|MP 8.01.28||Hematopoietic Stem-cell Transplantation for CNS Embryonal Tumors and Ependymoma|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/11:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
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. Bone-marrow stem cells may be obtained from the transplant recipient (ie, autologous HSCT) or from a donor (ie, allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates.
Hematopoietic Stem-Cell Transplantation for Brain Tumors
Autologous HSCT allows for escalation of chemotherapy doses above those limited by myeloablation and has been tried in patients with high-risk brain tumors in an attempt to eradicate residual tumor cells and improve cure rates. The use of allogeneic HSCT for solid tumors does not rely on escalation of chemotherapy intensity and tumor reduction but rather on a graft-versus-tumor (GVT) effect. Allogeneic HSCT is not commonly used in solid tumors and may be used if an autologous source cannot be cleared of tumor or cannot be harvested.
CNS Embryonal Tumors
Classification of brain tumors is based on both histopathologic characteristics of the tumor and location in the brain. Central nervous system (CNS) embryonal tumors are more common in children and are the most common brain tumor in childhood. CNS embryonal tumors are primarily composed of undifferentiated round cells, with divergent patterns of differentiation. It has been proposed that these tumors be merged under the term primitive neuroectodermal tumor (PNET); however, histologically similar tumors in different locations in the brain demonstrate different molecular genetic alterations. Embryonal tumors of the CNS include medulloblastoma, medulloepithelioma, supratentorial PNETs (pineoblastoma, cerebral neuroblastoma, ganglioneuroblastoma), ependymoblastoma, and atypical teratoid/rhabdoid tumor (AT/RT).
Medulloblastomas account for 20% of all childhood CNS tumors. The other types of embryonal tumors are rare by comparison. Surgical resection is the mainstay of therapy with the goal being gross total resection with adjuvant radiation therapy, as medulloblastomas are very radiosensitive. Treatment protocols are based on risk stratification, as average or high risk. The average-risk group includes children older than 3 years, without metastatic disease, and with tumors that are totally or near totally resected (<1.5 cm² of residual disease). The high-risk group includes children aged 3 years or younger, or with metastatic disease, and/or subtotal resection (>1.5 cm 2 of residual disease).(1)
Current standard treatment regimens for average-risk medulloblastoma (postoperative craniospinal irradiation with boost to the posterior fossa followed by 12 months of chemotherapy) have resulted in 5-year overall survival (OS) rates of 80% or better.(1) For high-risk medulloblastoma treated with conventional doses of chemotherapy and radiotherapy, the average event-free survival (EFS) at 5 years ranges from 34 to 40% across studies.(2) Fewer than 55% of children with high-risk disease survive longer than 5 years. The treatment of newly diagnosed medulloblastoma continues to evolve, and in children younger than age 3 years, because of the concern of the deleterious effects of craniospinal radiation on the immature nervous system, therapeutic approaches have attempted to delay and sometimes avoid the use of radiation and have included trials of higher-dose chemotherapeutic regimens with autologous HSCT.
Supratentorial PNETs (sPNET) are most commonly located in the cerebral cortex and pineal region. The prognosis for these tumors is worse than for medulloblastoma, despite identical therapies.(2) After surgery, children are usually treated similarly to children with high-risk medulloblastoma. Three- to 5-year OS rates of 40 to 50% have been reported, and for patients with disseminated disease, survival rates at 5 years range from 10 to 30%.(3)
Recurrent childhood CNS embryonal tumor is not uncommon, and depending on which type of treatment the patient initially received, autologous HSCT may be an option. For patients who receive high-dose chemotherapy and autologous HSCT for recurrent embryonal tumors, objective response is 50 to 75%; however, long-term disease control is obtained in fewer than 30% of patients and is primarily seen in patients in first relapse with localized disease at the time of relapse.(3)
Ependymoma is a neuroepithelial tumor that arises from the ependymal lining cell of the ventricles and is, therefore, usually contiguous with the ventricular system. An ependymoma tumor typically arises intracranially in children, while in adults a spinal cord location is more common. Ependymomas have access to the cerebrospinal fluid and may spread throughout the entire neuroaxis. Ependymomas are distinct from ependymoblastomas due to their more mature histologic differentiation. Initial treatment of ependymoma consists of maximal surgical resection followed by radiotherapy. Chemotherapy usually does not play a role in the initial treatment of ependymoma. However, disease relapse is common, typically occurring at the site of origin. Treatment of recurrence is problematic; further surgical resection or radiation therapy is usually not possible. Given the poor response to conventional-dose chemotherapy, high-dose chemotherapy with autologous HSCT has been investigated as a possible salvage therapy.
Note: Other CNS tumors include astrocytoma, oligodendroglioma, and glioblastoma multiforme. However, these tumors arise from glial cells and not neuroepithelial cells. These tumors are considered separately in policy No. 8.01.31
Note: Due to their neuroepithelial origin, peripheral neuroblastoma and Ewing’s sarcoma may be considered PNETs. However, these peripheral tumors are considered separately in policy No. 8.01.34.
Embryonal Tumors of the CNS
Autologous hematopoietic stem-cell transplantation may be considered medically necessary as consolidation therapy for previously untreated embryonal tumors of the central nervous system (CNS) that show partial or complete response to induction chemotherapy, or stable disease after induction therapy (see Policy Guidelines).
Autologous hematopoietic stem-cell transplantation may be considered medically necessary to treat recurrent embryonal tumors of the CNS.
Tandem autologous hematopoietic stem-cell transplant is investigational to treat embryonal tumors of the CNS.
Allogeneic hematopoietic stem-cell transplantation is investigational to treat embryonal tumors of the CNS.
Autologous, tandem autologous and allogeneic hematopoietic stem-cell transplant is investigational to treat ependymoma.
BlueCard/National Account Issues
- State mandates requiring coverage for autologous bone marrow transplantation offered as part of NIH-approved clinical trials of autologous bone marrow transplantation.
- Some plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapies, including autologous bone marrow transplantation.
- Some contracts or certificates of coverage (e.g., FEP) may include specific conditions in which autologous bone marrow transplantation would be considered eligible for coverage.
This policy was originally created in December 1998 and was updated regularly with searches of the MEDLINE database. The most recent literature search was performed through October 8, 2013. Following is the summary of the key literature to date.
Central Nervous System Embryonal Tumors
Newly Diagnosed Central Nervous System Embryonal Tumors
Supartentorial Primitive Neuroectodermal Tumor
Chintagumpala et al. reviewed event-free survival (EFS) of 16 patients with newly diagnosed supratentorial primitive neuroectodermal tumor (sPNET) treated with risk-adapted craniospinal irradiation and subsequent high-dose chemotherapy with autologous hematopoietic stem-cell transplantation (HSCT) between 1996 and 2003.(4) Eight patients were considered at average risk, and 8 were at high risk (defined as the presence of residual tumor larger than 1.5 cm 2 or disseminated disease in the neuroaxis). Median age at diagnosis was 7.9 years (range, 3-21 years). Seven patients had pineal primitive neuroectodermal tumor (PNET). After a median follow-up of 5.4 years, 12 patients were alive. Five-year EFS and overall survival (OS) for the patients with average-risk disease were 75% (±17%) and 88% (±13%), respectively, and for the high-risk patients 60% (±19%) and 58% (±19%), respectively. No treatment-related toxicity deaths were reported. The authors concluded that high-dose chemotherapy with stem-cell support after risk-adapted craniospinal irradiation allows for a reduction in the dose of radiation needed to treat nonmetastatic, average-risk sPNET, without compromising EFS.
Fangusaro et al. reported outcomes for 43 children with newly diagnosed sPNET treated prospectively in 2 serial studies (Head Start 1 [HS1] and Head Start 2 [HS2]) between 1991 and 2002 with intensified induction chemotherapy followed by myeloablative chemotherapy and autologous HSCT.(2) There were no statistical differences between HS1 and HS2 patient demographics. After maximal surgical resection, patients underwent induction chemotherapy. If, after induction, the disease remained stable or there was partial or complete response, patients underwent myeloablative chemotherapy with autologous HSCT (n=32). Patients with progressive disease at the end of induction were not eligible for consolidation. Five-year EFS and OS were 39% (95% confidence interval [CI], 24 to 53%) and 49% (95% CI, 33 to 62%), respectively. Patients with nonpineal tumors did significantly better than patients with pineal PNETs (2-year and 5-year EFS of 57% vs 23% and 48% vs 15%, respectively, and 2-year and 5-year OS of 70% vs 31% and 60% vs 23%, respectively). Sixty percent of survivors were alive without exposure to radiation therapy.
Massimino et al reported outcomes for 28 consecutive patients with noncerebellar PNET treated from 2000 to 2011 with a high-dose drug schedule (methotrexate, etoposide, cyclophosphamide, carboplatin with or without vincristine) with autologous stem-cell rescue, followed by 1 of 2 radiation treatment options.(5) For the first 15 patients, HDC and stem-cell rescue was followed by hyperfractionated accelerated craniospinal irradiation (CSI) with 2 high-dose thiotepa courses following CSI (for the 1st 15 patients); for subsequent cases, CSI was replaced with focal radiotherapy for patients whose tumors were nonmetastatic and not progressing during induction chemotherapy. Three- and 5-year progression-free survival (PFS) rates were 69±9% and 62±10%, respectively; 3- and 5-year EFS rates were 59±10% and 53±10%, respectively; and 3- and 5-year OS rates were 73±9% and 52± 11%, respectively. Eleven children died at a median of 32 months after their diagnosis (range, 5-49 months), 8 due to their tumor, 1 due to multiorgan failure after the first myeloablative treatment, and 2 due to acute myeloid leukemia and myelodysplastic syndrome, which developed 23 and 34 months after their primary diagnosis. For the 25 patients who were able to tolerate the entire schedule, including at least 1 myeloablative course, the 5-year PFS and OS rates were 67±11% and 61±11%, respectively. Five-year PFS did not differ for patients with pineal tumors versus those with nonpineal tumors (5-year PFS 83±15% vs 54±12%, respectively;p=NS).
Lester et al conducted a retrospective review of 26 patients (11 children, 15 adults) with CNS PNET to evaluate clinical outcomes and prognostic factors.(6) Overall, 5-year disease-free survival (DFS) was 78% for pediatric patients and 22% for adult patients (p=0.004); 4-year OS was 67% for pediatric patients and 33% for adult patients (p=0.07). More pediatric patients were treated with HDC with stem-cell transplant
than adult patients (82% vs 27%). In unadjusted analysis, compared with standard chemotherapy, treatment with HDC with stem-cell transplant was associated with improved OS (hazard ratio [HR], 0.3; 95% CI, 0.1 to 1.0; p=0.05).
Dhall et al reported outcomes for children younger than 3 years of age at diagnosis of nonmetastatic medulloblastoma, after being treated with 5 cycles of induction chemotherapy and subsequent myeloablative chemotherapy and autologous HSCT.(7) Twenty of 21 children enrolled completed induction chemotherapy, of whom 14 had a gross total surgical resection and 13 remained free of disease at the completion of induction chemotherapy. Of 7 patients with residual disease at the beginning of induction, all achieved a complete radiographic response to induction chemotherapy. Of the 20 patients who received consolidation chemotherapy, 18 remained free of disease at the end of consolidation. In patients with gross total tumor resection, 5-year EFS and OS were 64% (±13%) and 79% (±11%), respectively, and for patients with residual tumor, 29% (±17%) and 57% (±19%), respectively. There were 4 treatmentrelated deaths. The need for craniospinal irradiation was eliminated in 52% of the patients, and 71% of survivors avoided irradiation completely, with preservation of quality of life and intellectual functioning.
Gajjar et al reported the results of risk-adapted craniospinal radiotherapy followed by HDC and autologous HSCT in 134 children with newly diagnosed medulloblastoma.(8) After tumor resection, patients were classified as having average-risk disease (n=86), defined as 1.5 cm² or less residual tumor and no metastatic disease, or high-risk disease (n=48), defined as greater than 1.5 cm² residual disease or metastatic disease localized to the neuroaxis. A total of 119 children completed the planned protocol. Five-year OS was 85% (95% CI, 75% to 94%) among the average-risk cases and 70% (95% CI, 54% to 84%) in the high-risk patients. Five-year EFS was 83% (95% CI, 73% to 93%) and 70% (95% CI, 55% to 85%) for average- and high-risk patients, respectively. No treatment-related deaths were reported.
Bergthold et al reported outcomes for 19 young (age, <5 years) children with classical or incompletely resected medulloblastoma treated with high-dose busulfan-thiotepa with autologous HSCT, followed by posterior fossa irradiation.(9) Subjects were treated at a single center from 1994 to 2010. On pathology, 14 patients had classic medulloblastoma, while 3 had desmoplastic/nodular medulloblastoma and 1 had
medulloblastoma with extensive nodularity. The median follow-up was 40.5 months (range, 14.5-191.2 months). At 3 and 5 years, EFS and OS were 68% (95% CI, 45% to 84%) and 84% (95% CI, 61% to 94%), respectively. Treatment failures occurred in 6 children at a median time of 13 months (range, 5.8-30.7 months) after HSCT. The authors conclude that high OS is possible with focal brain irradiation in the
setting of HSCT for medulloblastoma.
Atypical Teratoid/Rhabdoid Tumor
Lee et al retrospectively reviewed the medical records of 13 patients diagnosed with atypical teratoid/rhabdoid tumor (AT/RT) who were treated at their institute at Seoul National Children’s University Hospital (Korea).(10) The median age was 12 months (range, 3-67 months), and 7 patients were younger than 1-year-old at the time of diagnosis. Three patients (23%) underwent HDC and autologous HSCT. The authors assessed the impact on OS in these 3 patients, as compared with the remaining 10 patients undergoing other chemotherapy regimens. No statistical difference in OS was observed between these 2 groups (p=0.36); however, the median survival was reported to be higher in the HSCT group (15 months) compared with the non-HSCT group (9 months).(10)
Recurrent Central Nervous System Embryonal Tumors
Relapsed Supratentorial Primitive Neuroectodermal Tumor
Raghuram et al performed a systematic review of the literature regarding the outcome of patients with relapsed sPNET treated with HDC and autologous HSCT.(11) Eleven observational studies published before 2010 met their inclusion criteria; 4 of these were prospective case-series. The 11 studies consisted of 46 patients diagnosed with relapsed sPNET or pineoblastoma who received autologous HSCT for treatment of relapse. Of those, 15 patients were children younger than 3 years of age, and 15 were pineoblastomas. With a median follow-up of 40 months (range, 3-123 months) 15 patients were reported alive. Thirteen patients (of 15 survivors) did not receive craniospinal irradiation. The 12-month OS rate of the cohort was 44.2±7.5 months. Twelve-month OS for children younger than 36 months was 66.7±12.2 months, while for older children, 12-month OS was 27.8±10.6 (p=0.003). Twelve-month OS was 20.0±10.3 for those patients with pineoblastoma versus 54.6±9.0 for those with nonpineal sPNETs (p<0.001). Cox regression analysis revealed pineal location as the only independent adverse prognostic factor.(11) Based on these pooled results, HDC with HSCT might lead to survival primarily in younger children with relapsed sPNET, even in the absence of concomitant use of radiotherapy, whereas the outcome in older children and/or in a pineal location is poor with this modality.
Dunkel et al report an expanded series with longer follow-up using autologous HSCT for previously irradiated recurrent medulloblastoma.(12,13) Twenty-five patients were treated between 1990 and 1999 and included 18 males and 7 females with a median age at diagnosis of 11.5 years (range, 4.2-35.5 years). Median age at the time of HSCT was 13.8 years (range, 7.6-44.7 years). All patients had previously
received postoperative external beam radiation with (n=15) or without (n=10) chemotherapy. The median time from diagnosis to disease relapse or progression was 29.8 months (range, 5.3-114.7 months). Stage at the time of relapse was M0 n=6, M1 n=1, M2 n=8, and M3 n=10 (M0=no evidence of subarachnoid or hematogenous metastasis, M1=tumor cells found in cerebrospinal fluid, M2=intracranial tumor beyond primary site, M3=gross nodular seeding in spinal subarachnoid space). HDC before HSCT consisted of carboplatin, thiotepa, and etoposide. Treatment-related mortality was 12% within 30 days of transplant. Tumor recurred in 16 patients at a median of 8.5 months after HSCT (range, 2.3-58.5 months). Median OS was 26.8 months (95% CI, 11.9 to 51.1 months) and EFS and OS at 10 years post-HSCT was 24%
for both (95% CI, 9.8 to 41.7%). The authors concluded that this retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma.
In the earlier publication, Dunkel et al reported the outcomes of 23 patients with recurrent medulloblastoma treated with high-dose carboplatin, thiotepa, and etoposide.(13) Seven patients were event-free survivors at a median of 54 months, with OS estimated at 46% at 36 months. HSCT was expected to be most effective with minimal disease burden. Thus, Dunkel et al suggested increased surveillance for recurrence or aggressive surgical debulking at the time of recurrence. The authors also acknowledged the potential for effects of patient selection bias on their results, because not all patients eligible for the protocol were enrolled.
Grodman et al reported outcomes of 8 patients with relapsed medulloblastoma with metastasis (n=7) and relapsed germinoma (n=1) who received dose-intensive chemotherapy with autologous HSCT.(14) Mean age was 12.9 years (range, 5-27.8 years). Mean survival posttransplant was 4.8 years (range, 8-160+ months). The 2-year and 5-year OS rates were 75% and 50%, respectively.
Kostaras et al conducted a systematic review of therapies for adults with relapsed medulloblastoma, including HDC with HSCT.(15) The authors identified 13 publications including 66 adult patients treated with HSCT for recurrent/relapsed medulloblastoma. Limitations to the available studies include the fact that all are small case series, case reports, or retrospective reviews. The single study with a comparison group identified in the review, which included 10 patients treated with HSCT, reported that patients with medulloblastoma treated with HDC with HSCT at recurrence had improved OS compared with historical controls treated with conventional chemotherapy at recurrence (OS, 3.47 years vs 2 years; p=0.04). The authors conclude, “Although the data are limited, the collective published evidence for this treatment modality suggests a role for HDCT [high dose chemotherapy] plus stem cell transplantation in the management of well-selected adult patients with recurrent medulloblastoma.”
Relapsed Embryonal Tumors: Multiple Types
Gill et al reported outcomes for 23 adult patients (≥18 years) treated for recurrent embryonal central nervous system (CNS) tumors between 1976 and 2004, comparing HDC with autologous HSCT (n=10) with a historic control group of patients treated with conventional-dose chemotherapy (n=13).(16) In the HSCT group, 6 patients received tandem autologous transplants. Autologous HSCT was associated with
increased survival (p=0.044) and a longer time to disease progression (TTP) (p=0.028). Median TTP for the conventional versus HSCT group was 0.58 years and 1.25 years, respectively. Median survival was 2.00 years and 3.47 years, respectively. There were no long-term survivors in the conventional chemotherapy group. With a median follow-up of 2.9 years, 5 of the HSCT patients were alive, 4 without disease progression. In a comparison of outcomes between the patients who received a single versus tandem transplant, there was improvement in TTP favoring tandem transplant (p=0.046), but no difference in survival was observed (p=0.132).
Bode et al reported the results of the intensive-chemotherapy treatment arm of a nonrandomized stratified protocol for the treatment of relapsed cerebral PNET, in which patients could receive intensive chemotherapy, potentially high-dose, or oral chemotherapy.(17) The intensive-chemotherapy arm included 72 patients, 59 who had disseminated disease. Patients received 2 courses of carboplatin and etoposide; those who had CR or PR on magnetic resonance imaging received 2 more cycles of carboplatin and etoposide followed by HDC with carboplatin, etoposide, and thiotepa, with stem-cell rescue. For the cohort of 72 patients, median PFS and OS were 11.6 months (95% CI, 10.1 to 13.1 months) and 21.1 months (95% CI, 15.7 to 26.5 months), respectively. Compared with patients with nonmedulloblastoma
PNETS, patients with medulloblastoma had longer PFS (12.6 months vs 3.1 months; p=0.004), but not significantly different OS (22.6 months vs 12.3 months; p=0.1). Twenty-four patients received HDC following CR/PR on induction therapy, along with 3 patients with stable disease; for those patients, the median PFS and OS were 8.4 months (95% CI, 7.7 to 9.1 months) and 20.2 months (95% CI, 11.7 to 28.8 months), respectively. Twenty-two patients who had good response to standard chemotherapy and received HDC with stem-cell support were compared with 12 patients who had good response to standard chemotherapy but did not receive subsequent HDC. Median PFS and OS did not significantly differ between those who did and did not receive HDC.
Kim et al reported outcomes for 13 patients with refractory or relapsed medulloblastoma or PNET treated with combination HDC (irinotecan, vincristine, cisplatin, cyclophosphamide, etoposide), with an objective tumor response rate of 38.5%.(18) However, while the authors note that patients could concurrently receive radiotherapy, surgery, and/or HDC and stem-cell rescue, it is not specified how many patients received
stem-cell support, making it difficult to determine the benefit from specific intervention components.
Tandem Transplant for CNS Embryonal Tumors
In 2014, Dufour et al reported outcomes for patients with newly diagnosed high-risk medulloblastoma and supratentorial PNET treated with tandem HDC with autologous stem-cell support followed by conventional craniospinal radiotherapy.(19) Twenty-four children older than age 5 years were treated from 2001 to 2010, 21 with newly diagnosed high-risk medulloblastoma (disseminated medulloblastoma or medulloblastoma with residual tumor volume >1.5 cm2 or MYCN amplification) and 3 with sPNET. Patients received 2 courses of conventional chemotherapy with carboplatin/etoposide, followed by 2 courses of high-dose thiotepa followed by stem-cell rescue and craniospinal radiotherapy. Twenty-three patients received 2 courses of HDC, while 1 patient received only 1 course of high-dose thiotepa due to
seizures. Median follow-up was 4.4 years (range, 0.8-11.3 years). Three-year EFS and OS were 79% (95% CI, 59% to 91%) and 82% (95% CI, 62% to 93%), respectively, while 5-year EFS and OS were 65% (95% CI, 45% to 81%) and 74% (95% CI, 51% to 89%), respectively.
In 2013, Sung et al reported the results of reduced-dose craniospinal radiotherapy followed by tandem double HDC with autologous HSCT in 20 children older than 3 years of age with high-risk medulloblastoma (17 with metastatic disease, 3 with postoperative residual tumor >1.5 cm² without metastasis).(20) The tumor relapsed/progressed in 4 patients, and 2 patients died of toxicity during the second transplant. Fourteen (70%) patients remained event-free at a median follow-up of 46 months (range, 23-82 months) from diagnosis. Late adverse effects evaluated at a median of 36 months (range, 12-68 months) after tandem HSCT included hypothyroidism, growth hormone deficiency, sex hormone deficiency, hearing loss, and renal tubulopathy.(20)
In 2013, Friedrich et al reported the results of double tandem high-dose chemotherapy with autologous HSCT in 3 children younger than 4 years of age with metastatic sPNET.(21) These patients also received preventive craniospinal radiotherapy; they had residual disease before HSCT, but no evidence of disease after transplant (survival range, 2-10 years).(21)
Park et al reported the results of tandem double HDC with autologous HSCT in 6 children younger than 3 years of age with newly diagnosed AT/RT.(22) No treatment-related death occurred during the tandem procedure, and 5 (of 6) patients were alive at a median follow-up of 13 months (range, 7-64) from first HSCT. Although 3 patients remained progression-free after tandem HSCT, the effectiveness of this modality is unclear because all survivors received radiotherapy, as well as tandem HSCT.(22)
Sung et al reported the results of a single or tandem double HDC with autologous HSCT in 25 children with newly diagnosed high-risk or relapsed medulloblastoma or PNET following surgical resection.(23) Three-year EFS for patients in CR or PR and less than PR at first HDC was 67% or 16.7%, respectively. For 19 cases in CR or PR at first HDC, 3-year EFS was 89% in the tandem double group and 44% in the single high-dose chemotherapy group, respectively. Four treatment-related deaths occurred, and in 4 of 8 young children, craniospinal radiotherapy was successfully withheld without relapse.
Allogeneic Transplant for CNS Embryonal Tumors
The use of allogeneic HSCT for CNS embryonal tumors consists of rare case reports with mixed results.(24-26)
Literature regarding autologous HSCT for the treatment of ependymoma primarily consists of small case series. Sung et al reported the results of tandem double HDC with autologous HSCT in 5 children younger than 3 years of age with newly diagnosed anaplastic ependymoma.(27) All patients were alive at median follow-up of 45 months (range, 31-62) from diagnosis, although tumor progressed at the primary
site in 1 patient. No significant endocrine dysfunction occurred except for hypothyroidism in 1 patient, and 1 patient had significant neurologic injury from primary surgical treatment.(27) The results of this very small case series indicate that treatment with tandem HSCT is feasible in very young children with anaplastic ependymoma and that this strategy might also be a possible option to improve survival in these patients
without unacceptable long-term toxicity. Further studies with larger patient cohorts are needed to confirm these results.
Mason et al reported on a case series of 15 patients with recurrent ependymoma.(28) Five patients died of treatment-related toxicities, 8 died from progressive disease, and 1 died of unrelated causes. After 25 months, 1 patient remains alive but with tumor recurrence. The authors concluded that their high-dose regimen of thiotepa and etoposide was not an effective treatment of ependymoma. Grill et al similarly
reported a disappointing experience in 16 children treated with a thiotepa-based high-dose regimen.(29)
A small series reported 5-year EFS of 12% (±6%) and OS of 38% (±10%) among 29 children younger than 10 years of age who received autologous HSCT following intensive induction chemotherapy to treat newly diagnosed ependymoma.(30) Importantly, radiation-free survival was only 8% (±5%) in these cases. The results of these series, although limited in size, further suggest HSCT is not superior to other previously reported chemotherapeutic approaches.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in October 2014 identified several ongoing trials of HSCT for CNS embryonal tumors or ependymoma.
Tandem High Dose Chemotherapy and Autologous Stem Cell Rescue for High Risk Pediatric Brain Tumors (NCT01342237) – This is a nonrandomized, phase 2 trial to evaluate tandem HDC with topotecan and melphalan followed by autologous HSCT in pediatric patients with high-risk CNS tumors, including newly diagnosed medulloblastoma, CNS PNET, AT/RT, choroid plexus carcinoma, pineoblastoma with residual tumor greater than 1.5 cm 2 after operation or with leptomeningeal seeding at diagnosis, all high-grade malignant brain tumors in patients younger than age 3 years, and recurrent embryonal brain tumors and CNS germ cell tumors. Enrollment is planned for 33 subjects; the estimated study completion date was February 2014.
- Combination Chemotherapy, Radiation Therapy, and an Autologous Peripheral Blood Stem Cell Transplant in Treating Young Patients With Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System (NCT00653068) – This is a nonrandomized, phase 3 trial to evaluate EFS and OS rates for children with AT/RT treated with surgery, HDC combined with HSCT, and radiotherapy. Enrollment is planned for 70 subjects; the estimated study completion date is April 2015.
- Treatment of Patients With Newly Diagnosed Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, or Atypical Teratoid Rhabdoid Tumor (NCT00085202) – This is a nonrandomized, phase 3 trial to compare 2 different radiotherapy regimens given together with chemotherapy and autologous HSCT in the treatment of pediatric patients with histologicallyconfirmed medulloblastoma, sPNET, or AT/RT. Enrollment is planned for 416 subjects; the estimated final study completion date is September 2018.
- Combination Chemotherapy With or Without Etoposide Followed By an Autologous Stem Cell Transplant in Treating Young Patients With Previously Untreated Malignant Brain Tumors (NCT00392886) – This is a nonrandomized, phase 3 trial to compare 2 alternative induction chemotherapy regimens (with or without etoposide) followed by autologous HSCT for the treatment of multiple types of brain tumor, including posterior fossa medulloblastoma or PNET, primary CNS AT/RT, and ependymoma. Enrollment is planned for 120 subjects; the estimated
study completion date was December 2010. The study listing has not been verified since October 2010.
- Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma (NCT00336024) – This is a randomized, phase 3 trial to compare 2 alternative induction chemotherapy regimens (with or without methotrexate) followed by autologous HSCT for the treatment of newly diagnosed sPNET or high-risk medulloblastoma. Enrollment is planned for 96 subjects; the estimated study completion date is September 2018.
Summary of Evidence
Data from single-arm studies using high-dose chemotherapy (HDC) with autologous hematopoietic stemcell transplantation (HSCT) to treat newly diagnosed central nervous system (CNS) embryonal tumors have shown an improved survival benefit (both event-free survival [EFS] and overall survival [OS]), particularly in patients with disease that is considered high risk. In addition, the use of autologous HSCT has allowed for a reduction in the dose of radiation needed to treat both average- and high-risk disease, with preservation of quality of life and intellectual functioning, without compromising survival.
Data from single-arm studies using HDC with autologous HSCT to treat newly diagnosed CNS embryonal tumors have shown comparable or improved survival (both EFS and OS) compared with historical controls treated with conventional therapy, with or without radiotherapy, particularly in patients with disease that is considered high risk.
Similarly, data from single-arm studies using autologous HSCT to treat recurrent CNS embryonal tumors have shown comparable or improved survival compared with historical controls treated with conventional therapy for some patients. The results from a 2012 systematic review of observational studies in patients with relapsed supratentorial primitive neuroectodermal tumor (sPNET) suggest that a subgroup of infants
with chemo-sensitive disease might benefit from autologous HSCT, achieving survival without the use of radiotherapy, whereas the outcome in older children and/or in pineal location is poor with this modality.
Tandem autologous HSCTs have been investigated for CNS embryonal tumors and appear to be associated with rates of OS and EFS comparable with single autologous HSCT. Tandem transplants may allow reduced doses of craniospinal irradiation, with the goal of avoiding long-term radiation damage. However, most studies used standard-dose irradiation, making the relative benefit of tandem autologous HSCT uncertain, and the amount of evidence is limited.
The data on the use of allogeneic HSCT for CNS embryonal tumors are limited.
The use of HSCT for ependymoma has not shown a survival benefit compared with the use of conventional approaches. Therefore, the use of HSCT for ependymoma is considered investigational.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network Practice Guidelines 2014
National Comprehensive Cancer Network guidelines on treating CNS tumors do not address the use of autologous HSCT in treating ependymomas. For medulloblastoma and sPNET, autologous HSCT for recurrent disease with maximum safe resection is a category 2A recommendation.(31)
U.S. Preventive Services Task Force Recommendations
Medicare National Coverage
There is no national coverage determination (NCD) for hematopoietic stem-cell transplant. In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Mueller S, Chang S. Pediatric brain tumors: current treatment strategies and future therapeutic approaches. Neurotherapeutics. 2009;6(3):570-586.
- Fangusaro J, Finlay J, Sposto R, et al. Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer. 2008;50(2):312-318.
- National Cancer Institute Physician Data Query (PDQ®). Childhood Central Nervous System Embryonal Tumors (last modified August 1, 2013).
http://www.cancer.gov/cancertopics/pdq/treatment/childCNSembryonal/healthprofessional. Accessed September 10, 2014.
- Chintagumpala M, Hassall T, Palmer S, et al. A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET. Neuro Oncol. 2009;11(1):33-40.
- Massimino M, Gandola L, Biassoni V, et al. Evolving of therapeutic strategies for CNS-PNET. Pediatr Blood Cancer. Dec 2013;60(12):2031-2035. PMID 23852767
- Lester RA, Brown LC, Eckel LJ, et al. Clinical outcomes of children and adults with central nervous system primitive neuroectodermal tumor. J Neurooncol. Aug 13 2014. PMID 25115737
- Dhall G, Grodman H, Ji L, et al. Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head Start” I and II protocols. Pediatr Blood Cancer. 2008;50(6):1169-1175.
- Gajjar A, Chintagumpala M, Ashley D, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 2006;7(10):813-820.
- Bergthold G, El Kababri M, Varlet P, et al. High-dose busulfan-thiotepa with autologous stem cell transplantation followed by posterior fossa irradiation in young children with classical or incompletely resected medulloblastoma. Pediatr Blood Cancer. May 2014;61(5):907-912. PMID 24470384
- Lee JY, Kim IK, Phi JH, et al. Atypical teratoid/rhabdoid tumors: the need for more active therapeutic measures in younger patients. J Neurooncol. Apr 2012;107(2):413-419. PMID 22134767
- Raghuram CP, Moreno L, Zacharoulis S. Is there a role for high dose chemotherapy with hematopoietic stem cell rescue in patients with relapsed supratentorial PNET? J Neurooncol. Feb 2012;106(3):441-447. PMID 21850536
- Dunkel I, Gardner S, Garvin J, et al. High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. Neuro Oncol. 2010;12(3):297-303.
- Dunkel IJ, Boyett JM, Yates A, et al. High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children’s Cancer Group. J Clin Oncol. 1998;16(1):222-228.
- Grodman H, Wolfe L, Kretschmar C. Outcome of patients with recurrent medulloblastoma or central nervous system germinoma treated with low dose continuous intravenous etoposide along with dose-intensive chemotherapy followed by autologous hematopoietic stem cell rescue. Pediatr Blood Cancer. 2009;53(1):33-36.
- Kostaras X, Easaw JC. Management of recurrent medulloblastoma in adult patients: a systematic review and recommendations. J Neurooncol. Oct 2013;115(1):1-8. PMID 23877361
- Gill P, Litzow M, Buckner J, et al. High-dose chemotherapy with autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system. Cancer. 2008;112(8):1805-1811.
- Bode U, Zimmermann M, Moser O, et al. Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial. J Neurooncol. Sep 2 2014. PMID 25179451
- Kim H, Kang HJ, Lee JW, et al. Irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide for refractory or relapsed medulloblastoma/PNET in pediatric patients. Childs Nerv Syst. Oct 2013;29(10):1851-1858. PMID 23748464
- Dufour C, Kieffer V, Varlet P, et al. Tandem high-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuro-ectodermic tumors. Pediatr Blood Cancer. Aug 2014;61(8):1398-1402. PMID 24664937
- Sung KW, Lim do H, Son MH, et al. Reduced-dose craniospinal radiotherapy followed by tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk medulloblastoma. Neuro Oncol. Mar 2013;15(3):352-359. PMID 23258845
- Friedrich C, von Bueren AO, von Hoff K, et al. Treatment of young children with CNS-primitive neuroectodermal tumors/pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens a d
radiotherapy. Neuro Oncol. Feb 2013;15(2):224-234. PMID 23223339
- Park ES, Sung KW, Baek HJ, et al. Tandem high-dose chemotherapy and autologous stem cell transplantation in young children with atypical teratoid/rhabdoid tumor of the central nervous system. J Korean Med Sci. Feb 2012;27(2):135-140. PMID 22323859
- Sung KW, Yoo KH, Cho EJ, et al. High-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk or relapsed medulloblastoma or supratentorial primitive neuroectodermal tumor. Pediatr Blood Cancer. 2007;48(4):408-415.
- Lundberg JH, Weissman DE, Beatty PA, et al. Treatment of recurrent metastatic medulloblastoma with intensive chemotherapy and allogeneic bone marrow transplantation. J Neurooncol. 1992;13(2):151–155.
- Matsuda Y, Hara J, Osugi Y, et al. Allogeneic peripheral stem cell transplantation using positively selected CD34+ cells from HLA-mismatched donors. Bone Marrow Transplant. 1998;21(4):355–360.
- Secondino S, Pedrazzoli P, Schiavetto I, et al. Antitumor effect of allogeneic hematopoietic SCT in metastatic medulloblastoma. Bone Marrow Transplant. 2008;42(2):131-133.
- Sung KW, Lim do H, Lee SH, et al. Tandem high-dose chemotherapy and autologous stem cell transplantation for anaplastic ependymoma in children younger than 3 years of age. J Neurooncol. Apr 2012;107(2):335-342. PMID 22081297
- Mason WP, Goldman S, Yates AJ, et al. Survival following intensive chemotherapy with bone marrow reconstitution for children with recurrent intracranial ependymoma: a report of the Children’s Cancer Group. J Neurooncol. 1998;37(2):135-143.
- Grill J, Kalifa C, Doz F, et al. A high-dose busulfan-thiotepa combination followed by autologous bone marrow transplantation in childhood recurrent ependymoma. A phase-II study. Pediatr Neurosurg. 1996;25(1):7-12.
- Zacharoulis S, Levy A, Chi SN, et al. Outcome for young children newly diagnosed with ependymoma, treated with intensive induction chemotherapy followed by myeloablative chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer. 2007;49(1):34-40.
- National Comprehensive Cancer Network (NCCN). Central Nervous System Cancers 2014; http://www.nccn.org/professionals/physician_gls/PDF/cns.pdf. Accessed September 10, 2014.
|CPT||38204||Management of recipient hematopoietic cell donor search and cell acquisition|
|38205||Blood-derived hematopoietic progenitor cell harvesting for transplantaion, per collection, allogeneic|
|38208||Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing, per donor|
|38209||;thawing of previously frozen harvest with washing, per donor|
|38210||Specific cell depletion with harvest, T cell depletion|
|38211||Tumor cell depletion|
|38212||Red blood cell removal|
|38214||Plasma (volume) depletion|
|38215||Cell concentration in plasma, mononuclear, or buffy coat layer|
|38220||Bone marrow; aspiration only|
|38221||Bone marrow; biopsy, needle or trocar|
|38230||Bone marrow harvesting for transplantation; allogeneic|
|38232||bone marrow harvesting for transplnation; autologous|
|38240||Bone marrow or blod-derived [eropheral stem-cell transplatation; allogeneic|
|ICD-9 Procedure||41.00||Bone marrow transplant, not otherwise specified|
|41.01||Autologous bone marrow transplant without purging|
|41.02||Allogeneic hone marrow transplant with purging|
|41.03||Allogeneic bone marrow transplant without purging|
|41.04||Autologous hematopoietic stem-cell transplant without purging|
|41.05||Allogeneic hematopoietic stem cell transplant without purging|
|41.06||Cord blood stem cell transplant|
|41.07||Autologous hematopoietic stem-cell transplant with purging|
|41.08||Allogeneic hematopoietic stem-cell transplant with purging|
|41.09||Autologous bone marrow transplant with purging|
|41.91||Aspiration of bone marrow from donor for transplant|
|99.79||Other therapeutic apheresis (includes harvest of stem cells)|
|ICD-9 Diagnosis||191.0–191.9||Malignant neoplasm of brain code range|
|HCPCS||Q0083, Q0084, Q0085||Chemotherapy administration code range|
J9000, J9001, J9010, J9015, J9017, J9020, J9025, J9027, J9031, J9035, J9041, J9045, J9050, J9055, J9060, J9062, J9065, J9070, J9080, J9090, J9091, J9092, J9093, J9094, J9095, J9096, J9097, J9098, J9100, J9110, J9120, J9130, J9140, J9150, J9151, J9160, J9165, J9170, J9175, J9178, J9181, J9182, J9185, J9190, J9200, J9201, J9202, J9206, J9208, J9209, J9211, J9212, J9213, J9214, J9215, J9216, J9217, J9218, J9219, J9225, J9226, J9230, J9245, J9250, J9260, J9261, J9263, J9264, J9265, J9266, J9268, J9270, J9280, J9290, J9291, J9293, J9300, J9303, J9305, J9310, J9320, J9340, J9350, J9355, J9357, J9360, J9370, J9375, J9380, J9390, J9395, J9600, J9999
|Chemotherapy drugs code range|
|G0265||Bryopreservation, freezing and storage of cells for thereapeutic use, each cell line|
|G0266||Thawing and expansion of frozen cells for therapeuticuse, each cell line|
|G0267||Bone marrow or peripheral stem-cell harvest, modification or treatment to eliminate cell type(s) (e.g., T cells, metastic carcinoma)|
|S2150||Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services)|
|ICD-10-CM (effective 10/1/15)||C71.0-C71.9||Malignant neoplasm of brain|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are only used for inpatient services.|
|30243G0, 30243X0, 30243Y0||Percutaneous transfusion, central vein, bone marrow or stem cells, autologous, code list|
|30243G1, 30243X1, 30243Y1||Percutaneous transfusion, central vein, bone marrow or stem cells, nonautologous, code list|
|07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ||Surgical, lymphatic and hemic systems, extraction, bone marrow, code list|
|Type of Service||Therapy|
|Place of Service||Inpatient/Outpatient|
Ependymoma, High-dose Chemotherapy
Ependymoblastoma, High-dose Chemotherapy
High-dose chemotherapy with autologous stem-cell support for PNET and ependymoma
Medulloblastoma, High-dose Chemotherapy
Neuroblastoma, Central, High-dose Chemotherapy
Pinealblastoma, High-dose Chemotherapy
Primitive Neuroectodermal Tumors (PNET), High-dose Chemotherapy
|12/01/99||Add to Therapy section||New policy
Policy represents revision of 8.01.15 to focus entirely on PNET. Policy statement unchanged
|08/15/01||Replace policy||Policy revised to correct type: Page 2 of this policy (under the 2nd “Note”) refers to another policy [No. 8.01.15], but should refer instead to policy No. 8.01.34|
|10/08/02||Replace policy||Policy updated and references added; no change in policy statement|
|07/15/04||Replace policy||Policy updated with literature review for the period of May 2002 through May 2004; policy statement unchanged|
|09/27/05||Replace policy||Policy updated with literature review for the period of May 2004 through August 2005; reference number 3 updated; policy statement unchanged|
|04/17/07||Replace policy||Policy updated with literature search; policy statement added to indicate that multiple-cycle high-dose chemotherapy (with or without associated radiotherapy) and autologous stem-cell support (i.e., tandem transplants) is investigational. Reference number 5 updated; reference numbers 3, 4, and 8 added. Code table updated.|
|05/08/08||Replace policy||Policy updated with literature search; references 1 and 2 added; other references renumbered. No change to policy statements|
|11/12/09||Replace policy||Policy extensively revised with literature search through September 2009; policy title changed to remove “highdose chemotherapy” and to change PNET to embryonal tumors. Policy statement changed regarding autologous
consolidation therapy in patients with previously untreated embryonal tumors showing complete or partial response to, or stable disease after, induction therapy; now considered medically necessary. Other policy statements reworded and separated to address ependymoma and embryonal CNS tumors specifically; however, the intent of the statements remains the same. References 1–8 and 14 added
|11/11/10||Replace policy||Policy revised with literature search through October 2010. References 7, 12-14 added. No change to policy statements.|
|11/10/11||Replace policy||Policy updated with literature search. No references added; no change in policy statements.|
|11/08/12||Replace Policy||Policy updated with literature search. References 7, 8, 13 and 18 added; no change in policy statements.|
|11/14/13||Replace policy||Policy updated with literature search through October 8, 2013. References 13 and 14 added, references 3 and 24 updated; no change in policy statements.|
|11/13/14||Replace policy||Policy updated with literature review through September 30, 2014. References 5-6, 9, 15, and 17-19 added. Policy statements unchanged.|