Revisiting the role of dose intensity in hematological malignancies

To improve the clinical outcomes of patients with hematologic and solid tumor malignancies, the trend in oncology has been to capitalize on the concept of dose intensity. The data supporting a direct relationship between dose intensity and outcome in animal tumor models is substantial. Data exist in preclinical models that the amount of killing of certain types of tumor cells is directly related to the total dose and duration of exposure to a certain drug. Dose-response curves for most chemotherapy agents are usually sigmoidial in shape with a threshold, a lag phase, a linear phase, and then a plateau phase. In many cases, the steepness of the dose-response curve for a chemotherapy drug is related to the sensitivity of the particular type of tumor cell to that specific drug. Thus, there is a specific plateau response in which higher levels of the drug will not kill more tumor cells. In patients, it is not true though that the plateau dose of a drug is equivalent to the maximum tolerated dose. Skipper [1] and Schabel [2] reported that the chemotherapy dose-response curve for the majority of tumors was in the linear phase. In animals transplanted with tumor cells, Skipper [1] showed that a reduction in the linear curve of the dose-response curve results in the inability to cure cancer. For example, a 20% reduction in drug dose results in a 50% reduction in cure rates. Thus, although complete remission can be seen with the lower doses of drugs, the problem is that residual viable tumor cells in time cause relapse. In addition, a twofold increase in drug dose can lead to a 10-fold increase in initial tumor killing. This data shows that dose intensity is important to determine the initial degree of response, while cumulated dose correlates best with survival and duration of response. Hryniuk et al. [3] studied the outcome of various types of human tumor based on exposure to dose intensity. Dose intensity is defined simply as the amount of chemotherapy drug administered per unit of time regardless of the schedule used or administration route [4]. Increasing dose intensity may be accomplished by either increasing the dosage in the same time frame (the use of myeloablative chemotherapy and a stem cell transplant, or the administration of highdose cytarabine for acute myeloid leukemia) or shortening the intervals between treatments courses, so-called dosedense therapy. Thus, dose-intensity approaches increase the exposure of the tumor cells to supertherapeutic levels of cytotoxic drugs or increase the time of exposure of the tumor to drug levels which may or may not be elevated. In the later dose-dense case, depending on tolerance, the total amount of therapy given in a unit of time, such as every month, is higher than usually given in more conventional regimens. Myelosuppression has been the major limiting toxicity to administer dose-intense therapy. But the use of human recombinant growth factors such as granulocyte colonystimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or the use of hematopoietic stem cell rescue has overcome this limitation. In addition, the use of erthyropoietin agents such as erythropoietin has also decreased the need for blood transfusions. However, hematopoietic cytokines are used rather than stem cells to overcome the effects of hematological toxicity to keep patients on schedule for dose-dense treatment. In this review, we will critically summarize the evidence for dose-intense therapy as standard therapy in the treatment of certain hematological malignancies, including acute myeloid leukemia (AML), lymphoma (Hodgkin’s and non-Hodgkin’s), and multiple myeloma (MM).