Hematopoietic Cell Transplantation for Breast Cancer

Number: 0507

Policy

Aetna considers autologous hematopoietic cell transplantation for breast cancer experimental and investigational because its effectiveness for this indication has not been established.

Aetna considers tandem hematopoietic cell transplantation for breast cancer experimental and investigational because its effectiveness for this indication has not been established.

Aetna considers allogeneic hematopoietic cell transplantation for breast cancer experimental and investigational because its effectiveness for this indication has not been established.

Exception: Aetna will cover autologous hematopoietic cell transplantation, tandem hematopoietic cell transplantation, or allogeneic hematopoietic cell transplantation for breast cancer when it is performed in a clinical trial sponsored or authorized by the National Cancer Institute (NCI) or the Federal Food and Drug Administration (FDA).  Four randomized controlled clinical trials showed that autologous hematopoietic cell transplantation was either similar to or more harmful than standard-dose chemotherapy.  Doubts have risen concerning falsification of data from the Bezwoda study from South Africa, the only randomized, controlled trial that showed that autologous hematopoietic cell transplantation had any clinical benefits over standard-dose chemotherapy.

Note: Aetna will continue to cover autologous hematopoietic cell transplantation, tandem hematopoietic cell transplantation, or allogeneic hematopoietic cell transplantation off-trial when dictated by state mandates or other requirements.

See also CPB 0634 - Non-myeloablative Hematopoietic Cell Transplantation (Mini-Allograft / Reduced Intensity Conditioning Transplant).

Background

Appropriate treatment for breast cancer depends on the stage of the cancer, the patient's overall health, and other patient characteristics, such as estrogen receptor status, age, and menopausal status.  Treatment may include surgery, radiation, standard-dose chemotherapy, hormonal therapy, or a combination of these.  Despite a lack of research showing that high-dose chemotherapy (HDC) with autologous stem cell support (AuSCS) is effective in increasing survival, this approach has become an increasingly common treatment strategy for women with breast cancer.

High-dose chemotherapy/AuSCS is based on the concept that some of the chemotherapeutic drugs used in standard-dose chemotherapy might kill more cancer cells if given at much higher doses.  However, high doses are very toxic to the bone marrow, and techniques had to be developed to restore a patient's ability to make blood cells after HDC by infusing stem cells harvested prior to treatment from either the patient's bone marrow (ABMT) or peripheral blood (PBSCT).  Collectively, these techniques are known as AuSCS.  The HDC/AuSCS procedure was initially used as a treatment for metastatic disease; however, its use has expanded to women with very high-risk primary breast cancer that has spread to multiple lymph nodes, but is not yet widely metastatic.

Early published results of small uncontrolled phase I and II trials and large retrospective studies of women with metastatic breast cancer (MBC) suggested the potential for higher response rates and increased survival with HDC.  However, the results from these early uncontrolled studies were contradicted by several subsequently published randomized controlled clinical trials.  In April 1999, the American Society of Clinical Oncologists (ASCO) released preliminary results of 4 randomized controlled phase III trials.  Two of the studies examined the use of HDC/AuSCS in the adjuvant treatment of women with very high-risk primary breast cancer defined as cancer that has spread to at least 10 lymph nodes.  Two studies examined the use of HDC/AuSCS for the treatment of advanced, MBC.  The early data from these multi-center studies indicated that, at the present time, there is no difference in overall survival (OS) between HDC/AuSCS and standard, lower doses of chemotherapy.

The only controlled clinical trial showing higher response rates for HDC/AuSCS than standard-dose chemotherapy was a study first published in 1995 by Bezwoda and his colleagues from the University of Witwatersrand, South Africa.  This study involved 90 patients with MBC who were randomized to receive either HDC/AuSCS or a lower dose regimen of chemotherapy not requiring ABMT.  The researchers found a significantly higher overall response rate for patients who received HDC/AuSCS (95 %) compared with standard-dose chemotherapy (53 %). Upon further analysis, many experts in the field have agreed that this study of small size (45 in the HDC/AuSCS group and 45 in the standard) was poorly designed, contained major flaws in scientific research, and that its results are insufficient to prove the superiority of HDC/AuSCS.  The standard-dose chemotherapy regimen used in the Bezwoda study is not commonly used.  While the results of the HDC/AuSCS group are better than the results of standard-dose regimens in most published studies, the median survival times of groups of patients from several published studies of standard-dose regimens are about the same or better than the median survival times of HDC/AuSCS patients in the Bezwoda study.  The 45-week median survival seen in patients in the standard-dose group was shorter than the 68-week median survival seen in previously reported standard-dose groups.  The length of time the response lasted in the Bezwoda study standard-dose group (34 weeks) was also shorter than that seen in standard-dose studies (41 weeks).  In addition, the follow-up time in the Bezwoda study was short.  Half of the patients were in the study for less than 1½ years (72 weeks); the others were in the study for at most 2½ years.

Given the preliminary nature of the data, the conflicting initial results, and the specific differences in the study designs, it is not yet possible to draw definitive conclusions about the role of HDC/AuSCS in breast cancer.  In order to safeguard the public from false claims, inaccuracies, and premature conclusions, initial results such as these often require additional years of follow-up to see if the results are sustained, and must also be verified by other investigators to ensure that there were no flaws or biases in the methodology.  Despite public sentiment for treatment availability, there is insufficient outcomes data available from controlled clinical trials published in peer-reviewed literature to draw firm conclusions regarding the superiority of HDC/AuSCS over standard-dose chemotherapy in treating breast cancer.

A systematic evidence review prepared for the Cochrane Collaboration (Farquhar et al, 2005a) stated that there is insufficient evidence to support the routine use of HDC with autograft for women with early poor prognosis breast cancer.  Furthermore, Farquhar et al (2005b) stated that although there is evidence that HDC and autograft improves event-free survival (EFS) compared to conventional chemotherapy, there is no evidence of benefit in OS for women with MBC.  The authors concluded that "[h]igh dose chemotherapy with bone marrow or stem cell transplantation should not be given to women with metastatic breast cancer outside of clinical trials."

Pedrazzoli and associates (2003) evaluated autologous hematopoietic stem cell transplantation for breast cancer using data from the European Group for Blood and Marrow Transplantation Registry from 1990 to 1999.  The authors stated that continued investigation HDC with autologous stem cell transplantation is still needed.

In a randomized controlled trial (n = 885), Rodenhuis et al (2003) reported that HDC with autologous peripheral-blood hematopoietic progenitor-cell transplantation improved relapse-free survival among patients with stage II or III breast cancer and 10 or more positive axillary lymph nodes.  This benefit may be confined to patients with HER-2/neu-negative tumors.  On the other hand, Tallman et al (2003), in a randomized controlled study (n = 511), concluded that the addition of HDC and autologous hematopoietic stem-cell transplantation to 6 cycles of adjuvant chemotherapy with cyclophosphamide (CY), doxorubicin, and fluorouracil might reduce the risk of relapse but did not improve the outcome among patients with primary breast cancer and at least 10 involved axillary lymph nodes.  The authors stated that conventional-dose adjuvant chemotherapy remains the standard of care for such patients.

Zander et al (2004) compared the effects of HDC followed by autologous hematopoietic stem-cell support with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more positive axillary lymph nodes (n = 307).  These researchers concluded that there was a trend in favor of HDC with respect to EFS, but without statistical significance.  Further investigation is needed to ascertain the effect of HDC as compared with SD-CT as adjuvant treatment in high-risk primary breast cancer.  In a multi-center randomized controlled study (n = 785), Peters et al (2005) found that high-dose cyclophosphamide (CY), cisplatin, and carmustine with stem-cell support was not superior to intermediate-dose CY, cisplatin, and carmustine with G-CSF support but without stem cells for EFS or OS among all randomized women with high-risk primary breast cancer.  This in agreement with the findings of Leonard et al (2004) who found that autograft-supported, HDC is not superior to conventional chemotherapy in patients with breast cancer who have multiple involved lymph nodes.

In a 12-year follow-up study on the use of HDC/AuSCS for patients with high-risk primary breast carcinoma (n = 78), Hanrahan et al (2006) reported that there is no recurrence-free survival or OS advantage for these patients treated with HDC/AuSCS after standard dose chemotherapy with 5-fluorouracil, doxorubicin and CY.  These authors stated that there remains no conclusive evidence to support a role of HDC/AuSCS in patients with high-risk primary breast cancer, and it continues to be an investigational technology.

Furthermore, Schmid et al (2005) compared up-front tandem HDC and standard combination therapy in patients with MBC (n = 93).  Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDC with CY, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation.  High-dose chemotherapy was repeated after 6 weeks.  Patients were stratified by menopausal and hormone-receptor status.  The primary objective was to compare complete response (CR) rates.  This trial failed to show a benefit for up-front tandem HDC compared with standard combination therapy.  Also, HDC was associated with more acute adverse effects.

Bishop (2004) noted that the prognosis is poor and the options are limited for patients with MBC, particularly for those who had been treated with taxanes and anthracyclines.  Murine models have shown that allogeneic T cells are capable of eliciting graft-versus-tumor (GVT) effects against breast cancer, inhibiting growth of breast cancer cell lines in vivo, providing the rationale to pursue allogeneic adoptive cellular therapy as a strategy to treat MBC.  However, the clinical application of allogeneic hematopoietic stem cell transplantation (alloHSCT) was limited by concerns over toxicity and unproven effectiveness.  The development of non-myeloablative conditioning regimens (i.e., reduced intensity conditioning (RIC) transplant or mini-allograft), which have less treatment-related mortality but preserve the T-cell mediated GVT effects, led to increased investigation of alloHSCT in MBC.  Early reports of non-myeloablative alloHSCT indicate that a clinical GVT effect against breast cancer does exist.  The responses, observed in 20 to 40 % of patients, appear to be associated with the development of complete donor lymphoid chimerism and may be delayed.  In its current form, alloHSCT by itself is unlikely to result in complete eradication of MBC; however, it may serve as a therapeutic platform to complement and enhance the effects of existing cytotoxic therapies and immunotherapies (e.g., trastuzumab), as well as therapies under development (e.g., vaccines).  Current data on alloHSCT for MBC should be interpreted cautiously and carefully used for the design of future studies to fully ascertain the clinical effectiveness of this form of adoptive cellular therapy in MBC.

Baron and Sandmaier (2005) stated that recent retrospective studies comparing hematopoietic stem cell transplantation after myeloablative or non-myeloablative regimens suggested that the use of non-myeloablative conditioning might be associated with lower transplant-related toxicity, lower non-relapse mortality, and at least similar intermediate-term progression-free survival (PFS).  These investigators concluded that hematopoietic stem cell transplantation following non-myeloablative conditioning might become the procedure of choice also for younger patients.  Phase III clinical trials are needed to determine outcomes for different diseases and age groups.

In a phase III clinical trial, the Southwest Oncology Group (SWOG)/Intergroup study 9623 (Moore et al, 2007) compared treatment with an anthracycline-based adjuvant chemotherapy regimen followed by HDC with autologous hematopoietic progenitor cell support (AHPCS) with a modern dose-dense dose-escalated (non-standard) regimen including both an anthracycline and a taxane.  Patients in  this study had operable breast cancer involving 4 or more axillary lymph nodes and had completed mastectomy or breast-conserving surgery.  They were randomly assigned to receive sequential dose-dense and dose-escalated chemotherapy with doxorubicin, paclitaxel, and CY (group 1), or 4 cycles of doxorubicin and CY followed by HDC with AHPCS (group 2).  The primary end point of this study was disease-free survival (DFS).  Among 536 eligible patients, there was no significant difference between the 2 arms for DFS or OS.  Estimated 5-year DFS was 80 % (95 % confidence interval [CI]: 76 % to 85 %) for dose-dense therapy and 75 % (95 % CI: 69 % to 80 %) for transplantation.  Estimated 5-year OS was 88 % (95 % CI: 84 % to 92 %) for dose-dense therapy and 84 % (95 % CI: 79 % to 88 %) for transplantation.  The authors concluded that there is no evidence that transplantation was superior to dose-dense dose-escalated therapy.  Furthermore, transplantation was associated with an increase in toxicity and a possibly inferior outcome, although the hazard ratios were not significantly different from 1.

Gradishar (2007) noted that the clinical trial by SWOG, as well as those that preceded it, has failed to identify a group of breast cancer patients for whom HDC confers a significant advantage over non-marrow-ablative chemotherapy approaches.  Notably, the "standard" chemotherapy regimen used for group 1 in this trial should not be viewed as a standard regimen for use in routine clinical practice.  These doses of doxorubicin, paclitaxel, and CY have not proven superior to the lower doses that are used more commonly.  In fact, previous clinical trials have shown that higher doses of doxorubicin, CY, and paclitaxel increase the number of adverse events without enhancing outcomes.

In a systematic review and meta-analysis on HDC for poor prognosis breast cancer, Fraquhar et al (2007) concluded that there is insufficient evidence supporting routine use of HDC with autograft for treating early poor prognosis breast cancer.

In a multi-center, randomized study, Crump et al (2008) examined PFS, OS, and quality of life in women with MBC receiving HDC plus autologous stem-cell transplantation (ASCT) compared with standard-dose therapy.  A total of 386 women with MBC and no prior chemotherapy for metastatic disease were registered.  After initial response to anthracycline- or taxane-based induction chemotherapy, 224 patients were randomly assigned: 112 to high-dose CY, mitoxantrone, and carboplatin chemotherapy and ASCT (HDCT), and 112 to standard therapy (ST).  Median age was 47 years (range of 25 to 67 years).  Thirty-two percent of women randomly assigned had estrogen and progesterone receptor-negative breast cancer, 42 % had visceral metastases, and 58 % had bone metastases.  Complete remission rates before random assignment were 11 % for those receiving HDC and 12 % for those receiving ST.  After a median follow-up of 48 months, 79 deaths were observed in the HDC arm and 77 deaths were observed in the ST arm; 7 patients (6 %) in the HDC arm died as a result of toxicity.  The median OS was 24 months for the HDC arm (95 % CI: 21 to 35 months) and 28 months for ST (95 % CI: 22 to 33 months; hazard ratio [HR], 0.9; 95 % CI: 0.6 to 1.2; p = 0.43).  Progression-free survival was 11 months for HDC and 9 months for ST (HR, 0.6 in favor of HDCT; 95 % CI: 0.5 to 0.9; p = 0.006).  The authors concluded that HDC did not improve OS in women with MBC when used as consolidation after response to induction chemotherapy.

Ueno et al (2008) reviewed 66 women with poor-risk MBC from 15 centers to describe the effectiveness of allogeneic hematopoietic cell transplantation (HCT).  Median follow-up for survivors was 40 months (range of 3 to 64 months).  A total of 39 patients (59 %) received myeloablative and 27 (41 %) RIC regimens.  More patients in the RIC group had poor pre-transplant performance status (63 % versus 26 %, p = 0.002).  The RIC group developed less chronic graft-versus-host disease (GVHD) (8 % versus 36 % at 1 year, p = 0.003).  Treatment-related mortality rates were lower with RIC (7 % versus 29 % at 100 days, p = 0.03).  A total of 9 of 33 patients (27 %) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a GVT effect.  Progression-free survival at 1 year was 23 % with myeloablative conditioning and 8 % with RIC (p = 0.09).  Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: p = 0.03), consistent with a GVT effect, but this did not affect PFS.  The authors stated that these findings support the need for pre-clinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.

Fleskens and colleagues (2010) reported the findings of 15 patients with chemo-sensitive MBC who underwent RIC allo-SCT between 1999 and 2006.  The pre-transplant conditioning regimen consisted of fludarabine (25 mg/m(2) at days -5 to -1) and CY (60 mg/kg at days -2, -1).  Stem cells were from human leukocyte antigen (HLA)-matched sibling donors.  The treatment-related mortality was 2/15 (13 %).  Median PFS and OS were 144 days (43 to 509 days) and 303 days (122 to 1376 days), respectively.  The 1-year PFS was 20 %, and the 1-year and 2-year OS was 40 and 20 %, respectively.  No objective tumor responses were observed, but the relatively long PFS does suggest a graft-versus-tumor effect.  Although RIC using this CY/fludarabine regimen is feasible, the efficacy in this set of patients was limited.  The authors concluded that future clinical trials should be performed to improve the knowledge of mechanisms of anti-tumor effects in breast cancer.

Berry et al (2011a) noted that adjuvant HDC with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival.  Individual trials have had limited power to show overall benefit or benefits within subsets.  These investigators assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support.  Prospectively defined primary end points were relapse-free survival (RFS) and OS.  They compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and adjusted for clinically relevant co-variates.  Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status.  Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69 % were pre-menopausal, 29 % were post-menopausal, and 2 % were unknown menopausal status; 49.5 % were HmR-positive; 33.5 % were HmR-negative, and 17 % were unknown HmR status.  The median follow-up was 6 years.  After analysis was adjusted for co-variates, HDC was found to prolong RFS (hazard ratio [HR], 0.87; 95 % CI: 0.81 to 0.93; p < 0.001) but not OS (HR, 0.94; 95 % CI: 0.87 to 1.02; p = 0.13).  For OS, no co-variates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC.  Younger patients had a significantly better RFS on HDC than did older patients.  The authors concluded that adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit.  Whether HDC benefits patients in the context of targeted therapies is unknown.

Berry et al (2011b) stated substantial interest in supporting HDC with bone marrow or autologous hematopoietic stem-cell transplantation in the 1980s and 1990s led to the initiation of randomized trials to evaluate its effect in the treatment of metastatic breast cancer.  These researchers identified 6 randomized trials in metastatic breast cancer that evaluated high doses of chemotherapy with transplant support versus a control regimen without stem-cell support.  They assembled a single database containing individual patient information from these trials.  The primary analysis of OS was a log-rank test comparing high dose versus control.  They also used Cox proportional hazards regression, adjusting for known co-variates.  We addressed potential treatment differences within subsets of patients.  The effect of HDC on OS was not statistically different (median, 2.16 versus 2.02 years; p = 0.08).  A statistically significant advantage in progression-free survival (median of 0.91 versus 0.69 years) did not translate into survival benefit.  Subset analyses found little evidence that there are groups of patients who might benefit from HDC with hematopoietic support.  The authors concluded that OS of patients with metastatic breast cancer in the 6 randomized trials was not significantly improved by HDC; any benefit from high doses was small.  No identifiable subset of patients seems to benefit from HDC.

Pedrazzoli et al (2014) noted that the effectiveness of HDC and autologous hemopoietic progenitor cell transplantation (AHPCT) for BC patients has been an area of intense controversy among the medical oncology community.  These researchers evaluated the effectiveness and toxicity of this procedure in a large cohort of high-risk primary BC patients who underwent AHPCT in Italy.  A total of 1,183 patients receiving HDC for high-risk BC (HRBC) (greater than 3 positive nodes) were identified in the Italian registry.  The median age was 46 years, 62 % of patients were pre-menopausal at treatment, 60.1 % had endocrine-responsive tumors, and 20.7 % had a HER2-positive tumor.  The median number of positive lymph nodes (LN) at surgery was 15, with 71.5 % of patients having greater than or equal to 10 positive nodes.  Seventy-three percent received an alkylating agent-based HDC as a single procedure, whereas 27 % received epirubicin or mitoxantrone-containing HDC, usually within a multi-transplantation program.  The source of stem cells was peripheral blood in the vast majority of patients.  Transplantation-related mortality was 0.8 %, whereas late cardiac and secondary tumor-related mortality were around 1 %, overall.  With a median follow-up of 79 months, median DFS and OS in the entire population were 101 and 134 months, respectively.  Subgroup analysis demonstrated that OS was significantly better in patients with endocrine-responsive tumors and in patients receiving multiple transplantation procedures; HER2 status did not affect survival probability.  The size of the primary tumor and number of involved LN negatively affected OS.  Adjuvant HDC with AHPCT has a low mortality rate and provided impressive long-term survival rates in patients with high-risk primary BC.  The authors concluded that these findings suggested that this treatment modality should be proposed in selected HRBC patients and further investigated in clinical trials.

Moreover, an UpToDate review on "Treatment protocols for breast cancer" (Brenner et al, 2014) as well as National Comprehensive Cancer Network’s clinical practice guideline on "Breast cancer" (Version 3.2014) do not mention the use of stem cell/ hematopoietic cell transplantation as a therapeutic option.

Boudin and associates (2016) evaluated the outcome of patients affected with different subtypes of MBC following treatment with HDC and autologous hematopoietic progenitor cell transplantation (AHSCT). All consecutive female patients treated for MBC with HDC and AHSCT at the Institut Paoli-Calmettes between 2003 and 2012 were included.  Patient, tumor and treatment characteristics were collected.  Patients were categorized in 3 subtypes based on hormonal receptor and HER2 status of the primary tumor: luminal (L), (HR+/HER2-), HER2 (HER2+, any HR), and triple negative (TN) (HER2- and HR-). The main objective was the analysis of OS according to the immunohistochemical (IHC) subtypes. A total of 235 patients were included, median age was 46 years (range of 21 to 62).  Median follow up was 53.28 months (95 % CI: 45.12 to 57.6).  The TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95 % CI: 11.76 to 44.4) compared to 44.64 months (95 % CI: 40.32 to 67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (p < 0.01).  In the multi-variate analysis, the TN subtype retained an independent poor prognosis value compared to the luminal subtype, with a HR of 2.03 (95 % CI: 1.26 to 3.29, p = 0.037).  The authors concluded that HDC-AHSCT did not change the prognostic value of IHC subtypes in MBC patients; and OS favorably compared with data available in the literature on similar groups of patients.  They stated that these findings provided additional information and options for patients with MBC and who could potentially benefit of HDC-AHSCT.

In a retrospective study, Martino and colleagues (2016) evaluated toxicity and effectiveness of adjuvant HDC and AHSCT in 583 high-risk BC patients (greater than 3 positive nodes) who were transplanted between 1995 and 2005 in Europe. All patients received surgery before transplant, and 55 patients (9.5 %) received neoadjuvant treatment before surgery.  Median age was 47.1 years; 57.3 % of patients were pre-menopausal at treatment, 56.5 % had endocrine-responsive tumors, 19.5 % had a HER2-negative tumor, and 72.4 % had greater than or equal to 10 positive lymph nodes at surgery; 79 % received a single HDC procedure.  Overall transplant-related mortality was 1.9 %, at 0.9 % between 2001 and 2005, whereas secondary tumor-related mortality was 0.9 %. With a median follow-up of 120 months, OS and DFS rates at 5 and 10 years in the whole population were 75 % and 64 % and 58 % and 44 %, respectively.  Subgroup analysis demonstrated that rates of OS were significantly better in patients with endocrine-responsive tumors, less than 10 positive lymph nodes, and smaller tumor size; HER2 status did not affect survival probability.  The authors concluded that adjuvant HDC with AHSCT has a low mortality rate and provided impressive long-term survival rates in patients with high-risk BC.  They stated that these findings suggested that this treatment modality should be considered in selected high-risk BC patients and further investigated in clinical trials.

In a Cochrane review, Farquhar and colleagues (2016) compared the safety and effectiveness of HDC and autograft (either autologous BMT or SCT) with conventional chemotherapy for women with early poor prognosis BC.  These investigators searched the Cochrane Breast Cancer Group Specialized Register, Medline (1966 to October 2015), Embase (1980 to October 2015), the World Health Organization (WHO)'s International Clinical Trials Registry Search Platform, and ClinicalTrials.gov on October 21, 2015.  Randomized controlled trials (RCTs) comparing HDC and autograft (BMT or SCT) versus chemotherapy without autograft for women with early poor prognosis BC were selected for analysis.  Two review authors selected RCTs, independently extracted data and assessed risks of bias.  They combined data using a Mantel-Haenszel fixed-effect model to calculate pooled risk ratios (RRs) and 95 % CIs.  They evaluated the quality of the evidence using GRADE methods.  Outcomes were survival rates, toxicity and quality of life.  The authors concluded that there is high-quality evidence of increased treatment-related mortality (TRM) and little or no increase in survival by using HDC with autograft for women with early poor prognosis BC.

Boudin and associates (2017) noted that studies evaluating HDC with autologous hematopoietic stem cell transplantation (HDC-ACSH) in the treatment of MBC, locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) have in common lack of biomarker information, in particular the HER2 status.  In this study, all consecutive female patients treated for BC with HDC and AHSCT at Institut Paoli Calmettes between 2003 and 2012 were included.  Patients were categorized in 3 subtypes based on hormonal receptor (HR) and HER2 status of the primary tumor:
  1. luminal,
  2. (HR+/HER2-), and
  3. HER2 (HER2+, any HR) and triple negative (TN) (HER2- and HR-).

The main objective was the analysis of OS according to the IHC subtypes.  A total of 377 patients were included.  For MBC, the TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95 % CI: 11.76 to 44.4) compared to 44.64 months (95 % CI: 40.32 to 67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (p < 0.01).  For IBC, HER2 subgroup appeared to have the best prognosis with a 5-year OS of 89 % (95 % CI: 64 to 97) compared to 57 % (95 % CI: 33 to 76) for the TN subgroup (HR 5.38, 95 % CI: 1.14 to 25.44; p = 0.034).  For CSLA, luminal subgroup appeared to have the best prognosis with a 5-year OS of 92 % (95 % CI: 71 to 98) against 75 % (95 % CI: 46 to 90) for HER 2 subtype and 70 % (95 % CI: 97 to 88) for TN subtype (p = 0.301).  The authors concluded that HDC-ACSH did not change the prognosis value of IHC subtype in BC patients.

Karadurmus and colleagues (2018) stated that alloHSCT is primarily used in patients with relapsed or high-risk hematologic malignancies, and the efficacy of this treatment has been substantially demonstrated.  The principles of alloHSCT consist of maximal tumor cytoreduction with HDC and adequate immunosuppression in order to provide engraftment of donor stem cells as well as GVT effect.  The controversial and disappointing results of studies investigating HDC with autologous stem cell rescue in patients with solid tumors have led to development of novel approaches such as adoptive T-cell therapies (ATCT), targeted therapies and alloHSCT with RIC regimens, which aim to create and take advantage of a GVT effect in order to induce more durable responses.  The advantages of alloHSCT over autologous HSCT for metastatic BC are mainly 2-fold: cancer-free graft and immune-mediated GVT effects mediated by HLA-compatible donor T-cells.  These immune-mediated effects led to a transition from a chemotherapy-based approach to an immunotherapy-based approach in the management of BC. The switch from targeting maximal tumor cytoreduction via HDC to induction of immune GVT effects also gave rise to development of RIC and non-myeloablative (NMA) regimens instead of conventional myeloablative conditioning regimens.  RIC regimens substantially reduced the high transplant-related morbidity and mortality, while allowing for a complete myeloid/lymphoid engraftment.  As a result, alloHSCT may become an appropriate treatment option for the elderly and medically fragile patients with metastatic BC.  The authors concluded that a GVT effect does exist against metastatic BC and may play a key role in tumor response.  If conditioning regimen-related toxicities are reduced and response rates are increased via advances in innovative treatments such as immunotherapy, ATCT and targeted therapies, this treatment modality might be included in the armamentarium of treatments for BC.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes not covered for indications listed in the CPB:
38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogenic
38206     autologous
38230 Bone marrow harvesting for transplantation; allogenic
38241 Hematopoietic progenitor cell (HPC); autologous transplantation

HCPCS codes not covered for indications listed in the CPB:
S2150 Bone marrow or blood-derived stem-cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days pre-and post-transplant care in the global definition

ICD-10 codes not covered for indications listed in the CPB:
C50.011 - C50.929 Malignant neoplasm of breast
C79.81 Secondary malignant neoplasm of breast
D05.00 - D05.92 Carcinoma in situ of breast

The above policy is based on the following references:

  1. Antman KH, Tiersten A. High-dose chemotherapy for breast cancer: Evolving data. Oncology (Huntingt). 1999;13(9):1215-1219.
  2. Antman KH, Heitjan DF, Hortobagyi GN. High-dose chemotherapy for breast cancer. JAMA. 1999;282(18):1701-1703.
  3. Antman KH. Critique of the high-dose chemotherapy studies in breast cancer: A positive look at the data. J Clin Oncol. 1999;17(11 Suppl):30-34.
  4. Antman KH. High-dose chemotherapy in breast cancer: The end of the beginning? Biol Blood Marrow Transplant. 2000;6(5):469-475.
  5. Antman KH. Randomized trials of high dose chemotherapy for breast cancer. Biochim Biophys Acta. 2001;1471(3):M89-M98.
  6. Baron F, Sandmaier BM. Current status of hematopoietic stem cell transplantation after nonmyeloablative conditioning. Curr Opin Hematol. 2005;12(6):435-443.
  7. Bergh J, et al Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTCb supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy“, Scandinavian Breast Cancer Study Group. Abstract presented at ASCO annual meeting; 1999.
  8. 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(a);29(24):3214-3223.
  9. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autologous hematopoietic stem-cell transplantation in metastatic breast cancer: Overview of six randomized trials. J Clin Oncol. 2011(b);29(24):3224-3231.
  10. Bezwoda WR, Seymour L, Dansey RD. High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol. 1995;13(10):2483-2489. (Retracted)
  11. Bezwoda WR. High dose chemotherapy with haematopoietic rescue in breast cancer. Hematol Cell Ther. 1999;41(2):58-65.
  12. Bezwoda WR. Randomised, controlled trial of high dose chemotherapy (HD-CNVp) vs. standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer. Abstract presented at ASCO annual meeting; 1999.
  13. Bishop MR. Allogeneic hematopoietic stem cell transplantation for metastatic breast cancer. Haematologica. 2004;89(5):599-605.
  14. Blomqvist C, Elomaa I, Rissanen P, et al. Influence of treatment schedule on toxicity and efficacy of cyclophosphamide, epirubicin, and fluorouracil in metastatic breast cancer: A randomized trial comparing weekly and every-4-week administration. J Clin Oncol. 1993;11(3):467-473.
  15. Boudin L, Chabannon C, Sfumato P, et al. Immunohistochemical subtypes predict survival in metastatic breast cancer receiving high-dose chemotherapy with autologous haematopoietic stem cell transplantation. Eur J Cancer. 2016;57:118-126
  16. 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.
  17. Brenner T, Duggal S, Natale J, Wirth SM. Treatment protocols for breast cancer. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed March 2014.
  18. Bull JM, Tormey DC, Li SH, et al. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978;41(5):1649-1657.
  19. Buzdar AU, Hortobagyi GN. Recent advances in adjuvant therapy of breast cancer. Semin Oncol. 1999;26(4 Suppl 12):21-27.
  20. 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. 2005;16(5):726-734.
  21. Crown J, Coiffier B, Cortes-Funes H, et al. ESTIC position paper: High-dose chemotherapy for breast cancer, investigation should continue. Ann Oncol. 1999;10(8):903-905.
  22. 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.
  23. Damon LE, Hu WW, Stockerl-Goldstein KE, et al. High-dose chemotherapy and hematopoietic stem cell rescue for breast cancer: Experience in California. Biol Blood Marrow Transplant. 2000;6(5):496-505.
  24. Demirer T, Barkholt L, Blaise D, et al; EBMT Solid Tumors Working Party. Transplantation of allogeneic hematopoietic stem cells: An emerging treatment modality for solid tumors. Nat Clin Pract Oncol. 2008;5(5):256-267.
  25. Falkson G, Gelman R, Falkson CI, et al. Factors predicting for response, time to treatment failure, and survival in women with metastatic breast cancer treated with DAVTH: A prospective Eastern Cooperative Oncology Group study. J Clin Oncol. 1991;9(12):2153-2161.
  26. Falkson G, Tormey DC, Carey P, et al. Long-term survival of patients treated with combination chemotherapy for metastatic breast cancer. Eur J Cancer. 1991;27(8):973-977.
  27. 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. 2005b;(3):CD003142.
  28. Farquhar C, Marjoribanks J, Basser R, Lethaby A. 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. 2005a;(3):CD003139.
  29. 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.
  30. Farquhar CM, Marjoribanks J, Lethaby A, Basser R. High dose chemotherapy for poor prognosis breast cancer: Systematic review and meta-analysis. Cancer Treat Rev. 2007;33(4):325-337.
  31. 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.
  32. Fornier M, Munster P, Seidman AD. Update on the management of advanced breast cancer. Oncology (Huntingt). 1999;13(5):647-658; discussion 660, 663-664.
  33. Gradishar WJ. High-dose chemotherapy and breast cancer . . . one more time! Journal Watch, April 13, 2007. Available at: http://womens-health.jwatch.org/cgi/collection/breast-cancer. Accessed June 18, 2007.
  34. Gratwohl A, Baldomero H, Rosti G. High-dose chemotherapy for breast cancer. Bone Marrow Transplant. 2000;26(6):599.
  35. Hanrahan EO, Broglio K, Frye D, et al. Randomized trail of high-dose chemotherapy and autologous hematopoietic stem cell support for high-risk primary breast carcinoma. Cancer. 2006;106(11):2327-2336.
  36. Hohaus S, Martin S, Schneeweiss A, et al. Adjuvant high-dose therapy with peripheral blood stem cell support for patients with high-risk breast cancer. Cancer Chemother Pharmacol. 1999;44 Suppl:S13-S17.
  37. Hortobagyi GN, Buzdar AU, Theriault RL, et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst. 2000;92(3):225-233.
  38. Hortobagyi GN. High-dose chemotherapy for primary breast cancer: Facts versus anecdotes. J Clin Oncol. 1999;17(11 Suppl):25-29.
  39. Hudis CA, Munster PN. High-dose therapy for breast cancer. Semin Oncol. 1999;26(1):35-47.
  40. Institute for Clinical Systems Improvement (ICSI). High-dose chemotherapy with autologous stem cell support for the treatment of breast cancer. Technology Assessment No. 2. Bloomington, MN: ICSI; updated April 2002.
  41. Institute for Quality and Efficiency in Health Care (IQWiG). Autologous stem cell transplantation for breast cancer. Executive Summary. IQWiG Reports – Commission No. N05-03E. Cologne, Germany; IQWiG; October 15, 2009.
  42. Karadurmus N, Sahin U, Bahadir Basgoz B, et al. A review of allogeneic hematopoietic stem cell transplantation in metastatic breast cancer. Int J Hematol Oncol Stem Cell Res. 2018;12(2):111-116.
  43. Klefstrm P, Nuortio L. Levamisole in the treatment of advanced breast cancer. A ten-year follow-up of a randomized study. Acta Oncol. 1991;30(3):347-352.
  44. 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.
  45. Lotz JP, Cure H, Janvier M, et al. High-dose chemotherapy with haematopoietic stem cell transplantation for metastatic breast cancer patients: Final results of the French multicentric randomised CMA/PEGASE 04 protocol. Eur J Cancer. 2005;41(1):71-80.
  46. Lotz JP, et al. High-dose chemotherapy (HD-CT) with hematopoietic stem cells transplantation (HSCT) for metastatic breast cancer (MBC): Results of the French protocol PEGASE 04. Fédération Nationale des Centres de Lutte Contre le Cancer & Société Française de Greffe de Moelle, Paris, France. Abstract presented at ASCO annual meeting; 1999.
  47. Marino P, Siani C, Roche H, Moatti JP. Impact of uncertainty on cost-effectiveness analysis of medical strategies: The case of high-dose chemotherapy for breast cancer patients. Int J Technol Assess Health Care. 2005;21(3):342-350.
  48. Martino M, Lanza F, Pavesi L, et al;European Group for Blood and Marrow Transplantation Solid Tumor Working Party. High-dose chemotherapy and autologous hematopoietic stem cell transplantation as adjuvant treatment in high-risk breast cancer: Data from the European Group for Blood and Marrow Transplantation Registry. Biol Blood Marrow Transplant. 2016;22(3):475-481.
  49. Mayer A, Earl H. Whither high-dose chemotherapy in breast cancer? Breast Cancer Res. 2001;3(1):8-10.
  50. Miller KD, Sledge GW Jr. The role of chemotherapy for metastatic breast cancer. Hematol Oncol Clin North Am. 1999;13(2):415-434.
  51. Miller KD, Sledge GW. High-dose chemotherapy in breast cancer -- the perils of history uncontrolled. Medscape Womens Health. 2000;5(3):E1.
  52. Moore HC, Green SJ, Gralow JR, et al; Southwest Oncology Group/Intergroup Study 9623. Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. J Clin Oncol. 2007;25(13):1677-1682.
  53. National Comprehensive Cancer Network. Breast cancer. NCCN Clinical Practice Guidelines in Oncology v 3.2014. Fort Washington, PA: NCCN; 2014.
  54. Nieto Y, Champlin RE, Wingard JR, et al. Status of high-dose chemotherapy for breast cancer: A review. Biol Blood Marrow Transplant. 2000;6(5):476-495.
  55. Nitz UA, Mohrmann S, Fischer J, et al. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: Results of a multicentre phase III trial. Lancet. 2005;366(9501):1935-1944.
  56. No authors listed. EBMT International Conference on High-Dose Chemotherapy in Breast and Ovarian Cancer. 14-16 September 2000. Florence, Italy. Abstracts. Bone Marrow Transplant. 2000;26 Suppl 1:S1-S44.
  57. No authors listed. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: An Italian multicentre trial. Italian Multicentre Breast Study with Epirubicin. J Clin Oncol. 1988;6(6):976-982.
  58. Pedrazzoli P, Ferrante P, Kulekci A, et al. Autologous hematopoietic stem cell transplantation for breast cancer in Europe: Critical evaluation of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry 1990 -1999. Bone Marrow Transplantation. 2003;32:489-494.
  59. Pedrazzoli P, Martinelli G, Gianni AM, et al; of Gruppo Italiano per il Trapianto di Midollo Osseo, Cellule staminali emopoietiche e terapia cellulare (GITMO) – Sezione Tumori Solidi. 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. 2014;20(4):501-506.
  60. Peters WP, et al. 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): Preliminary Results of CALGB 9082/SWOG 9114/NCIC MA-13. Abstract presented at ASCO annual meeting; 1999.
  61. Peters WP, Rosner GL, Vredenburgh JJ, et al. Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: A report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol. 2005;23(10):2191-2200.
  62. Rizzieri DA, Vredenburgh JJ, Jones R, et al. Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support. J Clin Oncol. 1999;17(10):3064-3074.
  63. 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.
  64. 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.
  65. Schneeweiss A, Hensel M, Goerner R, et al. Comparison of double and triple high-dose chemotherapy with autologous blood stem cell transplantation in patients with metastatic breast cancer. Stem Cells. 2001;19(2):151-160.
  66. Shpall EJ, Jones RB, Bearman SI, et al. Peripheral blood stem cell transplantation in breast cancer. Baillieres Best Pract Res Clin Haematol. 1999;12(1):219-232.
  67. Stadtmauer EA. Phase III randomized trial of high-dose chemotherapy (HDC) and stem cell support (SCT) shows no difference in overall survival or severe toxicity compared to maintenance chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) for women with metastatic breast cancer who are responding to conventional induction chemotherapy: The Philadelphia Intergroup Study (PBT-01), ECOG, U. of Pennsylvania. Abstract presented at ASCO annual meeting; 1999.
  68. Stebbing J, Slater S, Slevin M. Breast cancer (metastatic). In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; June 2006.
  69. 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.
  70. Ueno NT, Rizzo JD, Demirer T, et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant. 2008;41(6):537-545.
  71. Vij R, DiPersio J, Brown R, et al. Outcomes of high-dose chemotherapy and autologous stem cell transplant in isolated locally recurrent breast cancer: A multicenter evaluation. Bone Marrow Transplant. 2000;26(9):947-953.
  72. 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.
  73. Zander AR, Schmoor C, Kröger 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.