CHICAGO—Results from two published prospective randomized clinical trials of women with ductal carcinoma in situ (DCIS) show that radiotherapy after wide excision reduces local recurrence by 7% to 15%, said Melvin J. Silverstein, MD, who does not believe radiotherapy is suitable for all women with this form of breast disease.
“My reputation is that I don’t want to give radiotherapy to anybody. That’s not true; I give it to a lot of people. I just don’t want to give it to everybody,” he said at the Second Annual Lynn Sage Breast Cancer Symposium, sponsored by Northwestern University Medical School.
Dr. Silverstein, professor of surgery, Keck School of Medicine, University of Southern California, and director of the Harold E. and Henrietta C. Lee Breast Center, Los Angeles, noted that radiotherapy is expensive, inconvenient for patients, and confers only a slight benefit in some subgroups of patients.
Radiotherapy also is a one-shot intervention. “If you give radiotherapy for DCIS and get an invasive recurrence, you can’t give it again. If you don’t give it initially and get an invasive recurrence, you can re-excise and irradiate,” he said.
He noted that radiotherapy complicates the performance of skin-sparing mastectomy for invasive recurrence. “Doing a skin-sparing mastectomy is more difficult because you have vascular changes secondary to irradiation,” he said.
Finally, the most compelling reason not to use radiotherapy for all patients with DCIS, he said, is that the prospective randomized trials have not shown a benefit in the single most important endpoint, breast cancer mortality, regardless of treatment. “Why give an expensive, time-consuming, potentially harmful treatment when there is no proven survival benefit?” he asked.
Since 1995, Dr. Silverstein and his colleagues have been trying to devise a reproducible scheme to select women who might be able to avoid radiotherapy after excision of DCIS. After testing more than 30 histologic factors, they settled on tumor size, margin width, and pathologic classification (based on nuclear grade and comedo-type necrosis) as the basis for the Van Nuys Prognostic Index (VNPI).
In an observational study of 560 patients who underwent breast-conserving procedures, there was little or no local recurrence after wide excision in 163 women with DCIS who had small, well-excised, low-grade tumors and therefore low VNPI scores of 3 or 4. The finding suggested that these women might be treated with excision alone.
Although women with large, high-grade lesions with close margins and higher VNPI scores achieved the greatest benefit from radiotherapy, there still was a 50% local recurrence rate, suggesting that these patients might be better managed by re-excision or mastectomy, he said.
Dr. Silverstein stated that complete tissue processing and 3D reconstruction of the lesion were used to determine tumor size and that this was difficult to reproduce from lab to lab. He, therefore, decided that the distance between DCIS and the closest inked margin was the most reproducible aspect of the VNPI and could be used by itself as a surrogate marker. In one observational study, Dr. Silverstein found a very small benefit from radiotherapy for 174 patients with margins of 10 mm or greater. In addition, there was no difference in local recurrence rates between younger and older women with margins of 10 mm or more.
Based on these data, Dr. Silverstein feels that the most important cause of local failure is inadequate excision. He asked, “Is radiotherapy required for all cases of breast preservation? I don’t think so. The key to the future is to figure out which lesions will become invasive and to treat them more aggressively.”
Lawrence Wickerham, MD, associate director of the NSABP (National Surgical Adjuvant Breast and Bowel Project), acknowledged that Dr. Silverstein’s experience with single center studies has yielded promising findings. “Although we can’t say it is wrong, it is hard to say that it is absolutely correct. Observational studies, if conducted meticulously, are appropriate for generating hypotheses. However, they are fraught with methodological bias that can skew results,” Dr. Wickerham said.
The greatest potential bias arises from the use of historical controls or control patients who were not treated concurrently. “To be effective, historical controls have to be the same as the experimental group—the same diagnosis, patient characteristics, and evaluation,” he said. “That is extremely difficult to do in this country, because medical care gets better, and patients change.”
He cited improvements in mammography that have led to earlier breast cancer diagnosis and pointed to bone marrow transplant for breast cancer to show the problem of using historical controls. “The enthusiasm for bone marrow transplants was the result of comparisons with historical controls. That enthusiasm has diminished as randomized clinical trial results have become available,” he said.
Dr. Wickerham stressed that the results of recent randomized clinical trials of treatment for DCIS support radiotherapy as an adjunct to excision. After 8 years of follow-up, NSABP B-17 revealed a 5% significant difference in the rate of noninvasive disease for patients who received radiotherapy. Studies of various segments of the patient population were unable to find any group of women who would not benefit from radiotherapy, regardless of margin or histologic subtype.
“The risk of ipsilateral breast tumor recurrence is incredibly small in a group of 100 patients who have low-grade lesions that are excised widely. But if you have one woman with this disease, her risk is either zero or 100%. Based on the information I have today, I would feel that offering her radiotherapy increases her chances of being in that zero-risk group,” Dr. Wickerham said.
