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News Archive: Michigan Oncology Journal Fall 98

Post-Mastectomy Chest Wall Irradiation: An Ongoing Controversy

-Allen S. Lichter, M.D. and Lori J. Pierce, M.D.

For more than 50 years, clinical researchers have been studying the role of post-mastectomy chest wall irradiation in the management of patients with local/regional breast cancer. The impetus for these studies is relatively straightforward. In some patients, especially those with positive axillary nodes, mastectomy is followed months to years later with a local recurrence on the chest wall. The risk of such an event is, over time, somewhere in the range of 10 to 30 percent (1). The risk of chest wall recurrence increases with the number of positive lymph nodes and also with the size of the primary tumor. Thus patients with T3 primary tumors (greater than 5 cm) who have positive nodes have a risk of local recurrence that is 30 percent or more.

Effectiveness of Radiation
When radiation is utilized in the post-mastectomy setting, the risk of chest wall recurrence decreases substantially to around 5 percent. This effect of decreased chest wall recurrence has been seen in every trial of chest wall radiation ever performed.

In some trials, disease-free survival is increased in radiated patients and meta-analysis suggest that the risk of dying from breast cancer is also reduced (2). Many practitioners would argue that chest wall radiation is worth using in high-risk populations - typically for women with large primaries or four or more positive axillary lymph nodes - solely on the basis of reduced local recurrence and increased disease-free survival.

Most practitioners would agree that a local chest wall recurrence is a psychologically devastating event for most patients and, if the disease cannot be controlled with a combination of surgery and radiation, can be a devastating physical event as well. Clinical experience indicates that half or fewer of local chest wall failures ultimately can be controlled, thus giving way to the argument that preventing such failures is superior to attempting to treat them when they occur (3).

New Clinical Trial Evidence
However, many investigators have insisted that chest wall radiation should not be routinely employed in high-risk women unless it could be shown to increase overall survival. Until recently, evidence for overall survival benefit stemming from irradiation was elusive. Technical factors, especially those associated with treating the internal mammary lymph nodes and the attendant increased radiation to the heart, led to an increase in cardiac mortality that canceled any survival benefit that might have been a by-product of radiation (4).

However, two recent trials were published in October 1997, which show clear survival benefits with the use of chest wall irradiation. The trials, one from Denmark (5) and one from Canada (6), are summarized in Table 1. Both trials treated node positive patients who were premenopausal (the Danish trial had about 10 percent of its patients who were T3, N0). All women in the trial received CMF chemotherapy and half were randomized to receive chest wall radiation. The results of the studies are shown in Figure 1. The results are strikingly similar with a 7 to 8 percent increase in overall survival at 10 to 15 years following treatment.

Critique of the Trials
There have been many criticisms leveled at these two trials, and certainly no trial is free from all methodological concerns. Probably the most serious critique concerns the high rate of local failure seen in these studies. The axillary lymph node dissection, especially in the Danish trial, was limited, and the number of nodes recovered was far less than the typical lymph node dissection done in the United States. Consequently, nearly half the local failures were in the axilla, whereas in this country an axillary failure is uncommon after a level I, II axillary dissection.

Thus, there is concern that chest wall and regional irradiation in both of these studies simply made up for less than ideal surgery, and some investigators speculate that if a more complete surgical procedure was performed, the results of these trials would have been negative. Nonetheless, one thing is clearly shown by these two trials: a reduction in local failures can lead to a reduction in breast cancer metastasis and an improvement in overall survival. This is an extremely important concept (7).

Since post-mastectomy chest wall irradiation in high-risk patients has added to the local effectiveness of surgery in every trial ever done, one might speculate that even if more complete surgery were performed and the local failure rate in the control group was lowered, radiation would still add to the outcome of these patients, albeit, not to the extent that it did in these trials. In order to clarify this point more completely, a new study of post-mastectomy chest wall irradiation has been proposed by the authors. While it will take some additional time to develop the results from this study, a well-performed trial in the United States should go a long way towards finally ending all controversy concerning the effectiveness of chest wall irradiation in the treatment of breast cancer.

Today's Recommendations
In the meantime, what shall we recommend for patients who are treated prior to the activation of the national study or who refuse entry into the study once it is activated? At the University of Michigan, patients with four or more positive axillary lymph nodes are routinely treated with radiation therapy post mastectomy (8). This is true for pre- and post-menopausal patients and is based on the increased local control that radiation can offer, to say nothing of the possible increase in overall survival stemming from this therapy.

All patients who have T3 or T4 primaries receive radiation, as well as those patients with positive margins following mastectomy. In pre-menopausal patients, we consider radiation to the chest wall for those women with one to three positive nodes because of the increase in survival seen in this subset of patients in the Vancouver study cited previously. Virtually all women who are candidates for chest wall radiation will also be receiving systemic chemotherapy. Our own style of treatment is to deliver all the chemotherapy up front and then follow with the chest wall radiation as the final therapeutic intervention.

Summary
In summary, chest wall radiation adds to the local control in high-risk patients, namely those with four or more positive lymph nodes and/or large primary tumors. Studies from Canada and Denmark indicate that this therapy may also be associated with a survival advantage, especially in pre-menopausal patients. Additional clinical research proposed by our group will help further clarify the role of post-mastectomy chest wall irradiation. An excellent summary of this subject is written by Recht et al in the August 1998, Journal of Clinical Oncology (9).

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References
1. Fowble B. Postmastectomy radiation: then and now. Oncology. 11: 213-239, 1997.
2. Early Breast Cancer Trialists' Collaborative Group. Effects of radiotherapy and surgery in early breast cancer. N Engl J Med. 333: 1444-1455, 1995.
3. Stadler B, Kogelnik H. Local control and outcome of patients irradiated for isolated chest wall recurrences of breast cancer. Radiotherapy and Oncology. 8: 105-111, 1987.
4. Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 12: 447-453, 1994.
5. Overgaard M, Hansen P, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med. 237: 949-955, 1997.
6. Ragaz J, Jackson S, Ian N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 337: 956-962, 1997.
7. Hellman S. Stopping metastases at their source. N Engl J Med. 337: 996-997, 1997.
8. Pierce L. Defining the role of post-mastectomy radiotherapy: the new evidence. Oncology. 10: 991-1002, 1996.
9. Recht A, Bartelink H, Fourquet A, Fowble B, et al. Postmastectomy radiotherapy: Questions for the twenty-first century. J Clin Oncol. 16(8): 2886-2895, 1998.

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Table 1.
Post-Mastectomy Radiotherapy Trials

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