Subject:
Hematopoietic Stem Cell Transplantation for Breast Cancer
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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The use of high-dose chemotherapy (HDC) and hematopoietic stem cell transplantation (HSCT), instead of standard dose chemotherapy, has been used in an attempt to prolong survival in women with high-risk nonmetastatic and metastatic breast cancer.
Background
Hematopoietic Stem-Cell Transplantation
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 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 a separate policy on Cord Blood as a Source of Stem Cells (Policy #012) under the Surgery Section.
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 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 HSCT
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 prior to 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 prior to engraftment, but not GVHD.
The conventional (“classical”) practice of allogeneic HSCT involves administration of cytotoxic agents (eg, 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 non–self 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 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 nonrelapse mortality 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.
HSCT in Solid Tumors in Adults
HSCT 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 high-dose chemotherapy (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. With the advent of reduced-intensity 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.
Related Policies
Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
I. The guiding principle of this policy is the New Jersey State Mandate on High Dose Chemotherapy and Autologous Bone Marrow (ABMT) or Peripheral Stem Cell Transplant (PSCT).
The ensuing statements represent the interpretation of the law by Horizon Blue Cross Blue Shield of New Jersey (Horizon BCBSNJ) which must be strictly observed when handling pre-authorizations, claims, inquiries, and other matters pertaining to high-dose chemotherapy with stem cell support.:
A. The law only applies to autologous bone marrow or peripheral stem cell transplant for the treatment of cancer. Medical necessity criteria must NOT be applied to these cases. They are automatically eligible for coverage under the law.
[INFORMATIONAL NOTE: Please note that self-insured accounts are exempt from the law. However, they have the option to adopt the law.
Policy Statement II of this policy deals with eligibility and medical necessity criteria which must be applied specifically to those self-insured accounts which opted NOT to adopt the law.]
B. In cases of multiple, repeat, or tandem autologous bone marrow or peripheral stem cell transplant procedures for the same member, the first or initial transplant is automatically covered under the law. However, subsequent transplant procedures are NOT automatically covered under the law but are subject to medical necessity criteria.
C. The law applies to contracts delivered, issued, executed or renewed in New Jersey. Services rendered outside New Jersey are covered by the law as long as the member has a contract that is written or issued in New Jersey and permits coverage for non-emergency services out-of-network.
D. Exclusions to the law:
Policy Statement II of this policy addresses medical necessity criteria as it applies to the following requests for:
- an allogeneic bone marrow or peripheral stem cell transplant.
- treatment of non-cancerous conditions even if it involves autologous bone marrow or peripheral stem cell transplant.
- mini-transplants or non-myeloablative transplantssince they are allogeneic transplants.
II. The following criteria are only applicable to self-insured accounts which opted NOT to adopt the law (or other contracts which may be exempt from the law) and any other applicable exclusions to the law as enumerated in the above Policy Statement I.D. (i.e., allogeneic bone marrow or allogeneic peripheral stem cell transplant):
[INFORMATIONAL NOTE: Also refer to a separate policy on Cord Blood as a Source of Stem Cells (Policy #012) under the Surgery Section of this database.
Please note that Horizon Blue Cross Blue Shield of New Jersey has agreed to participate in a voluntary state-wide program to provide coverage for routine costs associated with all phases of approved cancer clinical trials in New Jersey.]
A. This procedure is subject to the specific terms of the member's contract.
[INFORMATIONAL NOTE: Also refer to a separate policy on Transplant Donor and Recipient Policy (Policy #003) under the Surgery Section.]
B. Medical necessity is established based on review of the following information:
1. Stage to which the malignancy has progressed;
2. Clinical history of the member including results of diagnostic procedures performed (i.e., laboratory, pathology, radiology), and previous modes of therapy with results;
3. Treatment protocol of the facility where the procedure is being performed.
C. Single or tandem autologous stem cell transplantation is not considered medically necessary to treat any stage of breast cancer.
[NOTE: Randomized trials of autologous hematopoietic stem cell transplantation (HSCT) versus standard dose chemotherapy for patients with high-risk non-metastatic or metastatic breast cancer have not shown a survival advantage with HSCT, with greater treatment-related mortality and toxicity. Therefore, autologous HSCT is considered not medically necessary for this indication.]
[INFORMATIONAL NOTE: Before making a determination that this procedure is investigational, please refer to Policy Statement I of this policy for the applicability of the New Jersey State Law on High Dose Chemotherapy (HDC) and Autologous Bone Marrow Transplant (BMT) or Peripheral Stem Cell Transplant (PSCT).
In addition, please be aware that in cases of multiple, repeat, or tandem autologous bone marrow or peripheral stem cell transplant procedures, the first or initial transplant is automatically covered under the law. For further details, please refer to Policy Statement I of this policy for the applicability of the law, and Policy Statement II of this policy for the medical necessity criteria.]
D. Allogeneic stem-cell transplantation is considered investigational to treat any stage of breast cancer.
Medicare Coverage:
Per NCD 110.23, CMS has determined that insufficient data exists to establish definite conclusions regarding the efficacy of AuSCT for solid tumors other than neuroblastoma. Therefore, AuSCT for Breast Cancer is not considered reasonable and necessary within the meaning of §l862(a)(1)(A) of the Act and is not covered. For additional information, refer to National Coverage Determination (NCD) for Stem Cell Transplantation (Formerly 110.8.1) (110.23). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.
Medicaid Coverage:
FIDE-SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
[Summary of Evidence: Randomized trials of autologous hematopoietic cell transplantation (HCT) versus standard dose chemotherapy for patients with high-risk nonmetastatic or metastatic breast cancer have not shown a survival advantage with HCT, and have shown greater treatment-related mortality and toxicity. Therefore, autologous HCT is considered not medically necessary for this indication.
Nonrandomized studies using reduced-intensity or myeloablative allogeneic HCT for metastatic breast cancer have suggested a possible graft-versus-tumor effect, but remains investigational for this indication.
SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
National Comprehensive Cancer Network guidelines (v.1.2019) do not address the use of HCT in the treatment of breast cancer.
U.S. Preventive Services Task Force Recommendations Not applicable.
National Cancer Institute- 2017 “...regarding metastatic disease, treatment guidelines note that no overall survival or relapse-free survival benefit was noted for patients receiving high dose chemotherapy with stem cell support compared with conventional chemotherapy. Because of the absence of data suggesting a benefit from high dose chemotherapy with stem cell support, this should be considered only as part of a clinical trial”
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.]
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Hematopoietic Stem Cell Transplantation for Breast Cancer
High Dose Chemotherapy with Hematopoietic Stem Cell Support for Breast Cancer
Allogeneic Bone Marrow Transplant, Breast Cancer
Autologous Bone Marrow Transplant, Breast Cancer
Bone Marrow Transplant, Breast Cancer
Breast Cancer, High Dose Chemotherapy
Stem Cell Transplant, Breast Cancer
Tandem Transplantation, Breast Cancer
Transplantation, Bone Marrow/Stem Cell for Breast Cancer
References:
1. Vogl DT, Stadtmauer EA. High-dose chemotherapy and autologous hematopoietic stem cell transplantation for metastatic breast cancer: a therapy whose time has passed [editorial]. Bone Marrow Transplant. Jun 2006;37(11):985-987. PMID 16708060
2. Stadtmauer EA, O'Neill A, Goldstein LJ, et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med. Apr 13 2000;342(15):1069-1076. PMID 10760307
3. Leonard RC, Lind M, Twelves C, et al. Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. J Natl Cancer Inst. Jul 21 2004;96(14):1076-1083. PMID 15265969
4. Rodenhuis S, Bontenbal M, Beex LV, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. Jul 3 2003;349(1):7-16. PMID 12840087
5. Tallman MS, Gray R, Robert NJ, et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med. Jul 3 2003;349(1):17-26. PMID 12840088
6. Zander AR, Kroger N, Schmoor C, et al. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol. Jun 15 2004;22(12):2273-2283. PMID 15111618
7. Hortobagyi GN. What is the role of high-dose chemotherapy in the era of targeted therapies? [editorial]. J Clin Oncol. Jun 15 2004;22(12):2263-2266. PMID 15111620
8. Farquhar C, Marjoribanks J, Basser R, et al. High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Database Syst Rev. 2005(3):CD003142. PMID 16034887
9. Farquhar C, Marjoribanks J, Basser R, et al. High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer. Cochrane Database Syst Rev. 2005(3):CD003139. PMID 16034886
10. Hanrahan EO, Broglio K, Frye D, et al. Randomized trial of high-dose chemotherapy and autologous hematopoietic stem cell support for high-risk primary breast carcinoma: follow-up at 12 years. Cancer. Jun 1 2006;106(11):2327-2336. PMID 16639731
11. Coombes RC, Howell A, Emson M, et al. High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol. May 2005;16(5):726-734. PMID 15817602
12. Farquhar CM, Marjoribanks J, Lethaby A, et al. High dose chemotherapy for poor prognosis breast cancer: systematic review and meta-analysis. Cancer Treat Rev. Jun 2007;33(4):325-337. PMID 17382477
13. Crump M, Gluck S, Tu D, et al. Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. J Clin Oncol. Jan 1 2008;26(1):37-43. PMID 18025439
14. Biron P, Durand M, Roche H, et al. Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer. Bone Marrow Transplant. Mar 2008;41(6):555-562. PMID 18037940
15. Zander AR, Schmoor C, Kroger N, et al. Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up. Ann Oncol. Jun 2008;19(6):1082-1089. PMID 18304964
16. Nieto Y, Shpall EJ. High-dose chemotherapy for high-risk primary and metastatic breast cancer: is another look warranted? Curr Opin Oncol. Mar 2009;21(2):150-157. PMID 19532017
17. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials. J Clin Oncol. Aug 20 2011;29(24):3214-3223. PMID 21768471
18. Wang J, Zhang Q, Zhou R, et al. High-dose chemotherapy followed by autologous stem cell transplantation as a first-line therapy for high-risk primary breast cancer: a meta-analysis. PLoS One. 2012;7(3):e33388. PMID 22428041
19. Martino M, Ballestrero A, Zambelli A, et al. Long-term survival in patients with metastatic breast cancer receiving intensified chemotherapy and stem cell rescue: data from the Italian registry. Bone Marrow Transplant. Mar 2013;48(3):414-418. PMID 22863724
20. Pedrazzoli P, Martinelli G, Gianni AM, et al. Adjuvant high-dose chemotherapy with autologous hematopoietic stem cell support for high-risk primary breast cancer: results from the Italian national registry. Biol Blood Marrow Transplant. Apr 2014;20(4):501-506. PMID 24374214
21. Kroger N, Frick M, Gluz O, et al. Randomized trial of single compared with tandem high-dose chemotherapy followed by autologous stem-cell transplantation in patients with chemotherapy-sensitive metastatic breast cancer. J Clin Oncol. Aug 20 2006;24(24):3919-3926. PMID 16921043
22. Schmid P, Schippinger W, Nitsch T, et al. Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol. Jan 20 2005;23(3):432-440. PMID 15659490
23. Carella AM, Bregni M. Current role of allogeneic stem cell transplantation in breast cancer. Ann Oncol. Oct 2007;18(10):1591-1593. PMID 17846023
24. Ueno NT, Rizzo JD, Demirer T, et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant. Mar 2008;41(6):537-545. PMID 18084340
25. Fleskens AJ, Lalisang RI, Bos GM, et al. HLA-matched allo-SCT after reduced intensity conditioning with fludarabine/CY in patients with metastatic breast cancer. Bone Marrow Transplant. Mar 2010;45(3):464-467. PMID 19633692
26. Deeg HJ, Sandmaier BM. Determining eligibility for allogeneic hematopoietic cell transplantation. In: UpToDate, Chao NJ, Rosmarin AG (Eds), UpToDate, Waltham, MA. (Accessed on June 8, 2017.)
27. Burstein H, Hayes D, Vora S. Adjuvant chemotherapy for HER2-negative breast cancer. In : UpToDate, Chao NJ, Rosmarin AG (Eds), UpToDate, Waltham, MA. (Accessed on March 15, 2018.)
28. Taghian A, El-Ghamry M, Merajver S. Inflammatory breast cancer: Clinical features and treatment. In : UpToDate, Chao NJ, Rosmarin AG (Eds), UpToDate, Waltham, MA. (Accessed on March 15, 2018.)
29. Burstein H. Adjuvant chemotherapy for HER2-negative breast cancer. In : UpToDate, Hayes D, Vora S (Eds), UpToDate, Waltham, MA. (Accessed on May 3, 2019.)
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
38204
38205
38206
38207
38208
38209
38210
38211
38212
38213
38214
38215
38220
38221
38230
38240
38241
38242
HCPCS
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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