BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Transplant for Solid Tumors in Children
Chapter: Surgery: Procedures
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013
Description

Solid Tumors of Childhood

Solid tumors of childhood are defined as those not arising from myeloid or lymphoid cells.  Some of the most common solid tumors of childhood are neuroblastoma, Ewing’s sarcoma/Ewing’s Sarcoma Family of Tumors, Wilms’ tumor, rhabdomyosarcoma, osteosarcoma, and retinoblastoma.

The prognosis for pediatric solid tumors has improved over the last two decades, mostly due to the application of multiagent chemotherapy and improvements in local control therapy (including aggressive surgery and advancements in radiation therapy).  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 HDC (high-dose chemotherapy) with SCS, in an effort to improve event-free survival (EFS) and overall survival (OS).

Phase III studies with HDC and SCS have clearly shown improvement in outcomes for patients with high-risk neuroblastoma, and HDC and autologous stem-cell transplant as consolidation therapy has become the preferred treatment in these patients.

This type of therapy has also been used to treat the other childhood solid tumors addressed in this policy.  Some studies have shown benefit while others have not, and conclusions have been drawn mainly from small, nonrandomized and retrospective trials or case reports.  This is due, in part, to the relative rarity of these pediatric cancers.  Prospective clinical trials are necessary to identify specific high-risk groups, with randomization to compare HDC with SCS to standard therapy.

Peripheral Neuroblastoma

Neuroblastoma is the most common extracranial solid tumor of childhood, with two-thirds of the cases presenting in children younger than five years of age.  These tumors originate where sympathetic nervous system tissue is present, within the adrenal medulla or paraspinal sympathetic ganglia.  They are remarkable for their broad spectrum of clinical behavior, with some undergoing spontaneous regression, others differentiating into benign tumors, and still others progressing rapidly and resulting in patient death.

Patients with neuroblastoma are stratified into prognostic risk groups (low, intermediate, and 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.  It is well established that MYCN amplification is associated with rapid tumor progression and a poor prognosis, even in the setting of other coexisting favorable factors.  Loss of heterozygosity (LOH) at chromosome arms 1p and 11q occurs frequently in neuroblastoma.  Although 1p LOH is associated with MYCN amplification, 11q is usually found in tumors without this abnormality.  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 in patients with low- and intermediate-risk disease.  Although the use of these LOH markers in assigning treatment in patients is evolving, they may prove useful to stratify treatment.

Clinical stage of disease is based upon the International Neuroblastoma Staging System (INSS) as follows:

  • Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; lymph nodes negative for tumor.
  • Stage 2A: Localized tumor with incomplete gross excision; lymph nodes negative for tumor.
  • Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral lymph nodes positive for tumor.
  • Stage 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.
  • Stage 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.
  • Stage 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 one year of age.

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

In general, most patients with low-stage disease have excellent outcomes with minimal therapy, and with INSS stage one disease, most patients can be treated by surgery alone.  Most infants, even with disseminated disease, have favorable outcomes with chemotherapy and surgery.  In contrast, most children older than one year with advanced-stage disease die due to progressive disease, despite intensive multimodality therapy, and relapse remains common.  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’s Sarcoma and the Ewing Family of Tumors

Ewing’s sarcoma family of tumors (ESFT) encompasses a group of tumors that have in common 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 gene with one of the members of the ETS 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 the diagnosis.  Included in ESFT are “classic” Ewing’s sarcoma of bone, extraosseous Ewing’s, 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’s 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’s sarcoma favors induction chemotherapy, with local control consisting of surgery and/or radiation (dependent on tumor size and location), followed by adjuvant chemotherapy.  Multiagent chemotherapy, surgery, and radiation therapy have improved the progression-free survival (PFS) in patients with localized disease to 60%–70%.  The presence of metastatic disease is the most unfavorable prognostic feature, and the outcome for patients presenting with metastatic disease is poor, with 20%–30% PFS.  Other adverse prognostic factors that may categorize a patient as having “high-risk” Ewing’s 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’s has not always been consistently defined in the literature.  Thirty to forty percent of patients with ESFT experience disease recurrence and patients with recurrent disease have a 5-year EFS and OS rate of less than 10%. 

Rhabdomyosarcoma

Rhabdomyosarcoma (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, and pharyngeal), genitourinary tract, and extremities.  Most children with RMS present with localized disease, and with conventional multimodal therapy, the cure rate in this group is 70%–80%.  However, approximately 15% of children present with metastatic disease, and despite the introduction of new drugs and intensified treatment, the 5-year survival is 20%–30% for this “high-risk” group. 

Wilms’ Tumor

Wilms’ tumor, the most common primary malignant renal tumor of childhood, is highly sensitive to chemotherapy and radiation, and current cure rates exceed 85%.  Tumor histology is a strong and independent prognostic factor with tumors generally divided into two categories: favorable histology and unfavorable (or anaplastic) histology.  Anaplastic histology is defined as microscopic areas within the tumor with nuclear atypia and abnormal mitotic figures.  Anaplasia may be focal or diffuse; tumors with diffuse anaplasia have a poorer prognosis.  Ten to 15% of patients with histologically favorable tumors and 50% of patients with anaplastic tumors have tumor progression or relapse, and the outcome for patients with relapse is poor.  Other adverse prognostic features include stage IV disease, tumors with any histologic findings recurring in the abdomen after radiation therapy, recurrence within six months of nephrectomy or recurrence after initial three-drug therapy. 

Osteosarcoma

Osteosarcoma is a primary malignant bone tumor that is characterized by formation of bone or osteoid by the tumor cells.  Osteosarcoma occurs predominantly in the appendicular skeleton of adolescents.  In children and adolescents, more than 50% of these tumors arise from bones around the knee.  Most treatment protocols for osteosarcoma use neoadjuvant chemotherapy, surgical resection of the tumor (and/or metastases), followed by adjuvant chemotherapy. Prognostic factors include site and size of the primary tumor, presence of metastases at the time of diagnosis, resection adequacy, and tumor response to preoperative chemotherapy (measured as percent of tumor necrosis in the resection specimen).  Patients with localized disease have a much better prognosis than those with metastatic disease, and the prognosis for those with metastatic disease is determined, in part, by the number and surgical resectability of the metastases.  Overall EFS for patients with metastatic disease at diagnosis is about 20%–30%.

Retinoblastoma

Retinoblastoma is the most common primary tumor of the eye in children.  It may occur as a heritable (40%) or nonheritable (60%) tumor.  Cases may be unilateral or bilateral, with bilateral tumor almost always occurring in the heritable type.  The type of treatment depends on the extent of disease.  Retinoblastoma is usually confined to the eye, and with current therapy has at least a 90% cure rate.  However, once disease has spread beyond the eye, survival rates drop significantly; 5-year disease-free survival is reported to be less than 10% in those with extraocular disease.  Extraocular disease may be localized to the soft tissues surrounding the eye, or to the optic nerve, extending beyond the margin of resection.  Further extension may result in involvement of the brain and meninges, with subsequent seeding of the cerebrospinal fluid, as well as distant metastases to the lungs, bone, and bone marrow.

Policy

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan 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 or contract, the benefit plan or contract will govern.

Coverage

Coverage for evaluation of and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of solid tumors in children are identified in the grids below.

Neuroblastoma:

Allogeneic

May be considered medically necessary for initial treatment of high-risk neuroblastoma and to treat recurrent or refractory neuroblastoma.

Is considered experimental, investigational and unproven for salvage allogeneic transplant for relapsed neuroblastoma after prior failed autologous transplant or as initial treatment of low- or intermediate-risk neuroblastoma.

Autologous

 

May be considered medically necessary for initial treatment of high-risk neuroblastoma and to treat recurrent or refractory neuroblastoma.

Is considered experimental, investigational and unproven as initial treatment of low- or intermediate-risk neuroblastoma.

Tandem or Triple Stem-Cell Transplant

Is considered experimental, investigational and unproven. 

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven. 

Ewing’s Sarcoma: 

Allogeneic

May be considered medically necessary to consolidate remission of high-risk Ewing’s sarcoma or as salvage therapy for those with residual, recurrent, or refractory disease.

Is considered experimental, investigational and unproven as initial treatment or to consolidate remission of low- or intermediate-risk Ewing’s sarcoma.

Autologous

 

May be considered medically necessary to consolidate remission of high-risk Ewing’s sarcoma or as salvage therapy for those with residual, recurrent, or refractory disease.

Is considered experimental, investigational and unproven as initial treatment or to consolidate remission of low- or intermediate-risk Ewing’s sarcoma.

Tandem or Triple Stem-Cell Transplant

Is considered experimental, investigational and unproven. 

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven. 

Other solid tumors (including but not limited to):Wilm’s Tumor, Osteosarcoma, Retinoblastoma, Rhabdomyosarcoma: 

Allogeneic

Is considered experimental, investigational and unproven.

Autologous

Is considered experimental, investigational and unproven.

Tandem or Triple Stem-Cell Transplant

Is considered experimental, investigational and unproven. 

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven.

Rationale

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) (i.e., blood or marrow) transplant is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood or bone marrow stem-cells. 

Peripheral Neuroblastoma

In the 1990s, some studies attributed an improvement in the treatment of high-risk neuroblastoma to the use of myeloablative doses of chemotherapy with autologous SCS.  However, none of these studies involved a randomized comparison, and selection bias may have influenced results. Since then, three well designed, randomized trials have been conducted and have supported these findings, as summarized here.

In a study published in 1999, Matthay and colleagues randomly assigned 129 children with high-risk neuroblastoma to a combination of myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow, and compared their outcomes to those of 150 children randomly assigned to intensive nonmyeloablative chemotherapy.  The three year EFS (event-free survival) rate among patients assigned to transplantation was 43 +/- 6% versus 27 +/- 5% among those assigned to continuation chemotherapy (p=0.027).  However, overall survival in the two groups was not significantly different, with three year estimates of 43% or 44% for those assigned to transplant or those to continued chemotherapy, respectively (p=0.87).

In a study published in 2005, Berthold and colleagues randomly assigned 295 patients with high-risk neuroblastoma to myeloablative therapy (melphalan, etoposide, and carboplatin) with autologous SCS or to oral maintenance chemotherapy with cyclophosphamide.  The primary endpoint was EFS with secondary endpoints of OS and treatment-related deaths.  Intention-to-treat analysis showed that the patients who received the myeloablative therapy had an increased three year EFS compared with the oral maintenance group (47% [95% CI: 38–55] vs. 31% [95% CI: 23–39]), but did not have significantly increased three year overall survival (62% [95% CI: 54–70] vs. 53% [95% CI: 45–62] p=0.0875).  Two patients died from therapy-related complications during induction, no patients who received oral maintenance therapy died from treatment-related toxic effects, and five patients who received the myeloablative therapy died from acute complications related to the therapy.

In a study published in 2005, Pritchard and colleagues reported the results of a randomized, multicenter study that involved 167 children with stage three or four neuroblastoma that were treated with standard induction chemotherapy and then underwent surgical resection of their tumor.  Sixty-nine percent of the patients (n=90) who achieved complete or good partial response to the induction chemotherapy were eligible for randomization to HDC (melphalan) with autologous SCS or 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 five year EFS and OS was seen in children older than one year of age with stage four disease (n=48 children with stage four; five year EFS 33% vs. 17% in the melphalan vs. NFT group p=0.01).

Since myeloablative consolidation for treatment of high-risk neuroblastoma has been shown to improve EFS in these randomized studies (only Pritchard showed improved OS in the group with stage four disease and older than one year of age), it is considered by some investigators to be the preferred treatment in these patients.

Ewing’s Sarcoma and the Ewing Family of Tumors

During the 1980s and 1990s, several small series, case reports, and a report from the European Bone Marrow Transplant Registry suggested that consolidation with HDC and SCS could improve the outcome for patients with high risk ESFT. 

These aforementioned studies were characterized by small numbers of patients, and comparison of the studies was difficult for several reasons.  Within each report, patients often received a variety of chemotherapeutic regimens and many of the 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 for stem-cell reconstitution autologous peripheral blood stem cells, some autologous bone marrow, and others allogeneic bone marrow.

Subsequently, in 2001, Meyers and colleagues reported on a prospective study with HDC and autologous stem-cell reconstitution in patients with Ewing’s sarcoma metastatic to bone and/or bone marrow that showed conflicting results compared to the previous studies.  Thirty-two eligible patients were enrolled and given standard induction chemotherapy consisting of five cycles of cyclophosphamide-doxorubicin-vincristine, alternating with ifosfamide-etoposide. Twenty-three patients proceeded to the HDC consolidation phase with melphalan, etoposide, total body irradiation (TBI), and SCS (of the nine patients who did not proceed, two were secondary to toxicity and four to progressive disease).  Three patients died during the high-dose phase.  Two-year EFS for all eligible patients was 20% and 24% for the 29 patients who received the high-dose consolidation therapy.  The study concluded that consolidation with HDC, TBI, and autologous stem-cell support failed to improve the probability of EFS for this cohort of patients when compared with a similar group of patients treated with conventional therapy.  The authors noted that their findings differ from some previous studies and stated that some previous studies suffered from heterogeneous patient populations.  The authors concluded that future trials of HDC and SCS must be conducted prospectively, with identification of a group at high risk for failure, and all patients entering the study at the same point in therapy.

EURO-EWING (European Ewing Tumour Working Initiative of National Groups) 99: A Phase III, randomized, controlled, multicenter (international) study for patients with Ewing’s sarcoma is in progress.  Approximately 1,200 patients are expected to enroll.  The primary objective is to compare the EFS and OS of patients with tumors of the Ewing's family treated with standard induction chemotherapy comprising vincristine, dactinomycin, ifosfamide, and etoposide (VIDE) followed by consolidation chemotherapy comprising vincristine, dactinomycin, and ifosfamide versus high-dose busulfan and melphalan (Bu-Mel) followed by autologous peripheral blood stem cell (PBSC) transplantation with or without radiotherapy and/or surgery.  The study includes both patients with localized disease and those with metastases, includes three arms for low-, intermediate-, and high-risk patients, and is the first randomized approach of HDC with SCS in high-risk Ewing’s patients.  The anticipated end date for this study is March 2010.

Rhabdomyosarcoma

HDC with SCS has been evaluated in a limited number of patients with “high-risk” RMS (stage four or relapsed) in whom complete remission is achieved after standard induction therapy.  Data are relatively scarce, due in part to the rarity of the condition.  Weigel and colleagues reviewed and summarized published data on the role of HDC with SCS in the treatment of metastatic or recurrent rhabdomyosarcoma, which involved a total of 389 patients from 22 studies.  Based on all of the data analyzing EFS and OS, they concluded that there was no significant advantage to undergoing this type of treatment.

Carli and colleagues conducted a prospective nonrandomized study of 52 patients with metastatic RMS, who were in complete remission after induction therapy and subsequently received HDC (“megatherapy”) and SCS and compared them to 44 patients who were in remission after induction therapy who subsequently received conventional chemotherapy.  No significant differences existed between the two study groups (i.e., no differences in clinical characteristics, induction chemotherapy received, sites of primary tumor, histologic subtype, age, or presence/extent of metastases).  Three-year EFS and OS were 29.7% and 40%, respectively, for the HDC/SCS group and 19.2% and 27.7%, respectively, for the group that received standard consolidation chemotherapy.  The difference was not statistically significant (p=0.3 and 0.2 for EFS and OS, respectively).  The median time after chemotherapy to relapse was 168 days for the HDC group, and 104 days for the standard chemotherapy group (p=0.05).  Therefore, although there was some delay to relapse, there was no clear survival benefit from using HDC and SCS compared to conventional chemotherapy.

COG-ARST0431 is an ongoing Children’s Oncology Group (COG) clinical trial for patients with metastatic RMS, regardless of age and histology.  The trial will evaluate high-dose combination chemotherapy and radiation therapy.  In reviewing the trial outline, it appears that the chemotherapy doses are nonmyeloablative as SCS is not included, and G-CSF will be administered.  No current Phase III trials with myeloablative regimens and SCS for rhabdomyosarcoma were identified in reviewing the National Cancer Institute (NCI) clinical trial database.

Wilms’ Tumor

Most studies of HDC and SCS for high-risk Wilms’ tumor have been very small series or case reports; however, improved survival rates over historical controls have been reported.  A Phase II study in progress is evaluating the survival rates of patients with relapsed or recurrent Wilms’ tumor assigned to one of three treatment regimens that may or may not include HDC and autologous SCS.  Expected enrollment is 75 with an anticipated completion date of November 2008.

Osteosarcoma

Rare small series and case reports are available examining the use of HDC and SCS in osteosarcoma, without a clear benefit in overall outcome.

Review of the NCI clinical trial database did not return any current trials examining HDC and SCS in patients with high-risk osteosarcoma.

Retinoblastoma

Most studies of HDC and SCS for high-risk retinoblastoma have been very small series or case reports, however, the results have been promising in terms of prolonging disease-free survival in these patients, particularly those without central nervous system involvement.

A single-arm, Phase III trial is underway to estimate the proportion of children with extraocular retinoblastoma who achieve long-term EFS after HDC and SCS compared to historical controls. The estimated date of completion of the trial is July 2009.

Tandem or Triple Stem-Cell Transplant and Donor Leukocyte Infusion (DLI) for solid tumors in children are considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

In summary, to date, the use of HDC with SCS has become the preferred treatment for children with “high-risk” neuroblastoma, after randomized studies have shown improved EFS and OS.  For ESFT, one of the more recently published studies showed conflicting results from previous studies which have supported the current policy.  However, this study was small and nonrandomized.  A large Phase III trial (EURO-EWING 99) is underway, and will likely serve to guide future treatment options for ESFT.  Prospective clinical trials, with randomization (when possible) are needed to compare outcomes for the other solid pediatric tumors addressed in this policy treated with HDC with SCS versus standard chemotherapy.

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. 

ICD-9 Codes

41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79, 170, 170.0, 170.1, 170.2, 170.3, 170.4, 170.5, 170.6, 170.7, 170.8, 170.9, 171, 171.0, 171.2, 171.3, 171.4, 171.5, 171.6, 171.7, 171.8, 171.9, 189.0, 190.5, 194.0 

Procedural Codes: 36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 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, 86849, 86950, 86985, 88240, 88241, S2140, S2142, S2150
References
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  35. Fish, J.D., Grupp, S.A. Stem cell transplantation for neuroblastoma. Bone Marrow Transplant (2008) 41(2):159-65.
  36. Spreafico, F., Bisogno, G., et al. Treatment of high-risk relapsed Wilms tumor with dose-intensive chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic stem cell support: Experience by the Italian association of pediatric hematology and oncology. Pediatric Blood and Cancer (2008) Feb 21 [Epub ahead of print].
  37. High-Dose Chemotherapy with Hematopoietic Stem-Cell Support for Solid Tumors of Childhood. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2008 May) Therapy 8.01.34.
History
September 2013  New 2013 BCBSMT medical policy.
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Stem-Cell Transplant for Solid Tumors in Children