Breast Disease - Volume 14, issue 1

Authors: Seidman, Andrew D.

Article Type: Introduction

DOI: 10.3233/BD-2001-14101

Citation: Breast Disease, vol. 14, no. 1, pp. 1-1, 2001

Authors: Hennessy, Bryan | Kennedy, M. John

Article Type: Research Article

DOI: 10.3233/BD-2001-14102

Citation: Breast Disease, vol. 14, no. 1, pp. 3-7, 2001

Authors: Strobl, Frank J. | Stadtmauer, Edward A.

Article Type: Research Article

Abstract: The survival for patients with advanced breast cancer following conventional combination chemotherapy remains limited. Attempts to circumvent drug resistance have involved high-dose chemotherapy along with autologous hematopoietic stem cell support. Despite this, relapse remains the primary cause of death. Breast tumor cells are commonly found in hematopoietic stem cell collections. The role of reinfused occult tumor cells in malignant relapse following high-dose chemotherapy has yet to be determined but is likely to have a negative impact. Strategies to decrease stem cell contamination under investigation include: (1) improved regimens for stem cell mobilization, (2) enhanced techniques for tumor cell detection, (3) …targeted tumor cell purging and (4) alternative sources of stem cells. These approaches hold promise for improving the outcome of patients undergoing high-dose chemotherapy and stem cell reinfusion for poor-prognosis breast cancer. Show more

DOI: 10.3233/BD-2001-14103

Citation: Breast Disease, vol. 14, no. 1, pp. 9-19, 2001

Authors: Hryniuk, William

Article Type: Research Article

Abstract: The concept of dose intensity provides a starting point for studying dose-response relationships. The summation dose intensity method (SDI) is an improvement over previous methods of calculating dose intensity because it accounts for differences in drug activity and allows the dose intensity of combinations containing the different drugs to be compared on one scale. It may also ultimately prove useful in defining the contribution of cumulative dose and dose size. Results from initial randomized trials testing dose intensification in breast cancer suggested but did not confirm its importance because dose size and cumulative dose were usually increased concurrently. Results from …several recent trials in which dose intensity was increased while cumulative dose was held constant suggest that dose intensity may not be pre-eminent, but that both dosage parameters affect outcome. In addition, there may be a threshold dose intensity that must be exceeded before treatment causes tumor regression. From both retrospective analyses and prospective trials of adjuvant chemotherapy, it is clear that the subsets of patients who benefit most from dosage increases are those with poor prognostic factors. Larger dose sizes contribute more toxicity but, within the conventional range, probably contribute little independent therapeutic benefit. In contrast, reduced size doses of non-antimetabolites given at very short intervals may reduce acute toxicity, maintain dose intensity above threshold, and allow delivery of larger cumulative amounts of chemotherapy. This dose dense strategy may produce results superior to the use of fewer but larger doses. Show more

DOI: 10.3233/BD-2001-14104

Citation: Breast Disease, vol. 14, no. 1, pp. 21-30, 2001

Authors: Miller, Kathy D. | Rahman, Zia U. | Sledge Jr., George W.

Article Type: Research Article

Abstract: All research is subject to bias that may systematically distort results. Though over 50 types of bias in analytical research have been identified and many classification schemes proposed, this review focuses on the special problem of selection bias in clinical trials. We demonstrate the systematic nature of selection bias in clinical research. We describe the common sources of selection bias in clinical trials including the (inappropriate) use of historical controls, stage migration, inclusion/exclusion criteria, the use of multiple subset analyses, and investigator bias. We then move from the general to the specific, using the recent experience of high dose chemotherapy …for breast cancer as an illustrative example. Finally, we suggest means to avoid falling into the many selection bias traps that often confront clinical researchers. Show more

DOI: 10.3233/BD-2001-14105

Citation: Breast Disease, vol. 14, no. 1, pp. 31-40, 2001

Authors: Partridge, Anne H. | Bunnell, Craig A. | Winer, Eric P.

Article Type: Research Article

Abstract: High-dose chemotherapy with autologous stem cell support for the treatment of breast cancer can have a profound effect on patients’ quality of life (QOL). This article reviews findings from studies assessing QOL before, during, and after high-dose chemotherapy. The impact of high-dose therapy on overall QOL and specific aspects of QOL including physical functioning, symptoms, psychosocial/emotional and cognitive functioning, sexual functioning, and role functioning is considered. High-dose chemotherapy with stem cell transplant results in largely transient impairment of overall QOL and physical functioning, with subsequent improvement to baseline or better over time. Despite these encouraging global QOL findings, many patients …continue to suffer considerable symptoms and concerns attributable to their transplant long after completion of the therapy. Additional research in this area is needed to optimize QOL for patients receiving high-dose chemotherapy. Show more

DOI: 10.3233/BD-2001-14106

Citation: Breast Disease, vol. 14, no. 1, pp. 41-50, 2001

Authors: Elias, Anthony D.

Article Type: Research Article

Abstract: Dose intensification of particular chemotherapy agents can produce high, complete and overall response rates in women with locally advanced or metastatic breast cancer. High dose chemotherapy with stem cell rescue is currently a controversial strategy, not only as a component of the standard of care, but even as an investigative field. This review covers the preclinical and clinical underpinnings of high dose therapy for breast cancer, including selected phase II trials and the phase III trials reported to date in both metastatic and locally advanced breast cancer. Proof of principle for the clinical utility of this approach requires …further maturation of data and completion of ongoing randomized trials. Nonetheless, the clinical results are sufficiently compelling to support ongoing research and grants, particularly in the effort to develop multicycle high dose approaches and to integrate new agents and new modalities, such as immunotherapy, into the framework of high dose therapy. Show more

Keywords: Breast Cancer, hematopoietic stem cell support, transplant, high dose chemotherapy, review

DOI: 10.3233/BD-2001-14107

Citation: Breast Disease, vol. 14, no. 1, pp. 51-68, 2001

Authors: McCarthy, Nicole | Kasten-Sportès, Claude | Gress, Ronald E.

Article Type: Research Article

Abstract: High risk and metastatic breast cancer remain a major therapeutic challenge. Although the role of high dose chemotherapy followed by stem cell transplantation (SCT) in the overall treatment strategy is not yet well defined, it is clear that new forms of therapy such as immunotherapy will be needed to cure the majority of patients with advanced disease. We review important considerations for immunotherapy in the post-transplantation period. Experimental and clinical data suggest that immunotherapy may be most effective in a state of minimal residual disease such as that achieved following SCT. However, high dose therapy and autologous SCT result …in an iatrogenic immune deficiency, which compounds the suppression of the immune system associated with tumor itself. Understanding reconstitution of a functional immune system post transplantation is critical in devising clinically effective immune interventions. A review of the clinical studies of post transplant immunotherapy for breast cancer is presented including autologous and allogeneic strategies, as well as perspectives for future development. Show more

DOI: 10.3233/BD-2001-14108

Citation: Breast Disease, vol. 14, no. 1, pp. 69-79, 2001

Authors: Norton, Larry

Article Type: Research Article

DOI: 10.3233/BD-2001-14109

Citation: Breast Disease, vol. 14, no. 1, pp. 81-89, 2001

Authors: Armstrong, Deborah K. | Davidson, Nancy E.

Article Type: Research Article

Abstract: 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. Show more

DOI: 10.3233/BD-2001-14110

Citation: Breast Disease, vol. 14, no. 1, pp. 91-97, 2001