NEW YORKThe 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
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
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 its 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.
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.
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. Paclitaxels
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.