Hematopoietic Cell Transplantation in the Treatment of Germ Cell Tumors

POLICY NUMBER

A.8.01.35

DESCRIPTION

Therapy for germ cell tumors is generally dictated by several factors, including disease stage, tumor histology, primary site of tumor, and response to chemotherapy. Patients with unfavorable prognostic factors may be candidates for hematopoietic cell transplantation (HCT).

Germ Cell Tumors

Germ cell tumors are composed primarily of testicular neoplasms as well as ovarian and extragonadal germ cell tumors (no primary tumor in either testis or ovary). Germ cell tumors are classified by their histology, stage, prognosis, and response to chemotherapy.

The most common testicular germ cell tumors are seminomas; all other histologic types are collectively referred to as nonseminomatous tumors. Nonseminomatous tumor types include embryonal cell tumor, yolk sac tumor, and teratomas. Malignant germ cell tumors of ovarian origin are classified as dysgerminomas or nondysgerminomas. Similarly, nondysgerminomas include immature teratomas, embryonal cell tumors, yolk sac tumor, polyembryoma, and mixed germ cell tumors.

StagingStage depends 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 to 3) when available, are grouped by similar prognoses. Markers used for germ cell tumors include human beta-chorionic gonadotropin, lactate dehydrogenase, and alpha fetoprotein. However, most patients with pure seminoma have normal alpha fetoprotein concentrations. For testicular tumors, stages IA to B tumors are limited to the testis (no involved nodes or distant metastases) and no marker elevations (S0); Stages IIA to 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 to C have distant metastases and/or marker elevations greater than specified thresholds (S2 to 3).

Germ cell tumors also are divided into good-, intermediate-, or poor-risk categories based on histology, site, and extent of the primary tumor, and 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 human chorionic gonadotropin and/or lactate dehydrogenase. There are no poor-risk pure seminomas, but mixed histology tumors and seminomas with elevated alpha fetoprotein (due to the mixture with nonseminomatous components) are managed as nonseminomatous germ cell tumors. Good- and intermediate-risk non-seminomatous germ cell tumors 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.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT). These cells can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in 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 HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this policy, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

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

POLICY

No 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 cell transplantation may be considered medically necessary as salvage therapy for germ cell tumors:

• in individuals with favorable prognostic factors that have failed a previous course of conventional-dose salvage chemotherapy; or

• in individuals with unfavorable prognostic factors as initial treatment of first relapse (i.e., without a course of conventional-dose salvage chemotherapy) and in individuals with platinum-refractory disease. (See Policy Guidelines for prognostic factors.)

Tandem autologous hematopoietic cell transplantation or transplant with sequential high-dose chemotherapy may be considered medically necessary for the treatment of testicular tumors either as salvage therapy or with platinum-refractory disease.

Autologous hematopoietic cell transplant is considered investigational as a component of first-line treatment for germ cell tumors.

Allogeneic hematopoietic 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 cell transplantation.

POLICY EXCEPTIONS

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.

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 GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

The favorable and unfavorable prognostic factors listed below are derived from the current National Comprehensive Cancer Network guidelines and DeVita et al. textbook Cancer: Principles and Practice of Oncology (2015, pp. 988-1004).

Individuals 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. Individuals with unfavorable prognostic factors are those with an extra testicular primary site, an incomplete response to initial therapy, high levels of serum markers, high-volume disease, or relapsing mediastinal nonseminomatous germ cell tumors.

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 Mental Health Disorders, 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 medical necessity, “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 HISTORY

3/25/2004: 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 Hematopoietic 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 aboutFEP 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; addedCPT 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.

08/27/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38242. Removed deleted code CPT 96445 and replaced with CPT code 96446.

09/15/2015: Policy description updated. Policy statements unchanged. Policy Guidelines section updated to add medically necessary and investigative definitions.

05/26/2016: Policy number A.8.01.35 added.

09/30/2016: Code Reference section updated to add the following new ICD-10 procedure codes: 30230G2, 30233G2, 30240G2, 30243G2, 30230G3, 30233G3, 30240G3, 30243G3, 30230G4, 30233G4, 30240G4, 30243G4, 30230Y2, 30233Y2, 30240Y2, 30243Y2, 30230Y3, 30233Y3, 30240Y3, 30243Y3, 30230Y4, 30233Y4, 30240Y4, and 30243Y4.

02/20/2017: Policy description updated regarding FDA regulations. Policy statements unchanged.

12/21/2017: Code Reference section updated to add new 2018 CPT code 38222. Revised descriptions for CPT codes 38220 and 38221 effective 01/01/2018. Removed deleted ICD-10 procedure codes 30230G1, 30233G1, 30240G1, 30243G1, 30230Y1, 30233Y1, 30240Y1, 30243Y1 and ICD-9 procedure codes 41.02, 41.03, 41.05, and 41.08.

03/09/2018: Policy description updated regarding germ cell tumor types. Policy statement revised to state that tandem autologous HCT or transplant with sequential high-dose chemotherapy may be considered medically necessary for the treatment of testicular tumors either as salvage therapy or with platinum-refractory disease. It previously stated: Tandem or sequential autologous HCT may be considered medically necessary for the treatment of testicular tumors either as salvage therapy or with platinum-refractory disease. Policy Guidelines updated to add indications for patients with unfavorable prognostic factors.

03/18/2019: Policy description updated to remove information regarding treatment for germ cell tumors. Policy statements unchanged. Code Reference section updated to remove deleted HCPCS code G0364 and CPT code 86822.

09/24/2019: Code Reference section updated to add new ICD-10 procedure codes 30230U2, 30233U2, 30240U2, 30243U2, 30230U3, 30233U3, 30240U3, 30243U3, 30230U4, 30233U4, 30240U4, and 30243U4, effective 10/01/2019.

02/25/2020: Policy description updated regarding hematopoietic cell transplantation and conditioning for hematopoietic cell transplantation. Policy statements unchanged.

03/26/2021: Policy description updated. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

10/01/2021: Code Reference section updated to add new ICD-10 diagnosis codes C56.3 and C79.63 effective 10/01/2021.

12/21/2021: Code Reference section updated to make note of deleted codes.

02/18/2022: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding favorable and unfavorable prognostic factors.

11/29/2022: Code Reference section updated to remove deleted ICD-10 procedure codes 30230G0, 30240G0, 30230Y0, 30240Y0, 30230G2, 30240G2, 30230G3, 30240G3, 30230G4, 30240G4, 30230U2, 30240U2, 30230U3, 30240U3, 30230U4, 30240U4, 30230Y2, 30240Y2, 30230Y3, 30240Y3, 30230Y4, and 30240Y4.

03/13/2023: Policy reviewed. Policy statements and Policy Guidelines updated with minor wording changes.

12/21/2023: Code Reference section updated to revise the code description for CPT code 96446, effective 01/01/2024.

02/27/2024: Policy reviewed; no changes.

04/08/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association Policy # 8.01.35

CODE REFERENCE

This 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.

Covered Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.