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DESCRIPTIONHematopoietic Stem-Cell Transplantation
Hematopoietic stem-cell transplantation (SCT) 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 radiation therapy. Bone marrow stem cells may be obtained from the transplant recipient (autologous SCT) or from a donor (allogeneic SCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft versus host disease.
Immunologic compatibility between infused stem cells and the recipient is not an issue in autologous SCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic SCT. 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 HLA A, B, and DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.
Two or more planned courses of high-dose chemotherapy (HDC) and stem-cell support are referred to as “tandem transplantation.” Tandem transplants are typically administered at intervals of 2–6 months, contingent on recovery from treatment-related toxicity.
Conventional Preparative Conditioning for Hematopoietic Stem-Cell Transplantation
The conventional practice of allogeneic stem-cell transplantation (SCT) involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow failure. The beneficial treatment effect in this procedure results from chemotherapeutic eradication of malignant cells with an associated immune-mediated graft-versus-malignancy effect. While such treatment may eliminate the malignant cells, patients are as likely to die from opportunistic infections, graft-versus-host disease, and organ failure as from the underlying malignancy.
Autologous SCT necessitates myeloablative chemotherapy to eradicate cancerous cells, with subsequent engraftment and repopulation of the bone marrow space with hematopoietic progenitor cells. Patients who undergo autologous SCT are susceptible to toxicities related to chemotherapy and opportunistic infections prior to engraftment, but not graft-versus-host disease.
Reduced-Intensity Conditioning for Allogeneic SCT
Reduced-intensity conditioning (RIC) refers to chemotherapy regimens that seek to reduce adverse effects secondary to bone marrow toxicity while retaining the beneficial graft-versus-malignancy effect of allogeneic transplantation. These regimens do not eradicate the patient’s hematopoietic ability, thereby allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) even without a transplant. Patients who undergo RIC with allogeneic SCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. A number of different cytotoxic regimens, with or without radiotherapy, may be used for RIC allotransplantation. They represent a continuum in their effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation.
SCT in Solid Tumors
SCT is an established treatment for certain hematologic malignancies; however, its use in solid tumors in adults continues to be largely experimental. Initial enthusiasm for the use of autologous transplant with the use of HDC and stem cells for solid tumors has waned with the realization that dose intensification often fails to improve survival, even in tumors with a linear-dose response to chemotherapy. (1) With the advent of nonmyeloablative allogeneic transplant, interest has shifted to exploring the generation of alloreactivity to metastatic solid tumors via a graft-versus-tumor effect of donor-derived T cells.
Germ-cell tumors (GCT) are composed primarily of testicular neoplasms (seminomas or nonseminomatous GCT) but also include ovarian and extragonadal GCTs (e.g., retroperitoneal or mediastinal tumors). GCTs are classified according to their histology, stage, prognosis, and response to chemotherapy.
Histologies include seminoma, embryonal carcinoma, teratoma, choriocarcinoma, yolk sac tumor, and mixed GCTs. Seminomas are the most common; all other types are collectively referred to as nonseminomatous GCT.
Stage is dependent on location and extent of the tumor, using the American Joint Committee on Cancer’s TNM system. TNM stages, modified by serum concentrations of markers for tumor burden (S0-3) when available, are grouped by similar prognoses. Markers used for GCTs include human beta-chorionic gonadotropin (HCG), lactate dehydrogenase (LDH), and alpha fetoprotein (AFP). However, most patients with pure seminoma have normal AFP concentrations. For testicular tumors, Stages IA-B have tumors limited to the testis (no involved nodes or distant metastases) and no marker elevations (S0); Stages IIA-C have increasing size and number of tumor-involved lymph nodes, and at least one marker moderately elevated above the normal range (S1); and Stages IIIA-C have distant metastases and/or marker elevations greater than specified thresholds (S2-3).
GCTs also are divided into good-, intermediate-, or poor-risk categories based on histology, site, and extent of primary tumor, and on serum marker levels. Good-risk pure seminomas can be at any primary site, but are without nonpulmonary visceral metastases or marker elevations. Intermediate-risk pure seminomas have nonpulmonary visceral metastases with or without elevated HCG and/or LDH. There are no poor-risk pure seminomas, but mixed histology tumors and seminomas with elevated AFP are managed as nonseminomatous GCTs. Good- and intermediate-risk non-seminomatous GCTs have testicular or retroperitoneal tumors without nonpulmonary visceral metastases, and either S1 (good risk) or S2 (intermediate) levels of marker elevations. Poor-risk tumors have mediastinal primary tumors, or nonpulmonary visceral metastases, or the highest level (S3) of marker elevations.
Therapy for GCT is generally dictated by stage, risk subgroup, and tumor histology. Testicular cancer is divided into seminomatous and nonseminomatous types for treatment planning because seminomas are more sensitive to radiation therapy. Stage I testicular seminomas may be treated by orchiectomy with or without radiation or single-dose carboplatin adjuvant therapy. Nonseminomatous stage I testicular tumors may be treated with orchiectomy with or without retroperitoneal lymph node dissection. Higher stage disease typically involves treatment that incorporates chemotherapy. First-line chemotherapy for good- and intermediate-risk patients with higher-stage disease is usually 3 or 4 cycles of a regimen combining cisplatin and etoposide, with or without bleomycin depending on histology and risk group. Chemotherapy is often followed by surgery to remove residual masses. Second-line therapy often consists of combined therapy with ifosfamide/mesna and cisplatin, plus vinblastine, paclitaxel, or etoposide (if not used for first-line treatment). Patients whose tumors are resistant to cisplatin may receive carboplatin-containing regimens. The probability of long-term continuous complete remission diminishes with each successive relapse. The probability of long-term continuous complete remission diminishes with each successive relapse.
POLICYNo benefits will be provided for a covered transplant procedure or a transplant evaluation unless the Member received prior authorization through case management from Blue Cross & Blue Shield of Mississippi.
Single autologous hematopoietic stem-cell transplantation may also be considered medically necessary as salvage therapy for germ-cell tumors:
Autologous stem-cell transplant may be considered medically necessary to treat patients with germ-cell tumors in second complete remission or in second relapse.
Tandem or sequential autologous hematopoietic stem-cell transplantation may be considered medically necessary for the treatment of testicular tumors either as salvage therapy or with platinum-refractory disease.
Autologous stem-cell transplant is considered investigational as a component of first-line treatment for poor-risk germ-cell tumors, or as initial treatment of a first relapse (i.e., in lieu of a course of conventional chemotherapy).
Allogeneic stem-cell transplant is considered investigational to treat germ-cell tumors, including, but not limited to its use as therapy after a prior failed autologous hematopoietic stem-cell tranplantation.
POLICY EXCEPTIONSFederal 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.
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.
POLICY GUIDELINESThe term partial response is defined as at least a 50% reduction in tumor burden.
The term refractory is defined as a less than 50% reduction in tumor burden. Therefore, tumors that exhibited a 30% reduction in tumor burden, for example, would be considered refractory. Tumor response can be measured using serial computed tomography (CT) scans, or levels of circulating tumor markers, such as alpha fetoprotein.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
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 # 8.01.35 per approval by Medical Policy Advisory Committee (MPAC)
6/25/2004: Code Reference section completed
11/18/2004: Reviewed by MPAC; no changes
10/26/2005: Code Reference section updated: CPT-4 codes: 38230 added; HCPCS: G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added; J9000-J9999 deleted; ICD-9 Procedure 41.01, 41.09 added, "(harvest) of stem cells" added to Covered Codes: CPT-4 codes: 38204 86812, 86813, 86816, 86817, 86821, 86822 added; ICD-9 Procedure 41.02. 41.03 added to Non-Covered Codes
03/10/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy.
9/18/2007: Policy reviewed, no changes
12/20/2007: Coding updated per 2008 CPT/HCPCS revisions
1/06/2009: Policy reviewed. No changes.
10/6/2009: Code reference section updated. New ICD-9 diagnosis code 209.74 added to covered table. HCPC codes G0265, G0266 and G0267 deleted from covered table due to codes were deleted as of 12-31-2007.
03/17/2010: Title -removed "High-Dose Chemotherapy" changed "Support" to "Transplantation." Description section was extensively revised to remove High-Dose Chemotherapy, Bone Marrow & Peripheral Blood. Added Hematopoietic Stem-Cell Transplantation, Conventional Preparative Conditioning for Hematopietic Stem-Cell Transplantation, Reduced-Intensity Conditioning for Allogeneic SCT, SCT in Solid Tumors, and staging and therapy language for Germ-Cell Tumors. Policy Exceptions section was revised to include language about FEP and State/and School Employee subscribers. Code Reference section was updated as follows: added instructions for coding in conjunction with 38207 - 38215; added ICD-9 procedure code 41.00 to covered code table; revised descriptions of ICD-9 procedure codes 41.04 & 41.07; added ICD-9 diagnosis code 158.9 to covered code table; removed deleted HCPCS Code G0363; added CPT Codes 86825 and 86826 to non-covered codes table and added HCPCS Codes S2140 & S2142 to non-covered codes table.
04/28/2010: Policy description updated. Policy statement added to indicate that tandem-sequential autologous SCT may be considered medically necessary in certain types of testicular cancers. Terminology revised in the first and last policy statements for clarity; intent unchanged.
08/03/2011: Deleted the following policy statement: Except as noted above for treatment of certain testicular tumors, tandem or sequential autologous hematopoietic stem-cell transplantation is considered investigational to treat germ-cell tumors of any stage.
05/09/2012: Policy reviewed; no changes.
08/09/2013: Policy reviewed; no changes.
SOURCE(S)Blue Cross Blue Shield Association Policy # 8.01.35
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.