When should postmastectomy radiation therapy be utilized?

OVERVIEW: A number of important questions about the role of radiation therapy in primary breast cancer are being evaluated in current clinical trials. One of the few local therapy questions addressed by the 2000 NIH Consensus Conference was postmastectomy radiation therapy in women with one to three positive nodes. A major Intergroup trial now addressing this question is particularly salient because of several recently reported randomized studies suggesting a survival benefit in this population. The question of whether improved local disease control affects long-term survival is provocative, but consistent with data from the International Breast Cancer Overview that demonstrated fewer breast cancer deaths in women in receiving local radiation therapy. This effect was confounded by an increased mortality from cardiovascular complications, which was attributed to prior, imprecise radiation therapy techniques. Many researchers believe that the benefits of radiation therapy — like adjuvant systemic therapy — exist in a continuum, with the greatest absolute benefit occurring in patients with the greatest risk for recurrence.

Would you recommend postmastectomy radiation therapy for the following patients?

RADIATION THERAPY OVERVIEW

When you obtain better local control with radiotherapy or with surgery that reduces the risk of local recurrence, you also get some decrease in the long-term mortality from breast cancer. An absolute reduction of about 20% in local recurrence seems to go with an absolute reduction of about five percent in long-term mortality from breast cancer 10 or 15 years later.

The meta-analysis of the older radiotherapy trials suggested no net benefit. When you look separately at the breast cancer related deaths and the other deaths, better local control does matter in terms of long-term breast cancer survival.

—Richard Peto, FRS

POSTMASTECTOMY RADIATION THERAPY

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. Although this is comparable to the 16 percent actuarial rate seen in the British Columbia trial at 10 years, it is strikingly different from the Danish studies, where the crude rates of locoregional recurrence were approximately 30 percent.

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.

—Lori Pierce, MD
2000 NIH Consensus Conference. Abstract

RADIATION THERAPY OVERVIEW

The most recent Overview involved the examination of the deaths of more than 10,000 women out of a total of about 20,000 women in 40 randomized trials worldwide. No clear effect of radiotherapy on total mortality was found, but the study found highly significant differences in breast cancer deaths and non-breast cancer deaths. Both of these changes were highly significant. The change in non-breast cancer deaths emerged later than the change in breast cancer deaths, the difference being 1.0% for breast cancer mortality and 3.0% for non-breast cancer mortality at 10 years. Most of the excess non-breast cancer deaths were due to vascular disease, which increased by 30%.

—Jack Cuzick, PhD
2000 NIH Consensus Conference. Abstract

NIH CONSENSUS CONFERENCE CONCLUSION

There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy will benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary tumor. ... At this time, the role of postmastectomy radiotherapy for women with one to three positive lymph nodes remains uncertain and is being examined in a randomized clinical trial.

—2000 NIH Consensus Statement. Full-Text

INDIVIDUALIZING POSTMASTECTOMY RADIATION THERAPY

This is a very interesting question that challenges the concept we’ve had for so many years that breast cancer is a systemic disease. While one can quibble with aspects of the Danish and British Columbia trials, it is important that the subset that seemed to benefit the most in terms of survival — women with small tumors with a limited number of positive nodes — is consistent with everything else we believe about aggressive local-regional therapy.

The ongoing Intergroup trial is very important. This study is using modern radiotherapy techniques. One would hope that the incidence of late cardiac morbidity is going to be very low. In the non protocol setting, we evaluate these one to three node-positive cases individually. We discuss radiation therapy in patients with large nodal metastases, extracapsulary extension and large primary tumors, particularly with lots of lymphatic invasion in the breast. We also discuss this option in a woman who is very anxious to minimize her risk of failure and wants to opt for treatments that may give very little benefit. Node-positive disease is a continuum. I suspect that this will also be true of the benefits of postmastectomy radiation therapy.

—Monica Morrow, MD

POSTMASTECTOMY LOCAL RECURRENCE (LR) WITH OR WITHOUT DISTANT METS (DM) IN 4 ECOG TRIALS (MEDIAN OF 12.1 YEARS OF FOLLOW-UP)

Recht A 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;17:1689-1700. Abstract

SWOG-S9927: PHASE III RANDOMIZED STUDY OF POSTMASTECTOMY RADIOTHERAPY IN WOMEN WITH STAGE II BREAST CANCER WITH ONE TO THREE POSITIVE NODES OPEN PROTOCOL

STUDY CONTACT Stephen Barrow Edge, Chair, Ph: 716-845-5789 American College of Surgeons Oncology Group Lawrence Bruce Marks, Chair, Ph: 919-668-5640 Cancer and Leukemia Group B Eric Alan Strom, Chair, Ph: 713-792-3400 Eastern Cooperative Oncology Group Thomas Michael Pisansky, Chair, Ph: 507-284-4655 North Central Cancer Treatment Group Lawrence J Solin, Chair, Ph: 215-662-7267 Radiation Therapy Oncology Group Lori J Pierce, Chair, Ph: 734-936-7810 Southwest Oncology Group

DANISH BREAST CANCER COOPERATIVE GROUP (DBCG) 82B RANDOMIZED TRIAL: POSTOPERATIVE RADIOTHERAPY IN HIGH-RISK PREMENOPAUSAL BREAST CANCER PATIENTS GIVEN ADJUVANT CHEMOTHERAPY No Protocol Link

10 YEAR RESULTS

Overgaard M et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949-955. Abstract

DANISH BREAST CANCER COOPERATIVE GROUP RANDOMIZED DBCG 82C TRIAL: POSTOPERATIVE RADIOTHERAPY IN HIGH-RISK POSTMENOPAUSAL BREAST CANCER PATIENTS GIVEN ADJUVANT TAMOXIFEN No Protocol Link

10 YEAR RESULTS

Overgaard M et al. Postoperative radiotherapy in high-risk post-menopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641-1648. Abstract

BRITISH COLUMBIA RANDOMIZED TRIAL: ADJUVANT RADIOTHERAPY AND CHEMOTHERAPY IN NODE-POSITIVE PREMENOPAUSAL WOMEN WITH BREAST CANCER No Protocol Link

17 YEAR RESULTS

Ragaz J et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Me d 1997;337:956-962. Abstract Ragaz J et al. Postmastectomy radiation (RT) outcome in node (N) positive breast cancer patients among N 1-3 versus N4+ subset: Impact of extracapsular spread (ES). Update of the British Columbia randomized trial. Proc ASCO 1999; Abstract 274.

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