BOSTONVarious approaches to chemoradiation therapy for
breast cancer offer advantages and disadvantages, and the challenge
remains to choose the approach that best matches a patients
characteristics, Harvard University radiation oncologist Abram Recht,
MD, said at a minisymposium at the San Antonio Breast Cancer conference.
The objectives of combined-modality therapy are to minimize the
risk of locoregional failure and simultaneously minimize the risk of
sys-temic failure, said Dr. Recht, associate professor at
Harvards Joint Center for Radiation Therapy. At the same
time, we hope to avoid interactions between treatment modalities that
might interfere with these goals. We also wish to avoid interactions
that might worsen the cosmetic outcome or increase the complication rate.
It may or may not be possible to do all these things simultaneously,
he said, and we might have to make tradeoffs. Clearly, trying
to do all these things at once is not a trivial problem.
Dr. Recht briefly reviewed the pros and cons of four approaches to chemoradiation:
Radiation therapy followed by chemotherapy.
Chemotherapy followed by radiation therapy.
Sandwich therapy, with radiation therapy administered between
two courses of chemotherapy.
Concurrent chemotherapy and radiation therapy.
Until recently, relatively few data existed to define the role
of sequential combined-modality therapy, he said. One
noteworthy study (N Engl J Med 334:1356-1361, 1996) provided
some of the first evidence of what we might have expected intuitively.
A total of 244 patients were randomized to receive radiation therapy
and then chemotherapy following breast-conserving surgery and
axillary node dissection, or to receive the same chemoradiation
combination, beginning with chemotherapy.
At 5 years of follow-up, patients who received radiation therapy
first had a lower rate of local failure (5% vs 14% in patients who
received chemotherapy first), but a higher rate of systemic failure.
Analysis of factors associated with local failure identified surgical
margin status as the most important predictor.
If margin status was unknown, early radiation therapy was
associated with no local failures, compared with a 20% rate in
patients who had delayed irradiation.
If margins were positive, the failure rate was 14% with
early irradiation and 26% with delayed irradiation.
If margins were uninvolved but close (within 1 mm of the
specimen edge), early radiation therapy was associated with no
failures, compared with 13% in patients who had delayed irradiation.
Negative margins provided somewhat confounding data: two
failures in the group who received early irradiation vs none in the
The practice of sandwich, or split-course, chemotherapy has raised
some concerns about the wisdom of interrupting drug therapy.
Unfortunately, few data exist on either side of the issue. There
are no data showing it is actually a problem, Dr. Recht said.
In fact, there are some data suggesting it might not be a problem.
A study reported by the International Breast Cancer Study Group
randomized patients to three groups: (1) three cycles of CMF, (2) six
cycles of CMF delivered continuously over 6 months, or (3) six cycles
of CMF given in split courses of three cycles each over 12 months.
Five-year disease-free survival showed slight improvement with six
cycles vs three but no difference according to whether the six cycles
were given over 6 months or 12 months.
I think it brings home the fact that we know very little about
how the kinetics of tumor growth should impact our treatments,
Dr. Recht said. The idea of dose-dense chemotherapy has been
designed to overcome problems at a very early point, but it may be
that many, if not most, breast cancers proliferate relatively slowly,
so that it doesnt make any difference how long it takes to give chemotherapy.
Concurrent chemotherapy and irradiation has attracted increasing
interest, especially for patients who have locally advanced or
early-stage breast cancer. The availability of drugs such as
paclitaxel [Taxol] and mitoxantrone [Novantrone], which might lend
themselves to concurrent therapy better than a drug such as
doxorubicin, also has helped stimulate interest in concurrent
therapy, he said.
By starting chemotherapy and radiation therapy soon after surgery,
you might get some synergistic effect, Dr. Recht said.
A subtle but important point is that it might allow you to
avoid treatment breaks between therapy cycles.
From the patients point of view, concurrent therapy shortens
the overall length of a treatment program, which might be an
acceptable tradeoff for the potentially increased acute toxicity, he noted.
A review of different chemoradiation strategies employed at the
Joint Center showed no difference in the rate of local failure
following breast-conserving surgery whether radiation preceded
chemotherapy, whether a sandwich strategy was employed, or whether
chemotherapy and irradiation were given concurrently, Dr. Recht said.
However, patients who had four or more positive lymph nodes and
factors associated with poor prognosis predominantly started with
chemotherapy. Those patients had a much higher rate of local failure,
consistent with the concept that early irradiation reduces the risk
of local failure.
Sequential May Be Preferred
Dr. Rechts own preference for patients who have
breast-conserving surgery is to give chemotherapy and radiation
therapy sequentially, rather than concurrently, except for patients
enrolled in clinical studies that are carefully designed to minimize toxicity.
In patients who have microscopically negative margins (tumor-free
margin width greater than 1 mm), radiotherapy probably can be given
safely after 12 to 24 weeks of chemo-therapy, Dr. Recht said,
although he admits to being still a little nervous about
waiting to start radiation until after the prolonged chemotherapy
programs. Starting radiation therapy 16 to 20 weeks after the
last breast surgery should result in a low risk of local failure,
even in patients with close margins.
For some patients who have microscopically positive margins,
concurrent therapy might be worth the toxicity for patients who have
conservative surgery. Alternatively, mastectomy might be considered.