by Dr. C.H. Weaver M.D. 2/2020
One of the largest and best controlled clinical trials evaluating the use of high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) to treat patients with early stage breast cancer and more than 9 involved axillary lymph nodes continues to show survival benefit 20 years from receiving treatment. (10)
In the 1990’s HDC and ASCT was increasingly used to treat breast cancer and other solid tumors based on its success in curing certain individuals with lymphoma, leukemia, and multiple myeloma. HDC continue to be the standard of care for many cancers but became out of favor as a treatment option for breast cancer due to conflicting study results and concerns about side effects.
The use of HDC for the treatment of breast cancer was based on the idea that breast cancer treatment could be improved if higher doses of chemotherapy could be administered and this has been borne out to be true. A standard treatment for high risk early stage breast cancer today is “dose-dense” chemotherapy which is widely used instead of HDC and ASCT and requires the use of “blood cell growth boosters” to ensure the chemotherapy can be safely administered in a timely manner.
The current reported trial results are from a “pivotal” study conducted between 1993 and 1999 where 885 women younger than 56 with early stage breast cancer and at least 4 involved axillary lymph nodes were treated with either conventional dose fluorouracil, epirubicin, and cyclophosphamide chemotherapy or HDC and ASCT. The HDC regimen was similar to the conventional regimen but replaced the last cycle with high-dose cyclophosphamide, thiotepa, and carboplatin.
The study authors have reported that among patients with more than 9 involved axillary lymph nodes HDC significantly improves outcomes 20 years from the initiation of treatment. HDC significantly improved overall survival; 44% of HDC treated patients survive today compared to only 30% of women treated with conventional chemotherapy. The relapse-free survival rate was also improved; 39% of patients who received HDC survive without cancer recurrence compared with 27% after conventional chemotherapy.
HDC was also associated with improved overall survival in a subgroup with triple-negative breast cancers, as 52.9% of these patients were alive at 20 years compared with 37.5% of those in the conventional-dose chemotherapy.
The study authors concluded that this “long-term follow-up confirms survival benefit of HDC in breast cancer patients with more than 9 involved ALN and suggests benefit in TNBC patients.” Doctors and patients are now faced with the questions of whether HDC could serve as a more cost effective platform for the incorporation of precision cancer medicines than dose dense therapy?(1,10)
The following general conclusions can currently be drawn regarding high-dose chemotherapy with autologous stem cell transplant for the adjuvant treatment of breast cancer:
- No clinical studies have demonstrated that conventional-dose chemotherapy is superior to high-dose chemotherapy treatment.
- Published clinical trials demonstrate that high-dose chemotherapy reduces the risk of cancer and improves outcomes by about 10% to 15%.
- Certain high-dose chemotherapy regimens may be more toxic than lower or conventional-dose chemotherapy. Current treatment-related mortality rates of high dose chemotherapy in the United States and Europe are consistently in the order of 0-2%.
- The delivery of conventional chemotherapy has markedly changed in recent years and has largely been replaced by dose dense therapy for high risk early stage disease. Dose-dense chemotherapy involves chemotherapy doses given close enough together that cancer cells do not have time to recover between treatments.
- Cumulative incidence of second malignancies at 20 years -- most commonly breast cancer -- was similar between groups, at 12.1% in the high-dose arm and 16.2% in the standard-dose arm.
What Did The Early High Dose Chemotherapy Trials Show?
High-Dose Chemotherapy Reduced the Risk of Cancer Recurrence and Prolongs Survival for Women with High Risk Early Stage Breast Cancer
Researchers from The Netherlands initially reported that high-dose chemotherapy reduced the number of cancer recurrences and improved survival in women with stage II and III breast cancer, and the current 20 year follow up data is from this group of women.
After 3 years, 35% of the women who received the standard-dose chemotherapy regimen and 23% who received the high-dose therapy had a recurrence of cancer, or relapse. Survival rates were 79% for those in the standard-dose chemotherapy group, compared with 89% in the high-dose chemotherapy group.
At 5 years, survival without cancer recurrence was achieved in 71.5% of patients treated with high-dose therapy, compared with 59.1% of those treated with standard chemotherapy and overall survival was 78.2% in the group of patients treated with high-dose therapy, compared with 71% for those treated with standard chemotherapy.
Researchers from Germany published in the Lancet, that high-dose chemotherapy and stem cell transplantation improved outcomes over conventional therapy in stage III breast cancer. Their trial included 403 patients with cancer spread to an average of nine axillary (under the arm) lymph nodes. Patients were treated with either high-dose chemotherapy with stem cell transplantation or dose-dense chemotherapy. Approximately half of the patients treated with high-dose chemotherapy and stem cell transplantation underwent one regimen of chemotherapy followed by a transplant, while the other half underwent a tandem transplant.
At a follow-up of over 4 years, patients treated with high-dose chemotherapy had improved outcomes:
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- Event-free survival (no recurrences of cancer, no death, no second cancers) rates were 60% in patients treated with high-dose therapy, compared with 44% in patients treated with dose-dense therapy.
- Overall survival was 75% for patients treated with high-dose therapy and 70% for patients treated with dose-dense therapy.
- Median overall survival has not yet been reached for patients treated with high-dose chemotherapy; it was 75.9 months for those treated with dose-dense therapy.
- Women younger than 35 years, those with cancers greater than 4 centimeters in diameter, those with more aggressive-type cancers (according to how abnormal cells appear under the microscope), and those with hormone-receptor negative cancers derived the greatest benefit from treatment with high-dose chemotherapy.
Several French researchers evaluated the impact of one cycle of high-dose chemotherapy and an autologous stem cell transplant following standard dose treatment in 314 stage II-III breast cancer patients and at least 7 involved lymph nodes. Following surgery, all patients received 4 cycles of 5-flourouracil, cyclophosphamide and epirubicin. 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 tamoxifen 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. The 16% lower chance of relapse in the high-dose chemotherapy group suggests a potential ultimate long-term survival benefit.
The results of the only U.S. trial to address this question conflicted with the results of the European trials. In the 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 (tamoxifen).
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 Taxol. 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.(gg)
Some Breast Cancer Patients With Advanced Disease May Also Benefit from High-Dose Therapy
Women with treated breast cancer are said to have no evident disease (NED) when all disease disappears; however, women with advanced breast cancer who are rendered NED usually have a recurrence despite continued conventional dose chemotherapy. Such patients appear to have an improved outcome following high-dose chemotherapy with autologous stem cell support.
Researchers at the University of Colorado recently analyzed data from 50 women with metastatic breast cancer who were treated with high-dose chemotherapy after achieving an NED status. The average survival without cancer recurrence for patients in this study was 55 months and the average overall survival was 80 months. At an average follow-up of 64 months, 60% of patients survived, 50% without cancer recurrence.(pp)
Researchers associated with the Cancer and Leukemia Group B (CALGB) and the Autologous Blood and Marrow Transplant Registry (ABMTR) evaluated data from approximately 1,000 patients with metastatic breast cancer who were treated with either high-dose chemotherapy and stem cell transplant or standard-dose chemotherapy between 1980 to 1995.
Survival was greater within the first 15 months following therapy for patients treated with standard-dose chemotherapy. However, three and five year survival rates were higher for patients treated with high-dose chemotherapy. The results from this data indicate that high-dose chemotherapy and stem cell transplantation may improve long-term survival in some patients with metastatic breast cancer. (ee) (FF)
Understanding High Dose Chemotherapy
High-dose chemotherapy generally kills more cancer cells than moderate doses, but this treatment also results in more side effects. One particular side effect is damage to the blood-producing hematopoietic stem cells. These cells are immature blood cells produced in the bone marrow that mature into red blood cells (which carry oxygen to tissues), white blood cells (which fight infection), and platelets (which aid in blood clotting).
To restore stem cells that are depleted by high-dose chemotherapy, patients may undergo an autologous stem cell transplant. An autologous stem cell transplant involves collection of the patient’s own stem cells prior to chemotherapy; these cells are then re-infused after chemotherapy to help the bone marrow recover.
- Steenbruggen TG, Steggink LC, Seynaeve CM. High-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (HSCT) in high-risk breast cancer (BC) patients with ≥4 involved axillary lymph nodes (ALN): 20-year follow-up of a randomized phase 3 study. Presented at: 2018 ESMO Congress; Munich, Germany: October 19-23, 2018. Abstract 187O.
- Rodenhuis S, Bontenbal M, van Hoesel GCM, et al. Efficacy of high-dose alkylating chemotherapy in HER/neu-negative breast cancer. Annals of Oncology. epub. on January 30, 2006, doi;a0.a093/annonc/mdl001.
- Hanrahan EO, Broglio K, Frye D, et al. Randomized trial of high-dose chemotherapy and autologous hematopoietic stem cell support for high-risk primary breast cancer. Follow-up at 12 years. Cancer. 2006;106:2327-2336.
- 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;366:1935-1944.
- Proceedings from the 37th Annual Meeting of the American Society of Clinical Oncology, Vol 20, Abstract No. 30, pp 8a, 2001.
- Proceedings of the American Society of Clinical Oncology Thirty-Sixth Annual Meeting, Vol 19, Abstract 286, page 74a, 2000.
- Berry D, Broadwater G, Klein J, et al. High-dose versus standard chemotherapy in metastatic breast cancer: comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry. Journal of Clinical Oncology. 2002:20;743-750.
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- Proceedings from the 37th Annual Meeting of the American Society of Clinical Oncology, Vol 20, Abstract 102, page 26a, 2001.
- Steenbruggen TG, et al "High-dose chemotherapy with hematopoietic stem cell transplant in patients with high-risk breast cancer and 4 or more involved axillary lymph nodes -- 20-year follow-up of a phase 3 randomized clinical trial" JAMA Oncol 2020; DOI: 10.1001/jamaoncol.2019.6276.