Some of the earliest randomized trials in all of clinical medicine, conducted in the 1950s, tested the use of radiation therapy (RT) in patients with invasive breast cancer treated with mastectomy. Subsequently, beginning in the 1960s, trials of breast-conserving surgery combined with RT compared with mastectomy were started. Over time, considerable information has been accumulated on the use of RT in patients with invasive breast cancer, both after mastectomy and after breast-conserving surgery.

In this issue of the Journal of Clinical Oncology, there are three timely reviews by experts in the field on the status of RT in invasive breast cancer. Two of these reviews summarize the latest information (primarily from randomized clinical trials) on the use of RT after mastectomy and after breast-conserving surgery. The third review summarizes the latest information on the promising innovative approach of accelerated partial breast irradiation. All the reviews discuss the current state of the art and identify areas of opportunities.

There are a couple of major themes in these reviews.

One is the important issue of assessing the value of RT separately when used in the absence of, or in conjunction with, adjuvant systemic therapy. Given the demonstrated value of adjuvant systemic therapy in improving relapse-free and overall survival, systemic therapy (hormonal therapy and/or chemotherapy) is now typically used in patients with invasive breast cancer. In the absence of systemic therapy, RT reduces local recurrence after either mastectomy or breast-conserving surgery by about 70%.

Theoretically, the use of adjuvant systemic therapy by itself might lower local recurrence (lessening the need for RT), interact with RT to make RT more or less effective, and/or provide spatial complementarity (RT for local and systemic therapy for systemic disease) to improve survival when both are used. What has, in fact, been serendipitous, is that these systemic therapies—hormonal therapy more than chemotherapy—interact with RT to substantially improve local tumor control. More important is the finding that RT, when used with systemic therapy, decreases distant metastases and improves survival. For those of us who grew up in the early “Fisherian” Era (circa National Surgical Adjuvant Breast and Bowel Project Trial B-04),11 where systemic therapy was not used and RT was found not to influence survival, this new finding is a dramatic one. It suggests that when systemic therapy is effective at controlling micrometastatic disease, it is important to obtain local tumor control. Eventually, it is anticipated that systemic therapy will advance in its effectiveness so that no local therapy is needed; however, until now, the use of systemic therapy has increased the role of local therapy.

Of note in the Danish postmastectomy trials testing RT in patients treated with adjuvant systemic therapy, there was about a 30% rate of local recurrence in the absence of RT, and RT resulted in a 10% absolute improvement in survival. If the benefit of RT is proportional, as is seen with most therapies in breast cancer, and acts through its reduction in local recurrence, it would suggest that patients with a 15% rate of local recurrence would have a 5% absolute improvement in survival. Unfortunately, given the failure to accrue to the large randomized trial of postmastectomy RT in patients with one to three positive nodes treated with adjuvant systemic therapy (a group with an anticipated local recurrence rate of about 15%), this extrapolation remains conjectural.

Another major theme in these reviews is the need to balance the benefits of RT against its costs, complications, and inconvenience. One of the most serious complications seen with RT for breast cancer, particularly for left-sided cancers, is increased late cardiac mortality. Early techniques of breast cancer RT, especially those techniques which intended to treat the internal mammary nodes, resulted in substantial doses of RT to the heart. It is fortunate that improved RT techniques, especially with the use of computed tomography–based simulation, allow for exclusion of the entire heart in the high-dose areas. Efforts are continuing to identify patients who do not require RT, and these efforts are summarized in the previously mentioned reviews in this issue. At present, there are no predictive factors for RT, that is, the benefit from RT in reducing local recurrence is proportionally similar in all subgroups. Therefore, the emphasis has been on identifying prognostic factors where the risk of local recurrence without RT is sufficiently low such that RT is not justified. One of the latest innovations (discussed in detail in one of the reviews6) is that by restricting RT to only the part of the breast that can contained the primary cancer, the daily dose of RT can be increased and treatment can be completed in 1 week rather than 5 to 6 weeks. It is also hoped that in addition to making RT more convenient, such an approach might lessen complications and increase the utilization of breast-conserving therapy; however, there are limited long-term results using this approach and no results yet from randomized clinical trials comparing it to conventional whole breast irradiation.

REFERENCES

  ^{1. Jones JM, Ribeiro GG: Mortality patterns over 34 years of breast cancer patients in a clinical trial of post-operative radiotherapy. Clin Radiol 40:204-208, 1989
  2. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 312:665-673, 1985
  3. Veronesi U, Sacozzi R, Del Vecchio M, et al: Comparing radical mastectomy with quadrantectomy, axillary dissection and radiotherapy in patients with small cancers of the breast. N Engl J Med 305:6-11, 1981
  4. Pierce LJ: The use of radiotherapy after mastectomy: A review of the literature. J Clin Oncol 23:1706-1717, 2005
  5. Whelan T: Use of conventional radiotherapy as part of breast-conserving treatment. J Clin Oncol 23:1718-1725, 2005
  6. Arthur DW, Vicini FA: Accelerated partial breast irradiation as part of breast conservation therapy. J Clin Oncol 23:1726-1735, 2005
  7. Early Breast Cancer Trialists’ Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Lancet 355:1757-1770, 2000
  8. Morrow M, Harris JR: Local management of invasive breast cancer, in Harris JR, Lippman ME, Morrow MM, et al (eds): Diseases of the breast, third edition. Lippincott, Williams and Wilkins, Philadelphia, 2004, p.718-744
  9. Whelan TJ, Julian J, Wright J, et al: Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220-1229, 2000
  10. Vinh-Hung V, Verschraegen C: Breast conserving surgery with or without radiotherapy: Pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 96:115-121, 2004
  11. Fisher B, Redmond C, Fisher ER, et al: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 312:674-681, 1985
  12. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337:949-955, 1997
  13. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353:1641-1648, 1999
  14. Hurkmans CW, Cho BCJ, Damen E, et al: Reduction of cardiac and lung complication probabilities after breast irradiation using conformal radiotherapy with or without intensity modulation. Radiother Oncol 62:163-171, 2002
  15. Coleman CN, Wallner PE, Abrams JS: Inflammatory breast issue. J Natl Cancer Inst 95:1182-1183, 2003}

Jay R. Harris
Journal of Clinical Oncology, Vol 23, No 8 (March 10), 2005: pp. 1607-1608
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.11.048

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston, MA