Medical Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Solid Tumors in Children

Number:SUR703.044

Effective Date:06-15-2018

Coverage:

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Autologous hematopoietic stem-cell transplantation (HSCT) may be considered medically necessary for:

Initial treatment of high-risk neuroblastoma,

Recurrent or refractory neuroblastoma,

Initial treatment of high-risk Ewing sarcoma,

Recurrent or refractory Ewing sarcoma, and

Metastatic retinoblastoma.

Autologous HSCT is considered experimental, investigational and/or unproven as initial treatment of low- or intermediate-risk neuroblastoma, initial treatment of low- or intermediate-risk Ewing sarcoma, and for other solid tumors of childhood including, but not limited, to the following:

Rhabdomyosarcoma,

Wilms’ tumor,

Osteosarcoma, or

Retinoblastoma without metastasis.

Allogeneic (following myeloablative or nonmyeloablative preparative regimen) HSCT is considered experimental, investigational and/or unproven for treatment of pediatric solid tumors.

Tandem autologous HSCT may be considered medically necessary for high-risk neuroblastoma, characterized by an age older than 1 year, disseminated disease, MYCN oncogene amplification, and unfavorable histopathological findings. (Refer to Description section for neuroblastoma staging and risk grouping information.)

Tandem autologous HSCT is considered experimental, investigational and/or unproven for the treatment of all other types of pediatric solid tumors except high-risk neuroblastoma, as was noted above.

Salvage allogeneic HSCT for pediatric solid tumors is considered experimental, investigational and/or unproven including but not limited to the following indications:

Relapsed neuroblastoma or Ewing’s sarcoma after a failed autologous transplant,

Failure to respond as an initial treatment of low- or intermediate risk neuroblastoma, or

Allogeneic transplant for any stage of Ewing’s sarcoma as an initial treatment.

NOTE 1:

Relapse is defined as tumor recurrence after a prior complete response.

Primary refractory disease is defined as not achieving a complete remission after initial standard-dose (i.e., myeloablative) chemotherapy.

NOTE 2: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.

Description:

Hematopoietic Stem-Cell Transplantation (HSCT)

HSCT refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem-cells in it are antigenically “naive” and thus, are associated with a lower incidence of rejection or graft-versus-host disease (GVHD).

Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

Solid Tumors of Childhood

Solid tumors of childhood arise from mesodermal, ectodermal, and endodermal cells of origin. (1) Some common solid tumors of childhood are neuroblastoma, Ewing sarcoma/Ewing sarcoma family of tumors (ESFT), Wilms tumor, rhabdomyosarcoma (RMS), osteosarcoma, and retinoblastoma.

The prognosis for pediatric solid tumors has improved more recently, mostly due to the application of multiagent chemotherapy and improvements in local control therapy (including aggressive surgery and advancements in radiotherapy). (2) However, patients with metastatic, refractory, or recurrent disease continue to have poor prognoses, and these “high-risk” patients are candidates for more aggressive therapy, including autologous HSCT, in an effort to improve event-free survival (EFS) and overall survival (OS).

NOTE 3: Other solid tumors of childhood include germ-cell tumors, which are considered in medical policy SUR703.045, Hematopoietic Stem-Cell Transplantation in the Treatment of Germ-Cell Tumors. For solid tumors classified as embryonal tumors arising in the central nervous system (CNS), refer to medical policy SUR703.039, Hematopoietic Stem-Cell Transplantation for Central Nervous System Embryonal Tumors and Ependymoma and for and for CNS tumors derived from glial cells (i.e., astrocytoma, oligodendroglioma, or glioblastoma multiforme) review medical policy SUR703.042, Hematopoietic Stem-Cell Transplantation for Malignant Astrocytomas and Gliomas.

Descriptions of the solid tumors of childhood addressed in this medical policy are as follows.

Peripheral Neuroblastoma

Neuroblastoma is the most common extracranial solid tumor of childhood, (1) with approximately 90% of cases presenting in children younger than 5 years of age. (3) These tumors originate where sympathetic nervous system tissue is present, within the adrenal medulla or paraspinal sympathetic ganglia, but have diverse clinical behavior depending on a variety of risk factors.

Patients with neuroblastoma are stratified into prognostic risk groups (low, intermediate, high) that determine treatment plans. Risk variables include age at diagnosis, clinical stage of disease, tumor histology, and certain molecular characteristics, including the presence of the MYCN (myelocytomatosis viral related) oncogene. Tumor histology is categorized as favorable or unfavorable, according to the degree of tumor differentiation, proportion of tumor stromal component, and index of cellular proliferation. (4) It is well-established that MYCN amplification is associated with rapid tumor progression and a poor prognosis, (5) even in the setting of other coexisting favorable factors. Loss of heterozygosity (LOH) at chromosome arms 1p and 11q occurs frequently in neuroblastoma. (6) Although 1p LOH is associated with MYCN amplification, 11q is usually found in tumors without this abnormality. (6) Some recent studies have shown that 1p LOH and unbalanced 11q LOH are strongly associated with outcome in patients with neuroblastoma, and both are independently predictive of worse progression-free survival (PFS) in patients with low- and intermediate-risk disease. (4) Although the use of these LOH markers in assigning treatment in patients is evolving, they may prove useful to stratify treatment.

In the early 1990s, a uniform clinical staging system based on surgical resectability and distant spread, the International Neuroblastoma Staging System (INSS), (4) was adopted by pediatric cooperative groups (see Table 1).

Table 1. International Neuroblastoma Staging System (4)

Stage

Description

1

Localized tumor with complete gross excision, with or without microscopic residual disease; lymph nodes negative for tumor.

2A

Localized tumor with incomplete gross excision; lymph nodes negative for tumor.

2B

Localized tumor with or without complete gross excision, with ipsilateral lymph nodes positive for tumor.

3

Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration or by lymph node involvement.

4

Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S.

4S

Localized primary tumor as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (marrow involvement less than 10%), limited to children younger than 1 year of age.

The low-risk group includes patients younger than 1 year of age with stage 1, 2, or 4S with favorable histopathologic findings and no MYCN oncogene amplification. High-risk neuroblastoma is characterized by age older than 1 year, disseminated disease, MYCN oncogene amplification, and unfavorable histopathologic findings.

In 2009, the International Neuroblastoma Risk Group Staging System proposed a revised staging system, which incorporated pretreatment imaging parameters instead of surgical findings (see Table 2). (7)

Table 2. International Neuroblastoma Risk Group Staging System (7)

Stage

Description

L1

Localized tumor not involving vital structures as defined by the list of image-defined risk factors and confined to one body compartment.

L2

Locoregional tumor with presence of one or more image-defined risk factors.

M

Distant metastatic disease (except stage MS).

MS

Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow.

Table Key:

L: local/localized/locoregional;

M: metastatic.

In general, most patients with low-stage disease have excellent outcomes with minimal therapy; and with INSS stage-1 disease, most patients can be treated by surgery alone. (8) Most infants, even with disseminated disease, have favorable outcomes with chemotherapy and surgery. (8) In contrast, most children older than 1 year with advanced-stage disease die due to progressive disease, despite intensive multimodality therapy, (8) and relapse remains common.

For intermediate-risk disease, moderately intensive multiagent chemotherapy is the mainstay of therapy. (9) Surgery is needed to obtain a diagnosis, and the extent of resection necessary to obtain an optimal outcome is not clearly established. (10) Patients at high-risk have historically had very low (<15%) long-term OS. Current therapy for high-risk disease typically includes an aggressive multimodal approach with chemotherapy, surgical resection, and radiotherapy. (11)

Treatment of recurrent disease is determined by the risk group at the time of diagnosis and the extent of disease and age of the patient at recurrence.

Ewing Sarcoma Family of Tumors (ESFT)

ESFT encompasses a group of tumors that share some degree of neuroglial differentiation and a characteristic underlying molecular pathogenesis (chromosomal translocation). The translocation usually involves chromosome 22 and results in fusion of the EWS (Ewing sarcoma) gene with one of the members of the ETS (E-twenty-six) family of transcription factors, either FLI1 (90%-95%) or ERG (5%-10%). These fusion products function as oncogenic aberrant transcription factors. Detection of these fusions is considered to be specific for the ESFT and helps further validate diagnosis. Included in ESFT are “classic” Ewing sarcoma of bone, extraosseous Ewing, peripheral primitive neuroectodermal tumor (pPNET), and Askin tumors (chest wall).

Most commonly diagnosed in adolescence, ESFT can be found in bone (most commonly) or soft tissue; however, the spectrum of ESFT has also been described in various organ systems. Ewing is the second most common primary malignant bone tumor. The most common primary sites are the pelvic bones, the long bones of the lower extremities, and the bones of the chest wall.

Current therapy for Ewing sarcoma typically includes induction chemotherapy, followed by local control with surgery and/or radiation (dependent on tumor size and location), followed by adjuvant chemotherapy. Multiagent chemotherapy, surgery, and radiotherapy have improved PFS in patients with localized disease to 60% to 70%. (12) The presence of metastatic disease is the most unfavorable prognostic feature, and the outcome for patients presenting with metastatic disease is poor, with 20% to 30% PFS. Other adverse prognostic factors that may categorize a patient as having “high-risk” Ewing are tumor location (e.g., patients with pelvic primaries have worse outcomes), larger tumor size, and older age of the patient. However, “high-risk” Ewing has not always been consistently defined in the literature. (69)

Rhabdomyosarcoma (RMS)

RMS, the most common soft tissue sarcoma of childhood, shows skeletal muscle differentiation. The most common primary sites are the head and neck (e.g., parameningeal, orbital, pharyngeal), genitourinary tract, and extremities. (13) Specific treatment is based on tumor location, resection, and node status, and may involve surgery, radiotherapy, and chemotherapy. (14) Five-year survival rates for RMS increased between 1975 and 2010 from 53% to 67% in children younger than 15 years and from 30% to 51% in 15- to 19-year-olds. (13)

Approximately 15% of children present with metastatic disease, and despite the introduction of new drugs and intensified treatment, the 5-year survival is 20% to 30% for this “high-risk” group. (15, 16) Similarly, post relapse mortality is very high. The prognosis of metastatic disease is affected by tumor histology, age at diagnosis, the site of metastatic disease, and the number of metastatic sites. (13)

Wilms Tumor

Wilms tumor is the most common primary malignant renal tumor of childhood. (70) In the United States, Wilms tumor is staged using the National Wilms Tumor Study system, which is based on surgical evaluation before chemotherapy (see Table 3). (17)

Table 3. National Wilms Tumor Study Staging (17)

Stage

Description

I

a) Tumor is limited to the kidney and completely excised;

b) The tumor was not ruptured before or during removal;

c) The vessels of the renal sinus are not involved beyond 2 mm;

d) There is no residual tumor apparent beyond the margins of excision.

II

a) Tumor extends beyond the kidney but is completely excised;

b) No residual tumor is apparent at or beyond the margins of excision;

c) Tumor thrombus in vessels outside the kidney is stage II if the thrombus is removed en bloc with the tumor.

III

Residual tumor confined to the abdomen:

a) Lymph nodes in the renal hilum, the periaortic chains, or beyond are found to contain tumor;

b) Diffuse peritoneal contamination by the tumor;

c) Implants are found on the peritoneal surfaces;

d) Tumor extends beyond the surgical margins either microscopically or grossly;

e) Tumor is not completely resectable because of local infiltration into vital structures.

IV

Presence of hematogenous metastases or metastases to distant lymph nodes.

V

Bilateral renal involvement at the time of initial diagnosis.

In the United States, National Wilms Tumor Study and Children’s Oncology Group protocols rely on primary resection for unilateral tumors, followed by escalating levels of chemotherapy and radiation depending on tumor stage and other prognostic factors. Tumor histology, tumor stage, molecular and genetic markers (e.g., loss of heterozygosity at chromosome 16q), and age (>2 years) are all associated with increased risks of recurrence and death. Wilms tumors are highly sensitive to chemotherapy and radiation, and current cure rates exceed 85%. (18) Between 10% and 15% of patients with favorable histology and 50% of patients with anaplastic tumors, experience tumor progression or relapse. (18)

Similar risk-adapted strategies are being tested for the 15% of patients who experience relapse. Success rates after relapse range from 25% to 45%. For patients with adverse prognostic factors (histologically anaplastic tumors, relapse <6 to 12 months after nephrectomy, second or subsequent relapse, relapse within the radiation field, bone or brain metastases), EFS is less than 15%. (19)

Osteosarcoma

Osteosarcoma is a primary malignant bone tumor and the most common bone cancer in children and adolescents; it is characterized by formation of bone or osteoid by the tumor cells. Peak incidence occurs around puberty, most commonly in long bones such as the femur or humerus. Osteosarcomas are characterized by variants in the TP53 tumor suppressor gene.

The prognosis of osteosarcoma has greatly improved, with 5-year survival rates increasing between 1975 and 2010 from 40% to 76% in children younger than 15 years and from 56% to 66% in 15- to 19-year olds. Prognostic factors for patients with localized disease include site and size of the primary tumor, presence of metastases at the time of diagnosis, resection adequacy, and tumor response to neoadjuvant chemotherapy. For patients with recurrent osteosarcoma, the most important prognostic factor is surgical resectability. There is a 5-year survival rate of 20% to 45% in patients who had complete resection of metastatic pulmonary tumors and a 20% survival rate for patients with metastatic tumors at other sites. (20)

Retinoblastoma

Retinoblastoma is the most common primary tumor of the eye in children. It may occur as a heritable (25%-30%) or nonheritable (70%-75%) tumor. (21) Cases may be unilateral or bilateral, with bilateral tumors almost always being the heritable type. Treatment options depend on the extent of disease. Retinoblastoma is usually confined to the eye, and with current therapy has a high cure rate. However, once disease spreads beyond the eye, survival rates drop significantly; 5-year disease-free survival (DFS) is reported to be less than 10% in those with extraocular disease, and stage 4B disease (i.e., disease metastatic to the CNS) has been lethal in virtually all cases reported. (22)

The strategy for nonmetastatic disease depends on the disease extent, but may include focal therapies (e.g., laser photocoagulation, cryotherapy, plaque radiotherapy), intravitreal chemotherapy, intra-arterial chemotherapy, systemic chemotherapy, enucleation, or a combination. (23) For metastatic disease, intensive multimodal therapy with HDC, with or without radiotherapy, is standard care.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (71) Hematopoietic stem-cells are included in these regulations.

Rationale:

This policy was originally created in 1990, moved to this policy in 2010. This policy has been updated periodically with reviews of the MedLine database. The most recent literature review was performed through June 2017. While the coverage of this policy does not address myeloablative (MA) or reduced intensity conditioning (RIC) prior to hematopoietic stem-cell transplantation (HSCT), discussion of HSCT outcomes maybe influenced by the type of preparative conditioning completed prior to the transplantation. The following is a summary of the key literature to date.

Peripheral Neuroblastoma

Single Autologous HSCT

Systematic Reviews

A 2013 Cochrane review evaluated high-dose chemotherapy (HDC) and autologous HSCT for high-risk neuroblastomas. (24) Reviewers identified 3 randomized controlled trials (RCTs) that included 739 children with high-risk neuroblastoma (Matthay et al. [1999], (25) Berthold et al. [2005], (26) Pritchard et al. [2005], (27) detailed in the RCT section below). The review was updated in 2015 with no new studies identified, although a manuscript reporting additional follow-up data for one of these RCTs was noted. (28) The primary objective was to compare the efficacy of MA therapy with conventional therapy. Selected studies all used the age of 1 year as the cutoff point for pretreatment risk stratification. A statistically significant difference in event-free survival (EFS) was observed in favor of MA therapy over conventional chemotherapy or no further treatment (3 studies, 739 patients; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67 to 0.90). A statistically significant difference in overall survival (OS) was reported in favor of MA therapy over conventional chemotherapy or no further treatment (2 studies, 360 patients; HR=0.74; 95% CI, 0.57 to 0.98). When additional follow-up data were included in analyses, the difference in EFS remained statistically significant (3 studies, 739 patients; HR=0.79; 95% CI, 0.70 to 0.90), but the difference in OS was no longer statistically significant (2 studies, 360 patients; HR=0.86; 95% CI, 0.73 to 1.01). Metaanalysis of secondary malignant disease and treatment-related death did not show any statistically significant differences between treatment groups. Data from 1 study (379 patients) showed a significantly higher incidence of renal effects, interstitial pneumonitis, and veno-occlusive disease in the MA group compared with conventional chemotherapy, whereas for serious infections and sepsis, no significant differences between treatment groups were identified. No information on quality of life was reported.

RCTs

Three well-designed, randomized trials have assessed autologous HSCT in the treatment of high-risk neuroblastoma. In a study published in 1999, Matthay et al. randomized 129 children with high-risk neuroblastoma to a combination of MA chemotherapy, total body irradiation, and transplantation of autologous bone marrow and compared their outcomes to those of 150 children randomized to intensive nonmyeloablative chemotherapy; both groups underwent a second randomization to receive subsequent 13-cis-retinoic acid (cis-RA) or no further therapy. (25) The 3-year EFS rate among patients assigned to transplantation was 43% versus 27% among those assigned to continuation chemotherapy (p=0.027). However, OS rates for both groups did not differ significantly, with 3-year estimates of 43% or 44% for those assigned to transplant and to continued chemotherapy, respectively (p=0.87).

Long-term results from this trial were reported in 2009 after a median follow-up of 7.7 years (range, 130 days to 12.8 years). (29) Five-year EFS for patients who underwent autologous transplant was 30% versus 19% for those who underwent nonmyeloablative chemotherapy (p=0.04). Five-year OS rates from the second randomization of patients who underwent both random assignments were 59% (SD [standard deviation] =8%) for autologous transplant/cis-RA, 41% for autologous transplant/no cis-RS, and, for nonmyeloablative chemotherapy, 38% and 36% with and without cis-RA. Authors concluded that MA chemotherapy and autologous HSCT resulted in a significantly better 5-year EFS and OS rates.

In a 2005 study, Berthold et al. randomized 295 patients with high-risk neuroblastoma to MA therapy (melphalan, etoposide, carboplatin) with autologous HSCT or to oral maintenance chemotherapy with cyclophosphamide. (26) The primary end point was EFS, with secondary end points of OS and treatment-related deaths. Intention-to-treat (ITT) analysis showed that patients who received the MA therapy had an increased 3-year EFS compared with the oral maintenance group (47% [95% CI, 38% to 55%] versus 31% [95% CI, 23% to 39%]), but did not have significantly increased 3-year OS (62% [95% CI, 54% to 70%] vs 53% [95% CI, 45% to 62%]; p=0.088). Two patients died from therapy-related complications during induction; no patients who received oral maintenance therapy died from treatment-related toxic effects; and 5 patients who received MA therapy died from acute complications related to the therapy.

In 2005, Pritchard et al. reported the results of a randomized, multicenter trial that involved 167 children with stage 3 or 4 neuroblastoma treated with standard induction chemotherapy who then underwent surgical resection of their tumor. (27) Sixty-nine percent of the patients (n=90) who achieved complete response (CR) or partial response (PR) to the induction chemotherapy were eligible for randomization to HDC (melphalan) with autologous HSCT or to no further treatment (NFT). Seventy-two percent (n=65) of the eligible children were randomized, with 21 surviving at the time of the analysis (median follow-up, 14.3 years). A significant difference in the 5-year EFS and OS rates were seen in children older than 1 year of age with stage 4 disease (48 children with stage 4; 5-year EFS, 33% for HDC vs 17% for NFT; p=0.01).

Observational Studies

The use of HSCT in patients with high-risk neuroblastoma has been supported in clinical practice. For example, in 2016, Proust-Houdemont et al. reported on a 30-year single-center series including 215 patients with stage 4, high-risk neuroblastoma treated with HDC (busulfan) with HSCT. (30) In this cohort, 5-year EFS and OS rates were 35.1% and 40%, respectively, and improved from baseline to the end of reporting period.

Tandem Autologous HSCT

RCTs

A pilot multicenter phase III study was completed in 2016 targeting high-risk neuroblastoma, with results published by Park et al. (72) The RCT compared tandem versus single consolidation HSCT. Six hundred fifty-two patients were eligible for randomization and received 6 cycles of HDC, including 2 cycles of dose-intensive cyclophosphamide/topotecan followed by autologous peripheral blood stem-cell collection. Randomization occurred at end of induction to single autologous HSCT with carboplatin-etoposide-melphalan (CEM) or tandem autologous HSCT with thiotepa-cyclophosphamide (TC) followed by a modified CEM (TC:CEM). Patients with non-MYCN amplified stage 3 (age >18 months) or stage 4 (age 12-18 months) tumors were non-randomly assigned to a single autologous HSCT. EFS and OS were analyzed as ITT. Median age was 3.1 years, 88% (N=574 patients) had stage 4 disease and 38.2% (N=249 tumors) had MYCN amplification. A total of 355 patients were randomized (CEM N=179 patients and TC:CEM N=176 patients) and 27 patients were non-randomly assigned (non-amplified group). Of the randomized patients, 249 received post-consolidation immunotherapy. The treatment-related mortality was 2.6%. The secondary measure outcome results have yet to be published for the non-MYCN amplified patients as time-frame for follow-up is targeted for up to 3 years. Per ClinicalTrials.gov, there has been no statistical analysis provided for the EFS patients non-randomly assigned to the single CEM stage 3 or 4 non-MYCN amplified tumor/unfavorable or indeterminate histopathology/diploid DNA content patients.

Nonrandomized Comparative Studies

In 2010, Sung et al. reported on a retrospective analysis of the efficacy of single versus tandem autologous HSCT in patients older than 1 year of age newly diagnosed with stage 4 neuroblastoma from 2000 to 2005 who were enrolled in the Korean Society of Pediatric Hematology-Oncology registry. (31) Patients were intended to receive a single (n=70) or tandem (n=71) autologous HSCT at diagnosis; 57 and 59 patients underwent single and tandem transplantation as scheduled, respectively. Between groups, patient characteristics were similar with the exception of a higher proportion in the tandem group having bone metastases. Median follow-up was 56 months (range, 24-88 months) from diagnosis. Transplant-related mortality (TRM) occurred in 9 patients in the single transplant group and in 8 in the tandem group (2 after the first transplant and 6 after the second). The ITT survival rate for 5-year EFS for single versus tandem was 31.3% and 51.2%, respectively (p=0.03). When the survival analysis only included patients who proceeded to transplant, the probability of relapse-free survival (RFS) after the first transplant was higher in the tandem group (59.1%, SD=13.5%) than the single group (41.6%, SD=14.5%; p=0.099). The difference was statistically significant when the analysis focused on patients who did not achieve a CR before the first transplant (55.7% versus 0%, p=0.012). The authors concluded that tandem HSCT for high-risk neuroblastoma is superior to single HSCT in terms of survival, particularly in patients without CR before HSCT.

In 2008, Ladenstein et al. reported on more than 4000 transplants for primary (89%) and relapsed (11%) neuroblastoma over 28 years in 27 European countries in the European Group for Blood and Marrow Transplantation (EGBMT) registry. (32) Procedures included single autologous (n=2895), tandem autologous (n=455), and allogeneic HSCT (n=71). Median age at the time of transplantation was 3.9 years (range, 0.3-62 years), with 77 patients older than age 18 years. Median follow-up from HSCT was 9 years. TRM decreased over time in registry patients who only received autologous transplants. Five-year OS rates were 37% for the autologous groups (single and tandem) and 25% for the allogeneic group. Five-year OS for single versus tandem autologous HCT was 38% versus 33%, respectively (p=0.105).

Single-Arm Studies

In 2006, George et al. reported on a 4-institution, single-arm clinical trial to evaluate tandem autologous HSCT in pediatric patients with high-risk neuroblastoma (n=82) enrolled between 1994 and 2002. (33) Median age at diagnosis was 35 months (range, 6 months to 18 years). Three- and 5-year OS rates were 74% (95% CI, 62% to 82%) and 64% (95% CI, 52% to 74%), respectively.

In 2002, Kletzel et al. reported on a single-center pilot study evaluating the outcomes for 25 consecutive newly diagnosed high-risk neuroblastoma patients and 1 with recurrent disease treated with triple-tandem autologous HSCT. (34) After stem-cell rescue, patients were treated with radiotherapy to the primary site. Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Seventeen patients completed all 3 cycles of high-dose therapy and stem-cell rescue, 2 patients completed 2 cycles, and 3 patients completed 1 cycle. One toxicity-related death occurred, and 1 patient died from complications of graft failure. Median follow-up was 38 months, and the 3-year EFS and OS rates were 57% and 79%, respectively.

In 2000, Grupp et al. reported outcomes for a phase 2 trial involving 55 children with high-risk neuroblastoma who underwent tandem autologous HSCT. (35) Five patients completed the first HSCT course but not the second. There were 4 toxicity-related deaths. With a median follow-up of 24 months from diagnosis, 3-year EFS was 59%.

Case Series

In 2016, in a retrospective analysis of prospectively collected data, Pasqualini et al. reported on a series of 26 patients with very high-risk neuroblastoma treated with tandem autologous HSCT from 2004 to 2011 at a single center. (36) Criteria for “very high-risk” included stage 4 neuroblastoma at diagnosis or relapse, age over 1 year at diagnosis, less than a PR of metastases, and more than 3 metaiodobenzylguanidine spots after 2 lines of conventional chemotherapy in patients under 10 years old or no CR of metastases after 1 line of conventional chemotherapy in patients over 10 years old. Median age was 4.4 years (range, 1-15.9 years). Of the 26 patients, 22 were stage 4 at diagnosis; 4 patients had a stage 3 tumor at diagnosis and a metastatic relapse. Three-year EFS and OS rates after diagnosis were 37.3% (95% CI, 21.3% to 56.7%) and 69.0% (95% CI, 49.7% to 83.4%), respectively.

In 2007, Kim et al. retrospectively analyzed 36 patients with high-risk (stage 3 or 4) neuroblastoma who underwent a single autologous HSCT (n=27) or a tandem autologous HSCT (n=9) at a children’s hospital in Seoul, Korea, between 1996 and 2004. (37) Disease-free survival (DFS) of patients who underwent double HSCT was similar to that of those who underwent a single autologous HSCT (p=0.5).

In 2003, Marcus et al. reported on outcomes for 52 children with stage 4 or high-risk stage 3 neuroblastoma treated with induction chemotherapy, surgical resection of the tumor when feasible, local radiotherapy, and consolidation with tandem autologous HSCT. (38) Radiotherapy was given if gross or microscopic residual disease was present before the MA cycles (n=37). Of the 52 consecutively treated patients analyzed, 44 underwent both transplants, 6 underwent a single transplant, and 2 progressed during induction. The 3-year EFS was 63%, with a median follow-up of 29.5 months.

In 2005, von Allmen et al. reported on a retrospective series from the same center as Marcus et al., with some overlap in patients. (39) The updated series included 76 patients with previously untreated high-risk stage 3 or 4 neuroblastoma treated with aggressive surgical resection with or without local radiotherapy followed by tandem autologous HDC and stem-cell rescue. Overall EFS for the series was 56%.

Allogeneic HSCT

In recent years, neuroblastoma has not been among the most common indication to be treated with allogeneic HSCT. (72) A report of the HSCT activity in pediatric cancers between 2008 to 2014 was published by Khandelwal et al. in 2017. (72) Leukemia was the most common indication for an allogeneic transplant (94%). The role of autologous HSCT is well established to treat neuroblastoma, in contrast to the role of allogeneic HSCT being controversial. (73) Hale et al. reported allogeneic HSCT may cure some neuroblastoma patients, particularly when following a prior autologous HSCT. The data reviewed did not address patient selection or the strategy used for patients whether to follow an autologous HSCT or not.

Section Summary: Peripheral Neuroblastoma

No studies directly comparing single autologous and tandem autologous HSCT for high-risk neuroblastoma have been published, which includes the Park et al. study presented to the American Society of Clinical Oncology in 2016. (74) . Randomized trials comparing single autologous HSCT with conventional chemotherapy have reported EFS rates for the patients who underwent HSCT ranging from 43% to 47% at 3 years and 30% at 5 years. Case series on the use of tandem autologous for high-risk neuroblastoma have reported 3-year EFS rates ranging from 57% to 63%. A retrospective analysis of a registry of patients with newly diagnosed high-risk neuroblastoma reported 5-year EFS rates for single and tandem autologous HSCT of 31% and 51%, respectively (p=0.03). The literature is scant when accessing allogeneic HSCT as an option for patients with neuroblastoma

Ewing Sarcoma Family of Tumors (ESFT)

Single Autologous HSCT

During the 1980s and 1990s, several small series, case reports, and a report from the EGBMT Registry suggested that autologous HSCT could improve outcomes for patients with high-risk ESFT. (40) These early results support use of HSCT for high-risk ESFT.

Subsequently, in 2001, Meyers et al. reported on a prospective study with autologous HSCT in 32 patients with newly diagnosed Ewing sarcoma metastatic to bone and/or bone marrow. Induction therapy consisted of 5 cycles of cyclophosphamide-doxorubicin-vincristine, alternating with ifosfamide-etoposide. (41) Twenty-three patients proceeded to the consolidation phase with melphalan, etoposide, total body irradiation, and autologous HSCT (of the 9 patients who did not proceed, 2 were secondary to toxicity and 4 to progressive disease). Three patients died during the HDC phase. Two-year EFS for all eligible patients was 20% and 24% for the 29 patients who received the high-dose consolidation therapy. Trialists concluded that consolidation with HDC, total body irradiation, and autologous stem-cell support failed to improve EFS for this cohort of patients compared with a similar group of patients treated with conventional therapy. Authors noted that their findings differed from some previous studies, and that the previous studies suffered from heterogeneous patient populations. They concluded that future trials of autologous HSCT must be conducted prospectively, identify a group at high-risk for failure, and enroll all patients in the study at the same point in therapy.

Gardner et al. (2008) reported the results of 116 patients with Ewing sarcoma who underwent autologous HSCT (80 as first-line therapy, 36 for recurrent disease) between 1989 and 2000. (42) Five-year rates of progression-free survival (PFS) in patients who received HSCT as first-line therapy were 49% (95% CI, 30% to 69%) for those with localized disease at diagnosis and 34% (95% CI, 22% to 47%) for those with metastatic disease at diagnosis. For the population with localized disease at diagnosis and recurrent disease, the 5-year probability of PFS was 14% (95% CI, 3% to 30%). The authors concluded that PFS rates after autologous HSCT were comparable with rates seen in patients with similar disease characteristics treated with conventional therapy.

In 2010, Ladenstein et al. reported on patients with primary disseminated multifocal Ewing sarcoma (PDMES) who were included in the Euro-EWING 99 trial. (43) From 1999 to 2005, 281 patients with PDMES were enrolled in the Euro-EWING 99 R3 study; the Euro-EWING 99 committee stopped enrollment to this group and release the data. Median age was 16.2 years (range, 0.4-49 years). Patients with isolated lung metastases were not part of the analysis. The recommended treatment consisted of induction chemotherapy, HDC, autologous HSCT, and local treatment to the primary tumor (surgery and/or radiation or neither). Induction therapy was completed by 250 (89%) of patients. One hundred sixty-nine (60%) of the patients proceeded to HSCT. One patient died during induction therapy from sepsis. HDC TRM consisted of 3 patients dying within the first 100 days after high-dose therapy, 1 from acute respiratory distress syndrome and 2 from severe veno-occlusive disease and septicemia; late deaths included 3 patients who died 1 to 1.5 years after high-dose therapy. After a median follow-up of 3.8 years, the estimated 3-year EFS and OS rates for all 281 patients were 27% and 34%, respectively.

Tandem Autologous HSCT

In 2015, Loschi et al. reported on a series of 18 patients with PDMES under age 25 treated with tandem HSCT at a single institution from 2002 to 2009. (44) Of the 18 patients with PDMES planned for tandem HSCT, 15 (83%) received the first HSCT, and 13 (72%) received the full-tandem HSCT program, due to progressive disease before stem-cell harvest could be obtained. Eleven patients had no disease progression by the end of the HSCT program, but 9 of the 11 had relapsed, at a median delay of 6.2 months (range, 2.5-14.1 months). Median EFS and OS rates were 13.5 and 17.3 months, respectively.

Section Summary: ESFT

Studies of HSCT in patients with ESFT are characterized by small numbers of patients, and comparisons across studies were difficult for several reasons. Within each report, patients could have received a variety of chemotherapeutic regimens, and many studies did not share the same patient eligibility criteria (and in some, the definition of high-risk included patients with criteria that did not result in inferior prognosis). In addition, some studies used allogeneic HSCT. The risk-adjusted system used in Euro-EWING 99 may allow best selection of patients appropriate for treatment.

Rhabdomyosarcoma (RMS)

Weigel et al. (2001) reviewed and summarized published evidence on the role of autologous HSCT in the treatment of metastatic or recurrent RMS from 22 studies (total N=389 patients). (45) Based on all of the evidence analyzing EFS and OS rates, they concluded that there was no significant advantage to undergoing this type of treatment.

McDowell et al. (2010) reported the results of the International Society of Paediatric Oncology study MMT-98, for pediatric patients from 48 centers with metastatic RMS entered into the study from 1998 to 2005. (46) A total of 146 patients enrolled (age range, 6 months to 18 years). Patients were risk-stratified and treated accordingly. One hundred one patients were considered poor-risk (poor-risk group [PRG]) if they were older than 10 years of age or had bone marrow or bone metastases. Planned therapy for the PRG was induction therapy, sequential HDC, peripheral blood autologous HSCT, and maintenance therapy. Seventy-nine (78.2%) of the 101 PRG patients underwent the high-dose therapy, after which 67.1% achieved a PR or CR. Sixty-seven of the 101 poor-risk patients received local treatment - 37 radiation alone, 10 surgery alone, and 20 both modalities. No treatment-related deaths were reported in the PRG. Three- and 5-year EFS rates for the PRG were 16.5% and 14.9%, respectively, with 3- and 5-year OS rates of 23.7% and 17.9%, respectively (HR=2.46; 95% CI, 1.51 to 4.03; p<0.001).

Klingebiel et al. (2008) prospectively compared the efficacy of 2 HDC treatments followed by autologous stem-cell rescue versus an oral maintenance treatment (OMT) in 96 children with stage 4 soft tissue sarcoma (88 of whom had RMS). (47) Five-year OS probability for the whole group was 0.52 (SD=0.14) for the patients who received OMT (n=51) and 0.27 (SD=0.13) for the transplant group (n=45; p=0.03). For the patients with RMS, 5-year OS probability was 0.52 (SD=0.16) with OMT and 0.15 (SD=0.12) with transplant (p=0.001). The authors concluded that transplant failed to improve prognosis in metastatic soft tissue sarcoma but that OMT could be a promising alternative.

Carli et al. (1999) conducted a prospective nonrandomized study of 52 patients with metastatic RMS, who were in CR after induction therapy and subsequently received HDC (megatherapy) and autologous HSCT, and compared them to 44 patients who were in remission after induction therapy who subsequently received conventional chemotherapy. (48) No significant differences existed between groups (i.e., clinical characteristics, induction chemotherapy received, sites of primary tumor, histologic subtype, age, presence/extent of metastases). Three-year EFS and OS rates were 29.7% and 40%, respectively, for the autologous HSCT group and 19.2% and 27.7%, respectively, for the chemotherapy group. Differences were not statistically significant for EFS (p=0.3) or for OS (p=0.2). Median time to relapse after chemotherapy was 168 days for the autologous HSCT group and 104 days for the standard chemotherapy group (p=0.05). Although use of autologous HSCT delayed time to relapse, there was no clear survival benefit compared with conventional chemotherapy.

Section Summary: RMS

Autologous HSCT has been evaluated in a limited number of patients with high-risk RMS (stage 4 or relapsed) in whom CR is achieved after standard induction therapy. Evidence is relatively scarce, due in part to the rarity of the condition. The role of stem-cell transplantation of any type for this cancer is not established.

Wilms’ Tumor

A 2010 individual patient data meta-analysis reported on the efficacy of autologous HSCT in recurrent Wilms tumor for studies published between 1984 and 2008 that reported survival data. (49) Six studies were included (total N=100 patients). (18, 50-54) Patient characteristics and treatment methods were similar across studies, although there was variation in the preparative regimens used. Patients were between the ages of 11 months and 16 years and had similar primary tumor stage, relapse location, and time to relapse. The 4-year OS rate among the 100 patients was 54.1% (95% CI, 42.8%-64.1%), and the 4-year EFS rate (based on 79 patients) was 50.0% (95% CI, 37.9%-60.9%). In multivariate analysis, site of relapse and histology were important predictors for survival; patients who did not have a lung-only relapse were at approximately 3 times higher risk of death or recurrence (HR=3.5) than patients who relapsed in the lungs only (HR=2.4), and the patients with unfavorable histology had approximately twice the risk of death compared with those with favorable histology. For all 6 studies, reviewers compared the survival rates for patients treated with autologous HSCT to patients treated with conventional chemotherapy. In general, the chemotherapy-treated patients had similar or improved 4-year survival rates compared with the HSCT group; however, there was a suggestion that patients with lung-only stage 3 and 4 relapse could benefit from autologous HSCT; they had a 21.7% survival advantage over chemotherapy (however, the confidence interval ranges were very wide): 4-year OS rates for the stage 3 and 4 patients with lung only relapse treated with HSCT were 74.5% (95% CI, 51.7% to 87.7%) and 52.8% (95% CI, 29.7% to 71.5%) for chemotherapy.

Section Summary: Wilms Tumor

The evidence on the use of autologous HSCT for high-risk Wilms tumor consists of small series or case reports. For some subgroups - particularly patients with lung-only stage 3 and 4 relapse - some analyses suggested that HSCT could be associated with a survival benefit.

Osteosarcoma

In 2016, Venkatramani et al. reported on outcomes from a protocol in which patients with newly diagnosed, biopsy-proven high-grade osteosarcoma with less than 90% tumor necrosis after preoperative chemotherapy were treated with 3 courses of HDC with autologous HSCT. (55) The study enrolled 52 patients with localized osteosarcoma, most commonly of the femur (52%) from 1999 to 2006 who underwent definitive surgery; 6 patients withdrew prior to surgery, and 6 after surgery. Under the study’s initial protocol, those with less than 90% tumor necrosis were intended for HSCT following HDC with melphalan and cyclophosphamide, and those with good tumor response were allocated to standard chemotherapy. However, after the first 18 patients received HSCT, interim analysis showed a 2-year EFS rate of 41%, which was less than the objective of 75% EFS compared with historical data of 55% by treating 48 patients with nonmetastatic disease who showed less than 90% necrosis following preoperative chemotherapy. Subsequently, all patients were enrolled to the standard therapy arm. Forty patients were evaluable after a median follow-up of 39 months. The 5-year EFS and OS rates were 62% (95% CI, 36% to 80%) and 74% (95% CI, 44% to 90%), respectively, for patients treated on the standard chemotherapy arm. The 5-year EFS and OS rates were 28% (95% CI, 10% to 49%) and 48% (95% CI, 23% to 69%), respectively, for patients treated on the HSCT arm.

In 2015, Hong et al. reported on a retrospective series of 19 patients with high-risk osteosarcoma treated with autologous HSCT at a single center from 2006 to 2013. (56) Median age at diagnosis was 11.8 years (range, 5.4-15.7 years). The indications for HSCT were tumor necrosis less than 90% (n=8), initial metastasis (n=2), relapse (n=2), or a combination of tumor necrosis less than 90%, initial metastasis, and/or progression (n=6). At a mean follow-up of 31 months (range, 1-91 months), OS was 78.3% and EFS was 67.4%.

Additional small series and case reports have examined the use of autologous HSCT in osteosarcoma. (57) Autologous HSCT has been successful in inducing short-lasting remissions but has not shown an increase in survival. (58)

Section Summary: Osteosarcoma

The evidence on the use of autologous HSCT for osteosarcoma include small case series and case reports. The use of stem-cell transplantation of any type is not established for this cancer.

Retinoblastoma

Localized Retinoblastoma

No studies focusing on autologous HSCT for patients with localized retinoblastoma were identified in literature searches.

Metastatic Retinoblastoma

Most studies of autologous HSCT for metastatic retinoblastoma have been very small series or case reports. (59-62)

For example, Dunkel et al. (2010) reported on outcomes for 15 consecutive patients with stage 4A metastatic retinoblastoma who presented between 1993 and 2006 and were treated with HDC and autologous HSCT. (63) Twelve patients had unilateral retinoblastoma and 3 had bilateral disease. Metastatic disease was not detected at diagnosis but became clinically evident at a median of 6 months (range, 1-82 months) post-enucleation. Patients had metastatic disease to bone marrow (n=14), bone (n=10), the orbit (n=9), and/or the liver (n=4). Two patients progressed before HSCT and died. Thirteen patients underwent HSCT, and 10 are retinoblastoma-free in first remission at a median follow-up of 103 months (range, 34-202 months). Three patients experienced recurrence 14 to 20 months’ post-diagnosis of metastatic disease, (2 in the CNS [central nervous system] and, in the mandible), and all died of their disease. Five-year retinoblastoma-free survival and EFS rates were 67% (95% CI, 38% to 85%) and 59% (31% to 79%), respectively. Six of the 10 patients who survived received radiotherapy. Three patients developed secondary osteosarcoma at 4, 9, and 14 years’ post-diagnosis of metastatic disease, 2 in previously irradiated fields, and 1 in a nonirradiated field. The authors concluded that HSCT was curative for most patients treated in their study with stage 4A retinoblastoma.

Dunkel et al. (2010) also reported outcomes for 8 patients diagnosed with stage 4B retinoblastoma between 2000 and 2006 treated with the intention of autologous HSCT. (22) Seven patients had leptomeningeal disease and 1 had only direct extension to the CNS via the optic nerve. At the time of diagnosis of intraocular retinoblastoma, 3 patients already had stage 4B disease; the other 5 patients developed metastatic disease at a median of 12 months (range, 3-69 months). Two patients progressed before HSCT, and 1 patient died due to toxicity during induction chemotherapy. Of the 5 patients who underwent HSCT, 2 are event-free at 40 and 101 months. One of the event-free survivors received radiotherapy (external beam plus intrathecal radioimmunotherapy), and the other did not receive any radiation. Three patients had tumor recurrence at 3, 7, and 10 months post-HSCT. The authors concluded that HSCT could be beneficial for some patients with stage 4B retinoblastoma, but longer follow-up would be necessary to determine whether it is curative in this population.

Section Summary: Retinoblastoma

The results have been promising in terms of prolonging DFS in patients with metastatic disease, particularly those without CNS involvement (stage 4A). Given that clinical prognosis is very poor for patients with metastases, results showing survival of some patients for 3 or more years after HSCT may provide evidence to demonstrate a benefit in survival. The role of stem-cell transplantation has not been established in therapy of patients with localized retinoblastoma.

Comparative Effectiveness Review

In 2012, the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) published a comparative effectiveness review on the use of HSCT in the pediatric population for the Agency for Healthcare Research and Quality (AHRQ). (64) The following conclusions were offered:

Neuroblastoma: The body of evidence on OS with tandem HSCT compared with single HSCT for the treatment of high-risk neuroblastoma was insufficient to draw conclusions.

Ewing sarcoma family of tumors: Low-strength evidence on OS suggests no benefit with single HSCT compared with conventional therapy for the treatment of high-risk ESFT.

o The body of evidence on OS with tandem HSCT compared with single HSCT for the treatment of high-risk ESFT and OS is insufficient to draw conclusions.

Rhabdomyosarcoma: Moderate-strength evidence on OS suggests no benefit with single HSCT compared with conventional therapy for the treatment of high-risk metastatic RMS.

o The body of evidence on OS with single HSCT compared with conventional therapy for the treatment of high-risk RMS of mixed tumor type is insufficient to draw conclusions.

o The body of evidence on OS with single HSCT compared with conventional therapy for the treatment of congenital alveolar RMS, cranial parameningeal RMS with metastasis, or the use of allogeneic transplantation for metastatic RMS was insufficient to draw conclusions.

Wilms tumor: Low-strength evidence on OS suggests no benefit with single HSCT compared with conventional therapy for the treatment of high-risk relapsed Wilms’ tumor.

Osteosarcoma: This condition was not addressed.

Retinoblastoma: Low-strength evidence on OS suggests no benefit with single HSCT compared with conventional therapy for the treatment of extraocular retinoblastoma with CNS involvement.

Miscellaneous

A Cochrane systematic review published in 2014 addressed the use of autologous HSCT compared with standard-dose chemotherapy to treat nonrhabdomyosarcoma soft tissue sarcomas. (68) This review did not include any of the tumor types addressed in this medical policy.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 4.

Table 4. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

Peripheral Neuroblastoma

NCT01704716

High-Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)

2700

Sep 2017

Ewing sarcoma

NCT00987636

Phase III, Open Label, Multi-centre, Randomized Controlled International Study in Ewing Sarcoma

1383

Mar 2018

Retinoblastoma

NCT00554788

Combination Chemotherapy, Autologous Stem-cell Transplant, and/ or Radiation therapy in Treating Young Patients with Extraocular Retinoblastoma

60

Feb 2017 (ongoing)

Unpublished

Wilms’ tumor

NCT00025103

Protocol For the Treatment of Relapsed and Refractory Wilms’ Tumor and Clear Cell Sarcoma of the Kidney (CCSK)

75

Nov 2008 Terminated (futility)

NCT00141765

Myeloablative Chemotherapy with Stem-cell Rescue for Rare Poor Prognosis Cancers

25

Feb 2010 Terminated (enrollment)

Peripheral Neuroblastoma

NCT00567567

Phase III Randomized Trial of Single vs. Tandem Myeloablative Consolidation Therapy for High-Risk Neuroblastoma

665

Dec 2015

Table Key:

NCT: national clinical trial.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

In 2017 Blue Cross Blue Shield Association (BCBSA) requested and received clinical input from 2 physician specialty societies (American Society for Blood and Marrow Transplantation [ASBMT] and American Society of Clinical Oncology [ASCO]). Input was sought to help determine the appropriate use in clinical practice of HSCT for children who have metastatic retinoblastoma, late-stage Wilms tumor, or osteosarcoma.

Both clinical experts acknowledged that the current evidence is quite limited, given the small number of studies and patients.

“It is important to recognize how rare some of these cancers, and particular indications are. For example, there are only 200-300 new cases of retinoblastoma diagnosed each year. The number of those that would be considered metastatic, would be significantly lower (<10%). Due to these small numbers, the chance of performing the gold standard randomized controlled clinical trial of transplant versus chemo and/or radiation is nearly impossible.”

“Metastatic retinoblastoma: the current evidence is just not enough to make any good conclusions - small numbers of studies/ patients”

“Osteosarcoma showed absolutely no evidence for any role of high dose chemotherapy.”

Furthermore, the rare clinical context of these conditions may be considered.

“While the amount of data is limited regarding the role of autologous stem-cell transplant in this setting [i.e., metastatic retinoblastoma], the small case reports and case series show a signal that outcomes may be improved with this aggressive treatment approach.”

“Similar with Wilms tumor, modern chemotherapy regimens provide excellent long-term survival, therefore, the numbers of patients with recurrent disease are extremely small, making quality clinical trials very difficult to design. Evidence would indicate that there may be a signal that HDC followed by autologous stem-cell transplant may provide improved survival in certain high-risk groups, such as those with isolated pulmonary recurrence.”

Practice Guidelines and Position Statements

American Society for Blood and Marrow Transplantation (ASBMT)

In 2015, the ASBMT published consensus guidelines for clinically appropriate indications for HSCT based on best prevailing evidence. The following was excerpted from original publication. (65) Indications for HSCT in pediatric patients with the solid tumors types addressed in this review are outlined in Table 5.

Table 5. ASBMT Indications for HSCT in Pediatric Patients with Solid Tumors (65)

Indication and Disease Status

Allogeneic HSCTa

Autologous HSCTa

Ewing sarcoma, high-risk or relapse

D

S

Soft tissue sarcoma, high-risk or relapse

D

D

Neuroblastoma, high-risk or relapse

D

S

Wilms tumor, relapse

N

C

Osteosarcoma, high-risk

N

C

Table Key:

ASBMT: American Society for Blood and Marrow Transplantation;

HSCT: hematopoietic stem-cell transplant/transplantation;

a: “Standard of Care (S): This category includes indications that are well defined and are generally supported by evidence in the form of high quality clinical trials and/or observational studies (e.g., through CIBMTR [Center for International Blood and Marrow Transplant Research] or EBMT [European Society for Blood and Marrow Transplantation]).”

“Standard of Care, Clinical Evidence Available (C): This category includes indications for which large clinical trials and observational studies are not available. However, HSCT has been shown to be an effective therapy with acceptable risk of morbidity and mortality in sufficiently large single- or multi-center cohort studies. HSCT can be considered as a treatment option for individual patients after careful evaluation of risks and benefits. As more evidence becomes available, some indications may be reclassified as ‘Standard of Care’.”

“Developmental (D): Developmental indications include diseases where pre-clinical and/or early phase clinical studies show HSCT to be a promising treatment option. HSCT is best pursued for these indications as part of a clinical trial. As more evidence becomes available, some indications may be reclassified as ‘Standard of Care, Clinical Evidence Available’ or ‘Standard of Care’.”

“Not Generally Recommended (N): Transplantation is not currently recommended for these indications where evidence and clinical practice do not support the routine use of HSCT. The effectiveness of non-transplant therapies for an earlier phase of a disease does not justify the risks of HSCT. Alternatively, a meaningful benefit is not expected from the procedure in patients with an advanced phase of a disease. However, this recommendation does not preclude investigation of HSCT as a potential treatment and transplantation may be pursued for these indications within the context of a clinical trial.”

National Comprehensive Cancer Network (NCCN)

Current NCCN guidelines or comments on HSCT related to the cancers addressed in this review are summarized in Table 6. (66, 67) Other tumor types are not addressed in NCCN guidelines. 

Table 6. NCCN Guidelines (66, 67)

Year

NCCN Guideline

Tumor Type

NCCN Comments

V.2.2017

Bone Cancer (66)

Osteosarcoma

HSCT not addressed.

V.2.2017

Bone Cancer (66)

Ewing Sarcoma

High dose chemotherapy followed by stem-cell transplant (HDT/SCT) has been evaluated in patients with localized as well as metastatic disease. HDT/SCT has been associated with potential survival benefit in patients with non-metastatic disease. However, studies that have evaluated HDT/SCT in patients with primary metastatic disease have shown conflicting results…. HDT/SCT has been associated with improved long-term survival in patients with relapsed or progressive Ewing sarcoma in small, single-institution studies. The role of this approach is yet to be determined in prospective randomized studies.”

V.1.2017

Soft Tissue Sarcoma (67)

Rhabdomyosarcoma

HSCT not addressed.

Table Key:

NCCN: National Comprehensive Cancer Network;

V: version;

HSCT: hematopoietic stem-cell transplant/transplantation;

HCT: hematopoietic cell transplantation;

SCT: stem-cell transplant. 

NCCN guidelines do not make recommendations for HSCT in the setting of peripheral neuroblastoma, neuroblastoma, or retinoblastoma.

Summary of Evidence

Peripheral Neuroblastoma

For individuals with high-risk or relapsed peripheral neuroblastoma who receive single or tandem autologous hematopoietic stem-cell transplantation (HSCT), the evidence includes randomized controlled trials (RCTs) and systematic reviews of those trials. Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related mortality and morbidity. In pooled analysis, patients with high-risk neuroblastoma treated with first-line treatment with single autologous HSCT with myeloablative conditioning had significantly improved event-free survival (EFS) compared with standard therapy. Similarly, well-designed randomized trials comparing tandem autologous HSCT with conventional therapy showed improvements in EFS for children with high-risk neuroblastoma. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Ewing’s Sarcoma Family of Tumors (ESFT)

For individuals with high-risk Ewing sarcoma who receive single or tandem autologous HSCT, the evidence includes single-arm studies. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. Although early nonrandomized studies were promising, more recent prospective nonrandomized study results have been mixed in terms of whether HSCT has extended survival compared with typical conventional therapy. Additional studies, including a randomized trial, are ongoing; they compare HSCT with conventional therapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

Rhabdomyosarcoma (RMS)

For individuals with RMS who receive single autologous HSCT, the evidence includes nonrandomized comparative studies and case series. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. Available studies have not demonstrated improvements in overall survival or EFS with HSCT. Additional research is needed to demonstrate a benefit with autologous HSCT for pediatric RMS. The evidence is insufficient to determine the effects of the technology on health outcomes.

Wilms Tumor, Osteosarcoma or Retinoblastoma

For individuals with Wilms tumor, osteosarcoma, or localized or metastatic retinoblastoma who receive single autologous HSCT, the evidence includes case series and 1 prospective single-arm trial. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. Although comparing outcomes to conventional therapies is difficult given the limited evidence, for 2 tumor types - metastatic Wilms tumor and metastatic retinoblastoma - the poor prognosis of the cancer with conventional therapies suggests that the incremental improvement in survival with HSCT may be a significant benefit. However, the overall body of evidence is limited. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input obtained by Blue Cross Blue Shield Association, in 2017, supported the use of HSCT for metastatic retinoblastoma. Therefore, HSCT may be considered medically necessary for this indication. HSCT remains experimental, investigational and/or unproven for retinoblastoma without metastases.

Allogeneic HSCT

Very little evidence is available on the use of allogeneic HSCT for pediatric solid tumors, either upfront or as salvage therapy after a failed autologous HSCT. A large retrospective review of the use of allogeneic HSCT for high-risk neuroblastoma (32) failed to show a survival benefit over autologous HSCT and was associated with a higher risk of TRM. Additionally, the lack of recently published data through 2017, does not support the use of allogeneic HSCT as a treatment for any pediatric solid tumor, including neuroblastoma. Therefore, allogeneic HSCT remains experimental, investigational and/or unproven for the treatment of pediatric solid tumors.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

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31. Sung KW, Ahn HS, Cho B, et al. Efficacy of tandem high-dose chemotherapy and autologous stem-cell rescue in patients over 1 year of age with stage 4 neuroblastoma: the Korean Society of Pediatric Hematology-Oncology experience over 6 years (2000-2005). J Korean Med Sci. May 2010; 25(5):691-7. PMID 20436703

32. Ladenstein R, Pötschger U, Hartman O, et al. 28 years of high-dose therapy and SCT for neuroblastoma in Europe: lessons from more than 4000 procedures. Bone Marrow Transplant. Jun 2008; 41(suppl 2):S118-27. PMID 18545256

33. George RE, Li S, Mederios Nancarrow C, et al. High-risk neuroblastoma treated with tandem autologous peripheral-blood stem-cell-supported transplantation: long-term survival update. J Clin Oncol. Jun 20 2006; 24(18):2891-6. PMID 16782928

34. Kletzel M, Katzenstein HM, Haut PR, et al. Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol. May 1 2002; 20(9):2284-92. PMID 11980999

35. Grupp SA, Stern JW, Bunin N, et al. Rapid-sequence tandem transplant for children with high-risk neuroblastoma. Med Pediatr Oncol. Dec 2000; 35(6):696-700. PMID 11107149

36. Pasqualini C, Dufour C, Goma G, et al. Tandem high-dose chemotherapy with thiotepa and busulfan-melphalan and autologous stem-cell transplantation in very high-risk neuroblastoma patients. Bone Marrow Transplant. Feb 2016; 51(2):227-31. PMID 26524264

37. Kim EK, Kang HJ, Park JA, et al. Retrospective analysis of peripheral blood stem-cell transplantation for the treatment of high-risk neuroblastoma. J Korean Med Sci. Sep 2007; 22(suppl):S66-72. PMID 17923758

38. Marcus KJ, Shamberger R, Litman H, et al. Primary tumor control in patients with stage 3/4 unfavorable neuroblastoma treated with tandem double autologous stem-cell transplants. J Pediatr Hematol Oncol. Dec 2003; 25(12):934-40. PMID 14663275

39. von Allmen D, Grupp S, Diller L, et al. Aggressive surgical therapy and radiotherapy for patients with high-risk neuroblastoma treated with rapid sequence tandem transplant. J Pediatr Surg. Jun 2005; 40(6):936-41; discussion 941. PMID 15991174

40. Meyers PA. High-dose therapy with autologous stem-cell rescue for pediatric sarcomas. Curr Opin Oncol. Mar 2004; 16(2):120-5. PMID 15075902

41. Meyers PA, Krailo MD, Ladanyi M, et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol. Jun 1 2001; 19(11):2812-20. PMID 11387352

42. Gardner SL, Carreras J, Boudreau C, et al. Myeloablative therapy with autologous stem-cell rescue for patients with Ewing sarcoma. Bone Marrow Transplant. May 2008; 41(10):867-72. PMID 18246113

43. Ladenstein R, Pötschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol. Jul 10 2010; 28(20):3284-91. PMID 20547982

44. Loschi S, Dufour C, Oberlin O, et al. Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant. Aug 2015; 50(8):1083-8. PMID 26030048

45. Weigel BJ, Breitfeld PP, Hawkins D, et al. Role of high-dose chemotherapy with hematopoietic stem-cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol. Jun-Jul 2001; 23(5):272-6. PMID 11464981

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Policy History:

Date Reason
6/15/2018 Reviewed. No changes.
12/15/2017 Document updated with literature review. The following coverage statement was removed, “Allogeneic HSCT [hematopoietic stem-cell transplantation] may be considered medically necessary for initial treatment of high-risk neuroblastoma and to treat recurrent or refractory neuroblastoma.” The following wording was removed from the allogeneic HSCT experimental, investigational and/or unproven coverage statement, “except high-risk neuroblastoma and the treatment of recurrent or refractory neuroblastoma, as was noted above.” Therefore, the allogeneic HSCT experimental, investigational and/or unproven coverage statement becomes, “Allogeneic (following myeloablative or nonmyeloablative preparative regiment) HSCT is considered experimental, investigational and/or unproven for the treatment of pediatric solid tumors.” The following indication was added to the autologous HSCT medically necessary coverage statement, “metastatic retinoblastoma”. The following change was made to retinoblastoma in the autologous HSCT experimental, investigational and/or unproven coverage statement, “retinoblastoma without metastasis”.
7/1/2016 Reviewed. No changes.
9/15/2015 Document updated with literature review. Coverage unchanged. Title changed from Stem-Cell Transplant for Solid Tumors in Children.
6/1/2014 Document updated with literature review. The following was added: 1) Tandem stem-cell support may be considered medically necessary for the treatment of high-risk neuroblastoma; 2) Allogeneic stem-cell support is considered experimental, investigational and/or unproven as a salvage allogeneic transplant for relapsed Ewing’s sarcoma after prior failed autologous transplant or as an allogeneic transplant for any stage of Ewing’s sarcoma as an initial treatment; 3) Autologous stem-cell support may be considered medical necessary for initial treatment of high-risk Ewing’s sarcoma; 4) Hematopoietic progenitor cell boost is considered experimental, investigational and/or unproven; 5) Any use of short tandem repeat (STR) markers for the treatment of neuroblastoma may be considered medically necessary; and 6) All other uses of STR markers is considered experimental, investigational and/or unproven if not listed in the coverage section..
4/1/2010 New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem-cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies. Stem-cell transplant continues to be medically necessary when stated criteria are met. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem-cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies.

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