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. Bone marrow stem cells may be obtained from the transplant recipient (autologous HSCT) and can be harvested from bone marr, 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 No. 70150.

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 three 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 two-three 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 two 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 three 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.

Policy:
Autologous hematopoietic stem-cell transplantation is INVESTIGATIONAL as a treatment of malignant astrocytomas and gliomas. (The latter diagnosis includes both glioblastoma multiforme and oligodendroglioma.)

Benefit Application:
BlueCard/National Account Issues
The following considerations may supersede this policy:

• State mandates requiring coverage for autologous hematopoietic stem-cell transplantation (HSCT) offered as part of clinical trials of HSCT approved by the National Institutes of Health (NIH).
• Some Plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapies, including autologous HSCT.
• Some contracts or certificates of coverage (e.g., FEP) may include specific conditions in which autologous HSCT would be considered eligible for coverage.

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 percent, 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 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 percent, 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 percent. 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.^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 oligodendrogliomas⁸ or those undergoing radiation therapy for high-grade gliomas⁹ 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 percent) 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, five (18 percent) succumbed to treatment-related toxicities within approximately two months of transplantation, 17 (63 percent) had disease progression while five survived and were alive a median of 11 years (range: 8 – 13 years) after transplantation. Overall survival rates at four years were 40 ± 14 percent for transplant patients versus seven ± 4 percent with conventional chemotherapy (p = 0.018, hazard ratio [HR]: 1.9; 95 percent 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.

An updated literature search in July 2012 identified no controlled studies that would change the conclusions of this policy. A comprehensive review article identified in the search did not report any evidence for the role of HSCT in this disease.¹² Thus, the policy statement is unchanged.

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.

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Cairncross G, Swinnen L, Bayer R et al. Myeloablative chemotherapy for recurrent aggressive oligodendroglioma. Neuro Oncol 2000; 2(2):114-9.
9. 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.
10. 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.
11. 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.
12. Ricard D, Idbaih A, Ducray F et al. Primary brain tumours in adults. Lancet 2012; 379(9830):1984-96.

Coding Section

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. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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