Is High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Breast Cancer Patients a Done Deal?

Abstract

““…we have yet to cure advanced breast cancer – in particular, metastatic disease. What we have previously considered to be completely negative data do not truly represent a negative outcome for high-dose chemotherapy with autologous stem cell transplantation in breast cancer.”

In cancer statistics for the USA in 2009, breast cancer was ranked first in cancer incidence in the female population, with an estimated 192,370 cases. For cancer-related mortality, breast cancer was ranked second among women, with an estimated 40,170 deaths [1]. The favorable survival outcome in breast cancer is mainly owing to two factors: the detection of early-stage disease by the common use of screening mammography and the advance of adjuvant systemic treatment, including chemotherapy, hormone therapy, or HER2-targeted therapy, to eliminate micrometastases after definitive breast cancer surgery. However, it is estimated that approximately 30–50% of patients with early to locally advanced stages of breast cancer have relapses despite the use of adjuvant treatment after surgery. In addition, approximately 5–10% of patients present with metastatic disease at diagnosis. Patients with either relapsed metastatic disease or initial metastatic disease are considered incurable by conventional treatment. However, breast cancer has demonstrated significant chemosensitivity, and systemic treatment is known to prolong survival and induce significant symptom relief. The median survival of patients with metastatic breast cancer who undergo chemotherapy treatment is 24 months, and 2–5% of those patients have long-term survival durations of 10 years [2]. Therefore, most research in breast cancer management is focused on improving breast cancer outcome in two areas. One is preventing relapse in patients with high-risk early-stage to locally advanced stage of breast cancer. The other is prolonging survival or even eliminating disease in patients with metastatic breast cancer. High-dose chemotherapy with autologous hematopoietic stem cell transplantation is being tested to address both of these needs. In this article, we explain why we believe that, despite inconclusive results thus far, this treatment should have an ongoing role in breast cancer management under clinical trials.

Most of the chemotherapeutic agents used in cancer management have demonstrated a dose–response relationship. Therefore, increasing the dose of the chemotherapy might be expected to result in more tumor cells being killed. However, normal cells in the body, such as bone marrow cells, are also susceptible to the cytotoxic effect of high-dose chemotherapy. To address this dilemma, hematopoietic stem cell transplantation was developed as a rescue process for high-dose chemotherapy treatment. In this process, hematopoietic stem cells of the patient are collected and stored before high-dose chemotherapy is administered to the patient. After the high-dose chemotherapy treatment, the hematopoietic stem cells collected previously will be reinfused back to the patient to restore a normal hematopoietic system.

In the late 1980s and early 1990s, multiple Phase II studies of the use of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in either high-risk primary breast cancer or metastatic breast cancer demonstrated significant favorable outcomes compared with historical data. These positive results prompted significantly increased use of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in breast cancer as a routine treatment. However, the true benefit of this treatment in breast cancer needed to be proven in randomized Phase III trials. Since the late 1990s, a total of 15 randomized trials of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in high-risk primary breast cancer and eight trials in metastatic breast cancer have been described.

Of the 15 trials in high-risk primary breast cancer [3 –17], 13 were already published [3,4,7 –17], with four of them updated after longer follow-up. Two were still in preliminary form [5,6]; one of these has been updated. Together, these 15 trials enrolled a total of more than 6000 patients. One study, that of the West German Study Group reported by Nitz et al., showed significant benefit in both relapse-free survival and overall survival [13]. A second study, the PEGASE 01 study reported by Roche et al., showed significant benefit in relapse-free survival but not in overall survival [5]. However, the PEGASE 01 study was only presented in preliminary form in 2001, and it has not been updated. In 2007, Berry et al. presented the first meta-analysis using individual data from all 15 trials; this analysis showed a significant benefit of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in relapse-free survival but not in overall survival [18]. Subgroup analysis failed to show a benefit in any particular subpopulation.

“…high-dose chemotherapy and autologous hematopoietic stem cell transplantation is not for every breast cancer patient.”

Of the eight trials in metastatic breast cancer [19 –27], seven were already published [19,20,22 –27], with one of them updated after longer follow-up. One was still in preliminary form [21]. Together, these eight trials enrolled a total of more than 1000 patients. Six trials showed significant benefit in progression-free survival but not in overall survival. One of them, the PEGASE 04 study, showed significant benefit in both progression-free survival and overall survival [23]. In 2008, Berry et al. presented a meta-analysis using individual data from six of the eight trials; this analysis showed a significant benefit in progression-free survival and a trend of benefit in overall survival [28]. Subgroup analysis suggested that young patients (less than 50 years old) and patients with only soft tissue involvement will benefit from this treatment.

Since the presentation of Berry et al.'s meta-analyses of the high-risk primary breast cancer and metastatic breast cancer trials, many have considered the argument for high-dose chemotherapy with autologous hematopoietic stem cell transplantation in breast cancer to be over owing to a lack of definite overall survival benefit. However, there are still reasons to believe that this treatment plays a role in breast cancer management and deserves further investigation.

First, not all patients in those trials had biomarker information, such as HER2 and hormone-receptor status. Without complete biomarker information, the meta-analysis was not able to address biomarker-based subgroups of patients who would benefit from high-dose chemotherapy with autologous hematopoietic stem cell transplantation.

Second, although the studies of Berry et al. are the first true meta-analyses for this treatment in breast cancer, the heterogeneity of the trials may still affect the result of the analysis. This heterogeneity is particularly significant in terms of the chemotherapy regimens used. The high-dose regimens varied in the types of agents, numbers of agents, doses, schedules and numbers of cycles of treatment. Since the chemotherapy regimen is the main tumor-killing force in the trial, such a heterogeneous difference in the regimens used among the trials could significantly affect the final outcome.

Third, some studies did show significant eventfree (relapse-free or progression-free) survival and overall survival benefit, such as the West German Study Group trial in high-risk primary breast cancer and the PEGASE 04 studies in metastatic breast cancer. The positive results of those studies suggests that in the right setting with the right patients, there will be a role for high-dose chemotherapy and autologous hematopoietic stem cell transplantation.

“…when the treatment related toxicity is within acceptable level, a benefit in event-free survival (relapse-free survival or progression-free survival) should not be ignored.”

Fourth, one cannot ignore that the 2008 meta-analysis of trials for metastatic breast cancer showed that there were survival benefits in certain groups of patients [28]. Clearly, high-dose chemotherapy and autologous hematopoietic stem cell transplantation is not for every breast cancer patient. However, in a well-selected group of patients, such as those with metastatic breast cancer who are younger than 50 years or who have soft tissue involvement; this kind of treatment clearly has a substantial benefit.

Fifth, the result of overall survival is used traditionally as the final determination of the effectiveness of a new treatment modality. This concept is now being challenged in oncology trials. In the setting of high-risk primary breast cancer, the primary purpose of any adjuvant treatment is to prevent relapse. Therefore, relapse-free survival should be considered a significant marker of any treatment's efficacy. Among the 15 trials in high-risk primary breast cancer, although only two trials showed a significant benefit in relapse-free survival, others actually showed a trend in benefit in relapse-free survival. The meta-analysis of all 15 trials also showed a benefit in relapse-free survival. In the setting of metastatic breast cancer, since it is considered incurable, disease progression is almost inevitable. Any treatment that could delay the progression should also be considered significant. Among the eight metastatic breast cancer trials, seven showed significant benefit in progression-free survival. The meta-analysis of six of them also confirmed a benefit in progression-free survival. This finding strongly suggests that there is a role for high-dose chemotherapy and autologous hematopoietic stem cell transplantation in delaying disease progression. Therefore, when the treatment-related toxicity is within acceptable level, a benefit in event-free survival (relapse-free survival or progression-free survival) should not be ignored.

“…instead of simply giving up on a potential treatment modality, it is more logical and practical to refine and improve this existing modality in addition to developing new modalities in the clinical trial setting.”

Looking back at all the previous trials, there is certainly room for improvement. We propose the following measures to improve the use of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in breast cancer. One is to define a standard regimen used in high-dose chemotherapy with autologous hematopoietic stem cell transplantation in breast cancer. Many of the old regimens used are no longer considered to have high enough doses. A second proposed measure is to investigate the use of different approaches to combining high-dose chemotherapy with autologous hematopoietic stem cell transplantation. One example is the use of the tandem approach of the West German Study Group in which a second high-dose chemotherapy with autologous hematopoietic stem cell transplantation is administered right after the first one. A third proposed measure is to determine the role of adding immunotherapy or target-specific therapy to the chemotherapy in high-dose chemotherapy with autologous hematopoietic stem cell transplantation. We recently published a pilot study of the use of IL-2 and granulocyte–macrophage colony-stimulating factor for immunomodulation to the high-dose chemotherapy with autologous hematopoietic stem cell transplantation in metastatic breast cancer [29]. With a median follow-up of 790.5 days, the 3-year progression-free survival rate was 31% and 3-year overall survival rate was 57%. Another study by Recchia et al. reported the use of IL-2 and 13-cis-retinoic acid after high-dose chemotherapy with autologous hematopoietic stem cell transplantation in high-risk primary breast cancer [30]. With a median follow-up of 61 months, the 5-year relapse-free survival was 76% and the 5-year overall survival rate was 85%. A fourth measure is to continue searching for the proper subgroup of patients who will benefit from this kind of treatment. In particular, the use of PET–computed tomography scanning or measurement of circulating tumor cells may provide a more accurate way of defining tumor response to standard-dose chemotherapy. A good partial response or complete response to standard-dose chemotherapy is an important prognostic and predictive factor in selecting patients for high-dose chemotherapy with autologous stem cell transplantation in breast cancer.

For the past decade, systemic treatment for high-risk primary breast cancer and metastatic breast cancer has significantly advanced in terms of new therapeutic agents and new treatment delivery systems. We recognize the outcome for breast cancer has also improved significantly compared with that for other solid tumors. However, we have yet to cure advanced breast cancer – in particular, metastatic disease. What we have previously considered to be completely negative data do not truly represent a negative outcome for high-dose chemotherapy with autologous stem cell transplantation in breast cancer. Therefore, instead of simply giving up on a potential treatment modality, it is more logical and practical to refine and improve this existing modality in addition to developing new modalities in the clinical trial setting.

Footnotes

This research is supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant CA016672. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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