Subject:
Autologous Hematopoietic Cell Transplantation for Malignant Astrocytomas and Gliomas
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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Malignant glial tumors are usually resistant to conventional treatment approaches. Autologous hematopoietic stem-cell transplantation has been investigated as a treatment for malignant astrocytomas and gliomas.
Background
Hematopoietic Stem-Cell Transplantation
Hematopoietic stem-cell transplantation (HSCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole-body radiation therapy. Bone marrow stem cells may be obtained from the transplant recipient (autologous HSCT) and can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease. Cord blood is discussed in greater detail in Policy # 012 - Cord Blood as a Source of Stem Cells (Policy #012) under the Surgery Section of this database.
Preparative Conditioning for Hematopoietic Stem-Cell Transplantation
Autologous HSCT necessitates myeloablative chemotherapy to eradicate cancerous cells from the blood and bone marrow, thus permitting subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic progenitor cells. As a consequence, autologous HSCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment but not graft-versus-host disease.
Astrocytomas and Gliomas
Diffuse fibrillary astrocytomas are the most common type of brain tumor in adults. These tumors are classified histologically into 3 grades of malignancy: grade II astrocytoma, grade III anaplastic astrocytoma, and grade IV glioblastoma multiforme. Oligodendrogliomas are diffuse neoplasms that are clinically and biologically most closely related to diffuse fibrillary astrocytomas. However, these tumors generally have better prognoses than diffuse astrocytomas, with mean survival times of 10 years versus 2–3 years, respectively. In addition, oligodendrogliomas appear to be more chemosensitive than other types of astrocytomas. Glioblastoma multiforme is the most malignant stage of astrocytoma, with survival times of less than 2 years for most patients.
Treatment of primary brain tumors focuses on surgery, either with curative intent or optimal tumor debulking. Surgery may be followed by radiation therapy and/or chemotherapy. Survival after chemoradiotherapy is largely dependent on the extent of residual tumor after surgical debulking. Therefore, tumors arising in the midline, basal ganglia, or corpus callosum or those arising in the eloquent speech or motor areas of the cortex, which typically cannot be extensively resected, have a particularly poor outcome. Treatment of children younger than 3 years is complicated by the long-term effects of radiation therapy on physical and intellectual function. Therefore, in young children, radiation of the central nervous system (CNS) is avoided whenever possible.
Note: Astrocytomas and gliomas arise from the glial cells. Tumors arising from the neuroepithelium constitute a separate category of malignancies that include CNS neuroblastoma, medulloblastoma, ependymoblastomas, and pinealoblastomas. Collectively these tumors may be referred to as primitive neuroectodermal tumors (PNETs). Ependymomas also arise from the neuroepithelium but, because of their more mature histologic appearance, are not considered a member of the PNET family. The use of high-dose chemotherapy in tumors arising from the neuroepithelium is addressed separately in policy policy # 044 (Hematopoietic Stem Cell Transplantation for CNS Embryonal Tumors and Ependymoma).
Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
I. The guiding principle of this policy is the New Jersey State Mandate on High Dose Chemotherapy and Autologous Bone Marrow (ABMT) or Peripheral Stem Cell Transplant (PSCT).
The ensuing statements represent the interpretation of the law by Horizon Blue Cross Blue Shield of New Jersey (Horizon BCBSNJ) which must be strictly observed when handling pre-authorizations, claims, inquiries, and other matters pertaining to high-dose chemotherapy with stem cell support:
A. The law only applies to autologous bone marrow or peripheral stem cell transplant for the treatment of cancer. Medical necessity criteria must NOT be applied to these cases. They are automatically eligible for coverage under the law.
[INFORMATIONAL NOTE: Please note that self-insured accounts are exempt from the law. However, they have the option to adopt the law upon renewal of the contract.
Policy Statement II of this policy deals with eligibility and medical necessity criteria which must be applied specifically to those self-insured accounts which opted NOT to adopt the law.]
B. In cases of multiple, repeat, or tandem autologous bone marrow or peripheral stem cell transplant procedures for the same member, the first or initial transplant is automatically covered under the law. However, subsequent transplant procedures are NOT automatically covered under the law but are subject to medical necessity criteria.
C. The law applies to contracts delivered, issued, executed or renewed in New Jersey. Services rendered outside New Jersey are covered by the law as long as the member has a contract that is written or issued in New Jersey.
D. Exclusions to the law:
Policy Statement II of this policy addresses medical necessity criteria as it applies to the following requests for:
- an allogeneic bone marrow or peripheral stem cell transplant.
- treatment of non-cancerous conditions even if it involves autologous bone marrow or peripheral stem cell transplant.
- mini-transplants or non-myeloablative transplants since they are allogeneic transplants.
II. The following criteria are only applicable to self-insured accounts which opted NOT to adopt the law (or other contracts which may be exempt from the law) and any other applicable exclusions to the law as enumerated in the above Policy Statement I.D. (i.e., allogeneic bone marrow or allogeneic peripheral stem cell transplant):
[INFORMATIONAL NOTE: Also refer to a separate policy on Cord Blood as a Source of Stem Cells (Policy #012) under the Surgery Section of this database.]
A. This procedure is subject to the specific terms of the member's contract.
[Also refer to a separate policy on Transplant Donor and Recipient Policy (Policy #003) under the Surgery Section of this database.]
B. Medical necessity is established based on review of the following information:
1. Stage to which the malignancy has progressed;
2. Clinical history of the member including results of diagnostic procedures performed (i.e., laboratory, pathology, radiology), and previous modes of therapy with results;
3. Treatment protocol of the facility where the procedure is being performed.
C. Autologous hematopoietic stem cell transplantation is considered investigational as a treatment of malignant astrocytomas and gliomas. (The latter diagnosis includes both glioblastoma multiforme and oligodendroglioma.)
Before making a determination that this procedure is investigational, please refer to Policy Statement I of this policy for the applicability of the New Jersey State Law on High Dose Chemotherapy (HDC) and Autologous Bone Marrow Transplant (BMT) or Peripheral Stem Cell Transplant (PSCT).
[Please refer to a separate policy on Hematopoietic Stem Cell Transplantation for CNS Embryonal Tumors and Ependymoma (Policy #044) under the Treatment Section of this database.
Medicare Coverage:
Autogolous HSCT (AuSCT) is not considered reasonable and necessary under §l862(a)(1)(A) of the Social Security Act and is not covered under Medicare (NCD 110.23 effective 10/03/2016) for individuals with Malignant Astrocytomas and Gliomas. CMS has determined that insufficient data exists to establish definite conclusions regarding the efficacy of AuSCT for solid tumors other than neuroblastoma. See NCD 110.23: Available at: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=366&ncdver=1&bc=AgAAgAAAAAAAAA%3d%3d&.
Medicaid Coverage:
FIDE-SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
[RATIONALE: The published literature consists primarily of single-institution case series.
Bouffet and colleagues reported on a series of 22 children and young adults with high-grade gliomas treated with autologous hematopoietic stem-cell transplantation (HSCT).(1) The response rate was 29% with 1 complete and 3 partial responses. However, the authors concluded that survival with this procedure was no better than that reported with conventional treatments. Heideman and colleagues reported on a case series of 13 pediatric patients with bulky disease or recurrent disease treated with HSCT plus radiotherapy.(2) While the overall response rate was 31%, the authors similarly concluded that overall survival was no better than conventional treatment regimens. Finlay and colleagues reported on a 1996 case series of 45 children and young adults with a variety of recurrent central nervous system (CNS) tumors, including gliomas, medulloblastomas, ependymomas, and primitive neuroectodermal tumors.(3) Of the 18 patients with high-grade gliomas, the response rate was 29%. The median survival of this group was 12.7 months. Of the 5 long-term survivors, all had high-grade glioma with minimal residual disease at the time of transplantation. Based in part on these results, the authors recommended aggressive surgical debulking before this procedure is even considered. Studies focusing on the use of autologous HSCT in adults with glioblastoma multiforme reported results similar to those in children, being most successful in those with minimal disease at the time of treatment, with an occasional long-term survivor.(4, 5)
A review by Brandes and colleagues concluded that the high drug doses used in this treatment caused excessive toxicity that was not balanced by a significant improvement in survival.(6) Additional reports on small, uncontrolled series of patients with pontine gliomas,(7) recurrent oligodendrogliomas,(8) or those undergoing radiation therapy for high-grade gliomas (9) also did not suggest that this treatment improves survival. In a Phase II study, Abrey and colleagues evaluated hematopoietic stem-cell transplantation in 39 patients with newly diagnosed oligodendroglioma.(10) The authors reported the median follow-up of surviving patients was 80.5 months, with 78 months progression-free survival. The overall survival median had not been reached, and 18 patients (46%) had relapsed.
A nonrandomized study compared survival outcomes of 27 children (age, 0.4–22 years) with recurrent malignant astrocytomas who underwent myeloablative chemotherapy and autologous HSCT with outcomes in a matched historical cohort (n=56) that received standard chemotherapy regimens following tumor recurrence.(11) Among the 27 children who received myeloablative chemotherapy and autologous HSCT, 5 (18%) succumbed to treatment-related toxicities within approximately 2 months of transplantation, 17 (63%) had disease progression, while 5 survived and were alive a median of 11 years (range: 8–13 years) after transplantation. Overall survival rates at 4 years were 40 ± 14% for transplant patients versus 7 ± 4% with conventional chemotherapy (p=0.018, hazard ratio [HR]: 1.9; 95% confidence interval [CI]: 1.1–3.2). The results of this study suggest myeloablative chemotherapy with autologous HSCT can produce long-term survival among children with recurrent malignant astrocytoma. However, lack of a contemporaneous treatment comparison group precludes conclusions as to the relative efficacy of this approach.
A comprehensive review article identified in the search did not report any evidence for the role of HSCT in this disease. (12)
Summary
The data on the use of autologous hematopoietic stem-cell transplantation for malignant astrocytomas and gliomas, consisting of case series, has, in general, shown no survival benefit compared to conventional therapy with increased treatment-related toxicity. Therefore, this is considered investigational for this indication.
National Cancer Institute Physician Data Query (PDQ) Clinical Trials Database
A search in June 2013 found one active U.S. Phase II trial of hematopoietic stem-cell transplantation for newly diagnosed central nervous system tumors, including glioblastoma multiforme and gliosarcoma (NCT00669669). This study is currently recruiting participants (N=24) with the estimated completion date of February 2017.
National Comprehensive Cancer Network (NCCN) Guidelines
The 2019 NCCN Guidelines on Central Nervous System Cancers (Version 1.2019) do not list hematopoietic stem-cell transplantation as a treatment option for patients with astrocytomas or gliomas.
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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:
Autologous Hematopoietic Cell Transplantation for Malignant Astrocytomas and Gliomas
Hematopoietic Cell Transplantation for Malignant Astrocytomas and Gliomas
Hematopoietic Stem Cell Transplantation for Malignant Astrocytomas and Gliomas
High Dose Chemotherapy with Hematopoietic Stem Cell Support for Malignant Astrocytomas and Gliomas
Allogeneic Bone Marrow Transplant, Malignant Astrocytomas and Gliomas
Astrocytoma, High Dose Chemotherapy
Autologous Bone Marrow Transplant, Malignant Astrocytomas and Gliomas
Bone Marrow Transplant, Malignant Astrocytomas and Gliomas
Glioblastoma Multiforme, High Dose Chemotherapy
Glioma, High Dose Chemotherapy
Malignant Astrocytoma, High Dose Chemotherapy
Oligodendroglioma, High Dose Chemotherapy
Stem Cell Transplant, Malignant Astrocytomas and Gliomas
Transplantation, Bone Marrow/Stem Cell for Malignant Astrocytomas and Gliomas
References:
1. New Jersey State Mandate P.L. 1995, c. 100 (C.17:48-6k) approved May 9, 1995, which requires health insurers to offer benefits for certain treatment of cancer under certain conditions and supplementing several New Jersey Statutes.
2. Bouffet E, Mottolese C, Jouvet A et al. Etoposide and thiotepa followed by ABMT (autologous bone marrow transplantation) in children and young adults with high-grade gliomas. Eur J Cancer 1997; 33(1):91-5.
3. Heideman RL, Douglass EC, Krance RA et al. High-dose chemotherapy and autologous bone marrow rescue followed by interstitial and external-beam radiotherapy in newly diagnosed pediatric malignant gliomas. J Clin Oncol 1993; 11(8):1458-65.
4. Finlay JL, Goldman S, Wong MC et al. Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children's Cancer Group. J Clin Oncol 1996; 14(9):2495-503.
5. Linassier C, Benboubker L, Velut S et al. High-dose BCNU with ABMT followed by radiation therapy in the treatment of supratentorial glioblastoma multiforme. Bone Marrow Transplant 1996; 18 Suppl 1:S69-72.
6. Fernandez-Hidalgo OA, Vanaclocha V, Vieitez JM et al. High-dose BCNU and autologous progenitor cell transplantation given with intra-arterial cisplatinum and simultaneous radiotherapy in the treatment of high-grade gliomas: benefit for selected patients. Bone Marrow Transplant 1996; 18(1):143-9.
7. Brandes AA, Palmisano V, Pasetto LM et al. High-dose chemotherapy with bone marrow rescue for high-grade gliomas in adults. Cancer Invest 2001; 19(1):41-8.
8. Bouffet E, Raquin M, Doz F et al. Radiotherapy followed by high dose busulfan and thiotepa: a prospective assessment of high dose chemotherapy in children with diffuse pontine gliomas. Cancer 2000; 88(3):685-92.
9. Cairncross G, Swinnen L, Bayer R et al. Myeloablative chemotherapy for recurrent aggressive oligodendroglioma. Neuro Oncol 2000; 2(2):114-9.
10. Jakacki RI, Siffert J, Jamison C et al. Dose-intensive, time-compressed procarbazine, CCNU, vincristine (PCV) with peripheral blood stem cell support and concurrent radiation in patients with newly diagnosed high-grade gliomas. J Neurooncol 1999; 44(1):77-83.
11. Abrey LE, Childs BH, Paleologos N et al. High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma: long-term follow-up. Neuro Oncol 2006; 8(2):183-8.
12. Finlay JL, Dhall G, Boyett JM et al. Myeloablative chemotherapy with autologous bone marrow rescue in children and adolescents with recurrent malignant astrocytoma: outcome compared with conventional chemotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer 2008; 51(6):806-11.
13. Ricard D, Idbaih A, Ducray F et al. Primary brain tumours in adults. Lancet 2012; 379(9830):1984-96.
14. Massimino M, Cohen KJ, Finlay JL. Is there a role for myeloablative chemotherapy with autologous hematopoietic cell rescue in the management of childhood high-grade astrocytomas? Pediatr Blood Cancer 2010 Apr;54(4):641-3.
15. UpToDate. Experimental treatment approaches for high-grade gliomas. Literature review current through May 2016; topic last updated March 17, 2016.
16. National Comprehensive Cancer Network (NCCN) Guidelines. Central Nervous System Cancers. Version 1.2015, 05/01/2015.
17. UpToDate. Management of recurrent high-grade gliomas. Literature review current through April 2016; topic last updated April 28, 2016.
18. Batchelor T, Shih HA, Carter BS. Management of recurrent high-grade glioma. In: UpToDate, Loeffler JS, Wen PY, Eichler AF (Eds), UpToDate, Waltham, MA. (Accessed April 10, 2017.)
19. Adair, J. E., et al. (2014). Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. J Clin Invest 124(9): 4082-4092.
20. Batchelor T, Shih HA, Carter BS. Management of recurrent high-grade glioma. In: UpToDate, Loeffler JS, Wen PY, Eichler AF (Eds), UpToDate, Waltham, MA. (Accessed March 11, 2019.)
21. NCCN Clinical Practice Guidelines in Oncology. Central Nervous System Cancers. Version 1.2019 - March 5, 2019. NCCN.Org
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*
38204
38206
38208
38209
38210
38211
38212
38213
38214
38215
38220
38221
38230
38232
38241
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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