Mounting Evidence for Postmastectomy Locoregional Radiation Therapy
Mounting Evidence for Postmastectomy Locoregional Radiation Therapy
The recommendations derived from the existing clinical trials of postmastectomy adjuvant radiation therapy seem to parallel the lessons learned from the trials of postoperative adjuvant chemotherapy conducted during the previous 20 to 30 years. From the various meta-analyses of adjuvant chemotherapy trials, we have learned that patient subgroupswhen arranged from negative lymph nodes to positive nodes to increasing number of positive nodesall have nearly the same proportion of reduction in risk of recurrence. However, the absolute difference in risk of recurrence is much greater in the subgroup of patients with multiple positive lymph nodes. These principles probably hold true for postmastectomy radiation therapy as well.
This paper by Marks and colleagues is very good, although it seems to overstate the populations who may benefit from postmastectomy radiation. The formidable task in the next several years is to identify patients with an increased odds of local recurrence, notwithstanding the current systemic therapy and modern surgical techniques used in this country. These will be women for whom the addition of radiation therapy would result in significant improvements in local control and, hopefully, survival rates. It would then be worth adding 6 weeks of radiotherapy to the breast cancer treatment regimen, which can already consist of modified radical mastectomy, with or without immediate reconstruction, several months of intravenous chemotherapy, and then 5 years of tamoxifen (Nolvadex). The concept of absolute reduction in risk is important to discuss thoroughly with the patient since the complications of radiation therapy can be more severe and disabling than the complications of adjuvant chemotherapy.
Does Postmastectomy Radiation Improve Local Control and Survival?
The authors statistical presentation is excellent. Their conclusion that postmastectomy radiation improves local control and survival is new, however.
At the San Antonio Breast Cancer Symposium in 1998, Dr. Timothy Whelan of Hamilton, Ontario, presented a meta-analysis of 18 studies initiated between 1974 and 1982. The trials met the specific criteria of randomization after mastectomy and axillary lymph node dissection, use of the same adjuvant therapy in both arms (although sequencing of radiation and chemotherapy varied), and median follow-up of at least 5 years. When the two large Danish trials[1,2] were removed from statistical consideration, the odds ratio for recurrence and mortality was 0.89, which was not statistically significant. With the inclusion of the Danish trials, the meta-analysis supported the concept that local radiation therapy significantly reduces the risk of recurrence and death.
The Danish trials[1,2] and the recent British Columbia trial were somewhat unusual. The relatively high rates of local recurrence in the control arms of these trials had not been anticipated but might be explained by the extent of axillary surgery. The median number of axillary lymph nodes excised was 7 in the Danish trial and 11 in the British Colombia trial. I disagree with the comment by Marks et al that the median number of lymph nodes removed in the United States is similar to that reported in these trials. That number may be correct if the lymph nodes appear to be negative intraoperatively, but when positive lymph nodes are recognized intraoperatively by the surgeon, the median number of lymph nodes retrieved should be considerably greater than 11.
Surgical technique plays a critical, but hard to quantify, role in determining the risk of local failure. For example, the recent report on the Danish trial showed that the local failure rate was 40% for the 133 patients in whom only 0 to 3 lymph nodes were recovered, as compared with 32% for the 511 patients in whom 5 to 9 lymph nodes were removed, and 27% for the 211 patients in whom 10 lymph nodes were excised.
The Eastern Cooperative Oncology Group (ECOG) trial, which followed more than 2,000 patients for over 12 years, showed a similar trend related to a decreased number of lymph nodes examined and local recurrence. In this study, 79% of women had 11 or more lymph nodes excised. Overall, the study noted a much lower local recurrence rate without the use of radiation therapy than was observed in the European trials.
Risk of Lymphedema and Reconstruction Difficulties
The authors touch only lightly on the risk of lymphedema. There was three times the incidence of symptomatic lymphedema due to chest wall radiation in the British Colombia trial (9% vs 3%), probably because of scatter at the level of the larger lymphatic channels in the axilla When an axillary field is added to an axillary dissection, a majority of women will develop lymphedema, and to an extreme degree. In the title of the present paper, an axillary field is implied in the term locoregional radiotherapy.
There is also the issue of reconstruction after mastectomy, either immediate or delayed, which this article avoids. Permanent changes caused by radiation usually preclude certain kinds of simple reconstructions, such as implants. Only relatively young, healthy women with adequate adipose tissue who can tolerate autologous (flap) tissue reconstructions may be candidates for reconstruction after postmastectomy radiation therapy. In the era of managed care, the cost of postmastectomy radiation also is a potential disadvantage.
Although this is an evolving research field, in 1999 I believe that women with > 10 positive lymph nodes will continue to receive postmastectomy radio-therapy and women with 4 to 9 positive lymph nodes will also be recommended for radiation therapy, with the strongest recommendation made for those with higher numbers of positive nodes. Women with one to three positive nodes will be considered for postmastectomy radiation based, in part, on other clinical factors, eg, surgical margins.
1. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997.
2. Overgaard M, Hansen PS, Overgaard J, et al: Randomized trial evaluating postoperative radiotherapy in high-risk postmenopausal breast cancer patients given adjuvant tamoxifen: Results from the DBCG 82 c trial (abstract). Radiother Oncol 48 (suppl 1):S78, 1998.
3. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997.
4. Recht A, Gray R, Davidson NE, et al: Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17:1689-1700, 1999.