- Email: [email protected]
Surgery and hormone therapy trends in octogenarians with invasive breast cancer
The American Journal of Surgery (2016) 211, 541-545
Midwest Surgical Association
Surgery and hormone therapy trends in octogenarians with invasive breast cancer Olga Kantor, M.D.a, Catherine Pesce, M.D.b, Erik Liederbach, B.S.b, Chi-Hsiung Wang, Ph.D.c, David J. Winchester, M.D.b, Katharine Yao, M.D.b,* a
Department of Surgery, University of Chicago, Chicago, IL, USA; bDepartment of Surgery, NorthShore University HealthSystem, Evanston Hospital, Evanston, IL, USA; cCenter for Biomedical Research Informatics, Research Institute, NorthShore University Health System, Evanston, IL, USA KEYWORDS: Primary endocrine therapy; Hormone therapy; Breast cancer; Elderly
Abstract BACKGROUND: There has been a trend toward minimizing surgery in elderly women with estrogen receptor-positive (ER1) breast cancer. METHODS: Using the National Cancer Data Base, we selected 95,357 women R80 years with invasive, ER1 breast cancer. Chi-square test and logistic regression were used to analyze trends in surgery and hormone therapy. RESULTS: From 2004 to 2012, 90% of women were treated with surgery first and 10% were treated with primary nonoperative management. Of those undergoing nonoperative management, 72% received endocrine therapy and 27% had no treatment. The rate of primary nonoperative treatment doubled from 7% in 2004 to 14% in 2012. Multivariate logistic regression adjusted for patient, facility, and tumor factors identified more advanced clinical stage, older age, African-American race, and treatment at Academic facilities as independent predictors of receiving primary nonsurgical management. CONCLUSIONS: There has been an increase over time in primary nonoperative management of ER1 breast cancer in octogenarians. Ó 2016 Elsevier Inc. All rights reserved.
In 2013, 43% of all new invasive breast cancers were in women age 65 or older,1 and with an aging population that is living longer, this is projected to increase. There has been an increasing trend toward minimizing breast
There were no relevant financial relationships or any sources of support in the form of grants, equipment, or drugs. The authors declare no conflicts of interest. * Corresponding author. Tel.: 11-847-570-1327; fax: 11-847-5702930. E-mail address: [email protected] Manuscript received July 13, 2015; revised manuscript November 25, 2015 0002-9610/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.11.005
cancer treatment in the elderly population, particularly in patients with hormone receptor-positive cancers. Radiation after breast conserving surgery and axillary staging have shown no survival benefit for elderly women with early stage breast cancer in randomized clinical trials, and have been incorporated into National Comprehensive Cancer Network guidelines as optional for women R70 years with early stage, hormone-receptor positive tumors.2,3 Primary endocrine therapy in the elderly has also been investigated in several randomized trials, and meta-analysis of these trials found no difference in overall survival between patients treated with primary endocrine therapy compared with surgery, although there
542 was an increased progression-free survival in the surgery arm.4 Nonsurgical management for breast cancer has been studied mainly in Europe, although there have been a few studies in the United States that have examined the primary approach to the elderly patient with a hormone receptorpositive breast cancer.5 In fact, an international comparison of European and the US population-based registries found that nonoperative management of breast cancer is significantly more common in many countries in Europe than in the United States.6 We used the National Cancer Data Base (NCDB) to examine treatment trends for patients treated with primary nonoperative management (endocrine therapy or observation) in women R80-year old with estrogen receptor-positive (ER1) invasive breast cancer. We hypothesize that most elderly women are still undergoing upfront surgery for their breast cancer despite the increased number of hormonal agents available to patients today and the high rate of upfront hormonal therapy in other countries.
The American Journal of Surgery, Vol 211, No 3, March 2016 nodes examined. Staging information was in accordance with the American Joint Committee on Cancer 7th edition.9 Primary nonoperative treatment was considered to be treatment with endocrine therapy alone, treatment with endocrine therapy before surgery, and no documented treatment modality. The NCDB only captures data for the first course of treatment, which usually encompasses the first year of treatment. All analysis was performed using SPSS statistical software (SPSS for Windows, version 19; Chicago, IL). All statistical tests were 2-sided, and a P value of %.05 was considered statistically significant. Chi-square tests and both univariate and multivariate logistic regression models were used to examine factors associated with increased likelihood of receiving primary nonsurgical treatment compared with a surgery-first approach. Odds ratio (OR) greater than 1 signified higher odds of receiving primary nonsurgical treatment. Confidence intervals (CI) are reported at a 95% significance level.
Results Methods The NCDB is a joint project of the American College of Surgeons Commission on Cancer and the American Cancer Society that captures information on approximately 70% of all newly diagnosed cancers in the United States.7 All data collected are compliant with the privacy requirements of the Health Insurance Portability and Accountability Act. Institutional review board approval was not required for this study as the collected information was deidentified, no protected health information was reviewed, and the analysis was retrospective. The breast cancer NCDB participant user file was used to identify women age 80 or older with ER1 breast cancer from 2004 to 2012 who had completely documented information on treatment with surgery and hormone therapy, who received all or part of their care at the reporting facility, and had 2 or less lifetime cancer diagnoses. Patients with in situ or metastatic disease and who underwent adjuvant or neoadjuvant chemotherapy were excluded, which left 95,357 women for the analysis. Patient demographics and tumor characteristics were grouped into categorical variables for analysis. Patient covariates included age, race, and comorbidities (Charlson and/or Deyo index8 of 0 to 1 was considered minimal comorbidity, and index of R2 was considered severe comorbidity). Women greater than 90 years old are categorized as 90-year old in the NCDB. Facility covariates included facility type and location; tumor covariates included clinical stage (cStage); and treatment covariates included breast surgery, axillary surgery, hormone therapy, and radiation therapy. Neoadjuvant hormone therapy was defined as hormone therapy given before surgical treatment. Sentinel node biopsy was defined as 1 to 4 nodes examined, and axillary lymph node dissection was defined as at least 10
We identified 95,357 women age 80 or older with nonmetastatic, invasive ER1 breast cancer from 2004 to 2012. The mean age at diagnosis was 84 6 3 years. 85,824 (90%) patients were Caucasian, 5,678 (6%) were African American, 2,427 (3%) were Hispanic, and 1,138 (1%) were Asian-Pacific Islander. A total of 73,919 (78%) had minimal comorbidities, and 4,805 (5%) had severe comorbidities. At presentation, 42,272 (44%) women were cStage I; 4,427 (21%) were cStage II; and 4,427 (5%) were cStage III. Another 28,894 (30%) had unknown or undocumented clinical stage at presentation. Ultimately, 88,185 (93%) women were treated with surgery (54,789 [62%] with lumpectomy and 33,396 [38%] with mastectomy), 44,465 (58%) with endocrine therapy, and 30,915 (32%) with radiation therapy. Overall 65,250 women (69%) had axillary nodal sampling (40,037 [61%] with sentinel node biopsy and 13,741 [21%] with axillary lymph node dissection). A total of 86,103 (90%) of women were treated with surgery as the first line of treatment and 9,254 (10%) were treated nonsurgically as the first line of treatment. The treatment approach and breakdown of treatments received in our cohort is described in Fig. 1. The rate of primary nonsurgical treatment doubled over the time frame of the study from 7% in 2004% to 14% in 2012 (P , .01) among the entire cohort of octogenarians. The breakdown of the time trends of each type of primary nonsurgical option is shown in Fig. 2. When we compared characteristics of patients that had primary nonsurgical treatment to those that had surgery first, we found that patients that had primary nonsurgical treatment were more likely to be 86 to 90 years of age (54% vs 32%), African American (11% vs 6%), have severe comorbidities (7% vs 5%), have clinical stage III disease at
O. Kantor et al.
Surgery/HT trends in octogenarians
Figure 1
543
Treatment approach for women R80 years old with invasive ER1 breast cancers, 2004 to 2012.
presentation (23% vs 5%), and be treated at an Academic facility (30% vs 22%) compared with patients that had surgery first (all P values ,.01). On multivariate analysis adjusted for year of diagnosis, age, race, comorbidities, facility type and location, and clinical stage, the strongest independent predictors of receiving primary nonsurgical management were more recent year of diagnosis (OR 1.99 [CI 1.79 to 2.21] for 2012 compared with 2004), older age (OR 2.14 [CI 2.05 to 2.24] for 86 to 90-year old compared with 80 to 85-year old), African American race (OR 2.14 [CI 2.05 to 2.24] compared with Caucasian), treatment at an Academic facility (OR 1.62 [CI 1.50 to 1.74] compared with community cancer centers), and increasing clinical stage (cStage II: OR 2.89 [CI 2.72 to 3.05]; cStage III: OR 9.15 [CI 8.49 to 9.87], both compared with cStage I).
Comments In this study, rate of treatment with endocrine therapy as the first line of therapy more than doubled from 2004 to 2012, and the more recent year of breast cancer diagnosis was a significant independent predictor of primary
Figure 2 Trends in primary nonsurgical treatment over time among total cohort of octogenarians, 2004 to 2012. n 5 95,357.
nonoperative therapy after adjustment for other covariates. Endocrine therapy in the neoadjuvant setting with both tamoxifen and aromatase inhibitors has been shown to be effective in decreasing tumor burden and halting disease progression in women of all ages.10 Although retrospective studies of primary endocrine therapy have generally shown an association with increased breast-cancer specific mortality,5 randomized trials of primary endocrine therapy have demonstrated similar survival outcomes to patients treated with surgery.4 An international comparison of cancer registries in the United States and Europe demonstrated a high degree of variation in the rates of nonsurgical management for elderly patients. For women aged 85 to 89 years, 1% of women in Germany, 4% of women in the United States, 28% of women in the Netherlands, and 55% of women in Ireland did not receive any breast surgery. Despite these variations, similar survival patterns were seen across countries in women over age 75.6 It is possible that the publication of the randomized trials of neoadjuvant endocrine therapy and primary endocrine therapy has contributed to the increased utilization of primary endocrine therapy in the United States, and may also partially explain why the rate of primary endocrine therapy is higher at Academic centers. Our study is one of the first to demonstrate a racial disparity in patients receiving primary nonoperative therapy, with African American women being almost 2-times more likely to have primary nonoperative therapy than Caucasians. In a demographically matched cohort of African American and Caucasian women from the Surveillance, Epidemiology, and End-Results data, African American women were also more likely to have no treatment, even when matched by characteristics of disease at presentation.11 Patient perceptions, attitudes, and education contribute to the selection of the first line of treatment in elderly women. The perceived risk of complications may also contribute. The risk of complications after breast
544 surgery increases with age, the most common being hematoma, seroma, and cardiovascular risks of anesthesia. Side effects of endocrine therapy include hot flashes, dizziness, or nausea and are similar among patients of all ages. Interestingly, studies have shown that quality of life in elderly women does not seem to be affected by a cancer diagnosis and was maintained or even improved in patients on endocrine therapy.12 A British survey study of attitudes about primary endocrine therapy vs surgery in elderly women found that most women had a preference quickly based on past experiences and personal goals and values.13 Patients of African-American race may have different personal values and experiences than Caucasian patients, which may contribute to the differences in treatment among different races. Our study has several limitations including the retrospective nature of the data and missing data points. In addition, all patients over 90 are coded as age 90 for privacy reasons in the NCDB, so there is no ability to analyze that group separately. The information on treatment is for the primary treatment course and only encompasses approximately 1 year from diagnosis. Thus, there is no way to know if a patient who started with nonsurgical management eventually had surgery many years later. Because of this limitation, there is no way to distinguish the intent of treatment with endocrine therapy as a first-line neoadjuvant therapy or intended as primary endocrine therapy alone. In conclusion, we found an increasing trend toward primary nonsurgical management in octogenarians which is mostly accounted for by patients treated with primary endocrine therapy. Age, race, and more advanced clinical stage were all strong independent predictors of primary nonsurgical management. It would be interesting to examine if the predictors of nonsurgical management in elderly women with hormone negative tumors are similar to those with hormone-positive tumors. Future studies are needed to further evaluate the patient attitudes and beliefs that influence choice of treatment for breast cancer in the elderly.
References 1. American Cancer Society. Breast Cancer Facts & Figures 2013-2014. Atlanta: American Cancer Society, Inc; 2013. 2. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013;31:2382–7. 3. International Breast Cancer Study GroupRudenstam CM, Zahreieh D, Forbes JF, et al. Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Trial 10-93. J Clin Oncol 2006; 24:337–44. 4. Morgan J, Wyld L, Collins KA, et al. Surgery versus primary endocrine therapy for operable breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev 2014;1:CD004272. 5. Van Leeuwen BL, Rosenkranz KM, Bedrosian I, et al. The effect of under-treatment of breast cancer in women 80 years of age and older. Crit Rev Oncol Hematol 2011;79:315–20.
The American Journal of Surgery, Vol 211, No 3, March 2016 6. Kiderlen M, Bastiaannet E, Walsh PM, et al. Surgical treatment of early stage breast cancer in elderly: an international comparison. Breast Cancer Res Treat 2012;132:675–82. 7. Bilimoria KY, Stewart AK, Winchester DP, et al. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol 2008;15:683–900. 8. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45:613–9. 9. Edge S, Byrd DR, Compton CC, et al. AJCC cancer Staging Manual. 7th ed. New York: Springer. 10. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrazole, tamoxifen, or both in combination: the Immediate Preoperative Anastrazole, Tamoxifen, or Combined with Tamoxifen (IMPAT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5109–16. 11. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA 2013;310:389–97. 12. Reimer T, Gerber B. Quality-of-life considerations in the treatment of early-stage breast cancer in the elderly. Drugs Aging 2010;27: 791–800. 13. Lifford KJ, Witt J, Burton M, et al. Understanding older women’s decision making and coping in the context of breast cancer treatment. BMC Med Inform Decis Mak 2015;15:45.
Discussion Discussant Dr. Andrea Madrigano (Chicago, IL): Given what you have learned from this database, what would be your selection criteria for those that you would treat with primary surgery vs primary endocrine therapy? And do you even think there is a role for sentinel lymph node biopsy in this patient population? And, number 3, I encourage you to do the more difficult study, looking at the same group of patients who have human epidermal growth factor receptor 2 positive triple negative or node positive disease. Dr. Kantor: In regard to your first question about the neoadjuvant endocrine therapy, international geriatric guidelines for breast cancer recommend primary endocrine therapy as a good option for patients with multiple comorbidities, patients with poor functional status or those who wish to avoid surgery. And neoadjuvant therapy with hormone therapy has been shown to be effective and safe for patients of all ages. At our institution, we have had a lot of success with elderly patients that presented with large ER1 tumors, putting them on a course of neoadjuvant endocrine therapy and having success in shrinking their tumor to a size that was amenable to lumpectomy, which is obviously a much smaller and shorter, safer surgery in this elderly population. So I think in either of those patient groups, endocrine therapy as first-line would be very appropriate. For the elderly patient that is very healthy and that presents with a small tumor, the surgery first approach would be more appropriate and should definitely be considered. In terms of the axilla, National Comprehensive Cancer Network guidelines do consider axillary staging optional
O. Kantor et al.
Surgery/HT trends in octogenarians
for elderly patients because of the lack of definitive evidence of survival benefit with axillary staging. I think in most of this patient population, octogenarians with ER1 cancer, we could probably avoid axillary staging in most of these patients. However, all breast care now is individualized. So if we were, for instance, to have a young, healthy 80-year-old who probably has a 15-year life expectancy and we think the oncologists would be willing to give them a course of chemotherapy if they did have node positive disease, we would certainly consider axillary staging with Sentinal node biopsy. Or in the patient that presents with clinically node positive disease, we would still consider axillary staging. And as for your 3rd comment about the harder patient population for triple negatives and human epidermal growth factor receptor 2 positive, I think you are absolutely right, that is a much more difficult patient population to manage, because we do not have the benefit of being able to place those patients on neoadjuvant endocrine therapy and see what their response is. And I think that would be an interesting thing to look into in the future, at least what the trends are. Dr. James G. Tyburski (Detroit, MI): I have a quick question. In your opening slides, you had marked differences in the rates by countries. I am going to ask you to speculate, or in your reading of this, can you give us a reason or enlighten us why the rates are so much different in primary operative therapy? Dr. Kantor: I think that there is probably a lot of differences. Obviously, the insurance schemes are very different among these countries, and so the wait to have a surgical procedure might actually significantly impact the desire to have the surgical procedure in some of these elderly women. I think also all of these randomized studies of primary endocrine therapy, they all come of Europe. And so I think it is being used more there and is more commonplace, where it is something that has not really been incorporated into our own national guidelines in the United States. And so I think that it might also be one of the reasons that it is being used more there, because of the trials that have taken place. Dr. Constantine Godellas (Maywood, IL): So the one thing to remember about the NCDB, and you talked about
545 it a little bit is, this is providing with you data. To take this and make treatment decisions is a big leap. And so you have got these patients that can go from hospital to hospital, and we can not capture those data points in the NCDB database, because somebody could get treated at one place and say that they never got treatment. They could go to another place a year later and show up in this. So it is hard to extrapolate that data. It is just something to think about before we just tell everyone that they shouldn’t have treatment for their breast cancer although they are 80 years old. Dr. Kantor: That is an excellent point. We did exclude patients that were coded as being treated outside the facility that they were diagnosed at so that we were able to capture the data points, but it is certainly possible that they, then, had surgery at a later point at a different hospital and that was not able to be captured in our data. So that is an important point to take away. Dr. Theodor Asgeirsson (Grand Rapids, MI): What I find interesting here is that the discussion of octogenarians is, what we have to be thinking about, of course, is their quality of life, not so much the quantity, and it is been shown in the world that I work in colorectal surgery that 80 plus patients that go under an operation have, despite a curative operation, have 20% mortality within 1 year. So I think that is something that needs to be taken into account when decisions are made. I think maybe the Europeans are on to something with less invasiveness. And my question is, do we know anything about mortality rates in this elderly patient population compared with the United States and Europe based on how they differentiate their treatment strategies? Dr. Kantor: In the graph that I showed at the beginning of the presentation, that is a comparison study of Europe that compared 11 European countries to the United States, and they looked at survival patterns for patients with stage 1 and 2 breast cancers, and they really found no survival differences in either of those groups, despite these wide variations in breast surgery patterns, and they also noted variations in systemic therapy and axillary surgery, as well. And despite all of those, there really were no differences between the different countries.
Midwest Surgical Association
Surgery and hormone therapy trends in octogenarians with invasive breast cancer Olga Kantor, M.D.a, Catherine Pesce, M.D.b, Erik Liederbach, B.S.b, Chi-Hsiung Wang, Ph.D.c, David J. Winchester, M.D.b, Katharine Yao, M.D.b,* a
Department of Surgery, University of Chicago, Chicago, IL, USA; bDepartment of Surgery, NorthShore University HealthSystem, Evanston Hospital, Evanston, IL, USA; cCenter for Biomedical Research Informatics, Research Institute, NorthShore University Health System, Evanston, IL, USA KEYWORDS: Primary endocrine therapy; Hormone therapy; Breast cancer; Elderly
Abstract BACKGROUND: There has been a trend toward minimizing surgery in elderly women with estrogen receptor-positive (ER1) breast cancer. METHODS: Using the National Cancer Data Base, we selected 95,357 women R80 years with invasive, ER1 breast cancer. Chi-square test and logistic regression were used to analyze trends in surgery and hormone therapy. RESULTS: From 2004 to 2012, 90% of women were treated with surgery first and 10% were treated with primary nonoperative management. Of those undergoing nonoperative management, 72% received endocrine therapy and 27% had no treatment. The rate of primary nonoperative treatment doubled from 7% in 2004 to 14% in 2012. Multivariate logistic regression adjusted for patient, facility, and tumor factors identified more advanced clinical stage, older age, African-American race, and treatment at Academic facilities as independent predictors of receiving primary nonsurgical management. CONCLUSIONS: There has been an increase over time in primary nonoperative management of ER1 breast cancer in octogenarians. Ó 2016 Elsevier Inc. All rights reserved.
In 2013, 43% of all new invasive breast cancers were in women age 65 or older,1 and with an aging population that is living longer, this is projected to increase. There has been an increasing trend toward minimizing breast
There were no relevant financial relationships or any sources of support in the form of grants, equipment, or drugs. The authors declare no conflicts of interest. * Corresponding author. Tel.: 11-847-570-1327; fax: 11-847-5702930. E-mail address: [email protected] Manuscript received July 13, 2015; revised manuscript November 25, 2015 0002-9610/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.11.005
cancer treatment in the elderly population, particularly in patients with hormone receptor-positive cancers. Radiation after breast conserving surgery and axillary staging have shown no survival benefit for elderly women with early stage breast cancer in randomized clinical trials, and have been incorporated into National Comprehensive Cancer Network guidelines as optional for women R70 years with early stage, hormone-receptor positive tumors.2,3 Primary endocrine therapy in the elderly has also been investigated in several randomized trials, and meta-analysis of these trials found no difference in overall survival between patients treated with primary endocrine therapy compared with surgery, although there
542 was an increased progression-free survival in the surgery arm.4 Nonsurgical management for breast cancer has been studied mainly in Europe, although there have been a few studies in the United States that have examined the primary approach to the elderly patient with a hormone receptorpositive breast cancer.5 In fact, an international comparison of European and the US population-based registries found that nonoperative management of breast cancer is significantly more common in many countries in Europe than in the United States.6 We used the National Cancer Data Base (NCDB) to examine treatment trends for patients treated with primary nonoperative management (endocrine therapy or observation) in women R80-year old with estrogen receptor-positive (ER1) invasive breast cancer. We hypothesize that most elderly women are still undergoing upfront surgery for their breast cancer despite the increased number of hormonal agents available to patients today and the high rate of upfront hormonal therapy in other countries.
The American Journal of Surgery, Vol 211, No 3, March 2016 nodes examined. Staging information was in accordance with the American Joint Committee on Cancer 7th edition.9 Primary nonoperative treatment was considered to be treatment with endocrine therapy alone, treatment with endocrine therapy before surgery, and no documented treatment modality. The NCDB only captures data for the first course of treatment, which usually encompasses the first year of treatment. All analysis was performed using SPSS statistical software (SPSS for Windows, version 19; Chicago, IL). All statistical tests were 2-sided, and a P value of %.05 was considered statistically significant. Chi-square tests and both univariate and multivariate logistic regression models were used to examine factors associated with increased likelihood of receiving primary nonsurgical treatment compared with a surgery-first approach. Odds ratio (OR) greater than 1 signified higher odds of receiving primary nonsurgical treatment. Confidence intervals (CI) are reported at a 95% significance level.
Results Methods The NCDB is a joint project of the American College of Surgeons Commission on Cancer and the American Cancer Society that captures information on approximately 70% of all newly diagnosed cancers in the United States.7 All data collected are compliant with the privacy requirements of the Health Insurance Portability and Accountability Act. Institutional review board approval was not required for this study as the collected information was deidentified, no protected health information was reviewed, and the analysis was retrospective. The breast cancer NCDB participant user file was used to identify women age 80 or older with ER1 breast cancer from 2004 to 2012 who had completely documented information on treatment with surgery and hormone therapy, who received all or part of their care at the reporting facility, and had 2 or less lifetime cancer diagnoses. Patients with in situ or metastatic disease and who underwent adjuvant or neoadjuvant chemotherapy were excluded, which left 95,357 women for the analysis. Patient demographics and tumor characteristics were grouped into categorical variables for analysis. Patient covariates included age, race, and comorbidities (Charlson and/or Deyo index8 of 0 to 1 was considered minimal comorbidity, and index of R2 was considered severe comorbidity). Women greater than 90 years old are categorized as 90-year old in the NCDB. Facility covariates included facility type and location; tumor covariates included clinical stage (cStage); and treatment covariates included breast surgery, axillary surgery, hormone therapy, and radiation therapy. Neoadjuvant hormone therapy was defined as hormone therapy given before surgical treatment. Sentinel node biopsy was defined as 1 to 4 nodes examined, and axillary lymph node dissection was defined as at least 10
We identified 95,357 women age 80 or older with nonmetastatic, invasive ER1 breast cancer from 2004 to 2012. The mean age at diagnosis was 84 6 3 years. 85,824 (90%) patients were Caucasian, 5,678 (6%) were African American, 2,427 (3%) were Hispanic, and 1,138 (1%) were Asian-Pacific Islander. A total of 73,919 (78%) had minimal comorbidities, and 4,805 (5%) had severe comorbidities. At presentation, 42,272 (44%) women were cStage I; 4,427 (21%) were cStage II; and 4,427 (5%) were cStage III. Another 28,894 (30%) had unknown or undocumented clinical stage at presentation. Ultimately, 88,185 (93%) women were treated with surgery (54,789 [62%] with lumpectomy and 33,396 [38%] with mastectomy), 44,465 (58%) with endocrine therapy, and 30,915 (32%) with radiation therapy. Overall 65,250 women (69%) had axillary nodal sampling (40,037 [61%] with sentinel node biopsy and 13,741 [21%] with axillary lymph node dissection). A total of 86,103 (90%) of women were treated with surgery as the first line of treatment and 9,254 (10%) were treated nonsurgically as the first line of treatment. The treatment approach and breakdown of treatments received in our cohort is described in Fig. 1. The rate of primary nonsurgical treatment doubled over the time frame of the study from 7% in 2004% to 14% in 2012 (P , .01) among the entire cohort of octogenarians. The breakdown of the time trends of each type of primary nonsurgical option is shown in Fig. 2. When we compared characteristics of patients that had primary nonsurgical treatment to those that had surgery first, we found that patients that had primary nonsurgical treatment were more likely to be 86 to 90 years of age (54% vs 32%), African American (11% vs 6%), have severe comorbidities (7% vs 5%), have clinical stage III disease at
O. Kantor et al.
Surgery/HT trends in octogenarians
Figure 1
543
Treatment approach for women R80 years old with invasive ER1 breast cancers, 2004 to 2012.
presentation (23% vs 5%), and be treated at an Academic facility (30% vs 22%) compared with patients that had surgery first (all P values ,.01). On multivariate analysis adjusted for year of diagnosis, age, race, comorbidities, facility type and location, and clinical stage, the strongest independent predictors of receiving primary nonsurgical management were more recent year of diagnosis (OR 1.99 [CI 1.79 to 2.21] for 2012 compared with 2004), older age (OR 2.14 [CI 2.05 to 2.24] for 86 to 90-year old compared with 80 to 85-year old), African American race (OR 2.14 [CI 2.05 to 2.24] compared with Caucasian), treatment at an Academic facility (OR 1.62 [CI 1.50 to 1.74] compared with community cancer centers), and increasing clinical stage (cStage II: OR 2.89 [CI 2.72 to 3.05]; cStage III: OR 9.15 [CI 8.49 to 9.87], both compared with cStage I).
Comments In this study, rate of treatment with endocrine therapy as the first line of therapy more than doubled from 2004 to 2012, and the more recent year of breast cancer diagnosis was a significant independent predictor of primary
Figure 2 Trends in primary nonsurgical treatment over time among total cohort of octogenarians, 2004 to 2012. n 5 95,357.
nonoperative therapy after adjustment for other covariates. Endocrine therapy in the neoadjuvant setting with both tamoxifen and aromatase inhibitors has been shown to be effective in decreasing tumor burden and halting disease progression in women of all ages.10 Although retrospective studies of primary endocrine therapy have generally shown an association with increased breast-cancer specific mortality,5 randomized trials of primary endocrine therapy have demonstrated similar survival outcomes to patients treated with surgery.4 An international comparison of cancer registries in the United States and Europe demonstrated a high degree of variation in the rates of nonsurgical management for elderly patients. For women aged 85 to 89 years, 1% of women in Germany, 4% of women in the United States, 28% of women in the Netherlands, and 55% of women in Ireland did not receive any breast surgery. Despite these variations, similar survival patterns were seen across countries in women over age 75.6 It is possible that the publication of the randomized trials of neoadjuvant endocrine therapy and primary endocrine therapy has contributed to the increased utilization of primary endocrine therapy in the United States, and may also partially explain why the rate of primary endocrine therapy is higher at Academic centers. Our study is one of the first to demonstrate a racial disparity in patients receiving primary nonoperative therapy, with African American women being almost 2-times more likely to have primary nonoperative therapy than Caucasians. In a demographically matched cohort of African American and Caucasian women from the Surveillance, Epidemiology, and End-Results data, African American women were also more likely to have no treatment, even when matched by characteristics of disease at presentation.11 Patient perceptions, attitudes, and education contribute to the selection of the first line of treatment in elderly women. The perceived risk of complications may also contribute. The risk of complications after breast
544 surgery increases with age, the most common being hematoma, seroma, and cardiovascular risks of anesthesia. Side effects of endocrine therapy include hot flashes, dizziness, or nausea and are similar among patients of all ages. Interestingly, studies have shown that quality of life in elderly women does not seem to be affected by a cancer diagnosis and was maintained or even improved in patients on endocrine therapy.12 A British survey study of attitudes about primary endocrine therapy vs surgery in elderly women found that most women had a preference quickly based on past experiences and personal goals and values.13 Patients of African-American race may have different personal values and experiences than Caucasian patients, which may contribute to the differences in treatment among different races. Our study has several limitations including the retrospective nature of the data and missing data points. In addition, all patients over 90 are coded as age 90 for privacy reasons in the NCDB, so there is no ability to analyze that group separately. The information on treatment is for the primary treatment course and only encompasses approximately 1 year from diagnosis. Thus, there is no way to know if a patient who started with nonsurgical management eventually had surgery many years later. Because of this limitation, there is no way to distinguish the intent of treatment with endocrine therapy as a first-line neoadjuvant therapy or intended as primary endocrine therapy alone. In conclusion, we found an increasing trend toward primary nonsurgical management in octogenarians which is mostly accounted for by patients treated with primary endocrine therapy. Age, race, and more advanced clinical stage were all strong independent predictors of primary nonsurgical management. It would be interesting to examine if the predictors of nonsurgical management in elderly women with hormone negative tumors are similar to those with hormone-positive tumors. Future studies are needed to further evaluate the patient attitudes and beliefs that influence choice of treatment for breast cancer in the elderly.
References 1. American Cancer Society. Breast Cancer Facts & Figures 2013-2014. Atlanta: American Cancer Society, Inc; 2013. 2. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013;31:2382–7. 3. International Breast Cancer Study GroupRudenstam CM, Zahreieh D, Forbes JF, et al. Randomized trial comparing axillary clearance versus no axillary clearance in older patients with breast cancer: first results of International Breast Cancer Study Trial 10-93. J Clin Oncol 2006; 24:337–44. 4. Morgan J, Wyld L, Collins KA, et al. Surgery versus primary endocrine therapy for operable breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev 2014;1:CD004272. 5. Van Leeuwen BL, Rosenkranz KM, Bedrosian I, et al. The effect of under-treatment of breast cancer in women 80 years of age and older. Crit Rev Oncol Hematol 2011;79:315–20.
The American Journal of Surgery, Vol 211, No 3, March 2016 6. Kiderlen M, Bastiaannet E, Walsh PM, et al. Surgical treatment of early stage breast cancer in elderly: an international comparison. Breast Cancer Res Treat 2012;132:675–82. 7. Bilimoria KY, Stewart AK, Winchester DP, et al. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol 2008;15:683–900. 8. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45:613–9. 9. Edge S, Byrd DR, Compton CC, et al. AJCC cancer Staging Manual. 7th ed. New York: Springer. 10. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrazole, tamoxifen, or both in combination: the Immediate Preoperative Anastrazole, Tamoxifen, or Combined with Tamoxifen (IMPAT) multicenter double-blind randomized trial. J Clin Oncol 2005;23:5109–16. 11. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA 2013;310:389–97. 12. Reimer T, Gerber B. Quality-of-life considerations in the treatment of early-stage breast cancer in the elderly. Drugs Aging 2010;27: 791–800. 13. Lifford KJ, Witt J, Burton M, et al. Understanding older women’s decision making and coping in the context of breast cancer treatment. BMC Med Inform Decis Mak 2015;15:45.
Discussion Discussant Dr. Andrea Madrigano (Chicago, IL): Given what you have learned from this database, what would be your selection criteria for those that you would treat with primary surgery vs primary endocrine therapy? And do you even think there is a role for sentinel lymph node biopsy in this patient population? And, number 3, I encourage you to do the more difficult study, looking at the same group of patients who have human epidermal growth factor receptor 2 positive triple negative or node positive disease. Dr. Kantor: In regard to your first question about the neoadjuvant endocrine therapy, international geriatric guidelines for breast cancer recommend primary endocrine therapy as a good option for patients with multiple comorbidities, patients with poor functional status or those who wish to avoid surgery. And neoadjuvant therapy with hormone therapy has been shown to be effective and safe for patients of all ages. At our institution, we have had a lot of success with elderly patients that presented with large ER1 tumors, putting them on a course of neoadjuvant endocrine therapy and having success in shrinking their tumor to a size that was amenable to lumpectomy, which is obviously a much smaller and shorter, safer surgery in this elderly population. So I think in either of those patient groups, endocrine therapy as first-line would be very appropriate. For the elderly patient that is very healthy and that presents with a small tumor, the surgery first approach would be more appropriate and should definitely be considered. In terms of the axilla, National Comprehensive Cancer Network guidelines do consider axillary staging optional
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for elderly patients because of the lack of definitive evidence of survival benefit with axillary staging. I think in most of this patient population, octogenarians with ER1 cancer, we could probably avoid axillary staging in most of these patients. However, all breast care now is individualized. So if we were, for instance, to have a young, healthy 80-year-old who probably has a 15-year life expectancy and we think the oncologists would be willing to give them a course of chemotherapy if they did have node positive disease, we would certainly consider axillary staging with Sentinal node biopsy. Or in the patient that presents with clinically node positive disease, we would still consider axillary staging. And as for your 3rd comment about the harder patient population for triple negatives and human epidermal growth factor receptor 2 positive, I think you are absolutely right, that is a much more difficult patient population to manage, because we do not have the benefit of being able to place those patients on neoadjuvant endocrine therapy and see what their response is. And I think that would be an interesting thing to look into in the future, at least what the trends are. Dr. James G. Tyburski (Detroit, MI): I have a quick question. In your opening slides, you had marked differences in the rates by countries. I am going to ask you to speculate, or in your reading of this, can you give us a reason or enlighten us why the rates are so much different in primary operative therapy? Dr. Kantor: I think that there is probably a lot of differences. Obviously, the insurance schemes are very different among these countries, and so the wait to have a surgical procedure might actually significantly impact the desire to have the surgical procedure in some of these elderly women. I think also all of these randomized studies of primary endocrine therapy, they all come of Europe. And so I think it is being used more there and is more commonplace, where it is something that has not really been incorporated into our own national guidelines in the United States. And so I think that it might also be one of the reasons that it is being used more there, because of the trials that have taken place. Dr. Constantine Godellas (Maywood, IL): So the one thing to remember about the NCDB, and you talked about
545 it a little bit is, this is providing with you data. To take this and make treatment decisions is a big leap. And so you have got these patients that can go from hospital to hospital, and we can not capture those data points in the NCDB database, because somebody could get treated at one place and say that they never got treatment. They could go to another place a year later and show up in this. So it is hard to extrapolate that data. It is just something to think about before we just tell everyone that they shouldn’t have treatment for their breast cancer although they are 80 years old. Dr. Kantor: That is an excellent point. We did exclude patients that were coded as being treated outside the facility that they were diagnosed at so that we were able to capture the data points, but it is certainly possible that they, then, had surgery at a later point at a different hospital and that was not able to be captured in our data. So that is an important point to take away. Dr. Theodor Asgeirsson (Grand Rapids, MI): What I find interesting here is that the discussion of octogenarians is, what we have to be thinking about, of course, is their quality of life, not so much the quantity, and it is been shown in the world that I work in colorectal surgery that 80 plus patients that go under an operation have, despite a curative operation, have 20% mortality within 1 year. So I think that is something that needs to be taken into account when decisions are made. I think maybe the Europeans are on to something with less invasiveness. And my question is, do we know anything about mortality rates in this elderly patient population compared with the United States and Europe based on how they differentiate their treatment strategies? Dr. Kantor: In the graph that I showed at the beginning of the presentation, that is a comparison study of Europe that compared 11 European countries to the United States, and they looked at survival patterns for patients with stage 1 and 2 breast cancers, and they really found no survival differences in either of those groups, despite these wide variations in breast surgery patterns, and they also noted variations in systemic therapy and axillary surgery, as well. And despite all of those, there really were no differences between the different countries.