High Dose Chemotherapy for Stage IV Breast Cancer
Stage IV breast cancer was traditionally been considered an incurable cancer. In the mid to late 1980’s the average patient with stage IV breast cancer treated with low-dose chemotherapy survived 8-10 months before their cancer relapsed and less than 5% of patients could expect to survive 5 years without their cancer recurring. In 1988, the results of a small clinical trial treating 22 women with stage IV breast cancer treated with high-dose chemotherapy and autologous stem cell transplant were published. Fourteen percent of these patients treated with high-dose chemotherapy survived without their cancer recurring beyond 5 years. By 1997, these patients had been observed over 10 years and the original 14% remain alive without a relapse of their cancer and appear cured of their disease. It is important to understand that because over 50% of patients with stage IV breast cancer relapse, it is not useful to compare the response rate to chemotherapy, the average duration of survival or time to relapse. When evaluating treatment strategies in stage IV breast cancer, patients should compare the percent of patients alive with or without relapse 3-5 years from treatment to determine whether a treatment is truly superior.
Over the years since the original publication describing high-dose chemotherapy for the treatment of stage IV breast cancer, thousands of women have been treated. All of the more recent publications demonstrate that the complete remission rate for high-dose chemotherapy as initial treatment for stave IV breast cancer is 40%-60%, the mortality from therapy has decreased to 1%-5% and the number of patients alive without evidence of cancer recurrence is 15%-25% 4-5 years from treatment. The results from two clinical trials comparing high-dose to lower dose chemotherapy have also been published.
In one clinical trial published in 1997, women in complete remission after induction chemotherapy were treated with high-dose chemotherapy or no further treatment. At 5 years from diagnosis, 24% of the women treated with immediate high-dose chemotherapy survived without disease recurrence, compared to only 8% of the women who did not receive further treatment.
Researchers from several medical centers, however, more recently treated 553 women, ages 18 to 60 years, with 4 to 6 cycles of a standard-dose chemotherapy combination. Then, patients in a complete or a partial remission were assigned to receive additional therapy with either continued standard-dose chemotherapy or a single course of high-dose chemotherapy. Results showed that, of the 553 women treated, 10.5% had a complete response and 46% had a partial response to the initial standard-dose chemotherapy. Then, 110 patients were assigned to receive the additional high-dose chemotherapy and 89 patients were assigned to receive the additional standard-dose chemotherapy. The 3-year survival rates were 38% for those receiving the standard chemotherapy, and 32% for those receiving the high-dose chemotherapy. Twelve percent of those in the standard-dose group had no progression of disease, compared with only 6% in the high-dose group. Furthermore, there were more side effects in the high-dose therapy group, including one treatment-related death.
This study suggested that there were no differences in survival between the standard-dose and high-dose chemotherapy regimens in women with metastatic breast cancer who had a complete or partial response to initial standard-dose therapy. However, the number of women treated in this trial does not allow the identification of any subsets of women that might benefit more than the overall group from the high-dose regimen.
High-dose chemotherapy and autologous stem cell transplant treatment for previously untreated stage IV breast cancer appears safe; however, the benefit of this treatment approach is currently unknown. It is known that many factors may influence an individual patient’s potential outcome if treated with high-dose chemotherapy. Patients without prior treatment, those with small amounts of cancer, and those whose cancer responds to conventional chemotherapy all do better. Additional clinical trials directly comparing conventional chemotherapy treatments to high-dose chemotherapy treatments are currently ongoing to help determine which patients may benefit most from high-dose chemotherapy treatment.
Strategies to Improve 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 or after 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. To learn more about techniques for removing cancer cells from the stem cell product, select Autologous Stem Cell Collection and Processing.