Dose intensity and high dose therapy. Two different concepts

“Dose response” refers to a direct relationship between the amount of chemotherapy administered and observed degree of antitumor effect. What is often implied by the term is the administration of pulsed, high dose therapy, resulting in very high peak concentrations. Clinically, this has been translated as multiple alkylating agent‐based regimens requiring intensive supportive care and associated with substantial morbidity and an appreciable mortality risk. Such regimens typically are given as consolidation after an initial period of standard outpatient therapy and may require autologous hematopoietic stem cell support. “Dose intensity” is defined as the amount of drug administered per unit of time, typically reported in mg/m²/ week. This is a more precise term than “dose response.” A dose‐intensive regimen may or may not be one associated with high peak concentrations. For example, prolonged or continuous administration of an agent like cyclophosphamide may be quite dose‐intensive, but will be associated with lower peak concentrations and less acute toxicity than a sigsilarly dose‐intensive, pulsed high dose regimen of the same drug. Retrospective analyses and prospective, randomized trials suggest the importance of dose intensity in the treatment of breast cancer. The evidence that high dose therapy (associated with high peak plasma levels) is beneficial in breast cancer rests on a number of Phase II trials. In the setting of poor prognosis Stage IV disease, these trials suggest little improvement in median survival, but better long term survival (at or beyond 2 years) in 15–25% of such patients. This benefiting cohort appears to be in unmaintained disease free remission, whereas standard therapy in the past has almost never produced such remissions in the poor prognosis subgroup of Stage IV disease. In the setting of high risk Stage II disease, Phase II trials of similar high dose therapy indicate a higher proportion of patients who are free of recurrence at 2‐3 years than expected from available historic controls. Randomized trials are now underway in Stage IV poor prognosis patients and in Stage II high risk patients to see whether the apparent improvements in outcome associated with pulsed high dose chemotherapy can be validated prospectively. The regimens under study in these randomized trials include agents that require autologous support with harvested bone marrow and/or peripheral blood progenitor cells. Such obligate stem cell support carries with it the risk of tumor cell contamination in the collection and subsequent iatrogenic dissemination of disease. The frequency and magnitude of this contamination are under study, and methods to purge the autologous collection of tumor cells are under development, but both types of research are embryonic. Alternative approaches to pulsed, high dose chemotherapy not requiring autologous stem cell support exist, and reported results in poor prognosis Stage IV disease appear comparable to those achieved by obligate stem cell programs. Development of genetically engineered hematopoietic growth factors has facilitated approaches to improved dose intensity as well as to pulsed high dose consolidation. Thrombocytopenia and mucositis, however, are little affected by the available growth factors. Further improvements in therapeutic index for both approaches may result from new growth factors now under study. The use of peripheral blood progenitor cells shortens thrombocytopenia after high dose regimens. A new area of investigation involves the suppression of negative regulators of hematopoiesis (e. g., tumor necrosis factor), which may be overexpressed after bone marrow injury by high dose therapy. The future may involve combining concepts of dose response (e. g., dose intensive induction to pulsed consolidation). Optimal results are likely to be achieved through the integration of dose response with other approaches (local irradiation to high risk sites, biologic response modifiers).