New Approaches in the Management of Breast Cancer
New Approaches in the Management of Breast Cancer
The 3rd Investigators’ Workshop, sponsored by The University of Texas M. D. Anderson Cancer Center, included five separate scientific sessions. The topics covered were colorectal carcinoma, lung carcinoma, breast carcinoma, miscellaneous tumors including lymphomas, and novel uses of topoisomerases, including enhancement of radiation-induced cytotoxicity.
Three publications are intended as a result of the workshop, held on July 13-16, 2000, in St. Croix, US Virgin Islands. This volume is devoted to breast malignancies, and includes discussions of chemotherapeutic regimens, hormonal therapy, and novel delivery of therapeutic agents. The first volume that was published in March 2001 was devoted to gastrointestinal malignancies. Volume 3 will be published in summer 2001, and it will cover novel agents in lung and other malignancies.
The purpose of these annual workshops is to review the latest data on new agents, with a particular focus on the broadly used agent irinotecan (CPT-11, Camptosar). Investigators from around the world are invited to present current research. The forums are highly interactive and frank, thus allowing exchange of new ideas and directions. In addition to stimulating research, another purpose of these workshops is to develop enduring material for wider distribution to those who did not attend this workshop. This and the other volumes described above are intended to fulfill that mission.
Trials and Trends Reviewed
In this volume, Maureen Trudeau discusses the design and rationale of the soon-to-be-initiated MA.21 phase III, randomized study of adjuvant chemotherapy. The study compares two standard therapies: CEF (cyclophosphamide [Cytoxan, Neosar], epirubicin [Ellence], fluorouracil [5-FU]) and AC ® T (doxorubicin [Adriamycin], cyclophosphamide, followed by paclitaxel [Taxol]). A third arm of the study tests dose-dense, dose-intense EC ® T regimen (epirubicin, cyclophosphamide, followed by paclitaxel). Dr. Trudeau reviews the data from previous clinical trials, and offers a perspective on identifying optimal chemotherapeutic regimens based on these data and those expected from the MA.21 study.
Michael Untch and colleagues discuss new chemotherapeutic agents and strategies designed to increase survival following adjuvant therapy (ie, dose intensification and sequential therapy). Results of a multicenter German trial comparing a dose-intense EC regimen with sequential EC and cyclophosphamide/methotrexate/5-FU (CMF) showed increased disease-free survival in the dose-intense arm, but no significant improvement in overall survival at the 2-year mark. Longer follow-up may be required. Other related trials of neoadjuvant therapy with dose-dense and dose-intense chemotherapeutic regimens, plus the addition of new agents such as the humanized monoclonal antibody trastuzumab (Herceptin) are discussed.
Two updates on chemotherapy regimens that incorporate epirubicin are provided by PierFranco Conte and colleagues. In the first paper, the results of their phase I/II study in first-line therapy of the combination of docetaxel (Taxotere) and epirubicin are presented. The authors also discuss an ongoing phase III trial of epirubicin plus paclitaxel in the adjuvant setting, and present preliminary toxicity data. In their second paper, Dr. Conte et al present data from studies of new combinations of anthracyclines and taxanes developed to improve responses to first-line therapy by such means as adding agents with nonoverlapping toxicity and diverse mechanisms of action. The authors’ GET study with gemcitabine (Gemzar)/epirubicin/paclitaxel achieved a relatively high response rate of 92%.
Hormonal strategies are also integral parts of the management of breast carcinoma in both the adjuvant and metastatic settings. James Ingle discusses how new agents, such as aromatase inactivators/inhibitors, are being evaluated in sequence, in lieu of, or in combination with tamoxifen (Nolvadex), the present hormonal agent of choice, to improve the therapeutic index in these settings. His article discusses chemoprevention of breast cancer with tamoxifen and anti-aromatase agents, and provides numerous references. He hypothesizes that estrogen genotoxicity plays a role in breast cancer development, and aromatase inactivators could be employed as chemopreventive agents in patients with high-risk genotypes.
Reviewing the numerous clinical trials of tamoxifen in early-stage breast cancer, Eleftherios Mamounas notes that the majority of data indicate that by 5 years of tamoxifen hormonal therapy, greater proportions of patients may harbor tamoxifen-resistant residual or micrometastatic tumor cells; further hormone treatment might stimulate growth. Dr. Mamounas describes a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial among patients treated for 5 years with tamoxifen. Patients were then randomized to receive either 2 years of exemestane (Aromasin) or placebo to determine whether addition of an aromatase inhibitor (to decrease estrogen stimulation) prolongs survival and time to treatment failure.
Anne Hamilton and Franco Muggia present a discussion of the use of estramustine (Emcyt), a non-nitrogen mustard linked to estradiol, in taxane-refractory breast (and hormone-resistant prostate) cancers. Phase II studies suggest that the combination of estramustine and the taxanes resulted in synergistic activity; however, thromboembolic events occurred in 10% of patients. New approaches to improve the tolerability of estramustine are also discussed.
Joseph Treat and colleagues conclude the volume by discussing liposomal encapsulation of chemotherapeutic agents as a strategy to alter not only the pharmacokinetic profile and attenuate toxicity, but to overcome multidrug resistance. In an amply referenced review, Dr. Treat looks at the rationale and extensive data for liposomal-encapsulated doxorubicin in breast cancer (and other cancers). He also summarizes data for liposomal paclitaxel, and provides an update on his group’s phase I clinical trial with this agent in advanced malignancies.
In conclusion, I believe that the data presented at The University of Texas M. D. Anderson Cancer Center Investigators’ Workshop provide new insights about the trends and practices in various areas of oncology. I hope you, the reader, will find this information stimulating and useful in designing new trials.