The quality of life after high-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) (i.e., blood or marrow) transplant is of utmost importance. In aplastic anemia and malignancies, there is the expectation of improved status after HDC and HSC. Conversely, quality of life outcomes (measured by growth, skeletal development dysfunction, and neuropsychological) for patients with storage diseases is gradually being defined. Because of these long-term problems, non-malignant or maldevelopment indications for HDC and HSCs should not be reviewed with criteria similar to that for malignancies.
This policy was initially based on a literature search for studies published through 1999 with periodic searches through 2013. Following is the summary of the key literature to date.
CNS Embryonal Tumors
Chintagumpala and colleagues 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 (HDC) with autologous stem-cell support (AuSCS) 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 cm2 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 HDC with stem-cell support (SCS) 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 and colleagues reported outcomes for 43 children with newly diagnosed sPNET treated prospectively on two serial studies (Head Start 1 [HS1] and Head Start 2 [HS2]) between 1991 and 2002 with intensified induction chemotherapy followed by myeloablative chemotherapy and AuSCS. (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 response (PR) or complete response (CR), patients underwent myeloablative chemotherapy with AuSCS (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]: 24–53%) and 49% (95% CI: 33–62%), 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.
Dhall and colleagues 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 AuSCS. (5) 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 treatment-related 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 and colleagues reported the results of risk-adapted craniospinal radiotherapy followed by HDC and AuSCS in 134 children with newly diagnosed medulloblastoma. (6) After tumor resection, patients were classified as having average-risk disease (n=86), defined as equal to or less than 1.5 cm2 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: 75–94%) among the average-risk cases and 70% (95% CI: 54–84%) in the high-risk patients. Five-year EFS was 83% (95% CI: 73–93%) and 70% (95% CI: 55–85%) for average- and high-risk patients, respectively. No treatment-related deaths were reported.
Lee and colleagues 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). (7) 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 AuSCS. The authors assessed the impact on OS in these 3 patients, as compared to 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 SCS group (15 months) compared to the non-SCS group (9 months). (7)
Raghuram and colleagues performed a systematic review of the literature regarding the outcome of patients with relapsed sPNET treated with HDC and AuSCS. (8) 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 AuSCS 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 non-pineal sPNETs (p<0.001). Cox regression analysis revealed pineal location as the only independent adverse prognostic factor. (8) Based on these pooled results, high-dose chemotherapy 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 and colleagues report an expanded series with longer follow-up using AuSCS for previously irradiated recurrent medulloblastoma. (9, 10) Twenty-five patients were treated between 1990 and 1999 and consisted of 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 SCS 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, 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 prior to SCS 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 SCS (range: 2.3-58.5 months). Median OS was 26.8 months (95% CI: 11.9-51.1 months) and EFS and OS at 10 years post-SCS was 24% for both (95% CI: 9.8-41.7%). The authors concluded that this retrieval strategy provides long-term EFS for some patients with previously irradiated recurrent medulloblastoma.
In the earlier publication, Dunkel and colleagues reported the outcomes of 23 patients with recurrent medulloblastoma treated with high-dose carboplatin, thiotepa, and etoposide. (10) Seven patients were EFS at a median of 54 months, with OS estimated at 46% at 36 months. SCS was expected to be most effective with minimal disease burden. Thus, Dunkel and colleagues 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, since 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 AuSCS. (11) Mean age was 12.9 years (range: 5–27.8 years). Mean survival post-transplant was 4.8 years (range: 8–160+ months). The 2-year and 5-year OS rates were 75% and 50%, respectively.
Gill and colleagues reported outcomes for 23 adult patients (18 years or older) treated for recurrent embryonal CNS tumors between 1976 and 2004, comparing HDC with AuSCS (n=10) with a historic control group of patients treated with conventional-dose chemotherapy (n=13). (12) In the SCS group, 6 patients received tandem autologous transplants. AuSCS 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 SCS 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 SCS 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).
Park and colleagues reported the results of tandem double HDC with AuSCS in 6 children younger than 3 years of age with newly diagnosed atypical teratoid/rhabdoid tumor (AT/RT). (13) 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 SCS. Although 3 patients remained PFS after tandem SCS, the effectiveness of this modality is unclear, because all survivors received radiotherapy, as well as tandem SCS. (13)
Sung and colleagues reported the results of a single or tandem double high-dose chemotherapy with AuSCS in 25 children with newly diagnosed high-risk or relapsed medulloblastoma or PNET following surgical resection. (14) Three-year EFS for patients in complete remission (CR) or partial remission (PR) and less than PR at first high-dose chemotherapy was 67% or 16.7%, respectively. For 19 cases in CR or PR at first high-dose chemotherapy, 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.
The use of AlloSCS for CNS embryonal tumors consists of rare case reports with mixed results. (15-17)
Literature regarding AuSCS for the treatment of ependymoma primarily consists of small case series. Sung and colleagues reported the results of tandem double HDC with AuSCS in 5 children younger than 3 years of age with newly diagnosed anaplastic ependymoma. (18) All patients were alive at median follow-up of 45 months (range 31–62) from diagnosis, although tumor progressed at the primary site in one patient. No significant endocrine dysfunction occurred except for hypothyroidism in one patient, and one patient had significant neurologic injury from primary surgical treatment. (18) The results of this very small case series indicate that treatment with tandem SCS 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 and colleagues reported on a case series of 15 patients with recurrent ependymoma. (19) 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 and colleagues similarly reported a disappointing experience in 16 children treated with a thiotepa-based high-dose regimen. (20)
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 AuSCS following intensive induction chemotherapy to treat newly diagnosed ependymoma. (21) Importantly, radiation-free survival was only 8% (+/- 5%) in these cases. The results of these series, although limited in size, further suggest SCS is not superior to other previously reported chemotherapeutic approaches.
Additional Infusion Treatments for CNS Embryonal Tumors and Ependymoma
More data is needed on the use of tandem/triple stem-cell transplant, AlloSCS, and donor leukocyte infusion (DLI) for CNS embryonal tumors. For ependymoma, there is a lack of data for treatment of this condition when using tandem/triple stem-cell transplant, AuSCS, AlloSCS and DLI.
As with DLI, HPC Boost has a positive response rate for relapse following AlloSCS. (25) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. However, the data is insufficient for the use of HPC Boost following AlloSCS for treatment of non-hematological malignancies to lessen post-transplant graft failures. (25, 26, 27, 28)
Short Tandem Repeat (STR) Markers
Following SCS therapy, it is important to determine whether the new blood forming system is of the donor or the recipient, based upon the proportion of donor and recipient cells. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (26. 27) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of central nervous tumors, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (26, 27, 28, 29, 30, 31)
National Comprehensive Cancer Network (NCCN) Guidelines:
For medulloblastoma and sPNET, AuSCS for recurrent disease with maximum safe resection, the 2012 NCCN gave a category 2A recommendation. (32) The 2012 NCCN guidelines on treating CNS tumors do not address the use of AuSCS in treating ependymomas.
National Cancer Institute (NCI) Clinical Trial Database (PDQ®):
- A Phase III study of combination chemotherapy, radiation therapy, and an autologous peripheral blood SCS in treating young patients with AT/RT (NCT00653068, COGACNS0333) is active. The primary purpose of this multi-center study (being undertaken in 87 trial sites across the U.S., Australia, and Canada) is to determine the EFS and OS of children (birth to 21 years of age) with AT/RT treated with surgery, HDC combined with SCS, and radiation therapy. Expected enrollment is 70 patients, with an estimated trial completion date of June 2017.
- A Phase III study of radiation therapy and combination chemotherapy followed by AuSCS in patients with newly diagnosed medulloblastoma, sPNET, or AT/RT (NCT00085202, SJCRH-SJMB03) is active. The purpose of the study is to compare two different regimens of radiation therapy when given together with chemotherapy and AuSCS. Projected accrual is 413 patients, and estimated date of study completion is September 2018.
- A Phase III pilot study of induction chemotherapy followed by consolidation myeloablative chemotherapy comprising thiotepa and carboplatin with or without etoposide followed by AuSCS in pediatric patients with previously untreated malignant brain tumors (NCT00392886; CHLA-HEAD-START-III) is closed. The study compares two alternative induction regimens prior to myeloablative chemotherapy and SCS. Expected enrollment was 120 patients, with an estimated trial completion date in December 2010. The publication date of this study is presently unknown.
- A Phase III randomized study of intensive induction chemotherapy comprising vincristine, etoposide, cyclophosphamide, and cisplatin with or without high-dose methotrexate and leucovorin followed by consolidation chemotherapy comprising carboplatin and thiotepa and peripheral SCS rescue in pediatric patients with newly diagnosed sPNET or high-risk medulloblastoma (NCT00336024, COG-ACNS0334) is active. The study was intended to compare the response rate of induction therapy with or without methotrexate and leucovorin. Expected enrollment is 96 patients, with an estimated trial completion date of September 2018.
- No Phase III randomized trials using SCS for recurrent embryonal CNS tumors are identified.
Data from single-arm studies using AuSCS to treat newly diagnosed CNS embryonal tumors have shown an improved survival benefit (both EFS and OS), particularly in patients with disease that is considered high-risk. In addition, the use of AuSCS 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 AuSCS to treat recurrent CNS embryonal tumors have shown improved survival benefit for some patients.
More data on the use of tandem/triple, allogeneic transplants and DLI for CNS embryonal tumors are needed and are considered experimental, investigational and unproven.
The use of SCS (tandem/triple, autologous, and allogeneic) for ependymoma has not shown a survival benefit compared to the use of conventional approaches, and the coverage regarding ependymoma remains experimental, investigational and unproven. As far as the use of DLI in the treatment of ependymoma, the coverage remains experimental, investigational and unproven due to the lack of peer reviewed scientific literature.
Based on a search of scientific literature in the MedLine database through March 2013, HPC boost to reduce the graft failure process and STR markers to monitor engraftment chimerism for the treatment of embryonal tumors of the CNS or ependymoma are considered experimental, investigational, and unproven due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.