Dose intensity and high dose therapy. Two different concepts

Abstract

"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 similarly 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.(ABSTRACT TRUNCATED AT 400 WORDS)