Adjuvant Postmastectomy Radiotherapy: Review of Treatment Guidelines and Techniques

Lori Pierce, M.D.

Essentially every randomized trial conducted to date to examine the effects of radiotherapy following surgery in early-stage breast cancer has demonstrated a benefit of locoregional control by the addition of radiotherapy. This was evident in the recent update of the meta-analysis of postoperative radiotherapy for early-stage disease, where a two-thirds reduction in local recurrence was seen following radiotherapy (EBCTCG, 2000).

There is controversy, however, on whether this benefit can significantly impact the risk of systemic recurrence and improve overall survival. The meta-analysis demonstrated a significant reduction in breast cancer mortality in patients receiving radiotherapy, with a 13.2 percent proportional reduction in breast cancer-related deaths following radiotherapy. This reduction was counterbalanced, however, by a 21.2 percent proportional increase in non-breast-cancer deaths, primarily vascular, in women who received radiotherapy. It has been well-documented that the cardiac toxicity seen in the meta-analysis is primarily attributable to radiotherapy equipment and techniques used in earlier trials that are obsolete by today's standards. These results, however, underscore the importance of careful planning of treatment in the delivery of radiotherapy in maximizing a breast cancer patient's overall survival.

Examination of patients following mastectomy and chemotherapy in node-positive breast cancer has shown rates of isolated locoregional failure ranging from 13 percent to 40 percent, accounting for a third to a half of all relapses (Recht, 1999). Factors that undoubtedly contribute to this broad range include various tumor characteristics, such as extent of axillary node involvement, tumor size, presence of lymphatic invasion, estrogen receptor (ER) status, and tumor grade, as well as clinical factors, such as length of followup and (possibly) choice of systemic therapy. In some trials, chemotherapy has been shown to reduce the risk of locoregional recurrence by 40 to 50 percent; in other studies, however, there has been no perceivable effect. Locoregional recurrences also occur despite myeloablative doses of chemotherapy used in transplant studies. Thus, the inconsistent results seen with chemotherapy support the need for radiotherapy to achieve maximal locoregional control.

The locoregional sites at risk following mastectomy include the chest wall, supra- and infraclavicular nodes, internal mammary nodes, and axilla. The patterns of failure reported in most node-positive series show the chest wall and the clavicular regions to be the most common sites of failure following mastectomy, and they are the sites where locoregional radiotherapy is justified. Clinical recurrences at the internal mammary and axillary regions, on the other hand, are uncommon, occurring in less than 5 percent of cases. One exception to this pattern was seen in the Danish postmastectomy radiotherapy randomized trials reported by the Danish Breast Cancer Cooperative Group (Overgaard, Hansen, Overgaard, et al., 1997; Overgaard, Jensen, Overgaard, et al., 1999). In those trials, the axilla was found to be the second most common site of locoregional recurrence (after the chest wall) among patients randomized not to receive radiotherapy, with 13 percent of patients having an axillary failure as the first failure site. This high failure rate is attributed to a more limited axillary dissection than the procedure typically performed by U.S. surgeons. Due to the rarity of axillary failures in the United States, and the fact that the risk of lymphedema increases with axillary irradiation following surgical dissection, the full axilla is generally not encompassed in the radiotherapy field.

A decision to irradiate the internal mammary nodes is a controversial one. Extended radical mastectomy series have shown that patients with positive axillary nodes are at risk for internal mammary involvement in up to 50 percent of cases. In theory, these cells could serve as a nidus for distant dissemination if left untreated. Despite this concern, no trials to date have shown a significant benefit in overall survival for patients treated in the internal mammary region; a significant benefit, however, has been shown for patients treated for positive axillary nodes and medial lesions (Le, Arriagada, deVathaire, et al., 1990). A large multi-institutional trial sponsored by the European Organization for Research and Treatment of Breast Cancer (EORTC) is currently in progress to assess the benefit of internal mammary (and supraclavicular) radiotherapy in the presence of contemporary systemic therapy. Although it is still unproven whether treatment of these nodes affects survival in the era of aggressive chemotherapy, it is clear that if the internal mammary nodes are to be irradiated, careful planning is critical to minimize cardiac toxicity.

Prior to the publication of reports on the recent randomized trials demonstrating a survival benefit with the addition of postmastectomy radiotherapy (Overgaard, Hansen, Overgaard, et al., 1997; Overgaard, Jensen, Overgaard, et al., 1999; Ragaz, Jackson, Le, et al., 1997), radiotherapy was indicated solely to reduce the risk of locoregional failure in patients deemed to be at high risk, including patients with locally advanced disease and early stage cancers associated with multiple positive nodes (four or more), where the risk of locoregional recurrence is generally 20 percent or more. Recent trials have shown a survival benefit following radiotherapy in all node-positive women, but the degree of benefit is unclear in patients with one to three positive nodes. Part of the dilemma is based upon the discrepancy in the rates of locoregional failure without radiotherapy in those trials in comparison to failure rates reported in American series. The recent report by Recht and colleagues of the patterns of failure found in studies conducted by the Eastern Cooperative Oncology Group notes that the risk of locoregional failure was 13 percent at 10 years in patients with one to three positive nodes (Recht, Gray, Davidson, et al., 1999). Although this is comparable to the 16 percent actuarial rate seen in the British Columbia trial at 10 years (Ragaz, Jackson, Le, et al., 1997), it is strikingly different from the Danish studies, where the crude rates of locoregional recurrence were approximately 30 percent (Overgaard, Hansen, Overgaard, et al., 1997; Overgaard, Jensen, Overgaard, et al., 1999). Based upon these results, the statement produced from the consensus conference convened by the American Society for Therapeutic Radiology and Oncology to address the controversies regarding patient selection for postmastectomy radiotherapy stated that while there was a consensus that patients with four or more positive lymph nodes should receive radiation therapy, the data were less clear for patients with one to three positive nodes (Harris, Halpin-Murphy, McNeese, et al., 1999). A randomized trial was strongly encouraged to study the degree of benefit in women with one to three positive nodes.

Based upon these concerns and recommendations, a trial sponsored by the Southwestern Oncology Group recently began for women with one to three nodes treated with mastectomy and chemotherapy, with a randomization to locoregional radiotherapy versus observation. Emphasis will be placed upon radiotherapy techniques that minimize potential cardiac toxicity.

References

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomized trials. Lancet 2000;355:1757-70.

Harris JR, Halpin-Murphy P, McNeese M, Mendenhall NP, Morrow M, Robert NJ, et al. Consensus statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 1999;44:989-90.

Le M, Arriagada R, deVathaire F, Dewar J, Fontaine F, Lacour J, et al. Can internal mammary chain treatment decrease the risk of death for patients with medial breast cancers and positive axillary lymph nodes? Cancer 1990;66:2313-8.

Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949-55.

Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen. Danish Breast Cancer Cooperative Group. Lancet 1999;353:1641-8.

Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956-62.

Recht A, Gray R, Davidson NE, Fowble BL, Solin LJ, Cummings FJ, 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 1999;17:1689-700.

Recht A. Locoregional failure rates in patients with involved axillary nodes after mastectomy and systemic therapy. Semin Radiat Oncol 1999;9:223-9.

Home · Search