Current Status of Radiation in the Treatment of Breast Cancer
Current Status of Radiation in the Treatment of Breast Cancer
Dr. Small is to be commended for a well-written succinct review of the role of radiation therapy in the treatment of breast cancer. As he notes, there is still controversy in the management of these patients. However, as more evidence-based data are accumulated, the role of radiation therapy is being clarified.
Dr. Small describes selected patients with low-risk ductal carcinoma in situ (DCIS), as assessed by the Van Nuyes index, who may be treated with wide excision alone. However, the majority of patients with DCISparticularly those with comedo necrosis, high nuclear grade, or close surgical marginsbenefit from breast irradiation after local tumor excision, as do intermediate- risk patients, who have a 12% to 15% local recurrence rate after excision alone. In fact, one analysis found no breast relapses in a similar group of patients with intermediate-risk DCIS who received breast irradiation. Protocol Radiation Therapy Oncology Group (RTOG) 98-04, which is randomizing patients with DCIS after local excision to tamoxifen (Nolvadex) alone or combined with breast irradiation should elucidate the need for irradiation in good-risk DCIS patients.
With regard to breast-conservation therapy in patients with invasive breast cancer, there are not six but eight prospective randomized trials that show equivalent local tumor control and survival when compared with radical or modified radical mastectomy for different tumor sizes (Table 1).[4-11]We agree with Dr. Small that even patients with tumors measuring 1 cm or smaller may benefit from breast irradiation after local tumor excision. However, not every patient with breast cancer is eligible for conservation therapy. The absolute and relative contraindications for this approach are summarized in Table 2. By following the selection guidelines for breast-conservation therapy (which were summarized by Recht et al), optimal results can be achieved.
As use of adjuvant chemotherapy increases in patients with breast cancer, there are frequent discussions regarding whether adjuvant chemotherapy or breast irradiation should be delivered first in some patients, based on tumor characteristics and pathologic findings. In a randomized study, Recht et al found that patients who received chemotherapy first had a slightly higher incidence of breast relapses but a lower incidence of distant metastasis, compared with patients treated initially with breast irradiation. However, in patients with extensive intraductal component or close or positive surgical margins, the breast relapse rate was significantly higher when radiation therapy was delayed for more than 16 weeks to allow the administration of chemotherapy.
At our institution, therefore, patients who are at a high risk of breast relapse are considered for radiation therapy after surgery, but those at higher risk for distant metastasis are treated with adjuvant chemotherapy followed by breast irradiation. A regimen of cyclophosphamide (Cytoxan, Neosar) and doxorubicin for four cycles administered over 12 weeks after surgery followed by breast irradiation has substantially reduced the risk of breast relapses.
Treatment of Regional Lymph Nodes
In the past, standard treatment for the axillary lymph nodes was dissection of levels I and II, but as Dr. Small notes, treatment of regional lymph nodes has undergone significant change. I agree with Solin, who, in an editorial, stated that regional lymphatic irradiation was unnecessary in patients with stage I and II tumors with a pathologically negative axilla. In patients with a positive axilla and four or more positive nodes, accepted treatment for many years has been radiation therapy to the regional lymphatics. However, more recent data from Overgaard et al[16,17] and Ragaz et al document an improvement in disease-free and overall survival in patients with one to three axillary lymph nodes and support irradiation of the lymphatics in these patients as well.
As Dr. Small notes, treatment of the axillary lymph nodes with irradiation is associated with a slightly higher probability of recurrence (2% to 3%). In our experience, the incidence of axillary node recurrences in 75 patients treated with irradiation alone (without node dissection) is 2%.
Sentinel Node Biopsy
The increasing popularity of the sentinel node biopsy[19-21] merits a review of the guidelines for the management of the axilla. Even though this procedure is associated with a high rate of accuracy in determining the presence of positive axillary lymph nodes (over 95%, as confirmed by complete axillary dissection specimens),[19,21,22] I believe these patients should be followed for several years so that the incidence of axillary lymph node failure can be assessed when only a sentinel node biopsy and no complete axillary dissection or radiation therapy to the axilla has been performed. McMasters et al noted that although sentinel node biopsy has the potential to enhance the accuracy of breast cancer staging, it is important to determine the false-negative and false-positive rates of sentinel node biopsy in multicenter studies, as suggested by Krag et al.
Nasser et al reported that pathologic assessment of the axillary nodes is complicated by the occasional presence of occult axillary lymph node metastases in "node-negative" breast cancer.
Barbera et al randomized 118 patients to sentinel node dissection or conventional four-node dissection. About 16% of the sentinel node specimens were negative by conventional pathologic analysis but positive by immunohistochemical staining for breast cancer cells.
In addition, Dowlatshahi et al reported that, when sentinel nodes from 52 patients were sectioned at 2-mm intervals, only 6 (12%) were found to harbor tumor metastasis on hematoxylin-and-eosin sections, compared with 30 (58%) when the same lymph nodes were sectioned with cytokeratin. These findings would explain some of the recurrences in patients initially classified as having "negative lymph nodes."
Postmastectomy Radiation Therapy
Dr. Small carefully reviewed the recent trials reported by Overgaard et al[16,17] and Ragaz et al that indicated a benefit in locoregional tumor control as well as disease-free and overall survival in patients treated with a modified or radical mastectomy, adjuvant chemotherapy, and postoperative irradiation to the chest wall and regional lymphatics. In these reports, patients with one to three positive axillary lymph nodes achieved the same benefit in terms of overall survival as did patients with four or more positive lymph nodes.
In a later report (as noted by Dr. Small), Ragaz et al again found a significant survival advantage (65% vs 49%) in the irradiated group of patients compared to the nonirradiated group, who had one to three positive axillary lymph nodes with extensive nodal or extracapsular tumor extension. We agree that it is important to support the RTOG randomized trial of postmastectomy radiation therapy to elucidate the benefit of this strategy in this select group of patients.
The issue of internal mammary irradiation obviously has not been settled. In surgical series many years ago, Veronesi et al and Handley observed a high rate of internal mammary lymph node metastasis in patients treated with extended mastectomy or with biopsy of the internal mammary nodes. However, the actual incidence of clinical failures at this site is very low (1% to 2%). As Fowble et al pointed out, internal mammary lymph node irradiation is not beneficial in most patients with breast cancer.
Cost-Effectiveness of Therapy
In a health-care environment concerned with cost, it will be important to document the cost benefit of radiation therapy in patients with breast cancer. I am not aware of specific studies conducted in patients treated with breast-conservation therapy. However, Marks et al and, more recently, Dunscombe et al demonstrated that postmastectomy radiation therapy is cost-effective because it substantially decreases the cost of treatment of locoregional failures. Moreover, a reduction in the incidence of distant metastasis and better overall survival, as reported in the trials conducted by Overgaard et al and Ragaz et al, should also decrease the cost of treatment for patients who develop metastatic disease after locoregional failure.
In summary, Dr. Small is to be congratulated for his review of the status of radiation therapy in the treatment of breast cancer. The majority of patients who undergo breast-conservation therapy should receive breast irradiation. In patients treated with chest wall and regional lymphatic irradiation after mastectomy and adjuvant chemotherapy, increased local tumor control and disease-free and overall survival have been documented in prospective clinical trials and other nonrandomized studies. The issues surrounding regional lymphatic irradiation have not been completely elucidated and will require additional prospective clinical investigation.
The management of the patient with breast cancer is an integrated multidisciplinary effort involving many professionals, including the diagnostic radiologist, pathologist, surgeon, radiation and medical oncologist, and psychosocial staff. We must continue to strongly support well-designed prospective clinical trials such as those sponsored by the National Surgical Adjuvant Breast and Bowel Project, other cooperative groups in the United States, and the European Organization for Research and Treatment of Cancer to optimize the treatment of patients with various stages of breast cancer.
1. Silverstein MJ, Lagios MD, Groshen S, et al: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340:1455-1461, 1999.
2. Solin LJ, Yeh IT, Kurtz J, et al: Ductal carcinoma in situ (intraductal carcinoma) of the breast treated with breast-conserving surgery and definitive irradiation: Correlation of pathologic parameters with outcome of treatment. Cancer 71:2532-2542, 1993.
3. Radiation Therapy Oncology Group Protocol 98-04: Phase III trial of tamoxifen alone vs tamoxifen plus radiation therapy for good risk duct carcinoma in-situ (DCIS) of the female breast. Beryl McCormick, Radiation Oncology Chair. Reston, American College of Radiology.
4. Atkins H, Hayward HL, Klugman DJ, et al: Treatment of early breast cancer: A report after 10 years of a clinical trial. Br Med J 2:423-429, 1972.
5. Veronesi U, Zucali R, Del Vecchio M: Conservative treatment of breast cancer with QUART technique. World J Surg 9:676-681, 1985.
6. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 320:822-828, 1989.
7. Glatstein E, Straus K, Lichter A, et al: Results of the NCI early breast cancer trial, pp 32-33. Paper presented at the NIH Consensus Development Conference, June 18-21, 1990.
8. van Dongan JA: Randomized clinical trial to assess the value of breast conserving therapy in stage I and II breast cancer: EORTC Trial 10801, pp 26-27. Paper presented at the NIH Consensus Development Conference, June 18-21, 1990.
9. van Dongen JA, Voogd AC, Fentiman IS, et al: Long-term results of randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 Trial. J Natl Cancer Inst 92:1143-1150, 2000.
10. Blicher-Toft A: A Danish randomized trial comparing breast conservation with mastectomy in mammary carcinoma, pp 28-31. Paper presented at the NIH Consensus Development Conference, June 18-21, 1990.
11. Sarrazin D, Le MG, Arriagada R, et al: Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 14:177-184, 1989.
12. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356-1361, 1996.
13. Danforth DN, Findlay PA, McDonald HD, et al: Complete axillary lymph node dissection for stage I-II carcinoma of the breast. J Clin Oncol 4:655-662, 1986.
14. Solin LJ: Regional lymph node management in conservation treatment of early stage invasive breast carcinoma. Int J Radiat Oncol Biol Phys 26:709-710, 1993.
15. Perez CA, Taylor ME: Breast: Stage Tis, T1, and T2 tumors, in Perez CA, Brady LW (eds): Principles and Practice of Radiation Oncology, 3rd ed, pp 1269-1414. Philadelphia, Lippincott-Raven, 1998.
16. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997.
17. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353:1641-1648, 1999.
18. Ragaz A, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997.
19. Giuliano AE, Jones RC, Brennan M, et al: Sentinel lymphadenectomy in breast cancer. J Clin Oncol 15:2345-2350, 1997.
20. Borgstein PJ, Pijpers R, Comans EF, et al: Sentinel lymph node biopsy in breast cancer: Guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 186:275-283, 1998.
21. Veronesi U, Paganelli G, Galimberti V, et al: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 349:1864-1867, 1997.
22. Krag D, Weaver D, Ashikaga T, et al: The sentinel node in breast cancer: A multicenter validation study. N Engl J Med 339:941-946, 1998.
23. McMasters KM, Giuliano AE, Ross MI, et al: Sentinel lymph node biopsy for breast cancer: Not yet the standard of care. N Engl J Med 339:990-995, 1998.
24. Nasser IA, Lee AKC, Bosari S, et al: Occult axillary lymph node metastases in "node-negative" breast cancer. Hum Pathol 24:950-957, 1993.
25. Barbera D, Ellis I, Geraghty J: Micrometastases in sentinel node in breast cancer (abstract 275). Abstracts and proceedings from the European Cancer Conference 10, Vienna, Austria, September 12-16, 1999.
26. Dowlatshahi K, Fan M, Bloom KJ, et al: Occult metastases in the sentinel lymph nodes of patients with early stage breast carcinoma: A preliminary study. Cancer 86:990-996, 1999.
27. Ragaz A, Jackson SM, Le N, et al: Survival gains of locoregional radiation (RT) in breast cancer with 1-3 positive axillary nodes (N1-3): Locoregional recurrences are not a useful guide to predict the benefit of the RT: An update from the British Columbia randomized trial (abstract). Proc Am Soc Clin Oncol 19:82, 2000.
28. Lacour J, Bucalossi P, Cacera E, et al: Radical mastectomy versus radical mastectomy plus internal mammary dissection: Five-year results of an international cooperative study. Cancer 37:206-214, 1976.
29. Veronesi U, Valagussa P: In efficacy of internal mammary nodes dissection in breast cancer surgery. Cancer 47:170-175, 1981.
30. Handley RS: Carcinoma of the breast. Ann R Coll Surg Engl 57:59-66, 1975.
31. Fowble B, Hanlon A, Freedman G, et al: Internal mammary node irradiation neither decreases distant metastases nor improves survival in stage I and II breast cancer. Int J Radiat Oncol Biol Phys 47:883-894, 2000.
32. Marks LB, Hardenbergh PG, Winer ET, et al: Assessing the cost-effectiveness of postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys 44:91-98, 1999.
33. Dunscombe P, Samant R, Roberts G: A cost-outcome analysis of adjuvant postmastectomy locoregional radiotherapy in premenopausal node-positive breast cancer patients. Int J Radiat Oncol Biol Phys 48:977-982, 2000.