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.
Primitive Neuroectodermal Tumor (PNET) of the Central Nervous System (CNS)
Initial therapy of CNS PNETs focuses on neurosurgical resection, plus radiation therapy with or without adjuvant conventional-dose chemotherapy; 60% of children survive five years or more with this approach. In patients with residual tumor or recurrent disease, further surgery or radiation therapy usually is not an option, and conventional chemotherapy rarely is successful. Therefore, HDC for CNS PNET has focused primarily on residual or recurrent disease. The most common CNS PNET is medulloblastoma, and thus, most studies focus on this diagnosis.
This policy was initially based on a literature search for studies published through 1999. No comparative trials were found. The largest case series included 23 patients with recurrent medulloblastoma treated with high-dose carboplatin, thiotepa, and etoposide. Seven patients were event-free survivors at a median of 54 months, with overall survival estimated at 46% at 36 months. In contrast, the median survival after recurrent medulloblastoma treated with conventional therapy may be as low as five months. HDC 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.
Other CNS PNETs are uncommon and include pinealblastoma, ependymoblastoma, and central neuroblastoma. There were few data regarding high-dose therapy for these rare tumors, although it was thought that the results with medulloblastoma may be extrapolated to other PNETs.
An updated literature search was conducted in May 2002 for studies published since 1999. The only new data were from a study including 53 patients with newly diagnosed medulloblastoma or supratentorial PNETs, 19 of whom had high-risk disease and 34 had average-risk disease. After surgery and radiotherapy, the study used four cycles of HDC with cyclophosphamide, cisplatin, and vincristine, followed by autologous stem-cell support. Patients with high-risk disease also received topotecan between surgery and radiotherapy. Early actuarial analysis of outcomes yielded estimates of 94% progression-free survival at two years for average-risk patients and 74% for high-risk patients.
Subsequent literature searches identified no new randomized clinical trial publications that would alter the policy statement. Two recent clinical series report outcomes in children with newly diagnosed medulloblastoma or PNET. In the first study (n=134 cases), following maximum tumor resection, all patients received risk-adapted craniospinal radiotherapy followed by four cycles of cyclophosphamide-based HDC with autologous stem-cell rescue. After resection, patients were classified as having average-risk disease (<1.5 cm2 residual tumor and no metastatic disease) or high-risk disease (>1.5 cm2 residual tumor or metastatic disease localized to the neuraxis). Five-year overall survival (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 event-free survival (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. These results provide further support for the use of dose-intensive chemotherapy in high-risk medulloblastoma cases. In the second series, single or tandem double HDC with autologous stem-cell rescue was administered to 25 children with newly diagnosed high-risk or relapsed medulloblastoma or PNET following surgical resection. 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, three year EFS was 89% in the tandem double group and 44% in the single HDC group, respectively. Four treatment-related deaths occurred, and in four of eight young children craniospinal radiotherapy was successfully withheld without relapse. These results also suggest HDC may improve the survival of children with newly diagnosed high-risk medulloblastomas or PNET, but further study in RCTs is needed to establish the role of the tandem approach.
Additional Review of Literature Through 2008
The National Cancer Institute (NCI) Physician Data Query (PDQ®) database lists the following ongoing Phase III randomized clinical trials for PNETs:
- Phase III study of radiotherapy, high-dose cisplatin, vincristine, and cyclophosphamide, and autologous stem-cell rescue in patients with newly diagnosed medulloblastoma, supratentorial primitive neuroectodermal tumor, or atypical teratoid rhabdoid tumor (SJCRH-SJMB03). The estimated date of completion is August 2010.
- Phase III pilot study of induction chemotherapy followed by consolidation myeloablative chemotherapy comprising thiotepa and carboplatin with or without etoposide and autologous hematopoietic stem cell rescue in pediatric patients with previously untreated malignant brain tumors (CHLA-HEAD-START-III). Active as of April, 22, 2008.
- Phase III randomized study of intensive induction chemotherapy comprising vincristine, etoposide, cyclophosphamide, and cisplatin in combination with high-dose methotrexate and leucovorin calcium followed by consolidation chemotherapy comprising carboplatin and thiotepa and peripheral blood stem cell rescue compared to the complete response rate in patients given the same regimen without high-dose methotrexate and leucovorin calcium (COG-ACNS0334). Active as of April 22, 2008—estimated completion in October 2007.
The 2007/2008(v.1.2008) National Comprehensive Cancer Network Guidelines on Central Nervous System Cancers do not address HDC with stem-cell support for PNET of the CNS.
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, HDC has been investigated as a possible salvage therapy. Literature published through 1999 regarding HDC for ependymoma consisted primarily of small case series. For example, Mason and colleagues reported on a case series of 15 patients with recurrent ependymoma. Five patients died of treatment-related toxicities, eight died from progressive disease, and one died of unrelated causes. After 25 months, one 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.
Literature searches failed to identify new randomized, controlled trial data on outcomes of HDC with hematopoietic stem-cell support for patients with ependymoma. 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 HDC and autologous SCT following intensive induction chemotherapy to treat newly diagnosed ependymoma. Importantly, radiation-free survival was only 8% (+ 5%) in these cases. The results of these series, although limited in size, further suggest HDC with SCT is not superior to other previously reported chemotherapeutic approaches.
Additional Review of Literature Through 2008
An updated literature search resulted in no reports of clinical trials that would alter the policy statement.
Patients with ependymoma are eligible to participate in the CHLA-HEAD-START-III trial (noted in the previous section).
The 2007/2008 National Comprehensive Cancer Network Guidelines on Central Nervous System Tumors do not address HDC with stem-cell support for ependymoma in the pediatric population.
Tandem or Triple Stem-Cell Transplant and Donor Leukocyte Infusion (DLI) for PNETs and ependymoma are considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.