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

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

3. 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).

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 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.