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Defining the Role of Post-Mastectomy Radiotherapy: The New Evidence

Defining the Role of Post-Mastectomy Radiotherapy: The New Evidence

It is ironic that the issue of aggressive local therapy for breast cancer has re-emerged as a controversial issue in the early 1990s, almost 100 years after Halsted proposed this theory in the early 1890s [1]. Since that time, both survival and quality of life seemed to have improved for patients with breast cancer, due to more sophisticated and effective treatments. Nonetheless, as Drs. Pierce and Lichter point out in their article, the precise balance between the benefits and risks of aggressive local therapy still remains to be defined.

Does More Aggressive Local Therapy Make a Difference?

The resolution of this issue initially lies in the definition of "benefit." As Pierce and Lichter discuss, one must separate issues of local vs systemic recurrence. Most investigators agree that more intense local therapy results in a decreased risk of local recurrence when compared to less intense local therapy.

However, is a reduction in local recurrence, by itself, an acceptable indication for prophylactic therapy? There are at least three potential reasons for routinely treating all patients with prophylactic local therapy:

1) to avoid the emotional distress of a local recurrence;

2) to avoid uncontrollable symptomatic local disease (so-called local "shambles"); and/or

3) to reduce the chances of future mortality.

Unfortunately, it has not been established that prevention of local recurrence reduces any of these end points. Few, if any, studies have specifically addressed the issue of quality of life and patient perceptions in groups of women who have or have not received prophylactic chest wall radiotherapy after mastectomy. Likewise, results from a few retrospective series and only a single prospective study suggest that the use of prophylactic radiation therapy decreases the incidence of "uncontrolled" local disease [2].

Such data are very difficult to glean from most clinical studies. Rather, most authors report on only the incidence of any local recurrences (controllable or not) that occur before the onset of systemic disease. Local recurrences that develop subsequent to distant metastases are often ignored, and whether or not they can be adequately controlled is often not stated. Thus, the incidence of absolute control during a patient's lifetime is usually not reported accurately [3].

Pierce and Lichter argue appropriately that systemic recurrence and survival may be more meaningful end points for assessing the effects of local therapy. Does any local therapy reduce mortality? The answer to this question is, of course, yes. Between 60% to 80% of all patients with primary breast cancer can be cured with local therapy alone. Furthermore, results from the randomized studies of mammography screening indicate that early detection and local treatment improve survival relative to delayed local treatment.

Does More Aggressive Local Therapy Reduce the Risk of Distant Metastasis?

If we conclude that local therapy alone cures a substantial fraction of patients and that early local therapy improves survival relative to delayed local treatment, we might reasonably infer that improvements in local therapy may make a difference in overall survival. Pierce and Lichter provide an elegant review of the current data on whether more aggressive local therapy (in this case, post-mastectomy radiotherapy) improves overall survival while decreasing local recurrence. They make the cogent point that the earliest trials focusing on this issue consistently demonstrated a decrease in local recurrence but failed to show any evidence of an improvement in overall survival.

It has been argued that these early studies were performed in an era of out-dated radiotherapy techniques and in the absence of effective systemic therapy. Results from more modern studies, especially those conducted by the Danish Breast Cancer Cooperative Group and the Vancouver Group, suggest that the issue of post-mastectomy radiotherapy needs to be readdressed [4,5]. We applaud the suggestion by Pierce and Lichter that a new randomized trial should be considered in the United States. It is less certain whether we should now recommend the routine delivery of post-mastectomy radiotherapy to patients at high risk of local recurrence.

What Are the Risks and Costs of Radiation Therapy?

With currently available techniques, post-mastectomy radiation therapy appears to pose a substantially lower risks than were observed with the techniques used in the 1940s and '50s [6,7]. Nonetheless, these risks still include pulmonary, cardiac, and neuromuscular damage and the potential for a second malignancy. None of these appears to occur in more than 5% of all patients [6,7].

Of these complications, perhaps the most feared is late cardiac dysfunction. The precise risk of this complication is not established. Studies from our center and elsewhere have suggested the possibility of enhanced subacute cardiac damage in patients treated with high cumulative doses of adjuvant doxorubicin and left-sided irradiation [8]. However, we have reviewed our experience with patients who received doxorubicin at cumulative doses of less than 200 mg/m² in a recently reported randomized trial, and we have seen no increase in subacute mortality, regardless of the side treated [9]. Furthermore, a comparison of patients who received chest-wall radiation therapy to either the right or left side at the Joint Center for Radiation Therapy suggested no difference in non-breast cancer mortality in patients who did not receive chemotherapy [10].

Post-mastectomy radiation therapy results in a substantial increase in the cost of care, both in terms of direct and indirect expenses. A course of chest wall radiotherapy requires approximately 4 to 6 weeks of daily treatment and, on average, costs between $10,000 and $15,000. Furthermore, it results in lost time from work, increased transportation costs, and, possibly, additional elder- and child-care costs. Thus, recommendations for routine post-mastectomy chest wall radiation therapy require a careful assessment of both local and systemic benefits and results. Such an analysis is best performed in the context of a randomized clinical trial.

Do Biologic Changes Lead to Local Recurrence?

The issue of prevention of local recurrence raises several interesting biologic questions. Why is the chest wall, especially the mastectomy scar, the most frequent site of breast cancer recurrence? Local recurrence may simply be secondary to insufficient surgical resection and/or surgical contamination of fields during the resection itself. Alternatively, microenvironmental changes in the area of a healing scar, such as local production of various growth factors and other cytokines, may induce anchorage and growth of hematologic metastases [11].

Insufficient data exist to fully resolve any of these theories. However, new trials of chest wall therapy will provide an excellent opportunity to incorporate correlative studies on the biology of local recurrence.

Summary

In summary, the issue of more aggressive local therapy for patients with newly diagnosed primary cancers remains controversial. The authors are to be praised for their recommendation that a prospective randomized trial be mounted to address this issue. We strongly support this recommendation.

References

1. Halsted WS: The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June, 1889, to January, 1894. Johns Hopkins Hosp Rep 4:297-350, 1894-1895.

2. Rutqvist L: Adjuvant radiation therapy versus surgery alone in operable breast cancer: Long-term follow-up of a randomized clinical trial. Radiother Oncol 26:104-110, 1993.

3. Gelman R, Gelber R, Henderson IC, et al: Improved methodology for analyzing local and distant recurrence. J Clin Oncol 8:548-555, 1990.

4. Overgaard M, Christensen J, Johansen H, et al: Evaluation of radiotherapy in high-risk breast cancer patients: Report from the Danish Breast Cancer Cooperative Group (DBCG 82) trial. Int J Radiat Oncol Biol Phys 19:1121-1124, 1990.

5. Ragaz J, Jackson S, Le N, et al: Can adjuvant locoregional radiotherapy (XRT) reduce systemic recurrences in stage 1-11 breast cancer patients? Recurrence analysis of the British Columbia randomized trial. Proc Am Soc Clin Oncol 15:121, 1996.

6. Lingos TI, Recht A, Vicini F, et al: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21:355-360, 1991.

7. Pierce SM, Recht A, Lingos TI: Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 23:915-923, 1992.

8. Harrigan P, Otis D, Recht A, et al: The effect of adjuvant radiation therapy on cardiac events in breast cancer patients treated with doxorubicin. Proc Am Soc Clin Oncol 14:102a, 1995.

9. Harrigan P, Recht A, Payne S, et al: Treatment-related cardiac toxicity from doxorubicin (DOX) and radiation therapy (RT) in patients treated with breast-conserving therapy. Proc ASTRO (in press).

10. Nixon A, Gelman R, Bornstein B, et al: Non-breast cancer mortality after conservative surgery and radiation therapy (RT) to the left breast. Proc ASTRO (in press).

11. Fisher B, Saffer E, Rudock C, et al: Effect of local or systemic treatment prior to primary tumor removal on the production and response to a serum growth-stimulating factor in mice. Cancer Res 49:2002-2004, 1989.

 
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