Dose intensity for breast cancer: where do we go from here?

Strategies utilizing high-dose chemotherapy for treatment of breast cancer have been the subject of significant controversy over the past decade. Disappointing results from randomized phase III trials in metastatic and high-risk, early stage breast cancer have tempered enthusiasm for this approach. A significant problem with large, randomized phase III trials is that improvements in therapy and supportive care cannot be rapidly incorporated into treatment, and the question under study may quickly become obsolete. The most appropriate approach for testing newer treatments may be to build on the information gained from sequential phase I and phase II studies until there is sufficient promise to warrant randomized phase III studies. The basis of most past clinical trials of high-dose therapy in breast cancer has been the use of chemotherapeutic agents at doses that are poorly tolerated without hematopoietic support. It is clear, however, that high-dose chemotherapy has significant effects on the immune system. Immune reconstitution after high-dose, marrow ablative chemotherapy is associated with transient alterations in immune surveillance, immune recognition, and immune responses. Immune therapy represents a distinct mechanism that has the potential to eradicate chemotherapy-resistant tumor cells. The development of graft-versus-host disease after allogeneic transplantation has been associated with a decreased risk of recurrence in hematologic malignancies. Breast cancer is a potential target for this graft-versus-tumor effect in allogeneic transplantation and in trials designed to induce a transient immune antitumor effect by pharmacologic means. Circulating tumor cell antigens are elevated after high-dose chemotherapy, providing a rationale for studies evaluating vaccine strategies after high-dose therapy. The minimal tumor burden after high-dose therapy also presents an opportunity to evaluate the use of non-myelosuppressive, targeted therapies in conjunction with high-dose therapy. Finally, the use of multiple cycles of high-dose therapy to replace standard-dose therapy has the potential to avoid the development of drug resistance. It is clear that there are multiple, promising avenues of investigation that utilize high-dose chemotherapy for the treatment of breast cancer. The most significant question is whether the climate exists to support these studies.