High dose chemotherapy (with or without associated radiotherapy) and autologous bone marrow, stem cell, or progenitor cell support meets primary coverage criteria for effectiveness and is covered for the treatment of recurrent disease, refractory disease, or residual tumor in patients with medulloblastoma and other primitive neuroectodermal tumors (PNETs) (ependymoblastoma, pineoblastoma).

 

Tandem transplants are not covered based on a specific exclusion in the member benefit contract.

 

Allogeneic transplant after previous high dose chemotherapy with autologous stem cell support is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness. .

 

For contracts without primary coverage criteria, allogeneic transplant after previous high dose chemotherapy with autologous stem cell support is considered investigational and is not covered.  Investigational services are an exclusion in the member certificate of coverage.

 

High dose chemotherapy with autologous bone marrow, stem cell or progenitor cell support for the treatment of neuroblastoma is addressed in a separate policy.

Initial therapy of CNS PNETs focuses on neurosurgical resection, plus radiation therapy with or without adjuvant conventional-dose chemotherapy; 60% of children survive 5 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 5 months. HDC was expected to be most effective with minimal disease burden. Thus, Dunkel and colleagues suggested increased surveillance for recurrence, or aggressive surgical debunking 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 pinealoblastoma, 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 4 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 2 years for average-risk patients and 74% for high risk patients.

 

An August 2002 search of the National Cancer Institute (NCI) database on ongoing clinical trials (Physician Data Query [PDQ] database) identified 2 open Phase II trials of HDC plus autologous stem-cell support specifically focused on medulloblastoma or other CNS PNETs. The first uses intensive melphalan and cyclophosphamide for patients with recurrent medulloblastoma (or CNS germ-cell tumors) while the second uses thiotepa plus carboplatin for patients with recurrent medulloblastoma or supratentorial PNETs. The search did not identify any Phase III trials for these patients.

 

Initial treatment of ependymoma consists of maximal surgical resection followed by radiotherapy. Chemotherapy typically 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, 8 died from progressive disease, 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.

 

An updated search conducted in May 2002 for studies published since 1999 failed to identify any new data on outcomes of HDC with autologous stem-cell support for patients with ependymoma. A search of NCI’s PDQ database in August 2002 did not identify any trials of this therapy specifically focused on ependymoma. However, patients with ependymoma were eligible to participate in 4 trials on patients with a variety of malignant brain tumors.

 

An updated literature search was conducted through April 2008. No reports of clinical trials were found 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.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

 

 

 

 

 

 

 

Massimino et al reported outcomes for 28 consecutive patients with non-cerebellar PNET treated from 2000 to 2011 with a high-dose drug schedule (methotrexate, etoposide, cyclophosphamide, and carboplatin with or without vincristine) with autologous stem cell rescue, followed by one of two radiation treatment options (Massimino, 2013).  For the first 15 patients, high-dose chemotherapy and stem cell rescue was followed by hyperfractionated accelerated craniospinal irradiation (CSI) with two 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 non-metastatic and not progressing during induction chemotherapy. Three- and 5-year PFS rates were 69 ± 9% and 62 ± 10%, respectively; 3- and 5-year event-free survival (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), eight due to their tumor, one due to multiorgan failure after the first myeloablative treatment, and two 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 non-pineal tumors (5-year PFS 83±15% vs 54±12%, respectively; P=nonsignificant).

 

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 stem cell transplant, followed by posterior fossa irradiation (Bergthold, 2014). 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 six 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.

 

Kostaras et al conducted a systematic review of therapies for adults with relapsed medulloblastoma, including high-dose chemotherapy with stem cell transplant (Kostaras, 2013). The authors identified 13 publications including 66 adult patients treated with stem cell transplant 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 stem cell transplant, reported that patients with medulloblastoma treated with high-dose chemotherapy with stem cell transplant 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.”

 

Bode et al reported results 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 (Bode, 2014). The intensive-chemotherapy arm included 72 patients, 59 who had disseminated disease. Patients received 2 courses of carboplatin and etoposide; those who had complete or partial remission on MRI received two more cycles of carboplatin and etoposide followed by high-dose chemotherapy 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) months, respectively. Compared with patients with non-medulloblastoma 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 high-dose chemotherapy following complete/partial remission 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 high-dose chemotherapy with stem cell support were compared with 12 patients who had good response to standard chemotherapy but did not receive subsequent high-dose chemotherapy. Median PFS and OS did not significantly differ between those who did and did not received high-dose chemotherapy.

 

Kim et al reported outcomes for 13 patients with refractory or relapsed medulloblastoma or PNET treated with combination high dose chemotherapy (irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide), with an objective tumor response rate of 38.5% (Kim, 2013). However, while the authors note that patients could concurrently receive radiotherapy, surgery, and/or high-dose chemotherapy 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.

 

In 2014, Dufour et al reported outcomes for patients with newly-diagnosed high-risk medulloblastoma and supratentorial PNET treated with tandem high-dose chemotherapy with autologous stem cell support followed by conventional craniospinal radiotherapy (Dufour, 2014). Twenty-four children over the age of 5 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 high-dose chemotherapy, while one patient received only 1 course of high-dose thiotepa due to seizures. Median follow up was 4.4 years (range 0.8 to 11.3 years). Three-year EFS and OS were 79% (95% CI 59 to 91%) and 82% (95% CI 62 to 93%), respectively, while five-year EFS and OS were 65% (95% CI 45 to 81%) and 74% (95% CI 51 to 89%), respectively.

 

 

 

 

 

 

 

 

 

 

 

 

In a study including 26 adult and pediatric patients with sPNET treated with a variety of modalities, Lester and colleagues evaluated factors prognostic for OS and disease-free survival (DFS), including treatment with HSCT (Lester, 2014). Compared with treatment with standard chemotherapy, HSCT was associated with a nonsignificant tendency toward improved DFS (hazard ratio [HR] 0.4, 95% CI 0.1 to 1.0, P=0.07) and improved OS (HR 0.3, 95% CI 0.1 to 1.0, P=0.05). However, these results are confounded by higher rates of HSCT use in children, who had better OS and DFS overall.

 

 

 

 

Sung and colleagues reported prospective follow-up of 13 children with atypical teratoid rhabdoid tumors who received tandem HDC and autologous HCT (Sung, 2016). Five of the children were less than 3 years old; the remaining 8 were 3 years or older. Tandem HDC/auto-HCT was administered after 6 cycles of induction chemotherapy with deferred radiotherapy until age 3 unless the tumor showed relapse or progression in the younger children. Reduced-dose radiotherapy was administered either after 2 cycles of induction chemotherapy or after surgery with tandem HDC/auto-HCT after 6 cycles of induction chemotherapy in the older children. All 5 younger children died from disease progression. Four of the 8 older children remained progression-free with median follow-up of 64 months.