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Postmastectomy Radiation and Survival in Older Women With Breast Cancer

Benjamin D. Smith, Bruce G. Haffty, Arti Hurria, Deron H. Galusha, Cary P. Gross

From the Departments of Therapeutic Radiology and Internal Medicine, Yale University School of Medicine, New Haven, CT; Department of Radiation Oncology, University of Medicine and Dentistry New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ; and the Department of Medicine, Memorial-Sloan Kettering Cancer Center, New York, NY

Address reprint requests to Benjamin D. Smith, MD, 2200 Berquist Dr, Ste 1, Lackland Air Force Base, TX 78236-9908; e-mail: bensmith{at}alumni.rice.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Clinical trials indicate that postmastectomy radiation therapy (PMRT) improves survival for women age younger than 70 years with high-risk breast cancer. However, for women age 70 years or older, the benefits of PMRT are unknown. As recent evidence suggests that certain adjuvant treatments appropriate for younger women may only be marginally beneficial for older women, we sought to determine whether PMRT improves survival for older women with breast cancer.

METHODS: Using the Surveillance, Epidemiology and End Results Medicare data spanning 1992 to 1999, we identified 11,594 women age 70 years or older treated with mastectomy for invasive breast cancer. A proportional hazards model adjusted for clinical-pathologic covariates tested whether PMRT was associated with improved overall survival for low-risk (T1/2 N0), intermediate-risk (T1/2 N1), and high-risk (T3/4 and/or N2/3) patients.

RESULTS: A total of 502 (7%) of 7,416 low-risk, 242 (11%) of 2,145 intermediate-risk, and 785 (38%) of 2,053 high-risk patients received PMRT. Median follow-up was 6.2 years. For low- and intermediate-risk patients, PMRT was not associated with survival. For high-risk patients, PMRT was associated with a significant improvement in survival (hazard ratio, 0.85; 95% CI, 0.75 to 0.97; P = .02). Five-year adjusted survival was 50% for patients not treated with PMRT or chemotherapy, 56% for patients treated with PMRT only, 57% for patients treated with chemotherapy only, and 59% for patients treated with both PMRT and chemotherapy.

CONCLUSION: PMRT is associated with improved survival for older women with high-risk breast cancer. Randomized clinical trials are urgently needed to confirm this finding and define optimal treatment strategies for this patient group.

	INTRODUCTION

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Women age 70 years or older account for one third of breast cancer diagnoses¹ and comprise a rapidly growing demographic.² Nevertheless, older women have been substantially underrepresented in breast cancer clinical trials,^3-9 and as a result treatment strategies for older women have been extrapolated from clinical trials conducted in younger women. For example, because clinical trials indicated that postmastectomy radiation therapy (PMRT) improves survival for younger women with intermediate- and high-risk breast cancer,^3-7,10 PMRT is considered for older women with intermediate-risk breast cancer and often recommended for older women with high-risk breast cancer.^11,12

However, recent evidence suggests that age at diagnosis may strongly influence the natural history of breast cancer,^13-18 and therefore certain adjuvant treatments that are appropriate for younger women may only be marginally beneficial for older women.¹⁸ As a result, the benefits of adjuvant treatment must be critically assessed in elderly populations, and cannot simply be extrapolated from studies conducted in younger women.

We therefore used the Surveillance, Epidemiology and End Results (SEER) Medicare database to determine whether adjuvant PMRT was associated with a survival benefit for older women at low-, intermediate-, and high-risk for recurrence after mastectomy. The SEER Medicare database is ideal for investigating this question, as it contains a representative sample of older cancer patients, detailed clinical-pathologic information regarding the index cancer, and long-term follow-up.

	METHODS

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Data Source
The National Cancer Institute's SEER Medicare database tracks incident malignancies in Medicare beneficiaries who reside within 11 geographic regions accounting for 14% of the United States' population.^19,20

Study Sample
From 1992 through 1999, 60,717 women age 70 years or older were diagnosed with breast cancer in the SEER Medicare cohort. Clinical exclusion criteria were as follows: no invasive component (n = 6,679); histology not consistent with epithelial origin (n = 1,355); not pathologically confirmed (n = 1,791); distant metastasis (n = 3,332); history of prior malignancy (n = 1,706); bilateral disease (n = 51); not treated with mastectomy (n = 31,329); received neoadjuvant chemotherapy (n = 527); leaving 24,829 who met all clinical criteria. Of these, 16,486 had complete information regarding key clinical-pathologic variables (exclusions: 1,479 unknown tumor size; 3,101 unknown nodal status; 5,656 unknown estrogen receptor [ER] and/or progesterone receptor [PR] status; and 264 unknown SEER historic stage).

We also excluded patients with any second cancer diagnosed within 9 months of the index breast cancer (n = 748), as billing records could not discriminate between procedures performed for the index cancer versus the second cancer. Patients with inadequate Medicare records (976 without Part A and B coverage; 3,446 without fee-for-service coverage spanning an interval from 12 months prediagnosis to 9 months postdiagnosis) were also excluded, leaving 11,594 for the analysis.

Outcome
The primary outcome was overall survival as estimated by the Kaplan-Meier method. Breast cancer-specific mortality was not included as an outcome given its questionable validity as reported by SEER.²¹

Treatment-Related Variables
Surgery was determined from both SEER and Medicare claims (Mastectomy: International Classification of Diseases-9 [ICD-9] procedure codes 85.41, 85.42, 85.43, 85.44, 85.45, 85.46, 85.47, 85.48; Current Procedural Terminology [CPT] codes 19.180, 19.182, 19.200, 19.220, 19.240).^20,22-25 The most extensive surgical procedure reported by SEER or Medicare during the first 9 months after diagnosis was considered the definitive surgery. Treatment with radiation was determined using both SEER and Medicare claims (ICD-9 procedure codes 92.21 to 92.27 and 92.29; ICD-9 diagnosis codes V58.0, V66.1, V67.1; CPT codes 77401 to 77525 and 77761-77799; Revenue Center Codes 0330 and 0333).^20,23-27 Patients were considered to have received radiation if either SEER or Medicare reported treatment with radiation within 9 months of diagnosis. Treatment with chemotherapy within 6 months of diagnosis was determined from Medicare claims (ICD-9 procedure code 99.25; ICD-9 diagnosis codes V58.1, V66.2, V67.2; CPT codes 96,400-96549; HCPCS codes J9000-J9999, Q0083-Q0085; and Revenue Center Codes 0331, 0332, 0335).^28,29 Adjuvant endocrine therapy is not reported.

Patient-Related Variables
Patient characteristics included age at diagnosis, race, year of diagnosis, marital status,^30,31 SEER registry, urban/rural residence, median income of census tract or zip code,²¹ percent of adults in census tract or zip code with less than 12 years education,²¹ and number of physician visits on separate days spanning a prediagnosis interval of 12 months to 1 month.³² A modified Charlson comorbidity index^33-35 was calculated using Part A and Part B claims spanning a prediagnosis interval of 12 months to 1 month. To enhance specificity, Part B diagnosis codes were included only if they appeared either more than once over a time interval exceeding 30 days or in Part A claims as well.^36,37 Receipt of the influenza vaccine (ICD-9 diagnosis codes V0481; CPT code 90,658; HCPCS code G0008) was included because it has been shown to reduce mortality and is also a surrogate marker for health status.^38,39

Tumor-Related Variables
Tumor characteristics as reported by SEER included size, grade, histology,⁴⁰ T4 disease, and laterality. Margin status and lymph-vascular space invasion are not reported.

Hospital-Related Variables
The teaching status of the hospital where initial breast surgery was performed was determined using the Hospital Cost Report Information Systems data.⁴¹

Statistical Analysis
Unadjusted associations between covariates and receipt of PMRT and chemotherapy were tested using Pearson's ². Predictors of overall survival were identified using a Cox proportional hazards model adjusted for treatment, patient, tumor, and hospital covariates significant at P of .25 or less in unadjusted analysis. The model was stratified by SEER region and year of diagnosis to account for variation with geography and time. Patients were right censored at the date of last follow-up, December 31, 2003. Patients who died within 9 months of diagnosis were censored at the time of death, as they may not have lived long enough to receive PMRT or chemotherapy. The proportional hazards assumption was tested using an interaction term of PMRT with time.

Current consensus guidelines recommend: treatment with PMRT for high-risk patients (T3/4 and/or N2/3); consideration of PMRT for intermediate-risk patients (T1/2 N1); and omission of PMRT for low-risk patients (T1/2 N0).^11,12,42,43 We analyzed separate adjusted Cox models for each of these clinically relevant subgroups. Similarly, we also analyzed separate adjusted Cox models for hormone receptor positive and negative tumors.

All statistical analyses were two tailed with P of .05 or less and were conducted using SAS version 9.1 (SAS Institute, Cary, NC). The Yale University Human Investigations Committee (New Haven, CT) approved this study and granted a waiver of informed consent.

	RESULTS

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Baseline Characteristics
Of 11,594 patients identified, median age was 77 years (interquartile range, 73 to 81), 10,227 patients (88%) were white, and 565 patients (5%) were black. Median tumor size was 2.0 cm (interquartile range, 1.2 to 3.0), 8,297 patients (72%) had ductal histology, 9,565 patients (82%) were ER positive, and 3,909 patients (34%) had pathologically involved regional lymph nodes. A total of 1,529 patients (13%) received PMRT and 1,490 patients (13%) received chemotherapy. Concordance between SEER and Medicare claims was high for both radiation ( = 0.77) and surgery ( = 0.92). The associations between PMRT, chemotherapy, and key patient and tumor treatment characteristics are presented in Table 1. Factors correlated with increased utilization of PMRT included young age (P < .0001), black race (P = .008), no comorbid illness (P < .0001), large tumor size (P < .0001), clinical stage T4 (P < .0001), high tumor grade (P < .0001), lobular histology (P < .0001), and multiple involved lymph nodes (P < .0001).

View larger version (16K): [in this window] [in a new window]   Fig 1. Utilization of postmastectomy radiation therapy (PMRT) and chemotherapy by risk group. The percentage of patients treated with PMRT only, chemotherapy only, or both PMRT and chemotherapy stratified by risk group. Low risk (T1/2 N0); intermediate risk (T1/2 N1); high risk (T3/4 and/or N2/3); PMRT (postmastectomy radiation therapy).

View larger version (16K): [in this window] [in a new window]   Fig 2. Adjusted survival curves stratified by risk group. (A) Low risk (T1/2 N0); (B) intermediate risk (T1/2 N1); (C) high risk (T3/4 and/or N2/3). Adjusted Kaplan-Meier survival curves for patients treated with neither postmastectomy radiation therapy (PMRT) nor chemotherapy (Chemo); PMRT only; chemotherapy only; and PMRT and chemotherapy. P values are reported in Table 3.

Within the high-risk group, both PMRT (HR, 0.85; 95% CI, 0.75 to 0.97; P = .02) and chemotherapy (HR, 0.76; 95% CI, 0.65 to 0.88; P = .0002) were associated with improved survival (Table 3). The interaction between PMRT and follow-up time was not significant (P = .95), indicating that the proportional hazards assumption was satisfied. In addition, the interaction between PMRT and chemotherapy was not significant (P = .32), indicating that the association between PMRT and improved survival was similar for patients who did and did not receive chemotherapy. Further, the interaction of PMRT with lobular histology was not significant (P = .59), suggesting that the survival benefit associated with PMRT was not significantly different for women with lobular as compared to ductal histology. Five-year adjusted survival was 50% for patients not treated with PMRT or chemotherapy, 56% for patients treated with PMRT only, 57% for patients treated with chemotherapy only, and 59% for patients treated with both PMRT and chemotherapy (P = .02 for PMRT; P = .0002 for chemotherapy; Fig 2C).

Multivariate Analysis: According to Hormone Receptor Status
Among patients with ER- or PR-positive tumors, PMRT was not associated with a survival benefit for those in the low-risk and intermediate-risk groups (Table 4A). For patients with ER- or PR-positive tumors in the high-risk group, PMRT (HR, 0.86; 95% CI, 0.74 to 0.99; P = .04) and chemotherapy (HR, 0.77; 95% CI, 0.64 to 0.91; P = .003) were associated with improved overall survival (Table 4A).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
In this population-based cohort study of women age 70 years or older treated with mastectomy for newly diagnosed breast caner, PMRT was associated with a survival benefit for high-risk patients (T3/4 and/or N2/3), but not for low-risk (T1/2 N0) or intermediate-risk (T1/2 N1) patients. These findings help to define appropriate indications for PMRT in older women with breast cancer.

Prior studies have demonstrated that PMRT confers a survival benefit for both premenopausal and postmenopausal women with intermediate- and high-risk breast cancer.^3-6,10,44,45 Clinical trials indicated that the 10-year risk of locoregional recurrence was 25% to 35% for patients who did not receive PMRT versus 8% to 13% for patients who did receive PMRT.^3-6 This reduction in risk of locoregional recurrence resulted in a 9% to 10% absolute improvement in 10-year overall survival. However, because these trials excluded women age 70 years or older, guidelines from the American Society of Clinical Oncology (ASCO) state that there is "insufficient evidence to recommend or suggest how age should be used to modify decisions to use or not use PMRT."¹²

To address this issue, Truong et al⁴⁶ reported the risk of locoregional recurrence among 939 women age 70 years or older treated with mastectomy without PMRT. Only high-risk patients (tumor size > 5 cm and/or 4 positive lymph nodes) experienced a risk of locoregional recurrence similar to the control arms of the PMRT clinical trials,^3,4,6 suggesting that perhaps only older women with high-risk breast cancer would experience a significant survival benefit from PMRT. Our results support this hypothesis, as radiation was associated with a 15% relative reduction in the risk of death and a 6% absolute improvement in 5-year overall survival for older women with high-risk breast cancer, but was not associated with a survival benefit for older women with low- or intermediate-risk breast cancer.

Because some,^46,47 though not all,^48,49 observational studies have reported ER negativity as a risk factor for locoregional and distant recurrence after mastectomy, the survival benefit associated with PMRT was analyzed separately for hormone-receptor positive and negative subgroups. For older women with high-risk ER- or PR-positive tumors, PMRT was associated with a statistically significant 14% relative reduction in the risk of death. For the much smaller subset of older women with high-risk ER- and PR-negative tumors, PMRT was associated with a 20% relative reduction in the risk of death, yet this association failed to reach statistical significance.

Although current clinical guidelines from the American Society for Therapeutic Radiology and Oncology (ASTRO)⁴² and the ASCO recommend adjuvant PMRT as standard treatment for patients of any age with high-risk breast cancer, only 38% of older women with high-risk breast cancer actually received PMRT in this population-based cohort. Thus, between 1992 through 1999, approximately 60% of older women with high-risk breast cancer did not receive a potentially life-saving and relatively nontoxic^6,12 adjuvant therapy. Further studies are indicated to determine whether utilization of PMRT has increased since the publication of consensus guidelines by ASTRO in 1999⁴² and ASCO in 2001,¹² and to identify potential barriers to receipt of PMRT, such as patient or physician bias against PMRT, lack of access to radiation facilities, and other sociodemographic factors.

Our study has certain limitations. First, in any retrospective observational study, unobserved confounders that are correlated with receipt of the intervention and with the outcome of interest may introduce treatment assignment bias. For example, if healthier patients were more likely to receive PMRT, then PMRT would be associated with a survival benefit, even if PMRT itself did not improve survival. However, our finding that PMRT was associated with a survival benefit only for high-risk patients suggests that treatment assignment bias did not introduce a global bias in favor of PMRT. Presumably, PMRT improves overall survival by lowering the risk of breast cancer death, though the absence of reliable data regarding cause of death precludes testing of this important hypothesis. Another limitation concerns absence of data regarding adjuvant endocrine therapy. However, prior studies indicate that type of local therapy does not correlate with tamoxifen prescription⁵⁰ and compliance,⁵¹ suggesting that absence of data regarding adjuvant endocrine therapy should not introduce a strong directional bias.⁵⁰ Finally, our finding of an association between PMRT and inferior survival for intermediate-risk, ER- and PR-negative patients was unexpected and may be a manifestation of type I error or imbalanced, unmeasured confounders.

In this study, receipt of PMRT was determined using the combination of the radiotherapy variable reported by SEER and billing claims for receipt of radiotherapy reported by Medicare. This method has previously been shown to identify more patients who received radiotherapy than either SEER or Medicare data alone.^26,27 However, this method has yet to be validated against the gold standard of medical record review. In addition, SEER Medicare data does not report any information regarding radiotherapy doses and target volumes.

Despite these limitations, our results provide strong evidence for substantial heterogeneity in adjuvant treatment patterns among women age 70 years or older, indicating that at present no clear standard of care exists for the adjuvant treatment of older women with high-risk breast cancer. Specifically, between 1992 through 1999, 21% of patients received PMRT alone, 15% received chemotherapy alone, 17% received both PMRT and chemotherapy, and 49% received neither. This current lack of consensus points to the need for clinical trials to define optimal adjuvant treatment for older women with high-risk breast cancer. Overall survival may not be the most appropriate end point for such trials, as the increased burden of noncancer death in the elderly may attenuate the survival benefit gained from adjuvant therapy.⁵² As an alternative, trials should explore novel end points such as health-related quality of life, disease-related symptom scores, and functional status.

Finally, our study identified other important prognostic factors among older women with breast cancer. For example, we found an association between unmarried marital status and increased risk of death. Similarly, prior studies indicate that unmarried women are more likely to be diagnosed with advanced breast cancer, less likely to receive definitive therapy, less likely to receive appropriate follow-up care, and more likely to die from breast cancer.^30,31 Future research is indicated to determine if targeted psychosocial interventions will improve outcomes for unmarried older women. In addition, consistent with prior studies,^45,53,54 we found an association between lobular histology and decreased risk of death. Paradoxically, lobular histology, as compared with ductal histology, is associated with a higher risk of stage IIIB or stage IIIC disease, a higher number of involved axillary lymph nodes, and a lower response rate to chemotherapy.⁵⁴ Despite differences in the biology of ductal and lobular breast cancer, we did not find a difference in the effectiveness of PMRT for these two histologies, although this issue also merits further study.

Summary
In this population-based cohort study, adjuvant PMRT was associated with a survival benefit for women age 70 years or older with high-risk (T3/4 and/or N2/3) breast cancer. However, only 38% of high-risk patients actually received PMRT in this cohort treated between 1992 and 1999, and further studies are indicated to determine current utilization of PMRT and barriers to receipt of PMRT. Randomized clinical trials are urgently needed to further define optimal adjuvant treatment strategies for older women with breast cancer.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Benjamin D. Smith, Bruce G. Haffty, Arti Hurria, Deron H. Galusha, Cary P. Gross Financial support: Benjamin D. Smith, Bruce G. Haffty Administrative support: Benjamin D. Smith Provision of study materials or patients: Benjamin D. Smith, Bruce G. Haffty Collection and assembly of data: Benjamin D. Smith, Deron H. Galusha Data analysis and interpretation: Benjamin D. Smith, Bruce G. Haffty, Arti Hurria, Cary P. Gross Manuscript writing: Benjamin D. Smith, Bruce G. Haffty, Arti Hurria, Cary P. Gross Final approval of manuscript: Benjamin D. Smith, Bruce G. Haffty, Arti Hurria, Deron H. Galusha, Cary P. Gross

 

	ACKNOWLEDGMENTS

 
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. We acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development and Information, Centers for Medicare and Medicaid Services; Information Management Services Inc; and the SEER program tumor registries in the creation of the SEER Medicare database.

	NOTES

 
Supported by the American Society of Clinical Oncology Young Investigator Award and Oncology Career Development Award, the Breast Cancer Research Foundation, Beeson Career Development Awards (K23 AG026749-01 and 1 K08 AG24842) and the Claude D. Pepper Older Americans Independence Center at Yale University (P30AG21342).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted March 20, 2006; accepted August 10, 2006.

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