 mg/vial powder was approved on February 27, 2009. The indications and doses are identical to the capsule and to be given as a 90 minute intravenous infusion.
Anaplastic astrocytoma is a malignancy affecting astrocytes in the brain. 6% of adult brain tumors are anaplastic astrocytomas with a 27% 5-year survival rate. Surgery is first-line treatment with radiation therapy as a standard adjuvant. Chemotherapy is given after radiation therapy. Glioblastomas are the most common and most lethal adult brain tumor, with a 5% 5-year survival rate. Surgery on these tumors often leads to recurrence and radiation therapy must be given adjunctively. Temodar® has been studied post-radiation therapy to increase survival, yet malignant gliomas eventually will progress even with chemotherapy.
Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)
A. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis.
B. Temozolomide (Temodar®) is medically necessary for the following FDA-approved indications:
- For the treatment of adult members with refractory anaplastic astrocytoma who have, experienced disease progression on a drug regimen containing a nitrosourea and procarbazine
- For the treatment of adult members with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.
C. The initial and continuation therapy with temozolomide (Temodar®), when medically necessary, will be covered for up to 6 months at the FDA-recommended dose for the following indications:
- Newly Diagnosed High Grade Glioma (Concomitant Phase): 75 mg/m2 daily for 42 days concomitant with focal radiotherapy followed by maintenance Temodar® for 6 cycles. Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. Subsequently, for cycles 2-6, the dose is escalated to 200 mg/m2, if the CTC non-hematologic toxicity for Cycle 1 is Grade ≤2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥1.5 x 109/L, and the platelet count is ≥100 x 109/L. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.
[INFORMATIONAL NOTE: During initiation, Temodar® dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: Absolute neutrophil count ≥1.5 x 109/L, Platelet count ≥100 x109/L, Common toxicity criteria (CTC) non-hematological toxicity ≤Grade 1 (except for alopecia, nausea and vomiting) ]
- Refractory Anaplastic Astrocytoma: 150 - 200 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle.
[INFORMATIONAL NOTE: For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are above 1.5 x 109/L (1500/µL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are above 100 x 109/L (100,000/µL), the Temodar® dose may be increased to 200 mg/m2/day for 5 consecutive days per 28-day treatment cycle.
For both indications, during treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of Temodar®) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L (1500/µL) and the platelet count exceeds 100 x 109/L (100,000/µL). The next cycle of Temodar® should not be started until the ANC and platelet count exceeds these levels.]
- For continuation therapy: member must continue to meet initial criteria, show response to treatment as indicated by stabilization of disease or decrease in tumor size/tumor spread, and have absence of unacceptable toxicities (e.g. myelosuppression such as neutropenia, thrombocytopenia, leukopenia, lymphopenia)
D. Temozolomide (Temodar®) is medically necessary for the following off-label uses:
- Bone Cancer - Ewing's Sarcoma, Mesenchymal chondrosarcoma: Preferred therapy when used in combination with irinotecan with or without vincristine in members
- With or without radiation therapy for relapse; OR
- For progressive disease following primary treatment; OR
- As second-line therapy for metastatic disease; OR
- Adult Intracranial and Spinal Ependymoma (excluding Subependymoma): Consider as single-agent treatment for progression or recurrent disease, if received prior RT and any of the following:
- Gross total or subtotal resection
- Localized recurrence
- Evidence of metastasis (brain, spine, or CSF)
- Adult Low-Grade Infiltrative Supratentorial Astrocytoma/Oligodendroglioma (excluding Pilocytic Astrocytoma): Treatment for recurrent or progressive low-grade disease with concurrent radiation followed by temozolomide alone
- Adult Medulloblastoma: recurrence therapy as a single agent for disease progression in patients who have received prior chemotherapy
- Anaplastic Gliomas:
- Adjuvant treatment as as a single agent
- with concurrent fractionated external beam radiation therapy (RT) followed by temozolomide alone for anaplastic oligodendroglioma (1p19q codeleted), anaplastic astrocytoma, or anaplastic oligoastrocytoma, NOS
- following fractionated external beam RT for anaplastic astrocytoma or anaplastic oligoastrocytoma, NOS
o Treatment of recurrent disease as a single agent or in combination with bevacizumab
- Glioblastoma:
- Adjuvant treatment following resection with or without carmustine polymer
- with concurrent radiation therapy followed by temozolomide alone for patients with good performance status (PS; Karnofsky Performance Status [KPS] ≥60); OR
- with concurrent standard brain radiation therapy (RT) followed by temozolomide alone plus alternating electric field therapy for patients with good performance status (PS) and Karnofsky Performance Status (KPS) ≥60
- concurrent with or after hypofractionated brain RT for patients ≤70 years with poor PS (KPS <60)
- with concurrent hypofractionated brain RT followed by temozolomide alone for patients >70 years with good PS (KPS ≥60)
- as chemotherapy alone for patients >70 years with good PS (KPS ≥60) and methylated MGMT promoter status
- Treatment of recurrent disease as a single agent or in combination with bevacizumab
- Limited Brain Metastases:
- Single-agent treatment for recurrent brain metastases in patients with stable systemic disease or reasonable systemic treatment options
- Extensive Brain Metastases:
- Single-agent treatment for recurrent brain metastases in patients with stable systemic disease or reasonable systemic treatment options
- Primary CNS Lymphoma:
- Induction therapy
- in combination with high-dose methotrexate and rituximab
- in combination with high-dose methotrexate and rituximab followed by post-RT temozolomide
- Consider for consolidation therapy in patients with complete response or complete response unconfirmed (CRu) to induction therapy
- in combination with high-dose methotrexate and rituximab
- in combination with high-dose methotrexate and rituximab followed by post-RT temozolomide
- Treatment as a single agent or in combination with rituximab for relapsed or refractory disease
- may be considered in patients who received prior whole brain radiation therapy
- in patients who received a prior high-dose methotrexate-based regimen without prior radiation therapy (RT) after previous response with long duration (≥12 months) to prior regimen
- in combination with whole brain RT or involved field RT in patients who received a prior high-dose methotrexate-based regimen without prior RT after no response or short response duration (<12 months) to prior regimen
- in patients who received prior high-dose chemotherapy with stem cell rescue after previous response with long duration (≥12 months)
- Cutaneous Melanoma: Therapy for metastatic or unresectable disease as second-line or subsequent therapy for disease progression or after maximum clinical benefit from BRAF targeted therapy
- Neuroendocrine Tumors of the Gastrointestinal Tract, Lung and Thymus (Carcinoid Tumors):
- Consider for management of locoregional (stage IIIA/B) thymic disease
- with radiation for incomplete resection and/or positive margins
- with or without radiation for locally unresectable disease
- Consider for management of locoregional bronchopulmonary disease
- for use without radiation for unresetable disease, and for use with radiation for unresectable intermediate grade (atypical) histology
- Management of locoregional advanced bronchopulmonary/thymic disease and/or distant metastases
- consider in select patients with intermediate grade (atypical) histology that are intermediate grade/atypical tumors with Ki-67 proliferative index and mitotic index in the higher end of the defined spectrum
- consider if progression on first-line therapy
- Consider for poorly controlled carcinoid syndrome(Lung and Thymus Only) in combination with
- either octreotide LAR or lanreotide for persistent symptoms (ie. flushing, diarrhea)
- telotristat for persistent diarrhea
- Neuroendocrine Tumors of the Pancreas
- For the management of bulky, symptomatic, and/or progressive locoregional advanced disease and/or distant metastatic disease
- as a single agent
- in combination with capecitabine
- Neuroendocrine and Adrenal Tumors - Poorly Differentiated (High Grade)/Large or Small Cell
- Primary treatment with or without capecitabine
- with or without radiation as neoadjuvant or adjuvant therapy, or chemotherapy alone for resectable disease
- for locoregional unresectable or metastatic disease
- Pheochromocytoma/Paraganglioma: Primary treatment as a single agent for distant metastases
- Small Cell Lung Cancer (SCLC): subsequent chemotherapy for patients with performance status 0-2 as a single agent for
- Relapse within 6 months following complete or partial response or stable disease with initial treatment; OR
- Primary progressive disease
- Angiosarcoma: single-agent palliative therapy for angiosarcoma
- Rhabdomyosarcoma: therapy for
- Pleomorphic rhabdomyosarcoma as single-agent palliative therapy; OR
- Nonpleomorphic rhabdomyosarcoma in combination with vincristine and irinotecan
- Solitary Fibrous Tumor/Hemangiopericytoma: in combination with bevacizumab for the treatment of solitary fibrous tumor and hemangiopericytoma
- Soft Tissue Sarcoma of the Extremity/Superficial Trunk, Head/Neck: single-agent palliative chemotherapy for synchronous stage IV or recurrent disease with disseminated metastases
- Soft Tissue Sarcoma - Retroperitoneal/Intra-Abdominal: Single-agent palliative chemotherapy for unresectable or progressive disease
- Uterine Sarcoma: single agent for:
- Recurrent or metastatic disease which has progressed following prior cytotoxic chemotherapy
- Uveal Melanoma: Consider as single agent therapy for distant metastatic disease
- Adult medulloblastoma
- Treatment for recurrence as a single agent in patients who have received prior chemotherapy
- Primary Cutaneous Lymphomas - Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders
- Therapy for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions, or cutaneous ALCL with regional nodes (excludes systemic ALCL), as a single agent for relapsed/refractory disease with CNS involvement
- Primary Cutaneous Lymphomas - Mycosis Fungoides/Sezary Syndrome Systemic therapy as treatment for CNS involvement with
- Stage IIB MF with limited tumor lesions refractory to multiple previous therapies, with or without skin-directed therapy
- Relapsed or refractory stage IIB MF with generalized tumor lesions, with or without skin-directed therapies
- Stage IIB MF with generalized tumor lesions that is refractory to multiple previous therapies or progression
- Relapsed or persistent stage III MF, with or without skin-directed therapies
- Stage III MF that is refractory to multiple previous therapies
- Relapsed or persistent stage IV Sezary syndrome
- Relapsed or persistent stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control
- Large cell transformation (LCT) with limited cutaneous lesions that is refractory to multiple previous therapies
- Relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy
E. The use of temozolomide (Temodar®) is considered investigational in all other conditions including but not limited to:
Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.
Medicaid Coverage:
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Alkylating Agent
Temozolomide
Temodar
References:
1. Addeo R, Caraglia M, Faiola V, et al. Concomitant treatment of brain metastasis with Whole Brain Radiotherapy (WBRT) and Temozolomide (TMZ) is active and improves Quality of Life. BMC Cancer 2007;7-18.
2. AHFS Drug Information. American Society of Health-System Pharmacists, Inc. 2008.
3. Bafaloukos D, Tsoutsos D, Kalofonos H et al. Temozolomide and cisplatin versus temozolomide in patients with advanced melanoma : a randomized phase II study of the Hellenic Cooperative Oncology Group. Annals of Oncology 2005;16:950-957.
4. Boogerd W, de Gast GC, Dalesio O et al. Temozolomide in advanced malignant melanoma with small brain metastases- Can we withhold cranial irradiation Cancer 2007;109:306-12.
5. Caraglia M, Addeo R, Costanzo R et al. Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumors. Cancer Chemother Pharmacol 2006;57:34-39.
6. De Sio L, Milano GM, Castellano A, et al. Temozolomide in resistant or relapsed pediatric solid tumors. Pediatr Blood Cancer 2006;47:30-36.
7. Garcia M, del Muro XG, Tres A et al. Phase II multicenter study of temozolomide in combination with interferon alpha-2b in metastatic malignant melanoma. [Abstract] Melanoma Research 2006;16:365-370.
8. Gogas H, Polyzos A, Stavrinidis I et al. Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group. Annals of Oncology 2006;17:1835-41.
9. Hofmann M, Kiecker F, Wurm R et al. Temozolomide with or without radiotherapy in melanoma with unresectable brain metastases. Journal of Neuro-Oncology 2006;76:59-64.
10. Hwu W, Lis E, Menell JH, et al. Temzolomide plus thalidomide in patients with brain metastases from melanoma. Cancer 2005;103:2590-97.
11. Hwu W, Panageas KS, Menell JH et al. Phase II study of temozolomide plus pegylated interferon-á-2b for metastatic melanoma. Cancer 2006;106:2445-51.
12. Kaufmann R, Spieth K, Leiter U et al. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol 2005; 23:9001-07.
13. Krown SE, Niedzwiecki D, Hwu W et al. Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain. Cancer 2006; 107: 1883-90.
14. Kushner BH, Kramer K, Modak S, et al. Irinotecan plus temozolomide for relapsed or refractory neuroblastoma. J Clin Oncol 2006:24:5271-76.
15. Laber DA, Okeke RI, Arce-Lara C, et al. A phase II study of extended dose temozolomide and thalidomide in previously treated patients with metastatic melanoma. J Cancer Res Clin Oncol 2006;132:611-16.
16. Micromedex Health Series. Thomson Gateway. [Available at: http://www.thomsonhc.com/hcs/librarian/PFPUI/AH1fgpoxqU9YR]
17. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Melanoma. Version 1.2020. Available at http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf.
18. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Central Nervous System Cancers. Version 1.2020. Available at http://www.nccn.org/professionals/physician_gls/PDF/cns.pdf.
19. Ranson M, Hersey P, Thompson D et al. Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naïve patients with metastatic cutaneous melanoma. J Clin Oncol 25:2540-45.
20. Rubie H, Chisholm J, Defachelles AS, et al. Phase II study of temozolomide in relapsed or refractory high-risk neurobblastoma : a joint Societe Francaise des Cancers de l’Enfant and United Kingdom Children Cancer Study Group- New Agents Group Study. J Clin Oncol 2006;24:5259-64.
21. Schadendorf D, Hauschild A, Ugurel S et al. Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study. Annals of Oncology 2006;17:1592-97.
22. Temodar® (Temozolomide) Prescribing Information. Schering Corporation. Kenilworth, NJ 10/2017.
23. Temozolomide. National Comprehensive Cancer Network: Drugs and Biologics Compendium. [Available at http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/HTML/Temozolomide.asp (accessed 1/2020).]
24. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Neuroendocrine Tumors. Version 1.2020. Available at http://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf (accessed 1/2020)
25. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: T-Cell Lymphoma. Version 1.2020. Available at: https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf. (Accessed 1/2020).
26. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Central Nervous System Cancers. Version 1.2020. Available at http://www.nccn.org/professionals/physician_gls/ pdf/cns.pdf (accessed 1/2020)
27. Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004;22:2101-2107.
28. Jordon T, Cushing T, and Dietrich J. Treatment of Pituitary Tumors with Temozolomide: A Case Series. Neurology. 2014;82(10 Supplement):P3-330.
29. Temozolomide. National Comprehensive Cancer Network: Drugs and Biologics Compendium. [Available at http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/HTML/Temozolomide.asp (accessed 1/202019).]
30. Temodar. Clinicaltrial.gov. Accessed on 1/16/20. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=temodar&cntry=&state=&city=&dist=
31. Temodar - PubMed - NCBI.” Current Neurology and Neuroscience Reports., U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/pubmed.
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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