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© The Author 2006. Published by Oxford University Press.
ARTICLE |
Effectiveness of Radiation Therapy for Older Women With Early Breast Cancer
Affiliations of authors: Departments of Therapeutic Radiology (BDS, BGH) and Internal Medicine (CPG, GLS, DHG), Yale University School of Medicine, New Haven, CT; Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center (JEB), New York, NY; Department of Radiation Oncology, University of Medicine and Dentistry New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ (BGH)
Correspondence to: Benjamin D. Smith, MD, Department of Therapeutic Radiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520–8040 (e-mail: bensmith{at}alumni.rice.edu).
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ABSTRACT |
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 TopNotes Abstract IntroductionPatients and methodsResultsDiscussionReferences |
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Background: Recent clinical trials have questioned the necessity of breast radiation therapy for older women with early breast cancer. However, the effectiveness of radiation therapy for older women in the community setting has not been addressed. Methods: We used the Surveillance, Epidemiology, and End Results (SEER)–Medicare database from January 1, 1992, through December 31, 1999, to identify 8724 women aged 70 years or older treated with conservative surgery for small, lymph node–negative, estrogen receptor–positive (or unknown receptor status) breast cancer. We used a proportional hazards model to test whether radiation therapy was associated with a lower risk of a combined outcome, defined as a second ipsilateral breast cancer reported by SEER and/or a subsequent mastectomy reported by Medicare claims. All statistical tests were two-sided. Results: Radiation therapy, compared with no radiation therapy, was associated with a lower risk of the combined outcome (hazard ratio = 0.19, 95% confidence interval = 0.14 to 0.28). Radiation therapy was associated with an absolute risk reduction of 4.0 events per 100 women at 5 years (i.e., from 5.1 events without radiation therapy to 1.1 with radiation therapy) and 5.7 events per 100 persons at 8 years (i.e., from 8.0 events without radiation therapy to 2.3 with radiation therapy) (P<.001, log-rank test). Radiation therapy was most likely to benefit those aged 70–79 years without comorbidity (number needed to treat [NNT] to prevent one event = 21 to 22 patients) and was least likely to benefit those aged 80 years or older with moderate to severe comorbidity (NNT = 61 to 125 patients). Conclusion: For older women with early breast cancer, radiation therapy was associated with a lower risk of a second ipsilateral breast cancer and subsequent mastectomy. Patients aged 70–79 years with minimal comorbidity were the most likely to benefit, and older patients with substantial comorbidity were least likely to benefit.
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INTRODUCTION |
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TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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For many years, breast radiation therapy after conservative surgery has been a standard of care for patients with early breast cancer (1–4). However, a recent randomized trial from the Cancer and Leukemia Group B (trial C9343) explored whether breast radiation therapy was necessary in those aged 70 years and older with small, estrogen receptor (ER)–positive (or unknown ER status), clinically lymph node–negative breast cancer treated with conservative surgery and tamoxifen (5). Although radiation therapy conferred a statistically significant reduction in the risk of local–regional relapse, the absolute risk reduction was only three events per 100 persons at 5 years of follow up.
Given the small absolute benefit of radiation therapy, coupled with its cost (6) and morbidity (5), new clinical guidelines have recommended omission of breast radiation therapy for women who meet the entry criteria for trial C9343 (7). Although meaningful differences may exist between patients who enroll in clinical trials and those in the general population (8–11), the effectiveness of breast radiation therapy in the community setting has not been addressed (12). Identification of those who are most—and least—likely to benefit from breast radiation therapy would allow clinicians to tailor their treatment recommendations appropriately.
To address these critical issues, we identified patients in the Surveillance, Epidemiology, and End Results (SEER)–Medicare database who would have been eligible for the C9343 trial. We investigated whether radiation therapy was associated with a lower risk of a second breast cancer event—i.e., a combined outcome defined as a second ipsilateral breast cancer as reported by SEER and/or a subsequent mastectomy as reported by Medicare claims.
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PATIENTS AND METHODS |
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TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Data Source
The National Cancer Institute's SEER–Medicare database tracks incident malignancies in Medicare beneficiaries, linking tumor-specific variables coded by local SEER registries to Medicare claims. During the study period of January 1, 1992, through December 31, 1999, data were available from 11 tumor registries representing approximately 14% of the United States' population (13).
Study Sample and Outcomes
From 1992 through 1999, 60 717 women aged 70 years or older with breast cancer were identified in the database. The following women were excluded because they would not have met entry criteria for trial C9343: tumor size not reported or greater than 2.0 cm (26 161 patients excluded); no invasive component (6679 patients excluded); histology not consistent with epithelial origin (1355 patients excluded); clinical stage T4 (5004 patients excluded); ER-negative status (6454 patients excluded); involved regional lymph nodes (13 799 patients excluded); distant metastasis at presentation (3332 patients excluded); stage not reported (2611 patients excluded); not treated with breast-conserving surgery (33 859 patients excluded); history of prior malignancy (1706 patients excluded); bilateral disease (51 patients excluded); and disease not pathologically confirmed (1797 women excluded). Thus, 13 319 patients met all clinical entry criteria (patients could also be excluded for more than one reason; a total of 9413 patients were excluded solely because of treatment with mastectomy).
Within this clinical group, patients with a second primary cancer diagnosed within 9 months after the index primary were excluded (435 patients) because billing records could not discriminate between procedures performed for the index cancer versus the second cancer. Patients with inadequate Medicare records (641 patients without Part A and B Medicare coverage and 3547 patients without fee-for-service coverage from 12 months before diagnosis to 9 months after diagnosis) were also excluded, leaving 8932 patients with adequate baseline Medicare claims (patients could, again, be excluded for more than one reason).
Cancer-specific treatments received within 9 months of initial diagnosis were considered to represent treatment for the index cancer (14). A sensitivity analysis tested whether inclusion of treatments received within only 6 months or up to 12 months after initial diagnosis would alter the study results. The follow-up period began 9 months after diagnosis and continued through December 31, 2002. The primary outcome—a second breast cancer event—was a combined outcome defined as a second ipsilateral, pathologically confirmed, invasive breast cancer reported by SEER and/or a subsequent mastectomy reported by Medicare claims. The secondary outcome was risk of repeat breast-conserving surgery reported by Medicare claims. Breast-conserving surgery was not included in the primary outcome because it may be performed to rule out cancer and is, therefore, not specific for local relapse.
Medicare claims do not consistently report laterality for breast surgical procedures. Because laterality is important in establishing a second ipsilateral versus contralateral event, we excluded two patients with unknown laterality at initial diagnosis and 206 patients reported by SEER as experiencing any contralateral breast event in the follow-up period. The final cohort therefore included 8724 patients aged 70 years or older who were treated with conservative surgery for small, lymph node–negative, invasive breast cancer that was ER–positive (or of unknown ER status). A sensitivity analysis tested whether inclusion of patients with contralateral breast events would alter the study results.
Treatment-Related Variables
Initial surgery was determined from the site-specific surgery variable in SEER and from Medicare claims (breast-conserving surgery: International Classification of Diseases-9 [ICD-9] Procedure Codes 85.20, 85.21, 85.22, 85.23, or 85.25; Current Procedural Terminology Codes 19110, 19120, 19125, 19160, or 19162; mastectomy: ICD-9 Procedure Codes 85.41, 85.42, 85.43, 85.44, 85.45, 85.46, 85.47, or 85.48; or Current Procedural Terminology Codes 19180, 19182, 19200, 19220, or 19240) (15–19). The most aggressive surgical procedure reported by SEER or Medicare within 9 months of diagnosis was considered the definitive surgery. Treatment with radiation therapy was obtained from SEER data and Medicare claims (ICD-9 Procedure Codes 92.21–92.27 or 92.29; ICD-9 Diagnosis Codes V58.0, V66.1, or V67.1; Current Procedural Terminology Codes 77401–77525 or 77761–77799; or Revenue Center Codes 0330 or 0333) (14,16–20). Patients were considered to have received radiation therapy if either SEER or Medicare reported treatment with radiation therapy within 9 months of diagnosis. Treatment with chemotherapy within 9 months of diagnosis was determined from Medicare claims (ICD-9 Procedure Code 99.25; ICD-9 Diagnosis Codes V58.1, V66.2, or V67.2; Current Procedural Terminology Codes 96400–96549; Health Care Procedure Coding System Codes J9000–J9999 or Q0083–Q0085; or Revenue Center Codes 0331, 0332, or 0335) (16–19,21,22). The method of axillary lymph node assessment was determined from SEER data (pathologic assessment if at least one lymph node was sampled, otherwise a clinical assessment).
Other Variables
Patient characteristics included age at diagnosis, race (white, black, white Hispanic, Asian/Pacific Islander, or other/unknown), year of diagnosis, marital status (widowed, married, single, separated/divorced, or unknown), SEER registry, urban versus rural residence (big metropolitan, metropolitan, urban, less urban, or rural), median income of census tract or zip code (census tract data were used if available, otherwise zip code data were used) (23), percentage of adults in census tract or zip code with less than 12 years education (census tract data were used if available, otherwise zip code data were used) (23), and number of physician visits on separate days during a prediagnosis interval from 12 months to 1 month. Distance from the patient's zip code to the nearest radiotherapy facility was calculated from radiotherapy facility zip codes provided by the American College of Radiology (ZIPFind Deluxe 5.0, Xionetic Technologies, Inc., Bozeman, MT). A modified Charlson comorbidity index (24–26) was calculated from Part A and Part B Medicare claims during a prediagnosis interval from 12 months to 1 month. To enhance specificity, Part B diagnosis codes were included only if they appeared more than once over a period of more than 30 days or in Part A claims as well (27,28).
Tumor characteristics included size, location within the breast (inner quadrant, outer quadrant or central, overlapping, or unknown) (29), grade (well differentiated, moderately differentiated, poorly or undifferentiated, or unknown), histology (ductal, lobular, or other) (30), ER status (positive, borderline, negative, or unknown, as reported by SEER), progesterone receptor status (positive, borderline, negative, or unknown, as reported by SEER), and laterality (right or left). Hospital characteristics included teaching status (yes or no), which was self-reported in the Hospital Cost Report Information Systems files available for 1996, 1998, and 2000 (31). Data regarding surgical margin status and adjuvant endocrine therapy were not reported by SEER–Medicare. All variables are summarized in Appendix A.
Statistical Analysis
Because the risk of local relapse at 5 and 8 years is a commonly reported endpoint in breast cancer clinical trials (3–5,32,33), the unadjusted risk of each outcome at 5 and 8 years was estimated by use of the Kaplan–Meier method. The Kaplan–Meier method was selected to provide estimates that could be directly compared with the results of trial C9343. Unadjusted associations between radiation therapy and outcomes were tested by use of the log-rank test. Patients were censored at the time of death, loss of Medicare Part A or B coverage, or loss of fee-for-service coverage. If none of these events occurred, patients were censored at the end of the follow-up period, December 31, 2002.
The hazard functions of the groups receiving radiation therapy or no radiation therapy were approximately parallel, indicating that the proportional hazards assumption was satisfied. Therefore, the adjusted relationship between breast radiation therapy and local relapse was determined with a Cox proportional hazards model adjusted for patient, tumor, treatment, and hospital covariates that were considered statistically significant at a P value of less than or equal to .25 in unadjusted analyses. Clinically relevant covariates including age at diagnosis, tumor size, histology, ER status, comorbidity, and treatment with chemotherapy were included in the final model, regardless of their unadjusted P values. Covariates lacking linear relationships with the outcome were entered as categorical (dummy) variables, with missing values as a dummy category. The model was stratified by SEER region and the year of diagnosis to account for variations with geography and time. Prespecified interaction terms were used to determine whether the effect of radiation therapy differed with respect to age, comorbidity, tumor size, histology, and ER status.
The adjusted number needed to treat (NNT) indicates the number of patients who require breast radiation therapy to prevent one local relapse and accounts for the competing risk of death from any cause. The adjusted NNT was calculated by dividing the unadjusted NNT by the survival probability point estimate (34). The unadjusted NNT is the reciprocal of the absolute risk reduction estimated with the Kaplan–Meier method. This method assumes that radiation therapy does not affect overall survival through 8 years of follow-up, an assumption that is supported by the results of trial C9343 and other clinical trials (3–5,32). For example, if radiation therapy conferred a 4% absolute improvement (unadjusted) in the risk of local relapse at 5 years and if 50% of patients were alive at 5 years, then the unadjusted NNT would be 25 patients (i.e., 1/0.04), and the adjusted NNT would be 50 patients (i.e., 25/0.50).
All statistical analyses were two-sided with an 
value of less than or equal to .05 and were conducted with SAS version 9.1 (SAS Institute, Cary, NC). The Yale School of Medicine Institutional Review Board approved this study and granted a waiver of informed consent.
Comparison Cohort
To determine whether the benefit associated with radiation therapy was sensitive to the eligibility criteria for trial C9343, we formed a comparison cohort consisting of patients who failed to meet the entry criteria for trial C9343 because their age was 66–69 years, their tumor size was 2.1–5.0 cm, or their tumor was ER negative. For each subgroup in the comparison cohort, the unadjusted risk of a second breast cancer event and the absolute risk reduction associated with radiation therapy were calculated by use of the Kaplan–Meier method.
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RESULTS |
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TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Baseline Characteristics
Of the 8724 patients identified, median age was 77 years (interquartile range [IQR] = 73 to 82 years), 7842 (90%) were white, and 365 (4%) were black. Median tumor size was 1.0 cm (IQR = 0.8 to 1.5 cm), 6353 (73%) had ductal histology, and 1789 (21%) had unknown ER status. Comorbidity was absent in 5666 (65%), mild in 1916 (22%), moderate to severe in 884 (10%), and unknown in 258 (3%). A total of 6360 patients (73%) received breast radiation therapy and 255 (3%) received chemotherapy. Treatment with radiation therapy was associated with younger age, lack of comorbid illness, treatment with chemotherapy, and pathologic axillary lymph node assessment (Table 1). Concordance between SEER and Medicare claims was high for both radiation therapy (
= .79) and surgery ( = .90).
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Unadjusted Risk of Primary and Secondary Outcomes
Median follow-up was 5.0 years (IQR = 3.5 to 7.0 years). Of the 8724 patients included in the analysis, 84 patients (1.0%) experienced a second ipsilateral breast cancer reported by SEER data, and 166 patients (1.9%) underwent subsequent mastectomy as reported by Medicare claims. Radiation therapy was associated with a reduced risk for a second ipsilateral breast cancer (P<.001, Fig. 1, A, and Table 2), subsequent mastectomy (P<.001, Fig. 1, B, and Table 2), and the combined outcome of either a second ipsilateral breast cancer and/or subsequent mastectomy (i.e., a second breast cancer event) (P<.001, Fig. 1, C, and Table 2). At 5 years, the risk of a second breast cancer event was 5.1% (95% confidence interval [CI] = 4.1 to 6.2) in patients receiving no radiation therapy and 1.1% (95% CI = 0.79 to 1.4) in patients treated with radiation therapy (Table 2). At 8 years, the risk of a second breast cancer event increased to 8.0% (95% CI = 6.2 to 9.8) in patients receiving no radiation therapy and 2.3% (95% CI = 1.7 to 2.9) in patients treated with radiation therapy (Table 2). Of the 8724 patients included in the analysis, 794 (9%) patients underwent repeat breast-conserving surgery. Radiation therapy was not associated with risk of this outcome (P = .83) (Fig. 1, D).
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Adjusted Analysis
After adjusting for patient, tumor, treatment, and hospital characteristics, breast radiation therapy remained associated with a reduced risk of a second breast cancer event (the combined outcome) (hazard ratio [HR] = 0.19, 95% CI = 0.14 to 0.28; P<.001; Table 3). Radiation therapy was also associated with a reduced risk for each component of the combined outcome (for a second ipsilateral breast cancer reported by SEER, HR = 0.13, 95% CI = 0.07 to 0.23; P<.001; and for subsequent mastectomy reported by Medicare, HR = 0.21, 95% CI = 0.14 to 0.31; P<.001) (Table 4). The effect size associated with radiation therapy was stable regardless of whether the model was unadjusted, adjusted only for age, or fully adjusted (Table 4).
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Breast radiation therapy was associated with a large benefit for those with lobular histology (Pinteraction = .02), with an 8-year second breast cancer event risk of 16% (95% CI = 5.5 to 27) in patients receiving no radiation therapy, compared with a risk of 0.38% (95% CI = 0.00 to 1.1) in patients treated with radiation therapy (adjusted HR = 0.018, 95% CI = 0.002 to 0.14; P<.001). Besides radiation therapy, other covariates associated with a second breast cancer event included being a member of the black race compared with being white (HR = 2.22, 95% CI = 1.18 to 4.21; P = .01), having a widowed marital status compared with having a married marital status (HR = 0.69, 95% CI = 0.49 to 0.97; P = .03), and having a progesterone receptor–negative status compared with having a positive status (HR = 1.49, 95% CI = 1.00 to 2.22; P = .05). Age, comorbidity, tumor size, and ER status were not associated with risk of a second breast cancer event, and the interaction of radiation therapy with these variables was not statistically significant. In a sensitivity analysis, the adjusted relationship between radiation therapy and risk of a second breast cancer event was not altered by inclusion of patients who experienced a contralateral breast cancer or by inclusion of treatments received within 6 or 12 months of diagnosis.
Number Needed to Treat
Among women who met the entry criteria for trial C9343, the absolute risk reduction associated with radiation therapy increased over time. At 5 years, the absolute risk reduction was 4.0 events (95% CI = 2.9 to 5.1) per 100 patients (i.e., from 5.1 events without radiation therapy to 1.1 events with radiation therapy). At 8 years, the absolute risk reduction increased to 5.7 events (95% CI = 3.8 to 7.6) per 100 patients (i.e., from 8.0 events without radiation therapy to 2.3 events with radiation therapy) (Table 2). Hence, women who lived longer were more likely to benefit from radiation therapy. For example, among those aged 70–74 years without comorbid illness, 8-year survival was 84% (95% CI = 83 to 86). This subgroup was most likely to benefit from radiation therapy, with an adjusted NNT of 21 patients (95% CI = 16 to 31) (Table 5). Other patient groups who were more likely to benefit from radiation therapy included those aged 75–79 years without comorbid illness (adjusted NNT = 22 patients, 95% CI = 17 to 33), those aged 70–74 years with mild comorbidity (adjusted NNT = 24 patients, 95% CI = 18 to 36), those aged 75–79 years with mild comorbidity (adjusted NNT = 28 patients, 95% CI = 21 to 42), and those aged 80–84 years without comorbid illness (adjusted NNT = 29 patients, 95% CI = 22 to 43). Patients aged 85 years and older with moderate to severe comorbidity were least likely to benefit from radiation therapy, with an 8-year survival of 14% (95% CI = 7.2 to 21) and an adjusted NNT of 125 patients (95% CI = 94 to 185) (Table 5).
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Comparison Cohort
The comparison cohort comprised 5551 women who would have been ineligible for the C9343 trial because of being aged 66–69 years, having a tumor of 2.1–5.0 cm, or having an ER-negative tumor. When compared with the cohort eligible for trial C9343, the adjusted risk of a second breast cancer event was larger for the cohort ineligible for trial C9343 (HR = 1.5, 95% CI = 1.2 to 1.8; P<.001). However, the interaction term of radiation therapy with eligibility status was not statistically significant (P = .17), indicating that the relative benefit associated with radiation therapy was similar for the eligible and ineligible cohorts.
Although the relative benefit associated with radiation therapy was similar for both cohorts, the absolute benefit associated with radiation therapy was greater for the ineligible cohort. At 8 years, the absolute risk reduction was 7.7 events per 100 patients (95% CI = 3.9 to 11) for the ineligible cohort (i.e., from 11.7 events without radiation therapy to 4.0 events with radiation therapy) and 5.7 events per 100 patients (95% CI = 3.8 to 7.6) for the eligible cohort (i.e., from 8.0 events without radiation therapy to 2.3 events with radiation therapy). The benefit of radiation therapy was present for all subgroups of patients ineligible for trial C9343. For example, among patients aged 66–69 years, the absolute risk reduction was 10 events per 100 patients at 8 years (95% CI = 2.8 to 17) (i.e., from 13.3 events without radiation to 3.3 events with radiation) (Fig. 2). Similarly, among patients with a tumor of 2.1–5.0 cm, the absolute risk reduction was 7.3 events per 100 patients at 8 years (95% CI = 1.2 to 13) (i.e., from 10.9 events without radiation to 3.6 events with radiation) (Fig. 2). Finally, among patients with ER-negative tumors, the absolute risk reduction was 6.7 events per 100 patients at 8 years (95% CI = –0.02 to 16) (i.e., from 11.3 events without radiation to 4.6 events with radiation) (Fig. 2).
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DISCUSSION |
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TopNotesAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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In this community-based cohort of older women with early breast cancer, the 5-year risk of a second breast cancer event, defined as a second ipsilateral breast cancer reported by SEER and/or subsequent mastectomy reported by Medicare, was 5.1% (95% CI = 4.1 to 6.2) in patients treated without radiation therapy and 1.1% (95% CI = 0.79 to 1.4) in patients treated with radiation therapy. These results are remarkably consistent with those of the Cancer and Leukemia Group B C9343 randomized trial, in which the risk of local–regional relapse was 4% (95% CI = 2 to 7) without radiation therapy and 1% (95% CI = 0 to 2) with radiation therapy (Table 2) (5). However, our results also indicate that important, readily identifiable characteristics can determine which patients are most likely to benefit from radiation therapy. For example, radiation therapy was associated with a large benefit among women with lobular histology. In addition, healthy women aged 70–79 years were more likely to experience the benefit associated with radiation therapy, with a NNT of 21 to 22 patients. This value is comparable to those of other accepted interventions, such as antihypertensive therapy, in which 21 women require 10 years of treatment to prevent one coronary heart disease event (35).
In contrast, patients of advanced age or with moderate to severe comorbid illness were less likely to experience the benefit associated with radiation therapy. Identification of patients unlikely to benefit from radiation therapy will serve to minimize the number of older women unnecessarily exposed to the morbidity (5), cost (6), and inconvenience of breast radiation therapy. Paradoxically, identification of patients unlikely to benefit from radiation therapy may also serve to reduce utilization of mastectomy. In this study, 41% of patients were excluded solely because of treatment with mastectomy. Traditionally, mastectomy has been recommended for older women with early breast cancer because it will obviate the need for breast radiation therapy. However, among women unlikely to benefit from radiation therapy, this indication for mastectomy is no longer relevant; such patients should therefore receive conservative surgery without radiation therapy.
Refining the appropriate indications for radiation therapy in older women is a matter of substantial public health importance. In 2005, more than 24 000 women in the United States were diagnosed with a breast cancer that met the inclusion criteria for trial C9343 (36,37) (Appendix B). By 2030, when the elderly population is expected to double (38), this number will approach 50 000. Given the growing number of elderly cancer patients, future studies should consider the benefits of adjuvant therapy in light of the competing risk of death from other causes. Although this approach has not previously been adopted in studying cancer therapy, earlier studies used this approach to estimate the benefits of preventive interventions such as antihyperlipidemic therapy (39) or cancer screening (34).
The current study confirms that being younger than 70 years old, having a tumor of more than 2 cm in diameter, or having an ER-negative tumor (i.e., exclusion criteria outlined in trial C9343) define a patient group at higher risk for a second breast cancer event. In addition, the absolute benefit associated with radiation therapy was greater for women who would have been excluded from trial C9343. Therefore, although the conclusions of clinical trials are often extrapolated to other patient groups (40), radiation therapy should remain a standard of care for women who do not meet the inclusion criteria for trial C9343.
One important contrast between the current study and trial C9343 concerns the role of radiation therapy in preventing subsequent mastectomy. Although radiation therapy, compared with no radiation therapy, was associated with a lower risk of subsequent mastectomy in this population-based cohort, radiation therapy did not lower the risk of subsequent mastectomy in trial C9343. These results suggest that women who do not receive radiation therapy and who subsequently develop an in-breast recurrence may be more likely to undergo mastectomy in the community setting than in the clinical trial setting.
Our study has several limitations. Although treatment with tamoxifen may reduce the risk of local relapse (41,42), information regarding tamoxifen prescription and compliance are not available in the SEER–Medicare data. During the study period, however, tamoxifen was considered the standard of care (43) and was prescribed for nearly 90% of older women in the community setting (44). Further, in prior studies, rates of tamoxifen prescription and compliance did not appear to differ substantially between patients treated with and without breast radiation therapy, indicating that the absence of tamoxifen data should not introduce a large directional bias (44,45). In addition, the similar event risks in the no-radiation group of the current study and the tamoxifen-only arm of trial C9343 provide reassurance that the absence of tamoxifen data should not introduce a substantial bias. Margin status is also not available in SEER–Medicare data. However, these data would probably bias our results toward the null because patients with involved margins may be more likely to receive breast radiation therapy (46). Finally, the outcome of a second ipsilateral breast cancer reported by SEER does not capture all in-breast recurrences; therefore, subsequent mastectomy as reported by Medicare claims was used as a marker of in-breast recurrence. Although Medicare claims for mastectomy are highly accurate (15), laterality of mastectomy is infrequently reported. Thus, despite the exclusion of patients with contralateral breast cancers reported by SEER, it remains possible that a fraction of mastectomies identified in Medicare claims were performed on the contralateral breast.
Although randomized trials are generally considered to produce the highest level of evidence in clinical research, a recent investigation (47) asserts that carefully designed observational cohort studies may provide estimates of treatment effects that are highly reproducible and valid. For example, the effect size of breast radiation therapy in this observational study (HR = 0.19, 95% CI = 0.14 to 0.28) is consistent in direction and magnitude with those in a recent meta-analysis conducted on randomized clinical trials of breast radiation therapy (HR = 0.33, 95% CI = 0.29 to 0.38) (2). This consistency strengthens the validity of our study conclusions and underscores the importance of observational data when evaluating the role of radiation therapy in the general population.
In the general population of patients aged 70 years or older with small, ER-positive (or of unknown ER status), lymph node–negative breast cancer, radiation therapy after breast-conserving surgery is associated with a lower risk of a second ipsilateral breast cancer and subsequent mastectomy. For those with lobular histology and for those aged 70–79 years with minimal comorbidity, the benefit associated with radiation therapy is similar to that of other accepted medical interventions. For women who do not meet the strict age, size, and hormone receptor criteria outlined for trial C9343, the absolute benefit of radiation therapy is substantial, and radiation therapy should remain the standard of care.
Appendix A. Variables and Their Definitions
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* Medicare billing claims included the Medicare Provider and Analysis Review File for inpatient hospitalizations, the Outpatient File (outpatient claims from hospitals), and the Carrier Claims File (physician service claims). To identify billing codes, we used the International Classification of Disease, 9th ed. (ICD-9) (16,17) for hospital-related diagnoses and procedures, Current Procedural Terminology (CPT) (18,19) for physician services and procedures, and the Health Care Procedure Coding System (HCPCS) J and Q codes for chemotherapy. Medicare claims were available through 2002.
Surveillance, Epidemiology, and End Results (SEER) data are available in the Population Entitlement and Diagnosis Summary File through 1999. To increase follow-up, cases of breast cancer reported by SEER between 2000 and 2002 were linked to the SEER–Medicare data by use of a crosswalk file.
Appendix B. Incidence of Breast Cancers Meeting Criteria of Trial C9343 in 2005
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NOTES |
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B. D. Smith is supported by the American Society of Clinical Oncology Young Investigator Award and the Breast Cancer Research Foundation. C. P. Gross's efforts are supported by a Beeson Career Development Award (1 K08 AG24842) and the Claude D. Pepper Older Americans Independence Center at Yale (P30AG21342). G. L. Smith is supported by National Institutes of Health/National Institute of General Medical Sciences Medical Scientist Training Grant GM07205. None of the sponsors had a role in data collection or analysis, the decision to submit the study for publication, or the writing of the manuscript.
We thank Dr. Jean Owen, American College of Radiology, for providing the master list of radiotherapy facility zip codes. This study used the linked Surveillance, Epidemiology, and End Results (SEER)–Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development and Information, Centers for Medicare & Medicaid Services; Information Management Services, Inc.; and the SEER Program tumor registries in the creation of the SEER–Medicare database.
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Manuscript received November 21, 2005; revised March 9, 2006; accepted March 30, 2006.
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