BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Transplant for Breast Cancer
Chapter: Transplant
Current Effective Date: December 27, 2013
Original Effective Date: February 15, 2012
Publish Date: September 27, 2013
Revised Dates: March 22, 2012; September 10, 2013
Description

The use of hematopoietic stem-cell transplantation (HSCT) has been investigated for treatment of patients with breast cancer. Hematopoietic stem cells are infused to restore bone marrow function following cytotoxic doses of chemotherapeutic agents with or without whole body radiation therapy.

Breast cancer comprises several different types that are distinguished mostly by their rate of growth and tendency to spread to other organs. Staging is based on the degree of spread of the disease. The use of high-dose chemotherapy (HDC) and 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, stage II, stage III and stage IV disease. The stages are defined as follows:

  • High-risk stage II - involvement of four or more axillary lymph nodes without metastasis outside the axilla;
  • Stage IIIA - presence of fixed axillary lymph nodes, OR primary tumor larger than 5 centimeters with involvement of axillary lymph nodes;
  • Stage IIIB - presence of brawny induration of the skin overlying the breast due to involvement of lymphatics (also known as inflammatory breast cancer) OR any size primary tumor, having involvement of ipsilateral internal mammary nodes;
  • Stage IV - presence of distant metastases (involvement of the axilla, chest wall, internal mammary nodes or contralateral breast is defined as locoregional disease and does not constitute distant disease).

NOTE:  The stage of disease refers to the stage identified at the time of consideration for HDC, and not the stage at the time of the original diagnosis of breast cancer.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Investigational

Coverage of, evaluation for, and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of breast cancer at any stage is identified in the grid below.

NOTE: SCT may be known by different terminology and used interchangeably. Hereinafter, SCT will be known as stem-cell support (SCS) throughout the balance of this medical policy. 

Allogeneic

Is considered experimental, investigational and unproven for breast cancer.

Autologous

Is considered experimental, investigational and unproven for breast cancer.

Tandem or Triple Stem-Cell Support

Is considered experimental, investigational and unproven for breast cancer.

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven for breast cancer.

Hematopoietic Progenitor Cell Boost (Stem-Cell Boost)

Is considered experimental, investigational and unproven for breast cancer.

Any use of short tandem repeat (STR) markers for the treatment of breast cancer is considered experimental, investigational and unproven.

Rationale

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) transplant is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, umbilical cord blood, or bone marrow stem-cells. 

History of Hematopoietic Stem-Cell Transplant for Breast Cancer

In the late 1980s and early 1990s, initial results of Phase II trials for breast cancer and autologous stem-cell support (AuSCS) were promising, showing high response rates in patients with metastatic disease who underwent high-dose consolidation, with a subset of up to 30% remaining disease-free for prolonged periods. (1) In the early 1990s, larger prospective comparisons of conventional-dose chemotherapy to HDC with SCS were initiated but accrued slowly, with up to a decade from initiation to the reporting of results. (1) The first results from randomized trials at a single institution in early stage and metastatic disease showed survival benefits but were ultimately shown to have been based on fraudulent data. (1) In the interim, however, the treatment became almost standard of care, while many patients received HDC off protocol, further reducing accrual to ongoing randomized trials. (1) The results of the randomized trials were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) and published as abstracts beginning in 1999 and showed little survival benefit; subsequently, the number of HSCT procedures performed for breast cancer has fallen from thousands every year to only a few. (1)

HDC with Autologous Stem-Cell Support (AuSCS)

Initially, this policy was based on two Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments in 1996 and 1999. (2, 3) During the 1996 TEC Assessment, the focus was on HDC/AuSCS to treat metastatic (i.e., Stage IV) breast cancer, while the 1999 Assessment focused on HDC/AuSCS for adjuvant therapy of high-risk primary (i.e., Stage II/III) breast cancer.

Conclusions of the 1996 BCBSA TEC Assessment (2) were as follows:

Twelve studies were reviewed with a total of 459 patients. These included:

  • A trial from South Africa (published in 1995 and discredited in 2001 because of scientific misconduct [4, 5]) that randomized patients not previously treated for metastatic breast cancer to HDC/AuSCS or to conventional-dose therapy;
  • A crossover trial (still published only as an abstract) that randomized complete responders after induction chemotherapy to immediate consolidation with HDC/AuSCS or to HDC/AuSCS delayed until relapse; and
  • Ten uncontrolled series.

The TEC Assessment also reviewed registry data showing marked decreases in transplant-related mortality between 1992 and 1994 that were attributable to improvements in supportive care and the shift from bone marrow to mobilized peripheral blood progenitors as the source of hematopoietic stem cells. The (now discredited) South African trial (mentioned earlier in this Rationale) reported longer survival for patients in the HDC arm (median 1.7 years), although survival in the conventional-dose arm (median 0.9 years) was shorter than reported with conventional regimens used most commonly in the United States. The crossover trial reported longer disease-free survival (median, 0.85 vs. 0.32 years) but shorter overall survival (median, 1.7 years vs. 3.2 years) in the immediate than in the delayed HDC arm. When combined with results of uncontrolled studies, the balance of evidence available in 1996 suggested that HDC/AuSCS yielded survival durations at least equivalent to those after conventional-dose therapy. Although acute treatment-related morbidity was more severe, the duration of therapy was much shorter with HDC/AuSCS. Therefore, the BCBSA Medical Advisory Panel (MAP) concluded HDC/AuSCS met the BCBSA TEC criteria for patients with previously untreated, responsive, or relapsed metastatic breast cancer but not for those with metastatic disease that is refractory to chemotherapy. Since available evidence was insufficient to determine whether outcomes of either treatment alternative were superior, patients were encouraged to seek this treatment in the context of continued clinical trials.

Conclusions of the 1999 BCBSA TEC Assessment (3) were as follows:

Surgery excises all evident disease for most patients with Stage II/III breast cancer (except those with inflammatory breast cancer). Adjuvant (i.e., postoperative) radiation therapy reduces relapse and improves survival. For those at high risk, adjuvant chemotherapy further reduces recurrence and metastasis and also extends survival. Evidence reviewed for this TEC Assessment, comparing HDC/AuSCS with conventional-dose chemotherapy for adjuvant treatment, included:

  • Two small randomized trials (39–41 patients per arm), a case-control study (60 patients per group), and six uncontrolled series (combined n=302) of patients with 10 or more positive lymph nodes;
  • Two uncontrolled series (combined n=116) of patients with 4–9 positive nodes; and
  • Three uncontrolled series (combined n=86) of patients with non-metastatic inflammatory breast cancer.

For patients with 10 or more positive nodes, the two randomized trials (one published as an abstract) reported 60%–70% survival at five years, with no statistically significant differences between treatment arms. The case-control study and the uncontrolled series suggested longer duration of overall survival (OS) and disease-free survival (DFS) than in previous studies of conventional-dose adjuvant therapy in patients with 10 or more positive nodes. However, the case-control study only matched for a subset of known risk factors. Also, patients treated with HDC/AuSCS in uncontrolled series were generally younger and had better performance status than those given conventional-dose adjuvant therapy. Thus, the analysis could not exclude contributions of patient selection bias to outcome differences. Consequently, the BCBSA MAP found available evidence insufficient to permit conclusions, and HDC/AuSCS did not meet the BCBSA TEC criteria for adjuvant therapy of Stage II/III breast cancer in patients with 10 or more positive nodes. HDC/AuSCS also failed the BCBSA TEC criteria for patients with four to nine positive nodes or those with inflammatory breast cancer, since the lack of controlled studies, small sample sizes, and inadequate follow-up did not permit conclusions.

In May 1999 at an ASCO (American Society of Clinical Oncology) annual meeting, highly publicized results were presented from randomized trials of HDC for adjuvant therapy of high-risk primary breast cancer (three studies) or for metastatic breast cancer (two studies). These preliminary results did not change the conclusions of the 1996 and 1998 BCBSA TEC Assessments (2, 3) Results of these studies are summarized as follows.

The PBT-1 trial (6) randomized patients with a complete response (CR) or partial response (PR) to induction therapy for previously untreated metastatic breast cancer to HDC/AuSCS (n=101) or to conventional-dose maintenance chemotherapy (n=83) for up to two years. Of 553 patients enrolled and given initial induction therapy, only 310 achieved a PR (n=252) or CR (n=58), and only 199 were randomized. Of 72 partial responders assigned to the HSCT arm after initial induction therapy, only 5 (7%) were converted to CRs. Median survival (24 vs. 26 months) and OS at three years (32% vs. 38%) did not differ between arms. There also were no statistically significant differences between arms in time to progression or progression-free survival (PFS) at three years. While treatment duration was substantially shorter for those randomized to HDC/AuSCS, acute morbidity was markedly more severe than after conventional-dose maintenance.

PEGASE-04, a small (total n=61) French randomized trial (7) for patients with chemotherapy-sensitive metastatic breast cancer, reported a significantly longer median duration of PFS for those in the HDC arm (27 vs.16 months; p=0.04). The median duration of overall survival (OS) also was longer in the HDC arm, although this difference was not statistically significant (36 vs.16 months; p=0.08).  

Preliminary results of a CALGB/Intergroup trial (ASCO abstract No. 2) (8), for patients with 10 or more positive nodes, did not show statistically significant survival differences between the HDC and conventional chemotherapy arms. However, the data was not yet sufficiently mature, since the designated endpoint of the trial required a 5-year follow-up, and this interim analysis was based on a median follow-up of 37 months. A Scandinavian Breast Cancer Study Group trial (9) on patients with eight or more positive nodes also reported no significant difference in event free survival (EFS) or OS between the HDC and conventional arms at a median follow-up of 24 months. However, the control arm in this study received an individualized and dose-escalated regimen with higher cumulative doses than those in the HDC arm. This “tailored” regimen increased the combined incidence of secondary leukemia and myelodysplasia. A South African study (10) for patients with 10 or more positive nodes was unique in reporting improved median relapse-free survival (RFS) in the HDC arm. However, this trial also was unique since all patients were treated with HDC immediately without initial conventional-dose adjuvant chemotherapy. [Note also that this trial was discredited in 2000 based on evidence of scientific misconduct.] All three trials reported higher incidences of severe non-lethal toxicity in the HDC arms. Also, no data was reported from ongoing randomized trials for patients with 4-9 positive lymph nodes.

Of the two trials for metastatic breast cancer presented at ASCO in 1999, only the PBT-1 trial was published as a peer-reviewed journal article. Published results confirmed those reported at the meeting. However, some reviewers criticized this trial since few PRs were converted to CRs in the high-dose arm, and since only a minority of those enrolled was subsequently randomized.

Of the three trials for adjuvant therapy of high-risk primary breast cancer presented at the 1999 ASCO meeting (8, 9, 10), only the Scandinavian study was published as a peer-reviewed article (11). Published results confirmed those reported at the meeting. Although an update was presented at the 2001 ASCO meeting, (12) the CALGB (Cancer and Leukemia Group B)/Intergroup trial had not yet published final outcomes. A small pilot trial from the Netherlands with 81 patients randomized to HDC/AuSCS or conventional-dose therapy and a median of seven years’ follow-up reported no differences in OS or DFS at five years. (13) Several larger randomized trials, including the study sponsored by the National Cancer Institute (NCI) for patients with four to nine positive nodes, had completed accrual and were continuing to follow up patients. (14, 15, 16, 17, 18, 19) Although several had reported interim results as meeting presentations, reviewers generally agreed that definitive conclusions required final analyses and peer-reviewed publications. (14, 15, 16, 17, 18, 19)

Two additional trials were reported at ASCO meetings in 2000 and 2001, but were available only as abstracts. A small crossover study, limited to women whose disease did not progress after induction therapy for bone-only metastases, reported modest improvement in PFS (but no effect on overall survival) from immediate compared with delayed HDC/AuSCS. (20) A larger Canadian randomized trial without crossover reported interim results at 19 months median follow-up. (21) In this analysis, PFS was longer (but OS was equivalent) for those randomized to HDC/AuSCS. However, grade three and four toxicities were more common after HDC/AuSCS. Definitive conclusions required longer follow-up and analysis of final outcomes.

During 2003 and 2004, four trials reported final outcomes analyses from randomized comparisons of HDC/AuSCS versus conventional doses for adjuvant therapy of high-risk non-metastatic breast cancer. (22, 23, 24, 25) Two of the studies involved women with at least 4 positive axillary lymph nodes, and the other 2 involved at least 10 positive lymph nodes. The 4 studies pooled included 2,337 patients.

Evidence from these trials did not support the conclusion that HDC/AuSCS improved outcomes when compared with conventional-dose adjuvant therapy, as no OS difference was seen in any of the studies. An editorial that accompanied one report briefly reviewed and commented on factors contributing to diffusion of HDC/AuSCS into routine practice without adequate testing in randomized clinical trials (RCTs). (26) The author also pointed out that of 10 adjuvant therapy trials comparing high-dose to conventional-dose regimens (pooled n=4,521), none reported a statistically significant benefit in OS for the HDC/AuSCS arm, and only one reported improved DFS. However, eight trials lacked adequate statistical power, likely from two factors: slow accrual leading to early closure, and overly optimistic expectations on the magnitude of benefit. The editorialist also suggested that meta-analysis of these trial results might be useful to test whether further studies are warranted for any subgroup (e.g., younger patients with tumors that are high grade or lack hormone receptors). He noted that meta-analysis has been useful to estimate the benefit from adjuvant chemotherapy with various conventional-dose regimens. The editorial concluded that the major lesson from the past decade’s work on HDC/AuSCS “…is that good ideas and good hypotheses are insufficient justification for routinely adopting a therapeutic strategy…” without adequate testing in rigorous, adequately powered, comparative trials. A recent review also concluded that HDC/AuSCS does not improve RFS or OS of women with high-risk breast cancer. (27)

A Cochrane systematic review and meta-analysis published in July 2005 pooled data from six RCTs on metastatic breast cancer reported through November 2004 (N=438 randomized to HDC/AuSCS, 412 to conventional dose therapy). (28) The relative risk for treatment-related mortality was significantly higher in the arm randomized to HDC/AuSCS (15 vs. 2 deaths; RR=4.07; 95% CI: 1.39, 11.88). Treatment-related morbidity also was more severe among those randomized to HDC/AuSCS. OS did not differ significantly between groups at one, three, or five years after treatment. Statistically significant differences in EFS at one year (RR=1.76; 95% CI: 1.40, 2.21) and five years (RR=2.84; 95% CI: 1.07, 7.50) favored the HDC/AuSCS arms. Only one of the six included trials had followed up all patients for at least five years. Reviewers recommended further follow-up for patients randomized in the other five trials. They also concluded that, in the interim, patients with metastatic breast cancer should not receive HDC/AuSCS outside of a clinical trial, since available data showed greater treatment-related mortality and toxicity without improved OS.

A second Cochrane systematic review and meta-analysis, also published in July 2005, included data from 13 RCTs on patients with high-risk (poor prognosis) early breast cancer (N=2,535 randomized to HDC/AuSCS, 2,529 to conventional dose therapy). (29) Treatment-related mortality was significantly greater among those randomized to HDC/AuSCS (65 vs. 4 deaths; RR=8.58; 95% CI: 4.13, 17.80). Treatment-related morbidity also was more common and more severe in the high-dose arms. There were no significant differences between arms in OS rates at any time after treatment. EFS was significantly greater in the HDC/AuSCS group at three years (RR=1.12; 95% CI: 1.06, 1.19) and four years (RR=1.30; 95% CI: 1.16, 1.45) after treatment. However, the two groups did not differ significantly with respect to EFS at five and six years after treatment. There was also no statistically significant difference between groups in the incidence of secondary malignancies at five to seven years of follow-up. Quality of life scores were significantly worse in the HDC/AuSCS arms than in controls soon after treatment, but differences were no longer statistically significant by one year. Reviewers concluded available data were insufficient to support routine use of HDC/AuSCS for patients with poor-prognosis early breast cancer.

HDC with Allogeneic Stem-Cell Support (AlloSCS)

There are inadequate studies to evaluate outcomes of HDC with allogeneic stem-cell support (AlloSCS) in the treatment of breast cancer. Although several uncontrolled studies subsequently were published on use of non-myeloablative conditioning regimens for allotransplants, data still were lacking from controlled trials. (30, 31) Furthermore, evidence is scant for an immunologic graft-versus-tumor effect after allotransplants for breast cancer. Moreover, a 1999 BCBSA TEC Assessment (32) found inadequate data regarding the use of HDC/AlloSCS as salvage therapy after a failed prior course of HDC/AuSCS.

Hanrahan and colleagues, with a median follow-up of 12 years, demonstrated no RFS or OS advantage for patients with high-risk primary breast cancer treated with HDCT after standard dose chemotherapy (n=39). (33) Coombes and colleagues on AuSCS as adjuvant therapy for primary breast cancer in women free of metastatic disease, with a median follow-up of 68 months. (34) A total of 281 patients were randomly assigned to receive standard chemotherapy or HDC with HSCT. They found no significant difference in RFS or OS (OS hazard ratio [HR]: 1.18, 95% CI: 0.80-1.75, p=0.40).

Tandem or Triple Stem-Cell Transplant

Tandem or triple stem-cell transplant for breast cancer is considered experimental, investigational and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature. Several uncontrolled pilot or Phase II trials reported results after two or three sequential cycles of HDC/AuSCS for patients with metastatic, (35, 36, 37, 38, 39, 40)  high-risk operable (39) or inflammatory breast cancer (41, 42) However, data were unavailable from randomized studies that directly compared outcomes of tandem transplants with those of either single transplants or conventional-dose regimens.

Kroger and colleagues reported on the comparison of single versus tandem AuSCS in 187 patients with chemotherapy-sensitive metastatic breast cancer. (43) Only 52 of 85 patients completed the second HDC cycle in the tandem arm, mostly due to withdrawal of consent (most common reason), adverse effects, progressive disease, or death. The rate of CR was 33% in the single-dose arm versus 37% in the tandem arm (p=0.48). Although there was a trend toward improved PFS after tandem HSCT, median OS tended to be greater after single versus tandem HDC (29 vs. 23.5 months, respectively; p=0.4). The authors concluded that tandem HSCT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter OS and higher toxicity compared with single HDT in spite of a trend of improved PFS.  

Donor Leukocyte Infusion (DLI)

Donor Leukocyte Infusion (DLI) for breast cancer is considered experimental, investigational and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

2013 Update

A search of peer reviewed literature through October 2012 was conducted. The following is a summary of the key literature recently reviewed the experience with HCST and breast cancer to date.

Autologous Stem-Cell Transplantation for Breast Cancer

A systematic review and meta-analysis published in 2007 included RCTs comparing autologous HSCT to standard-dose chemotherapy in women with early, poor prognosis breast cancer, which included 13 trials to September 2006 with 5,064 patients. (44) Major conclusions were that, at 5 years, EFS approached statistical significance for the high-dose group, but no OS differences were seen. There were more transplant-related deaths in the high-dose group. The end conclusion was that there was insufficient evidence to support routine use of AuSCS for treating early, poor prognosis breast cancer.

Crump and colleagues reported the results of a randomized trial of women who had not previously been treated with chemotherapy and had metastatic breast cancer or locoregional recurrence after mastectomy. (45) After initial response to induction therapy, 112 women were allocated to standard chemotherapy and 112 to AuSCS. After a median follow-up of 48 months, 79 deaths were observed in the high-dose group and 77 in the standard chemotherapy group. No difference in OS was observed between the 2 groups after a median follow-up of 48 months, with a median OS of 24 months in the HSCT group (95% CI: 21–35 months) and 28 months for the standard chemotherapy group (95% CI: 22–33 months; HR: 0.9; 95% CI: 0.6–1.2; p=0.43).

Biron and colleagues reported the results of a Phase III, open, multicenter, prospective trial of women with metastatic breast cancer (and/or local or regional relapse beyond curative treatment by surgery or radiation). (46) After a CR or at least 50% PR to induction therapy, 88 women were randomly assigned to HSCT and 91 to no further treatment. No OS difference was seen between the 2 groups, with 3-year survival of 33.6% in the high-dose group and 27.3% in the observation group (p=0.8).

Zander and colleagues reported survival data after 6 years of follow-up (47) on a trial that had previously been reported after 3.8 years of follow-up. (44) Women with surgically resected breast cancer and axillary lymph node dissection with 10 or more positive axillary lymph nodes but no evidence of metastatic disease were randomly assigned to standard chemotherapy (n=152) or HSCT (n=150). No difference in OS was observed; the estimated 5-year OS rate in the standard arm was 62% (95% CI: 54-70%) and 64% (95% CI: 56-72%) in the high-dose transplant group.

Nieto and Shpall performed a meta-analysis of all randomized trials published or updated since 2006, focusing on those that compared HDC with standard-dose chemotherapy for high-risk primary breast cancer. (48) The meta-analysis of 15 randomized trials involving patients with high-risk primary breast cancer or metastatic disease (n=6,102) detected an absolute 13% EFS benefit in favor of HDC and AuSCS (p=0.0001) at a median follow-up of 6 years. The absolute differences in disease-specific and OS did not reach statistical significance (7 % and 5%, respectively). Subset analyses suggested that HDC could be particularly effective in patients with triple negative tumors (hormone receptor and HER2-negative). The authors concluded that HDC remains a valid research strategy in certain subpopulations with high-risk primary breast cancer, for example those with triple negative tumors.

Allogeneic Stem-Cell Transplantation for Breast Cancer

To date, AlloSCS for breast cancer has mostly been used in patients who have failed multiple lines of conventional chemotherapy. (49)

Ueno and colleagues reported the results of AlloSCS in 66 women with poor-risk metastatic breast cancer from 15 centers that underwent transplantation between 1992 and 2000. (50) Thirty-nine (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. A total of 17 (26%) patients had received a prior AuSCS. Median follow-up time for survivors was 40 months (range 3–64 months). Treatment-related mortality was lower in the RIC group (7% vs. 29% at 100 days; p=0.03). PFS at 1 year was 23% in the myeloablative group versus 8% in the RIC group (p=0.09). OS rates after myeloablative conditioning versus the RIC group were 51% (95% CI: 36–67%) versus 26% (95% CI: 11–45%) [p=0.04] at 1 year, 25% (95% CI: 13–40%) versus 15% (95% CI: 3–34%; p=0.33) at 2 years, and 19% (95% CI: 8–33%) versus 7% (95% CI: <1–25%; p=0.21) at 3 years, respectively.

Fleskens and colleagues reported the results of a Phase II study of 15 patients with metastatic breast cancer treated with HLA-matched reduced-intensity AlloSCS. (51) Median patient age was 49.5 years (range: 39.7-60.8 years), and all patients had been extensively pretreated and had undergone at least 1 palliative chemotherapy regimen for metastatic disease. Treatment-related mortality was 2/15 (13%). One-year PFS was 20% and 1- and 2-year OS was 40% and 20%, respectively. The authors noted no objective tumor responses but concluded that the relatively long PFS suggests a graft-versus-tumor (GVT) effect.

Additional Infusion Treatments for Breast Cancer

Schmid and colleagues published results of 93 patients without prior chemotherapy for metastatic breast cancer who were randomly assigned to standard-dose chemotherapy or double HDC with AuSCS. (52) The primary study objective was to compare CR rates. Objective response rates for the patients in the high-dose group were 66.7% versus 64.4% for the standard group (p=0.82). There were no significant differences between the 2 treatments in median time to progression, duration of response, or OS (OS 26.9 months vs. 23.4 months for the double high-dose arm versus the standard arm, respectively; p=0.60).

Donor leukocyte infusion (DLI) to treat any stage of breast cancer is considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

As with DLI, HPC Boost has a positive response rate for relapse following AlloSCS. (53) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. However, the data is insufficient for the use of HPC Boost following AlloSCS for treatment of non-hematological malignancies to lessen post-transplant graft failures. (53, 54, 55, 56)

Short Tandem Repeat (STR) Markers

Following SCS therapy, it is important to determine whether the new blood forming system is of the donor or the recipient, based upon the proportion of donor and recipient cells. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (57, 58) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of breast cancer, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (57, 58, 59, 60, 61, 63)

Clinical Guidelines

2013 National Comprehensive Cancer Network guidelines do not address the use of HSCT in the treatment of breast cancer. (63)

As of October 2012, the National Cancer Institute clinical trials database showed no ongoing Phase III trials for HSCT for breast cancer.

Summary

Randomized trials of AuSCS 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. However, nonrandomized studies using reduced-intensity or myeloablative AlloSCS for metastatic breast cancer has suggested a possible graft-versus-tumor effect.

As of October 2012, no clinical trials have been published that would alter the current policy statement; thus the use of SCS, as a single treatment or infusion, tandem or triple stem-cell transplant and DLI in autoimmune disorders, listed in the coverage statement, remains experimental, investigational and unproven.

Based on a search of scientific literature in the MedLine database through March 2013, HPC boost to reduce the graft failure process and STR markers to monitor engraftment chimerism for the treatment of breast cancer are considered experimental, investigational, and unproven due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.  

Rationale for Benefit Administration
 
ICD-9 Codes

Experimental, Investigational and Unproven for all codes.  41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79

ICD-10 Codes

Experimental, Investigational and Unproven for all codes.  30230G0, 30230G1, 30233G0, 30233G1, 30240G0, 30240G1, 30243G0, 30243G1, 30250G0, 30250G0, 30250G1, 30253G0, 30253G1, 30260G0, 30260G1, 30263G0, 30263G1, 3E03005, 3E03305, 3E04005, 3E04305, 3E05005, 3E05305, 3E06005, 3E06305, 6A550Z2, 6A551Z2, 6A550ZT, 6A550ZV, 6A551ZT, 6A551ZV

Procedural Codes: 36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241, S2140, S2142, S2150
References
  1. 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):985-7.
  2. High-Dose Chemotherapy with Autologous Stem-Cell Support in the Treatment of Metastatic Breast Cancer. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1996 June) 11(3):1-27.
  3. High-Dose Chemotherapy with Autologous Stem-Cell Support in the Treatment of High-Risk, Primary Breast Cancer. Chicago, Illinois: Blue Cross Blue Shield Association - Technology Evaluation Center Assessment Program (1999 February) 13(24):1-36.
  4. Weiss, R.B., Gill, G.G., et al. An on-site audit of the South African trial of high-dose chemotherapy for metastatic breast cancer and associated publications. Journal of Clinical Oncology (2001) 19(11):2771-7.
  5. Weiss, R.B., Rifkin, R.M., et al. High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet (2000); 355(9208):999-1003.
  6. Stadtmauer, E.A., O’Neill, L.J., et al. Phase III randomized trial of high-dose chemotherapy and stem cell support shows no difference in overall survival or severe toxicity compared to maintenance chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil for women with metastatic breast cancer who are responding to conventional induction chemotherapy: The Philadelphia Intergroup Study (PBT-1). Annual Meeting American Society of Clinical Oncology. (1999) 18:1a (abstract no. 1).
  7. Lotz, J.P., Cure, H., et al. High dose chemotherapy with hematopoietic stem cells transplantation for metastatic breast cancer. Results of the French protocol PEGASE-04.  Annual Meeting American Society of Clinical Oncology (1999) 18:43a (abstract no. 161).
  8. Peters, W.P., Rosner, G., et al. A prospective randomized comparison of two doses of combination alkylating agents are consolidation after CAF in high risk primary breast cancer involving ten or more axillary lymph nodes: Preliminary results of CALGB (Cancer and Leukemia Group B) 9082/SWOG9114/NCIC MA-13. Annual Meeting American Society of Clinical Oncology (1999) 18:1a (abstract no. 2).
  9. The Scandinavian Breast Cancer Study Group 9401. Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTC, supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy. Annual Meeting American Society of Clinical Oncology (1999) 18:2a (abstract no. 3).
  10. Bezwoda, W.R. Randomized controlled trial of high dose chemotherapy versus standard dose chemotherapy for high risk, surgically treated primary breast cancer. Annual Meeting American Society of Clinical Oncology (1999) 18:2a (abstract no. 4).
  11. Bergh, J., Wiklund, T., et al. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomized trial. Scandinavian Breast Group 9401 study. Lancet (2000) 356(9239):1384-91.
  12. Peters, W.P., Rosner, G., et al. Updated results of a prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): CALGB 9082/SWOG 9114/NCIC Ma-13. Annual Meeting American Society of Clinical Oncology (2001) 20:21a (abstract no. 81).  
  13. Schrama JG, Faneyte IF, Schornagel JH et al. Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years of follow-up. Ann Oncol 2002; 13(5):689-98.
  14. Baynes, R.D., Dansey, R.D., et al. High-dose chemotherapy and hematopoietic stem cell transplantation for breast cancer: past or future? Seminars in Oncology (2001) 28(4):377-88.
  15. Pedrazzoli, P., Siena, S. Clinical results in 2001 show high dose therapy and hematopoietic progenitor cell transplantation as a therapeutic option for breast cancer. Haematologica (2001) 86(9):900-7.
  16. Antman KH. A critique of the eleven randomized trials of high-dose chemotherapy for breast cancer. European Journal of Cancer (2001) 37(2):173-9.
  17. Dicato, M. High-dose chemotherapy in breast cancer: where are we now? Seminars in Oncology (2002); 29(3 suppl 8):16-20.
  18. Gerrero, R.M., Stein, S., et al. High-dose chemotherapy and stem cell support for breast cancer: where are we now? Drugs Aging (2002) 19(7):475-85.
  19. Schmid, P., Possinger, K. High-dose chemotherapy in high-risk primary breast cancer. Onkologie (2002) 25(2):112-20.
  20. Madan, B., Broadwater, G., et al. Improved survival with consolidation high-dose cyclophosphamide, cisplatin and carmustine (HD-CPB) compared with observation in women with metastatic breast cancer (MBC) and only bone metastases treated with induction Adriamycin, 5-fluorouracil and methotrexate (AFM): a phase III prospective randomized comparative trial. Annual Meeting American Society of Clinical Oncology (2000) 19:48a (abstract no. 184).
  21. Crump, M., Gluck, S., et al. A randomized trial of high-dose chemotherapy (HDC) with autologous peripheral blood stem cell support (ASCT) compared to standard therapy in women with metastatic breast cancer: a National Cancer Institute of Canada (NCIC) Clinical Trials Group study. Annual Meeting American Society of Clinical Oncology (2001) 20:21a (abstract no. 82).
  22. Leonard, R.C., Lind, M., et al. Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. Journal of the National Cancer Institute (2004) 96(14):1076-83.
  23. Rodenhuis, S., Bontenbal, M., et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. New England Journal of Medicine (2003) 349(1):7-16.
  24. Tallman, M.S., Gray, R., et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. New England Journal of Medicine (2003) 349(1):17-26.
  25. Zander, A.R., Kroger, N., 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. Journal of Clinical Oncology (2004) 22(12):2273-83.
  26. Hortobagyi, G.N. What is the role of high-dose chemotherapy in the era of targeted therapies? Journal of Clinical Oncology (2004) 22(12):2263-6.
  27. Carlson, R.W., Wheatley, K. High-dose chemotherapy and stem cell transplantation does not improve relapse-free or overall survival in women with high-risk breast cancer. Cancer Treatment Reviews (2004) 30(1):131-7.
  28. Farquhar, C., Marjoribanks, J., 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 Systematic Review (2005); (3):CD003139.
  29. Farquhar, C., Marjoribanks, J., et al. High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Database Systematic Reviews (2005) (3):CD003142.
  30. Bregni, M., Dodero, A., et al. Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. Blood (2002) 99(11):4234-6.
  31. Carella, A.M., Beltrami, G., et al. Combined use of autografting and non-myeloablative allografting for the treatment of hematologic malignancies and metastatic breast cancer. Cancer Treatment and Research (2002) 110:101-12.
  32. Salvage HDC/AlloSCS for Relapse following HDC/AuSCS for Non-Lymphoid Solid Tumors. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1999 July) 14(11):1-9.
  33. Hanrahan, E.O., Broglio, K., 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):2327-36.
  34. Coombes, R.C., Howell, A., 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. Annals of Oncology (2005) 16(5):726-34.
  35. Elias, A.D., Richardson, P., et al. A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer. Bone Marrow Transplant (2001) 27(3):269-78.
  36. Elias, A.D., Richardson, P., et al. A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer: sequential phase I/II studies. Bone Marrow Transplant (2001) 28(5):447-54.
  37. Pecora, A.L., Lazarus, H.M., et al. Effect of induction chemotherapy and tandem cycles of high-dose chemotherapy on outcomes in autologous stem cell transplant for metastatic breast cancer. Bone Marrow Transplant (2001) 27(12):1245-53.
  38. Schrama, J.G., Baars, J.W., et al. Phase II study of a multi-course high-dose chemotherapy regimen incorporating cyclophosphamide, thiotepa, and carboplatin in stage IV breast cancer. Bone Marrow Transplant (2001) 28(2):173-80.
  39. Somlo, G., Chow, W., et al. Tandem-cycle high-dose melphalan and cisplatin with peripheral blood progenitor cell support in patients with breast cancer and other malignancies. Biology of Blood and Marrow Transplantation (2001) 7(5):284-93.
  40. Sayer, H.G., Schilling, K., et al. Double high-dose chemotherapy with adriamycin, paclitaxel, cyclophosphamide, and thiotepa followed by autologous peripheral blood stem cell transplantation in women with metastatic breast cancer. Journal of Cancer Research and Clinical Oncology (2003) 129(6):361-6.
  41. Dazzi, C., Cariello, A., et al. Neoadjuvant high dose chemotherapy plus peripheral blood progenitor cells in inflammatory breast cancer: a multicenter phase II pilot study. Haematologica (2001) 86(5):523-9.
  42. Macquart-Moulin, G., Viens, P., et al. High-dose sequential chemotherapy with recombinant granulocyte colony-stimulating factor and repeated stem-cell support for inflammatory breast cancer patients: does impact on quality of life jeopardize feasibility and acceptability of treatment? Journal of Clinical Oncology (2000) 18(4):754-64.
  43. Kroger, N., Frick, M., et al. Randomized trial of single compared with tandem high-dose chemotherapy followed by autologous stem-cell transplantation in patient with chemotherapy-sensitive metastatic breast cancer. Journal of Clinical Oncology (2006); 24(24):1919-26.
  44. 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):325-37.
  45. 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.
  46. 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):555-62.
  47. 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):1082-9.
  48. 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):150-7.
  49. Carella AM, Bregni M. Current role of allogeneic stem cell transplantation in breast cancer. Ann Oncol 2007; 18(10):1591-3.
  50. Ueno NT, Rizzo JD, Demirer T et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant 2008; 41(6):537-45.
  51. 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):464-7.
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  54. Slatter, M.A., Bhattacharya, A., et al. Outcome of boost hematopoietic stem cell transplant for decreased donor chimerism or graft dysfunction in primary immunodeficiency. Bone Marrow Transplantation (2005) 35:683-9.
  55. Larocca, A., Piaggio, G., et al. A boost of CD35+-selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation. The Hematology Journal (2006) 91(7):935-40.
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  57. Borrill, V., Schlaphoff, T., et al. The use of short tandem repeat polymorphisms for monitoring chimerism follow bone marrow transplantation: a short report. Hematology (2008 August) 13(4):210-4.
  58. Crow, J., Youens, K., et al. Donor cell leukemia in umbilical cord blood transplant patients: a case study and literature review highlighting the importance of molecular engraftment analysis. Journal of Molecular Diagnostics (2010 July) 12(4):530-7.
  59. Park, M., Koh, K.N., et al. Clinical implications of chimerism after allogeneic hematopoietic stem-cell transplantation in children with non-malignant diseases. Korean Journal of Hematology (2011 December) 46(4):258-64.
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History
October 2011 New Policy for BCBSMT. Codes already sent with other Hematopoietic Stem-Cell Transplant policies.
March 2012 Policy updated with literature search; no references added; reference 22 updated. No change to policy statements
September 2013 Policy formatting and language revised.  Title changed from "Hematopoietic Stem-Cell Transplantation for Breast Cancer" to "Stem-Cell Transplant for Breast Cancer".  Added to the policy statement that tandem or triple stem-cell support, donor leukocyte infusion, hematopoietic progenitor cell boost, and any use of short tandem repeat markers are considered experimental, investigational, and unproven.
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Stem-Cell Transplant for Breast Cancer