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Spring 1998, Vol.5, No.1
High Dose Chemotherapy with Stem Cell Support for Breast Cancer Linda Vahdat, M.D. Introduction For the first time in five decades, 1997 US cancer statistics document a decreasing overall mortality from cancer, although breast cancer mortality has remained relatively stable. Breast cancer was responsible for 41,000 total deaths in 1997, and remains the major cause of death in 15-54 year old American women.1 While early detection has improved the outcome for early stage disease, survival at 10 years remains approximately 15% for those with large primary tumors or at least 10 involved lymph nodes, and less for the 10% of patients who initially present with metastatic breast cancer. (See Table 1 for staging). Standard treatments for high-risk adjuvant therapy patients have produced disappointing results, and for those with metastatic disease the goal was, until recently, essentially palliative2,3. Consequently, the development and evaluation of new treatment appropriately focuses not only on patients with metastatic disease, but also on patients who are at a particularly high risk of relapse. Rationale for Dose Intensive Therapy in Breast Cancer The delivery of the highest possible doses of chemotherapy appears to be a necessary event in laboratory models of breast cancer4,5. The concept of dose-intensity (drug dose administered in mg/m2/week) was emphasized by Hryniuk and colleagues for the purpose of quantifying dose response effects using breast cancer as a model6. They concluded that chemotherapy regimens should be designed to maximize the overall dose administered over time (dose intensity), as opposed to achieving the highest peak dose. This concept is the subject of ongoing debate and multiple clinical trials. Myelosuppression is frequently the dose-limiting side effect of many of the active agents in breast cancer chemotherapy. The recent availability of hematopoietic growth factors and use of autologous marrow or blood derived stem cells limits the duration of the aplasia associated with very high dose therapy. The use of hematopoietic stem cells from peripheral blood produces more rapid hematologic recovery after high dose chemotherapy resulting in decreased morbidity and mortality. Dose-Intensive Therapy with Autologous Stem Cell Support The use of high dose chemotherapy for breast cancer is rapidly increasing in North America as supportive care technology becomes more readily available. To determine trends in autologous transplant for breast cancer over a 6 year period, the Autologous Blood and Marrow Transplant Registry (ABMTR) studied 5886 women who underwent high dose therapy with autologous stem cell support. This study reveals that the number of patients transplanted per year is increasing substantially, that a higher percentage of patients are being transplanted for early stage disease compared to 5 years ago (7% in 1989 vs. 50% in 1995), and that mortality has markedly decreased from 22% in 1989 to 5% in 1995.7 Review of Clinical Trials Initial studies evaluated single agents and then combinations in women with advanced refractory disease. While responses were observed supporting the importance of dose, responses were generally short and disease free survival was rare. Untreated or Responding Metastatic Breast Cancer: Evidence exists both for and against restricting high dose therapy only to patients who respond to conventional doses of chemotherapy. Presumed advantages include maximal tumor cytoreduction prior to a consolidative high dose treatment, as well as an in vivo assay of tumor sensitivity. If tumor cell contamination of the stem cell product is important, then several cycles of conventionally dosed chemotherapy prior to their collection may provide in vivo purging8. In contrast, conventional doses of chemotherapy could theoretically induce multidrug or specific resistance or allow growth of moderately resistant clones. Most patients currently treated receive conventionally-dosed induction therapy for purely practical reasons such as disease control during evaluation, as well as planning for an available bed and obtaining insurance approval in anticipation of bone marrow transplantation. Table 1: Breast Cancer Staging Summary, TNM System Stage I - Invasive tumors without metastases, localized to the breast Stage II(A,and B) - Regional lymph node metastases Stage III(A and B) - Regional lymph node metastases with fixed nodes Stage IV - Distant or supraclavicular lymph node metastases Derived from Yeatman, T.J. and Bland, K.I. Staging of breast cancer. In: Bland, K.I. and Copeland, E.M., ed. The Breast. Philadelphia:W.B. Saunders, 1991: 313-330. Breast Cancer Responding to Standard Dose Chemotherapy: Multiple regimens comprising a varied number and schedule of drugs are used in patients responding to conventional dose chemotherapy. At least 42 single institution studies utilize a single high dose cycle of therapy. Complete response (CR, i.e., complete remission) rates average 37% (range 18-72%) and 10-20% of patients are disease-free at five years9. Registry data corroborate these observations with an 18% estimated disease free survival at 3 years. About 32% of those in complete remission, 13% of those in partial remission and 7% of those not responding to pre-transplant conventional dose chemotherapy will remain disease free at 3 years7. Prognostic variables: Several institutions now have sufficient follow-up and large enough data bases to retrospectively identify factors which are associated with prognosis after high dose chemotherapy. Complete response prior to 10 or following 11 high dose chemotherapy (whether from chemotherapy, radiation or surgical resection of residual disease) is the strongest predictor of long term disease free survival in virtually all studies. New Strategies in High Dose Therapy Single institution and ABMTR data reproducibly show that a complete response is the single most important prognostic factor associated with prolonged disease-free survival. Strategies used to attempt to increase the percentage of patients who achieve a CR (in the hope that a higher CR rate will translate into an increased proportion of patients with prolonged disease-free survival), include incorporation of new active drugs and the use of multiple high dose cycles. New drugs: Inclusion of newer cytotoxic agents into established high dose regimens is under investigation. Response rates vary (17 to 100%) with an extremely short follow-up period12-16. Non-cytotoxic approaches include the development of anti-angiogenesis agents,17 inhibitors of signal transduction,18 and matrix metalloproteinases19. A tandem transplant regimen piloted by the group at Columbia includes paclitaxel at doses up to 825 mg/m2 as the first high dose cycle in a regimen that builds on the tandem transplant regimen developed by Ayash et al. Multicycle chemotherapy: Sequences of single-agent and combination chemotherapy regimens are currently in clinical trials. Overall, multicycle chemotherapy produces complete response rates up to 93% depending on the regimen20. Immunologic strategies: The setting of minimal residual disease after recovery from high dose therapy may present a unique opportunity for various immunologic strategies from the use of biological response modifiers or vaccines to induction of an autologous graft versus tumor effect. The rationale for attempting to induce a graft versus tumor effect derives from observations that patients with leukemia who develop even mild graft versus host disease (GVHD) after allogeneic marrow transplant have a reduced relapse rate21. Cyclosporine A, interferon-g, interleukin-2 (IL-2)) and other agents are currently under evaluation for immune activation or clinical benefit 22-24 via any number of heterogeneous mechanisms. Gene Therapy: A recently completed phase I trial in advanced cancers conducted at Columbia demonstrates that the human multidrug resistance (MDR) gene can be safely and efficiently transduced into stem cells and expression maintained for at least 4 months25. In fact certain adenovirus vectors alone have been demonstrated to lyse tumor cells26. Additional applications for gene therapy may ultimately include the transduction of suicide genes into neoplastic cells27. Monoclonal Antibodies (MoAb) used after High Dose Chemotherapy: Growth factors and their receptors play a regulatory role in cell proliferation and have been implicated in oncogenesis28. Her-2/neu monoclonal antibodies (or the like) may have a role after high dose chemotherapy in the setting of minimal residual disease. Autologous Stem Cell Transplant In Patients with Stage II, III or Inflammatory Breast Cancer Patients with 10 or more involved axillary lymph nodes or inflammatory breast cancer have a dismal prognosis with less than 20% survival at 10 years despite combined modality therapy. Hence trends over the past decade reflect studies of a more aggressive approach at diagnosis for this subset of patients . The ABMTR data reveal that high dose chemotherapy with autologous stem cell support for patients with locally advanced disease accounted for 49% of patients in 1995 as compared to 6% in 1989. Pooled results estimate 63% without relapse at three years for Stage II and III disease and 42% for inflammatory breast cancer, however phase II data from single institutions in the ABMTR must be cautiously interpreted as patients for transplant are more carefully selected with computer tomography of the brain and marrow biopsies. Randomized Trials In Patients with Breast Cancer Stage IV Breast Cancer: To date, one randomized trial has been reported of high dose versus conventional dose chemotherapy as initial treatment for women with stage IV breast cancer29. Bezwoda et al. randomized 90 patients to receive 2 cycles of high dose cyclophosphamide, mitoxantrone, and etoposide or six to eight courses of conventional dose cyclophosphamide, mitoxantrone, and vincristine. The complete response rate (51% vs. 4%), overall response rate (95% vs. 53%), disease-free survival (80 weeks vs. 34 weeks) and overall survival (90 weeks vs. 45 weeks) were superior in the high dose arm. Although there were many valid criticisms of this small trial it confirms the importance of dose in the treatment of breast cancer. Stage II and III Breast Cancer: At the Netherlands Cancer Institute, 95 patients with an apical axillary lymph node biopsy positive for breast cancer were entered into a study of 3 courses of FEC (5-fluorouracil, epirubicin, cyclophosphamide). Responders were then randomized to an additional cycle of FEC followed by surgery, radiation and tamoxifen for 2 years, or an additional cycle of FEC followed by CTCb (cyclophosphamide, thiotepa, carboplatin) with peripheral blood progenitor support. Of the 78 randomized patients there was no difference in disease-free or overall survival at a median follow-up of 36 months30. Quality of Life and Cost Effectiveness Major advances in supportive care over the past 5 years have substantially reduced the time to engraftment, morbidity (e.g., pancytopenia) and cost associated with transplant31. The net result is that dose intense regimens can now be relatively safely and efficiently tested in breast cancer. Most patients resume a relatively normal lifestyle within 2 to 4 months after transplant in the absence of progressive disease. If the complete remissions prove to be durable (15% disease-free beyond 5 years), the cost per year of life saved was estimated to be quite cost effective at $17,000 as compared to $45,000 per year of life saved by renal dialysis32,33. In fact, many centers now administer high dose chemotherapy in the outpatient setting which may further contribute to decreased cost. Summary Of High Dose Chemotherapy In Breast Cancer A single high dose chemotherapy treatment can produce 5 year disease-free survivorship in 10 to 20% of patients with Stage IV breast cancer. The optimal treatment strategy and duration, as well as the subset that derives benefit are continually refined. However, the data continue to support the position that the best disease free survival is observed for patients in complete remission (or with evidence of sclerosis of bony metastases on scans) at the end of therapy. Morbidity and mortality continue to decline as supportive care improves, making higher doses a safe treatment strategy. The role of post-transplant consolidation strategies to treat minimal residual disease is currently under investigation. For Stage II breast cancer, accrual to randomized trials addressing the question of optimal dose and schedule are due to be reported in the year 2000. Preliminary results for high-dose therapy in Stage III breast cancer are encouraging; however, longer follow-up is needed. There are currently at least sixteen randomized trials underway in Stage II (> 3 positive lymph nodes) or Stage III breast cancer. Most studies include conventional dose anthracycline-based chemotherapy followed by randomization to high dose chemotherapy versus either standard dose or no further therapy. For metastatic disease, a major priority is the design of more effective regimens using newer cytotoxic or biologic agents, treatment schedules or a combined modality approach. Major advances in supportive care continue to decrease the time to engraftment, morbidity and cost associated with the transplant. Usually, most curative treatments are cost-effective, however overemphasis on the dollar cost may potentially compromise the design of newer and perhaps more effective regimens. These treatments eventually become less toxic and expensive as side effects are anticipated and efficiencies of scale are introduced. References 1. Parker S, Tong T, Bolden S, Wingo P. Cancer Statistics, 1997. CA Cancer J Clin. 1997;47(1):5-27. 2. Clark G, Sledge GW, Osborne CK, McGuire WL. Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol 1987;5:55-61. 3. Mick R, Begg CB, Antman K, Korzun AH, Frei III E. Diverse prognosis in metastatic breast cancer: who should be offered alternative initial therapies? Breast Cancer Res Treat 1989;13:33-38. 4. Frei III E, Canellos GP. Dose, a critical factor in cancer chemotherapy. Am J Med 1980;69:585-594. 5. Frei III E, Antman K, Teicher B, Eder P, Schnipper L. Bone marrow autotransplantation for solid tumors-prospects. J Clin Oncol 1989;7:515-26. 6. Hryniuk WM, Bush H. The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 1984;2:1281-1287. 7. Antman K, Rowlings P, Vaughn W, et al. High dose chemotherapy with autologous hematopoietic stem cell support for breast cancer in North America. J Clin Oncol 1997;15(5):1870-79. 8. Vredenburgh J, Peters W, Rosner G, et al. Detection of tumor cells in the bone marrow of stage IV breast cancer patients receiving high-dose chemotherapy: the role of induction chemotherapy. Bone Marrow Transplant 1995;16(6):815-21. 9. Vahdat L, Antman K. Dose-intensive chemotherapy in breast cancer. In: Armitage J, Antman K, eds. High dose cancer therapy: pharmacology, hematopoietins, stem cells. 2nd ed. Philadelphia: Williams and Wilkins, 1995:802-23. 10. Rowlings P, Antman K, Horowitz M, et al. Breast cancer working committee of the Autologous Bone Marrow Transplant Registry (ABMTR). Proc Am Soc Clin Oncol 1995;14:325 (abstract 966). 11. Dasgupta A, Rajagopal C, Efird J, et al. High dose cyclophosphamide/carboplatin and autologous bone marrow transplantation/peripheral blood stem cell transplantation for metastatic breast cancer : An analysis of prognostic factors. Proc Am Soc Hematol 1994;85:(abstract 3757). 12. Stemmer S, Jones R, Bearman S, Purdy M, Myers S, Shpall E. Intensive taxol/cyclophosphamide/cisplatin with autologous hematopoietic cell support. Proc Am Soc Clin Oncol 1994;13(abstract 222):105. 13. Spitzer G, Champlin R, Seong D, et al. Repetitive high-dose therapy (HDT) tolerance and outcome in stage IV breast cancer. Seventh International Symposium On Autologous Bone Marrow Transplantation, Dicke KA, Keating A, (Eds.)Arlington, TX 1994. 14. Vukelja S, Baker W, Burrel L, et al. High-dose taxol, cyclophosphamide, and cisplatin with stem cell support in treatment of metastatic breast cancer. Autologous Bone Marrow Transplantation, Proceedings of the International Symposium, Dicke KA, Armitage JO, Dicke-Evinger MJ, (Eds.)Arlington, TX 1994:74. 15. 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Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation. Blood 1992;79 (2):517-526. 25. Hesdorffer C, Ayello J, Ward M, et al. A phase I clinical trial using MDR-transduced marrow and/or peripheral blood CD34+cells. Proc Amer Soc Clin Oncol 1997;16:88a (abstract 310). 26. Izbecka E, Kim D, Degen D, VonHoff D. Effects of ONYX adenovirus preparations on human tumor colony forming units. Proc Amer Soc Clin Oncol 1997;16:433a (abstract 1554). 27. Talmadge J, Watanabe T, Kuxzynski C, et al. Purging properties of p53 adenovirus-mediated gene transfer into breast cancer cells using protocols which are nontoxic for human C34+ cells. Proc Amer Assoc Cancer Res 1997;38:6 (abstract 37). 28. Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-182. 29. Bezwoda W, Seymour L, Dansey R. High dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 1995;13(10):2483-2489. 30. Rodenhuis S, Richel D, Baars J, et al. A randomized single-institution study of high dose chemotherapy with cyclophosphamide, thiotepa and carboplatin in high-risk breast cancer. Proc Amer Assoc Can Res 1997;38((abstract 2927)):438. 31. Nemunaitis J, Rabinowe SN, Singer JW, et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid malignancy: Pooled results from three randomized double-blind, placebo controlled trials. N Engl J Med 1991;324:1773-8. 32. Hillner BE, Smith TJ, Desch CE. Estimating the cost-effectiveness of autologous bone marrow transplantation for metastatic breast cancer. Proc Am Soc Clin Oncol 1991;10:46 (abstract 60). 33. Hillner BE, Smith TJ, Desch CE. Efficacy and cost-effectiveness of autologous bone marrow transplantation in metastatic breast cancer estimates using decision analysis while awaiting clinical trial results. JAMA 1992;267:2055-2061.
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