Latest Review Date:  November 2024

Category: Surgical

POLICY:

Single or tandem autologous hematopoietic stem-cell transplantation is considered investigational to treat any stage of breast cancer.

Allogeneic hematopoietic stem-cell transplantation is considered investigational to treat any stage of breast cancer.

DESCRIPTION OF PROCEDURE OR SERVICE:

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 non-metastatic and metastatic breast cancer.

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).

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 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. Consequently, 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 (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 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 non-relapse 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 lympho-ablation, 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 non-myeloablative, 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 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 (GVT) effect of donor-derived T cells.

KEY POINTS:

The most recent literature review was performed through November 7, 2024.

Summary of Evidence

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.

Nonrandomized studies using reduced-intensity or myeloablative allogeneic HSCT for metastatic breast cancer have suggested a possible graft-versus-tumor effect, but remains investigational for this indication.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

NCCN guidelines (V4.2022) do not address the use of HSCT in the treatment of breast cancer.

Table 1. American Society for Transplantation and Cellular Therapy (2020)

(N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental.)

National Cancer Institute (NCI)

The National Cancer Institute does not mention the use of stem cell transplant in Breast Cancer Treatment (Adult) (PDQ®)–Health Professional Version (Updated: September 2, 2020).

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Hematopoietic stem cell transplantation for breast cancer, stem cell transplant, breast cancer, HSCT, autologous SCT, allogeneic SCT

APPROVED BY GOVERNING BODIES:

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 the Code of Federal Regulation title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING: 

CPT Codes:

HCPCS:

REFERENCES:

1. 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 2011; 29(24):3214-3223.
2. 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 2008; 41(6):555-562.
3. Boudin L, Chabannon C, Sfumato P, et al. Impact of Her2 and BRCA1/2 status in high-dose chemotherapy and autologous stem cells transplantation in the treatment of breast cancer: The Institut Paoli Calmettes' experience. Bull Cancer. 2017; 104(4):332-343.
4. Breast Cancer. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.v.4.2022. Available online at: www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Accessed October 6, 2022.
5. Carella AM, Bregni M. Current role of allogeneic stem cell transplantation in breast cancer. Ann Oncol 2007; 18(10):1591-1593.
6. 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 randomized trial. Ann Oncol 2005; 16(5):726-734.
7. 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 2008; 26(1):37-43.
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 early poor prognosis breast cancer. Cochrane Database Syst Rev 2005; (3):CD003139.
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 metastatic breast cancer. Cochrane Database Syst Rev 2005; (3):CD003142.
10. Farquhar C, Marjoribanks J, Lethaby A, Azhar M. 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. 2016 ;(5):CD003139.
11. Farquhar CM, Marjoribanks J, Lethaby A et al. High dose chemotherapy for poor prognosis breast cancer: systematic review and meta-analysis. Cancer Treat Rev 2007; 33(4):325-337.
12. 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 2010; 45(3):464-467.
13. 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 2006; 106(11):2327-2336.
14. Hortobagyi GN. What is the role of high-dose chemotherapy in the era of targeted therapies? J Clin Oncol 2004; 22(12):2263-2266.
15. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
16. Karadurmus, N., Sahin, U., Bahadir Basgoz, B., Arpaci, F., & Demirer, T. (2018). A Review of Allogeneic Hematopoietic Stem Cell Transplantation in Metastatic Breast Cancer. International journal of hematology-oncology and stem cell research, 12(2), 111–116.
17. 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 2006; 24(24):3919-3926.
18. 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 2004; 96(14):1076-1083.
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 2013; 48(3):414-418.
20. National Cancer Institute (NCI). Cancer Types. Physician Data Query (PDQ®) Health Professional Version. Accessed October 2021. Available at URL address: https://www.cancer.gov/types/breast/patient/breast-treatment-pdq
21. National Comprehensive Cancer Network.  Invasive Breast Cancer. Clinical Practice Guidelines in Oncology. (V.2.2019)  Available online at www.nccn.org/professionals/physician_gls/PDF/ breast.pdf.  Last accessed August 28, 2019. 
22. National Comprehensive Cancer Network® (NCCN). NCCN GUIDELINES™ Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Accessed October 2021. Available at URL address: http://www.nccn.org/https://www.nccn.org/professionals/physician/pdf/breast_blocks.pdf
23. Nieto Y, Shpall EJ. High-dose chemotherapy for high-risk primary and metastatic breast cancer: is another look warranted? Curr Opin Oncol 2009; 21(2):150-157.
24. 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 2013.
25. 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 2003; 349(1):7-16.
26. 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 2005; 23(3):432-440.
27. 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 2000; 342(15):1069-1076.
28. Steenbruggen TG, Steggink LC, Seynaeve CM, et al. High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020;6(4):528-534.
29. 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 2003; 349(1):17-26.
30. Ueno NT, Rizzo JD, Demirer T et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant 2008; 41(6):537-545.
31. Vogl DT, Stadtmauer EA. Editorial: high-dose chemotherapy and autologous hematopoietic stem cell transplantation for metastatic breast cancer: a therapy whose time has passed. Bone Marrow Transplant 2006; 37(11):985-987.
32. 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.
33. 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 2004; 22(12):2273- 2283.
34. 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 2008; 19(6):1082-1089.

POLICY HISTORY:

Medical Policy Group, December 2012 (2)

Medical Policy Administration Committee, December 2012

Available for comment December 12, 2012 through January 26, 2013

Medical Policy Panel, January 2013

Medical Policy Group, March 2013 (2): Policy updated with literature search no change to policy statements. Key Points and References Updated

Medical Policy Panel, February 2014

Medical Policy Group, February 2014 (3):  2014 Updates to Key Points & References; no change in policy statement.

Medical Policy Panel, February 2015

Medical Policy Group, February 2015 (2): 2015 Updated Key Points and Coding; no change to policy statement.

Medical Policy Panel, July 2016

Medical Policy Group, July (7): 2016 No new literature available; no change to policy statement. Retiring policy.

Medical Policy Group, December 2017. Annual Coding Update 2018. Added new CPT code 38222 effective 1/1/18 to the Current Coding section.  Updated verbiage for revised CPT codes 38220 and 38221.

Medical Policy Group, August 2019 (3): 2019 Updates to Key Points, Practice Guidelines and Position Statements, and References. A peer reviewed literature analysis was completed and no new information was identified that would alter the coverage statement of this policy.

Medical Policy Group, October 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements, and References. A peer reviewed literature analysis was completed and no new information was identified that would alter the coverage statement of this policy. Policy statement updated to remove “not medically necessary,” no change in intent.

Medical Policy Group, October 2022 (3): 2022 Updates to Key Points, Practice Guidelines and Position Statements, and Approved by Governing Bodies. Reviewed by consensus. References added. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, October 2023 (5): Reviewed by consensus. Updates to Key Points, Benefit Application, and References. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, November 2024 (5): Reviewed by consensus. Updates to Key Points and References. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.