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Therapy for germ-cell tumors is generally dictated by several factors, including disease stage, tumor histology, site of tumor primary and response to chemotherapy. Patients with unfavorable prognostic factors may be candidates for hematopoietic stem-cell transplantation (HSCT).
Hematopoietic 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. 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 “naïve” and thus are associated with a lower incidence of rejection or graft versus host disease (GVHD). Cord blood is discussed in greater detail in the Placental and Umbilical Cord Blood as a Source of Stem Cells medical policy.
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).
Conventional Preparative Conditioning for Hematopoietic Stem-Cell Transplantation
The success of autologous HSCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. As a consequence, autologous HSCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment but usually not GVHD.
The conventional (“classical”) practice of allogeneic HSCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect mediated by nonself immunologic effector cells that develop after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HSCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.
Reduced-Intensity Conditioning for Allogeneic HSCT
Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in traditional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HSCT 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.
For the purposes of this Policy, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (traditional) regimens.
Germ-cell tumors (GCT) are composed primarily of testicular neoplasms (seminomas or nonseminomatous tumors) 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 (B-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 (due to mixture with nonseminomatous components) 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.
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 be considered medically necessary as salvage therapy for germ-cell tumors:
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 germ-cell tumors.
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.
Patients with favorable prognostic factors include those with a testis or retroperitoneal primary site, a complete response to initial chemotherapy, low levels of serum markers, and low volume disease. Patients with unfavorable prognostic factors are those with an incomplete response to initial therapy or relapsing mediastinal nonseminomatous germ-cell tumors.
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.
07/17/2014: Policy reviewed; description updated. Policy statement revised to remove the medically necessary statement: Autologous stem-cell transplant may be considered medically necessary to treat patients with germ-cell tumors in second complete remission or in second relapse. Investigational statement on autologous stem-cell transplant revised to state that autologous stem-cell transplant is considered investigational as a component of first-line treatment for germ-cell tumors. It previously stated: 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). Policy guidelines updated to add information regarding prognostic factors and to remove information defining partial response and refractory.
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.