Postmastectomy Radiation TherapyLocal Control Improves Survival
ABSTRACTS & COMMENTARY
Synopsis: Two large, prospective, randomized trials demonstrate that premenopausal women with node-positive breast cancer who receive adjuvant chemotherapy have a significantly improved rate of local tumor control and overall survival when they also receive radiation therapy to the involved breast and node groups.
Sources: Overgaard J, et al. N Engl J Med 1997;337: 949-955; Ragaz J, et al. N Engl J Med 1997;337: 956-962.
The routine use of adjuvant radiation therapy following mastectomy has fallen out of favor in the past decade, primarily due to the failure of randomized trials to detect a significant improvement in overall survival from added radiation therapy. Thus, use of radiation therapy has been restricted to clinical situations in which local control of breast cancer from a primary surgical procedure has been felt to be sub-optimal. Radiation therapy was commonly employed when the primary tumor was greater than 5 cm in diameter, when the surgical margin was positive for tumor, or when more than four lymph nodes were involved with tumor.
Long-term results from two large, randomized trials involving premenopausal node-positive women, all of whom received systemic adjuvant chemotherapy, suggest that radiation therapy should be used routinely, not only to improve local disease control, but to improve overall survival. The first study, from the Danish Breast Cancer Cooperative Group, enrolled high-risk premenopausal women with any of the following features: positive lymph nodes, tumor size greater than 5 cm, or invasion of the skin or pectoralis fascia. The surgical treatment consisted of a total mastectomy with stripping of the pectoralis fascia and preservation of the pectoralis muscles, and dissection of level I and some of the level II lymph nodes. Chemotherapy consisted of CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and 5-fluorouracil 600 mg/m2) given intravenously every four weeks for a total of eight cycles starting 2-4 weeks after surgery. Patients were randomly assigned to receive systemic therapy only or chemotherapy with radiation therapy delivered to a total dose of 50 Gy to the chest wall, supraclavicular fossa, axilla, and internal mammary lymph nodes over five weeks. Radiation therapy was started after the first cycle of chemotherapy and the chemotherapy resumed 1-2 weeks after radiation therapy was completed.
Seventeen hundred eight women were randomly assigned, and median follow-up was 114 months (9.5 years). Patients receiving combined modality adjuvant therapy had an improvement in local control (91% vs 68%), disease-free survival at 10 years (48% vs 34%), and overall survival (54% vs 45%) compared to women receiving CMF chemotherapy alone. Tumor size, number of positive lymph nodes, and degree of tumor differentiation were all significant prognostic factors for disease-free and overall survival, and all subgroups of patients appeared to benefit from the use of radiation therapy. The median number of lymph nodes examined in these patients was only seven; however, no differences in disease-free or overall survival were found in the subgroups based on the number of nodes examined (0-3, 4-9, > 9).
The second trial was conducted by the British Columbia Cancer Agency and included all premenopausal women who were found to have positive axillary nodes after a modified radical mastectomy (median number of nodes examined was 11). All patients received CMF at the same doses as in the Danish study, delivered every 21 days rather than every 28 days. Initially, chemotherapy was given for 12 months, but the duration of treatment was reduced to six months in 1981. Patients were randomly assigned to receive chemotherapy alone or CMF plus radiation therapy. Radiation therapy was delivered with a cobalt-60 source to the chest wall, axilla, supraclavicular fossa, and internal mammary nodes between the fourth and fifth cycles of chemotherapy.
Three hundred eighteen patients were randomly assigned and followed for a median of 12.5 years. At 15 years, patients receiving radiation therapy experienced significantly improved local tumor control (87% vs 67%), disease-free survival (50% vs 33%), breast cancer-specific survival (57% vs 47%), and overall survival (54% vs 48%). The benefit from radiation therapy was similar for patients with 1-3 or more than four postive lymph nodes. Radiation therapy was well-tolerated, with arm edema occurring in 15 of 154 patients receiving radiation therapy and in five patients treated without radiation therapy. Intervention for treatment of arm edema was required in only six patients. A similar number of contralateral breast cancers developed in each group. Only one patient developed heart failure, and that patient had also received doxorubicin when she had developed metastatic disease.
COMMENTARY
The long-term results of these well-conducted randomized trials support the use of radiation therapy in addition to adjuvant chemotherapy in premenopausal women with node-positive breast cancer. Prior trials had shown that adjuvant radiation therapy decreased local relapse rates, but this had not translated into an overall survival benefit. Some of the studies were too small to reliably detect a small benefit. Others included patients with small primary tumors or who did not have positive lymph nodes, groups unlikely to benefit dramatically from additional local therapy.1 That local/regional radiation therapy improves local control and decreases distant dissemination was also demonstrated in the Stockholm radiation therapy study.2 Arriagada and colleagues found a relative risk of 0.63 in the likelihood of developing metastatic disease in patients with histologically involved axillary nodes in those who received radiation therapy compared to those who did not.2
One factor contributing to the failure of prior studies to show a survival advantage for patients receiving adjuvant radiation therapy was an increased rate of deaths unrelated to cancer, usually cardiac deaths. Older radiation therapy trials used treatment techniques that led to an increased risk of cardiovascular mortality in women with left-sided primary tumors who received direct photon fields to the left internal mammary node chain.3 Modern CT-based, three-dimensional treatment planning can lower the dose of radiation delivered to the heart, even when the left internal mammary chain is included in the field. A re-examination after longer periods of follow-up of the prior randomized trials using meta-analysis found a survival trend in favor of adjuvant radiation therapy.4 Thus, the magnitude of the survival advantage may increase further as techniques that improve the therapeutic ratio of radiation therapy are more widely applied. The two recent publications showed no increase in cardiac toxicity for women with left-sided primary tumors. However, the period of follow-up is still too short to evaluate whether the risk of second solid tumors from the radiation therapy will significantly detract from the overall survival advantage.
These results imply that chemotherapy is suboptimal at eradicating local/regional metastases. It is not clear whether the use of doxorubicin in the adjuvant chemotherapy arms would have given better results and reduced the apparent benefit of adding radiation therapy. It is also unclear whether combined modality therapy using doxorubicin in the chemotherapy regimen would increase the rate of development of heart failure. However, it does seem clear that improved local control leads to a reduced rate of metastatic disease. It is not entirely clear what impact these findings will have on breast cancer mortality. More women are presenting with node-negative disease and small primary tumors detected by mammography. Others who might have been affected by these results are opting for lumpectomy, and radiation therapy has been an integral part of breast-conserving therapy. Thus, these studies will mainly influence the management of premenopausal women with positive lymph nodes who opt for modified radical mastectomy as the treatment for their primary tumor. All such women should be evaluated for radiation therapy. The combination of chemotherapy to eradicate micrometastatic disease and radiation therapy delivered to the chest wall and regional lymphatics to maximize local/regional control appears to be the best strategy to optimize disease-free and overall survival. Whether postmenopausal women will experience similar benefit from adjuvant radiation therapy has not yet been formally proved, but it would appear that the same principles apply.
References
1. Cuzick J, et al. Cancer Treat Rep 1987;71:15-29.
2. Arriagada R, et al. J Clin Oncol 1995;13:2869-2878.
3. Rutqvist LE, et al. Int J Radiat Oncol Biol Phys 1992;22:887-896.
4. Cuzick J, et al. J Clin Oncol 1994;12:447-453.
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