Current breast cancer clinical trials

A number of important research questions on 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.



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

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

Ragaz J et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 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.

SELECT PUBLICATIONS

Cuzick J. Overview: Postmastectomy radiotherapy. NIH Consensus Conference on Early Breast Cancer, 2000. Abstract

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. Abstract

Harris JR et al. Consensus statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 1999;44:989-90. Abstract

Katz A et al. Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 2000;18(15):2817-27. Abstract

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;17:1689-700. Abstract

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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

INDIVIDUALIZING DECISIONS ON 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, and one would hope that the incidence of late cardiac morbidity is going to be very low. In a nonprotocol setting, we evaluate these one to three node-positive cases individually and 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

CONTINUUM OF POSTMASTECTOMY RADIATION THERAPY BENEFITS
Some of the controversy in the one to three node subset is quite akin to what happened in adjuvant chemotherapy early on in its development. We used to think that patients with large numbers of nodes benefited, but patients with small numbers of nodes did not. Then we recognized that patients with small numbers of nodes benefited, but we thought patients with no nodes did not. Now we recognize that even patients with no nodes in certain subsets can benefit. This principle applies across the spectrum of disease that systemic chemotherapy reduces risk of failure; however, the absolute benefit is harder and harder to see as the absolute risk of failure gets smaller. I think the same must be true in postmastectomy chest wall radiation. It almost certainly must help patients with one to three positive nodes. The question is, “What is their absolute risk of failure and is the benefit of the reduction conferred by postmastectomy chest wall radiation worth taking?” With the uncertainty surrounding the one to three node-positive group, we have proposed a trial for both pre- and postmenopausal patients to assess this. This trial — sponsored through SWOG — is now open and will be run through the Intergroup. There is a huge subgroup of women out there who fit into this category, and we hope that clinicians will enroll their patients in this study.

—Allen Lichter, MD
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