ASCT - Stage II-III Breast Cancer

Overview of Autologous Stem Cell Transplant

A variety of factors ultimately influence a patient's decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of high-dose chemotherapy and autologous stem cell transplant for the treatment of stage II-III breast cancer. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.

Treatment of stage II-III breast cancer incorporates surgery, radiation, chemotherapy, and hormonal therapies in order to achieve the best results. Since the original publication describing the potential use of high-dose chemotherapy and autologous stem cell transplantation for the treatment of primary breast cancer in 1993, thousands of women have been treated with high-dose chemotherapy and dozens of small clinical trials have been published describing the outcomes of women receiving this therapy. High-dose chemotherapy is safe, well tolerated, and may improve a patient’s chance of survival.

At initial diagnosis, the number of axillary lymph nodes involved with breast cancer accurately predict a patient's chance of survival. Patients with greater numbers of involved lymph nodes have a higher chance of cancer recurrence. Patients with more than 10 involved lymph nodes have a greater than 60% chance of breast cancer recurrence and are considered to be at especially high risk. Therefore, the early experience using high-dose chemotherapy as treatment of breast cancer was limited to women with more than 10 involved axillary lymph nodes. Several large clinical trials that directly compare high-dose chemotherapy and autologous stem cell transplantation to lower dose or conventional-dose chemotherapy as primary treatment of breast cancer are completed and the results will be published in the next few years. Until the results of these large, direct comparisons are available, the current status of high-dose chemotherapy and autologous stem cell transplantation for the treatment of breast cancer can be summarized by the following three publications.

The initial publication describing the use of high-dose chemotherapy and autologous stem cell transplantation for the treatment of primary breast cancer was reported in 1993. In this clinical trial, 85 women with stage II or III breast cancer involving 10 or more axillary lymph nodes were treated with surgery to remove the breast cancer followed by standard chemotherapy, high-dose chemotherapy and autologous bone marrow transplantation, and radiation. Radiation was not used in the first few patients. A high rate of local relapse led to radiation being used in all patients. The results of this trial demonstrated that 72% of women receiving high-dose chemotherapy and autologous bone marrow transplantation were alive without their disease recurring 3-5 years from beginning treatment. These results were 20-34% better than similar patients treated with lower or conventional-dose chemotherapy. The toxicity of the high-dose chemotherapy treatment strategy was significant in that 12% of patients died from complications of treatment.

A second major clinical trial was published and reported the outcome of women with stage II-III breast cancer involving 10 or more axillary lymph nodes treated with a high-dose chemotherapy treatment strategy and autologous stem cell transplantation. In this clinical trial, 57% of women were alive without evidence of disease recurrence 5 years from the beginning of treatment. Only 1 of 63 patients died from complications of treatment. The study compared the results of the high-dose chemotherapy and autologous stem cell transplantation strategy to results previously reported by the same doctors treating patients in the same hospital with a lower or conventional-dose chemotherapy treatment strategy. This direct comparison suggested that there was an approximate 40% improvement in the likelihood of being alive without evidence of disease recurrence for women treated with the high-dose chemotherapy/autologous stem cell transplantation strategy.

5-Year Results of 3 Trials Evaluating High-Dose Chemotherapy and Autologous Stem Cell Transplantation for the Treatment of Women with Stage II-III Breast Cancer and > 10 Involved Axillary Lymph Nodes
  Trial Published in:
  1993 1997 1998
Survival 79% 70% 72%
Survival without Disease Recurrence 72% 57% 57%
Mortality from Treatment 12% ~1% >
Days in Hospital ¾ 30 12

In 1998, the results of the first multi-center clinical trial evaluating high-dose chemotherapy and autologous stem cell transplantation for the treatment of women with primary breast cancer were reported. This trial was conducted in several community hospitals under the care of multiple physicians. This multi-center trial evaluated a single strategy combining conventional chemotherapy treatment followed by high-dose chemotherapy and autologous peripheral blood stem cell transplantation in women with stage II-III breast cancer involving 10 or more axillary lymph nodes. The therapy was administered in outpatient community cancer programs and stem cells collected from peripheral blood as opposed to bone marrow were used to support the high-dose chemotherapy. The overall treatment strategy was very well tolerated, with the average patient completing treatment in just over 4 months. On average, patients received one red blood cell transfusion and one platelet transfusion to support their therapy and were in the hospital an average of 12 days. No patients died from direct toxicity attributable to high-dose chemotherapy. The patients in this clinical study have now been followed for 3-6½ years. Fifty-seven percent of patients are alive without evidence of disease recurrence at 5 years from initial treatment.

In summary, these three clinical trails demonstrated that a treatment strategy incorporating surgery, high-dose chemotherapy and autologous stem cell transplantation, local radiation, and hormonal therapy for the treatment of patients with stage II-III breast cancer is:

  • Safe, with a 1% mortality attributable to treatment.
  • May improve survival 10-20%.
  • Can be delivered in a community-based outpatient setting.

Status of Phase III Clinical Trials

Researchers from several French medical centers evaluated the impact of one cycle of high-dose chemotherapy and an autologous stem cell transplant following standard dose treatment in 314 breast cancer patients. All patients in this study had stage II-III breast cancer and at least 7 involved axillary lymph nodes. Following surgery, all patients received 4 cycles of 5-flourouracil, cyclophosphamide and Ellence®. One group of patients then received one cycle of high-dose chemotherapy and an autologous stem cell transplant, while the other group of patients received no further treatment. All patients received radiation therapy to the breast and Nolvadex® for positive hormonal receptor positive cancer. Approximately 39 months following the completion of treatment, the cancer-free survival for the conventionally treated group was 55%, compared to 70.8% for patients receiving high-dose chemotherapy. Overall survival was 84% for patients receiving conventional-dose therapy and 86% for patients receiving high-dose therapy. Longer follow-up is necessary to definitively assess the high-dose chemotherapy advantage in terms of survival; however, the 16% lower chance of relapse in the high-dose chemotherapy group suggests a potential ultimate long-term survival benefit. Only one person died from treatment related complications in the group receiving high-dose therapy.

These results are consistent with a previous multi-center clinical trial conducted by Dutch researchers also evaluating the role of high-dose chemotherapy in women with breast cancer. In this study, almost 900 patients with stage II-III breast cancer received conventional-dose chemotherapy followed by either high-dose chemotherapy and an autologous stem cell transplant or no further therapy. Three years following the completion of treatment, cancer recurrences occurred in 35% of patients who only received standard therapy, compared with only 23% who received high-dose therapy. Moreover, survival rates were 79% for patients who received standard therapy, compared with 89% who received high-dose therapy. Results from this study indicate a significant benefit from high-dose chemotherapy compared to standard therapy alone for patients with stage II-III breast cancer.

Overall, these studies indicate that high-dose chemotherapy followed by autologous stem cell transplantation is superior treatment compared to conventional-dose chemotherapy in reducing the number of cancer recurrences in patients with stage II and III breast cancer and improving survival.

The results of the only U.S. trial to address this question, however, appear to conflict with the results of the two European trials. In this U.S. clinical study, patients with high-risk stage II and III breast cancer involving 10 or more axillary lymph nodes were treated with either standard CAF chemotherapy followed by high-dose chemotherapy and an autologous stem cell transplant or lower doses of the same drugs that were administered in the high-dose chemotherapy treatment group. It is important to note that both of these treatment options were non-standard. The lower-dose chemotherapy was still higher than what is considered to be standard chemotherapy. Standard treatment of breast cancer at the time of this study design was CAF chemotherapy or AC chemotherapy. Patients in both groups were also treated with radiation and Nolvadex®.

A preliminary analysis performed at approximately 3 years from initiation of treatment shows that patients treated with high-dose chemotherapy were significantly less likely to experience cancer recurrence compared to patients treated with the lower-dose chemotherapy treatment strategy. Patients treated with high-dose chemotherapy, however, were more likely to die as a complication of treatment, with 6.3% of these patients dying, compared to no patients treated with lower-dose chemotherapy. Although high-dose chemotherapy reduced cancer recurrence, it also increased the risk of death. As a result, the complication of treatment-related death decreased the overall survival benefit. Three years following treatment, 68% of patients who received high-dose chemotherapy were alive without cancer recurrence, compared to 64% of patients who were treated with lower-dose chemotherapy.

Again, it is crucial to understand that both groups of patients in this study received non-standard treatment because the lower-dose chemotherapy that was offered was still higher than standard chemotherapy. Therefore, in the conventional medical setting, patients will not be receiving the lower-dose treatment approach that was utilized in this study, but instead are likely to receive treatment with AC or CAF with or without paclitaxel. Neither of these standard approaches was compared to high-dose chemotherapy in the U.S. study; however, results from the European study suggested that they were inferior treatments when compared to high-dose chemotherapy.

The following conclusions can currently be drawn regarding high-dose chemotherapy with autologous stem cell transplantation for the adjuvant treatment of breast cancer:

1. No clinical studies of any kind have demonstrated that conventional-dose chemotherapy utilizing standard treatment regimens is superior to high-dose chemotherapy treatment.

2. All 3 published clinical trials have demonstrated that high-dose chemotherapy reduces the risk of cancer recurrence 3-5 years in comparison to standard treatment regimens.

3. One European study has demonstrated that high-dose chemotherapy improves a patient’s survival in comparison to standard treatment and the other two studies have not yet shown a survival benefit. Because patients with breast cancer may survive several years before a recurrence occurs, the follow-up period for these studies is currently inadequate to definitively state that there will be no survival benefit. Patients should also realize that the treatment of recurrent cancer is associated with a less than 5% chance of long-term survival and that currently the best chance of cure is with initial adjuvant treatment, not treatment of recurrent cancer.

4. Certain high-dose chemotherapy regimens may be more toxic than lower or conventional-dose chemotherapy. In the U.S. trial, 6.3% of patients died from side effects related to the high-dose chemotherapy regimen; however, this is attributable to the specific high-dose chemotherapy treatment regimen utilized in this study, as the regimen was particularly toxic. Current treatment-related mortality rates of high dose chemotherapy in the United States are consistently in the order of 0-2% and were no different than standard treatment in both European studies

5. Both the delivery of conventional chemotherapy and high-dose chemotherapy has markedly changed since the initiation of the U.S. study over 5 years ago. In general, high-dose chemotherapy is associated with less toxicity than shown in this trial. Additionally, lower or conventional dose chemotherapy may be improving in its ability to reduce cancer recurrence. Current data suggests, however, that it is unlikely that lower or conventional dose chemotherapy will ever produce cure of more patients than high-dose chemotherapy. In moving forward, the best therapeutic choice for women seeking optimal treatment of breast cancer may be combining the best conventional or lower-dose chemotherapy strategies with high-dose chemotherapy and other treatment strategies.

Strategies to Improve Treatment of Breast Cancer with High-Dose Chemotherapy and Autologous Stem Cell Transplant

The main reason patients with breast cancer fail treatment is relapse. Relapse of breast cancer occurs because the high-dose chemotherapy is either unable to kill all the cancer cells in the patient and/or because cancer cells "contaminating" the stem cells are infused back into the patient. The majority of relapses occur because all the cancer cells were not destroyed by the high-dose chemotherapy treatment. However, some relapses may be due to infusion of breast cancer contaminated stem cells. Doctors are performing clinical trials designed to improve the treatment of breast cancer with high-dose chemotherapy that include the following approaches alone or in combination:

Increased Treatment before High-Dose Chemotherapy: One strategy to improve outcomes is to increase the effectiveness of induction therapy so that patients have significant reduction in the number of malignant cells in the body before high-dose chemotherapy.

Increased Dose Intensity: Since more treatment kills more cancer cells, increasing the intensity of treatment delivered to the cancer cells by utilizing high doses of anti-cancer therapies or by delivering multiple cycles of high-dose therapy is one strategy to improve cure rates. While increasing the intensity of treatment may kill more cancer cells, this approach may also damage normal cells and increase the toxicity or side effects of therapy.

Monoclonal Antibodies: Monoclonal antibodies are a treatment that can locate cancer cells and kill them directly without harming normal cells. Herceptin® (trastuzumab) is the first monoclonal antibody approved by the Food and Drug Administration for the treatment of breast cancer. Herceptin® recognizes a protein on the cancer cell surface of 1 in 3 patients with breast cancer. In order to be treated with Herceptin® your doctor must test the breast cancer cells for the protein that Herceptin® recognizes. This protein is called Her 2-neu. Herceptin® or other monoclonal antibodies are not substitutes for other cancer treatments but have the advantage of being administered during or after high-dose chemotherapy and killing cancer cells by a different method than chemotherapy with the goal of improving the total treatment. Clinical trials are currently being performed to determine whether monoclonal antibodies administered during high-dose chemotherapy can improve survival or cure rates.

Minimal Residual Disease: Following cancer treatment, patients often achieve a complete remission, (complete disappearance of the cancer). Unfortunately many patients in remission still experience a relapse of their cancer. This is because not all the cancer cells were destroyed. Doctors refer to the this as a state of "minimal residual disease". Many doctors believe that applying additional cancer treatments when only a few cancer cells remain represents the best opportunity to prevent the cancer from returning. In addition to monoclonal antibodies, several centers are investigating vaccines which stimulate the body's immune system to kill breast cancer cells. None of these vaccines are yet approved by the Food and Drug Administration but are being evaluated on clinical trials. Biologic modifiers that stimulate the immune system are being evaluated to prevent or delay relapses after autologous stem cell transplantation. One such agent that is being tested in patients with breast cancer is interleukin-2. Newer biologics agents are in the developmental phase.

Cell Processing: When stem cells are collected from a patient for infusion after high-dose chemotherapy, cancer cells may contaminate the stem cell collection. Although the majority of cancer relapses occurring after high-dose chemotherapy and autologous stem cell transplant occur because the high-dose chemotherapy did not kill all the cancer cells, it is possible that some patients may also relapse from infusion of the cancer cells "contaminating" the stem cells. Many techniques are being evaluated that effectively remove cancer cells from the stem cell collection. It is currently unknown whether enough cancer cells can be removed to decrease relapse rates.