Abstract & Commentary
Synopsis: Pathologic margin status is arguably the most important factor in patient selection for breast conservation. Terms used to describe margin status vary, and tend to be left to the discretion of the treating physician. Although most people can agree on what a negative margin is, there are no set definitions for close or involved margins. It is the latter, compromised, margins that present a challenge for the treating radiation oncologist who wishes to achieve durable local control. This study at Thomas Jefferson University Hospital could not show a dose-response effect in their group of patients with a positive surgical margin treated to high doses.Source:DiBiase SJ, et al.Int J Radiat Oncol Biol Phys. 2002;53:680-686.
Dibiase and colleagues performed a retrospective analysis of stage I and II breast cancer patients treated with breast conservation surgery and radiotherapy from 1978-1994 in order to determine whether higher doses of RT are effective in lowering the risk of ipsilateral breast tumor recurrence (IBTR) in patients with positive margins. Among 733 patients treated, 641 had margin status data available. There was no attempt to achieve clear margins at the time of initial biopsy. Following a later re-excision and axillary dissection, the resection cavity bed was shaved "as if peeling an onion from the inside out." Surgical margins were declared positive if any tumor was found in the shaved margin biopsy. Twenty percent of patients (n = 132) were deemed to have positive margins by this method.
All patients received 45 Gy to the ipsilateral breast with 6MV photons via an opposed tangential field technique prescribed to the 90% isodose envelop. This was followed by either an electron boost or an iridium-192 brachytherapy boost. Patients in the low-dose group (n = 592; 92%) received 60-65 Gy while those in the high- dose group (n = 49; 8%) received 65-76 Gy. There were 213 patients who were boosted with electrons, and 428 who underwent a brachytherapy boost. Median boost dose was 20 Gy. Among the positive margin patients, 105 were in the low-dose group and 27 were in the high-dose group. Fifty-eight percent of the positive margin patients were boosted with Ir-192, and the rest received an electron boost. One quarter of all patients in the study received adjuvant chemotherapy, with no difference between the positive and negative margin groups. Seventeen percent of all patients received tamoxifen, but no P values were provided.
Median follow-up was 52 months (r, 2-154 mos). Local recurrence was scored as a tumor of the same histology and quadrant as the index lesion. The actuarial 5 and 10-year local control rates for all patients with negative margins were 94% and 88%, compared with 85% and 67% for patients with positive margins (P = .001). Disease-free and overall survival rates were also statistically significantly better in the negative margin group. As one might anticipate, there was no difference in the local recurrence rate between patients with negative margins who received high vs. low doses of RT (P = .34). In the positive margin group, 15/105 patients (14%) in the low-dose group had a local recurrence, while 3/27 in the high-dose group (11%) developed local recurrences (P = .67). Of the 3 high-dose recurrences, 1 patient in the 65-66 Gy range recurred, and 2 recurred after doses of 70-71 Gy. Eleven patients received 66-67 Gy, 14 received 70-71 Gy, and 1 got 76 Gy.
Multivariate analysis showed that stage and margin status were significant factors in determining local control. DiBiase et al concluded that doses beyond 65 Gy are ineffective at overcoming the adverse influence of positive surgical margins. They recommend that patients with positive margins undergo re-excision to obtain clear margins before adjuvant radiotherapy is administered.
Comment by Edward J. Kaplan, MD
While the Thomas Jefferson University Hospital experience engenders some factors which are peculiar to their program, it also highlights many issues that we all must consider when evaluating a patient for adjuvant radiotherapy following breast conservation surgery. The "onion peeling" resection cavity biopsy technique sounds a bit idiosyncratic, and the dichotomous positive/negative margin descriptions neglect the fine points of margin evaluation alluded to above, such as close and focally positive margins. We really don’t know what the exact final margin status was for the patients declared to have positive margins. It seems likely that some number of patients actually had close margins and not focally positive margins, though after reading the paper it is probably safe to say that none had grossly involved margins. Most centers do make some effort to extirpate the whole lesion at the time of initial biopsy, rather than go back a second time as DiBiase et al almost always did. I would also suggest that patients boosted with the 2 different techniques may not achieve identical results. Low-dose rate brachytherapy boosts are not very widely practiced, and, in fact, DiBiase et al did not disclose the breakdown for the high- and low-dose groups by boost style.
Even though the numbers of patients in the study sound impressive, what this paper is really about is the 27 patients with positive margins who received high doses of adjuvant RT. A median follow-up of just more than 4 years for the entire group is on the low side based on the findings presented in similar papers, where it has been suggested that RT might delay and not prevent local recurrences. And with only 3 recurrences in this small group, it seems like it would be difficult to draw any meaningful conclusions.
Freedman et al from Fox Chase Cancer Center looked at their experience with 1262 stage I and II patients treated from 1979-1992.1 They delivered 60 Gy to patients with negative margins, 64 Gy to patients with close margins (< 2 mm), and 66 Gy to patients with positive margins. At 5 years, there was no significant difference in the incidence of IBTRs, but at 10 years patients with positive margins had a 12% cumulative LR rate and those with close margins had a 14% cumulative recurrence rate compared to 7% for patients with negative margins (P = .04). Obedian and Haffty from Yale evaluated 871 patients with a median follow-up of 13 years who were treated from 1970-1990.2 Median dose was 64 Gy. Local control rates were 98% for patients with negative (n = 278) and close margins (< 2 mm; n = 47), and 82-83% for patients with indeterminate or positive margins. Unlike Freedman’s paper, the Yale group concluded that close margins were equivalent to negative margins in local control potential. The group from the Joint Center in Boston reviewed available slides for 533 patients with early stage breast cancer treated from 1976-1987 with a median follow-up exceeding 10 years.3 Their definition of a focally positive margin was one which contained tumor in < 3 low power fields, and close margins were < 1 mm. Doses ranged from 60-72.5 Gy. For patients with either negative or close margins, the LR rate was 7%. For patients with extensively positive margins, the LR rate was 27%. Patients with focally positive margins had an intermediate LR rate of 14%. There was no observable trend for the risk of LR among patients with margins from 0.1 to > 5 mm. Interestingly, they found that patients with focally positive margins who received adjuvant chemotherapy had a LR rate identical to those patients with negative or close margins, ie, 7%. This was not addressed in the Thomas Jefferson paper, and neither was the potential confounding factor of young age. It is well known that younger women have higher LR rates, even with clear margins.
For the time being, I feel comfortable recommending postoperative radiotherapy for patients with negative, close, and focally positive margins. Those with extensively positive margins should undergo reexcision or submit to mastectomy. Meanwhile, results from the EORTC 22881/10882 boost vs. no boost trial are pending. There were 5569 patients with early breast cancer who received 50 Gy in 20 fractions following lumpectomy. Patients with clear margins were randomized to no boost vs. 16 Gy, and those with "microscopically incomplete resections" were randomized to 10 Gy vs. 25-26 Gy. Three-year follow-up results on cosmetic outcome have been published,4 and now we have to wait for the local recurrence data to mature. Unfortunately, the DiBiase et al study does not add much to our knowledge base, but it does serve to keep us focused on the question at hand.
Dr. Kaplan is Acting Chairman, Department of Radiation Oncology, Cleveland Clinic Florida, Ft. Lauderdale; Medical Director, Boca Raton Radiation Therapy Regional Center, Deerfield Beach, FL.
1. Freedman G, et al. Int J Radiat Oncol Biol Phys. 1999; 15:1005-1015.
2. Obedian E, Haffty BG. Cancer J Sci Am. 2000;6:28-33.
3 Park CC, et al. J Clin Oncol. 2000;18:1668-1675.
4. Vrieling C, et al. Radiother Oncol. 2000;55:219-32.