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Elderly women with breast cancer often die due to other causes regardless of primary endocrine therapy or primary surgical therapy
The Breast 20 (2011) 365e369
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Elderly women with breast cancer often die due to other causes regardless of primary endocrine therapy or primary surgical therapy M.J. Traa a, b, *, C.M.E.M. Meijs b, M.A.C. de Jongh b, E.C.H.M. van der Borst b, J.A. Roukema a, b a
CoRPS - Center of Research on Psychology in Somatic Diseases, Department of Medical Psychology and Neuropsychology, Tilburg University, PO Box 90153, 5000 LE, Tilburg, The Netherlands b St. Elisabeth Hospital, Department of Surgery, PO Box 90151, 5000 LC, Tilburg, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 October 2010 Received in revised form 21 December 2010 Accepted 20 January 2011
Survival and cause of death was investigated for Primary Surgical Therapy (PST) and Primary Endocrine Therapy (PET). Of women aged 75 years 113 patients received PET, 233 patients underwent PST. PST gave better survival, although this group was younger (p < 0.001). During follow-up the percentage of deaths due to breast cancer was similar and stable in both groups. Increased age was associated with a higher risk on death due to other causes (HR 1.11; CI 1.07e1.14), not on death due to breast cancer (HR 0.94; CI 0.87e1.01). The association of type of treatment and death due to breast cancer was not different between both groups in univariate analyses (HR 0.78; CI 0.44e1.39). In the multivariate model this non-significance remained after correcting for tumor size and age (HR 0.68; CI 0.33e1.42). Treatment should not be based merely on surgical treatment. PET may be an acceptable alternative. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Elderly women Primary endocrine therapy Survival Cause of death
Introduction The elderly represent the fastest growing segment of the population in the United States and in Europe,1 therefore, the incidence of diseases of the elderly such as breast cancer are increasing.2 Over 30% of breast carcinomas occur among women aged 75 and older.3,4 In addition, the treatment of breast cancer has changed substantially during the last decades improving the overall prognosis.5 An increasing incidence combined with an improving prognosis will result in a substantial incline in the prevalence of breast cancer in women aged 75 years during the next decades. Currently, the treatment policy for breast cancer patients usually consists of a multi-disciplinary treatment with a combination of surgery, chemotherapy, radiotherapy, and endocrine therapy. This multi-disciplinary treatment can be quite burdensome for the patient, especially with regard to elderly women. Elderly women with breast cancer are a heterogeneous patient population which often suffers from substantial co-morbid diseases, mostly increasing with age. These co-morbid diseases increase the risk of death due to other causes, thereby decreasing the relative impact of breast cancer on survival.6
* Corresponding author. CoRPS - Center of Research on Psychology in Somatic Diseases, Department of Medical Psychology, Tilburg University, PO Box 90153, 5000 LE, Tilburg, The Netherlands. Tel.: þ31 13 466 41 29; fax: þ31 13 466 20 67. E-mail address: [email protected] (M.J. Traa). 0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2011.01.013
Primary endocrine therapy (PET) is a non-curative alternative for primary surgical therapy (PST) which was first described in the early 1980s.5,7 PET may be an acceptable alternative for elderly women with breast cancer since the biological features of breast cancer are more favourable in elderly women, with tumors being of a lower grade with increased oestrogen receptor expression.8,9 However, this is counterbalanced by larger primary tumors and higher rates of locally advanced and metastatic disease at diagnosis.9 PET with tamoxifen is found to be associated with inferior local disease control but non-inferior survival compared to PST in elderly women with breast cancer.10 In a cohort of women with reduced life-expectancy, owing to significant co-morbid disease, and oestrogen positive tumors, PET may be an appropriate treatment choice.10 However, the trend towards treating women aged 75 years with PET varies over countries. In the UK, its use is widespread, with up to 42% of all women >70 being treated this way, regardless of whether co-morbidity is documented.10 In contrary, PET is not a treatment option in the USA, and is rarely used in Australia.11 In the Netherlands decent research, acceptance and experience regarding PET is limited.12 The growing group of elderly women with breast cancer and the insufficient amount of data on treatment results make it desirable to conduct research that addresses these issues. The goal of the current study was therefore to evaluate the results of 20 years of treatment in which PET was found justifiable for women, aged 75
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years and older with operable breast cancer, in terms of local tumor control (local tumor progression in the PET group and locally recurrent disease in the PST group), metastasis, and cause of death at two, five, and ten years follow-up. The PET group was compared to a group of women treated with PST in the same time period. Method Patients and procedure Since 1985 treatment and follow-up data of all breast cancer patients are registered prospectively at the Department of Surgery of the St. Elisabeth Hospital, Tilburg, The Netherlands. The current study included breast cancer cases occurring between 1985 and 2005 among women aged 75 years or older at time of diagnosis. After diagnosis treatment options were discussed with the patient. PST could range from intentional curative treatment according to the Dutch guidelines for breast cancer (breast conserving surgery or total mastectomy with sentinel node procedure and/or complete axillary dissection, eventually accomplished with adjuvant radiotherapy and/or systemic treatment), to only tumorectomy without any adjuvant treatment. However, a substantial part of these elderly women was relatively unfit for surgery because of significant co-morbid diseases, such as cardio-pulmonary disease or a mental condition, and a few patients refused surgery. Those patients were treated with PET (i.e. tamoxifen). A few elderly women with advanced breast cancer (n ¼ 5) were not seen primary at the Department of Surgery, but at the Department of Internal Medicine. Therefore, these patients were not registered in the prospective database. For these patients’ data on initial treatment, tumor size, local tumor control, metastasis, survival, and cause of death were retrospectively recorded. Some patients were reluctant to undergo diagnostic procedures, thus, of these patients neither histologic proof of malignancy nor hormone receptor status was available. Furthermore, the evaluation of hormone receptor status was not a standard procedure in the early years, so for quite a few patients hormone receptor status was unknown. Data on local tumor control, metastasis, survival, and cause of death were retrieved from the medical records. If the medical records were insufficient, the patient’s general practitioner was contacted for further information. Nevertheless, in some cases patients were never evaluated on local tumor control, metastasis, or their cause of death. If data on the investigated outcome variable was unknown patients were excluded from the analyses, thus resulting in a different number of patients included in the different analyses. Two cohorts were analyzed: PET versus PST. Tumor size was recorded into two groups according to clinical, or if available pathologic, TNM classification. The first group consisted of T1 and T2 tumors, the latter group of T3 and T4 tumors. Patients diagnosed with a Ductal Carcinoma in Situ (DCIS) were excluded from the analyses. In a few cases patients had a metastasis diagnosed prior to the time of the breast cancer diagnosis, in these cases the date when the metastasis was diagnosed was set at the diagnostic date for the primary breast cancer in order to prevent negative values in the development of metastasis analyses. Some patients had a tumor in both breasts at time of diagnosis, in these cases the pathology records of the most invasive tumor were used. Data were analyzed on local tumor control, the development of distant metastasis, survival, and cause of death. Statistical analyses To compare the two cohorts, PET and PST, independent Student’s t-test was used to test differences in the continuous variables age and mean follow-up time, while chi-square tests were used to test
the difference in the categorical variables tumor size, hormone receptor status, adjuvant chemotherapy, adjuvant radiotherapy, and adjuvant hormonal therapy (for the PST group). Additional chi-square tests were performed to compare PET versus PST in terms of local tumor control, the development of distant metastasis, survival, deaths due to breast cancer, and deaths due to other causes at two, five, and ten years follow-up. The relationship between type of treatment, tumor size, and age on (i) death due to breast cancer and (ii) death due to other causes was first investigated with univariate survival analyses using Cox proportional hazard models. In the final analyses, multivariate Cox proportional hazards model was used to investigate the effect of type of treatment on (i) death due to breast and (ii) death due to other causes, hereby adjusting for age and tumor size. Statistical differences were indicated if p ¼ <0.005 and all reported p-values were two-sided. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS version 17.0). Results Patient characteristics Between 1985 and 2005 in total 2471 patients received breast cancer treatment at the St. Elisabeth Hospital. Of these patients, 346 women were aged 75 years and included in the current study. Patient characteristics are presented in Table 1. PET was received by 113 (32.7%) patients, 233 (67.3%) patients underwent PST. The mean age of patients treated with PET was 83.5 years (SD ¼ 4.6), whereas the mean age of PST patients was 78.6 years (SD ¼ 3.3), illustrating a significantly older PET group compared to the PST group (p < 0.001). The mean follow-up period for the PET group was 4.1 years, the mean follow-up period for the PST group was 6.5 years. Significantly more patients were hormone receptor positive in the PET group (p < 0.0001). Significantly less patients in the PET group received adjuvant radiotherapy (p ¼ 0.002), whereas in both cohorts Table 1 Patient characteristics. Characteristic
PET (n ¼ 113)
PST (n ¼ 233)
p-value
Age
83.5 (SD ¼ 4.6)
78.6 (SD ¼ 3.3)
<0.001
Mean follow-up period in years
4.1 (SD ¼ 3.7)
6.5 (SD ¼ 4.1)
0.06
Tumor group 1 (T1 and T2) 2. (T3) Missing or DCIS
65 (57.5%) 23 (20.4%) 25 (22.1%)
185 (79.4%) 40 (17.2%) 8 (3.4%)
0.07
Positive receptor status Yes No Missing
52 (46.0%) 5 (8.2%) 56 (49.6%)
128 (54.9%) 56 (24.0%) 49 (21.0%)
<0.0001
Adjuvant chemotherapy Yes No Missing
2 (1.8%) 111 (98.2%) 0 (0.0%)
1 (0.4%) 232 (99.6%) 0 (0.0%)
0.25
Adjuvant radiotherapy Yes No Missing
9 (8.0%) 104 (92.0%) 0 (0.0%)
49 (21.0%) 184 (79.0%) 0 (0.0%)
0.002
Adjuvant endocrine therapy Yes No Missing
NA NA NA
122 (52.4%) 110 (47.2%) 1 (0.4%)
NA
Note: percentages are presented between brackets. A p-value of <0.05 is considered significant. NA ¼ Not Applicable.
M.J. Traa et al. / The Breast 20 (2011) 365e369 Table 2 Deaths due to breast cancer and deaths due to other causes for the PET and PST groups. Follow-up period
Death due to breast cancer
Death due to other causes
p-value
Two-year follow-up PET (n ¼ 110) PST (n ¼ 232)
9 (23.7%) 10 (27.0%)
29 (76.3%) 27 (73.0%)
0.739
Five-year follow-up PET (n ¼ 100) PST (n ¼ 220)
15 (25.4%) 28 (23.9%)
44 (74.6%) 56 (65.9%)
0.421
Ten-year follow-up PET (n ¼ 78) PST (n ¼ 180)
16 (21.6%) 39 (29.8%)
58 (78.5%) 91 (69.5%)
0.324
367
Table 3 Local recurrences for the PST group and local tumor progression for the PET group. Follow-up period
No
Yes
p-value
Two-year follow-up PET (n ¼ 72) PST (n ¼ 200)
70 (79%) 190 (95%)
2 (3%) 10 (5%)
0.74
Five-year follow-up PET (n ¼ 48) PST (n ¼ 157)
40 (83%) 142 (90%)
8 (17%) 15 (10%)
0.17
Ten-year follow-up PET (n ¼ 18) PST (n ¼ 68)
6 (33%) 52 (76%)
12 (67%) 16 (24%)
0.001
Note: percentages are presented between brackets. A p-value of <0.05 is considered significant.
Note: percentages are presented between brackets. A p-value of <0.05 is considered significant.
very few patients received chemotherapy (p ¼ >0.05). In the PST group 122 (52.4%) patients received adjuvant chemotherapy. Survival and cause of death At all follow-up points relatively more patients survived in the PST group. The number of survivors for the PST group was 195 (84.1%) at two years follow-up, 136 (61.8%) at five years follow-up, and 50 (27.8%) at ten years follow-up, whereas for the PET group these rates were 72 (65.5%), 41 (41.0%), and 4 (5.1%) respectively (data not shown). However, for each time period there were no significant differences between the two groups on deaths due to breast cancer and deaths due to other causes (Table 2). In both groups, at all follow-up points, a much lower percentage of patients died due to breast cancer
compared to the deaths due to other causes. The number of deaths due to breast cancer and deaths due to other causes are also presented graphically in Fig. 1 for the PET group and Fig. 2 for the PST group. Local tumor control and metastasis The local recurrences in the PST group and the local tumor progression in the PET group at two, five, and ten years follow-up is presented in Table 3. Only at ten-year follow-up there was significant less tumor control in the PST group (p ¼ 0.001). In four PET patients (4.2%) tumor progression made salvage surgery inevitable. Three of these cases occurred within the first two years of followup and one patient received the additional surgery between twoand five-year follow-up. Table 4 shows the number of distant metastasis at two, five, and ten years follow-up for both groups. In the PET group significantly more metastasis occurred at two (p ¼ <0.0001), five (p ¼ 0.03), and ten years follow-up (p ¼ 0.001). Confounders of death due to breast cancer
Fig. 1. The number of deaths due to breast cancer and deaths due to other causes for the PET group.
The univariate Cox proportional hazards model revealed that the association of type of treatment and death due to breast cancer was not significantly different between the PET and the PST group (HR 0.78; CI 0.44e1.39). The relationship between age and death due to breast cancer was also not significant (HR 0.94; CI 0.87e1.01). An advanced tumor stage resulted in an associated higher risk of death due to breast cancer (HR 4.56; CI 2.58e8.07). In the final multivariate model the relationship between type of treatment and death due to breast cancer was adjusted for age and tumor size, which showed that the effect of type of treatment on death due to breast cancer remained non-significant (HR 0.68; CI 0.33e1.42).
Table 4 The development of distant metastasis for the PET and PST groups.
Fig. 2. The number of deaths due to breast cancer and deaths due to other causes for the PST group.
Follow-up period
No
Yes
p-value
Two-year follow-up PET (n ¼ 85) PST (n ¼ 206)
60 (71%) 182 (88%)
25 (29%) 24 (12%)
< 0.001
Five-year follow-up PET (n ¼ 67) PST (n ¼ 176)
42 (63%) 135 (77%)
25 (37%) 41 (23%)
0.03
Ten-year follow-up PET (n ¼ 30) PST (n ¼ 101)
5 (17%) 51 (51%)
25 (83%) 50 (49.5%)
0.001
Note: percentages are presented between brackets. A p-value of <0.05 is considered significant.
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Confounders of death due to other causes Additional univariate Cox proportional hazards model analyses were performed for the outcome measure death due to other causes. The PET group revealed a higher association of death due to other causes compared to the PST group (HR 0.56; CI 0.42e0.78). Higher age was associated with a higher risk of death due to other causes (HR 1.11; CI 1.07e1.14). In addition, an advanced tumor stage resulted in an associated higher risk of death due to other causes (HR 1.55; CI 1.04e2.32). When the effect of type of treatment on death due to other causes was adjusted for age and tumor size, the effect lost its significance (HR 0.96; CI 0.62e1.47). Discussion We analyzed the prospectively registered data of two cohorts of women, aged 75 years or older, with breast cancer: PST and PET. At long term follow-up PET provided similar results compared to PST in terms of deaths due to breast cancer. The deaths due to breast cancer remained rather constant during the follow-up period. In addition, age increased the risk of death due to other causes, but not the risk of death due to breast cancer. This finding is in line with the results of earlier studies 13,14 and may to some extent explain the fewer survivors in the PET group, since this group was significantly older. Overall, few women who initially received PET had to undergo additional surgery, indicating a sufficient effect of PET in most cases. There are several limitations that need to be addressed. First of all, comparison of the two distinguished groups is difficult as, in fact, they have only two characteristics in common: breast cancer and old age. Therefore, a potential referral bias cannot be excluded. For example, surgeons who chose to discuss the possibility of PET with their patients may only have discussed it with those patients of higher age with more health and cognitive problems, hence patients with a worse performance status. In addition, in patients who received surgical treatment the type of surgery is also influenced by their performance status and the risk of treatment. Surgeons may choose to perform less invasive surgeries (e.g., tumorectomy) in patients with a worse health status and a higher risk of treatment, which may explain the relatively high percentage of local recurrences and metastasis in this group. Additionally, data of our cohort were collected over a substantial period of time in which available treatments, early detection, screening, and the public awareness developed substantially perhaps resulting in a time bias. A high number of patients were included, however, most PET patients were included in the later years, resulting in a shorter mean follow-up. Finally, in the earlier years receptor status was not verified in many elderly patients, and especially not in the PET group, as at that time receptor analysis was not possible on biopsy-material alone. Thus, some patients in the PET group may have received PET while they were not receptor positive, this may have influenced the results in the PET group in a negative way. These limitations are all due to the observational nature of this study. However, it is ethically not possible to plan randomized trials that compare unconventional treatments without curative effort with settled, known to be curative treatments. For that reason, observational studies, such as the current one, are the only source of evidence on the effect of therapeutic options in elderly patients.15 Furthermore, the data collection was not flawless. Unfortunately, there has been no registration of morbidity, co-morbid diseases, the experienced quality of life, and treatment adherence. However, treatment morbidity and pre-existing co-morbid diseases may have important therapeutic and prognostic consequences. For instance, in PET treatment morbidity and pre-existing co-morbid diseases may influence the patient’s quality of life, which can
influence their treatment adherence, which influences treatment outcomes. Even though the interest, together with incidence, in the elderly cancer patients continues to increase these patients still remain a group on which little research is conducted.16e18 Compared to their younger counterparts elderly patients may have similar survival rates19,20 and otherwise-healthy elderly patients have a similar tolerance to, and outcome with, standard surgical treatment.20e22 These results indicate that treatment decisions should not be based solely on an advancing age. The first step in developing better care for these patients is to consider the performance status of the patient (instead of solely considering their age) and the age specific characteristics of the cancer.23 However, we should even go a step further and take into account how different treatments may affect the patient’s quality of life. Patient-centered outcomes, such as quality of life, are now regarded as a key measurement in assessing outcomes of interventions, especially when clinical outcomes are comparable. For elderly women prolongation of survival may not be the primary goal, however, maintaining quality of life is crucial. Balancing the risk and burden of treatment against the benefits in order to maintain quality of life is extremely important and may lead physicians to search for less radical, non-curative though sufficient, treatments. To our knowledge no studies are available that use quality of life as an outcome measure of the different treatments modalities for elderly breast cancer patients. Prospective studies are warranted to determine more extensive treatment results of the different treatment modalities and especially on PET, hereby also investigating quality of life and treatment adherence to PET. As a result, we hopefully can re-define optimal breast cancer therapy for the elderly breast cancer patients. Conclusion Elderly women with breast cancer have a higher chance of death due to other causes than their breast cancer. Results were quite similar for PET and PST in terms of local tumor control and deaths due to breast cancer. A risk of “overtreatment” arises when treatment decisions are merely based on standard all-ages treatment protocols. Surgical treatment might be burdensome for elderly patients, on the other hand, PET caries the risk of non-responders and disease recurrence. However, in selected cases PET may be an acceptable alternative. Further research is warranted to determine optimal treatment results hereby taking into account not only the performance status of the patient and the age specific characteristics of the tumor but also quality of life. Conflict of Interest Statement None declared. Ethical approval The study was approved by the medical ethical commission of the St. Elisabeth hospital. Acknowledgements None declared. References 1. Kosiak B, Sangl J, Correa-de-Araujo R. Quality of health care for older women: what do we know? Womens Health Issues 2006 Mar;16(2):89e99.
M.J. Traa et al. / The Breast 20 (2011) 365e369 2. Kimmick GG, Balducci L. Breast cancer and aging. Clinical interactions. Hematol Oncol Clin North Am 2000 Feb;14(1):213e34. 3. Louwman WJ, Voogd AC, van Dijck JA, Nieuwenhuijzen GA, Ribot J, Pruijt JF, et al. On the rising trends of incidence and prognosis for breast cancer patients diagnosed 1975e2004: a long-term population-based study in southeastern Netherlands. Cancer Causes Control 2008 Feb;19(1):97e106. 4. Thomson CS, Brewster DH, Dewar JA, Twelves CJ. Improvements in survival for women with breast cancer in Scotland between 1987 and 1993: impact of earlier diagnosis and changes in treatment. Eur J Cancer 2004 Mar;40(5): 743e53. 5. Vervoort MM, Draisma G, Fracheboud J, van de Poll-Franse LV, de Koning HJ. Trends in the usage of adjuvant systemic therapy for breast cancer in the Netherlands and its effect on mortality. Br J Cancer 2004 Jul 19;91(2):242e7. 6. Hamaker ME, Schreurs WH, Uppelschoten JM, Smorenburg CH. Breast cancer in the elderly: retrospective study on diagnosis and treatment according to national guidelines. Breast J 2009 Jan;15(1):26e33. 7. Preece PE, Wood RA, Mackie CR, Cuschieri A. Tamoxifen as initial sole treatment of localised breast cancer in elderly women: a pilot study. Br Med J (Clin Res Ed) 1982 Mar 20;284(6319):869e70. 8. Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000 Apr 5;92(7):550e6. 9. Wyld L, Reed M. The role of surgery in the management of older women with breast cancer. Eur J Cancer 2007 Oct;43(15):2253e63. 10. Hind D, Wyld L, Reed MW. Surgery, with or without tamoxifen, vs tamoxifen alone for older women with operable breast cancer: Cochrane review. Br J Cancer 2007 Apr 10;96(7):1025e9. 11. Craft PS, Zhang Y, Brogan J, Tait N, Buckingham JM. Implementing clinical practice guidelines: a community-based audit of breast cancer treatment. Australian Capital Territory and South Eastern New South Wales Breast Cancer Treatment Group. Med J Aust 2000 Mar 6;172(5):213e6.
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12. Bergman L, van Dongen JA, van OB, van Leeuwen FE. Should tamoxifen be a primary treatment choice for elderly breast cancer patients with locoregional disease? Breast Cancer Res Treat 1995 Apr;34(1):77e83. 13. Read WL, Tierney RM, Page NC, Costas I, Govindan R, Spitznagel EL, et al. Differential prognostic impact of comorbidity. J Clin Oncol 2004 Aug 1;22(15):3099e103. 14. Houterman S, Janssen-Heijnen ML, Verheij CD, Louwman WJ, Vreugdenhil G, van der Sangen MJ, et al. Comorbidity has negligible impact on treatment and complications but influences survival in breast cancer patients. Br J Cancer 2004 Jun 14;90(12):2332e7. 15. Bouchardy C, Rapiti E, Blagojevic S, Vlastos AT, Vlastos G. Older female cancer patients: importance, causes, and consequences of undertreatment. J Clin Oncol 2007 May 10;25(14):1858e69. 16. Mitka M. Too few older patients in cancer trials: experts say disparity affects research results and care. JAMA 2003 Jul 2;290(1):27e8. 17. Stewart JH, Bertoni AG, Staten JL, Levine EA, Gross CP. Participation in surgical oncology clinical trials: gender-, race/ethnicity-, and age-based disparities. Ann Surg Oncol 2007 Dec;14(12):3328e34. 18. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA 2004 Jun 9;291(22):2720e6. 19. Ganz PA, Guadagnoli E, Landrum MB, Lash TL, Rakowski W, Silliman RA. Breast cancer in older women: quality of life and psychosocial adjustment in the 15 months after diagnosis. J Clin Oncol 2003 Nov 1;21(21):4027e33. 20. Law TM, Hesketh PJ, Porter KA, Lawn-Tsao L, McAnaw R, Lopez MJ. Breast cancer in elderly women: presentation, survival, and treatment options. Surg Clin North Am 1996 Apr;76(2):289e308. 21. Audisio RA, Bozzetti F, Gennari R, Jaklitsch MT, Koperna T, Longo WE, et al. The surgical management of elderly cancer patients; recommendations of the SIOG surgical task force. Eur J Cancer 2004 May;40(7):926e38. 22. Gennari R, Audisio RA. Breast cancer in elderly women. Optimizing the treatment. Breast Cancer Res Treat 2008 Jul;110(2):199e209. 23. Hughes KS. Why do we believe that breast cancer in the elderly is the same as breast cancer in young women? Drugs Aging 2008;25(1):47e8.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Elderly women with breast cancer often die due to other causes regardless of primary endocrine therapy or primary surgical therapy M.J. Traa a, b, *, C.M.E.M. Meijs b, M.A.C. de Jongh b, E.C.H.M. van der Borst b, J.A. Roukema a, b a
CoRPS - Center of Research on Psychology in Somatic Diseases, Department of Medical Psychology and Neuropsychology, Tilburg University, PO Box 90153, 5000 LE, Tilburg, The Netherlands b St. Elisabeth Hospital, Department of Surgery, PO Box 90151, 5000 LC, Tilburg, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history: Received 13 October 2010 Received in revised form 21 December 2010 Accepted 20 January 2011
Survival and cause of death was investigated for Primary Surgical Therapy (PST) and Primary Endocrine Therapy (PET). Of women aged 75 years 113 patients received PET, 233 patients underwent PST. PST gave better survival, although this group was younger (p < 0.001). During follow-up the percentage of deaths due to breast cancer was similar and stable in both groups. Increased age was associated with a higher risk on death due to other causes (HR 1.11; CI 1.07e1.14), not on death due to breast cancer (HR 0.94; CI 0.87e1.01). The association of type of treatment and death due to breast cancer was not different between both groups in univariate analyses (HR 0.78; CI 0.44e1.39). In the multivariate model this non-significance remained after correcting for tumor size and age (HR 0.68; CI 0.33e1.42). Treatment should not be based merely on surgical treatment. PET may be an acceptable alternative. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Elderly women Primary endocrine therapy Survival Cause of death
Introduction The elderly represent the fastest growing segment of the population in the United States and in Europe,1 therefore, the incidence of diseases of the elderly such as breast cancer are increasing.2 Over 30% of breast carcinomas occur among women aged 75 and older.3,4 In addition, the treatment of breast cancer has changed substantially during the last decades improving the overall prognosis.5 An increasing incidence combined with an improving prognosis will result in a substantial incline in the prevalence of breast cancer in women aged 75 years during the next decades. Currently, the treatment policy for breast cancer patients usually consists of a multi-disciplinary treatment with a combination of surgery, chemotherapy, radiotherapy, and endocrine therapy. This multi-disciplinary treatment can be quite burdensome for the patient, especially with regard to elderly women. Elderly women with breast cancer are a heterogeneous patient population which often suffers from substantial co-morbid diseases, mostly increasing with age. These co-morbid diseases increase the risk of death due to other causes, thereby decreasing the relative impact of breast cancer on survival.6
* Corresponding author. CoRPS - Center of Research on Psychology in Somatic Diseases, Department of Medical Psychology, Tilburg University, PO Box 90153, 5000 LE, Tilburg, The Netherlands. Tel.: þ31 13 466 41 29; fax: þ31 13 466 20 67. E-mail address: [email protected] (M.J. Traa). 0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2011.01.013
Primary endocrine therapy (PET) is a non-curative alternative for primary surgical therapy (PST) which was first described in the early 1980s.5,7 PET may be an acceptable alternative for elderly women with breast cancer since the biological features of breast cancer are more favourable in elderly women, with tumors being of a lower grade with increased oestrogen receptor expression.8,9 However, this is counterbalanced by larger primary tumors and higher rates of locally advanced and metastatic disease at diagnosis.9 PET with tamoxifen is found to be associated with inferior local disease control but non-inferior survival compared to PST in elderly women with breast cancer.10 In a cohort of women with reduced life-expectancy, owing to significant co-morbid disease, and oestrogen positive tumors, PET may be an appropriate treatment choice.10 However, the trend towards treating women aged 75 years with PET varies over countries. In the UK, its use is widespread, with up to 42% of all women >70 being treated this way, regardless of whether co-morbidity is documented.10 In contrary, PET is not a treatment option in the USA, and is rarely used in Australia.11 In the Netherlands decent research, acceptance and experience regarding PET is limited.12 The growing group of elderly women with breast cancer and the insufficient amount of data on treatment results make it desirable to conduct research that addresses these issues. The goal of the current study was therefore to evaluate the results of 20 years of treatment in which PET was found justifiable for women, aged 75
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years and older with operable breast cancer, in terms of local tumor control (local tumor progression in the PET group and locally recurrent disease in the PST group), metastasis, and cause of death at two, five, and ten years follow-up. The PET group was compared to a group of women treated with PST in the same time period. Method Patients and procedure Since 1985 treatment and follow-up data of all breast cancer patients are registered prospectively at the Department of Surgery of the St. Elisabeth Hospital, Tilburg, The Netherlands. The current study included breast cancer cases occurring between 1985 and 2005 among women aged 75 years or older at time of diagnosis. After diagnosis treatment options were discussed with the patient. PST could range from intentional curative treatment according to the Dutch guidelines for breast cancer (breast conserving surgery or total mastectomy with sentinel node procedure and/or complete axillary dissection, eventually accomplished with adjuvant radiotherapy and/or systemic treatment), to only tumorectomy without any adjuvant treatment. However, a substantial part of these elderly women was relatively unfit for surgery because of significant co-morbid diseases, such as cardio-pulmonary disease or a mental condition, and a few patients refused surgery. Those patients were treated with PET (i.e. tamoxifen). A few elderly women with advanced breast cancer (n ¼ 5) were not seen primary at the Department of Surgery, but at the Department of Internal Medicine. Therefore, these patients were not registered in the prospective database. For these patients’ data on initial treatment, tumor size, local tumor control, metastasis, survival, and cause of death were retrospectively recorded. Some patients were reluctant to undergo diagnostic procedures, thus, of these patients neither histologic proof of malignancy nor hormone receptor status was available. Furthermore, the evaluation of hormone receptor status was not a standard procedure in the early years, so for quite a few patients hormone receptor status was unknown. Data on local tumor control, metastasis, survival, and cause of death were retrieved from the medical records. If the medical records were insufficient, the patient’s general practitioner was contacted for further information. Nevertheless, in some cases patients were never evaluated on local tumor control, metastasis, or their cause of death. If data on the investigated outcome variable was unknown patients were excluded from the analyses, thus resulting in a different number of patients included in the different analyses. Two cohorts were analyzed: PET versus PST. Tumor size was recorded into two groups according to clinical, or if available pathologic, TNM classification. The first group consisted of T1 and T2 tumors, the latter group of T3 and T4 tumors. Patients diagnosed with a Ductal Carcinoma in Situ (DCIS) were excluded from the analyses. In a few cases patients had a metastasis diagnosed prior to the time of the breast cancer diagnosis, in these cases the date when the metastasis was diagnosed was set at the diagnostic date for the primary breast cancer in order to prevent negative values in the development of metastasis analyses. Some patients had a tumor in both breasts at time of diagnosis, in these cases the pathology records of the most invasive tumor were used. Data were analyzed on local tumor control, the development of distant metastasis, survival, and cause of death. Statistical analyses To compare the two cohorts, PET and PST, independent Student’s t-test was used to test differences in the continuous variables age and mean follow-up time, while chi-square tests were used to test
the difference in the categorical variables tumor size, hormone receptor status, adjuvant chemotherapy, adjuvant radiotherapy, and adjuvant hormonal therapy (for the PST group). Additional chi-square tests were performed to compare PET versus PST in terms of local tumor control, the development of distant metastasis, survival, deaths due to breast cancer, and deaths due to other causes at two, five, and ten years follow-up. The relationship between type of treatment, tumor size, and age on (i) death due to breast cancer and (ii) death due to other causes was first investigated with univariate survival analyses using Cox proportional hazard models. In the final analyses, multivariate Cox proportional hazards model was used to investigate the effect of type of treatment on (i) death due to breast and (ii) death due to other causes, hereby adjusting for age and tumor size. Statistical differences were indicated if p ¼ <0.005 and all reported p-values were two-sided. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS version 17.0). Results Patient characteristics Between 1985 and 2005 in total 2471 patients received breast cancer treatment at the St. Elisabeth Hospital. Of these patients, 346 women were aged 75 years and included in the current study. Patient characteristics are presented in Table 1. PET was received by 113 (32.7%) patients, 233 (67.3%) patients underwent PST. The mean age of patients treated with PET was 83.5 years (SD ¼ 4.6), whereas the mean age of PST patients was 78.6 years (SD ¼ 3.3), illustrating a significantly older PET group compared to the PST group (p < 0.001). The mean follow-up period for the PET group was 4.1 years, the mean follow-up period for the PST group was 6.5 years. Significantly more patients were hormone receptor positive in the PET group (p < 0.0001). Significantly less patients in the PET group received adjuvant radiotherapy (p ¼ 0.002), whereas in both cohorts Table 1 Patient characteristics. Characteristic
PET (n ¼ 113)
PST (n ¼ 233)
p-value
Age
83.5 (SD ¼ 4.6)
78.6 (SD ¼ 3.3)
<0.001
Mean follow-up period in years
4.1 (SD ¼ 3.7)
6.5 (SD ¼ 4.1)
0.06
Tumor group 1 (T1 and T2) 2. (T3) Missing or DCIS
65 (57.5%) 23 (20.4%) 25 (22.1%)
185 (79.4%) 40 (17.2%) 8 (3.4%)
0.07
Positive receptor status Yes No Missing
52 (46.0%) 5 (8.2%) 56 (49.6%)
128 (54.9%) 56 (24.0%) 49 (21.0%)
<0.0001
Adjuvant chemotherapy Yes No Missing
2 (1.8%) 111 (98.2%) 0 (0.0%)
1 (0.4%) 232 (99.6%) 0 (0.0%)
0.25
Adjuvant radiotherapy Yes No Missing
9 (8.0%) 104 (92.0%) 0 (0.0%)
49 (21.0%) 184 (79.0%) 0 (0.0%)
0.002
Adjuvant endocrine therapy Yes No Missing
NA NA NA
122 (52.4%) 110 (47.2%) 1 (0.4%)
NA
Note: percentages are presented between brackets. A p-value of <0.05 is considered significant. NA ¼ Not Applicable.
M.J. Traa et al. / The Breast 20 (2011) 365e369 Table 2 Deaths due to breast cancer and deaths due to other causes for the PET and PST groups. Follow-up period
Death due to breast cancer
Death due to other causes
p-value
Two-year follow-up PET (n ¼ 110) PST (n ¼ 232)
9 (23.7%) 10 (27.0%)
29 (76.3%) 27 (73.0%)
0.739
Five-year follow-up PET (n ¼ 100) PST (n ¼ 220)
15 (25.4%) 28 (23.9%)
44 (74.6%) 56 (65.9%)
0.421
Ten-year follow-up PET (n ¼ 78) PST (n ¼ 180)
16 (21.6%) 39 (29.8%)
58 (78.5%) 91 (69.5%)
0.324
367
Table 3 Local recurrences for the PST group and local tumor progression for the PET group. Follow-up period
No
Yes
p-value
Two-year follow-up PET (n ¼ 72) PST (n ¼ 200)
70 (79%) 190 (95%)
2 (3%) 10 (5%)
0.74
Five-year follow-up PET (n ¼ 48) PST (n ¼ 157)
40 (83%) 142 (90%)
8 (17%) 15 (10%)
0.17
Ten-year follow-up PET (n ¼ 18) PST (n ¼ 68)
6 (33%) 52 (76%)
12 (67%) 16 (24%)
0.001
Note: percentages are presented between brackets. A p-value of <0.05 is considered significant.
Note: percentages are presented between brackets. A p-value of <0.05 is considered significant.
very few patients received chemotherapy (p ¼ >0.05). In the PST group 122 (52.4%) patients received adjuvant chemotherapy. Survival and cause of death At all follow-up points relatively more patients survived in the PST group. The number of survivors for the PST group was 195 (84.1%) at two years follow-up, 136 (61.8%) at five years follow-up, and 50 (27.8%) at ten years follow-up, whereas for the PET group these rates were 72 (65.5%), 41 (41.0%), and 4 (5.1%) respectively (data not shown). However, for each time period there were no significant differences between the two groups on deaths due to breast cancer and deaths due to other causes (Table 2). In both groups, at all follow-up points, a much lower percentage of patients died due to breast cancer
compared to the deaths due to other causes. The number of deaths due to breast cancer and deaths due to other causes are also presented graphically in Fig. 1 for the PET group and Fig. 2 for the PST group. Local tumor control and metastasis The local recurrences in the PST group and the local tumor progression in the PET group at two, five, and ten years follow-up is presented in Table 3. Only at ten-year follow-up there was significant less tumor control in the PST group (p ¼ 0.001). In four PET patients (4.2%) tumor progression made salvage surgery inevitable. Three of these cases occurred within the first two years of followup and one patient received the additional surgery between twoand five-year follow-up. Table 4 shows the number of distant metastasis at two, five, and ten years follow-up for both groups. In the PET group significantly more metastasis occurred at two (p ¼ <0.0001), five (p ¼ 0.03), and ten years follow-up (p ¼ 0.001). Confounders of death due to breast cancer
Fig. 1. The number of deaths due to breast cancer and deaths due to other causes for the PET group.
The univariate Cox proportional hazards model revealed that the association of type of treatment and death due to breast cancer was not significantly different between the PET and the PST group (HR 0.78; CI 0.44e1.39). The relationship between age and death due to breast cancer was also not significant (HR 0.94; CI 0.87e1.01). An advanced tumor stage resulted in an associated higher risk of death due to breast cancer (HR 4.56; CI 2.58e8.07). In the final multivariate model the relationship between type of treatment and death due to breast cancer was adjusted for age and tumor size, which showed that the effect of type of treatment on death due to breast cancer remained non-significant (HR 0.68; CI 0.33e1.42).
Table 4 The development of distant metastasis for the PET and PST groups.
Fig. 2. The number of deaths due to breast cancer and deaths due to other causes for the PST group.
Follow-up period
No
Yes
p-value
Two-year follow-up PET (n ¼ 85) PST (n ¼ 206)
60 (71%) 182 (88%)
25 (29%) 24 (12%)
< 0.001
Five-year follow-up PET (n ¼ 67) PST (n ¼ 176)
42 (63%) 135 (77%)
25 (37%) 41 (23%)
0.03
Ten-year follow-up PET (n ¼ 30) PST (n ¼ 101)
5 (17%) 51 (51%)
25 (83%) 50 (49.5%)
0.001
Note: percentages are presented between brackets. A p-value of <0.05 is considered significant.
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Confounders of death due to other causes Additional univariate Cox proportional hazards model analyses were performed for the outcome measure death due to other causes. The PET group revealed a higher association of death due to other causes compared to the PST group (HR 0.56; CI 0.42e0.78). Higher age was associated with a higher risk of death due to other causes (HR 1.11; CI 1.07e1.14). In addition, an advanced tumor stage resulted in an associated higher risk of death due to other causes (HR 1.55; CI 1.04e2.32). When the effect of type of treatment on death due to other causes was adjusted for age and tumor size, the effect lost its significance (HR 0.96; CI 0.62e1.47). Discussion We analyzed the prospectively registered data of two cohorts of women, aged 75 years or older, with breast cancer: PST and PET. At long term follow-up PET provided similar results compared to PST in terms of deaths due to breast cancer. The deaths due to breast cancer remained rather constant during the follow-up period. In addition, age increased the risk of death due to other causes, but not the risk of death due to breast cancer. This finding is in line with the results of earlier studies 13,14 and may to some extent explain the fewer survivors in the PET group, since this group was significantly older. Overall, few women who initially received PET had to undergo additional surgery, indicating a sufficient effect of PET in most cases. There are several limitations that need to be addressed. First of all, comparison of the two distinguished groups is difficult as, in fact, they have only two characteristics in common: breast cancer and old age. Therefore, a potential referral bias cannot be excluded. For example, surgeons who chose to discuss the possibility of PET with their patients may only have discussed it with those patients of higher age with more health and cognitive problems, hence patients with a worse performance status. In addition, in patients who received surgical treatment the type of surgery is also influenced by their performance status and the risk of treatment. Surgeons may choose to perform less invasive surgeries (e.g., tumorectomy) in patients with a worse health status and a higher risk of treatment, which may explain the relatively high percentage of local recurrences and metastasis in this group. Additionally, data of our cohort were collected over a substantial period of time in which available treatments, early detection, screening, and the public awareness developed substantially perhaps resulting in a time bias. A high number of patients were included, however, most PET patients were included in the later years, resulting in a shorter mean follow-up. Finally, in the earlier years receptor status was not verified in many elderly patients, and especially not in the PET group, as at that time receptor analysis was not possible on biopsy-material alone. Thus, some patients in the PET group may have received PET while they were not receptor positive, this may have influenced the results in the PET group in a negative way. These limitations are all due to the observational nature of this study. However, it is ethically not possible to plan randomized trials that compare unconventional treatments without curative effort with settled, known to be curative treatments. For that reason, observational studies, such as the current one, are the only source of evidence on the effect of therapeutic options in elderly patients.15 Furthermore, the data collection was not flawless. Unfortunately, there has been no registration of morbidity, co-morbid diseases, the experienced quality of life, and treatment adherence. However, treatment morbidity and pre-existing co-morbid diseases may have important therapeutic and prognostic consequences. For instance, in PET treatment morbidity and pre-existing co-morbid diseases may influence the patient’s quality of life, which can
influence their treatment adherence, which influences treatment outcomes. Even though the interest, together with incidence, in the elderly cancer patients continues to increase these patients still remain a group on which little research is conducted.16e18 Compared to their younger counterparts elderly patients may have similar survival rates19,20 and otherwise-healthy elderly patients have a similar tolerance to, and outcome with, standard surgical treatment.20e22 These results indicate that treatment decisions should not be based solely on an advancing age. The first step in developing better care for these patients is to consider the performance status of the patient (instead of solely considering their age) and the age specific characteristics of the cancer.23 However, we should even go a step further and take into account how different treatments may affect the patient’s quality of life. Patient-centered outcomes, such as quality of life, are now regarded as a key measurement in assessing outcomes of interventions, especially when clinical outcomes are comparable. For elderly women prolongation of survival may not be the primary goal, however, maintaining quality of life is crucial. Balancing the risk and burden of treatment against the benefits in order to maintain quality of life is extremely important and may lead physicians to search for less radical, non-curative though sufficient, treatments. To our knowledge no studies are available that use quality of life as an outcome measure of the different treatments modalities for elderly breast cancer patients. Prospective studies are warranted to determine more extensive treatment results of the different treatment modalities and especially on PET, hereby also investigating quality of life and treatment adherence to PET. As a result, we hopefully can re-define optimal breast cancer therapy for the elderly breast cancer patients. Conclusion Elderly women with breast cancer have a higher chance of death due to other causes than their breast cancer. Results were quite similar for PET and PST in terms of local tumor control and deaths due to breast cancer. A risk of “overtreatment” arises when treatment decisions are merely based on standard all-ages treatment protocols. Surgical treatment might be burdensome for elderly patients, on the other hand, PET caries the risk of non-responders and disease recurrence. However, in selected cases PET may be an acceptable alternative. Further research is warranted to determine optimal treatment results hereby taking into account not only the performance status of the patient and the age specific characteristics of the tumor but also quality of life. Conflict of Interest Statement None declared. Ethical approval The study was approved by the medical ethical commission of the St. Elisabeth hospital. Acknowledgements None declared. References 1. Kosiak B, Sangl J, Correa-de-Araujo R. Quality of health care for older women: what do we know? Womens Health Issues 2006 Mar;16(2):89e99.
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