Opportunities and Challenges Mark New Era of Adjuvant Breast Cancer Therapy

NEW YORK—The field of adjuvant therapy for breast cancer has entered an era marked by great opportunities and challenges.

The opportunities lie in the potential of new therapeutic agents, new combinations and dosing strategies, and the continued evolution of biologic therapies.

The challenges reside in the unanswered questions related to optimal use of individual agents and combinations, New York oncologist Dr. Larry Norton said at a satellite meet-ing held in conjunction with the San Antonio Breast Cancer Symposium and sponsored by Bristol-Myers Squibb.

‘Future Looks Bright’

“We still have lots of room for improvement,” said Dr. Norton, head of the Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer. “However, at this point, I think the future of adjuvant therapy looks quite bright.”

The research and practice of adjuvant therapy have progressed fairly rapidly. Dr. Norton pointed out that the first clinical trial of adjuvant chemotherapy began in 1958.

“In the view of many oncologists, the modern era of adjuvant therapy began a little over two decades ago with the first clinical evaluation of L-PAM [melphalan] and then the CMF regimen,” he said.

Until recently, CMF (cyclophosphamide, methotrexate, and fluorouracil) represented the standard for adjuvant chemotherapy, and the com-bination has remained the most widely used adjuvant regimen.

“Many of us have been in this business for so long that we forget what a short history adjuvant therapy has. This is a very, very young field,” Dr. Norton said.

The development of new cytotoxic agents has built upon the 25% reduction in risk of recurrence afforded by CMF. For example, the addition of anthracyclines to CMF improved risk reduction by another 12%. The addition of paclitaxel (Taxol) to the combination of doxorubicin (Adriamycin) and cyclophosphamide (AC) results in a further 22% reduction in the risk of recurrence and a 21% reduction in mortality risk.

The benefits of adding paclitaxel “are over and above what you get with AC, which is added to what you get with CMF, which provided the initial benefit over giving nothing at all,” Dr. Norton said. “Essentially, we have had a doubling of the CMF effect.”

Despite advances in adjuvant therapy, questions remain about the role of individual agents, which ones to use and how. Dose escalation, though widely used in strategies involving high-dose chemotherapy, remains largely unproven.

“The fact that high-dose chemotherapy is used so widely off-study in the United States is remarkable, being that there is no randomized evidence yet to support that very toxic and sometimes fatal therapy,” he said.

Role of Dose Escalation

The role of dose escalation has been muddied recently by evidence that “it’s not just a matter of giving more drug to kill more cells, but it might actually relate to the kinds of cells being treated,” Dr. Norton said.

He pointed to a CALGB (Cancer and Leukemia Group B) evaluation of FAC (fluorouracil, doxorubicin, cyclophosphamide), showing that higher doses of doxorubicin appeared to provide greater benefit. However, closer inspection of the data showed that the benefit was limited to patients who overexpressed the HER-2 gene.

The role of dose escalation is further confounded by imprecise terminology. Dose intensity, Dr. Norton said, is the number of milligrams per square meter of drug. “If you give 60 mg/m² of doxorubicin, that is dose intensity as compared to 40 mg/m²,” he said.

But, in fact, he said, not only the total amount of drug given must be considered but also the amount of time over which it is given.

“We coined the term dose density to distinguish dose escalation by drug intensity (giving more drug) from dose escalation by shortening the duration over which the drug is given,” Dr. Norton said.

The concept of dose density evolved in response to mathematical models suggesting that recurrence is linked to regrowth of cancer cells between cycles of therapy, he said. Shortening the interval between cycles should help minimize this regrowth.

Sequential Therapy

The order or sequence of drug combinations may also influence outcome. In an ongoing Intergroup trial coordinated by investigators from CALGB, both sequence and dose density are being evaluated. The trial, which was expected to complete patient accrual in March, will evaluate the combination of doxorubicin and cyclophosphamide, followed by paclitaxel.

One group of patients will repeat therapy every 3 weeks, while another group will receive therapy on a 2-week schedule, aided by growth factor support. Within each treatment arm, a second randomization will take place, so that half the patients in each arm will receive doxorubicin, followed by paclitaxel, followed by cyclophosphamide.

A pilot study of a similar regimen given on a 2-week schedule resulted in disease-free status in 80% of very high risk patients after 3.5 years (Semin Oncol 23:58-64, 1996).

Another investigation will evaluate weekly paclitaxel given with a conventional AC regimen. Dr. Norton said that some evidence suggests weekly administration of the taxane reduces toxicity without adversely affecting antitumor activity.

Patients in the trial also will be randomized to receive Herceptin with paclitaxel, and they will be randomly assigned to receive the cardioprotective agent dexrazoxane (Zinecard) with the AC regimen.

Data accumulated from studies to date suggest that “dose density and sequential therapy have been a victory, if we use the right agents,” Dr. Norton commented. “It looks like these strategies work with a number of different agents. Paclitaxel’s effectiveness makes it particularly attractive to use in this way.”

On the horizon, work continues toward development of vaccines, agents and strategies for biologic modulation, and improved hormonal therapies. New and potentially more effective therapies should continue to evolve from improved knowledge of the biology of breast cancer, Dr.Norton concluded.