Wednesday, September 01, 2004

Our Friend the Atom III.....
Three hits from this weeks New England Journal of Medicine.
The first:Tamoxifen with or without Breast Irradiation in Women 50 Years of Age or Older with Early Breast Cancer

Background We determined the effect of breast irradiation plus tamoxifen on disease-free survival and local relapse in women 50 years of age or older who had T1 or T2 node-negative breast cancer.

Methods Between December 1992 and June 2000, 769 women with early breast cancer (tumor diameter, 5 cm or less) were randomly assigned to receive breast irradiation plus tamoxifen (386 women) or tamoxifen alone (383 women). The median follow-up was 5.6 years.

Results The rate of local relapse at five years was 7.7 percent in the tamoxifen group and 0.6 percent in the group given tamoxifen plus irradiation (hazard ratio, 8.3; 95 percent confidence interval, 3.3 to 21.2; P<0.001), p="0.004)." p="0.049),"

So the disease-free survival rate after five years was 84 percent in the Tamoxifen only group compared to 91 percent in the Tamoxifen+XRT group. Local recurrence was 7.7 percent in the Tamoxifen only group and 0.6 percent in the Tamoxifen+XRT group after five years. These rose to 17.6 and 3.5 percent,respectfully, after eight years. There was a slight increase in ipsilateral axillary recurrence in the Tamoxifen-only group. As has been shown repeatedly, there was no difference as to overall survival.

And now the second:Lumpectomy plus Tamoxifen with or without Irradiation in Women 70 Years of Age or Older with Early Breast Cancer
Background In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy.

Methods Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor–node–metastasis classification), estrogen-receptor–positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer–specific survival, the time to distant metastasis, and overall survival.

Results The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). p="0.94)."

Again, radiation rules the day with a three percent reduction (96% to 99%) of local recurrence after Tamoxifen+XRT. While the XRT group had more adverse effects such as retraction or hyperpigmentation when compared to the Tamoxifen only group, most of those resolved within 1 year and all within four years. Both studies had about 700 patients. One problem I had with the second study was this statement:
All women underwent lumpectomy (i.e., partial mastectomy or a wide local excision) with a clear margin, defined by the absence of tumor on the inked pathological margins. Axillary-node dissection was allowed but was discouraged

So some of these women may have been understaged. Now for some tidbits from the editorial:Breast Radiotherapy after Lumpectomy - No Longer Always Necessary:
Does this absolute difference in the rate of local recurrence of 3 percent matter clinically, when weighed against the cost of the use of additional resources and treatment-related adverse effects? An overview of 40 trials in this field has confirmed that local radiotherapy is associated with an increase in deaths from cardiac and other causes, which nullifies a long-term reduction in deaths from breast cancer Modern radiotherapy techniques, including three-dimensional treatment planning and intensity-modulated radiotherapy, with cardiac shielding, can minimize the risk of cardiac irradiation in most patients Some side effects persist, and the CALGB investigators reported an increased incidence of breast pain, fibrosis, breast edema, and poor cosmetic results in the group that received radiotherapy. In addition, breast radiotherapy is resource-intensive and time-consuming for the patient and may decrease the quality of life There is, of course, the counterargument that not having radiotherapy may increase a woman's anxiety about the possibility of recurrence and could require more frequent follow-up. On balance, nevertheless, there are clear advantages in identifying subgroups in a large population of elderly women who do not require radiotherapy after lumpectomy and tamoxifen......

Against this background, what course should we recommend to older women with small, hormone-receptor–positive breast tumors who have undergone lumpectomy? The Canadian trial indicates that women under the age of 70 years should still receive radiotherapy in addition to tamoxifen. This is frustrating advice, because although it is clear that the majority of women treated with lumpectomy and tamoxifen alone would not have a relapse, we still cannot confidently predict which women will be in the majority. We are entering an era in which the use of molecular markers, gene-expression profiles, and other molecular prognostic indicators is being investigated as a means of individualizing adjuvant medical therapies,15 and there is no reason why the same approach should not be applied to radiotherapy. Future trials of radiotherapy should be required to include tissue biopsy for prospective molecular analyses and informed consent for this type of research.

As our understanding of breast cancer has evolved, so has our ability to treat it in the most effective, minimally invasive way possible. We have gone from the morbid Halstead radical mastectomy to local resections and perioperative radiation. Clear margins are becoming recognized as a more important risk factor than absolute tumor size. We are witnessing the evolution of the axillary dissection from a requirement to an operation of historical interest.

So the take-home is: for a small, selected group of patients (older than 70, small tumors, receptor positive) then benefit of radiation may not outweigh the morbidity, given the less aggressive course of breast cancer in the older population. This may prove to be a hard sell, given the fact that 899 of the 1572 patients eligible to enroll in the first trial declined.

Cross-posted at Galen's Log

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