Pros and Cons of Different Approaches to Chemoradiation

BOSTON—Various approaches to chemoradiation therapy for breast cancer offer advantages and disadvantages, and the challenge remains to choose the approach that best matches a patient’s 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 Harvard’s 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 delayed group.

Sandwich Therapy

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.”

No Differences?

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 doesn’t make any difference how long it takes to give chemotherapy.”

Concurrent Therapy

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 patient’s 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. Recht’s 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.