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Hematopoietic Stem-Cell Transplantation for Solid Tumors
Hematopoietic stem-cell transplantation (HSCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs, with or without whole body radiotherapy. Stem cells may be obtained from the transplant recipient (autologous HSCT) or can be harvested from a donor (allogeneic HSCT). Stem cells may 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.
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 using cellular, serologic, or molecular techniques. Human leukocyte antigen (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 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 2 decades, mostly due to the application of multiagent chemotherapy and improvements in local control therapy (including aggressive surgery and advancements in radiotherapy). 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).
Notes: Other solid tumors of childhood include germ cell tumors, which are considered separately in the Hematopoietic Stem Cell Transplantation as a Treatment of Germ Cell Tumors medical policy. For solid tumors classified as embryonal tumors arising in the central nervous system, see the Hematopoietic Stem-Cell Transplantion for CNS Embryonal Tumors and Ependymoma medical policy. For tumors derived from glial cells (i.e., astrocytoma, oligodendroglioma, or glioblastoma multiforme), see the Autologous Stem-Cell Transplantation for Malignant Astrocytomas and Gliomas medical policy. Cord blood is discussed in greater detail in the Placental Umbilical Cord Blood as a Source of Stem Cells medical policy.
Descriptions of the solid tumors of childhood that are addressed in this policy are as follows.
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 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 (PFS) 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 on the International Neuroblastoma Staging System (INSS) as follows:
Definition of Low-, Intermediate-, and High-Risk Neuroblastoma
The low-risk group includes patients less than 1 year of age with stage I, II, or IVS with favorable histopathologic findings and no MYCN oncogene amplification. High-risk neuroblastoma is characterized by an age older than 1 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 1 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 1 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 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 radiotherapy have improved the 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 (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. 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, the most common primary malignant renal tumor of childhood, is highly sensitive to chemotherapy and radiation, and current cure rates exceed 85%. Ten to 15% of patients with favorable histology and 50% of patients with anaplastic tumors experience tumor progression or relapse. Similar to newly diagnosed Wilms tumor, relapsed Wilms tumor is a heterogeneous disease, and current treatment strategies stratify intensity and scheduling of the treatment modalities based on prognostic features. For newly diagnosed disease, the most important prognostic features are stage and histology. Similar risk-adapted strategies are being attempted for the 15% of patients who experience relapse. Success rates after relapse range from 25%–45%. For patients with adverse prognostic factors (histologically anaplastic tumors, relapse less than 6–12 months after nephrectomy, second or subsequent relapse, relapse within the radiation field, bone or brain metastases) event-free survival is less than 15%. However, recent trials with HDC and autologous HSCT have reported 3- or 4-year OS rates from 60%–73%.
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. The prognosis of localized osteosarcoma has greatly improved over the last 30 years, with OS rates increasing from 10% with surgery alone (usually amputation) to 70% with the introduction of neoadjuvant chemotherapy and limb-sparing surgery. However, 30%–40% of patients with non-metastatic osteosarcoma of the extremities experience recurrent disease, most commonly in the lungs. Mean 5-year post-relapse survival rate is approximately 28%, with some groups having a 0% OS rate. Prognostic factors for recurrence 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). Overall EFS for patients with metastatic disease at diagnosis is about 20%–30%.
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, and stage 4b disease has been lethal in virtually all cases reported. 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. Stage 4a disease is defined as distant metastatic disease not involving the central nervous system (CNS), and stage 4b is defined as metastatic disease to the CNS.
POLICYNo benefits will be provided for a covered transplant procedure or a transplant evaluation unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.
Autologous hematopoietic stem-cell transplantation may be considered medically necessary for initial treatment of high-risk neuroblastoma.
Autologous hematopoietic stem-cell transplantation may be considered medically necessary to treat primary refractory or recurrent neuroblastoma.
Autologous hematopoietic stem-cell transplantation may be considered medically necessary for initial treatment of high-risk Ewing’s sarcoma and recurrent or refractory Ewing's sarcoma.
Tandem autologous hematopoietic stem-cell transplantation may be considered medically necessary for high-risk neuroblastoma.
Autologous hematopoietic stem-cell transplantation support is considered investigational as initial treatment of low- or intermediate-risk neuroblastoma.
Autologous hematopoietic stem-cell transplantation is considered investigational as initial treatment of low- or intermediate-risk Ewing's sarcoma.
Salvage allogeneic hematopoietic stem-cell transplantation for pediatric solid tumors that relapse after autologous transplant or fail to respond is considered investigational.
Autologous hematopoietic stem-cell transplantation for other solid tumors of childhood is considered investigational, including but not limited to the following:
Tandem autologous hematopoietic stem-cell transplantation is considered investigational for the treatment of all other types of pediatric solid tumors except high-risk neuroblastoma, as noted above.
Allogeneic (myeloablative or nonmyeloablative) hematopoietic stem-cell transplantation is considered investigational for treatment of pediatric solid tumors.
POLICY EXCEPTIONSFor Federal Employee Program (FEP) subscribers, the Service Benefit Plan includes specific conditions in which autologous or allogeneic blood or marrow stem cell transplants would be considered eligible for coverage.
For State and School Employee subscribers, all bone marrow/stem cell transplants must be certified as medically necessary by the Plan’s Utilization Review Vendor. No benefits will be provided for any transplant procedure unless prior approval for the transplant is obtained from the Plan’s Utilization Review Vendor.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Hematopoietic stem-cell transplantation refers to any source of stem cells, i.e., autologous, allogeneic, syngeneic, or umbilical cord blood.
Relapse is defined as tumor recurrence after a prior complete response.
Primary refractory disease is defined as a tumor that does not achieve a complete remission after initial standard-dose chemotherapy.
The policy statement regarding multiple hematopoietic stem-cell transplants (i.e., tandem or multiple) only mentions neuroblastoma, as that is the only indication in this policy in which studies regarding multiple-cycle therapy have been published.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
POLICY HISTORY3/25/2004: See policy "High-Dose Chemotherapy with Hematopoietic Stem Cell Support for Malignancies" prior to 3/25/2004, separate policy developed and aligned with BCBSA policy # 8.01.34 per approval by Medical Policy Advisory Committee (MPAC)
7/1/2004: Code Reference section completed
11/18/2004: Reviewed by MPAC; no changes
10/28/2005: Code Reference section updated; CPT-4 code 38230 added, ICD-9 procedure codes 41.01,41.02, 41.03, 41.09 added; HCPCS codes G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added, J9000-J9999 deleted
3/16/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy
5/21/2007: Policy reviewed, no changes
12/20/2007: Coding updated per 2008 CPT/HCPCS revisions
5/9/2008: Policy reviewed, no changes
10/6/2009: Code reference section updated. New ICD-9 diagnosis code 209.73 added to covered table. HCPC codes G0265, G0266 and G0267 deleted from covered table due to codes were deleted as of 12-21-2007.
04/26/2010: Policy title and statement revised to remove “High-Dose Chemotherapy” and to change “Stem-Cell Support” to “Stem-Cell Transplantation.” Policy description updated with recent literature regarding solid tumors. Policy statement revised to indicate that multiple cycle high-dose chemotherapy and hematopoietic stem-cell support (i.e., tandem or multiple transplants) is considered investigational for treatment of neuroblastoma. The policy guidelines were updated based on this new policy statement. FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826.
02/23/2011: Policy statement revised to state specifically that “tandem autologous-autologous” HSCT is considered investigational and that “allogeneic (myeloablative or nonmyeloablative)” HSCT is considered investigational in treatment of pediatric solid tumors.
06/22/2011: Policy description and statement unchanged. Deleted outdated references from Sources section.
07/12/2012: Policy description updated. Policy statement revised to indicate that tandem autologous hematopoietic stem-cell transplantation may be considered medically necessary for high-risk neuroblastoma and remains investigational for all other indications.
08/07/2013: Policy reviewed; no changes.
07/08/2014: Policy reviewed; description updated. Policy statement on salvage allogeneic hematopoietic stem-cell transplantation revised to remove "neuroblastoma or other" from the policy statement. It previously stated: Salvage allogeneic hematopoietic stem-cell transplantation for neuroblastoma or other pediatric solid tumors that relapse after autologous transplant or fail to respond is considered investigational.
08/26/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38241; removed deleted HCPCS code G0363, and removed deleted code CPT 96445 and replaced with CPT code 96446.
09/15/2015: Policy description updated regarding immunologic compatibility. Policy statements unchanged. Policy Guidelines section updated to add medically necessary and investigative definitions.
05/26/2016: Policy number added.
09/30/2016: Code Reference section updated to add the following new codes: ICD-10 procedure codes 30230G2, 30230G3, 30230G4, 30233G2, 30233G3, 30233G4, 30240G2, 30240G3, 30240G4, 30243G2, 30243G3, 30243G4, 30230Y2, 30230Y3, 30230Y4, 30233Y2, 30233Y3, 30233Y4, 30240Y2, 30240Y3, 30240Y4, 30243Y2, 30243Y3, and 30243Y4; and ICD-10 diagnosis codes C49.A0 - C49.A9.
SOURCE(S)Blue Cross Blue Shield Association policy # 8.01.34
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.