Archived Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Malignant Astrocytomas and Gliomas

Number:SUR703.042

Effective Date:07-15-2017

End Date:06-14-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Hematopoietic stem-cell transplantation is considered experimental, investigational and/or unproven as a treatment of malignant astrocytomas and gliomas, including both glioblastoma multiforme and oligodendroglioma.

NOTE: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.

Description:

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. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood 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 (GVHD).

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the Class I and Class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

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 that arise 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.

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 pineoblastomas. 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.

NOTE: The use of high-dose chemotherapy in tumors arising from the neuroepithelium is addressed separately in Medical Policy SUR703.039.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (15) Hematopoietic stem-cells are included in these regulations.

Rationale:

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell transplant (HSCT) (i.e., blood or marrow) is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, bone marrow, or umbilical cord blood stem-cells.

The literature search of the MedLine database for this medical policy was updated through May 2017. The following is a summary of the key literature to date.

Astrocytomas

A 2008 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. (1) 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 (OS) 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 2012 comprehensive review article identified in the literature search did not report any evidence for the role of HSCT in this disease. (2)

Gliomas

Bouffet et al. (3) reported on a series of 22 children and young adults with high-grade gliomas treated with autologous HSCT. The response rate was 29% with one complete and three partial responses. However, the authors concluded that survival with this procedure was no better than that reported with conventional treatments. Heideman et al. (4) reported on a case series of 13 pediatric patients with bulky disease or recurrent disease treated with HSCT plus radiotherapy. While the overall response rate was 31%, the authors similarly concluded that overall survival was no better than conventional treatment regimens. Finlay et al. (5) reported on a 1996 case series of 45 children and young adults with a variety of recurrent CNS tumors, including gliomas, medulloblastomas, ependymomas, and primitive neuroectodermal tumors. 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 five 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. (6, 7)

A 2001 review by Brandes et al. (8) concluded that the high drug doses used in this treatment caused excessive toxicity that was not balanced by a significant improvement in survival. Additional reports on small, uncontrolled series of patients with pontine gliomas (9), recurrent oligodendrogliomas, (10) or those undergoing radiation therapies for high-grade gliomas (11) also did not suggest that this treatment improves survival. In a 2006 Phase II study, Abrey et al. (12) evaluated hematopoietic stem-cell transplantation in 39 patients with newly diagnosed oligodendroglioma. The authors reported the median follow-up of surviving patients was 80.5 months and with 78 months progression-free survival. The OS median had not been reached and 18 patients (46%) had relapsed.

Recent studies on autologous HSCT are limited. However, one study was published by Egan et al. reporting on a specific HDC regimen followed by autologous HSCT for patients with recurrence of malignant brain tumors. (13) Twenty-seven patients aged 3-46 years were enrolled. Diagnoses included high-grade glioma (n=12); medulloblastoma/primitive neuro-ectodermal tumor (PNET) (n=9); central nervous system (CNS) germ cell tumor (n=4); ependymoma (n=1); and spinal cord PNET (n=1). Prolonged survival (life expectancy of >3 months) was noted in several patients including those with recurrent high-grade glioma, medulloblastoma and CNS germ cell tumor. The authors concluded continued study is needed, particularly for the chemotherapy regimen.

Ongoing and Unpublished Clinical Trials

Some currently ongoing trials that might influence this review is listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT00669669

O6-Benzylguanine-Mediated Tumor Sensitization with Chemo protected Autologous Stem Cell in Treating Patients with Malignant Gliomas

24

Dec 2017

NCT01505569

Auto Transplant for High-Risk or Relapsed Solid or CNS Tumors

20

Jan 2019

NCT00638898

Busulfan, Melphalan, Topotecan Hydrochloride, and Stem-Cell Transplant in Treating Newly Diagnosed or Relapsed Solid Tumor

25

Apr 2019

Table Key:

NCT: National Clinical Trial.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) Guidelines:

The 2016 NCCN Guidelines on Central Nervous System Tumors (v.1.2016) do not list hematopoietic HSCT as a treatment option for patients with astrocytomas or gliomas. (14)

Summary of Evidence

The data on the use of hematopoietic stem-cell transplantation (HSCT) for malignant astrocytomas and gliomas has in general shown no survival benefit compared to conventional therapy, with increased treatment-related toxicity. One small study emerged recently, with several more ongoing that may show some benefit. However, more additional studies are warranted to demonstrate positive outcomes of astrocytomas and gliomas following autologous HSCT. Therefore, HSCT is considered experimental, investigational and/or unproven for the treatment of malignant astrocytomas and gliomas, which includes both glioblastoma multiforme and oligodendroglioma.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. 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. Dec 2008; 51(6):806-11. PMID 18802947

2. Ricard D, Idbaih A, Ducray F, et al. Primary brain tumors in adults. Lancet. May 26 2012; 379(9830):1984-96. PMID 22510398

3. 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. Euro J Cancer. Jan 1997; 33(1):91-5. PMID 9071906

4. 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. Aug 1993; 11(8):1458-65. PMID 8336185

5. 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. Sep 1996; 14(9):2495-503. PMID 8823328

6. 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. Sep 1996; 18(suppl 1): S69-72. PMID 8899180

7. 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. Jul 1996; 18(1):143-9. PMID 8832007

8. 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. PMID 11291555

9. 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. Feb 1 2000; 88(3):685-92. PMID 10649264

10. Cairncross G, Swinnen L, Bayer R, et al. Myeloablative chemotherapy for recurrent aggressive oligodendroglioma. J Neuro-Oncol. Apr 2000; 2(2):114-9. PMID 11303620

11. 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 Neuro-Oncol. Aug 1999; 44(1):77-83. PMID 10582673

12. 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. J Neuro-Oncol. Apr 2006; 8(2):183-8. PMID 16524945

13. Egan G, Cervone KA, Philips PC, et al. Phase I study of temozolomide in combination with thiotepa and carboplatin with autologous hematopoietic cell rescue in patients with malignant brain tumors with minimal residual disease. Bone Marrow Transplant. Apr 2016; 51(4):542-5. PMID 26726947

14. NCCN – Central Nervous System Cancers – NCCN Clinical Practice Guidelines in Oncology, Version.1.2016. National Comprehensive Cancer Network. Available at <www.nccn.org> (accessed on June 15, 2017).

15. Food and Drug Administration (FDA). Tissue and Tissue Products. Available at <http://www.fda.gov> (accessed September 22, 2015).

16. Autologous Hematopoietic Stem-Cell Transplantation for Malignant Astrocytomas and Gliomas. (Archived) Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2013 July) Therapy 8.01.31.

Policy History:

Date Reason
7/15/2017 Document updated with literature review. Coverage unchanged.
6/1/2016 Reviewed. No changes.
1/15/2015 Document updated with literature review. Coverage language modified, without change to coverage position. CPT/HCPCS code(s) updated. Title changed from: Stem-Cell Transplant for Malignant Astrocytomas and Gliomas.
10/15/2013 Document updated with literature review. The following was added: 1) Donor leukocyte infusion and hematopoietic progenitor cell boost are considered experimental, investigational and unproven; and 2) Any related services for the treatment of malignant astrocytomas and gliomas, such as short tandem repeat (STR) markers, are considered experimental, investigational and unproven. O therwise, coverage unchanged. Description and Rationale significantly revised. Document title changed from Stem-Cell Transplant for Astrocytomas and Gliomas.
4/1/2010 New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem Cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies. Stem cell transplant remains experimental, investigational and unproved when used to treat astrocytomas and gliomas. NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem Cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies.

Archived Document(s):

Back to Top