- Email: [email protected]
Radiation Use and Long-Term Survival in Breast Cancer Patients With T1, T2 Primary Tumors and One to Three Positive Axillary Lymph Nodes
Int. J. Radiation Oncology Biol. Phys., Vol. 71, No. 4, pp. 1022–1027, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
doi:10.1016/j.ijrobp.2007.11.036
CLINICAL INVESTIGATION
Breast
RADIATION USE AND LONG-TERM SURVIVAL IN BREAST CANCER PATIENTS WITH T1, T2 PRIMARY TUMORS AND ONE TO THREE POSITIVE AXILLARY LYMPH NODES THOMAS A. BUCHHOLZ, M.D.,* WENDY A. WOODWARD, M.D., PH.D.,* ZHIGANG DUAN, B.MED. M.S.,y SHENYING FANG, M.S.,y JULIA L. OH, M.D.,* WELELA TEREFFE, M.D.,* ERIC A. STROM, M.D.,* GEORGE H. PERKINS, M.D.,* TSE-KUAN YU, M.D., PH.D.,* KELLY K. HUNT, M.D.,z FUNDA MERICBERNSTAM, M.D.,z GABRIEL N. HORTOBAGYI, M.D.,y AND SHARON H. GIORDANO, M.D., M.P.H.y Departments of *Radiation Oncology, y Breast Medical Oncology, and z Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Background: For patients with Stage II breast cancer with one to three positive lymph nodes, controversy exists about whether radiation as a component of treatment provides a survival benefit. Methods and Materials: We analyzed data from patients with Stage II breast cancer with one to three positive lymph nodes diagnosed from 1988–2002 in the Surveillance, Epidemiology, and End Results registry and compared the outcome of 12,693 patients treated with breast-conservation therapy with radiation (BCT + XRT) with the 18,902 patients treated with mastectomy without radiation (MRM w/o XRT). Results: Patients treated with BCT + XRT were younger, were more likely to be treated in recent years of the study period, more commonly had T1 primary tumors, and had fewer involved nodes compared with those treated with MRM w/o XRT (p < 0.001 for all differences). The 15-year breast cancer–specific survival rate for the BCT + XRT group was 80% vs. 72% for the MRM w/o XRT group (p < 0.001). Cox regression analysis showed that MRM w/o XRT was associated with a hazard ratio for breast cancer death of 1.19 (p < 0.001) and for overall death of 1.25 (p < 0.001). The survival benefit in the BCT + XRT group was not limited to subgroups with high-risk disease features. Conclusions: Radiation use was independently associated with improved survival for patients with Stage II breast cancer with one to three positive lymph nodes. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation in randomized clinical trials. Ó 2008 Elsevier Inc. Mastectomy, Radiation, Breast cancer, Stage II.
the benefits of postmastectomy radiation suggested that all patients with lymph node–positive disease benefited from this adjuvant treatment (1–3). However, other large studies investigating local-regional failure patterns after mastectomy and systemic treatments identified subpopulations of patients with lymph node–positive breast cancer for whom the risk of local-regional recurrence was low. In the United States, most patients with lymph node–positive disease who were treated with mastectomy underwent standard axillary Level I–II lymph node dissection and receive systemic therapy. For patients with Stage II breast cancer with one to three positive lymph nodes who were treated by using this approach, studies reported that 10-year local-regional recurrence risk was less than 15% (4–6). Conversely, randomized trials from Europe
INTRODUCTION Radiation therapy has an important role in the multidisciplinary management of patients with breast cancer. The most recently published meta-analysis by the Early Breast Cancer Trialists’ Cooperative Group indicated that radiation decreased the probability of local-regional recurrence and improved overall survival when used as a component of breastconservative therapy, and for patients with positive lymph nodes, when used after mastectomy and axillary clearance (1). Indications for when to use radiation after mastectomy are unclear despite more than 50 years of study. Results from the Early Breast Cancer Trialists’ Cooperative Group meta-analysis and the most recent randomized trials that investigated
PA, November 5–9, 2006. Supported in part by the Nellie B. Connally Breast Cancer Research Fund and the Arlette and William Coleman Foundation. Conflict of interest: none. Received Sept 4, 2007, and in revised form Nov 9, 2007. Accepted for publication Nov 9, 2007.
Reprint requests to: Thomas A. Buchholz, M.D., Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcolmbe Boulevard, Unit 1202, Houston, TX 77030. Tel: (713) 563-2335; Fax: (713) 563-6940; E-mail: [email protected] Presented at the 48th Annual Meeting of the American Society of Therapeutic Radiology and Oncology (ASTRO), Philadelphia, 1022
Radiation use for one to three positive lymph nodes d T. A. BUCHHOLZ et al.
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Table 1. Demographic and disease characteristics of the study populations
Diagnosis year
Age group (y)
Race
SEER registry
Tumor size (cm) Positive nodes Grade
Estrogen receptor status Progesterone receptor status
BCT + XRT (%)
MRM w/o XRT (%)
(n = 12,693)
(n = 18,902)
p*
2.22 2.26 2.49 3.14 5.14 5.46 5.59 6.33 7.13 7.72 10.34 10.14 10.52 10.46 11.05 19.22 30.21 24.31 18.35 7.92 76.70
6.62 6.25 5.86 5.91 7.89 7.28 6.88 7.02 6.70 5.88 6.43 6.80 6.59 7.29 6.59 17.47 23.37 21.76 22.06 15.35 75.11
<0.0001
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 25–44 45–54 55–64 65–74 $75 White non-Hispanic Black Hispanic Other San FranciscoOakland Connecticut Detroit Hawaii Iowa New Mexico Seattle Utah Atlanta Alaska San Jose Los Angeles Rural Georgia 0–2.0 2.1–5.0 1 2 3 1 2 3 Unknown Positive
8.13 7.03 8.14 15.65
9.18 7.09 8.61 12.44
9.77 10.12 3.66 7.49 4.47 15.93 0.06 6.85 0.09 5.61 20.19 0.10 66.23 33.77 62.37 25.30 12.33 13.40 40.31 35.77 10.52 67.96
10.79 14.24 2.97 13.17 4.60 10.83 0.03 7.85 0.23 5.29 17.22 0.34 50.97 49.03 54.61 29.09 16.31 8.34 34.27 36.87 20.52 57.34
Negative Unknown Positive
17.92 14.13 58.73
16.44 26.22 49.18
Negative Unknown
24.59 16.68
22.44 28.38
<0.0001
0.0027
<0.0001
<0.0001 <0.0001 <0.0001
<0.0001
<0.0001
Abbreviations: BCT + XRT = breast-conservative therapy with radiation; MRM w/o XRT = modified radical mastectomy without radiation; SEER = Surveillance, Epidemiology, and End Results. * Chi-square test.
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Table 2. Cox multivariable regression analysis for breast cancer deaths
Fig. 1. Freedom from breast cancer death curves for patients treated with breast conservative therapy with radiation (BCT + RT; dark line) vs. those treated with mastectomy without radiation (MRM w/o RT; lighter line). BCT + RT had improved breast cancer survival with a Cox adjusted hazard ratio (HR) of 1.19.
and Canada in which less extensive axillary surgery was performed reported a local-regional recurrence rate of 30% or greater for patients with one to three positive nodes (2, 3). With the lower absolute risk of persistent local-regional disease in the United States series, the local-regional benefits of radiation would be predicted to be much less than those reported from the European and Canadian trials. Consequently, whether adjuvant radiation would favorably affect survival for this cohort of patients treated in the United States is unknown. The question of whether adjuvant radiation provides a therapeutic advantage for patients with Stage II disease and one to three positive lymph nodes treated by using a modified radical mastectomy and standard systemic therapies would be addressed best through a prospective randomized trial. The potential benefits associated with radiation for this cohort would be predicted to be modest, and as such, a relatively large sample size would be needed. Such a trial was initiated in the United States, but unfortunately failed to meet accrual goals. An alternative method to study this question is to retrospectively investigate data within a large US database. This method was used by Smith et al. (7), who analyzed benefits of postmastectomy radiation in the Surveillance, Epidemiology, and End Results (SEER) data set by comparing the outcome of patients treated with mastectomy with those treated with mastectomy and radiation. This study found radiation use to be associated with improved survival in patients with more advanced nodal disease, but did not find radiation use to be independently associated with improved survival in patients with one to three positive lymph nodes. However, it is likely that hidden biases affected these results because the decision to use radiation after mastectomy was not randomized. Here, we use an alternative comparison to study the benefits of radiation for patients with Stage II disease with one to three positive lymph nodes by using SEER data. We compared patients with this stage disease treated with breast-conservation therapy with radiation (BCT + XRT)
Hazard 95% Hazard Ratio Ratio Confidence Limits
Variable
p
MRM w/o XRT vs. BCT + XRT 1989 vs. 1988 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Age 45–54 vs. 25–44 (y) 55–64 65–74 75–84 African American vs. White Hispanic Other Tumor size (continuous variable) 2 vs. 1 Positive nodes 3 Grade 2 vs. Grade 1 Grade 3 Unknown grade ER-negative vs. ER-positive ER unknown PR-negative vs. PR-positive PR unknown
<0.0001
1.187
1.099–1.282
0.8018 0.7195 0.2147 0.1494 0.2101 0.2503 0.0507 0.0058 0.0002 <0.0001 <0.0001 0.0060 0.1171 0.8853
0.982 1.032 0.895 0.885 0.897 0.903 0.838 0.768 0.677 0.652 0.557 0.679 0.722 1.070
0.849–1.135 0.871–1.222 0.750–1.067 0.750–1.045 0.757–1.063 0.758–1.075 0.701–1.001 0.637–0.927 0.551–0.831 0.528–0.805 0.437–0.710 0.515–0.895 0.481–1.085 0.429–2.667
0.1208 0.7487 0.7522 0.0005
0.929 0.984 1.016 1.229
0.846–1.020 0.891–1.086 0.920–1.122 1.093–1.380
<0.0001 0.4519 0.0149 <0.0001
1.394 1.051 0.844 1.332
1.263–1.537 0.923–1.197 0.736–0.967 1.293–1.373
<0.0001 <0.0001
1.186 1.476
1.100–1.278 1.355–1.607
<0.0001 <0.0001 <0.0001
2.311 3.636 2.439
1.832–2.915 2.891–4.573 1.927–3.087
<0.0001 0.1865
1.523 1.144
1.368–1.696 0.937–1.397
<0.0001 0.0436
1.505 1.220
1.355–1.672 1.006–1.480
Abbreviations: MRM w/o XRT = modified radical mastectomy without radiation; BCT + XRT = breast-conservative therapy with radiation; ER = estrogen receptor; PR = progesterone receptor.
with patients treated with mastectomy without radiation (MRM + XRT). Our rationale for this approach was that radiation is indicated for all patients treated with breast conservation. Therefore, unlike its use after mastectomy, fewer disease-related biases would affect radiation-use patterns in patients treated with breast conservation. METHODS AND MATERIALS We queried the SEER registry of patients with breast cancer diagnosed from 1988 to 2002 by using selection criteria of women with malignant breast cancer, diagnosis year 1988–2002, American Joint Cancer Commission–defined Stage II disease, one to three positive lymph nodes, and age at diagnosis of 25–85 years. Women who had
Radiation use for one to three positive lymph nodes d T. A. BUCHHOLZ et al.
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Fig. 2. Freedom from breast cancer death curves for patients treated with breast conservative therapy with radiation (BCT + RT) vs. those treated with mastectomy without radiation (MRM w/o RT) according to primary disease stage. BCT + RT had improved breast cancer survival in both subsets of patients. bilateral breast cancer or another primary cancer were excluded from this study. Finally, 2,976 patients treated with mastectomy and who received radiation as a component of their primary treatment (13.6% of the mastectomy population) and 3,854 patients treated with breast conservation who did not receive radiation (23.3%) were excluded. The SEER network of cancer registries was established in 1973, and data for the treatment years of this study included Connecticut, Iowa, Hawaii, New Mexico, Utah, the metropolitan areas of San Francisco-Oakland and Detroit, and registries in Seattle-Puget Sound and Atlanta. In 1992, registries from Los Angeles, San Jose-Monterey, and the Alaska Native Tumor registry were added. The case ascertainment rate from the SEER registries was reported to be 97.5% (8). Ascertainment of inpatient treatment also was high, with sensitivity of 95% for mastectomy or lumpectomy, but ascertainment for such outpatient treatments as radiation may be somewhat lower (9). Despite this limitation, the SEER database remains the authoritative source of population-based information for cancer incidence and survival in the United States. The resulting study population consisted of 12,693 patients treated with BCT + XRT and 18,902 patients treated with MRM w/o XRT. All patients included had Stage II breast cancer with one to three positive lymph nodes. Differences between the two populations were tested by using chi-square test for categorical variables and t test for continuous variables. Breast cancer–specific and overall survival rates were calculated by using the Kaplan-Meier method, with differences between the two groups tested by means of the log-rank test. For the purpose of breast cancer–specific survival, deaths from breast cancer were determined by using the International Classification of Diseases, Ninth Revision code of 1749 or International Classification of Diseases, Tenth Revision code of C509 ascertained from death certificates. Multivariable analysis was performed using the Cox regression model. Statistical analyses were performed using SAS software (version 8.02; SAS Institute, Cary, NC).
was treated during the more recent years of the study, had a lower percentage of African-American patients, had different geographic regions of treatment, had smaller tumor sizes and lower numbers of positive lymph nodes, had lower grade disease, and had a greater percentage of estrogen receptor– positive and/or progesterone receptor–positive disease. Figure 1 shows Kaplan-Meier breast cancer–specific survival curves for the two groups. The 10-year rates were 84.2% for the BCT + XRT group vs. 78.2% for the MRM w/o XRT group (p < 0.001). The 10-year overall survival rates were also significantly different (74.3% vs. 63.1%; p < 0.001). Results of a multivariable Cox regression analysis for the end point of breast cancer–specific survival are listed in Table 2. Treatment with MRM w/o XRT was independently associated with worse breast cancer–specific survival with a hazard ratio of 1.19 (p < 0.001). The hazard ratio for treatment with MRM w/o XRT for the end point of overall survival was 1.25 (p < 0.001). Figure 2 shows breast cancer–specific survival curves for the two groups of patients stratified according to T stage. In patients with T1 disease with one to three positive lymph nodes and patients with T2 disease with one to three positive lymph nodes, radiation use was associated with improved survival. A similar finding was noted when patients were divided according to whether they had one, two, or three positive lymph nodes (Fig. 3). As shown in these curves and data from the Cox multivariable analysis listed in Table 2, BCT + XRT was associated with improved outcome in each subgroup. We also evaluated data according to grade and age and found that survival advantages associated with BCT + XRT treatment were not limited to patients with high-grade vs. intermediate-/low-grade disease or younger patients (data not shown).
RESULTS Table 1 lists disease and demographic characteristics of the two comparative populations of this study. As indicated, there were a number of statistical differences between the two groups. Specifically, the BCT + XRT population was younger,
DISCUSSION Data from this report suggest that radiation use may offer a therapeutic advantage for patients with Stage II disease
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with one to three positive lymph nodes. This advantage was seen in patients with T1 and T2 disease and across all numbers of positive lymph nodes. Using the SEER database to investigate the benefits of radiation use for patients with Stage II disease and one to three positive lymph nodes has advantages and disadvantages. The primary advantage of this method is that it provides a large sample size that permits detection of small absolute differences in outcome. Furthermore, it represents standards of US practice patterns, which may provide more clinically relevant data for patients in the United States compared with randomized studies performed in Europe and Canada. The primary disadvantage of using SEER to investigate this question is that it provides retrospective data. Therefore, decisions concerning the choice of mastectomy vs. breast-conserving surgery or use of radiation treatment for patients included in this study were made by treating physicians and patients, which introduces biases. There are many sources of bias that should be considered when interpreting the data in this study. For example, we excluded the 13.6% of patients undergoing mastectomy with Stage II disease with one to three positive lymph nodes who received postmastectomy radiation. It is likely that some of these patients were given radiation because of aggressive disease features, such as lymphovascular space invasion or positive surgical margins, which are variables not captured within SEER. By excluding these patients, the remaining cohort who did not receive postmastectomy radiation becomes a more favorable subset. Similarly, by excluding the 23.3% of breast-conservation patients who were not treated with radiation, the study BCT + XRT cohort may have been biased toward having less favorable disease. Conversely, biases likely also exist in the opposite direction. As listed in Table 1, there were clearly differences in populations that resulted from selection criteria used for type of surgical therapy. For example, patients with smaller tumors and fewer positive nodes more often were treated with breast conservation. We performed a multivariate analysis to attempt to account for some of these differences, but it is likely that additional unrecognized biases also influenced our results. For example, given the more recent years of treatment in the BCT + XRT group, it is likely that a greater percentage of patients in this cohort were treated with a more prolonged course of chemotherapy that included a taxane. It also is possible that BCT + XRT may be offered more commonly in centers with a greater levels of expertise in breast cancer than centers that more commonly treat patients with Stage II breast cancer with mastectomy. Similar biases need to be considered when interpreting the previously reported study of Smith et al. (7). These investigators studied the question of postmastectomy radiation benefit using the SEER database by comparing the population of patients treated with mastectomy alone vs. those treated with mastectomy and radiation (7). These investigators appropriately performed multivariate analysis and found no statistical survival advantage with the use of postmastectomy radiation for patients with Stage II disease and one to three positive lymph nodes. However, as previously indicated, important
Volume 71, Number 4, 2008
Fig. 3. Freedom from breast cancer death curves for patients treated with breast conservative therapy with radiation (BCT + RT) vs. those treated with mastectomy without radiation (MRM w/o RT) according to number of positive lymph nodes (LN). BCT + RT had improved breast cancer survival in all three subsets of patients.
patient and pathologic variables that can affect recurrence rates and radiation use patterns are not accounted for in SEER analyses. In addition, our results and results of previous SEER data concerning this topic may have been affected by possible underascertainment of adjuvant radiotherapy by SEER (10). SEER also does not provide details for radiation dose, treatment fields, or whether treatment was completed, and no data were available concerning adjuvant systemic therapies. Accordingly, because results from Smith et al.
Radiation use for one to three positive lymph nodes d T. A. BUCHHOLZ et al.
(7) and our results differ, the true benefits of radiation for this cohort of patients on the basis of the data available within SEER are unknown. The method we used to investigate the benefits of radiation for patients with Stage II disease with one to three positive lymph nodes and results we found are similar to a previously published meta-analysis. This meta-analysis investigated the outcome of patients who participated in randomized clinical trials and compared breast-conservation treatment with radiation vs. treatment with a modified radical mastectomy. This study found that for patients with positive lymph nodes, treatment with breast conservation with radiation was associated with a lower risk of death (hazard ratio, 0.69; p = 0.03) than those treated with mastectomy without radiation (11). Conversely, outcomes were equivalent in trials that allowed postmastectomy radiation to be used. The most recent randomized trials showing the value of radiation for patients with Stage II disease with one to three positive lymph nodes are the Danish Cooperative Breast Cancer Group 82b trial and 82c trials and Vancouver British Columbia trial. All three trials randomly assigned patients treated with mastectomy and systemic treatments to the use or omission of postmastectomy radiation. In the Danish trials, 62% of enrolled patients had one to three positive lymph nodes (2). In the Vancouver BC trial, 58% of the study participants had one to three positive lymph nodes (3). In both studies, radiation use led to a survival advantage. However, as previously noted, the local-regional recurrence risk for patients with Stage II disease with one to three positive lymph
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nodes who participated in these trials was significantly greater than the risk seen in the US cohort with similar stage disease (4–6, 12). To further investigate this, the investigators of the Danish trials recently published updated data from their studies and evaluated the outcome of only patients with one to three positive lymph nodes who had eight or more lymph nodes recovered. Even with a more complete axillary dissection, patients who received postmastectomy radiation had a significantly lower risk of local-regional recurrence at 15 years (4% vs. 27%; p < 0.001) and statistically significant improvement in survival (57% vs. 48%; p < 0.001) (13). Additional randomized trial data concerning the benefits of radiation for patients with one to three positive lymph nodes will not be available for some time. The US trial designed to investigate this question closed because of poor accrual, and a new European trial was initiated, but will require an additional 5–10 years before mature results become available. Therefore, uncertainty continues about whether all patients with one to three positive lymph nodes should be recommended to receive radiation. In conclusion, we found that radiation use as a component of breast conservation therapy is associated with a survival advantage compared with treatment with mastectomy without radiation for patients with Stage II disease with one to three positive lymph nodes. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation by randomized clinical trials.
REFERENCES 1. Early Breast Cancer Trialist’s Group: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087–2106. 2. Nielsen HM, Overgaard M, Grau C, et al. Loco-regional recurrence after mastectomy in high-risk breast cancer—Risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials. Radiother Oncol 2006;79:147–155. 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 2005;97:116–126. 4. Katz A, Strom EA, Buchholz TA, et al. Loco-regional recurrence patterns following mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 2000;18:2817–2827. 5. Recht A, Gray R, Davidson NE, et al. Locoregional failure ten years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 1999;17: 1689–1700. 6. Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: Results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 2004;22:4247–4254.
7. Smith BD, Smith GL, Haffty BG. Postmastectomy radiation and mortality in women with T1-2 node-positive breast cancer. J Clin Oncol 2005;23:1409–1419. 8. Zippin C, Lum D, Hankey BF. Completeness of hospital cancer case reporting from the SEER Program of the National Cancer Institute. Cancer 1995;76:2343–2350. 9. Malin JL, Kahn KL, Adams J, et al. Validity of cancer registry data for measuring the quality of breast cancer care. J Natl Cancer Inst 2002;94:835–844. 10. Du X, Freeman JL, Goodwin JS. Information on radiation treatment in patients with breast cancer: The advantages of the linked Medicare and SEER data. Surveillance, Epidemiology and End Results. J Clin Epidemiol 1999;52:463–470. 11. Morris AD, Morris RD, Wilson JF, et al. Breast-conserving therapy vs mastectomy in early-stage breast cancer: A metaanalysis of 10-year survival. Cancer J Sci Am 1997;3:6–12. 12. Truong PT, Woodward WA, Thames HD, et al. The ratio of positive to excised nodes identifies high-risk subsets and reduces inter-institutional differences in locoregional recurrence risk estimates in breast cancer patients with 1-3 positive nodes: An analysis of prospective data from British Columbia and the M.D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 2007;68:59–65. 13. 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 2007;82:247–253.
doi:10.1016/j.ijrobp.2007.11.036
CLINICAL INVESTIGATION
Breast
RADIATION USE AND LONG-TERM SURVIVAL IN BREAST CANCER PATIENTS WITH T1, T2 PRIMARY TUMORS AND ONE TO THREE POSITIVE AXILLARY LYMPH NODES THOMAS A. BUCHHOLZ, M.D.,* WENDY A. WOODWARD, M.D., PH.D.,* ZHIGANG DUAN, B.MED. M.S.,y SHENYING FANG, M.S.,y JULIA L. OH, M.D.,* WELELA TEREFFE, M.D.,* ERIC A. STROM, M.D.,* GEORGE H. PERKINS, M.D.,* TSE-KUAN YU, M.D., PH.D.,* KELLY K. HUNT, M.D.,z FUNDA MERICBERNSTAM, M.D.,z GABRIEL N. HORTOBAGYI, M.D.,y AND SHARON H. GIORDANO, M.D., M.P.H.y Departments of *Radiation Oncology, y Breast Medical Oncology, and z Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Background: For patients with Stage II breast cancer with one to three positive lymph nodes, controversy exists about whether radiation as a component of treatment provides a survival benefit. Methods and Materials: We analyzed data from patients with Stage II breast cancer with one to three positive lymph nodes diagnosed from 1988–2002 in the Surveillance, Epidemiology, and End Results registry and compared the outcome of 12,693 patients treated with breast-conservation therapy with radiation (BCT + XRT) with the 18,902 patients treated with mastectomy without radiation (MRM w/o XRT). Results: Patients treated with BCT + XRT were younger, were more likely to be treated in recent years of the study period, more commonly had T1 primary tumors, and had fewer involved nodes compared with those treated with MRM w/o XRT (p < 0.001 for all differences). The 15-year breast cancer–specific survival rate for the BCT + XRT group was 80% vs. 72% for the MRM w/o XRT group (p < 0.001). Cox regression analysis showed that MRM w/o XRT was associated with a hazard ratio for breast cancer death of 1.19 (p < 0.001) and for overall death of 1.25 (p < 0.001). The survival benefit in the BCT + XRT group was not limited to subgroups with high-risk disease features. Conclusions: Radiation use was independently associated with improved survival for patients with Stage II breast cancer with one to three positive lymph nodes. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation in randomized clinical trials. Ó 2008 Elsevier Inc. Mastectomy, Radiation, Breast cancer, Stage II.
the benefits of postmastectomy radiation suggested that all patients with lymph node–positive disease benefited from this adjuvant treatment (1–3). However, other large studies investigating local-regional failure patterns after mastectomy and systemic treatments identified subpopulations of patients with lymph node–positive breast cancer for whom the risk of local-regional recurrence was low. In the United States, most patients with lymph node–positive disease who were treated with mastectomy underwent standard axillary Level I–II lymph node dissection and receive systemic therapy. For patients with Stage II breast cancer with one to three positive lymph nodes who were treated by using this approach, studies reported that 10-year local-regional recurrence risk was less than 15% (4–6). Conversely, randomized trials from Europe
INTRODUCTION Radiation therapy has an important role in the multidisciplinary management of patients with breast cancer. The most recently published meta-analysis by the Early Breast Cancer Trialists’ Cooperative Group indicated that radiation decreased the probability of local-regional recurrence and improved overall survival when used as a component of breastconservative therapy, and for patients with positive lymph nodes, when used after mastectomy and axillary clearance (1). Indications for when to use radiation after mastectomy are unclear despite more than 50 years of study. Results from the Early Breast Cancer Trialists’ Cooperative Group meta-analysis and the most recent randomized trials that investigated
PA, November 5–9, 2006. Supported in part by the Nellie B. Connally Breast Cancer Research Fund and the Arlette and William Coleman Foundation. Conflict of interest: none. Received Sept 4, 2007, and in revised form Nov 9, 2007. Accepted for publication Nov 9, 2007.
Reprint requests to: Thomas A. Buchholz, M.D., Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcolmbe Boulevard, Unit 1202, Houston, TX 77030. Tel: (713) 563-2335; Fax: (713) 563-6940; E-mail: [email protected] Presented at the 48th Annual Meeting of the American Society of Therapeutic Radiology and Oncology (ASTRO), Philadelphia, 1022
Radiation use for one to three positive lymph nodes d T. A. BUCHHOLZ et al.
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Table 1. Demographic and disease characteristics of the study populations
Diagnosis year
Age group (y)
Race
SEER registry
Tumor size (cm) Positive nodes Grade
Estrogen receptor status Progesterone receptor status
BCT + XRT (%)
MRM w/o XRT (%)
(n = 12,693)
(n = 18,902)
p*
2.22 2.26 2.49 3.14 5.14 5.46 5.59 6.33 7.13 7.72 10.34 10.14 10.52 10.46 11.05 19.22 30.21 24.31 18.35 7.92 76.70
6.62 6.25 5.86 5.91 7.89 7.28 6.88 7.02 6.70 5.88 6.43 6.80 6.59 7.29 6.59 17.47 23.37 21.76 22.06 15.35 75.11
<0.0001
1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 25–44 45–54 55–64 65–74 $75 White non-Hispanic Black Hispanic Other San FranciscoOakland Connecticut Detroit Hawaii Iowa New Mexico Seattle Utah Atlanta Alaska San Jose Los Angeles Rural Georgia 0–2.0 2.1–5.0 1 2 3 1 2 3 Unknown Positive
8.13 7.03 8.14 15.65
9.18 7.09 8.61 12.44
9.77 10.12 3.66 7.49 4.47 15.93 0.06 6.85 0.09 5.61 20.19 0.10 66.23 33.77 62.37 25.30 12.33 13.40 40.31 35.77 10.52 67.96
10.79 14.24 2.97 13.17 4.60 10.83 0.03 7.85 0.23 5.29 17.22 0.34 50.97 49.03 54.61 29.09 16.31 8.34 34.27 36.87 20.52 57.34
Negative Unknown Positive
17.92 14.13 58.73
16.44 26.22 49.18
Negative Unknown
24.59 16.68
22.44 28.38
<0.0001
0.0027
<0.0001
<0.0001 <0.0001 <0.0001
<0.0001
<0.0001
Abbreviations: BCT + XRT = breast-conservative therapy with radiation; MRM w/o XRT = modified radical mastectomy without radiation; SEER = Surveillance, Epidemiology, and End Results. * Chi-square test.
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Table 2. Cox multivariable regression analysis for breast cancer deaths
Fig. 1. Freedom from breast cancer death curves for patients treated with breast conservative therapy with radiation (BCT + RT; dark line) vs. those treated with mastectomy without radiation (MRM w/o RT; lighter line). BCT + RT had improved breast cancer survival with a Cox adjusted hazard ratio (HR) of 1.19.
and Canada in which less extensive axillary surgery was performed reported a local-regional recurrence rate of 30% or greater for patients with one to three positive nodes (2, 3). With the lower absolute risk of persistent local-regional disease in the United States series, the local-regional benefits of radiation would be predicted to be much less than those reported from the European and Canadian trials. Consequently, whether adjuvant radiation would favorably affect survival for this cohort of patients treated in the United States is unknown. The question of whether adjuvant radiation provides a therapeutic advantage for patients with Stage II disease and one to three positive lymph nodes treated by using a modified radical mastectomy and standard systemic therapies would be addressed best through a prospective randomized trial. The potential benefits associated with radiation for this cohort would be predicted to be modest, and as such, a relatively large sample size would be needed. Such a trial was initiated in the United States, but unfortunately failed to meet accrual goals. An alternative method to study this question is to retrospectively investigate data within a large US database. This method was used by Smith et al. (7), who analyzed benefits of postmastectomy radiation in the Surveillance, Epidemiology, and End Results (SEER) data set by comparing the outcome of patients treated with mastectomy with those treated with mastectomy and radiation. This study found radiation use to be associated with improved survival in patients with more advanced nodal disease, but did not find radiation use to be independently associated with improved survival in patients with one to three positive lymph nodes. However, it is likely that hidden biases affected these results because the decision to use radiation after mastectomy was not randomized. Here, we use an alternative comparison to study the benefits of radiation for patients with Stage II disease with one to three positive lymph nodes by using SEER data. We compared patients with this stage disease treated with breast-conservation therapy with radiation (BCT + XRT)
Hazard 95% Hazard Ratio Ratio Confidence Limits
Variable
p
MRM w/o XRT vs. BCT + XRT 1989 vs. 1988 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Age 45–54 vs. 25–44 (y) 55–64 65–74 75–84 African American vs. White Hispanic Other Tumor size (continuous variable) 2 vs. 1 Positive nodes 3 Grade 2 vs. Grade 1 Grade 3 Unknown grade ER-negative vs. ER-positive ER unknown PR-negative vs. PR-positive PR unknown
<0.0001
1.187
1.099–1.282
0.8018 0.7195 0.2147 0.1494 0.2101 0.2503 0.0507 0.0058 0.0002 <0.0001 <0.0001 0.0060 0.1171 0.8853
0.982 1.032 0.895 0.885 0.897 0.903 0.838 0.768 0.677 0.652 0.557 0.679 0.722 1.070
0.849–1.135 0.871–1.222 0.750–1.067 0.750–1.045 0.757–1.063 0.758–1.075 0.701–1.001 0.637–0.927 0.551–0.831 0.528–0.805 0.437–0.710 0.515–0.895 0.481–1.085 0.429–2.667
0.1208 0.7487 0.7522 0.0005
0.929 0.984 1.016 1.229
0.846–1.020 0.891–1.086 0.920–1.122 1.093–1.380
<0.0001 0.4519 0.0149 <0.0001
1.394 1.051 0.844 1.332
1.263–1.537 0.923–1.197 0.736–0.967 1.293–1.373
<0.0001 <0.0001
1.186 1.476
1.100–1.278 1.355–1.607
<0.0001 <0.0001 <0.0001
2.311 3.636 2.439
1.832–2.915 2.891–4.573 1.927–3.087
<0.0001 0.1865
1.523 1.144
1.368–1.696 0.937–1.397
<0.0001 0.0436
1.505 1.220
1.355–1.672 1.006–1.480
Abbreviations: MRM w/o XRT = modified radical mastectomy without radiation; BCT + XRT = breast-conservative therapy with radiation; ER = estrogen receptor; PR = progesterone receptor.
with patients treated with mastectomy without radiation (MRM + XRT). Our rationale for this approach was that radiation is indicated for all patients treated with breast conservation. Therefore, unlike its use after mastectomy, fewer disease-related biases would affect radiation-use patterns in patients treated with breast conservation. METHODS AND MATERIALS We queried the SEER registry of patients with breast cancer diagnosed from 1988 to 2002 by using selection criteria of women with malignant breast cancer, diagnosis year 1988–2002, American Joint Cancer Commission–defined Stage II disease, one to three positive lymph nodes, and age at diagnosis of 25–85 years. Women who had
Radiation use for one to three positive lymph nodes d T. A. BUCHHOLZ et al.
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Fig. 2. Freedom from breast cancer death curves for patients treated with breast conservative therapy with radiation (BCT + RT) vs. those treated with mastectomy without radiation (MRM w/o RT) according to primary disease stage. BCT + RT had improved breast cancer survival in both subsets of patients. bilateral breast cancer or another primary cancer were excluded from this study. Finally, 2,976 patients treated with mastectomy and who received radiation as a component of their primary treatment (13.6% of the mastectomy population) and 3,854 patients treated with breast conservation who did not receive radiation (23.3%) were excluded. The SEER network of cancer registries was established in 1973, and data for the treatment years of this study included Connecticut, Iowa, Hawaii, New Mexico, Utah, the metropolitan areas of San Francisco-Oakland and Detroit, and registries in Seattle-Puget Sound and Atlanta. In 1992, registries from Los Angeles, San Jose-Monterey, and the Alaska Native Tumor registry were added. The case ascertainment rate from the SEER registries was reported to be 97.5% (8). Ascertainment of inpatient treatment also was high, with sensitivity of 95% for mastectomy or lumpectomy, but ascertainment for such outpatient treatments as radiation may be somewhat lower (9). Despite this limitation, the SEER database remains the authoritative source of population-based information for cancer incidence and survival in the United States. The resulting study population consisted of 12,693 patients treated with BCT + XRT and 18,902 patients treated with MRM w/o XRT. All patients included had Stage II breast cancer with one to three positive lymph nodes. Differences between the two populations were tested by using chi-square test for categorical variables and t test for continuous variables. Breast cancer–specific and overall survival rates were calculated by using the Kaplan-Meier method, with differences between the two groups tested by means of the log-rank test. For the purpose of breast cancer–specific survival, deaths from breast cancer were determined by using the International Classification of Diseases, Ninth Revision code of 1749 or International Classification of Diseases, Tenth Revision code of C509 ascertained from death certificates. Multivariable analysis was performed using the Cox regression model. Statistical analyses were performed using SAS software (version 8.02; SAS Institute, Cary, NC).
was treated during the more recent years of the study, had a lower percentage of African-American patients, had different geographic regions of treatment, had smaller tumor sizes and lower numbers of positive lymph nodes, had lower grade disease, and had a greater percentage of estrogen receptor– positive and/or progesterone receptor–positive disease. Figure 1 shows Kaplan-Meier breast cancer–specific survival curves for the two groups. The 10-year rates were 84.2% for the BCT + XRT group vs. 78.2% for the MRM w/o XRT group (p < 0.001). The 10-year overall survival rates were also significantly different (74.3% vs. 63.1%; p < 0.001). Results of a multivariable Cox regression analysis for the end point of breast cancer–specific survival are listed in Table 2. Treatment with MRM w/o XRT was independently associated with worse breast cancer–specific survival with a hazard ratio of 1.19 (p < 0.001). The hazard ratio for treatment with MRM w/o XRT for the end point of overall survival was 1.25 (p < 0.001). Figure 2 shows breast cancer–specific survival curves for the two groups of patients stratified according to T stage. In patients with T1 disease with one to three positive lymph nodes and patients with T2 disease with one to three positive lymph nodes, radiation use was associated with improved survival. A similar finding was noted when patients were divided according to whether they had one, two, or three positive lymph nodes (Fig. 3). As shown in these curves and data from the Cox multivariable analysis listed in Table 2, BCT + XRT was associated with improved outcome in each subgroup. We also evaluated data according to grade and age and found that survival advantages associated with BCT + XRT treatment were not limited to patients with high-grade vs. intermediate-/low-grade disease or younger patients (data not shown).
RESULTS Table 1 lists disease and demographic characteristics of the two comparative populations of this study. As indicated, there were a number of statistical differences between the two groups. Specifically, the BCT + XRT population was younger,
DISCUSSION Data from this report suggest that radiation use may offer a therapeutic advantage for patients with Stage II disease
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with one to three positive lymph nodes. This advantage was seen in patients with T1 and T2 disease and across all numbers of positive lymph nodes. Using the SEER database to investigate the benefits of radiation use for patients with Stage II disease and one to three positive lymph nodes has advantages and disadvantages. The primary advantage of this method is that it provides a large sample size that permits detection of small absolute differences in outcome. Furthermore, it represents standards of US practice patterns, which may provide more clinically relevant data for patients in the United States compared with randomized studies performed in Europe and Canada. The primary disadvantage of using SEER to investigate this question is that it provides retrospective data. Therefore, decisions concerning the choice of mastectomy vs. breast-conserving surgery or use of radiation treatment for patients included in this study were made by treating physicians and patients, which introduces biases. There are many sources of bias that should be considered when interpreting the data in this study. For example, we excluded the 13.6% of patients undergoing mastectomy with Stage II disease with one to three positive lymph nodes who received postmastectomy radiation. It is likely that some of these patients were given radiation because of aggressive disease features, such as lymphovascular space invasion or positive surgical margins, which are variables not captured within SEER. By excluding these patients, the remaining cohort who did not receive postmastectomy radiation becomes a more favorable subset. Similarly, by excluding the 23.3% of breast-conservation patients who were not treated with radiation, the study BCT + XRT cohort may have been biased toward having less favorable disease. Conversely, biases likely also exist in the opposite direction. As listed in Table 1, there were clearly differences in populations that resulted from selection criteria used for type of surgical therapy. For example, patients with smaller tumors and fewer positive nodes more often were treated with breast conservation. We performed a multivariate analysis to attempt to account for some of these differences, but it is likely that additional unrecognized biases also influenced our results. For example, given the more recent years of treatment in the BCT + XRT group, it is likely that a greater percentage of patients in this cohort were treated with a more prolonged course of chemotherapy that included a taxane. It also is possible that BCT + XRT may be offered more commonly in centers with a greater levels of expertise in breast cancer than centers that more commonly treat patients with Stage II breast cancer with mastectomy. Similar biases need to be considered when interpreting the previously reported study of Smith et al. (7). These investigators studied the question of postmastectomy radiation benefit using the SEER database by comparing the population of patients treated with mastectomy alone vs. those treated with mastectomy and radiation (7). These investigators appropriately performed multivariate analysis and found no statistical survival advantage with the use of postmastectomy radiation for patients with Stage II disease and one to three positive lymph nodes. However, as previously indicated, important
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Fig. 3. Freedom from breast cancer death curves for patients treated with breast conservative therapy with radiation (BCT + RT) vs. those treated with mastectomy without radiation (MRM w/o RT) according to number of positive lymph nodes (LN). BCT + RT had improved breast cancer survival in all three subsets of patients.
patient and pathologic variables that can affect recurrence rates and radiation use patterns are not accounted for in SEER analyses. In addition, our results and results of previous SEER data concerning this topic may have been affected by possible underascertainment of adjuvant radiotherapy by SEER (10). SEER also does not provide details for radiation dose, treatment fields, or whether treatment was completed, and no data were available concerning adjuvant systemic therapies. Accordingly, because results from Smith et al.
Radiation use for one to three positive lymph nodes d T. A. BUCHHOLZ et al.
(7) and our results differ, the true benefits of radiation for this cohort of patients on the basis of the data available within SEER are unknown. The method we used to investigate the benefits of radiation for patients with Stage II disease with one to three positive lymph nodes and results we found are similar to a previously published meta-analysis. This meta-analysis investigated the outcome of patients who participated in randomized clinical trials and compared breast-conservation treatment with radiation vs. treatment with a modified radical mastectomy. This study found that for patients with positive lymph nodes, treatment with breast conservation with radiation was associated with a lower risk of death (hazard ratio, 0.69; p = 0.03) than those treated with mastectomy without radiation (11). Conversely, outcomes were equivalent in trials that allowed postmastectomy radiation to be used. The most recent randomized trials showing the value of radiation for patients with Stage II disease with one to three positive lymph nodes are the Danish Cooperative Breast Cancer Group 82b trial and 82c trials and Vancouver British Columbia trial. All three trials randomly assigned patients treated with mastectomy and systemic treatments to the use or omission of postmastectomy radiation. In the Danish trials, 62% of enrolled patients had one to three positive lymph nodes (2). In the Vancouver BC trial, 58% of the study participants had one to three positive lymph nodes (3). In both studies, radiation use led to a survival advantage. However, as previously noted, the local-regional recurrence risk for patients with Stage II disease with one to three positive lymph
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nodes who participated in these trials was significantly greater than the risk seen in the US cohort with similar stage disease (4–6, 12). To further investigate this, the investigators of the Danish trials recently published updated data from their studies and evaluated the outcome of only patients with one to three positive lymph nodes who had eight or more lymph nodes recovered. Even with a more complete axillary dissection, patients who received postmastectomy radiation had a significantly lower risk of local-regional recurrence at 15 years (4% vs. 27%; p < 0.001) and statistically significant improvement in survival (57% vs. 48%; p < 0.001) (13). Additional randomized trial data concerning the benefits of radiation for patients with one to three positive lymph nodes will not be available for some time. The US trial designed to investigate this question closed because of poor accrual, and a new European trial was initiated, but will require an additional 5–10 years before mature results become available. Therefore, uncertainty continues about whether all patients with one to three positive lymph nodes should be recommended to receive radiation. In conclusion, we found that radiation use as a component of breast conservation therapy is associated with a survival advantage compared with treatment with mastectomy without radiation for patients with Stage II disease with one to three positive lymph nodes. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation by randomized clinical trials.
REFERENCES 1. Early Breast Cancer Trialist’s Group: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087–2106. 2. Nielsen HM, Overgaard M, Grau C, et al. Loco-regional recurrence after mastectomy in high-risk breast cancer—Risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials. Radiother Oncol 2006;79:147–155. 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 2005;97:116–126. 4. Katz A, Strom EA, Buchholz TA, et al. Loco-regional recurrence patterns following mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 2000;18:2817–2827. 5. Recht A, Gray R, Davidson NE, et al. Locoregional failure ten years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 1999;17: 1689–1700. 6. Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: Results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 2004;22:4247–4254.
7. Smith BD, Smith GL, Haffty BG. Postmastectomy radiation and mortality in women with T1-2 node-positive breast cancer. J Clin Oncol 2005;23:1409–1419. 8. Zippin C, Lum D, Hankey BF. Completeness of hospital cancer case reporting from the SEER Program of the National Cancer Institute. Cancer 1995;76:2343–2350. 9. Malin JL, Kahn KL, Adams J, et al. Validity of cancer registry data for measuring the quality of breast cancer care. J Natl Cancer Inst 2002;94:835–844. 10. Du X, Freeman JL, Goodwin JS. Information on radiation treatment in patients with breast cancer: The advantages of the linked Medicare and SEER data. Surveillance, Epidemiology and End Results. J Clin Epidemiol 1999;52:463–470. 11. Morris AD, Morris RD, Wilson JF, et al. Breast-conserving therapy vs mastectomy in early-stage breast cancer: A metaanalysis of 10-year survival. Cancer J Sci Am 1997;3:6–12. 12. Truong PT, Woodward WA, Thames HD, et al. The ratio of positive to excised nodes identifies high-risk subsets and reduces inter-institutional differences in locoregional recurrence risk estimates in breast cancer patients with 1-3 positive nodes: An analysis of prospective data from British Columbia and the M.D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 2007;68:59–65. 13. 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 2007;82:247–253.