High-Dose Therapy and Stem Cell Transplantation
The use of high-dose therapy and stem cell transplantation for the
treatment of both hematologic malignancies and solid tumors has increased dramatically
over the past several years. A report from the International Bone Marrow Transplant
Registry (IBMTR) and the Autologous Bone Marrow Transplant Registry (ABMTR) in 1997
described data available for more than 65,000 transplants, which represented about 40% of
the allogeneic transplants performed worldwide since 1964 and approximately 50% of the
autologous transplants performed in North and South America since 1989.1 The
past several years have seen substantial changes in the field of allogeneic and autologous
stem cell transplantation including improvements in graft-vs-host disease prevention and
treatment, increased utilization of alternative donors, and a shift from the use of bone
marrow to peripheral blood stem cells, especially in patients undergoing autologous stem
cell transplantation. Stem cell transplantation has become standard therapy for several
malignancies. One example is the use of allogeneic bone marrow transplantation for the
treatment of leukemia and certain lymphomas. Yet, despite the broad application of this
therapy, as well as the substantial improvements in clinical outcomes and
treatment-related mortality, the use of high-dose therapy remains controversial for the
treatment of certain malignancies, most notably breast cancer and other solid tumors. This
edition of Cancer Control focuses on several aspects of stem cell transplantation,
including recent advances in management, as well as several controversies in the
utilization of this therapy.
A major limitation of allogeneic bone marrow transplantation has
been the problem of graft-vs-host disease. Graft-vs-host disease accounts for significant
morbidity following HLA-identical sibling transplants and, in the case of a less well
matched donor such as an unrelated donor, the risk of graft-vs-host disease can limit the
applicability of otherwise potentially curative therapy for patients with leukemia,
lymphoma, or other malignancies. Strategies to maximize medical prophylaxis and treatment
through nonspecific immunosuppression mechanisms have provided substantial improvements in
limiting the incidence and extent of graft-vs-host disease. Unfortunately, the costs of
severe immunosuppression remain obvious. Stephen J. Noga, MD, PhD, and Paul V.
O’Donnell, MD, PhD, present an interesting prospective on the role of graft
engineering in decreasing the morbidity of graft-vs-host disease while exploiting the
benefits of graft-vs-tumor effects. This outstanding state-of-the-art review provides a
balanced overview of the current applications of graft engineering and explores the future
of this technology in improving clinical outcomes following transplantation.
The use of high-dose therapy for the treatment of breast cancer has
seen tremendous growth over the past several years. Between 1989 and 1995, autotransplant
for breast cancer increased sixfold, and after 1992, breast cancer became the most common
indication for high-dose therapy for patients reported to the ABMTR.2 Yet,
despite the widespread application of this therapy, the use of high-dose therapy for the
treatment of breast cancer remains controversial. Unfortunately, few prospective,
randomized clinical trials address the role of dose intensity in the treatment of breast
cancer.3 Benjamin Djulbegovic, MD, and colleagues eloquently describe the
process of clinical decision making and the rational use of the available medical
literature for the application of high-dose therapy in the management of patients with
early-stage, high-risk breast cancer. They describe a method for comparing the benefits
and risks of standard-dose therapy to high-dose therapy in an attempt to define the
circumstances under which high-dose chemotherapy could be used in the management of these
patients. This mathematical model has broad implications for a variety of clinical
situations, especially in areas where few randomized, controlled clinical trial data
exist.
With increased utilization of autologous stem cell grafts and
emerging technology to select, with either positive or negative selection techniques, a
relatively "pure" population of CD34+ committed progenitor cells from both bone
marrow and peripheral blood, the role of contamination of the stem cell product takes on
increased clinical significance. Whether contaminating tumor cells detected in the stem
cell product play a role in relapse or simply reflect overall tumor burden and thus define
a patient population less likely to achieve a complete response to high-dose therapy
remains an area of active clinical investigation and controversy. Thomas J. Moss, MD,
addresses several issues related to tumor cell contamination of the stem cell graft
including the methods of detection and the incidence of minimal residual disease in the
stem cell product, the role of the "mobilization" technique in contaminating the
stem cell product, the clinical significance of tumor cells detected in the bone marrow
and stem cell product, and the role of purging of the stem cell product. This extensive
review of the available literature not only provides an excellent overview but also
defines future areas for clinical research.
Future therapeutic interventions will depend on appropriate analysis
of the available medical literature, as well as consideration of the economic impact of
treatment decisions. Susan E. Beltz, PharmD, and Gary C. Yee, PharmD, FCCP, provide an
excellent description of the emerging field of pharmacoeconomics. This article provides a
comprehensive overview of the principles of cost analysis and related topics and includes
examples of the utility of these types of analyses. These considerations will become
increasingly important, especially as long-term outcome data become available from
prospective, randomized clinical trials.
Increased utilization of stem cell transplantation is likely due to
continued advances in supportive care with concomitant decreases in treatment-related
mortality. Rod Quilitz, PharmD, describes the role of several new antifungal agents in the
management of the posttransplant patient. These agents have had a significant impact in
decreasing treatment-related deaths due to invasive fungal infections in the
posttransplant setting. This article provides an excellent overview of these important
aspects of supportive care in the transplant patient population with implications for
improving clinical outcomes for all patients receiving dose-intensive therapy.
In summary, the use of both allogeneic and autologous stem cell
transplantation will likely continue to increase over the next several years due to
improvements in technology that result in decreased toxicity and improved efficacy. The
rational use of transplantation, including the appropriate patient population to be
treated, will be defined as the results of carefully planned clinical trials addressing
multiple aspects of the transplant process become available.
Karen K. Fields, MD
Program Leader, Blood and Marrow
Transplant Program
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida
References
1. Horowitz MM, Rowlings PA. An update from the International Bone Marrow Transplant
Registry and the Autologous Blood and Marrow Transplant Registry on current activity in
hematopoietic stem cell transplantation. Curr Opin Hematol. 1997; 4:395-400.
2. Antman KH, Rowlings PA, Vaughan WP, et al. High-dose chemotherapy with autologous
hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol.
1997;15:1870-1879.
3. Savarese DM, Hsieh C, Stewart FM. Clinical impact of chemotherapy
dose escalation in patients with hematologic malignancies and solid tumors. J Clin
Oncol. 1997;15:2981-2995.
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