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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2075-2077 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.5200
One to Three Versus Four or More Positive Nodes and Postmastectomy Radiotherapy: Time to End the DebateDepartment of Radiation Oncology, Duke University Medical Center, Durham, NC The role of postmastectomy radiotherapy (PMRT) has been controversial for decades, accounting for countless presentations, debates, and papers. It was reasonably clear from the beginning that PMRT improved locoregional control. Much of the controversy has had to do with whether PMRT improved survival. The evidence is now strong that PMRT does indeed improve survival, both from individual studies1-3 and from reviews and meta-analyses.4-8 The Gebski et al4 analysis is particularly significant because, unlike many meta-analyses, this study controlled for the quality of the radiotherapy. The more recent studies demonstrate an absolute survival benefit of approximately 5% to 10% and approximately 66% to 75% relative reduction in locoregional recurrence. There should no longer be much doubt in the minds of oncologists as to the value of PMRT. Controversy continues to exist, however, as to the clinical characteristics of patients who would benefit significantly from PRMT. Because the risk of locoregional recurrence increases with the number of positive axillary lymph nodes, a widely adopted approach has been to apply PMRT only in patients with four or more positive axillary nodes, and not to those with one to three positive nodes. The rationale for this approach is nicely summarized in a prior Journal of Clinical Oncology editorial.9 If one believes that the ratio between locoregional failures avoided and breast cancer deaths prevented is approximately four to one, the group with four or more positive node group will enjoy the largest benefits in both locoregional control and survival. We have a number of concerns with this thesis, however. First, though this approach seems logical, it is not supported by the available data. In the Overgaard and Ragaz studies (Table 1), the absolute magnitude of the overall survival benefit afforded by PMRT is similar in the patients with one to three versus four or more positive lymph nodes.1-3 Many have criticized these studies for the degree of axillary surgery (median number of recovered nodes, seven in Overgaard and 11 in Ragaz), compared with a larger number of recovered nodes in some other studies. To address this criticism, a recent analysis from the Danish trials10 considered the subset of 1,152 node-positive patients with eight or more nodes removed (ie, > median). The overall 15-year survival rate was increased by 9% in patients with either one to three positive nodes or four or more positive nodes, with a disconnect between improvement in local control and survival. Although the patients with four or more positive nodes had a far greater improvement in local control with RT than did the group with one to three nodes, the survival benefits were similar in both groups.
The explanation advanced by the authors seems plausible. Improvements in locoregional control will yield survival benefits only if there is systemic tumor control as well. Because patients with four or more positive axillary nodes are likely, on average, to harbor a higher systemic subclinical disease burden than those with one to three positive nodes, improvements in locoregional control will be less likely to translate into a survival benefit in the four or more node group. Thus, the ratio between locoregional failures avoided and breast cancer deaths prevented may not be constant across patient subgroups. Further, as the efficacy of systemic therapy increases, the impact of PMRT on survival may also increase. In this regard, local and systemic therapies are synergistic rather than competitive.11 Second, some argue that a more complete axillary dissection would have moved most of the patients with one to three positive nodes in the Overgaard and Ragaz studies into the group with four or more positive nodes. This issue has been studied by several investigators. Danforth et al12 and Saha et al13 found that 64% to 71% of patients with one to three positive nodes after limited level I dissection (median, 10 nodes) would remain in the group with one to three positive nodes with a more complete dissection. Using mathematical models based on clinical data, Kiricute et al14 and Iyer et al15 computed that approximately 50% of patients with two positive nodes after limited dissection will remain in the group with one to three positive nodes with a more complete dissection. Thus, approximately 50% to 70% of the patients in the group with one to three positive nodes from the original Overgaard and Ragaz studies would likely remain in the same group with a more complete dissection. Thus, the often-heard suggestion that most of the patients with one to three nodes in the Overgaard and Ragaz studies would have had four or more nodes with a more complete dissection is not consistent with the data. Third, the subsetting of patients into groups with one to three versus four or more positive nodes is an artificial distinction originating in the early days of adjuvant systemic therapy for breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) was perhaps the first to do this, with initial benefits from adjuvant chemotherapy observed only in those with four or more positive lymph nodes.16 Later studies demonstrated the utility of systemic therapy in patients with one to three, or even zero, involved nodes.17-23 The artificial distinction of one to three nodes versus four or more was adopted by radiation oncologists as well. We, unfortunately, have been less vigilant in removing this from our lexicon. The published data clearly demonstrate that there is no magical change occurring at the 3 to 4 nodal boundary level. Locoregional relapse risk increases approximately linearly with the number of positive axillary nodes.1,24-27 In light of the above, consider the manuscript by Katz et al28 in this issue of JCO. They present a nomogram that can be applied to patients with positive sentinel nodes to predict their risk of harboring four or more involved nodes. A sophisticated statistical analysis has been conducted on 402 patients with one to three involved sentinel nodes who subsequently underwent completion axillary dissection. The study implies, of course, that less treatment, particularly radiotherapy—and perhaps chemotherapy as well—may be appropriate for those with fewer than four involved nodes. Those who subscribe to this point of view may indeed find this nomogram helpful. We do not find it helpful, because it perpetuates this arbitrary one to three versus four or more distinction. We believe that comprehensive PMRT is appropriate for the great majority of node-positive patients undergoing mastectomy. Some selection based on other clinical and biologic factors may be important and appropriate. For example, Cheng et al29 developed a model to predict locoregional recurrence and the impact of PMRT on survival. In addition to axillary nodal status, estrogen-receptor status, lymphovascular space invasion, and age at diagnosis were all found to be significant. Similarly, Truong et al30 suggested that young age, medial tumor location, ER-negative status and greater than 25% of nodes positive were also predictors for a higher risk of locoregional recurrence. It is likely that other more sophisticated biologic factors, such as gene expression profiling, will also be helpful in this regard. We would like to express some concerns about an apparent double standard in the treatment of breast cancer patients with small numbers of positive lymph nodes. Typically, such individuals receive aggressive chemotherapy programs, perhaps based on limited data with relatively short follow-up. For example, consider the introduction of paclitaxel into widespread clinical use after the initial Cancer and Leukemia Group B report.31,32 Such aggressiveness with systemic therapy suggests that a consistent approach be followed with reasonably aggressive radiotherapy as well. Additionally, the use of PMRT is supported by large trials with long follow-up. Ongoing European trials such as the Selective Use of Postoperative Radiotherapy After Mastectomy trial as well as biologic predictors may resolve some of the issues raised here. Until further data are available, however, we believe the great majority of patients with any involved axillary lymph nodes should be strongly considered for PMRT. Lastly, concerns regarding the toxicity of PMRT, we believe, have been overstated by Katz et al.28 With modern treatment planning techniques, it is generally quite feasible to avoid the heart, and minimize lung exposure.33-37 Arm edema is a relatively uncommon event when the RT fields are designed to limit exposure of the dissected axillary tissues. Obviously, there are always some risks associated with any treatment, and one needs to carefully consider the overall clinical situation and comorbidities to assure a favorable therapeutic ratio. Further, since the survival benefits in postmenopausal women appear to accrue 5 or more years after PMRT, the patient's life expectancy must be considered as well. It is time that we dispense with the artificial partitioning of patients into groups with one to three versus four or more positive nodes.38 Additional study of the biologic and genetic factors that lead to locoregional and systemic recurrence will assist to further define which patients are most likely to benefit from PMRT.39 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Lawrence B. Marks, Varian Medical Systems Research Funding: Lawrence B. Marks, National Institutes of Health, Lance Armstrong Foundation, Department of Defense Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Manuscript writing: Lawrence B. Marks, Jing Zeng, Leonard R. Prosnitz Final approval of manuscript: Lawrence B. Marks, Jing Zeng, Leonard R. Prosnitz
ACKNOWLEDGMENTS We thank Jessica Hubbs for her assistance in the preparation of this manuscript. REFERENCES
1. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337:949-955, 1997 2. 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[CrossRef][Medline] 3. Ragaz J, Olivotto IA, Spinelli JJ, et al: Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 97:116-126, 2005 4. Gebski V, Lagleva M, Keech A, et al: Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: A clinical perspective. J Natl Cancer Inst 98:26-38, 2006 5. Giordano SH, Kuo YF, Freeman JL, et al: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419-424, 2005 6. Rutqvist LE, Rose C, Cavallin-Stahl E: A systematic overview of radiation therapy effects in breast cancer. Acta Oncol 42:532-545, 2003[CrossRef][Medline] 7. Van de Steene J, Soete G, Storme G: Adjuvant radiotherapy for breast cancer significantly improves overall survival: The missing link. Radiother Oncol 55:263-272, 2000[CrossRef][Medline] 8. Whelan TJ, Julian J, Wright J, et al: Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220-1229, 2000 9. Olivotto IA, Truong PT, Chua B: Postmastectomy radiation therapy: Who needs it? J Clin Oncol 22:4237-4239, 2004 10. Overgaard M, Nielsen HM, Overgaard J: Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials. Radiother Oncol 82:247-253, 2007[CrossRef][Medline] 11. Marks LB, Prosnitz LR: "One to three" or "four or more"?: Selecting patients for postmastectomy radiation therapy. Cancer 79:668-670, 1997[CrossRef][Medline] 12. Danforth DN Jr, 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 13. Saha S, Farrar WB, Young DC, et al: Variation in axillary node dissection influences the degree of nodal involvement in breast cancer patients. J Surg Oncol 73:134-137, 2000[CrossRef][Medline] 14. Iyer RV, Hanlon A, Fowble B, et al: Accuracy of the extent of axillary nodal positivity related to primary tumor size, number of involved nodes, and number of nodes examined. Int J Radiat Oncol Biol Phys 47:1177-1183, 2000[CrossRef][Medline] 15. Kiricuta CI, Tausch J: A mathematical model of axillary lymph node involvement based on 1446 complete axillary dissections in patients with breast carcinoma. Cancer 69:2496-2501, 1992[CrossRef][Medline] 16. Fisher B, Ravdin RG, Ausman RK, et al: Surgical adjuvant chemotherapy in cancer of the breast: Results of a decade of cooperative investigation. Ann Surg 168:337-356, 1968[Medline] 17. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976[Abstract] 18. Bonadonna G, Moliterni A, Zambetti M, et al: 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: Cohort study. BMJ 330:217, 2005 19. EBCTCG: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women—Early Breast Cancer Trialists’ Collaborative Group. Lancet 339:71-85, 1992[Medline] 20. Fisher B, Carbone P, Economou SG, et al: 1-Phenylalanine mustard (L-PAM) in the management of primary breast cancer. A report of early findings. N Engl J Med 292:117-122, 1975[Abstract] 21. Fisher B, Dignam J, Tan-Chiu E, et al: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93:112-120, 2001 22. Horton J: 1995 Oxford breast cancer overview: Preliminary outcomes. Cancer Control 3:78-79, 1996[Medline] 23. Mansour EG, Gray R, Shatila AH, et al: Survival advantage of adjuvant chemotherapy in high-risk node-negative breast cancer: Ten-year analysis—An intergroup study. J Clin Oncol 16:3486-3492, 1998[Abstract] 24. Donegan WL, Perez-Mesa CM, Watson FR: A biostatistical study of locally recurrent breast carcinoma. Surg Gynecol Obstet 122:529-540, 1966[Medline] 25. Fowble B, Gray R, Gilchrist K, et al: Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 6:1107-1117, 1988 26. Marks LB, Hardenbergh P, Prosnitz LR: Mounting evidence for postmastectomy locoregional radiation therapy. Oncology (Williston Park) 13:1123-1142, 1144, 1999[Medline] 27. Ragaz J, 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 28. Katz A, Smith BL, Golshan M, et al: Nomogram for the prediction of having four or more involved nodes for sentinel lymph node-positive breast cancer. J Clin Oncol 26:2093-2098, 2008 29. Cheng SH, Horng CF, Clarke JL, et al: Prognostic index score and clinical prediction model of local regional recurrence after mastectomy in breast cancer patients. Int J Radiat Oncol Biol Phys 64:1401-1409, 2006[CrossRef][Medline] 30. Truong PT, Olivotto IA, Kader HA, et al: Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 61:1337-1347, 2005[CrossRef][Medline] 31. Giordano SH, Duan Z, Kuo YF, et al: Impact of a scientific presentation on community treatment patterns for primary breast cancer. J Natl Cancer Inst 98:382-388, 2006 32. Goble S, Bear HD: Emerging role of taxanes in adjuvant and neoadjuvant therapy for breast cancer: The potential and the questions. Surg Clin North Am 83:943-971, 2003[CrossRef][Medline] 33. Hardenbergh PH, Bentel GC, Prosnitz LR, et al: Postmastectomy radiotherapy: Toxicities and techniques to reduce them. Semin Radiat Oncol 9:259-268, 1999[CrossRef][Medline] 34. Pierce LJ, Butler JB, Martel MK, et al: Postmastectomy radiotherapy of the chest wall: Dosimetric comparison of common techniques. Int J Radiat Oncol Biol Phys 52:1220-1230, 2002[CrossRef][Medline] 35. Pedersen AN, Korreman S, Nystrom H, et al: Breathing adapted radiotherapy of breast cancer: Reduction of cardiac and pulmonary doses using voluntary inspiration breath-hold. Radiother Oncol 72:53-60, 2004[CrossRef][Medline] 36. Chen MH, Cash EP, Danias PG, et al: Respiratory maneuvers decrease irradiated cardiac volume in patients with left-sided breast cancer. J Cardiovasc Magn Reson 4:265-271, 2002[CrossRef][Medline] 37. Krauss DJ, Kestin LL, Raff G, et al: MRI-based volumetric assessment of cardiac anatomy and dose reduction via active breathing control during irradiation for left-sided breast cancer. Int J Radiat Oncol Biol Phys 61:1243-1250, 2005[CrossRef][Medline] 38. Vinh-Hung V, Storme G: No nodal cutoff in node-positive breast cancer women treated with mastectomy. Breast Cancer Res Treat 98:173-178, 2006[CrossRef][Medline] 39. Cheng SH, Horng C-H, West M, et al: Genomic prediction of locoregional recurrence after mastectomy in breast cancer. J Clin Oncol 24:4594-4602, 2006 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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