SAN ANTONIOIs adjuvant radiotherapy necessary for all breast cancer patients undergoing breast-conserving therapy? Prospective, randomized studies from the NSABP indicate that it is, Norman Wolmark, MD, said in a minisymposium held in conjunction with the San Antonio Breast Cancer meeting.
But based on a retrospective study from The Breast Center, Van Nuys, Calif, incorporating the Van Nuys Prognostic Index, Melvin Silverstein, MD, believes there is a DCIS subset that can safely forgo radiotherapy.
Dr. Wolmark, of the the University of Pittsburgh and chairman of the NSABP, said that a randomized prospective NSABP trial, B-21, designed to determine whether tamoxifen(Drug information on tamoxifen) (Nolvadex) could replace radiotherapy in women with very small, noninvasive tumors, has had "abysmal" accrual, because US physicians don't want to give up radiotherapy.
Until such trials are completed, Dr. Wolmark recommends basing treatment on data from the B-17 protocol, which randomized 818 patients to lumpectomy alone (with free margins) or lumpectomy plus radiotherapy to the ipsilateral breast. To date, these patients have been followed for an average of 7.5 years.
The most recent analysis continues to show that "radiotherapy significantly and unequivocally reduces the incidence of subsequent ipsilateral noninvasive and invasive cancer," Dr. Wolmark said.
He noted that in this study, tumor size did not predict for recurrence. Margin status and comedo necrosis were independent prognostic discriminants, but in patients with uninvolved margins who received radiotherapy, comedo necrosis did not increase the risk of ipsilateral tumor recurrence. In other words, he said, the addition of radiotherapy wipes out comedo necrosis as a prognostic discriminant when margins are not involved.
"It is fine to hypothesize about possible biologic interactions that could identify a subset of patients who do not benefit from radiotherapy," he said, "but we must not be deterred from using randomized prospective trials to answer the very basic questions relative to DCIS."
Dr. Silverstein, director of The Breast Center at Van Nuys, maintained in his talk that "subset analysis is important." He noted that B-17 was designed to show only whether radiotherapy "works" in preventing recurrence in DCIS. "It does work," he said, "but now we want to know which patients it works in, how well it works, and if there are patients who don't need radiation."
In his series, 418 DCIS patients treated with excision alone (219) or excision plus radiotherapy (199) have been followed for almost six years, with data projected to seven years. "These patients are highly selected and nonrandomized; they chose the treatment they wanted," he said.
There have been 66 local recurrences in the breast to date, 95% at or near the primary cancer. "This hammers home the point that, in all likelihood, these patients were inadequately excised," he said. Of these recurrences, 45% were invasive, with five distant metastases, "much more than I would like."
To do a subset analysis, the researchers reviewed 30 prognostic factors; by multivariate analysis, only three were found to be significant: tumor size, margins, and the Van Nuys classification, made up of two biologic markers, comedo necrosis and nuclear grade.
In this system, lesions are classified as group 1 (low or intermediate grade, no comedo necrosis), group 2 (low or intermediate grade, with comedo necrosis), and group 3 (high grade with or without comedo necrosis).
The cases were then divided by size and margins into groupings that "made statistical sense and gave three different outcomes," Dr. Silverstein said. Tumors 15 mm or less were designated small; 16 to 40 mm, intermediate; and 41 or more, large. Margins of 10 mm were considered wide; 1 to 9 mm, intermediate; and 1 mm, narrow.
They then devised a simple for-mula, assigning a score for histopathologic classification (1 point for group 1, 2 points for group 2, and 3 points for group 3); tumor size (1 point for small, 2 for intermediate, and 3 for large); and margins (1 point for wide, 2 for intermediate, and 3 for narrow). "So the best a tumor can be scored is 3 and the worst is 9," he said.
The Van Nuys series, scored by this system, broke down into three statistically significant groups: Those with a score of 3 to 4 had a very low recurrence rate; those with a score of 5 to 7 had an intermediate recurrence rate; and those scoring 8 to 9 had a high recurrence rate.
The most important point, Dr. Silverstein said, is that among the 119 patients who scored between 3 and 4, outcome did not differ significantly whether or not they received radiotherapy. Among the 259 patients who scored 5 to 7, radiotherapy decreased the local recurrence rate by 13%.
In the high-risk group scoring 8 to 9 on the index, five-year local recurrence rates were very poor: 60% with radiation and 100% without.
Dr. Silverstein noted that the data need to be prospectively verified, but he believes a simple guideline can be derived from these results, namely: For a score of 3 to 4, consider excision only; for a score of 5 to 7, consider excision plus radiotherapy; for a score of 8 to 9, consider mastectomy.
Thorough Tissue Processing
Dr. Silverstein emphasized that to use the Van Nuys Prognostic Index, researchers must process the tumor tissue in the same thorough manner as is done at The Van Nuys Breast Center. In their protocol, stereotactic core biopsy is performed first to determine malignancy, and he calls this the key to complete excision. "If you know the diagnosis, then you're not afraid to be aggressive in the amount of tissue you remove," he said.
Typically, four wires are used to bracket the entire lesion (see below), which is then removed with a wide excision. Hemoclips are placed on the specimen, and multiple view specimen radiograms are taken to determine that the margins are clear. The specimen is then color coded on all six surfaces and sectioned at 2 to 3 mm intervals. Such thorough sectioning is necessary to determine the true size of the tumor and to rule out the presence of microinvasion.
In answer to a question from the audience, Dr. Silverstein acknowledged that this type of pathology processing is expensive, running about $300 to $400 per case, and is becoming financially more difficult to do in the managed care era.
Dr. Wolmark added that implementing the Van Nuys protocol in today's environment "would be an enormous task," but, he said, if the value of the Van Nuys system were confirmed in a randomized, prospective trial, "I think we would find a way to implement all the techniques necessary to support that approach."
At present, however, in Dr. Wolmark's opinion, this approach remains a hypothesis that "cannot be recommended as a universal algorithm for the treatment of DCIS, particularly since it is not concordant with the findings of the NSABP."