An Argument Against Routine Use of Radiotherapy for Ductal Carcinoma In Situ

Why does the debate over the appropriate treatment of ductal carcinoma in situ (DCIS) continue? Three widely publicized multi-institutional randomized trials have addressed this question,[1-4] and all have reached largely the same conclusion. Radiation therapy reduces the risk of local recurrence of DCIS by approximately 50%. Despite this fact, a significant percentage of DCIS patients (50% or more in many settings) in consultation with their clinicians opt to undergo excision alone and forgo radiotherapy. The paper by Silverstein summarizes the argument for this less aggressive approach in a clear and straightforward manner. The major rationale for this position is that several studies from single institutions have clearly shown that the clinical behavior of DCIS is not the same in all cases and that, in many situations, the expected benefit from radiotherapy is quite low. In fact, one of the more remarkable aspects of DCIS is its profound heterogeneity,[5] seen in its pathology, mammographic appearance, and clinical manifestations. Margin Status
The contention of Dr. Silverstein that many cases of DCIS do not benefit from radiation therapy after excision is undoubtedly true and well supported by a large body of evidence. First, the factors involved in local recurrence after excision of DCIS are well known and accepted. These include margin status, grade and pattern of spread, and overall extent of the individual DCIS lesion. Of these, margin status is certainly the most important,[6] but it is also clear from abundant experience that larger, higher-grade lesions with more irregular margins may have spread in ducts that go unnoticed unless excision margins are extended to approximately 1 cm. This means that the lower-grade, smaller lesions that often tend to be remarkably rounded and consist of clustered lobular units and ducts may require less effort at margin determination for excision because the spread of these tumors is more confined and easily detected. Case Definition
Dr. Silverstein raises an important point that has not been addressed specifically in many studies but is borne out by excellent supportive evidence. His point is that larger, high-grade DCIS lesions must be approached quite differently from the smaller varieties.[3] Thus, the major misleading mythology in the treatment of DCIS is that these lesions are all the same. Indeed, it is case definition and its precision that has led some therapeutic studies somewhat astray. For example, the final summary of the important National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 study used mammographic measures to indicate the size of the lesions.[7] At least 30% of the cases were not centrally reviewed in this area of difficult histopathology. Also in this study, the number of local recurrences among cases that had not been irradiated was extremely large-more than 10% at 5 years. This is to be understood against the backdrop of studies with careful case definition and a small number of cases, particularly of low-grade lesions at 5 years without radiation therapy. Thus, it is clear that NSABP B-17 is a study of women who had more than a 10% local recurrence rate with or without radiation therapy, and that experience cannot be compared with studies of carefully defined, smaller lesions in which virtually no local recurrences occurred at 5 and even 10 years after adequate determination of margin status at surgical excision without radiation therapy. We seem to be discussing two kinds of studies: those with careful case definition and individual case follow-up, and those with poor case definition and evaluation of overall therapeutic efficacy. Careful case definition would seem to be more important for large studies that are evaluating therapy, in order to identify patients who do not need treatment. This would seem preferable to showing that the treatment is effective in a certain percentage of cases and then averaging all the cases, including many that did not need the therapy. The design of the other important large, multicenter trial performed in Europe had similar drawbacks, and this trial found some recurrences of highgrade invasive cancers-even some cases with lymph node metastases. Most importantly, the majority, if not all, of these life-threatening local recurrences developed among patients who initially had high-grade DCIS.[3] At this time, we must recognize that case definition and the precise histologic character of excised lesions must be documented.[8] It is also clear from several studies that low-grade lesions may have smaller margins than 1 cm, but the proof of principle for Dr. Silverstein, Dr. Lagios, and their colleagues- that any DCIS excised to a 1-cm margin should have no untoward consequences without radiation therapy-represented a banner moment in this controversy. Conclusions
In summary, thousands of women have been treated for DCIS with surgical excision to negative margins and careful, continued mammographic follow- up. The rates of local recurrence are small (often 0% at 5 to 8 years), particularly among patients with low-grade and smaller lesions (less than 1 to 1.5 cm in size). Also, the rare local recurrences are regularly similar in grade, unless residual disease remains untended for a prolonged number of years.[9] Many centers in North America and Europe are treating one-half or more of their DCIS patients in this conservative manner. The nature and rate of recurrences elsewhere in the treated breast (not in the original segment or quadrant) or in the contralateral breast are less well understood, are analogous to disease in the contralateral breast after a mastectomy, and should be regarded as separate events. In stark contrast, the cases of excised DCIS not treated further by radiation in the large NSABP and European Organization for Research and Treatment of Cancer (EORTC 10853) trials have had local recurrence rates of 10% or more. Although the local recurrences in patients with low-grade lesions probably pose little threat to life, it is also clear that, even with radiation, recurrences of high-grade lesions may be associated with invasive cancer of a life-threatening nature. Clearly, precise case definition including evaluation of margins should be mandatory in individually treated women (as well as in any further trials conducted in this disease). It is also important to detail the size, grade, and invasive nature of local recurrences rather than to simply regard a "local recurrence" as an event not mandating further definition.