XRT to Prevent Local Breast Cancer Recurrence: A Little More is Better
Abstract & Commentary
Synopsis: The European Organization for Research and Treatment of Cancer (EORTC) has been examining the effects of an additional dose of 16 Gy beyond the typical 50 Gy to prevent local breast cancer recurrence in women with Stage I or II disease after breast conserving surgery and axillary node dissection. Although it is likely to take several more years to demonstrate a survival advantage for those who received the additional dose, analysis at 5 years demonstrates a clear advantage with regard to local recurrence. The boost dose was not associated with additional toxicity.
Source: Bartelink H, et al. N Engl J Med. 2001;345: 1378-1387.
There is well-established evidence that breast irradiation reduces the rate of local recurrence after breast conserving surgery for cancer. The standard dose of irradiation—50 Gy—has not been examined in a large, randomized trial. Bartelink and colleagues report the results of an EORTC trial in which patients with Stage I or II breast cancer after lumpectomy and axillary node dissection were treated with either conventional dose radiation or conventional dose with an additional boost of 16 Gy given in 2 Gy fractions.
During a median follow-up of 5.1 years, local recurrences were observed in 182 of the 2657 patients in the standard treatment group and 109 of the 2661 patients in the additional-radiation group. The 5-year actuarial rates of local recurrence were 7.3% (95% CI, 6.8-7.6) and 4.3% (95% CI, 3.8-4.7) (P = 0.001), yielding a hazard ratio for local recurrence of 0.59 (95% CI, 0.43-0.81) associated with an additional dose. Local recurrence was greatest in patients younger than 40 years of age, and in this group the beneficial effects of the additional dose of radiation were most significant. For this group, the rate of local recurrence was 19.5% with standard treatment and 10.2% with additional radiation (hazard ration, 0.46 [99% CI, 0.23-0.89], P = 0.002). There was no observed increased local toxicity produced by the added dose of radiation.
This study was powered to detect a difference in survival at 10 years, but, upon review of the data at 5 years, the difference in local recurrence was clearly significant. However, at 5 years, survival free of distant metastases and overall survival were similar in the 2 treatment groups, with rates of 87% and 91%, respectively. Thus, it is too early to conclude whether the additional radiation will result in improvement in these important outcomes.
Comment by William B. Ershler, MD
The B-06 trial of the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated that after microscopically complete excision, irradiation to the whole breast with a dose of 50 Gy reduced the rate of local recurrence from 35% to 10%.1 Since then, the 50 Gy dose has become the standard prescribed treatment. One purpose of the EORTC trial was to establish whether radiation beyond that dose would achieve even better results, and whether it could be accomplished without additional toxicity. Analysis at a median of 5 years post-therapy reveals positive findings. There is clearly less local recurrence with the added boost, and this with no added toxicity. There was approximately 40% less local recurrence in those receiving additional therapy.
Upon rigorous statistical analysis, Bartelink et al found that the groups at highest risk for local recurrence were, as expected, the ones most likely to benefit from the additional therapy. Included were young women (40 years and younger), in whom local recurrence rates dropped from nearly 20% to approximately 10%. Similarly, other risk factors, such as size of the primary, axillary node involvement and ER/PR status, were predictive of subgroups most likely to benefit from the boost.
As time passes, we will be learning more from this large and well-constructed EORTC trial. If it turns out that disease-free and overall survival are similarly enhanced by this additional therapy, it will not take long before standard radiation approaches after lumpectomy are adjusted upward. Certainly, local recurrences were not diminished to zero, and with the lack of additional short- or long-term toxicity with the added boost, investigators will be tempted to examine even higher doses or schedules.
Short of the survival data, however, is there enough here to change the standard 50 Gy approach? The only marginal improvements seen in those older than 50 years of age, and particularly in postmenopausal women with ER/PR positive tumors, when balanced with the added expense and inconvenience of 8 additional treatments would suggest that universal recommendations should not be applied. Furthermore, enrollment of patients older than the age of 70, which is approximately the median age of breast cancer in the United States, was not allowed in this trial. For these older patients, there will remain no data that would support additional therapy.
On the other hand, for young patients, with or without other negative prognostic factors, this study would support an additional boost of adjuvant XRT after lumpectomy. Even if later data indicate no improvement in overall survival, the reduction in local recurrence and the prevention of the need for salvage therapy would make such an approach worthwhile.
Reference
1. Fisher B, et al. N Engl J Med. 1995;333:1456-1461.